OCULAR PHARMACOKINETICS,ROUTESOF DRUG ADMINISTRATION

Dr. Jeevan JacobJunior ResidentDept. Of Pharmacology

INTRODUCTION

Ocular administration of drug is primarily associated

with the need to treat ophthalmic diseases.

Major classes of drugs used are :

Miotics

Mydriatics

anti-inflammatories

Anti-infectives

Surgical adjuvents

Diagnostics

These drugs are meant for local therapy and not for

systemic action.

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.

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 & lipophilic molecules

• Trans cellular transport: transport between corneal epithelium & stroma.

GENERAL PATHWAY FOR OCULAR ABSORPTION

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 barriers6. Physico-chemical properties of drugs7. Active ion transport at cornea

Pharmacokinetics of ocular drug administration

Tear fluid

Precorneal epithelial corneal stroma

Drug pool surface epithelium epithelium

aqueous

Nasolacrymal conjunctiva metabolism humor

Drainage system

Elimination

Ophthalmic preparation:

Ophthalmic preparations are sterile products that are

intended to be applied topically to cornea or instilled

in the space between the eyeball and lower eyelid.

Conventional ocular formulations for ocular drug delivery:

1. Solutions

2. Suspensions

3. Ointments

4. Gels

5. Emulsions

Solution

Dilute with tear and wash away through lacrimal

apparatus.

Usually do not interfere with vision of patient.

To be Administered at frequent intervals.

Suspension

Longer contact time.

Irritation potential due to the particle size of the drug.

Ointment

Longer contact time and greater storage stability.

Producing film over the eye and blurring vision.

Interfere with the attachment of new corneal epithelial

cells to their normal base.

CLASSIFICATION OF OPHTHALMIC DOSAGE

FORMS:

A) Based on Route of Administration

• 1.Topical Soln: Multiple Dose container With Preservatives.

• 2. Intra-ocular Soln: For Surgery, Single dose, Without preservative.

• 3.Ophthalmic Soln Injections: Intra-ocular injection, given in eye tissues, without preservative.

B) Based on Physical Form

• 1. Aqueous Soln.

• 2. Suspension.

• 3. Ointments.

• 4. Gels.

• 5. Eye Lotions.

• 6. Solid Inserts.

OCULAR CONTROL RELEASE SYSTEM:

OPHTHALMIC INSERTS

Definition:- Solid or Semisolid in nature.

- Placed in lower Fornix

- Composed of Polymeric vehicle containing drug.

Role Of Polymer In ODDS.

Solution Viscosity : Solution Drainage.

Polymer Mucoadhesive Vehicle: Retained in the eye due to non-

covalent bonding with conjuctival mucine.

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

APPROACHES TO IMPROVE TOPICAL DELIVERY OF

DRUGS

1. To prolong the contact time of drug with corneal surface

2. To enhance corneal permeability either by mild or transient

structural alteration of corneal epithelium or modification of

chemical structure of drug molecules.

Recent trends:1. Polymeric solutions

2. Phase transition systems

3. Mucoadhesive/ bioadhesive dosage forms

4. Collagen shields

5. Pseudolatices

6. Ocular penetration enhancers

7. Ocular Iontophoresis

TYPES OF OCULAR CONTROL RELEASE

SYSTEM

A) NON-ERODIBLE :

1.Ocusert:

Developed by Alza Corporation,

Oval flexible ocular insert,

Release Rate:20-40mg/hr

for 7day

Consist of-

Annular ring : Impregnated with Ti02 : For Visibility

Part Material

Drug Reservoir Pilocarpine

Carrier material Alginic acid

Rate controller Ethylene vinyl acetate copolymer

Energy Source Conc. Of Pilocarpine

Delivery Portal Copolymer membrane

2. CONTACT LENS :

Presoaked Hydrophilic lens.Drug Release : within 1st 30 MinRelease rate is up to : 180 hr.

3. Diffusional Inserts :Central reservoir of drug enclosed in Semi permeable or micro porous membrane for diffusion of drug.Diffusion is controlled by Lacrimal Fluid penetrating through it.

B) ERODIBLE INSERTS

1.Lacrisert:Sterile, Rod Shaped device.Use:-Dry eye treatment, Keratitis Sicca.

2.SODI: Soluble Ocular Drug Insert.Small water soluble developed for Cosmonauts who could not use their eye drop in liquid condition.Composition : Acryl amide, Vinyl Pyrolidone, Ethylacrylate.

In 10-15 sec Softens;In 10-15 min. turns in Viscous Liquids;After 30-60min. Becomes Polymeric Solution.

ADVANTAGES OF SODI :

Single SODI application :replaces 4-12 eye drops Instillation,

or 3-6 application of

Ointments.

Once a day treatment of Glaucoma & Trachoma.

3)Minidisc:It is made up of counter disc with Convex front & Concave back

surface in contact with eye ball.

4-5mm in diameter.

Composition : Silicon based pre polymer.

Hydrophilic or Hydrophobic.

Drug release from 170 hr.

C) NANOPARTICLE:

•For water soluble drugs. •Size:10-1000nm •Drug is Dispersed, Encapsulated, or Absorbed •Produced by Emulsion Polymerization •Polymerization is carried out by :

•Chemical initiation, Gamma irradiation, Visible light.

•Emulsifier stabilizes polymer particle •Polymer used are Biodegradable. •E.g. :- Nanoparticle of Pilocarpine

D) LIPOSOME

•Biodegradable, Non-toxic in nature.•Vesicle composed of lipid membrane enclosed in an aqueous volume.•Formed when matrix of phospholipids is agitated in aqueous medium to disperse two phase.•Phospholipids used are : Phophotidylcholine, Phophotidic acid, Sphingomyline, Phosphotidyleserine, Cardiolipin

THE NEW OPHTHALMIC DELIVERY SYSTEM

(NODS)

Delivers precise amount of drug to the eye.

Device consists of medicated film attached to paper cover and

handled by a short and thin membrane.

All components are packed individually and sterilized by gamma

irradiation.

Membrane dissolves in lacrimal fluid and delivers the drug.

Study result: NODS produced 8-fold increase in bioavailability

for pilocarpine with respect to standard eye drop formulation.

RETROMETABOLIC DRUG DESIGN (RMDD)

Basic principle: Drug metabolism consideration.

Metabolism results in structural changes to molecule which in turn

causes changes in physico-chemical properties of parent molecule

New Drug design: SAR (structural activity relationship), and

SMR (structural metabolic relationship) are used in combination. This

approach of drug design is called RMDD.

ADVANCES IN OCULAR DRUG DELIVERY

1. Ophthalmic gel for pilocarpinePoloxamer 407 (low viscosity, optical clarity, mucomimetic property)

2. Ophthalmic prodrugDipivalyl epinephrine (Dipivefrin)Lipophilic increase in corneal absorptionEsterase within cornea and aqueous humor

3. Continuous delivery system based upon the osmotic propertyThin flat layer, contoured three-dimensional unitConform to the space of the upper cul-de-sacDelivery of diethyl carbamazine in ocular onchocerciasis

4. GEL DELIVERY SYSTEM

Biodegradable polyisobutyl-cyano acrylate (PIBCA) colloidal particulate

system of pilocarpine to incorporate it into a Pluronic F127 (PF 127)-based

gel delivery system.

5. Mucoadhesive Polymer.

Mucoadhesive polymer, the tamarind seed polysaccharide, as a delivery

system for the ocular administration of hydrophilic and hydrophobic

antibiotics.

CONCLUSION & FUTURE OUTLOOK

Ocular drug delivery has to overcome unique barriers.

Development of ophthalmic drug delivery systems at present

include polymeric gels, colloidal systems, cyclodextrins, collagen

shields.

Activated gel-forming systems are preferred to hydro gels.

Colloidal systems have convenience in maintaining drug activity at

the site of action & is suitable for poorly soluble drugs.

New tendency of research in ophthalmic drug delivery system is

directed towards combination of several drug delivery technologies.