Ocular Drug Delivery System

:Prepared By:Dr. Yamini D. Shah

Roshni S. Vora

L. M. College of Pharmacy, Ahmedabad, Gujarat, India

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OBJECTIVE

To review and study ocular drug delivery system.

To study various factors affecting ocular absorption.

To know various approaches ot improve drug absorption.

To study mechanism of drug absorption.

INTRODUCTION

They are specialized dosage forms designed to be instilled onto the

external surface of the eye (topical), administered inside

(intraocular) or adjacent (periocular) to the eye or used in

conjunction with an ophthalmic device.

The most commonly employed ophthalmic dosage forms are

solutions, suspensions, and ointments.

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But these preparations when in stilled into the eye are rapidly

drained away from the ocular cavity due to tear flow and lachrymal

nasal drainage.

Eye is the most easily accessible site for topical administration of a

medication.

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.

The newest dosage forms for ophthalmic drug delivery are: gels,

gel-forming solutions, ocular inserts , intravitreal injections and

implants.

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Major classes of drugs used are

Miotics e.g. pilocarpine Hcl

Mydriatics e.g. atropine

Cycloplegics e.g. atropine

Anti-inflammatories e.g. corticosteroids

Anti-infectives (antibiotics, antivirals and antibacterials)

Anti-glucoma drugs e.g. pilocarpine Hcl

Surgical adjuncts e.g. irrigating solutions

Diagnostic drugs e.g. sodiumfluorescein

Anesthetics e.g. tetracaine

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COMPOSITION OF EYE

Water - 98%,

Solid -1.8%,

Organic element

Protein - 0.67%,

sugar - 0.65%,

NaCl - 0.66%

Other mineral element

sodium, potassium and ammonia - 0.79%.

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Anatomy and Physiology of the Eye

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Human eye

Diameter 23 mm

Structure comprises of three layers

1.Outermost coat : The clear, transparent cornea and the white, opaque

sclera

2.Middle layer : The iris anteriorly, the choroid posteriorly, and the

ciliary body at the intermediate part

3.Inner layer : Retina (extension of CNS)

Cornea

Epithelium-stroma-endothelium (fat-water-fat structure)

Penetration of the drug depends on Oil-water partition coefficient

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Corneal Cross Section

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Fluid systems in eye

1. Aqueous humor

Secreted from blood through epithelium of the ciliary body.

Secreted in posterior chamber and transported to anterior chamber.

2. Vitreous humor

Secreted from blood through epithelium of the ciliary body.

Diffuse through the vitreous body.

Lacrimal glands

Secrete tears & wash foreign bodies.

Moistens the cornea from drying out.

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The sclera : The protective outer layer of the eye, referred to as the

“white of the eye” and it maintains the shape of the eye.

The cornea : The front portion of the sclera, is transparent and allows

light to enter the eye. The cornea is a powerful refracting surface,

providing much of the eye's focusing power.

The choroid : is the second layer of the eye and lies between the sclera

and the retina. It contains the blood vessels that provide nourishment to

the outer layers of the retina.

The iris : is the part of the eye that gives it color. It consists of muscular

tissue that responds to surrounding light, making the pupil, or circular

opening in the center of the iris, larger or smaller depending on the

brightness of the light.

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The lens is a transparent, biconvex structure, encased in a thin

transparent covering. The function of the lens is to refract and

focus incoming light onto the retina.

The retina is the innermost layer in the eye. It converts

images into electrical impulses that are sent along the optic

nerve to the brain where the images are interpreted.

The macula is located in the back of the eye, in the center of

the retina. This area produces the sharpest vision.

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Mechanism Of Ocular Absorption

Non-Corneal Absorption

• Penetration across Sclera & Conjuctiva

into Intra Ocular tissues• Non-Productive: because penetrated drug

is absorbed by general circulation

Corneal Absorption

• Outer Epithelium: rate limiting barrier,

with pore size 60å,Only access to small

ionic & lipohilic molecules• Trans cellular transport: transport

between corneal epithelium & stroma.

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General Pathway For Ocular Absorption

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Factors Affecting Intraocular Bioavailability

1. Inflow & outflow of lacrimal fluids.

2. Efficient naso-lacrimal drainage.

3. Interaction of drug with proteins of lacrimal fluid.

4. Dilution with tears.

5. Corneal barriers

6. Physico-chemical properties of drugs

7. Active ion transport at cornea,

8. Limited and poor corneal permeability

9. Metabolism

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Factors affecting drug availability:

1. Rapid solution drainage by gravity, induced lachrymation, blinking

reflex, and normal tear turnover.

The normal volume of tears = 7 ul,

The blinking eye can accommodate a volume of up to 30 ul without

spillage,

The drop volume = 50 ul

2. Superficial absorption of drug into the conjunctiva and sclera and

rapid removal by the peripheral blood flow

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3. Low corneal permeability (act as lipid barrier) Transport of hydrophilic and macromolecular drugs

occurs through scleral route. Lipophilic agents of low molecular weight follow

transcorneal transport by passive diffusion.

4. Metabolism

Enzymatic biotransformation

Esterases, oxidoreductases, Peptidases, Glucuronide

Sulfate transferases, Lysosomal enzymes

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Corneal Absorption

Poor Bioavialability

Protective mechanism (short residence time)

BlinkingReflex lacrimation,

Nasolacrimal drainage

Anatomy of eye

Barrier properties of cornea

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Approaches To Improve Ocular Drug Delivery

1. Viscosity enhancers

2. Eye ointments

3. Gel

4. Prodrug

5. Penetration enhancers

6. Liposomes

7. Niosomes

8. Nanosuspension

9. Microemulsion

10. Nanoparticles/nanospheres

11. 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 cp 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, CMC

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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.

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POLYMER MECHANISM

Lutrol FC – 127 and Poloxamer 407

Viscosity increased when their temperature raised to eye temperature.

Cellulose acetate phthalate latex

Coagulates when its native pH 4.5 raised by tear fluid to pH 7.4

Gelrite Forms clear gel in the presence of cations

EXAMLE OF POLYMER

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OCULAR DELIVERY SYSTEMS

CONVENTIONAL VESICULAR

CONTROLED RELEASE PARTICULATE

o IMPLANTSo HYDROGELSo DENDRIMERSo IONTOPORESISo COLLAGEN SHIELDo POLYMERIC

SOLUTIONSo CONTACT LENSESo CYCLODEXRINo MICROONEEDLEo MICROEMULSION

So NANO

SUSPENSION

o MICROPARTICLESo NANOPARTICLES

o LIPOSOMESo NIOSOMESo DISCOMESo PHARMACOSOMES

ADVANCED

o SCLERAL PLUGS

o GENE DELIVERY

o Si RNAo STEM CELL

o SOLUTIONo SUSPENSIONo EMULSIONo OINTMENTo INSERTo GELS

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Classification Of Ocular Drug Delivery Systems

LIQUIDS

Solutions

Suspensions

Powders for reconstitution

Sol to gel systems

SOLID

Ocular inserts

Contact lenses

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Ideal Ophthalmic Delivery System

Good corneal penetration.

Prolong contact time with corneal tissue.

Simplicity of instillation for the patient.

Non irritative and comfortable form.

Appropriate rheological properties.

Inert and stable.

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Eye Drops

o 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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Advantages And Disadvantages Of Eye Drops

Dosage form Advantages Disadvantages

Solutions 1. Convenience2. Usually do not interfere

with vision of patient.

1. Rapid precorneal elimination.2. Non sustained action.3. To be Administered at frequent

intervals.Suspension 1. Patient compliance.

2. Best for drug with slow dissolution.

3. Longer contact time

1. Drug properties decide performance loss of both solutions and suspended particles.

2. Irritation potential due to the particle size of the drug.

Emulsion 1. Prolonged release of drug from vehicle

1. Blurred vision.2. patient non compliance.

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Ointment

• Prolongation of drug contact time with the external ocular

surface can be achieved using ophthalmic ointment vehicle.

• The ointment base is sterilized by heat and appropriately

filtered while molten to remove foreign particulate matter.

Ointment base is sterilized by heat and filtered while molten

to remove foreign particulate matter.

It is then placed into a sterile steam jacketed

to maintain the ointment in a molten state and excipients

are added

The entire ointment may be passed

through a previously sterilized colloid mill

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• Advantages

1. Longer contact time and greater storage stability.

2. Flexibility in drug choice.

3. Improved drug stability.

• Disadvantages

1. Sticking of eyes lids.

2. Blurred vision.

3. Poor patient compliance

4. Interfere with the attachment of new corneal epithelial cells to their

normal base.

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• Gels

1. Ophthalmic gels are composed of mucoadhesive polymers that

provide localized delivery of an active ingredient to the eye. Such

polymers have a property known as bioadhesion.

2. These polymers are able to extend the contact time of the drug

with the biological tissues and there by improve ocular

bioavailability.

Advantages

3. Longer contact time and Greater storage stability.

Disadvantages

4. Blurred vision but less then ointment. And Poor patient

compliance.

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VESICULAR SYSTEM : LIPOSOMES

Liposomes are biocompatible and biodegradable lipid vesicles made

up of natural lipids and about 25 –10 000 nm in diameter.

They are having an intimate contact with the corneal and

conjunctival surfaces which is desirable for drugs that are poorly

absorbed, the drugs with low partition coefficient, poor solubility or

those with medium to high molecular weights and thus increases the

probability of ocular drug absorption.

Vesicle composed of phospholipid bilayer enclosing aqueous

compartment in alternate fashion. It is Biodegradable, Non-toxic in

nature.

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Types : 1. MLV

2. ULV-SUV(upto 100 nm)

3. LUV(more than 100 nm)

Polar drugs are incorporated in aqueous compartment while

lipophilic drugs are intercalated into the liposome membrane.

Phospholipids used- Phosphotidylcholine, Phosphotidic acid,

Sphingomyline, Phosphotidyleserine, Cardiolipine.

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ADVANTAGESDrugs delivered intact to

various body tissues.

Liposomes can be used

for both hydrophilic and

hydrophobic drug.

Possibility of targeting and

decrease drug toxicity.

The size, charge and other

characteristics can be

altered according to drug

and desired tissue.

DISADVANTAGESTheir tendency to be up

taken by reticular

endothelial system.

They need many

modification for drug

delivery to special organs.

Costly.

Stability problem and

oxidative degradation.

Requires special packaging

and storing facility.

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Degradation And Drug Release Of Liposomes

1. Endocytosis 2. Fusion

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Niosomes

The major limitations of liposomes are chemical instability, oxidative

degradation of phospholipids, cost and purity of natural phospholipids.

To avoid this niosomes are developed as they are chemically stable as

compared to liposomes and can entrap both hydrophobic and

hydrophilic drugs.

Niosomes are non-ionic surfactant based multilamellar (>0.05µm),

small unilamellar (0.025-0.05µm) or large unilamellar vesicles

(>0.1µm) in which an aqueous solution of solute(s) is entirely enclosed

by a membrane resulted from organization of surfactant

macromolecules as bilayers.

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They are non toxic and do not require special handling

techniques.

Niosomes are nonionic surfactant vesicles that have potential

applications in the delivery of hydrophobic or amphiphilic drugs.

STRUCTURAL COMPONENTS USED

• Surfactants (dialkyl polyoxy ethylene ether non ionic

surfactant)

• Cholesterol.

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ADVANTAGES

The vesicle suspension being water based offers greater patient

compliance over oil based systems.

Since the structure of the niosome offers place to accommodate hydrophilic,

lipophilic as well as ampiphilic drug moieties, they can be used for a

variety of drugs.

The characteristics such as size, lamellarity etc. of the vesicle can be varied

depending on the requirement.

The vesicles can act as a depot to release the drug slowly and offer a

controlled release.

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They are osmotically active and stable.

They increase the stability of the entrapped drug.

Improves therapeutic performance of the drug by protecting it

from the biological environment and restricting effects to target

cells, thereby reducing the clearance of the drug.

Drawbacks

Physical instability.

Aggregation.

Leaking of entrapped drug.

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Pharmacosomes

This term is used for pure drug vesicles formed by the amphiphilic

drugs.

The amphiphilic prodrug is converted to pharmacosomes on

dilution with water.

Since many drugs are also amphiphiles, they can form the vesicles.

Advantages

Drug metabolism can be decreased.

Controled release profile can be achieved.

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DISCOMES

• Soluble surface active agents when added in critical amount to

vesicular dispersion leads to solubilization or breakdown of vesicles

& translates them into mixed micellar systems

e.g: Egg yolk phosphatidyl choline liposomes by the addition

of non ionic surfactants of poly oxy ethylene cetyl ether till the

lamellar and mixed lamellar coexist

Advantages

• Minimal opacity imposes no hinderance to vision

• Increased patient compliance

• Zero order release can be easily attained

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Advantages Of Vesicular Systems

1. No difficulty of insertion as in the case of ocular inserts.

2. No tissue irritation and damage as caused by penetration enhancers.

3. Provide patient compliance as there is no difficulty of insertion as

observed in the case of inserts.

4. The vesicular carriers are biocompatable and have minimum side effects.

5. Degradation products formed after the release of drugs are biocompatable.

6. They prevent the metabolism of drugs from the enzymes present at

tear/corneal epithelium interface.

7. Provide a prolong and sustained release of drug.

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OCULAR INSERTSNONERODABLE

OCUSERT

ERODABLESODI

COLLAGEN SHIELDSOCUFIT SR

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NON ERODIBLE INSERTS

OCUSERT

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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OCUSERT

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• ADVANTAGES

Reduced local side effects and toxicity.

Around the clock control of drug.

Improved compliance.

• DISADVANTAGES

Retention in the eye for the full 7 days.

Periodical check of unit.

Replacement of contaminated unit

Expensive.

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ERODIBLE INSERTS 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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• LACRISERTS

Sterile 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.

• SODI (Soluble ocular drug inserts)

.Small oval wafer.

Sterile thin film of oval shape.

Weighs 15-16 mg.

Lacriserts

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• Minidisc

Countered disc with a convex front and a concave back

surface.

Diameter – 4 to 5 mm.

• Composition

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. Minidisc

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CONTACT LENS• Contact lenses can be a way of providing

extended release of drugs into the eye.

• Conventional hydrogel soft contact lenses have

the ability to absorb some drugs and release them

into the post lens lachrymal fluid, minimizing

clearance and sorption through the conjunctiva.

• Their ability to be a drug reservoir strongly

depends on the water content and thickness of the

lens, the molecular weight of the drug, the

concentration of the drug loading solution and

the time the lens remains in it.

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Type Advantages Disadvantages

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.

Advantages And Disadvantages Of Ocular Inserts

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Control Delivery Systems

1. Implants

1. Implants have been widely employed to extend the release of drugs

in ocular fluids and tissues particularly in the posterior segment.

2. Implants can be broadly classified into two categories based on their

degradation properties:

(1) Biodegradable

(2) Nonbiodegradable

3. With implants, the delivery rate could be modulated by varying

polymer composition.

4. Implants can be solids, semisolids or particulate-based delivery

systems.

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For chronic ocular diseases like cytomegalo virus (CMV)

retinitis, implants are effective drug delivery system. Earlier

non biodegradable polymers were used but they needed

surgical procedures for insertion and removal.

Presently biodegradable polymers such as Poly Lactic Acid

(PLA) are safe and effective to deliver drugs in the vitreous

cavity and show no toxic signs.

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Iontophoresis

In Iontophoresis direct current drives ions into cells or tissues. For

iontophoresis the ions of importance should be charged molecules of

the drug.

If the drug molecules carry a positive charge, they are driven into the

tissues at the anode; if negatively charged, at the cathode.

Requires a mild electric current which is applied to enhance ionized drug

penetration into tissue.

Ocular iontophoresis offers a drug delivery system that is fast, painless,

safe, and results in the delivery of a high concentration of the drug to a

specific site.

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• Ocular iontophoresis delivery is not only fast, painless and safe but it

can also deliver high concentration of the drug to a specific site.

• Ocular iontophoresis has gained significant interest recently due to its

non-invasive nature of delivery to both anterior and posterior segment.

• Iontophoretic application of antibiotics may enhance their bactericidal

activity and reduce the severity of disease

• Can overcome the potential side effects associated with intraocular

injections and implants.

• Iontophoresis is useful for the treatment of bacterial keratitis.

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Iontophoresis

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Dendrimer

• Dendrimers can successfully used for different routes of drug

administration and have better water-solubility, bioavailability and

biocompatibility.

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.

Selection of aqueous phase, organic phase and surfactant/co-surfactant

systems are critical parameters which can affect stability of the system.

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Nanosuspensions

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.

For commercial preparation of nanosuspensions, techniques

like media milling and high-pressure homogenization have

been used.

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Advance System

• Design of Punctal Plug

1. Punctal plugs are placed in the tear duct (punctum) to release

a variety of drugs.

2. Currently targeting the treatment of glaucoma and ocular

hypertension

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• Design of Replenish Mini Pump

1. Micro-electromechanical system that delivers continuous or

bolus-targeted drugs to both the anterior and posterior

segments.

2. Refillable drug reservoir (via 31 gauge needle) that is

capable of storing and delivering up to 12 months.

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• Design of ODTx

1. Non-biodegradable implant that is comprised of multiple

sealed reservoirs containing individual doses of drugs.

2. Implant is injected into the vitreous.

3. Drug is released by creating an opening via laser.

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• I-vation™

1. A solid triamcinolone acetnoide implant, can delivery up to

24 months.

2. Phase I showed positive outcome, phase 2 was terminated

before completion.

3. Also, has polysaccharide-based matrix for protein delivery

(eureka™ duet)

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• Vitrasert®

1. (Ganciclovir-CMV retinitis) and Retisert® (fluocinolone

acetonide-chronic non infectious uveitis).

2. Are FDA approved

3. These devices are solid sustained-release devices, typically

made of PLGA, capable of delivering drug for up to 30

months.

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