INTRODUCTION:

Eye is one of the most senstive part of human body and organ of vision^[1]. The anatomy of eye is that: Eye is divided into two major segments: Anterior segments and Posterior segments^[2]. The anterior portions of the eye refer to about one-third of the eye and include aqueous humor, conjunctiva, pupil, cornea, iris, ciliary body and lens, suspensory ligaments. Aqueous is a thin, watery fluid located in the anterior and posterior chambers of the eye^[1,2,3]. The anterior chamber lies between the iris and the inner surface of the cornea.

The posterior chamber is located behind the iris and in front of the lens^[1,3,4]. Aqueous humour is a fluid that is thin, transparent same as like plasma. 99.9% of water is the major constitution and other 0.1% is consists of sugars, vitamins, proteins and other nutrients. This fluid upholds the cornea and the lens, and gives the eye its shape. Conjunctiva is that part of eye that consists of mucous membrane that covers the front of the eye and covering the anterior eyeball up to the edge of cornea. The transparent layer forming the front of eye is known as cornea. Spherical shell is formed by cornea and sclera which makes outer wall of the eye ball. In the centre of the iris of the eye there is hole located called as pupil that allows light to strike the retina and appears black because light rays entering the pupil are either absorbed after diffuse reflections within the eye that mostly miss exiting the narrow pupil or absorbed after by the tissues inside the eye directly. Iris is the colored portion of the eye positioned between the cornea and the lens. The iris largely consists of connective tissue containing pigment cells, muscle fibres and blood vessels. The important functions of the iris are to control light entry to the retina and to reduce intraocular light scatter. Ciliary body has a specialized structure that unites the iris with the choroid. The lens is composed of transparent, flexible tissue and is located behind the iris and pupil. This part of the eye helps to focus light and images on your retina. Lens is composed of hard nucleus and soft cortex, bounded by capsule. Suspensory ligament of lens is a series of fibers that connects the ciliary body of the eye with the lens. The remaining second third segment is posterior segment includes choroid, retina, optic nerve, retinal pigment epithelium, sclera, and vitreous humor. Choroid is that part of the eye that is made up of connective tissue, blood vessels and pigment cells. The choroid is the intermediate between sclera and retina. The functional of choroid is to provide oxygen and nutrition to outer retinal layers. The innermost layer of the eye is retina. It has more than 120 million light-sensitive photoreceptor cells that detect light and convert it into electrical signals. Focused light images are converted into nerve impulses through retina. Retina consists of tight junctions between the endothelial cells of the retinal blood vessels and the retinal-pigmented epithelium (RPE)^[3]. Sclera is the white, outer layer of the eyeball, tough, fibrous membrane that helps to maintain the spherical shape of the eyeball. The pigmented layer of retina or retinal pigment epithelium is the pigmented cell layer just outside the neurosensory retina. Optic nerve is the second cranial nerves involved in vision and movement of the eyes are the optic nerve. Sensory nerve for vision is known as optic nerve. Information from the eyes to the brain is transmitted through the optic nerve. The space between the lens and the retina of your eye is filled by clear and colourless fluid constituents are of collagen, proteins, salts and sugars. The space in the eye between the lens and the retina is filled by vitreous humor that is a transparent, colorless, gelatinous mass. It makes up four-fifths of the volume of the eyeball. Fluid like near the centre, and near the edges is a part in the eye known as vitreous humour. The vitreous humour is in contact with the retina.^[3-9]

Fig 1: Structure of eye.

Individual part of the eye including anterior and posterior segment may elicited different disease, infections or allergies. Ocular drug delivery system is the delivery system that is used to instill into the eye and treat the eye disease, eye infections, or allergies. Although this is a challenging task for scientists and formulators to develop ocular drug delivery system with therapeutic development.

The major limitation of ocular drug delivery system is the short residence time. The medication is eliminated rapidly through immediate eye blinking after instillation of drugs. Further, the lacrimal fluid washes off the drugs form cul de sac. A major portion of the administered dose drains into the nasolacrimal duct. All the above discussed limitations lead to reduced bioavailability in ocular cavity. Thus this is very challenging task to formulate a drug with effective therapeutic window and the drug whose residence is large^[10,11]. The pH of eye is 7.2. Individual part of the eye including anterior and posterior may elicited different disease. Ataxia of the anterior segment of the eye are leading causes of ocular morbidity. Such conditions include dry eye conditions, hereditary disorders infections and traumas of various types, inflammatory reactions and cataract. Posterior segment eye disease epidemiologically is commonly defined as diseases of the retina, choroid and optic nerve and primarily involves diabetic retinopathy, glaucoma and age-related macular degeneration.^[12,13].

The advantages of ocular drug delivery systems are:

It gives the ease of convenience and its application is needle free, also there is no need of trained personnel assistance for the application, self-medication, thus improving patient compliances compared to parenteral routes.

Good penetration of hydrophilic drug, low molecular weight drugs can be obtained through the eye.

Rapid absorption and fast onset of action takes place because of large absorption surface area and high vascularisation. There is the avoidance of hepatic first pass metabolism and thus there is the possibility for dose reduction compared to oral delivery.

Ocular drug delivery has better patient compliance ^[1,3].

Disadvantages of Ocular Drug Delivery Systems:

The physiological condition is the limited permeability of cornea resulting into low absorption of ophthalmic drugs.

A major portion of the administered dose drains into the lachrymal duct and thus can cause unwanted systemic side effects.

Short duration of the therapeutic effect results from the rapid elimination of the drug through the immediate eye blinking and tear flow. Therefore frequent dosing regimen results^[1,3].

Delivery routes:

There are many delivery routes of administration for treatment of the eye. To treat the eye from disease and infections many formulation of conventional dosage forms takes place like suspensions, emulsions, solutions and ointments. These above conventional dosage forms are limited only to certain disease.

Solutions:

Solutions are the liquid preparation contain drug substances which are used in ocular drug delivery. This type of delivery system is one of the most convenient, non-invasive, safe, patient compliance and effective. The advantage of topical solution is that administration is very easy. The drug substance must be active on surface of eye or internal region of eye after passing through cornea or conjunctiva. These solution preparations also have some disadvantages such as poor bioavailability and poor stability. The formulation is limited only to anterior segment of eye. Only about 30-50µl of ophthalmic solution is delivered using a dropper, due to limited holding capacity of pre-corneal area. To solve these problems like stability, bioavailability or to improve drug contact time of solution formulation are solved by extensive work done by researchers by using various additives such as enhancing viscosity, using permeation enhancers using preservatives and changing the pH of these formulations. By the modification of the corneal integrity permeation enhancers are used to improve the corneal uptake. Chelating agents, preservatives, surface active agents and bile salts were studied as other additives and regarded as permeation enhancers. The examples that are used for improving ocular delivery as permeation enhancers are ethylenediaminetetra acetic acid sodium salt, polyoxyethylene glycol ethers (lauryl, stearyl and oleyl), Benzalkonium chloride, sodium taurocholate, saponins and cremophor. Solutions improves ocular drug bioavailability by addition of permeation enhancers but few studies revealed a local toxicity with permeation enhancers are going to takes place. Hence, for the modification of the effect of permeation enhancers research is still being conducted and evaluation of their safety on corneal tissues^[14,15]. Hornof et al evidenced that when polycarbophil-cysteine was used as an excipient then it did not damage the corneal tissue integrity and he also suggested that it could be very safe for use in ocular formulations. For Hydrophobic drug molecules in aqueous solution Cyclodextrins act as carriers. This assists to deliver drugs to the surface of biological membrane.^[16]

Saari et al.compared the effect of 0.7% dexamethasone-CD eye drops applied once daily with 0.1% dexamethasone sodium phosphate applied three times a day for post-cataract inflammation. Twenty cataract patients who underwent pharmacoemulsification cation and intraocular lens implantation were randomly divided into two postoperative treatment groups. The results were concluded that 0.7% dexamethasone-CD eye drops applied once daily would be a more effective postoperative anti-inflammatory medication than 0.1% dexamethasone sodium phosphate applied three times a day. After three weeks of the operation, the mean best-corrected visual acuity was normal and there were no significant differences between the two test groups. No side effects were observed and compliance was good in both groups. It should be noted that the 0.7% dexamethasone-CD eye drops would applied once daily, making the patient compliance more likely^[17].

Emulsion:

An emulsion is a biphasic system composed of two immiscible phases that forms a system consisting of dispersed phase and continuous phase. Emulsion increase the bioavailability of the encapsulated drugs as well as the solubility of drug. The chief formulation mechanism to yield this design is based on two types of emulsions—oil-in-water (O/W) and water-in-oil (W/O). To be applied in the delivery of drugs to ocular tissues the favorite type is the O/W rather than W/O, mainly due to less induction of irritation in the target tissues as well as improved tolerance of the eye to O/W emulsions^[24]. In ocular administration, micro- and nanoemulsions are honored due to the small size of the droplets. They are structured as follow: an aqueous phase, a lipophilic phase and a surfactant phase. A co-surfactant may be required in some cases. This dispersed system has the advantages of not requiring much energy because of its spontaneously formation^[18].

The examples of currently marketed ocular emulsions in the United States are Restasise™, Refresh Endura® (a non-medicated emulsion for eye lubrication) and AzaSite®. The application of emulsion improves precorneal residence time, provides sustain drug release and thereby enhancing ocular bioavailability that helps in future prospective for use, drug corneal permeation. The improved anti-inflammatory activity of prednisolone derivative, 0.05% [3H] difluprednate, with emulsion as vehicle was demonstrated by Tajika et al. It becomes confirmed that in the rabbit eye, emulsion could deliver drug to the anterior ocular tissues with small amount of drug reaching posterior tissues by using single and multiple topical drop instillation. Highest radioactivity in cornea followed by iris-ciliary body > retina-choroid > conjunctiva > sclera > aqueous humor > lens > and vitreous humor was revealed by single topical drop and multiple topical drop instillation studies. The results from this study suggests difluprednate emulsion as a potential candidate for treating anterior ocular inflammations. Mucoadhesive polymers such as chitosan and hydroxypropyl methyl cellulose ether for emulsion coating have been introduced by several researchers. Chitosan surface coating improves precorneal residence time of API; this result is concluded by conducting studies and thereby ocular bioavailability. O/w emulsion that was loaded with Indomethacin was prepared employing castor oil and polysorbate-80 and the resultant emulsion was surface coated by chitosan. Comparative studies were conducted in male albino rabbits with topical drop instillation between in vivo studies for chitosan coated vs non-coated Indomethacin emulsions. Emulsion surface coating with chitosan improves emulsion mean residence time and also half-life by 1.5 and 1.8 times, respectively relative to non-coated emulsion have been showed by Tear fluid pharmacokinetic study. Indomethacin concentrations were determined in cornea, conjunctiva and aqueous humor, post 1 h of emulsion instillation. Concentrations of indomethacin with emulsion system were found to be about 5.3 and 8.2 times higher in cornea corresponding to conjunctiva and aqueous humor^[19-21].

Suspensions:

These are liquid pharmaceutical preparations, non-invasive ocular topical drop carrier system. Ocular suspensions are forms of dispersions of finely divided insoluble drug particles suspended in an aqueous medium containing dispersing and solubilizing agent. We can also say that the carrier solvent system is a saturated solution of API.Drug using for the purpose a hydrophilic solvent possessing an agent of dispersion or a suspension obtaining a final solution with a saturated character. The suspension type conventional drug delivery system leads to enhance the contact time of drug with the tissue by retaining in precorneal pocket. This type of drug delivery system also increases the time of therapeutic action. Duration of drug action for suspension is depends upon the particle size. Drug absorbed into ocular tissues from precorneal pocket has been replenishes by smaller size particle. Larger particle size helps in retaining the particles for longer time and slow drug dissolution. Thus, an ideal particle size is expected to result in optimum drug activity. To treat ocular bacterial infections over worldwide several suspensions are formulated. The advanced suspension (TobraDex ST®) consists of tobramycin (0.3%), and steroid, dexamethasone (0.05%). The advanced new formulation had very low settling over 24 h (3%) relative to marketed Tobra-Dex® (66%) is observed by suspension settling studies. Ocular distribution studies showed that higher tissues concentrations of dexamethasone and tobramycin in rabbits treated with TobraDex ST® relative to Tobra-Dex®. Against Staphylococcus aureus and Pseudomonas aeruginosa new suspension formulation was found to be more effective than TobraDex®. Dexamethasone concentration in aqueous humor is higher than TobraDex® concluded by clinical studies including human subjects. This urge the new suspension formulation to be an alternative to marketed suspension as the new suspension possesses better formulation characteristics, pharmacokinetics, bactericidal characteristic and patient compliance than marketed TobraDex® suspension^[22-24].

Ointments:

Another class of carrier systems developed for topical application is ophthalmic ointments. Mixture of semisolid and a solid hydrocarbon (paraffin) that has a melting point at physiological ocular temperature (34 °C) are used to make up the ocular ointment. The choice of hydrocarbon is dependent on biocompatibility. Ocular bioavailability improvement takes place by ointments and also sustains the drug release. Another class of carrier systems developed for topical application is ophthalmic ointments^[25]. Glycopeptides antibiotic with an excellent activity against aerobic and anaerobic gram positive bacteria and methicillin and cephem resistant Staphylococcus aureus (MRSA) is Vancomycin HCl (VCM). No appropriate topical formulation was available in the market rather than VCM which consists of better activity than others. In a normal eye better ocular tissue permeability of VCM was not expected but in ocular disease treatment few clinical effects of VCM solution were reported. Due to broken ocular barrier system the reason for the observed effects was hypothesized, which might have improved drug permeation. In another study by Eguchi et al, four different ointment formulations with varying concentrations (0.03%, 0.10%, 0.30% and 1.00%) of vancomycin were prepared in 1:4 mixtures of liquid paraffin and vaseline. Rabbit model of MRSA keratitis infection was used for evaluating the efficacy of formulations after topical application. The observation was made as that numerous infiltrates were found in corneas with abscesses at low drug concentrations, i.e., 0.03% and 0.10%. It was observed that over 14 day study period no recurrence of keratitis in any eye shown on treatment of animals with 0.3% formulation. Therefore, 0.3% vancomycin ointment was suggested to be adequate and effective to resolve corneal MRSA keratitis^[26,27].

There are many limitations of conventional dosage forms. Several conventional ocular drug delivery systems have been available for the treatments but, the major limitation of conventional ocular drug delivery system is the short residence time. The medication is eliminated rapidly through immediate eye blinking after instillation of drugs. Further, the lacrimal fluid washes off the drugs form cul de sac. A major portion of the administered dose drains into the nasolacrimal duct. All the above discussed limitations lead to reduced bioavailability in ocular cavity. So to overcome these limitations the novel approach of drug delivery system has been formulated and investigated.

Novel drug delivery system:

Nanomicelles:

The most commonly used carrier systems to formulate therapeutic agents in to clear aqueous solutions are nanomicelles. Nanomicelle consists of amphiphilic molecules that self-assemble in aqueous media to form organized supramolecular structures can possess in their nature an intrinsic capacity to be polymers or surfactants. Preparation of micelles can be done in various sizes (10-1000 nm) and shapes conditional on the molecular weights of the core and corona forming blocks. Capability of delivering poorly water-soluble drugs and of protecting molecules such as proteins or peptides is compassed if nanomicelles possess exterior hydrophilic polar heads and an interior hydrophobic fatty acyl chain ^[28-30]. Recently, Cholkar et al have examined in detail about ocular barriers and application of nanomicelles based technology in ocular drug delivery. The reasons for being indulge interest in this formulation is due to their high drug encapsulation capability, ease of preparation, small size, and hydrophilic nanomicellar corona generating aqueous solution. In addition, the bioavailability of the therapeutic drugs in ocular tissues is enhancing by micellar formulation and suggesting that better therapeutic outcomes takes place. For the investigation of the applicability of nanomicelles in ocular drug delivery several proofs of concept studies have been conducted^[31]. Civiale et al. (2009) used the nanomicelle carrying dexamethasone to anterior eye segment by PEHAC (16). In vivo, Scientists took samples from the aqueous humor of rabbits to study the concentration–time curve of dexamethasone. The results showed that: the PEHAC (16) nanomicelles formulation carrying dexamethasone, compared with the dexamethasone suspension, had higher bioavailability. At the same time, the area under the concentration–time curve of the dexamethasone nanomicelles formulation was 40% higher than the dexamethasone suspension in control group. It was concluded that the nanomicelles formulations are the viable option to delivery ocular drugs to anterior segment of eyes^[32]. Researchers have also take advantages of nanomicelles for ocular gene delivery. Attempts had been made by Liaw et al to deliver the topical drop cornea by the help of gene therapy. For the development of micelles as a vehicle for gene delivery the major examples are: Copolymer, poly (ethylene oxide)-poly (propylene oxide)-poly (ethylene oxide) (PEO-PPO-PEO). This polymeric system accurately transferred plasmid DNA with LacZ gene in rabbit and mice ocular tissues. Results were promising and indicated the potential application of copolymers in DNA transfer will enhance the bioavailability of the therapeutic drugs in ocular tissues, suggesting better therapeutic outcome. Several proofs of concept studies have been supervise to examine the applicability of nanomicelles in ocular drug delivery^[33].

Implants:

For the treatment of both posterior and anterior segment eye diseases ocular implants have been extensively used. Biodegradable and non-biodegradable polymers have been employed in the fabrication of intraocular implants. The positive attribute involves overcoming of the blood-retina barrier, allowing drug directly into the target site delivery at therapeutic levels, prolonged drug delivery and reduction of the side effects frequently observed with intravitreal injections and systemic administration. The implants containing biodegradable polymers can be of two types of systems either matricial (monolithic) or reservoir systems. The drug can also be released by diffusion through the matrix pores. In reservoir systems, the membrane generally degrades slower than in drug diffusion^[35,36]. Non-biodegradable polymeric implants can be presented in the form of two systems; matrix (monolithic) or reservoir systems. In the matrix system, the drug is diffuse, homogeneously, inside the polymeric matrix or adsorbed onto the surface. Slow diffusion of the drug through the matrix provides its controlled or sustained release. In the reservoir-type system, the drug is surrounded by a permeable non-degradable membrane whose thickness and permeability properties can control the diffusion of the drug into the body.

Okaba et al. prepared and evaluated biodegradable scleral implant for the sustained release of steroid betamethasone phosphate to the posterior segments of the eye. The implant exerted good compatibility in eye and there was no significant toxicity to the retina during the experimental studies^[37,38].

Dong et al. for the treatment of experimental chronic uveitis in rabbit eyes developed that contains the CsA and the glycolide-co-lactide-co-caprolactone copolymer (PGLC). The results demonstrated that severity was observed in case of inflammation in eyes accompanied by no treatment, non-medicated implant, and oral CsA than in those with CsA-PGLC DDS at all time points. One group with oral CsA administration was intentionally included in this study for comparing the drug toxicity with the CsA-PGLC implant group. That types of the implants will be very productive whose concentration of CsA released in the eyes will be within the therapeutic range to suppress inflammation, and in the ocular tissues no intraocular toxicity was noticeable for future purpose^[39]. There is an example of intravitreal biodegradable implant such as Posurdex® (Allergan, USA) that contains PLGA and dexamethasone and is currently undergoing phase III clinical trials. This controlled delivery system has been designed and used for the future purpose as for the treatment of macular edemas secondary to retinal vein occlusion, diabetic macularedema, uveitis, and Irvine- Gass syndrome. For the treatment of experimental uveitis in rabbit eye non-biodegradable implants for the sustained release of dexamethasone has been prepared by Cheng et al. It was observed that these types of implants were effective in suppressing induced inflammation and for approximately 105 days the releasing of drugs takes place^[40].

Microneedles:

It has been demonstrated by Jiang et al. that using a hollow glass microneedle the delivery of model drug sulforhodamine and microparticles/nanoparticles formulations. In this study borosilicate cylindrical glass micropipette tubes with 1.5mm outer diameter and 0.86 mm internal diameter are used to fabricate the hollow microneedle. The microneedles at first applied into the scleral tissue and then microneedles were demonstrate to insertion at a depth of 700–1080mm and comeback to defined heights to allow injection of 10–35mL of fluid that contains either soluble drug molecule sulforhodamine B or nanoparticles suspensions from an individual MN. However, spreading enzymes (hyaluronidase and collagenase) were necessary to dissolve the tissue components so as to allow accommodation of the microparticles^[41].

A study was done using eyes of human corpses establish that microneedles coated with drugs, namely sulforhodamine, verified rapid dissolution of the therapeutic molecule within the sclera^[42].In a recent in vivo study, Gilger et al used the 33G hollow MNs, 850 μm in height, to deliver triamcinolone acetonide (TA) to the SCS. This study have reported that 0.2mg and 2.0 mg of the SCS TA was as valid in reducing inflammation as 2.0mg of TA by IVT in a model of acute posterior uveitis inflammation. Furthermore, there was no evidence of adverse effect – i.e. increase in IOP, drug toxicity, or hemorrhage following MN application^[43,44]. Patel et al. was able to reported on his study that microneedles optimized for suprachoroidal delivery were safe enough to be applied obtaining also suitable patterns of controlled drug release^[45]. Song et al designed MN-based pen type device to enhance the reliability of MN insertion, so as to allow easy insertion into a small target region of ocular tissue^[46].

Nanoparticles:

Nanoparticles are colloidal carriers and the range of size is between 10 to 1000nm. For ophthalmic delivery, the constituents of nanoparticles include lipids, proteins, natural or synthetic polymers such as poly (lactide-co-glycolide) (PLGA), sodium alginate albumin, chitosan polylactic acid (PLA) and polycaprolactone. Nanoparticles that are loaded with drug can be nanocapsules or nanospheres. In nanospheres; drug is uniformly distributed throughout polymeric matrix although in nanocapsules, drug is enclosed inside the polymeric shell. From some time, nanoparticles has achieve attention for ocular drug delivery. Several researchers have made try to develop drug loaded nanoparticles for delivery to both anterior and posterior ocular tissues^[47,48]. The nanoparticle-encapsulating drugs are of two types: Nanocapsules and nanospheres. The first have the drug encapsulated in the interior of the polymeric lattice formed. The second have the drug homogeneously dispersed along the polymeric lattice ^[49,50].

For ocular drug delivery nanoparticles represents a promising candidate because of small size of particles leading to low irritation and sustained release property and this can leads to avoiding frequent administration of drugs. However, nanoparticles may also be eliminated rapidly from precorneal pocket just like aqueous solutions. Hence, to improve precorneal residence time topical administration nanoparticles with mucoadhesive properties have been developed time. For the improvement of precorneal residence time of nanoparticles Polyethylene glycol (PEG), chitosan and hyaluronic acid are commonly used. For the improvement of precorneal residence of nanoparticles Chitosan coating is widely used. The charged of chitosan is positive and hence it binds to negatively charged corneal surface and thereby improves precorneal residence and decreases clearance^[51,55].

A nanoparticulate system can be appropriately manipulated to meet the requirements of each application. The particle size can be controlled, affecting the drug release and delivery profile significantly. Their extremely small size allows their penetration through tight junctions and increases the surface to volume ratio, strongly affecting its release profile^[52].

Zhang et al. explored dexamethasone-loaded PLGA nanoparticles (average size: 232nm) injected intravitreally in rabbits and found the particles exhibiting sustained release up to 50 days in the vitreous, with a relatively constant mean concentration of 3.85mg/l over 30 days, compared with a solution of dexamethasone which was not detectable 7 days after injection^[53]. Musumeci et al reported that PLGA-PEG nanoparticles that were loaded with melatonin are most effective and he also exposed that significant intraocular pressure (IOP) lowering effect compared with melatonin loaded PLGA nanoparticles and aqueous solution of equivalent concentration in the rabbit eye. It was figure out that reduced zeta potential of nanoparticles made up from PLGA-PEG than the PLGA are going to show better and longer interaction between the nanoparticles and eye surface that is leading to higher hypotensive effect for prolonged period. By using intravitreal injection, nanoparticles migrate through the retinal layers and it helps the drug to accumulate in the RPE cells. The PLA nanoparticles were present in rat RPE tissues up to 4 mol by using single intravitreal injection which propose that nanoparticles have great potential for achieving steady and continuous delivery to the back of the eye^[54].

Liposomes:

Ocular drug delivery can utilize the liposomes which can be used to encapsulate the hydrophilic and hydrophobic drugs. The liposomes has been distributed in different size usually ranges from 0.08 to 10.00 μm and based on the size and phospholipid bilayers, liposomes can be classified as small unilamellar vesicles (10–100 nm), large unilamellar vesicles (100–300 nm) and multilamellar vesicles (contains more than one bilayer)^[55]. The membrane components of liposomes are stable and can be twisted without disturbing their chemical or mechanical properties, probably allowing injection through small gauge^[55,56,57]. Polymers have been used to formulate the liposome from a lipid bilayer vesicle and by which the inner aqueous core helps to be remain separated from the exterior aqueous environment. Liposomes has a major application as ophthalmic delivery because it represents ideal delivery systems due to excellent biocompatibility, cell membrane like structure and also its basic feature is that it has ability to encapsulate both hydrophilic and hydrophobic drugs. Liposomes after exemplify have been considered as good effectiveness for both anterior and posterior segment ocular delivery in several research studies^[58]. A variety of drugs and molecules including proteins, nucleotides, and plasmids can be encapsulated within this aqueous compartment^[55]. Natarajan and collaborators studied, on the delivery of latanoprost that was encapsulated within liposomes and applied in the anterior portion of the ocular globe exhibit a capacity to reduce the intraocular pressure in the eye of a rabbit, for a time range of 50 days.^[59,60,61,]. Acyclovir liposomes that were loaded with cationic and anionic were prepared by incorporating stearylamine and dicetylphosphate (DP), as cationic and anionic charge-inducing agents, respectively^[62]. De Sa et al. used liposomes as a potential ocular delivery system for voriconazole for the management of corneal keratitis. The liposomes had a drug encapsulation efficiency of about 80% and were stable for at least 30 days in solution and 90 days after lyophilization^[58]. For improving its antibacterial effect and its ability of penetrating cells Nicolosi et al prepared the fusidic acid coated by liposome. The results showed that the antibacterial ability of fusidic acid has been improved dramatically when it was coated by liposome, at the same time, the effective drug concentration and the dose decreased. It is supposed that the liposome increase the liquidity of bacterial cell^[63].

Dendrimers:

It is defined as the macromolecular compounds and it consists of a series of branches that are used to surround an inner core. Dendrimers are branched star-shaped structure and they are composed of polymeric nanocarriers. The size of dendrimers ranges in nanometer. Some commonly used dendrimers are based on poly (aryl ethers), polyamides (polypeptides), polyesters, polyamidoamines, polyamines and carbohydrates, of which polyamidoamines (PAMAM) are the most common and commercially available. These branched polymeric systems of dendrimers are obtainable in different molecular weights with terminal end amine, hydroxyl or carboxyl functional group. The utilization of conjugate targeting moieties may takes place through the terminal functional group. Drug delivery as carrier systems is being employed by dendrimers. For delivering the drugs; selection of molecular weight, size, surface charge, molecular geometry and functional group are critical. Embodiment or incorporation of wide range of drugs, hydrophobic as well as hydrophilic are taken up by highly branched structure of dendrimers. In ocular delivery of drugs PAMAM (poly (amidoamids)) dendrimers is highly used. Ocular drug delivery systems give great attention to dendrimers. Dendrimers have well-defined size tailorable structure and potentially favorable ocular biodistribution. Surface modified PAMAM dendrimers with carboxylic or hydroxyl surface groups, have been reported in increasing residence time and improving bioavailability of pilocarpine in the eye. Conjugating of dendrimers with polyethylene glycol (PEG), create hydrogels that are used for cartilage tissue production and for sealing ophthalmic injuries. Consequently, the improvement of ocular drug delivery by dendrimers may be a promising method for clinical applications^{[64,65,68,69]}.

Dendrimers composed of polyamido groups are widely used in drug delivery systems, where both hydrophilic and lipophilic drugs can be encapsulated^[66]. Vandamme et al demonstrated the application that for miotic and mydriatic activity PAMAM dendrimers are being used as ophthalmic vehicles for delivery of pilocarpine nitrate and tropicamide. In this study, rabbits were used for study. For that the fluorescein in saline and in PAMAM solutions were used to studied the mean ocular residence time in rabbit eye. The reference bioadhesive polymer is Fluorescein in 0.2% w/v Carbopol solution. It was concluded that in case of PAMAM solutions and 0.2% w/v Carbopol solution the mean ocular residence time was significantly higher compared to saline. For increasing ocular residence time and therapy enhancing ocular bioavailability and achieving better therapeutic outcomes the use of dendrimers could be another option and will be the best option. In albino rabbits, the activities like miotic and mydriatic have been shown when there was a co-administrated of PAMAM dendrimers with pilocarpine nitrate and tropicamide ^[67,69].

In-situ gelling systems:

In-situ gelling systems is defined as that it is the polymeric solutions which forms the viscoelastic gel by undergoing sol-gel phase transition in response to environmental stimuli or by having change in environment of the dosage form. By change in temperature, pH and ions the process of gelation has been came out or can also be induced by UV irradiation. For ocular delivery, researchers studied toward development of thermosensitive gels which results to changes in temperature. Poloxamers, multiblock copolymers made of polycaprolactone, polyethylene glycol, poly (lactide), poly (glycolide), poly (Nisopropylacrylamide) and chitosan are the examples of thermogelling polymers that have been reported for ocular delivery. Temperature dependent micellar aggregates were formed through the thermosensitive polymers and that micellar aggregates was used to gellify after a further temperature increment due to aggregation or packing. For drug delivery, the solution state has formed by mixing these polymers with drugs and in situ gel depot at physiological temperature has been forming by administering this solution^[70.71]. These thermosensitive gels determine hopeful results for enhancing ocular bioavailability for both anterior and posterior segment. Gratieri T et al. had formulated an ocular delivery system that includes in its formulation polymer like poloxamer/chitosan and formulated the insitu forming gel with prolonged retention time for ocular delivery. Chitosan improves the mechanical strength and texture properties of poloxamer formulations and also instillation of the poloxamer^[72]. Khateb et al. by using the combination of Pluronic (PF127 and PF-68) and sodium alginate had investigated the insitu gelling system containing ofloxacin using a combination of Pluronic (PF127 and PF-68) and sodium alginate. The incorporation of Pluronic F68 to Pluronic F127 solutions was found to the rising of the sol-gel temperature of binary formulation to above the physiological range of temperatures. The superior in vitro drug retention performance on glass surfaces and freshly excised bovine corn were exhibited by 20% (w/w) Pluronic F127 in comparison with other formulations. Additionally, in vivo evaluation in rabbits demonstrated that a retention performance of 20% (w/w) Pluronic F127 was higher than that of Pluronic F68. Furthermore, the slug mucosa irritation assay and bovine corneal erosion studies demonstrated no significant irritation was observed that resulted from these polymers and their combinations^[73]. Related to the anterior and posterior sections of the eye, these thermosensitive formulations revealed good results by increasing the bioavailability of the drugs^[74,75].

The results of research studies clearly signify that there are many advantages that come in rescue from the use of thermosensitive gels. The advantages of using thermosensitive gels includes; provides sustained drug release, prolong contact time of drugs with the cornea, less frequency of applications, reduced side effects.

In conclusion, for the treatment of chronic ocular diseases thermosensitive gels may be a useable option for the delivery of drugs for treating chronic ocular diseases.

Contact lens:

There are many disadvantages that are takes place from topical ocular administration of drugs by eye drops such as patient compliance, low bioavailability, frequent instillation requirement, potential systemic side effects. So overcome these disadvantages contact lenses has been used and designed and these disadvantages are potential systemic side effects low bioavailability, frequent instillation requirement, patient compliance. To release ocular medication properly therapeutic contact lenses can be considered as an excellent alternative⁷⁶. Contact lens is used after loading of drug, this type of system have been developed for delivery of drugs by the route of ocular delivery. The drugs that are used for this type of delivery are such as β-blockers, antihistamines and antimicrobials. The hypothesis is come in rescue that when there is a presence of contact lens, the residence time between drug molecules and the post-lens tear film has been become longer which results in less drug inflow into the nasolacrimal duct which is going to led to higher drug flux through cornea. By soaking the contact lens in drug solutions the drug loading phenomena in contact lens takes place. By comparing the conventional eye drops with the soaked contact lens it signify that contact lens are of higher efficiency in delivering drug^[77,78]. Higher bioavailability of dexamethasone (DX) from poly (hydroxyethyl methacrylate) (PHEMA) contact lenses in comparison to eye drops has been observed by Kim et al. It was observed that in reality contact lens are better than drops, these soaked contact lenses suffers from disadvantages of short term drug release and inadequate drug loading. To overcome these difficulties, particle-laden contact lenses and molecularly imprinted contact lenses have been developed. In particle-laden contact lenses, the vesicles are used such as liposomes, nanoparticles or microemulsion and in these vesicle drug is going to entrapped and then these vesicles are dispersed in the contact lens material^[79].

CONCLUSION:

For decades, a major challenge to ocular scientist has been occurred for delivering a drug to targeted ocular tissues. Some drawbacks were takes place when there was administration of drug solutions as topical drop with conventional formulations which come up with the introduction of different carrier systems for ocular delivery. For the development of safe and patient compliant novel drug delivery strategies many enormous efforts are being put into ocular research. When there is the onset of nanotechnology, new techniques, devices and their applications in drug delivery is developing great interest to ocular scientists. Encapsulation of drug molecules are being done into nanosized carrier systems or devices and are being delivered by invasive/non-invasive or minimally invasive mode of drug administration. The nanocarriers/devices help to reduce the dosing frequency. Nanoparticles, liposomes, nanomicelles, nanosuspensions and dendrimers, contact lens, microneedles and several other nanotechnology based carrier systems are being developed and studied. Some of these are manufactured at large scale and are applied clinically. The benefits are being given to the patient body by using nanotechnology by minimizing the drug induced toxicities and vision loss. Nanocarriers/devices has a sustain drug release pattern; improve specificity, when targeting moieties are used. However, for reach at targeted ocular tissue there is still need of developing a carrier system, including post non-invasive mode of drug administration, back of the eye tissues. Now a days, ocular drug delivery systems are expected to result in a topical drop formulation that retains high precorneal residence time, avoids non-specific drug tissue accumulation and deliver therapeutic drug levels into targeted ocular tissue both anterior and posterior. In near future, ocular drug delivery system may replace invasive mode of drug administration to back of the eye such as periocular and intravitreal injection.

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Received on 21.06.2020 Modified on 31.07.2020

Asian J. Res. Pharm. Sci. 2021; 11(1):71-80.

DOI: 10.5958/2231-5659.2021.00012.6