Final Report Gajendra Sharma

8/6/2019 Final Report Gajendra Sharma

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1. INTRODUCTION

Drug delivery is the method or process of administering a pharmaceutical compound

to achieve a therapeutic effect in humans or animals, Drug delivery technologies are

patent protected formulation technologies that modify drug release profile, absorption,

distribution and elimination for the benefit of improving product efficacy and safety,

as well as patient convenience and compliance. Most common methods of delivery

include the preferred non-invasive peroral (through the mouth), topical (skin),

transmucosal (nasal, buccal/sublingual, vaginal, ocular and rectal) and inhalation

routes. Many medications such as peptide and protein, antibody, vaccine and gene

based drugs, in general may not be delivered using these routes because they might be

susceptible to enzymatic degradation or can not be absorbed into the systemiccirculation efficiently due to molecular size and charge issues to be therapeutically

effective. For this reason many protein and peptide drugs have to be delivered by

injection. For example, many immunizations are based on the delivery of protein

drugs and are often done by injection.

Eye, an organ of vision that detects light.

Eyes are organs that detect light, and send signals along the optic nerve to the

visual and other areas of the brain. Complex optical systems with resolving power

have come in ten fundamentally different forms, and 96% of animal species

possess a complex optical system. Image-resolving eyes are present in cnidaria,

mollusks, chordates, annelids and arthropods.

The simplest "eyes", in even unicellular organisms, do nothing but detect whether thesurroundings are light or dark, which is sufficient for the entrainment of circadian

rhythms. From more complex eyes, retinal photosensitive ganglion cells send signals

along the retinohypothalamic tract to the suprachiasmatic nuclei to effect circadian

adjustment.

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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. Therefore, the target tissue absorbs a very small fraction 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. One of the new classes

of drug delivery systems, polymeric film oculardrug delivery systems/ocular inserts,which are gaining worldwide accolade, release drugs at a pre-programmed rate for a

longer period by increasing the pre-corneal residence time.

Eye is a highly specialized organ of photoreception, the organ of the sense of sight,

and it serves as a model structure for the evaluation of drug activity. In no other organ

can practitioner. Without surgical or mechanical intervention. So will observe the

activity of the drug being administered. With such modern instrumentation as the

biomicroscope and the secular microscope the ophthalmologist can readily view most

of the ocular disease or dysfunction. Although ocular disease can be treated by system

route of drug administration, drudge dosed topically on the eye can Pete rate the

cornea and gain access to discussed tissues.

The eye topically absorbs less than 10 of the drugs contained in the eye drop. Theremainder is lost by drainage either by spillage or normal tear turnover, nonproductive

drug absorption (mainly by conjunctiva) and binding of the drug to proteins and other

components of tear fluids[l] Ophthalmic absorption of drugs has many limitations as

compared to the gastrointestinal absorption. Such as

The reduced residence time of an instilled ophthalmic dose.

Non- productive absorption/adsorption[2]

The small surface area offered by the cornea for the absorption.

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Tearing in the eye which dilutes and rapidly drains a portion of the instilled dose

into the nasolacrimal duct thereby reducing corneal absorption.

The narrow pH range offered by the eye.

Tear evaporation.

Drug protein interaction.

Kabs

Personal Cavity------ Cornea

Kloss

Elimination processes

Scheme 1.

Instilled Dose

Drug

metabolism

Normal tear turn over

Scheme 2. Elimination of instilled dose via different routes

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Optimization of relevant formulation parameters can increase the ocular availability

and then the dose and therefore systemic concentration can be reduced while

maintaining therapeutic ocular concentrations.

Like most others products in the medical armamentarium, ophthalmic products are

currently undergoing a process termed optimization new modes of delivering a drug

to the eye are being explored and efforts made for improving the topical

bioavailability of ophthalmic drugs. Generally efforts have been directed along the

following lines:

1. Prolongation of the ocular residence time of the medicine.

2. enhancement of corneal permeability (enhancer approach)

3. increasing drug penetration characteristic(chemical approach)

4. use of phase transition systems

5. use of liposomes preparation

6. use of cyclodextrins

7. use of Nan particle preparation

Ideal ophthalmic drug delivery must be able to sustain the drug release and to remain

in the vicinity of front of the eye for prolong period of time. Consequently it is

imperative to optimize ophthalmic drug delivery, one of the way to do so is by

addition of polymers of various grades, development of viscous gel, development of

colloidal suspension or using erodible or non erodible insert to prolong the precornealdrug retention[6,7]. Bioadhesive systems utilized can be either microparticle

suspension[8] or polymeric solution[9]. For small and medium sized peptides major

resistance is not size but charge, it is found that cornea offers more resistance to

negatively charged compounds as compared to positively charged compounds.

Following characteristics are required to optimize ocular drug delivery system:

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Good corneal penetration.

Prolong contact time with corneal tissue.

Simplicity of instillation for the patient.

Non irritative and comfortable form (viscous solution should not provoke

lachrymal secretion and reflex blinking)

Appropriate rheological properties and concentrations of the viscous system.

Although lot of alternative dosage forms have been tested to avoid the drawbacks of

conventional ophthalmic dosage form in last few years, each has been found to be

deficient in one or more ways. The focus of this review is on the recent developments

in topical ocular drug delivery systems, the characteristic advantages and limitations

of each system.

For ailments of the eye, topical administration is usually preferred over systemic

administration for obvious reasons:

The systemic toxicity of many ophthalmic drugs, The rapid onset of action , and

The smaller does required compared to the systemic route

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2. OCULAR DYSFUNCTION AND DISEASES

Different diseases can affect the functioning of the eye. The most commonly

encountered diseases:

2.1 Diseases of Conjunctive, e.g. Conjunction

Conjunctives may be caused by exogenous factoreds (microorganisms foreign bodies

or chamicals) or allergic response) common symptoms are irritation and itching

following by inflammation photophobia and watering of eyes

2.2 Diseases of Cornea.

Corneal edema keratitis and corneal illness anterior segment of the eye.

2.3 Glaucoma.

Glaucoma is the condition of the eye in which an elevation of intraocular pressure

leads to progressive cupping and atrophy of the optic nerve head, deterioration of the

visual fields and ultimately blindness

2.4 Diseases of the Lens e.g. Cataract

Cataract may be defined as opacity in the lens that results in decreased visual activity,

glare and contrast sensitivity. Cataract may be classified as

Nuclear cataract: when opacity is found in lens nucleus.

Cortical cataract: when opacity is found in lens cortex. Posterior sub capsular cataract; when opacity is found in the back of lens adjacent

to lens capsule.

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2.5 Acanthamoeba Keratitis

Corneal infection with acanthamoeba is believed or result from direct corneal contact

with contaminated material or water contact lenses remain the most common risk

factor for developments of acanthamoeba keratitis.

Recent studies have noted additional risk factor 40-91% of contact lens wearers these

factors include swimming with lenses, irregular or inadequate dis-infection cleaning

the lens case with tap water minor corneal trauma and exposure to contaminated

water.

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3. ABSORPTION OF DRUGS IN EYE

It is often assumed that drugs administered into the eye are rapidly and totally

absorbed .however, contrary to this belief, the moment drugs is placed in the lower

cul-de-sac of eye; several factors immediately begin to affect the availability of

drugs .absorption of drugs takes place either through corneal or no corneal route. The

no corneal route involves intraocular tissues. This route is however not productive as

it restrains the entry of drug into aqueous humor maximum absorption thus takes

place through cornea, which leads the drug into aqueous humor.

The goal of ophthalmic drug delivery systems has traditionally been maximize ocular

drug absorption rather to minimize systemic absorption.

For ailments of the eye, topical administration is usually preferred over systemic

administration for obvious reasons:

The systemic toxicity of many ophthalmic drugs,

The rapid onset of action , and

The smaller does required compared to the systemic route

3.1 Drug Elimination From Lacrimal Fluid

Designing formulations and delivery systems for ophthalmic use has always intrigued

the formulator as most of the volume of liquid dosage forms liquid solutionsuspensions and liposome's is either drained from conjunctivital into nasolachrymal

duct or is cleared from pre corneal area resulting in poor bio-availability of drugs

.drugs are mainly from the pre corneal lacrimal fluid by solution drainage, lacrimation

and nonproductive absorption to the conjunctive 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 .

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3.1.1 Spillage Of Drug By Over Flow

The normal volume of tears is 7 ul and if blinking does not occur the human eye can

accommodate 30 ul without spillage from the palpebral fissure. With an estimated

drop volume of 50 ul, 70% of administered dose is expelled from the eye by over flow

and if blinking occurs only the residual volume approximately 10 ul is left indicating

that 90% of the dose is expelled.

3.1.2 Dilution Of Drug By Tear Turns OverTear turn out to have a major share in removing drug solution from conjunctivital cul-

de-sac. Normal human tear turn over is approximately 16% per minute, which is

stimulated by many factors like drug entity, pH, tonicity of dosage from and

formulation adjuvants. These factors render topical applications of ophthalmic

solutions into cul-de-sac extremely inefficient

3.1.3 Nasolacrimal Drainage /Systemic Drug Absorption

Most of the administered drug is lost through nasolacrimal drainage immediately after

dosing .the drainage allows drugs to be systemically absorbed across the nasal mucosa

and the gastrointestinal tract leading to multifarious effects. One such drug is timolol,

which possess serous risk on systemic absorption. It was reported that 450 cases side

effects of timolol resulting in deaths of 32 patients due to bronchospasm and

cardiovascular effects. Another mechanism that competes for the drug absorption into

the eye is the superficial absorption of drug into pleural and bulbar conjunctive with

concomitant removal from the ocular tissues by peripheral blood streams.

3.1.4 Enzymatic Metabolism

Enzymatic metabolism may operate in the per corneal space or in the corneal, which

results in the further loss of those drug entities possessing labile bonds. Competing

with the foregoing forms of drugs removal is the Tran corneal absorption, the routethat effectively brings the drugs though absorption into the aqueous humor .clearly the

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physiological barriers restraining the entry of drug into eye are formidable, restricting

the bioavailability to 1-3% of the instilled dose .in order to overcome this, frequent

doses of drugs at very high concentration are recommended. This type of pulsed

dosing not only results in extreme fluctuation in ocular drug concentration but also

leads to many untoward side-effects.

3.2 Trans Corneal Penetration

Tran corneal penetration of drug is mainly affected by corneal barriers.

Physicochemical properties of drugs and active ion transport systems present at

cornea.

Successful delivery of drugs into the eye is extremely complicated because the eye

isprotected by a series of complex defense mechanisms that make it difficult to

achieve an effective concentration of the drug within the target area of the eye. Drugs

delivered in classical ophthalmic dosage forms (eye drops) into the lower cul-de-sac

have a poor bioavailability due to these complex defense mechanisms. Furthermore,

drugs administered systemically for their ocular action have poor access to the eye

tissue because of the blood- aqueous barrier, which prevents drugs from entering the

extravascular retinal space and the vitreous body.

After topical administration of an ophthalmic drug solution, the drug has to cross a

succession of anatomical barriers before reaching the systemic circulation. These

barriers (as shown figure) can be commonly classified as precorneal and corneal

barriers.

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Fig No. 2

3.2.1 Precorneal Barriers

The precorneal barriers are the first barriers that slow down the penetration of an

active ingredient into the eye. They are comprised of the tear film and the conjunctiva.

1. TEAR FILM: Precorneal tear film can be considered as being made up of three

layers. These layers are

a. Superficial lipid layer: The superficial lipid layer is 0 .1 mm thick and derived

from the meibomian glands and the accessory sebaceous glands of Zeiss. This

layer is composed of esters, triacylglycerols, free sterols, sterol esters, and free fattyacids.

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(nyaropnIIIc)

Drug--protein pHinteraction difference

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b. Aqueous layer: The aqueous layer is about 7 mm thick and secreted by the

lachrymal gland and the accessory glands of Krauss and Wolfring. This layer

Stroma (hydrophilic) Poor bioavailability Epithelium (lipophilic) Noncornealabsorption Limited permeability of cornea Endothelium (lipophilic) Normal tear

turnover Dilution gradient for transport Drainage Nasolacrimal drainage Overflow

Drug metabolism Precorneal factors (trilamellate structure) pH difference Drug

protein interaction contains inorganic salts, glucose, and urea as well as

biopolymers, proteins, and glycoproteins.

c. Mucus layer: The mucus layer forms the bottom layer of the tear film lyingadjacent to and wetting the corneal epithelium. It is elaborated by the goblet cells

of the conjunctiva and forms a bridge between the hydrophobic corneal epithelial

surface and the aqueous layer of the tear film lying immediately above it. The

composition of mucus varies widely depending on the animal species, the

anatomical location, and the normal or pathological state of the organism. Its

major constituents are the high molecular weight glycoproteins capable of forming

slimy and viscoelastic gels containing more than 95% water. These glycoproteinsform disulfide as well as ionic bonds and physical entanglements, and consist of a

peptide backbone, a major portion of which is covered with carbohydrates

(grouped in various combinations) such as galactose, fructose, N-acetyl

glucosamine, and sialic acid. At physiological pH, the mucus network usually

carries a significant negative charge because of the presence of sialic acid and

sulfate residues.

The tear film fulfills several important functions in the eye such as formation and

maintenance of a smooth refracting surface over the cornea, lubrication of the eyelids,

transportation of metabolic products (02 and C02) to and from the epithelial cells and

cornea, and elimination of foreign substances and bactericidal action. Tear film

factors that can influence the ocular bioavailability of a drug are as follows:

1. Solution drainage rate to the nasolachrymal duct

2. Lacrimation and tear turnover causing dilution

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3. Drug binding to tear proteins resulting in a lower free drug concentration for

ocular absorption

4. Enzyme metabolization of drugs

5. Electrolyte composition of tears

6. pH and buffer capacity of tears, which can also influence the therapeutic effect

of drugs, their toxicity, and their stability After ocular instillation, aqueous eye

drop solutions and suspensions mix with the tear fluid and are dispersed over

the eye surface. The greater part of the applied drug Superficial oily layer

Corneal epithelial cells Mucous layer Aqueous layer.

Fig No. 3

3.2.2 Corneal Barriers

The stratified corneal epithelium acts as a protective barrier against invasion of foreign molecules and also as a barrier to ion transport. The corneal epithelium consist

of a basal layer of columnar cells, two to three layers of wing cells and shaped

superficial cells. In healthy corneal epithelium intercellular tight junctions (zonal

occludes) completely surround the most superficial between wing cells and basal

cells. This allows the Para cellular diffusion of 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. It was found by perfusion studies that small molecules (glycerol, MW92 ,0.6 mm and PEG200, 400)

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are able to penetrate through intercellular spaces of corneal epithelium, but inulin

(MW 5000, 1.5 nm) and horseradish peroxide (MW 40,00, about 3nm) are molecules

that are too large for paracellular penetration across the epithelium.

Corneal stroma is a highly hydrophilic tissue containing mostly water. Due to

relatively open structure, drugs with molecular size up to 500000 can diffuse in

normal stroma. Hydrophilic corneal of most lipophilic drugs. The corneal

endothelium is responsible for maintaining Normal corneal hydration and it has been

estimated that drugs with molecular dimensions up to about 20 nm can diffuse across

normal epithelium.

3.2.3 Physiochemical Properties Of Drug.

Transcelluiar 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 space while

lipophilic drugs prefer the transcelluiar route. For topically applied drugs, passive

diffusion along their concentration gradient is the main permeation mechanism. On

the contrary, Na-K-ATPase pump is involved in corneal transport system. While for

drug-loaded nanoparticles of poly (e-caprolactone) nanocapsules and insulin have

been reported to follow endocentric pathway Lipophilicity, solubility, molecular size

and shape, charge and degree of ionization also affect the route and rate of penetration

through cornea. Chemical equilibrium between ionized and unionized drug in eye

drop and in lacrimal fluid affect the penetration of ionizable drug e.g. weak acid and

weak bases. Unionized species usually penetrates the lipid membranes more easily.

For example pilocarpine (free base) and timolol base penetrate better than its ionized

form.

Various esterases, peptidases, proteases and other enzymes are present in the ocular

tissue including cornea. Consequently, many ocularly applied drugs are metabolized

during or after absorption (e.g. pilocarpine, levobunolol, and epinephrine).

3.3 Non-Corneal Absorption

Apart from corneal route topically applied ocular drugs may be absorbed through non-corneal route. This route involves drug penetration across the bulbar conjunctiva and

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underlying sclera into the uveal tract and vitreous humor. This route is important for

hydrophilic and large molecules, such as insulin and p-amminoclonidine, which have

poor corneal permeability.

Tight junctions of the superficial conjunctival epithelium are main barrier for drug

penetration. Conjunctivae permeabilities for hydrophilic drugs are typically an order

of magnitude greater than their corneal permeability. The limiting molecular size for

conjunctival penetration is between 20000 and 40000.

Ocularly applied drugs penetrate across the sclera through perivasular spaces, through

the aqueous media of gel-like mucopolysachrides or through empty spaces within

collagen network. Sclera is more permeable in comparison to cornea.

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4. FORMULATION AND APPROACHES TO

IMPROVE OCULAR BIOAVAILABILITY

4.1 Ophthalmic Inserts :

Ophthalmic inserts are defined as preparations with a solid or semisolid consistency

the size and shape of which are especially designed for ophthalmic application viz

rods or shields These inserts are placed in the lower fornex and less frequently in the

upper fornix or on the cornea They are usually composed of a polymeric vehicle

contating the drug and are mainly used for topical therapy further advantages of

inserts over other drug delivery systems are Accurate dosing Absence of preservativesIncreased shelf life due to the absence of water. These are classified according to their

solubility behavior and bioerodibility

OPHTHALMIC INSERTS

Insoluble

Soluble

Bioerodible

4.1.1 Insoluble Inserts

Insoluble inserts can be classified into three categories

Osmotic systems

Hydrophilic contact lenses

Diffusion

Each class of insert stows a different drug release profile. Diffusion and osmotic

systems contain a reservoir that is in contact with the inner surface of the drug rate

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and contracts the compartment containing the drug, so that the active compound is

forced through the single drug release aperture.

4.1.1.2 Contact Lenses

The initial use of contact lenses was for vision correction. The use of contact lenses

has been extended as potential drug delivery devices by presoaking them in drug

solution. The main advantage of this system is the possibility of correcting vision and

releasing drug simultaneously . contact lenses are composed of a hydrophilic of

hydrophilic polymer that 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 as cross-links are stretched until a final swelling(equilibrium)

is reached .

Refojo has subdivided contact lenses into five groups, namely

Rigid

Semi rigid

Elastomeric

Soft hydrophilic

Bio polymeric

Rigid contact lenses have the disadvantage of being composed of polymers (e.g. ,

pmma) hardly permeable to moisture and oxygen .more over , these systems are not

suitable for prolonged delivery of drug to the eye and their rigidity makes them very

uncomfortable to wear, the permeability problem was resolved using gas permeable

polymers such as cellulose acetate butyrate. However the discomfort associated with

the foreign object and long adaptation period remain the shortcomings of rigid contact

lenses . for this reason soft hydrophilic contact lenses were developed for prolonged

release of drugs such as pilocarpine, chloramphenicol and tetracycline , and

prednisolone sodium phosphate .the most commonly used polymer in the composition

of these types of lenses is HEMM copolymerzied with PVP .shell and baker have

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shown that drug release from presoaked contact lenses was extremely rapid , with an

in vivo residence time in general not longer than 24h disposable contact lenses have

been commercially available for many years already , and the continued progress

made in polymer chemistry should facilitate the development of this type of inserts.

Soft Contact Lenses

These form a special class of insoluble ophthalmic inserts. The most widely used

material for these is poly-2-hydroxyethyl methacrylate. Its copolymers with PVP are

used both to correct eyesight and to hold and deliver drugs. The latter is possible

because of the tendency of its constituent polymers to absorb up to 80% water (163).

The active ingredient is incorporated either by prior soaking or instillation after fitting

the lens, or both. Since the drug is not bound to the matrix, it dissolves rapidly in the

tears and its release cannot be accurately controlled. However, a controlled release

could be obtained by binding the active ingredient via biodegradable covalent

linkages

4.1.1.3 Diffusional Inserts

Diffusional inserts consists of a central reservoir of drug enclosed in specially

designed semi permeable or micro porous membranes allowing the drug to diffuse

from the reservoir at a precisely determined rate. Drug release from such a system is

controlled by the lachrymal fluid permeating through the membrane until a sufficient

internal pressure is reached to drive the drug out of the reservoir. These diffusional

systems prevent a continuous decrease in release rate by the use of a barrier

membrane of fixed thickness , resulting in a zero order release pattern.

Ocusert is undoubtedly the most commonly described insoluble insert in the literature

this flat , flexible , elliptical device consist of a pilocarpine reservoir with alginic

acid , a mixture surrounded on both sides by a membrane of ethylene- vinyl acetate

copolymer . the devices is encircled by a retaining ring impregnated with titanium

dioxide. Two types of ocusert are available for humans: the pilo-20 and pilo-40,

providing two different release rates for pilocarpine (20 ug/ and 40 ug/h respectively)

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over a period o seven days .these are solid devices intended to be placed in the

conjucnctival sac and to deliver the drug at a comparatively slow rate.

These devices might present valuable advantage, such as:

Increased ocular permanence with respect to standard vehicles hence

prolonged drug activity and a higher drug bio availability .

Increased ocular contact time .

Accurate dosing (theoretically all of the drug is retained at the absorption site)

Capability to provide in some cases a constant rate of drug release .

Possible reduction to systemic absorption which occurs freely with standard

eye drops via the nasal mucosa:

Better patient compliance resulting from a reduced frequency of medication

and a lower incidence of visual and systemic side -effects.

Possibility of targeting internal ocular tissues through non corneal conjuntival

- scleral penetration routes and

Increased shelf life with respect to eye drops due to the absence of water 2.

Another potential advantage of ocular insert therapy is the possibility of promoting non-corneal drug penetration, thus increasing the efficacy of some

hydrophilic drugs that are poorly absorbed through the cornea.

4.1.2 Soluble Inserts

These consist of all monolithic polymeric devices that at the of their release are no

longer present in the either because of dissolution or erosion. These devices are

further classified into the following.

4.1.2.1 Soluble Ophthalmic Drug Inserts (Sodi)

A SODI is a soluble copolymer of acryl amide, N-vinyl pyrrolidone and ethyl acryl

ate. It is in the form of sterile thin films or wafers of oval shape, weighing 15 to 16

mg. After introduction into the upper conjunctival sac, the SODI softens in 10 to 15

sec, conforming to the shape of the eyeball; in the next 10 to 15 min the film turnsinto a polymeric clot, which gradually dissolves within lhr, while releasing the drug.

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Release of the drug from the SODI is proposed to occur in two stages: hydration of

the matrix by penetration of dissolution medium; and diffusion of the medium deep

into the matrix and back-diffusion of the dissolved active principle [31]. Problemsassociated with these films include individual tolerance and trained personnel for its

application.

4.1.2.2 Bioadhesive Ophthalmic Drug Inserts (Bodi)

The main problem encountered with conventional ophthalmic inserts is their site of

application and the risk of expulsion from the site. To over come this drawback, a

new type of ophthalmic insert incorporating a water-soluble bioadhesive component

in its formulation has been developed to decrease the risk of expulsion and ensure

prolonged residence in the eye, combined with controlled drug release.

These inserts, named BODI, are totally eliminated so that they do not need to be

removed, thus limiting manipulation to insertion only A BODI based on gentamicin,

obtained by extrusion of a mixture of polymers, 5mm long by 2mm in diameter,showing a release time of about 72 hr has been reported. The BODI drastically

diminished the risk of expulsion. Tolerance studies confirmed the validity of the

concept[32].

4.1.2.3 Collagen Shields/Bioerodible Inserts

Succinylated collagen was used to fabricate erodible inserts for placement in the

fornix for long term delivery of gentamicin into the eye. Collagen shields are

manufactured from porcine scleral tissue, which bears a collagen composition similar

to that of the human cornea. The shields are hydrated before being placed on the eye,

having been stored in a dehydrated state. The drug is loaded into the collagen shield

simply by soaking it in the drug solution.

It forms a clear, pliable, thin film, approximately 0.1 mm in thickness, with a basecurve of 9mm that conforms to the corneal surface. Designed to slowly dissolve

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within 12, 24, or 72 hr, the shield has stimulated much interest as a potential sustained

ocular delivery system. As the shields dissolve, they provide a layer of collagen

solution that seems to lubricate the surface of the eye, minimize rubbing of the lids on

the cornea, and foster epithelial healing. Moreover, shields are not individually fit for

each patient (as are soft contact lenses), the insertion technique is difficult, and

expulsion of the shield may occur . Also, the shields are not fully transparent and thus

reduce visual acuity.

ADVANTAGES OF OCULAR INSERTS

Ocular inserts offer several advantages, which can be summarized as follows:

(a) Increased ocular residence, hence a prolonged drug activity and a

higherbioavailability with respect to standard vehicles;

(b) Possibility of releasing drugs at a slow, constant rate;

(c) Accurate dosing (contrary to eye drops that can be improperly instilled by the

patient and are partially lost after administration, each insert can be made to

contain a precise dose which is fully retained at the administration site);

(d) Reduction of systemic absorption (which occurs freely with eye drops via thenaso-laerimal duct and nasal mucosa);

(e) Better patient compliance, resulting from a reduced frequency of administration

and a lower incidence of visual and systemic side-effects;

(f) Possibility of targeting internal ocular tissues through non-corneal (conjunctival

scleral) routes;

(g) Increased shelf life with respect to aqueous solutions;

(h) Exclusion of preservatives, thus reducing the risk of sensitivity reactions;

(i) Possibility of incorporating various novel chemical/ technological approaches.

Such as pro-drugs, mucoadhesives, permeation enhancers, microparticulates, salts

acting as buffers, etc. The potential advantages offered by inserts clearly explain why

an active interest has been dedicated to these dosage forms in recent years, and why

efforts to introduce them on the pharmaceutical market continue. Of course, not all of

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the benefits listed above can be present in a single, ideal device. Each type of insert

represents a compromise between the desirable properties inherent to solid dosage

forms and negative constraints imposed by the structure and components of the insert

itself, by fabrication costs, as well as by the physical/physiological constraints of the

application site.

DISADVANTAGES OF OCULAR INSERTS

The disadvantages of ocular inserts are as follows:

(a) A capital disadvantage of ocular inserts resides in their 'solidity', i.e., in

the

fact that they are felt by the (often oversensitive) patients as an extraneous

body in the eye. This may constitute a formidable physical and psychological

barrier to user acceptance and compliance.

(b) Their movement around the eye, in rare instances, the simple removal

is

made more difficult by unwanted migration of the insert to the upper fornix,

(c) The occasional inadvertent loss during sleep or while rubbing the eyes,

(d) Their interference with vision, and

(e) Difficult placement of the ocular inserts (and removal, for insoluble

types).

4.2 Formulation Of Ocuscrts

While preparing ocuserts following factors are required to be considered

4.2.1 Polymers

The release of drug from ocuserts depends on the concentration & nature of the

polymers. So proper selection of the polymer in proper concentration should be done

before formulation the ocuserts. Different polymers which are used for the ocusert

formulation include.

Hydroxypropylmethylcellulose

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Ethyl Cellulose

Sodium Carboxy methyl cellulose

Methyl cellulose

Cellulose acetate

Sodium alginate

Eudragits etc,

4.2.2 Plasticizers

The polymer should be compatible with the drug .it should be nontoxic and nonirritantto eye and in proper concentration.

Example-

PEG 400

PEG 600

Glycerin

Dibutylphthalate

Diethyalphthalate

4.2.3 Prepration

Generally ocuserts are prepared by solvent casting method :-

4.2.3.1 Preparation Of The Rate Controlling Membrane-

The polymers are dissolved in solvent and plasticizer is added to this slurry and

sonicated it.this solution is casted on some mould (mercury surface.) after drying at

room temperature for 24 hrs circular films of specified diameter are cut.

4.2.3.2 Preparation Of The Drug Reservoir-

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The polymer with drug are dissolved in solvent and plasticizer is added to this slurry

and sonicated it.this solution is casted on some mould (mercury surface.) after drying

at room temperature for 24 hrs circular films of specified diameter are cut.

4.2.3.3 Sealing Of The Rate Controlling Membrane And Drug Reservoir-

The sealing is done by sandwiching the drug reservoir between two rate controlling

membranes.it is done in such a way so as to control the release from periphery.

4.3 Dosage Forms Affecting Precorneal Parameters / Conventional Dosage

Forms

The diseases of the eyes are being treated with conventional ocular formulations ( eye

solutions , suspensions ointments, gels) these are associated with patient and

bioavailability related disadvantages maximizing personal drug absorption and

minimizing the personal drug loss can improve topical bioavailability. Several

formulation approaches have been tread like use of viscosity enhancers, penetration

enhancers in order to improve ocular availability of drugs[7] topical ocular delivery

systems like solutions , suspensions, emulsions, ointments gels have some

disadvantages as compared to ocuserts which are outlined as under

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TABLE .1 CONVENTIONAL OCULAR DRUG DELIVERY SYSTEMS

S.NO. DOSAGE FORM DISADVANTAGES

1 SOLUTIONS RAPID PRECORNEAL LOSS LOSS OF

BOTH SOLUTION AND SUSPENDED

SOLID NO SUSTAINED ACTION

2 SUSPENSIONS DRUG PROPERTIES DECIDE

PERPFORMANCEA LOSS OF BOTH

SOLUTION AND SUSPENDEDSOLID

3 EMULSIONS PATIENT NON COMPLIANCE BLURRED

VISION POSSIBLE OLL ENTRAPMANT

4 OINTMENTS STICKING OF EYE LIDS POOR PATINT

COMPLIANCE BLURRED VISION NO

TRUE SUSTAINED EFFECT DRUG

CHOICE LIMITED BY PARTITION

COEFFCIENT NO RATE CONTROL ON

DIFFUSION MATTED EYELIDS AFTER

USE

4.3.1 Aqueous Gels/ Hydrogels

In order to increase the contact time between the drug and the ocular surface, and thus

improve the biovailability of the applied drug, a number of water-soluble or insoluble

natural, synthetic, and semi-synthetic viscous vehicles have been developed during

the last 50 years. The aqueous gels typically utilize such polymers as polyvinyl

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alcohol (PVA), polyacrylamide, poloxamer, hydroxypropyl methylcellulose (HPMC),

and carbomer.

Swellable water-insoluble polymers, called hydrogels, or polymers having peculiar

characteristics of swelling in aqueous medium give controlled drug delivery systems.The release of a drug from these systems occurs via the transport of the solvent into

the polymer matrix, leading to its swelling. The final step involves the diffusion of the

solute through the swollen polymer, leading to erosion / dissolution.but they have the

disadvantage of producing blurred vision[8]. There is no rate control on the diffusion

of the drug from the gels. The drawbacks of difficulty in sterilization and easy

bacterial contamination have thus far limited their large scale production and clinical

use. Moreover, these agents are usually biocompatible

4.3.1.1 Viscosity-Imparting Agents

Viscosity-increasing polymers are usually added to ophthalmic drug solutions on the

premise that an increased vehicle viscosity should correspond to a slower elimination

from preocular area and hence a greater Tran corneal penetration of the drug into the

anterior chamber [9]. The polymers used include PVA, polyvinylpyrrolidine (PVP),

methylcellulose, hydroxyethyl cellulose, HPMC, and hydroxypropyl cellulose (HPC).

An increase in viscosity of a formulation by addition of Anthon gum, which is a

polysaccharide, was found to delay the clearance of the instilled solution by the tear

flow. The corneal contact time of these formulation was evaluated over a period of

more than 20 min by gamma scintigraphy [10], Saettone et all indicated that the

retention of drug in the precorneal tear film is not strictly related to the viscosity of

the vehicle, but rather to the surface spreading characteristics of the vehicle and to the

ability of a polymer to drag water as the vehicle spreads over the ocular surface with

each blink.

4.3.1.2 Use Of Cyclodextrins To Increase The Solubility Of Drugs In Aqueous

Eye Drop Solutions

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The solubilizing abilities of cyclodextrins depend largely on their abilities to form

water-soluble drug-cyclodextrin complexes. Cyclodextrins act as true carriers by

keeping the hydrophobic drug molecules in solution and delivering them to the

surface of the biological membrane, where the relatively lipophilic membrane has a

much lower affinity for the hydrophilic cyclodextrin molecules and therefore they

remain in the aqueous vehicle system or aqueous tear fluid. An optimum

bioavailability would be expected when just enough cyclodextrin (10 um in size.

A newer concept in suspensions is the use of micro spheres or micro particulates.

These are drug containing small polymeric particles that are suspended in a liquid

carrier medium.

Newer approaches such as the use of mucoadhesive particulates [13], pH-responsive

particulates, nanoparticles [14,15], etc., have also been used to formulate micro

particulate dosage forms. These dosage forms show significantly higher and sustained

delivery in the eye [16,17].

4.3.3 Ophthalmic Sprays

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Brij 35, Brij 78, Brij 98, ethylenediaminetetraacetic acid (EDTA)[7], bile salts, and

bile acids.

Another class of permeation promoters is calcium chelators like EDTA, which act by

loosening tight junctions between superficial epithelial cells, thus facilitating

paracellular transport [7]. The ca2+ depletion does not act directly on the tight

junctions; rather it includes global changes in the cell including disruption of act in

filaments and adherent junctions, leading to diminished cell adhesion and activation

of protein kinases.

Grass and Robinson were among the first to emphasize toe positive effect of chelating

agents on corneal drug absorption. They found that 0.5% EDTA doubled the ocular

absorption of topically applied glycerol and cromolyn sodium. Newton et al. reported

that azone, a transdermal absorption promoter, increased the ocular delivery of

instilled cyclosporine and enhanced its immunosuppressant activity. Various

penetration enhancers, azone, hexamethylene Lau amide, hexa-methylene

octanamide, and decylmethyl suffixed, were studied for their effect on cimetidine and

all of them were found to enhance the corneal permeability of cimetidine. The effect

of azone on a series of structurally unrelated drugs, ranging from hydrophilic to

lipophilic character, was also studied.

4.3.4.2 Bioadhesive Polymers

Conventional aqueous solutions topically applied to the eye have the disadvantage

that most of the instilled drug is lost within the first 15-30 sec after instillation, due toreflex tearing and drainage via the nasolacrimal duct. One of the goals in ophthalmic

research has been directed toward an increase of drug absorption and duration of

contact time. The most frequent approach to achieve improved drug efficacy is

exemplified by the use of viscosities solutions. Nevertheless, viscosity alone cannot

significantly prolong the residence time.

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This can be considered, in part as premise of using bioadhesive polymers to enhance

drug absorption. The capacity of some polymers to adhere to the mucin coat covering

the conjunctive and the corneal surfaces of the eye form the basis for ocular

mucoadhesion. These systems markedly prolong the residence time of a drug in the

conjunctival sac, since clearance is now controlled by the much slower rate of mucus

turnover than the tear turnover rate. Bioadhesive polymers are usually

macromolecular hydrocolloids with numerous hydrophilic functional groups and

possess the correct charge density [23]. These bioadhesive polymers can be natural,

synthetic, or semi-synthetic in nature. The synthetic polymers, such as polycyclic

acid, polycarbophil, and biopolymers, notably hyaluronic acid, a ubiquitous

component of animal extra cellular tissue, have shown a prolonged retention in ocular

tissues.

These synthetic mucoadhesives, including water-soluble polymers that are linear

chains and water-insoluble polymers that are swell able networks joined by cross

linking agents, are the most commonly used bioadhesive in ophthalmic drug delivery

systems. Typically, these polymers have high molecular weight (5000-10000 da),

cannot cross biological membranes, and include cellulose (CMC), or are ploy anionicin nature, like polycyclic (PAA). The ocular concentration of timolol improved three-

to nine fold in the presence of sodium CMC compared with non viscous eye drops[24]

According to Robinson, the best bioadhesive polymers are polyanions such as

polyacrylic acids, i.e., Carbopol 934P, polycarbophil, and CMC.

Chitosan a polycationic biopolymer obtained by alkaline deacetylation of chitin, is a

bioadhesive vehicle suitable for ophthalmic formulations since it exhibits several

favorable biological properties such as biodegradability, non-toxicity, and

biocompatibility.

4.3.5 Phase Transition Systems

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These systems, when instilled into the cul-de-sac, shift from the liquid form to the gel

or solid phase. In case of poloxamer 407, the viscosity of the solution increase when

its temperature is raised to the eye temperature [25], and the cellulose acetate

phthalate latex coagulates when its native pH of 4.5 is raised by the tear fluid to pH

7.4 Gel rite- an ion-activated, in situ-gelling polymer, forms a clear gel in the

presence of cations, e.g., calcium or sodium ions present in the tears, and increases the

corneal residence time and in turn the bioavailability of the drug [26].

The author suggest that such systems can be formulated as drug-containing liquids

suitable for administration by instillation into the eye, which upon exposure to

physiological condition will shift to the gel (semi-solid) phase, thus increasing the precorneal residence time and enhancing the ocular bioavailability of the drug.

4.3.6 Vesicular /Colloidal Systems

These are represented as liquid-retentive drug delivery systems containing the drug in

a carrier. They give a sustained and prolonged release of the medicament, thus

eliminating frequent dosing, and the reduction in does leads to a decreased incidence

of side effects. They can be used to target the drug molecule to a specific tissue. The

carriers used should be biocompatible, non-irritant, and biodegradable. The various

vesicular systems being used in ocular drug delivery include the following.

4.3.6.1 Liposomes

A liposome is defined as a structure consisting of one or more concentric spheres of

lipid bilayers separated by water or aqueous buffer compartments with a diameter ranging from 80nm to lOOum. Thus, liposomes can accommodate both hydrophilic

and lipophilic compounds.

According to their size, liposomes are known as either small unilamellar vesicles

(SUV) (10-100nm) or large unilamellar vesicles (LUV) (100-3000nm). If more

bilayers are present they are referred to as multilamellar vesicles (MLV). Depending

on the composition, liposomes can have a positive, negative, or neutral surface

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charge. In vitro liposome-corneal interaction studies showed that liposomes were

taken up by the cornea in the order MLV+>SUV+MLV->SUV->MLV=SUV. The

reason for this apparent difference is not clear, but it is known that the corneal

epithelium is thinly coated with negatively-charged mucin to which the positive

surface charge of the liposomes may absorb more strongly.

Liposomes are a potentially useful ocular drug delivery system due to the simplicity

of preparation and versatility in physical characteristics, but suffer from the

disadvantage of instability, limited drug-loading capacity, and technical difficulties in

obtaining a sterile liposome preparation.

4.3.6.2 Mo somes

In order to circumvent the limitations of liposomes such as chemical instability,

oxidative degradation of phospholipids, cost , and variable purity of natural

phospholipids, vesicle formation by some members of the dialkyl polyoxyethylene

ether non-ionic surfactant series has been suggested. It is reported that a vesicular

system is formed when a mixture of cholesterol and a single-alkyl chain, non-ionic

surfactant is hydrated. The resultant vesicles, termed "noisome", can entrap solutes,

are osmotically active, and relatively stable.

Furthermore, their "disc" shape provides for a better fit in the cul-de-sac of the eye.

4.3.6.3 Pharmacosomes

This is the term used for pure drug vesicles formed by the amphophilic drugs. Any

drug possessing a free carboxyl group or an active hydrogen atom (-OH, NH2) can be

esterified (with or without a spacer group) to the hydroxyl group of a lipid molecule,

thus generating an amphiphilic prod rug. The amphiphilic prod rug is converted to

pharmacosomes on dilution with water. The pharmacosomes show greater shelf,

stability, facilitated transport across the cornea, and a controlled release profile.

4.3.6.4 Nanoparticles/Nanospheres

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Nanoparticles are among the most widely studied colloidal systems over the past two

decades. These are polymeric colloidal particles, ranging from lOnm to lum, in which

the drug is dissolved, entrapped, encapsulated, or adsorbed . They are further

classified into Nan spheres (small capsules with a central cavity surrounded by a

polymeric membrane) or Nan capsules (solid matricidal spheres).

Several authors suggest that the better efficiency of Nan capsules is due to their

bioadhesive properties, resulting in an increase in the residence time and biological

response. However, some authors observed that nanoparticles consisting of poly

damaged the corneal epithelium by disrupting the cell membranes

4.3.7 Chemical Delivery Systems

A chemical delivery system (CDS), is an inactive species obtained by chemical

modifications of the active agent based on metabolic considerations. Conceptually, a

CDS upon its administration will undergo several predictable enzymatic

transformations via inactive intermediates and finally deliver the active species to the

target site . In order to enhance the partitioning and corneal bioavailability of topically

applied drugs, intensive research is being done on the prod rug approach, which is

also a type of CDS.

This approach to enhance corneal drug absorption has met successful commercial

realization as well. The method includes modification of the chemical structure of the

drug molecule, thus making it selective, site-specific, and a safe ocular drug delivery

system. Epinephrine penetration was improved 10-fold by formulating a prod rug.Other drugs with increased penetrability through prod rug formation are

phenylephrine , timolol, pilocarpine albuterol, idoxuridine, etc.

Soft drugs and site-specific chemical delivery systems are the other two novel

chemical approaches of drug design.

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5. EVALUATION FOR OCULAR INSERTS

Uniformity of thickness

Uniformity of weight

Uniformity of drug content

Invitro drug dissolution studies

Drainz eye irritation test

Percentage moisture loss

Percentage moisture absorption

Sterility testInvivo studies

Stability studies

Drug Content:- Ophthalmic inserts were dissolved in distilled water by shaking and

this solution was kept for 10-15 min to get a clear solution. Drug content was then

determined spectrophotometrically at 276 nm after proper dilution. The results given

are the mean of five determinations.

In Vitro Release:- Semipermeable membrane obtained from Sigma which has

molecular wt cut off 12,000 Daltons, was used in this study. This membrane was tied

to one end of the open cylinder which acts as donor compartment. The ophthalmic

disc was placed inside the compartment. The semipermeable membrane acted as

corneal epithelium. Then the open-ended cylinder was placed over a beaker

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examined for any signs of irritation before treatment and were observed up to 12 h

(Kaur et al, 2000).

Stability Studies:- The ophthalmic insert was stored in the amber colored glass

bottles at 2 different temperatures (30 C and 45 C) for a period of 2 months. The

samples were withdrawn at every 10 day intervals and the physical features of the

samples were analysed. Percentage of drug content was determined.

Sterlity Test:- comply with test for sterlity,droppers supplied separately also comply

with these test.Remove the dropper out of package using aseptic precautions and

transfer it in to a tube contining suitable culture meadium so that it is completely

immersed , Incubate and carry out the test for sterility.

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6. CURRENTLY AVAILABLE INSERTS OF OCULAR DRUG

TABLE - 2

Drug Anti glaucoma Type of Insert Carrier

Pilocarpine Soluble HPC/D

Lactose/glyceryl Palmito-RS

Pilocarpine Soluble PVA/XG/HPMG/GDE

Udragit RS 30 D

Pilocarpine PVP

Pilocarpine Soluble Alginate; MC

Pilocarpine Soluble HPC; PVM/MA

Pilocarpine Soluble HA; HAE

Pilocarpine Biodegradable PVMMA

Pilocarpine Biodegradable GelatinatePilocarpine Insoluble(diffusion) Ehtylene

Alginate

Pilocarpine Insoluble(Contact lens) MOPTSS/TEGDM/CH

Insolube(Osmotic) Ethylene viny

Timolol Soluble HPC

Timolol Soluble HPC;PVA;PVA/carob

Timolol Soluble/biodegradable PVA;HPC;PVMMA PVA

Tilisolol Soluble HPM

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40

ChloramphenicolSolublePVAErythromycinSolubleCopolymers of N-VinylpyrrolidoneGentamicimSolubleCollagenGentamicimSolubleHPC

/EC/Carbopol 934PGentamicimBioerodibleGelatinGentamicim anddexamethasoneSolubleHPC/EC/Carbopol 934PGentamicim anddexamethasoneSolubleHPC/EC/Carbopol934PTobramycinSolubleCollagenTobramycin orChlorampheniolSolubleCollagenTetracycline orChlorampheniolInsolublePMM

Antibacterial


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7. CONCLUSION

Over the past two decades, many oral drugs have been designed in consideration of

physicochemical properties to attain optimal pharmacokinetic properties. This

strategy significantly reduced attrition in drug development owing to inadequate

pharmacokinetics during the last decade.

On the other hand, most ophthalmic drugs are generated from reformulation of other

therapeutic dosage forms. Therefore, the modification of formulations has been used

mainly as the approach to improve ocular pharmacokinetics.

However, to maximize ocular pharmacokinetic properties, a specific molecular design

for ocular drug is preferable. Passive diffusion of drugs across the cornea membranes

requires appropriate lipophilicity and aqueous solubility. Improvement of such

physicochemical properties has been achieved by structure optimization or prodrug

approaches.

This review discusses the current knowledge about ophthalmic drugs adapted from

systemic drugs and molecular design for ocular drugs.The above study as brief

concluded that the absorption behavior and ocular membranes penetration of topically

applied drugs, and the various approaches for enhancement of ocular drug penetration

in the eye.

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BIBLIOGRAPHY

1. Robinson,J.R.Lee,V.H.L.2 ND Edition, 1987.Controlled Drug Deliver,

Marcel Dekker, 50.

2. Saettone,Macro,Fabrizio200.Progress&Problems in Ophthalmic drug

Delivery Business Briefing, Pharmatech. 1-5.

3. Bhaskaran,Shamala,Lakshmi,P.K.Harish,C.D.2005.Topical Ocular

Drug Delivery -A Review. Indian J. Pharm . Sci. 67.404-408.

4. Vyas,S.P.Khar, R.K.I stedition , 2002. Controlled Drug delievery ,

Concepts and Advances,Vallabj Parkashan,NewDelhi.384-395.

5. Gerald,Hecht,PHD,20 lhedition,2000 Remington,the Science and

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6. Kristin M. Hammersmith,2006.Dignosis and management of

Avanthamoeba keratitis. Current opinion in Ophth. 17, 327-331.

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8. Johanson,S. Pedersen. E.R. Prause, J.U Arch. Ophthalmol. Scand

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12. leBourlias. C. Acar, L Zia, H. Sado P.A Needdham T. Leverge,R.Progr. retin. Eye Res. 1998,17,33-58

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14. lenaerts, B, gurny r. In Biodhesives Drug delivery Systems ,

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35. Lawrenson,J.G.;Edgai\DJ 7.;Gudegeo,N;Burns,J.M.;Geraint,M;

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