An Integrative Analysis of Ocular Drug Delivery: Insights into Ocular Anatomy, Pathology, and Advanced Biocomposite and Nanotechnological Therapeutics

Abstract

The complex anatomy and protective barriers of the eye, including the corneal epithelium, rapid tear clearance, and blood-ocular barriers, significantly limit topical ocular drug delivery, resulting in bioavailability as low as 1–5% with traditional formulations such as eye drops, ointments, and suspensions. This review thoroughly examines the obstacles in ocular drug delivery across major eye disorders—including glaucoma, cataracts, age-related macular degeneration, bacterial and fungal keratitis, diabetic retinopathy, and dry eye syndrome. It further underscores cutting-edge treatment platforms such as in situ gels, ocular inserts, and diverse nanocarriers—liposomes, nanoparticles, niosomes, dendrimers, nanosuspensions, and microemulsions—augmented by advanced techniques like iontophoresis and sonophoresis. Mucoadhesive biopolymers such as chitosan, PVA, and Carbopol, along with cutting-edge nanocomposites, drive advancements by markedly improving ocular retention, enhancing corneal penetration, and enabling sustained drug release while reducing irritation and systemic toxicity. Innovations in drug delivery have markedly improved patient adherence by minimising dosing intervals and enabling accurate delivery to posterior eye conditions such as glaucoma and age-related macular degeneration. Emerging research will focus on engineering hybrid nanocarriers that combine gene therapy and tissue engineering, aiming to boost stability, scalability, and accelerate effective clinical translation.

Keywords

Introduction

The complex anatomy of the eye and how it protects itself make it very difficult to design devices for delivering drugs to the eyes that sustain a long-lasting, effective medication concentration ^[(1)].Drug molecules cannot pass through the stroma, endothelium, or epithelial layers of the corneal barrier, a nonvascularized barrier. The surface area of the tissue is less than that of the conjunctiva, but the epithelium of the cornea is more permeable [^(2,3)]. There can be significant systemic absorption when blood and lymphatic vessels are present ^[(4)]. Some conjunctival goblet cells secrete a mucus that coats the conjunctiva and cornea, and contributes to the tear film. The stratum of the lachrymal gland not only hydrates, cleans, lubricates, and defends against infections, but it also acts as a barrier to the uptake of medications. The dynamic fluid known as the lachrymal layer is constantly renewed, as well as shortening the time the medications are on the eye's surface. Moreover, aldehyde and ketone reductases and esterases ^[(5)] are metabolic enzymes found in the ocular tissues that can break down and lessen the effectiveness of medications. A significant quantity of the medication is lost after treatment due to these physiological and anatomical restrictions ^[(6)]. Research shows that just between 1% and 2% of medications distributed throughout the body enter the vitreous cavity. This is mostly because of blockages from the blood–retinal barrier, which mainly regulates drug entry and selectively allows more lipophilic molecules to pass through. The medication molecules enter the back of the eye ^[(7)]. A huge amount of dosage of the medication is frequently conducted as a result, which has serious systemic adverse effects. Consequently, it is preferable to increase the drug's corneal and/or conjunctival penetration to treat disorders that impact the eye's posterior region. Intraocular along periocular illnesses are two types of eye disorders. Common ocular disorders that impact the region surrounding the eye include persistent bacterial infections, conjunctivitis, and blepharitis of the eye ^[(8)]. Treatment of the inside of the eye is challenging, including glaucoma along with infections of the retina, iris, vitreous humour, and aqueous fluid. In therapeutic settings, ocular drops are the most commonly applied topical eye medications. Eye drops marketed for use tend to be less effective and require more frequent use. Commercial eye drops need to be applied more frequently. They are often less effective, as a significant portion of the medication is lost through tear flow within the nasal tubes and conjunctiva. This loss can lead to unwanted adverse consequences as well as reduced medication use, as that medication may enter either the digestive tract or the systemic circulation. Often, it is challenging to adhere to the frequent dosage regimen, leading to inadequate medication concentration and unsuccessful treatment. The precorneal, dynamic, and static barriers can only allow 5% of the supplied dosage to pass through ^[(9)]. Moreover, gels and ointments have a relatively longer half-life, but their bioavailability is reduced since tear fluid rapidly dilutes them and causes them to flow out. These include the blinking reflex action. Nasolacrimal drainage, lacrimal secretion, and the small capacity of the Cul-de-sac (approx 30 μL) are hindered by the barriers of cells in the cornea, conjunctiva, and epithelium, as well as their metabolic constraints, which can lead to reduced medication absorption due to degradation. These create barriers to the effective administration of medications topically toward the chambers in front and behind, as well as the stroma of the cornea. Nowadays, topical ocular drug delivery systems that can get past these obstacles are a potential approach to treating ocular conditions, including retinitis pigmentosa, macular degeneration, cataracts, glaucoma, and diabetic retinopathy. Due to the type of distribution mechanism, the eyes retain an effective concentration of the medication for a considerable amount of time after the dose is given. Furthermore, the distribution mechanisms must be non-intrusive, maintain visual acuity, and avoid infection, irritation, and inflammation. Additionally, it ought to enable the medication to get to the ocular location of the action by navigating the barrier of the cornea and tear film ^[(10)]. Numerous factors, including viscosity, surface tension, pH, and osmolarity, influence the development of ophthalmic preparations. To increase the bioavailability of medications in the eyes, the rate at which ocular formulations drain can be decreased by either method using mucoadhesive nanoformulations, thereby improving the viscosity ^[(11)]. To get over these obstacles and preserve higher medication concentrations in tissues, research on ocular drug delivery is currently centred on creating novel, secure, and palatable compositions. Besides the standard ophthalmic dosage, to increase bioavailability, Many researchers have put a lot of effort into developing novel ocular drug delivery systems, including ions or thermosensitive in situ gelling polymers, ocular films, dendrimers, liposomes, and micro/nanoparticles in aqueous suspensions, gels, ointments, and solutions to improve ocular administration, patient compliance, and reduce adverse effects ^[(12–14)]. Precorneal retention is thought to be improved by these technologies, which improve medication bioavailability and corneal penetration, thereby increasing patient compliance by increasing dose frequency. Polymers used in ocular delivery systems should be safe, non-reactive, stable, mucoadhesive, biocompatible. With this in mind, research has been conducted on utilising natural polysaccharides, including chitosan, xanthan, and alginate, to develop innovative drug delivery methods. Biopolymers can be used in ocular applications because the products are non-toxic, non-immunogenic, noncarcinogenic, and biocompatible. It is also mucoadhesive. There has been considerable interest in developing new biocomposite materials with high performance and desired functions by creatively combining various types of biomaterials ^[(15)]. A composite material is made up comprising two or more constituent elements with physicochemical characteristics that differ greatly from one another. A single entity can have two or more components that differ significantly from one another. The integration Adding nanostructured elements to hydrogels has also emerged as the prominent method for developing innovative materials having a variety of functions, to address specific biology and clinical issues ^[(16)].

ANATOMY AND PHYSIOLOGY OF THE EYE:

The eye works like a globe suspended in the ocular orbit, focusing, transmitting, and detecting incoming light. This specific arrangement of tissues is thought to contribute to the eye's distinctive role in vision. 

• Sclera: The extracellular matrix of the sclera consists of proteoglycans and collagen fibres. In this context, scleral permeability diminishes as the radius of the molecule increases. The collagen fibre composition in the posterior sclera is looser compared to that in the anterior sclera. The dimensions of the human sclera are 0.9-1.0 mm around the optic nerve, 0.39 + 0.17 mm at the equator, and 0.53 + 0.14 mm at the limbus. The permeability of human capsules decreases with higher lipophilicity and hydrophobicity. The sclera is a strong outer covering that protects the surface of the globe. A spherical shape continues to be a focal point of study. Hydrophilic capsules tend to diffuse more readily than their lipophilic counterparts into the aqueous medium contained within the proteoglycans in the fibre matrix. The cost of a medication can also influence its ability to pierce the sclera, because they stick to the negatively charged proteoglycan matrix; positively charged capsules may have less permeability. This circular structure integrates three layers: the inner retina, the middle choroid, and the outer choroid. The thick, fibrous sclera protects the outermost layers of the skin. The cornea, located at the front of the eye, which lets light in, remains transparent.  A colored iris is formed by the modification of the choroid layer of the sclera at the front, densely populated with blood vessels. The iris can come in various colours, such as blue, green, brown, hazel, or grey.
• Conjunctiva: The conjunctiva, which is visible from the outside of the globe, is a delicate, translucent membrane located within the eyelids. The conjunctiva comprises structural components, including the submucosa, epithelium, and substantial vascularisation of the substantia propria. Within the bulbar epithelium, there are five to seven flexible layers. The corneal epithelial cells are closely linked together, resulting in a highly impermeable conjunctiva that gives it a palisade-like appearance rather than a pavement-like one. Only the cornea permits molecules larger than 5000 Da to pass through, while the conjunctiva allows those as small as 20,000 Da to penetrate. Furthermore, the primary challenge concerning drug clearance has been identified as the limited drug passage through the human conjunctiva, which can absorb two to thirty times more medication than the cornea. Various intersubject variability studies have indicated that age impacts both the maximum conjunctival density and the total number of 1.5 million mobile globular cells. A minor change in goblet mucin density, which largely presents as a concentration of tear mucin, is mainly responsible for both atopic and vernal keratoconjunctivitis. 
• Choroid: The choroid layer, located behind, supplies nutrients to its outer areas and absorbs excess light. This thin, moderately vascularized membrane contains blood vessels. Excess mild at the retina can lead to blurred vision, which the choroid helps prevent by absorbing this surplus mild. Blood flow through the choroid operates at one of the fastest rates in the body. The choroid is linked asymmetrically to an inner floor of the sclera through the lamina fascia.
• Retina: The human retina, located in the rear of the eye, the human retina captures light that travels through the vitreous humour, pupil, lens, cornea, and aqueous fluid, essentially acting as a "screen" that generates an image. Besides forming images, the retina gathers the data contained in those images and relays it to the brain in a format that the body can use. Highly sensitive and lining the inner eye, the retina consists of photoreceptive rods and cones, along with nerve fibres connecting them. In these cells, the optic nerve transforms light into nerve impulses, which are then sent to the brain.
• Iris: The amount of light that reaches the eye is controlled by the colored part of the eye, the Iris. This thin, circular membrane can contract and expand, located behind and in front of the cornea and lens. It adjusts the pupil's size to regulate the amount of light that reaches the eye.
• Lens: The lens is a clear structure contained within a thin capsule. Positioned behind the pupil and surrounded by ciliary muscles, as light travels through the eye, it is bent (first by the cornea). The lens sharpens the light to form an image on the retina. The adjustment in lens shape, known as accommodation, occurs through the contraction and relaxation of the ciliary muscles.
• Optic Nerve: Made up of over a million nerve fibres, Nerve impulses are transmitted from the retina to the brain via the optic nerve. The brain is then able to interpret the visual information delivered by these nerve signals. The optic disk, located at the front, represents the visible aspect of the retina-receiving optic nerve.
• Pupil: A black hole in the iris is called the pupil, which limits how much light reaches the eye. While often perceived as the darker centre, the pupil can more accurately be described as the circular opening in the iris that permits light to reach the eye.
• Cornea: Cornea has a radius of (7-8) mm and approximately one-sixth of the fovea's surface area. It contains vascular tissue that derives nutrients and oxygen from the tear. The point where the cornea and sclera meet contains fluid, aqueous humour, and blood vessels. The stroma, Descemet's membrane, epithelium, Bowman's layer, and endothelium are the five layers that make up the cornea, which serves as a crucial entry point for medications. Its thickness is between 0.5 and 0.7 mm. The epithelial layer of the cornea is highly resistant to drug absorption, unlike other epithelia, such as those found in the intestine, nasal passages, bronchi, and trachea. About five to six layers of squamous stratified cells make up the epithelium, each measuring 50 to 100 μm thick, with about one mobile layer being replaced daily. The stroma, also known as the substantia propria, consists of around 85% water and contains 200–250 collagenous lamellae, accounting for about 90% of the cornea's overall thickness. These lamellae help maintain the membrane's transparency while providing energy to the structure. Due to the porous arrangement of the stroma, hydrophilic solutes can easily diffuse through it. The endothelium produces the Descemet's membrane. It sits between the endothelium and the stroma ^{[(17), (18)].}

BARRIERS TO THE OCULAR DRUG DELIVERY SYSTEM:

Precorneal Barriers:

• Capacity of Cul-De-Sac: This term refers to both a deeper depression in the upper lid and a shallow pocket in the lower lid where the bulbar and palpebral conjunctiva meet. The cul-de-sac has a 30 μl capacity. If the lower eyelid reverts to its native position, this capability would be lowered to (70–80) %. An allergy and irritation of the eyes further diminish the capacity of the Cul-De-Sac ^[(18)]. Because a drug's activity is directly correlated with its residence time and concentration, the drug's concentration in the eye would decrease due to the limited capacity of the Cul-De-Sac, lowering its therapeutic efficacy. Lacrimal fluid drug loss: Ocular fluid drainage is one of the most troublesome issues in the precorneal region. Lacrimation, solution drainage, as well as poor absorption of the conjunctiva, which might lead to medication loss from lacrimal fluids ^[(19)]. The metabolism of the drug and protein binding would also inhibit medicine absorption of the medicine ^[(18)]. Frequent replenishment of lacrimal fluid helps maintain the eyes moisturised and free from dust and bacteria. To be successful, the duration of residence for the prescribed formula must be followed, which can be achieved in various ways.
• Corneal Barrier: The corneal barriers serve as a robust protection against harm from chemicals and machinery. It improves the convergence of light on the retina. There are three distinct parts: the Stroma, the Cortical layer, and the Endothelium. There are five to seven cell layers that comprise the epithelium, which are tightly connected. Stroma is a watery, thick stratum. The epithelium blocks hydrophilic and large molecules of medications, whereas the stroma blocks lipophilic compounds ^[(20)]. The endothelium protects the cornea's transparency and allows medicines and macromolecules that are hydrophilic to get into the aqueous humour. The degree of ionisation, charge, molecular weight, and hydrophobicity of drugs all affect their ability to permeate the cornea. Trans corneal penetration is the phase that limits the rate at which drugs move from lacrimal fluid to aqueous humour ^[(18)].
• Ocular Blood Barriers: They help keep foreign chemicals out of the bloodstream. They are classified into two types: BAB and BRB, which are the blood-aqueous and blood-retinal barriers, respectively. The blood-aqueous barrier, situated in the anterior region of the eye, prevents several substances in the eye from being penetrated by the intraocular environment. The blood-aqueous barrier enables tiny and lipophilic medicines to pass. These medicines move faster compared to bigger, hydrophilic molecules in the anterior compartment. Pilocarpine has been shown to have a greater rate of clearance compared to inulin ^[(18)]. Blood-retinal barrier, or the posterior region, is made up of retinal pigment epithelium and the endothelium, which stops harmful chemicals, preventing components of water and plasma from getting to the retina ^[(21)].

OCULAR DISEASES:

• Cataract: Cataracts are the primary cause of blindness globally. About 40–60% of people worldwide who are blind are brought on by cataract complications ^[(22)]. The National Program stated that, when it comes to the prevention of cataracts, which cause blindness and vision impairment, they account for 62.6% of preventable blindness in India ^[(23)]. Cloudiness or obstruction of the eye's lens is the possible definition of cataract. Risk factors include poor diet, smoking, genetic determinism, diabetes, and exposure to UV radiation. Three categories of cataracts exist: posterior subcapsular, cortical, and nuclear. The protein known as crystallin controls the transparency and clarity of the lenses ^[(24)]. Changes in the genes and α, β, and γ crystallin cause cataracts to form early, which are linked to them. Carotid triggers are exposure to lipophilic chemicals, oxidative stress, and glycation, all of which raise the calcium content of the lens and result in crystallinity. Hydroxyl radicals and hyperglycemia are the two main mediators of oxidative stress. The treatment option for Surgery may be avoided with anti-cataract medicines. These days, cataract-preventing substances are removed through surgical removal of opaque lenses. Nonetheless, Surgery may be avoided with anti-cataract medicines. Cataract-preventing compounds are antioxidants with multiple uses that can chelate and hunt down radicals ^[(24)]. Curcumin, lanosterol, resveratrol, and metformin are a few examples of anti-cataract medicines ^[(25)].
• Glaucoma: One well-known optic neuropathy condition is glaucoma. Early symptoms include impaired vision, which later develops into irreversible blindness. It results in the degeneration of retinal ganglion cells and the gradual degradation of axons in the optic nerve, which results in blindness ^[(26)]. Because of the uneven formation or blockage of the aqueous humour, in many cases, it is linked to elevated intraocular pressure (IOP) ^[(27)]. Risk factors include nearsightedness, migraine, diabetes, age, race, and retinal vascular calibre. Women are more likely than men to have glaucoma; in 2010, they accounted for 59% of all cases of glaucoma, 70% of angle closure glaucoma, and 55% of open-angle glaucoma ^[(22)]. The global incidence is projected to reach 112 million by 2040, up from an estimated 76 million in 2020 ^[(25)]. Glaucoma comes in two varieties: angles that are open angles and closed angles. The characteristics of open-angle glaucoma, which is asymptomatic, include A visual field that shows the blockage of aqueous humour drainage through the trabecular meshwork, as well as optic disc cupping, but the higher level of pressure brought on by the obstruction of outflow channels, which is what defines a closed angle ^[(26)]. By 2040, there will be 112 million glaucoma sufferers, up from the current 76 million ^[(25)]. Owing to oxidative and nitrative processes, glaucoma developed. Glutathione peroxidase, catalase, and superoxide dismutase are only a handful of the several antioxidant enzymes found in aqueous humour. As people age, their level declines, which raises their IOP. Alterations in the equilibrium between antioxidants and oxidants have an impact on how glaucoma develops ^[(28)]. Anti-glaucoma medications help modify drainage or aqueous humour production. Numerous studies to improve the treatment of glaucoma have been reported ^{[(27),(29)–(30,31)]}. ElKasabgy and Abd-Elsalam developed topical olaminosomes filled with the agomelatine that exhibited exceptional anti-glaucoma properties ^[(27)]. To increase brimonidine tartrate's ocular retention and activity, Topical niosomes produced from proniosomal gel were developed by Eldeep et al ^[(31)].
• Macular Degeneration Associated with Age or AMD: AMD is a significant cause of blindness that occurs in wealthy countries. The predominance after the age of 50 increases [(26)AMD is responsible for around 8.7% of blindness occurrences globally ^[(32)]. In 2020, AMD afflicted roughly 196 million people, and that number is predicted to increase by 2040, reaching 288 million ^[(33)]. This is a complex degenerative condition that impacts the rear of the eye. Immobility, smoking, advanced age, and an imbalanced diet are among the risk factors, which include elevated blood pressure. Although AMD does not presently have a cure, adequate therapy may reduce its progression ^[(34)]. AMD can be split into two categories: moist (neovascular) and dry. Bruch's membrane atrophy and abnormal angiogenesis, or new blood vessel development in the retinal epithelium, are characteristics of AMD separation, and drusen, or yellow deposits beneath the retina ^[(35)]. AMD could be classified as wet (neovascular or exudative) or dry (atrophic or non-exudative). AMD's main characteristics are aberrant angiogenesis, or Drusen, or yellow deposits beneath the retina, Atrophy, and Bruch's membrane separation, which are caused by the formation of new blood vessels in the retinal epithelium ^[(36)]. Additionally, biodegradable red blood cell kinase and protein kinase inhibitors are used intravitreally to treat diabetic macular oedema. Prolonged release was found for roughly six months. Age-related neovascular oedema and macular degeneration ^[(25)].
• Conjunctivitis: Conjunctivitis is the most commonly reported eye ailment.
  Simply said, it is conjunctival tissue inflammation. All racial groups, genders, and ages are affected. The aetiology determines whether the condition is infectious or non-infectious; infectious conjunctivitis is caused by microbial infection, while allergic matters and irritants induce non-infectious conjunctivitis ^[(2]. Redness, tears, increased secretions, and eye irritation are all signs of conjunctivitis. About 40% of people have allergic conjunctivitis worldwide ^[(37)]. Infectious antimicrobial or non-infectious anti-inflammatory medicines can be applied topically to treat conjunctivitis.
• Retinoblastoma: Usually affecting children under five, retinoblastoma is a malignant tumour that damages the retina. If treatment is not received, 99% of cases of retinoblastoma result in blindness and finally death. In roughly one out of every 20,000 live births ^[(29)]. Its prevalence is the same for both sexes. The protein known as retinoblastoma is produced by the tumour suppressor gene RB1, which is the cause. One-sided (60%) or bilateral (40%) could be the case ^[(22)]. Retinoblastoma can be treated with systemic chemotherapy, cryotherapy, surgery, and radiation therapy. New research indicates that the generation of compensatory proangiogenic factors and the development of angiogenic blood vessels are an essential step in the course of treatment.^[(38)]
• Fungal Keratitis: A healthy cornea would not permit Fungal keratitis, which only occurs in corneas that have been wounded since it is a fungal infection. Candida tropicalis, Candida glabrata, Candida parapsilosis, Candida krusei, and Candida albicans are among the fungi responsible for it ^[(38)]. In impoverished countries of the third world, 40% of infectious keratitis is caused by fungus ^[(22)]. Leprosy, diabetes, HIV positivity, contact lenses, trauma, and previous corneal surgery are all possible risk factors, as are topical corticosteroids. Fungal keratitis promotes stromal inflammatory activity, damages corneas, and hinders wound healing. MiRNA expression may be impacted by corneal irritation ^[(39)]. Antifungal drugs are applied locally or taken orally to treat fungal keratitis. If drugs don't work, corneal surgery can be required. Vision loss may persist even after surgery. The treatment of fungal keratitis is covered in numerous papers. Topical Sertaconazole nitrate-loaded cubosomes were developed by Younes et al. and enhanced antifungal efficacy in mixed micelles ^{[(25), (39–43)]}.   
• Diabetic Retinopathy: It is a distinct vascular outcome of the two forms of diabetes. Type II diabetes affects about 60% of the population, and all type I diabetics get diabetic retinopathy after 20 years. The development of DR is triggered by oxidative stress and inflammation, which are generated by the increase of proinflammatory mediators. It is the third most common reason behind blindness in the US. Blindness is caused by two factors: cataract and corneal blindness. They can be avoided with early diagnosis and treatment, appropriate blood pressure management, and glucose control ^[(25)]. Both proliferative and non-proliferative forms of it result in progressive retinal degeneration over time. Medication, vitrectomy, and laser photocoagulation are used to treat diabetic retinopathy. Laser photocoagulation avoids blindness by sealing bleeding blood vessels; however, treatment does leave scars from lasers. Surgical extraction of blood and vitreous gel from the rear of the eye's leaky capillaries is known as a vitrectomy; however, this treatment only temporarily stops the bleeding and does not prevent it from happening again ^[(22)]. One pharmacological therapeutic option for reducing retinal oedema is corticosteroid injections. Corticosteroids with continuous release, as well as an implant that affects the circuits that induce inflammation. Aflibercept and ranibizumab, two anti-VEGF drugs used in current therapy, halt VEGF expression, which decreases oedema and blood leakage.^[(44)]
• Bacterial Keratitis: If not treated promptly, A potentially blinding corneal disorder called infectious keratitis can result in considerable vision loss. If just 50% of eyes receive the appropriate antibiotic treatment, they will recover optically after a wait. Parasites, bacteria, viruses, fungi, and protozoa all have the potential to cause it. Among the common risk factors for infectious keratitis are corneal sensory impairment, contact lens wear, recent eye surgery, ocular surface illness, dry eyes, lid deformity, long-term topical steroid use, and systemic immunosuppressive therapy. Streptococcus pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, and coagulase-negative and Serratia species are common pathogens. The majority of instances of bacterial keratitis in the community are treated empirically and do not require culture. When a corneal ulcer is large, central, and spreads from the middle to the deep stroma, along with pain, it is advisable to scrape it for culture and sensitivity. Concurrent presence of a corneal abscess or hypopyon, an anterior chamber response, or poor vision that does not respond to the use of broad-spectrum antibiotics. Recent research has revealed an increase in microbes' resistance to antimicrobial medicines. Microorganisms gain resistance brought on by latent chromosomal gene expression and chromosomal mutation via induction or genetic material exchange via transformation. Despite the administration of a broad range of antibiotics, this could result in the sickness process continuing to progress ^[(45)].
• Dry Eye Disease: A preocular tear film is known as dry eye syndrome (DES), a condition that affects the ocular surface and causes eye pain. Dry eyes, ocular surface disease (OSD), keratitis sicca, sicca syndrome, keratoconjunctivitis sicca (KCS), xerophthalmia, and dysfunctional tear syndrome (DTS) are alternative names for DES. Keratoconjunctivitis sicca translates to corneal and conjunctival dryness. Perhaps it would help to know that the word "desiccate" in English also incorporates the word "sicca." Sjögren's syndrome is another term for dry eyes, which occur when too few tears are produced by the eyes ^[(46),((47)].

DOSAGE FORMS:

Liquid dosage forms:

• Eye drops: The most practical, non-invasive, and patient-friendly approach to preparing the eyes is the topical eye drops. Ocular drops encounter several challenges during therapy. According to the study, many patients experienced trouble administering the drops. Furthermore, tear leakage, which increases with the number of eye drops used, might cause solution loss or dilution. Furthermore, because the eye pocket is so small, it is impossible to measure how much medication is absorbed into the eye tissue. A common preservative, benzoalkonium chloride, can also cause several problems, including the separation of corneal epithelial cells at their margins, which limits cell division and widens intercellular gaps in superficial corneal cells. Cyclodextrin is utilised as a hydrophobic molecule carrier to increase the topical eye drop's bioavailability, as a permeation enhancer to increase active ingredient uptake, and as a viscosity enhancer to extend contact time. ^[(48)]
• Eye Suspension: Ocular suspensions are aqueous solvent-based hydrophobic drug dispersions. Their conjunctival cul-de-sac drug retention causes a longer contact time. The tear fluid's particle size, solubility, and rate of dissolving are all crucial factors to consider during preparation. Smaller particles (less than 10 μm) dissolve fast and are less retained on the eye surface. Eye pain and tears can result from particles bigger than 10 μm. Ocular suspension has the drawback of being unstable. They can't be kept in the freezer since the particles don't spread out easily, but instead group together. The solubility and bioavailability of the medication will also be impacted by changes in crystal size during storage. After taking them, you can experience blurred vision. The high-pressure homogenising technique exhibited enhanced ocular distribution of posaconazole in a polymer blend including xanthan gum and Carbopol 974P, as well as increased stability, antifungal effectiveness, and retention. An ultra-fine rebamipide ocular solution was produced using a liquid-liquid shear method at high speed. This formulation improved stability, decreased particle size, and increased transparency ^[(25),(48)].
• Eye Emulsion: Eye Emulsions are solubilised biphasic systems that have been stabilised or improved using surfactants. One benefit of ocular emulsions is their capacity to distribute hydrophobic medications. The oil-in-water (O/W) emulsion provides higher bioavailability, longer contact time, and less eye irritation [(49)]. Using high-pressure homogenization to create a nanoemulsion distribution in the eyes of polymyxin B sulfate and dexamethasone acetate. To increase ocular adhesion, a positive charge inducer was used. The final formulation showed improved stability, reduced particle size, and longer retention length [(50)]. Triamcinolone acetonide microemulsion was produced via water titration. It demonstrated better permeability and lower particle sizes ^[(51)].

Semi-solid dosages:

• In Situ Gel: The term In Situ Gel refers to low-viscosity fluids that transform into viscoelastic gels in the dead end in the dead end of the cornea as the polymer structure changes. Physiological environment changes, such as temperature, pH, and ion levels. The thick gels reduce drainage and provide a longer contact period than conventional eyedrops. Carbopol, chitosan, sodium alginate, xanthan gum, gellan gum, gelrite (Merck & Co., San Diego, CA, US), pluronic, polyxamers, and pluronic copolymers have all been shown to undergo the sol-gel transition. ^[(52–56)]
• Ocular Inserts: Ocular inserts are solid eye devices (with an 8 mm diameter) that contain a pharmaceutical spread across a matrix system or polymer reservoir to improve precorneal contact, extend medication, sustain therapeutic medication concentrations in the targeted tissues, and ensure bioavailability. Examples of some natural and synthetic materials include sodium alginate, collagen, gelatin, Eudragit RS-100 and RL-100, p-HEMA, polyethene oxide, cellulose acetate, phthalate, and hydroxy propyl methyl cellulose, which are useful for modulating the rate and mechanism of release. ^{[(55,57–59)]}
• Ocular ointment: Solid and semisolid hydrocarbons, such as paraffin, are combined to form an ointment that does not irritate the eyes and melts at body temperature. In general, ointments are divided into two categories: simple-based ointments, which have a single continuous phase, and compound-based ointments, which have a two-phase structure similar to an eye emulsion. The ointment breaks down into tiny droplets when administered to the eye, and these droplets remain in the conjunctival sac for a considerable amount of time. This technique improves and extends medicine absorption by acting as a conjunctival sac drug repository, which is the primary advantage of ointment. Several desirable characteristics should be present while designing an ointment, including uniformity, non-irritating properties for the eye, ease of fabrication, and the absence of significant vision blurring. Although ophthalmic ointments can improve and extend the absorption of medication, they have a significant drawback that may reduce their effectiveness. Visual impairment and intermittent discomfort induced by ointment application may result in poor patient compliance. As a result, it is frequently used before retiring to bed.^[(60)]

Nanotechnology-based ocular drug delivery system:

 More recently, vibrant methods have been used to address eye-related problems. One system being explored for administering medication to the eye's front and back is the operation of nanotechnology in optical phrasings.

 Results grounded on nanotechnology can be finagled with suitable flyspeck sizes to minimise vexation to the eye while optimising bioavailability and comity. Among the nanocarriers developed for optical medicine delivery are liposomes, nanoparticles, nanosuspensions, nanomicelles, and dendrimers. Some of these have demonstrated implicit benefits in enhancing optical bioavailability ^[(9)].

• The main obstacles and developments in ocular medication delivery emphasise how conventional approaches, particularly for the posterior eye segment, have drawbacks such as inadequate permeability, limited bioavailability, and ineffective medication distribution, even though they can cure some eye conditions. The study highlights that several challenges remain, including difficulties in manufacturing, stability and safety issues, high production costs, and limited clinical translation. The majority of research to date has been limited to in vitro or animal models, making it challenging to evaluate human applications. Future research, according to the review, should concentrate on improving the size, charge, stability, and biocompatibility of nanocarriers, creating non-invasive systems that can get past ocular barriers, improving sustained release, and improving assessment models and techniques. Furthermore, combining gene therapy, exosomes, and tissue engineering could create new avenues for efficient drug delivery to the eyes. Overall, the analysis concludes that innovative nanocarrier-based ocular delivery systems have a lot of clinical potential, but their translation into clinical use will need coordinated efforts in research, development, and large-scale manufacture. ^[(61)]

• Liposomes:

 Liposomes are globular vesicles made from lipids, range in size from 0.08-10.00 μm, and are made up of cholesterol as well as phospholipids. They're compatible with natural systems, can be broken down by the body, and are flexible, enabling the use of both hydrophilic and hydrophobic medicines at the same time. 

Multitudinous studies have employed liposomes to enhance their stability, targeted action, bioavailability, and capability to access the cornea. Research into liposomes has concentrated ontheir capacity to deliver specific compounds to specific locales and release them over extended periods. Fahmy et al. employed a thinfilm hydration system to produce liposomes that carried latanoprost and thymoquinone, which were laterally administered via subconjunctival injection for glaucoma treatment. The liposomes loaded with the medicine showed an encapsulation effectiveness of 88% and flyspeck sizes lower than 0.2 μm. In vivo and in vitro medicine release assays indicated that these medicine-loaded liposomes could lower intraocular pressure for over 84 hours, outperforming the test phrasings. ^[(62)]

• Reaching therapeutic medication levels in ocular tissues is challenging because of several penetration barriers, from the tear film to the cornea, even though the topical route is the most popular way for treating eye illnesses. Because liposomal drug delivery systems may encapsulate both hydrophilic and hydrophobic medicines, they have become attractive carriers to solve these issues. However, the drawbacks of conventional liposomes include drug leakage, aggregation, instability, and susceptibility to phagocytosis. Some of these disadvantages have been mitigated by advances in surface modification, and more recent liposome generations have made it possible to distribute drugs more effectively and sustainably. These developments have demonstrated effectiveness in domains like cancer therapy, with various formulations entering clinical trials. Despite these developments, liposomal systems are still only used in preclinical phases for topical ophthalmic medication delivery. The passage implies that both immunoliposomes and cationic liposomes have potential for wider usage in ocular medication administration; identifying appropriate target molecules on corneal epithelial cells could increase specificity. ^[(63)]

• Nanoparticles:

Nanoparticles are colloidal patches that measure between 10 and 1000 nanometers in size. Common factors of optical nanoparticles include natural or artificial polymers such as chitosan, albumin, sodium alginate, and polylactic acid, proteins, and lipids as well. Medicine-loaded nanoparticles can take the form of nanocapsules or nanospheres.  The medication is somewhat dispersed throughout the polymeric matrix in nanospheres, but in nanocapsules, it's confined within the polymeric external subcaste. Over the past few decades, there has been an increase in interest in using nanoparticles to deliver medicines to the eye. Numerous experimenters have tried to create medication-loaded nanoparticles that can enter both the front and the back of the eye. ^[(64)]

• By providing more potent substitutes for conventional eye drops, ointments, and emulsions, nanotechnology has revolutionised ocular medicine delivery. Conventional techniques are simple and safe, but they frequently have short retention times on the surface of the eye and poor bioavailability. Nanoparticles, nanosuspensions, nanoemulsions, liposomes, nanomicelles, niosomes, nanocrystals, and dendrimers are examples of nanocarrier-based systems that improve drug solubility, ocular tissue contact, and penetration into the anterior and posterior eye segments. These systems can increase therapeutic efficacy while lowering irritation and inflammation. The use of nanotechnology to administer medications for diseases like glaucoma, autoimmune uveitis, age-related macular degeneration, and corneal or choroidal neovascularisation has advanced significantly, according to research. However, due to possible nanoparticle toxicity, certain studies have highlighted safety concerns, underscoring the need for additional research to guarantee safe clinical application. ^[(65)]

• Dendrimers:

Dendrimers are made of organic polymers that form a globular shape by extending branches from a central core. The patches are ideal for administering medications to the eye because of their high loading capacity, flexible exterior functional groups, and the regulated release of medications. Water-soluble dendrimers, like liposomes, are formed by incorporating hydrophilic groups into the external branches, allowing them to interact with water. Hydrophilic medicines can be attached to colourful functional groups located at the ends of the polymeric branches. Since poly(amidoamine) (PAMAM) dendrimers are available commercially, their use in optical gene therapy is on the rise. Dendrimers are notable for their capacity to inhibit endosomal acidification. ^[(66)]

• The intricate physiology of the eye and numerous obstacles, particularly in the posterior segment, make ocular medication administration difficult. From traditional formulations like eye drops and ointments to sophisticated systems like in situ gels, inserts, and colloidal carriers, research has progressed over the last 20 years. Dendrimers have demonstrated significant promise as long-acting drug delivery methods among them. They are adaptable carriers that can improve medication solubility, distribution, and targeting due to their tunable size, shape, and surface characteristics. According to studies, dendrimers can act as corneal adhesives, transfer medications to the retina, prolong corneal drug residence times, and offer neuroprotection. Their preclinical success indicates considerable potential for future therapeutic applications, even though they have not yet received approval for clinical ocular usage. ^[(67)]

• Niosomes:

Niosomes represent a distinct type of tone- assembling nonionic delivery system. These are bilayered nanovesicles composed of lipid-grounded nanocarriers able to recapitulate both hydrophilic and lipophilic composites. They enhance the optical bioavailability by making them accessible at any pH.

Although niosomes share characteristics with liposomes, similar to biodegradability, biocompatibility, low toxicity, nonimmunogenicity,and strong chemical stability , their effectiveness in transporting proteins to optical apkins is presently underinvestigation.^[(68)]

Niosomes are sufficiently small to help optical discharge and enhance the retention of medicines on the eye's surface. Gugleva and associates found that combining sorbitan monostearate (Span60) and cholesterol resulted in niosomes with a high effectiveness in recapitulating doxycycline hyclate.The eyes of the mice permitted the slower release rate of the drug effectively. ^[(69)]

• Niosomes are showing promise as topical ocular medication delivery nanocarriers because they can get past obstacles associated with the eyes that restrict drug absorption and bioavailability. Because only a small portion of the medication reaches ocular tissues, traditional eye drops frequently call for high dosages and frequent administration. On the other hand, niosomes provide benefits such as improved corneal penetration, higher bioavailability, and prolonged drug release. In contrast to liposomes, which are prone to oxidative breakdown and necessitate costly purification and storage techniques, these non-ionic surfactant vesicles are simple to manufacture, biocompatible, and economical. The stability and ocular retention of niosomes can be further enhanced by embedding them in in situ gels or coating them with mucoadhesive polymers such as chitosan, carbopol, or hyaluronic acid. ^[(70)]

• Nanosuspension:

Nanosuspensions are colloidal systems that are stabilised through the addition of polymers or surfactants, which disperse medicine patches that are lower than one micron. These systems can effectively deliver specifics that are hydrophobic in nature. When employed for optical medicine delivery,nanosuspensions offer several benefits, such as extended retention times in the precorneal area, enhanced bioavailability for medicines that don't dissolve in the aqueous eye, reduced irritation to optical areas, ease of expression into eye drops, and the possibility of sterilisation.

 Pignatello et al. created a nanosuspension system for delivering ibuprofen (IBU) to the eyes using EudragitRS100®.Their expression demonstrated a controlled release and a mean flyspeck size with a positive charge. In vivo studies conducted on rabbits with convinced miosis showed repression of the response. Still, following the operation of the nanosuspension, the free medicine concentration in the conjunctival sac wasn't significantly high. The expression increased the IBU attention in the eye's watery humour without causing toxicity or vexation. ^[(70]

• The development of several nanomedicines that assisted in overcoming the ocular barriers is summarised in this article. Numerous studies have shown that the medications have improved residence time, bioavailability, biodistribution, and biocompatibility. Many systems, including liposomes, hydrogel, NLC (nanostructured lipid carrier), SLN (solid lipid nanoparticles), and polymeric micelles, have been studied to deliver the therapeutic dose at a controlled rate and to increase the bioavailability of medications. Numerous ocular conditions, including ARMD (Age-Related Macular Degeneration), dry eye, uveitis, choroidal neovascularisation, conjunctivitis, and glaucoma, have been successfully treated by medications included in various nanocarriers. Different studies with promising outcomes will continue to be conducted in the era of conventional and nanomedicine drug delivery systems. ^[(71)]

Innovative Forms of Ocular Dosage:

• Microemulsion: Microemulsions are innovative medicine delivery systems for the eyes that mostly consist of oil and combinations of water and a surfactant. These microemulsions offer benefits such as improved solubility, enhanced corneal penetration, and increased thermodynamic stability. One of the most important factors influencing the microemulsion system's stability is the choice of aqueous phase and organic phase, both the surfactant/cosurfactant combination and the phase. After using Brij 97 to generate microemulsions, Cyclosporine A was added, encapsulated in hydrogels composed of 2-hydroxyethyl methacrylate (p-HEMA). A study on in vitro release demonstrated that cyclosporine was released from these formulations over a period of 20 days. A phase transition system powered by microemulsion was created and assessed for the ocular delivery of pilocarpine hydrochloride. This technique uses monolaurate of sorbitan. Together with water and ethyl oleate as the oil phase, polyoxyethylene sorbitan mono-oleate functions as a nonionic surfactant. Several phase transitions occurred in the system, affecting its viscosity according to the amount of water present. High ocular bioavailability was indicated by the longest duration of action and maximum miotic impact shown by both liquid crystalline and microemulsion formulations. For this reason, microemulsions that experience phase separation when in contact with watery environments, such as tears, can act as effective ocular delivery systems. They offer fluidity while boosting viscosity upon application, thereby enhancing ocular retention and maintaining therapeutic efficacy. Different microemulsions were used to formulate several ophthalmic drugs like timolol, sirolimus, and chloramphenicol, leading to enhanced Bioavailability, stability, and solubility. ^[(72)]         

• Iontophoresis: Iontophoresis employs a low-density electrical current to improve the drug movement through different epithelial surfaces, such as skin, nails, and ocular structures. The initial study of Wirtz conducted iontophoresis for ocular delivery in 1908 and studied the topical administration of zinc salts for the treatment of corneal ulcers. This noninvasive method enables the movement of ionised medications across membranes via low electrical currents. The passage of drugs through membranes happens through two mechanisms: migration and electroosmosis. Ocular iontophoresis is divided into transcorneal, corneoscleral,or transscleral types, with the latter being especially significant. This method is noninvasive and easy to use, allowing for dosage modulation and the delivery of various drugs or genes to address multiple ophthalmic issues impacting the posterior eye. Nonetheless, it has several drawbacks, such as requiring multiple treatments, a short half-life, and possible side effects, including slight pain in some cases. Sonophoresis, also known as ultrasound, employs ultrasound waves at frequencies above 20 kHz to improve drug absorption through the skin and eyes. Ultrasound is generally used on the epithelium with an emulsion suspension or other coupling media that aid in the transmission of the acoustic field. A recent study improved the intra-scleral distribution of serum-bound fluorescein isothiocyanate by using sonophoresis in an ex vivo rabbit eye model using albumin. Utilising a frequency of 1 MHz and an intensity of 0.05 W/cm2, a duration of exposure lasting 30 seconds. The results showed that sonophoresis increased the trans-scleral permeation of the protein by 1.6 times while not harming ocular tissues. ^[(72)]

• The intricate structure of the eye presents substantial obstacles to ocular medication administration. Ocular iontophoresis is one noninvasive method that has great potential to get past these obstacles. Clinical trials and animal studies have previously demonstrated the viability of iontophoresis, which provides efficient, painless medication administration with improved patient compliance. Optimising clinical protocols requires ongoing development in drug formulations, smart accessories, and device design. However, excessive expenses, limited finances, and a lack of clinical experience prevent wider use. To make iontophoresis a widely used ocular therapy technique, future studies should concentrate on enhancing effectiveness, safety standards, and cost. ^[(73)]
• Ocular iontophoresis is a promising noninvasive method that improves drug delivery to both the anterior and posterior segments of the eye. It uses a small electrical current to enhance the penetration of charged drugs through ocular tissues, overcoming barriers that limit topical formulations. Preclinical studies have shown that transscleral iontophoresis of dexamethasone phosphate achieves intraocular concentrations 50–100 times higher than topical instillation in rabbit models, supporting its potential for clinical use. Clinical trials with the EyeGate II system and EGP-437 in conditions like noninfectious anterior uveitis, dry eye, non-necrotising scleritis, and macular oedema have shown promising outcomes. This approach may reduce or eliminate the need for daily corticosteroid eye drops, improving adherence and reducing risks such as elevated intraocular pressure. However, it may be more expensive than topical treatments and requires in-office procedures. Other sustained-release methods, such as surface and subconjunctival implants, OTX-TP (for glaucoma), OTX-DM (for allergic conjunctivitis and postoperative inflammation), and Dextenza (FDA-approved for post-surgical inflammation), punctal plugs, are being developed. Future studies compare the safety and efficacy of iontophoresis settings, dosage schedules, and drug formulations with both traditional and cutting-edge drug delivery techniques. All things considered, ocular iontophoresis provides a safe, regulated, and effective technique to administer drugs, which could revolutionise ophthalmic practice and enhance patient quality of life. ^[(74)]

CONCLUSION

This review underscores the key obstacles in ocular drug delivery, including significant precorneal drug elimination, the formidable corneal barrier of epithelium, and systemic blood-ocular defences, all of which severely limit the efficacy of conventional eye drops to a mere 1–5% bioavailability. Combining mucoadhesive polymers like PVA and chitosan with nanocarriers—such as liposomes, nanoparticles, and in situ gels—creates advanced biocomposite systems that significantly improve drug retention, enhance tissue penetration, and enable controlled and sustained release. These platforms constitute a transformative advancement in managing widespread ocular diseases, including bacterial keratitis, glaucoma, and dry eye syndrome.

REFERENCES

1. Gaudana R, Jwala J, Boddu SHS, Mitra AK. Recent perspectives in ocular drug delivery. Vol. 26, Pharmaceutical Research. 2009. p. 1197–216.
2. Hosoya KI, Lee VHL, Kim KJ. Roles of the conjunctiva in ocular drug delivery: A review of conjunctival transport mechanisms and their regulation. In: European Journal of Pharmaceutics and Biopharmaceutics. 2005. p. 227–40.
3. Pahuja P, Arora S, Pawar P. Ocular drug delivery system: A reference to natural polymers. Vol. 9, Expert Opinion on Drug Delivery. 2012. p. 837–61.
4. Barar J, Reza Javadzadeh A, Omidi Y. Ocular novel drug delivery: impacts of membranes and barriers. Expert Opin Drug Deliv. 2008;5(5):567–81.
5. Duvvuri S, Majumdar S, Mitra AK. Role of Metabolism in Ocular Drug Delivery. Vol. 5, Current Drug Metabolism. 2004.
6. Urtti A. Challenges and obstacles of ocular pharmacokinetics and drug delivery. Vol. 58, Advanced Drug Delivery Reviews. 2006. p. 1131–5.
7. Mannermaa E, Vellonen KS, Urtti A. Drug transport in corneal epithelium and blood-retina barrier: Emerging role of transporters in ocular pharmacokinetics. Vol. 58, Advanced Drug Delivery Reviews. 2006. p. 1136–63.
8. Pflugfelder SC, Karpecki PM, Perez VL. Treatment of blepharitis: Recent clinical trials. Vol. 12, Ocular Surface. Elsevier Inc.; 2014. p. 273–84.
9. Patel A. Ocular drug delivery systems: An overview. World J Pharmacol. 2013;2(2):47.
10. Lai SK, Wang YY, Hanes J. Mucus-penetrating nanoparticles for drug and gene delivery to mucosal tissues. Vol. 61, Advanced Drug Delivery Reviews. 2009. p. 158–71.
11. Colo G Di, Zambito Y, Burgalassi S, Serafini A, Saettone MF. Effect of chitosan on in vitro release and ocular delivery of ofloxacin from erodible inserts based on poly(ethylene oxide) [Internet]. Available from: www.elsevier.com/locate/ijpharm
12. De Campos AM, Diebold Y, Carvalho ELS, Sánchez A, Alonso MJ. Chitosan Nanoparticles as New Ocular Drug Delivery Systems: in Vitro Stability, in Vivo Fate, and Cellular Toxicity. 2004.
13. Wadhwa S, Paliwal R, Paliwal SR, Vyas SP. Hyaluronic acid modified chitosan nanoparticles for effective management of glaucoma: Development, characterization, and evaluation. J Drug Target. 2010 May;18(4):292–302.
14. 10.1016@s1461-53479800087-x.
15. Merino S, Martín C, Kostarelos K, Prato M, Vázquez E. Nanocomposite hydrogels: 3D polymer-nanoparticle synergies for on-demand drug delivery. Vol. 9, ACS Nano. American Chemical Society; 2015. p. 4686–97.
16. Song F, Li X, Wang Q, Liao L, Zhang C. Nanocomposite hydrogels and their applications in drug delivery and tissue engineering. Vol. 11, Journal of Biomedical Nanotechnology. American Scientific Publishers; 2015. p. 40–52.
17. Achouri D, Alhanout K, Piccerelle P, Andrieu V. Recent advances in ocular drug delivery. Vol. 39, Drug Development and Industrial Pharmacy. 2013. p. 1599–617.
18. Singh M, Bharadwaj S, Lee KE, Kang SG. Therapeutic nanoemulsions in ophthalmic drug administration: Concept in formulations and characterization techniques for ocular drug delivery. Vol. 328, Journal of Controlled Release. Elsevier B.V.; 2020. p. 895–916.
19. Hon-leung Lee V, Robinsonx JR. Mechanistic and Quantitative Evaluation of Precorneal Pilocarpine Disposition in Albino Rabbits. Vol. 68. 1979.
20. Ahmed S, Amin MM, El-Korany SM, Sayed S. Corneal targeted fenticonazole nitrate-loaded novasomes for the management of ocular candidiasis: Preparation, in vitro characterization, ex vivo and in vivo assessments. Drug Deliv. 2022;29(1):2428–41.
21. Drug delivery to the retina: challenges and opportunities 46.
22. Krishnaswami V, Kandasamy R, Alagarsamy S, Palanisamy R, Natesan S. Biological macromolecules for ophthalmic drug delivery to treat ocular diseases. Vol. 110, International Journal of Biological Macromolecules. Elsevier B.V.; 2018. p. 7–16.
23. Chitra PS, Chaki D, Boiroju NK, Mokalla TR, Gadde AK, Agraharam SG, et al. Status of oxidative stress markers, advanced glycation index, and polyol pathway in age-related cataract subjects with and without diabetes. Exp Eye Res. 2020 Nov 1;200.
24. Randazzo J, Zhang P, Makita J, Blessing K, Kador PF. Orally active multi-functional antioxidants delay cataract formation in streptozotocin (type 1) diabetic and gamma-irradiated rats. PLoS One. 2011;6(4).
25. Ahmed S, Amin MM, Sayed S. Ocular Drug Delivery: a Comprehensive Review. Vol. 24, AAPS PharmSciTech. Springer Science and Business Media Deutschland GmbH; 2023.
26. Leske MC. Open-angle glaucoma - An epidemiologic overview. In: Ophthalmic Epidemiology. 2007. p. 166–72.
27. Abd-Elsalam WH, ElKasabgy NA. Mucoadhesive olaminosomes: A novel prolonged release nanocarrier of agomelatine for the treatment of ocular hypertension. Int J Pharm. 2019 Apr 5;560:235–45.
28. Aslan M, Cort A, Yucel I. Oxidative and nitrative stress markers in glaucoma. Vol. 45, Free Radical Biology and Medicine. 2008. p. 367–76.
29. Sayed S, Abdelmoteleb M, Amin MM, Khowessah OM. Effect of Formulation Variables and Gamma Sterilization on Transcorneal Permeation and Stability of Proniosomal Gels as Ocular Platforms for Antiglaucomal Drug. AAPS PharmSciTech. 2020 Apr 1;21(3).
30. Eldeeb AE, Salah S, Ghorab M. Formulation and evaluation of cubosomes drug delivery system for treatment of glaucoma: Ex-vivo permeation and in-vivo pharmacodynamic study. J Drug Deliv Sci Technol. 2019 Aug 1;52:236–47.
31. Emad Eldeeb A, Salah S, Ghorab M. Proniosomal gel-derived niosomes: an approach to sustain and improve the ocular delivery of brimonidine tartrate; formulation, in-vitro characterization, and in-vivo pharmacodynamic study. Drug Deliv. 2019 Jan 1;26(1):509–21.
32. Anderson OA, Bainbridge JWB, Shima DT. Delivery of anti-angiogenic molecular therapies for retinal disease. Vol. 15, Drug Discovery Today. 2010. p. 272–82.
33. Wong WL, Su X, Li X, Cheung CMG, Klein R, Cheng CY, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: A systematic review and meta-analysis. Lancet Glob Health. 2014 Feb;2(2).
34. Birch DG, Fong &, Liang Q, Liang FQ. International Journal of Nanomedicine Age-related macular degeneration: a target for nanotechnology derived medicines Age-related macular degeneration: a target for nanotechnology derived medicines. Int J Nanomedicine [Internet]. 2007;2(1):65–77. Available from: https://www.tandfonline.com/action/journalInformation?journalCode=dijn20
35. Kourlas H, Schiller DS. Pegaptanib Sodium for the Treatment of Neovascular Age-Related Macular Degeneration: A Review. Vol. 28, Clinical Therapeutics. 2006.
36. Agban Y, Thakur SS, Mugisho OO, Rupenthal ID. Depot formulations to sustain periocular drug delivery to the posterior eye segment. Vol. 24, Drug Discovery Today. Elsevier Ltd; 2019. p. 1458–69.
37. Azari AA, Barney NP. Conjunctivitis: A systematic review of diagnosis and treatment. Vol. 310, JAMA. American Medical Association; 2013. p. 1721–9.
38. Corson TW, Samuels BC, Wenzel AA, Geary AJ, Riley AA, McCarthy BP, et al. Multimodality imaging methods for assessing retinoblastoma orthotopic xenograft growth and development. PLoS One. 2014 Jun 5;9(6).
39. Boomiraj H, Mohankumar V, Lalitha P, Devarajan B. Human corneal microRNA expression profile in fungal keratitis. Invest Ophthalmol Vis Sci. 2015 Dec 1;56(13):7939–46.
40. Younes NF, Abdel-Halim SA, Elassasy AI. Corneal targeted Sertaconazole nitrate loaded cubosomes: Preparation, statistical optimization, in vitro characterization, ex vivo permeation and in vivo studies. Int J Pharm. 2018 Dec 20;553(1–2):386–97.
41. Younes NF, Abdel-Halim SA, Elassasy AI. Solutol HS15 based binary mixed micelles with penetration enhancers for augmented corneal delivery of sertaconazole nitrate: Optimization, in vitro, ex vivo and in vivo characterization. Drug Deliv. 2018;25(1):1706–17.
42. Sayed S, Elsayed I, Ismail MM. Optimization of β-cyclodextrin consolidated micellar dispersion for promoting the transcorneal permeation of a practically insoluble drug. Int J Pharm. 2018 Oct 5;549(1–2):249–60.
43. Said M, Aboelwafa AA, Elshafeey AH, Elsayed I. Central composite optimization of ocular mucoadhesive cubosomes for enhanced bioavailability and controlled delivery of voriconazole. J Drug Deliv Sci Technol. 2021 Feb 1;61.
44. Bolinger MT, Antonetti DA. Moving past anti-VEGF: Novel therapies for treating diabetic retinopathy. Vol. 17, International Journal of Molecular Sciences. MDPI AG; 2016.
45. Wong RLM, Gangwani RA, Yu LWH, Lai JSM. New treatments for bacterial keratitis. Vol. 2012, Journal of Ophthalmology. 2012.
46. Phadatare SP, Momin M, Nighojkar P, Askarkar S, Singh KK. A Comprehensive Review on Dry Eye Disease: Diagnosis, Medical Management, Recent Developments, and Future Challenges. Advances in Pharmaceutics. 2015 Jan 28;2015:1–12.
47. Fang G, Yang X, Wang Q, Zhang A, Tang B. Hydrogels-based ophthalmic drug delivery systems for treatment of ocular diseases. Vol. 127, Materials Science and Engineering C. Elsevier Ltd; 2021.
48. Li Q, Li Z, Zeng W, Ge S, Lu H, Wu C, et al. Proniosome-derived niosomes for tacrolimus topical ocular delivery: In vitro cornea permeation, ocular irritation, and in vivo anti-allograft rejection. European Journal of Pharmaceutical Sciences. 2014 Oct 1;62:115–23.
49. Pandey SS, Maulvi FA, Patel PS, Shukla MR, Shah KM, Gupta AR, et al. Cyclosporine laden tailored microemulsion-gel depot for effective treatment of psoriasis: In vitro and in vivo studies. Colloids Surf B Biointerfaces. 2020 Feb 1;186.
50. Li X, Muller RH, Keck CM, Bou-Chacra NA. Mucoadhesive dexamethasone acetate-polymyxin B sulfate cationic ocular nanoemulsion - Novel combinatorial formulation concept. Pharmazie. 2016 Jun 1;71(6):327–33.
51. Raval N, Khunt D, Misra M. Microemulsion-based delivery of triamcinolone acetonide to posterior segment of eye using chitosan and butter oil as permeation enhancer: an in vitro and in vivo investigation. J Microencapsul. 2018 Jan 2;35(1):62–77.
52. Balasubramaniam J, Pandit JK. Ion-Activated In Situ Gelling Systems for Sustained Ophthalmic Delivery of Ciprofloxacin Hydrochloride. Drug Deliv. 2003;10:185–91.
53. Lin HR, Sung KC. Carbopol / pluronic phase change solutions for ophthalmic drug delivery [Internet]. Vol. 69, Journal of Controlled Release. 2000. Available from: www.elsevier.com/locate/jconrel
54. Gupta H, Velpandian T, Jain S. Ion-and pH-activated novel in-situ gel system for sustained ocular drug delivery. J Drug Target. 2010 Aug;18(7):499–505.
55. Deshpande PB, Dandagi P, Udupa N, Gopal S V., Jain SS, Vasanth SG. Controlled release polymeric ocular delivery of acyclovir. Pharm Dev Technol. 2009 Sep 22;00(00):090922062554009–10.
56. Ma W Di, Xu H, Nie SF, Pan WS. Temperature-responsive, Pluronic-g-poly(acrylic acid) copolymers in situ gels for ophthalmic drug delivery: Rheology, in vitro drug release, and in vivo resident property. Drug Dev Ind Pharm. 2008 Mar;34(3):258–66.
57. Charoo NA, Kohli K, Ali A, Anwer A. Ophthalmic delivery of ciprofloxacin hydrochloride from different polymer formulations: In vitro and in vivo studies. Drug Dev Ind Pharm. 2003;29(2):215–21.
58. Hsiue GH, Guu JA, Cheng CC. Poly(2-hydroxyethyl methacrylate) "lm as a drug delivery system for pilocarpine. Vol. 22, Biomaterials. 2001.
59. Colo G Di, Burgalassi S, Chetoni P, Fiaschi MP, Zambito Y, Saettone MF. Gel-forming erodible inserts for ocular controlled delivery of ofloxacin [Internet]. Vol. 215, International Journal of Pharmaceutics. 2001. Available from: www.elsevier.com/locate/ijpharm
60. Guleria R, Soni A, Thakur P, Barwal S. OCULAR DRUG DELIVERY SYSTEM [Internet]. Vol. 10, Certified Journal ? 73 Thakur et al. World Journal of Pharmaceutical and Life Science. 2024. Available from: www.ijrti.org
61. Li S, Chen L, Fu Y. Nanotechnology-based ocular drug delivery systems: recent advances and future prospects. Vol. 21, Journal of Nanobiotechnology. BioMed Central Ltd; 2023.
62. Gorantla S, Rapalli VK, Waghule T, Singh PP, Dubey SK, Saha RN, et al. Nanocarriers for ocular drug delivery: Current status and translational opportunity. Vol. 10, RSC Advances. Royal Society of Chemistry; 2020. p. 27835–55.
63. Agarwal R, Iezhitsa I, Agarwal P, Abdul Nasir NA, Razali N, Alyautdin R, et al. Liposomes in topical ophthalmic drug delivery: an update. Vol. 23, Drug Delivery. Taylor and Francis Ltd; 2016. p. 1075–91.
64. Ramesh Y, Kothapalli CB, Reddigari JRP. A NOVEL APPROACHES ON OCULAR DRUG DELIVERY SYSTEM. Journal of Drug Delivery and Therapeutics. 2017 Nov 15;7(6).
65. Omerovi? N, Vrani? E. Application of nanoparticles in ocular drug delivery systems. Health Technol (Berl). 2020 Jan 1;10(1):61–78.
66. Tian B, Bilsbury E, Doherty S, Teebagy S, Wood E, Su W, et al. Ocular Drug Delivery: Advancements and Innovations. Vol. 14, Pharmaceutics. MDPI; 2022.
67. Yavuz B, Bozda? Pehlivan S, Ünlü N. Dendrimeric systems and their applications in ocular drug delivery. The Scientific World Journal. 2013;2013.
68. Shastri DH, Silva AC, Almeida H. Ocular Delivery of Therapeutic Proteins: A Review. Vol. 15, Pharmaceutics. MDPI; 2023.
69. Khiev D, Mohamed ZA, Vichare R, Paulson R, Bhatia S, Mohapatra S, et al. Emerging nano-formulations and nanomedicines applications for ocular drug delivery. Vol. 11, Nanomaterials. MDPI AG; 2021. p. 1–19.
70. Durak S, Rad ME, Yetisgin AA, Sutova HE, Kutlu O, Cetinel S, et al. Niosomal drug delivery systems for ocular disease—recent advances and future prospects. Vol. 10, Nanomaterials. MDPI AG; 2020. p. 1–29.
71. Qamar Z, Qizilbash FF, Iqubal MK, Ali A, Narang JK, Ali J, et al. Nano-Based Drug Delivery System: Recent Strategies for the Treatment of Ocular Disease and Future Perspective. Recent Pat Drug Deliv Formul. 2019 Dec 30;13(4):246–54.
72. Kumari B. Ocular drug delivery system: Approaches to improve ocular bioavailability. GSC Biological and Pharmaceutical Sciences. 2019 Mar 30;6(3):001–10.
73. Wei D, Pu N, Li SY, Wang YG, Tao Y. Application of iontophoresis in ophthalmic practice: an innovative strategy to deliver drugs into the eye. Drug Deliv. 2023;30(1).
74. Perez VL, Wirostko B, Korenfeld M, From S, Raizman M. Ophthalmic drug delivery using iontophoresis: Recent clinical applications. Vol. 36, Journal of Ocular Pharmacology and Therapeutics. Mary Ann Liebert Inc.; 2020. p. 75–87.