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SUBCONJUNCTIVAL DRUG DELIVERY

SYSTEM (STRATEGIES)

ATHAR SHAMIM

M.PHARM 2nd SEM

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CONTENTSCONTENTS

• INTRODUCTION• ANATOMY AND PHYSIOLOGY OF EYE• BARRIERS• FORMULATION CONSIDERATIONS• IDEAL CHARACTERISTICS• DRUG DELIVERY SYSTEMS• EVALUATION• ADVANTAGES AND DISADVANTAGES• CONCLUSION• REFERENCES

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INTRODUCTION• Eye diseases are commonly encountered in day to day life,

which are cured or prevented through the conventionally used

dosage forms like eye drops, ointments, etc., Ocular drug

delivery systems are intended for installation into the cul-de-sac,

i.e., the space between the eye ball and the eye lids. Delivery to

the internal parts of the eye still remains troublesome due to the

anatomical and protective structure of the eye. Drugs may be

delivered to the eye through the application of four primary

modes of administration: topical, systemic, intravitreal, and

periocular.

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ANATOMY AND PHYSIOLOGY OF EYE

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Eye and lacrimal drainage Eye and lacrimal drainage systemsystem

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ROUTES OF DRUG DELIVERY ROUTES OF DRUG DELIVERY IN EYEIN EYE

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BARRIERS FOR DRUG ABSORPTIONPrecorneal ConstraintsIt include –• Solution drainage• Lacrimation• Tear dilution• Tear turnover• Conjunctival absorption

Corneal constraints

• Cornea as rate limiting barrier• Anatomy of cornea 1.Outer-

Epithelium(lipophilic), 2.Middle-

Stroma(hydrophilic), 3.Inner-

Endothelium(lipophilic

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OCULAR ABSORPTION 8

Corneal Absorption

Depend upon physicochemical properties of drug

Only access to small ionic & lipophilic molecules

Outer Epithelium: rate limiting barrier

Trans cellular transport: transport between corneal epithelium & stroma

e.g. pilocarpine

Non-Corneal Absorption

Penetration across Sclera & Conjunctiva into Intra Ocular tissues

Non-Productive: because penetrated drug is absorbed by general circulation.

Minor pathway

Important for drug with low corneal permeability

e.g. inulin

GENERAL PATHWAY FOR OCULAR GENERAL PATHWAY FOR OCULAR ABSORPTIONABSORPTION

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FORMULATION CONSIDERATIONS

•Physicochemical characteristics of drug and

polymers.

•Buffering capacity and pH.

• Instillation volume.

•Osmotic pressure.

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Ideal characteristics of ocular drug delivery system

• Good corneal penetration.

• Prolong contact time with corneal tissue.

• Non irritative and non toxic.

• Good rheological properties.

• Non greasy

• Patient compliance.

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12DRUG DELIVERY SYSTEMS TO EYE:

IMPLANTSDENDRIMERSIONTOPHORESISMICROEMULSIONMICRONEEDLENANOSUSPENSIONCONTACT LENSES

APPROACHES TO IMPROVE DRUG DELIVRY1. Viscosity enhancers 2. Eye ointments3. Gel 4. Prodrug5. Penetration enhancers 6. Liposomes 7. Niosomes 8. Nanosuspension 9. Microemulsion10. Nanoparticles/nanospheres11. In situ-forming gel

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Enhancement of bioavailability

1.Increase in viscosity of formulation leads to decrease in drainage.

2.Slows elimination rate from the precorneal area and enhance

contact time.

3.Generally hydrophilic polymers, eg. Methyl cellulose, polyvinyl

alcohols, polyacrylic acids, sodium carboxy methyl cellulose,

carbomer is used.

4.A minimum viscosity of 20 cst is needed for optimum corneal

absorption.

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Use of penetration enhancers

1.Act by increasing corneal uptake by modifying the integrity

of the corneal epithelium.

2.Substances which increases the permeability characteristics of

the cornea by modifying the integrity of corneal epithelium are

known as penetration enhancers.

Modes of actions

1.By increasing the permeability of the cell membrane.

2.Acting mainly on tight junctions.

e.g. Caprylic acid, sodium caprate, Azone

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PRODRUGS

1.Prodrugs enhance corneal drug permeability through modification

of the hydrophilic or lipophilicity of the drug.

2.The method includes modification of chemical structure of the

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

ocular drug delivery system.

3. Drugs with increased penetrability through prodrug formulations

are epinehrine, phenylephrine, timolol, pilocarpine.

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USE OF MUCOADHESIVES IN OCULAR DRUG DELIVERY

1. Polymereric mucoadhesive vehicle: Retained in the eye due to

noncovalent bonding with conjuctival mucine.

2. Mucine is capable of picking of 40-80 times of weight of water.

3. Thus prolongs the residence time of drug in the conjuctival sac.

4. Mucoadhesives contain the dosage form which remains adhered

to cornea until the polymer is degraded or mucus replaces

itself.

Types

1.Naturally Occurring Mucoadhesives - Lectins, Fibronectins

2.Synthetic Mucoadhesives - PVA,Carbopol, carboxy methyl

cellulose, cross-linked polyacrylic acid.

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Phase Transition System

1.Solution that are liquid in the container and thus

can be instilled as eye drop becomes gel on contact

with the tear fluid and provide increased contact

time with the possibility of improved drug absorption

and increased duration of therapeutic effect.

2.Liquid-gel phase transition-dependent delivery

system vary according to the particular polymer

employed and their mechanism for triggering the

transition to a gel phase in the eye take advantage of

change in temperature, pH, ion sensitivity, or

lysozymes upon contact with tear fluid.

EYE DROPo Drugs which are active at eye or eye surface are widely

administered in the form of Solutions, Emulsion and

Suspension.

o Various properties of eye drops like hydrogen ion

concentration, osmolality, viscosity and instilled volume can

influence retention of a solution in the eye.

o Less than 5 % of the dose is absorbed after topical

administration into the eye.

o The dose is mostly absorbed to the systemic blood circulation

via the conjunctival and nasal blood vessels.

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•OINTLENTS AND GELS

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Prolongation of drug contact time with the external ocular surface can be

achieved using ophthalmic ointment vehicle,flaxibality in drug

choice,improved drug stability but, the major drawback of this dosage form

like, blurring of vision and blinking of eyelids can limits its use. These

products will stay on eyes longer than eye drops.

•INSERTSOcular insert are sterile preparation that prolong residence time of drug with a

controlled release manner and negligible or less affected by naso-lacrimal

damage. The ocular inserts maintain an effective drug concentration in the

target tissues and yet minimize the number of applications.

OCUSERTOCUSERT

The Ocusert therapeutic system is a flat, flexible, elliptical

device designed to be placed in the inferior cul-de-sac

between the sclera and the eyelid and to release Pilocarpine

continuously at a steady rate for 7 days.

The device consists of 3 layers…..

1. Outer layer - ethylene vinyl acetate copolymer layer.

2. Inner Core - Pilocarpine gelled with alginate main polymer.

3. A retaining ring - of EVA impregnated with titanium di

oxide

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• ADVANTAGESADVANTAGES

Reduced local side effects and toxicity.

Around the clock control of drug.

Improved compliance.

• DISADVANTAGESDISADVANTAGES

Retention in the eye for the full 7 days.

Periodical check of unit.

Replacement of contaminated unit

Expensive.

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The solid inserts absorb the aqueous tear fluid and gradually erode or

disintegrate. The drug is slowly leached from the hydrophilic matrix.

They quickly lose their solid integrity and are squeezed out of the eye with eye

movement and blinking.

Do not have to be removed at the end of their use.

Three types :

• 1. Lacriserts

• 2. Sodi

• 3. Minidisc

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• LACRISERTSLACRISERTSSterile rod shaped device made up of hydroxyl propyl cellulose

without any preservative.For the treatment of dry eye syndromes.It weighs 5 mg and measures 1.27 mm in diameter with a length

of 3.5 mm.It is inserted into the inferior fornix.• SODISODISoluble ocular drug inserts.Small oval wafer.Sterile thin film of oval shape.Weighs 15-16 mg.Use – glaucoma.Advantage – Single application. Lacriserts

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• MinidiscMinidisc

Countered disc with a convex front and a concave back surface.

Diameter – 4 to 5 mm.

• CompositionComposition

Silicone based prepolymer-alpha-w-dis (4-methacryloxy)-butyl

poly di methyl siloxane. (M2DX)

M-Methyl a cryloxy butyl functionalities.

D – Di methyl siloxane functionalities.

Pilocarpine, chloramphenicol.

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Minidisc

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Erodible inserts Effective.Flexiblility in drug type & dissolution rate.Need only be introduced into eye & not removed.

Patient discomfort.Requires patient insertion.Occasional product.

Non-erodible inserts

Controlled rate of release.Prolonged delivery.Flexibility for type of drug selected.Sustained release.

Patient discomfort.Irritation to eye.Tissue fibrosis.

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Type Advantages Disadvantages

2.VESICULAR SYSTEMS

• LIPOSOMES: Liposomes are vesicles composed of lipid membrane enclosing

an aqueous volume. These structures are formed simultaneously when a matrix

of phospholipids are agitated in an aqueous medium to disperse the two phases.

They are having an intimate contact with the corneal and conjunctival surfaces

which is desirable for drugs that are poorly absorbed.

• NIOSOMES AND DISCOMES : Niosomes are nonionic surfactant vesicles

that have potential applications in the delivery of hydrophobic or amphiphilic

drugs. Discomes are discoidal vesicles and may act as potential drug delivery

carriers by releasing the drug in a sustained manner at the ocular site.

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•PHARMACOSOMES: Drugs possessing a free carboxyl

group or an active hydrogen atom can be esterified to the

hydroxyl group of a lipid molecule, thus generating an

amphiphilic prodrug. This amphiphilic prodrug is converted to

pharmacosomes on dilution with water. pharmacosomes show

greater shelf stability, facilitated transport across the cornea,

and a controlled release profile.

3.CONTROLLED RELEASE

• IMPLANTS: implants are effective drug delivery system for chronic

ocular diseases like cytomegalovirus (CMV), retinitis. Intravitreal implants

of fluocinolone acetonide were developed for the treatment of posterior

segment.

• DENDRIMERS: Dendrimers are repetitively branched molecules and can

be successfully used for ocular drug administration and have better water-

solubility, bioavailability and biocompatibility.

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•IONTOPHORESIS: Iontophoresis is a noninvasive technique for ocular

drug delivery. In iontophoresis the drug solution is in contact with the cornea

in an eye-cup bearing an electrode and the diffusion of drug occurs by

electrical potential difference.

•MICROEMULSION: Microemulsion is dispersion of water and oil

stabilized using surfactant and co-surfactant to reduce interfacial tension and

usually characterized by small droplet size(100 nm), higher thermodynamic

stability and clear appearance. They reduce the frequency of administration as

compared to the conventional systems.

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•NANOSUSPENSION: Nanosuspensions have emerged as a promising

strategy for the efficient delivery of hydrophobic drugs because they

enhanced not only the rate and extent of ophthalmic drug absorption but

also the intensity of drug action with significant extended duration of

drug effect.

•CONTACT LENSES: Water soluble drugs soaked in drug solutions

can be absorbed through Contact lenses. The drug saturated contact

lenses are placed in the eye which releases the drug in eye for a long

period of time. For prolongation of ocular residence time of the drugs,

hydrophilic contact lenses can be used.

4.PARTICULATE SYSTEMS (NANOPARTICLES AND MICROPARTICLES)

• Nanoparticles are prepared using bioadhesive polymers to provide

sustained effect to the entrapped drugs. An optimal corneal penetration of

the encapsulated drug was reported in presence of bioadhesive polymer

chitosan.

• Microemulsions have a transparent appearance, with thermodynamic

stability and a small droplet size in the dispersed phase (aqueous and

nonaqueous phase) (<1.0μm). Microspheres of poly lacto gylcolic acid

(PLGA) are prepared for topical ocular delivery.

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5.ADVANCED DRUG DELIVERY SYSTEMS

• Several kinds of viruses including adenovirus, retrovirus,

adeno-associated virus, and herpes simplex 140virus, have

been manipulated for use in gene transfer and gene therapy

applications. The advanced delivery systems such as gene

delivery, SiRNA, stem cells that prolong the contact time of

the dosage form with the surface of the eye and facilitate non-

invasive administration.

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6. Microneedle: Microneedle had shown prominent in vitro penetration into sclera and

rapid dissolution of coating solution after insertion while in vivo drug level was found to be significantly higher than the level observed following topical drug administration like pilocarpine.

7. Mucoadhesive Polymers: They are basically macromolecular hydrocolloids with plentiful

hydrophilic functional groups, such as hydroxyl, carboxyl, amide and sulphate having capability for establishing electrostatic interactions

A mucoadhesive drug formulation for the treatment of glaucoma was developed using a highly potent beta blocker drug, levobetaxolol (LB) hydrochloride and partially neutralized poly acrylic acid (PAA).

Evaluation of ocular drug delivery system

• Thickness of the film.

• Drug content.

• Irritancy test.

• Percentage moisture loss.

• In vitro drug release.

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ADVANTAGES• Localized drug delivery is possible.

• Drops are easy to apply and have good patient acceptance.

• Intravitreal , periocular sub-conjuctival injections improve drug absorption

and have no systemic toxicity.

• Micro particles , Nanoparticles, liposomes increase half life of drug.

• ocular inserts increased ocular residence releasing drugs

at a slow and constant rate.

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DISADVANTAGES

•Physical instability of the dosage form.

•Frequent administration reqired with conventional

systems.

•Leaking of entrapped drug.

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REFERENCES

• Text book of pharmaceutical sciences by Remington.

• Novel and controlled drug delivery by N.K Jain.

• Patel Vishal, Agrawal Y.K. CURRENT STATUS AND

ADVANCED APPROACHES IN OCULAR DRUG DELIVERY

SYSTEM, Journal of Global Trends in Pharmaceutical

Sciences, Vol.2, Issue 2, pp -131-148.• www.vision-care-guide.com• www.google/images/eye/anatomy& physiology

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