Contents

Introduction

Anatomy and physiology of the eye

Mechanism of ocular absorption

Factors affecting intraocular bioavailability

Approaches to improve ocular drug delivery

Classification of ocular drug delivery systems

Eye drops

Eye ointment

Introduction

• Ophthalmic preparations are specialized dosage formsdesigned to be instilled onto the external surface of the eye(topical) or administered inside the eye (intraocular).

• The purpose may be therapeutic, prophylactic or palliative.

• The most commonly employed ophthalmic dosage formsare solutions, suspensions, and ointments.

• The newest dosage forms for ophthalmic drug delivery are: gels, gel-forming solutions, ocular inserts , intravitrealinjections and implants.

Anatomy & physiology of EyeHuman eye

Diameter 23 mm

Consist 3 layes-

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).

The Cornea:

The cornea is transparent and allows light to enter the eye. It is a

powerful refracting surface, providing much of the eye's focusing

power.

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

Penetration of the drug depends on oil-water partition coefficient.

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 choroids 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 opening in the

center of the iris, larger or smaller depending on the brightness of the light.

The lens is a transparent, biconvex structure, encased in a thin transparentcovering. The function of the lens is to refract and focus incoming lightonto the retina.

The retina is the innermost layer in the eye. It converts images intoelectrical impulses that are sent along the optic nerve to the brain where theimages are interpreted.

The macula is located in the back of the eye, in the center of the retina.This area produces the sharpest vision.

The inside of the eyeball is divided by the lens into two fluid-filledsections.

The larger section at the back of the eye is filled with a colorlessgelatinous mass called the vitreous humor.

The smaller section in the front contains a clear, water-like materialcalled aqueous humor.

The conjunctiva is a mucous membrane that begins at the edge of thecornea and lines the inside surface of the eyelids and sclera, whichserves to lubricate the eye.

Lacrimal glands

Secrete tears & wash foreign bodies.

Moistens the cornea & prevent

from drying out.conjunctiva

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 & lipohillic molecules.

Trans cellular transport: transport between corneal epithelium &

stroma.

Mechanism of ocular absorption

Corneal absorption

Poor Bioavailability

Protective mechanism (short

residence time)

Blinking

Reflex lacrymation,

Nasolacrimal drainage

Anatomy of eye

Barrier properties of cornea

Factors affecting drug availability:

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

reflex, and normal tear turnover.

The normal volume of tear = 7 µl

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

spillage

The drop volume = 50 µl

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

removal by the peripheral blood flow

3. Low corneal permeability (act as lipid barrier)

In general:

-Transport of hydrophillic and macromolecular drugs occurs

through scleral route.

-Lipophillic agents of low molecular weight follow transcorneal

transport by passive diffusion.

4. Metabolism

Enzymatic biotransformation

Esterases, oxidoreductases, Peptidases, Glucuronide

Sulfate transferases, Lysosomal enzymes.

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

Approaches to improve ocular drug delivery

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 are used.

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

absorption.

Use of penetration enhancers

1. Substances which increases the permeability characteristics of the

cornea by modifying the integrity of corneal epithelium are known

as penetration enhancers.

2. Act by increasing corneal uptake by modifying the integrity of

the corneal epithelium.

Modes of actions

1. By increasing the permeability of the cell membrane.

2. Acting mainly on tight junctions.

e.g. dimetylsulfoxide(DMSO), laurocapram.

Prodrugs

1. Prodrugs enhance corneal drug permeability through modification

of the hydrophilicity 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.

USE OF MUCOADHESIVES IN OCULAR DRUG DELIVERY

Polymeric mucoadhesive vehicle: Retained in the eye due to

noncovalent bonding with conjuctival mucine.

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

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

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.

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.

POLYMER MECHANISM

Lutrol FC – 127 and Poloxamer 407 Viscosity increases when their

temperature raises 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

Example of polymer

LIQUIDS

Solutions

Suspensions

Powders for reconstitution

Sol to gel systems

SEMISOLIDS

Ointments

Gels

SOLIDS

Ocular inserts

Contact lenses

INTRAOCULAR DOSAGE FORM

Injections

Irrigating solutions

Implants

Classification of Ocular Drug Delivery System

Ideal Ophthalmic Delivery System

Good corneal penetration.

Prolong contact time with corneal tissue.

Simplicity of instillation for the patient.

Non irritant and comfortable form.

Appropriate rheological properties.

Inert and stable.

Eye dropsEye drops are sterile solutions, suspensions or emulsions intended for

instillation in the eye.

Solutions are Manufactured by dissolution of the active ingredients and

the excipients into all portion of water and sterilization of this solution

done.

If the drug is not sufficiently soluble, it can be formulated as a

suspension.

Topical ophthalmic emulsions generally are prepared by dissolving or

dispersing the active ingredient(s) into an oil phase, adding suitable

emulsifying agent and mixing with water vigorously to form a uniform

oil-in-water emulsion.

Ophthalmic products contains drugs of various categories

including –

Miotics e.g. Pilocarpine HCl

Mydriatics e.g. Atropine

Anti-inflammatories e.g. Corticosteroids

Anti-infectives (antibiotics, antivirals and antibacterials)

Anti-glucoma drugs e.g. Pilocarpine Hcl

Diagnostic drugs e.g. Sodium fluorescein

Anesthetics e.g. Tetracaine

formulation

Eye drop should be sterile and should contain

preservatives to avoid microbial contamination when

container is open.

•The preservative for ophthalmic use includes-

benzalkonium chloride

chlorbutanol

phenylmercuric acetate

phenylmercuric nitrate etc.

Eye drops are sterilized by autoclaving at 121°C for 15

minutes.

• Bacterial filters are used to avoid thermal degradation.

e.g.- preservative chlorbutanol hydrolyzes at high

temperature.

The order of surfactant toxicity is :

anionic > cationic >> nonionic .

• several nonionic surfactants are used in relatively low

Concentration to aid in dispersing steroids in suspensions

and to achieve or to improve solution clarity.

• Those principally used are the sorbitan ether esters of

oleic acid ( polysorbate or tween 20 and 80 ).

pH adjustment is very important as pH affects-1- To render the formulation more stable

2- The comfort, safety and activity of the product.Eye irritation

increase in tear fluid secretion

Rapid loss of medication.

3- To enhance aqueous solubility of the drug.

4- To enhance the drug bioavailability

5- To maximize preservative efficacy

Note: If buffers are required there capacity is controlled to be as low as possible( low buffer capacity) thus enabling the tear to bring the pH of the eye back to thephysiological range .

Lachrimal fluid is isotonic with blood having an isotonicity value

Corresponding to that of 0.9% NaCl solution

e.g. Mannitol, NaCl , KCl buffer.

Polyvinyl alcohol, methylcellulose, hydroxypropyl

methylcellulose, hydroxyethylcellulose, and carbomers,are

commonly used to increase the viscosity of solution and

suspensions (to retard the rate of setting of particles) They increase

the ocular contact time , there by decreasing the drainage rate,

increase the mucoadhesiveness and Increasing the bioavailability .

Disadvantage : produce blurring vision as when dry, form a dry

film on the eye lids. make filteration more difficult .

commercial viscous vehicles are :

1. polyvinyl alcohol (liquifilm)

2. hydroxypropyl methylcellulose (isopto)

Ophthalmic drop (using purifies water USP) as the solvent.

Purified water meeting USP standards may be obtained by :

Distillation, deionization, or reverse osmosis.

Oils have been used as vehicles for several topical eye drops

products that are extremely sensitive to moisture.

When oils are used as vehicles in ophthalmic fluids, they must

be of the highest purity.

Not for injection. For external use only. Shake well before use

(if it is suspension).

Administration:-Pull down the eyelid.

-Tilting the head backwards.

-Look at the ceiling after the tip is pointed close to the lower cul-de-

sac.

-Apply a slight pressure to the rubber bulb

or plastic bottle to allow a drop to fall into

the eye.

-Do not squeeze lids.

To prevent contamination:-Clean hands

-Do not touch the dropper tip to the eye and surrounding tissue

Eye drops have been packaged almost entirely in plastic dropper

bottles

The main advantage of the Drop-Trainer are:

- Convenience of use by the patient

- Decreased contamination potential

- Lower weight

- Lower cost

The plastic bottle and dispensing tip is made of low-density

polyethylene (LDPE) resin, which provides the necessary

flexibility and inertness.

The cap is made of harder resin than the bottle.

A special plastic ophthalmic package made of polypropylene is

introduced. The bottle is filled then sterilized by steam under

pressure at 121°C.

Powder for reconstitution use glass containers , owing to their

heat-transfer characteristics, which are necessary during the freeze-

drying processes.

The glass bottle is made sterile by dry-heat or steam autoclave

sterilization.

Amber glass is used for light-resistance.

Dosage form Advantages Disadvantages

Solutions 1. Convenience

2. 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.

Advantages and Disadvantages of Eye Drops

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.

The ointment base selected for an ophthalmic ointment must be

nonirritating to the eye and must permit the diffusion of the active

ingredient throughout the secretions bathing the eye.

EYE ointment

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

Packaging:

Ophthalmic ointment are packaged in :

1.Small collapsible tin tube usually holding 3.5g of product. the pure tin

tube is compatible with a wide range of drugs in petrolatum-based

ointments.

2.Aluminum tubes have been used because of their lower cost and as an

alternative of tin.

3.Plastic tubes made from flexible LDPE resins have also been

considered as an packaging material.

•Filled tubes may be tested for leakers.

•The screw cap is made of polyethylene or polypropylene.

•The tube can be a source of metal particles and must be cleaned

carefully before sterilization (by autoclaving or ethylene oxide).

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.

5. Matting of eyelids

Evaluation of the ophthalmic product is done by

following tests:

1. Sterility Test

2. Clarity Test

3. Leakage Test

4. Metal particles in ophthalmic ointment

Evaluation tests

Sterility Tests :

Ophthalmic products should be free from anaerobic and aerobic bacteria and fungi.

Sterility tests are therefore performed by the:

1. Membrane filtration method.

2. Direct - inoculation method.

In the Membrane filtration method :

• A solution of test product (1%) is prepared in isopropyl myristate and allowed to penetrate through cellulose nitrate filter with pore size 0.45 μ m.

• If necessary, gradual sunction or pressure is applied to aid filtration.

The membrane is then washed three times with 100 - ml quantities of sterile diluting and rinsing fluid and transferred aseptically into fluid thioglycolate medium (FTM) and soybean – casein digest medium (SBCD) .

The membrane is finally incubated for 14 days.

Growth on FTM indicates the presence of anaerobic and aerobic bacteria.

Growth on Soybean casein digest medium indicates the presence of fungi and aerobic bacteria.

Absence of any growth in both these media establishes the sterility of the product.

In the Direct - inoculation technique :

1 part of the product is diluted with 10 parts of sterile diluting and

rinsing fluid with the help of an emulsifying agent .

Incubate in Fluid thioglycolate medium (FTM) and soybean –

casein digest (SCDM) media for 14 days .

In both techniques, the number of test articles is based on the batch

size of the product.

If the batch size is less than 200 the containers, either 5% of the

containers or 2 containers (whichever is greater) are used.

If the batch size is more than 200, 10 containers are used for

sterility testing .

Clarity is tested by visual inspection of containers under light and

against a black and white background.

Instrumental methods of evaluation is based on the principles of

light scattering, light absorption and electrical resistance which are

used to count particle and particle size distribution.

Unwanted mobile insoluble matter other than gas bubbles are

present in the given product are detected.

It may be dangerous when the particle size is larger than R.B.C.

and may block the blood vessel.

Clarity Test:

This test is mandatory for ophthalmic products, which evaluates

the intactness of the ointment tube and its seal.

Ten sealed containers are selected, and their exterior surfaces are

cleaned.

They are horizontally placed over absorbent blotting paper .

maintained at 60 ± 3 ° C for 8 h.

The test passes if leakage is not observed from any container.

If leakage is observed, the test is repeated with an additional 20

tubes.

The test passes if not more than 1 container shows leakage out of 30

tubes .

Leakage test :

This test is required only for ophthalmic ointments.

The presence of metal particles will irritate the corneal or

conjunctival surfaces of the eye.

It is performed using 10 ointment tubes.

The content from each tube is completely removed onto a clean

60 - mm - diameter Petri dish which possesses a flat bottom.

The lid is closed and the product is heated at 85 °C for 2 hours.

Once the product is melted and distributed uniformly, it is cooled

to room temperature.

The lid is removed after solidification.

The bottom surface is then viewed through an optical microscope

at 30× magnification.

Test for Metal Particles:

The viewing surface is illuminated using an external light source positioned at 45 ° on the top.

The entire bottom surface of the ointment is examined, and the number of particles 50 μm or above are counted using a calibrated eyepiece micrometer.

The USP recommends that the number of such particles in 10 tubes should not exceed 50, with not more than 8 particles in any individual tube.

Limits are not met, the test is repeated with an additional 20 tubes.

In this case, the total number of particles in 30 tubes should not

exceed 150, and not more than 3 tubes are allowed to contain more

than 8 particles, the test passes.

•Carter S.J., “Dispensing for pharmaceutical by Cooper

and gunn”, CBS Publisher. p.p.634-661

•Jain N.K., Gupta G.D. “Modern dispensing pharmacy”,

Published by Pharma book syndicate. p.p. 13.3-14.9

•Mithal B.M., “Text of pharmaceutical formulation”,

Vallabh prakashan. p.p. 268-278

•Felton L., “Remington’s essential of pharmaceutics”,

published by pharmaceutical press. p.p.541-562

References