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Ocular Drug Delivery: a Comprehensive Review

• Review Article
• Open access
• Published: 14 February 2023
• Volume 24 , article number  66 , ( 2023 )

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• Sadek Ahmed   ORCID: orcid.org/0000-0002-0190-9502 1 ,
• Maha M. Amin 1 &
• Sinar Sayed 1  

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The human eye is a sophisticated organ with distinctive anatomy and physiology that hinders the passage of drugs into targeted ophthalmic sites. Effective topical administration is an interest of scientists for many decades. Their difficult mission is to prolong drug residence time and guarantee an appropriate ocular permeation. Several ocular obstacles oppose effective drug delivery such as precorneal, corneal, and blood-corneal barriers. Routes for ocular delivery include topical, intravitreal, intraocular, juxtascleral, subconjunctival, intracameral, and retrobulbar. More than 95% of marketed products exists in liquid state. However, other products could be in semi-solid (ointments and gels), solid state (powder, insert and lens), or mixed ( in situ gel). Nowadays, attractiveness to nanotechnology-based carries is resulted from their capabilities to entrap both hydrophilic and lipophilic drugs, enhance ocular permeability, sustain residence time, improve drug stability, and augment bioavailability. Different in vitro , ex vivo, and in vivo characterization approaches help to predict the outcomes of the constructed nanocarriers. This review aims to clarify anatomy of the eye, various ocular diseases, and obstacles to ocular delivery. Moreover, it studies the advantages and drawbacks of different ocular routes of administration and dosage forms. This review also discusses different nanostructured platforms and their characterization approaches. Strategies to enhance ocular bioavailability are also explained. Finally, recent advances in ocular delivery are described.

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Introduction

Eye is a very sensitive organ with a sophisticated physiology. It is composed of anterior and posterior segments. Generally, quality of life is significantly influenced by visual impairment resulted from various diseases. Cataract is the main cause of blindness worldwide. About 40–60% of blindness in the world is caused as a complication of cataract [ 1 ]. Early cataract development results from mutations in α, β, and γ crystallin and its associated genes [ 2 ]. Glaucoma is a well-known optic neuropathy disease that is connected with elevation in intraocular pressure (IOP). It leads to permanent blindness in the late stage [ 3 ]. Furthermore, vision impairment is also related to aging, diabetes, and fungal infection. Examples of ocular diseases include age-related macular degeneration (AMD), diabetic retinopathy (DR), retinoblastoma, and fungal keratitis. A new study valued that approximately 76 million people suffered from glaucoma, 196 million people with AMD, and 92.6 million have DR [ 1 ].

Although many potent drugs are available to treat most of ocular complaints, there are many ocular barriers such as tear film, corneal, conjunctival, and blood-ocular barriers that hinder their therapeutic efficacy. Conventional eye drops are wasted by blinking and tear flow. Therefore, their bioavailability is minimized to less than 5% [ 4 ]. Cornea is composed of epithelium, stroma, and endothelium. Epithelium allows only the passage of small and lipophilic drug. However, stroma allows the passage of hydrophilic drugs [ 5 ]. Endothelium conserves the transparency of the cornea and affords selective entry for hydrophilic drugs and macromolecules into the aqueous humor. The conjunctiva provides a minor impact to drug absorption compared to the cornea, though certain macromolecular nanomedicines, peptides, and oligonucleotides penetrate to the deep layers of the eye absolutely through these tissues. Blood-ocular barriers prevent the passage of xenobiotic compounds into the blood stream. They are classified into blood-aqueous barrier (BAB) in the anterior segment and blood-retinal barrier (BRB) in the posterior segment of the eye [ 6 ].

Ocular formulations are intended to be applied on the anterior surface (topical route) of the eye, delivered intraocularly (inside the eye), periocularly (subtenon or juxtascleral), or in combination with ocular devices. Ocular dosage forms could be liquid, semi-solid, solid, or mixed. Liquid dosage include drops, suspension, and emulsion. Eye drops represent more than 95% of the marketed ocular products [ 7 ]. They are used for delivering the medication into the anterior part of the eye but with short residence time [ 5 ]. Ocular suspensions and emulsions have the ability to deliver hydrophobic drugs, but may lead to blurred vision. Ocular gels and ointments (semi-solid) could significantly enhance residence time. Solid dosage forms could be used to deliver water-sensitive drugs (powder), provide zero order release model (insert), or sustain residence time (therapeutic contact lens) [ 7 ].

Effective ocular absorption necessitates appropriate corneal penetration along with effective precorneal residence time, so as to reach and preserve an acceptable drug concentration with the minimum quantity of the active therapeutic constituent. Nanosystems are innovative technologies developed to get through ocular obstacles, shield the drug from the biological environment, sustain drug residence time, and improve corneal permeation across biological barriers [ 8 ]. Characterization of the constructed nanosystems is of great importance to ensure its ability to accomplish the required activity. There are many approaches for characterization such as visual appearance, stability, size, zeta potential, possible interactions, pH measurement, and other important ex vivo and in vivo evaluations [ 6 ]. This review highlights the gaps in other published reviews regarding the ocular drug delivery. It described comprehensively ocular drug delivery from different points such as the various anatomical features of the eye, different ocular diseases, obstacles to ocular delivery, different routes of ocular administration, classification of dosage forms, numerous nanostructured platforms, characterization approaches, strategies to improve ocular delivery, and future technologies.

Anatomy of the Eye

Human eye is a very sensitive and complex organ. Figure  1 illustrates the anatomy of human eye [ 6 ]. Human eye is composed of anterior and posterior chambers. The anterior segment is composed of tear film, cornea, pupil, lens, and ciliary body. The posterior segment is composed of conjunctiva, sclera, choroid, retina, vitreous humor, and optic nerve. The structure and quantity of tears are controlled by orbital glands and epithelial secretions. Cornea is the front portion of the eye that conveys and focuses light into the eye. It is divided into epithelium, stroma, and endothelium. The epithelium is made of five to seven layers of firmly connected cells. Stroma is a water-based compact layer. The endothelium preserves the transparency of the cornea [ 6 ]. Iris is the colored portion of the eye which controls the quantity of light penetrating the eye. The dark center opening in the middle of the iris is called pupil. The pupil changes its size according to the available light. Lens is transparent portion that focuses the light into retina. The ciliary body is made of pigmented and non-pigmented ciliary epithelia, a stroma, and ciliary muscles. Capillaries of ciliary body allow communication between anterior and posterior segments [ 7 ]. Vitreous humor is a gel-like, clear, avascular connective tissue that exists between the eye lens and the retina. It is made of 99.9% water, hyaluronic acid, ions, and collagen [ 7 ]. The conjunctiva is a delicate transparent membrane lining inside the eyelids and shelter the frontal surface of the sclera. It is a mucous membrane that is composed of three layers, an outer epithelium, a substantia propria enclosing nerves, lymphatic and blood vessels, and a submucosa layer linked to the sclera [ 9 ]. The sclera is a continuous of cornea. It is made of collagen and mucopolysaccharides. Choroid is vascular layer that is located between retina and sclera. The retina is thin film of tissue composed of neural and glial cells covering the back of the eye. It produces electrical impulses that are delivered through the optic nerve to the brain [ 7 ].

Anatomy of the eye [ 6 ]

Ocular Diseases

Cataract is chief cause of loss of vision worldwide. About 40–60% of blindness in the world is caused as a complication of cataract [ 1 ]. As said by the National Programme for Control of Blindness and Visual Impairment, the major reason of avoidable blindness in India is cataract (62.6%) [ 2 ]. Cataract could be defined as the development of cloudiness/opacification in the eye lens. The risk factors include exposure to UV light, diabetes, bad nutrition, genetic determinism, and smoking. Cataract could be divided into three types: cortical, nuclear, or posterior subcapsular. The clearness and transparency of lens is regulated by crystallin protein [ 10 ]. Alterations in α, β, and γ crystallin and its associated genes are responsible for the early cataract development. Triggers to cataract are glycation, oxidative stress, and exposure to lipophilic compounds which result in increasing calcium level in the lens plus crystallin accumulation. Oxidative stress is mediated by hyperglycemia and hydroxyl radicals. Nowadays, surgical removal of opaque lens is the treatment choice. However, the early employment of anti-cataract agent may minimize surgical treatment. Anti-cataract agents are multifunctional antioxidants with radical hunting and chelation ability [ 10 ]. Examples of anti-cataract agents include curcumin, lanosterol, resveratrol, and metformin [ 11 ].

Glaucoma is a famous optic neuropathy disease. Symptoms start with blurred vision that progresses into irreversible blindness in the late stage. It leads to blindness as a result of slow deterioration of optic nerve axon and fatality of retinal ganglion cells [ 3 ]. It is commonly connected with elevation in intraocular pressure (IOP) because of irregular formation or obstruction of the aqueous humor [ 12 ]. Risk factors include age, race, diabetes, genetics, nearsightedness, migraine, and retinal vascular caliber. Glaucoma is more common in women population as they represent 55% of open angle glaucoma, 70% of angle closure glaucoma, and 59% of all forms of glaucoma in 2010 [ 1 ]. Worldwide incidence is estimated at 76 million at 2020 and is expected to elevate to 112 million by 2040 [ 13 ]. There are two types of glaucoma: open angle and closed angle. Open angle glaucoma has no symptoms and is characterized by enlarging optic disc cupping and visual field that results in elevated prevention of drainage of aqueous humor through trabecular meshwork. However, closed angle is characterized by the elevated pressure resulted from the blockage of outflow pathways [ 3 ]. About 76 million people suffered from glaucoma and the number is expected to reach 112 million by 2040 [ 14 ]. Glaucoma developed as a result of oxidative and nitrative processes. There are many antioxidant enzymes in aqueous humor for example superoxide dismutase, catalase, and glutathione peroxidase. Their level is decreased as a result of aging and that leads to elevated IOP. Change the equilibrium between oxidants and antioxidants influence the progression of glaucoma [ 15 ]. Anti-glaucoma drugs help to adjust either aqueous humor formation or drainage. Many studies were published to enhance glaucoma treatment [ 12 , 16 , 17 , 18 ]. Abd-Elsalam and ElKasabgy developed topical agomelatine-loaded olaminosomes with remarkable anti-glaucoma activity [ 12 ]. Eldeep et al . developed topical proniosomal gel-derived niosomes to improve ocular retention and activity of brimonidine tartrate [ 18 ].

Age-Related Macular Degeneration (AMD)

AMD is one of the main causes of loss of vision in developed countries. It is more frequent above the age of 50 years. [ 3 ]. About 8.7% of worldwide blindness is initiated by AMD AMD [ 19 ]. Nearly 196 million people suffered from AMD at 2020 and the number is expected to reach 288 million by 2040 [ 20 ]. It is a multifactorial degenerative complaint involving the posterior segment of the eye. Risk factors include aging, smoking, bad nutrition, high blood pressure, and immobility. There is no remedy for AMD till now, but its progression may be reduced by proper medications [ 21 ]. AMD could be divided into two types, dry (atropic or non-exudative) and wet (neovascular or emulative). Irregular angiogenesis (development of new blood vessels) in the retinal epithelium is the main character of AMD and results in drusen (yellow deposits under the retina), atropy, and separation of bruch’s membrane [ 22 ]. Many cellular growth factors are increased during angiogenesis due to the irregularities in corresponding metabolic pathways as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (FGF), and epithelial growth factor (EGF). A new approach for treatment of AMD involves juxtascleral injections of anecortave cortisone that showed prolonged release for 6 months in the choroid and retina [ 23 ]. Moreover, intravitreal injection of the biodegradable Rho kinase and protein kinase C inhibitor for handling diabetic macular edema and neovascular age-related macular degeneration exhibited prolonged release for about 6 months [ 24 ].

Conjunctivitis

Conjunctivitis is generally the most frequent ocular compliant. It is simply the inflammation of conjunctival tissue. It affects all ages, races, and genders [ 25 ]. According to the cause, it may classified into infectious or non-infectious. Infectious conjunctivitis results from microbial infection, while non-infectious conjunctivitis results from allergens and irritants [ 25 ]. Symptoms of conjunctivitis include eye redness, eye discomfort, tears, and elevated eye secretions. Prevalence of allergic conjunctivitis is nearly 40% of global population [ 26 ]. Treatments of conjunctivitis include topical administration of antimicrobial (infectious) or anti-inflammatory agents (non-infectious).

Diabetic Retinopathy (DR)

Diabetic retinopathy is particular vascular complication related to both types of diabetes mellitus. About 60% of patients of type II and all patients of type I diabetes have a certain extent of retinopathy after 20 years of diabetes. Oxidative stress and inflammation result from the upregulation of proinflammatory mediators initiated by hyperglycemic disorders are the cause of development of DR. It is the third major trigger to blindness in the USA. After cataract and corneal blindness, the first and second triggers to blindness. It is avoidable if distinguished and cured early plus the effective management of blood glucose and blood pressure [ 27 ]. It has two types, proliferative and non-proliferative and both of them result eventually in progressive damage to the retina. Nowadays, diabetic retinopathy is managed through laser photocoagulation, vitrectomy, and pharmacological treatments. Laser photocoagulation works by closing the leaky blood vessels and possibly avoids blindness, but results in laser scar. Vitrectomy is a surgical removal of vitreous gel and blood from leaking vessels in the back of the eye, but this procedure provides only short-term relief and does not obstruct further leaking of blood [ 1 ]. Pharmacological treatments include intravitreous injections of corticosteroids to decrease the swelling of macula. Also, sustained release corticosteroids implant that interferes the inflammatory pathways. Modern management with anti-VEGF agents (Ranibizumab and Aflibercept) prevents the expression of VEGF and thus reduce blood leakage and edema [ 28 ].

Retinoblastoma

Retinoblastoma is a malignant tumor distressing the retina and mainly prevails in children younger than 5 years old. Untreated retinoblastoma leads to blindness and finally mortality (99%). Its frequency is about 1 out of 20,000 live births [ 29 ]. Its occurrence rate is equal in both gender. It is caused due to mutation in tumor suppressor gene RB1 encoding for retinoblastoma protein. It could be unilateral (60%) or bilateral (40%) [ 1 ]. The handling choices of retinoblastoma include radiotherapy, cryotherapy, systemic chemotherapy, and surgery. Latest studies propose that release of compensatory proangiogenic factors and angiogenic blood vessels development are the vital phases for treating retinoblastoma [ 30 ].

Fungal Keratitis

Fungal keratitis occurs only in traumatic cornea, since healthy cornea would not allow any fungal infection. It is caused by different fungus like Candida albicans , Candida glabrata , Candida tropicalis , Candida krusei , and Candida parapsilosis [ 31 ]. Fungal keratitis represents 40% of the contagious keratitis in developing countries of third world [ 1 ]. Risk factors may be ocular (trauma, contact lens, prior corneal surgery, and topical corticosteroids) or systemic (diabetes, HIV positivity, and leprosy). Fungal keratitis leads to impaired wound healing, corneal ulceration, and stromal inflammatory infiltration. The corneal inflammation may alter miRNA expression [ 32 ]. Oral or topical antifungal drugs are used to treat fungal keratitis. Corneal surgery approach could be required when the medicines are useless. In some situations, vision may not be restored even after surgery. Many papers consider the treatment of fungal keratitis. Younes et al . developed topical Sertaconazole nitrate loaded cubosomes and mixed micelles with enhanced safety and antifungal activity [ 33 , 34 , 35 , 36 , 37 ]. Figure  2 illustrates various ocular diseases [ 1 ].

Various ocular diseases affecting the two segments of the eye [ 1 ]

Obstacles to Ocular Delivery

Precorneal barriers, capacity of cul-de-sac.

Figure  3 explains different ocular barriers. Cul-de-sac is a shallow pocket in the lower eyelid where palpebral and bulbar conjunctiva meet in the lower eyelid and the deeper recess in the upper eyelid. The maximum capacity of cul-de-sac is 30 μL in humans. The movement of the lower eyelid to its regular place would reduce this capacity to 70–80%. Inflammation and allergic response of the eye would also minimize capacity of the cul-de-sac [ 6 ]. Since the activity of any drug is directly related to its residence time and concentration. The low capacity of cul-del-sac would reduce the concentration of the drug in the eye, thereby reducing the therapeutic activity.

Schematic diagram of physiological ocular barriers

Loss of Drug from Lacrimal Fluid

Drainage of the administrated ocular solution is a major barrier in precorneal region. Loss of drug from lacrimal fluid could happen as a result of lacrimation, solution drainage, and non-productive absorption in the conjunctiva [ 38 ]. Also, drug metabolism and protein binding would further obstruct drug absorption [ 6 ]. Continuous renewal of lacrimal fluid helps maintaining eye hydration, preventing pathogens or dust from retaining on the eye. In order to maintain effective drug activity, residence time of the administrated formula must be sustained which could be achieved by different mechanisms.

Corneal Barriers

The cornea provides a resistant obstacle to different chemical and mechanical injuries. It also supports light convergence on the retina. It is divided into epithelium, stroma, and endothelium. The epithelium is formed of five to seven layers of firmly linked cells. Stroma is a water-based compact layer. The epithelium is a barrier for hydrophilic drugs and large molecules, whereas the stroma is a barrier for lipophilic drugs [ 5 ]. The endothelium preserves the transparency of the cornea and provides selective access for hydrophilic drugs and macromolecules into the aqueous humor. As a general rule, drug molecular weight, charge, degree of ionization, and hydrophobicity influence the corneal permeation. Hence, the trans-corneal permeation is known as rate limiting step for drug transfer from the lachrymal fluid into the aqueous humor [ 6 ].

Blood-Ocular Barriers

They prevent the entry of foreign compounds into the blood stream. They are classified into blood-aqueous barrier (BAB) and blood-retinal barrier (BRB). BAB is an anterior portion of the eye that prevents the access of many compounds in the intra-ocular milieu. BAB allows the passage of lipophilic and small drugs. These drugs are eliminated from the anterior compartment faster than hydrophilic and larger molecules. For example, the clearance rate of pilocarpine was found to be faster than inulin [ 6 ]. BRB is a posterior portion of the eye that is made of the retinal endothelial cells and the retinal pigment epithelial cells. It prevents the access of dangerous materials, water, and plasma components into the retina [ 39 ].

Routes for Ocular Drug Delivery

Figure  4 illustrates different routes for ocular drug delivery [ 7 ].

Different routes for ocular drug delivery [ 7 ]

Topical Administration

Topical administration is the most common route for ocular drug delivery that represents more than 95% of marketed ocular products. It is non-invasive route, but with low bioavailability (<5%) due to insufficient corneal permeation and short residence time [ 4 ]. Moreover, bioavailability is reduced by tear drainage, blinking and entering the systemic circulation through the nasolacrimal pathway. Topical delivery necessitates frequent and high dose concentration, which could result in serious side effects. Also, frequent dosing could influence the patient compliance [ 4 , 5 ]. Topical route is unsuitable for handicapped and elder patients [ 7 ]. The topical administration of terconazole in the form of bilosomes showed enhanced drug permeation and safety [ 40 ]. Topical administration of sertaconazole nitrate as mixed micelles or cubosomes revealed high corneal uptake and corneal retention [ 33 , 34 ]. β-cyclodextrin-based micellar system demonstrated higher ex vivo and in vivo permeation of itraconazole and higher antifungal activity [ 35 ]. The topical administration of dorzolamide hydrochloride in the form of proniosomal gels showed controlled ex vivo permeation, increased stability, and improved bioavailability [ 16 ]. Table I reveals more examples of topical administration.

Intracameral Injections

Intracameral injections involve injection of antibiotic directly into the anterior segment of the eyeball or in the vitreous cavity. It is done usually subsequent to cataract surgery to avoid endophthalmitis initiated by a contagion of the eye that can occur after cataract surgery. Recently, the application of intracameral injection for treatment of glaucoma using hydrogel functionalized with vinyl sulfone and thiol groups was published [ 73 ].

Intravitreal Injections/Implants

Intravitreal injection is a delivery of medicine into the vitreous that is close to the retina at the back of the eye. A new approach for treatment of glaucoma includes a single intravitreal injection of vitamin E/poly-lactic-co-glycolic acid microspheres enclosing glial cell line derived neurotrophic factor. This approach provided a prolonged release for 6 months. Similar results was obtained after intravitreal injection of polymer-free dexamethasone dimer implants [ 52 ]. Intravitreal injection of the biodegradable Rho kinase and protein kinase C inhibitor for handling diabetic macular edema and neovascular age-related macular degeneration exhibited prolonged release for about 6 months [ 24 ]. Additional examples are mentioned in Table I .

Juxtascleral Injections

Juxtascleral injections are used for treatment of some posterior part complaints that cannot be handled through conventional topical route. It is used for the treatment of cystoid macula edema, trauma, and diabetic-related conditions. A new approach for treatment of AMD involves juxtascleral injections of anecortave cortisone that showed prolonged release for 6 months in the choroid and retina [ 23 ]. Advanced trans-scleral microneedles have been formulated to carry adeno-associated viruses for retinal gene treatment [ 55 ]. Table I shows further examples.

Retrobulbar Injection

Retrobulbar route involves the injection of a needle through the eyelid and orbital fascia to deliver the medication behind the globe into the retrobulbar space. Retrobulbar injection of amphotericin B showed higher antifungal efficacy than intravenous injection [ 58 ]. Retrobulbar injection of chlorpromazine is used to manage blind painful eyes [ 59 ]. Retrobulbar injection of triamcinolone is utilized to handle macular edema resulted from retinal vein occlusion [ 60 ].

Subconjunctival Injection

Subconjunctival injection is frequently used in cases of very low drug penetration into the anterior part of the eye after topical administration. Subconjunctival injection of steroids fabricated as PEGylated liposome for handling of uveitis showed sustained anti-inflammatory activity and targeting the required ocular tissue for 1 month as minimum [ 61 ]. The administration of PLGA nanoparticle of brinzolamide by subconjunctival injection showed successful handling of IOP for 10 days [ 62 ]. Significant lowering in corneal inflammation and squamous metaplasia was ensured via subconjunctival injection of human mesenchymal stromal cells in mice with graft versus host disease [ 63 ]. Table I shows extra examples.

Irrigating Solutions

They are solutions made under aseptic condition without the inclusion of preservatives. They are used as balanced salt by surgeons to eradicate blood, cellular waste, and maintain the appropriate hydration volume of the eye [ 74 ]. There are many examples that intensifies the importance of these solutions. For example, minimizing the cataract surgical duration and avoiding pupil miosis by using ketorolac (0.3% w/v) and phenylephrine (1% w/v) in the irrigation solutions [ 66 ]. Table I shows more examples.

Iontophoresis

Iontophoresis is a technique used to carry medications into the posterior segment of the eye. It involves the usage of voltage gradient. Novel systems involve the employment of microneedle-based instruments. They had doubled the amount of formula delivered to the back of the eye compared to suprachoroidal injection [ 75 ]. The combinations of iontophoretic delivery and contact lens results in 550–1300-times shorter duration than drug uptake into choroidal capillaries [ 76 ]. Short-duration iontophoresis of acyclovir prodrug resulted in higher permeation and bioavailability [ 69 ]. Ocular iontophoresis of dexamethasone phosphate revealed higher efficacy in managing non-infectious anterior uveitis [ 70 ]. Table I shows more examples.

Dosage Forms

Liquid dosage forms.

Eye drops represent more than 95% of the marketed ocular products. They deliver the medication into the anterior part of the eye. Their advantages include easy administration and accepted stability. However, their disadvantages include low retention time (<5 min.), poor bioavailability, and serious side effect resulted from the frequent administration of high concentration [ 77 ]. Several nanosystem platforms had been developed to solve their drawbacks. Cyclosporine was formulated as a mucoadhesive nanosystem utilizing poly (D-L-lactide)-b-dextran. Nanoprecipitation technique was adopted for the formulation. The final product demonstrated small particle size, enhanced permeability, and drug retention [ 43 ]. Formulation of the antibacterial hesperetin as micellar system showed minute particle size, high percentage entrapment efficacy, greater penetration, and enhanced efficacy [ 44 ]. More examples are illustrated in Table II . Figure  5 illustrates different ocular dosage forms.

Classification of ocular dosage forms

Eye Suspensions

Ocular suspensions represent dispersions of hydrophobic drug in aqueous solvent. They have enhanced contact time because of drug retention in the conjunctival cul-de-sac. Particle size, solubility, and dissolution rate in the tear fluid are extremely important during the preparation process [ 102 ]. Generally, particle size  <10 µm has greater solubility, enhanced dissolution rates, and poor retention on the ocular surface. However, particles of  >10 µm could result in ocular irritation and stimulated tearing [ 103 ]. Disadvantages of ocular suspension include poor stability. They cannot be stored in freezer as the particles tend to agglomerate and fail to disperse easily. Also, change in crystal size during the storage will influence both solubility and bioavailability of the drug. A blurred vision after their administration could also result. Improved ocular administration of posaconazole in polymer system of carbopol 974P and xanthan gum using high pressure homogenizing technique showed enhanced stability, antifungal activity, and prolonged retention [ 46 ]. High speed liquid–liquid shear technique was adopted to formulate ultra-fine rebamipide ophthalmic suspension. This formula showed enhanced transparency, small particle size, and improved stability [ 45 ]. Table II states more examples.

Eye Emulsions

An emulsion is a solubilized biphasic system due to the inclusion of surfactants or stabilizers. Advantages of eye emulsions include ability to deliver hydrophobic drugs; oil-in water (O/W) emulsion is less irritant to the eye, enhanced contact time and bioavailability [ 104 ]. The ocular delivery of dexamethasone acetate and polymyxin B sulfate was enhanced by the formation of nanoemulsion by high-pressure homogenization. A positive charge inducer was incorporated to enhance ocular adhesion. The resulted formula showed enhanced stability, reduced particle size, and enhanced retention time [ 84 ]. Water titration method was adopted for the construction of triamcinolone acetonide microemulsion. It showed minimized particle size and improved permeability [ 85 ]. Additional results are clarified in Table II .

Semisolid Dosage Forms

Eye gels are a semisolid dosage form containing high water quantity. They have enhanced retention time and bioavailability because of their viscosity. Although gels contain large quantity of water, blurred vision could still result. Various polymers could be used to prepare ocular gels like polyacrylic acid, acrylic acids, hydroxypropyl methylcellulose, and carboxymethyl cellulose [ 105 ]. Coacervation technique was used to prepare a proniosomal gel of curcumin with effective reduction in particle size and improvement of anti-inflammatory activity [ 89 ]. An increase in the ex vivo permeability and retention time of pilocarpine was demonstrated via formation of phytantriol-based lyotropic liquid crystalline gel. That gel was formed by vortex method [ 90 ]. Additional examples are mentioned in Table II .

Eye Ointments

Eye ointments are semisolid dosage form containing white petrolatum and mineral oil. They are administrated to the lower eyelid only at bedtime due to its interference with vision. They are commonly used among young patients. They have anhydrous nature making them a good choice for lipophilic and moisture sensitive drugs. They have higher retention time and bioavailability in comparison with solutions [ 106 ]. Avaclyr® is an ocular ointment enclosing the antiviral acyclovir that was approved in 2019 for herpetic keratitis. Also, Lotemax® enclosing the anti-inflammatory loteprednol etabonate. Both of them showed enhanced corneal penetration and drug release [ 92 ].

Solid Dosage Forms

Eye powders.

They are sterile solid dosage form of water-sensitive drugs. They are administrated in injectable forms as intracameral injection of cefuroxime, moxifloxacin, and voriconazole. Cefuroxime and moxifloxacin are reconstituted in saline, while voriconazole is reconstituted in water. Both cefuroxime and voriconazole solutions are stable for 7 days after reconstitution. However, moxifloxacin solution is stable for 24 weeks [ 107 , 108 ].

Ocular Inserts

Ocular inserts are solid dosage form of biodegradable polymers. They show zero order drug release model. Advantages of inserts include high residence time, sustain drug delivery, constant release, and reduced side effects [ 109 ]. Electrospinning technique was adopted for the construction of triamcinolone acetonide-loaded nanofibers. They showed reduced particle size, systemic absorption, and side effects [ 93 ]. Also, sustained bimatoprost activity for many months was proved after incorporation of its insert [ 110 ]. Table II shows more examples.

Therapeutic Contact Lens

New studies showed that therapeutic contact lens could enhance bioavailability by  >50% as a consequence to sustained residence time and close contact with the cornea [ 111 ]. Their residence time is 10 folds the conventional eye drops [ 112 ]. They also reduce required doses, interval between doses and systemic absorption [ 113 ]. There are many techniques to enclose the drug inside contact lens as molecular imprinting, ion ligation, soaking, and use of nanoparticles [ 77 , 114 , 115 ]. Obstacles to their clinical use include protein attachment, ion and oxygen permeation, drug loss during manufacture or storage, transmittance, and swelling of the lens [ 7 ]. Dexamethasone contact lens was prepared by encapsulation technique. It showed 200-fold drug retention in the retina matching with conventional eye drops [ 116 ]. In order to reduce rapid drug release, chips of either timolol, bimatoprost, or hyaluronic acid have been used [ 111 ]. Extra examples are given in Table II .

Mixed Dosage Forms

In situ gel.

They are polymeric solutions of low viscosity. They converted into pseudo-plastic gels in contact with tear fluid. They have sustained contact time compared to simple solutions [ 117 ]. There are three types of in situ gel according to the transition properties: temperature, ionic, or pH sensitive [ 118 ]. In situ gel of ciprofloxacin with hydroxypropyl methylcellulose and sodium alginate (ion-sensitive) showed enhanced residence time and sustained drug release [ 98 ]. Thermosensitive in situ gel of hydrocortisone butyrate revealed extended drug release and avoided burst release [ 99 ]. Thermosensitive in situ gel of ketorolac tromethamine showed improved mucoadhesive properties with prolonged release of drug up to 12 h [ 119 ]. Table II shows more examples about in situ gel.

Nanostructured Platforms

They were discovered in the mid-1960s [ 120 ]. Advantages of liposomes include safety, biodegradation, simple preparation techniques, and improved bioavailability [ 121 ]. They are spherical nanocarriers made of one or more concentric lipid bilayers. They could carry lipophilic drug in the lipid area, while the interior could entrap hydrophilic drugs. Changing the formation technique and their composition could alter their surface charge, sensitivity to ion or pH, or temperature changes and the resulted particle size [ 120 ]. Generally, the corneal epithelium has a negative charge; therefore, a positively charged liposomes would have high adherence, longer retention time, and better absorption. These outcomes will reduce the interval between doses and improve patient satisfaction [ 122 ]. Zhang and Wang created a liposomal system composed of phosphatidylcholine, cholesterol, α-tocopherol, and chitosan. The resulted formula showed high percent entrapment, sustained activity, and enhanced efficacy [ 47 ]. Lin et al . used phosphatidylcholine, stearylamine, cholesterol, and hyaluronic acid. The finished product revealed better corneal uptake, high drug targeting, improved percent entrapment, and prolonged penetration [ 123 ]. Cheng et al . constructed liposomal system formed of soybean phosphatidylcholine, cholesterol, chitosan, and dicetylphosphate. This formula showed superior corneal permeation and improved activity [ 124 ]. Vicario-de-la-Torre et al . used phosphatidylcholine, cholesterol, sodium hyaluronate, trehalose, borate, and vitamin E to form a stable formula with enhanced safety, ocular adhesion, and hydration [ 125 ]. Other studies are briefly described in Table III . Figure  6 shows different nanostructured platforms [ 8 ].

Illustration of numerous nanostructured platform [ 8 ]

Niosomes are bilayered nanocarriers composed of self-aggregated non-ionic surfactants. They are biodegradable, biocompatible, enclose both hydrophilic and lipophilic drugs and non-immunogenic. They could prolong drug release and enhance its permeability and efficacy [ 161 , 162 ]. Disadvantages of niosomes include chemical instability and possible hydrolysis, accumulation or loss of drug [ 18 ]. Cholesterol or its derivative is added to improve rigidity and stability of niosomes [ 8 ]. Elmotasem and Awad developed a niosomal system composed of span 60, cholesterol, poloxamer 407, hydroxypropyl methylcellulose, cyclodextrin, and chitosan. The resulted formula showed high drug entrapment, enhanced corneal permeation and activity [ 48 ]. Kaur et al . studied niosomal system composed of span 60, cholesterol, and chitosan. The finished product revealed higher activity, reduced side effects, and prolonged release [ 129 ]. Aggarwal et al . improved the duration of action and efficacy of acetazolamide using span 60, cholesterol, and Carbopol® 934P [ 130 ]. Zubairu et al . developed a niosomal system of gatifloxacin composed of span 60, cholesterol, and chitosan. The optimized formula showed enhanced antimicrobial activity, no toxicity, and superior ocular permeation [ 49 ]. More investigations are concisely mentioned in Table III .

Nanoemulsions

They are potential carriers for ocular delivery. Oils in water nanoemulsions are composed of dispersed oil phase that is stabilized by surfactants in an aqueous medium. They provide a reservoir for lipophilic drugs and interact with the lipids of tear film providing a sustained drug release [ 87 , 163 ]. Surfactants are important for the interaction with the surface of the cornea, plus enhancing drug solubility [ 8 ]. Drawbacks of nanoemulsions include blurred vision if the particle size exceeds 100 nm due to development of milky formulation and reduced ocular tolerance due to high surfactant concentration [ 163 ]. Akhter et al . developed nanoemulsions system of cyclosporine A. Many oils, chitosan, Carbopol®, and Transcutol® P were incorporated. The resulted formula revealed enhanced drug retention, safety, and efficacy [ 87 ]. Oleic acid, polysorbate 80, poloxamer 188, chitosan, and polymyxin B were used by Bazán Henostroza et al ., to improve stability, mucoadhesion, and antibiotic activity of rifampicin [ 50 ]. Soltani et al . constructed nanoemulsions of ketotifen fumarate utilizing Eudragit® RL 100 and polyvinyl alcohol. Enhanced corneal permeation and sustained release were obtained [ 88 ]. Additional findings are listed in Table III .

Nanosuspensions

They are colloidal nanocarriers constituted of lipophilic or semi-lipophilic drugs, suspended in a dispersion medium and stabilized by surfactants or polymers [ 121 ]. Their advantages include sustained drug release, increased residence time, and enhanced drug solubility and bioavailability [ 161 ]. The most commonly used mucoadhesive agents in nanosuspensions are Eudragit® polymers. Pignatello et al . developed a nanosuspensions of cloricromene composed of Eudragit® RS and RL 100 and Tween 80. The resulted formula showed enhanced stability, corneal residence time, and permeation [ 136 ]. Ahuja et al . used Eudragit® S100 and poloxamer 188 to form nanosuspensions of diclofenac with enhanced percent entrapment, prolonged release, and increased anti-inflammatory activity [ 83 ]. Khan et al . employed Eudragit® RL100 to increase percent entrapment, sustain drug release, and enhance pilocarpine activity [ 137 ]. Extra results are briefly listed in Table III .

Nanomicelles

They are nanocarriers composed of anionic, cationic, or zwitterionic surfactants. They may be spherical, cylindrical, or star-shaped. They could entrap both hydrophilic and lipophilic drugs. They have simple preparation techniques, reduced toxicity, increased bioavailability, increased stability, and enhanced permeation. They could deliver drugs to both segments of the eye (anterior and posterior portions) [ 161 ]. Yingfang et al . developed nanomicelles of pimecrolimus using polyethylene glycol and poly (ε-caprolactone) as co-polymers. The resulted formula showed enhanced percent entrapment, sustained release, and enhanced activity [ 141 ]. Liu et al . enhanced ocular permeation and prolonged release of tacrolimus utilizing amino-terminated poly(ethylene glycol)-block-poly(D,L)-lactic acid and hydroxypropyl methylcellulose [ 142 ]. Terreni et al . used hyaluronic acid to sustain the release, increase permeation, and activity of cyclosporine A [ 143 ]. Table III briefly lists additional studies.

Polymeric Nanoparticles

Polymeric nanoparticles could be divided according to their structure and preparation method into nanospheres and nanocapsules. Nanospheres are small solid spheres composed of a dense polymeric network. They have a matrix type composition with a great surface area. The drug could be adsorbed on the surface or entrapped within the particle. However, nanocapsules are a small liquid core enclosed by a polymeric membrane. The drug could be adsorbed on the capsule surface or entrapped within the liquid core [ 121 ]. Polymeric nanoparticles could reach both segments of the eye. They improve patient compliance particularly in chronic complaints due to their small particle size. They have a prolonged drug release, improved permeation, and reduced elimination rate [ 161 ]. Yu et al . developed polymeric nanoparticles for dexamethasone utilizing glycol chitosan, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, and N-hydroxysuccinimide. They showed enhanced retention time, sustained release, and small particle size [ 51 ]. Bodoki et al . sustained the release and enhanced the efficacy of lutein using poly(lactic-co-glycolic acid), tween 80, and Poloxamer 407 [ 164 ]. Abdel-Rashid et al . enhanced ocular permeation and efficacy of acetazolamide employing chitosan, span 60, Tween® 80/20, and sodium tripolyphosphate [ 145 ]. More examples are concisely mentioned in Table III .

Solid Lipid Nanoparticles

They are a solid lipid matrix enclosing hydrophilic and lipophilic drugs [ 161 ]. Examples of lipids used to prepare solid lipid nanoparticles include triglycerides, fatty acids, steroids, and waxes. They do not require organic solvents since surfactants stabilize the lipid dispersion [ 165 ]. They are biodegradable, biocompatible, safe, and of low-cost preparation [ 165 ]. They showed enhanced ocular retention time, permeability, prolonged release, and improved bioavailability [ 161 ]. Ahmad et al . developed solid lipid nanoparticles loaded with etoposide employing Gelucire® 44/14 and Compritol® ATO 888. The resulted formula demonstrated sustained release, improved safety, and activity [ 149 ]. Tatke et al . constructed triamcinolone acetonide-loaded solid lipid nanoparticles utilizing Pluronic® F-68 and gellan gum. The finished formula ensured improved residence time and increased delivered concentration [ 150 ]. A mucoadhesive solid lipid nanoparticles of tobramycin was successfully examined by Chetoni et al . The system composed of stearic acid, Epikuron 200, and sodium taurocholate. Higher concentration of tobramycin in both segments of the eye was demonstrated [ 151 ].

Nanostructured Lipid Carriers

They are considered a second generation of lipid nanoparticles, composed of around 30% of liquid lipids but the finished formula is solid, with no crystalline structure [ 161 ]. The liquid oil droplets provide additional space for drug in lipid matrix leading to higher drug content compared to solid lipid nanoparticles. They show controlled release, small toxicity, and enhanced activity. Aytekin et al . studied nanostructured lipid carriers loaded with riboflavin utilizing Compritol® ATO 888, Gelucire® 44/14, Miglyol® 812, Cremophor® EL, Transcutol® P, and stearylamine. The finished product demonstrated superior corneal residence time, permeation, and safety [ 153 ]. Pai and Vavia constructed etoposide-loaded nanostructured lipid carriers using many solid and liquid lipids, glyceryl stearyl citrate, and chitosan. The resulted formula reveled sustained and improved activity [ 154 ]. Yu et al . used Compritol® 888 ATO, Miglyol® 812 N, Cremophor® EL, soy lecithin, carboxymethyl chitosan, genipin, and poloxamer F127 to formulate nanostructured lipid carriers of baicalin. Investigations showed increased corneal permeation, retention time, and safety [ 166 ]. More investigations are succinctly stated in Table III .

Nanocrystals

The drug represents a major composition of nanocrystals, being enclosed and stabilized by other excipients. They have small particle size, simple formation techniques, high mucoadhesion properties, and improved bioavailability [ 162 ]. Tuomela et al . created brinzolamide-loaded nanocrystals using poloxamer F68/ F127, polysorbate 80, and hydroxypropyl methycellulose. The finished formula revealed immediate dissolution and improved efficacy [ 157 ]. Romero et al . developed cationic nanocrystals of dexamethasone and polymyxin B using benzalkonium chloride and cetylpyridinium chloride. The resulted preparation revealed small particle size, enhanced retention time, and safety [ 158 ]. Orasugh et al . formulated a cellulose nanocrystals of pilocarpine. Sustained drug release and safety were demonstrated [ 167 ]. Nanocrystals could be promising nanocarriers to be investigated in the near future in details.

They are star-shaped or tree-shaped highly branched 3D structure, composed of repetitive molecules enclosing a central core [ 162 ]. They are suitable for delivery of both hydrophilic and lipophilic drugs due to their several terminal groups [ 161 ]. They showed increased residence time, prolonged activity, improved bioavailability, targeted delivery, and antimicrobial properties. They could transfer medications to both segments of the eye [ 8 ]. Lancina et al . developed brimonidine tartrate-loaded dendrimers using methoxy-polyethylene glycol. Sustained release and improved activity were achived [ 168 ]. Mishra and Jain studied dendrimers entrapping acetazolamide. Increased residence time, prolonged release, and activity were confirmed [ 169 ]. Holden et al . developed timolol maleate-loaded dendrimers utilizing polyethylene glycol. The finished formula showed improved permeation and increased cellular uptake [ 170 ]. Table III clarifies briefly more studies about dendrimers.

They are bicontinuous cubic liquid crystalline nanocarriers constructed by emulsification of lipids in water with the aid of stabilizer. They are stable, entrap high amount of drugs due to its large surface area, easy to prepare, biodegradable, and relatively safe [ 17 ]. El deep et al . formulated brimonidine tartrate-loaded cubosomes utilizing glyceryl monooleate and poloxamer 407. The resulted formula revealed sustained release, improved permeation, and bioavailability [ 17 ]. Younes et al . developed sertaconazole nitrate-loaded cubosomes using DL-α-Monoolein, pluronic® F127, Brij® 58, pluronic® F108, Tween 80, and polyvinyl alcohol. Improved permeation, stability, and efficacy were achieved [ 33 ]. Gaballa et al . developed cubosomal system of beclomethasone dipropionate employing glyceryl monooleate. Improved corneal permeation and anti-inflammatory activity were demonstrated [ 91 ].

Olaminosomes

Olaminosomes are mainly formed of oleic acid, oleylamine, and surfactant. Oleic acid is natural unsaturated free fatty acid. Oleic acid is safe, biodegradable, and biocompatible. Thus, oleic acid is often used in the preparation of ocular nanocarriers [ 12 ]. Oleylamine is an unsaturated fatty amine derived from oleic acid. It has the extensively used as surfactant or co-stabilizer. It is generally used in food and drug products as a result of its well-accepted safety [ 171 ]. Olaminosomes have a small particle size, high drug entrapment ability, improved corneal permeation, safety, and activity. Abd-Elsalam and ElKasabgy developed agomelatine-loaded olaminosomes. The optimum formula showed enhanced permeation and improved activity [ 12 ].

Bilosomes are bilayered nanocarriers containing bile salts. They have high drug entrapment, minute particle size, accepted zeta potential, accepted safety, enhanced corneal permeation, and activity. Abdelbary et al . developed terconazole-loaded bilosomes using cholesterol, span 60, and edge activator. The resulted formula showed great entrapment, improved permeation, and enhanced activity [ 40 ].

Characterization of Nanocarriers

Visual appearance.

Figure  7 shows briefly the approaches used to characterize ocular nanocarriers. Visual appearance depends on the particle size, surfactant, and oil concentration and type. Nanosystems could be transparent, translucent to milky white. Transparency is estimated by percentage transmittance (% T) using a UV spectrophotometer at 520 nm [ 6 ]. Small particles permit light transmission resulting in translucent or transparent appearance. High % T indicates absence of visual disturbance. However, gelation would reduce the transparency by 15% [ 172 ].

Approaches to characterize ocular nanocarriers

Stability of different nanosystems could be determined through short-term stability (3 months), centrifugation test, heating–cooling cycle, freeze–thaw cycles, and storage at elevated temperatures. All tests are followed by visual evaluation [ 6 , 36 ]. The structure of the constructed formula determine the storage condition which could be at ambient temperature (25 ± 2°C) [ 33 , 34 , 36 ] or refrigerated (4–8°C) [ 31 , 173 ].

Size and Uniformity Analysis

Particle size (PS) and poly-dispersity index (PDI) are the determined variable. They are estimated by dynamic light scattering (DLS) or photon correlation spectroscopy (PCS) using either Zetasizer devices (Malvern) or Coulter Counter particle size analyzer [ 6 ]. The ratio of the standard deviation to the mean droplet size is known as a PDI. Regarding PDI, a value of 0 indicates homogenous system, while a value of 1 indicates heterogeneous system [ 174 ]. Generally, small PS and PDI are desirable for ocular drug delivery since they increase patient compliance and enhance corneal permeability and corneal bioavailability [ 33 ]. PS is affected by homogenization time, surfactants type, surfactants amount, lipids type, and lipids quantity. Using high amount of lipid would increase the viscosity of the medium resulting in high difficulty to break the particles and hence large PS [ 33 ]. However, high surfactant concentration would allow more coverage for the surface of nanosystem; consequently prevent additional growth in the PS [ 12 ]. Using surfactant with low hydrophilic-lipophilic balance (HLB) value would increase the hydrophobicity of the medium and decrease the free energy resulting in smaller PS [ 41 ]. Increasing the homogenization time would reduce the PS [ 33 ]. However, the efficacy of sonication process might be reduced if the fatty acid had a high melting point as a result of the increased viscosity of the formula [ 175 ].

Zeta Potential

Zeta potential (ZP) is an indicator of physical stability of the formed nanosystem. It is determined through electrophoretic movement of particles in an electrical field. Generally, ZP around ± 20 mV is appropriate for electrostatic attachment with the cornea surface. In addition, ZP ensures the stability because of electrostatic repulsion between the particles. It is high recommended to dilute the formed nanosystem prior to ZP determination [ 6 ]. Effective precorneal retention time is achieved when the absolute value of ZP lies between 20 and 40 mV. It has been demonstrated that ZP value + 40 mV of Catioprost (Latanoprost — cationic emulsion) revealed a comparable effect as Xalatan (commercial eye solution) for reducing IOP but have a superior ocular tolerance profile [ 176 ]. Also, cubosomal formula with ZP =  −30.2 mV showed better bioavailability and activity compared to Alphagan P® eye drops [ 17 ].

Morphological

Transmission electron microscopy (TEM) and atomic force microscopy (AFM) approaches are valuable to ensure the results of dynamic light scattering (DLS) or photon correlation spectroscopy (PCS) [ 173 ]. TEM of the nanoemulsion referred by Tayel et al . showed spherical and homogenous structure with no aggregates. TEM was in harmony with the results obtained by PCS [ 135 ]. In addition to, the AFM examination of the nanoemulsion referred by Dukovski et al . revealed spherical structure with the same size as resulted from PCS [ 177 ]. TEM of the mixed micelles constructed by Younes et al. revealed spherical shape, with no accumulation and was comparable to DLS [ 34 ].

Refractive Index

The refractive index (RI) is detected by Abbe’s refractometer and employed to detect the water content of soft contact lenses. It is important to confirm that the nanosystem will not cause a blurred vision [ 178 ]. The optimum RI for ocular delivery is  <1.476 since the RI of tear fluid ranged from 1.34 to 1.36 [ 178 ]. Ismail et al . obtained acceptable RI (1.334 to 1.338) for the formed nanoemulsion [ 179 ]. The mixed micelles constructed by Fahmy et al . showed adequate RI (1.348) [ 36 ].

Surface Tension

Tate’s law indicates that there is a direct relation between drop volume and surface tension. The volume of the drop regulates the amount of drug that reaches the eye. Surface tension is measured by tensiometer. Generally, the most appropriate dose for ocular delivery is 5–15 μL. However, commercial eye drops give 25.1 and 56.4 μL. Surfactants could condense the droplet size [ 180 ]. A surface tension below 35 mN/m results in painful ocular administration, while high surface tension leads to minor film stability. For ocular delivery, surface tension between 40 and 50 mN/m is required [ 181 ]. Dukovski et al . discovered that both chitosan and ibuprofen could reduce surface tension as a result of their surface-active properties [ 177 ].

Rheological Measurement

Low viscosity nanosystem allows beneficial compliance with minor blinking pain. However, high viscosity nanosystem could prolong contact time, reduce frequency of dose, and increase bioavailability, but also results in patient discomfort [ 177 ]. The appropriate viscosity for ocular preparation is between 2 and 3 mPa.s [ 6 ].

Drug Distribution

Both percent entrapment efficiency (% EE) and percent drug loading (% DL) are used to examine diffusion of drug inside the nanosystems. % DL indicates the mass ratio of drugs to the mass of the nanosystem; however, % EE reflects the incorporation of drugs within the nanosystem during the formulation process. Generally, % DL depends on the structure and physical and chemical properties of the carrier material; however, % EE depends on drug hydrophobicity, molecular weight, and structure. Additionally, obtaining high %DL is more difficult than high % EE for most nanosystems [ 182 ]. Prior to determination of amount of the drug, the formula may be subjected to ultrafiltration, ultracentrifugation, gel filtration, or microdialysis [ 6 , 34 , 36 ]. Said et al . determined % EE of voriconazole-loaded cubosomes after ultracentrifugation [ 37 ]. % EE of rifampicin-loaded nanoemulsion and ibuprofen-loaded nanoemulsion was conducted after ultrafiltration [ 50 , 177 ] Lin et al. estimated both % EE and % DL for the constructed micellar system [ 183 ].

pH Measurement

pH determination is important to ensure safety and efficacy of nanosystems. Acidic (pH < 4) or alkaline (pH > 10) solution would harm the eye [ 37 ]. Also, pH from 4 to 8 would significantly enhance drug permeation [ 31 ]. The pH of ocular preparation usually ranged from 3.50 to 8.50 [ 37 ]. pH of the formed cubosomes referred by Said et al . was (6.20 ± 0.01) [ 37 ]. Micellar system constructed by Fahmy et al. revealed acceptable pH value (7.41 ± 0.01) [ 36 ].

Isotonicity and Osmolality

Osmolality measurements are based on the colligative properties of tears or ocular nanosystem known as the freezing point, boiling point, vapor pressure, and osmotic pressure. Osmolality of open eyes is ranged from 231 to 446 mOsm/kg due to fluid evaporation. Ocular preparation with osmolality lower than 100 mOsm/kg or greater than 640 mOsm/kg was considered an eye irritant. Osmolality is restored within 1 or 2 min subsequent to administration of the non-isotonic preparation [ 6 ].

Ocular Retention

Ocular retention is important since it will reduce the frequency of doses and improve drug bioavailability. Ocular retention largely depends on surface area of nanosystem, since large surface area will enhance residence time. Ocular retention is determined by texture analysis method, modified balance method, fluorescence retention method, γ-scintigraphy, and rheological synergism after mixing with mucoadhesive polymer [ 6 ]. As a general rule, the force needed to detach eyelid during normal blink is about 0.2 N and 0.8 N during strong blink [ 184 ]. For chitosan-coated cyclosporine nanoemulsions, the resulted force of detachment was 0.153 N [ 87 ].

Ocular Biocompatibility

Draize test.

It’s a traditional in vivo test to detect possible irritation potential of the formed nanosystems. It may be also used for cosmetics [ 185 ]. Draize test relays on scoring system from 0 (no irritation) to ‏3 (inflammation and redness) for the cornea, iris, and conjunctivae [ 18 ]. For example, Ismail et al . utilized the test on rabbits to compare between nanoemulsions of travoprost and Travatan® eye drops. Safety of the constructed formula was confirmed [ 179 ]. Also Eldeep et al . used Draize test to confirm safety of the topically applied niosomes of brimonidine tartrate against Alphgan P® [ 18 ].

Hen’s Egg Test

Because of the existence similarities between chorioallantoic membrane (CAM) and vascularization of mucosal tissue of humans, this technique is used to detect possible ocular irritation from nanosystem. The score is given based on clotting, bleeding, and hyperemia on CAM blood vessels [ 186 ]. For example, Mahboobian et al . examined the safety of the formed nanoemulsion versus negative control (PBS, pH = 7.4) and positive control (sodium dodecyl sulfate). Study was accomplished on freshly fertilized hens egg at 37 ± 0.5°C and relative humidity of 67 ± 5% RH for 10 days with regular rotation every 12 h. Irritation consequences such as hemorrhage or hypermia were evaluated by visual inspection. Safety of the nanoemulsion was demonstrated by the end of the experiment [ 186 ].

Corneal Permeation

Ability of the nanosystem to penetrate through cornea is studied through various in vivo , ex vivo, and in vitro tests. The in vivo models usually utilized the rodents (rabbit, rat, or mouse); however, in vitro and ex vivo models used epithelial cells layer cultures, reconstructed cornea, or excised cornea [ 6 ]. Also, different permeation chambers are available like Franz-type diffusion cell, modified Franz diffusion cell, modified using chamber, horizontal perfusion cells, modified Erlenmeyer flask diffusion cell, and polycarbonate corneal perfusion chamber [ 6 ]. Different permeation parameters are estimated to evaluate the permeation potential of nanosystem. Permeation parameters include the amount of drug permeated per unit area (µg/cm 2 ), average flux (J max ), permeability coefficient, and the enhancement ratio (ER) [ 5 , 34 ].

Possible Interactions

Differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR) are important techniques to detect possible interaction between the components of nanosystems [ 173 ]. They also assure complete entrapment of the drug. For example, the specific peaks of vancomycin, poly (d, l-lactide- coglycolide), and Eudragit® RS 100 were preserved ensuring the absence of chemical interactions [ 187 ], while complete entrapment of dorzolamide hydrochloride was confirmed by disappearance of its characteristic peak from DSC thermogram [ 16 ].

Approaches to Enhance Ocular Delivery

Improvement of corneal permeability.

Figure  8 shows concisely the approaches used to enhance ocular delivery. One of the approaches to enhance drug bioavailability following topical administration is increasing corneal permeability. For example, changing membrane components and/or disrupting epithelial tight junctions using surfactants, permeation enhancers, calcium chelating agents [ 188 ], and modifying physicochemical characters of the ionized drug using ion pairs [ 189 ]. On the other hand, enzymatic transformation of prodrug would convert it into the active after appropriate permeation [ 190 ]. Finally, applying a low-intensity electrical current (iontophoresis) would enhance drug permeation by electrorepulsion and electroosmosis effects.

Approaches to enhance ocular delivery

Improvement of Corneal Retention Time

One of the techniques to increase corneal retention time is inclusion of excipients. Excipients could be a viscosity increasing polymers. However, high viscous eye drops are irritating for many patients, do not provide an accurate dose and result in blurred vision [ 191 ]. In situ gel has sustained contact time compared to simple solutions [ 117 ]. There are three types of in situ gel according to the transition properties: temperature, ionic, or pH sensitive [ 118 ]. In situ gel of ciprofloxacin with hydroxypropyl methylcellulose and sodium alginate (ion-sensitive) showed enhanced residence time and sustained drug release [ 98 ]. More examples of in situ gel were previously mentioned in Table II . The mucus gel layer covering the ocular surface is made of mucins, a class of at least 20 O-glycosyl proteins with anionic charge. Excipients permitting attachment to this mucus gel layer provide a sustained residence time [ 191 ]. Chitosan is a commonly used mucoadhesive polymer by virtue of its polycationic nature and the existence of many reactive amino groups capable of interactacting with mucin layer. Kaur et al . studied niosomal system composed of span 60, cholesterol, and chitosan which revealed higher activity, reduced side effects, and prolonged release [ 129 ]. Cyclodextrins are widely used cyclic glycopyranose oligosaccharides. They have the ability to enhance drug solubility and to attach covalently to mucoadhesive polymers to prolong residence time [ 191 ]. Sayed et al . used β-cyclodextrin to enhance ocular delivery of itraconazole [ 35 ]. Many colloidal delivery nanosystems have been employed to enhance ocular delivery. They have the ability to carry different drugs, increase bioavailability, reduce frequency and potential side effects, and improve patient’s compliance. Different ocular nanosystems were previously stated in Table III . Also, solid polymeric devices have been developed as authorized sustained release ocular dosage forms. However, solid strategies are frequently not accepted by patients because of discomfort and interference with vision. Sustained bimatoprost activity for many months was proved after incorporation of its insert [ 110 ]. Dexamethasone contact lens was prepared by encapsulation technique. It showed 200 fold drug retention in the retina matching with conventional eye drops [ 116 ]. More examples of solid dosage forms were formerly listed in Table II .

Future Technologies

Smart nano-micro platforms.

Smart denotes to nano-micro matrix that can considerably change their mechanical, thermal, and/or optical properties in a manageable or expectable means, and they can achieve sensing triggering roles with stimuli-responsive features. Unlike conventional nanocarriers, the smart nano-micro platforms can reveal precise reaction to exogenous (light, sound, and magnetic field) or endogenous (pH, reactive oxygen species, and biological molecules such as DNA and enzymes) factors resulting in accomplishing many functions, e.g., site-specific drug delivery, bio-imaging, and detection of bio-molecules. These fascinating techniques have extended into ocular delivery in recent years. Generally, these revolutionary systems have been used for cancer diagnosis and management, to enhance the bioavailability of drugs/agents, minimize side effects, and augment safety and efficacy [ 192 , 193 ]. Tsujinaka et al . successfully delivered sunitinib microparticles that effectively inhibit the intraocular inflammation in mice model up to 6 months [ 194 ]. Rodriguez et al. constructed solid lipid nanoparticles that carry miRNA as gene therapy [ 195 ]. Basuk et al. demonstrated photo-modulated release of pre-loaded bevacizumab using visible light [ 196 ].

Extracellular Vesicles (Exosomes)

Extracellular vesicles are a sort of organelle that is produced by different cell types. Various bioactive compounds for example proteins, lipids, RNAs, and DNAs are enclosed within extracellular vesicles. They have a nano-size behave as a strong intercellular trigger that can start different physiological and pathological consequences. Under pathological situations, they could be produced by immune cells and control the inflammation progressions. They have a well-recognized role in immune-mediated eye diseases, such as Sjogren’s syndrome and corneal allograft rejection [ 197 ]. Also, they could encourage renewal of corneal tissue by stimulating the production of different matrix components. Additional investigations are required to develop ocular delivery systems based on exosomes. Tang et al . constructed exosomes of pluripotent stem cell-derived mesenchymal stem cells to hasten the restorative process of the corneal epithelium [ 198 ]. Zhu et al. developed exosomes derived from lens epithelial cells to load doxorubicin to prevent posterior capsular opacification [ 199 ].

Tissue Engineering

Tissue engineering investigations are classified into two types. First type is additive tissue engineering which substitutes cells or tissue or tries to permit the growth of something that is no longer there. The second type is arrestive tissue engineering that prevents irregular growth. Both additive and arrestive tissue engineering could be performed utilizing nanosystems. Examples of nanosystem-based tissue engineering include check of retinal ganglion cell viability [ 200 ], retinal ganglion cell repair [ 201 ], formulation of nanofiber scaffolds [ 202 ], corneal endothelial cell transplantation [ 203 ], and inhibition of retinal cell apoptosis [ 204 ]. Scientists begun to examine if nanotools and nanomaterials could be used to restore neural function of eye’s nerve cells.

Innovations in Clinical Trials

Continuous clinical trials for different dosage forms give the lead for pioneer treatment. For example, pilocarpine topical cream (semi-solid) for the treatment of presbyopia. It is a multicenter, randomized, double-masked, placebo-controlled, parallel group phase 2 trial evaluating the safety and efficacy of the cream. The study starts at January 3, 2022 and will continue till May 2023. Moreover, Cequa™ (Cyclosporine) ophthalmic emulsion (twice daily). This is a phase 4, multicenter, single arm, and 12-week study. An example of solid dosage form includes Dextenza 0.4 Mg (dexamethasone) ophthalmic insert. The study is performed to assess the efficacy and safety of Dextenza insert for the treatment of pain and inflammation following corneal transplant surgery.

Conclusions

The effective management of ophthalmic diseases remains a difficult mission as a result of existence of many ocular obstacles in the anterior and posterior sections of the eye. There are many ocular routes of administration that are used in order to deliver the medication into the targeted site of action such as topical, intraocular, periocular, or in conjugation with ocular devices. Several approaches and technologies have been adopted in order to minimize dosing interval, administrated dose, and unwanted effects and to enhance ocular retention time, drug permeation efficacy, and ocular bioavailability via controlled and sustained drug delivery systems. These advanced technologies have improved drug efficacy and shown good biocompatibility which suggest that they might have wide applications in the management and treatment of ocular diseases. In the future, more innovations are predicated in the ocular drug delivery systems in order to enhance and preserve the health of the eye, to improve patient compliance, and to accomplish superior results in the management of ocular diseases.

Data Availability

Data is available within the article.

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Conceptualization: S.A., M.M.A., and S.S.; software: S.A.; formal analysis: S.A., M.M.A., and S.S.; investigation: S.A., M.M.A., and S.S.; resources: S.A, M.M.A, and S.S.; writing—original draft preparation: S.A.; writing—review and editing: M.M.A. and S.S.; supervision: M.M.A. and S.S. All authors have read and agreed to the published version of the manuscript.

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Ahmed, S., Amin, M.M. & Sayed, S. Ocular Drug Delivery: a Comprehensive Review. AAPS PharmSciTech 24 , 66 (2023). https://doi.org/10.1208/s12249-023-02516-9

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DOI : https://doi.org/10.1208/s12249-023-02516-9

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Ocular Drug Delivery to the Retina: Current Innovations and Future Perspectives

Affiliation.

• 1 Department of Ophthalmology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam 13620, Korea.
• PMID: 33467779
• PMCID: PMC7830424
• DOI: 10.3390/pharmaceutics13010108

Treatment options for retinal diseases, such as neovascular age-related macular degeneration, diabetic retinopathy, and retinal vascular disorders, have markedly expanded following the development of anti-vascular endothelial growth factor intravitreal injection methods. However, because intravitreal treatment requires monthly or bimonthly repeat injections to achieve optimal efficacy, recent investigations have focused on extended drug delivery systems to lengthen the treatment intervals in the long term. Dose escalation and increasing molecular weight of drugs, intravitreal implants and nanoparticles, hydrogels, combined systems, and port delivery systems are presently under preclinical and clinical investigations. In addition, less invasive techniques rather than intravitreal administration routes, such as topical, subconjunctival, suprachoroidal, subretinal, and trans-scleral, have been evaluated to reduce the treatment burden. Despite the latest advancements in the field of ophthalmic pharmacology, enhancing drug efficacy with high ocular bioavailability while avoiding systemic and local adverse effects is quite challenging. Consequently, despite the performance of numerous in vitro studies, only a few techniques have translated to clinical trials. This review discusses the recent developments in ocular drug delivery to the retina, the pharmacokinetics of intravitreal drugs, efforts to extend drug efficacy in the intraocular space, minimally invasive techniques for drug delivery to the retina, and future perspectives in this field.

Keywords: hydrogel; implant; intravitreal injection; nanoparticle; ocular drug delivery.

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Conflict of interest statement

The authors declare no conflict of interest.

Schematic of several ocular drug…

Schematic of several ocular drug administration routes: (1) topical route, (2) subconjunctival route,…

Schematic depicting the latest advancement…

Schematic depicting the latest advancement in multiple ocular drug delivery systems: ( 1…

Schematic displaying intraocular distribution and…

Schematic displaying intraocular distribution and elimination pathways of standard anti-VEGF intravitreal treatment and…

Summary of current development and…

Summary of current development and human clinical trials for enhanced ocular drug delivery…

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Nanotechnology-based ocular drug delivery systems: recent advances and future prospects

• Shiding Li 1 , 2   na1 ,
• Liangbo Chen 1 , 2   na1 &
• Yao Fu 1 , 2  

Journal of Nanobiotechnology volume  21 , Article number:  232 ( 2023 ) Cite this article

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Ocular drug delivery has constantly challenged ophthalmologists and drug delivery scientists due to various anatomical and physiological barriers. Static and dynamic ocular barriers prevent the entry of exogenous substances and impede therapeutic agents' active absorption. This review elaborates on the anatomy of the eye and the associated constraints. Followed by an illustration of some common ocular diseases, including glaucoma and their current clinical therapies, emphasizing the significance of drug therapy in treating ocular diseases. Subsequently, advances in ocular drug delivery modalities, especially nanotechnology-based ocular drug delivery systems, are recommended, and some typical research is highlighted. Based on the related research, systematic and comprehensive characterizations of the nanocarriers are summarized, hoping to assist with future research. Besides, we summarize the nanotechnology-based ophthalmic drugs currently on the market or still in clinical trials and the recent patents of nanocarriers. Finally, inspired by current trends and therapeutic concepts, we provide an insight into the challenges faced by novel ocular drug delivery systems and further put forward directions for future research. We hope this review can provide inspiration and motivation for better design and development of novel ophthalmic formulations.

Graphical abstract

Introduction

The eye, a highly complex, isolated and specialized organ, is the most significant sensory organ of the human body because about 80% of all sensory input is acquired via the eye [ 1 ]. Anatomically, ocular tissues are protected by dynamic and static barriers [ 2 ]. Tear turnover, reflex blinking, and nasolacrimal drainage prevent foreign substances away from the eye surface [ 2 , 3 ]. The eyelid, conjunctiva and corneal epithelium cover and protect the eye surface [ 4 ]. In addition, the blood- aqueous barriers (BAB) and blood-retina barriers (BRB) limit the entry of compounds from the systemic circulation [ 5 ]. This defense system is further assisted by enzymes and other barriers (sclera, retinal etc.) [ 6 , 7 ].

Although there are multiple protective mechanisms, the eyeball is still vulnerable to infection, trauma and other injuries due to its communication with the outside [ 8 ]. The World Health Organization reports that at least 2.2 billion people around the world have visual impairment [ 9 ]. Ocular diseases, such as keratitis [ 10 ], cataract [ 11 ], glaucoma [ 12 ], age-related macular degeneration (AMD) [ 13 ] and diabetic retinopathy (DR) [ 14 ] can seriously damage the patients' visual acuity and affect their life quality. The National Eye Institute estimated that the annual economic burden associated with eye conditions and vision impairment in the US is about $139 billion [ 15 ].

Drug therapy is the primary treatment for most eye diseases [ 16 ]. Delivering drugs to target eye tissues at the desired therapeutic concentration without damaging healthy tissues is a current research hotspot [ 17 ]. Ocular drug delivery systems (ODDS) are designed to: (1) overcome ocular barriers to deliver drugs to target eye tissues, (2) improve drug stability and treatment efficiency, (3) prolong drug retention time and reduce dosing frequency, (4) enable multiple drug combinations, and (5) improve patient adherence and reduce drug-related adverse events [ 18 , 19 ].

Traditional administration methods, such as topical eye drops, conjunctival and scleral administration, intracameral administration, intravitreal injection, retrobulbar injection and systemic administration, are widely used clinically and have achieved certain therapeutic effects [ 20 ]. However, as mentioned earlier, the presence of ocular barriers poses a significant challenge for therapeutics in terms of reaching the intended site and staying there for a sufficient duration. As a result, the bioavailability of these therapeutics is often limited, typically less than 5% [ 21 ].

With the development of nanotechnology, dynamic progress has been made in the field of ocular drug delivery, which provides new therapeutic interventions for ocular diseases [ 21 , 22 ]. Compared with traditional drug administration, nanocarriers offer numerous advantages, including the capacity to overcome ocular barriers, promote transcorneal permeability, prolong drug residence time, reduce drug degradation, reduce dosing frequency, improve patient compliance, achieve sustained/controlled release, drug targeting and gene delivery [ 23 ]. Novel drug carriers, such as nanomicelles, nanoparticles (NPs), nanoemulsions (NEs), microemulsions, nanofibers, dendrimers, liposomes, niosomes, nanowafers, microneedles (MNs), have been investigated for the therapy of anterior and posterior ocular diseases [ 24 ].

In this review, we attempted to provide a holistic overview of novel ODDS reported in the past five years. First, we described the specific anatomy of the eye and the ocular barriers, illustrating the key factors that lead to the low bioavailability of the therapeutics. Subsequently, based on the current treatment status of ophthalmic diseases, several conventional and alternative routes of administration were summarized and compared, especially their limitations and innovative progress. Then, we discussed the recent advances in novel nanocarriers, such as nanomicelles, NPs, nanosuspensions, microemulsions, dendrimers, liposomes, etc. and highlighted some recent research. In particular, we also introduced gene therapy, exosome and self-nano emulsifying drug delivery systems (SNEDDS), which have huge potential in ocular drug delivery. In view of the reports of these ODDS, we highlighted their characteristics to assist with future related research. Meanwhile, ophthalmic drugs currently on the market or still in clinical trials were summarized, as well as the recent patents of nanocarriers. Finally, inspired by current trends and therapeutic concepts, we focused on novel non-invasive ODDS to overcome ocular barriers, sustain drug release, and maintain effective drug levels at the therapeutic target. Although most current research is still in the basic research stage, ocular drug delivery based on nanotechnology is expected to become the main means of ocular drug therapy.

The anatomy and barriers of the eye

The anatomical structure of the eyeball can be divided into the anterior and posterior segments based on the lens. Figure  1 illustrates the anatomy of the human eye. The anterior segment includes the cornea, conjunctiva, iris, ciliary body, aqueous humor and lens, while the posterior segment includes the sclera, choroid, retina and vitreous body [ 25 , 26 ].

The anatomy of the eye

Various absorption barriers exist in the human eye (Fig.  2 ) [ 27 ]. They are briefly divided into static and dynamic barriers to prevent foreign substances, including therapeutic agents, from targeting various eye tissues [ 28 ]. Static barriers of the eye mainly include cornea, conjunctiva, sclera, vitreal barrier, BAB and BRB, while dynamic barriers primarily include tear film, tear turnover, nasolacrimal duct drainage, conjunctival and choroidal blood flow and lymphatic clearance [ 29 , 30 , 31 ]. These barriers limit the passive absorption of diverse therapeutic molecules, thereby reducing the ocular bioavailability of different agents. Details are described below to understand the absorption barriers further.

Copyright 2022, Drug Delivery and Translational Research

Drug delivery barriers in ocular routes [ 26 ]. The absorption barriers of the eye mainly include tear film barrier, corneal barrier, conjunctival and scleral barriers, vitreal barrier, blood-aqueous barrier, blood-retinal barrier.

Tear film, tear turnover, nasolacrimal duct drainage

The tear film is a thin, transparent fluid layer consisted of three layers: a surface lipid layer, an intermediate aqueous layer, and an inner mucin layer [ 32 ]. The lipid and water layers act as barriers for hydrophilic and hydrophobic drugs, respectively [ 33 ]. Mucins are negatively charged macromolecules that attract or repel drugs through electrostatic interactions and protect the eye's surface from harmful external stimuli and pathogens [ 34 ]. At the same time, the non-specific binding of drugs to tear enzymes (such as lysozyme), mucin layers, and proteins (such as albumin) prevents drugs from reaching the cornea and anterior chamber [ 35 ].

In addition, tear turnover increases after topical insolation of drugs, resulting in rapid clearance of drug molecules through nasolacrimal drainage (within one to two minutes) [ 6 , 36 ]. Meanwhile, due to the limited surface area of the eye, ~ 30 μL of the drug dropped into the eye is quickly expelled down the lacrimal passage until the tear fluid returns to the normal volume (7–9 μL) [ 37 ]. Approximately 60% of the drug is eliminated 2 min after treatment with topical eye drops. After 8 min, the drug is diluted to 0.1%, and after 15 to 25 min, almost all the active ingredients are removed from the corneal surface [ 38 ].

The healthy cornea is a clear, avascular tissue and the main barrier for foreign substances to enter the anterior chamber [ 39 ]. Structurally, it comprises five layers: the outer epithelium, Bowman's membrane, intermediate stroma, Descemet's membrane and endothelial layer [ 40 ]. The barriers preventing drug penetration into parenchyma are mainly epithelial, stromal and endothelial layers [ 41 ].

The corneal epithelium is characterized by tight junctions within the surface cell layer [ 37 ]. Due to its lipophilicity, it is an obvious obstacle, especially for hydrophilic compounds [ 42 ]. Besides, the existence of cytochrome P450 (drug-degrading enzymes) and drug efflux pumps in epithelial cells is another reason for low drug bioavailability [ 43 , 44 , 45 ]. In contrast, the highly hydrated matrix structure is a layered arrangement of collagen fibers immersed in the extracellular matrix, hindering the diffusion of lipophilic drugs [ 46 ]. The endothelial cells act as a leakage barrier to aqueous humor due to the presence of gap junctions [ 47 ]. These features make the cornea a primary barrier that obstructs drug delivery to the anterior segment of the eye [ 48 ].

Conjunctival and scleral barriers

The alternative route of drug entry into the eye after topical instillation is the non-corneal route comprised of the conjunctiva and sclera [ 7 , 49 ]. The conjunctiva, a mucous membrane formed by a vascularized epithelial group and an inner stromal layer, is located on the eyelid's posterior surface and in the cornea's outer region [ 50 ]. It forms and maintains the tear film and protects the ocular surface from environmental pathogens [ 51 ]. Besides, the conjunctiva has a surface area that is around 17 times bigger than that of the cornea, making it more permeable than the cornea and offering a superior pathway for the absorption of macromolecules and hydrophilic compounds [ 52 , 53 ].

Nevertheless, the conjunctiva is highly vascularized. Rather of staying localized in the intraocular segment, medicines that penetrate the conjunctiva can be systematically absorbed from the conjunctival sac or nasal cavity and distributed throughout the body [ 16 , 54 ]. This mechanism can lead to huge drug loss into the systemic circulation, reducing bioavailability within the ocular region [ 54 ]. To enhance drug efficacy, high concentrations of the drug and repeated instillations are usually necessary to achieve the desired therapeutic effect. However, this approach can negatively impact patient compliance and increase the likelihood of side effects [ 55 ].

After clearance from the conjunctiva, the drug travels through the sclera to the anterior segment (transscleral route). The sclera is the white part of the eye and appears as an opaque, hard sheath that wraps around the outer layer of the eyeball [ 56 ]. It has relatively high permeability and a larger surface area than the cornea. The scleral penetration is mainly determined by the size of the drug molecule instead of its lipophilicity [ 41 ]. Scleral thickness seems to be a critical factor in transscleral drug delivery [ 57 ]. The spread of the drug across the sclera occurs through the perivascular space and between the scleral fibrils, eventually reaching the choroid and the retina [ 58 ].

The blood-aqueous barrier

The blood-aqueous barrier, consisting of the non-pigmented ciliary body of the iris vasculature and the epithelial tissue of the endothelial cells, is the main barrier in the anterior segment of the eye, which prevents the non-specific entry of various solutes in the intraocular environment [ 59 ]. The permeability of drugs across the BAB is determined by the osmotic pressure and physicochemical properties of drug molecules [ 60 ]. Lipophilic and small-molecule drugs can pass through the BAB and exit the anterior compartment more rapidly than hydrophilic and large-molecule drugs. For instance, pilocarpine was discovered to have a faster clearance rate than inulin [ 61 ]. It remains a challenge for ocular drug delivery due to its specialized tissue barriers that can hinder therapeutic efficacy.

The blood-retinal barrier

The blood-retinal barrier comprises internal and external components and is the most important barrier in the posterior part of the eye [ 62 ]. The inner BRB is formed by tight junctions between retinal capillary endothelial cells, while the outer BRB is formed by close junctions between retinal pigment epithelial cells [ 63 ]. The BRB prevents water, plasma components and toxic substances from entering the retina [ 64 ]. At the same time, it may also limit the access of drug molecules to the intraocular environment [ 65 ]. Hence, BRB is necessary to keep the eye as a privileged place to maintain normal visual function [ 66 ].

Ocular diseases

At present, more than 500 kinds of eye diseases are known, such as glaucoma, macular degeneration, diabetic retinopathy, dry eye disease (DED), etc. The prevalence of ocular diseases is steadily increasing due to changing eye usage patterns and the ageing population. These conditions profoundly impact individuals' health and quality of life, emphasizing the urgent need for effective interventions. Drug therapy undoubtedly plays a pivotal role in treating many ocular diseases.

Glaucoma, an eye disease characterized by progressive vision loss, is the second leading cause of blindness worldwide after cataracts [ 67 ]. It is estimated that the number of glaucoma patients will increase to 111.8 million by 2040 [ 68 ]. High intraocular pressure (IOP) is an essential feature of glaucoma [ 69 ]. Elevated intraocular pressure can induce the loss of corneal endothelial cells [ 70 ]. In addition, high intraocular pressure can also compress the retinal blood vessels, leading to the damage of retinal ganglion cells and optic nerve [ 71 ].

Although glaucoma is considered a multifactorial disease, current treatment mainly focuses on lowering intraocular pressure to slow or reduce subsequent visual loss [ 72 ]. Treatment usually begins with topical anti-glaucoma medications. However, the bioavailability of topical administration is below 5% due to high precorneal loss and low corneal penetration [ 37 , 48 , 73 ]. At the same time, frequent ocular administration decreases patient compliance [ 74 ]. Therefore, it is necessary to use nanotechnology to effectively deliver drugs, improve bioavailability and maintain the efficacy of anti-glaucoma drugs.

Age-related macular degeneration

AMD is the third leading cause of severe irreversible vision loss globally, and the number of AMD patients worldwide is expected to increase to nearly 300 million by 2040 [ 75 ]. It is clinically divided into early AMD and late AMD. The clinical symptoms of early AMD include: medium size stone fruit and retinal pigment changes, and late AMD is classified as neovascular (also called wet or exudative) or non-neovascular (also called atrophic, dry or non-exudative), which may lead to central vision loss and legal blindness [ 76 ].

High doses of zinc and antioxidant vitamin supplements can slow disease progression from early to advanced stages [ 77 ]. Intravitreal injection (IVT) of anti-vascular endothelial growth factors (VEGF) (such as bevacizumab (Bev), aflibercept, etc.) effectively treats neovascular AMD, but it's still invasive [ 78 ]. Therefore, exploiting new drug delivery systems for personalized drug delivery is particularly important.

Diabetic retinopathy

Diabetic retinopathy is a chronic complication of diabetes and the leading cause of vision loss and blindness globally [ 79 ]. In severe cases, retinal detachment can gradually manifest as blurred vision, ocular floaters, distorted vision, and even partial or complete vision loss [ 80 ].

Clinically, if laser treatment is performed in time, retinal circulation can be improved, avoiding vitreous hemorrhage and retinal neovascularization. However, for patients with macular oedema, it is usually necessary to inject anti-VEGF to treat macular oedema and improve vision [ 81 ]. Unfortunately, regular intravitreal injections may cause damage to the ocular tissue, and not all patients respond optimally [ 82 , 83 ]. Vitrectomy is needed in case of fundus hemorrhage or proliferative vitreoretinopathy [ 84 ]. Given the low bioavailability of drugs, potential adverse effects, and inevitable risks in major surgery, novel drug delivery methods are required to bring new ideas for the therapy of DR.

Dry eye disease

Dry eye disease, known as dry keratoconjunctivitis, is a multifactorial ocular surface disease [ 85 ]. It is characterized by tear film instability, hypertonicity, inflammation, ocular surface damage, and nerve paresthesia [ 86 ]. The global prevalence of dry eye is five to 50% [ 87 ]. The symptoms of DED include ocular irritation, pain, soreness, foreign body sensation, and decreased vision. DED seriously affects the quality of patients' lives, causes psychological anxiety, and adds a huge economic burden to society [ 88 , 89 ]. To date, the pathogenesis of DED has not been fully elucidated, and most researches perceived that inflammation is the core of its pathogenesis [ 90 ].

The diagnosis and treatment of DED can be divided into two main categories: dehydration type and evaporation type [ 86 ]. Common drug treatments include artificial tears, local secretagogues, corticosteroids, and immunosuppressants; however, there are side effects such as ocular discomfort, low patient compliance, elevated intraocular pressure, and glaucoma [ 91 ]. Exploiting new drug delivery methods to overcome ocular barriers and improve drug bioavailability is particularly critical.

Traditional routes of drug administration

The traditional routes of administration mainly include topical administration, conjunctival and scleral administration, intracameral administration, intravitreal injection, retrobulbar injection, systemic routes et al. [ 41 ]. The traditional routes of ocular drug administration are shown in Fig.  3 . Depending on the routes of administration, one or more ocular barriers must be bypassed to allow the drug to reach the targeted site. Table 1 outlines several traditional routes of administration and their associated advantages and limitations.

Routes of drug administration for ocular delivery. They mainly contain topical administration, subconjunctival and transscleral administration, intracameral administration, intravitreal injection and systemic administration et al.

Topical administration

Topical administration is the most common and straightforward route of ocular drug administration [ 41 ]. Compared with systemic administration, it has the advantages of (1) being relatively non-invasive, (2) minimizing systemic side effects of the drug, and (3) the relative ease of patient administration [ 92 , 93 ]. Therefore, ophthalmic solutions are the first choice for treating many eye diseases, such as infection, inflammation, DED, glaucoma, and allergy [ 94 ]. It is estimated that topical ophthalmic solutions account for 95% of the commercially available products in the global ophthalmic medicines market [ 95 ].

However, due to the unique physiological and anatomical structure of the eye, drug delivery in the eye is limited, and bioavailability is usually less than 5% [ 96 ]. High drug concentrations and repeated instillation are commonly needed to improve the efficacy of drug administration through the local route, which may lead to poor patient compliance and numerous side effects [ 6 ].

There are two main strategies to improve ocular bioavailability after topical administration: (a) increase the pre-corneal retention time, and (b) enhance the permeability of corneal, scleral, or conjunctival drugs [ 16 ]. Various approaches have been proposed to prolong drug residence time after topical administration, including prodrugs, mucus osmotic particles, enhancers, collagen corneal shields, and therapeutic contact lenses [ 97 ]. In addition, nanocarriers also open up new windows for liquid and semi-solid formulations to increase drug availability [ 48 ].

Subconjunctival and transscleral administration

Subconjunctival administration is a minimally invasive and effective route to deliver drugs to the anterior or posterior eye chamber, avoiding the corneal and blood-aqueous barriers, potential adverse effects and first-pass metabolism of some systemic agents [ 98 , 99 ]. However, the subconjunctival route may result in drug loss due to blood and lymphatic drainage through the conjunctiva [ 55 , 100 ].

Similarly, transscleral administration is a simple, minimally invasive, and more suitable method for patients. This route can bypass the obstacles in the anterior part of the eye [ 101 ]. At the same time, the large surface area of the sclera (about 95% of the total surface area of the eye) offers the chance of delivering antioxidants, neuroprotective agents or anti-angiogenic agents to targeted sites in the retina [ 102 ]. It has been demonstrated that molecules up to 70 kDa can easily penetrate the sclera, whereas molecules that cross the cornea are under 1 kDa [ 99 ]. However, due to the dynamic barriers, the intraocular bioavailability of this method is lower than that of the direct intravitreal injection route [ 41 , 103 ].

Intracameral administration

Intracameral administration injects drugs directly into the eye's anterior chamber [ 104 ]. This local delivery approach avoids the adverse effects and first-pass metabolism with some systemic agents. At the same time, it also avoids the cornea, conjunctiva, and BAB [ 105 ]. Thus, intracameral injections allow relatively easy and efficient drug delivery to the anterior segment of the eye [ 106 , 107 ]. Currently, intracameral injections are used for prophylactic antibiotics or anesthetics associated with eye surgeries [ 108 , 109 , 110 , 111 ].

However, administration in the anterior chamber can't deliver drugs to the posterior chamber of the eye. At the same time, drugs in the anterior chamber usually require reorganization, dilution, sterility, special preparations without preservatives, and appropriate concentrations and doses [ 112 ]. Corneal endothelial cell toxicity and toxic anterior segment syndrome may occur if incorrect doses and preparations are used [ 113 ].

Intravitreal injection

Intravitreal injection is a preferred method of medicine administration in the posterior part of the eye to treat ophthalmic diseases in the eyeball [ 114 ]. Due to vitreous fluid turnover, free drugs can be removed quickly after IVT injections [ 3 ]. Frequent IVTs are required to achieve good therapeutic results, which may result in side effects such as retinal detachment, eyeball infection, endophthalmitis and elevated intraocular pressure [ 115 , 116 ]. Therefore, the optimal protocol for IVT is a one-time injection of the drug without retracting the needle and keeping the eyeball system closed.

Recent studies have focused on maintaining therapeutic effects, prolonging treatment intervals and protecting normal ocular tissues. NPs, intravitreal implants, hydrogels, combinatorial systems, and minimally invasive techniques are under preclinical and clinical investigations, which act as safer and more efficient alternatives to combat ophthalmic diseases [ 24 , 117 ].

Retrobulbar injection

The retrobulbar route involves injecting needles through the eyelid and orbital fascia to deliver drugs to the retrobulbar space [ 118 , 119 ]. Retrobulbar injection of triamcinolone acetonide treats macular oedema caused by retinal vein occlusion [ 120 ]. The antifungal effect of retrobulbar injection of amphotericin B is higher than intravenous injection [ 121 ]. Retrobulbar injection of chlorpromazine is used to treat painful blind eyes [ 122 ].

Systemic administration

Systemic administration (including parenteral and oral dosing) is an alternative method of drug delivery. At present, systemic administration has been used to deliver antibodies, antibiotics, and carbonic anhydrase inhibitors to treat diseases such as endophthalmitis, elevated intraocular pressure, and uveitis [ 123 , 124 , 125 , 126 ]. Nevertheless, due to the ocular barriers and the tight junctions of the retinal pigment epithelium that allow only one to two per cent of the drug to reach the retinal and vitreous regions, frequent administrations are required to obtain the desired therapeutic effect, which may contribute to systemic side effects and poor patient compliance [ 108 , 127 ]. Therefore, it is not an ideal mode of administration.

Pharmacokinetics

Based on the ocular barriers and drug administration described above, ocular pharmacokinetics, including penetration and elimination, are discussed in detail. As shown in Fig. 4  [ 6 , 128 ], it mainly contains the following pathways: (1) through the tears and cornea into the anterior chamber, (2) non-corneal permeation into the anterior uvea through the conjunctiva and sclera, (3) drug from the bloodstream cross BAB to the anterior chamber, (4) drug from the aqueous humor cross BAB to the systemic circulation, (5) drug elimination from the aqueous humor to the trabecular meshwork and Schlemm's canal, (6) drug distribution from the circulation through BRB to the posterior segment of the eye, (7) intravitreal administration, (8) elimination from the vitreous body into the posterior compartment via an anterior route, and (9) elimination from the vitreous body via a posterior route through BRB.

The pathways of drug metabolism. According to the arrows in the figure, there are nine major pathways of drug metabolism, as described in detail above

Nanotechnology-based ocular drug delivery systems

To overcome ocular drug delivery barriers and improve drug bioavailability, novel drug delivery systems have been developed. Nanocarriers' development offers many advantages, including overcoming ocular barriers, promoting transcorneal permeability, prolonging drug residence time, reducing the dosing frequency, improving patient compliance, reducing drug degradation, achieving sustained/controlled release, drug targeting and gene delivery [ 23 ]. Many ocular drug delivery systems such as nanomicelles, NPs, nanosuspensions, NEs, microemulsions, nanofibers, dendrimers, liposomes, niosomes, nanowafers, MNs and exosomes (Fig.  5 ), have shown splendid delivery potential in both vitro and vivo studies, enhancing drug permeability across the ocular barriers and prolonging the residence time in the eye [ 23 , 129 ].

Nanotechnology based drug delivery systems for ocular application

Nanomicelles

Nanomicelles are core–shell nanocarriers formed by spontaneous assembly of amphiphilic copolymers with hydrophobic groups as the core and hydrophilic groups as the outer shell [ 130 ]. Usually, the particle size ranges from 10 to 100 nm and can be divided into three categories: polymers, surfactants, and multi-ion composite nanomicelles [ 131 ]. Besides, hydrophobic interactions, hydrogen bonds, electrostatic interactions, etc., are the driving forces for polymer micelle formation [ 132 ]. Positive micelles are generally formed when the hydrophobic moiety forms clusters within the core and the hydrophilic moiety is aligned outwards to increase contact with water. Likewise, when the opposite arrangement occurs, the aggregates are referred to as reverse micelles [ 133 ]. Positive micelles are used to encapsulate, solubilize, and deliver hydrophobic drugs, whereas reverse nanomicelles are used to encapsulate and deliver hydrophilic drugs [ 134 ]. The unique chemical structure of nanomicelles can solubilize drugs internally, reduce adverse reactions, improve the stability of drugs, and have a sustained release effect, regarded as safe alternatives for ocular drug delivery [ 135 , 136 ].

Cyclosporine is an immunomodulatory drug employed in treating DED. Given its relatively high molecular weight and poor permeability, Ghezzi et al. prepared micelles using tocopherol polyethene glycol 1000 succinate (TPGS) and Solutol®HS15 for cyclosporine delivery. Meanwhile, the addition of α-linolenic acid was evaluated based on the results of using fatty acids for micelle preparation [ 137 , 138 ] and drug loading [ 139 , 140 ]. Also, the effect of TPGS as a corneal permeability promoter and irreversible changes in tissue permeability were analyzed. It was demonstrated that TPGS micelles (approximately 13 nm in size), loaded with 5 mg/mL cyclosporine, facilitated drug retention in the cornea and sclera and possessed good tolerance for ocular applications [ 141 ].

Besides, XU et al. developed chitosan oligosaccharide-valylvaline-stearic acid (CSO-VV-SA) nanomicelles and hydrogen-castor oil 40/octyl alcohol 40 (HCO-40/OC-40) hybrid nanomicelles for topical ocular drug delivery. Neither nanomicelles produced significant cytotoxicity in human corneal or conjunctival epithelial cells. Dexamethasone in both nanomicelles was detectable in rabbit tears for over 3 h. Notably, the delivery efficiency of CSO-VV-SA nanomicelles was not inferior to HCO-40/OC-40 hybrid nanomicelles at both cellular and animal levels, which suggested that CSO-VV-SA nanomicelles would have further potential for clinical translation as novel drug delivery carriers [ 142 ].

Traditional intravitreal injection of anti-VEGF into the posterior part of the eye to treat retinal diseases is invasive and accompanied by various complications. A nano-micelle drug delivery system composed of polyethene glycol (PEG), polypropylene glycol, and polycaprolactone (PCL) fragments was developed to avoid these. The copolymer EPC (nEPC) locally delivers aflibercept to the posterior segment of the eye via the corneal-scleral routes. Animal experiments have shown that aflibercept-loaded nEPCs (nEPCs + A) can penetrate the cornea in an ex vivo porcine eye model and deliver aflibercept to the retina to promote choroidal neovascularization (CNV) regression in a mouse model of laser-induced CNV. Besides, nEPCs + A showed good biocompatibility and intrinsic anti-angiogenic properties. These findings suggest that nEPCs may be promising candidates for further clinical applications [ 143 ].

NPs are colloidal drug carriers with ideal sizes ranging from 10 to 100 nm [ 21 ]. They are mainly divided into polymer and lipid NPs [ 144 ]. NPs used in ocular preparations are composed of lipids, proteins, and natural or synthetic polymers such as albumin, sodium alginate, chitosan, polylactide-coglycolide (PLGA), polylactic acid (PLA), and PCL [ 145 ]. Besides, the surface charge of NPs highly affects their effective ocular absorption. Since corneal and conjunctival tissues have negatively charged surfaces, cationic NPs have a higher retention time on the ocular surface than anionic NPs [ 146 ].

To date, NPs have been used widely to deliver drugs to the targeted tissue in the eye, with the advantages of: (1) smaller and less irritating; (2) providing sustained drug release to avoid repeated dosing; (3) preventing non-specific uptake or premature degradation; (4) providing better absorption and improving intracellular penetration; and (5) targeted delivery to desired tissues [ 42 , 147 , 148 , 149 ].

As a synthetic polymer, PLGA has been widely used to prepare NPs for ocular drug release due to its biodegradability, excellent biocompatibility, and capacity to modulate drug release by altering molecular weight, terminal groups, and the lactide-to-glycoside ratio [ 150 , 151 ]. The US Food and Drug Administration (FDA) has approved various drug delivery products with PLGA.

In one study, chitosan-coated polylactide-glycolic acid NPs (CS-PLGA NPs) were developed to deliver Bev (an anti-VEGF drug used widely for treating DR) to the posterior chamber of the eye. The confocal laser scanning microscopy and pharmacokinetics showed that CS-PLGA NPs had better permeability than the traditional drug solution, with higher concentrations of Bev (above 22 ng/mL for 6 weeks) in the posterior ocular tissues. In the retinopathy model, subconjunctival injection of CS-PLGA NPs significantly reduced the level of VEGF in the retina for 12 weeks compared with local and intravitreal injections. Thus, CS-PLGA NPs can potentially be used to target the retina for drug delivery [ 152 ].

Kim et al. delivered NPs loaded with the drug latanoprost into the eye by iontophoretic method to treat glaucoma. These NPs were made of PLGA and had the advantages of releasing the latanoprost sustainably and prolonging the drug residence time. The 300 nm NPs showed the most durable drug effect in vivo. It lasted more than 7 days and increased its efficacy by approximately 23-fold compared to Xalatan ® (a commercially available latanoprost eye drop), which offers a new strategy for prolonging the efficacy of drugs and reducing the frequency of drug administration in the treatment of glaucoma [ 153 ].

Likewise, Nguyen et al. developed hollow polylactic acid NPs and innovatively investigated the role of shell thickness in developing long-acting drug carriers to treat glaucoma effectively. Among the four NPs with an adjustable shell thickness of 10 to 100 nm (~ 10, 40, 70, and 100 nm), a medium-thickness shell (~ 40 nm) manifested the most effective release curve of pilocarpine and sustained relief of high IOP for more than 56 days in the rabbit glaucoma model, which may protect the structural integrity of the corneal endothelium, as well as attenuate retinal and optic nerve degeneration (Fig.  6 ). Thus, this finding implies the potential of the shell thickness effect in developing long-acting drug delivery systems that can be used to treat some chronic eye disorders [ 154 ].

The representative images of rabbit eyes taken with a slit-lamp biomicroscope after intracameral administration of pilocarpine-loaded HPLA NP (st10, st40, st70, and st100) dispersions or BSS buffer (Ctrl group) at 0 ( a ) and 56 ( b ) days. c The scores of slit-lamp examinations at 56 days d Central corneal thickness at 56 days. e The histology of corneal tissues at 56 days postoperatively

In contrast to polymeric NPs, lipidic formulations are known to be less stable for sustained drug release. Recently, adding polymers to lipidic NPs formulations has gained wide interest in increasing the stability of nanocarriers [ 16 ]. Schnichels et al. investigated lipid DNA NPs functionalized for the loading of brimonidine through specific aptamers and via hydrophobic interactions with double-stranded micelles. Both NP types significantly reduced IOP in living animals. Overall, IOP reduction was observed in 74% (SEM: ± 3%) and 54% (SEM: ± 1%) of the number of animals treated with two types of DNA NPs once daily for 5 weeks, compared to the animals treated with the original brimonidine(36%, SEM: ± 3%). Importantly, NPs loaded with brimonidine showed no toxicity and improved efficacy. In conclusion, these drug delivery systems offer great opportunities to treat glaucoma [ 155 ].

To improve the biocompatibility of the NPs, it is worth noting that the combination of biomimetic technology and NPs has brought new ideas for non-invasive drug delivery to the eye. Chen et al. reported adhesive and therapeutic biomimetic nanocoatings on ocular surfaces using sebocyte membranes with integrin-β1 overexpressed to coat NPs. The NPs specifically bind to the Arg-Gly-Asp sequence of fibronectin in the ocular epithelium, which is critical in supplementing the lipid layer, stabilizing the tear film and prolonging the retention time for 24 h. In mouse and rabbit DED models, dexamethasone-loaded nanocoatings effectively reduced corneal opacity and inflammatory cytokine levels, improved corneal epithelial recovery and restored tear secretion. This study provides new insights to protect the ocular surface and prolong the retention time of the drug [ 156 ].

Similarly, Li et al. developed an alternative anti-angiogenic agent based on hybrid cell-membrane-coated NPs for the non-invasive treatment of choroidal neovascularization (Fig.  7 ). The fusion of erythrocyte membrane protected the mixed membrane-coated NPs from phagocytosis by macrophages. The retinal endothelial cell membrane coating provides isotype targeting and binding ability to VEGF. In laser-induced CNV mouse models, intravenous injection of the NPs effectively inhibited ocular angiogenesis. The inhibition rates of migration and invasion were ~ 77.5% and ~ 78.5%, respectively. At the same time, excellent treatment results were achieved in reducing the leakage and area of CNV, analyzed by fluorescein angiography and indocyanine green angiography. In conclusion, biomimetic anti-angiogenic nano agents open a new window for the non-invasive treatment of CNV [ 157 ].

 The schematic illustration of hybrid cell-membrane-cloaked biomimetic nanoparticles taking advantage of the targeting property of REC and the immune evasion capability of RBC for the therapy of laser-induced CNV. A The process of preparing hybrid cell-membrane-coated NPs. B Intravenous administration of NPs absorbs proangiogenic factors, leading to the blocking of their influences on the endothelial cells of the host neovascularization

Although NPs show promise for treatment of ophthalmic diseases, there are still significant constraints that prevent them from being widely used in clinical practice. These limitations include inadequate drug loading, premature drug release during storage, difficulty in achieving homogeneous particle dispersion, and toxic effects related to the concentration of the surfactants [ 22 ]. More studies should be conducted to promote the clinical translation of NPs.

Nanosuspensions

The nanosuspension consists only of submicron colloidal dispersions of drug nanocrystals. Surrounded by stabilizers, it is one of the most promising approaches for delivering poorly soluble active ingredients [ 158 , 159 ]. Unlike conventional matrix-framed nano-systems, nanosuspension does not require a carrier material. It contains 100% pure drug NPs in the nanometer range and is usually stabilized by surfactants or polymers [ 160 ]. They have the advantages of increased residence time, sustained drug release, and enhanced drug solubility [ 161 ].

To improve the bioavailability of moxifloxacin hydrochloride, Josyula et al. used an ion-pairing method to fabricate an insoluble moxifloxacin–pamoate (MOX-PAM) complex, which was further formulated as a mucus-penetrating nanosuspension eye drops (MOX-PAM NS). Compared with Vigamox ® (commercial formulation) in healthy rats, MOX-PAM NS significantly increased ocular drug absorption with about 1.6-fold greater C max and had better antibacterial effects. Treatment with MOX-PAM NS administered once daily was similar to that with Vigamox ® administered three times daily in a rat model of ocular Staphylococcus aureus infection. These results demonstrated nanosuspension's high translational and clinical relevance [ 162 ]. Moreover, nanosuspensions have been used as a platform for ocular delivery of immunosuppressive agents [ 163 , 164 ].

Furthermore, nanosuspensions can also be combined with other nanotechnology. Triamcinolone acetonide (TA) is a synthetic corticosteroid widely used to treat several inflammatory conditions. One study developed a hybrid nanosuspension and dissolving MNs system for effective and minimally invasive transscleral delivery of the hydrophobic drug TA. After optimization, TA NS was incorporated into the MN array by high-speed centrifugation to form a bilayer structure. TA NS-loaded MNs were strong enough to penetrate the excised porcine sclera, with an insertion depth greater than 80% of the needle height, and dissolved rapidly (< 3 min). Notably, the transscleral deposition study showed that the amount of TA deposited in the sclera after 5 min application of NS-loaded MN was 56.46 ± 7.76 μg/mm 2 , which was 4.5-fold higher than that of common drug-loaded MN (12.56 ± 2.59 μg/mm. 2 ) [ 165 ].

Despite these encouraging nanosuspension results, the stability issues related to nanosuspensions remain unresolved. The stability properties of electrostatic and steric stabilizers, the maximum achievable particle size and physical stability are key factors that need further study [ 166 ].

Nanoemulsions

Nanoemulsion is a transparent or translucent, thermodynamically unstable but kinetically stable system with sizes ranging from 20 to 500 nm [ 167 , 168 ]. According to the classification of the dispersed phase system, NEs are mainly divided into (1) water-in-oil (w/o) NEs: continuous phase-containing dispersion of water droplets, (2) oil-in-water (o/w) NEs: continuous phase-containing dispersion of oil droplets, and (3) bi-continuous NEs: oil microdomains and water intermingled in the system, and various NEs modifications [ 169 ].

Based on nanotechnology, NEs are widely used as non-invasive, cost-effective drug delivery vehicles and can be easily scaled up for commercial production. Besides, compared with traditional drug delivery methods, NEs have the advantages of prolonged anterior corneal retention time, sustained drug release, high penetration ability, enhanced ocular bioavailability, and easy sterilization improvement [ 170 , 171 , 172 , 173 ]. At the same time, it can also be used to treat different eye diseases, such as DED [ 174 ], fungal keratitis [ 175 ], herpes simplex keratitis infection [ 176 ], glaucoma [ 177 ], etc.

Dukovski et al. developed a functional cationic ophthalmic NE with 0.05% (w/w) chitosan and nonsteroidal anti-inflammatory drugs loaded, using chitosan as the cationic and lecithin as the anionic surfactant. In an ex vivo porcine cornea model, NPs extended the drug retention time on the ocular surface, stabilized the tear film and acted on inflammatory components, providing a possibility for the therapy of DED [ 174 ].

Bacterial keratitis is a serious eye infection which can result in severe visual disability. Youssef et al. prepared a ciprofloxacin-loaded nanoemulsion (CIP-NE) using oleic acid and Labrafac ® lipophilic WL 1349 as the oil phase and Tween ® 80 and Poloxamer 188 as surfactants. Optimized nanoemulsion was spherical in shape and showed a globule size, zeta potential, and polydispersity index of 121.6 ± 1.5 nm, −35.1 ± 2.1 mV, and 0.13 ± 0.01, respectively, with 100.1 ± 2.0% drug content. The in vitro release and ex vivo trans-corneal permeation studies showed sustained release and 2.1-fold enhanced penetration compared with commercial ciprofloxacin, suggesting that the CIP-NE formulation might be used as a promising nanocarrier to enhance the therapeutic efficacy of bacterial keratitis [ 178 ].

Travoprost is a synthetic prostaglandin F2α analogue used in the therapy of glaucoma. Given its water insolubility and oiliness, new delivery systems must be proposed to improve its bioavailability and maintain its release. Ismail et al. used the travoprost nanoemulsion as a novel carrier, exhibiting suitable nanodroplet size, zeta potential, refractive index, pH, controlled release, and adequate stability under accelerated conditions. Compared with Travatan ® eye drops, travoprost nanoemulsion has a short-term safety profile, improved bioavailability, and sustained IOP reduction for 60 h. Therefore, travoprost nanoemulsion is a good ocular delivery vehicle for the therapy of glaucoma [ 179 ].

Although NEs can be used in ocular preparations, NEs still have some drawbacks, such as eye irritation and low viscosity. In addition, NEs are thermodynamically unstable and may decompose over time through various physicochemical mechanisms, such as gravitational separation, flocculation, Oswald maturation, and coalescence [ 22 ]. Future studies should focus on physicochemical analysis, toxicity analysis in vivo and in vitro tests, and optimization of some formulation development parameters, further promoting the transformation of NE-based drug delivery to clinical application.

Microemulsions

Microemulsions have colloidal dispersions composed of specific proportions with different phases, including aqueous phase, oil phase, cosurfactant, and surfactant. Their droplet sizes range from 10 to 100 nm [ 180 ]. Based on the types and amount of surfactant in the formulation, microemulsions can be divided into three categories: o/w, w/, and bi-continuous structures [ 181 ]. Typically, o/w microemulsion has a higher water comparison, while w/o microemulsion has a higher oil comparison. Microemulsions have been extensively explored as a drug delivery vehicle for ocular preparations to overcome various obstacles and reduce the frequency of daily eye drops [ 182 ].

Microemulsions are the most potential submicron drug carriers, especially for poorly water-soluble drugs. At the same time, microemulsions are thermodynamically stable, inexpensive and relatively simple to produce [ 183 ]. Various researches have demonstrated the efficiency of microemulsions in delivering multiple drugs to different issues of the eye.

For instance, Mahran et al. used oleic acid, Cremophor EL, and propylene glycol to prepare microemulsion preparations loaded with TA for treating uveitis. Different pseudo-ternary phase diagrams were also constructed using the water titration method, and the formulation composed of oil, surfactant-co-surfactant (1:1), and water (15:35:50%w/w, respectively) turned out to be most effective (complete drug release within 24 h). In a uveitis-induced rabbit model, the developed TA-loaded microemulsion observably reduced inflammation signs, protein content, and inflammatory cells compared to commercially available suspensions [ 184 ].

Besides, Santonocito et al. used a novel microemulsion system (NaMESys) to deliver sorafenib to the retina. It has shown that NaMESys carrying 0.3% sorafenib (NaMESys-SOR) has good cytocompatibility and tolerability. It can also reduce pro-inflammatory and proangiogenic mediators in a robust model of proliferative retinopathy. Furthermore, NaMESys-SOR significantly inhibited the mRNA expression of tumor necrosis factor-alpha (20.7%) and inducible nitric oxide synthase (87.3%) in retinal ischemia–reperfusion rats compared with the control group. In addition, NaMESys-SOR also observably inhibited 54% of the neovascularization lesions in mice with laser-induced CNV. The findings show that NaMESys eye drops may effectively deliver various drugs to the retina [ 185 ].

Interestingly, some researchers have found that the methylglyoxal (MGO) concentration in Manuka honey is quite high and can effectively manage bacterial overload. Based on these, D. Rupenthal et al. prepared liquid crystal microemulsions containing alpha-cyclodextrin-complexed Manuka honey and evaluated their antimicrobial function at relatively low MGO concentrations. The results showed that 100 mg/kg MGO formulation had significantly higher antibacterial activity against Staphylococcus aureus (especially at a density of 1 × 106 CFU/mL) in vitro than each of its individual components. Importantly, no corneal or conjunctival irritation was observed at concentrations consistent with accidental exposure to the ocular surface, which may provide new ideas for treating blepharitis [ 186 ].

In conclusion, these findings are worth further investigating the other therapeutic potential of the microemulsion, facilitating the continued exploration of novel drug delivery technologies.

Nanofibers are 1–100 nm diameter fibers [ 187 ]. Various natural polymers (such as chitosan, fibronectin, gelatin, collagen, silk, and ethyl cellulose) or synthetic polymers (such as PLA, PLGA and PCL) or combinations thereof can be used to produce nanofibers through the electrospinning process [ 188 ].

Nanofibers have the advantages of a high surface-to-volume ratio, high porosity, adjustable mechanical properties, strong drug-loading capacity, high encapsulation efficiency, and simultaneous delivery of multiple therapeutic agents [ 189 ]. In addition, nanofibers can help drugs cross physiological barriers and target tissues, providing long-term controlled drug release while minimizing drug distribution in other parts of the body [ 190 ]. These properties make it a unique candidate for drug delivery applications, diagnosis and treatment of various diseases, especially chronic eye diseases that need frequent administration [ 191 , 192 ].

MEL exerts neuroprotective effects on retinal damage and neuronal damage associated with several chronic and degenerative eye diseases, such as AMD, DR, and glaucoma [ 193 , 194 ]. Unfortunately, the short half-life and low bioavailability of MEL plasma (3–15%) limit the therapeutic effect [ 195 , 196 ]. Romeo et al. used electrospinning to prepare polyvinyl alcohol (PVA) and PLA nanofibers. Both nano-systems were loaded with various concentrations of MEL (0.1, 0.3 and 0.5% w/w). PVA nanofibers release MEL quickly (within 20 min) and completely, whereas PLA nanofibers provide a slow and controlled release of MEL. Interestingly, the addition of Tween®80 provides faster dissolution and approximately a 20-fold increase in expansion properties. Based on the obtained results, the formulated MEL-supported nanofibers may be a promising carrier with improved biopharmaceutical properties for the ocular delivery of MEL [ 197 ].

Furthermore, nanofibers can be loaded with multiple drugs. Rohde et al. developed electrospun polymer fibers with gentamicin and dexamethasone, which are used to treat bacterial conjunctivitis. Upon contact with the ocular surface, the nanofibers are immediately dissolved in the tear fluid, quantitatively releasing the two active substances. The recovery rate was over 92% by fluorescence and quantitative chromatographic methods. In the pig microfluidic corneal model, the eye retention time was significantly longer than that of traditional eye drops. After 20 min of eye drops, the availability of drugs on the ocular surface increased by 342%. Notably, the polymer has good biocompatibility and sufficient storage stability for antibacterial activity within 12 weeks [ 198 ].

Similarly, Tawfik and his partners developed coaxial PLGA and polyvinylpyrrolidone nanofibers loaded with the antibiotic moxifloxacin hydrochloric acid and the anti-scarring agent pirfenidone for the treatment of corneal abrasion. Pirfenidone was fully released from the outer layer of PLGA after 24 h, and about 70% of moxifloxacin hydrochloride was released from the inner layer of polyvinylpyrrolidone within the same time. In addition, a single dose of fiber was as effective in inhibiting infection as four doses of moxifloxacin hydrochloride, supporting the potential of dual drug-loaded nanofiber systems as once-daily eye implants for treating corneal abrasion [ 199 ].

Because of the nanofiber extracellular matrix-like structure, its production method is less costly and simpler than many nanostructured drug delivery systems [ 200 , 201 , 202 ]. In addition, nanofibers can be combined with other technologies. One study combined nanofibers with hydrogels for intravitreal anti-VEGF drug delivery. This modulated, injectable, biodegradable hydrogel nanofiber system can change the peptide concentration to adjust the dose, providing a broad application prospect for treating wet age-related macular degeneration [ 203 ]. Likewise, a double network patch was designed by compounding electrospinning nanofibers of thioketal-containing polyurethane (PUTK) with a reactive oxygen species (ROS)-scavenging hydrogel (RH) fabricated by cross-linking poly with thioketal diamine and 3,3’-dithiobis. The PUTK/RH patch has good transparency, high tensile strength, hydrophilicity and strong antioxidant activity. In a rat corneal alkali burn model (Fig.  8 ), the corneal fluorescein staining showed that the mean fluorescence intensity in PUTK/RH group decreased to 39.0 ± 6.7 AU, compared to the alkaline burn group (53.4 ± 10.5 AU) on day 3. Furthermore, PUTK/RH patch can accelerate corneal wound healing by inhibiting inflammation, promoting epithelial regeneration and reducing scar formation, which may be a new therapeutic strategy for the alkali burned cornea [ 204 ].

A – C The fluorescein-staining photographs of rat corneas transplanted with HAM and PUTK/RH patch after alkali burn. D Mean fluorescence intensity. The corneal epithelial defects (green region) are marked by white arrows point to. n = 5,*P< 0.05

Besides, a visual device was developed using commercial contact lenses as substrate, metal-coated nanofiber mesh as conductor, and in-situ electrochemical deposition of poly (3, 4-ethylenedioxythiophene)/poly (styrene sulfonate) as adhesive material. This hydrogel contact lens has high permeability, excellent wettability, optical transparency and mechanical compliance. A study involving rabbit eyes demonstrated the safety of wearing this contact lens continuously for 12 h; no notable corneal wear or irritation was observed. This finding highlights the lens's high level of safety and its potential to serve as a versatile platform for eye health monitoring and drug administration [ 205 ].

Dendrimers are nano-sized (usually 2–100 nm), symmetric, hyperbranched and typically tree-shaped or star-shaped structures with repeating molecules surrounding a central core [ 206 , 207 ]. They have high capacities for drug encapsulation and conjugation and the functionalization of surface groups [ 23 , 208 ]. Besides, dendrimers are highly versatile in function and can be designed into multifunctional biological macromolecules by modifying the surface for various applications, which have been widely used in hydrophilic and lipophilic drugs delivery, nucleic acid delivery (gene, miRNA/siRNA), macromolecular delivery, and other biomedical applications [ 37 , 209 ].

Astodrimer sodium (SPL7013) is a polyanionic dendrimer with antiviral activity. Romanowski et al. evaluated ocular tolerance and anti-adenovirus potency of topical SPL7013 in the rabbit eye model with adenovirus (HAdV5) ocular infections. In a tolerance study, rabbits were treated with 3% SPL7013, control, or 0.5% cidofovir an the Draize scale was used to evaluate the scores on 0, 1, 3, 4, 5, 7, 9, 11 and 14 days. Compared with the control, 3% SPL7013 and 0.5% cidofovir significantly shortened the duration of HAdV5 shedding. Moreover, 3% SPL7013 induced a Draize score of "minimal" to "almost no irritation". These findings suggest that 3% SPL7013 is suitable for treating adenoviral eye infections [ 210 ].

In a clinically relevant rat model of AMD, Kambhampati et al. discovered that systemic hydroxy-terminated poly-amidoamine dendrimer-triamcinolone acetonide conjugates.

(D-TA) were selectively taken up by activated microglia/macrophages and retinal pigmented epithelium, which are essential in disease progression. D-TA significantly inhibited choroidal neovascularization (> 80%, > 50-fold better than free drug). Meanwhile, in ex vivo studies of human postmortem diabetic eyes, dendrimers were also ingested into choroidal macrophages. These findings show systemic hydroxyl dendrimer drugs can be used alone or combined with current anti-vascular endothelial growth factors to provide a new approach to treating AMD [ 211 ].

Recently, Wang and co-workers developed dendrimer gel particles (DHPs), which combine the advantages of dendrimers, hydrogels, and NPs. The delivery efficiency and efficacy of two anti-glaucoma drugs, brimonidine tartrate and timolol maleate, were tested by loading them into dendrimer gel particles of different sizes. The results showed that nano-in-nano DHP (nDHP, ~ 200 nm) was superior to μDHP3 (3 μm) and μDHP10 (9 μm) in terms of cytocompatibility, degradability, drug release kinetics, and corneal permeability. Compared with conventional drug solutions, nDHP increased drug corneal permeability by 17-fold. In addition, in vivo experiments showed that nDHP showed a significant IOP lowering effect after once daily administration for 7 days. The BT/nDHP reduced IOP by 4.5 mmHg in 4 h, which was 2.6 times more effective than BT/PBS eye drops on average. Besides, the IOP reduction in the BT/nDHP group was fourfold higher than that in the BT/PBS group at day 7 (Fig.  9 ). These findings indicate that nDHPs can be used for precision drug delivery and open a new window for combining multiple nanotechnologies [ 212 ].

a The in vivo IOP of normotensive rats was reduced following 7 days of daily topical application of BT/nDHP and BT/PBS. * P < 0.05. b The daily adjusted averages of △ IOP at 12 PM. Each formulation is administered as 2 × 5 μL of 0.1% w/v BT for 7 days

In conclusion, dendrimers provide practical solutions to the solubility, distribution, and targeting problems faced by ocular drug delivery, making them effective carriers for ophthalmic applications. However, the clinical translation of this system is hampered by multiple formulation procedures, difficulties in large-scale production, cytotoxicity, and low drug loading [ 22 ]. A lot of research is still needed in the future.

Liposomes are lipid vesicles consisting of one or more phospholipid bilayers with a central water compartment diameter of 0.025 to 10 µm [ 213 ]. Hydrophilic or lipophilic drugs can be encapsulated in them, which are widely used in the therapy of retinal diseases. For instance, verteporfin liposome is the first FDA-approved drug for treating AMD [ 214 ]. In addition, liposomes can adhere to the cornea, which are excellent carriers for drugs with low partition coefficient, low solubility, high molecular weight and poor absorption [ 215 , 216 ]. The positive charge on the liposomes allows them to bind to the negatively charged mucin coating on the corneal epithelium. For example, the positively charged liposomes increased the trans-corneal flow of penicillin G fourfold, indicating enhanced corneal permeability [ 217 ].

Besides, Tavakoli et al. evaluated how the properties of these liposomes (particle size, surface charge, surface coating) affect their retinal penetration In an in vitro bovine explant system. The data indicate that small liposomes (≈50 nm) can penetrate the retina, whereas large liposomes (≈100 nm) cannot, underlining the importance of particle size. In addition, PEGylation and anionic surface charge favor the distribution of retinal liposomes. In conclusion, this study expands the understanding of the ocular barrier and provides valuable information for designing enhanced retinal drug delivery systems [ 215 ].

One study reported a cationic liposome eye drop loaded with tacrolimus (FK506) for treating dry eyes. Tacrolimus liposomes have a diameter of approximately 300 nm and a surface charge of + 30 mV. Cationic liposomes can interact with the anionic eye surface, prolonging the eye retention time and enhancing tacrolimus in the cornea.FK506 liposomes have also been shown to reduce ROS and DED-related inflammatory factors, which have excellent potential for treating ocular diseases [ 218 ].

Although liposomes have numerous advantages, limited drug loading capacity, short shelf life, and sterilization issues restrict their use [ 219 ].

Niosomes are self-assembled vesicles formed by hydrating non-ionic surfactants, cholesterol, or other amphiphilic molecules [ 220 ]. They are structurally similar to liposomes and have been developed as an alternative delivery system to liposomes. The advantages of niosomes over liposomes include chemical stability, longer storage time, and continuous drug administration [ 37 , 221 ]. Moreover, niosomes are biodegradable and non-immunogenic [ 222 ]. As a multifunctional drug delivery system, lipophilic and hydrophilic drugs can be encapsulated into membrane bodies with improved drug stability and bioavailability [ 223 , 224 ].

Epalrestat is a drug that inhibits the polyol pathway and protects the diabetic eye from damage associated with sorbitol production and accumulation. Kattar et al. designed cationic ionophores composed of polysorbate60, cholesterol, and 1, 2-di-O-octadecyl-3-trimethylammonium propane to deliver the drug. Compared with contact lenses containing epalrestat or free drug solution, niosomes could encapsulate more drug (encapsulation efficiency 99.76%), increase the apparent solubility, protect the drug from premature degradation, and promote drug delivery to the intraocular tissues (75% drug release within 20 days). In addition, drugs encapsulated in niosomes show better biocompatibility. Hence, the niosomes are expected to encapsulate and carry therapeutic drugs through the eye to meet the requirements of a controlled drug system for treating diabetic eyes [ 225 ].

To better treat glaucoma, Allam et al. mixed betaxolol-loaded niosomes into pH-responsive in situ gels to further prolong precorneal drug retention. The optimized niosomes had a high encapsulation efficiency (69 ± 4.8%), a negative surface charge, and a nanoscale hydrodynamic diameter. After the instillation of the niosomal gel loaded with betaxolol into rabbit eyes, IOP was consistently reduced, and the relative bioavailability of betaxolol was significantly increased (280 and 254.7%) compared with commercially available eye drops. Therefore, using niosomal pH-triggered in situ gel for ophthalmic drug delivery is a promising glaucoma treatment technique [ 226 ].

Similarly, Fathalla et al. incorporated latanoprost niosomes into gels to prolong the anti-glaucoma effect of latanoprost. Non-specific interactions of latanoprost with the surfactant resulted in more than 88% drug encapsulation efficiency. This gel reduced IOP in normotensive rabbits for 3 days, with prolonged release and no irritating effect on rabbit eyes compared with normal Xalatan ® eye drops. The study's results confirmed the potential of latanoprost niosomal gel to prolong drug release, reduce the frequency of administration, and possibly improve patient compliance [ 227 ].

Despite the many advantages of niosomes, low drug loading, encapsulated drug leakage, physical instability, and high production cost limit the application of niosomes in drug delivery [ 22 ]. These are complex challenges that need to be addressed in the future.

The nanowafers are small transparent disks that can be applied to the eye's surface with a fingertip and withstand continuous blinks without displacement. The slow drug release from the nanowafers prolongs the retention time of the drug on the ocular surface and facilitates drug absorption [ 228 ]. Coursey and co-workers have developed a dexamethasone-loaded nanowafer (Dex-NW) for the therapy of DED. In the experimental mouse dry eye model, administering only two doses of Dex-NW over a 5-day treatment period was comparable to the efficacy of topical Dex eye drops administered twice daily during the same treatment period. Dex-NW showed better therapeutic effects than topical Dex eye drops, confirming the efficacy and translational potential of the nanochip drug delivery system for DED [ 228 ]. In addition, nanowafers can also be used as protective membranes for corneal surface damage in DED [ 229 ].

Furthermore, Yuan et al. demonstrated the in vivo efficacy of axitinib-loaded nanowafers in treating corneal neovascularization in a mouse eye burn model. Laser scanning confocal imaging and reverse transcription-polymerase chain reaction studies have shown that once-daily administration of axitinib-loaded nanowater was twice as effective as topical eye drops twice a day [ 230 ].

Recently, a study reported PVA nanowafers loaded with PnPP-19, a synthetic peptide designed from a toxin existing in the spider's venom and having a hypotensive effect on the eyes of rats. Compared to common eye drops. the device prolonged the delivery time of the peptide on the ocular surface and maintained its fluorescence intensity for more than 180 min. Besides, PVA nanowafers could enhance PnPP-19 diffusion into the eye tissues, with continued fluorescent on the cornea after 24 h. These findings prove the potential of nanowafers to treat glaucoma [ 231 ].

To date, the polymers and drugs used to develop the nanowafers are already in clinical use. Besides, the nanowafers can be easily dropped onto the eye surface through the fingertips of patients without any clinical procedures. Therefore, it’s promising that the nanowafers can be quickly translated into clinical trials for human use.

Contact lenses

Contact lenses are hard or soft polymer devices that fit the cornea to correct refractive errors. They can be composed of hydrophilic or hydrophobic polymers [ 232 ]. Based on the designed materials, there are two main types of contact lenses: soft contact lenses, which are made of hydrogels or silicone hydrogel polymers, and rigid gas-permeable contact lenses [ 233 ]. Drug-loaded contact lenses can be in close contact with the cornea, prolong drug retention time, and improve ocular bioavailability by at least 50% [ 234 , 235 ]. Therapeutic contact lenses can decrease the required drug dose, frequency of administration, and systemic drug absorption [ 236 ]. However, water content, oxygen permeability, transparency, and mechanical property pose challenges for drug delivery, especially for patients who are strange to wear contact lenses [ 237 ]. The combination of nanotechnology and contact lenses has revolutionized drug delivery in the eye.

Immersion of contact lenses in drug-containing NPs (preferably < 100 nm) is the most common, simplest, and most cost-effective method of manufacture [ 238 ]. For example, contact lenses immersed in zinc oxide NPs (20–40 nm) showed antibacterial activity against ocular microorganisms such as Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa and Escherichia coli [ 239 ]. In addition, NPs containing drugs can be coated on the surface of the contact lens. Sahadan et al. developed a silicone hydrogel contact lens coated with phomopsidione NPs that allowed the sustained release of phomopsidione for 48 h and could be used to treat keratitis [ 240 ].

Likewise, Jiao et al. used a novel polyacrylamide semi-interpenetrating network hydrogel consisting of quaternary ammonium chitosan and tannic acid to construct a novel antibacterial and antioxidant contact lens. The antibacterial test showed that the contact lens had a good bactericidal effect on Staphylococcus aureus and Escherichia coli (almost 100%). Besides, tannic acid could alleviate oxidative stress and protect cells from ROS-induced cytotoxicity. Hence, this drug-free antibacterial and antioxidant contact lens is a promising option for treating ocular infectious and inflammatory diseases [ 241 ].

Ding et al. developed a contact lens device with embedded microtubes to treat glaucoma. This device can improve drug bioavailability, decrease the risk of adverse effects and prolong drug release time for 45 days. More importantly, as IOP fluctuates, the curvature of the contact lens changes, which in turn triggers more drug release, making it an adaptive drug-release device that potentially provides dynamic and adaptive anti-glaucoma treatment [ 242 ]. It is believed that in the future, the combination of contact lenses and nanotechnology will have more applications in the therapy of ophthalmic diseases.

Hydrogels comprise a three-dimensional network of hydrophilic polymer chains with high water retention capacity. In situ, gels are administered as a liquid and transformed into a gel upon eye contact [ 243 ]. Heat-responsive, pH-responsive, and ion-responsive materials are the three primary stimulation-responsive materials most widely employed to develop gel systems for ocular medication administration. Recent hydrogel advances offer great opportunities for ophthalmic drug delivery to treat ocular diseases [ 244 , 245 ]. Since hydrogels can improve the therapeutic effect of ophthalmic drugs through the following mechanisms, including (1) prolonging the retention time of drugs at the site of drug delivery, (2) sustained drug release at the target site, and (3) the co-delivery of multiple drugs to their function [ 97 , 116 , 246 , 247 ].

The combination of nanotechnology and hydrogels has significantly progressed the treatment of ocular diseases [ 18 ]. Various nanoformulations such as NPs, nanomicelles, MNs, and nanofibers have been combined to prepare composite systems to further prolong the retention time of drugs on the ocular surface and improve their bioavailability [ 248 ]. Some representative hydrogels used in ocular drug delivery will be detailed in the following sections and emphasized with a few appealing examples.

Fang et al. developed a polypseudorotaxane hydrogel for treating anterior uveitis by mixing Soluplus micelles (99.4 nm) with cyclodextrins solutions. The optimized hydrogel exhibited shear thinning and sustained release properties. In the endotoxin-induced rabbit uveitis model, the hydrogel significantly improved the drug retention ability (21.2 folds), corneal permeability (1.84 folds), intraocular bioavailability (17.8 folds), and anti-inflammatory effect compared with drug solutions. In addition, cytotoxicity and eye irritation studies also confirmed the good biocompatibility of the hydrogel. In conclusion, this study demonstrated that γ- cyclodextrins-based hydrogels have great potential for treating anterior uveitis [ 249 ].

Patients with wet AMD require an intravitreal injection of Bev or other drugs. Jung et al. developed an in situ formed hydrogel consisting of Bev and hyaluronic acid cross-linked to poly (ethylene glycol) diacrylate, which was slowly released after Bev injection into the suprachoroidal space of the eye using MNs. The in-situ formed Bev-hyaluronic acid hydrogel was well tolerated and released Bev for over 6 months in the rabbit eye, which could be used in treating posterior ocular diseases in the future [ 250 ].

Recently, Gao et al. developed an injectable antibody-loaded supramolecular nanofiber hydrogel by mixing betamethasone phosphate, the gold-standard anti-VEGF agent for AMD, with CaCl2. This betamethasone phosphate-based hydrogel can release anti-VEGF to inhibit retinal vascular proliferation, attenuate CNV for a long time, and remove ROS to reduce local inflammation (Fig.  10 ). Notably, the duration of anti-VEGF can be effective for approximately threefold longer than conventional administration, can reduce the frequency of administration and improve patient compliance [ 251 ].

The long-term effect of the laser-induced mice CNV model using Anti-VEGF@BetP-Gel. a Experimental design to evaluate the impact of Anti-VEGF@BetP-Gel. b Fluorescence IVIS imaging demonstrating the in vivo retention of IgG-Cy5.5 at various time periods after intravitreal injection of free IgG-Cy5.5 or IgG-Cy5.5@BetP-Gel. c H&E-stained transverse CNV sections after 4 weeks intravitreal injection. d The typical fluorescein fundus angiography images of laser-induced mice CNV model taken at 1, 2, and 4 weeks following intravitreal injection. e The graded and measured angiogenic vascular leakage values

In short, combining hydrogels and nanotechnology expands the range of biomedical applications and opens new windows for ocular drug delivery.

Microneedles

Microneedle technology is an attractive, minimally invasive strategy with the advantages of easy drug administration, controlled drug release, and low manufacturing cost [ 252 ]. It has been widely studied for transdermal delivery of various therapeutic drugs (e.g., anti-diabetes, anti-obesity drugs, and vaccines) [ 253 ]. Various MNs have been exploited and tested, such as solid MNs, hollow MNs, and dissolved MNs [ 254 , 255 ]. Due to its excellent patient tolerance and efficacy have prompted researchers and pharmacists to explore its use in treating ocular diseases.

Fungal keratitis (FK), an infectious corneal disease, is a serious cause of visual impairment worldwide. Shi et al. manufactured a dissolved microneedle array patch based on PLA and hyaluronic acid to treat FK. Among them, a 30% PLA-hyaluronic acid MN patch reversibly penetrated the corneal epithelial layer, and the cornea recovered completely within 12 h. More importantly, it demonstrated that the therapeutic effect of self-implantation of drug-loaded MN patches as a controlled release reservoir for local drug delivery is much better than that of eye drops in the rabbit model of FK. Hence, the MN patch serves as an ocular drug delivery system with efficient and rapid corneal healing ability, which may also open a new avenue for the clinical treatment of FK [ 256 ].

Besides, Cui et al. developed cryo-MNs for the ocular delivery of living bacteria. In cell experiments, the device delivered predatory Bdellovibrio bacteriovorus, which could successfully inhibit the proliferation of gram-negative bacteria. In a mouse ocular infection model, infection was reduced by nearly six-fold after 2.5 days of treatment, and corneal thickness and morphology were unaffected; this brings new insights for the safe and effective delivery of novel antimicrobial agents to the impermeable ocular surface [ 257 ].

Lee et al. developed a self-plugging MN (SPM) to perform intraocular drug delivery and seal the scleral tissues at the same time. SPMs were fabricated by a thermal stretching process and then coated with a drug-loaded polymer carrier and a biocompatible hydrogel. Each coating functional layer was characterized and explained in vitro and ex vivo experiments. The 10 mm-long SPM released over 95% of the coated drug (27.9 μg) gradually within 24 h. Furthermore, the ability of SPM to achieve rapid closure and sustained intraocular delivery was confirmed using a porcine model [ 258 ].

However, MN products' performance and quality evaluation involves several vital technical parameters, such as bending property, loading capacity, and safety in use. At the same time, MNs can cause tissue damage and have high technical requirements for clinicians, so there is still a long distance to realize the clinical transformation of MNs.

Other promising ocular drug delivery methods

Gene therapy.

Gene therapy is a hot topic in the research of modern ophthalmic diseases. There are two strategies for gene therapy: (1) restoring the function of nonfunctional or missing proteins (gene addition or gene editing) and (2) knocking down proteins to block their function (gene silencing) [ 259 ].

The eye has important features well suited for gene therapy: well-defined anatomy, relative immunological privilege, accessibility, simplicity of diagnosis, and one eye can be used as an experimental target and the other as a control in the same subject [ 259 ]. There are more than 350 hereditary eye diseases, including choroiditis, retinitis pigmentosa, Leber congenital amaurosis, etc., involving various genetic loci [ 260 , 261 ]. In addition, gene therapy approaches are also being exploited and extended to diseases not unrelated to a single genetic defect, such as corneal and retinal vascular disease or AMD [ 262 , 263 ]. Gene delivery systems primarily include viral vectors, non-viral vectors, gene editing techniques (mainly CRISPR-Cas9), and epigenetic treatments with antisense oligonucleotide (ASO) and RNAi therapeutics [ 264 ].

Viral vectors

Viral vectors are often therapeutic gene vectors due to their high transduction efficiency. Several viral vectors, such as adenovirus, adeno-associated virus (AAV), retrovirus and lentivirus, have been widely used in ocular gene therapy [ 265 , 266 ].

Among them, AAVs are tiny (~ 26 nm diameter), non-enveloped, icosahedral-structured capsid, single-stranded DNA, non-pathogenic viruses and the most common viral vectors used for ocular gene therapy [ 267 ]. Both dividing and nondividing cells can be transduced with AAV vectors. They are not integrated into the host cell genome but live in the cells as free DNA [ 267 ]. Recombinant AAVs can deliver various genetic materials to control protein expression within cells and alleviate some ocular disorders. The FDA has approved two human-using AAV-based gene therapies, and many are in clinical trials [ 268 ]. A study employing AAV as a vector may alleviate the problems of repeated intravenous injections to induce a systemic blockade of VEGF-A, which is normally expressed in human retina [ 269 ]. Anti-angiogenic microRNAs have also been used to lessen the number of corneal neovascularization through recombinant adeno-associated viruses multi-targeted biotherapy [ 270 ].

However, viral vectors have some limitations, such as potential mutagenesis, limited loading capacity (< 5 kb for AAV), poor immunoreactivity, and high production costs, resulting in unaffordability for patients [ 271 ]. Therefore, several alternative strategies, such as non-viral vector systems and NPs, are being developed.

Non‑viral vectors

Compared with viral vectors, non-viral vectors are less immunogenic and pathogenic [ 272 ]. Besides, non-viral vectors are generally low-cost, easy to manufacture, and the size of the involved genes is unrestricted. [ 273 ]. Many non-viral vectors, such as NPs, dendrimers, liposomes, polymers, naked DNA, and peptide-based vectors, have been used for gene therapy in the eye [ 168 , 264 ].

For example, Ma et al. fabricated redox-responsive quasi-mesoporous magnetic nanospheres (rMMNs) with an iron oxide core and disulfide bond-bridged polyethyleneimine shell. These rMMNs are highly loaded with miR-30a-5p through electrostatic interactions and then efficiently release miRNA under a glutathione-dominant microenvironment. The rMMNs up-regulate the level of miR-30a-5p by targeting the transcription factor E2F7 and inhibiting the malignant phenotype of ocular melanoma. In addition, rMMNs play a role in promoting cancer cell apoptosis by regulating M1-like macrophage polarization and activating the Fenton reaction. Therefore, rMMNs are attractive miRNA vectors for gene therapy and can enhance pro-inflammatory immunity in melanoma and other cancers [ 274 ].

In a notable study by Ribeiro et al., lipoplexes were developed utilizing sodium alginate as an adjuvant and strategically coated with hyaluronic acid (HA-LIP). This innovative approach facilitated siRNA delivery to retinal cells, inhibiting Casp3 expression and attenuating retinal degeneration caused by excessive LED light exposure. The safety of HA-LIP was confirmed through electroretinogram measurements, clinical assessments, and histology. These findings highlight the potential of HA-LIP as a non-viral vector for siRNA delivery, opening up promising avenues for treating various retinal diseases [ 275 ].

Antisense oligonucleotide, RNAi, CRISPR-Cas9

ASOs are brief (12–24 nt) single-stranded nucleic acids (DNA or RNA) that bind to specific complementary mRNA targets by Watson–Crick base pairing to regulate gene expression. [ 276 ]. In a phase 1b/2 clinical trial of Leber congenital amaurosis type 10, intravitreal antisense oligonucleotide sepofarsen had a manageable safety profile and showed clinically relevant visual improvement [ 277 ].

The RNAi pathway is expressed through sequence-specific double-stranded RNA genes. RNAi regulates mRNA stability and cell translation using double-stranded small interfering RNA (siRNA) or short hairpin RNA (shRNA) complementary to their target RNA [ 276 ]. Among them, siRNA is a nucleotide duplex of about 20 bp in length, which can specifically couple and guide the degradation of target genes in cells, modify the relevant signal pathways for therapeutic intervention [ 278 ]. Wang et al. used polyethene glycol grafted branched polyethyleneimine as a non-viral gene vector to interfere with platelet-derived growth factor alpha receptor and block the epithelial-mesenchymal transition process of cells by gene silencing technology to achieve an anti-fibroblast effect (Fig.  11 ). This study provides a feasible and promising clinical idea for using RNAi technology to develop non-viral gene vectors to prevent fibroblast eye disease [ 279 ].

Representative images of the immunofluorescence assays. a , b The nuclei are stained blue with DAPI, the fibrous membrane of the vitreous cavity is marked by the red arrows. c , d The red arrows indicate the retinal pigment cell layer. e , f The expression of PDGFR-α and Fibronectin

The CRISPR-Cas9 system is an engineered endonuclease directed by a short RNA comprising a complementary region with 20-nucleotides long that can recognize target DNA sites through complementary base pairing and precisely create nicks or cuts in the genome [ 280 ]. The incision is then repaired using non-homologous end-joining mechanisms (NHEJ) or homology-directed repair (HDR) [ 281 ]. Due to its simple structure, it has become the most popular genome editing tool and has gained utility in disease modelling, genetic screening, epigenome editing, cell tagging, and gene therapy applications [ 282 ].

X-linked form of hereditary retinal degeneration caused by mutations in the Retinitis Pigmentosa GTPase Regulator (RPGR) gene is a challenge for gene therapy. The majority are frameshift mutations in the OFR15 exon, a highly repetitive, purine-rich region of the RPGR. The RPGR reading frame may be restored in partly mutated photoreceptors using CRISPR/Cas9 targeted ablation of ORF15, followed by repair via non-homologous end joining, which then corrects gene function in vivo [ 283 ]. Besides, CRISPR-Cas9 with guide RNAs increased VEGF gene ablation in human cells in vitro with a slight increase in off-target activity and demonstrated the possibility of CRISPR-Cas9 causing genetic ablation in vivo, which might be affected by multiple factors in the body [ 284 ].

Recently, the delivery of gene editing agents as ribonucleoproteins in vivo has been shown to have a safety advantage over nucleic acid delivery. Banskota et al. developed engineered DNA-free virus-like particles (eVLPs) that efficiently package and deliver the base editor or Cas9 ribonucleoprotein. A single injection of eVLPs into mice achieved therapeutic levels of base editing in multiple tissues, such as reducing serum Pcsk9 levels by 78% after 63% liver editing and partially restoring visual function in a mouse model of genetic blindness. The eVLPs combine the critical advantages of viral and non-viral delivery and are promising vectors for therapeutic macromolecular delivery [ 285 ].

In conclusion, advances in the field of gene therapy and gene editing have brought hope for the treatment of eye diseases. At the same time, with the development of nanotechnology, the prospect of gene therapy for eye diseases will be broader and clinical transformation will be achieved faster.

Exosomes are nanoscale vesicles with a 30–150 nm diameter and consist of lipid bilayers, proteins, and genetic material [ 286 ]. The diagram of exosomal molecular composition is shown in Fig.  12 [ 287 ]. Almost all types of cells in the human body secrete exosomes, which act as a vital role in intercellular communication, inflammatory response and immune regulation [ 288 ]. Due to their natural, non-toxic, and biodegradable properties, exosome is an ideal candidate for drug delivery to treat many diseases, such as cancer, cardiovascular diseases, neurodegenerative diseases, and so on [ 289 , 290 ]. As natural carriers, exosomes have a higher barrier-crossing ability and safety than synthetic nano-drug carriers and are more capable of delivering various drugs or bioactive molecules among eye diseases.

Copyright 2021, Cell Commun Signal

Diagram of exosomal molecular composition. Reprinted with permission.

Pathological angiogenesis is a hallmark of numerous vision-threatening diseases. Dong et al. used exosome as a carrier for intraocular delivery of the anti-angiogenic peptide KV11 into the retinal vasculature by retroorbital injection, which greatly enhanced the inhibitory effect of KV11 on neovascularization. Besides, this is a less invasive modality compared to intravitreal injection. Therefore, EXO KV11 may be an effective nanotherapeutic agent for treating pathological angiogenesis in retinopathy [ 291 ].

In addition, Tian et al. engineered exosomes derived from regulatory Treg cells (rEXS) and used a peptide linker to conjugate them with anti-VEGF antibodies (aV). This nano-drug exploited the ability of rEXS to localize to neovascular lesions. Meanwhile, the peptide adaptor was cleaved by matrix metalloproteinases in inflammatory lesions and released rEXS and aV to inhibit inflammation and the activity of VEGF. In mouse and nonhuman primate CNV models, aV binding to rEXS resulted in a five-fold longer intraocular retention time than soluble proteins. Besides, a 3.5-fold increase in aV accumulation was detected in CNV lesions, and the controlled release of aV by matrix metalloproteinases-mediated cleavage also contributes to the efficacy. These findings provide new ideas for more effective treatment of CNV [ 292 ].

Also, Zhou et al. reported that exosomes derived from mesenchymal stromal cells (MSC-exo) were administered as eye drops. In a mouse model of DED, MSC-exos reprogram pro-inflammatory M1 macrophages to an immunosuppressive phenotype through Mir-204-mediated IL-6/IL-6R/Stat3 pathway targeting, facilitating dry eye therapy. MSC-exo maintains ocular surface homeostasis and corneal transparency by regulating the balance between M1 and M2 macrophages on the ocular surface [ 293 ]. Furthermore, exosomes derived from the umbilical cord mesenchymal stem are used in clinical trials to alleviate dry eye symptoms (NCT04213248).

Exosomes are a subtype of extracellular vesicle (EV). To avoid alterations in tear balance, tear film stability, pH and osmolality changes [ 294 ], researchers are exploring new approaches, including fusing drug-carrying liposomes with EVs to improve bioavailability [ 295 ]. Notably, EVs designed to be produced by implanted cells have recently been reported [ 296 ]. This technique provides a unique route for the production of engineered exosomes in vivo.

In summary, exosomes exhibit key characteristics that make them highly attractive as therapeutic drug carriers, particularly their ability to target multiple therapeutic payloads, benign safety, and low immunogenicity potential. However, the optimal isolation method for specific exosome applications, the heterogeneity of extracellular vesicle preparations, and the availability of appropriate methods and equipment still require extensive studies to verify.

Self-nano emulsifying drug delivery systems

SNEDDS are mixtures of oil phases, surfactants, and cosurfactants or cosolvents [ 297 ]. After aqueous phase dispersion and slight agitation, SNEDDS can spontaneously form oil-in-water NEs with droplet sizes below 200 nm [ 298 ]. Moreover, spontaneous emulsification occurs when the entropy change favoring dispersion surpasses the energy needed to expand the surface area of the dispersion [ 299 , 300 ]

The surfactant and lipid components used in SNEDDS can synergistically promote the absorption of drugs in the gastrointestinal tract, which is one of the emerging strategies to improve the availability of oral administration. Furthermore, these components can be easily modified to make SNEDDS suitable for hydrophilic and hydrophobic drugs [ 301 ]. For example, Lopez-Cano et al. prepared a self-emulsified osmo-protective ophthalmic microemulsion (O/A) with an internal oily phase (1.2%), an external aqueous phase (96.3%), cosolvents (1%), and surfactants (1.5%). Scanning electron microscopy and cryo-transmission electron microscopy demonstrated that all formulations exhibited sphere-shaped morphology with good cell tolerance (≈100%) and could be stable at 8 ℃ for 9 months. These findings manifest that self-emulsified microemulsions can be a novel drug delivery system for treating ocular diseases [ 302 ].

Besides, to improve the bioavailability of amphotericin B (AmpB), which is one of the most commonly used drugs for treating severe fungal infections, Kontogiannidou et al. prepared an oral formulation by combining AmpB-loaded SNEDDS with room temperature ionic liquids of imidazolium. This hybrid system enhanced the solubility of AmpB and exhibited good biocompatibility [ 303 ].

Although SNEDDS show considerable advantages over conventional drug delivery systems, there are still some limitations that require further investigation:(1) the content of vehicles in SNEDDS is usually very high, and the safety should be considered, (2) the risk of drug precipitation, (3) the capacity of improving drug loading and targeting, (4) knowledge of in vivo pharmacokinetics of SNEDDS is still a grey area, especially in human volunteers [ 304 ]. It is believed that SNEDDS will be more widely used in ophthalmology in the future.

Characterization of nanotechnology-based drug delivery systems

Nanotechnology refers to treating structures at the nanoscale level, which ranges in size from 1 to 100 nm and is proportionally comparable to peptide drugs [ 17 ]. Their basic physicochemical properties, such as visual appearance, size, zeta potential, refractive index, pH, retention, viscosity, osmolality, biodegradability, surface charge, hydrophobicity and biodegradability are closely related to their therapeutic efficacy in the ocular pathological environment [ 23 , 305 ]. Therefore, we characterized nanocarriers' physicochemical and biological properties to provide new ideas for better design of effective novel delivery systems.

Visual appearance

Most NPs present a transparent, translucent, or translucent to milky appearance, depending on the size of the particle, the surfactant or cosurfactant, and the concentration or type of oil. The transparency of nanocarriers can be checked by measuring the transmittance (%T) at 520 nm using a UV spectrophotometer [ 61 , 306 ].

Particle size (PS) and polydispersity index (PDI)

PS and PDI are essential characteristics of nanocarriers and the main determinants of physical stability. These parameters are mainly estimated by dynamic light scattering or photon correlation spectroscopy [ 61 , 307 ]. Particles with a smaller size penetrate the inner mucin layer of the tear film more quickly and have higher aqueous humor absorption than larger particles [ 307 , 308 ]. For PDI, 0 represents a homogeneous system, and 1 represents a heterogeneous system [ 309 ]. PDI values less than 0.1 and close to 1 indicate good and poor quality of the colloidal system, respectively [ 61 ]. Small PS and PDI are generally preferred for ocular drug delivery because they provide better stability, biodistribution properties and high patient compliance [ 23 ].

Microscopic techniques were used to study the morphology of nanocarriers. Electron microscopy approaches, including transmission electron microscopy (TEM), freeze-fracture transmission electron microscopy (FF-TEM), and negative staining transmission electron microscopy (NS-TEM), are preferred for liquid samples, while scanning electron microscopy is used for solid samples [ 220 ]. In addition, TEM and atomic force microscopy (AFM) techniques can be used to reconfirm the results obtained from photon correlation spectroscopy or dynamic light scattering measurements [ 310 ].

Zeta Potential (ZP)

Zeta potential is an indicator of the physical stability of a nano-system. It is determined by the electrophoretic motion of particles in an electric field and is one of the most studied parameters [ 311 ]. The surface potential is able to be measured using the laser Doppler anemometry, and the magnitude of ZP indicates the degree of electrostatic repulsion between two neighboring particles [ 220 ]. Typically, a zeta potential of about ± 20 mV is suitable for electrostatic attachment to the corneal surface [ 61 ]. High zeta potential values (> ± 30 mV) can stabilize the nanoformulations by electrostatic repulsion [ 23 ]. Besides, positively charged particles are more suitable for enhancing electrostatic interactions with negatively charged ocular surfaces, showing better bioavailability and activity [ 312 , 313 ].

Stability issues such as creaming, flocculation, Ostwald ripening, coalescence, and precipitation are essential obstacles in developing nanocarriers [ 23 ]. The stability of different nano-systems can be estimated by short-term stability (3 months), centrifugation test, freeze–thaw cycle, heating–cooling cycle and high-temperature storage [ 314 ]. A promising approach to improve biological stability is pegylated. As a hydrophilic non-ionic polymer with high chain flexibility, PEG-coated or coupled on the surface of nanocarriers can prevent macrophage clearance by reducing contact with the surrounding environment (oxidants, enzymes, and other degraders) [ 315 , 316 , 317 ]. Besides, in vivo drug flux studies have shown that pegylated nanostructured lipid carriers have nearly twofold higher levels of ciprofloxacin in all ocular tissues than non-pegylated nanostructured lipid carriers at 2 h after administration [ 315 ].

Refractive index (RI)

Refractive index is measured by Abbe’s refractometer to determine soft contact lenses' water content, salinity and sugar concentration [ 318 ]. The tear RI was generally between 1.340 and 1.360. Therefore, the recommended RI value for ocular formulations must be < 1.476 [ 319 , 320 ]. For instance, the RI values of intraocular NEs prepared by Ismail et al. ranged from 1.334 to 1.338, which was satisfactory to meet the demands [ 179 ].

pH measurement plays a critical role in preparing stable and non-irritating ocular formulations. It has been reported that acidic (pH < 4) or alkaline (pH > 10) solutions can cause chemical damage to the eye [ 61 ]. Therefore, the appropriate pH of topical ophthalmic formulations ranges from 6.6 to 7.8 [ 321 ]. Compared with Travatan ® eye drops, the pH value of the prepared NEs is between 5.5 and 5.9, which is suitable for ocular instillation and can treat DED [ 179 ].

Ocular retention is a fundamental property of ocular delivery systems because it prolongs the duration of drug action, reduces the frequency of drug administration, and improves drug bioavailability [ 17 ]. Nanosystems with larger surface areas, such as thin films, hydrogels, have longer diffusion and contact time on the corneal surface, which enhance eye retention. In general, γ-scintigraphy, texture analysis, fluorescence imaging and surface plasmon resonance spectroscopy are used to determine the intraocular retention of nano preparations [ 17 , 61 , 322 ].

The viscosity of ocular preparations is generally less than 20.0 mPa [ 323 ], while the appropriate viscosity of ocular preparations is generally 2–3 mPa [ 311 ]. It was reported that the nano-formulations with higher viscosity and lower surface tension could prolong retention times [ 324 ]. Synthetic polymers (such as polyacrylate and PVA) and natural polymers (such as hyaluronic acid, alginate) can be used as viscosity enhancers. For example, in vivo anterior corneal retention assay showed that the Chitosan Oligosaccharides-coated nanostructured lipid carrier increased 7.7-fold compared with the uncoated lipid carrier [ 325 ].

Osmolality/Isotonicity

Osmolality was determined based on four properties of ocular or tears formulation parameters known as vapor pressure, osmotic pressure, boiling point, and freezing point [ 326 ]. In addition, osmolality can also be measured in terms of the number of moles of solution per liter or kilogram [ 327 ]. It was reported that ocular preparations with osmolarity less than 100 mOsm/kg or more than 640 mOsm/kg were named as eye irritants depending on the droplet volume [ 61 ].

Drug loading and release

Drug loading and release are essential to the ocular drug delivery system. Nanocarriers require a high drug payload, which can improve biocompatibility and achieve better therapeutic effects [ 94 ]. The primary determinant of drug load is drug solubility. The drug is released continuously in nanocapsules with high encapsulation efficiency, and the release rate is critical to achieve an effective therapeutic effect and avoid drug toxicity. [ 328 ]. Pharmacokinetics can be studied via a series of in vivo and in vitro experiments. For example, the content of drugs can be detected in tears and aqueous humor through ELISA (Enzyme-linked Immunosorbent Assay) or HPLC (High Performance Liquid Chromatography) in vitro [ 329 , 330 ]. Alternatively, fluorescence-labeled drugs could be used and then detected by confocal microscopy in vivo [ 331 ]. Besides, the results can be analyzed by some pharmacokinetic parameters, such as the maximum drug concentration (Cmax), the time required to reach Cmax (Tmax), and the area under the concentration–time curve (AUC0-t) [ 332 ].

Biocompatibility and safety

Biocompatibility and safety are critical for nanocarriers. The primary safety concerns of nano-formulation arise from the surfactants and cationic lipids used in the formulation, which may damage corneal epithelial cells during long-term use [ 333 , 334 , 335 ]. The safety of eye preparations was evaluated by various tests, such as HEM-CAM test, Schimer's test, Draize's test, histopathological studies and cell viability studies [ 23 ]. Using surfactants and cationic lipids may create safety issues that should be further optimized and improved during development [ 333 ]. In the HEM-CAM test, ocular toxicity and irritation were predicted by observing the changes in blood vessels [ 336 ].

Approval and under clinical status of nanotechnology-based delivery systems for ocular diseases

With the increasing number of products on the market, the development of nanotechnology for the treatment of ocular diseases seems promising. Table 2 lists some FDA-approved nanocarriers for ocular diseases.

For example, Restasis ® was the first cyclosporine A (CsA) oil-in-water emulsion approved by the FDA for the treatment of DED in 2002 [ 337 ]. It used polysorbate-80 as an emulsifier and 0.5 mg/ml CsA was dissolved in castor oil. Importantly, the preservative-free emulsions (particle size 100–200 nm) effectively avoided the toxicity shown by earlier preservative-containing formulations. Nevertheless, Restasis ® is still accompanied by side effects such as epiphora, eye irritation and instillation pain [ 338 ].

Besides, Cequa ® is a nano-micellar formulation containing 0.09% CsA that is designed to improve drug delivery and penetration to ocular tissues. Cequa ® was approved by the FDA in 2018 for the treatment of DED [ 339 ]. The micellar formulation is composed of poly-oxygenated hydrogenated castor oil and octoxynol-40, which could form thermally stable micelles simultaneously by hydrogen bonding. The micelles have a particle size of 12–20 nm and a strong encapsulation ability to increase the CsA concentration tenfold [ 149 ]. In addition, Restasis ® (CsA), Eysuvis ® (loteprednol etabonate), Lacrisek ® (vitamin A palmitate and vitamin E), Cyclokat ® (CsA) and Artelac Rebalance ® (vitamin B12) are also used for the therapy of DED [ 22 , 23 ].

Ikervis ® was introduced in 2015 for the treatment of severe keratitis [ 340 ]. Xelpros ® can be used to treat glaucoma or ocular hypertension [ 341 ]. Verkazia ® and Besivance ® can be used for vernal keratoconjunctivitis and allergic conjunctivitis/keratitis, respectively [ 341 , 342 ].

Ozurdex ® contains a PLGA polymer matrix that provides long-term release of dexamethasone for up to 6 months. It was approved by the FDA in June 2009 for the treatment of macular edema [ 343 , 344 ]. Bromsite ® [ 345 ] and Eysuvis ® [ 346 ], which were based on Durasite technology and mucus penetrating particle technology respectively, extended the residence time of drugs and improved treatment efficiency.

In addition, as shown in Table 3 , many nano-based ocular drug delivery systems are currently in clinical testing stage, which further promote the delivery and development of ophthalmic drugs. Although the approval of nanocarriers has progressed slowly over the past two decades, more nanocarriers, including ocular nanomedicines, are expected to be available on the market in the near future.

To treat cataracts, a recent Phase II clinical trial (NCT03001466) involving in evaluating the therapeutic effect of a urea-loaded nanoparticulate system were conducted. Polymeric nanoparticles composed of Pluronic ® F-127 copolymers were used to enhance urea efficacy. In this clinical trial, patients in each group received either urea nanoparticles or balanced salt solution, with one drop of eye solution, five times a day for 8 weeks, and the scores of differences in 6-month visual acuity were measured [ 347 ].

INVELTYS are delivered as mucus penetrating particles for the treatment of postoperative inflammation and pain following eye surgery. The primary results of the clinical trial showed that INVELTYS, administered twice daily for 2 weeks, safely and effectively resolved postoperative ocular inflammation and subject-rated ocular pain after cataract surgery. The observed outcomes could be attributed to mucus penetrating particles that enable the drug to penetrate the tear film efficiently, facilitating drug release into targeting tissues [ 348 ].

Besides, in a recent Phase II clinical trial (NCT02466399), 80 participants with high IOP and open-angle glaucoma were recruited. The differences in intraocular pressure were measured after 3 months of treatment to compare the efficacy and safety of liposome latanoprost (POLAT-001) and latanoprost eye drops [ 349 ].

Recently, a multi-center open-labeled study (NCT02371746) is underway to evaluate the efficacy and safety of ENV 515 (travoprost) for treating ocular hypertension and glaucoma. AR-13503 (NCT03835884) and AR-1105 (NCT03739593) designed using PRINT technology as intravitreal implants for the treating AMD and DR are also in clinical trials [ 22 ].

Recent patents on ocular disease therapy

The application and approval of a patent is the final confirmation of the commercial interest in a particular product. In the past years, researchers and pharmaceutical companies have made great progress in developing ocular drug delivery and have obtained multiple patents. Table 4 lists some representative patents in nano-based ocular drug delivery systems.

To treat cataracts, a patent (CN105726484B) disclosed a composition of tetrandrine liquid crystal nanoparticle eye-drops. The eye-drops were composed of matrix material, stabilizer, penetrating agent and cationic materials etc. Importantly, this invention has the advantages of strong drug loading capacity; good biocompatibility, high biological viscosity, higher stability and the capacity to improve the patient's compliance [ 350 ]. Likewise, Jialu et al. invented, a puerarin and scutellarin lipid nanoparticle ophthalmic preparation, with large membrane surface area and high drug carrying capacity. This patent (CN108066315A) opens up a new window for the treatment of cataract [ 351 ].

Peter et al. were patented for demonstrating that NPs, microparticles and implants are formed by polymer-drug a ssociations, with the ability to easily administer the required dose and deliver several drugs over extended periods of time (US20190070302A1). In addition, they disclosed that multiblock conjugates in the form of nonlinear copolymer-drug performed better and had fewer side effects compared to administration alone. The patent could be used to treat uveitis and wet AMD [ 366 ].

A patent (KR20200000395A) disclosed a composition of a nanoemulsion consisted of an active ingredient cyclosporine in a highly dissolved state and an emulsifier in an aqueous vehicle, which can improve the stability of medicine. The ideal particle size of nanoemulsion is 100 nm, with a narrow particle distribution. This application is effective for the treatment of DED, conjunctivitis and other ocular diseases [ 372 ].

Similarly, Application KR20200053205A provides a nano-emulsion eye drop consisting of cyclosporine, a solubilizer, a solvent and a stabilizer. Nanoemulsions have a droplet size of 20 nm or less, which facilitates penetration of the ocular barriers. Importantly, the nanoemulsion eye drop can improve stability and patient compliance, which are also used for the treatment of DED [ 373 ].

Challenges and future perspectives

In this review, we first introduced the anatomy and barriers of the eye, where effective treatments and drug delivery are significant challenges due to the diversity of the diseases and the presence of ocular barriers, especially in the posterior segment of the eye. Although traditional drug administration has achieved certain efficacy in treating ocular diseases, some limitations remain, such as poor permeability, ineffective distribution, and insufficient bioavailability. Novel drug delivery methods, such as nanomicelles, NPs, nanosuspensions, microemulsions, dendrimers, liposomes, contact lenses, aqueous gels, MNs, and other novel drug delivery methods can significantly improve the efficacy of current treatment. At the same time, continued innovation in gene delivery and exosomes seems to be very exciting for drug delivery.

Despite some progress in developing novel ocular drug delivery systems, several challenges still exist. These include the complexity of production technology and processes, which limit the clinical translation of nanotechnology-based ocular drug delivery systems. Additionally, there is a need to improve the stability and safety of nanocarriers to minimize potential complications. Many new drug delivery techniques are primarily tested in animal experiments or in vitro studies, lacking comprehensive in vivo evaluations in human eyes. The targeting capabilities of nanocarriers need enhancement, and their metabolic fate within the eye remains unclear. Furthermore, these technologies' high technical requirements and manufacturing costs have hindered their commercial production and widespread clinical application. Addressing these challenges is crucial to advance ocular drug delivery and promoting its successful implementation in clinical practice.

In the future, more efforts should be paid to developing novel non-invasive ODDS that can overcome the ocular barriers, prolong the drug release time, and sustain therapeutical concentration at the lesion targets. Thus, nanocarriers' size, zeta potential, refractive index, safety, stability, pH, surface tension and osmotic pressure, of nanocarriers ought to be optimized. At the same time, more in vitro and in vivo experiments should be carried out, animal models more similar to human eye diseases should be established, and the evaluation methods of therapeutic effect should be further improved to better predict the safety and efficacy of delivery vectors. In addition, gene therapy, exosomes, and tissue engineering also provide new directions for ocular drug delivery.

In summary, the advantages of novel drug-delivery systems for ocular applications are undeniable, and these innovative nanocarriers will be increasingly used in clinical practice in the future.

Availability of data and materials

Not applicable.

Abbreviations

Adeno-associated virus

Atomic force microscopy

Amphotericin B

Antisense oligonucleotide

Anti-VEGF antibodies

Blood-aqueous barrier

Betamethasone phosphate

Bevacizumab

Blood-retinal barrier

Brimonidine tartrate

Ciprofloxacin-loaded nanoemulsion

Choroidal neovascularization

Cyclosporine A

Chitosan oligosaccharide-valylvaline-stearic acid

Chitosan-coated polylactide-glycolic acid nanoparticles

Dexamethasone-loaded nanowafer

Dendrimer gel hydrogel particles

Dynamic light scattering

Dendrimer-triamcinolone acetonide

Extracellular vesicle

Food and drug administration

Freeze-fracture transmission electron microscopy

Fungal keratitis

Hyaluronic acid

Liposomes coated with hyaluronic acid

Hydrogen-castor oil 40/octyl alcohol 40

Homology-directed repair

Intraocular pressure

Methylglyoxal

Moxifloxacin–pamoate

Exosomes derived from mesenchymal stromal cells

Nanostructured microemulsions system

NaMESys carrying sorafenib

Copolymer EPC

Aflibercept loaded nEPCs

Non-homologous end joining mechanisms

Nanoparticles

Nanosuspension

Negative staining transmission electron microscopy

Oil-in-water

• Ocular drug delivery systems

Polycaprolactone

Polydispersion index

Polyethylene glycol

Polylactic acid

Polylactide-coglycolide,

Thioketal-containing polyurethane

Polyvinyl alcohol

Exosomes derived from regulatory Treg cell

Reactive oxygen -scavenging hydrogel

Redox-responsive quasi-mesoporous magnetic nanospheres

Scanning electron microscopy

Short hairpin RNA

Small interfering RNA

Self-plug-type microneedle

Triamcinolone acetonide

Transmission electron microscopy

Tocopherol polyethylene glycol 1000 succinate

Vascular endothelial growth factor

Water-in-oil

Zeta potential

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (82271041, 82201136), the Disciplinary Crossing Cultivation Program of Shanghai Jiao Tong University (YG2022QN055), the Basic Research Programs of Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine (JYZZ152), Shanghai Key Clinical Specialty and Shanghai Eye Disease Research Center (2022ZZ01003).

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Shiding Li and Liangbo Chen have contributed equally to this work.

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Department of Ophthalmology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

Shiding Li, Liangbo Chen & Yao Fu

Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200011, China

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SL and LC contributed equally to this work. SL and LC drafted the manuscript and created all the figures. SL, LC and YF discussed the concepts of the manuscript. All authors read and approved the final manuscript.

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Li, S., Chen, L. & Fu, Y. Nanotechnology-based ocular drug delivery systems: recent advances and future prospects. J Nanobiotechnol 21 , 232 (2023). https://doi.org/10.1186/s12951-023-01992-2

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• Nanotechnology
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• Characterizations
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Revolutionizing ocular drug delivery: recent advancements in in situ gel technology

• Susanta Paul   ORCID: orcid.org/0000-0003-0550-8412 1 ,
• Subhabrota Majumdar 2 &
• Mainak Chakraborty 1  

Bulletin of the National Research Centre volume  47 , Article number:  154 ( 2023 ) Cite this article

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Metrics details

Ophthalmic in situ gel is a novel preparation. It can be instilled into the eye as a liquid but gels upon contact with the ocular surface, generating a sustained-release depot of the drug.

The main body of the abstract

Among drug delivery modalities, ocular drug administration requires careful study and parameter assessment. This is because the eyes are sensitive and require careful care. Conventional ocular administration techniques quickly eliminate formulated compounds, minimizing epithelial interaction. This review covers polymers used in ocular medication delivery, their uses, and their drawbacks. The in situ gelling mechanism converts liquid formulations into gels under certain physiological or environmental conditions. When they contact the ocular surface, in situ ocular gels undergo this transformation for medication administration. Different mechanisms drive this change, depending on the gel's formulation and desired properties. Temperature-, pH-, and ion-induced gelation are common processes of in situ ocular gel formation. The medicine's physicochemical qualities, desired drug release kinetics, ocular environment, and patient comfort determine the mechanism. Researchers can create ocular gels that transport medications, improve bioavailability, and increase patient compliance by carefully formulating and understanding the in situ gelation mechanism. These polymers are useful in prodrug research and ocular penetration enhancement. The article thoroughly discusses polymeric systems and creates a viable ophthalmic drug delivery formulation.

Short conclusion

In conclusion, in situ ocular gels advance ocular medication delivery. These gels overcome various difficulties of current delivery strategies for ocular therapeutics and provide a diverse and effective platform. In situ gelling, where the liquid formulation becomes a gel when it contacts ocular tissues, improves medication retention, bioavailability, and contact time.

The topical route of administration is the most frequent one for ophthalmic medications since it is easy to apply, it does not involve any kind of invasive procedure, and it is available to all patients. Unfortunately, it is not possible for medications to achieve efficacious concentrations when they are just applied topically. In addition to this, their bioavailability needs to be increased so that the number of times they need to be administered, as well as the severity of the negative effects that come along with it, can be reduced. For this reason, throughout the course of the last several decades, a significant amount of focus has been placed on the possibility of producing prolonged-release forms that are able to increase the precorneal residence period while simultaneously reducing the amount of medication that is lost as a result of tear production. Gel-based materials are one of these forms that have been investigated as a potential perfect delivery mechanism due to the fact that they belong to a very adaptable class that has a wide variety of potential uses in ophthalmology. These components can be found in therapeutic contact lenses, eye drops that contain gel, formulations that gel in situ, intravitreal injections, and intravitreal injections. The purpose of this review is to discuss the many different in situ gel-based materials and the primary functions that they serve in the field of ophthalmology.

Structure of the eye

The human eye is extraordinary and complicated, as shown in (Fig.  1 ). Front and back compartments. First, the tear film, cornea, pupil, lens, and ciliary body. The latter has conjunctiva, sclera, choroid, retina, vitreous body, and optic nerve. Orbital glands and epithelial secretions control tear volume. Light enters the eye through the cornea (Sridhar 2018 ). It has epithelium, stroma, and endothelium layers. The epithelium has some tightly connected cells, the stroma is a dense water layer, and the endothelium keeps the cornea transparent (Boote et al. 2020 ).

Schematic diagram of the eye demonstrating the sclera, cornea, iris, ciliary body, choroid, retina, vitreous humour, and optic nerve as well as the inside and outside segments of the eye. A gel called vitreous humour fills the interior of the eye

Iris colour affects retinal light. Pupils are black circles in the iris. The clear lens focuses light onto the retina, while the pupil size fluctuates with light. Both pigmented and non-pigmented ciliary epithelia have stomas and muscle-filled ciliary bodies. Ciliary body capillaries connect the eye's front and back (Rupenthal and Daugherty 2019 ). The vitreous humour, a clear, avascular gel, separates the lens from the retina. Water, hyaluronic acid, ions, and collagen cushion the eye.

The conjunctiva covers the sclera and lines the eyelids. The outer epithelium, the substantia propria (containing nerves, lymphatic and blood arteries), and the submucosa (attached to the sclera) make up this mucous membrane (Boote et al. 2020 ).

Collagen and mucopolysaccharides form the cornea's sclera. The exterior retinal layers are fed by the choroid, an interstitial layer between the retina and sclera. The retina is a thin layer of neuronal and glial cells that lines the eye. Electrical impulses from the optic nerve are processed by the brain as visual data (Boote et al. 2020 ).

Ocular barriers

Capacity of cul-de-sac.

Figure  2 illustrates ophthalmic obstacles. The cul-de-sac between the lower eyelid's palpebral and bulbar conjunctiva prevents foreign substances from entering the eye and enlarges the upper eyelid crease. 30 μL is the maximum ocular cul-de-sac volume. When the lower eyelid returns to its usual position, the capacity is lowered to 70–80% of the swelling, and allergic reactions can also diminish the volume. The tiny volume of the cul-de-sac reduces drug concentration in the eye, decreasing its therapeutic efficacy (Bachu et al. 2018 ).

Structure of ocular barriers. The figure represents two significant barriers for topical ocular medication delivery. Tear film barrier: rapid tear turnover and gel-like mucus. Corneal barrier: tight connections and five-layer structure

Drug loss by lacrimal fluid

Ocular solution drainage is a major precorneal challenge. Tears, solution drainage, and inadequate conjunctival absorption all cause drug loss. Protein binding and drug metabolism hinder medicine absorption (Ahmed et al. 2023 ). To keep eyes hydrated and keep foreign agents out, lacrimal fluid is constantly refreshed. Extending the formulation's residence period ensures pharmacological action (Agarwal et al. 2021 ).

Corneal barriers

The cornea shields and directs light to the retina (Mofidfar et al. 2021 ). Epithelium cells inhibit large molecules and hydrophilic medicinal agents. Hydrophilic thick stroma prevents lipophilic medicines (Varela-Fernández et al. 2020 ). The endothelium maintains corneal transparency and selectively lets hydrophilic drugs and macromolecules into the aqueous humour (Fig.  2 ). Drug ionization, molecular mass, charge, and hydrophobicity affect corneal penetration. Trans-corneal penetration inhibits tear-to-aqueous humour medication transfer (Ahmed et al. 2023 ).

Blood-ocular obstructions

Exogenous chemicals cannot reach the circulatory system because of the blood-retinal barrier (BRB) and the blood-aqueous barrier (BAB) (Mofidfar et al. 2021 ). BAB, which is found in the front of the eye, prevents the passage of many intraocular drugs but permits hydrophobic and smaller treatments (Lee et al. 2022 ). These drugs are eliminated from the body more quickly in the frontal region than hydrophilic and bigger drugs. Inulin clears more slowly than pilocarpine. In the back of the eye, BRB contains cells that make up the retinal pigment epithelium and endothelium. It shields the retina from toxins, water, and plasma (Bachu et al. 2018 ).

Ocular disorders

Cataracts cause 40–60% of blindness worldwide. According to the National Programme for Control of Blindness and Visual Impairment, cataracts cause 62.6% of preventable blindness in India (Rupenthal and Daugherty 2019 ). Sunlight, diabetes, malnutrition, genetic predisposition, and smoking can induce cataracts (Chanet al. 2022 ). Crystalline proteins make the lens translucent and classify cataracts as cortical, nuclear, or posterior subcapsular. Cataracts are linked to changes in α, β, and crystalline and their genes. Glycation, oxidative stress, and hydrophobic chemicals can raise calcium levels and lens crystalline protein buildup, causing cataracts. Hyperglycemia and hydroxyl radicals produce oxidative damage. Anti-cataract medicines may lessen the requirement for surgery (Dubald et al. 2018 ). These antioxidants chelate metal ions and scavenge free radicals. Curcumin, lanosterol, resveratrol, and metformin may treat cataracts.

Conjunctivitis

All ages, races, and genders suffer from conjunctivitis. It causes conjunctival oedema and might be infectious or non-infectious. Microbial infections produce infectious conjunctivitis, while irritants and allergens cause non-infectious. Conjunctivitis causes redness, irritation, excessive tearing, and ocular secretions. 40% of the globe has allergic conjunctivitis. Antibiotics or anti-inflammatories can be applied topically to treat conjunctivitis (Rupenthal and Daugherty 2019 ).

Diabetic retinopathy

Diabetes retinopathy affects both types of diabetes mellitus. 60% of type-2 diabetics and all type-1 diabetics have retinopathy after 20 years. Oxidative stress and inflammation induce diabetic retinopathy. After cataracts and corneal blindness, hyperglycemic disorders are the third leading cause of blindness worldwide (Sharma et al. 2021 ). Early detection and active blood glucose and blood pressure management can prevent it. Proliferative and non-proliferative diabetic retinopathy exist. Both can gradually destroy the retina. Laser photocoagulation and vitrectomy treat diabetic retinopathy, although they leave laser scars and provide only temporary relief. Interrupting inflammatory pathways with intravitreous corticosteroid injections or sustained-release implants can reduce macula swelling (Silva et al. 2021 ). Anti-VEGF medications (Ranibizumab and Aflibercept) minimize blood leakage and oedema (Fogli et al. 2018 ).

Retinoblastoma

Retinoblastoma is a cancerous retinal tumour that affects children under 5. Lack of treatments and a 99% death rate make retinoblastoma blinding. Retinoblastoma affects 1 in 20,000 live births, equally in both genders. Retinoblastoma is caused by a mutation in the tumour suppressor gene RB1 (Schaiquevich et al. 2022 ). Radiation, cryotherapy, systemic chemotherapy, and surgery can treat retinoblastoma. Recent research suggests treating retinoblastoma with proangiogenic hormones and blood vessel growth.

Fungal keratitis

Traumatized corneas get fungal keratitis, whereas healthy corneas do not. Candida tropicalis, Albicans, Krusei, Glabrata, and Parapsilosis can cause it. 40% of infectious keratitis cases occur in developing nations. Contact lenses, trauma, corneal surgery, corticosteroids, HIV positive, diabetes, and leprosy are risk factors for this illness (Masoumi et al. 2023 ). Fungal keratitis can slow wound healing, ulcerate the cornea, and inflame the corneal stroma, changing miRNA expression. Fungal keratitis can be treated with topical or oral antifungals or corneal surgery. Some surgeries did not restore eyesight. Fungal keratitis treatment trials are many. Nihal et al. developed a safer and more effective topical cubosome and mixed micelle sertaconazole nitrate formulation (Nihal et al. 2018 ).

Introduction to the ophthalmic drug delivery

Ophthalmic drug administration is a growing pharmaceutical specialty. It requires eyedrops to address macular degeneration, glaucoma, and dry eye condition. Since the eye is restricted, delivering drugs to it presents unique challenges (Conrady and Yeh 2021 ). Medication delivery must overcome eye barriers. These include the cornea, tear film, and blood-retina barrier. Since the eye movements are constant, it may be difficult to maintain drugs in place long enough for them to work. Eye drops, ointments, and injections have traditionally delivered ocular drugs (Shastri et al. 2023 ). These methods have systemic adverse effects, low absorption, and patient noncompliance. New in situ gel technology can revolutionize ocular medicine administration.

Current challenges with traditional ocular drug delivery approaches

Patients and doctors struggle with traditional ocular medication delivery. Eye drops, for example, have low bioavailability and lose a lot of medicine before reaching the intended site (Gote et al. 2019 ). The eye automatically expels foreign objects like eye drops, limiting how much medication can be given in a single dose.

Traditional ocular drug administration has poor bioavailability and patient compliance. Patients often forget to take their prescription or do it incorrectly, which increases medication loss and reduces treatment efficacy (Akhter et al. 2022 ). Eyedrops must be used often. Chronic ocular illnesses like glaucoma necessitate frequent, intrusive eye injections of medicine (Billowria et al. 2023 ). Treatment and control require these injections. This may increase the patient's stress, suffering, and risk of infection. These issues with conventional medication administration to the ocular segments highlight the need for an effective, patient-friendly, and targeted system. In situ gel was created for this.

The promise of in situ technology intended for ophthalmic drug delivery

In situ gel technology could deliver drugs. Glaucoma, ocular keratitis, and diabetic retinopathy are increasing. Thus, focused and effective medication administration is more important than ever (Perminaite et al. 2021 ). In situ gel technology outperforms traditional pharmaceutical administration methods. Directly applying medicine to the afflicted area in a regulated and prolonged manner improves therapeutic results. In situ gels' gel-forming polymers protect the ocular surface, minimizing injections and improving patient compliance. In situ gel technology has dramatically improved ocular medication delivery. Stimulus-responsive polymers can change their properties in response to stimuli like temperature or pH to improve drug delivery to specific ocular locations (Campos et al. 2020 ). pH and temperature are examples. Nanotechnology and in situ gel technology have also led to improved bioavailability and extended-release ocular medication delivery methods.

The In situ gel technique for ocular medication administration holds great promise. It could improve ocular condition management and patient outcomes (Okur et al. 2020 ). We should expect more inventive and effective medicine delivery options as research continues.

Advantages of in situ gelling approach over conventional ocular formulations

In situ ocular gels offer several advantages over conventional ocular formulations, making them a promising and innovative approach to ocular drug delivery. Some of the key advantages include:

Extended residence time: One of the primary benefits of in situ ocular gels is their ability to transform from a liquid to a gel-like state upon contact with the ocular surface. This transformation leads to prolonged contact and increased residence time on the eye, which is crucial for effective drug absorption and sustained therapeutic action.

Enhanced bioavailability: The prolonged contact time provided by in situ ocular gels allows for improved drug absorption and bioavailability. The gel's sustained release of the drug enables a more controlled and prolonged delivery profile, reducing the need for frequent administration and optimizing therapeutic outcomes.

Improved patient compliance: Conventional ocular formulations often require frequent administration due to their rapid clearance from the eye. In situ ocular gels can reduce the frequency of administration, leading to improved patient compliance and convenience. Patients are more likely to adhere to their treatment regimen when they don't need to administer drops multiple times a day.

Reduced systemic absorption: In situ ocular gels minimize the risk of systemic absorption of the drug, as they are designed to stay localized on the ocular surface and within the eye. This is particularly important for drugs with potential systemic side effects, as it reduces the exposure of the rest of the body to the drug.

Precise drug delivery: The gelation mechanism of in situ gels can be fine-tuned to release drugs at a controlled rate. This precision allows for tailored drug delivery profiles, ensuring that therapeutic concentrations are maintained over a desired period while minimizing the risk of over- or under-dosing.

Protection of sensitive drugs: In situ ocular gels can provide protection to sensitive drugs from degradation and elimination. The gel matrix can act as a barrier against environmental factors, such as tear fluid or enzymes, that could otherwise degrade the drug before it reaches its intended target.

Enhanced therapeutic efficacy: The sustained drug release provided by in situ ocular gels can lead to enhanced therapeutic efficacy. This is particularly beneficial for treating chronic ocular conditions, where maintaining a consistent drug concentration is essential for managing the disease effectively.

Reduced frequency of application: Due to their prolonged release characteristics, in situ ocular gels often require less frequent application compared to conventional eye drops. This convenience can significantly improve the patient's quality of life and overall treatment experience.

Overall, the advantages of in situ ocular gels make them a promising platform for overcoming the limitations of conventional ocular formulations and improving the effectiveness of ocular drug delivery while enhancing patient comfort and adherence.

Role of in situ gelling approach to deliver the drug to inner compartments of the eye

The in situ gelling approach offers a promising solution to address the major challenge in ocular drug delivery, which is effectively delivering drugs to the inner parts of the eye where tight junctions create a barrier to drug penetration. Tight junctions between cells in ocular tissues, such as the cornea and conjunctiva, restrict the movement of molecules, including drugs, making it difficult to achieve therapeutic concentrations in the inner parts of the eye, such as the retina or the aqueous humour.

Researchers can address this difficulty by employing an in situ gelling technique, which offers the advantages of prolonged drug exposure and improved drug penetration into the interior compartments of the eye. This technique demonstrates efficacy in addressing the challenge of drug delivery across tight junctions. In situ gelling formulations undergo a phase transition from a liquid state to a gel-like state when they come into contact with the ocular surface. The aforementioned alteration leads to an extended period of time during which the drug remains on the surface of the eye, hence enabling it to remain in close proximity to the tight junctions for an extended length. The viscoelastic nature of in situ gels facilitates their adherence to the ocular surface, including the cornea, conjunctiva, and adjacent tissues. The extended duration of contact enables enhanced interaction between the gel containing the drug and the ocular tissues, hence promoting improved drug permeation across tight junctions. In situ gels possess the capability to be formulated in a manner that facilitates the gradual release of the drug over a specific period. The present sustained release profile facilitates a consistent and regulated administration of the medication to the ocular regions, hence enabling the drug to surmount the obstacles presented by tight junctions. In situ gels have the capability to integrate penetration enhancers that facilitate the transportation of drugs over tight junctions. These enhancers have the ability to transiently disturb the integrity of tight junctions, thereby facilitating the translocation of the drug over these barriers and enabling its delivery to specific tissues. In situ gels have the capability to be produced with polymers and additives that are specifically designed to enhance medication delivery. The formulation can be modified to provide appropriate viscosity, mucoadhesive characteristics, and drug release kinetics in order to improve medication delivery to the interior compartments of the eye. In the context of ocular applications, in situ gels have the advantage of enabling direct application to the ocular surface, hence facilitating targeted drug administration to the desired site. This practise decreases the likelihood of systemic absorption and the potential adverse effects linked to the exposure of drugs to the entire system.

Researchers can efficiently boost medication delivery to the inner portions of the eye by leveraging the benefits of in situ gelling. This approach allows for the bypassing of tight junctions and facilitates the attainment of therapeutic drug concentrations in the targeted areas. The aforementioned methodology exhibits considerable promise in enhancing the management of diverse ocular ailments and disorders that impact the posterior segments of the ocular organ.

Mechanism of in situ gelling technology

In situ gel technology is a medicine delivery approach where a sol phase turns into a gel phase when it touches the body. The gel is given as a liquid and changes into a gel inside the eye, releasing the drug slowly (Okur et al. 2020 ). Ophthalmic medications benefit most from the technology's increased bioavailability and residence time at the target site. The gel stores active treatments and releases them slowly to maintain a steady medicine concentration (Rykowska et al. 2021 ). Polymers, lipids, and surfactants make the gel. These biocompatible, biodegradable, and medication-gelling ingredients are chosen.

In situ gel technology has fewer side effects, better patient compliance, and lower dosages than conventional drug delivery methods (Vigani et al. 2020 ). Ophthalmic medication distribution studies on it could revolutionize ocular disease treatment.

Sol–gel transition Organic substances like metal alkoxides or inorganic metal salts are often used as starting ingredients and called "sol."

The "sol–gel" technique hydrolyzes, polymerizes, or condenses the precursor to generate a colloidal solution or suspension. Complete polymerization and solvent loss cause the sol-to-gel phase transition (Vigani et al. 2020 ). Temperature, pH, and ionic activation can form in situ gelling systems. Liquid polymers that gel at the low critical solution temperature (LCST) are employed in temp-stimulated in situ gelling (Fan et al. 2022 ).

Polymeric agents with basic or acidic functional moieties inside the chain molecule generate the pH-convinced in situ gel, which undergoes a sol–gel state modification when the pH rises. Ion-elicited systems, excessively investigated as osmotically induced in situ gelling systems, occur when monovalent or divalent cations in lacrimal solution, such as Na+, Ca +2 , and Mg +2 , transform the polymer from sol to gel. Photon polymerization and enzymatic cross-linking can initiate sol–gel conversion. This work focuses on temperature sensitivity, pH change, and ion exchange-driven in situ gels. Gels work in situ via these mechanisms (Ni et al. 2020 ).

The pH-triggered gelling method

pH fluctuations also cause in situ gel to develop. This mechanism gels when pH changes. At pH, the formulation is a free-flowing solution that coagulates when the tear fluid raises the pH to 7.4. After instilling pH4.4 into the tear film, the very fluid latex quickly turns into a thick gel. All pH-sensitive polymers have acidic or basic groups that receive or release protons depending on environmental pH. Polyelectrolytes have many ionizable groups. Hydrogel swelling increases with external pH if the polymer contains weakly acidic (anionic) groups but decreases with weakly basic (cationic) groups.

Polymers utilized in the pH-responsive in situ gel system

Carbopol, a polyacrylic acid (PAA) polymer (Fig.  3 ), undergoes a sol–gel phase transition in an aqueous solution at a pH above its pK of roughly 5.5. PAA carboxylic groups receive and release protons at low and high pH. Due to the electrostatic repulsion of negatively charged groups, the PAA expands at high pH, releasing drug molecules into the environment.

Illustrating the effects of pH on carbopol gel formation. It shows a sol–gel phase transition in aqueous solution when the pH is increased. a Mechanism of pH triggered gelation. b Chemical structure of carbopol

The aforementioned variables display different traits, including higher numerical values and, in accordance, alkalinity. As a result of the negatively charged ions in poly (acrylic acid) (PAA) swelling at high pH conditions due to electrostatic repulsion, medicines are released into the surrounding media (Wu et al. 2019 ). This chemical is frequently used in the creation of ocular preparations with the goal of extending pre-corneal medication retention time. Comparing carbopol to other polymeric agents, it loses the benefit of having improved mucoadhesive properties. The interaction between polyacrylic acid and mucin, which occurs via four mechanisms—hydrogen bonding, electrostatic interaction, inter-diffusion, and hydrophobic interaction—is attributed to carbopol's mucoadhesive properties (Devasani et al. 2016 ). Despite having exceptional mucoadhesive properties, carbopol is severely constrained by its acidic nature, which can irritate and damage ocular tissues. As a result, new carbopol blends with various polymers, including HPMC and chitosan, were created in an attempt to address this issue.

Research progress in pH-sensitive in situ gelling system

This method has a great deal of potential for maintaining drug products stable and prolonging drug release. Wu et al. ( 2011 ) created pH-triggered gels with baicalin for continuous ocular drug distribution by combining carbopol 974P and HPMC E4M (0.6%, w/w) to thicken the gel. Methods for in vitro and in vivo testing, including gamma scintigraphic technique, microdialysis, rheometry, and confocal scanning light microscopy, were evaluated. According to the findings of the rheological study, the gel formation under biological conditions was significantly enhanced. Over the course of eight hours, the gel may continuously discharge the medication. Moreover, the C max and AUC values were found to be 3.6 and 6.1 times greater than the control solution, respectively (Wu et al. 2011 ). The gel formation mechanism is characterized by a sol-to-gel phase transformation in response to pH changes. Using polymeric agents that are pH-sensitive, also known as polyelectrolytes. (For example, the pH of the formulation is compared to the pH of the lacrimal fluid). Variations in the ionization state of the basic (ammonium) or acidic (carboxylic or phosphoric) groups present in the polyelectrolyte cause the sol–gel phase transition. The pKa values (3–10) and the molecular weight of the polymers determine the pH at which these groups ionize. The fluctuating ionization states of these groups influence the system's conformation, solubility, and expansion. Salt concentration, ionic strength, and temperature all have an effect on the gelling process and properties of certain pH-activated polymers. In another study, a group of researchers prepared ciprofloxacin-loaded bilosomes in situ gels for ocular delivery to minimize drug loss due to blinking reflex and nasolacrimal drainage. The goal of this study was to develop ciprofloxacin (CIP) loaded bilosomes (BLO) in situ gel for the improvement of therapeutic efficacy. The BLO was prepared by the thin-film hydration method and optimized by the Box − Behnken design. Cholesterol (CHO), surfactant (Span 60), and bile salt (sodium deoxycholate/SDC) were used as formulation factors. The optimized batch was then incorporated into the in situ gelling system using carbopol 934P and hydroxyl propyl methyl cellulose (HPMC K100M) gel base. The prepared in situ gelling system was evaluated for gelling capacity, viscosity, pH, in-vitro CIP release, ex-vivo permeation, and antimicrobial study. The prepared gel showed better gelling properties than conventional CIP gels with a viscosity of 145.85 cP in the gelling state. The formulation also exhibited sustained drug release and also showed better permeability than pure CIP (Alsaidan et al. 2022 ).

In situ gelling triggered by temperature

An interesting method for in situ gel generation involves the use of biopolymers whose transformation from sol to gel is prompted by temperature rises. Above the lower critical solution temperature, the temperature-sensitive smart polymers constrict and transition into a gel (Wei et al. 2020 ). The LCST is the temperature at which every component of a combination can be mixed in every possible quantity. This approach's ideal critical temperature is physiological and ambient; therefore, state change does not require any external heat sources other than body heat. This strategy aims to use poloxamer as a carrier for ocular medicine targeting by utilizing its in situ gel-forming characteristics (Luo et al. 2023 ). The phase conversion temperature of graft copolymers can be calculated using the temperature at which the meniscus first became immobile in each solution. These graft copolymers are a promising drug delivery system for long-term administration to the surface of the eye because of their bio-adhesive and thermos-gelling properties. The thermoresponsive approach that occurs above LCSTs according to the process of gel development starts as clear, homogeneous, freely flowing polymeric systems at temperatures below the LCST and changes to cloudy systems once they reach the LCST (Fig.  4 ). The turbidity of the solution is caused by buildup and enhanced light scattering, which follows the collapse of the polymeric chains. Phase separation separates the solution into a gel state and a solvent state, typically water, after the LCST. This is mostly due to an entropy consequence that, as the temperature rises, favours phase change.

Illustrating the effects of temperature on phase transition. It shows a sol–gel phase transition in aqueous solution when the temperature is increased above the lower critical solution temperature (LCST)

Polymers used in the temperature-activated in situ gel system

Poloxamers, triblock copolymers with hydrophobic propylene oxide and hydrophilic ethylene oxide domains, are amphiphilic (Wu et al. 2019 ). When their concentrations exceed 15% (w/w), the copolymers poloxamers or pluronics produce gels at physiological temperatures. Sol–gel phase change at increased temperatures was explained by several methods. These include polymer decomposition, micellar accumulation, and polymeric complex problems. Pluronic co-polymers come in a variety of grades and molecular masses (Almeida et al. 2013 ). L is for liquids, P for pastes, and F for flakes, depending on their physical properties. Poloxamers 338, 188, 407, and 237 are commonly used. Pluronic 407, also known as Poloxamer F-127, is a polypropylene oxide-polyethylene oxide copolymer. Its 70% ethylene oxide content makes this copolymer hydrophilic. F-127 is a co-polymer with a 12,000 Da molecular mass and a 1:2 PPO/PEO ratio. Non-toxic and less viscous below 4 °C. Poloxamer 407 gels at body temperature. Hydrogen connections make F-127 more soluble in low-temperature water than in high-temperature water (Popescu et al. 2023 ).

A polysaccharide sourced from tamarind seeds is commonly referred to as tamarind seed polysaccharide (TSP). Upon partial degradation by β-galactosidase, it exhibits the ability to form thermally revocable gels in a diluted aqueous phase. The sol–gel conversion temperature exhibits variability in response to the extent of galactose degradation (Darge et al. 2019 ). The potential of TSP gels for drug delivery via various routes such as oral, ocular, intraperitoneal, and rectal has been described in the literature. The solubility of TSP in water is significant, and gelation is observed when the level of galactose removal surpasses 35%.

Cellulose is a linear chain of several hundred to over ten thousand β (1 → 4) connected d-glucose molecules. Methylcellulose, sodium carboxymethyl cellulose (NaCMC), hydroxyethyl cellulose, and hydroxypropyl methylcellulose, are among the cellulose derivatives commonly employed in topical ocular preparations (Rahman et al. 2021 ). At concentrations ranging from 1 to 10%, the aqueous solutions of these substances exhibit a liquid state at low temperatures but undergo gelation upon exposure to heat. Cellulose derivatives have the ability to exhibit a high phase transition temperature, which can be reduced through physical or chemical modification. The critical temperature range for MC lies between 45 to 50 °C, while for HPMC, it is between 70 to 90 °C (Joshi 2011 ). The inclusion of sodium chloride has been detected to reduce the gel-forming temperature of MC to a range of 33–34 °C. Similarly, the conversion temperature of HPMC may be dropped to approximately 40 °C by reducing the hydroxypropyl molar replacement.

It is an amino polysaccharide made from chitin through fractional depolymerization and deacetylation (Wu et al. 2019 ). Chitin is a natural material that comes from arthropods most of the time. For commercial reasons, most chitin comes from the shells of marine animals like crabs, lobster, shrimp, squid, and krill (Piekarska et al. 2023 ). Chitosan has been shown to have many uses in biological applications because it is biocompatible, biodegradable, sticks to mucous membranes, and has low immunogenicity. In recent years, there has been a lot of interest in temperature-sensitive gels made from chitosan and polyols like glycerol, sorbitol, and ethylene glycol. Thiolated Chitosan (TCS) is made by attaching thiol groups to the main amino groups of chitosan. People are very interested in the TCS drug delivery system because it sticks well to mucous membranes and keeps drugs in the body for a long time. The fact that TCS gels are in place is due to the formation of both intermolecular and intramolecular disulfide bonds, which happen when thiol groups are oxidized at biological pH.

Research progress in temperature-sensitive in situ gelling system

Bellotti et al. improved the use of pNIPAAm temperature-sensitive hydrogels for treating glaucoma by changing the amount of PEG and the molecular mass. They did this to try to lower the LCST of the ophthalmic gel and get it to form gel quickly after being given. They also made sure that the sol–gel change of the hydrogel was the same in cold conditions. (Bellotti et al. 2019 ) The in vitro drug release curve shows that the glaucoma drug brimonidine tartrate can be released repeatedly for 28 days.

Osswald et al. ( 2017 ) prepared anti-VEGF (ranibizumab or aflibercept) microspheres by using poly (lactic-co-glycolic acid), and the prepared microspheres were then put into an injectable poly (N-isopropyl acrylamide)-based thermo-responsive hydrogel called drug delivery system (DDS). In vivo, a laser-induced rat model of choroidal neovascularization (CNV) was used to test how well the treatment worked. The CNV lesion area was evaluated and measured using fluorescein angiograms and a multi-Otsu thresholding method, respectively. Also, measures of the patient's intraocular pressure (IOP) and dark-adapted electroretinogram (ERG) were taken before and after the treatment. At 1, 2, 4, 8, and 12 weeks, these tests were done. During the study, the CNV lesions were much less serious in the anti-VEGF-loaded DDS group than in a control group of animals that did not get any treatment. This suggests that the DDS could be a big help in treating problems with the back of the eye (Osswald et al. 2017 ).

Jimenez et al. made a microsphere/temperature-responsive gel with sustained release properties to improve the ocular distribution of cysteamine, a reducing substance used to treat cystine crystals in cystinosis. The pNIPAAm-based temperature-responsive gel technology showed that a single drop of it released cysteamine over a 12-h period. After direct application, these results showed that cysteamine got to the eye in a good way, with a lot of drugs going into the cornea and not much going into the bloodstream (Jimenez et al. 2021 ).

In situ gelling triggered by ionic interaction

The sol–gel transition may be induced and polymer viscosity increased by anionic polysaccharides which crosslink with divalent (Mg 2+ and Ca 2+ ) and/or monovalent (Na +) cations available in the tear fluid. The cation concentration rises in direct amount to the rise in polymer viscosity. As a result, increasing tear creation to thin down viscous solutions would increase cation concentration and, in turn, polymer viscosity, extending the ocular retaining time of drugs, minimizing lacrimal drainage, and enhancing the bioavailability of drugs.

Polymers used in the ion-induced in situ gelling approach

Gellan gum is a type of polysaccharide that can make ion-sensitive hydrogels work better. Linear anionic heteropolysaccharides are the type of material in question. Dubashynskaya et al. ( 2019 ) found that it is made up of a repeated tetrasaccharide element made of glucuronic acid, rhamnose, and glucose in a ratio of 1:1:2. The polymer is made up of functional groups like carboxylic and hydroxyl groups, which can interact with other polymers through electrical attraction and hydrogen bonding, among other things. Gelrite® is an easy-to-find product that gels when it comes in touch with either monovalent or divalent cations. When given as a liquid into the cul-de-sac, the cations Na + , Mg 2+ , and Ca 2+ in the electrolytes of tear fluid have been shown to cause polymer gel to form (Chandra et al. 2022 ). When the right amount of calcium gluconate was added to gellan compositions, gellan calcium gluconate-STF gels were made that were much stronger than gellan-STF mixes that did not have calcium gluconate. Gelation can happen through either a process that is affected by temperature or one that is caused by cations. The likely process of gelation is the formation of double-helix junction zones, which then join together to form a three-dimensional framework by attaching hydrogen to water and linking with cations.

It is also a polysaccharide with a straight structure that comes from certain types of bacteria and brown seaweeds. The substance in question is a block copolymer made up of R-l-guluronate (G) and a-d-mannuronate (M) monomers linked in a (1–4) structure. The polymer has both homopolymeric sequences of M and G and areas that look like the repeated structure of disaccharides (MG). When sodium alginate comes in touch with the Ca 2+ in tears, calcium alginate is made. This is what causes sodium alginate to turn into a gel. The amount of -l-glucuronic acid and -d-mannuronic acid in the polymer determines how strong it is and how many holes it has. Alginate with a lot of guluronic acid gels better and needs less polymer to make a solid gel (Abka-Khajouei et al. 2022 ).

Pectins are a group of polysaccharides characterized by a polymer backbone primarily composed of α-(1,4)- d -galacturonic acid residues. Slight methoxy pectins, characterized by a unit of esterification below 50%, exhibit the ability to undergo gelation in aqueous solutions when exposed to free Ca 2+ , which facilitates cross-linking of the galacturonic acid chains. The water miscibility of pectin is a significant advantage, as it obviates the need for organic solvents in formulations (Gawkowska et al. 2018 ). A US patent has reported on the occurrence of in situ gelling of pectin persuaded by Ca 2+ in the tear fluid. Furthermore, the utilization of pectin-founded in situ gel has been observed to extend the time of drug release from various preparations, including acetaminophen, cimetidine, and theophylline.

Research development in ionic interaction In situ gelling system

Alginic acid and gellan gum are examples of commonly used polysaccharides that are activated by ions. Pseudomonas elodea produces deacetylated anionic extracellular polysaccharide gellan gum, which is composed of repeated units of -D-glucuronic acid, -L-rhamnose, and two -D-glucuronic acid residues. This polymer is composed of double helices in an aqueous solution at room temperature, which is held together by mild van der Waals forces. Upon interaction with the cations of the tear fluid, these helices assemble, causing the polymer to cross-link and form a complex with the cations in addition to hydrogen bonds with the water. Several in situ gelation techniques that are ion-stimulated have been described previously (Salunke and Patil 2016 ). Elmowafy et al. ( 2019 ) demonstrated that the in situ gelling technique is non-irritating and demonstrates the viability of in situ gel for buccal delivery. Using deacetylated gellan gum, Zhu et al. ( 2015 ) invented ion-activated ketotifen preparations for ophthalmic administration. According to Zhu et al. ( 2015 ), deacetylated gellan gum enhanced the capacity to prolong ocular residence time. Comparing equivalent doses of in situ formulations to conventional or regular ocular solutions, the in situ formulations exhibited significantly longer durations of action. In the production of bio-adhesive and ion-subtle hydrogels, the incorporation of weakly water-soluble medication is extremely challenging. Cyclodextrins are an example of a pharmaceutical excipient used to aid in the formulation of drugs with minimal solubility in water. The incorporation of hydroxypropyl-cyclodextrin into the in situ-produced gel resulted in enhanced fluconazole release and enhanced control. In situ ocular gel of brinzolamide was produced with gellan gum in addition to dimethyl sulfoxide, polyoxyl 35, castor oil, and polysorbate 80 and it was discovered that brinzolamide demonstrates greater therapeutic efficacy and a longer intraocular pressure-lowering effect in an in situ gel formulation than in conventional eye drops and tablets (Bhalerao et al. 2020 ).

Multiple stimuli approachable in situ gelation

The utilization of a mixture of polymers by using diverse gelling approaches, which have established better therapeutic value and patient acceptance. The multiple stimuli-responsive methods are the greatest effective method for ocular in situ gelling at the moment. Numerous studies using the same ophthalmic formulation with pH-responsive polymers, thermos-responsive polymeric agents, or ion-activated polymeric agents have been published recently (Agrawal et al. 2020 ).

Multiple stimuli-responsive in situ gelling approaches for ocular drug delivery involve utilizing various triggers to induce the transformation of a liquid ocular formulation into a gel-like state upon application to the eye. These stimuli can include changes in temperature, pH, ions, enzymes, and other environmental factors. By designing formulations that respond to multiple stimuli, researchers aim to achieve precise control over drug release and enhance therapeutic outcomes. Here are some examples of multiple stimuli-responsive in situ gelling approaches for ocular drug delivery:

Dual-responsive gels: Formulations can react to temperature and pH changes. A gel made of thermoresponsive and pH-sensitive polymers can phase transition when exposed to body temperature and tears. This dual-responsive method triggers ocular gelation, improving medication retention and release.

pH and enzyme dual-responsive gels: Some formulations can respond to pH and tear fluid enzymes. These enzymes catalyze gel-forming processes. Dual-responsive ocular medication delivery systems replicate the biological environment with a dynamic and adaptive mechanism.

Ion and temperature dual-responsive gels: Ion-sensitive and thermoresponsive polymers can respond to ocular temperature and tear fluid ionic composition. This method targets gelation by ion concentration and temperature, tailoring medication delivery.

Triple-responsive gels: Some formulations use pH, temperature, and ion concentration. These complex formulations allow complicated medication delivery profile customization due to better gelation and drug release control.

Sequentially responsive gels: These gels respond to stimuli sequentially. A formulation may first pre-gelate due to pH changes, then gel at temperature. This sequential technique is smart and versatile for drug administration.

Multiple stimuli-responsive in situ gelling methods could offer personalized and targeted ocular drugs. These formulations optimize drug release kinetics, bioavailability, patient comfort, and compliance by leveraging the complex interaction of visual triggers. However, due to complex stimulus interactions and the necessity for accurate gelation and drug release dynamics, designing and developing such systems is difficult.

Research progress in multiple stimuli-triggered in situ gelling system

Khan et al. ( 2015 ) designed and studied a new gelling method for sustained release in ocular drug distribution involving sparfloxacin encapsulated in methylcellulose and sodium alginate that is pH- and ion-triggered. At pH 4.7, the preparation was in the sol phase, but when the pH was increased to 7.4, it rapidly changed to the gel state. In contrast to ocular droplets, the sparfloxacin release from ocular in situ preparations was sustained for 24 h. The ex-vivo corneal penetration investigation of prepared in situ gel on goat eye revealed significantly higher permeability than conventional eye drops. Yu et al. ( 2017 ) designed a nepafenac in situ gel by combining poloxamer and carboxymethyl chitosan. When the pH and temperature were altered at a very low concentration, the PEO-PPO-PEO block copolymer underwent a modifiable sol–gel transformation. The cell counting kit-8 method demonstrated that at lower concentrations, the preparation was not toxic to corneal epithelial cells. The hydrogel release of nepafenac was sustained in the poloxamer-CMC/NP formulation. At 35 0 C and a pH of 7.4, the maximal rate of release was observed. Sodium alginate and methylcellulose are Ion and pH-elicited multiple stimuli in situ formulations that exhibited rapid gelation upon increasing the pH to 7.4 and sustained sparfloxacin release over a 24-h period (Yu et al. 2017 ). Chitosan and gellan gum encapsulated timolol maleate in situ ocular gel acted as multiple stimuli-responsive, exhibiting enhanced drug penetration through the cornea and retaining the therapeutic concentration of the drug at the corneal site for an extended period.

Nanoparticle-laden in situ gelling system

In recent decades, the concept of nanoparticles has gained in popularity. Various polymeric nanoparticles are used to deliver medications to their target sites at therapeutically appropriate rates and dosing schedules (Fig.  5 ). Nanoparticles range in size from 10 to a few nanometers (Pilipenko et al. 2021 ). The drug is dissolved and encapsulated in a polymeric matrix. Nanoparticles have shown great promise in the delivery of ocular-targeted medications. For the production of polymeric nanoparticles, a number of applicable methods exist. The organic solvent is used to dissolve the polymer. To create a water-in-oil (W/O) emulsion, the drug substance is fragmented or disseminated in a polymer solution and then emulsified in an aqueous solution. The organic solvent is then ejected by consistently agitating or increasing the temperature under pressure. The use of an organic solvent during the solvent evaporation process could be hazardous to human health.

In situ gel formation on the ocular surface. When administered into the eye, the formulation, which contains nanoparticles dispersed in the liquid phase, quickly transforms into gel in the cul-de-sac of the eye in response to environmental changes like pH, temperature, and ions before slowly releasing the medication under physiological conditions

The U.S. Food and Drug Administration imposed limits on the total amount of organic solvents permitted in injectable colloidal systems. For the creation of polymeric nanoparticles, however, the salting out method and supercritical fluids are frequently employed. Drug encapsulation in nanoparticles can be accomplished in one of two ways: either by integrating the drug during nanoparticle development or by incorporating the nanoparticles into a solution of the drug. Due to the fact that the incorporation procedure captured a substantial amount of medication, it is more effective than the latter method (Pilipenko et al. 2021 ). The nanoparticles containing the substance are then combined with the gel base for eye therapy. In situ gel formulations in innovative therapeutic agent distribution systems as colloidal transporters, such as lipid-centred Nano-carriers and nanosuspensions, have been proven to be the most effective method, resulting in an increase in the absorption of ocular therapeutics.

Research progress in the nanoparticle-laden in situ gelling system

Liu et al. ( 2016 ) created a curcumin-loaded ophthalmic nano-gel using cationic nanostructured phospholipid carriers and a temperature-sensitive gelling agent. Researchers examined preocular retention, in vitro release, corneal penetration, and ophthalmic irritation. Microdialysis assessed drug pharmacokinetics in aqueous humour. Curcumin nano-gel had a higher AUC than curcumin ocular drops, indicating improved bioavailability. The nonirritating optimized in situ gelling ocular insert had a significantly delayed T max , greater C max , and improved bioavailability. Al-Khateb et al. ( 2016 ) created microsphere-encapsulated ofloxacin ion-triggered in situ gel. In rabbit research, in situ gel with ofloxacin microspheres had higher bioavailability than commercial eye treatments. Ofloxacin-encapsulated microspheres in in situ gel formulation have a longer duration of action, reducing the requirement for repeated administration and improving patient compliance (Al-Khateb et al. 2016 ). Pandurangan et al. created an SLN-filled in situ gel encapsulating voriconazole for ocular delivery. Paradkar et al. created an in situ gel with natamycin-containing niosomes using Poloxamer 407 and HPMC K4M. The bioadhesive Natamycin niosomal in situ gel formulation showed a longer corneal retention time and a 24-h drug release time than existing products. The formulation also increased transcorneal permeability. To make ofloxacin-loaded nanocarriers, chitosan was a polymer matrix and STTP was an anionic cross-linker. Chitosan nanoparticulate in situ gel outperformed commercial ophthalmic treatments. In situ gelling increased levofloxacin nanoparticle ocular retention. Gupta et al. used PLGA to introduce levofloxacin nanoparticles to chitosan in situ gels. Gamma scintigraphy measured rabbit eye residential time (Al-Khateb et al. 2016 ). The nanoparticle-laden in situ gel preparations stayed on the eye longer than commercial versions. A comparable group reported that sparfloxacin nanoparticle-laden in situ gelling showed excellent sustained release. Poloxamer 407 and 188-encapsulated Loteprednol temperature-sensitive-nano emulsion was compared to the commercial formulation. In situ gel improved mean residential time and bioavailability by 2.54 times compared to standard formulations (Pandurangan et al. 2016 ).

Advantages of nanoparticle-laden in situ gelling approach

Ocular in situ nano-gels offer advantages over other medication delivery methods for eye disorders. They boost medication bioavailability. The gel's nanoparticles' small size helps drugs penetrate ocular tissues, increasing drug concentrations at the target site.

Ocular in situ nano-gels also regulate drug release. Ocular in situ nano-gels release drugs slowly, prolonging the therapeutic concentration at a chosen spot, unlike ocular drops, which may remove therapies quickly. Chronic eye problems require a long-term medication supply.

Ophthalmic in situ nano-gels are noninvasive and easy to use for patients and doctors. Biocompatible and biodegradable, they prevent unpleasant reactions and toxicity.

Ocular In situ nano-gels are a promising medicine delivery technique for eye disorders. Nanotechnology for ocular medicine delivery may improve as research continues.

Drawbacks & challenges of nanoparticle laden in situ gelling system

Ophthalmic in situ nano-gels have drawbacks like any medication delivery technique. Nano-gel stability is a major issue. Gels have a short shelf life and are easily damaged. Nano-gel size and shape also affect efficiency. They must be small enough to pierce the cornea and reach the target cells, but not too small to be removed from the eye.

Regulating nano-gel medication release is another issue. To maintain pharmacological efficacy, extended-release is important. Monitoring the release pace requires careful planning and testing.

Finally, ocular in situ nano-gels are complicated, making regulatory approval difficult. Smaller enterprises may find the clearance process lengthy and exclusive.

Despite these obstacles, ocular in situ nano-gels have enormous potential as drug delivery methods for treating several eye conditions. Further research and expansion can overcome these limits and improve technology to treat patients safely and effectively.

Recent advancements in in situ gelling technology for ophthalmic drug delivery

In situ gelling could revolutionize ocular drug administration. This method solves the issues with eye drops and ointments for ocular medicine administration.

The ocular surface turns in situ gels into a gel. They're temperature-sensitive. This extends drug release and bioavailability.

Recent advances in in situ gel technology have enabled the production of novel preparations with even more benefits, such as improved patient compliance and reduced dose frequency.

One of the most important advancements is the production of mucoadhesive in situ gels, which stick to the eye surface for a long time and allow for sustained drug release and improved therapeutic benefits. Another advancement is using in situ gels that release medication in response to physiological cues like pH or temperature. In general, in situ gel technology offers promising new ways to deliver ocular medicines and improve patient outcomes.

Advantages of in situ gel technology over other ocular drug delivery methods

The In situ gel technique for ocular drug delivery is popular due to its many benefits. The In situ gel technique provides sustained medication release. One of the technology's key advantages. This prolonged release keeps the medicine in the ocular tissue longer, improving therapy.

In situ gel reduces administration frequency, another benefit. Because the active therapeutics are supplied over a longer period of time, frequent drug delivery, which can be difficult for patients and increase treatment non-compliance, is eliminated. Patients choose in situ gel technology since it is painless and noninvasive.

In situ gel technology also makes hydrophilic and hydrophobic drugs easy to distribute. It reduces glaucoma, macular degeneration, and dry eye syndrome due to its flexibility.

In situ gel technology could revolutionize ocular medicine delivery because it is better than current methods.

Clinical studies and results using in situ gel technology for ocular drug delivery

In clinical trials, the in situ gel technique distributed ophthalmic medicines well. A team of researchers created an in situ gel containing timolol maleate, a glaucoma treatment, and compared it to standard ocular drops. The in situ gel sustained therapeutic agent release, maintaining therapeutic concentrations longer than standard eye drops. This improves patient adherence and reduces dosage frequency. In situ gels were studied for dry eye syndrome management. The gel formulation contained cyclosporine, and results showed that the in situ gel had a prolonged drug release profile like eye drops, improving clinical efficacy. These studies show that in situ gel technology can help distribute ocular medicinal ingredients and improve patient adherence. Ocular medicine delivery is expected to improve for people with various ocular conditions as research continues.

Potential future developments in in situ gelling technology

The In situ gel technique for ocular medication distribution seems promising. However, there is room for improvement. Nanotechnology could advance in situ gel compositions. Nanoparticles can improve drug solubility, stability, uptake, and ocular tissue delivery. Stimuli-triggered in situ gels are another focus. The gels respond to stimuli like temperature and pH to distribute medications in a controlled and targeted manner. This method improves medicine delivery and reduces side effects. Researchers are also studying biodegradable materials for in situ hydrogels. The gel's slow absorption by the body may improve patient comfort and eliminate elimination procedures. In general, in situ gelling strategies for delivering therapeutic compounds to the eye are promising and could improve ocular medication delivery.

Comparison of in situ gel technology to other ocular drug delivery methods

Drug administration to the eye has numerous methods. Due to its unique properties and advantages over conventional methods, in situ gel technology may be effective for drug delivery. The in situ gel technology's sustained release of pharmaceuticals keeps the medication in the eye longer, improving its efficacy. The In situ gel technique has this major advantage.

In contrast to eye drops, in situ gel technology releases medicine more slowly. This reduces medicine administration frequency. Its improved bioavailability means more drug is administered to the area that needs them, increasing its therapeutic efficacy.

Eye drops, on the other hand, are swiftly eliminated from the eye, reducing their efficacy.

Ocular implants are another approach to sustaining drug release. However, insertion and removal of the ocular inserts may cause discomfort, which may lead to non-compliance.

In conclusion, in situ gel technology offers sustained drug release, improved bioavailability, and less medication administration, making it a potential option for ocular drug delivery. In situ gelling is faster and less unpleasant than other topical pharmaceutical administration procedures.

In conclusion, in situ gel technology for ocular medication delivery may reduce the shortcomings of current drug delivery systems. In situ gels improve bioavailability, prolong drug release, and reduce dose frequency. Benefits boost patient acceptance and clinical outcomes.

Despite significant advances in this area, problems remain. In situ gelling procedures that maintain optimal medication concentration levels for long periods are a major challenge. Optimizing formulation parameters for in situ gel stability and safety is another challenge.

In situ gel technology for ophthalmic medication administration could develop stimuli-responsive devices that react to changes in the ocular environment. Nanotechnology and other advanced medication delivery methods can improve in situ gel efficacy and safety.

In situ formulation technology could transform ophthalmic medicine distribution and improve the quality of life for many ocular disease patients. As research progresses, in situ gels may become the preferred ocular drug delivery method.

Availability of data and materials

All the data and information are available to all authors.

Abbreviations

Blood-retinal barrier

Blood-aqueous barrier

Anti-Vascular endothelial growth factor

Lower critical solution temperature

Hydroxypropyl methylcellulose

Maximum plasma concentration

Maximum time to reach C max

Area under the curve

Poly (acrylic acid)

Poly(propylene oxide)

Poly(ethylene oxide)

Tamarind seed polysaccharide

Sodium carboxymethyl cellulose

Methylcellulose

Drug delivery systems

Thiolated Chitosan

Polyethylene glycol

Poly( N -isopropylacrylamide)

Choroidal neovascularization

Solid lipid nanoparticle

Sodium tripolyphosphate

Intraocular pressure

Polyvinyl alcohol

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Paul, S., Majumdar, S. & Chakraborty, M. Revolutionizing ocular drug delivery: recent advancements in in situ gel technology. Bull Natl Res Cent 47 , 154 (2023). https://doi.org/10.1186/s42269-023-01123-9

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Exploring hydrogel nanoparticle systems for enhanced ocular drug delivery.

1. Introduction

2. obstacles to efficiently delivering medications to the ocular system, 3. hydrogels in ocular drug delivery, 3.1. classification of hydrogels, 3.2. release mechanisms from hydrogel matrices, 3.3. controlled-release hydrogel systems, 4. pharmaceutical uses of hydrogels, 5. hydrogel nanoparticles, 5.1. alginate, 5.2. chitosan with ionic cross-links, 5.3. polyvinyl alcohol, 5.4. polyvinylpyrrolidone, 5.5. polyethylene oxide (peo) and poly ethyleneimine (pei), 5.6. poly-n-isopropylacrylamide, 6. nanotechnology in ocular disease therapy, 6.1. lipid-based nanoparticles, 6.2. nano suspensions, 6.3. nano emulsions, 7. current commercial formulations for ocular drug delivery, 8. conclusions, supplementary materials, author contributions, institutional review board statement, informed consent statement, data availability statement, conflicts of interest.

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Arabpour, Z.; Salehi, M.; An, S.; Moghtader, A.; Anwar, K.N.; Baharnoori, S.M.; Shah, R.J.; Abedi, F.; Djalilian, A.R. Exploring Hydrogel Nanoparticle Systems for Enhanced Ocular Drug Delivery. Gels 2024 , 10 , 589. https://doi.org/10.3390/gels10090589

Arabpour Z, Salehi M, An S, Moghtader A, Anwar KN, Baharnoori SM, Shah RJ, Abedi F, Djalilian AR. Exploring Hydrogel Nanoparticle Systems for Enhanced Ocular Drug Delivery. Gels . 2024; 10(9):589. https://doi.org/10.3390/gels10090589

Arabpour, Zohreh, Majid Salehi, Seungwon An, Amirhossein Moghtader, Khandaker N. Anwar, Seyed Mahbod Baharnoori, Rohan Jaimin Shah, Farshad Abedi, and Ali R. Djalilian. 2024. "Exploring Hydrogel Nanoparticle Systems for Enhanced Ocular Drug Delivery" Gels 10, no. 9: 589. https://doi.org/10.3390/gels10090589

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• Published: 07 September 2021

Recent advances in ocular drug delivery systems and targeting VEGF receptors for management of ocular angiogenesis: A comprehensive review

• Soumya Narayana 1 ,
• Mohammed Gulzar Ahmed 1 ,
• B. H. Jaswanth Gowda 1 ,
• Pallavi K. Shetty 1 ,
• Arfa Nasrine 1 ,
• M. Thriveni 1 ,
• Nadira Noushida 2 &
• A. Sanjana 1  

Future Journal of Pharmaceutical Sciences volume  7 , Article number:  186 ( 2021 ) Cite this article

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Angiogenic ocular diseases address the main source of vision impairment or irreversible vision loss. The angiogenesis process depends on the balance between the pro-angiogenic and anti-angiogenic factors. An imbalance between these factors leads to pathological conditions in the body. The vascular endothelial growth factor is the main cause of pathological conditions in the ocular region. Intravitreal injections of anti-angiogenic drugs are selective, safe, specific and revolutionized treatment for ocular angiogenesis. But intravitreal injections are invasive techniques with other severe complications. The area of targeting vascular endothelial growth factor receptors progresses with novel approaches and therapeutically based hope for best clinical outcomes for patients through the developments in anti-angiogenic therapy.

The present review article gathers prior knowledge about the vascular endothelial growth factor and associated receptors with other angiogenic and anti-angiogenic factors involved in ocular angiogenesis. A focus on the brief mechanism of vascular endothelial growth factor inhibitors in the treatment of ocular angiogenesis is elaborated. The review also covers various recent novel approaches available for ocular drug delivery by comprising a substantial amount of research works. Besides this, we have also discussed in detail the adoption of nanotechnology-based drug delivery systems in ocular angiogenesis by comprising literature having recent advancements. The clinical applications of nanotechnology in terms of ocular drug delivery, risk analysis and future perspectives relating to the treatment approaches for ocular angiogenesis have also been presented.

The novel ocular drug delivery systems involving nanotechnologies are of great importance in the ophthalmological sector to overcome traditional treatments with many drawbacks. This article gives a detailed insight into the various approaches that are currently available to be a road map for future research in the field of ocular angiogenesis disease management.

Visual impairment has become a major threat to all age category people globally. According to the reports, almost 246 million people are affected by subnormal vision, 285 million people with vision disabilities and 39 million people with blindness [ 1 , 2 ]. In India, more than 30 percent of people become blind before they cross 17 years of age and most of them are of less than 5 years [ 3 ]. Impairment in vision is also widespread among elderly individuals in various other forms [ 4 ]. According to a study conducted in Al-Madinah Al-Munawarah, Saudi Arabia, among diabetic patients ( n  = 690), 36.1% were found to be suffering from diabetic retinopathy (DR) of which 6.4% had proliferative disease [ 5 ]. An additional cross-sectional study conducted in Al Ain, United Arab Emirates reported DR in 19% of diabetic patients ( n  = 513). Almost all the patients were completely unaware of the condition of their retina [ 6 , 7 ]. Approximately 8.7% of worldwide blindness is occurred due to age-related macular degeneration (AMD) especially in aged patients [ 8 ]. Angiogenesis accounts for the formation of new blood vessels from the existing vasculature. The physiological angiogenesis process in the human body is the balance between anti-angiogenic and pro-angiogenic factors [ 9 ]. Disturbance of such balance leads to a pathological condition in the human body. During the conditions such as wound healing and peripheral arterial disease ischemic heart disease, the stimulation of angiogenesis will cure the disease. Wherein case of diseases such as rheumatoid arthritis, cancer and ophthalmic conditions, the inhibition of angiogenesis is the cure [ 10 ]. Global ocular morbidity is the main reason behind severe ocular angiogenesis. In ocular angiogenesis conditions, the angiogenic switch must be turned “on” for neovascularization progression [ 11 ]. It may lead to diseases like retinal vein occlusions, diabetic retinopathy, corneal neovascularization, age-related macular degeneration, retinopathy of prematurity, choroidal and retinal neovascularization, etc. Pro-angiogenic growth factors implicated in the development of pathological vessels in ocular diseases include endothelial growth factor (EGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), etc. [ 12 ]. The present review gives clear-cut knowledge on VEGF and their respective receptors with various regulations, affecting factors and available treatments with recent literature. It majorly focuses on numerous novel nanotechnology-based approaches in ocular drug delivery to treat many ocular conditions specifically angiogenesis to overcome traditional injection treatments that affect bioavailability and patient compliance.

Regulation of angiogenesis

In the human body, angiogenesis is involved in various processes [ 13 ]. In healthy adults, angiogenesis is a rare phenomenon, involved only locally and transiently under distinctive physiological and pathological conditions in the body. Angiogenesis is regulated by endogenous pro-angiogenic and anti-angiogenic factors (Table 1 ) [ 12 , 14 , 15 , 16 ]. Among all angiogenic and anti-angiogenic factors, VEGF is marked to be a highly critical regulator of ocular angiogenesis. Regulation of angiogenesis involved five steps, initially, angiogenic factors bind to endothelial cells leading to the degradation of basement membrane with the proliferation of endothelial cell, further, migration and also tube formation, elongation finally vessel stabilization (Fig.  1 ).

Regulation of angiogenesis (Steps: 1. Angiogenic factors bind to endothelial cells, 2. Basement membrane degradation, 3. Endothelial cell proliferation and migration, 4. Tube formation, elongation and remodeling and 5. Vessel stabilization.) [ 13 ]

Vascular endothelial growth factor (VEGF)

VEGF is a signal protein also known as vascular permeability factor. The VEGF family includes various members, i.e., VEGF-A, VEGF-B, VEGF-C, VEGF-D, placenta growth factor (PGF) and the viral VEGF homologue VEGF-E. VEGFs bind selectively with receptors namely VEGF receptor-1 (VEGFR-1), VEGFR-2, VEGFR-3, neuropilin-1 (NRP-1) and NRP-2 [ 34 ].

VEGF-A is one of the well characterized and highly investigated of the VEGF family members. Mainly it enhances the endothelium’s permeability by forming the intercellular gaps and fenestrations. Hence, it was originally known as a vascular permeability factor (VPF). Most commonly VEGF-A isoforms have been identified from six transcripts: VEGF 111 , VEGF 121 , VEGF 145 , VEGF 165 , VEGF 189 and VEGF 206 [ 19 ].

VEGF-B is mainly present in various tissues of the body, as well as the retina but it is greatly available in the region of skeletal and heart muscle. VEGF-B also contains two isoforms, VEGF-B 167 and VEGF-B 186 by alternative splicing, which signal through VEGFR-1 and NRP-1. Genetic studies showed the absence of VEGF-B in experimental mice is healthy, fertile and not affected with any vascular diseases. This concludes that VEGF-B is not responsible for angiogenesis [ 20 ].

It is expressed mainly in the region of the lungs, placenta and heart that further binds to the VEGFR-1 and NRP-1. The complex formation between VEGFR-1 and VEGFR-2 is due to the attachment of PGF to VEGFR-1 that in turn leads to the signaling of VEGF-A and stimulation of angiogenesis [ 19 , 35 ].

VEGF-C, VEGF-D and Viral VEGF homologue VEGF-E

Both VEGF-C and VEGF-D bind to VEGFR-2 and with lower affinity, it binds to VEGFR-3. It also stimulates the proliferation of endothelial cells and also migration both in vitro and in vivo. VEGF-E is also a potent angiogenic. The binding of VEGF-E to VEGFR-2 with greater affinity results in angiogenesis stimulation and vascular permeability thus increasing in viral infection [ 20 , 36 ].

VEGF receptors

VEGFs bind selectively with receptors namely VEGF receptor-1 (VEGFR-1), also called Flt-1; VEGFR-2, also called Flk-1; VEGFR-3, also called Flt-4; neuropilin-1 (NRP-1), and NRP-2. The VEGFRs belong to the family of the tyrosine-kinase receptor. The receptor dimerization is caused due to the binding of the ligand to an extracellular immunoglobulin-like domain. The angiogenic effect of VEGF-A was mediated by a vital receptor called VEGFR-2 [ 19 ].

Vascular endothelial growth factor receptor-1 (VEGFR-1) is also termed as fms-like tyrosine kinase-1 (Flt-1) which is having 180 kDa and is also seemingly linked to receptor tyrosine kinase (RTK). The VEGFR-2 and Flt-1 are majorly expressed on vascular endothelium, Even though some of the mRNA remains in the stroma of human placenta, monocytes and renal mesangial cells. With high affinity, VEGF-A 165 binds to VEGFR1 when compared with VEGF-A 121 [ 37 , 38 ].

VEGFR-2 is the second VEGF tyrosine-kinase receptor that is present on chromosome 4q12. It is also called a kinase-insert-domain containing receptor (KDR). This KDR is majorly expressed in the region where endothelial cells are abundantly present and were also replicated from a human endothelial cell cDNA library. Due to the ligands of VEGF family, the VEGFR-1 and VEGFR-2 convert the signals for endothelial cells [ 39 ].

VEGFR-3 is also called fms insert-like tyrosine kinase 4 (Flt-4). They have got the extracellular domain which is almost 80% homologue to the other VEGFRs. The VEGF-C and VEGF-D that belong to the family of VEGF are also associated with VEGFR-3. The Flt-4 is majorly expressed in lymphatic endothelium specifically in adult tissues which are usually not seen for VEGFR-1 and VEGFR-2 [ 40 ].

Neuropilins

The neuropilin-1 (NRP-1) and neuropilin-2 (NRP-2) are expressed in endothelial cells just like VEGFR-1 and VEGFR-2. It is particularly with less affinity binds to the VEGF-A 165 . The neuropilin-1 balances the development of blood vessels during the angiogenesis embryonic stage, conveying a major role for VEGFR-2 as a co-receptor [ 41 ].

Regulation of VEGF

VEGF is a crucial regulator of angiogenesis, in a condition of uncontrolled regulation of VEGF leads to pathological angiogenesis. As we have already discussed earlier, angiogenesis is a balance between the pro-angiogenic and anti-angiogenic factors if is there any imbalance between these factors that leads to pathological angiogenesis [ 42 ]. Although, many growth factors and cytokines are released in response to any damage in the tissue which leads to stimulation of angiogenesis either directly or indirectly through VEGF that is crucial in tissue repairing. The elevated pathological angiogenesis is occurred due to the stimulation of VEGF expression during pathophysiological conditions like diabetes mellitus and cancer. The literature data was supported this hypothesis by demonstrating suppression of neovascularization by the inhibition of VEGF or its effects. But, during the conditions like atherosclerosis, the elevated concentration of plasma VEGF might be an attempt to make up for the damage of tissue [ 43 , 44 ]. In all these pathological conditions, angiogenesis is stimulated by local tissue hypoxia. The ocular cells like muller cells, astrocytes, retinal pigmented epithelium, endothelial cells (EC) and ganglion cells secret and produce VEGF. In vitro studies showed that under hypoxic condition muller cells and astrocytes produces larger amounts of VEGF [ 45 ].

Effect of oxygen, nitric oxide, glucose and other growth factors on VEGF regulation

In various diseases like atherosclerosis, solid tumors, ocular diseases, etc., the stimulation of VEGF results in neovascularization and it is mainly due to the hypoxic condition. The major protein named hypoxia-inducible protein complex (HIPC) or hypoxia-inducible factor (HIF) is produced by hypoxia. The up-regulation of transcription of VEGF mRNA was occurred due to the activation of basic heteromeric helix–loop–helix transcriptional regulator. The production and stability of some VEGF isoforms are majorly due to the hypoxia condition. In terms of stability, the VEGF-A isoforms are highly sensitive to hypoxia, wherein the case of VEGF-B and VEGF-C mRNA has little or no effect on hypoxia [ 46 , 47 ]. The vascular endothelium and endothelial cells can release nitric oxide (NO) in response to VEGF. Additionally, during the VEGF-induced angiogenesis, the production of nitric oxide synthase (NOS) is also increased. A demonstration showed the part of NO in VEGF-induced angiogenesis on NOS knock-out mice as well as after inhibition of NOS, leads to angiogenesis depletion [ 48 , 49 ]. In the beginning, the increased expression of VEGF was believed to be from the hypoxic condition but it was the hypoglycemic condition. However, in later stages, it was reported that the cells exposed to hypoglycemia without HIF (hypoxia) elevated the expression and up-regulation of VEGF. The production of VEGF came back to the pre-experimental level in response to a balanced concentration of glucose suggesting the acute hypoglycemia is the sole responsible to activate angiogenesis mediated via VEGF. Also, pro-angiogenic growth factors such as fibroblast growth factor 4 (FGF 4), tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β), insulin-like growth factor I, PDGF, angiotensin-2, keratinocyte growth factor, interleukin 1 (IL-1) and IL-6 can alter the production of VEGF. It was also found that some of the anti-angiogenic growth factors such as the cytokines IL-10 and IL-13 can deduce the production of VEGF [ 50 , 51 ].

Angiogenesis inhibitors or vascular endothelial growth factor inhibitors (anti-VEGF)

The inhibition of VEGF-VEGFRs protein factors unlocked new prospects in medicine since they are the sole ones responsible for many pathological conditions such as angiogenesis and ocular vascular diseases. In many ocular neovascularization conditions, the hindrance of VEGF activity plays a major role in treating such conditions. In recent years, research to develop anti-VEGF has transformed the treatment of ocular angiogenic conditions. These are the most considered treatments for many conditions such as vein occlusions, myopic neovascularization of the choroid, retinopathy of prematurity (ROP), diabetic macular edema and choroidal neovascularization [ 52 , 53 ]. The FDA approved the ranibizumab for many treatments such as macular edema along with branch retinal vein occlusion (BRVO) and also for treating all angiographic subtypes of the subfoveal neovascularization of AMD [ 54 , 55 ]. Many literatures indicated short-term effects of ranibizumab on foveal thickness (FT) and visual acuity for about 1 week and 1 month, respectively, after injecting the ranibizumab. The short-term effects ranging from few minutes to hours, after injection of anti-VEGF drugs for BRVO have also been evaluated [ 56 ]. Bevacizumab is a full-length humanized recombinant monoclonal Immunoglobulin-G (IgG) anti-VEGF-A antibody [ 57 ] that is approved to treat many tumors by hindering all the VEGF-A isoforms. Since this therapy is economical compared to other treatments, it is the most widely used anti-VEGF medicine in ophthalmology [ 58 , 59 ]. Intravitreous bevacizumab, ranibizumab and aflibercept were potent and also safe in the treatment of diabetic macular edema that causes vision impairment. The mild loss of initial visual acuity was able to manage with help of all three agents with a slight difference between each other. Where, in case of severe loss of initial visual acuity, aflibercept played a better role in improving the vision [ 60 ]. In India, a high alert puts ophthalmologists in a legal and ethical dilemma. Commercial entities must not be allowed to dictate which drug should be used for which disorder. The safety of the patient must be the paramount concern and physicians and governmental agencies must ensure this by fair drug compounding practices. Strong leadership of national and international ophthalmological societies is needed to represent the scientific facts regarding bevacizumab to drug regulatory agencies globally [ 61 ]. The research initiatives continue at organizations and pharmaceutical companies globally to find a safe and effective medicine for AMD. The currently available anti-VEGF drugs in the market furnish a slight hope but the drawbacks associated with them are such as repeated intravitreal injections that lead to patient incompliance [ 62 ]. Many patients living in developing countries like India face an economic crisis due to these expensive treatments. Even though the bevacizumab is not officially approved to treat a wide range of ocular conditions, it has shown better results at a relatively low cost. Since extensive research is still going on. Thus, we may expect the many novel and potent drugs that can treat many ocular neovascular diseases (Table 2 ) [ 63 , 64 ].

Novel approaches in ocular drug delivery

The novel approach-based dosage forms in ophthalmic delivery may ray of hope for better therapies for the future, in the treatment of ocular angiogenesis (Table 3 ).

Ocular gene therapy

Gene therapy is a novel technique in the field of medicine which delivers the nucleic acids into the cells of a patient as the drug to treat diseases. It is the supplementation of an ineffective gene with a healthy working gene in defective target cells. Depending on the types of cells treated, the gene therapy can be divided into two types called germline and somatic gene therapy. Some of the techniques to achieve gene therapy are said to be inhibition gene therapy, gene augmentation therapy and scavenging specific cells. Ocular gene therapy is the introduction of an exogenous gene product into a host’s cell. The delivery of drugs to the ocular region is a hurdle due to the presence of many cellular barriers. These techniques can clear all the hurdles and challenges. To target a tissue, further development in this field with novel strategies may necessary [ 78 , 79 ].

Ocular inserts

Ocular inserts are tiny, thin, sterile, stratified solid pieces of a device placed into the conjunctival sac to deliver various drugs. Erodible and non-erodible are two types of ocular inserts. Ocular inserts also offer the advantages of increasing the contact time, better bioavailability of drugs and reducing the dosing frequency. Drug release profile from the ocular inserts depends on the following mechanism: diffusion, osmosis and bio-erosion. Within 24 h, the inserts can dissolve completely. The erosion of the inserts is majorly dependent on the type and concentration of polymer used. The pattern of drug release from the ocular inserts varies between individuals depending upon their physiological conditions. The non-erodible inserts consist of either matrix structure or reservoir that helps in sustaining the drug release [ 80 , 81 ].

Ocular implants

Ocular implant is an artificial material that is surgically implanted in the position of the eye, to improve impaired vision. For the delivery of drugs into a posterior region, the implants are surgically inserted anteriorly to the retinal region and posteriorly to the lens. There are two types of ocular implants biodegradable and non-biodegradable. Drugs are encapsulated by using biodegradable polymers like polylactic acid (PLA) and polylactic-co-glycolic acid (PLGA) are in a particular system of nanoparticles or microparticles. The polymers are usually viscous materials that help in releasing the drug for a prolonged period. But, the nanoparticles or microparticles can distribute unusually in the ocular conditions upon injection via needles due to their compact size and composition [ 82 ].

Microneedle technology

These are micron-sized needle configurations, designed using microelectronics industry devices. Besides, microneedles were designed for the delivery of drugs for transdermal delivery. Glass microneedles are made of borosilicate material. Generally, the microneedles were made by using stainless steel called solid microneedles (75–1000 μm in length). It is a minimally invasive technology where it can deliver the drug into the posterior region and also overcomes complications associated with intraocular injections. Mainly, microneedle technology in ophthalmic delivery can provide localized and target delivery of drug into the posterior region [ 83 , 84 ].

Iontophoresis

This is a novel technique to deliver various drugs to the target site of action. The drugs, specifically charged macromolecules can be delivered into the anterior and posterior segments. The delivery is mainly based on a basic principle of attraction/binding between opposite charges whereas repelling between same charges. The iontophoretic device consists of a continuous DC source with two electrodes. The mechanism of this device is placing of an ionized drug in the compartment of an electrode that bears the same charge and the ground electrode is placed at any region around the eye [ 85 ].

In situ gelling system

In situ gel is a novel approach to deliver the drug to the ocular region that is solution form before administration and converts into gel form to release the drug that is triggered by an external stimulus like pH, temperature, etc. [ 86 ]. Several mechanisms are involved in triggering the conversion of the solution to in situ gel such as a physical change in biomaterials such as exchange of solvent and cross-linking between solvent/swelling. Trigger due to physiological stimuli such as pH of body fluids and temperature of the body and chemical reactions. Trigger due to various chemical reactions such as photopolymerization, oxidation and reduction. In a temperature triggered system, when the temperature rises, the formulation converts into gel. The polymers like poloxamers are used to formulate these gels. In pH triggered in situ gel formation of gel is induced by a change in pH. Most of the anionic pH-sensitive polymers are based on polyacrylic acid (PAA) (carbopol, carbomer) or its derivatives. In the diffusion method, the solvent present in the solution of polymer will diffuse and enter the nearby tissue leading to the polymer precipitation. The ionic strength can also promote the formation of gel from the introduced polymeric solution. Gelrite is the best example of an ion-sensitive polymer. In the enzyme responsive process, gel formation can be occurred due to specific enzymes present in physiological conditions even in the absence of any chemicals like monomers and initiators. In photopolymerization process, the polymeric solution injected to the desired site will swell with help of a photo via fiber optic cables to sustain the drug release for a longer period [ 87 , 88 ].

Contact lens

Contact lenses are a thin type of plastic-shaped twisted type of cover that protects the eye. The contact lens can deliver the drug efficiently when compared with eye drops. Due to the longer contact time, the dosage frequency can be lowered with less systematic toxicity. The topical drug delivery to the ocular region became a major hurdle for scientists due to the various barriers like corneal barriers, conjunctival barriers, blood-retinal barriers and blood-aqueous barriers. The fabrication of polymeric nanoparticle embedded contact lens may prolong the delivery of drug leading to reduced frequency of administration which will improve patient compliance [ 89 , 90 ].

• Photothermal therapy

Photothermal therapy (PTT) is a novel treatment of choice for various medical complications; it is a minimally invasive, local treatment with less toxicity [ 91 ]. The mechanism involves the activation of a photosensitizing agent by using electromagnetic radiation to convert energy into heat to kill cancerous cells [ 92 ]. PTT has several advantages when compared with radiotherapy or chemotherapy; it specifically targets the unhealthy cell by its deep penetrating power without affecting surrounded healthy cells or tissues [ 93 ]. In photothermal therapy, cell death occurs due to the denaturation of proteins, lysis of membrane and evaporation of cytosol [ 94 ]. The ideal photosensitizing agent should have several characteristics like low toxicity to the cells, high solubility in biocompatible solution and ease in functionalization. Phosphorous photothermal agents exist in three allotropic forms, i.e., white phosphorous, red phosphorous and black phosphorous (BP) [ 95 ]. Among three allotropes of phosphorus, BP is the most stable at high temperature and high pressure. The most interesting properties of BP are its photothermal property, narrow band gaps, large specific surface area, high carrier mobility, good biodegradability and biocompatibility properties [ 96 ]. Studies have been shown that BP offers promising and better applications in the nano-field of technologies like bio-imaging, photothermal therapy and drug delivery fields. BP is a direct bandgap semiconductor in which band topology remains the same and also it has high carrier mobility [ 97 ]. Bulk silicon is another photothermal agent that has an indirect bandgap semiconductor, which means its valence band maximum and conduction band minimum have different momentum vectors. The photoluminescence effect of BP increases exponentially as the layer thickness decreases from 5 to 2 layers [ 97 , 98 ]. In silicon nanocrystals, the wavelength of photoluminescence is dependent on the diameter of nanocrystals. The photothermal effect is mainly the conversion of optical energy to thermal energy. In ocular phototherapy, the laser is the source of light [ 99 ]. Ocular phototherapy has wide application in the treatment of ocular tumors [ 100 ]. The study has been conducted to assess the safety and clinical efficacy of non-damaging photothermal therapy for the treatment of the retina. The study included 16 patients suffering from persistent central serous retinopathy who were treated with the PASCAL streamline at 577 nm wavelength, using 200 mm retinal spot sizes. They concluded that photothermal therapy was safe and it was improved visual acuity and resolution of subretinal fluid in patients suffering from chronic central serous retinopathy [ 101 ]. Another study was conducted to evaluate the effect of near-infrared (NIR) on photothermal therapy agents by using Ag@Oxides nanoprisms for uveal melanoma therapy. Silver oxide nanoparticles were prepared by a simple sol–gel route and irradiated with an 808 nm NIR laser. They concluded that Ag@oxides nanoparticles were demonstrated to be an efficient photothermal therapy agent for solid cancers by local delivery [ 102 ].

Artificial intelligence

For the last two decades, pharmaceutical scientists are developing novel techniques for targeted drug delivery with maximum efficacy by minimizing the side effects. Artificial intelligence (AI) is the branch of computer science also and it is the intelligence demonstrated by machines. Generation of new information, automated working system and prediction, continuous performance, monitoring various diseases is the main advantage of AI. AI technique enables prediction of pharmacokinetic responses including quantitative structural activity relationships, in vivo responses, etc. So, the incorporation of AI technology into the ophthalmic sector may be a ray of hope for the ocular drug delivery system [ 103 ].

Nanotechnology in ophthalmic drug delivery

Many researchers are facing huge problems in the sector of ocular drug delivery. The bioavailability of a drug is not up to the mark due to several ocular barriers [ 104 , 105 ]. Many literatures revealed that the particle size of the drug should be appropriate and narrow. It should also possess less irritation, more biocompatible and possess appropriate bioavailability to achieve ocular drug delivery [ 106 ]. Hence, the ideal ocular drug delivery system must be in the form of eye drops without inducing any irritation or blurred vision [ 107 ]. The topical delivery is the only efficient way to deliver the drug into the anterior segment of an eye but the only minute concentration of the drug will reach into the posterior segment of the eye. But the systemic administration will help to achieve a small quantity of drug in the target site of ocular tissues. However, the dose needed to obtain therapeutic efficacy may induce several drug-related side effects. Thus, the adoption of nanotechnology-based drug delivery such as liposomes, niosomes, solid lipid nanoparticles, nanosuspensions, nanoemulsions, nanomicelles and biodegradable microspheres could help in overcoming various toxicity and bioavailability issues of many drugs. The drugs that are intended to deliver to a specific target site for treating many ocular conditions could be achieved by surpassing the ocular barriers. These nanotechnology-based drug delivery systems can also help in sustaining the release of drugs by crossing several ocular barriers such as the blood-retinal barrier in the eye [ 108 ]. This can further improve the bioavailability of many drugs thereby increasing the therapeutic efficacy [ 109 ].

Nanoemulsions

They are fine dispersions of infinitesimal droplets of two immiscible liquids. They contain the dispersed phase, where the particles dispersed are in the nano- or submicron range. Generally, the nanoemulsions are made of one or more surfactants containing both hydrophilic and hydrophobic parts. The high-pressure homogenization is adapted to obtain the dispersed globules in a size range of below 100 nm with a translucent look. Since the nanoemulsions are globule-sized, the dispersions are thermodynamically unstable which requires more surfactants to stabilize. This can be the major reason behind the stickiness of the formulation. The phospholipids are one class, which is also commonly used in stabilizing the nanoemulsion formulation. The four major types of nanoemulsions are o/w, w/o, w/o/w, o/w/o type emulsion [ 110 , 111 , 112 ].

Nanosuspension

They usually consist of hydrophobic drugs that are suspended in the specific dispersion medium. The nanosuspensions can also be prepared using various polymers and resins to sustain the drug release and to achieve therapeutic efficacy by increasing bioavailability [ 113 ]. The polymers that are inert and biocompatible without causing any irritation to the iris, cornea, conjunctiva, etc. will be most suitable for ocular drug delivery. The various formulation techniques such as high-pressure homogenization, milling, emulsification-solvent, precipitation, supercritical fluid process, melt emulsification method, lipid emulsion/microemulsion template and solvent evaporation are used to design the nanoformulation [ 114 ].

Nanoparticles

They are defined as nano-sized particles, whose diameter ranges from 10 to 1000 nm. They are usually made using several types of biodegradable and biocompatible polymers, resins, phospholipids, etc., either occurred naturally (albumin, sodium alginate, chitosan, guar gum, xanthan gum, gelatine, etc.) or synthesized in the laboratory [polycyanoacrylate, poly(D,L-lactides), polylactides, etc.]. These can be used for delivering the drug to ocular tissues efficiently. The nanoparticles consist of three major properties such as larger surface area, highly mobile in the dispersed state and can exhibit what is known as quantum effects. Based on dimension nanoparticles can be classified as one-, two- and three-dimensional nanoparticles. The various techniques like emulsion solvent evaporation, double emulsion solvent evaporation, salting out, emulsions-diffusion method and solvent displacement/precipitation method are used to design the nanoparticles [ 115 , 116 ].

Nanomicelles

The nanomicelles are nano-sized (10–1000 nm), micellar-shaped, self-assembling and highly mobile colloidal-like dispersions consisting of a hydrophilic shell and hydrophobic core. They are made of lipids by arranging themselves in a circular form in the solution. The amphiphilic characteristic of fatty acids is responsible for forming a micellar structure since they contain both hydrophilic (polar) and hydrophobic (non-polar) sections. The core of the nanomicelles consists of hydrophilic chains that extend outward, leading to the formation of the clear formulation. Nanomicelles are classified as polymeric nanomicelles, surfactant nanomicelles and polyion complex nanomicelle. The main advantages of nanomicelles are can be prepared easily and finally yields very small size particles which lead to a larger surface area with higher absorption automatically increases the bioavailability of drugs also encapsulates a large number of drugs [ 117 ].

They are spherical vesicles containing a minimum of one hydrophobic (Lipid) bilayer. They are made of many non-toxic lipids and cholesterols such as phosphatidylcholine, phosphatidylethanolamine as far as they are compatible with each other. The liposome vesicles size under 10 to 100 nm can be named unilamellar vesicles and huge measured vesicles 100 to 300 nm. Liposomes are promising systems for drug delivery due to their size, amphiphilic properties and biocompatibility. The properties of the liposomes significantly vary upon their size, surface charge, preparing method and composition of lipid/cholesterol. Since they possess a specific surface charge, they can be used in delivering various drugs into the ocular tissues. For example, the negative charge bearing corneal surface can attract the positive surface charged liposomes [ 118 ].

The structure of niosomes is quite similar to liposomes except for the composition that is present in liposomes. They are mainly constituted of non-ionic surfactants. They tend to incorporate both hydrophobic and hydrophilic drugs. Unlike liposomes, they are chemically stable and less toxic due to the absence of phospholipids. This makes niosomes select over liposomes in drug delivery. They also exhibit flexibility in structural characterization due to their size, composition and fluidity. This can increase the sustained action of drugs with better bioavailability. The preparation and storage are quite simple in the case of liposomes compared to niosomes due to their composition of non-ionic surfactants over phospholipids [ 119 , 120 ].

They are one more novel drug delivery system for the ocular region. They are the macromolecular compounds composed of symmetric branches surrounding a central core (like a tree). These are the nano-sized polymeric system. The hydrophilic and lipophilic drugs in the central core and are entrapped with polymers. The drug can be either encapsulated inside the dendrimers or bonded to the surface functional groups to achieve drug loading. The preparation and functionalization of dendrimers are easy up to the generation 2 (G2) level, beyond that it will be difficult to fabricate since they are in the nano-size range. But, most of the drugs can be incorporated into the dendrimers of G2 level. Thus, it could be an efficient way to deliver drugs to the ocular region [ 121 ].

Polymeric micelles

Polymeric micelles are the novel drug delivery system used to target the drug into the specific site and release it in a controlled manner [ 122 ]. Polymeric micelles can be defined as nano-sized molecules of core–shell structure that are formed by the self-association of amphiphilic block copolymers when they are added to an aqueous solvent. Usually, polymeric micelles are spherical in shape and size in the range of 10–100 nm. These are widely used in drug delivery systems due to their low toxicity, nano-size, good biocompatibility and mainly high stability [ 123 ]. The release of drug from polymeric micelles depends on (i) physicochemical properties of the drug and copolymer (ii) method of preparation (iii) structure of micelle forming copolymer and drug (iv) localization of drug in the micelle [ 124 ]. The methods like drug dissolution, dialysis, oil in water emulsion, solvent evaporation, co-solvent evaporation and freeze-drying are commonly used to encapsulate the drug into micelles [ 125 ]. Due to their small size, it is easily penetrated through the ocular tissues and automatically increases the bioavailability of the drugs. The unique core–shell structure of polymeric micelles, hydrophobic drugs can incorporate within the micelle core will lead to increase the aqueous drug solubility [ 126 , 127 ].

Biodegradable microspheres

Microspheres are spherical microparticles with a size range between 1 and 1000 µm [ 128 ]. Biodegradable microspheres were prepared by using synthetic and natural biodegradable polymers [ 129 ]. Microspheres are mainly of two types, matrix and capsular. The microspheres were fabricated by using biodegradable natural and synthetic polymers [ 130 ]. Natural origin biodegradable polymers are sub-classified as polysaccharides and proteins. Polysaccharides are mainly derived from a plant (dextran, starch, pectin), animal (hyaluronic acid), microbial (xanthan, pullulan, alginic acid) and marine source (chitosan) [ 131 ]. Proteins are mainly from plant (gluten) animal (gelatin, collagen and albumin) and microbial (polyhydroxyalkanoates) origin. Synthetic biodegradable polymers are classified as polyesters [PLA, polylactic-co-glycolic acid (PLGA), polyglycolic acid (PGA), polycaprolactone (PCL) and polyphenylene ether (PPE)], polyorthoesters and polyanhydrides [ 132 ]. Diffusion, dissolution and surface erosion are the major mechanism by which drug release from biodegradable microspheres [ 133 ]. The biodegradable microspheres prepared by using various techniques like interfacial polymerization [ 134 ], in situ polymerization [ 135 ], phase separation [ 136 ], ionotropic gelation [ 137 ], emulsion solvent evaporation [ 138 ], double emulsion [ 139 ], spray drying [ 140 , 141 ], spray congealing and air suspension method [ 142 ]. In ocular drug delivery, biodegradable microsphere concept has been used to deliver the drug in a controlled manner and to the specific site. Biodegradable microspheres for the intravitreal delivery of acyclovir were formulated and characterized for various characteristics. These microspheres were prepared by spray drying technique which showed good encapsulation efficiency and in vitro dissolution mainly dependent on the molecular weight of the polymer. Also i n vivo evaluation evidenced that prepared formulation shown sustained release of acyclovir [ 143 ]. A study has been carried out for the controlled and extended release of bioactive aflibercept hydrogel for the treatment of ocular neovascular diseases and studied in vitro release of the drug. They fabricated aflibercept-loaded microspheres by using biodegradable synthetic polymers and concluded that the prepared microsphere hydrogel was safe and delivers aflibercept in a controlled and extended manner for the period of 6 months [ 144 ].

Advantages of nanotechnology-based anti-angiogenic therapy

Angiogenesis inhibitors are the revolutionized drug molecules to target existing tumor infiltrating blood vessels and to inhibit the formation of new blood vessels [ 178 ]. These agents mainly act on vascular endothelial growth factors and thereby inhibit the angiogenesis process. Currently, intravitreal injections are the treatment of choice but it is associated with several complications [ 179 ]. So, here alternative therapy for the treatment of pathological angiogenesis is the nanotechnology-based drug delivery to overcome several complications. Nano-approach-based drug delivery techniques play an important role to overcome the drawbacks of present therapy due to their interesting physicochemical properties like nano-sized particles, prolonged half-life, high targeting efficiency, high surface area and the small size of the particle may cross ocular barriers [ 180 ]. The study has been conducted for the topical delivery of anti-VEGF drugs for the treatment of choroidal neovascularization using cell penetrating peptides. They evaluated the biological efficacy of the topical anti-VEGF using cell penetrating peptide that is compared with the intravitreal anti-VEGF injections. They have shown that cell penetrating peptides have high penetrating capabilities and non-toxic to the eye. In this study, they delivered bevacizumab and ranibizumab to the posterior segment of mouse, rat and pig eyes. They concluded that topical delivery of anti-VEGF with cell penetrating peptide was efficacious as a single intravitreal injection. A study has been highlighted that within 24 h the cell penetrating peptide and anti-VEGF drug complexes were cleared from the retinal region [ 181 ]. Seah et al . reviewed on use of biomaterials for sustained delivery of anti-VEGF to treat retinal diseases. They summarized till date nanoformulations, biodegradable implants and hydrogels have emerged as a promising treatment technique. The anti-VEGF drug molecules or biologics are proteins with high molecular weight and these are very sensitive molecules for various environmental conditions. They discussed that biomaterials are the main agent which are involved in the sustained delivery of anti-VEGF drugs to the retina [ 182 ]. Selected biomaterials should fulfill several ideal characteristics like it should protect anti-VEGF molecule from degradation by protecting the tertiary and quaternary structure of the protein, should encapsulate a large amount of drugs in minimum volume to avoid intraocular pressure elevation on administration, should capable of sustaining the release of anti-VEGF for a longer period and finally should remain optically clear within the vitreous to avoid blurring of vision [ 183 ]. Liu et al . fabricated bevacizumab-loaded PLGA/PCADK (polycyclohexane-1,4-diyl acetone dimethylene ketal) microspheres. In vitro bioactivity test was proved through HET CAM assay and biocompatibility was evaluated using New Zealand white rabbits [ 184 ]. Sun et al . fabricated bevacizumab-loaded mesoporous silica nanoparticles. Bioactivity test proved through oxygen-induced retinopathy mouse model. Biocompatibility test proved with C57BL/6J mice [ 185 ]. Liu et al . fabricated hydrogel technology ranibizumab and aflibercept-loaded PLGA microspheres suspended in a hydrogel. Bioactivity studies proved on laser-induced choroidal neovascularization Long-Evans rat model. These studies showed that novel approach-based topical delivery of anti-VEGF drugs is the choice of a treatment system for pathological angiogenesis [ 144 , 186 ].

Potentials of nanotechnology-based ocular drug delivery systems for clinical applications

Currently in the pharmaceutical field, ocular drug delivery has become the most challenging area. To overcome this limitation targeted drug delivery system came into existence [ 187 ]. Nanotechnology emerged as a promising drug delivery system in the field of ocular therapy. Various nanotechnology-based products have been under investigation and few products have already been clinically approved by the United States Food and Drug Administration (USFDA) and are available for the treatment of medical conditions like autoimmune disorders, cancer, age-related macular degeneration, etc. Currently, many ocular delivery systems are in clinical trials and some products have already been introduced into the market [ 188 ]. The development of nanotechnology seems to be a ray of hope for the currently facing challenges. Pre-clinical/clinical/approved formulations (nano/micro) in ocular drug delivery system are listed in Table 4 .

Risk analysis

In the current review, we have presented the applications of novel approaches for the treatment of pathological ocular angiogenesis [ 209 ]. The literature survey represented the main aim to formulate these novel approaches and nanotechnology-based formulations to improve the uptake and for the better entrapment efficiency of drug which ultimately improves the therapeutic effect. But, stability was the major problem associated with the nano-based formulations [ 210 ]. The reason behind the low therapeutic efficacy of the nanoformulation is their ability to self-aggregate at low drug concentration, affecting the drug entrapment and ultimately leads to poor stability of the formulations. For example, it has been reported that self-aggregation of doxorubicin nanoformulation due to their high ionic strength ultimately leads to the high particle size and affects their drug entrapment efficiency [ 211 ]. The same problem was reported for the liposome formulation which increases in size due to their high ionic strength [ 212 ]. Another challenge is the swelling mechanism of nanoformulation. When swelling occurs, the size of the particles increases and this limitation can be fixed by controlling the swelling mechanism by using pH-sensitive coatings or the capping agents over the formulation. Finally, certain nanoformulations were failed to meet FDA quality profile and difficulties associated with formulation manufacturing, make nano-approach-based drugs formulation unfit for large-scale production. Thus, the upcoming research should focus on above mentioned challenges and concentrate on large-scale manufacturing of nanoformulations abiding by the guidelines of USFDA to resolve all the associated hurdles and inexpensively [ 188 , 213 ].

Future perspectives

The vision impairment and irreversible vision loss can be decreased or completely prevented by enormous research and developments necessitate the application of novel approaches and strategies. Novel approaches in the development of ocular dosage forms have very wide applications in the treatment of various ocular diseases. Topical delivery of drugs into the ocular region is one of the best approaches in ocular drug delivery in terms of patient compliance. Despite its seemingly easy way, they possess several limitations such as tear turnover, nasolacrimal drainage, blinking, induced lacrimation that leads to quick elimination of drug particles from the surface of the eye. This results in sub-therapeutic drug levels in the target tissue, particularly at the retinal level. Thus, novel approaches can assist in the manufacture of nano-based formulations. A very less amount of research was carried out on the above discussed approaches for ocular angiogenesis particularly. The application of nanomedicine in the ocular drug delivery area has shown great potential in the pharmaceutical field of research [ 104 ]. Nanomedicine also has its potential in improving the pharmacokinetic and pharmacodynamic properties of few therapeutic agents. Many nanoformulations are under the pre-clinical and clinical stage of development for the treatment of ocular diseases. Unfortunately, this nanotechnology-based drug delivery has few limitations when it enters the large-scale process. The reason behind the low therapeutic efficacy of the nanoformulation is their ability to self-aggregate at low drug concentration, affecting the drug entrapment and ultimately leads to poor stability of the formulations it again leads to the safety and toxicity issue of the prepared formulation. Also, other factors like size, shape, administration dose can influence toxicity in nanomedicine. So advanced nanofabrication technologies like particle replication in non-wetting templates (PRINT) [ 214 ] and the hydrogel template method have been introduced to create ocular nanomedicine. This technology can create uniform nanoparticles and microparticles with controlled shape, size and surface modification at a large scale. Another study conducted using the principle of PRINT technology is AR13503 implant, which was manufactured to provide sustained release of drugs for more than 2 months [ 214 , 215 ]. Considering the immense amount of past and present research on these techniques, there is potential and a ray of hope for better therapies for the future in the treatment of diseases and is with the eventual goal of stopping ocular angiogenesis. There are several areas to be explored for future research for the benefit of a novel therapy for ocular angiogenesis. Furthermore, the ongoing development of novel therapy or modification to current dosage forms in the context of ocular angiogenesis will be helpful to focus on the new strategy of medication for the treatment of angiogenesis.

As we discussed earlier, drug delivery to the ocular region became challenging to pharmaceutical scientists. The barriers which are present in the eye hinder ocular bioavailability mainly when the drugs are applied topically. So, novel approach-based drug delivery systems are of great importance in the pharmaceutical technology as well as the ophthalmological sector. Thus, for ocular disease management, the design and development of new techniques are mandatory. Only a few works can be seen specifically for ocular angiogenesis. Currently to treat ocular angiogenesis, intravitreal injections of anti-VEGF drugs are the revolutionized treatment. But, repeated intravitreal injections to the eyes lead to several serious complications. So, novel approach-based drug delivery techniques may be a ray of hope for better therapies for the future in the treatment of ocular angiogenesis. Also, the inclusion of novel techniques may be a road map for future research in the field of ocular angiogenesis disease management.

Availability of data and materials

All data and materials are available on request.

Abbreviations

Diabetic retinopathy

Age-related macular degeneration

Endothelial growth factor

Fibroblast growth factor

Platelet-derived growth factor

Platelet-derived growth factor receptor

• Vascular endothelial growth factor

Vascular endothelial growth factor receptor

Placenta growth factor

Vascular permeability factor

Receptor tyrosine kinase

Kinase-insert-domain containing receptor

Endothelial cells

Hypoxia-inducible protein complex

Hypoxia-inducible factor

Nitric oxide

Nitric oxide synthase

Tumor necrosis factor

Transforming growth factor

Interleukin

Retinopathy of prematurity

Branch retinal vein occlusion

Immunoglobulin-G

Polyacrylic acid

Generation 2

Matrix metalloproteinase

Pigment epithelium-derived factor

Small interfering ribonucleic acid

Messenger ribonucleic acid

Deoxyribonucleic acid

Leber congenital amaurosis

Microneedle

Polylactic acid

Black phosphorous

Near-infrared

Polylactic-co-glycolic acid

Polyglycolic acid

Polycaprolactone

Polyphenylene ether

Polycyclohexane-1,4-diyl acetone dimethylene ketal

Particle replication in non-wetting templates

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Soumya Narayana, Mohammed Gulzar Ahmed, B. H. Jaswanth Gowda, Pallavi K. Shetty, Arfa Nasrine, M. Thriveni & A. Sanjana

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Narayana, S., Ahmed, M.G., Gowda, B.H.J. et al. Recent advances in ocular drug delivery systems and targeting VEGF receptors for management of ocular angiogenesis: A comprehensive review. Futur J Pharm Sci 7 , 186 (2021). https://doi.org/10.1186/s43094-021-00331-2

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• Ocular drug delivery
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OCULAR DRUG DELIVERY SYSTEM – A REVIEW

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Ocular drug delivery has always been a challenge for ophthalmologists and drug-delivery scientists due to the presence of various anatomic and physiologic barriers. Inimitable static and dynamic ocular barriers not only exclude the entry of xenobiotics but also discourage the active absorption of therapeutic agents. Designing an ideal delivery scheme should include enhanced drug bioavailability and controlled release of drug at the site of action, which can overcome various ocular barriers. Conventional ophthalmic medications include the use of topical eye drops and intravitreal injections of anti–vascular endothelial growth factor agent for treatment of anterior and posterior segment disorders, respectively. Current inventions for anterior ocular segment disorders such as punctum plugs, ocular implants, drug-eluting contact lenses, and ocular iontophoresis represent state-of-the-art inventions for sustained and controlled drug release. Parallel efforts for ocular drug delivery technologies for back of the eye disorders have resulted in the approval of various intravitreal implants. Novel drug-delivery technologies, including nanoparticles, nanomicelles, dendrimers, microneedles, liposomes, and nanowafers, are increasingly studied for anterior and posterior disorders. To achieve patient compliance for back of the eye disorders, novel approaches for noninvasive delivery of potent therapeutic agents are on the rise. In this review article, we discuss past successes, present inventions, and future challenges in ocular drug-delivery technologies. This expert opinion also discusses the future challenges for ocular drug-delivery systems and the clinical translatable potential of nanotechnology from benchtop to bedside.

• Introduction

In the past two decades, the arena of ocular drug-delivery technologies has dynamically advanced and resulted in newer therapeutic interventions for chronic ocular disorders. The primary objectives of any ocular drug-delivery system are to maintain therapeutic drug concentrations at the target site, reduce dosage frequency, and overcome various dynamic and static ocular barriers. Most importantly, the drug-delivery system should cause no adverse ocular reactions and aim to achieve enhanced drug bioavailability. Ocular pathologic disorders are generally described as anterior segment and posterior segment disorders. Clinicians treat anterior segment disorders such as dry eye disease, cataract, and allergic conjunctivitis by topical eye drops. The major disadvantage of topically applied ophthalmic formulations is relatively low ocular bioavailability. This can be attributed to high tear-fluid turnover rates and high nasolacrimal drainage. Novel ocular drug-delivery systems include nanomicelles, nanoparticles, drug-eluting contact lenses, ocular inserts, and ocular devices that allow enhanced peroneal residence and enhance the bioavailability of the therapeutic agents ( Achouri et al., 2013 ; Fangueiro et al., 2016 ).

Ocular pathologic conditions involving the posterior segment generally result in vision loss due to damage to the retina. Hyperglycemia for a prolonged period of time can cause damage to the retinal endothelial cells, causing back of the eye disorders such as diabetic retinopathy (DR), diabetic macular edema (DME), and retinal vein occlusion (RVO). High oxidative stress, endoplasmic reticulum stress, and aging can damage the retinal pigmented epithelial cells (RPE) and Bruch’s membrane in the macular region, leading to the death of the photoreceptors. Such pathologic conditions can cause retinal degenerative disorders such as age-related macular degeneration (AMD) ( Yasukawa et al., 2004 ; Janoria et al., 2007 ). Retinal and choroidal neovascularization (CNV), evident in back of the eye disorders, is primarily due to overexpression of vascular endothelial growth factor (VEGF) receptor. Before the invention of anti-VEGF agents, the gold standard treatment of these disorders was the application of laser photocoagulation to lower overall oxygen demand of the retina. This therapy allowed suppression of CNV and retinal neovascularization. Since then, clinicians have introduced a plethora of anti-VEGF agents in the market, including pegaptanib, bevacizumab (off-label), ranibizumab, and aflibercept, for the treatment of back of the eye disorders with neovascularization. Clinicians administer these agents as intravitreal injections, which has drawbacks such as retinal hemorrhage and retinal detachment. Moreover, intravitreal injections lack patient compliance. Novel ocular drug-delivery technologies such as nanoformulations, implants, and other ocular devices allow enhanced drug residence time at the target tissue along with improvements in pharmacological response ( Peyman et al., 2009 ).

In this article, we present a comprehensive and detailed review of past successes, current inventions, and future challenges in anterior and posterior ocular drug-delivery systems. Developments in novel drug-delivery technologies can ultimately improve pharmacological action of drugs at the target tissue by elevating the concentrations and ocular bioavailability of the required therapeutic agent.

• Barriers to Ocular Drug Delivery and Routes of Drug Administration

Human ocular anatomy possesses static and dynamic ocular barriers to prevent toxic chemical substances, including therapeutic molecules, to reach various tissues of the eye. Ocular barriers of anterior and posterior segments retard the passive absorption of various therapeutic agents and thus reduce the ocular bioavailability of various drugs. Both static (corneal epithelium, corneal stroma, corneal endothelium, blood-aqueous barrier) and dynamic barriers (tear dilution, conjunctival barrier, and retinal-blood barrier) hinder drug absorption, affecting drug bioavailability of topical formulation (<5%) ( Chrai et al., 1973 , 1974 ). The globular shape of the human eye and precorneal factors such as blinking and continuous tear turnover reduce absorption of topically applied formulations ( Mishima et al., 1966 ; Lee and Robinson, 1986 ; Schoenwald, 1990 ) ( Fig. 1 ). The lipophilic corneal epithelium allows absorption of hydrophobic drugs but acts as a barrier for paracellular diffusion of hydrophilic drugs due to tight junctions ( Huang et al., 1983 ; Hornof et al., 2005 ). Corneal epithelia efficiently prevents absorption of more than 10-Å molecules, with a higher drug-distribution coefficient limiting the barrier for hydrophobic drugs. Therefore, drug absorption requires overcoming corneal epithelia efficiently. Decrease in transcorneal diffusion of drug through the aqueous humor and expression of efflux transporters on the plasma membrane of corneal cells are major restrictions for drug delivery to the targeted ocular tissues. The use of prodrugs, permeation enhancers, and recent use of nanomicelles can enhance permeability of the drug through the corneal barriers ( Cholkar et al., 2012 ; Huang et al., 2018 ).

Ocular anatomic barriers and routes of drug administration. Ocular barriers to topical administration (iv) of therapeutic agents to the anterior surface of the eye and to the posterior segment are illustrated. These include (A) tear film barrier; (B) corneal barrier; (C) vitreous barrier; (D) blood–retinal barrier and (E) blood–aqueous barrier. Various methods for drug delivery to the eye include; (I) intravitreal injection, (II) subconjuctival injection, (III) subretinal injection and (IV) topical administration. Topical administration of eye drops is one of the non-invasive route of administration and has minimum side effects. Intravitreal injections on the other hand are invasive, can cause retinal damage but can easily bypass all ocular barriers. While subconjuntival and subretinal injections can bypass some of the ocular barriers and are less invasive. ( Alqawlaq et al., 2012 ).

While in the posterior segment of the eye, the scleral, choroidal, and retinal epithelial and the blood-retinal barrier account for limiting ocular drug bioavailability. The sclera provides higher trans-scleral permeability than the cornea for hydrophilic compounds diffusing through the collagen network. Permeation through the sclera is largely dependent on molecular weight, molecular radius, and charge. Macromolecules exhibit lower penetration through scleral pores than small molecules. This is the reason why macromolecules, including anti-VEGF agents, exhibit low diffusion through the sclera and are administered by intravitreal injections ( Huang et al., 2018 ). The choroid is a vascular-natured dynamic barrier, which impedes drug delivery by the trans-scleral pathway ( Tsai et al., 2018 ). The retina is a significant limiting factor for diffusion of molecules with a larger radius and a molecular mass greater than 76 kDa ( Jackson et al., 2003 ). The inner limiting membrane of the retina severely confines the passage of macromolecules over 150-kDa molecular mass ( Mordenti et al., 1999 ; Jackson et al., 2003 ; Tao et al., 2007 ). Moreover, the inner limiting membrane progressively restricts molecules with a larger radius. Retinal pigmented epithelia and choriocapillaries collaboratively produce Bruch’s membrane. The thickness of Bruch’s membrane increases with age, inhibiting drug transport into tissues and draining hydrophobic drugs through systemic circulation ( Cholkar et al., 2012 ). The blood-retinal barrier (BRB) comprises two subdivisions, an outer BRB and an inner BRB. Both the outer BRB and inner BRB are permeation barriers between the blood and the retina having tight junction proteins between the cells ( Kamei et al., 1999 ; Achouri et al., 2013 ). The BRB also exhibits efflux transporters, which reduce bioavailability of several therapeutic agents ( Mitra, 2009 ; Vadlapatla et al., 2014 ). The blood-aqueous barrier consists of an epithelial and an endothelial barrier. The permeability of drugs through the blood-aqueous barrier is determined by osmotic pressure and physical-chemical characteristics of drug molecules ( Dubald et al., 2018 ). Ocular drug delivery presents a unique challenge due to its incredibly specialized tissue barriers that act as obstacles to therapies ( Gaudana et al., 2010 ). Table 1 summarizes present routes of ocular therapy administration, and Fig. 1 details the anatomic makeup, indicating how each therapy travels to its active site.

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Comparison of various routes of ocular drug administration: benefits and obstacles ( Gaudana et al., 2010 )

• Past Successes in Ocular Drug-Delivery Technologies

Drug Delivery to the Anterior Segment of the Eye

Topical delivery of ophthalmic formulations is the most preferred route for the delivery of therapeutic agents to the anterior segment of the eye. Ocular formulations (solutions, suspensions, emulsions, gels, and ointments) are most commonly used to treat common anterior segment disorders such as dry eye diseases, allergic conjunctivitis, and glaucoma ( Kaur and Kanwar, 2002 ). Topical ocular administration gains merit over systemic ocular administration. This is because topical administration is (i) relatively non-invasive, (ii) minimizes systemic side effects of the drug, (iii) avoides first pass metabolism, (iv) reduces drug dosage due to localized drug delivery (v) and increases patient compliance due to ease of topical administration. Factors limiting absorption of topically applied ophthalmic formulations are high tear turnover rate (1 µ l/ml), loss of drug due to rapid blinking, reflex tear production, and limited absorption due to the tear-film barrier ( Lee and Robinson, 1986 ; Schoenwald, 1990 ; Cholkar et al., 2013 ). To enhance the drug bioavailability, ophthalmic formulation requires a higher precorneal residence time and an enhanced drug penetration. Therefore, a drug-delivery system offering longer retention and a sustained release of the drug molecule to pass through these barriers is essential ( Khar et al., 2010 ; Reimondez-Troitiño et al., 2015 ). Novel drug-delivery technologies utilizing cyclodextrins, prodrugs, and colloidal systems such as nanoparticles, liposomes, and nanomicelles have been studied extensively ( Tirucherai and Mitra, 2003 ; Gunda et al., 2006 ; Vaka et al., 2008 ). Conventional eye drops in the form of solutions, suspensions, and emulsions have been used over a long period of time to treat anterior segment disorders. The following section describes topical ophthalmic formulations in detail.

Ophthalmic Solutions.

Topical eye drop solutions are patient-compliant, noninvasive, immediate-acting drug formulations. Eye drop solutions are instilled in the cul-de-sac, which is followed by a rapid first-order absorption into the corneal and conjunctival tissues. An increase in drug permeation and drug bioavailability can be attained by modifying the drug properties or properties of the drug-delivery system.

Modification of drug properties by utilizing prodrug strategy.

Drug molecules require appropriate lipophilic and hydrophilic properties to overcome the ocular tear barrier and to reach the corneal membrane. The prodrug approach modifies the physiochemical properties of the drug for better absorption of the drug by passive or active diffusion ( Mandal et al., 2016a , b ). Once the prodrug reaches the corneal tissue, cellular enzymes cleave it into the active drug. Dipivefrine (Propine, Allergan) is an ester prodrug of epinephrine, that demonstrates a 17-fold higher corneal permeation, resulting in 10 times higher epinephrine bioavailability in the corneal tissues than the unmodified drug. Cyclosporine-A is a lipophilic drug, which poses a challenge for formulation development and corneal permeation. UNIL088 [(1R,2R,E)-1-((2S,5S,11S,14S,17S,20S,23R,26S,29S,32S)-5-ethyl-11,17,26,29-tetraisobutyl-14,32-diisopropyl-1,7,10,16,20,23,25,28,31-nonamethyl-3,6,9,12,15,18,21,24,27,30,33-undecaoxo-1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriacontan-2-yl)-2-methylhex-4-en-1-yl N-(N-((1-acetoxyethoxy)carbonyl)-O-phosphono-L-seryl)-N-methylglycinate] is a hydrophilic prodrug of cyclosporine-A, demonstrating 25,000 times higher solubility than the parent drug at pH 7 ( Lallemand et al., 2005 ). Another prodrug of cyclosporine-A (OPPH008) was characterized, and its efficacy in the treatment of dry eye disease was determined. OPPH008 achieved higher tissue concentrations as compared with a cyclosporine-A ophthalmic emulsion (Restasis, Allergan) in rabbit ocular tissues ( Rodriguez-Aller et al., 2012 ). Prodrug strategy is also useful for reducing the dose of drugs with a narrow therapeutic index. Latanoprost is an ester prodrug of prostaglandin used to treat glaucoma. It has a higher bioavailability than the parent compound at lower doses ( Kompella et al., 2010 ; Alm, 2014 ).

Modification of formulation properties.

I. cyclodextrins for solubilizing hydrophobic drugs..

Cyclodextrins are cyclic oligosaccharides arranged in a truncated cone-like structure. Cyclodextrins allow hydrophobic drugs to form complexes, enhancing drug solubility and bioavailability. Such complexation also improves corneal residence time and reduces local tissue inflammation ( Achouri et al., 2013 ). Cyclodextrin complexation permits aqueous formulation of various drugs, including dexamethasone, chloramphenicol, and corticosteroids, for ocular disorders (Loftssona and Jarvinen, 1999; Loftsson and Stefansson, 2002; Sigurdsson et al., 2007 ). A study by Saari et al. (2006) concluded that 0.7% dexamethasone-cyclodextrin eye drops demonstrated significantly higher safety and efficacy as an anti-inflammatory medication for postcataract inflammation than 0.1% dexamethasone sodium phosphate eye drops.

II. Viscosity and permeation enhancers.

Ophthalmic formulations traditionally use viscosity enhancers to improve precorneal residence time of the drug. Various viscosity enhancers, such as hydroxyl propyl methylcellulose, polyalcohol, sodium carboxyl methylcellulose, and hydroxyl methylcellulose, improve drug retention time and absorption. Permeability of ophthalmic drugs is elevated by the addition of permeation enhancers ( Achouri et al., 2013 ). Such agents temporarily adjust the corneal and conjunctival surface to facilitate rapid drug penetration. Ophthalmic preservatives such as benzalkonium chloride, surfactants such as polyethylene glycol, ethers, EDTA, chelating agents, and bile salts are a few examples of permeation enhancers that raise drug bioavailability ( Burgalassi et al., 2001 ; van der Bijl et al., 2001 , 2002 ; Hornof and Bernkop-Schnurch, 2002). Despite the various advantages offered by penetration enhancers, these agents can cause tissue irritation and damage the corneal and conjunctival tissues ( Achouri et al., 2013 ).

Suspensions.

Ocular suspensions are a dispersion of finely divided insoluble drug particles suspended in an aqueous medium containing dispersing and solubilizing agents. The precorneal cavity retains drug particles in suspension, enhancing the contact time of the drug. The particle size of the drug determines the time required for the absorption of the drug molecules into corneal tissue, thus ultimately affecting the drug bioavailability. TobraDex ST, Alcon, Inc. is a suspension of (0.3%) tobramycin and (0.05%) dexamethasone indicated for bacterial ocular infections ( Scoper et al., 2008 ). TobraDex ST was developed from TobraDex to overcome the high viscosity of the initial formulation. TobraDex ST demonstrated higher tissue concentrations of the drugs tobramycin and dexamethasone in rabbits along with improvements in formulation quality and pharmacokinetic parameters. Clinical studies also showed similar results with higher concentrations of dexamethasone in the aqueous humor after TobraDex ST administration as compared with TobraDex. Yet another US Food and Drug Administration (FDA)–approved ophthalmic suspension is Besivance. (Bausch & Lomb) Besivance is a suspension of 0.6% besifloxacin and is prescribed to treat bacterial conjunctivitis. A multicenter, randomized, double-masked, vehicle-controlled clinical trial in adults and children demonstrated that administration of 0.6% besifloxacin ophthalmic suspension twice daily resulted in reduction of signs and symptoms of bacterial conjunctivitis ( Silverstein et al., 2011 ). In an another phase III study, 2% rebamipide suspension (OPC-12759) was effective for treatment of dry eye disease as compared with the control group ( NCT00885079 ). Also, the formulation was well tolerated and demonstrated high efficacy for the treatment of dry eye disease ( Diestelhorst et al., 1998 ; Kinoshita et al., 2012 ).

An emulsion is a biphasic system composed of two immiscible phases. Ophthalmic emulsions can offer advantages in improvement of drug solubility and bioavailability of previously water-insoluble drugs. Pharmaceutical emulsions can be widely categorized as water in oil and oil in water (o/w). Ophthalmic formulations widely use the o/w system, which consists of a hydrophobic drug mixed in oil and dispersed in an aqueous medium. An o/w emulsion is preferred over a water in oil emulsion for the reasons of better ocular tolerability and lower ocular irritation due to the external aqueous phase. Some examples of marketed ophthalmic eye drops are Restasis (Allergan), AzaSite (Akorn), Refresh Endura (Allergan), and Durezol (Alcon). Restasis is a 0.05% emulsion of cyclosporine-A indicated for the treatment of dry eye disease. AzaSite is a 1% azithromycin ophthalmic emulsion used to treat bacterial conjunctivitis and various other ocular infections, while Refresh Endura is a nonmedicated emulsion for dry eye disease ( Opitz and Harthan, 2012 ). Durezol is an emulsion of difluprednate, an anti-inflammatory corticosteroid used to treat anterior ocular uveitis. Studies have demonstrated that Durezol can be applied to treat DME and for the management of postoperative ocular pain and inflammation ( Korenfeld et al., 2009 ; Kang-Mieler et al., 2014 ). Emulsions can sustain drug release, improve corneal drug absorption, and prolong the formulation residence time in the precorneal cavity. This helps in enhancing the bioavailability of lipophilic drugs for the treatment of anterior segment disorders ( Liang et al., 2008 ).

Drug Delivery to Back of the Eye

Intravitreal injections of anti-vegf agents..

The first indication of VEGF in ophthalmology can be traced back to 1940, when a group of scientists proposed that a diffusible factor was responsible for normal vasculature development. Imbalance in the particular factor resulted in neovascularization evident in proliferative DR. By the late 1990s, VEGF was identified as a potential mediator of choroidal neovascularization and intraocular neovascularization for patients suffering from AMD ( Amin et al., 1994 ; Lopez et al., 1996 ). Proof-of-concept studies established that VEGF blockage resulted in inhibition of neovascularization in various animal models ( Aiello et al., 1995 ; Zhu et al., 1999 ; Campochiaro and Hackett, 2003 ) and indicated VEGF blockage can be a potential new approach to overcome retinal disorders involving neovascularization ( Adamis et al., 1996 ).

Forty years after cloning of VEGF, a humanized monoclonal antibody, bevacizumab (148 kDa), was developed as a VEGF-specific antibody. Bevacizumab was approved for treatment of various cancers, but soon its effectiveness in choroidal neovascularization was recognized. Currently, Avastin, Genentech (bevacizumab) is a realistic off-label treatment of wet AMD and DR. Pegaptanib sodium (Macugen, Bausch & Lomb) was the first antiangiogenic VEGF aptamer approved by the US FDA for the treatment of wet or nonvascular AMD in 2004. An intravitreal injection of pegaptanib sodium (pegylated anti-VEGF aptamer) alleviated the conditions of wet AMD and reduced vision loss ( Gragoudas et al., 2004 ; Ng et al., 2006 ). Subsequently, an F(ab) fragment of bevacizumab, ranibizumab (49 kDa), was developed by Genentech ( Presta et al., 1997 ). Ranibizumab demonstrated a higher binding affinity than pegatanib to VEGF and better penetration into the retinal layers as compared with bevacizumab ( Mordenti et al., 1999 ). Due to prior success of earlier clinical trials (phase I and phase II) of ranibizumab intravitreal injection, a phase III trial (MARINA) was conducted with 716 patients as a treatment of wet AMD. More than 94% of the patients in the treatment group showed signs of improved vision as compared with the control group ( P < 0.001) ( Rosenfeld et al., 2006 ). Now, Lucentis (ranibizumab intravitreal injection) has been approved for treatment of patients with neovascular (wet) AMD once every month (LUCENTIS, 2006). The most recent approved monoclonal antibody for the treatment of wet AMD is aflibercept (97 kDa), a recombinant fusion protein. Eylea (Regeneron Pharmaceuticals) (aflibercept, an intravitreal injection) acts by blocking the action of VEGF and inhibiting neovascularization. Aflibercept has revealed approximately 200 times higher binding affinity to VEGF as compared with ranibizumab. While ranibizumab only binds to the VEGF-A isoform ( Sarwar et al., 2016 ; Zhang et al., 2017 ), aflibercept binds to various isoforms of VEGFs (VEGF-A and VEGF-B) and placental growth factor. Binding of aflibercept to various growth factors suppresses all of the actions of VEGF and blocks many pathways, such as cell migration, cell proliferation, and cellular differentiation, leading to neovascularization. Both Eylea and Lucentis are biotech drugs extensively used in the form of intravitreal injections and now serve as the gold standard for the treatment of wet AMD and DME ( Chang et al., 2012 ; Rodrigues et al., 2018 ).

• Recent Inventions for Ocular Drug-Delivery Technologies

Anterior Segment Ocular Drug-Delivery Technologies

Punctum plugs..

Punctum plugs are biocompatible devices inserted in the tear ducts to block tear drainage. These are also known as occludes or lacrimal plugs, which have a size of 2–5 mm. Punctum plugs are noninvasive and can provide controlled drug release to the anterior segment of the eye. Construction of such ocular inserts is possible from nonbiodegradable and biodegradable materials. Nonbiodegradable punctum pug delivery systems (PPDS) are made from silicone, polycaprolactum, and hydroxyethyl methacrylate, which is intended to provide controlled drug release up to 180 days. After this period, the insert is removed. Recently, a PPDS (SmartPlug, Medennium Inc.) was developed from a thermosensitive hydrophobic acrylic polymer for the treatment of dry eye disease. The thermosensitive PPDS undergoes modification from rigid solid to a soft gel-like structure after insertion into the eye ( http://www.eyeconsultant.info/pdfs/smartplug.pdf ). Ocular Therapeutix (Bedford, MA) has developed OTX-TP (travoprost punctum plug insert) to deliver travoprost to the ocular tissues for 90 days. Currently, a phase III clinical trial is set for evaluating the safety and efficacy of OTX-TP for reduction of intraocular pressure (IOP) and ocular hypertension ( NCT02914509 ). Recently, Ocular Therapeutix also completed a phase III clinical study for the safety and efficacy of OTX-DP (dexamethasone punctum plug insert) for the treatment of chronic allergic conjunctivitis and for treatment of inflammation after cataract surgery as compared with a placebo punctum plug ( NCT02988882 , NCT02736175 ). High efficacy and safety of OTX-DP led to the US FDA approval of Dextenza (dexamethasone insert; Ocular Therapeutix) for the treatment of pain following ophthalmic surgery (Dextenza, 2018). The company has also developed OTX-TP2 (a prostaglandin trap), which can be used for the treatment of glaucoma and postoperative ocular care ( Kang-Mieler et al., 2014 ). Several clinical trials have been conducted to investigate the effectiveness of PPDS for the treatment of open-angle glaucoma, glaucoma, and ocular hypertension ( NCT00650702 , NCT01845038 ).

Subconjunctival/Episcleral Implants.

Ocular implants can be inserted into the anterior segment of the eye for controlled drug delivery for a prolonged period. Such implants can be surgically inserted into the subconjunctival region, aqueous humor, and episcleral region. These implants provide the advantage of sustained localized drug delivery and higher patient compliance as compared with topical eye drops. An insertion is made on the conjunctiva for the insertion of the implants. While some inserts are implanted in the junction between the conjunctiva and the sclera ( Nicoli et al., 2009 ), others are inserted into the aqueous humor ( Molokhia et al., 2013 ). Surodex (Allergan Inc.) is an example of an anterior segment insert, which is inserted into the anterior ocular segment post cataract surgery to alleviate postsurgery inflammation. Surodex is a rod-shaped biodegradable insert consisting of the drug dexamethasone using polymers such as poly lactide-co-glycolide (PLGA) and hydroxypropyl methyl cellulose, allowing sustained drug release for 7–10 days ( Tan et al., 1999 , 2001 ). A study demonstrated that a 7-day drug release with Surodex achieved higher concentrations as compared with maximum peak drug concentrations after topical treatment with dexamethasone eye drops ( Tan et al., 1999 ). Lux Biosciences developed a silicone-based episcleral implant (LX201) for delivery of cyclosporine-A to the anterior ocular tissues for a period of 1 year. In a phase III clinical study, Lux Biosciences also evaluated the effectiveness of LX201 to prevent corneal graft rejection ( NCT00447642 ).

Cul-de-sac Implants.

The cul-de-sac of the eye is a pocket-like depression where the bulbar and palpebral conjunctiva meet in the upper or lower eyelid. Ocular devices such as Lacrisert (Bausch & Lomb) and Ocusert (Akorn) are examples of cul-de-sac implants designed for drug delivery to the anterior segment of the eye. These devices are safer and less invasive than the conjunctival and episcleral implants. Lacrisert (Bausch & Lomb) is a hydroxypropyl cellulose implant inserted into the inferior cul-de-sac. The implant is suitable for patients with moderate to severe dry eye disease ( McDonald et al., 2009 ). Lacrisert decreased corneal sensitivity, recurrent corneal erosions, and exposure to keratitis. It is also effective for the treatment of conjunctival hyperemia ( Lacrisert, 1988 ). Lacrisert releases cellulose, allowing maintenance of tear film integrity. The implant acts as a lubricant and helps to protect the ocular surface. However, Lacrisert can cause discomfort. It causes foreign body sensation, ocular irritation, hypersensitivity, hyperemia, and blurry vision. Ocusert is a drug-eluting implant delivering pilocarpine over a period of 7 days and directed for the treatment of glaucoma. However, pilocarpine in the insert caused unwanted side effects, such as eyebrow ache and miosis. This resulted in removal of Ocusert from the market ( Pollack et al., 1976 ). Yet another cul-de-sac implant is DSP-Visulex (Aciont Inc., Salt Lake City, UT), which has completed a phase II clinical trial for the treatment of anterior uveitis ( NCT02309385 ). DSP-Visulex contains dexamethasone and is inserted into the bulbar conjunctiva ( Papangkorn et al., 2018 ).

Drug-Eluting Contact Lenses.

Drug-eluting contact lenses (CLs) are light-transparent corneal dressings acting as drug reservoirs and sustaining drug discharge near the postlens tear fluid for the treatment of anterior ocular disorders. Drug-loaded soft contact lenses are an innovative drug-delivery system to not only prolong and sustain drug release but also enhance drug penetration across the corneal epithelium as compared with conventional eye drops. Contact lenses can increase bioavailability of the drug by increasing the contact time of the drug ( Mandal et al., 2017a ). Various soft contact lenses have been developed for antifungal agents, which can prolong drug delivery up to 21 days ( Phan et al., 2014 ). A clinical trial was conducted for evaluation of the safety and efficacy of drug-eluting contact lenses for the management of glaucoma. The contact lenses are loaded with timolol maleate and dorzolamide HCl along with vitamin E as an additive for achieving sustained drug release ( NCT02852057 ). Various technologies have been used to load drugs on contact lenses instead of just soaking the lens with the drug. Recently, Gulsen and Chauhan (2004) advanced a novel drug-eluting contact lens, which embedded lidocaine-laden nanoparticles. The investigators studied the drug release from the formulation and observed a sustained lidocaine release in vitro over 7 to 8 days ( Gulsen and Chauhan, 2004 ). Similarly, Ciolino et al. (2009) fabricated a drug-eluting contact lens using a polymer-embedded matrix for ciprofloxacin and econazole. The in vitro data demonstrated a zero-order drug-release profile, which can sustain drug release up to 1 month ( Ali et al., 2007 ; Ciolino et al., 2009 ). Figure 2 depicts the advantage of soft drug-loaded contact lenses over conventional eye drops.

Ocular drug-delivery system using drug-loaded soft contact lenses. (A) Opthalmic drugs delivered though conventional eye drops. Majority of the drug administered gets drained a few minutes after instillation. (B) Drug delivery through molecularly imprinted soft contact lenses. This approach can increase the residence time of the drug molecules on the ocular surface increasing drug bioavailability as compared to conventional eye drop formulations. (Tashakori-Sabzevar F et al. 2015). MIP: molecularly imprinted polymer.

Contact lenses offer the highest drug bioavailability as compared with other noninvasive ophthalmic medications due to close proximity of the contact lens with the cornea. They also provide a significant dosing advantage as compared with frequent topical eye drops. Many drug-eluting contact lenses have been developed, but none of them are yet US FDA-approved. The major challenge faced by this therapy is successful demonstration of significantly higher safety and efficacy over conventional eye drops. A prolonged use of contact lenses can be associated with corneal toxicity ( Dumbleton, 2002 ). Many factors, including oxygen diffusion, microbial resistance, and effective and continuous drug release, are yet to be addressed for successful commercialization of contact lenses (Malthiery et al., 1989; Dixon et al., 2015 ).

Bioinspired hydrogels for drug-eluting CLs are the current state-of-the-art technology for ocular delivery. Most bioinspired contact lenses appear to reverse the engineering process to generate binding sites inside CLs for drug molecules which mimic the natural receptors. Such molecularly imprinted hydrogels with specific binding affinity used for making drug-eluting contact lenses allow enhanced drug loading and, consequently, prolong drug-release kinetics. Each synthetic molecules is designed selectively to fit a natural receptor in the human body to trigger the pharmacological effects. The bioinspired strategy contains the hydrogel polymers which form the spatial arrangement of the active site, where the drug can bind and be loaded on the CLs. Molecular imprinted CLs mimic this environment in synthetic receptors for higher drug loading in the CLs ( Alvarez-Lorenzo et al., 2019 ).

Ocular Iontophoresis.

Ocular iontophoresis is a method for active drug delivery utilizing mild electric charges for effective delivery through the ocular barriers. Iontophoresis enhances ocular drug delivery by utilizing electroporation (electric field–induced ocular tissue structure alteration and pore formation), electrophoresis (direct application of electric field), and electro-osmosis (convective solvent flow through an applied electric potential). Iontophoresis is a noninvasive method having advantages over invasive techniques requiring surgical interventions. This technique of drug permeation can be used for anterior and posterior ocular disorders by utilizing trans-corneal and trans-scleral routes, respectively. Trans-corneal iontophoresis can be used for treatment of anterior segment disorders such as corneal ulcers, dry eye disease, ocular inflammation, keratitis, and ocular uveitis. Trans-corneal iontophoresis is unsuitable for posterior segment delivery due to the presence of barriers such as the lens diaphragm and iris-ciliary. However, the trans-scleral pathway allows drug transport at the back of the eye due to avoidance of anterior segment barriers ( Molokhia et al., 2013 ). The success of iontophoresis-mediated drug delivery depends on several factors, such as charge density of the intended molecule, electric current applied, duration of treatment application, and position of electrode placement ( Molokhia et al., 2007 ; Gratieri et al., 2017 ).

Eyegate Pharmaceuticals Inc. has developed trans-scleral iontophoresis for delivering drugs in the intended target tissues. The company conducted several clinical trials on the safety and efficacy of a dexamethasone phosphate (EGF-437) formulation for distribution through the EyeGate II Delivery System for the treatment of dry eye disease, anterior uveitis, cataract, postoperative pain, anterior chamber inflammation, and anterior scleritis ( NCT01129856 , NCT02517619 , NCT03180255 , NCT01059955 ). EGF-437 delivered through the EyeGate II Delivery System resulted in reduction of dose frequency as compared with standard dexamethasone eye drops. The US FDA has granted an orphan drug designation for the delivery of EGF-437 through the EyeGate II Delivery System as a treatment option for corneal graft rejection. Iontophoresis is a valuable treatment option for patients who are nonresponsive to eye drop therapy ( Kompella et al., 2010 ). The treatment also resulted in fewer incidences of increased IOP and controlled drug delivery with lower iontophoresis dose (mA-min) ( http://www.eyegatepharma.com/technology/iontophoresis-delivery-system/ ). Visulex-P (Aciont Inc.) and OcuPhor (Iomed Inc., Salt Lake City, UT) are ocular iontophoresis systems currently under investigation for trans-scleral iontophoresis.

Iontophoresis has certain advantages over other ocular drug-delivery modalities, including injections and topical drops. It can achieve higher bioavailability and reduced clearance as compared with topical eye drops. Treatment with the iontophoresis method usually has better patient compliance as compared with ocular injections. Nonetheless, certain patients screened for ocular iontophoresis experienced some discomfort and burning sensation ( Parkinson et al., 2003 ). Posterior segment ocular disorders such as AMD, DR, DME, and central retinal vein occlusion (CRVO) require sustained drug delivery at higher doses. Aciont Inc. has evaluated the potential of ocular iontophoresis for the treatment of AMD by a Visulex-I-noninvasive ocular drug device for the delivery of Avastin (bevacizumab) and Lucentis (ranibizumab) through the trans-scleral route ( https://www.sbir.gov/sbirsearch/detail/1070943 ) ( Pescina et al., 2010 ). Table 2 summarizes currently available ocular drug-delivery devices in clinical trials for the management of anterior segment disorders.

Currently available ocular drug-delivery systems in clinical trials for the treatment of anterior segment disorders ( Kang-Mieler et al., 2014 )

Posterior Segment Ocular Drug-Delivery Technologies

Novel drug-delivery systems, such as implants, are currently used by the clinicians to sustain and prolong drug release to cure back of the eye disorders such as DR, AMD, DME, retinal vein occlusion (CRVO), and posterior uveitis. Intravitreal implants are injected or surgically implanted in the vitreous humor of the eye. Intravitreal implants can prolong the drug action up to many months and reduce the need for frequent intravitreal injection of therapeutic agents. Such frequent administration can cause retinal detachment and retinal hemorrhage, and can be painful for the patients. Such disadvantages of intravitreal injections can be minimized with the use of intravitreal implants. The following section illustrates various intravitreal ocular implants currently available in the clinic and those under clinical investigation.

Durasert Drug-Delivery Technology System.

The Durasert technology system (pSivida Corp., Watertown, MA) delivers drugs at various predetermined time points depending on the implant design. The drug release ranges from days to years. Durasert consists of a drug core with surrounding polymer layers. The drug release is a function of the polymer layer permeability. Vitrasert (Bausch & Lomb) is the first intravitreal drug-delivery system loaded with an antiviral drug (ganciclovir) for the treatment of cytomegalovirus retinitis. It utilizes the Durasert technology system and releases the active drug through a small opening in the insert for a period of 6–8 months ( Chang and Dunn, 2005 ). The Retisert intravitreal implant (Bausch & Laumb, Inc.) is a steroid-eluting device implanted surgically in the vitreous humor. Retisert releases fluocinolone acetonide up to 3 years into the vitreous humor ( Jaffe et al., 2006 ; Kempen et al., 2011 ). Retisert has received a fast-track US FDA approval for treatment of posterior uveitis as an orphan drug treatment. Posterior uveitis, also called choroiditis, is the inflammation of the choroid capillaries. This can lead to damage to the optic nerve and permanent loss of vision. Retisert contains a fluocinolone acetonide tablet encapsulated within a silicone elastomer cup containing an orifice made with a polyvinyl alcohol membrane ( Haghjou et al., 2011 ).

Iluvien (fluocinolone acetonide intravitreal implant, Alimera Sciences, Inc.) is the most recent US FDA-approved intravitreal injectable insert indicated for the treatment of DME. Multicenter, randomized clinical trials demonstrated that both a low dose and high dose of Iluvien resulted in a significant visual improvement with lower side effects. The onset of treatment was very rapid. Patients suffering from DME for more than 3 years had received almost twice the treatment effectiveness as compared with the control group ( Campochiaro et al., 2012 ; Cunha-Vaz et al., 2014 ). Iluvien is being evaluated in phase II clinical trials for its efficacy of dry AMD ( NCT00695318 ), wet AMD ( NCT00605423 ), and macular edema secondary to RVO as compared with Lucentis (ranibizumab) treatment ( NCT00770770 ).

NOVADUR Drug-Delivery Technology.

The NOVADUR (Allergan Inc.) system consists of therapeutic agents in a polymer matrix of PLGA. PLGA is a biodegradable and biocompatible polymer which breaks down to lactic and glycolic acid when it comes in contact with the vitreous humor fluid ( Haghjou et al., 2011 ). Ozurdex (Allergan) is a controlled-release intravitreal dexamethasone implant approved by the US FDA for the treatment of DME, RVO, and posterior uveitis ( Haller et al., 2011 ; Boyer et al., 2014 ; Sangwan et al., 2015 ). Ozurdex contains 0.7 mg of dexamethasone in a PLGA matrix which releases the drug up to 90 days. Mayer et al. (2012) recently investigated the effects of intravitreal bevacizumab followed by Ozurdex and Ozurdex monotherapy for the treatment of CRVO and macular edema. The research group concluded that there was no difference between the aforementioned treatment strategies for treatment of CRVO. However, for branched retinal vein occlusion, Ozurdex monotherapy resulted in a better functional outcome ( Mayer et al., 2012 ). Currently, a phase III clinical trial is being conducted for the possible effectiveness of intravitreal implant of Ozurdex monotherapy for the treatment of DME ( NCT00168389 ). PLGA containing brimonidine tartrate (Allergan) is another intravitreal implant in clinical trials for dry AMD ( NCT00658619 ) and retinitis pigmentosa ( NCT00661479 ). Brimonidine is an α 2 adrenergic agonist which releases neurotrophic factors such as ciliary neurotrophic factor and brain-derived neurotrophic factor ( Kim et al., 2007 ). Brimonidine protects retinal cells like photoreceptor cells, RPE and ganglion cells from apoptotic cell death. ( Zhang et al., 2009 ).

I-vation Triamcinolone Acetonide Drug-Delivery Technology.

I-vation TA (SurModics Inc.) is also an intravitreal drug-delivery implant for triamcinolone acetonide (TA). I-vation is a titanium helical coil implant coated with TA in a nonbiodegradable polymer. Preclinical experiments suggested that I-vation TA can sustain TA release in vivo up to 2 years. A phase I safety and preliminary efficacy study was conducted in 31 patients with DME after implantation of I-vation TA. The TA intravitreal implant was well tolerated by the patients as indicated by a minimal rise in IOP. The I-vation TA treatment also aided the reduction of macular thickness from baseline, indicating alleviation of DME ( Dugel et al., 2009 ).

Encapsulated Cell Technology.

Renexus (NT-501) is an encapsulated cell technology (ECT) for ocular implant of human RPE transfected with plasmid encoding ciliary neurotrophic factor. Renexus (NT-501) is under a phase III investigation for dry AMD, glaucoma, and retinitis pigmentosa ( NCT03316300 ). The implant consists of a hollow tube capsule consisting of a polymeric matrix which can be loaded with genetically modified cells ( Sieving et al., 2006 ; Emerich and Thanos, 2008 ). Various biocompatible polymers such as collagen and hyaluronic acid hydrogel are used for forming the ECT matrix. The implant capsule is semipermeable, allowing diffusion of proteins across the membrane but inhibiting the entry of immune cells. The genetically modified cells in the matrix draw nutrients from the surrounding tissue after implantation. The encapsulated cell technology is implanted in the pars plana and affixed to the sclera.

ECT can be advantageous as compared to other corticosteroid implants as they can secrete biologically active molecules for a prolonged period of time, requiring less frequent implant replacement. Kontturi et al. (2015) demonstrated genetically modified RPE capable of secreting soluble VEGF receptor to suppress VEGF activity in choroidal neovascularization and retinal neovascularization. This proof-of-concept study indicated that the human RPE cell line remained viable with a constant secretion of soluble VEGF-1 receptor up to 50 days ( Kontturi et al., 2015 ). Although the researchers found a modest VEGF inhibition in vivo model, this delivery technology displays promise for utilization of ECT to treat disorders such as wet AMD, DR, and DME. ECT can be considered as a versatile platform that can be used for secreting targeted therapeutic biotech drugs such as antibodies, antibody fragments, growth factors, cytokines, and prostaglandins for back of the eye disorders ( Tao, 2006 ). Wong et al. formulated an injectable composite alginate-collagen (CAC) matrix ECT gel having human retinal pigment epithelial cells and glial cell–derived neurotrophic factor (GDNF) secreted by HEK293 cells. The GDNF-secreting HEK293 cells were transfected with lipofectamine repressor (Tet R) DNA and pro–caspase 8 transcription DNA. Tet R can be used as a biosafety switch for the ECT drug-delivery system, whereas pro–caspase 8 can trigger the in-built apoptotic pathway in the retinal cells. The researchers witnessed a continuous supply of bioactive glial cell–derived GDNF in vitro and effective proliferation control in rat ocular tissues. Intravitreal injections of CAC ECT in rats with retinal damage resulted in decreased apoptosis of photoreceptor and retinal function loss. Similarly, dual intravitreal injections of the ECT resulted in further reduction of photoreceptor death and gain of retinal structure and function without compromising gel viability ( Fig. 3 ). The CAC ECT demonstrated high encapsulation efficiency of the transfected cells, high cell viability, and high mechanical stability of the implant without the use of immunosuppressant ( Wong et al., 2019 ). Thus, ECT can be considered as a safe, effective, and well controlled platform for the treatment of back of the eye disorders with retinal dysfunction ( Baranov et al., 2017 ).

ECT for back of the eye disorders. CAC ECT gel treatment on rats with inherited retinal degeneration. One or two units of GDNF-delivering CAC ECT gel was intravitreally injected into the eyes of dystrophic RCS/lav rats. (A) Representative H&E sections of nontreated, single, and double gel-treated rats showed different degrees of photoreceptor nuclei retention and organization in the outer nuclear layer (ONL). (B) ONL nuclei density was calculated by normalizing ONL count with retinal length. (C) Representative images showing the distribution of apoptotic cells (green) in the retina of nontreated, single, and double gel-treated animals detected by terminal deoxynucleotidyl transferase–mediated digoxigenin-deoxyuridine nick-end labeling (TUNEL) assay with 4’,6-diamidino-2-phenylindole (DAPI) nuclear counterstaining. (D) Density of apoptotic cells in the ONL. (E) Representative scotopic and photopic electroretinogram wave forms showing the retinal function of dystrophic rats receiving 1 or 2 U of GDNF-secreting gel. (F) Scotopic a-wave. (G) Scotopic b-wave. (H) Photopic b-wave. # P < 0.05; * P ≤ 0.02; ** P ≤ 0.005; *** P < 0.0005 by one-way ANOVA with Bonferroni post hoc test ( Wong et al., 2019 ). ERG, electroretinogram; INL, inner nuclear layer.

Suprachoroidal Drug Delivery Utilizing Hollow Microneedles and Microsurgical Cannulas.

Delivery of therapeutics at the suprachoroidal space has demonstrated promising potential for delivering therapeutic agents at the target tissue (retina and choroid) at a higher concentration. This can be confirmed from anatomic studies demonstrating the diffusion of therapeutic agents after drug delivery at the suprachoroid space ( Patel et al., 2012 ; Kadam et al., 2013; Chiang et al., 2016 ). Patel et al. (2012) demonstrated suprachoroid drug delivery through the posterior pars plana of a rabbit model using a hollow microneedle. The suprachoroid drug delivery was a minimally invasive procedure demonstrating safe delivery into the retina and choroid with no adverse effects. Gilger et al. (2013) reported the successful suppression of acute inflammation with corticosteroid delivered through the suprachoroid route in a porcine model of noninfectious posterior uveitis. Drug delivery through the suprachoroid route utilizing microsurgical cannulas in primate and procaine models has shown increased drug bioavailability. The researchers investigated delivery of triamcinolone acetonide and bevacizumab to evaluate the tolerability, safety, efficacy, and pharmacokinetics of suprachoroidal drug-delivery technology. Higher bioavailability of triamcinolone acetonide at the target tissue without deleterious side effects such as cataract and hypertension suggests its positive impact ( Olsen et al., 2006 ). In contrast, bevacizumab demonstrated low bioavailability at target tissue with faster diminishing therapeutic response as compared with intravitreal injections ( Olsen et al., 2011 ). Currently, various phase III clinical trials utilizing triamcinolone acetonide suprachoroidal injection along with various anti-VEGF agents are being investigated for the treatment of DME and posterior uveitis ( NCT03203447 , NCT02980874 , NCT01789320 ). Table 3 summarizes currently available ocular drug-delivery systems in clinical trials for the treatment of posterior segment disorders.

Currently available ocular drug-delivery systems in clinical trials for the treatment of posterior segment disorders ( Kang-Mieler et al., 2014 )

• Novel Ocular Drug-Delivery Technologies

Colloidal Nanocarriers for Anterior Segment Disorders

The chronic nature of many ocular disorders requires frequent and prolonged drug treatments. Along with this, ocular barriers reduce the bioavailability of the topically applied therapeutic agents to less than 5%. Recent developments in nanotechnology can provide opportunities to overcome drawbacks and limitations of conventional drug-delivery systems, such as low drug bioavailability and low drug permeation through ocular barriers. Nanocarriers can prolong drug action by sustained and controlled release of the drug, protect the drug from ocular enzymes, and aid in overcoming ocular barriers. This can greatly reduce the frequency of dosing and improve tissue concentrations of the drug for better pharmacological action. Colloidal nanocarriers including nanoparticles, nanomicelles, nanowafers, and microneedles are capable of encapsulating small molecules and biotech drugs for ocular delivery. The size of the nanocarriers ranges from 1 to 1000 nm. Nanoparticles greater than 10 µ m can cause foreign body sensation and ocular irritation ( Ali and Lehmussaari, 2006 ; Liu et al., 2012 ). Nanocarriers can also improve the ability of drug penetration into the deeper ocular tissues, decrease drug toxicity, and reduce precorneal drug loss taking place due to rapid tear turnover. Nanocarriers engineered from biodegradable and biocompatible polymers overcome ocular barriers and result in higher drug absorption in the anterior and posterior segments of the eye ( Reimondez-Troitiño et al., 2015 ). Nanomedicine for ocular drug delivery can be highly patient compliant and have a higher tolerability than conventional eye drops for anterior segment ocular disorders ( Vandervoort and Ludwig, 2007 ; Bachu et al., 2018 ; Mandal et al., 2019a ).

Nanomicelles.

Nanomicelles are colloidal drug-delivery systems that self-assemble in a solution and can entrap therapeutic agents at their core. Their size ranges from 10 to 200 nm, and they are made up of amphiphilic surfactants or block copolymers. Nanomicelles are formed instantaneously in a solution when the concentration of the polymers is above a specific concentration called the critical micellar concentration. Nanomicelles have the capacity to encapsulate hydrophobic drugs in the hydrophobic core of the micelles due to hydrophobic interactions. The hydrophilic corona interacts with the external aqueous fluid, increasing the solubility of a relatively lipophilic drug. This colloidal dosage form has the ability to form clear aqueous solutions which can be used as topical eye drops. Nanomicelles can be broadly classified as surfactant nanomicelles and polymeric nanomicelles. Cequa (Sun Pharmaceuticals Inc.) is a nanomicellar formulation of 0.09% cyclosporine-A recently approved by the US FDA for dry eye disease. Cequa demonstrated improved rapid onset of action as early as 4 weeks and improvement in tear production as compared with cyclosporine-A emulsion in phase II and phase III clinical trials ( Mandal et al., 2019a ). The in vivo studies of the nanomicellar formulation of cyclosporine-A conducted in rabbits demonstrated enhanced bioavailability in the anterior ocular tissues as compared with cyclosporine-A emulsion with no ocular adverse effects. Here, the nanomicellar system was prepared from a polymeric mixture of two low-molecular-weight surfactants, hydrogenated castor oil-40 and octoxynol-40, which resulted in formation of a clear solution of cyclosporine-A. Mitra et al. demonstrated efficient encapsulation and enhanced ocular pharmacokinetics of hydrophobic drugs such as voclosporin, cyclosporine-A, rapamycin, triamcinolone acetonide, cidofovir prodrug, and curcumin for the treatment of various anterior and posterior ocular disorders neutrotropic. Various surfactant polymers such as vitamin E tocopheryl polyethylene glycol succinate (Vit E TPGS); hydrogenated castor oil-40,60,100; and octoxynol-40 were used for entrapping hydrophobic drugs in the nanomicellar core ( Cholkar et al. 2015 , Mandal et al., 2017b , 2019b , Trinh et al., 2017 ). Mandal et al. demonstrated the entrapment of hydrophobic drug and hydrophilic peptides within the core of nanomicelles for ocular drug delivery. A lipid prodrug of cyclic cidofovir (B-C12-cCDF) was encapsulated within surfactant-based nanomicelles for antiviral drug delivery for cytomegalovirus retinitis, and multilayered nanomicelles were developed for the delivery of octeriotide peptide to the anterior segment of the eye ( Mandal et al., 2017b ). The researchers also demonstrated that a mixed micellar structure designed from a fixed ratio of low-molecular surfactants had a lower critical micellar concentration. This indicates that the nanomicellar structure is stable over dilution in the systemic fluids and will not result in premature drug release. These highly lipophilic agents form a clear solution when encapsulated in the nanomicelles. Also, nanomicelle aid is sustained, and release of the drug to the ocular tissue is controlled ( Cholkar et al., 2015 ; Mandal et al., 2017b , 2019b ; Trinh et al., 2017 ).

Nanomicelles constructed from block copolymers such as PLGA, polyethylene glycol (PEG), polycaprolactone (PCL), and polylactide are called polymeric nanomicelles. The polymers can be conjugated to form diblock (A-B type), triblock (A-B-A), or pentablock (A-B-C-B-A) copolymers. Block polymers have distinct hydrophilic and hydrophobic parts which impart the polymer amphiphilicity. Nanomicelles can solubilize hydrophobic drugs and improve their delivery to the ocular tissues. Methoxy poly(ethylene glycol) poly(lactides) diblock copolymer was used for constructing polymeric nanomicelles of Cyclosporine-A for efficient drug supply to the anterior ocular segment. The in-vivo results demonstrated excellent ocular biocompatibility and high ocular bioavailability of the nanomicellar formulation. The results suggested that methoxy poly(ethylene glycol) poly(lactides) nanomicelles encapsulating cyclosporine-A can be used for treatment of dry eye disease, prevention of corneal graft rejection, and treatment of autoimmune uveitis ( Di Tommaso et al., 2011 ). Polymeric micelles often offer certain advantages over surfactant micelles, such as sustained drug release and lower incidence of drug toxicity, whereas surfactant nanomicelles offer advantage of smaller nanomicellar size and rapid onset of action. Both surfactant and polymeric nanomicelles can be surface conjugated with various targeting moieties for higher drug transport through the ocular tissue ( Yellepeddi and Palakurthi, 2016 ). Nanomicellar delivery of nucleic acids like siRNA, microRNA, plasmidDNA, and oligonucleotides is an emerging field of research. Liaw and Robinson used a nonionic copolymeric system, poly (ethylene oxide)-poly (propylene oxide)-poly (ethylene oxide) (PEO-PPO-PEO) for gene delivery ( Liaw, Chang, and Hsiao, 2001 ). The polymeric nanomicelles encapsulated plasmid DNA with lacZ gene demonstrating greater delivery of the therapeutic cargo to the cells ( Tong et al., 2007 ) Nanomicelles also reduce drug toxicity, reduce drug degradation, improve drug permeation through the ocular tissues, and thus improve ocular bioavailability of lipophilic potent drugs ( Mandal et al., 2019a ).

Nanoparticles.

The size of drug-loaded nanoparticles can range from 50 to 500 nm to effectively overcome ocular barriers and to deliver the drug to the ocular tissue either by passive or active transport. A solution of nanoparticles (NPs) can be deposited in the cul-de-sac to attain sustained drug delivery over a prolonged period of time. The surface charge of the NPs highly influences their efficient ocular absorption. The cornea and the conjunctival tissues have a negatively charged surface. It is observed that cationic NPs have a higher retention time on ocular surfaces as compared with anionic NPs. This can enhance the drug permeation into the ocular surfaces ( Akhter et al., 2016 ). Colloidal NPs can also increase the solubility of highly hydrophobic drugs and increase the trans-corneal permeability of such agents. Various biodegradable and nonbiodegradable NPs for treating anterior and posterior segment ocular disorders have been developed. The commonly used polymers for nanoparticle (NP) ocular applications are PLGA, PEG, PCL, chitosan, albumin, and gelation ( Table 1 ). PLGA polymer is widely used for encapsulating various small-molecular and biotech drugs intended to treat anterior and posterior ocular disorders. PLGA undergoes biotransformation in vivo to form lactic and glycolic acid having minimal systemic toxicity. Hence, PLGA is widely used for ocular drug delivery. PLGA nanoparticles encapsulating anti-inflammatory corticosteroid fluocinolone acetonide were prepared by Guo et al. (2019) for the treatment of posterior uveitis and autoimmune uveitis ( Fig. 4 ). Cañadas et al. (2016) estimated the delivery of pranoprofen, a nonsteroidal anti-inflammatory drug entrapped in PLGA NPs. The in vitro study on a human retinoblastoma cell line demonstrated lower toxicity of pranoprofen PLGA NPs on the cells as compared with the free drug. Pranoprofen PLGA NPs were further demonstrated to be effective in corneal penetration on an ex vivo bovine model as compared with the drug alone. In vivo ocular anti-inflammatory activity and ocular pharmacokinetics of the formulation were studied in rabbit eyes. The corneal penetration of pranoprofen NPs was 4 times higher and had a quick onset of anti-inflammatory action. Pranoprofen NPs also showed prolonged retention on the corneal surface of the rabbit eyes, which resulted in significant reduction of corneal inflammation ( Cañadas et al., 2016 ). Connexin43 mimetic peptide has demonstrated efficacy in improving retinal ganglion cell survival after retinal ischemia. Rupenthal et al. and Bishat et al. evaluated connexin43 mimetic peptide PLGA NPs for retinal ischemia in zebrafish and live embryos. The study resulted in no toxicity to the ocular tissues ( Chen et al., 2015 ; Bisht and Rupenthal, 2018 ). Qiu et al. (2019) developed fenofibrate PLGA nanoparticles for the management of DR and AMD. Fenofibrate is an agonist of peroxisome proliferator-activated receptor α and has efficacy against DR. The in vivo studies in diabetic rats reduced retinal vascular leakage, ameliorated retinal dysfunctions, and downregulated the overexpressed VEGF-A and ICAM-1 at 8 weeks after one intravitreal injection of fenofibrate PLGA NPs ( Qiu et al., 2019 ). PLGA can also be used to encapsulate many well known anti-VEGFs, such as bevacizumab, ranibizumab, and aflibercept ( Elsaid et al., 2016 ; Sousa et al., 2017 ; Kelly et al., 2018 ). However the major problem associated with the intravitreal delivery of NPs is the floating of the particles in the vitreous humor and vision obstruction ( Bachu et al., 2018 ) ( Fig. 5 ).

TA-encapsulated methoxy PEG (mPEG)–PLGA nanoparticles for treating experimental autoimmune uveitis (EAU). (A–D) photographs taken by a hand-held retinal camera on day 12 after treatments: the EAU group (A), the mPEG-PLGA nanoparticle–treated group (B), the TA injection–treated group (C), the TA-loaded mPEG-PLGA nanoparticle–treated group (D), and clinical scores in the different groups (E).

In vivo efficacy of PLGA fenofibrate NPs (Feno-NP) on vascular leakage and vascular permeability measured with Fundus Fluorescein Angiography (FFA). Formation of subretinal neovascularization (SRNV) and intraretinal neovascularization (IRNV) evaluated by neovascular tufts in flat-mounted choroid and retina in Vldlr−/− mice 1 month after Feno-NP treatment. (A) Representative images of FFA. (B) Numbers of leakage spots in FFA. (C) Quantification of retinal vascular permeability. (D) Representative images of SRNV and IRNV in FFA. Scale bar, 1000 μ m. (E) Quantification of SRNV and IRNV in flat-mounted choroid and retina. Mean ± S.E.M. ( n = 8–16; one-way ANOVA followed by Bonferroni post hoc test). *** P < 0.001 vs. untreated Vldlr−/− mice; ### P < 0.001 vs. blank-NP–treated Vldlr−/− mice ( Qiu et al., 2019 ).

Nonsteroidal anti-inflammatory drugs such as ibuprofen, indomethacin, and flurbiprofen encapsulated in NPs can be used for the treatment of anterior segment ocular inflammation. Ibuprofen encapsulated in Eudragit RS100 (Evonik Health Care) NPs demonstrated improved drug concentrations in the aqueous humor of rabbit eyes in comparison with ibuprofen ocular solution (Pignatello et al., 2002). Eudragit RS100 was used to prepare flurbiprofen NPs for lowering anterior segment inflammation after surgical trauma. In vivo studies performed in rabbits demonstrated higher aqueous humor concentrations of flurbiprofen as compared with the control group ( Pignatello et al., 2002a , b ; Gupta et al., 2007 ; Cao et al., 2010 ). Biodegradable polymers such as PCL, PEG, PLGA, and poloxamer 188 were used for formulation of flurbiprofen-encapsulated nanoparticles. Topical administration of flurbiprofen nanoparticles demonstrated enhanced anti-inflammatory efficiency and minimal toxicity, such as ocular irritation, in the rabbit eyes ( Calvo et al., 1996 ; Valls et al., 2008 ). Chitosan is also a widely used anionic biocompatible and biodegradable polymer used to prepare NPs and can improve their precorneal residence time. Cyclosporine-A is a strong immunosuppressive agent which is used to treat dry eye disease. Chitosan can be used to prepare NPs entrapping cyclosporine-A, which has shown 2-fold improved precorneal residence and higher conjunctival permeability in rabbit eyes. Chitosan polymer can also be used for the delivery of lipophilic drugs, hydrophilic drugs, and polynucleotides to the anterior ocular surface ( De Campos et al., 2001 ; de la Fuente et al., 2010 ). Mitra et al. developed pentablock copolymers from polymers such as PEG, polylactide, PGA, PCL, and PLGA for making nanoparticles encapsulating hydrophilic drugs such as dexamethasone and macromolecules such as IgG, IgG(Fab), and various peptides for controlled drug delivery to the anterior as well as posterior sections of the eye ( Patel et al., 2016 ; Agrahari et al., 2017 ). Glaucoma is the leading cause of blindness throughout the world. Li et al. (2019) created a mouse model of glaucoma demonstrating elevated intraocular pressure after the administration of dexamethasone nanoparticles composed of pentablock copolymers. This can streamline the clinical evaluation of drug candidate for glaucoma ( Li et al., 2019 ). Current research is utilizing ligand-targeted functionalized nanoparticles for enhanced delivery of therapeutic agents as compared with nonfunctionalized nanoparticles. Targeting ligands can specifically target receptors and nutrient transporters on the conjunctiva and corneal surface. The CD44 hyaluronic acid receptor is located on the corneal and conjunctival cells. It was proven that hyaluronic acid surface–functionalized chitosan NPs encapsulating an oligomer demonstrated higher uptake in the ocular tissues as compared with NPs not surface functionalized with hyaluronic acid. Such NPs undergo active transportation mediated by the CD44 hyaluronic acid receptor utilizing the caveolin-dependent endocytosis pathway ( Contreras-Ruiz et al., 2011 ). Surface-functionalized nanoparticles with targeting agents such as peptides, antibodies, vitamins (such as biotin and folic acids), and aptamers have resulted in higher uptake as compared to the nonfunctionalized nanoparticles. Kompella et al. (2006) demonstrated that transferrin-conjugated NPs had 74% higher transport across the cornea and conjunctiva in ex vivo bovine eyes as compared with nontargeted NPs. Epigallocatechin-3-gallate is a natural polyphenol compound having antioxidant, anti-inflammatory, and antiangiogenesis activity and can have efficacy against CNV. Gelatin NPs were surface functionalized with hyaluronic acid and conjugated to an RGD peptide. Encapsulated epigallocatechin-3-gallate-RGD peptide was evaluated for treatment of corneal neovascularization (CNV). Lee et al. In vivo studies in a CNV mouse model showed fewer and thinner blood vessels for mice treated with topical epigallocatechin-3-gallate-RGD peptide NPs as compared with the blank NPs ( Lee et al., 2014 ). This result suggests a potential role of targeted nanoparticles for the treatment of CNV. Active targeting of NPs can provide efficient and rapid transport of cargo across the corneal and conjunctival epithelium. Nanoparticles can also serve as an effective vehicle for gene delivery. Gold NPs conjugated to a 2-kD polyethylenimine were evaluated for gene delivery to rabbit cornea. The researchers observed a high uptake of the gold NPs through the rabbit stroma and a gradual clearance over time ( Sharma et al., 2011 ).

Liposomes are used as ocular drug-delivery vehicles which can encapsulate hydrophilic and hydrophobic drugs. Polymers from a liposome form a lipid bilayer vesicle which separates the inner aqueous core from the exterior aqueous environment. Although liposomes have poor stability and a short half-life, they have been explored for ocular drug delivery for anterior segment disorders ( Law et al., 2000 ). Sun et al. (2008) entrapped short-chain-conjugated ceramide and C6-ceramide in liposomes and applied to the treatment of corneal inflammation in mice. Ceramides are known for their role as an antiproliferative and proapoptotic agents in sphingolipid metabolism. The C6-ceramide liposomal formulation demonstrated significant efficacy in corneal inflammation reduction in a murine model ( Sun et al., 2008 ). This implies an affirmative role of ceramide-loaded liposomes for treating anterior segment ocular inflammation ( Sun et al., 2008 ) ( Table 4 ). Hathout et al. (2019) showed that timolol maleate gelatinized liposome treatment resulted in lowering the IOP when evaluated in vivo on the eyes of glaucomatous rabbits. Song et al. developed a tocopheryl polyethylene glycol succinate (TPGS) modified nanoliposome ocular drug-delivery system for brinzolamide for the treatment of glaucoma. White New Zealand rabbits treated with brinzolamide liposomes maintained an effective reduction in IOP after drop instillation. Such results indicate a high potential for clinical translation for liposomal drug delivery of hydrophilic agents for the treatment of glaucoma. Ren et al. investigated azithromycin liposomes for the treatment of dry eye disease. In vivo pharmacodynamic studies in rats showed a reduction in the symptoms of dry eye disease, and the azithromycin liposomal treatment had higher safety and efficacy as compared with hyaluronic acid sodium eye drops ( Ren et al., 2018 ). Topical voriconazole liposomes were developed by de Sá et al. (2015) for fungal keratitis treatment. Liposome-mediated ocular drug delivery was also explored for posterior segment drug delivery. Bevacizumab (Avastin) was encapsulated by annexin A5–conjugated liposomes for drug delivery to the back of the eye by Davis et al. (2014) . The study reported that topical application of the liposomes could successfully deliver bevacizumab to the retinal tissue with a final concentration of 127 ng/g in rat retinal tissue and 18 ng/g in rabbit retinal tissue ( Davis et al., 2014 ).

Ocular drug-delivery systems investigated for anterior segment disorders (inflammation) ( Cholkar et al., 2013 )

Dendrimers.

Dendrimers are polymeric nanocarriers having a branched star-shaped structure. The size and shape of the dendrimer can be controlled and customized during the synthesis to form a dendrimer with specific functional groups and a specific architecture. These nanoconstructs have unique physiochemical properties such as high drug encapsulation and conjugation ability, high water solubility, monodispersity, and a plethora of functional groups on the surface for chemical modification. Hydrophilic and lipophilic drugs can either be conjugated to the surface of the dendrimer or be encapsulated by caging in the internal structure of the dendrimer ( Kalomiraki et al., 2015 ; Lancina and Yang, 2017 ). A polyamidoamine (PAMAM) polymer having carboxylic and hydroxyl functional groups is the most commonly used dendrimer for ocular drug delivery. High branching of the PAMAM polymer can lead to primary, secondary, and tertiary generations of the dendrimer nanocarrier. Soiberman et al. (2017) designed a gel formulation of the G4-PAMAM dendrimer with cross-linked hyaluronic acid, entrapping dexamethasone intended for the treatment of corneal inflammation. Subconjunctival injection of the dendrimer formulation led to reduction in central corneal thickness and improved corneal clarity in an alkali burn rat model, which was highly clinically relevant ( Soiberman et al., 2017 ). Another group of investigators evaluated the potential of dexamethasone-PAMAM dendrimers for the delivery to the back of the eye for the treatment of diseases such as DR and AMD. In vivo studies in rats showed that the drug-loaded dendrimers enhanced the ocular permeability of dexamethasone after subconjunctival injection as compared with the free drug ( Yavuz et al., 2016 ). Matrix metalloproteinases-9 (MMP-9) can trigger corneal damage and result in dry eye disease. Cerofolini et al. (2017) synthesized an MMP-9 inhibitor and solubilized with PAMAM dendrimers. The synthesized inhibitor had high binding affinity to MMP-9 and can be used for the treatment of corneal inflammation and dry eye disease ( Cerofolini et al., 2017 ). Vandamme and Brobeck (2005) entrapped tropicamide and pilocarpine nitrate in PAMAM dendrimers to study the effect of drug-release kinetics after altering the size, molecular weight, carboxylate and hydroxyl surface groups, and total number of amines present in the PAMAM dendrimer. In vivo results in New Zealand albino rabbits revealed higher drug residence time of dendrimers functionalized with carboxylic and hydroxyl functional groups ( Vandamme and Brobeck, 2005 ).

Microneedles.

Microneedle drug-delivery technology was originally used for overcoming the stratum corneum and was used for transdermal drug delivery ( Lee et al., 2008 ). The effectiveness of microneedles for transdermal drug-delivery systems inspired researchers to investigate their potential to treat anterior and posterior segment ocular disorders. This minimally invasive technique can also be applied for ocular drug delivery of hydrophilic and hydrophobic drugs. Solid stainless-steel microneedles (MNs) coated with drugs such as sunitinib malate and pilocarpine resulted in higher drug bioavailability in the anterior ocular segment compared with topical drop applications in vivo ( Jiang et al., 2007 ; Song et al., 2015 ). Microneedles can also be used to deliver therapeutic agents for the treatment of back of the eye disorders. Microneedle nanoparticles and microparticle suspension can be delivered to the suprachoroidal space ( Patel et al., 2011 ). Than et al. (2018) have shown a polymeric eye patch consisting of an array of detachable and biodegradable MNs for controlled and localized ocular drug delivery. These MNs could penetrate into the corneal layers and deliver antiangiogenic monoclonal antibody (DC101) for the treatment of CNV. The MNs were double layered with DC101 to provide biphasic drug-release kinetics to enhance the therapeutic efficacy of the MNs. The DC101 MN eye patch produced approximately 90% reduction in CNV in a CNV disease mouse model as compared with a topical eye drop. The researchers also suggested that the MN patch is minimally invasive and can be self-applied by patients on their corneas ( Than et al., 2018 ). Microneedles can greatly aid in increasing the bioavailability of a certain drug in a particular tissue by localizing the drug-delivery system. Microneedles can be a paradigm shift for the way ocular formulations are administered, but their current limitations demand further research in the field for desired clinical translation ( Thakur Singh et al., 2017 ) ( Fig. 6 ).

Microneedles for enhanced drug delivery to the cornea. Drug-loaded, DC101, and diclofenac microneedle (DL-MN) patch for synergistic effect. Mouse eyes were treated 2 days after being inflicted with alkali burn and examined on day 7. (A) Illustration of drug loadings in DL-MNs and representative images of differently treated eyes. (B) Quantifications of corneal neovascularization. The white dotted lines indicate the extent of neovascular outgrowth from the limbus. Statistical comparison between groups was performed using one-way ANOVA. * P < 0.05; ** P < 0.01 vs. control; # P < 0.05; ## P < 0.01 between indicated pairs ( Than et al., 2018 ). Diclo, Diclofenac; ED, eye drop; HA, hyaluronic acid; MeHA, methacrylated hyaluronic acid.

Nanowafers.

Nanowafers are small, transparent, rectangular membranes or circular discs containing drug loaded into nanoreservoirs which can be smeared on the ocular surface using a fingertip. Controlled drug release from the nanowafer can increase the residence and contact time of the drug with the corneal and conjunctival surfaces. This can aid in higher drug absorption into anterior ocular tissues. The nanowafer not only enhances the drug bioavailability but also acts as a protective polymer membrane to heal injured and abraded corneal surfaces commonly found in CNV and dry eye disease. This novel nanocarrier is designed from biodegradable and biocompatible polymers which can be eliminated over a period of time. Coursey et al. (2015) and Bian et al. (2016) developed a dexamethasone-loaded nanowafer (Dex-NW) for the treatment of dry eye disease. The nanowafer was fabricated using carboxymethyl cellulose polymer and consisted of an array of nano drug reservoirs filled with dexamethasone. The in vivo efficacy of Dex-NW was tested in a dry eye disease mouse model. Dex-NW was administered as once-a-day treatment on alternating days for a 5-day period of time. After the treatment duration, it was observed that Dex-NW was able to restore the corneal barrier function along with a healthy ocular surface which was similar to twice-a-day treatment of topically applied dexamethasone eye drops. Yet another interesting finding the scientists reported was that Dex-NW was effective in lowering the overexpression of inflammatory cytokines such as tumor necrosis factor- α , interferon- γ , interleukin-1 β , and interleukin-6. Also, the expression of inflammatory chemokines such as CXCL-10, CCL-5, and MMP-3 and MMP-9 was lowered ( Coursey et al., 2015 ; Bian et al., 2016 ). Axitinib-loaded nanowafers were developed by Yuan et al. for the treatment of CNV ( Yuan et al., 2015 ). A murine ocular burn model was used to evaluate the in vivo efficacy of axitinib-loaded nanowafers. The laser-scanning confocal imaging and reverse-transcription polymerase chain reaction results revealed that the once-a-day axitinib-loaded nanowafer was twice as effective as compared with axitinib daily topical eye drops ( Yuan et al., 2015 ). These findings have shown the potential of nanowafers for further evaluation in clinical trials.

Ocular Nanocarriers Currently Approved and under Clinical Investigation.

Nanocarriers, such as nanoparticles and nanomicelles, have been widely explored for their potential to cure anterior and posterior ocular disorders. Despite the plethora of research on nanocarriers, Cequa (0.09% cyclosporine-A ophthalmic nanomicellar solution) is the only nanotechnology-derived ophthalmic approved by the US FDA for dry eye disease (Cequa, 2018). Cequa is a preservative-free, clear, and sterile nanomicellar formulation of a highly hydrophobic drug, cyclosporine-A. The phase III clinical trials of Cequa were conducted in a total of 745 patients with dry eye disease. The study showed a statistically ( P < 0.0001%) significant increase in the primary endpoints of the study, Schirmer’s test (measurement of tear production), and secondary endpoints. Instillation site pain (22%) and hyperemia (6%) were the adverse effects noted with the clinical trial, which are a common scenario for the drugs evaluated in this category ( Sheppard et al., 2014 ; Tauber et al., 2015 ). The phase III results clearly established the safety and efficacy of Cequa (0.09% cyclosporine-A ophthalmic nanomicellar formulation) in mitigating the signs and symptoms of dry eye disease ( Mandal et al., 2019a ).

There are a handful of ophthalmic nanocarrier drugs currently being investigated in clinical trials to establish their safety and efficacy for the treatment of ocular disorders. A randomized, single-blind study is evaluating the efficacy of hydrating polymers and polyunsaturated fatty acid microemulsion for the treatment of dry eye disease ( NCT02908282 ). In a yet another randomized, single-blind phase II clinical trial, urea-loaded nanoparticles are being evaluated as a possible treatment of cataract management ( NCT03001466 ). A clinical study was conducted by Sun Yat-sen University to compare the efficacy of two tear substitutes, Tears Naturale Forte (Alcon Laboratories Inc.) and Liposic (Bausch & Lomb), for dry eye diseases ( NCT02992392 ). Aston University evaluated the efficacy of liposomal spray for dry eye disease in an interventional randomized study ( NCT02420834 ). Kala Pharmaceuticals (Waltham, MA) has developed nanoparticle-based mucus-penetrating particles of loteprednol etabonate (LE). LE is a corticosteroid, and encapsulating in mucus-penetrating particles can improve drug delivery across the ocular endothelial cells. Currently, Kala Pharmaceuticals is investigating the potential of Inveltys (KPI-121 1.0% LE) for relieving inflammation following ocular surgery ( NCT02793817 ) and KPI-121 0.25% LE for alleviating the symptoms of dry eye disease in a phase III clinical trial ( NCT03616899 ). The effect of KPI-121 1.0% and 0.25% LE is also being investigated for the treatment of diabetic macular edema and retinal vein occlusion ( NCT02245516 ).

Fewer nanoformulations in clinical trials can be attributed to the limitations in the industrial development and scale-up of nanoparticles. Another major challenge involved in the clinical translation of nanoparticles is the toxicity profile of various polymers used in nanoparticles ( Suresh and Sah, 2014 ). The majority of nanoparticles for ocular drug delivery are evaluated for their efficacy in vivo in mice, rats, and rabbits. Although rabbit ocular anatomy is similar and comparable to human ocular anatomy, rabbit ocular anatomy does not completely mimic human ocular anatomy. Rabbits have higher mucus production, higher surface sensitivity, and lower rate of blinking, which can result in better drug retention and drug penetration in comparison to human eyes ( Weng et al., 2017 ). It is also a challenge to achieve homogeneity of particle size and particle-size distribution for a nanoparticle formulation on an industrial scale. Optimization of various formulation parameters for nanoparticle preparation is still a challenging task for many pharmaceutical scientists. Dendrimers have been shown to cause blurring of vision ( Wadhwa et al., 2009 ). On the other hand, liposomes have limited long-term stability and lower drug-loading potential. Higher concentrations of surfactants in the nanoformulation can be associated with potential ocular toxicity ( Bachu et al., 2018 ). The recent US FDA approval of Cequa has led to an inception of the era of nanotechnology in ophthalmology. Despite limiting factors for the successful clinical translation of nanomedicine for ophthalmology, one can predict nanotechnology products being approved for ocular ailments in the near future ( Fig. 7 ).

Comparison of cyclosporine-A nanomicellar formulation (OTX-101, Cequa) and cyclosporine-A emulsion (Restasis) evaluated in New Zealand white rabbits after a single topical administration. Concentration was determined in ocular tissues such as superior bulbar conjunctiva (A), cornea (B), and sclera (C).

Noninvasive Drug-Delivery Systems for the Posterior Disorders

All marketed ophthalmic products used for the management of retinal disorders are invasive in nature. The intravitreal route is widely used for administration of biopharmaceutics to the back of the eye. This route is associated with various complications, such as intraocular inflammation, retinal detachment, glaucoma or intraocular pressure elevation, endophthalmitis, ocular hemorrhage, and cataract ( Mandal et al., 2018 ). The following section illustrates current-state scientific research pertaining to topical delivery of potent therapeutic interventions and drugs for back of the eye diseases.

Small Molecules.

Eye drops instilled topically are noninvasive and the most patient-compliant route of administration. Although the route is widely explored for anterior segment disorders, it remains a major challenge for delivering drugs at therapeutic concentrations at the back of the eye. Various static barriers, such as blood-retinal barrier and tear-film barrier, and dynamic barriers, such as clearance mechanisms by vitreous and aqueous humor, hinder the drug passage from the front to the back of the eye. TG100801 is a topical therapy which has demonstrated reduction in CNV in a murine model and edema reduction in rats with RVO ( Doukas et al., 2008 ). TG100801 is a small-molecule multikinase inhibitor prodrug which is cleaved to its active form by hydrolysis in the cornea. Due to the promising results of TG100801 in the preclinical setting, it was further advanced to clinical trials. Although TG100801 was well tolerated by patients, it did not demonstrate any efficacy for alleviating the condition of AMD ( NCT00509548 ). Pazopanib is another small-molecule multikinase inhibitor which was administered topically in a laser-induced CNV rat model ( Yafai et al., 2011 ). Similar to TG100801, pazopanib failed to demonstrate efficacy in patients with subfoveal CNV, secondary to AMD ( Singh et al., 2014 ). Along similar lines, acrizanib was investigated for reduction of nonvascular AMD in preclinical mouse models. Acrizanib is a VEGF receptor-2 inhibitor and demonstrated a 99% inhibitory effect for CNV, which was 3 times the daily topical application of 1% suspension in mice ( Adams et al., 2018 ). Despite positive preclinical evaluation of acrizanib in a mouse model, topically administered acrizanib is clinically ineffective for the treatment of AMD ( NCT02355028 ). Although some multikinase inhibitors have failed in clinical settings, topical delivery of therapeutic agents to the back of the eye is an active area of research. A multikinase inhibitor, PAN-90806, is currently being investigated in clinical trials (phase I/II) to assess its feasibility in AMD treatment ( NCT03479372 ). Topical application of a memantine drug (Namzaric, Actavis Plc.) was able to achieve a sufficient concentration in the retina to provide retinal neuroprotection ( Hughes et al., 2005 ). Another small-molecular drug, dorzolamide, was administered topically to inhibit carbonic anhydrase II in a rabbit model ( Inoue et al., 2004 ). Dexamethasone administered topically by iontophoresis showed promising results in a rabbit model. Topically administered dexamethasone by iontophoresis was further evaluated in clinical trials for macular edema. However, the clinical trial was terminated due to insufficient enrollment ( NCT02485249 ).

Biotech Drugs.

Biotech drugs such as antibodies or antibody fragments are high-molecular-weight charged compounds which cannot be easily absorbed by the lipid bilayer. Although topical delivery of small-molecular drugs to the back of the eye has shown some efficacy in clinical trials, the biologics face various ocular barriers to reach the posterior segment ( Ambati et al., 2000a ; Miao et al., 2013 ). Topically administered bevacizumab, an anti-VEGF IgG antibody, failed to reach the therapeutic concentration in the rabbit retina after topical dosing of 1.25 mg/0.05 ml six times daily for a week ( Ambati et al., 2000a ). However, topical administration of antibody against intercellular adhesion molecule 1 was able to achieve therapeutic concentrations at the retina, which resulted in successful inhibition of VEGF-induced leukostasis in the choroid ( Ambati et al., 2000b ). To further improve topical delivery of biologics to the back of the eye, colloidal nanoformulations such as liposomes and nanomicelles with various permeability enhancers were used. Williams et al. (2005) demonstrated that permeability enhancer sodium caprate can enhance the delivery of antibody fragment in a rabbit model. Platania et al. (2017) used annexin A5–associated liposomes for topical delivery of bevacizumab to the back of the eye. Various cell-penetrating peptides (CPPs) are increasingly being investigated for ocular delivery of proteins and peptides ( Fonseca et al., 2009 ). CPPs are a group of short cationic peptides which can enhance the membrane permeation and translocation of desired therapeutic cargo. Therapeutic agents administered with CPP enhance corneal and scleral permeability ( Fonseca et al., 2009 ). Wang et al. (2010) applied human immunodeficiency virus transactivator of transcription for CPP to topically deliver acidic fibroblast growth factor in a rat model. Similarly, Ozaki et al. (2015) proved that delivery of topically administered calpain inhibitory peptide conjugated to transactivator of transcription factor to the retina of the rat eye. Johnson et al. (2010) conjugated to green fluorescence protein with a peptide of ocular delivery, which highlights the pathway of drug disposition and absorption from the corneal epithelium to the retinal pigment epithelium. The most recent and promising study was conducted by de Cogan et al. (2017) . The researchers achieved therapeutic levels of bevacizumab in the posterior ocular tissues, such as the retina and choroid, by topical coadministration of the antibody and CPP poly-arginine-6 ( de Cogan et al., 2017 ). Nanoformulations may be applied as intravitreal injections as well as topical eye drops for back of the eye delivery ( Table 5 ).

Topically administered therapeutic agents for back of the eye disorders in various preclinical models ( Rodrigues et al., 2018 )

• Discussions: Challenges and Future Perspectives for Ocular Drug-Delivery Technologies

The shortcomings of the current ocular drug-delivery system, such as lower drug bioavailability for topically administered drugs and the invasive nature of posterior implants, create challenges, allowing novel technologies to rise with superior and effective treatment of ocular disorders. Ocular disorders such as cataract, dry eye disease, wet and dry AMD, glaucoma, DR, and DME are predicted to escalate in the next two decades. For a majority of the anterior segment disorders, eye drops are regarded as the safest and most convenient dosage form. Eye drops face the challenge of having low drug bioavailability at the target tissue. Controlled drug delivery with the help of nanoformulations such as nanomicelles, nanoparticles, liposomes, dendrimers, nanowafers, and microneedles can achieve high bioavailability of drugs at the anterior tissues, such as the conjunctiva and cornea. Currently, all treatments for back of the eye disorders are invasive in nature. Frequent intravitreal injections can lead to retinal detachment, hemorrhage, and discomfort to the patients. Design of a noninvasive sustained drug-delivery system for the posterior segment is challenging for ocular drug-delivery scientists. Thus, there is an urgent need for the development of novel noninvasive drug-delivery systems that can overcome ocular barriers, sustain drug release, and maintain effective drug levels at the back of the eye.

Novel ocular drug-delivery systems such as nanoparticles and nanomicelles face a major challenge for technology transfer and large-scale manufacturing. Nanotechnology has a high clinical translatable potential for treating various ophthalmic disorders. Nanotechnologies can have the capacity to replace traditional ophthalmic medications in the near future. Parallel efforts not only in novel product development but also in product scale-up are required.

• Acknowledgments

The authors thank Dr. Gerald Wyckoff, Interim Chair, Department of Pharmacology and Pharmaceutical Sciences, University of Missouri-Kansas City School of Pharmacy, and Dr. Abhirup Mandal, Postdoctoral Fellow in Bioengineering, Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, for their guidance and support of this article.

• Authorship Contributions

Wrote or contributed to the writing of the manuscript: Sicotte, Sikder, Gote, Pal.

• Received January 29, 2019.
• Accepted May 1, 2019.

This work was supported by Graduate Assistant Fund Scholarship 2018 to V.G. awarded by the University of Missouri-Kansas City Women’s Council.

https://doi.org/10.1124/jpet.119.256933 .

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• Treatments and Unmet Needs
• Identifying and Overcoming Barriers to New Treatments
• Market Potential
• Understanding Eye Diseases' Pathogeneses and Pathophysiologies
• Making the Transition from Bench to Bedside
• Conclusions and an Action Plan for Advancing Translational Research in Ophthalmic Drug Delivery
• Supplementary Materials
• Henry F. Edelhauser From the Department of Ophthalmology, Emory University, Atlanta, Georgia;
• Cheryl L. Rowe-Rendleman Omar Consulting Group, Princeton Junction, New Jersey;
• Michael R. Robinson Allergan Inc., Irvine, California;
• Daniel G. Dawson From the Department of Ophthalmology, Emory University, Atlanta, Georgia;
• Gerald J. Chader the Doheny Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, California;
• Hans E. Grossniklaus From the Department of Ophthalmology, Emory University, Atlanta, Georgia;
• Kay D. Rittenhouse Pfizer, La Jolla, California;
• Clive G. Wilson the Department of Pharmaceutical Sciences, University of Strathclyde, Glasgow, Scotland;
• David A. Weber MacuSight, Union City, California;
• Baruch D. Kuppermann the Gavin Herbert Eye Institute, University of California-Irvine Medical School, Irvine, California;
• Karl G. Csaky the Department of Ophthalmology, Duke University School of Medicine, Durham, North Carolina;
• Timothy W. Olsen From the Department of Ophthalmology, Emory University, Atlanta, Georgia;
• Uday B. Kompella the Department of Pharmaceutical Sciences, University of Colorado-Denver, Aurora, Colorado;
• V. Michael Holers Taligen Therapeutics, Boston, Massachusetts;
• Gregory S. Hageman the Department of Ophthalmology and Visual Sciences, Cell Biology and Functional Genomics Laboratory, The University of Iowa, Iowa City, Iowa;
• Brian C. Gilger the Department of Clinical Sciences, North Carolina State University, College of Veterinary Medicine, Raleigh, North Carolina;
• Peter A. Campochiaro Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland; and
• Scott M. Whitcup Allergan Inc., Irvine, California;
• Wai T. Wong the National Eye Institute, National Institutes of Health, Bethesda, Maryland.
• Corresponding author: Henry F. Edelhauser, Department of Ophthalmology, Emory University Eye Center, 1365B Clifton Road, Atlanta, GA 30322; [email protected] . 
• Footnotes 13   Present affiliation: John Moran Eye Center, University of Utah Health Science Center, Salt Lake City, Utah.
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Henry F. Edelhauser , Cheryl L. Rowe-Rendleman , Michael R. Robinson , Daniel G. Dawson , Gerald J. Chader , Hans E. Grossniklaus , Kay D. Rittenhouse , Clive G. Wilson , David A. Weber , Baruch D. Kuppermann , Karl G. Csaky , Timothy W. Olsen , Uday B. Kompella , V. Michael Holers , Gregory S. Hageman , Brian C. Gilger , Peter A. Campochiaro , Scott M. Whitcup , Wai T. Wong; Ophthalmic Drug Delivery Systems for the Treatment of Retinal Diseases: Basic Research to Clinical Applications. Invest. Ophthalmol. Vis. Sci. 2010;51(11):5403-5420. https://doi.org/10.1167/iovs.10-5392 .

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•   A better understanding must be developed of the nature and effect of dynamic physiologic processes of the eye, such as clearance mechanisms and metabolism of drugs in specific tissue layers. It was noted that the challenge of isolating the dynamic barriers during data acquisition currently prevents the direct comparison of one dynamic barrier to another. It was repeatedly emphasized that an understanding of the importance of each dynamic barrier is key to improving the design of current drug delivery systems. In addition, it was stressed during the conference that live animal model studies or noninvasive studies on live human subjects are needed, as ex vivo work may not fully address relevant live dynamic physiologic processes.
•   Each static anatomic barrier encountered for each specific drug delivery technique must be studied, so that all individual layers of tissue or ocular fluid cavities are more fully understood. For example, with periocular injection techniques, the permeability properties of the choroid, RPE, retina, and vitreous should be individually assessed and compared to existing data from studies on the sclera and Bruch's membrane.
•   Drug–protein or drug–pigment binding must be better characterized, to guide attempts to modify natural sustained-release mechanisms for drug delivery to the posterior segment.
•   More research is needed in formulation modifications that alter physicochemical properties of both new and old drugs in ways that facilitate delivery through known paracellular and transcellular pathways. Although the paracellular and transcellular passive diffusion pathways offer an advantage, in that one drug delivery method may be generalized to various drugs, the active transcellular carrier–mediated transporters across the BRB should be further studied as they permit site-specific targeting without the need to create transmembrane concentration gradients and aid in tissue-specific targeting.
•   Ophthalmic drug delivery via nanotechnology-based products (<1 μm in diameter) must be further explored, as it fulfills three crucial criteria of ophthalmic drug delivery by enhancing drug permeation, controlled drug release, and selective drug targeting.
•   Innovation and development of ophthalmic gene delivery deserve further study, given the extensive potential of this technology.
•   Improved cooperation between basic and applied science teams at academic institutions, where many novel drug delivery systems are discovered.
•   Cooperation between pharmaceutical companies and basic and applied science investigators, to facilitate the transfer of technology, which will enable the development and commercialization of novel products.
•   Uniform techniques for obtaining ocular tissue samples for comparative pharmacokinetic studies. Samples of posterior ocular tissues—including neuroretina (macula and peripheral retina), retinal pigment epithelium, choroid, and sclera—should be obtained in a consistent fashion, to improve data comparison.
•   Clear guidance, including early and frequent communication with regulatory agencies, to help sponsors select the appropriate path to regulatory approval of novel ocular drug delivery products.
•   Meetings and societies that accommodate discourse among basic, applied, and clinical researchers to help promote future collaborative activities in device and drug development and ophthalmic translational research.
•   Incentives for individuals and institutions that use a team science approach to train scientists and physicians to use translational strategies for problem-solving in ophthalmology.
•   Journals that, by encouraging and accepting translational research papers in such areas as preclinical testing results, development of analytical methods, strategies that enable development of investigational drugs, and critical analysis of trials that do not meet their endpoints, provide researchers with an outlet to publish translational work.

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Research progress of in-situ gelling ophthalmic drug delivery system

a Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China

b Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China

Yuanyuan Liu

Dereje kebebe.

e School of Pharmacy, Institute of Health Sciences, Jimma University, Jimma, Ethiopia

f School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300193, China

c Department of Experimental Department, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China

Shouying Du

d School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China

Zhidong Liu

Blindness and vision impairment are the most devastating global health problems resulting in a substantial economic and social burden. Delivery of drug to particular parts of the anterior or posterior segment has been a major challenge due to various protective barriers and elimination mechanisms associated with the unique anatomical and physiological nature of the ocular system. Drug administration to the eye by conventional delivery systems results in poor ocular bioavailability (<5%). The designing of a novel approach for a safe, simple, and effective ocular drug delivery is a major concern and requires innovative strategies to combat the problem. Over the past decades, several novel approaches involving different strategies have been developed to improve the ocular delivery system. Among these, the ophthalmic in-situ gel has attained a great attention over the past few years. This review discussed and summarized the recent and the promising research progress of in-situ gelling in ocular drug delivery system.

Graphical abstract

1. Introduction

The eye is a complex and unique part of the human organs that has been considered as the window to the human soul. Broadly, the human eye is divided into two segments that are anterior and posterior segments ( Fig. 1 ) [1] . The specific disease conditions of the eye are associated with each of these broad segments. For instance, conjunctivitis, glaucoma, blepharitis, and cataract are some of the diseases that affect the anterior segment of the eye, while diabetic retinopathy and age-related macular degeneration are known to affect the posterior segment [2] .

The anatomy of ocular system: the anterior segment involves conjunctiva, ciliary body, iris, pupil, anterior chamber, cornea and lens; the posterior segment consists of sclera, choroid, retina, macula and optic nerve.

Due to the unique structure of the eye, which inhibits the entry of drug molecules into the desired site, the ophthalmic delivery of the drug has been one of the most challenging tasks for a pharmaceutical scientist. Eye drops accounts for more than 90% of ophthalmic preparations on the markets. However, they are washed away from the eye and results in low ocular bioavailability (<5%) after topical administration [3] by different elimination mechanisms. This elimination process includes tear turnover, nasolacrimal drainage, protein binding, systemic absorption, enzymatic degradation and complex penetration barriers (Corneal Barrier, Blood Aqueous Barrier (BAB), and Blood Retinal Barrier (BRB)) [4] ( Fig. 2 ).

The critical barriers to ocular drug delivery systems: the Corneal Barrier: involves of epithelial layers attached together by tight junctions avoiding entry of drug particle followed by thick stroma and endothelial cells. The Blood Retinal Barrier (BRB): comprises of the inner BRB resulted from retinal capillaries. Blood Aqueous Barrier (BAB): made by the nonpigmented cells of the epithelium of the ciliary body, and the endothelium of the iris blood vessels.

One of the main drawbacks in ocular drug delivery is achieving and retaining of optimal concentration of drug at the desired site of action in the eye. Several ophthalmic dosage forms such as ointments, eye drop solutions, gels, and ocular inserts have been investigated in order to prolong the ocular residence time of drugs after the topical application to the eye. With these formulations, the corneal contact time has been increased to some extent. But, due to blurred vision and poor patient compliance resulted from ointments and inserts, respectively, they have not been fully accepted [5] . Furthermore, drugs that are administered systemically to exert their action in the ophthalmic system also have known to access poorly to the eye tissue [6] . Intravitreal and pertiocular routes are recommended in order to deliver drugs to the posterior part of the eye. However, there are disadvantages associated with these routes like the frequent intravitreal injections could be painful, thus affecting a patient compliance. The periocular route is easy for administration, but the static and dynamic barriers constitute a problem [7] .

The low bioavailability of medications from the conventional delivery system is resulted from a great extent of precorneal drug loss by nasolachrymal drainage. The rapid clearance of the topically applied drug into the eye often results in a short duration of pharmacological activity and, therefore, the need for a frequent dosing regimen. Moreover, 50%−100% of an instilled dose could undergo systemic absorption through drainage via the nasolachrymal duct. This could lead to a possible increased risk of unwanted systemic toxic effects [8] .

In last decades, various delivery systems such as using chemical permeability enhancers [6] , prodrugs [9] stimuli-responsive in-situ gel [10] , and drug delivery carriers such as liposomes [11] and nano- or microparticles [12] , noisomes [13] , dendrimers and microneedles [14] have been developed to increase ocular residence time, drug penetration across the ocular barriers and ophthalmic bioavailability. In-situ gelling system is one of the promising approaches to improve the retention time of drugs on the ocular surface. After instillation of the aqueous solution containing stimuli-responsive polymers such as pH-sensitive polymers, thermosensitive polymers, and ion-sensitive polymers, the viscous and mucoadhesive gels are formed on the eye surface [15] , subsequently, ocular retention time and ocular bioavailability of the ophthalmic drugs are improved. Therefore, in this review, we summarized and discussed the most recent research innovations in stimuli-responsive in-situ gelling system for ocular drug delivery system.

2. Anatomy of the ocular system

Generally, the eye is divided into two important segments: (1) The anterior segment which involves the cornea, conjunctiva, iris, pupil, ciliary body, anterior chamber, aqueous humor, lens and trabecular meshwork. (2) The posterior segment includes vitreous humor, sclera, retina, choroid, macula and optic nerve ( Fig. 1 ) [1] .

The cornea is the transparent and clear avascular part of the ocular system that forms the anterior most coat of the eye. Anatomically, the cornea is consist of five major layers. Corneal epithelium is the first layer, which is the most exterior [16] . The other layers include Bowman's membrane, stroma, Descemet's membrane and the endothelium layer [1] . Corneal permeability is the most essential factor that determines drug concentration in aqueous humor. For most of hydrophilic drugs, the epithelium is a rate-limiting barrier of transcorneal diffusion of drugs [17] . The stroma is owing to the hydrophilic nature, it acts as a barrier for the diffusion of highly lipophilic drugs [17] . The corneal stroma is mainly consisting of charged and highly organized hydrophilic collagen that inhibit the diffusion of hydrophobic molecules [18] .

Conjunctiva is a clear thin membrane that covers the sclera and lines the inner surface of the eyelid. It is consist of stratified epithelium (non-keratinized) and goblet cells. It provides protection to the eyes by secreting mucus that prevents entry of microorganisms and lubricating the eyes [1] . In humans, the conjunctiva occupies a 17-times larger surface area than the cornea. This allows for greater absorption of the drug to occur through the conjunctiva. Therefore, drugs are usually more permeable across the conjunctiva than the cornea. However, absorption of the drug via the conjunctiva is still not significant due to the existence of conjunctival blood capillaries and lymphatics, which leads to a considerable loss of drug into the systemic circulation, thereby reducing the overall ocular bioavailability [19] .

Aqueous humor consists of clear liquid that fills both the posterior and anterior chambers of the eye. The aqueous humor is non-vascular structure that must be transparent to allow light transmission, which provides nutrition for the cornea [1] . It contains excessive concentration of ascorbate which is about 15-fold the concentration in the plasma, and has a pH of 7.2 [16] . Its main function is to provide nutrients, eliminate waste from non-vascular tissues and control the intraocular pressure that keeps the convex shape of the cornea [20] .

The sclera is the whitish portion of the eye, opaque and elastic in nature, consisting of collagen fibers [1] . The solutes especially hydrophilic compounds are generally more permeable across the sclera than the cornea and the conjunctiva, because diffusion through sclera is mainly a matter of transport across an aqueous medium of proteoglycans or leaky spaces within the collagen network rather than diffusion across cellular membranes [19] . The sclera offers a protective outer layer, maintaining intraocular pressure and serving as the attachment portion for the extraocular muscles [17] .

The retina is a multiple layers and complex structure that consists of vascular, glial and neural, cells and nerve fibers [16] . The retina is a major barrier to ocular delivery of drug with larger molecular weight [19] .

3. In-situ gelling system

Ophthalmic in-situ gelling is comprising of environmentally sensitive polymers that will be altered structurally with the small changes in specific conditions like pH, temperature and ionic strength in the environment. In-situ forming gels are liquids during instillation into the eye and then undergoes rapid gelation in the cul-de-sac of the eye to form viscoelastic gels in response to environmental changes ( Fig. 3 ); lastly release the drug slowly under physiological conditions [21] . Consequently, the residence time of the gel formed in-situ will be extended and the drug is released in a sustained manner which leads to enhanced bioavailability, minimized systemic absorption and reduced frequent dosing regimen resulting to improved patient compliance [22] . Furthermore, some other potential advantages such as simple manufacturing process, ease of administration, and deliverance of accurate dose have been exhibited by in-situ gelling systems [23] .

In-situ forming gels process. The formulation is liquid when instilled into the eye which undergoes gel formation rapidly in the cul-de-sac of the eye in response to environmental changes such as pH, temperature and ion; finally release the drug slowly under physiological conditions.

3.1. Mechanisms of gelling system

In-situ gel formation may be achieved by a number of mechanisms including temperature- ( Fig. 4 ), pH- and ion-activated systems. Temperature triggered in-situ gel system which utilizes the temperature sensitive polymers that exist as a liquid form below its low critical solution temperature (LCST) and undergoes gelation when the environmental temperature reaches or is above the LCST [24] . The pH induced in-situ gel contains polymers which possess acidic or alkaline functional groups within the chain molecule and undergoes a sol-gel phase transition on change from a low pH to high pH environment [23] . Ion-activated systems are also known as osmotically triggered in-situ gel systems wherein the polymer undergoes a sol-gel transition due to changes of ionic concentration, which is typically triggered by mono or divalent cations in tear fluid particularly Na + , Mg 2+ and Ca 2+ [25] . In addition, sol-gel phase transition has known to be induced by enzymatic cross linking and photon polymerization [25] , [26] . However, the pH, temperature, and ion-induced in-situ gel are the most extensively studied approaches of in-situ gel, and the concern of this review.

The gelation process of thermosensitive in-situ gelling. When the temperature is below the gelation temperature (GT), it is clear solution with low viscosity, upon heating it to GT, the solution is converted to the gel with high viscosity.

3.2. Stimuli-responsive in-situ gel system

3.2.1. temperature-triggered in-situ gel systems.

The temperature sensitive in-situ gel is the oldest, the most extensively studied and common type of stimuli-responsive gel. It can be easily and precisely introduced into the eye in liquid form without producing irritation or blurred vision. The gel is formed at the precorneal temperature (35 °C) to endure the lachrymal fluid dilution without rapid precorneal elimination of instilled drug after administration [27] . It has been recommended that a good thermo-responsive ocular in-situ gel should possess the gelation temperature above the room temperature and undergo gel-sol transition at a pre-corneal temperature in order to avoid storing in a refrigerator before instillation, which may sometimes result in eye irritation due to cold nature [28] .

Polymers used in temperature triggered in-situ gel systems

Poloxamers (Pluronic)

Poloxamers are a triblock copolymer poly (ethylene oxide)-b-poly (propylene oxide)-b-poly (ethylene oxide) (PEO-PPO-PEO) exhibiting amphiphilic nature because of hydrophilic ethylene oxide domains and hydrophobic propylene oxide domains [29] ( Fig. 5 ). The triple block of copolymers PEO-PPO-PEO (Pluronics or Poloxamers) undergo gelation at body temperature in concentrations above 15% (w/w) [30] . The principal possible mechanisms have been proposed to explain the sol-gel phase transition at an increased temperature are the gradual desolvation of the polymer, enhanced micellar aggregation, and the increased entanglement of the polymeric network [26] . The pluronic triblock copolymers are existing on the market in different grades with different physical forms and molecular weights. Depending upon the physical description for the grades are given as L for liquid, P for paste and F for flakes. The commonly used poloxamers are 188 (F-68), 237 (F-87), 338 (F-108) and 407 (F-127) [31] . Pluronic F-127 (F-127) or Poloxamer 407 (P407) (copolymer PEO106-PPO70-PEO106) consists of ethylene oxide (70%) which contributes to its hydrophilic property. F-127 is a copolymer with molecular weight of 12 000 Da, a PEO/PPO ratio of 2:1, nontoxic, with low viscosity below 4 °C and forming a semisolid gel at body temperature. Furthermore, F-127 has better solubility in cold water than in hot water because of the hydrogen linkages at low temperatures [31] , [32] .

The chemical structure of some in-situ gel polymers.

Xyloglucan is a polysaccharide obtained from tamarind seeds, therefore it is often named tamarind seed polysaccharide (TSP), which when partially degraded by β-galactosidase displays thermally reversible gel formation in diluted aqueous solution ( Fig. 5 ). The sol-gel transition temperature is varying with the degree of galactose degradation [33] . TSP gels have been reported to have a potential for oral, ocular, intraperitonial and rectal drug delivery [23] , [33] . TSP is highly water-soluble and gelation occurs when the galactose elimination exceeds 35% [34] .

Cellulose derivatives

Cellulose is a polysaccharide containing a linear chain made up of several hundred to over ten thousand β (1→4) linked d -glucose units. The cellulose derivatives used in topical ophthalmic formulations are methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose (HPMC), sodium carboxymethyl cellulose (NaCMC) [34] . At low concentrations (1–10%), their aqueous solutions exist as a liquid but form gels upon heating. The high phase transition temperature exhibited by cellulose derivatives can be lowered by physical or chemical modification [35] . The transition temperature is between 40 and 50 °C for MC and between 75 and 90 °C for HPMC. Addition of sodium chloride is known to lowers the gelation temperature of MC to 32–34 °C, while the transition temperature of HPMC can be decreased to about 40 °C by lowering the hydroxypropyl molar substitution [36] .

Chitosan is an aminopolysaccharide ( Fig. 5 ) made from the partial deacetylation and depolymerization of chitin, which is found in the exoskeletons of arthropods, such as crustaceans [37] . Commercially, chitin is mainly derived from the shell wastes of shrimp, crab, krill, lobster, and squid [26] . Chitosan has been proven to possess many advantages in biomedical applications due to its biocompatibility, biodegradability, mucoadhesiveness with low immunogenicity and low cytotoxicity [38] . Recently, chitosan-based thermosensitive gels with different polyols such as ethylene glycol, glycerol, and sorbitol have attained much popularity [39] .

The derivatization of primary amino groups of chitosan (CS) by thiol groups results in the formation of Thiolated Chitosan (TCS). TCS based drug delivery system is gaining attention because it exhibits high mucoadhesive strength and extended drug release properties. TCS shows in-situ gelling properties because of the formation of intra and intermolecular disulfide bonds as a result of oxidation of thiol groups at physiological pH-values [40] .

Research progress in temperature triggered in-situ gel systems

Over the last decades, a large number of studies on temperature triggered in-situ forming system have been reported ( Table 1 ). To mention some of them, Li et al. formulated Brinzolamide drug-resin in-situ thermosensitive gelling system, using Poloxamer F127 in combination with Carbopol 934P. The optimal formulation displayed a gel formation at 33.2 ± 1.1 °C and the diffusion-controlled release of the model drug over a period of 8 h. The in vivo study suggested that the in-situ gel demonstrated a better ability in retaining the drug than commercial formulations [41] .

Some examples of thermo-sensitive in-situ gelling system.

Al-Khateb et al. also investigated the in-situ gelling system containing ofloxacin using a combination of Pluronic (PF-127 and PF-68) and sodium alginate. The incorporation of Pluronic F68 to Pluronic F127 solutions was found to rises the sol-gel temperature of binary formulation to above the physiological range of temperatures. The superior in vitro drug retention performance on glass surfaces and freshly excised bovine corn were exhibited by 20% (w/w) Pluronic F127 in comparison with other formulations. Additionally, in vivo evaluation in rabbits demonstrated that a retention performance of 20% (w/w) Pluronic F127 was higher than that of Pluronic F68. Furthermore, the slug mucosa irritation assay and bovine corneal erosion studies demonstrated no significant irritation was observed that resulted from these polymers and their combinations [42] .

Osswald et al. prepared an injectable microsphere-hydrogel by loading the antivascular endothelial growth factor, anti-VEGF (ranibizumab or aflibercept) into poly (lactic-co-glycolic acid) microspheres that were then suspended within an injectable poly(N-isopropylacrylamide)-based thermo-responsive hydrogel DDS. The efficacy was evaluated in vivo in a laser-induced rat model of choroidal neovascularization (CNV). CNV lesion area was measured and quantified by fluorescein angiograms and a multi-Otsu thresholding technique, respectively. Intraocular pressure (IOP) and dark-adapted electroretinogram (ERG) were also measured pre- and post-treatment (1, 2, 4, 8, and 12 weeks). The result has shown that the anti-VEGF-loaded DDS group had exhibited significantly smaller CNV lesion areas than a non-treatment group of animals throughout the study, which suggests that the DDS offer a significant benefit in the management of posterior segment eye diseases [43] .

The addition of cellulose derivates to Pluronic F12 hydrogels assist in increasing the bioavailability of the in-situ gel [44] , Morsi et al., prepared Ketorolac tromethamine nanodispersions formulated into thermo-sensitive in-situ gel using Eudragit RL100. The study demonstrated that reducing the concentration of Pluronic F-127 was found to increase the gelation time and gelling temperature of the in-situ gels. The incorporation of HPMC to pluronic F12 hydrogels has significantly improved the mucoadhesive strength of the gel [45] .

Addition of salts (NaCl and KCl) to in-situ gel system has known to decrease the gelation temperature. Bhowmik et al. examined the influence of different salts on the gelation properties, rheology and drug release of in-situ gel based on methylcellulose (MC). It was found that 5–7% (w/v) sodium chloride, 8–9% (w/v) potassium chloride, or 5% (w/v) sodium bicarbonate was capable of reducing the GT below physiological temperature, i.e. 37 °C. The duration of drug release increased from 1.5 h to 3–5 h from salt containing MC solutions depending on the concentration and the type of salt [46] . Similarly, Bhowmick et al. confirmed that the use of i-carrageenan with potassium chloride could effectively decrease the GT of the virgin MC solution from 60 °C to 33.5 °C which is below physiological temperature [47] .

The mixture of poloxamer with a mucoadhesive agent (chitosan) is known to extend the retention time of drugs for the treatment of ophthalmic diseases. Gratieri et al. formulated in-situ forming gel consisting the combination of poloxamer and chitosan. The results demonstrated that the addition of chitosan could improve the mechanical strength as well as texture properties of poloxamer formulations and the in-situ gel increased a four-fold retention time in comparison with a conventional solution [48] .

In addition to Poloxamer, Poly (N-isopropylacrylamide) (PN) has been widely used as thermo-responsive polymers. For instance, Hsiue et al. developed ophthalmic formulation using PN as the thermo-sensitive polymer. The clear solution of PN was known to form a gel upon the raising of temperature from the room temperature to about 32 °C. Epinephrine-loaded linear PN and crosslinked PN nanoparticles were developed and evaluated. The finding of the study showed that the pressure decreasing the activity of the formulation with linear PN and combination of linear PN and crosslinked nanoparticles lasted six-fold and eight-fold longer than that of the conventional eye drop, respectively [49] .

Recently, the studies have shown that copolymerization of PN with hyaluronic acid (HA) has increased the LCST of PN from 32 °C to above body temperature, which is more appropriate for the ophthalmic application. With this aim, Zhu et al. developed thermo-sensitive in-situ forming gelling formulation of Ketoconazole (KCL) based on PN/HA. The in vitro gelation, drug release, and antifungal activity were evaluated for the developed formulations. The gelation temperature of the PN—HA thermo-gelling solution was found 33 °C. The moderate release of KCL from in-situ gels without burst effects was exhibited. No macroscopic signs of irritation, redness, or other toxic effects were observed. The in vivo antimicrobial study indicated that KCL PN—HA in-situ gels displayed an improved cure percent as compared with commercial eye drops [3] .

Very recently, Iohara et al. developed a hydrophobically modified hydroxypropyl methylcellulose (HM-HPMC) gel formed thermo-responsive hydrogels by incorporation of small amount of α-Cyclodextrin (α-CD) into the solution. The formed HM-HPMC/α-CD gel exhibited a reversible sol-gel transition within the range of physiological temperature which was totally opposite to the temperature dependency has shown by the original HM-HPMC (without α-CD). The HM-HPMC/α-CD exhibited the rapid gelation on the ocular surface and a significantly improved ocular drug (diclofenac sodium) absorption [50] .

3.2.2. pH triggered in-situ gelling systems

This in-situ gelling system consists of pH-sensitive polymers which are polyelectrolytes contain an acidic (carboxylic or sulfonic) or a basic group (ammonium salts) that either accept or release protons in response to alteration in pH in the surrounding environment. At lower pH (pH 4.4), the formulation exists as a regular solution, however, it undergoes gel formation at pH 7.4, that is the pH of tear fluid.

Polymers used in pH triggered in-situ gel systems

The most commonly used pH-responsive polymers in ophthalmic preparation are Polyacrylic acid (PAA, Carbopol 940), polycarbophil, and cellulose acetate phthalate (CAP) [17] .

Carbopol (Polyacrylic acid)

Carbopol is a polyacrylic acid (PAA) polymer ( Fig. 5 ), that displays a sol-gel phase transition in aqueous solution as a result of raising the pH above its pK of about 5.5 [57] . The carboxylic groups of PAA accept and release protons at low pH values and high pH values, respectively. Therefore, at high pH, the PAA swells due to the electrostatic repulsion of the negatively charged groups, releasing the drug molecules to the environment [17] . It is extensively exploited in ocular formulation with the aim of improving pre-corneal retention time of drugs. Carbopol provides the benefit of exhibiting superior mucoadhesive properties as compared to other polymers. Mucoadhesive properties of carbopol is attributed to the interaction of poly(acrylic acid) with mucin that occurs by four mechanisms viz. electrostatic interaction, hydrogen bonding, hydrophobic interaction and inter diffusion [35] . Despite carbopol displays excellent mucoadhesive properties, the acidic nature of the gel is a major drawback which leads to irritation and damage to the eye tissues. Therefore, combinations of carbopol with other polymers including chitosan and HPMC were subsequently developed to overwhelmed this problem [25] .

Research progress in pH triggered in-situ gel systems

The in-situ pH-triggered gelling system has a great potential to keep drug product more stable and retain drug release ( Table 2 ). With this aim, our research group (Wu et al.) designed and evaluated pH-triggered gel containing Baicalin for sustained ophthalmic drug delivery using Carbopol 974P as the gelling agent along with HPMC E4M (0.6%, w/v) that was a viscosity enhancing agent. The in vitro and in vivo evaluations were conducted using confocal scanning light microscopy, rheometry, Gamma scintigraphic technique and microdialysis method. The result of rheological study displayed that the gel strength was significantly enhanced under physiological condition. The gel could provide sustained release of the drug over an 8 h period. Furthermore, the AUC and C max values were found 6.1-times and 3.6-times higher than those of the control solution, respectively [58] .

Some examples of pH-triggered in-situ gelling system.

In addition, our research group (Pang et al.) have confirmed that the ocular in-situ gel can reduce the systemic absorption of the drug and thus reduce the potential systemic toxicity. Brimonidine Tartrate in-situ gel was prepared using Carbopol 974 P and HPMC E4M, and its therapeutic efficacy and systemic absorption were compared with that of eye drop. The pharmacodynamics study on the eye of rabbit showed that the gel formulation could significantly decrease intraocular pressure (IOP) as compared to the eye drop. More importantly, the in vivo pharmacokinetic studies exhibited that the plasma AUC (0→∞) was found lower for the in-situ gel than the eye drop, which suggests the decreased systemic absorption [59] .

3.2.3. Ion-activated in-situ gel system

Ion-activated in-situ gelling systems form a crosslink with cations exists in the tear fluid (Na + , Ca 2+ and Mg 2+ ), thus forming a gel on the ocular surface, which give rise to an extended corneal contact time ( Table 3 ) [17] , [64] .

Some examples of ion-activated in-situ gelling system.

Polymers used in Ion-activated in-situ gel system

The most commonly used ion-activated polymers in ocular formulations are gellan gum (Gelrite ® ), hyaluronic acid and sodium alginates [65] .

Gellan gum are polysaccharides that can be used to induce ion-sensitive hydrogels. It is a linear anionic heteropolysaccharide ( Fig. 5 ) made up of a tetrasaccharide repeating unit of glucose, glucuronic acid and rhamnose in the ratio of 2:1:1 [66] . Gellan comprises hydroxyl and carboxylic functional groups, which may interact with other polymers via hydrogen bonding and/or electrostatic attractions [67] . A low-acetyl gellan gum is commonly available in the market as Gelrite ® , which undergoes gelation in the presence of mono- or divalent cations. The electrolytes of the tear fluid especially Na + , Mg 2+ and Ca 2+ cations are particularly known to induce gel formation of the polymer upon instillation as a liquid solution into the cul-de-sac [68] . The incorporation of optimal quantities of calcium gluconate to gellan formulations lead to the formation of gellan calcium gluconate-simulated tear fluid (STF) gels with a significantly higher strength than when gellan alone was mixed with STF [67] . It undergoes gelation by both temperature sensitive or cations induced mechanism. The possible mechanism of gelation includes the formation of double helical junction zones followed by aggregation of the double helical segments to form a three-dimensional network by hydrogen bonding with water and complexation with cations [26] .

Alginate/ Alginic acid

Alginate is a linear co-polysaccharide derived from brown seaweeds and some bacteria. Chemically it is a (1–4)-linked block copolymer of â- d -mannuronate (M) and its C-5 epimer R- l -guluronate (G), with residues arranged in homopolymeric sequences of both kinds and in region which approximate to the disaccharide repeating structure (MG) [69] . Sodium alginate undergoes gel formation as a result of calcium alginate formation by virtue of its interaction with a divalent cation (Ca 2+ ) present in lachrymal fluid (pH 7.4) [5] . Various properties of the polymer such as mechanical strength, porosity, etc. are highly depend on the ratio of β- d -mannuronic acid and α- l -glucuronic acid. Alginate with a high guluronic acid content exhibit a better gelling properties and minimize the concentration of polymer required to form stiff gel [26] .

Pectins are a polysaccharides family, where the polymer backbone mostly consists of α-(1,4)- d -galacturonic acid residues. Low methoxy pectins which are with a degree of esterification <50% can form gel in aqueous solution in the existence of free calcium ions, that cross link the galacturonic acid chains. Its water solubility is one of the important advantages of pectin, therefore organic solvents can be avoided in the formulations [70] . The in-situ gelling of pectin induced by calcium ions exists in lacrimal fluid has been reported in a US patent. In addition, pectin based in-situ gel has been used to prolong drug release from the formulations such as theophylline, acetaminophen, and cimetidine [71] .

Research progress in ion-activated in-situ gel systems

Various ion-activated in-situ gelling systems have previously been reported. Rupenthal et al. formulated ion-activated in-situ based on gellan gum, xanthan gum and carrageenan, and in vivo release, precorneal retention time and the ocular irritancy were characterized for the formulations. The results showed that the in-situ system was non-irritant with increased AUC and the miotic response of pilocarpine by 2.5-fold compared to an aqueous solution [64] .

Zhu et al. also developed an ion-activated ketotifen ocular formulations using a natural polysaccharide which is deacetylase gellan gum. The study demonstrated that deacetylase gellan gum had a potential to prolong the residence time of the formulation. The in-situ gels exhibited a characteristic sustained and extended drug effects behavior compared with the conventional eye drops at the same dose [72] .

Kesarla et al. formulated nanoparticles-loaded ophthalmic in-situ gel using the ion-sensitive polymer gellan gum used as a gelling agent which could form gel immediately and remained for the extended time of period. The developed formulation was found stable and displayed improved corneal contact time and minimizing the frequency of administration. The confocal microscopic study showed a clear cornea permeation of drug-loaded nanoparticles [73] . Tayel et al. developed a novel ion-sensitive in-situ ophthalmic nanoemulsion (NE) gels containing terbinafine hydrochloride. The optimized in-situ NE gel exhibited a significantly higher C max , delayed t max , prolonged mean residence time and enhanced ocular bioavailability [74] .

In the development of bioadhesive ion-sensitive hydrogels, the incorporation of the poorly water soluble drug is very challenging. Cyclodextrins (CDs) are beneficial pharmaceutical excipients that assist in the formulation of poorly aqueous soluble drugs. The inclusion of hydroxypropyl-β-cyclodextrin (HPBCD) in the in-situ formed gel has shown to allow a more effective control and a significant improvement in the fluconazole release [66] .

3.2.4. Multi-stimuli responsive in-situ gel

One of the recent excellent strategies in ocular in-situ gelling system is the use of a combination of polymers with the different gelling mechanism, which have shown an improved therapeutic efficacy and better patient compliance [20] . Over last current years, a number of investigations that involved the combination of thermo-responsive polymers, pH-sensitive polymers or ion-activated polymers in the same ophthalmic formulation have been reported ( Table 4 ).

Some examples of multi-stimuli responsive in-situ gelling system.

Khan et al. developed and evaluated sparfloxacin-loaded novel in-situ gelling system for sustained ophthalmic drug delivery using a combination of ion and pH activated gelling system, which were sodium alginate and methylcellulose, respectively. The formulation was in sol form at pH (4.7) and has undergone quick sol-gel transition upon raising pH to 7.4. The in-situ gel formulation demonstrated in vitro sustained release of sparfloxacin over a period of 24 h as compared to eye drop. The ex vivo corneal permeation study on goat eye revealed that a dramatically improved permeation as compared to eye drop [21] .

In addition, Yu et al. reported nepafenac in-situ gel using carboxymethyl chitosan (CMC) and poloxamer composed of PEO-PPO-PEO block copolymer which was found to undergo a reversible sol-gel transition upon a change in a temperature and/or pH at a very low concentration. The result of a CCK-8 (Cell Counting Kit-8) study showed that the formulation was not toxic to human corneal epithelial cells at a low concentration. The formulation of poloxamer-CMC/NP showed a sustained release of nepafenac from the hydrogel. The release rate was found to be maximum at 35 °C and pH 7.4 [79] .

Davaran et al. developed a dual thermo-/pH-responsive nanocarriers in-situ gel for ciprofloxacin. Ciprofloxacin released from the nanoparticles in-situ gelling system demonstrated an improved antimicrobial activity as determined by minimal inhibitory concentrations [80] . Gupta et al., also formulated in-situ gel using the combination of gellan gum (ion-sensitive) and chitosan (pH sensitive) so as to improve precorneal residence time of sparfloxacin. Accordingly, the developed sparfloxacin in-situ forming gel was found nonirritant and showed the prolonged retention at the corneal site with the prolonged drug release [81] .

3.3. Nano-in-situ gelling systems

Nowadays nanotechnology is the most emerging concept in pharmaceutical sciences [85] . Several nano-technology based formulations have been developed to extend ocular residence time and to improve bioavailability of ophthalmic drugs. However, nanoparticles have not mucoadhesive property, so are cleared out of eyes rapidly [86] . The suspending of fabricated nanoparticles in an in-situ gelling vehicle which undergoes sol to gel phase transition upon exposure to physiological condition is known to solve this problem. The nanoparticulate in-situ gel was designed to explore the double benefit of nanoparticles and in-situ gelling system, for its ophthalmic delivery ( Table 5 ) [60] , [87] . This results in extending the pre-corneal residence time of the nanoparticles and improving ocular bioavailability [26] .

Some examples of nanocarrier in-situ gelling system.

The formulations of in-situ gel in novel drug delivery system as colloidal carriers systems such as nanosuspensions, lipid-based nanocarriers, have proven to be the most effective strategy, causing an exponential increase in the bioavailability of the ophthalmic drugs. For instance, Liu et al. developed the curcumin (CUR)-loaded ocular nanogel by using cationic nanostructured lipid carriers (CNLC) and thermosensitive gelling agent. The in vitro release, corneal permeation, ocular irritation and preocular retention were evaluated. Also, the pharmacokinetic profile in the aqueous humor was evaluated by microdialysis technique. The AUC of the nanogel (CUR-CNLC-GEL) was found 9.24-times higher than those of curcumin solution (CUR-SOL), indicating a significantly improved bioavailability [88] .

Pandurangan et al. formulated solid lipid nanoparticles (SLNs)-loaded in-situ gel with voriconazole which was found to be a promising vehicle for ocular delivery with good stability and excellent zone of inhibition in the microbial assay of voriconazole [89] . Paradkar et al. developed a niosomal in-situ gel using Poloxamer 407 and HPMC K4M. The prepared Natamycin niosomal in-situ gel formulation exhibited an increased corneal retention time due to bioadhesive property of gel and displayed extended drug release up to 24 h which as compared to marketed products. The formulation was also found to exhibit a better transcorneal permeation [90] . Shukr et al. also formulated voriconazole-loaded in-situ gelling noisome for ocular inserts using span 40 and span 60 with pluronic F127 and pluronic L64. The optimized in-situ gelling ocular insert showed a significantly higher C max , delayed t max and increased bioavailability, and was found non-irritant [91] .

Microsphere-loaded ion-activated in-situ gel of ofloxacin (OFX) was also formulated. In vivo results in rabbits exhibited that OFX-loaded microspheres in-situ gel could improve the relative bioavailability by 11.7-times relative to the commercial OFX eye drops. Furthermore, the extended duration of action of OFX-loaded microspheres in-situ gel preparation is thought to avoid frequent administration, which improves patient compliance [92] .

Nofloxacin-loaded nanocarriers were designed utilizing chitosan as a matrix forming polymer, crosslinked by an anionic cross-linker sodium tripolyphosphate. The developed chitosan nanoparticulate in-situ gel exhibited superior performance over the marketed eye drops [60] . Levofloxacin nanoparticles laden in-situ gel was formulated and showed the improved ocular retention time. Gupta et al. designed nanoparticle laden in-situ gel encapsulated PLGA nanoparticle, containing levofloxacin, added into chitosan in-situ gel. Ocular retention was evaluated by gamma scintigraphy in rabbits. The developed nanoparticle laden in-situ gel formulation exhibited slow rate of clearance and retained at the corneal surface for more extended duration than commercially available formulation, in-situ gel and nanosuspension alone [93] . Furthermore, the same group of research confirmed for excellent sustained release of the nanoparticle in-situ gelling system containing sparfloxacin [94] .

More recently, Ahmed et al. formulated ketoconazole poly(lactide-co-glycolide) nanoparticles with subsequent loading into in-situ forming gel for ophthalmic drug delivery system. The in vitro release of the drug from the formulations loaded with nanoparticles displayed a sustained and greater drug release compared to free drug formulations. In addition, the in-situ gelling with nanoparticles showed improved antifungal activity in comparison to pure drug formulations. Alginate-chitosan in-situ gel containing optimized ketoconazole nanoparticles displayed higher drug permeation via epithelial cell lines [95] .

4. Clinical application of in-situ gelling

To date, some of in-situ gel formulations have been commercially available for ocular drug delivery ( Table 6 ). For instance, Timoptic-XE ® , containing timolol maleate (0.25% and 0.5%) in gellan gum has been available on market since 1994, which is applied topically on the eye to treat glaucoma. Furthermore, some of the patents on in-situ gel for ocular delivery system have been issued in the last decades, and are being summarized in Table 7 .

List ocular in-situ gels approved for market.

List of some patents of in-situ gelling system for ocular delivery.

5. Conclusions and future prospects

Despite the challenges in ocular drug delivery, over the past few years, many innovative approaches are being developed to overcome the problems associated with conventional of ophthalmic preparations. The in-situ gelling system is one the promising and extensively studied strategies that could prolong precorneal resident time and offer the sustained release drug delivery, thus improve ocular bioavailability and therapeutic efficacy and reduce systemic absorption and toxicity. Furthermore, due to its drug release sustaining ability and decrease the frequency of administration, in-situ gel could improve patient compliance. In in-situ gel formulation with different stimuli-responsive polymers that have high sensitivity to change in pH, temperature, and ion concentration are used. However, the combination of two or more stimuli-responsive polymers in the same formulation is known to exhibit greater compliance and improved therapeutic efficacy. Moreover, exploring the combination of different drug delivery approaches (i.e. nanoparticles loaded in-situ gelling) to develop in-situ gel has been the attractive strategies to improve ocular drug delivery system.

As the eye is the most essential and sensitive part of the body, the safety issues of ophthalmic formulations is critically important. The majorities of the cytotoxicity and irritability studies included in this review showed that no significant alterations or sign of toxicity due to the application of in-situ gel. However, further studies are required to evaluate the possible toxicity due to repeated and long term applications and materials for the preparation of nanoparticles in nano-gel systems. In addition, the increased viscosity of in-situ gel may cause some limitations like blurred vision and discomfort to patient resulting in a faster elimination due to reflex tears and blinks. Therefore, critical control of the viscosity should be taken into consideration during designing and optimization of in-situ gel formulation in order to reduce the limitations to the tolerable level.

Despite the promising potential of in-situ gel in ocular drug delivery, only a limited number of drugs in the form of in-situ gel are currently in clinical use. Consequently, further works should be done to explore this drug delivery system for the clinical application of other ophthalmic drugs.

At present, most of the ophthalmic in-situ gels were designed only for the formulations containing of single active ingredient. In the future, some more suitable strategies should be developed for the formula consisting of multiple ingredients such as Traditional Chinese Medicine in particular, which involves a multi-target approach to produce their action. Lastly, in the future, we expect the innovation of new and more reliable in-situ forming polymers which may be responsive to some biochemical markers associated with the disease conditions of the eye.

Conflict of interest

The authors affirm and confirm that there are no any conflict of interest issues with regard to the content of this article.