1. INTRODUCTION:

The human eye is a vital sensory organ that reacts to light and pressure, help to provide a three dimensional, moving image. The transverse size of a human adult eye is approximately 24.2 mm and the sagittal size is 23.7 mm and there is no significant difference between sexes and age groups. The eye is made up of three layers namely, the outer layer, known as fibrous tunic which is composed of cornea and sclera, the middle layer known as vascular tunic or uvea which consists of the choroid, ciliary body, pigmented epithelium and iris. The innermost layer is the retina, which gets its oxygenation from the blood vessels of the choroid as well as the retinal vessels. Rod and cone cells in the retina allow conscious light perception and vision including colour differentiation and the perception of depth. The human eye can differentiate about 10 million colours (1).

The term uveitis is used to describe intraocular inflammations and is a sight-threatening inflammation of uvea (the pigmented layer that lies between the inner retina and the outer fibrous layer composed of the sclera and cornea) (2). This intraocular inflammatory disease is a collection of conditions which were known to the ancient time. Intraocular inflammation reports by the Greeks and Chinese describe many conditions that we recognized nowadays as distinct entities, such as Behcet’s disease (3). The autoimmune disorder is known to cause uveitis such as ankylosing spondylitis, reactive arthritis, bowel inflammation, psoriasis, psoriatic arthritis, multiple sclerosis, etc. Uveitis is prevalent in worldwide. It has a predominance of 2.3 million people in the United States and blindness in 10% of uveitis cases and it affects slightly more woman than men (4). The incidence of uveitis in the Western world is 52.4 per 100, 000 and the prevalence is 115 per 100, 000 (5).

2. TYPES OF UVEITIS:

Uveitis is classified based on the ocular structures involved. International Uveitis Study Group Classified uveitis into categories such as anterior uveitis, intermediate uveitis, posterior uveitis and panuveitis. Anterior uveitis is the intraocular inflammation that involves the iris (iritis) and anterior part of the ciliary body that synthesizes aqueous humor, the fluid that fills the front of the eye. Anterior uveitis is the most frequent form of uveitis (42%–54%). The general symptoms of anterior uveitis are eye redness, pain, photophobia, loss of vision, tearing and lid puffiness may also be present. It may have some complications such as, the iris may stick against the lens of the eye and it also associated with a rise in intraocular pressure, which may cause glaucoma and can also cause fluid to accumulate in the retina which is responsible for central vision (6). Intermediate uveitis is a form of uveitis localized to the vitreous and peripheral retina. Primary sites of inflammation include the vitreous, pars planitis and posterior cyclitis. It can be an isolated eye disease or associated with the development of a systemic disease suchas multiple sclerosis or sarcoidosis. This idiopathic inflammatory syndrome mainly involves the anterior vitreous, peripheral retina and the ciliary body with minimal or no anterior segment or chorioretinal signs and is the common type of uveitis in children and young adults (7). Intermediate uveitis is characterized by the presence of white exudates over the pars plana or by the aggregation of inflammatory cells in the vitreous. Posterior uveitis involving the adjacent structures such as the retina, vitreous, optic nerve head, retinal vessels along with choroidal inflammation including Choroiditis, retinochoroiditis/chorioretinitis, Retinitis, Neuroretinitis, Granuloma, Mass lesions masquerading as uveitis. Posterior uveitis can be classified based on etiology and clinical characteristics of a lesion. Based on the etiology posterior uveitis is divided into two, Infective and Non-infective. Toxoplasmosis, Toxocariasis, Tuberculosis (TB), Syphilis, Bartonella Virus and Human immune deficiency virus are the infective causative agents likewise acute uveitis, white dot syndrome, geographic helicoid peripapillary choroidopathy, Multifocal choroiditis, Punctate inner choroidopathy are the noninfective causes for posterior uveitis. Panuveitis is a serious inflammation of the uveal tract of the eye. As per the International Uveitis Study Group (IUSG) panuveitis is defined as generalized inflammation of all three parts of the uvea (iris, ciliary body and choroid). It covers a large group of diverse diseases that affect not only the uvea but also the retina and vitreous humor (8). The common causes of panuveitis are tuberculosis, Vogt-Koyanagi-Harada syndrome, sympathetic ophthalmia, Behcet's disease and sarcoidosis. Panuveitis has poor visual outcome due to more widespread inflammation (9).

3. PATHOPHYSIOLOGY OF UVEITIS:

Uveitis is caused by autoimmune conditions, infections or trauma, but 50% of cases are idiopathic. Some causes of intraocular inflammation masquerade as uveitis but other causes such as malignancy. Infectious uveitis always results from hematogenous spread of infection from another part of the body to the highly vascular uvea (10). The most common infectious etiologies are herpetic infections and toxoplasmosis which cause about 20% of all types of uveitis cases. It depends on the specific etiology but in all types, there is an infringement in the blood-eye barrier which is similar to the blood-brain barrier normally prevents the cells and large protein entering into the eye. Ocular inflammation causes this barrier to break down and WBCs enter the eye. Neutrophils predominate in acute uveitis cases, and mononuclear cells predominate in chronic cases.An imbalance between inflammatory mechanism which inhibits the immune system and developed to purge the body of infectious organisms which can result in immune-mediated disease. The self-reactive T cells leave the thymus and reach the eye to contact with retinal antigens (11). A myeloid dendritic cell which stimulates T cells by enables the capturing ability of antigen. T lymphocytes (Tregs) produce anti-inflammatory cytokines such as IL-10 (interleukin) and TGF-β (transforming growth factor). Inflammatory components of the immune system include Th1 lymphocytes and Th17 lymphocytes which produce cytokines such as IL-17, IL-23 and TNF-α which hired leukocytes from the circulation and results in tissue damage which cause auto-immune uveitis. Cytokines such as IFN-γ (interferon) can be either protective or inflammatory that is depending on the timing with which they are produced. Th1 and Th17 cells, those participate in inflammation and auto-immune uveitis, Th17 cells play a role in the chronic phase of uveitis where the induced T lymphocytes defeat the inflammatory components of the immune system. The migration of Th1 and Th17 can cause breaking down of the blood-retinal barrier (12). Imperfect negative selection in the thymus results in export to the periphery of retinal antigen-specific T cells. Retinal antigens in the eye can be activated by retinal or cross-reactive antigens in the context of costimulatory signals, which escape from control of natural Tregs and differentiate into pathogenic effector T cells. Resisting local regulatory mechanisms, they break down the blood-retinal barrier, activate the retinal vasculature and recruit inflammatory leukocytes from the circulation. The resulting inflammation causes damage to the tissue and leakage of ocular antigens, activating eye-dependent systemic regulatory mechanisms.

In addition, cytokines involved in the pathogenesis of uveitis, the role of the complement pathway and retinal vascular endothelial cell-specific homing in uveitis is two major and emerging areas which will become important targets of potential therapeutics (13). In the various uveitic entities, treatment is targeted towards the mechanism of disease progression, like by stimulating the regulatory mechanisms or by inhibiting the inflammatory responses. An immune recovery uveitis (IRU) represents an inflammatory reaction to cytomegalovirus antigen in the eye; it includes the intraocular inflammation which is a reaction to altered retinal or glial cells adjacent to the healed CMV lesions or secondary to subclinical viral replication (14). Flow chart of pathophysiology of uveitis is represented in Figure.1.

Figure 1 pathogenesis of uveitis

4. DIAGNOSTIC TECHNIQUES:

Diagnosis of uveitis is challenging due to a wide range of etiologies. Delayed diagnosis may retard initiation of treatment leads to potentially serious consequences. Prompt diagnosis and initiation of therapy are important to avoid these serious complications. Investigations are helpful for the diagnosis and monitoring of disease activity or complications and adverse effects of treatment. Initial investigations include complete blood count (CBC) with differential erythrocyte sedimentation rate, chest radiography to exclude tuberculosis and sarcoidosis, and screening for infectious agents such as syphilis (15). A patient with uveitis is often present with nonspecific symptoms, such as blurry vision or a red-eye to headaches and severe photophobia. It should be considered in patients who retain a low visual acuity. Due to the various etiology, a patient with uveitis can be first evaluated by any medical professional, other than ophthalmologists, including general practitioners, rheumatologists, pulmonologists, and internal medicine specialists. Uveitis should be considered part of the differential diagnosis when a patient is first seen in any of these specialties. Uveitis is also a part of the differential diagnosis in patients with ocular symptoms and suffers from a systemic disorder or exhibit signs of a systemic disorder including arthritis, aphthous stomatitis, bowel complaints, or erythema nodosum. Infectious uveitis can be caused by the intraocular presence of microorganisms, an immunological reaction to microorganisms, or a combination of both. Non-infectious uveitis can be the first sign of an underlying systemic disorder. Blood tests have a limited diagnostic value because ocular involvement takes place in the chronic phase of a systemic infection, at which serology generally yields inadequate results. Another diagnosis option is an anterior chamber tap, through which aqueous humor is obtained for analysis for the presence of microorganisms by PCR (Polymerase chain reaction). This technique enables the comparison of locally produced antibodies against microorganisms to systemic antibody levels, called as Goldmann-Witmer coefficient (16). PCR analysis of intraocular fluid is a diagnostic test for infectious uveitis of the posterior segment and to determine the presence of microbial DNA. The recent introduction of interferon-γ release assays, like Quantiferon or T-spot which has revealed that latent tuberculosis is found more frequently in otherwise un-explained uveitis. Currently, there exists no validated test to diagnose true ocular tuberculosis since detection of mycobacteria in ocular fluids or tissue is difficult (17). It is important to exclude viruses and TB as causes of uveitis. PCR analysis of aqueous or vitreous humor for viral DNA is helpful to confirming the diagnosis of viral uveitis and quantifying viral load. The Goldmann-Witmer coefficient compares the level of intraocular antibody production against the virus to that of the serum. It is a useful test but not widely performed. Ocular TB is difficult to diagnose and criteria for tuberculous uveitis include residence or migration from endemic areas, suggestive ocular findings, positive tuberculin skin test (TST), positive interferon-gamma release (IGR) assay and positive treatment response. Extra-ocular evidence of TB aids in the diagnosis of ocular TB (18). Magnetic resonance imaging of the brain and cerebrospinal fluid analysis may also help in the diagnosis of primary central nervous system lymphoma, which can be associated with primary intraocular lymphoma. Ultrasound biomicroscopy test is valuable in assessing the ciliary body and pars plana. Ultrasonography is useful in evaluating uveitis, especially when fundus visualization is decreased due to media haze. It will assess the extent and density of vitritis, and detect posterior vitreous detachment, high reflective sclera-choroidal thickening in diffuse posterior scleritis due to scleral edema associated with fluid in Tenon’s space just posterior to the sclera (19).

Fundus photography, fundus fluorescein and indocyanine green angiography, fundus autofluorescence, and optical coherence tomography (OCT) are useful in diagnosis and monitoring of clinical course and therapeutic response in uveitis. Fundus fluorescein angiography technique is used to differentiate an active uveitis from inactive uveitis, and in the diagnosis of cystoid macular edema, choroidal neovascularization, retinal vasculitis, neovascularization, and ischemia. Ultra-wide field fluorescein angiography can detect changes in the peripheral retina in posterior uveitis, especially vasculitis, leakage, neovascularisation and capillary non-perfusion, which are often missed by conventional fluorescein angiograms (20). An ophthalmoscope is used to detect autofluorescence produced by fluorophores such as lipofuscin, which originate from photoreceptor outer segment and accumulate in retinal pigment epithelium cell. Patients with uveitis have such characteristic ocular signs and symptoms, associated systemic disorders, and laboratory abnormalities that the accurate diagnosis can be established beyond a reasonable doubt without any invasive studies of the eye. Tailored lab investigation is the right approach in identifying the etiology of the posterior uveitic entity. Laboratory tests are more useful in infective uveitis condition than in non-infective condition. There is a specific test for each entity. Intraocular fluid evaluation for polymerase chain reaction (PCR) and antibody titers help clinch the diagnosis. It is important to differentiate infective and non-infective uveitic conditions because their management is diametrically opposite. There is no universally accepted approach to the evaluation of uveitis.

5. TREATMENT APPROACHES:

Uveitis is one of the challenging diseases to treat. The treatment of uveitis is developing gradually with newer drugs and ingenious advances in ocular drug delivery. Generally used treatment approaches are by providing local or systemic oral steroids, immunosuppressant, biological and adjuvant therapy etc.

5.1 CORTICOSTEROIDS:

5.1.1 Local delivery of corticosteroids:

Corticosteroids are administered systemically, orally or by topically to achieve their action in the biological system. Topical route is suggested by ophthalmologist with increasing frequency and these are employed in the treatment of anterior uveitis. While comparing the corticosteroids, prednisolone acetate provides greater anti-inflammatory effect. This is due to its concentration and more penetration of prednisolone acetate into the cornea. The dosing frequency and the time of medication that contact with ocular surface is also influence the efficacy and suspensions have a higher degree of anti-inflammatory effect. The strength and dosage of the steroid depends on the severity of the inflammation in the eye. Vision loss in uveitis can usually be prevented by early treatment. Topical corticosteroids and cycloplegic agents remains the standard treatment for acute anterior uveitis^[21]. Side effects of corticosteroids includes elevated intraocular pressure, susceptibility to infections, impaired wound healing of cornea or sclera, corneal epithelial toxicity, and crystalline keratopathy. Iontophoresis is a noninvasive method of application of low current to an ionizable substance (drug) to increase its mobility across a surface by electrochemical repulsion. Iontophoresis delivery possesses two acidic protons (pK values of 1.9 and 6.4), making it highly water-soluble formulation with a high buffering capacity. It has a well-characterized safety and efficacy profiles for ophthalmic use. Hydroxide ions are produced by cathodic delivery, which drive the dexamethasone phosphate anions into the ocular tissues, by electrochemical repulsion. These hydroxyl ions (OH) increase the pH of the drug solution, shifting the equilibrium towards ionized state, and hence increasing the efficiency while buffering the formulation. The Delivery System for ocular tissues is a novel ocular iontophoresis system which is designed to deliver substantial levels of drug noninvasively into the anterior segments of the eye while minimizing systemic distribution. Side effect of iontophoresis includes itchiness of the treated area after treatment. Theperiocular steroids are indicated in moderate to severe uveitis, cystoid macular oedema and in the anterior chamber if inflammation is not responding to topical corticosteroids. It offers the benefit of higher, local and sustained drug to the eye with greater penetration. Posterior injections are administered by using Smith and Nozik technique (21, 22). It is effective in treating active intraocular inflammation and improving reduced visual acuity which is attributed to macular edema. Intravitreal injections and inserts have a major role in theuveitis. Triamcinolone acetonide is an intravitreal corticosteroid which is used to manage non-infectious intermediate and posterior uveitis and its complications are cystoid macular oedema due to direct action and it has greater efficacy. Dexamethasone intravitreal implant can reduce the risk of vision loss and also increases the speed of visual improvement (23). Intravitreal injections can cause some side effects such as, cataract, increased intraocular pressure, glaucoma, retinal detachment, vitreous haemorrhage and endophthalmitis (24). Systemic steroid plays an important role in the treatment of uveitis. The different steroids available for oral administration are Cortisone, hydrocortisone, prednisone, and fludrocortisone. Prednisone is the most common corticosteroid which is used orally in the treatment of intraocular inflammation. Methylprednisolone sodium succinate can be given intravenously over a period of more than 30 min for immediate control of vision threatening diseases (necrotizing scleritis, bilateral serous detachments) (25). Various side effects of systemically acting steroids include moon faces, weight gain, fat redistribution, increased acne, infections, hypertension, diabetes mellitus, fluid retention, rapid administration by intravenous administration can cause arrhythmias, cardiovascular collapse, and myocardial infarction.

5.2 IMMUNOSUPPRESSANT:

For non-infectious disease, systemic non-steroidal anti-inflammatory drugs such as diflunisal and celecoxib can be used as first-line therapy. These are not being effective or tolerated; immunomodulatory therapy commonly begins with the use of antimetabolites such as methotrexate and mycophenolate mofetil, which are possibly combined with a calcineurin inhibitor (26). There are three main classes of immunosuppressives which are widely used in addition to glucocorticosteroids. They are antimetabolites (azathioprine, methotrexate and mycophenolate mofetil), T cell inhibitors (cyclosporine and tacrolimus), and alkylating agents (cyclophosphamide and chlorambucil). Immunosuppressive agents are given when corticosteroid therapy is insufficient to control ocular inflammatory disease. They exert their action by killing the rapidly dividing clones of lymphocytes which cause inflammation. Azathioprine and Methotrexate are the low-dose immunosuppressive drugs, initiated before any intraocular surgery to control the inflammation (27).

5.3 BIOLOGICS:

Biologics (Biologic response modifiers) are produced by recombinant DNA or monoclonal antibody technology which is designed to block specific mediators of the cell-mediated immune response. These are not recommended as the first-line agent in uveitis patients because of their costs and long-term safety profiles. This is generally reserved for the cases where more conventional immunosuppression has either failed or poorly tolerated due to their adverse effects (28). The main biologics which are currently in use include anti-tumor necrosis factor-α (TNF-α), cytokine receptor antibodies and interferon-α (IFN-α). The main biologics which are currently in use includes anti-tumor necrosis factor-α (TNF-α), cytokine receptor antibodies and interferon-α (IFN-α). Infliximab, adalimumab and etanercept are three commercially available anti-TNF-α agents. Infliximab and adalimumab are monoclonal immunoglobulin G1 antibodies against TNF-α which can form stable bonds with the soluble and trans-membrane forms of TNF-α. Particularly infliximab has been found to be effective in reducing inflammation with relatively few serious adverse effects^[27]. The Cytokine receptor antibodies Daclizumab. Daclizumab is a humanized monoclonal antibody that targets the CD25 subunit of the human interleukin-2 receptor of T lymphocytes. A subcutaneous form is currently still undergoing trials but shows promise as a more accessible route of administration. Daclizumab has been found to be clinically beneficial in controlling the inflammation and, hence, preserving vision in birdshot chorioretinopathy, but is yet to be proved to be efficacious in the treatment of BD (29). Interferon-α (IFN-α) is the only candidate capable of producing long term remission of Bachet’s disease. IFN-α2a is a cytokine released in viral infections and the expression of genes, including cytokine-codifying genes, growth factors, pro-apoptotic factors and adhesion molecules are stimulated by INFs. Therefore, INFs are able to integrate both innate and adaptive immune responses. Bone marrow suppression, hepatotoxicity and renal toxicity are some of the common side effect exhibited by this therapy.

5.4 ADJUVANT THERAPY:

5.4.1 Cycloplegics:

Cycloplegics are important to stabilize and restore the blood-aqueous barrier, thus reducing the number of inflammatory cells and flare reaction (proteins leakage) in the anterior chamber in uveitis. Thus provide symptomatic effect for pain and discomfort, based on the duration of action cycloplegics classified into two categories namely short acting which include drugs like tropicamide, cyclopentolate and long acting cycloplegics includes homatropine and atropine (30).

5.4.2 Newer non-steroidal anti-inflammatory agents:

Newer NSAIDs are used for the reduction of ocular inflammation and pain following cataract surgery and in scleral inflammation. It is a potent inhibitor of the cyclooxygenase (COX)-2 enzymes and it has a highly lipophilic molecule which rapidly penetrates to produce early and sustained drug levels in all ocular tissues. Bromfenac is an NSAID agent, it can achieve therapeutic levels in the retina after topical application onto the cornea and it has some evidence of complications. It was proven to prevent macular oedema and ocular inflammation after cataract surgery in non-insulin-dependent diabetic patients. Bromfenac has better penetration into ocular tissue, and it has longer duration of anti-inflammatory activity. It is ineffective when given alone for uveitic muscular oedema, but it has a synergistic activity with intravitreal steroids (31).

5.4.3 Anti-vascular endothelial growth factor (anti-VEGF) therapy:

Vascular endothelial growth factor (VEGF) plays an important role in the pathogenesis of uveitic complications such as cystoid macular oedema (CMO), choroidal neovasularization (CNV) and retinal neovascularization (RNV). It refers to the treatment of neovascular macular degeneration and vascular diseases of the retina, which are characterized by a marked edematous and exudative component such as diabetic retinopathy and occlusion of the central retinal vein. Anti-VEGF therapy has changed the efficacy of treatment but not without drawbacks. Although severe ADRs were rarely observer/reported, every intravitreal injection sets patients at risk of endophthalmitis, intraocular inflammation, vitreous hemorrhage, retinal tear, retinal detachment and cataract (32).

5.5 CURRENT CONCEPTS IN INFECTIOUS UVEITIS MANAGEMENT:

The infectious posterior uveitis is caused by toxoplasmosis which is most common. Ocular toxoplasmosis is usually managed with systemic antitoxoplasma drugs such as Cotrimoxazole-sulphamethoxazole, trimethoprim, clindamycin, pyrimethamine, azithromycin, atovaquone, spiramycin and systemic steroids. In tropical countries, fungal infection is commonly seen. Recently voriconazole and intravitreal voriconazole can be used to treat the fungal infection in the eyes. In viral uveitis, to control the cytomegalovirus anterior uveitis, ganciclovir gel is usedtopically and intravitreal ganciclovir implants can be used to treat cytomegalovirus retinitis (33). The common drugs used in the treatment of uveitis – its specific uses and adverse drug reactions are mentioned in the table.1.

6. OCULAR DRUG DELIVERY:

Ocular drug delivery system has been a major challenge to the scientists due to its distinctive anatomy and physiology. Compared to other drug delivery system, ocular drug delivery has met with remarkable challenges caused by various ocular barriers such as different layers of cornea, sclera, retina and blood-retinal barriers (34). Topical instillation into the lower precorneal pocket is recommended route of administration for ocular drugs. Most of the topically administered drug is lost due to frequent blinking of the eye and only 20% of the administered dose is retained in the precorneal pocket. A driving force for passive diffusion across cornea is based on the concentration of drug available in the precorneal pocket. High corneal permeation with longer drug cornea contact time is required for the efficient ocular drug delivery of eye drops (35). There are various routes of administration for ocular drug delivery system. The selection of the route of administration depends on the target tissue which is explained below:

6.1 TOPICAL ROUTE:

Topical ocular drug administration is a consummate delivery by eye drops which is most convenient, safe and immediately active route of ocular drug administration but they have a short contact time with eye surface. The contact time of drug with the target tissue and duration of action can be enhanced or prolonged by the design of formulation such as gels, ointments and inserts.

6.2 SUBCONJUNCTIVAL ADMINISTRATION:

To deliver the drugs at increased levels to the uvea, subconjunctival route of administration is used. Nowadays, this type of drug administration has gained impetus for several reasons. Various researches in the pharmaceutical formulations have provided some new available possibilities to develop controlled release type of formulations to deliver the drugs (36).

6.3 INTRAVITREAL ADMINISTRATION:

Intravitreal is a route of administration, in which the drug is delivered into the eye. There are two methods in intravitreal administration namely, intravitreal injection and intravitreal implants which is a biodegradable sustained release intravitreal drug delivery system which will bring higher levels of the drug directly into the posterior segment while minimizing systemic absorption (37).

7. MECHANISM OF DRUG ABSORPTION BY OCULAR DRUG DELIVERY SYSTEM:

Drugs administered by instillation must penetrate into the eye by corneal and non-corneal routes. The non-corneal route involves drug diffusion across the conjunctiva and sclera which is important the drugs which are poorly absorbed across the corneal route.

7.1 CORNEAL PERMEATION:

The drugs penetrate across the corneal membrane which occurs from the precorneal space. The mixing of drug disposition in tears has a direct bearing on the absorption of drugs into the inner eye. The diffusional process across the corneal membrane results in the protective absorption of ophthalmic drugs. The rate and extent to which the transport process occur are based on the efficiency of the absorption process. The absorption of drug molecule across a biological membrane depends on the physicochemical characteristics of the permeating molecule and its interaction with the biological membrane. The cornea consists of three layers namely, epithelium, stroma and endothelium. The epithelium and endothelium layers contain 100 fold greater amounts of lipid materials when compared to the stroma.

7.2 NON-CORNEAL PERMEATION:

Diffusion of the drug molecule across the intracellular aqueous media is the primary mechanism of drug penetration in case of the structurally similar corneal stroma. The conjunctiva is composed of epithelial layer which covers the underlying stroma like cornea. The conjunctival epithelium offers substantially less resistance the corneal epithelium (38). Bioavailability of drugs administered in the ocular route is an important consideration. The ocular bioavailability can be affected by various physicochemical properties such as protein binding, drug metabolism and lacrimal drainage. Protein bound drugs are incapable of penetrating the corneal epithelium due to the size of the protein-drug complex. The other factors such as physicochemical characteristics of the drug substance and the product formulation are important. This is due to the cornea is the membrane-barrier containing both hydrophilic and lipophilic layers. The drugs which are highly water soluble do not penetrate the cornea (39).

The most common method for the administration of therapeutic agents in the treatment of ocular disease is the topical delivery of eye drops into the lower cul-de-sac cause poor bioavailability. The major problems which are encountered with solutions are the rapid and extensive elimination of the drugs precorneal because of solution drainage, lachrymation and non-productive absorption which cause undesirable side effects. To overcome the poor bioavailability of topically administered drugs involved the use of ointments which increases the contact time of drugs with the eye, reduce the dilution by tears and resists the nasolachrymal drainage which ensures the superior ocular bioavailability but it has a major problem of blurred vision and suspensions in which its efficiency show high variability due to inadequate dosing and lack of patients compliance. There are methods to achieve prolonged precorneal habitation time such as the use of hydrogels, liposomes, micro carrier systems, nano-carrier systems and inserts. They have the ability to increase contact time, prolonged drug release, reduced side effects (40).

8. BARRIERS IN OCULAR DRUG DELIVERY:

The ocular tissues can be reached either by local or systemic administration of a drug. The tissue barriers limit the access of drugs to their targets. Ocular drug delivery system faces significant challenges posed by various ocular barriers when compared with other parts of the body. Many of these barriers are inherent and unique to ocular anatomy and physiology making it a challenging task for drug delivery scientists. A study which combines multiple forms of uveitis would facilitate enrolment. The barrier of ocular administration faces two major challenges. First, an existing treatment for a one type of uveitis will not necessarily cure all types of uveitis. Second, related to disease heterogeneity which is the selection of an endpoint that is appropriate for clinical studies applicable to patients with different types of uveitis. The barriers to restrict intraocular drug delivery includes tear (Drug loss from ocular surface), cornea, conjunctiva, sclera, choroid membrane, retina, and blood-retinal barrier (41).

8.1 TEAR:

Tear have a direct bearing on efficiency of drug absorption into the eye. After instillation, the flow of lacrimal fluid removes instilled compounds from the surface of eye, which reduces the effective concentration of the administered drugs due to dilution by tear turnover approximately at 1µL/min, accelerated clearance and binding of the drug molecule to the tear protein. The dosing volume of instillation is 20-50µL whereas the actual size of cul-de-sac is only 7-10µL. the excess volume of drug may spill out from the eye or exit through the nasolacrimal duct.

8.2 CORNEA:

The three layers of cornea possess a different polarity and a rate-limiting structure for drug permeation. The corneal epithelium is lipophilic in nature and tight junctions of cells are formed to restrict paracellular drug permeation from the tear film. The highly hydrated structure of stroma acts as a barrier to permeation of lipophilic drugs. Corneal endothelium acts as a separating barrier between stroma and aqueous humor.

8.3. CONJUNCTIVA:

Conjunctiva of the eyelids and globe is a thin and transparent membrane, which is involved in the formation and maintenance of the tear film. The administrated drugs in the conjunctival or episcleral space cleared through blood and lymph. The conjunctival blood vessels do not form a tight junction barrier, which means drug molecules can enter into the blood circulation by pinocytosis or convective transport through paracellular pores in the vascular endothelial layer.The conjunctival lymphatics act as an efflux system for the efficient elimination from the conjunctival space (42).

8.4 SCLERA:

The sclera mainly consists of collagen fibers and proteoglycans embedded in an extracellular matrix. Scleral permeability has been shown to have a strong dependence on the molecular radius; scleral permeability decreases roughly exponentially with molecular radius. Hydrophobicity of drugs affects scleral permeability; increase of lipophilicity shows lower permeability; and hydrophilic drugs may diffuse through the aqueous medium of proteoglycans in the fiber matrix pores more easily than lipophilic drugs.

8.5 RETINA:

The drugs in the vitreous are eliminated by two main routes from anterior and posterior segments. All drugs are able to eliminate via the anterior route. The drugs can diffuse across the vitreous to the posterior chamber and, eliminate via aqueous turnover and uveal blood flow. Elimination of administered drug via the posterior route takes place by permeation across the retina. One of the barriers restricting drug penetration from the vitreous to the retina is the internal limiting membrane.

8.6 BLOOD-OCULAR BARRIER:

The eye is protected from the xenobiotics in the blood stream by blood-ocular barriers. These blood-ocular barriers have two parts namely, blood-aqueous barrier and blood-retina barrier. This barrier prevents the access of plasma albumin into the aqueous humor and also limits the access of hydrophilic drugs from plasma into the aqueous humor (43).

9. NOVEL OCULAR DRUG DELIVERY SYSTEM:

9.1 CURRENT RESEARCH PERSPECTIVE:

In order to increase the therapeutic efficacy, various approaches were proposed by multiple scientists in late 2000s, such as the development of sustained release fluocinolone acetonide pellets were prepared with polyvinyl alcohol and silicon, which can release 2µg/day and produced a good effect on inflammation, visual activity and reduction on cystoid macular edema (44). Studies on the feasibility of Daclizumab an interleukin-2 receptor antibody in the treatment of non-infectious posterior uveitis and intermediate uveitis to safely remove the dependence on the immunosuppressive regimens or systemic corticosteroids demonstrated that the daclizumab injections were well tolerated and exhibited no serious side effects. In most cases studied induction treatment of the drug with 2 mg/kg followed by 1 mg/kg maintenance treatments in an alternative week is safe and reduces the load necessary to treat the disease for 12-26 (45). Cyclosporine loaded biodegradable poly(dl-lactide-co-glycolide) co-polymer microspheres were designed, formulated and studied their safety and efficacy to avoid the difficulties of systemic or periocular therapy in patients with severe chronic posterior uveitis. A significant decrease in inflammatory signs, aqueous leukocyte counts, cellular infiltrate and protein levels were observed in rabbits with induced uveitis indicated their usefulness in uveitis treatment (46). A transscleral delivery formulation containing dexamethasone along with a vasoconstrictor 1% oxymetazoline delivered using Visulex®lens device in vivo revealed the superiority in the efficacy ofthe vasoconstrictor formulation in the treatment of uveitis (47). Controlled ocular delivery of MPA was achieved with a copolymer nanosuspension of methylprednisolone acetate (MPA) and poly(ethyl acrylate, methyl–methacrylate and chlorotrimethyl aminoethyl methacrylate) that can significantly reduce the inflammatory symptoms in endotoxin-induced uveitis (48).700-μg intravitreous drug delivery of dexamethasone in patients with uveitis precipitated persistent macular edema was proved to be well tolerated and resulted in a significant level of improvements and fluorescein leakage and in visual acuity. Dexamethasone loaded polylactic-glycolic acid (PLGA) microspheres for intravitreous injection formulation were studied for their short- and long-term ability to reduce ocular inflammation or uveitis. Inflammation was reduced in 15 days when treated with the formulation proved their efficacy in reducing the inflammation (49). Endotoxin-induced uveitis was treated effectively with rhodamine-conjugated liposomes of the vasoactive intestinal peptide in the hyaluronic acid gel. Gel formulation could result in a sustained delivery of VIP to the ocular and lymph node tissues and reduce the inflammation even though the intraocular injection of VIP-Rh-Lip failed (50).Low irritancy and improved anti-inflammatory ophthalmic emulsion of 0.1% flurbiprofen axetil was prepared which demonstrated better ocular biocompatibility but no significant difference in ocular bioavailability compared to the 0.03% FB-Na eye drops (51).

A retrospective case series review performed on CsA therapy attending children showed that Cyclosporin A therapy is safe in the medium term and effective in case of in refractory non-infectious childhood uveitis (52).

In situ gel forming system is a polymer solution which can be administered as liquid by instillation in the ocular cul-de-sac to form viscoelastic gel and this provides a response to environmental changes. Gelation can be triggered by temperature, pH, and ions. Three methods have been employed to cause phase transition on the surface such as change in temperature, pH, and electrolyte composition. An in-situ gelling system should be a low viscous, free flowing liquid to administration to the eye as drops. To increase the effectiveness, the drug should be contact with ocular surface. This may then prolong the residence time of the gel formed in-situ along with its ability to release drugs in a sustained manner will assist in increasing the bioavailability, reduce systemic absorption and reduce the need for frequent administration (53). Contact lenses are thin, curved in shape and made up of plastic which are designed to cover the cornea. Drug loaded in contact lens have been developed for ocular drug delivery of drugs such as β-blockers, antihistamines and antimicrobials. It is postulated that in presence of contact lens, drug molecules have longer residence time in the post-lens tear film which led to higher drug flux through cornea with less drug inflow into the nasolacrimal duct. Normally, the drug is loaded into the contact lens by soaking them in a drug solution that demonstrated higher efficiency in delivering drug compared to topical eye drops (54). These soaked contact lenses have some disadvantages of inadequate drug loading and short-term drug release. Particle-laden contact lenses which promising for extended ocular drug delivery and it should be it needs to be stored in drug saturated solutions to avoid drug loss during storage and molecularly imprinted contact lenses have been developed to overcome these problems. The imprinted contact lenses have also shown benefit in terms of both drug loading and drug release (55). Intraocular implants are specifically designed to provide localized controlled drug delivery over an extended period. These devices help in circumventing multiple intraocular injections and associated complications. Ocular implants are available as biodegradable and non-biodegradable drug releasing devices. Non-biodegradable implants offer long-lasting release by achieving near zero order release kinetics. These devices have to be surgically implanted and removed after drug depletion, which makes the treatment expensive and patient non-compliance. Also, adverse events such as endophthalmitis, pseudoendophthalmitis, vitreous haze and hemorrhage, cataract development and retinal detachment limit their application. The implant is inserted into the anterior chamber of eye to control inflammation in cataract patients. It provides sustained drug release for a period of 7–10 days with improved anti-inflammatory effect comparable to topical administration (56). Microneedle technique is an emerging and invasive mode of ocular drug delivery to posterior ocular tissues. It may provide an efficient treatment strategy for vision threatening posterior ocular diseases such as age related macular degeneration, diabetic retinopathy and posterior uveitis. This new microneedle technique may reduce the risk and complications associated with intravitreal injections such as retinal detachment, hemorrhage, cataract, endophthalmitis and pseudoendophthalmitis. Moreover, this strategy may help to circumvent blood retinal barrier and deliver therapeutic drug levels to the retina. Microneedles are designed to penetrate only hundreds of microns into the sclera, so that damage to deeper ocular tissues may be avoided (57). The ocular drug delivery systems provide local as well as systemic delivery of the drugs. The novel delivery systems offer more protective and effective means of the therapy even in inaccessible parts of eyes. Ocular delivery based formulations could be made more acceptable and excellent drug delivery systems by using the biodegradable and water soluble polymers like the hydrogels especially the in-situ gels (58).

9.2 NOVEL RESEARCH DIRECTION AND FUTURE PERSPECTIVE:

There is several techniques have been used for the treatment of ocular inflammation. Nanotechnology based ophthalmic formulations techniques are currently being followed for both anterior and posterior part of drug delivery. This system is based on particle size which can design to develop low irritation, adequate bioavailability and better compatibility. There are several nanocarriers to develop ocular drug delivery to improve ocular bioavailability such as nanoparticles, nanosuspensions, nano-crystals, liposomes, nanomicelles and dendrimers.

9.2.1 Nanoparticles:

Nanoparticles are defined as particles with a diameter less than 1 mm which may consist of biodegradable materials, such as natural or synthetic polymers, lipids, phospholipids and even metals. Nanoparticles made up of various biodegradable polymers like polylactide, polycyanoacrylate, natural polymers like chitosan, gelatine, sodium alginate and albumin are used effectively for efficient ocular drug delivery to the tissues. Nanoparticles are differing from macroscopic objects due to its sub-micron properties like high surface area and energy, and movement of the particles (Brownian motion). Size, morphology and physical state of the agents as well as molecular weight influence drug release and degradation of the nanoparticles. Surface charge of nanoparticles determines the performance of the nanoparticle system in the body. Particle size of topically applied colloidal carriers influences an absorption or permeation of drug through ocular barriers (59). Drug delivery to the posterior segment of eye by application of drug solution is very difficult. But the drug loaded with nano-particles to reach the posterior segment of ocular tissues and deliver drugs to targeted ocular tissues at effective therapeutic concentration.

Nanoparticles are employed as an alternative strategy for long term drug delivery to the posterior segment of ocular tissue surface. For posterior segment of ocular drug delivery, the disposition of nanoparticles depends on the size and surface property. Because of the rapid clearance and fast drug release, small size nanoparticles could not sustain retinal drug level. Therefore, it can be concluded that for prolonged transscleral drug delivery to the back of the eye, nanoparticles with slow drug release and low clearance by blood and lymphatic circulations are suitable ocular drug delivery (60).

9.2.2Nano-suspensions:

Nanosuspension is a colloidal dispersion of submicron drug particles formulated using polymers or surfactants. It emerges for the drug delivery of hydrophobic drugs. Ease of sterilization, ease of eye drop formulation, less irritation, increased precorneal residence time and increased ocular bioavailability exist as advantages of the formulation. nanosuspension carriers poorly watersoluble substances dispersed in a dispersed medium. This technique is used for the drug substance which forms crystals with higher energy content that insoluble in organic or aqueous media polymeric nano-suspension prepared from inert polymeric resins used as important drug delivery vehicles which are capable of prolonging drug release and increasing bioavailability. The positive charge on the nanoparticle surface facilitates their adhesion to the corneal surface. The use of nanosuspensions in ophthalmic formulations providing a great possibility to overcome the difficulties associated with ocular drug delivery system. The nanoparticles possess prolonged retention time in the ocular tissue so that the poorly soluble drugs can be administered as nanosuspension (61).

9.2.3NANO-CRYSTALS:

Nano-crystals are composed of 100% drug without any matrix materials with a size range between 220 and 500 nm. The drug nano-crystals can be considered as formulation approach for poorly watersoluble drugs. The major advantages of drug nano-crystals are applied by various route of administration including ophthalmic administration to create prolonged retention time.

9.2.4LIPOSOMES:

Liposomes are lipid vesicles with one or more phospholipid bilayers enclosing an aqueous core and the size ranging from 0.08 to 10.00 μm and liposomes are classified as unilamellar vesicles with size ranging from 10–100 nm), large unilamellar vesicles in the size of 100–300 nm and multilamellar vesicles which contains more than one bilayer. Liposomes represent ideal delivery systems for ophthalmic applications due to excellent biocompatibility, cell membrane like structure and ability to encapsulate both hydrophilic and hydrophobic drugs. Liposomes have demonstrated good effectiveness for both anterior and posterior segment ocular delivery in several research studies (62).

9.2.5NANOMICELLES:

Nanomicelles are commonly used carrier systems to formulate therapeutic agents into clear aqueous solutions. These are made with amphiphilic molecules. These nanomicelle molecules may be surfactant or polymeric in nature. Nanomicelles for ocular drug delivery can be divided into three catagories such as polymeric nanomicelles, surfactant nanomicelles and Polyionic complex (PIC) micelles. The former class, polymeric micelles are formed by amphiphillic polymers with distinct hydrophobic and hydrophilic segments. The polymer self-assembled to form micelles in aqueous solution, where the water insoluble segment forms the core and hydrophilic segment forms the corona. The self-assembly is not spontaneous and micelle formation is assisted by temperature. The mechanism of drug release from nanomicelles is dependent on the nature and strength of interactions between polymer and drug molecules, micelle stability in ocular tissues, polymer degradation and rate of diffusion of drug molecules from micelle core. In case of surfactant nanomicelles surfactant molecules have a hydrophilic head and hydrophobic tail. Hydrophilic head of surfactant molecules can be dipolar/zwitterionic, charged or anionic/cationic, or neutral/non-ionic. Commonly used surfactants for nanomicellar formulation are sodium dodecyl sulfate, dodecyltrimethylammonium bromide, ethylene oxide, Vitamin E TPGS, octoxynol-40 (non-ionic surfactants) and dioctanoyl phosphatidyl choline. A hydrophobic tail commonly comprises of a long chain of hydrocarbon and rarely includes a halogenated/oxygenated hydrocarbon chain. Polyionic complex micelles have been widely investigated as nanocarrier system for gene and antisense oligonucleotide delivery. PIC micelles have been explored extensively for the delivery of ionic hydrophilic therapeutics. This special class of micelles is formed by electrostatic interactions between polyion copolymers (comprised of neutral segment and ionic segment) and oppositely charged ionic species. The block copolymer is water soluble with very narrow polydispersity (63).

9.2.6 DENDRIMERS:

Dendrimers are macromolecular compounds made up of a series of branches around an inner core. They are effective systems for drug delivery because of their nanometer size range, ease of preparation and functionalization, and their ability to display multiple copies of surface groups for biological recognition processes. Because of these properties, they can be used as an effective vehicle for ophthalmic drug delivery. The bioadhesive polymers are used to improve drug delivery and release b optimizing contact with the absorbing area to prolong residence time and reduce dosage frequency. These bioadhesives are associated with side effects such as blurred vision and formation of veil in the corneal area which will lead to loss of eye sight. To avoid these problems dendrimers are used which are liquid or semi-solid in nature. Dendrimers are unique so that it will able to solubilize strongly and poorly water-soluble drugs into their inner surface (64).

10. CONCLUSION:

Uveitic emrging as a threatening disorder. Cases of emergent uveitis require immediate intervention to prevent visual loss. Recent medical advancement provides a better understanding of pathogenesis and treatment of uveitis. Since many disorders can cause uveitis. The management of severe cases of uveitis should be coordinated by an experimental multidisciplinary team. The use of biologics to treat uveitis has quickly extended in the past decade. Their achievement has underlined the key roles of inflammatory cytokines in the pathogenesis of inflammatory uveitis, principally TNF-α, IL-1, and IL-6. They have also refocused attention on T-cells and B-cells. Many patients with uveitis can benefit from a wide spectrum of biologics. These products are certainly useful when conventional immunosuppressor therapy fails or is not well tolerated, or also for treating concommitantophthmic and systemic inflammation which could benefit from these medicines.

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Received on 16.10.2018 Modified on 17.11.2018

Research J. Pharm. and Tech. 2019; 12(4):1997-2008.

DOI: 10.5958/0974-360X.2019.00334.2

S. No.	Drug Name	Specific uses	Adverse Drug Reaction
1	Difluprednate	Inflammation and pain associated with ocular surgery	Elevated Intraocular pressure, Posterior subcapsular, cataract formation, Secondary ocular infection, Perforation of the globe
2	Adalimumab	Treatment of non-infectious uveitis	Glaucoma, Cataract
3	Dexamethasone	Macular edema following branch retinal vein occlusion	Elevated intraocular pressure, Eye pain, Ocular hypertension, Anterior chamber cellular reaction, Cataract
4	Brimonidine tartrate	Ocular redness	Oral dryness, Ocular hyperaemia, Fatigue, Drowsiness, Blurred/abnormal vision
5	Fluocinolone acetonide	Chronic non-infectious posterior uveitis	Increased intraocular pressure, Eye pain, Visual acuity reduced, Conjunctival haemorrhage, Optic nerve disorder
6	Cyclopentolate Hydrochloride	Used as a Cycloplegic and mydriatic agent	Increased intraocular pressure, Drowsiness, Excitation and hyperactivity
7	Remicade	Treatment of refractory non-infectious uveitis	Malignancy, Autoimmunity, Congestive heart-failure exacerbation
8	Sirolimus	Chronic active anterior uveitis	Hypertension, Peripheral edema, Hypertriglyceridemia