The surface of the eye is rich in nutrients and consequently, supports a diverse range of microorganisms which constitutes the normal ocular flora. However acquisition of a virulent microorganism or uncontrolled growth of an existing organism due to lowered host resistance leads to infections of the external structures of the eye. Conjunctivitis and corneal ulcers are among the most common ocular infections and in more than 80% of cases, the infections are caused by Staphylococcus aureus, Streptococcus pneumoniae, or Pseudomonas aeruginosa.
Standard initial treatment consists of frequent instillation of eye drops with a broad-spectrum antibiotic. The drop application schedule requires strict discipline from the patient or care provider since a high and constant antibiotic concentration is intended at the site. However physiological constraints imposed by the protective mechanisms of the eye lead to low absorption of drugs, which results in a short duration of the therapeutic effect. Ocular therapy in the bacterial infections would be significantly improved if the precorneal residence time of drugs could be increased.
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Development of new drugs is difficult, expensive and rather time consuming, as it involves the processes like preclinical testing, investigational new drug application (IND), clinical trials, phase I, II, & III, new drug application (NDA) and FDA approval. Improving safety and efficacy of existing drugs is being attempted by using different methods such as individualizing drug therapy, dose titration and therapeutic drug monitoring and, most importantly, delivering drugs at controlled rates at targeted sites. Drug delivery systems could provide extended circulating half-lives so that less drug is required for therapeutic effectiveness relieving the patient From side effects caused by non-specific tissue uptake and provide protection against enzymatic degradation.
1.1 Problems in Ocular Drug Delivery
Topical delivery of eye drops into the lower cul-de-sac is the most common method for the administration of therapeutic agent in the treatment of ocular diseases. However, one of the major problems encountered with solutions is the rapid and extensive elimination of drugs from the precorneal lachrymal fluid by solution drainage, lachrymation and nonproductive absorption by the conjunctiva, which may cause undesirable side effects. It must be noted that this high drainage rate is due to the tendency of the eye to maintain its residence volume at 7-10 Î¼L permanently, whereas volumes topically instilled range from 20-50 Î¼L. In fact it has been demonstrated in vivo that 90% of the dose was cleared within 2 min for an instilled volume of 50 Î¼L and within 4 min for an instilled volume of 10 Î¼L. Consequently, the ocular residence time of conventional solutions is limited to a few minutes, and the overall absorption of a topically applied drug is limited.
Fig. no. 1 Schematic diagram represents low bioavailability of instilled dose
1.2 Approaches to Improve Ocular Bioavailability
Various approaches that have been attempted to increase the bioavailability and the duration of therapeutic action of ocular drugs can be divided into two categories. The first is based on the use of the drug delivery systems, which provides the controlled and continuous delivery of ophthalmic drugs. The second involves, maximizing corneal drug absorption and improve the ocular bioavailability of drug.
Fig. no. 2 Schematic diagram represents noval approach for ocular delivery
The aim of the present work was to design vesicular ocular drug delivery system of ofloxacin with permeation enhancer to overcome the disadvantages associated with conventional ophthalmic dosage forms (eye drops), to achieve long duration of action and to improve ocular bioavailability. Flouroquinolones are one of the promising groups of antibiotics currently being used topically to treat conjunctivitis and corneal ulcers. Ofloxacin has proved to possess superior antibacterial activity in-vivo and has better pharmacokinetic properties as compared with ciprofloxacin and norfloxacin. Ofloxacin is a broad-spectrum antibacterial agent with activities against gram-negative bacteria (E. coli, Klebsiela pneumoniae, Serratia species, Proteus species, Pseudomonas aerogenosa and H. influenza) and gram-positive bacteria (Staphylococcus species, Streptococcus enterococci). It is used in the treatment of kerato-conjunctivitis, blepharo-conjunctivitis, corneal ulcer, preoperative prophylaxis and other ocular infections. It has a plasma half-life of 5.7Â±1 hours.
OCULAR DRUG DESIGN AND DELIVERY: CHALLENGES
The eye as a portal for drug delivery is generally used for local therapy against systemic therapy in order to avoid the risk of eye damage from high blood concentrations of the drug, which is not intended. The Unique anatomy, physiology and biochemistry of the eye render this organ impervious to foreign substances, thus presenting a constant challenge to the formulator to circumvent the protective barriers of the eye without causing permanent tissue damage. Most ocular treatments like eye drops and suspensions call for the topical administration of ophthalmically active drugs to the tissues around the Ocular cavity. These dosage forms are easy to instill but suffer from the inherent drawback that the majority of the medication they contain is immediately diluted in the tear film as soon as the eye drop solution is instilled into the cul-de-sac and is rapidly drained away from the pre-corneal cavity by constant tear flow and lacrimo-nasal drainage. Normal dropper used with conventional ophthalmic solution delivers about 50-75Âµl per drop and portion of these drops quickly drain until the eye is back to normal resident volume of 7Âµl. Actual corneal permeability of the drug is quite low and very small corneal contact time of the about 1-2 min. in humans for instilled solution. Therefore the target tissue absorbs a very small fraction (~1-2%) of the instilled dose. For this reason, concentrated solutions and frequent dosing are required for the instillation to achieve an adequate level of therapeutic effect. But this type of pulse type dosing results in several side effects of ophthalmic products. In order to overcome the problems of conventional ocular therapy, such as short residence time, drug drainage, and frequent instillation; newer delivery systems are being explored, in general, to improve the ocular bioavailability of the drug.
Always on Time
Marked to Standard
ig No. 2 Absorption and dissipation pathway of a topically administered ophthalmic drug.
Various approaches, like viscosity enhancement, use of mucoadhesive, particulate drug delivery, vesicular drug delivery, prodrugs, and a number of solid polymeric inserts/disc have been developed as ocular drug delivery systems.
A 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. The viscosity enhancing agents such as methylcellulose are added to eye drop preparations or ophthalmic drug is formulated in water-insoluble ointment formulation to sustain the duration of intimate drug-eye contact. But these dosage forms gives only marginally more sustained drug-eye contact than eye drop solutions and do not yield a constant drug bioavailability as originally hoped. One of the new classes of drug delivery systems, polymeric film ocular drug delivery Systems/Ocular inserts, which are gaining worldwide accolade, has succeeded in significantly reducing dosing and release drugs at a pre-programmed rate for a longer period by increasing the pre-corneal residence time.
1.2 EYE: ANATOMICAL AND PHYSIOLOGICAL OVERVIEW
The human eye has a spherical shape with a diameter of 23 mm. The structural components of the eye ball are divided into three layers:
The outer most coat comprises of the clear, transparent cornea and white, opaque sclera ;
The middle layer comprises the iris anteriorly, the choroids posteriorly, and ciliary body as intermediate part ; and
The inner layer is the retina, which is an extension of the central nervous system.
Fig. No. 3 Schematic representation of the structure of the human eye.
The fluid systems in the eye, the aqueous humour and vitreous humour, also play an important role. Cornea is an optically transparent tissue that acts as a principal refractive element of the eye. The corneal diameter is about 11.7 mm with a radius of curvature of the anterior surface of about 7.8 mm. The corneal thickness is 0.5-0.7 mm and it is thicker in the center than in limbus. The cornea is composed of epithelium, Bowmen's membrane, stroma, Descement's membrane and endothelium. The relative thickness of corneal epithelium (50-90 mm), stroma and endothelium are about 0.1 mm, 1.0 mm, 0.01 mm respectively. The cornea and lens, whose shape is adjusted by the ciliary body, focus the light on retina, where receptors convert it into nerve signals that passes to the brain. A mesh of blood vessels, the choroid, supplies the retina with oxygen and sugar. Lacrimal glands secrete tears that wash foreign bodies out of the eye and keep the cornea from drying out. Blinking compresses and releases the lacrimal sac, creating a suction that pulls excess moisture from the eye's surface. The drugs in ophthalmic preparations reach inside of the eye through cornea. Because the structure of the cornea consists of epithelium, stroma, endothelium, which is equivalent to a fat water fat structure, the penetration of non- polar compounds through the cornea depends on their oil / water partition co-efficients.
Fig. No 4. Microphotograph of human cornea. The outermost layer of the cornea is the epithelium Ep, which rests on a basement membrane supported by a specialized layer of corneal stroma called Bowman's layer (membrane) BM. The corneal stroma (substantia propria) SP consists mainly of collagen lamellae. The inner surface of the cornea is formed by endothelial cells En, which are supported by Descemet's membrane DM.
The blood-ocular barrier normally keeps most drugs out of the eye. However, inflammation breaks down this barrier allowing drugs and large molecules to penetrate into the eye. As the inflammation subsides, this barrier usually returns.
The blood- ocular barrier is comprised of the following sites:
Blood-aqueous barrier: The ciliary epithelium and capillaries of the iris.
Blood-retinal barrier: Non-fenestrated capillaries of the retinal circulation and tight - junctions between retinal epithelial cells preventing passage of large molecules from choriocapillaries into the retina.
Fig.No.5 Schematic Diagram of the Blood-Ocular Barrier
. The retinal cell layers seen histologically consist of: RPE, retinal pigment epithelium; POS, photoreceptor outer segments; OLM, outer limiting "membrane"; ONL, outer nuclear layer; OPL, outer plexiform layer; INL, inner nuclear layer; IPL, inner plexiform layer; GCL, ganglion cell layer; NFL, nerve fiber layer; ILM, inner limiting "membrane".
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1.3 DRUG ABSORPTION AND DISPOSITION IN THE EYE
It is often assumed that drugs administered into the eye are rapidly and totally absorbed. However, contrary to this belief, the moment drug is placed in the lower cul-de-sac of eye, several factors immediately begins to affect the bioavailability of drug. Absorption of drugs takes place either through corneal or noncorneal routes. The noncorneal route involves absorption across the sclera and conjuctiva into the intraocular tissues. This route is, however, not productive as it restrains the entry of drug into aqueous humour. Maximum absorption thus takes place through cornea, which leads the drug into aqueous humour. The goal of ophthalmic drug delivery systems has traditionally been to maximize ocular drug absorption rather than to minimize systemic absorption.
Drug Elimination From Lacrimal Fluid
Ophthalmic liquid dosage forms like solutions, suspensions, and liposomes is either drained from conjunctival sac into nasolachrymal duct or is cleared from precorneal area resulting in poor bioavailability of drugs. Drugs are mainly eliminated from the precorneal lacrimal fluid by solution drainage, lacrimation and non productive absorption to the conjunctiva of the eye. These factors and the corneal barrier limit the penetration of the topically administered drug into the eye. Only a few percentage of applied dose is delivered into intraocular tissue, while the major part (50-100%) of the dose is absorbed systemically.
Precorneal constraints include,
Spillage of drug by over flow.
Dilution of drug by tears turnover.
Nasolacrimal drainage / systemic drug absorption.
Trans-corneal penetration mainly affected by corneal barrier, physicochemical properties of drug and active ion-transport system present at cornea.
Corneal epithelium is the main barrier for drug absorption into eye. Corneal epithelium acts as a protective barrier against foreign molecules and also as a barrier to ion transport. The corneal epithelium consists of a basal layer of columnar cells, squamous cells, polygonal shaped superficial cells. In a healthy corneal epithelium, intercellular tight junctions completely surround the most superficial cells, nevertheless the intercellular spaces are wider between wing cells and basal cells. This allows the paracellular diffusion of large molecules through these layers of cell only. Tight junctions serve as a selective barrier for small molecules and they completely prevent the diffusion of macromolecules via the paracellular route. Corneal stroma is a highly hydrophilic tissue, it acts as a rate-limiting barrier for ocular absorption of most lipophilic drugs. The corneal endothelium is responsible for maintaining normal corneal hydration.
Fig.No.6 Ocular penetration routes for drugs after topical, systemical and intravitreal administration. The main elimination pathways are indicated by bold arrows; the ocular barriers (BRB, blood-retinal barrier; BAB, blood-aqueous barrier) are indicated by a grey background.
Physiochemical properties of drug
Transcellular or paracellular pathway is the main route for drugs to penetrate across corneal epithelium. Hydrophilic drugs penetrate primarily through the paracellular pathway, which involves passive or altered diffusion through intercellular spaces while lipophilic drugs prefer the transcellular route. For topically applied drugs, passive diffusion along their concentration gradients, either transcellular or paracellular permeation, is the main permeation mechanism. Liphophilicity, solubility, molecular size and shape, charge and degree of ionization also affect the route and rate of penetration in cornea.
Ion Transport System
The corneal epithelium contains ionic channels that are selective for cation over anion and also contains an outwardly rectifying anion channel in the apical membrane and highly conductive potassium channel.
Fig.no.4 Permeation mechanisms across corneal epithelium. Passive paracellular (A) and transcellular (B) permeation. Transporter mediated influx and efflux across cell membrane (C) in the apical (1 and 2) and basolateral (3 and 4) side, respectively.
Various enzymes present in ocular tissue (protease, peptidase, and esterase) may metabolize many of ocular drugs during or after absorption.
2.2 (c) Non corneal absorption
This route involves drug penetration across the bulbar conjunctiva and underlying sclera in to the uveal tract and vitreous humor. This route is important for hydrophilic and large molecule with poor corneal permeability. Tight junctions of spherical conjunctival epithelium are main barrier of drug penetration. conjunctival permeability of particular drug have magnitude higher than that of corneal penetration through sclera is mainly through perivascular spaces, through the aqueous media of gel like mucopolysaccharide or through spaces between collagen network. Sclera has more permeability compare to cornea.
2.3 Conventional ocular delivery constrains
For the ailments of the eye, topical administration is usually preferred over systemic administration so as to avoid systemic toxicity, for rapid onset of action, and for decreasing the required dose. Though topical administration offers many advantages to treat disorders of anterior structures of the eye, it suffers from a serious disadvantage of poor bioavailability due to several biological factors (Fig. 6), which exist to protect the eye and consequently limit the entry of ocular drugs. The constraints in topical delivery of the eye are discussed below.
Fig no.6 Factors attributing to poor bioavailability of an ophthalmic formulation
Fig. No. 9 Pharmacokinetic Scheme Illustrating the precorneal fluid dynamics and the
distribution/disposition of pilocarpine in rabbits.
2.4 Disadvantage of topical ophthalmic formulations
They have poor bioavailability because of
a. Rapid precorneal elimination
b. Conjunctival absorption
c. Solution drainage by gravity
d. Induced lacrimation
e. Normal tear turn over
Frequent instillation of concentrated medication is required to achieve therapeutic effect.
Systemic absorption of drug and additives drained through nasolachrymal duct may result in undesirable effect.
The amount of drug delivered during external application may vary. The drop size of ocular medication is not uniform and dose delivered is generally not correct.
1.5 REQUISITES OF CONTROLLED OCULAR DELIVERY SYSTEMS
To overcome the side effects of pulsed dosing (frequent dosing and high concentration) produced by conventional systems.
To provide sustained and controlled drug delivery.
To increase the ocular bioavailability of drug by increasing corneal contact time. This can be achieved by effective coating or adherence to corneal surface, so that the released drug effectively reaches the anterior chamber.
To provide targeting within the ocular globe so as to prevent the loss to other ocular diseases.
To circumvent the protective barriers like drainage, lacrimation and diversion of exogenous chemicals into the systemic circulation by the conjunctiva.
To provide comfort and compliance to the patient and yet improve the therapeutic performance of the drug over conventional systems.
To provide the better housing of the delivery system in the eye so as the loss to other tissues besides cornea is prevented.
Two major approaches are being undertaken to improve topical delivery of drugs which are:
Approaches to prolong the contact time of drug with corneal surface
Approaches to enhance corneal permeability either by mild or transient structural alteration of corneal epithelium or by modification of chemical structure of the drug molecules.
1.6 APPROACHES DEVELOPED TO MAXIMIZE CORNEAL DRUG ABSORPTION AND MINIMIZE PRECORNEAL DRUG LOSS 5
TABLE NO: 1
Increased residence time
Increased corneal penetration
Rapid initial drainage rate Bioavailability are valid in animals but minimal in humans.
Gel at physiological pH
Less blurred vision than ointment.
No rate control on diffusion
Matted eyelids after use.
Best for drugs with slow dissolution.
Drug properties decide performance
Loss of both solution and suspended solid.
Flexibility in drug choice
Improved drug stability.
Drug choice limited by
No true sustaining effect.
Increased bioavailability of peptides & proteins.
Physio-chemical properties of the drug
Tissue irritation and damage.
Prolonged release of drug from vehicle
Enhanced pulsed entry.
Patient non compliance
Possible oil entrapment.
Increased corneal contact time.
Water soluble polymers face the disadvantage of having a short half - life.
Simple and convenient Drug
concentration achieved higher
levels in the cornea and aqueous humor.
Application of shield requires to anesthetize the cornea.
Prolonged sustained release of
Rapid disappearance from tear
costly and technological difficulties.
(such as liposomes,
No tissue irritation & drainage
Prolonged sustained release of drug, biocompatible
Limited drug loading
Unstable due to hydrolysis of phospholipids
Costly and technological difficulties.
1.7 OPTHALMIC INSERTS:
Ocular inserts are defined as sterile thin multilayered ,drug -impregnated, solid or semisolid consistency devices placed into cul -de - sac or conjunctival sac , whose size and shape are especially designed for opthalmic application .they are composed of a polymeric suport that may or may not contain drug.
1. Increasing the contact time and thus improve bioavailability.
2 .Providing prolonged drug release and thus a better efficacy.
3. Reduction of systemic side effects and thus reduces adverse effects.
4. Reduction of the number of administration and thus better patient compliance.
5. Administration of an accurate dose in the eye and thus a better therapy.
6. Increased shelf life with respect to solutions.
7. Exclusion of preservatives ,thus reducing the risk of sensitivity reactions.
8. A possibility of incorporating various novel chemical technological approach such as pro-drugs,microparticles, salts acting as buffers.
Desired criteria for controlled release of ocular insert are 11
Lack of explosion.
Ease of handling and insertion.
Non-interference with vision and oxygen permeability.
Reproducibility of release kinetics.
Ease of manufacturing.
It is designed to be inserted in the conjunctival folds of the upper or lower fornix at the junction between the palpebral conjunctiva of the upper or lower eyelid and bulbar conjunctiva of the eyeball, being held in position preferably in the extreme outer and inner end portions of the upper or lower fornix and prevented from moving downward or laterally respectively by the pressure and movement of the lid against the eyeball. The tapered end portions, at least in part, lie between the upper or lower tarsus and the eyeball, because they are conical, they serve to prevent the device moving laterally in the fornix whilst also providing a reduced pressure on the eyeball. There by providing increased comfort and tolerability for the patient.
Fig. No. 10. Application of ocular insert
1.7.2 HISTORY OF OCULAR INSERTS
The first solid medication (precursors of the present insoluble inserts) was used in the 19th century, which consisted of squares of dry filter paper, previously impregnated with dry solutions (e.g. atropine sulphate, pilocarpine hydrochloride). Small sections were cut and applied under eyelid. Later, lamellae, the precursors of the present soluble inserts, were developed. They consisted of glycerinated gelatin containing different ophthalmic drugs.13 Glycerinated gelatin 'lamellae' were present in official compendia until the first half of the present century. However, the use of lamellae ended when more stringent requirements for sterility of ophthalmic preparations were enforced. Nowadays, growing interest is observed for ophthalmic inserts as demonstrated by the increasing number of publications in this field in recent years.
Examples of the various types of inserts available or in development are presented in the table no. 2
TABLE NO. 2 HISTORY OF OCULAR INSERTS
Quigley et al. and Urquhart et al.
Flat, flexible elliptical insoluble device consisting of two layers enclosing a reservoir, used commercially to deliver pilocarpine for 7 days.
Khromow et al.
Small oval wafer, composed of a soluble copolymer consisting of acrylamide, N-vinyl pyrrolidone and ethyl acrylate, softens on insertion.
Bloomfield et al.
The use of collagen inserts as tear substitutes and as delivery systems for gentamicin.
Lamberts et al.
Rod-shaped device made from hydroxypropyl cellulose used in the treatment of dry eye syndrome as an alternative to artificial tears.
Lloyd et al.
Medicated solid polyvinyl alcohol flag that is attached to a paper covered handle. On application, the flag detaches and gradually dissolves, releasing the drug.
Bewa et al.
4-5 mm diameter contoured either hydrophilic or hydrophobic disc.
Gurtler et al.
Adhesive rods based on mixtures of hydroxypropyl cellulose, ethyl cellulose, polyacrylic acid and cellulose acetate phthalate.
Chetoni et al.
A cylindrical device containing mixtures of silicone elastomer and sodium chloride as a release modifier with a stable polyacrylic acid (PAA) or polymethylacrylic acid (PMA) interpenetrating polymer network grafted on to the surface.
Simamora et al.
Slabs of gelfoam impregnating with a mixture of drug and cetyl ester wax in chloroform.
Diestelhorst et al.
A preservative-free drop of hydrophilic polymer solution (hydroxypropylmethyl cellulose) that is freeze dried on the tip of a soft hydrophobic carrier strip, immediately hydrates in the tear film.
Mucoadhe-sive ocular insert.26
Bernkop-Schnurch et. al.
The inserts tested were based either on unmodified or thiolated poly (acrylic acid) for the controlled delivery of ophthalmic drugs and to evaluate its efficacy in vivo.
One-side-coated ocular insert.27
Sasaki et al.
Prepared by attaching a polypropylene tape on the one side of the polymer disc of poly (2-hydroxypropyl methacrylate) (HPM) containing Tilisolol as a model ophthalmic drug.
Molecularly imprinted soft contact lenses.96
Hiratani et al.
Soft contact lenses consisted of N,N-diethylacrylamide, methacrylic acid and ethylene glycol dimethacrylate. Timolol was used as a model drug.
New Ophthalmic Mydriatic Insert.97
Stephane et al.
New insoluble-matrix retropalpebral ophthalmic insert containing Phenylephrine and Tropicamide. Potential Alternative as Drug Delivery System Prior to Cataract Surgery.
Gelatin hydrogels and lyophi-lisates with potential application as ocular insersts.98
Madalina et al.
Hydrogels and lyophilisates were obtained by chemical crosslinking of gelatin using N-hydroxysuccinimide and N, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride.
Pilocarpine hydrochloride was used as a model drug.
Pijls et al.
The ocular insert consists of a pradofloxacin -loaded adherent hydrogel on a thin wire, which is coiled. The inner lumen of the coil was filled with a polymer rod made from a poly(2-hydroxyethyl methacrylate) hydrogel and loaded with the same drug SODI- Soluble Ophthalmic Drug Insert;
NODS- New Ophthalmic Delivery system;
BODI- Bioadhesive Ophthalmic Drug Insert
1.7.3 MECHANISM OF DRUG RELEASE
The mechanism of controlled drug release into the eye is as follows:
A. Diffusion, B. Osmosis, C. Bio-erosion.
In the Diffusion mechanism the drug is released continuously at a controlled rate through the membrane into the tear fluid. If the insert is formed of a solid non-erodible body with pores and dispersed drug. The release of drug can take place via diffusion through the pores. Controlled release can be further regulated by gradual dissolution of solid dispersed drug within this matrix as a result of inward diffusion of aqueous solutions.
In a soluble device, true dissolution occurs mainly through polymer swelling. In swelling-controlled devices, the active agent is homogeneously dispersed in a glassy polymer. Since glassy polymers are essentially drug-impermeable, no diffusion through the dry matrix occurs. When the insert is placed in the eye, water from the tear fluid begins to penetrate the matrix, then swelling and consequently polymer chain relaxation and drug diffusion take place. The dissolution of the matrix, which follows the swelling process, depends on polymer structure: linear amorphous polymers dissolve much faster than cross-linked or partially crystalline polymers. Release from these devices follows in general Fickian 'square root of time' kinetics; in some instances, however, known as case II transport, zero order kinetics has been observed.
In the Osmosis mechanism, the insert comprises a transverse impermeable elastic membrane dividing the interior of the insert into a first compartment and a second compartment; the first compartment is bounded by a semi-permeable membrane and the impermeable elastic membrane, and the second compartment is bounded by an impermeable material and the elastic membrane. There is a drug release aperture in the impermeable wall of the insert. The first compartment contains a solute which cannot pass through the semi-permeable membrane and the second compartment provides a reservoir for the drug which again is in liquid or gel form.
When the insert is placed in the aqueous environment of the eye, water diffuses into the first compartment and stretches the elastic membrane to expand the first compartment and contract the second compartment so that the drug is forced through the drug release aperture.
In the Bioerosion mechanism the configuration of the body of the insert is constituted from a matrix of bioerodible material in which the drug is dispersed. Contact of the insert with tear fluid results in controlled sustained release of the drug by bioerosion of the matrix. The drug may be dispersed uniformly throughout the matrix but it is believed a more controlled release is obtained if the drug is superficially concentrated in the matrix.
In truly erodible or E-type devices, the rate of drug release is controlled by a chemical or enzymatic hydrolytic reaction that leads to polymer solubilization, or degradation to smaller, water soluble molecules. These polymers, as specified by Heller34, may undergo bulk or surface hydrolysis. Erodible inserts undergoing surface hydrolysis can display zero order release kinetics; provided that the devices maintain a constant surface geometry and that the drug is poorly water-soluble.
1.7.4 CLASSIFICATION OF OCULAR INSERTS
The inserts have been classified, on the basis of their physico-chemical behavior, as soluble (S) or insoluble (I). Only the latter types can usually deliver drugs by a variety of methods at a controlled, predetermined rate, but need removal from the eye when 'empty'. Soluble (S) inserts, also generally defined by some authors as erodible (E), are monolytic polymeric devices that undergo gradual dissolution while releasing the drug, and do not need removal. It should be pointed out that, as indicated in the article, the terms 'soluble' and 'erodible' are not interchangeable, and correspond to distinct chemical processes, even if a clear-cut distinction between the two mechanisms is sometimes difficult. True dissolution occurs mainly through polymer swelling, while erosion corresponds to a chemical or enzymatic hydrolytic process.
Hence, Ocular inserts are classified as given below;
Insoluble ocular inserts
Soluble ocular inserts
Bio erodible ocular inserts.
Insoluble ocular inserts
Inserts made up of insoluble polymer can be classified into 2 categories:
A. Reservoir systems
B. Matrix systems.
A. Reservoir systems
Each class of inserts shows different drug release profiles. The reservoir systems can release drug either by diffusion or by an osmotic process. It contains, respectively, a liquid, a gel, a colloid, a semisolid, a solid matrix, or a carrier containing drug. Carriers are made of hydrophobic, hydrophilic, organic, natural or synthetic polymers.
They have been sub-classified into:
Diffusional inserts, E.g. 'Ocuserts'
Ocusert system is a novel ocular drug delivery system based on porous membrane. The release of drug from diffusional inserts/ Ocusert is based on a diffusional release mechanism. It consists of a central reservoir of drug enclosed in specially designed microporous membrane allowing the drug to diffuse from the reservoir at a precisely determined rate.
As pointed out by Urquhart, the Ocusert pilocarpine ocular therapeutic system, developed by Alza Corporation and first marketed in the U.S.A. in 1974, is notable for several reasons. This product was the first rate-controlled, rate specified pharmaceutical for which the strength is indicated on the label by the rate(s) of drug delivery in vivo, rather than by the amount of contained drug. It provides predictable, time-independent concentrations of drug in the target tissues, a feat impossible to achieve with conventional, quantity-specified, pulse entry ophthalmic medications.
The near-constant drug concentration in ocular tissues markedly improves the selectivity of action of pilocarpine. A major advantage is that two disturbing side effects of the drug, miosis and myopia, are significantly reduced, while reduction of intraocular pressure (IOP) in glaucoma patients is fully maintained.
Two types of Ocusert are available: the Pilo-20 and Pilo-40. The former delivers the drug at a rate of 20Âµg/hr for 7 days, and the latter at a rate of 40Âµg/h for 7 days. This device, which is certainly well familiar to the readers of this review, has been exhaustively described and discussed in a series of specialized papers. Briefly, it consists of a reservoir containing pilocarpine alginate enclosed above and below by thin EVA (ethylene-vinyl acetate) membranes. The insert is encircled by a retaining ring of the same material, impregnated with titanium dioxide. The dimensions of the elliptical device are (for the 20 Âµg/hr system): major axis, 13.4 mm, minor axis, 5.7 mm, thickness, 0.3 mm. The membranes are the same in both systems, but to obtain a higher release rate, the reservoir of the 40Âµg/hr system contains about 90 mg of di (2-ethylhexyl) phthalate as a flux enhancer.
When the insert placed in the eye, water from the tear fluid begins to penetrate the matrix, then swelling and consequently polymer chain relaxation and drug diffusion take place. The dissolution of the matrix, which follows the swelling process, depends on polymers structure, linear amorphous polymer dissolve much faster than cross - linked or partially crystalline polymers
The release rate from these diffusional devices present three distinct regions as shown in
Fig.No:12 Release rate from diffusional inserts
Region A: An initial usually high drug release rate corresponding to the establishment of anequilibrium between the reservoir and the eye surface.
Region B: Rate decreases to a plateau corresponding to a steady drug release rate.
Region C: A final decrease of the release rate corresponding to the exhaustion of the drug.
The principle for its operation can be described by the Ficks diffusion equation.
J = - DA dc/dx
J - Solute flux
D - Diffusion coefficient for the drug within the polymer
A - Area of membrane
dc/dx - Drug concentration gradient within the membrane along the
direction of drug flow.
E.g.: Pilocarpine Ocusert
Fig No. 13 Dimensions of Ocusert
The use of a hydrophobic membrane that does not interact with the environment so as to change the shape (area) or diffusional characteristics as well as a reservoir with excess drug (saturated solution) to provide thermodynamic force for the drug to diffuse continuously through the rate - controlling membrane should provide a steady zero-order release rate.
Fig.No.14 Schematic Diagram of an Ocusert System
2. Osmotic insert
The osmotic inserts are generally composed of a central part surrounded by a peripheral part and are of two types:
Type 1: The central part is composed of a single reservoir of a drug with or without an additional osmotic solute dispersed throughout a polymeric matrix, so that the drug is surrounded by the polymer as discrete small deposits. The second peripheral part of these inserts comprises a covering film made of an insoluble semi-permeable polymer. The osmotic pressure against the polymer matrix causes its rupture in the form of apertures. Drug is then released through these apertures from the deposits near the surface of the device.Type 2: The central part is composed of two distinct compartments. The drug and the osmotic solutes are placed in1 two separate compartments, the drug reservoir being surrounded by an elastic impermeable membrane and the osmotic solute reservoir by a semi-permeable membrane. The second peripheral part is similar to that of type1. The tear diffuse into the osmotic compartment inducing an osmotic pressure that stretches the elastic membrane and contracts the compartment including the drug, so that the active component is forced through the single drug release aperture.
B. Matrix systems
The second category, matrix system, is a particular group of insoluble ophthalmic devices mainly represented by contact lenses. It comprises of covalently cross linked hydrophilic or hydrophobic polymer that forms a three dimensional network or matrix capable of retaining water, aqueous drug solution or solid components. The hydrophilic or hydrophobic polymer swells by absorbing water. The swelling caused by the osmotic pressure of the polymer segments is opposed by the elastic retroactive forces arising along the chains or crosslinks are stretched until a final swelling (equilibrium) is reached.
1. Contact lenses
Contact lenses are shaped structures and initially used for vision correction. Their use has been extended as potential drug delivery devices by presoaking them in drug solutions. The main advantage of this system is the possibility of correcting vision and releasing drug simultaneously has proposed a subdivision of Contact lenses into 5 groups.
Rigid contact lenses have the disadvantage of being composed of polymers (e.g., Poly methyl methacrylic acid) hardly permeable to moisture and oxygen, a problem which has been overcome by using gas permeable polymers such as cellulose acetate butyrate. However, these systems are not suitable for prolonged delivery of drugs to the eye and their rigidity makes them very uncomfortable to wear. For this reason, soft hydrophilic contact lenses were developed for prolonged release of drugs such as pilocarpine, chloramphenicol and tetracycline prednisolone sodium phosphate. The most common used polymer in the composition of these types of lenses is hydroxy ethyl methyl metacrylic acid copolymerized with poly (vinyl pyrrolidone) or ethylene glycol dimethacrylic acid (EGDM). Poly (vinyl pyrrolidone) is used for increasing water of hydration, while EGDM is used to decrease the water of hydration. The soft hydrophilic contact lenses are very popular because they are easy to fit and are tolerated better. The drug incorporation into contact lenses depends on whether their structure is hydrophilic or hydrophobic. When contact lens (including 35 to 80% water) is soaked in solution, it absorbs the drug. Drug release depends markedly on the amount of drug, the soaking time of the contact lens and the drug concentration in the soaking solution.
II. Soluble ocular inserts
These soluble inserts offer the advantage of being entirely soluble so that they do not need to be removed from their site of application, thus limiting the intervention to insertion only.
They can be broadly divided in to two types, the first one being based on natural Polymers and the other on synthetic or semi-synthetic polymers.
A. Natural polymers
The first type of soluble inserts is based on natural polymer. Natural polymer used to produce soluble ophthalmic inserts is preferably collagen. The therapeutic agent is preferably absorbed by soaking the insert in a solution containing the drug, drying and re-hydrating it before use on the eye. The amount of drug loaded will depend on the amount of binding agent present, the concentration of the drug solution into which the composite is soaked as well as the duration of the soaking. As the collagen dissolves, the drug is gradually released from the interstics between the collagen molecules.
B. Synthetic and Semi-Synthetic Polymer
The second type of soluble insert is usually based on semi-synthetic polymers (e.g., cellulose derivatives) or on synthetic polymers such as polyvinyl alcohol A decrease of release rate can be obtained by using Eudragit, a polymer normally used for enteric coating, as a coating agent of the insert. Saettone et al. have observed in rabbits that Eudragit coated inserts containing pilocarpine induced a miotic effect of a longer duration, compared to the corresponding uncoated ones. However, the inherent problems encountered with these soluble inserts are the rapid penetration of the lachrymal fluid into the device, the blurred vision caused by the solubilization of insert components and the risk of expulsion due to the initial dry and glassy consistency of the device.13 Ethyl cellulose, a hydrophobic polymer, can be used to decrease the deformation of the insert and thus to prevent blurred vision. As for the risk of expulsion, several authors have incorporated carbomer, a strong but well tolerated bio-adhesive polymer.
The soluble inserts offer the additional advantage of being of a generally simple design, of being based on products well adapted for ophthalmic use and easily processed by conventional methods. The main advantage is decreased release rate, but still controlled by diffusion.
III. Bio-erodible ocular inserts
These inserts are formed by bio-erodible polymers (e.g. cross-linked gelatin derivatives, polyester derivatives) which undergo hydrolysis of chemical bonds and hence dissolution. The great advantage of these bio-erodible polymers is the possibility of modulating their erosion rate by modifying their final structure during synthesis and by addition of anionic or cationic surfactants.
A cross-linked gelatin insert was used by Attia et al. in order to increase bioavailability of dexamethasone in the rabbit eye. The dexamethasone levels in the aqueous humor were found to be four-fold greater compared to a dexamethasone suspension.
However, erodible systems can have significantly variable erosion rates based on individual patient physiology and lachrimation patterns, while degradation products and residual solvents used during the polymer preparation can cause inflammatory reaction.
Currently investigated ocular inserts containing anti-glaucoma, antibacterial, anti-inflammatory or anti-viral drugs for ocular delivery .