Ocular Drug Delivery: A Comprehensive Review PDF

AAPS PharmSciTech (2023) 24:66 https://doi.org/10.1208/s12249-023-02516-9 REVIEW ARTICLE Ocular Drug Delivery: a Comprehensive Review Sadek Ahmed1 · Maha M. Amin1 · Sinar Sayed1 Received: 21 November 2022 / Accepted: 14 January 2023 / Published online: 14 February 2023 © The Author(s)...

AAPS PharmSciTech (2023) 24:66 https://doi.org/10.1208/s12249-023-02516-9 REVIEW ARTICLE Ocular Drug Delivery: a Comprehensive Review Sadek Ahmed1 · Maha M. Amin1 · Sinar Sayed1 Received: 21 November 2022 / Accepted: 14 January 2023 / Published online: 14 February 2023 © The Author(s) 2023 Abstract The human eye is a sophisticated organ with distinctive anatomy and physiology that hinders the passage of drugs into tar- geted 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, intravit- real, 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 aug- ment 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. Keywords corneal barriers · in situ gel · nanocarriers · ocular delivery · retention time Introduction fungal keratitis. A new study valued that approximately 76 million people suffered from glaucoma, 196 million people Eye is a very sensitive organ with a sophisticated physiology. with AMD, and 92.6 million have DR. It is composed of anterior and posterior segments. Generally, Although many potent drugs are available to treat most quality of life is significantly influenced by visual impairment of ocular complaints, there are many ocular barriers such resulted from various diseases. Cataract is the main cause as tear film, corneal, conjunctival, and blood-ocular barri- of blindness worldwide. About 40–60% of blindness in the ers that hinder their therapeutic efficacy. Conventional eye world is caused as a complication of cataract. Early cata- drops are wasted by blinking and tear flow. Therefore, their ract development results from mutations in α, β, and γ crys- bioavailability is minimized to less than 5%. Cornea is tallin and its associated genes. Glaucoma is a well-known composed of epithelium, stroma, and endothelium. Epithe- optic neuropathy disease that is connected with elevation in lium allows only the passage of small and lipophilic drug. intraocular pressure (IOP). It leads to permanent blindness However, stroma allows the passage of hydrophilic drugs in the late stage. Furthermore, vision impairment is also. Endothelium conserves the transparency of the cor- related to aging, diabetes, and fungal infection. Examples nea and affords selective entry for hydrophilic drugs and of ocular diseases include age-related macular degenera- macromolecules into the aqueous humor. The conjunctiva tion (AMD), diabetic retinopathy (DR), retinoblastoma, and provides a minor impact to drug absorption compared to the cornea, though certain macromolecular nanomedicines, peptides, and oligonucleotides penetrate to the deep layers of * Sadek Ahmed the eye absolutely through these tissues. Blood-ocular bar- [email protected] riers prevent the passage of xenobiotic compounds into the 1 blood stream. They are classified into blood-aqueous bar- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Kasr El‑Aini, rier (BAB) in the anterior segment and blood-retinal barrier Cairo 11562, Egypt (BRB) in the posterior segment of the eye. 13 Vol.:(0123456789) 66 Page 2 of 29 AAPS PharmSciTech (2023) 24:66 Ocular formulations are intended to be applied on the drug delivery. It described comprehensively ocular drug anterior surface (topical route) of the eye, delivered intraocu- delivery from different points such as the various anatomi- larly (inside the eye), periocularly (subtenon or juxtascleral), cal features of the eye, different ocular diseases, obstacles or in combination with ocular devices. Ocular dosage forms to ocular delivery, different routes of ocular administration, could be liquid, semi-solid, solid, or mixed. Liquid dosage classification of dosage forms, numerous nanostructured include drops, suspension, and emulsion. Eye drops represent platforms, characterization approaches, strategies to improve more than 95% of the marketed ocular products. They are ocular delivery, and future technologies. used for delivering the medication into the anterior part of the eye but with short residence time. Ocular suspensions and emulsions have the ability to deliver hydrophobic drugs, Anatomy of the Eye but may lead to blurred vision. Ocular gels and ointments (semi-solid) could significantly enhance residence time. Solid Human eye is a very sensitive and complex organ. Figure 1 dosage forms could be used to deliver water-sensitive drugs illustrates the anatomy of human eye. Human eye is (powder), provide zero order release model (insert), or sus- composed of anterior and posterior chambers. The anterior tain residence time (therapeutic contact lens). segment is composed of tear film, cornea, pupil, lens, and Effective ocular absorption necessitates appropriate cor- ciliary body. The posterior segment is composed of con- neal penetration along with effective precorneal residence junctiva, sclera, choroid, retina, vitreous humor, and optic time, so as to reach and preserve an acceptable drug concen- nerve. The structure and quantity of tears are controlled by tration with the minimum quantity of the active therapeutic orbital glands and epithelial secretions. Cornea is the front constituent. Nanosystems are innovative technologies devel- portion of the eye that conveys and focuses light into the oped to get through ocular obstacles, shield the drug from eye. It is divided into epithelium, stroma, and endothelium. the biological environment, sustain drug residence time, and The epithelium is made of five to seven layers of firmly con- improve corneal permeation across biological barriers. nected cells. Stroma is a water-based compact layer. The Characterization of the constructed nanosystems is of great endothelium preserves the transparency of the cornea. importance to ensure its ability to accomplish the required Iris is the colored portion of the eye which controls the quan- activity. There are many approaches for characterization tity of light penetrating the eye. The dark center opening such as visual appearance, stability, size, zeta potential, in the middle of the iris is called pupil. The pupil changes possible interactions, pH measurement, and other important its size according to the available light. Lens is transparent ex vivo and in vivo evaluations. This review highlights portion that focuses the light into retina. The ciliary body is the gaps in other published reviews regarding the ocular made of pigmented and non-pigmented ciliary epithelia, a Fig. 1  Anatomy of the eye 13 AAPS PharmSciTech (2023) 24:66 Page 3 of 29 66 stroma, and ciliary muscles. Capillaries of ciliary body allow slow deterioration of optic nerve axon and fatality of retinal communication between anterior and posterior segments. ganglion cells. It is commonly connected with elevation Vitreous humor is a gel-like, clear, avascular connective tis- in intraocular pressure (IOP) because of irregular forma- sue that exists between the eye lens and the retina. It is made tion or obstruction of the aqueous humor. Risk fac- of 99.9% water, hyaluronic acid, ions, and collagen. The tors include age, race, diabetes, genetics, nearsightedness, conjunctiva is a delicate transparent membrane lining inside migraine, and retinal vascular caliber. Glaucoma is more the eyelids and shelter the frontal surface of the sclera. It is a common in women population as they represent 55% of open mucous membrane that is composed of three layers, an outer angle glaucoma, 70% of angle closure glaucoma, and 59% of epithelium, a substantia propria enclosing nerves, lymphatic all forms of glaucoma in 2010. Worldwide incidence is and blood vessels, and a submucosa layer linked to the sclera estimated at 76 million at 2020 and is expected to elevate to. The sclera is a continuous of cornea. It is made of col- 112 million by 2040. There are two types of glaucoma: lagen and mucopolysaccharides. Choroid is vascular layer open angle and closed angle. Open angle glaucoma has no that is located between retina and sclera. The retina is thin symptoms and is characterized by enlarging optic disc cup- film of tissue composed of neural and glial cells covering ping and visual field that results in elevated prevention of the back of the eye. It produces electrical impulses that are drainage of aqueous humor through trabecular meshwork. delivered through the optic nerve to the brain. However, closed angle is characterized by the elevated pressure resulted from the blockage of outflow pathways. About 76 million people suffered from glaucoma and the number is expected to reach 112 million by 2040. Ocular Diseases Glaucoma developed as a result of oxidative and nitrative processes. There are many antioxidant enzymes in aqueous Cataract humor for example superoxide dismutase, catalase, and glu- tathione peroxidase. Their level is decreased as a result of Cataract is chief cause of loss of vision worldwide. About aging and that leads to elevated IOP. Change the equilibrium 40–60% of blindness in the world is caused as a complica- between oxidants and antioxidants influence the progres- tion of cataract. As said by the National Programme sion of glaucoma. Anti-glaucoma drugs help to adjust for Control of Blindness and Visual Impairment, the either aqueous humor formation or drainage. Many studies major reason of avoidable blindness in India is cataract were published to enhance glaucoma treatment [12, 16–18]. (62.6%). Cataract could be defined as the development Abd-Elsalam and ElKasabgy developed topical agomela- of cloudiness/opacification in the eye lens. The risk fac- tine-loaded olaminosomes with remarkable anti-glaucoma tors include exposure to UV light, diabetes, bad nutri- activity. Eldeep et al. developed topical proniosomal tion, genetic determinism, and smoking. Cataract could gel-derived niosomes to improve ocular retention and activ- be divided into three types: cortical, nuclear, or posterior ity of brimonidine tartrate. subcapsular. The clearness and transparency of lens is regulated by crystallin protein. Alterations in α, β, Age‑Related Macular Degeneration (AMD) and γ crystallin and its associated genes are responsible for the early cataract development. Triggers to cataract AMD is one of the main causes of loss of vision in devel- are glycation, oxidative stress, and exposure to lipophilic oped countries. It is more frequent above the age of 50 years. compounds which result in increasing calcium level in the. About 8.7% of worldwide blindness is initiated by AMD lens plus crystallin accumulation. Oxidative stress is medi- AMD. Nearly 196 million people suffered from AMD ated by hyperglycemia and hydroxyl radicals. Nowadays, at 2020 and the number is expected to reach 288 million surgical removal of opaque lens is the treatment choice. by 2040. It is a multifactorial degenerative complaint However, the early employment of anti-cataract agent may involving the posterior segment of the eye. Risk factors minimize surgical treatment. Anti-cataract agents are mul- include aging, smoking, bad nutrition, high blood pres- tifunctional antioxidants with radical hunting and chela- sure, and immobility. There is no remedy for AMD till now, tion ability. Examples of anti-cataract agents include but its progression may be reduced by proper medications curcumin, lanosterol, resveratrol, and metformin.. AMD could be divided into two types, dry (atropic or non-exudative) and wet (neovascular or emulative). Irreg- Glaucoma ular angiogenesis (development of new blood vessels) in the retinal epithelium is the main character of AMD and Glaucoma is a famous optic neuropathy disease. Symptoms results in drusen (yellow deposits under the retina), atropy, start with blurred vision that progresses into irreversible and separation of bruch’s membrane. Many cellular blindness in the late stage. It leads to blindness as a result of growth factors are increased during angiogenesis due to 13 66 Page 4 of 29 AAPS PharmSciTech (2023) 24:66 the irregularities in corresponding metabolic pathways as Retinoblastoma vascular endothelial growth factor (VEGF), basic fibroblast growth factor (FGF), and epithelial growth factor (EGF). A Retinoblastoma is a malignant tumor distressing the retina and new approach for treatment of AMD involves juxtascleral mainly prevails in children younger than 5 years old. Untreated injections of anecortave cortisone that showed prolonged retinoblastoma leads to blindness and finally mortality (99%). release for 6 months in the choroid and retina. Moreo- Its frequency is about 1 out of 20,000 live births. Its occur- ver, intravitreal injection of the biodegradable Rho kinase rence rate is equal in both gender. It is caused due to mutation and protein kinase C inhibitor for handling diabetic macu- in tumor suppressor gene RB1 encoding for retinoblastoma lar edema and neovascular age-related macular degeneration protein. It could be unilateral (60%) or bilateral (40%). exhibited prolonged release for about 6 months. The handling choices of retinoblastoma include radiotherapy, cryotherapy, systemic chemotherapy, and surgery. Latest stud- Conjunctivitis ies propose that release of compensatory proangiogenic factors and angiogenic blood vessels development are the vital phases Conjunctivitis is generally the most frequent ocular compliant. for treating retinoblastoma. It is simply the inflammation of conjunctival tissue. It affects all ages, races, and genders. According to the cause, it may Fungal Keratitis classified into infectious or non-infectious. Infectious conjuncti- vitis results from microbial infection, while non-infectious con- Fungal keratitis occurs only in traumatic cornea, since healthy junctivitis results from allergens and irritants. Symptoms cornea would not allow any fungal infection. It is caused by of conjunctivitis include eye redness, eye discomfort, tears, and different fungus like Candida albicans, Candida glabrata, Can- elevated eye secretions. Prevalence of allergic conjunctivitis is dida tropicalis, Candida krusei, and Candida parapsilosis. nearly 40% of global population. Treatments of conjuncti- Fungal keratitis represents 40% of the contagious keratitis in vitis include topical administration of antimicrobial (infectious) developing countries of third world. Risk factors may be or anti-inflammatory agents (non-infectious). ocular (trauma, contact lens, prior corneal surgery, and topical corticosteroids) or systemic (diabetes, HIV positivity, and lep- Diabetic Retinopathy (DR) rosy). Fungal keratitis leads to impaired wound healing, corneal ulceration, and stromal inflammatory infiltration. The corneal Diabetic retinopathy is particular vascular complication related inflammation may alter miRNA expression. Oral or topical to both types of diabetes mellitus. About 60% of patients of antifungal drugs are used to treat fungal keratitis. Corneal sur- type II and all patients of type I diabetes have a certain extent gery approach could be required when the medicines are useless. of retinopathy after 20 years of diabetes. Oxidative stress and In some situations, vision may not be restored even after surgery. inflammation result from the upregulation of proinflammatory Many papers consider the treatment of fungal keratitis. Younes mediators initiated by hyperglycemic disorders are the cause et al. developed topical Sertaconazole nitrate loaded cubosomes of development of DR. It is the third major trigger to blindness and mixed micelles with enhanced safety and antifungal activity in the USA. After cataract and corneal blindness, the first and [33–37]. Figure 2 illustrates various ocular diseases. second triggers to blindness. It is avoidable if distinguished and cured early plus the effective management of blood glu- cose and blood pressure. It has two types, proliferative Obstacles to Ocular Delivery and non-proliferative and both of them result eventually in pro- gressive damage to the retina. Nowadays, diabetic retinopathy Precorneal Barriers is managed through laser photocoagulation, vitrectomy, and pharmacological treatments. Laser photocoagulation works by Capacity of Cul‑de‑sac closing the leaky blood vessels and possibly avoids blindness, but results in laser scar. Vitrectomy is a surgical removal of vit- Figure 3 explains different ocular barriers. Cul-de-sac is reous gel and blood from leaking vessels in the back of the eye, a shallow pocket in the lower eyelid where palpebral and but this procedure provides only short-term relief and does bulbar conjunctiva meet in the lower eyelid and the deeper not obstruct further leaking of blood. Pharmacological recess in the upper eyelid. The maximum capacity of cul-de- treatments include intravitreous injections of corticosteroids sac is 30 μL in humans. The movement of the lower eyelid to decrease the swelling of macula. Also, sustained release cor- to its regular place would reduce this capacity to 70–80%. ticosteroids implant that interferes the inflammatory pathways. Inflammation and allergic response of the eye would also Modern management with anti-VEGF agents (Ranibizumab minimize capacity of the cul-de-sac. Since the activity and Aflibercept) prevents the expression of VEGF and thus of any drug is directly related to its residence time and con- reduce blood leakage and edema. centration. The low capacity of cul-del-sac would reduce the 13 AAPS PharmSciTech (2023) 24:66 Page 5 of 29 66 Fig. 2  Various ocular diseases affecting the two segments of the eye concentration of the drug in the eye, thereby reducing the on the retina. It is divided into epithelium, stroma, and therapeutic activity. endothelium. The epithelium is formed of five to seven lay- ers of firmly linked cells. Stroma is a water-based compact Loss of Drug from Lacrimal Fluid layer. The epithelium is a barrier for hydrophilic drugs and large molecules, whereas the stroma is a barrier for lipo- Drainage of the administrated ocular solution is a major bar- philic drugs. The endothelium preserves the transparency rier in precorneal region. Loss of drug from lacrimal fluid of the cornea and provides selective access for hydrophilic could happen as a result of lacrimation, solution drainage, drugs and macromolecules into the aqueous humor. As a and non-productive absorption in the conjunctiva. Also, general rule, drug molecular weight, charge, degree of ioni- drug metabolism and protein binding would further obstruct zation, and hydrophobicity influence the corneal permeation. drug absorption. Continuous renewal of lacrimal fluid Hence, the trans-corneal permeation is known as rate limit- helps maintaining eye hydration, preventing pathogens or dust ing step for drug transfer from the lachrymal fluid into the from retaining on the eye. In order to maintain effective drug aqueous humor. activity, residence time of the administrated formula must be sustained which could be achieved by different mechanisms. Blood‑Ocular Barriers Corneal Barriers They prevent the entry of foreign compounds into the blood stream. They are classified into blood-aqueous barrier (BAB) The cornea provides a resistant obstacle to different chemical and blood-retinal barrier (BRB). BAB is an anterior portion and mechanical injuries. It also supports light convergence of the eye that prevents the access of many compounds in the 13 66 Page 6 of 29 AAPS PharmSciTech (2023) 24:66 Fig. 3  Schematic diagram of physiological ocular barriers intra-ocular milieu. BAB allows the passage of lipophilic and ocular products. It is non-invasive route, but with low bio- small drugs. These drugs are eliminated from the anterior availability (21 days and increased antifun- gal efficacy Dorzolamide Subconjunctival injection Prolonged reduction in IOP for 35 days Ketorolac and phenylephrine Irrigation solutions Minimizing the cataract surgical duration and avoiding pupil miosis Povidone iodine Irrigation solutions Reduced frequency of microbial contamination during surgery in anterior segment (used every 20 s) Hydrogen Irrigation solutions Protection of the corneal endothelial subsequent to cataract surgery Acyclovir Iontophoresis higher permeation and bioavailability Dexamethasone Iontophoresis higher efficacy in managing non-infectious anterior uveitis Besifloxacin Iontophoresis Increased bioavailability Pilocarpine Iontophoresis Reduced doses and increased permeability Abbreviations: VEGF, vascular endothelial growth factor 13 AAPS PharmSciTech (2023) 24:66 Page 9 of 29 66 fabricated as PEGylated liposome for handling of uveitis developed to solve their drawbacks. Cyclosporine was for- showed sustained anti-inflammatory activity and targeting mulated as a mucoadhesive nanosystem utilizing poly (D-L- the required ocular tissue for 1 month as minimum. lactide)-b-dextran. Nanoprecipitation technique was adopted The administration of PLGA nanoparticle of brinzolamide for the formulation. The final product demonstrated small by subconjunctival injection showed successful handling of particle size, enhanced permeability, and drug retention IOP for 10 days. Significant lowering in corneal inflam-. Formulation of the antibacterial hesperetin as micellar mation and squamous metaplasia was ensured via subcon- system showed minute particle size, high percentage entrap- junctival injection of human mesenchymal stromal cells in ment efficacy, greater penetration, and enhanced efficacy mice with graft versus host disease. Table I shows extra. More examples are illustrated in Table II. Figure 5 examples. illustrates different ocular dosage forms. Irrigating Solutions Eye Suspensions They are solutions made under aseptic condition without the Ocular suspensions represent dispersions of hydrophobic inclusion of preservatives. They are used as balanced salt drug in aqueous solvent. They have enhanced contact time by surgeons to eradicate blood, cellular waste, and maintain because of drug retention in the conjunctival cul-de-sac. the appropriate hydration volume of the eye. There are Particle size, solubility, and dissolution rate in the tear fluid many examples that intensifies the importance of these solu- are extremely important during the preparation process tions. For example, minimizing the cataract surgical duration. Generally, particle size 10 µm could result in Table I shows more examples. ocular irritation and stimulated tearing. Disadvantages of ocular suspension include poor stability. They cannot be Iontophoresis stored in freezer as the particles tend to agglomerate and fail to disperse easily. Also, change in crystal size during the Iontophoresis is a technique used to carry medications into storage will influence both solubility and bioavailability of the posterior segment of the eye. It involves the usage of the drug. A blurred vision after their administration could voltage gradient. Novel systems involve the employment also result. Improved ocular administration of posaconazole of microneedle-based instruments. They had doubled the in polymer system of carbopol 974P and xanthan gum using amount of formula delivered to the back of the eye compared high pressure homogenizing technique showed enhanced to suprachoroidal injection. The combinations of ionto- stability, antifungal activity, and prolonged retention. phoretic delivery and contact lens results in 550–1300-times High speed liquid–liquid shear technique was adopted to shorter duration than drug uptake into choroidal capillar- formulate ultra-fine rebamipide ophthalmic suspension. This ies. Short-duration iontophoresis of acyclovir prod- formula showed enhanced transparency, small particle size, rug resulted in higher permeation and bioavailability. and improved stability. Table II states more examples. Ocular iontophoresis of dexamethasone phosphate revealed higher efficacy in managing non-infectious anterior uveitis Eye Emulsions. Table I shows more examples. An emulsion is a solubilized biphasic system due to the inclusion of surfactants or stabilizers. Advantages of eye Dosage Forms emulsions include ability to deliver hydrophobic drugs; oil-in water (O/W) emulsion is less irritant to the eye, Liquid Dosage Forms enhanced contact time and bioavailability. The ocu- lar delivery of dexamethasone acetate and polymyxin B Eye Drops sulfate was enhanced by the formation of nanoemulsion by high-pressure homogenization. A positive charge inducer Eye drops represent more than 95% of the marketed ocular was incorporated to enhance ocular adhesion. The resulted products. They deliver the medication into the anterior part formula showed enhanced stability, reduced particle size, of the eye. Their advantages include easy administration and and enhanced retention time. Water titration method accepted stability. However, their disadvantages include low was adopted for the construction of triamcinolone aceton- retention time (24 h, Sus- tained reduction in IOP for 24 h Tacrolimus Eye drops Solution Increased drug solubility and enhanced ocular permeation Nepafenac Eye drops cyclodextrin nano-aggregate Improved the solubility and perme- ability of the drug Posaconazole Eye suspension polymer system Enhanced stability, antifungal activity, and prolonged retention Olopatadine Eye suspension Nanosuspension Reduced particle size, enhanced drug retention time, and pro- longed drug release Amphotericin B Eye suspension Nanosuspension Improved drug stability Diclofenac Eye suspension Nanosuspension Higher drug entrapment, sustained release and improved activity Dexamethasone acetate Eye emulsion Nanoemulsion Enhanced stability, reduced particle size and enhanced retention time Triamcinolone acetonide Eye emulsion Microemulsion Minimized particle size and improved permeability Erythromycin Eye emulsion Microemulsion Improved transparency, particle size, and permeation Cyclosporine A Eye emulsion Nanoemulsion Improved drug retention, safety, and activity Ketotifen Eye emulsion Nanoemulsion Enhanced corneal permeation and prolonged release Rifampicin Eye emulsion Nanoemulsion Improved permeation and antibiotic activity Curcumin Eye gel Proniosomal gel Effective reduction in PS and improvement of anti-inflamma- tory activity Pilocarpine Eye gel Liquid crystalline gel increase in the ex vivo permeability and retention time Ketoconazole Eye gel Proniosomal gels Increased bioavailability and ocular permeation Brimonidine tartrate Eye gel Proniosomal gels Improved ocular bioavailability and sustained drug release Dorzolamide hydrochloride Eye gel Proniosomal gels Enhanced drug efficacy and per- meation Beclomethasone dipropionate Eye gel Cubosomal gels Reduced particle size and increased drug permeation Dorzolamide hydrochloride Eye gel Cubogel Higher penetration, enhanced safety, and bioavailability Acyclovir and loteprednol eta- Eye ointment Ointment Enhanced corneal penetration and bonate drug release Triamcinolone acetonide Ocular insert Nanofiber Reduced particle size, systemic absorption, and side effects Ketorolac Ocular insert Microsphere Prolonged drug release (over sev- eral months) Tenoxicam Ocular insert Nanostructured formulation Superior drug diffusion, ex vivo and in vivo permeation Timolol Therapeutic contact lens Gold nanoparticles Encouraged outcomes in animal model to treat glaucoma 13 AAPS PharmSciTech (2023) 24:66 Page 11 of 29 66 Table II  (continued) Model drug Dosage form Carrier platform Essential results Reference(s) Flurbiprofen Therapeutic contact lens Nanoaggregates Sustained release of the drug Phomopsidione Therapeutic contact lens Nanoparticles Sustained release of drug for 48 h Ciprofloxacin In situ gel Nanoparticles Enhanced residence time and sus- tained drug release Hydrocortisone butyrate In situ gel Nanoparticles Extended drug release and avoided burst release Bimatoprost In situ gel Solid lipid nanoparticle Improved drug retention time and permeation Tenoxicam In situ gel Nanostructured formulation Enhanced drug permeation and safety Vancomycin In situ gel Niosomes Sustained release and enhanced activity of drug Semisolid Dosage Forms liquid crystalline gel. That gel was formed by vortex method. Additional examples are mentioned in Table II. Eye Gels Eye Ointments Eye gels are a semisolid dosage form containing high water quantity. They have enhanced retention time and bioavailability Eye ointments are semisolid dosage form containing white because of their viscosity. Although gels contain large quantity petrolatum and mineral oil. They are administrated to the of water, blurred vision could still result. Various polymers could lower eyelid only at bedtime due to its interference with be used to prepare ocular gels like polyacrylic acid, acrylic acids, vision. They are commonly used among young patients. hydroxypropyl methylcellulose, and carboxymethyl cellulose They have anhydrous nature making them a good choice for. Coacervation technique was used to prepare a pronioso- lipophilic and moisture sensitive drugs. They have higher mal gel of curcumin with effective reduction in particle size and retention time and bioavailability in comparison with solu- improvement of anti-inflammatory activity. An increase tions. Avaclyr® is an ocular ointment enclosing the in the ex vivo permeability and retention time of pilocarpine antiviral acyclovir that was approved in 2019 for herpetic was demonstrated via formation of phytantriol-based lyotropic keratitis. Also, Lotemax® enclosing the anti-inflammatory Fig. 5  Classification of ocular dosage forms 13 66 Page 12 of 29 AAPS PharmSciTech (2023) 24:66 loteprednol etabonate. Both of them showed enhanced cor- sustained contact time compared to simple solutions. neal penetration and drug release. There are three types of in situ gel according to the transition properties: temperature, ionic, or pH sensitive. In situ Solid Dosage Forms gel of ciprofloxacin with hydroxypropyl methylcellulose and sodium alginate (ion-sensitive) showed enhanced residence Eye Powders time and sustained drug release. Thermosensitive in situ gel of hydrocortisone butyrate revealed extended drug release They are sterile solid dosage form of water-sensitive drugs. and avoided burst release. Thermosensitive in situ gel They are administrated in injectable forms as intracameral of ketorolac tromethamine showed improved mucoadhesive injection of cefuroxime, moxifloxacin, and voriconazole. properties with prolonged release of drug up to 12 h. Cefuroxime and moxifloxacin are reconstituted in saline, Table II shows more examples about in situ gel. while voriconazole is reconstituted in water. Both cefuro- xime and voriconazole solutions are stable for 7 days after reconstitution. However, moxifloxacin solution is stable for Nanostructured Platforms 24 weeks [107, 108]. Liposomes Ocular Inserts They were discovered in the mid-1960s. Advantages Ocular inserts are solid dosage form of biodegradable poly- of liposomes include safety, biodegradation, simple prepara- mers. They show zero order drug release model. Advantages of tion techniques, and improved bioavailability. They are inserts include high residence time, sustain drug delivery, con- spherical nanocarriers made of one or more concentric lipid stant release, and reduced side effects. Electrospinning bilayers. They could carry lipophilic drug in the lipid area, technique was adopted for the construction of triamcinolone while the interior could entrap hydrophilic drugs. Changing acetonide-loaded nanofibers. They showed reduced particle the formation technique and their composition could alter size, systemic absorption, and side effects. Also, sustained their surface charge, sensitivity to ion or pH, or temperature bimatoprost activity for many months was proved after incor- changes and the resulted particle size. Generally, the cor- poration of its insert. Table II shows more examples. neal epithelium has a negative charge; therefore, a positively charged liposomes would have high adherence, longer reten- Therapeutic Contact Lens tion time, and better absorption. These outcomes will reduce the interval between doses and improve patient satisfaction New studies showed that therapeutic contact lens could. Zhang and Wang created a liposomal system composed enhance bioavailability by >50% as a consequence to sus- of phosphatidylcholine, cholesterol, α-tocopherol, and chi- tained residence time and close contact with the cornea. tosan. The resulted formula showed high percent entrapment, Their residence time is 10 folds the conventional eye drops sustained activity, and enhanced efficacy. Lin et al. used. They also reduce required doses, interval between doses phosphatidylcholine, stearylamine, cholesterol, and hyaluronic and systemic absorption. There are many techniques to acid. The finished product revealed better corneal uptake, high enclose the drug inside contact lens as molecular imprinting, drug targeting, improved percent entrapment, and prolonged ion ligation, soaking, and use of nanoparticles [77, 114, 115]. penetration. Cheng et al. constructed liposomal system Obstacles to their clinical use include protein attachment, ion formed of soybean phosphatidylcholine, cholesterol, chitosan, and oxygen permeation, drug loss during manufacture or stor- and dicetylphosphate. This formula showed superior corneal age, transmittance, and swelling of the lens. Dexametha- permeation and improved activity. Vicario-de-la-Torre et sone contact lens was prepared by encapsulation technique. al. used phosphatidylcholine, cholesterol, sodium hyaluronate, It showed 200-fold drug retention in the retina matching with trehalose, borate, and vitamin E to form a stable formula with conventional eye drops. In order to reduce rapid drug enhanced safety, ocular adhesion, and hydration. Other release, chips of either timolol, bimatoprost, or hyaluronic acid studies are briefly described in Table III. Figure 6 shows dif- have been used. Extra examples are given in Table II. ferent nanostructured platforms. Mixed Dosage Forms Niosomes In Situ Gel Niosomes are bilayered nanocarriers composed of self- They are polymeric solutions of low viscosity. They converted aggregated non-ionic surfactants. They are biodegradable, into pseudo-plastic gels in contact with tear fluid. They have biocompatible, enclose both hydrophilic and lipophilic drugs 13 AAPS PharmSciTech (2023) 24:66 Page 13 of 29 66 and non-immunogenic. They could prolong drug release and. The most commonly used mucoadhesive agents in enhance its permeability and efficacy [161, 162]. Disadvan- nanosuspensions are Eudragit® polymers. Pignatello et al. tages of niosomes include chemical instability and possible developed a nanosuspensions of cloricromene composed hydrolysis, accumulation or loss of drug. Cholesterol of Eudragit® RS and RL 100 and Tween 80. The resulted or its derivative is added to improve rigidity and stability formula showed enhanced stability, corneal residence time, of niosomes. Elmotasem and Awad developed a nioso- and permeation. Ahuja et al. used Eudragit® S100 mal system composed of span 60, cholesterol, poloxamer and poloxamer 188 to form nanosuspensions of diclofenac 407, hydroxypropyl methylcellulose, cyclodextrin, and chi- with enhanced percent entrapment, prolonged release, tosan. The resulted formula showed high drug entrapment, and increased anti-inflammatory activity. Khan et al. enhanced corneal permeation and activity. Kaur et al. employed Eudragit® RL100 to increase percent entrapment, studied niosomal system composed of span 60, cholesterol, sustain drug release, and enhance pilocarpine activity. and chitosan. The finished product revealed higher activity, Extra results are briefly listed in Table III. reduced side effects, and prolonged release. Aggar- wal et al. improved the duration of action and efficacy of Nanomicelles acetazolamide using span 60, cholesterol, and Carbopol® 934P. Zubairu et al. developed a niosomal system of They are nanocarriers composed of anionic, cationic, or gatifloxacin composed of span 60, cholesterol, and chitosan. zwitterionic surfactants. They may be spherical, cylindri- The optimized formula showed enhanced antimicrobial cal, or star-shaped. They could entrap both hydrophilic and activity, no toxicity, and superior ocular permeation. lipophilic drugs. They have simple preparation techniques, More investigations are concisely mentioned in Table III. reduced toxicity, increased bioavailability, increased stabil- ity, and enhanced permeation. They could deliver drugs to Nanoemulsions both segments of the eye (anterior and posterior portions). Yingfang et al. developed nanomicelles of pimecroli- They are potential carriers for ocular delivery. Oils in water mus using polyethylene glycol and poly (ε-caprolactone) as nanoemulsions are composed of dispersed oil phase that is co-polymers. The resulted formula showed enhanced percent stabilized by surfactants in an aqueous medium. They pro- entrapment, sustained release, and enhanced activity. vide a reservoir for lipophilic drugs and interact with the Liu et al. enhanced ocular permeation and prolonged release lipids of tear film providing a sustained drug release [87, of tacrolimus utilizing amino-terminated poly(ethylene 163]. Surfactants are important for the interaction with the glycol)-block-poly(D,L)-lactic acid and hydroxypropyl surface of the cornea, plus enhancing drug solubility. methylcellulose. Terreni et al. used hyaluronic acid Drawbacks of nanoemulsions include blurred vision if the to sustain the release, increase permeation, and activity particle size exceeds 100 nm due to development of milky of cyclosporine A. Table III briefly lists additional formulation and reduced ocular tolerance due to high sur- studies. factant concentration. Akhter et al. developed nanoe- mulsions system of cyclosporine A. Many oils, chitosan, Polymeric Nanoparticles Carbopol®, and Transcutol® P were incorporated. The resulted formula revealed enhanced drug retention, safety, Polymeric nanoparticles could be divided according to their and efficacy. Oleic acid, polysorbate 80, poloxamer 188, structure and preparation method into nanospheres and chitosan, and polymyxin B were used by Bazán Henostroza nanocapsules. Nanospheres are small solid spheres com- et al., to improve stability, mucoadhesion, and antibiotic posed of a dense polymeric network. They have a matrix activity of rifampicin. Soltani et al. constructed nanoe- type composition with a great surface area. The drug could mulsions of ketotifen fumarate utilizing Eudragit® RL 100 be adsorbed on the surface or entrapped within the particle. and polyvinyl alcohol. Enhanced corneal permeation and However, nanocapsules are a small liquid core enclosed by sustained release were obtained. Additional findings a polymeric membrane. The drug could be adsorbed on the are listed in Table III. capsule surface or entrapped within the liquid core. Polymeric nanoparticles could reach both segments of Nanosuspensions the eye. They improve patient compliance particularly in chronic complaints due to their small particle size. They They are colloidal nanocarriers constituted of lipophilic or have a prolonged drug release, improved permeation, and semi-lipophilic drugs, suspended in a dispersion medium reduced elimination rate. Yu et al. developed poly- and stabilized by surfactants or polymers. Their meric nanoparticles for dexamethasone utilizing glycol advantages include sustained drug release, increased resi- chitosan, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide dence time, and enhanced drug solubility and bioavailability hydrochloride, and N-hydroxysuccinimide. They showed 13 66 Page 14 of 29 AAPS PharmSciTech (2023) 24:66 Table III  Examples of Different Nanostructured Platforms. Description of the Examined Drug, Other Components, Nanostructured Platform, and Important Results Model drug Other components Nanostructured platform Important results Reference(s) Coenzyme Q10 Phosphatidylcholine, cholesterol, Liposomes Sustained activity and enhanced α-tocopherol and chitosan efficacy Hyaluronic acid Phosphatidylcholine, stear- Liposomes Improved entrapment and pro- ylamine, cholesterol longed penetration Triamcinolone acetonide Soybean phosphatidylcholine, Liposomes Showed superior corneal permea- cholesterol, chitosan and dice- tion and improved activity tylphosphate Fluconazole Hyaluronic acid and Carbopol® Liposomes Increased corneal uptake, 940 improved the antifungal activity Timolol maleate Chitosan Liposomes Improved ocular permeation, precorneal residence time and bioavailability Ibuprofen Lipoid® S100; stearylamine; Liposomes Sustained corneal permeation and cholesterol; silk fibroin improved safety Fluconazole Span 60, cholesterol, poloxamer Niosomes Enhanced corneal permeation and 407, and chitosan activity Timolol maleate Span 60, cholesterol, and chitosan Niosomes Reduced side effects and pro- longed release Acetazolamide Span 60, cholesterol, and Car- Niosomes Improved the duration of action bopol® 934P and efficacy Gatifloxacin Span 60, cholesterol, and chitosan Niosomes Enhanced antimicrobial activity Lomefloxacin Poloxamer 188, poloxamer 407, Niosomes Increased antimicrobial activity and hydroxypropyl methylcel- and enhanced corneal permea- lulose tion Natamycin Carboxymethylcellulose or Niosomes Increased drug entrapment and hydroxypropyl methylcellulose- increased bioavailability E4 Tacrolimus Hyaluronic acid Niosomes Sustained release and enhanced activity Cyclosporine A Chitosan, Carbopol®, and Trans- Nanoemulsions Enhanced drug retention, safety, cutol® P and efficacy Rifampicin Polysorbate 80, poloxamer 188, Nanoemulsions Improved stability, mucoadhesion and chitosan and antibiotic activity Ketotifen Eudragit® RL 100 and polyvinyl Nanoemulsions Enhanced corneal permeation and alcohol sustained release Timolol Chitosan, hydroxyethylcellulose, Nanoemulsions Increased permeability and polivinylalcohol and polyethyl- activity englycol Terbinafine hydrochloride Surfactants, co-surfactant and Nanoemulsions Sustained release and improved gellan gum bioavailability Cloricromene Eudragit® RS and RL 100 and Nanosuspensions Enhanced stability, corneal resi- Tween 80 dence time and permeation Diclofenac Eudragit® S100 and poloxamer Nanosuspensions Prolonged release and increased 188 activity Pilocarpine Eudragit® RL100 Nanosuspensions Sustained drug release and enhanced activity Itraconazole Chitosan, lysine and poloxamer Nanosuspensions Increased corneal permeation and 188 stability Piroxicam Eudragit® RS 100 and polyvinyl Nanosuspensions Sustained release and improved alcohol efficacy Methylprednisolone acetate Eudragit® RS 100 and polyvinyl Nanosuspensions Prolonged release and enhanced alcohol activity Pimecrolimus Using polyethylene glycol and Nanomicelles Sustained release and enhanced poly (ε-caprolactone) activity 13 AAPS PharmSciTech (2023) 24:66 Page 15 of 29 66 Table III  (continued) Model drug Other components Nanostructured platform Important results Reference(s) Tacrolimus Amino lactic acid and hydroxy- Nanomicelles Enhanced ocular permeation and propyl methylcellulose prolonged release Cyclosporine A Hyaluronic acid Nanomicelles Improved release and permeation Itraconazole β-cyclodextrin and polyethylene Nanomicelles Improved drug stability, permea- oxide tion and activity Dexamethasone Chitosan Nanomicelles Sustained activity and enhanced permeability Dexamethason Glycol chitosan Polymeric nanoparticles Enhanced retention time and sustained release Acetazolamide Chitosan and span 60 Polymeric nanoparticles Enhanced ocular permeation and efficacy 5-Fluorouracil Quaternary ammonium-chitosan Polymeric nanoparticles Increased ocular residence time conjugates, sodium tripolyphos- and bioavailability phate and hyaluronic acid Cyclosporine A Span 80 and hyaluronic acid Polymeric nanoparticles Increased cellular uptake and efficacy Norfloxacin Chitosan, sodium tripolyphos- Polymeric nanoparticles Prolonged residence time, phate and Carbopol® 934P Sustained release and improved efficacy Etoposide Gelucire® 44/14 and Compritol® Solid lipid nanoparticles Sustained release, improved ATO 888 safety and activity Triamcinolone acetonide Pluronic® F-68 and gellan gum Solid lipid nanoparticles Improved residence time and increased delivered concentra- tion Tobramycin Stearic acid, Epikuron 200 and Solid lipid nanoparticles Higher concentration in both seg- sodium taurocholate ments of the eye Indomethacin Hydroxypropyl-β-cyclodextrin Solid lipid nanoparticles Improved ocular permeation, and chitosan drug entrapment and delivery to both eye segments Riboflavin Compritol® ATO 888 and Gelu- Nanostructured lipid carriers Superior corneal residence time, cire® 44/14, permeation and safety Etoposide Glyceryl stearyl citrate and Nanostructured lipid carriers Sustained and improved activity chitosan Ibuprofen Many solid and liquid lipids and Nanostructured lipid carriers Increased corneal retention time, Pluronic® F-127 permeation and stability Ofloxacin Compritol® HD5 ATO, oleic Nanostructured lipid carriers Extended release and enhanced acid, Tween 80 and chitosan efficacy Brinzolamide Poloxamer F68/ F127 and poly- Nanocrystals Immediate dissolution and sorbate 80 improved efficacy Dexamethasone Benzalkonium chloride and Nanocrystals Enhanced retention time and cetylpyridinium chloride safety Acyclovir Cysteamine HCl Dendrimers Sustained release and improved stability Antisense oligonucleotides Penetratin, hyaluronic acid Dendrimers Enhanced retention time, perme- ability and distribution in the posterior segment Brimonidine tartrate Glyceryl monooleate and polox- Cubosomes Improved permeation and bio- amer 407 availability Sertaconazole nitrate Pluronic® F127, Brij® 58 and Cubosomes Improved permeation, stability pluronic® F108 and efficacy Agomelatine Oleic acid and oleylamine Olaminosomes Enhanced permeation and activity Terconazole Cholesterol, span 60 and edge Bilosomes Improved permeation and activity activator 13 66 Page 16 of 29 AAPS PharmSciTech (2023) 24:66 Fig. 6  Illustration of numerous nanostructured platform enhanced retention time, sustained release, and small improved bioavailability. Ahmad et al. developed particle size. Bodoki et al. sustained the release and solid lipid nanoparticles loaded with etoposide employing enhanced the efficacy of lutein using poly(lactic-co-glycolic Gelucire® 44/14 and Compritol® ATO 888. The resulted acid), tween 80, and Poloxamer 407. Abdel-Rashid formula demonstrated sustained release, improved safety, et al. enhanced ocular permeation and efficacy of aceta- and activity. Tatke et al. constructed triamcinolone zolamide employing chitosan, span 60, Tween® 80/20, acetonide-loaded solid lipid nanoparticles utilizing Plu- and sodium tripolyphosphate. More examples are ronic® F-68 and gellan gum. The finished formula ensured concisely mentioned in Table III. improved residence time and increased delivered concen- tration. A mucoadhesive solid lipid nanoparticles of tobramycin was successfully examined by Chetoni et al. Solid Lipid Nanoparticles The system composed of stearic acid, Epikuron 200, and sodium taurocholate. Higher concentration of tobramycin They are a solid lipid matrix enclosing hydrophilic and in both segments of the eye was demonstrated. lipophilic drugs. Examples of lipids used to pre- pare solid lipid nanoparticles include triglycerides, fatty acids, steroids, and waxes. They do not require organic Nanostructured Lipid Carriers solvents since surfactants stabilize the lipid dispersion. They are biodegradable, biocompatible, safe, and They are considered a second generation of lipid nanoparticles, of low-cost preparation. They showed enhanced ocu- composed of around 30% of liquid lipids but the finished for- lar retention time, permeability, prolonged release, and mula is solid, with no crystalline structure. The liquid oil 13 AAPS PharmSciTech (2023) 24:66 Page 17 of 29 66 droplets provide additional space for drug in lipid matrix lead- improved permeation and increased cellular uptake. ing to higher drug content compared to solid lipid nanoparti- Table III clarifies briefly more studies about dendrimers. cles. They show controlled release, small toxicity, and enhanced activity. Aytekin et al. studied nanostructured lipid carriers Cubosomes loaded with riboflavin utilizing Compritol® ATO 888, Gelu- cire® 44/14, Miglyol® 812, Cremophor® EL, Transcutol® P, They are bicontinuous cubic liquid crystalline nanocarriers and stearylamine. The finished product demonstrated superior constructed by emulsification of lipids in water with the aid of corneal residence time, permeation, and safety. Pai and stabilizer. They are stable, entrap high amount of drugs due to Vavia constructed etoposide-loaded nanostructured lipid car- its large surface area, easy to prepare, biodegradable, and rela- riers using many solid and liquid lipids, glyceryl stearyl cit- tively safe. El deep et al. formulated brimonidine tartrate- rate, and chitosan. The resulted formula reveled sustained and loaded cubosomes utilizing glyceryl monooleate and polox- improved activity. Yu et al. used Compritol® 888 ATO, amer 407. The resulted formula revealed sustained release, Miglyol® 812 N, Cremophor® EL, soy lecithin, carboxymethyl improved permeation, and bioavailability. Younes et chitosan, genipin, and poloxamer F127 to formulate nanostruc- al. developed sertaconazole nitrate-loaded cubosomes using tured lipid carriers of baicalin. Investigations showed increased DL-α-Monoolein, pluronic® F127, Brij® 58, pluronic® corneal permeation, retention time, and safety. More F108, Tween 80, and polyvinyl alcohol. Improved permea- investigations are succinctly stated in Table III. tion, stability, and efficacy were achieved. Gaballa et al. developed cubosomal system of beclomethasone dipropionate Nanocrystals employing glyceryl monooleate. Improved corneal permea- tion and anti-inflammatory activity were demonstrated. The drug represents a major composition of nanocrystals, being enclosed and stabilized by other excipients. They have Olaminosomes small particle size, simple formation techniques, high mucoad- hesion properties, and improved bioavailability. Tuomela Olaminosomes are mainly formed of oleic acid, oleylamine, et al. created brinzolamide-loaded nanocrystals using polox- and surfactant. Oleic acid is natural unsaturated free fatty acid. amer F68/ F127, polysorbate 80, and hydroxypropyl methycel- Oleic acid is safe, biodegradable, and biocompatible. Thus, oleic lulose. The finished formula revealed immediate dissolution acid is often used in the preparation of ocular nanocarriers. and improved efficacy. Romero et al. developed cationic Oleylamine is an unsaturated fatty amine derived from oleic nanocrystals of dexamethasone and polymyxin B using benza- acid. It has the extensively used as surfactant or co-stabilizer. lkonium chloride and cetylpyridinium chloride. The resulted It is generally used in food and drug products as a result of its preparation revealed small particle size, enhanced retention well-accepted safety. Olaminosomes have a small particle time, and safety. Orasugh et al. formulated a cellulose size, high drug entrapment ability, improved corneal permeation, nanocrystals of pilocarpine. Sustained drug release and safety safety, and activity. Abd-Elsalam and ElKasabgy developed ago- were demonstrated. Nanocrystals could be promising melatine-loaded olaminosomes. The optimum formula showed nanocarriers to be investigated in the near future in details. enhanced permeation and improved activity. Dendrimers Bilosomes They are star-shaped or tree-shaped highly branched 3D Bilosomes are bilayered nanocarriers containing bile salts. structure, composed of repetitive molecules enclosing a They have high drug entrapment, minute particle size, central core. They are suitable for delivery of both accepted zeta potential, accepted safety, enhanced corneal hydrophilic and lipophilic drugs due to their several terminal permeation, and activity. Abdelbary et al. developed tercon- groups. They showed increased residence time, pro- azole-loaded bilosomes using cholesterol, span 60, and edge longed activity, improved bioavailability, targeted delivery, activator. The resulted formula showed great entrapment, and antimicrobial properties. They could transfer medica- improved permeation, and enhanced activity. tions to both segments of the eye. Lancina et al. devel- oped brimonidine tartrate-loaded dendrimers using meth- oxy-polyethylene glycol. Sustained release and improved Characterization of Nanocarriers activity were achived. Mishra and Jain studied den- drimers entrapping acetazolamide. Increased residence Visual Appearance time, prolonged release, and activity were confirmed. Holden et al. developed timolol maleate-loaded dendrimers Figure 7 shows briefly the approaches used to characterize utilizing polyethylene glycol. The finished formula showed ocular nanocarriers. Visual appearance depends on the particle 13 66 Page 18 of 29 AAPS PharmSciTech (2023) 24:66 size, surfactant, and oil concentration and type. Nanosystems around ± 20 mV is appropriate for electrostatic attachment could be transparent, translucent to milky white. Transparency with the cornea surface. In addition, ZP ensures the stability is estimated by percentage transmittance (% T) using a UV because of electrostatic repulsion between the particles. It spectrophotometer at 520 nm. Small particles permit light is high recommended to dilute the formed nanosystem prior transmission resulting in translucent or transparent appearance. to ZP determination. Effective precorneal retention time High % T indicates absence of visual disturbance. However, is achieved when the absolute value of ZP lies between 20 gelation would reduce the transparency by 15%. and 40 mV. It has been demonstrated that ZP value + 40 mV of Catioprost (Latanoprost — cationic emulsion) revealed Stability a comparable effect as Xalatan (commercial eye solution) for reducing IOP but have a superior ocular tolerance pro- Stability of different nanosystems could be determined file. Also, cubosomal formula with ZP =  −30.2 mV through short-term stability (3 months), centrifugation test, showed better bioavailability and activity compared to heating–cooling cycle, freeze–thaw cycles, and storage at ele- Alphagan P® eye drops. vated temperatures. All tests are followed by visual evaluation [6, 36]. The structure of the constructed formula determine Morphological the storage condition which could be at ambient temperature (25 ± 2°C) [33, 34, 36] or refrigerated (4–8°C) [31, 173]. Transmission electron microscopy (TEM) and atomic force microscopy (AFM) approaches are valuable to ensure the results of dynamic light scattering (DLS) or photon correla- Size and Uniformity Analysis tion spectroscopy (PCS). TEM of the nanoemulsion referred by Tayel et al. showed spherical and homogenous Particle size (PS) and poly-dispersity index (PDI) are the structure with no aggregates. TEM was in harmony with determined variable. They are estimated by dynamic light the results obtained by PCS. In addition to, the AFM scattering (DLS) or photon correlation spectroscopy (PCS) examination of the nanoemulsion referred by Dukovski et al. using either Zetasizer devices (Malvern) or Coulter Counter revealed spherical structure with the same size as resulted particle size analyzer. The ratio of the standard deviation from PCS. TEM of the mixed micelles constructed by to the mean droplet size is known as a PDI. Regarding PDI, Younes et al. revealed spherical shape, with no accumulation a value of 0 indicates homogenous system, while a value of and was comparable to DLS. 1 indicates heterogeneous system. Generally, small PS and PDI are desirable for ocular drug delivery since they Refractive Index increase patient compliance and enhance corneal permeabil- ity and corneal bioavailability. PS is affected by homog- The refractive index (RI) is detected by Abbe’s refractom- enization time, surfactants type, surfactants amount, lipids eter and employed to detect the water content of soft con- type, and lipids quantity. Using high amount of lipid would tact lenses. It is important to confirm that the nanosystem increase the viscosity of the medium resulting in high dif- will not cause a blurred vision. The optimum RI for ficulty to break the particles and hence large PS. How- ocular delivery is 10) solu- to the mass of the nanosystem; however, % EE reflects the tion would harm the eye. Also, pH from 4 to 8 would incorporation of drugs within the nanosystem during the significantly enhance drug permeation. The pH of 13 66 Page 20 of 29 AAPS PharmSciTech (2023) 24:66 ocular preparation usually ranged from 3.50 to 8.50. ocular irritation from nanosystem. The score is given based pH of the formed cubosomes referred by Said et al. was on clotting, bleeding, and hyperemia on CAM blood vessels (6.20 ± 0.01). Micellar system constructed by Fahmy et. For example, Mahboobian et al. examined the safety al. revealed acceptable pH value (7.41 ± 0.01). 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 Isotonicity and Osmolality 37 ± 0.5°C and relative humidity of 67 ± 5% RH for 10 days with regular rotation every 12 h. Irritation consequences Osmolality measurements are based on the colligative proper- such as hemorrhage or hypermia were evaluated by visual ties of tears or ocular nanosystem known as the freezing point, inspection. Safety of the nanoemulsion was demonstrated by boiling point, vapor pressure, and osmotic pressure. Osmolality the end of the experiment. of open eyes is ranged from 231 to 446 mOsm/kg due to fluid evaporation. Ocular preparation with osmolality lower than Corneal Permeation 100 mOsm/kg or greater than 640 mOsm/kg was considered an eye irritant. Osmolality is restored within 1 or 2 min sub- Ability of the nanosystem to penetrate through cornea is sequent to administration of the non-isotonic preparation. 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 Ocular Retention cells layer cultures, reconstructed cornea, or excised cor- nea. Also, different permeation chambers are available Ocular retention is important since it will reduce the frequency like Franz-type diffusion cell, modified Franz diffusion cell, of doses and improve drug bioavailability. Ocular retention modified using chamber, horizontal perfusion cells, modified largely depends on surface area of nanosystem, since large Erlenmeyer flask diffusion cell, and polycarbonate corneal surface area will enhance residence time. Ocular retention perfusion chamber. Different permeation parameters is determined by texture analysis method, modified balance are estimated to evaluate the permeation potential of nano- method, fluorescence retention method, γ-scintigraphy, and system. Permeation parameters include the amount of drug rheological synergism after mixing with mucoadhesive poly- permeated per unit area (µg/cm2), average flux ­(Jmax), perme- mer. As a general rule, the force needed to detach eyelid ability coefficient, and the enhancement ratio (ER) [5, 34]. during normal blink is about 0.2 N and 0.8 N during strong blink. For chitosan-coated cyclosporine nanoemulsions, Possible Interactions the resulted force of detachment was 0.153 N. Differential scanning calorimetry (DSC) and Fourier trans- form infrared spectroscopy (FTIR) are important techniques Ocular Biocompatibility to detect possible interaction between the components of nanosystems. They also assure complete entrapment Draize Test of the drug. For example, the specific peaks of vancomycin, poly (d, l-lactide- coglycolide), and Eudragit® RS 100 were It’s a traditional in vivo test to detect possible irritation poten- preserved ensuring the absence of chemical interactions tial of the formed nanosystems. It may be also used for cos- , while complete entrapment of dorzolamide hydro- metics. Draize test relays on scoring system from 0 (no chloride was confirmed by disappearance of its characteristic irritation) to 3‫( ‏‬inflammation and redness) for the cornea, iris, peak from DSC thermogram. and conjunctivae. For example, Ismail et al. utilized the test on rabbits to compare between nanoemulsions of travo- prost and Travatan® eye drops. Safety of the constructed for- Approaches to Enhance Ocular Delivery mula was confirmed. Also Eldeep et al. used Draize test to confirm safety of the topically applied niosomes of Improvement of Corneal Permeability brimonidine tartrate against Alphgan P®. Figure 8 shows concisely the approaches used to enhance Hen’s Egg Test ocular delivery. One of the approaches to enhance drug bio- availability following topical administration is increasing Because of the existence similarities between chorioal- corneal permeability. For example, changing membrane lantoic membrane (CAM) and vascularization of mucosal components and/or disrupting epithelial tight junctions tissue of humans, this technique is used to detect possible using surfactants, permeation enhancers, calcium chelating 13 AAPS PharmSciTech (2023) 24:66 Page 21 of 29 66 agents , and modifying physicochemical characters of Future Technologies the ionized drug using ion pairs. On the other hand, enzymatic transformation of prodrug would convert it into Smart Nano‑Micro Platforms the active after appropriate permeation. Finally, apply- ing a low-intensity electrical current (iontophoresis) would Smart denotes to nano-micro matrix that can considerably enhance drug permeation by electrorepulsion and electroos- change their mechanical, thermal, and/or optical proper- mosis effects. ties in a manageable or expectable means, and they can achieve sensing triggering roles with stimuli-responsive Improvement of Corneal Retention Time features. Unlike conventional nanocarriers, the smart nano-micro platforms can reveal precise reaction to exoge- One of the techniques to increase corneal retention time nous (light, sound, and magnetic field) or endogenous (pH, is inclusion of excipients. Excipients could be a viscosity reactive oxygen species, and biological molecules such increasing polymers. However, high viscous eye drops are as DNA and enzymes) factors resulting in accomplish- irritating for many patients, do not provide an accurate ing many functions, e.g., site-specific drug delivery, bio- dose and result in blurred vision. In situ gel has imaging, and detection of bio-molecules. These fascinat- sustained contact time compared to simple solutions. ing techniques have extended into ocular delivery in recent There are three types of in situ gel according to the transi- years. Generally, these revolutionary systems have been tion properties: temperature, ionic, or pH sensitive. used for cancer diagnosis and management, to enhance In situ gel of ciprofloxacin with hydroxypropyl methyl- the bioavailability of drugs/agents, minimize side effects, cellulose and sodium alginate (ion-sensitive) showed and augment safety and efficacy [192, 193]. Tsujinaka et enhanced residence time and sustained drug release. al. successfully delivered sunitinib microparticles that More examples of in situ gel were previously mentioned effectively inhibit the intraocular inflammation in mice in Table II. The mucus gel layer covering the ocular sur- model up to 6 months. Rodriguez et al. constructed face is made of mucins, a class of at least 20 O-glycosyl solid lipid nanoparticles that carry miRNA as gene therapy proteins with anionic charge. Excipients permitting attach-. Basuk et al. demonstrated photo-modulated release ment to this mucus gel layer provide a sustained residence of pre-loaded bevacizumab using visible light. time. Chitosan is a commonly used mucoadhesive polymer by virtue of its polycationic nature and the exist- Extracellular Vesicles (Exosomes) ence of many reactive amino groups capable of interac- tacting with mucin layer. Kaur et al. studied niosomal Extracellular vesicles are a sort of organelle that is produced system composed of span 60, cholesterol, and chitosan by different cell types. Various bioactive compounds for which revealed higher activity, reduced side effects, and example proteins, lipids, RNAs, and DNAs are enclosed prolonged release. Cyclodextrins are widely used within extracellular vesicles. They have a nano-size behave as cyclic glycopyranose oligosaccharides. They have the abil- a strong intercellular trigger that can start different physiolog- ity to enhance drug solubility and to attach covalently to ical and pathological consequences. Under pathological situ- mucoadhesive polymers to prolong residence time. ations, they could be produced by immune cells and control Sayed et al. used β-cyclodextrin to enhance ocular deliv- the inflammation progressions. They have a well-recognized ery of itraconazole. Many colloidal delivery nano- role in immune-mediated eye diseases, such as Sjogren’s syn- systems have been employed to enhance ocular delivery. drome and corneal allograft rejection. Also, they could They have the ability to carry different drugs, increase encourage renewal of corneal tissue by stimulating the pro- bioavailability, reduce frequency and potential side effects, duction of different matrix components. Additional investiga- and improve patient’s compliance. Different ocular nano- tions are required to develop ocular delivery systems based systems were previously stated in Table III. Also, solid on exosomes. Tang et al. constructed exosomes of pluripo- polymeric devices have been developed as authorized sus- tent stem cell-derived mesenchymal stem cells to hasten the tained release ocular dosage forms. However, solid strat- restorative process of the corneal epithelium. Zhu et al. egies are frequently not accepted by patients because of developed exosomes derived from lens epithelial cells to load discomfort and interference with vision. Sustained bimato- doxorubicin to prevent posterior capsular opacification. prost activity for many months was proved after incorpora- tion of its insert. Dexamethasone contact lens was Tissue Engineering prepared by encapsulation technique. It showed 200 fold drug retention in the retina matching with conventional Tissue engineering investigations are classified into two eye drops. More examples of solid dosage forms types. First type is additive tissue engineering which were formerly listed in Table II. substitutes cells or tissue or tries to permit the growth of 13 66 Page 22 of 29 AAPS PharmSciTech (2023) 24:66 Fig. 8  Approaches to enhance ocular delivery something that is no longer there. The second type is arres- and will continue till May 2023. Moreover, Cequa™ (Cyclo- tive tissue engineering that prevents irregular growth. Both sporine) ophthalmic emulsion (twice daily). This is a phase additive and arrestive tissue engineering could be performed 4, multicenter, single arm, and 12-week study. An example utilizing nanosystems. Examples of nanosystem-based tissue of solid dosage form includes Dextenza 0.4 Mg (dexametha- engineering include check of retinal ganglion cell viabil- sone) ophthalmic insert. The study is performed to assess the ity , retinal ganglion cell repair , formulation of efficacy and safety of Dextenza insert for the treatment of nanofiber scaffolds , corneal endothelial cell transplan- pain and inflammation following corneal transplant surgery. tation , and inhibition of retinal cell apoptosis. Scientists begun to examine if nanotools and nanomaterials could be used to restore neural function of eye’s nerve cells. Conclusions Innovations in Clinical Trials The effective management of ophthalmic diseases remains a difficult mission as a result of existence of many ocular Continuous clinical trials for different dosage forms give obstacles in the anterior and posterior sections of the eye. the lead for pioneer treatment. For example, pilocarpine There are many ocular routes of administration that are used topical cream (semi-solid) for the treatment of presbyopia. in order to deliver the medication into the targeted site of It is a multicenter, randomized, double-masked, placebo- action such as topical, intraocular, periocular, or in conjuga- controlled, parallel group phase 2 trial evaluating the safety tion with ocular devices. Several approaches and technolo- and efficacy of the cream. The study starts at January 3, 2022 gies have been adopted in order to minimize dosing interval, 13 AAPS PharmSciTech (2023) 24:66 Page 23 of 29 66 administrated dose, and unwanted effects and to enhance 4. Elsayed I, Sayed S. Tailored nanostructured platforms for boosting ocular retention time, drug permeation efficacy, and ocular transcorneal permeation: Box-Behnken statistical optimization, comprehensive in vitro, ex vivo and in vivo characterization. Int J bioavailability via controlled and sustained drug delivery Nanomed. 2017;12:7947–62. https://​doi.​org/​10.​2147/​IJN.​S1503​66. systems. These advanced technologies have improved drug 5. Ahmed S, Amin MM, El-Korany SM, Sayed S. Corneal targeted efficacy and shown good biocompatibility which suggest that fenticonazole nitrate-loaded novasomes for the management of they might have wide applications in the management and ocular candidiasis: preparation, in vitro characterization, ex vivo and in vivo assessments. Drug Deliv. 2022;29(1):2428–41. treatment of ocular diseases. In the future, more innovations https://​doi.​org/​10.​1080/​10717​544.​2022.​21036​00. are predicated in the ocular drug delivery systems in order 6. Singh M, Bharadwaj S, Lee KE, Kang SG. Therapeutic nanoe- to enhance and preserve the health of the eye, to improve mulsions in ophthalmic drug administration: concept in formu- patient compliance, and to accomplish superior results in lations and characterization techniques for ocular drug delivery. J Control Release. 2020;328:895-916. https://​doi.​org/​10.​1016/j.​ the management of ocular diseases. jconr​el.​2020.​10.​025. 7. Maulvi FA, Shetty KH, Desai DT, Shah DO, Willcox MDP. Recent advances in ophthalmic preparations: ocular barri- Author Contribution Conceptualization: S.A., M.M.A., and S.S.; soft- ers, dosage forms and routes of administration. Int J Pharm. ware: S.A.; formal analysis: S.A., M.M.A., and S.S.; investigation: 2021;608:121105. https://​doi.​org/​10.​1016/j.​ijpha​rm.​2021.1​ 21105. S.A., M.M.A., and S.S.; resources: S.A, M.M.A, and S.S.; writing— 8. Silva B, Sao Braz B, Delgado E, Goncalves L. Colloidal nano- original draft preparation: S.A.; writing—review and editing: M.M.A. systems with mucoadhesive properties designed for ocular and S.S.; supervision: M.M.A. and S.S. All authors have read and topical delivery. Int J Pharm. 2021;606:120873. https://​doi.​ agreed to the published version of the manuscript. org/​10.​1016/j.​ijpha​r m.​2021.​120873. 9. Kels BD, Grzybowski A, Grant-Kels JM. Human ocular anat- Funding Open access funding provided by The Science, Technology & omy. Clin Dermatol. 2015;33(2):140–6. https://​d oi.​o rg/​1 0.​ Innovation Funding Authority (STDF) in cooperation with The Egyp- 1016/j.​clind​ermat​ol.​2014.​10.​006. tian Knowledge Bank (EKB). Funding Open access funding provided 10. Randazzo J, Zhang P, Makita J, Blessing K, Kador PF. Orally by The Science, Technology & Innovation Funding Authority (STDF) active multi-f