Because of the features of its drug disposition, the eye is the most significant organ. Generally speaking, topical administration is favored over systemic administration. Before a medication molecule may pass through the precorneal barriers and enter the cornea, it must first pass through the anatomical barrier(1). When administered topically, the medicine triggers the physiological defences against ocular drug transport, such as the formation of tears. The nasal cavity's larger surface area and higher permeability of the nasal mucosal membrane allow it to remove medications administered topically from the precorneal area of the nasal mucosal membrane's increased permeability and larger surface area(2). The typical dropper releases 50–75?l of fluid per drop, and some of these drops quickly drain, returning the eye to its typical resident volume of 7?l. Due to drug loss, very little medication is able to reach the cornea and interior tissue of the eye. The drug's actual corneal permeability is relatively low, and in people, the instilled solution typically has a corneal contact time of 1-2 minutes, compared to 10%. In reality, very little of the medication enters the cornea and reaches the intraocular tissue. The majority of ophthalmic medications are applied topically as eye drops, a dosage form made up of the medication suspended in an aqueous solution that has been buffered and isotonic(3). Preparations such as gels, ointments, liposomes, micro and nanoparticles, microspheres, and ocular minitablets (MT) or films can be used to accomplish ophthalmic CDDS. Precorneal medication retention can be increased by adding different polymers of varying grades to viscous gel, colloidal solution, or erodible or non-erodible inserts(4).

PHYSIOLOGY OF EYE:

The vitreous body, lens, and transparent cornea constituents of the eye. The anterior chamber of the eye is filled with 300 ?l of aqueous humor in humans. The four structures that make up the lacrimal apparatus are responsible for continuously cleaning and lubricating the eye: lacrimal glands, lacrimal canals, lacrimal sac, nasolacrimal duct. When the eyelids blink, the lacrimal fluid secreted by the lacrimal glands runs over the eyeball and is collected by the eyelids(5). Human lacrimal fluid, an isotonic aqueous solution with a pH of 7.4, has a volume of 7 ?l. As seen in the illustration, the anterior and posterior segments of the human eye are separated(6).

Figure 1 Physiology of Eye

Anterior Segment: The structure of the anterior segment consists of the lens, ciliary body, iris, limbus, anterior and posterior chambers, trabecular meshwork, Schlemm's canal, and zonule.

1. The cornea:

It refracts light entering the eye, which then travels through the pupil and onto the lens, serving an essential optical function.

2. Iris:

Slender and round, the iris is a contractile curtain situated behind the cornea and in front of the lens. The iris modifies the pupil's size to control the quantity of light that enters the eye.

3. Pupil:

being more appropriately defined as the circular aperture in the middle of the iris through which light enters the eye, pupil is commonly perceived as the dark "centre" of the eye.

4. Lens:

It is surrounded by the ciliary muscles and situated behind the pupil of the eye. It facilitates the refraction of light entering the eye. Light is focused by the lens onto the retina to create a picture.

5. Muscle of the Ciliary:

The central layer of the eye has a ring of smooth, striated muscles called the ciliary muscle. The lens's curvature is changed by the ciliary muscle's contraction and relaxation.

6. Eyelids:

The conjunctiva secretes significant amounts of fluid, mucins, and electrolytes, which aid in the production of the tear film.

7. Watery humor:

The outer or front chamber of the eye contains a jelly-like material called aqueous humor. Aqueous humor turnover in humans occurs at a rate of between 1% and 1.5% of anterior chamber volume each minute(7, 8).

The Lateral Section:

The vitreous, retina, sclera, choroid, and optic nerves make up the posterior section.

1. Sclera:

The strong white sheath that makes up the ball's outer covering is called the sclera. The tough, fibrous membrane that keeps the eye's roughly globular form in place.

2. The retina:

In the rear of the human eye is where the retina is found. The retina can be thought of as the "screen" onto which light that has entered the eye through the cornea, aqueous humour, pupil, lens, and vitreous humour before reaching the retina forms a picture.

3. Vitreous Humour:

In the human eye, the vitreous humor makes up around 80% of the eye. It is a thin, jelly-like substance that is completely transparent and occupies the space behind the eye's lens.

4. The optic nerve:

The nerve signals that travel from the eye to the brain are carried by the optic nerve. The brain can process the information on an image included in these nerve signals.

5. Macula:

The macula is the name for the retina's central region. Photoreceptor cells, which translate light into nerve signals, are highly concentrated in the macula.

6. Choroid:

It is a very thin, highly vascular membrane with a dark brown color that is pigmented to absorb excess light and keep eyesight from becoming blurry(9, 10).

OBSTACLES TO LIMITING INTRAOCULAR DRUG DELIVERY

1. Tear Film:

One of the precorneal barriers, tear film lowers the effective concentration of the medications administered because of drug molecule binding to the tear proteins and dilution by tear turnover (about 1 ?L/min).

2. Cornea

The cornea is made up of three layers: endothelium, stroma, and epithelium. It also has a mechanical barrier that prevents things from leaving the body from entering the eye.

3. The eyelid:

The thin, transparent membrane known as the conjunctiva on the globe and eyelids plays a role in the creation and upkeep of the tear film. The conjunctiva also has an abundant supply of lymphatics and capillaries.

4. Sclera:

Collagen fibers and proteoglycans embedded in an extracellular matrix make up the majority of the sclera.

5. Brucella Membrane/Choroid: One of the body's most vascularized tissues, the choroid supplies blood to the retina. Compared to the brain, it has 10 times more blood flow per unit of tissue weight.

6. The retina:

The posterior route of elimination occurs through retinal permeability. The medications in the subretinal fluid may, in an intact retina, theoretically be absorbed by the sensory retinal blood vessels or carried across the retinal pigment epithelium (RPE) and absorbed into the choroidal vessels or pass through the sclera.

7. The Blood-Retinal Divide:

Medication transport from blood into the retina is limited by the blood-retinal barrier (BRB). BRB is made up of retinal capillary endothelial cells at tight junctions. These endothelial vesicles are thought to be involved in either fluid phase or receptor-mediated endocytosis or transcytosis(1, 11, 12).

OCULAR DRUG DELIVERY SYSTEMS' BENEFITS

1. Simple convenience and needle-free administration of drugs without the requirement for skilled workers.
2. Support for self-medication administration, which 3. improves patient compliance over parenteral methods.
3. The eye can be used to get hydrophilic, low molecular weight medications with good penetration.
4. Due to the huge absorption surface area and quick beginning of action, rapid absorption and
5. Elevated vascularization. Therefore, ocular delivery of a relevant medicine would be a useful alternative to conventional administration routes in emergency treatment.
6. Steer clear of first-pass hepatic metabolism(10, 13-15).

OCULAR DRUG DELIVERY SYSTEMS' DRAWBACKS:

1. The physiological limitation is the cornea's restricted permeability, which results in a poor absorption of eye medications.
2. A significant amount of the dosage that is delivered can have unintended systemic adverse effects since it drains into the lacrimal duct.
3. The medication is rapidly eliminated from the body through tear flow and eye blinking, which shortens the duration of the therapeutic action and necessitates frequent dose schedules(16, 17).

BARRIERS FOR THE OCULAR DELIVERY

1. Drug leakage from the surface of the eyes

Following instillation, the lacrimal fluid flow flushes the injected chemicals off the eye's surface. The systemic absorption of the medicine rather than its ocular absorption is another cause of ineffective drug elimination.

2. Eye and lacrimal fluid barriers

Drug absorption from the lacrimal fluid into the eye is restricted by the corneal epithelium. The formation of tight connections by the corneal epithelial cells restricts the penetration of paracellular drugs. The conjunctiva's surface area is over 20 times larger than the cornea's, and its epithelium is generally more permeable.

3. Blood-ocular barriers

Blood-ocular barriers shield the eye from the xenobiotic in the bloodstream. The endothelial cells in the uvea make up the blood-eye barrier. This barrier restricts the entry of hydrophilic medicines from plasma into the aqueous humor and keeps plasma albumin from entering the aqueous humor(18, 19).

EYE INFECTIONS

Infections of the eyes can be caused by bacteria, fungus, or viruses.

Typical eye diseases include

1. Keratitis/corneal ulcerations

the illness that causes patients to have blurry or foggy corneas, red eyes, impaired vision, and oftentimes eye discomfort.

The primary causes of keratitis include parasites, bacteria, viruses, fungus, and protozoa.

2. The disease of the eyes

It is a severe kind of intraocular inflammation that affects the inner coats of the eyes as well as the ocular cavities. mostly brought on by E. Coli, Pseudomonas, streptococci, etc.

3. The condition of the eyes

The swelling (inflammation) or infection of the conjunctiva, the membrane lining the eyes, is known as conjunctivitis. It is primarily distinguished by cellular exudation and invasion. Bacterial conjunctivitis is most frequently caused by Staphylococcus aureus.

4. The trachoma

"Active trachoma" refers to the inflammation of the conjunctiva that often affects children, particularly those in preschool. It is distinguished by non-specific inflammation and white masses beneath the upper eyelid's surface. The bacterium Chlamydia trachomatis is the cause of this.

5. Eye Dryness

If the composition of tears is altered, insufficient tear production occurs, leading to dry eyes. In addition to causing ocular pain, dry eye disorders can also cause damage to the cornea(20, 21).

OCCULAR DRUG DELIVERY ROUTES

The three main routes by which ocular drugs are administered to the eye are intravitreal, retrobulbar, and topical local ocular (i.e., subconjunctival).

• Topical medication:

The most practical and patient-friendly method of medicine delivery, particularly for treating anterior segment disorders, is topical eye drops. Ocular medication delivery is one of the most difficult and unique methods of administration because of the architecture and physiology of the eye.

• The subconjunctival pathway:

Subconjunctival injections bypass the conjunctival epithelial barrier, which limits the pace at which water-soluble medications can permeate the skin. It is a kind of periocular injection method used for ocular drug administration, when a treatment is administered underneath the eyelid's conjunctiva or under the conjunctiva underneath it.

• Intravital pathway:

It is a method of administering medication or another chemical that gets the material into the vitreous fluid of the eye. Intravitreal simply means "inside the eye." An intravitreal approach has the benefit of having a therapeutic impact in the targeted retinal tissue right away(22, 23).

HOW DRUGS ARE ABSORBED THROUGH THE EYES?

When drugs are injected into the eye, they must first pass through the cornea before passing via the non-corneal pathways. These non-corneal methods entail drug diffusion via the sclera and conjunctiva.

• Corneal penetration: 

Drugs enter the cornea through the precorneal gap and pass through the corneal membrane. The majority of eye medications are efficiently absorbed due to the diffusion mechanism across the corneal membrane. The rate and degree at which the transport processes take place determine the effectiveness of the absorption process. The cornea may be thought of as consisting of three basic layers (epithelium, stroma, and endothelium) in terms of transcorneal drug permeability(24, 25).

• The drainage system of Naso-Lacrimal:

The secretory system, distributive system, and excretory system are the three components of the nasolacrimal drainage system. The secretory system is made up of reflex secretors, which have an efferent parasympathetic nerve supply and secrete in response to physical or emotional stimuli, and fundamental secretors, which are triggered by blinking and temperature changes brought on by evaporating tears. The lachrymal puncta, the superior, inferior, and common canaliculi, the lachrymal sac, and the nasolacrimal duct make up the excretory portion of the nasolacrimal drainage system. Illustrates how the mucosal membrane lining the ducts and lachrymal sac absorbs most of the tears, leaving the nasal channel unabated(26).

OPHTHALMIC PREPARATIONS

1. Solutions:

Compared to alternative dosage forms, sterile homogenous solution dosage forms offer several benefits in terms of formulation and ease of commercial production on a large scale. When creating an aqueous solution, a number of issues need to be taken into account. These include the drug's proper salt selection, solvent solubility, therapeutic systemic impact, ocular toxicity, formulation pKa, and pH influence. The solubility, stability, and corneal permeability of the drugs are among the other stability parameters. These factors are dependent on the formulation's pH, as well as on the ingredients' compatibility, solubility, tonicity, viscosity, and buffering capacity(27).

2.Vacancies

When it comes to complexity and difficulty, ophthalmic suspensions are more demanding than ophthalmic (aqueous) solutions. Numerous issues with the formulation of an ophthalmic solution surfaced, including nonhomogeneity in the dosage form, particle settling, cake formation, and particle aggregation(28).

3. Ointments for eyes.

The semi-solid medicines used for external application are called ointments. Paraffin, a blend of semisolid and solid hydrocarbons with a melting or softening point around body temperature and minimal ocular irritation, is typically used in their formulation. Ointments are helpful in maintaining medication release and increasing drug bioavailability(29).

4. Water-Based Gel

High molecular weight, cross-linked polymers combine to create a three-dimensional network in water to generate aqueous gels, also known as hydrogels. Compared to viscous solutions, gels allow for a longer residence duration in the precorneal region(30).

5. Drops of Eye

Drugs that are ocular or surface-active are frequently delivered as suspensions, emulsions, and solutions. Retention of a solution in the eye can be affected by a number of an eye drop's characteristics, including its viscosity, osmolality, hydrogen ion concentration, and injected volume(31).

6. Gels and Ointments

Ophthalmic ointment vehicles can be used to extend the duration of medication interaction with the external ocular surface and improve drug ocular bioavailability. However, the main negative effects of this dose form, such as matting of the eyelids and blurring of vision, might restrict its use(32).

7. Ophthalmic Inserts:

The goal of ophthalmic inserts is to stay in front of the eye for an extended amount of time. These solid devices are meant to be inserted into the conjunctival sac and slowly release the medication(33).

The following is an explanation of some of the ophthalmic inserts:

Ocular implant that is non-erodible:

The Ocusert and Contact lens are examples of non-erodible ocular implants. Ocusert is a multilayer structure made up of a drug core that is continuously diffused across a layer of copolymer membranes surrounding it on all sides. The sterile preparation known as an ocular insert (Ocusert) extends the drug's residence duration in a controlled release way while minimizing or negating the effects of nasolacrimal damage(34). The medication reservoir in an ocusert is made up of two transparent discs with microporous membrane made of ethylene-vinyl acetate copolymer sandwiched between a thin disc of pilocarpine-alginate complex. The tear fluid can enter the drug reservoir compartment through the microporous membranes, dissolving the medication from the complex, for example Alza-ocusert: Then, for four to seven days, pilocarpine molecules are delivered steadily at a rate of 20 to 40 ?g/h. used to treat glaucoma. The solubility of the medication, the thickness of the membrane, and the makeup of the polymers all affect how quickly drugs diffuse(9, 35).

Ocular erodible implant:

The commercialized erodible medication insert devices are Minidisc, SODI, and Laciserts.

1. 1. 1. Lacisert: Developed by Merck, Sharp, and Dohme in 1981,

Lacisert is a sterile rod-shaped device used to treat keratitis sicca and dry eye syndrome. By absorbing water from the cornea and conjunctiva, they work to lubricate the cornea by forming a hydrophilic layer. In the process of making lacrisert, no preservatives are utilized. It has a diameter of 12.7 mm and a length of 3.5 mm. It weighs 5 grams. Keratitis can be effectively treated with lacisert. Within a day, it evaporates(34).

1. 1. 2. Soluble Ocular Drug, or SODI A little oval wafer called an insert was created for cosmonauts who were unable to utilize eye drops while in weightlessness. It is an oval-shaped, sterile thin film composed of acrylamide, N-vinylpyrrolidone, and ethylacrylate. It is around 15–16 milligrams in weight. It is applied to the treatment of trachoma and glaucoma. It takes ten to fifteen seconds for it to get moist and squishy after being placed into the inferior cul-de-sac. The film distributes the medication for about 24 hours before changing into a viscous polymer mass after 10 to 15 minutes and then polymer solutions after 60 to 90 minutes(36).

Benefits of SODI

1. Daily therapy for trachoma and glaucoma.
2. A single dosage application takes the place of four to twelve eye drops or three to six ointments(37).

3. Minidisc:

In contact with the eye, the minidisc is made up of a contoured disc with a convex front and concave rear surface. With a 4-5 mm diameter, it resembles a little contact lens. The minidisc is composed of butyl-n-poly dimethyl-siloxane, a silicone-based pre-polymer ?-?-bis (4-methacryloxy). Hydrophilic or hydrophobic minidiscs allow for the extended release of both water-soluble and insoluble medications. It has a 170 hour medication release time(38).

3. Liposomes

Liposomes are naturally occurring lipid vesicles with a diameter of 25–10,000 nm that are biocompatible and biodegradable. They are in close contact with the surfaces of the cornea and conjunctiva, which is advantageous for medications that are poorly absorbed, have a low partition coefficient, or are poorly soluble. This raises the likelihood of ocular drug absorption. Niosomes and Discomes: The primary drawbacks of liposomes are their chemical instability, phospholipid oxidative breakdown, and the expense and impureness of naturally occurring phospholipids. Since niosomes may entrap both hydrophobic and hydrophilic medicines and are more chemically stable than liposomes, they were designed as a means of preventing this. Timolol maleate-loaded discoidal vesicles, or "discomes," based on non-ionic surface-active agents were created and their in vivo characteristics were assessed. Discomes have the potential to be drug delivery vehicles since they release the medication gradually into the ocular region(39).

4. Pharmacosomes

This phrase refers to pure drug vesicles that are produced by amphiphilic pharmaceuticals. When the amphiphilic prodrug is diluted with water, it becomes a pharmacosome. The pharmaceuticals exhibit improved stability on the shelf, easier corneal transit, and a regulated release profile(40).

5. Iontophoresis:

In this process, ions are injected into cells or tissues using a direct current. The important ions for iontophoresis should be the drug's charged compounds. At the anode, positively charged drugs are pushed into the tissues, and vice versa. In addition to being quick, painless, and safe, ocular iontophoresis administration can also deliver a high concentration of medication to a particular location(41).

6. Dendrimer:

Dendrimers have superior water solubility, bioavailability, and biocompatibility and may be effectively employed for various drug delivery routes. Solutions containing dendrimers with carboxylic and hydroxyl surface groups often have longer residence times(42).

7. Collagen Protector:

Collagen shield was created as a corneal bandage to aid in wound healing. It is essentially made of cross-linked collagen that is constructed from skin tissue from fetal calves. Corneal ulcer healing is aided by the use of an antibiotic topically combined with a shield. Tear fluid softens these devices and forms a thin, malleable film that dissolves over a period of 10, 24, or 72 hours.  It is biologically inert, has superior biocompatibility, and stable structure(12).

8. The microemulsion :

Small droplet size (100 nm), improved thermodynamic stability, and a clear appearance are typical characteristics of microemulsions, which are dispersions of water and oil stabilized using surfactant and cosurfactant to minimize interfacial tension. The solubility of the therapeutic molecule, such as indomethacin or chloramphenicol for eye illnesses, is significantly improved by optimizing these components(43).

9. nanoscale fragments:

The water-soluble medications are the primary focus of this strategy. Nanoparticles are particulate drug delivery systems that range in size from 10 to 1000 nm, and they can be used to distribute, encapsulate, or absorb drugs. The primary method used to create nanoparticles for ocular medication administration was emulsion polymerization. Polyalkylcyanoacrylates are the primary materials utilized in the production of ophthalmic nanoparticles. It is possible to add the medications before, during, or after the polymerization(28).

10. Prodrugs:

The best prodrugs for ocular therapy should not only have a high partition coefficient and increased lipophilicity, but also a high degree of enzyme susceptibility, which allows them to be either chemically or enzymatically metabolized to the active parent compound within the cornea or after corneal penetration(29).

11. Enhancers of Penetration:

Enhancing the permeability of corneal epithelial membranes increases drug transport across the cornea. Penetration enhancers can be utilized for this reason. Actin filament inhibitors, chemical substances, bile salts, surfactants, and chelators are a few examples of enhancers(44).

12. Phase Transfer Systems/Insitu Gel System:  The phase transition of a formulation from liquid to gel or solid phase occurs when these systems, absorbed into the cul-de-sac of the eye, increase the viscosity of the medicine in the precorneal region. leading to increased bioavailability due to slower corneal clearance. These systems can be affected by pH, temperature or ion activation(45).

13. Gene therapy:

Along with tissue engineering, gene therapy approaches to treat blindness caused by corneal disease are at the forefront of advanced biomedical research. Corneal diseases are the second leading cause of vision loss after cataracts. Several viruses, including adenovirus, retrovirus, adeno-associated virus, and herpes simplex virus, have been manipulated for use in gene transfer and gene therapy applications(46).

14. Stem cell therapy:

New cell therapies to restore vision are focused on two areas of the eye that are critical for visual function, the cornea and retina. The most successful ocular application has been the use of transplanted limbal stem cells. to regenerate corneal epithelium from a source other than the patient. Sources of limbal cells include donors, autografts, dead eyes, and (more recently) cells grown in culture. Stem cell therapy has shown great success in certain anterior segment diseases(47).

15.       Protein and Peptide Therapy:

The delivery of therapeutic proteins/peptides has received much attention in recent years. One such example is the intravitreal injection of ranibizumab. However; Several limitations such as membrane permeability, large size, metabolism and solubility must be taken into account, limiting their effective delivery. The eye route is not a favourable route for the systemic transport of such large molecules(48).

Table 1 Different Ocular drug delivery system is being studied.

PHARMACEUTICAL REQUIREMENTS (49-53)

1. Tonicity and tonic-regulating agents:

 tear fluid is isotonic with blood and its isotonic value corresponds to that of 0.9% sodium chloride solution. Ideally, an ophthalmic solution should have this isotonicity value. Common tonicity regulating ingredients are NaCl, KCl, buffer salts, dextrose.

2. pH control and buffers:

The pH and buffering of the ophthalmic solution are probably equally important for proper storage. In addition to stability effects, pH regulation can affect convenience, safety and product activity. Ideally, each product is buffered to a pH of 7.4, which is considered the normal physiological pH of tear fluid.

3. Stabilizers:

Stabilizers are ingredients that are added to a formulation to reduce the rate of degradation of the active ingredients. Antioxidants are the main stabilizers added to some ophthalmic solutions, mainly epinephrine and other oxygenating drugs. Ascorbic acid and acetylcysteine, sodium bisulfite, 8-hydroxyquinolone and isoascorbic acid are other commonly used antioxidants.

4. Surfactants:

the use of surfactants in the preparation of eye solutions is severely limited. Many nonionic surfactants are used in relatively low concentrations. Mainly used are sorbitan ethers of oleic acid (polysorbate or Tween 20 and 80) and polyoxyl-40-stearate.

5. Tissue thickening agents:

polyvinyl alcohol, methyl cellulose, HPMC, hydroxyethyl cellulose and carbomer are used to increase the viscosity of ophthalmic solutions and prevent them. Although the surface area is very small, its main advantage is to increase the eye contact time, which reduces the shrinkage rate and increases the bioavailability of the drug.

6. Excipient:

The eye drops are liquid, but only slightly, and use USP purified water as a solvent. All eye drops must be pure. When oils are used as vehicles for ophthalmic fluids, they must be very pure. Vegetable oils such as olive oil, castor oil and sesame oil were used in improvised combinations.

Table 2 Ocular Drug Delivery systems formulation Patents