INTRODUCTION:

Controlled and sustained delivery of ophthalmic drugs continues to remain a major focus area in the field of pharmaceutical drug delivery with the emergence of new, more potent drugs and biological response modifiers. The major objective of clinical therapeutics is to provide and maintain adequate concentration of drugs at the site of action. In ocular drug delivery, the physiological constraints imposed by the protective mechanisms of the eye lead to poor absorption of drugs with very small fractions of the instilled dose penetrating the cornea and reaching the intraocular tissues. The anatomy, physiology, and biochemistry of the eye render this organ highly impervious to foreign substances. A significant challenge to the formulator is to circumvent the protective barriers of the eye without causing permanent tissue damage. Development of newer, more sensitive diagnostic techniques and novel therapeutic agents continue to provide ocular delivery systems with high therapeutic efficacy.

An ocular drug delivery system is a new novel drug delivery system and this technique is incepted in the beginning of the last decade.

Literature survey reveals that not much work has been done in reference to anti-glaucoma, anti-diabetic, macular degeneration, retinal damage, dry eye syndrome, diabetic retinopathy and Sjögren’s disease.

The poor accessibility of a number of ocular regions to systemic circulation makes local delivery via topical administration the preferred route for the treatment of ocular diseases. Typical conditions that require ocular administration include eye infections (i.e, conjunctivitis) and corneal disorders (i.e, glaucoma). The biological barriers involved for ocular delivery are the permeability barriers posed by cornea and other regions, as well as the tear washout and blinking reflexes designed to remove foreign substances from the eye. Attempts to improve ocular bioavailability have been focused on overcoming precorneal solution drainage through manipulation of solution viscosity with polymers, use of mucoadhesive polymers, collagen shields, gels, nanoparticles, liposomes, latex systems, iontophoresis.etc. These ocular drug delivery systems, while limited in providing ideal bioavailability profiles, do provide opportunities for improvement. A better approach of ocular product behaviour coupled with formulation optimization can lead the way to development of newer ocular drug delivery systems¹.

The main goal of ocular drug delivery is controlled release of therapeutic concentrations to specific tissues while avoiding systemic spread of the formulation. However, the eye presents several anatomic and physiologic barriers that pose a major challenge for targeted drug delivery, especially to the posterior segment. The primary causes of vision impairment and blindness result from posterior segment diseases and corneal diseases. To tackle these sight-threatening diseases, a number of therapeutic methods have been investigated, ranging from topical eye drops to injections and implants. Thus, the development of effective delivery systems depends upon the understanding of how the ocular barriers affect the pharmacokinetics of drugs.

ANATOMY AND PHYSIOLOGY OF EYE:

The eye is a unique organ from anatomical and physiological point of view, in that it contains several highly different structures with specific physiological functions. For instance, the cornea and the crystalline lens are the only tissues in the body in addition to cartilage which have no blood supply, whereas choroid and ciliary processes are highly vascularized and exhibit very high blood flows. The retina with the optic nerve, an extension of the diencephalon of the central nervous system, has a very specific function in the visual perception and transduction phenomena. The eye has special attributes that allow local drug delivery and non-invasive clinical assessment of disease, but it is also a highly complex and unique organ, which makes understanding disease pathogenesis and ocular drug delivery challenging. The specific aim of designing a therapeutic system is to achieve the optimal concentration of a drug entity at the active site for the appropriate duration. Ocular disposition and elimination of a therapeutic agent is dependent upon its physicochemical properties as well as the relevant ocular anatomy and physiology. The primitive ophthalmic solutions, suspension, and ointment dosage forms are no longer sufficient to combat these diseases².

The eye has two segments^3-7- A smaller, transparent anterior segment that makes up one-sixth of the eyeball, and an opaque, posterior segment that forms the remaining five-sixths of the eyeball (Figure 1-1).

ANTERIOR PORTION:

Precorneal tear film: The precorneal tear film was thought to be a three layered structure consisting of a superficial oily layer, a middle aqueous layer, and an absorbed mucous layer secreted by various glands. Recent research suggests that the mucous fraction extends through the tear film.

Superficial oily layer is approximately 0.1µm thick and consists of wax and cholesterol esters. This layer prevents the evaporation from the underlying aqueous phase by a factor of 10- 20, preventing cornea from drying.

Aqueous layer lies below the oily layer and is the largest component of the tear film (6-10µm thick), consisting of watery lachrymal secretions provided by the numerous accessory lachrymal glands of Kraus and Wolfring.

Mucoid layer is secreted by the conjuctival goblet cells, the crypts of Henle, which are situated on the conjuctival surface Mucin is involved in adhesion of the aqueous phase to the underlying cornea, and thus keeps the cornea wettable.

Conjuctiva: Has a network of blood vessels to supply nutrients to the cells and remove waste products. It is pigmented that makes the retina appear black, thus preventing reflection of light within the eyeball. The conjuctiva lines the posterior surface of eyelids and covers the exterior surface of the cornea. The portion that lines the lids is called the palpebral conjuctiva; the portion covering the white eyeball is called bulbar conjuctiva. The palpebral conjuctiva is vascular and the bulbar conjuctiva is transparent. The area between the lids and the globe is termed the conjuctival sac.

Cornea: A curved band of strong, clear tissue on the surface of the eye, the cornea focuses the light onto the retina. Helps to maintain the shape of the anterior chamber of the eyeball. Is a pigmented muscular structure consisting of an inner ring of circular muscle and an outer layer of radial muscle. Its function is to help control the amount of light entering the eye so that: - too much light does not enter the eye which would damage the retina

The cornea is a transparent and a vascular tissue organized into 5 layers:

Ø Epithelium

Ø Bowman’s membrane

Ø Stoma

Ø Descement’s membrane, and

Ø Endothelium

Epithelial layer, Representing an important barrier to foreign matter, including drugs, is composed of 5-6 layers of epithelial cells. The basal epithelial cells lay on a basement membrane that is adjacent to Bowman’s membrane, a layer of collagen fibers. Constituting approximately 90% of the corneal thickness, the Stroma, a hydrophilic layer, is uniquely organized with collagen lamellae synthesized by keratocytes. These cells maintain corneal integrity by active transport processes and serve as a hydrophobic barrier. After that lie the two hydrophilic barriers, Descement’s membrane and endothelium. Hence drug absorption across the cornea necessitates penetrating the trilamenar hydrophobic-hydrophilic-hydrophobic domains of various anatomical layers.

Aqueous humor is an opaque, fibrous, protective outer structure. It is soft connective tissue, and the spherical shape of the eye is maintained by the pressure of the liquid inside. It provides attachment surfaces for eye muscles. Its main function is to keep the reasonably firm and it is secreted continuously by the ciliary body into the posterior chamber. It flows as a gentle stream through the pupil into the anterior chamber, and leaves the primarily by trabecular meshwork and canal of schlemm. From the canal of Schlemm, aqueous humor drains into the episclera venous plexus and into the systemic circulation.

The anterior chambers hold approximately 250µl of aqueous humor and the posterior chamber holds approximately 50 µl of aqueous humor.

Iris and Pupil: Iris- A part of the retina that is directly opposite the pupil and contains only cone cells. It is responsible for good visual acuity (good resolution).

Pupil- Is a thin protective covering of epithelial cells. It protects the cornea against damage by friction (tears from the tear glands help this process by lubricating the surface of the conjunctiva)

The iris is the most anterior portion of the uveal tract, which also includes the ciliary body and choroids. Differences in the iris color reflect individual variation in the number of melanocytes located in the Stroma.

Ciliary Body: Has suspensory ligaments that hold the lens in place. It secretes the aqueous humour, and contains ciliary muscles that enable the lens to change shape, during accommodation (focusing on near and distant objects). The ciliary body serves two specialized roles in the eye: secretion of aqueous humor by the epithelial bilayer and accommodation by the ciliary muscle.

Lens: A transparent biconvex structure is suspended by zonules, specialized fibers emanating from the ciliary body. The lens is approximately 10 mm in diameter and is enclosed in a capsule.

POSTERIOR PORTION

Because of the anatomical and vascular barriers to both local and systemic access, drug delivery to the eye’s posterior chamber is particularly challenging.

Sclera: The outermost coat of the eye, the sclera, covers the posterior portion of the globe. Numerous blood vessels pierce the sclera through emissaria to supply as well as drain the choroids, ciliary body, optic nerve and iris.

Choroids and Retina: The choroid is the middle pigmented vascular coat of the posterior five- sixth of the eyeball. It is continuous with the iris in the front. It lies between the retina and the sclera and prevents the passage of the light rays. The retina is a thin transparent, highly organized structure of neurons, glial cells, and blood vessels. Of all the structures within the eye, the neurosensory retina has been most widely studied.

Vitreous humor: Is a hole in the middle of the iris where light is allowed to continue its passage. In bright light it is constricted and in dim light it is dilated. The vitreous is a clear medium that makes up about 80% of the eye volume. It is a composed of 99% water bound with collagen type 2, hyaluronic acid, and proteoglcans. The vitreous also contains glucose, ascorbic acid, amino acids, and a number of inorganic salts.

Optic nerve: The optic nerve is a myelinated nerve conducting the retinal output to the central nervous system. It is composed of (1) an intraocular portion, which is visible as 1.5-mm optic disk in the retina (2) an intra orbital portion (3) an intracanalicular portion and (4) an intracranial portion.

BARRIERS TO OPHTHALMIC DRUG DELIVERY:^3-7

Systemic administration of a drug to treat ocular disease would require high concentrations of circulating drug in the plasma to achieve therapeutic concentrations in the aqueous humor which involved the increased risk of side effects. Topical administration is more direct, but conventional preparations of ophthalmic drugs, such as ointments, suspensions, or solutions are relatively inefficient as therapeutic systems. A large proportion of the topically applied drug is immediately drained from the conjuctival sac into the nasolachrymal duct or is cleared from precorneal area.

Precorneal Drainage: Drugs are mainly eliminated from the precorneal lachrymal fluid by the mechanisms shown in the fig1.2

Spillage of drug by overflow: The average tear volume in a human is 7 µl, 1 µl of which is contained in the precorneal tear film, and 3 µl in each of the tear margins. Prior to blinking, the tear volume in the palpebral fissure can increase to about 30 µl With an estimated drop volume of 50 µl, 70% of administrated dose is expelled from the eye by overflow and if blinking occurs only the residual volume approximately 10 µl is left indicating that 90% of the drug is expelled.

Fig. No.1.2 Major Mechanism of drug drainage through precorneal surface

Dilution of drug by tear turn over: Tears turn out to have a major share in removing drug solution from conjuctival cul-de-sac. Normal tear turnover is approx 16% per minute, which is stimulated by many factors like drug entity, pH, and tonicity of dosage form and formulation adjuvant.

Conjuctival absorption: Another mechanism that competes for drug the drug absorption into the eye is the superficial absorption of drug into palpebral and bulber conjuctiva with concomitant removal from the ocular tissues by peripheral blood stream.

Enzymatic metabolism: Enzymatic metabolism may operate in the precorneal space or in the cornea which, results in further loss of those drugs entities possessing labile bonds.

Nasolacrimal Drainage: An efficient drainage system exists to remove excess lacrimal fluid and cell debris from the precorneal area of the eye. Tears initially drains through the lacrimal puncta, which are small circular openings of the lachrymal canaliculi, they then pass through the mucous membrane lined lachrymal passages. This passage then opens into the lachrimal sac about 3 mm below its apex. At its lower end, it is continuous with the nasolacrimal duct that passes downwards to open into the inferior meatus of the nose with a valvular mechanism at its opening. The tears finally pass into the nasophrynx and so do the drug.

CLASSIFICATION OF OCULAR DRUG DELIVERY SYSTEMS:

These are classified as conventional and newer drug delivery systems. Most commonly available ophthalmic preparations are eye drops and ointments. But these preparations when instilled into the cul-de-sac are rapidly drained away from the ocular cavity due to tear flow and lacrimal nasal drainage. Only a small amount is available for its therapeutic effect resulting in frequent dosing⁸. Thus inefficient drug delivery into the eye occurs due to rapid tear turn over, lacrimal drainage and drug dilution by tears⁹. During administration, a part of an aqueous drop instilled in the patient’s cul-de-sac is inevitably lost by over flow/drainage, since the conjunctival pouch can accommodate only approximately 20 μL of added fluid^10-12.

VARIOUS INNOVATIVE APPROACH OF OCULAR DRUG DELIVERY SYSTEM:

A multitude of ocular dosage forms are available for delivery of drugs to the eye. These can be classified on the basis of their physical forms as follows:

1. Liquids: Solutions, Suspensions, Sol to gel systems, Sprays

2. Solids: Ocular inserts, Contact lenses, Corneal shield, Artificial tear inserts, Filter paper strips

3. Semi-solids: Ointments, Gels

4. Miscellaneous: Ocular iontophoresis, Vesicular systems, Mucoadhesive dosage forms, Particulates, Ocular penetration enhancers,Use of Hyaluronic acid, Use of Hydroxy Beta Cyclodextrin.

Liquids:

Liquids are the most popular and desirable state of dosage forms for the eye. This is because the drug absorption is fastest from this state. The slow release of the drug from the suspended solids provides a sustained effect for a short duration of time.

Solutions and Suspensions:^13-22

Solutions are the pharmaceutical forms most widely used to administer drugs that must be active on the eye surface or in the eye after passage through the cornea or the conjunctiva. The drug in the solution is in the solved state and may be immediately active. This form also have disadvantages; the very short time the solution stays at the eye surface, its poor bioavailability (a major portion i.e. 75% is lost via nasolacrimal drainage), the instability of the dissolved drug, and the necessity of using preservatives. A considerable disadvantage of using eye drops is the rapid elimination of the solution and their poor bioavailability. This rapid elimination is due to solution state of the preparation and may be influenced by the composition of the solution. The retention of a solution in the eye is influenced by viscosity, hydrogen ion concentration, the osmolality and the instilled volume. Extensive work has been done to prolong ocular retention of drugs in the solution state by enhancing the viscosity or altering the pH of the solution.

Sol to gel Systems:²³

The new concept of producing a gel in situ ( eg., in the cul-de-sac of the eye ) was suggested for the first time in the early 1980s. It is widely accepted that increasing the viscosity of a drug formulation in the precorneal region will leads to an increased bioavailability, due to slower drainage from the cornea. Several concepts for the in situ gelling systems have been investigated. These systems can be triggered by pH, temperature or by ion activation. An anionic polymeric dispersion shows a low visosity upto pH 5. 0, and will coacervate in contact with tear fluid due to presence of a carbonic buffer system which regulates the pH of tears. In situ gelling by a temperature change is produced when the temperature of polymeric dispersion is raised from 25 to 37°C. Ion activation of polymeric dispersion occurred due to the presence of cations in the tear fluid. Vadnere et al studied a number of pluronic polyols with the aim of determining factors which influence the transition temperature of the hydrogels. All of the pluronic polyols studied showed endothermic enthalpy change for the sol-gel process. The presence of sodium chloride, potassium chloride and sodium sulphate decreased the transition temperature whereas the opposite effect was observed with urea, alcohol and sodium dodecylsulfate. The enthalpy of gel formation was significantly changed by the added substances suggesting that entropy plays the major role in the gelation process.

Sprays:

Although not commonly used, some practitioners use mydriatics or cycloplegics alone or in combination in the form of eye spray. These sprays are used in the eye for dilating the pupil or for cycloplegic examination.

Solids:

The concept of using solids for the eye is based on providing sustained release characteristics.

Ocular inserts:^24-46

Ocular inserts are solid dosage form and can overcome the disadvantage reported with traditional ophthalmic systems like aqueous solutions, suspensions and ointments. The typical pulse entry type drug release behavior observed with ocular aqueous solutions (eye drops), suspensions and ointments is replaced by more controlled, sustained and continuous drug delivery using a controlled release ocular drug delivery system. The ocular inserts maintain an effective drug concentration in the target tissues and yet minimize the number of applications consonant with the function of controlled release systems.

Contact lenses:¹⁴

Contact lenses can absorb water soluble drugs when soaked in drug solutions. These drug saturated contact lenses are placed in the eye for releasing the drug for long period of time. The hydrophilic contact lenses can be used to prolong the ocular residence time of the drugs.

Corneal shield:⁴⁷

A non cross-linked homogenized, porcine scleral collagen slice is developed by a company (Bio-cor (Bausch and Lomb pharmaceuticals). Topically applied antibiotics have been used in conjunction with the shield to promote healing of corneal ulcers. Collagen shields are fabricated with foetal calf skin tissue and originally developed as a corneal bandage. These devices, once softened by the tear fluid, form a thin pliable film that confirms exactly to the corneal surface, and undergoes dissolution up to 10, 24 or 72 hours. Collagen film proved as a promising carrier for ophthalmic drug delivery system because of its biological inertness, structural stability and good biocompatibility. Gussler et al investigated the delivery of trifluoro thymidine (TFT) in collagen shields and in topical drops in the cornea of normal rabbits and corneas with experimental epithelial defects

Artificial tear inserts:⁴⁸

A rod shaped pellet of hydroxypropyl cellulose without preservative is commercially available (Lacrisert). This device is designed as a sustained release artificial tear for the treatment of dry eye disorders. It was developed by Merck, Sharp and Dohme in 1981

Filter paper strips:

Sodium fluorescein and rose Bengal dyes are commercially available as drug impregnated filter paper strips. These dyes are used diagnostically to disclose corneal injuries and infections such as herpes simplex, and dry eye disorders.

Semi-solids:^49-58

A wide variety of semisolids vehicles are used for topical ocular delivery which falls into two general categories: simple and compound bases. Simple bases refer to a single continuous phase. These include white petrolatum, lanolin and viscous gels prepared from polymers such as PVA, carbopol etc. Compound bases are usually of a biphasic type forming either water in oil or oil in water emulsions. A drug in either a simple or compound base provide an increase in the duration of action due to reduction in dilution by tears, reduction in drainage by way of a sustained release effect, and prolonged corneal contact time. The most commonly used semisolid preparation are ointments consisting of dispersion of a solid drug in an appropriate vehicle base. Semi-solids dosage forms are applied once or twice daily and provide sustained effects. The primary purpose of the ophthalmic ointment vehicle is to prolong drug contact time with the external ocular surface. But they present a disadvantage of causing blurring of vision and matting of eyelids. Semi-solids vehicles were found to prolong the ocular contact time of many drugs, which ultimately leads to an enhanced bioavailability.

Miscellaneous:

Ocular iontophoresis:^59,61,62

Iontophoresis (Greek iontos = ion; phoresis = to bear) is the process in which direct current drives ions into cells or tissues. When iontophoresis is used for drug delivery, the ions of importance are charged molecules of drug. If the drug molecules carry a positive charge, they are driven into the tissues at the anode; if negatively charged, at the cathode. Ocular iontophoresis offers a drug delivery system that is fast, painless, safe, and, in most cases, results in the delivery of a high concentration of the drug to a specific site. Increased incidence of bacterial keratitis, frequently resulting in corneal scarring, offers a clinical condition that may benefit from drug delivery by iontophoresis. Iontophoretic application of antibiotics may enhance their bactericidal activity and reduce the severity of disease; similar application of anti-inflammatory agents, could prevent or reduce vision threatening side effects. But the role of iontophoresis in clinical ophthalmology remains to be identified.

Vesicular systems:

Vesicular systems have been developed to provide improvement in ocular contact time, providing sustained effect and reducing side effects of the drug(s) entrapped.

Liposomes:^63-66

Liposomes are phospholipid-lipid vesicles for targeting the drugs to the specific sites in the body. Because of their structural versatility they can incorporate any kind of drug substance regardless of its solubility. They provide the controlled and selective drug delivery and improved bioavailability and their potential in ocular drug delivery appears greater for lipophilic than hydrophilic compounds. Liposomes are vesicles composed of a lipid membrane enclosing an aqueous volume. Liposomes offer the advantage of being completely biodegradable and relatively nontoxic but are less stable than particulate polymeric drug delivery systems. Liposomes were found to be potential delivery system for administration of a number of drugs to the eye.

OCULAR DISEASES:

Dark & Light aims at the eradication of preventable and treatable eye diseases. Early discovery and proper treatment can prevent further loss of eyesight.

According to WHO estimates:

Ø Approximately 314 million people worldwide live with serious vision impairment

Ø Of these, 45 million people are blind and 124 million have low vision

Ø Also included, 153 million people are visually impaired due to uncorrected refractive errors (near-sightedness, far-sightedness or astigmatism). In most cases, normal vision could be restored with eyeglasses or contact lenses.

Ø Yet 80% of blindness is avoidable - i.e. treatable and/or preventable.

Ø 90% of blind people live in low-income countries.

Ø Restorations of sight and blindness prevention strategies are among the most cost-effective interventions in health care.

Ø Infectious causes of blindness are decreasing as a result of public health interventions and socio-economic development. Blinding trachoma now affects fewer than 80 million people, compared to 360 million in 1985.

Ø Aging populations and lifestyle changes mean that chronic blinding conditions such as diabetic retinopathy are projected to rise exponentially.

Ø Women face a significantly greater risk of vision loss than men.

Ø Without effective, major intervention, the number of blind people worldwide has been projected to increase to 76 million by 2020.

The main causes of blindness and low vision are ^67,68,69,70

Cataract:

According to WHO definition: "Cataract is clouding of the lens of the eye which impedes the passage of light. Although most cases of cataract are related to the aging process, occasionally children can be born with the condition, or a cataract may develop after eye injuries, inflammation, and some other eye diseases."

Current situation:

There are estimated to be almost 18 million people who are bilaterally blind from cataract, representing almost half of all causes of blindness due to eye diseases globally. The proportion of blindness due to cataract among all eye diseases ranges from 5% in Western Europe, North America and the more affluent countries in the Western Pacific Region to 50% or more in poorer regions. The main non-modifiable risk factor is ageing. Other frequently associated risk factors are injury, certain eye diseases (e.g. uveitis), diabetes, ultraviolet irradiation and smoking. Cataract in children is due mainly to genetic disorders. Visually disabling cataract occurs far more frequently in developing countries than in industrialized countries, and women are at greater risk than men and are less likely to have access to services.

Trachoma:

Trachoma, which is the most common infectious cause of blindness, is caused by Chlamydia trachomatis. Children which have the active stages of the disease are the reservoir of infection, while blindness, which occurs after repeated episodes of infection, principally affects adults. Boys and girls are equally affected by active infection, while blindness is more common in women. Trachoma is a condition of poverty and is a focal disease, affecting communities that have poor water supplies and sanitation and poor health services. The organism is transmitted from person to person through direct and indirect contact and by flies.

Current situation:

Trachoma is endemic in 55 countries: Afghanistan, Algeria, Australia, Benin, Brazil, Burkina Faso, Cambodia, Cameroon, Central African Republic, Chad, China, Djibouti, Egypt, Eritrea, Ethiopia, Fiji, Gambia, Ghana, Guatemala, Guinea, Guinea-Bissau, India, Islamic Republic of Iran, Iraq, Kenya, Kiribati, Lao People’s Democratic Republic, Libyan Arab Jamahiriya, Malawi, Mali, Mauritania, Mexico, Morocco, Mozambique, Myanmar, Namibia, Nepal, Niger, Nigeria, Oman, Pakistan, Papua New Guinea, Senegal, Solomon Islands, Somalia, Sudan, Togo, Uganda, United Republic of Tanzania, Vanuatu, Vietnam, Yemen, Zambia and Zimbabwe. The estimated number of affected people has dropped from 360 million in 1985 to about 80 million today.

Trachoma affects the poorest and most remote rural areas of Africa, Asia, Central and South America, Australia and the Middle East. Updated reports on 36 countries are available, while 19 endemic countries have not yet reported data.

River blindness:

Onchocerciasis (river blindness) is caused by infection with the filarial parasite Onchocerca volvulus, which is transmitted by the blackfly species.

Current situation:

The vast majority of the 37 million infected people live in West, Central and East Africa, with smaller foci in Latin America and Yemen. In addition to eye disease and blindness, onchocerciasis also causes a range of skin diseases and other systemic conditions. Currently, about 300 000 people are blind from onchocerciasis.

Blepharitis:

Blepharitis is a chronic or long term inflammation of the eyelids and eyelashes. It affects people of all ages. Among the most common causes of blepharitis are:

Ø poor eyelid hygiene

Ø excess oil produced by the glands in the eyelids

Ø a bacterial infection (often styphylococcal)

Ø an allergic reaction

There are two ways in which blepharitis may appear. The most common and least severe, seborrheic Blepharitis, is often associated with dandruff of the scalp or skin conditions like acne. It usually appears as greasy flakes or scales around the base of the eyelashes and as a mild redness of the eyelid. Sometimes, it may result in a roughness of the (normally smooth) tissue that lines the inside of the eyelids; or chalazia, which are nodules on the eyelids (often painless and firm in texture). And, acute infection of the eyelids can result in styes.

Ulcerative Blepharitis is a less common, but more severe condition that may be characterized by matted, hard crusts around the eyelashes, which, when removed, leave small sores that may bleed or ooze. There may also be a loss of eyelashes, distortion of the front edges of the eyelids and chronic tearing. In severe cases, the cornea, the transparent covering of the front of the eyeball, may also become inflamed.

In many cases, good eyelid hygiene and a regular cleaning routine may control blepharitis. This routine can include:

Ø frequent scalp and face washing

Ø warm soaks of the eyelids

Ø eyelid scrubs

In cases where bacterial infection is the cause, eyelid hygiene may be combined with various antibiotics and other medications; and if the cause is an allergic reaction, the source of the reaction (eye makeup, for example) should be removed. Eyelid hygiene, in all cases, is particularly important upon awakening because debris can build up during sleep.

Chalazia and Styes:

A chalazion results from a blockage of one or more of the small oil producing glands (meibomian glands) that are found in the upper and lower eyelids. These blockages trap the oil produced by the glands and cause a lump on the eyelid that is usually about the size of a pea. These are usually relatively painless. If the chalazion becomes infected, the eyelid can become swollen, inflamed and more painful.

Styes are often confused with chalazia. Styes are infections or abscesses of an eyelid gland near an eyelash root or follicle.They generally occur nearer to the edge, or margin of the eyelid than do chalazia, where they form a red, sore lump similar to a boil or pimple.

In some cases, both chalazia and styes may come to a head and drain on their own without treatment. However, in most instances, they do not.

chalazion may be treated by applying hot compresses and/or antibiotic eye drops. In some cases, steroid drugs may be injected into or adjacent to the site of the chalazion. Styes may also be treated with hot compresses. Frequently, antibiotic and/or steroid eye drops or ointments may be needed.

Diabetic Retinopathy:

Diabetes is a condition that can interfere with the body's ability to use and store sugar. Diabetes can also, over time, weaken and cause changes in the small blood vessels that nourish the eye's light sensitive retina. When this occurs, it is called diabetic retinopathy. These changes may include leaking of blood, development of brush-like branches of the vessels and enlargement of certain parts of the vessels.

Diabetic retinopathy can seriously affect vision and, if left untreated, cause blindness. Since this disease can cause blindness, early diagnosis and treatment is essential. The beginning stages of diabetic retinopathy may cause blurriness in your central or peripheral (side) vision, or it may produce no visual symptoms at all. It mainly depends on where the blood vessel changes are taking place in your eye's retina (the light sensitive tissue at the back of the eye were images are focused). As diabetic retinopathy progresses, you may notice a cloudiness in your vision, blind spots or floaters. This is usually caused by blood leaking from abnormal new vessels which blocks light from reaching the retina.

In the advanced stages, connective scar tissue forms in association with new blood vessel growth, causing additional distortion and blurriness. Over time, this tissue can shrink and detach the retina by pulling it toward the center of the eye.

Current situation:

Diabetic retinopathy is responsible for 4.8% of the 37 million cases of blindness due to eye diseases throughout the world (i.e. 1.8 million persons). The proportion of blindness due to diabetic retinopathy ranges from close to 0% in most of Africa, to 3–7% in much of South-East Asia and the Western Pacific, to 15–17% in the wealthier regions of the Americas, Europe and the Western Pacific. At least 171 million people worldwide have diabetes, and this figure is likely to more than double by the year 2030, to 366 million. About 50% of persons with diabetes are unaware that they have the condition, although about 2 million deaths every year are attributable to complications of diabetes. After 15 years, about 2% of persons with diabetes become blind, and about 10% develop severe visual loss. After 20 years, more than 75% of patients will have some form of diabetic retinopathy.

Dry Eye:

The natural tears that eyes produce are composed of three layers:

Ø The outer oily layer

Ø The middle watery layer

Ø The inner mucus layer

Dry eye is the term used to describe eyes that do not produce enough tears or tears with the proper chemical composition in any of these layers.

Dry eye is most often a result of eyes' natural aging process. Most peoples' eyes tend to become drier as they age, but the degree of dryness varies and some people have more problems than others. In addition to age, dry eye can result from:

Ø Problems with normal blinking

Ø Certain medications like antihistamines, oral contraceptives and antidepressants

Ø Environmental factors like a dry climate and exposure to wind

Ø General health problems like arthritis or Sjogren's syndrome

Ø Chemical or thermal burns to the eye

Dry eye symptoms are often different in different people, but the following are commonly experienced by those whose tear production is inadequate:

Ø Irritated, scratchy, dry or uncomfortable eyes

Ø Redness of the eyes

Ø A burning sensation of the eyes

Ø A feeling of a foreign body in the eye

Ø Blurred vision

Ø Excessive watering as the eyes try to comfort an overly dry eye

Ø Eyes that seem to have lost the normal clear glassy luster

Possible treatments include:

Ø Frequent blinking to spread tears over the eye, especially when using a steady focus for an extended period

Ø Changing environmental factors like avoiding wind and dust and increasing the level of humidity

Ø Using artificial tear solutions and novel drug delivery system including ocular in situ gel.

Floaters and Flashes:

The small specks, "bugs" or clouds that may sometimes see moving in field of vision are called floaters. They are frequently visible when looking at a plain background, such as a blank wall or blue sky. These visual phenomena have been described for centuries; the ancient Romans called them muscae volitantes or "flying flies" since they can appear like small flies moving around in the air. Floaters are actually tiny clumps of gel or cellular debris within the vitreous, the clear jelly-like fluid that fills the inside cavity of the eye. Although these objects appear to be in front of the eye, they are actually floating in the fluid inside the eye and cast their shadows on the retina (the light-sensing inner layer of the eye). Moving eyes back and forth and up and down creates currents within the vitreous capable of moving the floater outside direct line of vision.

Glaucoma:

Glaucoma is an eye disease in which the passages that allow fluid in the eye to drain become clogged or blocked. This results in the amount of fluid in the eye building up and causing increased pressure inside the eye. This increased pressure damages the optic nerve which connects the eye to the brain. The optic nerve is the main carrier of vision information to the brain. Damage to its results in less information sent to the brain and a loss of vision.

The exact cause of glaucoma is not known and, it cannot currently be prevented. It is one of the leading causes of blindness in the U.S. But, if detected at an early stage and treated promptly, glaucoma can usually be controlled with little or no further vision loss. That's why regular optometric examinations are so important. People of all ages can develop glaucoma, but it most frequently occurs in people:

Ø who are over age 40

Ø who have a family history of glaucoma

Ø who are very nearsighted

Ø who are diabetic

Ø who are black

Of the different types of glaucoma, primary open angle glaucoma often develops gradually and painlessly, without warning signs or symptoms. This type of glaucoma is more common among blacks than whites. It can cause damage and lead to blindness more quickly in blacks, making regular eye examinations, including tests for glaucoma, particularly important for blacks over age 35. Another type, acute angle-closure glaucoma, may be accompanied by:

Ø blurred vision

Ø a loss of side vision

Ø appearance of colored rings around lights

Ø pain or redness in the eyes

Glaucoma can usually be treated effectively by using eye drops or other medicines.

Current situation:

WHO has estimated that 4.5 million people are blind due to glaucoma. Published projections indicate that 4.5 million people will be blind due to open-angle glaucoma and 3.9 million due to primary angleclosure glaucoma in 2010 (37). Furthermore, about 60.5 million people will have glaucoma by the year 2010 (44.7 million with open-angle glaucoma and 15.7 million with angle-closure glaucoma). Given the ageing of the world’s population, this number may increase to almost 80 million by 2020. The published projections also indicate that nearly half of the bilateral blindness attributable to glaucoma by 2020 will be caused by angle-closure glaucoma (11.2 million people).

Macular Degeneration:

Macular degeneration is the leading cause of central vision loss among older people. It results from changes to the macula, a portion of the retina, responsible for clear, sharp vision, and located on the inside back wall of the eye. The macula is many times more sensitive than the rest of the retina and without a health macula, seeing detail or vivid color is not possible.

There are several causes for macular degeneration. In one type, the tissue of the macula becomes thin and stops working well. This type is thought to be a part of the natural aging process in some people. In another, fluids from newly formed blood vessels leak into the eye and cause vision loss. If detected early, this condition can be treated with laser therapy, but early detection and prompt treatment is vital in limiting damage.

Current situation:

Age-related macular degeneration is responsible for 8.7% of all blindness (3 million persons) due to eye diseases, ranging from close to 0% in sub-Saharan Africa to 50% in industrialized countries. The number affected is expected to double by the year 2020 as a result of the ageing of the world’s population. The main risk factors are age, race, smoking, a family history of the condition, hypertension, high cholesterol, high fat intake and high body mass index. The complement factor H gene has also been implicated.

Early Detection of Retinitis Pigmentosa:

Retinitis pigmentosa, or RP, is the name given to one of a group of diseases which affect the retina of the eye. It is estimated that 400,000 Americans are affected by RP and other RP like inherited retinal degenerations.

Some of the most common symptoms of RP include night blindness and loss of peripheral (side) vision. Symptoms of RP often appear for the first time during the childhood or adolescent years. Stumbling over objects which seem to be in plain sight and "clumsiness" may be the first indications of a problem. The symptoms of RP generally worsen over a period of years. Although some RP patients with advancing age may become blind, most will retain at least some vision, and are classified as "legally blind". Each individual case differs.

Retinitis pigmentosa develops inside the pigmented layer of the retina. The retina is a delicate layer of cells that acts like the film in a camera. It picks up a picture and transmits it to the brain where "seeing" actually occurs. Two types of cells in the retina that participate in sending visual messages to the brain are the rod and cones. The rod-shaped cells are mostly used to help see "out of the corners of your eyes" (peripheral vision) and to see at night. The cone-shaped cells enable to distinguish colors, see during the day and help see with central vision.

When RP begins, the rod-shaped cells begin to lose their ability to function. As a result, people with this condition frequently have trouble seeing at night or in areas of dim light. It should be noted that poor and decreased night vision alone is not necessarily an indicator of retinitis pigmentosa. "Tunnel vision" is also a symptom of RP. The field of vision gradually narrows and to the RP patient, the effect is as though the person is constantly looking through a tunnel. As RP progresses to an advanced stage, may also have difficulty reading, distinguishing colors and seeing distant objects clearly. This is due to the deterioration of the cone-shaped cells.

IN-SITU FORMING GELS:

Eye is the most vital organ of body. The usual ophthalmic dosage forms are account for 90% of currently accessible ophthalmic formulations. The major trouble encountered is quick precornel drug loss. To improve ophthalmic drug bioavailability, there are considerable efforts directed towards newer drug delivery systems for ophthalmic administration. Newer research in ophthalmic drug delivery systems is directed towards a amalgamation of several drug delivery technologies, that includes to build up systems which is not only extend the contact time of the vehicle at the ocular surface, but which at the same time slow down the removal of the drug. There are various new dosage forms like insitu gel, collagen shield, minidisc, ocular film, ocusert, nanosuspension, nanoparticulate system, liposomes, niosomes, dendrimers, ocular iontophoresis etc. Conventional delivery systems often result in poor bioavailability and therapeutic response because high tear fluids turn over and dynamics cause rapid elimination of the drug from the eyes. So, to overcome bioavailability problems, ophthalmic in situ gels were developed.

The use of preformed hydrogels still has drawbacks that can limit their interest for ophthalmic drug delivery or as tear substitutes. They do not allow accurate and reproducible administration of quantities of drugs and, after administration; they often produce blurred vision, crusting of eyelids, and lachrymation. A new approach is to try to combine advantages of both solutions and gels, such as accuracy and facility of administration of the former and prolonged residence time of the later. Thus, in situ hydrogels can be instilled as eye drops and undergo an immediate gelation when in contact with eye. The liquid to semisolid phase change can be triggered by increased temperature, increased pH and ionic strength of the tear film.

The main aim of Pharmaco-therapeutics is the attainment of an effective drug concentration at the intended site of action for a sufficient period of time to elicit the response. A major problem being faced in ocular therapeutics is the attainment of an optimal concentration at the site of action. Poor bioavailability of drugs from ocular dosage forms is mainly due to the tear production, nonproductive absorption, transient residence time, and impermeability of corneal epithelium⁷¹.

Various problems encountered in poor bioavailability of the eye installed drugs are⁷²:

• Binding by the lachrymal proteins.

• Drainage of the instilled solutions;

• Lachrimation and tear turnover;

• Limited corneal area and poor corneal

• Metabolism;

• Non‐productive absorption/adsorption;

• Tear evaporation and permeability;

The poor bioavailability and therapeutic response exhibited by conventional ophthalmic solutions due to rapid precorneal elimination of the drug may be overcome by the use of a gel system that are instilled as drops into the eye and undergo a sol‐gel transition in the culdesac⁷³.

VARIOUS APPROACHES OF INSITU GELATION:

Ideally, an insitu gelling system should be a low viscous, free flowing liquid to allow for reproducible administration to the eye as drops, and the gel formed following phase transition should be strong enough to with stand the shear forces in the culdesac and demonstrated long residence times in the eye. In order to increase the effectiveness of the drug a dosage form should be chosen which increases the contact time of the drug in the eye. This may then prolonged residence time of the gel formed in situ along with its ability to release drugs in sustained manner will assist in enhancing the bioavailability, reduce systemic absorption and reduce the need for frequent administration leading to improved patient compliance ⁷⁴.

Depending upon the method employed to cause sol to gel phase transition on the ocular surface, the following types of systems are recognized:

Ø pH‐triggered systems: cellulose acetate phthalate(CAP) latex, carbopol, polymethacrilic acid(PMMA), polyethylene glycol (PEG), pseudolatexes.

Ø Temperature dependent systems: chitosan, pluronics, tetronics, xyloglucans, hydroxypropylmethyl cellulose or hypromellose (HPMC).

Ø Ion‐activated systems (osmotically induced gelation): gelrite, gellan, hyaluronic acid, alginates.

Ø UV induced gelation

Ø Solvent exchange induced gelation.

CONCLUSION:

Ophthalmic drug delivery system is burgeoning field in which most of the researchers are taking challenges to combat various problems related to this delivery. Steady advancement in the understanding of principles and processes governing ocular drug absorption and disposition and continuing technological advances have surely brought some improvements in the efficacy of ophthalmic delivery systems. The primary requirement of a successful controlled release product focuses on increasing patient compliance which the insitu gels offer. Exploitation of polymeric insitu gels for controlled release of various drugs provides a number of advantages over conventional dosage forms. Sustained and prolonged release of the drug, good stability and biocompatibility characteristics make the in situ gel dosage forms very reliable. Use of biodegradable and water soluble polymers for the insitu gel formulations can make them more acceptable and excellent drug delivery systems^75-76

Insitu activated gel‐forming systems seem to be favoured as they can be administered in drop form and produce appreciably less inconvenience with vision. Moreover, they provide better sustained release properties than drops. This type of dosage forms are used now a day in combat glaucoma, dry eye syndrome, Sjogren’s syndrome, ARMD, trachoma etc.^77-78

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Received on 02.03.2011 Modified on 15.03.2011

Research J. Pharm. and Tech. 4(6): June 2011; Page 872-882