2.3 Conjunctiva:

A thin, vascularized, fibrous, transparent, mucous membrane which act as a permeability barrier(10)(21). It consists of stratified squamous epithelial tissue underlying neurovasculature. The topical instilled formulation may redirect the intended absorption into vasculature of conjunctiva, where it drains into systemic circulation. This phenomenon, impede the ocular permeation and stimulates adverse effects. Being a protective tissue, it is mainly endowed by sensory nerve endings. And where it is closely associated by eyelids, anterior sclera and cornea the non-corneal absorption is contributed. Transepithelial electric resistance is one of the barrier properties(1)(22). The surface area is about 16 times than the cornea and has a leaky epithelium where it helps in drug absorption for hydrophilic drugs but the drug clearance is affected by its vascular nature. There is an absence of tight junction barrier due to the nature of blood vessels of conjunctiva; hence the drug molecules enter blood circulation via pinocytosis transport through pores in vascular endothelial layer(23)(24).

2.4 Sclera:

The Sclera is a white opaque layer of eye. It is an outer coat comprised of fibrous tissue and act as a protective membrane. Episclera covers the anterior surface and the lamina fusca covers the inner surface(1). It is a tough sheath and comprises of collagen fibers which appears as a dense bundles and in extracellular matrix a proteoglycans are embedded(25). This sclera mainly helps in maintaining the shape of the eye. It acts as a barrier that prevents the exogenous substances to enter into posterior tissues of ocular surface. Permeability of sclera has a stronger dependence on molecular radius, surface charge, physicochemical properties and whereas the scleral permeability roughly reduces with molecular radius(26). The drugs hydrophobicity is affected by permeability of sclera, whereas low permeability is shown for increased lipophilicity drugs, and being an aqueous medium through proteoglycans the hydrophilic drugs diffuses more easily than the lipophilic drugs. In addition the drug molecule charges may also affects the scleral permeability. While negative charge of proteoglycan matrix binding to positively charged compounds demonstrate a poor permeability(9)(20).

2.5 Choroid:

A vascularised coat of eye that is present in between peripheral sclera and retinal epithelium. An innervated tissue comprised of melanocytes with extracellular fluid. It consists of layers – suprachoroid, vascular layer and Bruch’s membrane. A transition zone called suprachoroid, is thick and comprised of collagen fibers (1). The blood supply to vascular layer is obtained by three sources, which are short and long ciliary arteries. Bruch’s membrane is an innermost layer which is present next to the retina. As there is an increase in age the thickness of Bruch’s membrane increases and leads to cross-linking of collagen fiber and glycosaminoglycan turnover. The permeability of compounds is affected as there is a change in the thickness of this membrane (20).

2.6 Retina:

Inner most layer which is vascularised, transparent and innervated segment of the eye. It lines two-third posterior portion of the ocular surface. It acts as a screen where the images are produced by the light, passes through various layers, and at last reaches the retina. The produced images then transfer signal to brain through optic nerve. It has shown that histologically retina have several layers;

1. Internal limiting membrane

2. Nerve fiber layer

3. Ganglion cell layer

4. Inner plexiform layer (IPL)

5. Inner nuclear layer

6. Outer plexiform layer

7. Outer nuclear layer

8. External limiting membrane

9. Photo-receptor layer (rods and cones) &

10. Retinal pigment epithelium (RPE)

RPE cells consist of tight junctions where the paracellular transport is restricted for polar positively charged hydrophilic small molecular compounds which are similar to corneal epithelium. A high concentration cones concentric is present within the macula in the retina region where focusing of light on this region provide best vision. A major obstruction in retinal delivery is blood retinal barrier BRB which is formed from the RPE and endothelium blood vessels (13) (25).

Blood Retinal Barrier:

BRB is one of the major barriers where it is comprised of inner and outer blood retinal barrier. Inner blood retinal barrier (iBRB) composed of retinal capillary endothelial cells while the outer blood retinal barrier (oBRB) consists of tight junctions of RPE cells (9). The drug penetration into the retina from blood is restricted by this BRB. The Muller cells and astrocytes help in regulating the exchange of compounds and providing support to tight junction. In order to maintain integrity and promote barriers property astrocytes are involved which also give protection in retinal circulation where the inner retinal cells are present (17). Absence of fenestrations in retinal endothelial cells and RPE avoid passive drug transport which is similar as in blood brain barriers BBB. Very small and lipophilic molecules undergo diffusion to retinal tissues by RPE from choroid. The receptor or ATP/energy dependent pinocytosis mediates the molecule transportation. Thus tight junction highly restricts the drug entry (20).

APPROACHES:

Topical drops:

Topical eye drops/conventional dosage form are those applied on the ocular surface for purposes such as to treat the anterior segment of eye and also for intraocular treatment (27). This dosage form is widely accepted and administered due to its ease of preparation/bulk scale-up, convenience in administration, patient compliance, formulation efficacy, cost effectiveness and it is also referred to be a non-invasive route generally (28). Most of the ocular treatment is provided with topical instillation of solutions as eye drops. And these topical drops accounts about 90% as marketed formulations to treat eye diseases. Frequent instillation of eye drops with a vastly concentrated solution is needed for soluble drug. On the other hand, reflux blinking is a cause for administered dose loss and about only 20% of the instilled topical dose in precorneal area gets retained. And this precorneal site loss itself has been a main problem encountered in ophthalmic topical drops which may be due to drainage and tear turnover. Meanwhile for passive diffusion of drug, concentration accessible at the precorneal site deeds as a driving force. A topically instilled drop about less than five percent only reaches the eye and gets absorbed while rest is absorbed systemically in blood circulation through blood vessels of nasal and conjunctiva. Corneal epithelium limits the ocular absorption, and thus for an efficient delivery of drug to ocular surface prolonging the contact time in cornea is optimum (8)(17). Thus this solution possesses disadvantage such as elimination in precorneal site, short residence time, poor permeability, less bioavailability, instability of drug, no sustained action and drug loss through drainage. Therefore in order to increase the contact time, bioavailability and permeability of ocular drug delivery several permeation enhancers are incorporated in topical eye drops. Viscosity enhancers are also added in the solutions to enhance the precorneal residence time, bioavailability and this upon topical instillation the viscosity of the formulation is enhanced (29)(30)(31). The nanocarriers based approach is also developed for enhancing the ocular eye drops penetration, and also the water solubility of hydrophobic and hydrophilic drugs is increased. It allow a site specific targeting in drug delivery (37).

Eye ointments:

Another carrier system / vehicle for ocular drug delivery by topical application are eye ointments. This may be one of the approaches to prolong the contact time of drug on the ocular surface (4)(8). Paraffin, a solid hydrocarbon and semisolid mixtures are used usually to formulate the ophthalmic ointments which have a capability to melt at the physiological temperature of eye (34^◦C) and it is also non-irritant. Based on the biocompatibility the hydrocarbons are chosen. The ointments may be either simple or compound bases where continuous phase is formed by simple bases and two phase system formed by compound bases (32)(33). Addition of therapeutic agent can be employed as solution and as well as micronized powder. Upon administration the ointments break into droplets and retains as depot in cul-de-sac for prolong period of time. The ocular bioavailability and sustained action may also be improved by ointments. Meanwhile there are some drawbacks of using ointments such as vision blurring, eyelids matting which leads to its limitation of use (34).

Gels:

Ocular gels are those which have gained a greater popularity in replacing ointments where it is more synthetic (30). In some cases the viscosity enhancers are added for enhancing the viscosity which leads to prolongation of precorneal residence time of the formulation on the ocular surface. Meanwhile, at elevated concentration of water the viscosity enhancers form viscous gel. The advantages involved in using the ophthalmic gels are comfortable, systemic exposure are decreased, dosing frequency is reduced and blurred vision is less than the ointments. Although the ophthalmic gels are more viscous, it obtains only limited bioavailability. The higher viscous nature of the ophthalmic gels leads to blurring of vision, matting of eyelids which results in fewer acceptances by patient (35).

Nanotechnology based delivery for ocular:

Various drug delivery approaches are developed for treating ocular diseases of which nanotechnology based approaches are involved in anterior as well as posterior portion treatment of eye. Particle size are appropriately formulated in nanotechnology based delivery system in order to ensure that it possess sufficient bioavailability, compatibility with ocular tissue, and lesser irritation (8). Occurrences of this nanotechnology based ocular system are safe, precise and provide possible targeting to the site. For the treatment of ocular surface numerous nanocarriers like nanomicelles, nanoparticles, nanosuspensions, liposomes and dendrimers are developed, of which some show a promising improvement in the bioavailability (36).

Nanomicelles:

Nanomicelles are nano-sized carriers where the therapeutic agents are formulated into aqueous clear solutions. It is composed of amphiphilic molecules and perhaps these molecules are polymeric or surfactant based (42). A great interest have been shown in developing nanomicellar formulation for ocular this may be due to the reason that the size is small, easy to formulate, drug encapsulation is high, and also the aqueous solution is generated by hydrophilic nanomicellar corona. Furthermore the micelles formulation improves the bioavailability of therapeutic moiety in ocular tissues and thus their therapeutic outcomes are resulted to be better. Demonstration of mixed nanomicelles formulation resulted in well tolerated and less irritation. Nanomicellar based drug delivery is a topical drops and comes under non-invasive route which is of gaining interest due to their smaller size, hydrophilic corona, retaining for longer time in the systemic circulation, and accumulation in the diseased tissues through EPR effect. Surfactant and polymer selection should be appropriate in order to aid this nanomicellar technique to delivery drugs at both anterior and as well as posterior portion of eye (8)(10).

Nanoparticles:

Nanoparticles are submicron, solid small matrix spheres. It is a colloidal polymeric carrier where it is composed of macromolecular units so that the drug can be dissolved, adsorbed, encapsulated, entrapped and/or attached covalently. The particle size of nanoparticles ranges from 10 – 1000nm (1µm) (5). Nanoparticles normally consist of proteins, lipids, natural and/or synthetic polymers for example chitosan, albumin, sodium alginate, polylactic acid (PLA) and poly (lactide-co-glycolide) (8). Nanoparticles could be classified into nanospheres and nanocapsules based on the drug dispersion and/or its coating onto polymeric matrix (2). Nanospheres are drug carriers in which the therapeutic agents are either incorporated or adsorbed onto it. Meanwhile in nanocapsules the drugs are surrounded by polymeric matrix (26). Nanocapsules possess better effect when compared with nanospheres this may be due to the bioadhesive properties of nanocapsules, which results in enhanced biological response and residence time on the ocular surface. These nanoparticles may also provide sustained release of drug and prolonged therapeutic action. In order to achieve it, the nanoparticles should retain in the cul-de-sac and the drug entrapped should release at appropriate rate. If drug release from particles is too fast, then there is a sustained release of drug and if it is too slow, the drug concentration in tears are too low for adequate penetration to ocular tissues. Nanoparticle drug carriers are a promising delivery system due to its smaller size which leads to less irritation and sustained action (35). The frequent administration of the formulation may also be minimized. Bioadhesive materials are used to fabricate the nanoparticles for enhancing the retention time in cul-de-sac, because without bioadhesion the elimination of nanoparticles exists at precorneal pocket which is as rapidly as aqueous solutions. Thus the residence time at precorneal site is enhanced by mucoadhesive property for topically administered nanoparticles (38).

Nanosuspension:

A colloidal dispersion with a submicron particles composed of poorly soluble drugs and the surfactants are used to stabilize them. It mainly consists of inert polymeric resins which is nothing but a colloidal carrier involved in enhancing the solubility of therapeutic moiety and hence the bioavailability (4). Nanosuspensions appear to be a promising approach for hydrophobic drug delivery and also act as a better formulation/dosage form when compared to conventional solutions and suspensions. Advantages of using this nanosuspension involve easy formulation, non-irritant, enhanced ocular bioavailability of insoluble drug in tears fluid, precorneal residence time is prolonged, better sterilization (39). It is believed that it is an efficient delivery system for hydrophobic drugs where the rate and extend of drug absorption is not only increased but also the drug action intensity with extended duration is obtained. Hydrophobic drug loaded nanoparticle suspension and drug embedded polymeric system typically possess particle size of range 100-400nm (43). After instillation the fine particles adhere to ocular tissues and there will be a formation of depot to release the drug after a period of time. Furthermore, the larger surface area of the nanoparticles provide sufficient rate of drug release and maintains an effective concentration of drug to accomplish a desired bioavailability. And also for sustained action Nanosuspension are incorporated in hydrogels and ocular inserts for predetermined period of time (7)(32).

Liposomes:

A lipid vesicular carrier, consisting of concentric bilayers of lipid enclosed with an aqueous medium which is amphiphilic in nature (1). The size range of liposomes is generally 0.08-10µm and based on the number of concentric lipid layers and aqueous compartment it can be either multi-(MLV) or unilamellar vesicles (4). The unilamellar vesicles further can be classified as small-(SUV) and large unilamellar vesicles (LUV) depending on the size. Generally most of liposomes formulations are prepared with phospholipids, stearylamine and choslesterol. When there is an agitation of mixture of phospholipids and aqueous medium the structure of liposomes are formed spontaneously. Liposomes as ophthalmic formulation serve as an ideal approach for drug delivery owing to its tremendous biocompatibility, capability of encapsulating both hydrophilic and lipophilic drugs and the structure is similar as the cell membrane (8). The drug incorporated in liposomes may gain penetration more across cornea due to the blend of lipid bilayer with tear film which may also possess high affinity with epithelial membrane of cornea. The drug absorption is also enhanced by liposomes which are due to the intimate contact of surfaces such as cornea and conjunctiva (12). This enhanced absorption is desirable for poorly soluble and absorbable drugs, and drugs whose partition coefficient is less. Studies have also demonstrated that liposomes are effective for both the portion anterior and posterior part of the eye. The surface charge determines the behaviour of liposomal delivery, where liposomes with positive charge get attracted to negative charged cornea than the neutral or liposome with negative charge (40)(41). It offers advantages such as biodegradable, biocompatible, reduction of toxicity by drugs, and provides site specific, sustained release of therapeutic agent. And also possess drawbacks such as less drug loading capacity, derisory stability, and difficulty in manufacturing as sterile formulation (4).

Dendrimers:

Dendrimers are highly branched, nanosized polymeric system and thus for targeting the site the terminal group are functionalized (8). It consists of an inner core to which sequence of branches are attached. It can be either structured as tree or star which adopt a shape of quasi-spherical with a size range of 2-10nm in diameter and also possess a unique molecular weight with functional group such as hydroxyl or carboxyl and amine at terminal end (32). Thus this functional group at the terminal end are used for conjugation of targeting moieties. Dendrimers are drug carrier system where the size, functional group, surface charge, molecular weight and geometry selection to deliver the therapeutic agents becomes critical. Being an highly branched carrier system it allow a wide range of therapeutic agents incorporation for both hydrophilic and lipophilic drugs. It has been reported that dendrimers, a branched polymeric carrier for ocular delivery is a promising approach. Thus PAMAM poly (amidoamine) a type of dendrimers is widely employed for drug delivery in ocular surface. The use of this dendrimers might be another approach in increasing the ocular bioavailability and residence time and therefore it is expected that they will be a improved therapeutic outcomes (8).

Niosomes:

Niosomal delivery for ocular was developed to circumvent the liposomal limitations such as cost, phospholipids purity and oxidative degradation, chemical instability as the niosomes are chemically stable and both hydrophilic and lipophilic drug entrapment may be done. It is a large bilayered vesicle of 12-16µm in size and consists of non-ionic surfactant (2). These niosomal vesicular systems are biodegradable, biocompatible, and non-toxic, thus also does not need any special techniques for handling (10). To increase the ocular bioavailability significantly the therapeutic agents are released independently of pH. The advantage involved in using niosomal ocular delivery is minimum systemic drainage since it is larger in size and has more residence time in ocular cul-de-sac due to their disc shape (44). These are preferred delivery system than the topical liposomes which may be due to its ease of handling and flexible nature. And also accordingly this niosomes may be modified for better therapeutic efficacy by the addition of appropriate excipients. Being non-ionic surfactant vesicular system it provide potential application for hydrophobic and amphiphilic drug delivery in ocular (10)(32).

In-situ gelling systems/ phase transition systems:

In-situ gels are referred to as polymeric solutions where there is a viscoelastic gel formation by the phase transition mechanism in response to physiological conditions. This in-situ gelling system is mainly triggered by the temperature, pH and ions or may also be induced through UV irradiation (8). It comprise of sensitive polymers where with specific temperature, pH and/or ionic strength changes this sensitive polymers itself are structurally altered to elicit the effect. Insitu gels upon instillation are in liquid form then later in cul-de-sac undergo gelation to form a gel or solid phase to enhance the viscosity at precorneal site resulting in increased bioavailability and slower the drainage of formulation at corneal site. Sol to gel approach can be obtained by triggering the temperature, pH and/or ion activation (45)(46).

Temperature triggered in-situ gelation:

Thermosensitive gels for ocular delivery are common and focused more in research which responds from temperature changes. Devoid of blurred vision and irritation this in-situ gel can be administered simply and precisely into the eye ball (8). At precorneal temperature of 35°C the gel formation occurs which endure the dilution of lachrymal fluid without any rapid elimination at the precorneal pocket after the instillation of drug. It is also recommended that gelation temperature should be above room temperature to be a good responsive temperature triggered ocular in-situ gel and in precorneal temperature it should possess sol-gel phase transition for avoiding refrigeration before administration because it may tend to cause ocular irritation in cold nature. Various thermogelling polymers are also involved in the formulation such as poloxamers (pluronic), polyethylene glycol, chitosan, poly (N-isopropylacrylamide), poly (glycolide), poly (lactide), xyloglucan and cellulose derivatives. These polymers are added up with therapeutic agent for drug delivery as solution which at specific physiological temperature undergoes gelling. It enhances bioavailability at anterior as well as posterior portion of the eye thus it is demonstrated to be a promising approach (45)(47).

pH triggered in-situ gelation:

pH sensitive carriers are utilised for this approach where they are polyelectolytes containing acidic group such as carboxylic/sulfonic and a basic group such as ammonium salts with alteration in pH the proton is either accepted or released. The formulation exists as solution at 4.4, a lower pH and rapidly a transition to gel at tear fluid pH 7.4 occurs. The frequently used polymers include polyacrylic acid (carbopol 940), cellulose acetate phthalate and polycarbophil (45).

Ion activated in-situ gelation:

The cations in tear fluid help polymeric dispersion to undergo ion activation. These ion activated in-situ gels are crosslinked in tear fluid which consists of cations such as Ca²⁺, Na²⁺ and Mg²⁺ and forms gel, which tend to increase the contact time at the corneal pocket. The polymers utilised for ion activated in-situ gel are gellan gum, sodium alginate and hyaluronic acid (45).

The chief advantage of in-situ activated gelling system is that possibility of accurate administration and improvement of precorneal retention time. In-situ gels also offers advantages such as ease of manufacturing and administration, patient acceptance, enhancement of ocular bioavailability, reduction in frequent dosing of formulation (12).

Contact lens:

It is a plastic disk which is thin, curve shaped and designed in such a way covering the cornea with a radius of about 5mm. The contact lenses after administration owing to surface tension get adhere to tear film (48). Hydrophilic drugs soaked in solution containing drug undergo absorption through these contact lens. And thus the therapeutic agents saturated in contact lenses releases the therapeutic agents after placing it in the eye for prolonged time period. Hydrophilic lenses are used widely for prolonging the residence time in the ocular surface. Encapsulation of therapeutic agents in nanoparticles and dispersing it in lens material, such as p-HEMA (poly-2-hydroxyethyl methacrylate) hydrogels is another way of incorporating therapeutic agents in the contact lens. Nanoparticle laden hydrogel contact lenses releases the therapeutic agents for few days. Thus by varying the loading capacity of nanoparticles in hydrogel the delivery rate of drug can be controlled (31). It produces better ocular bioavailability than the topical drops. And also by suspending these nanoparticles in thermogelling polymers the residence time can be prolonged. This approach serves a major benefit of prolonging the residence time which exists few minutes with eye drops in post tear films. Thus becomes an attractive alternative to the topical instilled eye drops (49). Since the residence time is lengthened by this approach the permeation of the drug is also higher at the targeted tissue through cornea. Contact lenses also offer advantages such as by increasing the transport of drug into cornea as well as conjunctiva. Meanwhile the drawbacks of contact lenses are that it causes toxicity to ocular (30)(60).

Collagen shield:

Collagens are regarded to be most helpful biomaterials since the biological characteristics existing in it includes biodegradability and poor antigenecity which serves as a primary resource for medicals. Collagen shields first undergo fabrication by porcine scleral tissue, where the collagen composition is as similar as human cornea. It is kept for hydration before placing it in the eye (29). Collagen shields are cross-linked, where foetal-calf skin is also used for fabrication and developed originally as corneal bandage. These corneal shields by tear fluid get softened and produce a thin film which is flexible, and approximately has a thickness of about 0.1mm, 14.5mm diameter and confirms to cornea (12). Collagen film is biologically inert, structurally stable and has a good biocompatibility thus it is proven to be a promising drug carrier and will be a efficient drug delivery approach for ophthalmic (31). Collagen shield when saturated in water soluble drug solution the collagen matrix act as reservoir, thus increases the contact time in the cornea. Collasomes to human eye be a promising approach for drug delivery. These collasomes are well tolerated because in carrier vehicles the particles containing collagen are suspended where the instillation becomes safe and effective. It also offers some disadvantages like; being not individually designed there will be a problem of comfort and shield expulsion shall occur (29).

Microemulsion:

A stable dispersion of oil/water, facilitated by combining surfactant and/or co-surfactant for reducing the interfacial tension (32). It is characterized as small droplet with size 100nm, clear appearance and greater thermodynamic stability. It helps in reducing the dosing frequency and also the ocular bioavailability of therapeutic agents is improved. In terms of manufacturing and sterilization, the microemulsion possesses a simple and cost effectiveness because of its thermodynamic stability. The structure of microemulsion provides solubilisation of hydrophobic drugs in oily phase therefore poorly- soluble drugs can be formulated. Thus microemulsions are recognized as a promising alternative approach for ophthalmic drug delivery. Microemulsion in-situ gelling approach is developed as a new vehicle to exploit benefits to ophthalmic delivery. The idea behind this approach is that encapsulation of therapeutic agents in the droplet which forms a microemulsion, and dispersing it in the polymer solutions that leads to gel formation upon electrolyte activation. It offers advantages such as sustained release; thereby the frequency of dosing is reduced. And higher concentration of utilising surfactant and/or co-surfactant, selection causes potential toxicity, the aqueous and organic phase also get affected by its stability (4)(50).

Microneedle:

Microneedles are array of needles which is micrometer sized or individual needle where the microelectronics tools are utilized for fabrication. Microneedle based approach is a minimal invasive route for treating posterior segment of eye. This technique is efficient in treating the vision menacing posterior diseases such as diabetic retinopathy, macular degeneration and posterior uveitis. Microneedle strategy can circumvent the BRB (blood retinal barrier) and helps in delivering the therapeutic agents to the retina (23). Microneedles to biological membranes creates micro-dimension transport pathway and also enhances the permeability of drugs across the barriers. Plenty of approaches have been developed for fabricating the microneedles in variety of size, shapes, materials and/or configurations. It has been developed as a physical method to avoid most of the side effects produced by the conventional injections in ocular delivery system. Being a custom designed device, this microneedles can penetrate into sclera only few hundred microns level, thus avoids the damage to deeper tissues of ocular. These microneedles deposit carrier system and/or therapeutic agents into sclera and a narrow space called “suprachoroidal space” (SCS) between the sclera and choroid. Therefore puncturing the sclera and drug depositing into it or facilitating the SCS may cause diffusion into deeper ocular tissues. Several microneedles are designed and various drug delivery routes are also evaluated (8)(23). A recent occurrence of microneedles for delivering the therapeutic agents to SCS (suprachoroidal space) is studied to be better targeting approach. It is developed with length same as that of sclera thickness, for a perpendicular insertion to sclera-choroid junction and referred as invasive method (51)(52).

Ocular inserts:

Inserts are thin, aseptic, drug loaded, multilayered, solid and/or semisolid dosage form which is placed in cul-de-sac whose dimensions are planned and constructed specifically for providing application in ocular. It also has an ability to conquer the impediment observed in traditional ocular delivery system (8). Of all approaches in ocular delivery system, the ocular inserts are investigated to be most precise because it controls the drug release by utilising polymer matrices and permeable membranes (39). The traditional ocular delivery systems are associated with some disadvantages such as pulse entry behaviour of releasing the drug, characterized by overdose, followed by decreased ocular bioavailability due to long time of under-dosing. Thus by using ocular inserts the disadvantages associated with the traditional delivery system can be overcome by a sustained, controlled and continuous delivery in target site by maintaining the concentration of drug effectively. Accurate drug dosing can be obtained by using these ocular inserts (4)(31). A novel occurrence of nanoparticles impregnated ocular inserts were developed which effectively delivers significant concentration of therapeutic agents to posterior portion of eye after topical administration. Drug loaded inserts reported less side effects than orally administered formulation (53). Utilizing various techniques a variety of inserts were designed to make the ocular inserts soluble, erodible and non-erodible. But it has gain minimum popularity due to its psychological factors like patient non-compliance and reluctance, self-insertion, occasional failures (membrane rupture and unnoticed expulsion), foreign substances sensation etc (29). It also possess inherent drawback such as rapid drainage away from precorneal cavity by two mechanism constant tear flow and lacrimal nasal drainage (61). The rate of drug release from tear fluid to ocular tissues when instilled is high and gets declines rapidly. This is due to transient period of over dosage and associated side effects (62). An innovative study was developed using ocular inserts to extend the release of drug for once a day and the formulation showed the drug release in independent concentration manner and was stable and intact in ambient condition (64).

Ocular implants:

Intraocular implants are employed specifically to provide controlled release of the drug over an extended time period. An ocular implant helps to circumvent intraocular injections and also complication associated with it (8). For posterior tissue drug delivery, implants by minor surgery through making an incision placed intravitreally at the pars plana located at anterior to retina and posterior to lens. Thus being a invasive route of delivery, implantation is gaining interest because of advantages associated with this device which includes releasing drug at therapeutic level to diseased tissues, sustained release, circumvent barriers and side effects is reduced (23). Various implantable devices are designed for treating diseases especially chronic vitreoretinal as ocular delivery system. These implants are drug releasing ocular devices depending on the polymers used it is available as biodegradable and as well as non-biodegradable (63).

Non-biodegradable implants:

It is a polymer-based approach composed of polymers such as EVA (ethylene vinyl acetate), polyvinyl alcohol (PVA). Non-erodible implants should be placed surgically in vitreous cavity and removed. These implants achieve near zero order kinetics thus offers a long-lasting drug release. The drug embedded in the implants is released approximately at the rate of 2µg/hr by diffusion over many months and during the next insertion can be removed (8)(39).

Biodegradable implants:

Since it is biodegradable in nature, does not requires surgical procedure to remove it therefore gains a advantage than non-biodegradable one. Most common polymers used for fabricating biodegradable implants includes PLGA, PGA (polyglycolic acid), PGA (polylactic acid). It does not leave residue in eye therefore this becomes an advantage of using biodegradable implants (8)(39).

Iontophoresis:

Ocular iontophoresis is described as non-invasive drug delivery system particularly designed and fabricated for treating both the segment of eye (8). It is considered as an active approach that utilises electrical current for transportation of ionized drugs across tissues and helps in delivering active molecules to the eye (31). This technique is mainly used for increasing the ionized compound penetration into the epithelial tissue of the ocular surface. The basic principle behind the iontophoresis method is that same charged ions undergo repulsion and opposite charged ions undergo attraction between them. Moreover, by electrorepulsion and/or electroosmosis the ionized compounds are driven to the ocular tissues (54). Based upon the applied time and current density this method potentially controls the drug penetration and only a less amount of electrical current is required. It is classified as trans-corneal, trans-scleral iontophoresis. Mainly for delivering the drug to the posterior portion trans-scleral iontophoresis is utilised. It possess recognizable advantages, in ocular delivery because of its non-invasiveness, easy application, increased penetration to target site and also drug delivery across several barriers in eye (55). It also has a capability of dosage modulation, broad range of delivering therapeutic agents to different ophthalmic diseases associated at posterior portion, patients acceptance. Meanwhile the drawback of iontophoresis are repeated administration, absence of sustained half-life, includes side effects such as mild pain however no risk of any infections. It can also be combined with other ocular approach (56).

Topical devices:

Drug loaded topical medical devices are developed as an alternative of conventional drug delivery system in order to overcome the obstacles and it uses mainly non-corneal route for absorption. Topical devices are placed by implantation or injection to vitreous chamber. Currently it is exploring an interest for treating the anterior portion of the eye.

Resorbable conjunctival devices:

These devices are positioned in conjunctival sac which gets dissolved and over time the drugs are secreted. The advantage includes non-invasiveness thus the removal is not required. Since the time of action of resorbable devices are limited (less than 24 hours) it needs a frequent administration. Thus developing resorbable devices is challenging because the material used and metabolites are to be non-toxic. Other challenges includes accidental drug loss prevention, that does not noticed always and the tear production is increased after positioning the devices where the risk of bulk drug release is enhanced.

Oval, ring and rod shaped conjunctival devices:

Various oval, ring or rod structured non-resorbable devices are developed. These devices are positioned under upper and lower eyelids in conjunctival sac and for the distribution of drugs non-corneal route is used. Thus the delivery of drug to posterior portion of eye is achieved through penetration via conjunctiva and sclera (57)(58).

Punctum plugs:

It consists of cylindrical core composed of drug microparticles where impermeable silicone shell surrounds it and covers 50% of the core, and towards the ocular surface the uncovered part is directed. Punctum plugs show a potential in drug delivery of the drugs as an ocular device. It is a small plug and mainly positioned in tear duct (57). Thus after the instillation of topical eye drops, in order to enhance the absorption of drug and its efficacy, prolongation of retention time, and drug drainage inhibition via nasolacrimal system are done by punctual plugs which act as an long-lasting approach. Another potential occurrence of puncta occlusion by punctual plugs is believed to be the most non-medical method of treating the dry eyes. The mechanism involved in plunctal plugs approach is that it increases the tear volume by occlusion of tear drainage route thus it provide treatment to dry eye syndrome(59).

CONCLUSION:

The complex nature in physiology of eye and the barriers affecting the efficacy of existing approaches had lead to the development of novel therapies. Consequently in order to overcome the obstacles and certain barriers which affect the existing treatment diverse therapies have been adopted thereby it can efficiently deliver the therapeutic agents to the ocular surface. Abundant efforts have been shown in ocular research for the development of safe and patient compliance novel drug delivery approaches. At recent times numerous researches have been developed as discussed in this article which is used for treating both anterior and posterior portion of the eye.

ACKNOWLEDGEMENT:

The authors would like to thank Department of Science and Technology – Fund for Improvement of Science and Technology Infrastructure in Universities and Higher Educational Institutions (DST-FIST), New Delhi for their infrastructure support to our department.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

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Received on 25.12.2018 Modified on 10.02.2019

Research J. Pharm. and Tech. 2019; 12(5):2527-2538.

DOI: 10.5958/0974-360X.2019.00426.8