1. INTRODUCTION:

The eye presents unique opportunities and challenges when it comes to delivery of pharmaceuticals. Ophthalmic drug delivery is one of the most interesting and challenging endeavors facing the pharmaceutical scientists.¹Utilization of the principal of controlled release as embodied by ocular inserts therefore offers an attractive alternative approach to the difficult problem of prolonging pre-corneal drug residence time.^2,3Ocuserts are defined as sterile preparations with a solid or semisolid consistency, whose size and shape are especially designed for ophthalmic application.⁴

All types of ocuserts consists of three components namely, a central drug reservoir in which the drug is incorporated in a polymer, rate controlling membrane which ensures the controlled release of medicament from the drug reservoir, and an outer annular ring meant for easy handling and proper insertion. Ocuserts increases corneal contact time, prolongs duration of action, improves bioavailability, reduces the frequency of administration and thus achieves better patient compliance. Uniform ocular drug level eliminates systemic side effects and provides undisturbed sleep due to extended drug activity throughout the night. It is also possible to administer the drug to inflamed eye due to sustained release of the medicament from ocusert. Furthermore, ocuserts are advantageous in saving time to the healthcare professionals. The zero order kinetics characteristics a sustained release type of delivery system whereby the drug is held in a reservoir and is released into the tear film at constant rate to provide a constant concentration in the corner which provides greatly improved compliance.^5,6 Thesepractical issues have stimulated the search for alternative methods for ocular drug delivery. Much of the work recently devoted to ocular inserts, which serves as the platform for the release of one or more active substances. It has become clear, however that the development of an ocular insert that reliably combines controlled release with absence of any irritation to the patient, poses a formidable technical challenge.⁷A basic concept in ophthalmic research and development is that the therapeutic efficacy of an ophthalmic drug can be greatly improved by prolonging its contact with the corneal surface. Ophthalmic inserts offer many advantages over conventional dosages forms, like increased ocular residence, possibility of releasing drug at a slow and constant rate, accurate dosing, exclusion of preservatives and increased shelf life. Design, construction and technology of ocular insert in a controlled and sustained ocular delivery device are gaining rapid improvement to overcome this constraints.^{8, 9}

Mechanism of Ocular Drug Absorption^{10, 11}:

Topical delivery into the cul-de-sac is, by far, the most common route of ocular drug delivery. Absorption from this site may,

1 Corneal

2 Non-corneal

Barriers avoiding drug delivery

Ocular Pharmacokinetics¹²:

The drug pharmacokinetics from the eye follows the following paths

· Transcorneal permeation from the lacrimal fluid into the anterior chamber.

· Non-corneal drug permeation across the conjunctiva and sclera into the anterior part.

· Drug distribution from the blood stream via blood-aqueous barrier into the anterior chamber.

· Elimination of drug from the anterior chamber by the aqueous humor turnover to the trabecular meshwork and scheme’s canal.

· Drug elimination from the aqueous humor into the systemic circulation across the blood-aqueous barrier.

· Drug distribution from the blood into the posterior eye across the blood-retina barrier.

· Intra vitreal drug administration.

· Drug elimination from the vitreous via E.g. posterior route across the blood-retina barrier.

· Drug elimination from the vitreous via anterior route to the posterior chamber.

Anatomy and function of the eye^13,14:

The eye is a spherical structure with a wall made up of three layers; the outer part sclera, the middle parts choroid layer, Ciliary body and iris and the inner section nervous tissue layer retina. The sclera is tough fibrous coating that protecting the inner tissues of eye which is white except for the transparent area at the front, and the cornea allows light to enter to the eye. The choroid layer, situated situated in the sclera, contains many blood vessels that modified at front of the eye as pigmented iris the coloured part of the eye (blue, green, brown, hazel, or grey.

The structure of the cornea^15,16:

The clear transparent bulge cornea situated at the front of the eye that conveys images to the back of the nervous system. The adult cornea has a radius of approximately 7-8mm that covers about one-sixth of the total surface area of the eye ball that is a vascular tissue to which provides nutrient and oxygen are supplied via lachrymal fluid and aqueous humor as well as from blood vessels of the junction between the cornea and sclera in fig.1 The cornea is made of five layers as epithelium, bowman’s layer, stroma, descemet’s membrane and endothelium that is main pathway of the drug permeation to eye. The epithelium made up of 5 to 6 layers of cells. The corneal thickness is 0.5– 0.7 mm in the central region. The main barrier of drug absorption into the eye is the corneal epithelium, in comparison to many other epithelial tissues (intestinal, nasal, bronchial, and tracheal) that is relatively impermeable. The epithelium is Squomous stratified, (5-6 layer of cells) with thickness of around 50-100 μm and turnover of about one cell layer every day. The basal cells are packed with a tight junction, to forming not only an effective barrier to dust particle and most microorganisms, and also for drug absorption. The transcellular or paracellular pathway is the main pathway to penetrate drug across the corneal epithelium. .the lipophilic drugs choose the transcellular route whereas the hydrophilic one chooses paracellular pathway for penetration (passive or altered diffusion through intercellular spaces of the cells). The Bowman’s membrane is an acellular homogeneous sheet with 8- 14μm thick situated between the basement membrane of the epithelium and the stroma. The stroma, or substania propria, composed of around 90% of the corneal thickness that contains about 85% water and about 200-250 collagenous lamellae. The lamellae provide physical strength while permitting optical transparency of the membrane. The hydrophilic solutes diffuse through the stroma’s open structure.The descemet’s membrane is secreted by the endothelium and lies between the stroma and the endothelium.

Conjunctiva^15,16:

The conjunctiva protects the eye and also involved in the formation and maintenance of the precorneal tear film. The conjunctiva is a thin transparent membrane lies in the inner surface of the eyelids and that is reflected onto the globe. The conjunctiva is made of an epithelium, a highly vascularised substantia propria, and a submucosa. The bulbar epithelium contains 5 to 7 cell layers. The structure resembles a pallisadeand not a pavemente corneal epithelium cells are connected by tight junctions, which render the conjunctiva relatively impermeable. The molecules up to 20,000 Da can cross the conjuctiva, while the cornea is restrict to molecules larger than 5000 Da. The human conjunctiva is about 2 and 30 times more absorption of drugs than the cornea and also proposed that loss of drug by this route is a major path for drug clearance. The highest density of conjunctiva is due the presence of 1.5 million globlet cell varying with age depended among the intersujects variability and age. The vernal conjunctivitis and atopic kerato conjunctivitis occurs due to the great variation in goblet cell density results only in a small difference in tear mucin concentration

Figure 1. Physiology of Eye

OPHTHALMIC INSERTS:¹⁷

In ocular inserts the films are directly applied in the cul-de-sac, improving ocular bioavailability by increasing the duration of contact within the corneal tissue, thereby reducing the frequency of administration

CLASSIFICATION OF OPHTHALMIC INSERTS:^{18, 19, 20, 21}

1) Non erodible:

· Ocuserts

· Contact lenses

· Diffusional inserts

2) Erodible:

· Lacrisert

· SODI

· Minidisc

Non erodible:

Ocuserts:

Developed by Alza Corporation.

Oval flexible ocular insert

Release Rate: 20-40 micrograms/hour for 7 days. It consists of annular ring impregnated with Ti02 for Visibility.

Merits of Ocuserts:

· Controlled rate of delivery,

· Greater drug absorption.

Demerits of Ocuserts:

· Patients uncomfort.

· Placement and removal of inserts.

Contact lenses:

· Pre-soaked Hydrophilic lens.

· Drug Release: within first 30 minutes.

· Alternate approach: incorporate drug either as solution or suspension of solid monomer mixture.

· Release rate is up to 180 hours.

Diffusional Inserts:

Central reservoir of drug enclosed in Semi permeable or micro porous membrane for diffusion of drug. Diffusion is controlled by lacrimal fluid penetrating through it. It prevents continues decrease in release rate due to barrier.

Release follows: Zero order kinetics

Erodible inserts:

Lacrisert:

· Sterile, Rod Shaped device.

· Composition: HPC without preservative.

· Weight: 5mg

· Dimension: Diameter: 12.5mm, Length: 3.5mm

· Use:-Dry eye treatment, Keratitis Sicca.

SODI(soluble ocular delivery insert):

Small water soluble developed for Cosmonauts by soviet scientists who could not use their eye drop in weightless conditions.

Composition: Acryl amide, Vinyl Pyrolidone, Ethylacrylate.

Weight 15-16 mg.

In 10-15 sec Softens; in 10-15 min. turns in Viscous Liquids; after 30-60min. Becomes Polymeric Solution.

Advantages of SODI:

Single SODI application replaces 4-12 eye drops Instillation or 3-6 application of Ointments.

Once a day treatment of Glaucoma and Trachoma

Minidisc: It is made up of counter disc with convex front and concave back surface in contact with eye ball.

Composition:

Silicon based pre polymer Hydrophilic or Hydrophobic. Drug release for 170 hr. Further increase in gentamycin sulphate to 320 hrs. Gamma irradiation and heat exposure may decrease release rate due to additional cross linking of polymer matrix.

EVALUATION OF INSERT:

Compatibility study^{22, 23}:

FTIR is helpful to confirm identity of drug and to detect the interaction of drug with polymers.

The drug polymer compatibility test was carried out using Fourier Transformer Infra red Spectrophotometer (FTIR). A base line correction was made by dried Potassium bromide. Infrared spectra of drug and polymers alone and combination with drug and polymers were recorded by FTIR Affinity 21 CE, Schimadzu.

Uniformity of thickness²⁴:

The thicknesses of the insert were determined using Micrometer gauze (Mitotoyo, Japan) at ten different points of each insert.

Folding Endurance²⁵:

Folding Endurance was determined by repeatedly folding the film at the same place till breaking or appearance of breaking signs. The number of times the film could be folded at the same place without breaking gives the folding endurance value

Tensile Strength²⁶:

It determines the flexibility of the film. The instrument used for the strength determination was tensile tester. Hook was inserted in the paper holder which was connected to one end of the film while the other end of the film strip of dimension 1 cm2 was fixed between the two iron screens to give support to the film. To this hook a thread was tied which was passed over the pulley and to hold the weight a small pan was attached to the other end. A small pointer, attached to the thread, which travels over the scale, was affixed on the base plate. Pulley system pulled the patch to determine tensile strength. To increase the pulling force, weights were progressively added to the pan till the patch was broken. The weights which were necessary to break the film were considered as its tensile strength. The tensile strength was calculated in kg/cm2 using the formula

Tensile Strength = Force at break /Cross sectional area of film*100

Drug content^{27, 28}:

Ocular insert was dissolved in simulated tear fluid. The resultant mixture was transferred to 50 ml volumetric flask and allows shaking for 1 h. Then after diluted up to the mark with simulated tear fluid. Similarly blank was prepared using drug free insert. Drug content was determined by UV Spectroscophotometer.

Surface pH²⁹:

The surface pH was determined by swelling the film in distilled water for 1hr. The pH of the film was determined by pH meter. The electrode of the instrument was dipped in the beaker containing the film till the reading flashed on the instrument. The reading was noted down. The same procedure was repeated thrice for the calculation of the mean.

% Moisture absorption^{30, 31}:

The percentage moisture absorption test was carried out to check physical stability or integrity of the film at humid condition. The films were weighed and placed in desiccator containing saturated solution of sodium chloride and 84% humidity was maintained. After three days, the films were taken out and reweighed.

Weight Uniformity³²:

Four films from all the batches (1cm2) were taken andthe weight of the film was determined by the single pan balance. The standard deviation was calculated from the average reading.

% Moisture loss³³:

The percentage moisture loss was carried out to check the integrity of the film at dry condition.

The films were weighted and kept in desiccator containing anhydrous calcium chloride. After three days, the films were taken out and reweighed.

Swelling index³⁴:

Three inserts were weighed and placed separately in beakers containing 4ml of distilled water. After a period of 5 minutes, the inserts were removed and the excess water on their surface was removed using a filter paper and then again weighed till there was no increase in the weight. The swelling index was then calculated by dividing the increase in weight by the original weight and was expressed as percentage.

Sterility testing³⁵:

The sterility testing of formulated films were done according to I. P. Direct inoculation method as described in Indian Pharmacopoeia. Ideal batches of film were used for sterility testing. All the samples were inoculated separately in to ATGM and SBCD media and incubated at 35ºC and 20-25ºC, respectively for 7 days. Similarly unsterilized samples of films were also inoculated separately in to ATGM and SBCD media and incubated at 35ºC and 20-25ºC, respectively for 7 days. A control evaluation was also carried out.

Stability studies³⁶:

The stability studies were performed by keeping the formulation D1at 4°C, 37°C and 50°C. The drug content and its physical appearance were checked after 7,15,30,60 days. Also, the sterility was checked in thioglycolate medium for UV sterilized films compared with unsterilized films.

Ageing study³⁷:

The inserts were stored in amber colored glass bottles at 3 different temperatures 40C, Room temperature (R.T.) and 370C for a period of 3 months. The samples were withdrawn after 30, 60 and 90 days and analyzed for physical appearance, drug content and sterility.

In vitro release study^3839,40:

The in vitro release of drug from the different ocular insert was studied using the classical standard cylindrical tube fabricated in the laboratory (bi-chambered donor receptor compartment model). A simple modification of glass tube of 15 mm internal diameter and 100 mm height. The diffusion cell membrane (Dialysis membrane) with molecular weight cut off 12000-14000 and pore size 2.4 nm was tied to one end of open cylinder, which acted as a donor compartment. An ocular insert was placed inside this compartment. The dialysis membrane acted as corneal epithelium. The entire surface of the membrane was in contact with the receptor compartment comprising of 25 ml of simulated tear fluid (pH 7.4) in a 100 ml beaker. The content of receptor compartment was stirred continuously using a magnetic stirrer and temperature was maintained at 37° ± 0.5°C. At specific intervals of time, 1 ml aliquot of solution was withdrawn from the receptor compartment and replaced with fresh buffer solution. The aliquot was analyzed for the drug content using UV-Vis spectrophotometer after appropriate dilutions against reference using simulated tear fluid.

OCUSERTS USING IN VARIOUS EYE DISEASES: ^{41, 42}

CONCLUSION:

Ocular drug delivery systems provide local as well as systemic delivery of the drugs. The limitations of existing medical therapies for ocular disorders include low drug bioavailability, no specificity, side effects, and poor treatment adherence to therapy. These limitations may be overcome through the use of sustained- release intraocular drug delivery systems. In the area of topical ocular administration, important efforts concern the design and the conception of new ophthalmic drug delivery systems able to prolong the residence time. The use of inserts, which are solid devices to be placed in the cul-de- sac or on the cornea, represents one of the possibilities to reach increased residence time. These solid ophthalmic devices present the advantage of avoiding a pulsed release due to multiple applications. Finally concluded that the present review work has been reveals that the ophthalmic disease and their treatment by using ocuserts.

ACKNOWLEDGEMENTS:

I solicit my deep sense of appreciation and love to my wonderful FATHER and MOTHER consider my self-privilege to have seen an entity of almighty in them. I consider myself as luckiest person being my sister RUPALI always there besides me during my ups and downs in my life and also thank to my teacher who will guide me for writing this review article. I am immensely thankful to G.I.P.E.R Limb Satara for their providing all facilities required for my work.

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Received on 29.08.2017 Accepted on 08.12.2017

Asian J. Pharm. Tech. 2017; 7 (4): 261-267.

DOI: 10.5958/2231-5713.2017.00038.1