OPHTHALMIC PROTEIN AND PEPTIDE DELIVERY

DEPARTMENT OF PHARMACEUTICS

AISSMS COLLEGE OF PHARMACY PUNE

24 SEPTEMBER 2009

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CONTENTS

• INTRODUCTION TO OPHTHALMIC PREPARATIONS

• ANATOMY & PHYSIOLOGY OF EYE• CORNEAL ABSORPTION & DRUG ACCESS• TYPES OF OPHTHALMIC DOSAGE FORMS• CHARACTERISTICS OF OPHTHALMIC

PREPARATIONS

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• INTRODUCTION TO PEPTIDES & PROTEINS• CLASSIFICATION OF PROTEINS • FUNCTIONS OF PROTEINS• STRUCTURE OF PROTEINS• BIOMEDICAL IMPORTANCE OF PROTEINS• NEED FOR PROTEIN & PEPTIDE DRUG DELIVERY

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• PEPTIDES AND EYE • MECHANISM OF PEPTIDE TRANSPORT• HANDLING PRECAUTIONS FOR PROTEIN &

PEPTIDE DRUGS• STERILISATION CONSIDERATIONS• REFERENCES

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INTRODUCTION : OPHTHALMIC PREPARATIONS ARE ADMINISTERED BY FOLLOWING WAYS • TOPICAL• INTRAOCULAR• PERIOCULAR

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• REQUIREMENTS :• STERILITY• TONICITY• TISSUE COMPATIBILITY• ABSENCE OF PYROGENS & PARTICULATE

MATTER

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• ANATOMY & PHYSIOLOGY OF EYE : CAN BE INSPECTED WITHOUT SURGICAL

INTERVENTION• EYELIDS : MECHANICAL PROTECTION OF GLOBE INNER SURFACES LUBRICATED BY TEARS

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• STRUCTURE & FUNCTION OF EYEBALL:

HOUSED IN ORBIT COMPOSED OF THREE LAYERS : OUTER FIBROUS LAYER MIDDLE VASCULAR LAYER NEURAL RETINAL LAYER

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• LACRIMAL SYSTEM : CONJUNCTIVAL & CORNEAL SURFACES

LUBRICATED BY TEAR FILM

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LACRIMAL GLANDS SECRETE CLEAR WATERY SECRETION WHICH CONTAINS :

• NUMEROUS SALTS• GLUCOSE• 0.7% PROTEIN INCLUDING ENZYME

LYSOZYME

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THERAPEUTIC TARGETS :• TOPICAL• INTERNAL TISSUE

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Minimum Dosage Volume Concept :• Difficult To Design Dropper Configuration• Patient Cant Sense Small Volumes of 5 to 7.5

micro leters

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CORNEAL ABSORPTION : Effective than scleral absorption Hydrophillic drugs slowly absorbed than

lipophilic drugs. Corneal permeability is similar for all ions

suggesting that passage is through extracellular space

Molecular diameter: 10-25 Å

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PASSIVE DIFFUSION OCCURS ACROSS CORNEAL MEMBRANE

HYDROPHILIC DRUGS : PARACELLULAR TRANSPORT

LIPOPHILIC DRUGS : TRANSCELLULAR TRANSPORT

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• SCLERAL ABSORPTION : SCLERAL ABSORPTION IS PREFERRED

ROUTE FOR HYDROPHILIC DRUGS

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SYSTEMIC ABSORPTION : PRIMARILY THROUGH CONTACT WITH

NASAL & CONJUCTIVAL MUCOSAE LIPOIDAL CORNEAL EPITHELIUM FORMS

RELATIVELY IMPERMEABLE BARRIER WHICH PREVENTS PEPTIDES FROM EASILY ENTERING INTO SYSTEMIC CIRCULATION

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OPHTHALMIC DOSAGE FORMS

• OPHTHALMIC SOLUTIONS• GEL FORMING SOLUTIONS• POWDERS FOR SOLUTION• OPHTHALMIC GELS• OPHTHALMIC OINTMENTS• OPHTHALMIC EMULSIONS• OCULAR INSERTS• OPHTHALMIC SUSPENSIONS

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OPHTHALMIC SOLUTIONS :• DOSE UNIFORMITY• BRIEF CONTACT TIME• VISION INTERFERENCE MINIMALGEL FORMING SOLUTIONS : AQUEOUS BASED SOLUTION CONTAINING POLYMER

SYSTEMPOWDERS FOR SOLUTION : LIMITED STABILITY IN SOLUTION

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OPHTHALMIC GELS : GEL FORMING POLYMERS SUCH AS

CARBOMER USEDOPHTHALMIC OINTMENTS : ANHYDROUS BASE : MINERAL OIL WHITE PETROLATUM

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OPHTHALMIC EMULSIONS : O/W EMULSIONS – LESS IRRITATINGOCULAR INSERTS : NON ERODIBLE : OCUSERT PILO ERODIBLE : LACRISERTOCUSERT PILO : ZERO ORDER DRUG RELEASE NOT USED NOW. LACRISERT : HYDROXYPROPYL CELLULOSE FOR DRY EYE SYNDROME

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OPHTHALMIC SUSPENSIONS : LESS THAN 10 micrometer PARTICLE SIZE IS IDEAL. VEHICLE : SATURATED SOLUTION OF DRUG INCREASED DURATION OF ACTION SOLUBILITY : SMALL PARTICLES RETENTION : LARGE PARTICLES OPTIMUM PARTICLE SIZE DESIRED.

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PROBLEMS :• DOSE NON UNIFORMITY• PATIENT NON COMPLIANCE• POLYMORPHIC CHANGE

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CHARACTERISTICS OF OPHTHALMIC PREPARATIONS :

• CLARITY• BUFFER & pH• TONICITY

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INTRODUCTION TO PEPTIDES & PROTEINS

GREEK WORD PROTOS : FIRST

MORE THAN 50 AMINO ACIDS : PROTEINS

LESS THAN 50 AMINO ACIDS : PEPTIDES

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FUNCTIONS OF PROTEINS : • ENZYMATIC CATALYSIS• STORAGE TRANSPORT OF SMALL MOLECULES• MUSCLE CONTRACTION• MECHANICAL SUPPORT : COLLAGEN• IMMUNE PROTECTION : ANTIBODIES• GROWTH CONTROL VIA HORMONES

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STRUCTURE OF PROTEINS : MADE OF 20 AMINO ACIDSPRIMARY STRUCTURESECONDARY STRUCTURETERTIARY STRUCTUREQUATERNARY STRUCTURE

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BIOMEDICAL IMPORTANCE : PROTEINS : ESSENTIAL BODY FUNCTIONSHORMONE : INSULINANTIBIOTIC PEPTIDE : Gramicidin AANTITUMOUR AGENT : BLEOMYCIN

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NEED FOR PROTEIN PEPTIDE DRUG DELIVERY :

ADVANCES IN BIO-TECHNOLOGY COST EFFECTIVE AVAILABILITY PARENTERAL ADMINISTRATION

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FACTORS LIMITING USEFULNESS : INSTABILITIES POOR DISPOSITION PROFILES SUITABLE DELIVERY SYSTEMS ARE THUS

NECESSARY

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PEPTIDES & EYE :• PEPTIDES FOR LOCAL EFFECT : • BACITRACIN : ANTIBIOTIC• CYCLOSPORINE : TO PREVENT CORNEAL ALLOGRAFT

REJECTION• SYSTEMIC DELIVERY :• PROTEOLYTIC ENZYMES • CORNEAL BARRIER : IMPERMEABLE

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ADVANTAGES OF OCULAR DELIVERY :• CONVENIENT• RAPID SYSTEMIC ABSORPTION • BYPASS FIRST PASS METABOLISM• DOSE SIZE CONTROLLED ACCURATELYDISADVANTAGES : LOW SYSTEMIC BIOAVAILABILITY

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OTHER CONSIDERATIONS :• EYE DROPS SHOULD BE DEVOID OF LOCAL

IRRITATION• PERMEATION ENHANCERS MAY BE NEEDED• NOT MORE THAN 2.5 mg PEPTIDE CAN BE PLACED

IN EYE : NOT MORE THAN 25 microliters OF 10% w/v solution can be endured.

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MECHANISM OF PEPTIDE TRANSPORT : DEPENDS ON SIZE • PARACELLULAR ROUTE IS FAVOURED• CORNEA OFFERS GREATER RESISTANCE FOR

NEGATIVELY CHARGED COMPOUNDS[SMALL & MEDIUM SIZED PEPTIDES]

• INTERCELLULAR SPACES CAN BE WIDENED BY INFLAMMATION OF CORNEA

• SYSTEMIC ABSORPTION OCCURS THROUGH CONTACT WITH NASAL MUCOSA

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HANDLING PRECAUTIONS : • MAJOR PROBLEMS : AGGREGATION &

DENATURATION• PROTEIN TENDS TO UNDERGO SELF

ASSOCIATION TO FORM AGGREGATES• MATERIALS PREVENTING AGGREGATION: GLYCEROL LYSINE EDTA ASPARTIC ACID GLUTAMIC ACID

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DENATURATION : PROTEIN LOSES SECONDARY TERTIARY &/or

QUATERNARY STRUCTURETEMPERATURE : AT HIGH TEMPERATURE S-S BONDS BROKEN NEW S-S BONDS ARE FORMEDPRESSURE : NOT MUCH SENSITIVE TO PRESSURE

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LYOPHILIZATION : WATER REMOVED SALTS ELECTROLYTES CONCENTRATEDADDITIVES FOR PROTECTION :GLYCEROL GLUCOSESUCROSE

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STERILIZATION : AUTOCLAVING : TOO HARSHRADIATION : FREE RADICAL FORMATIONFILTRATION : ASEPTIC PROCESSING FOLLOWED

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REFERENCES :1) Lang JC, Roehrs RE. Ophthalmic Preparations.In : Troy DB, editor.

Remington : The Science and Practice of Pharmacy. 21st ed. Volume I Philadelphia : Lippincott Williams & Wilkins ; 2005.p.850-862

2) Agrawal S, Udupa N. Protein and peptide drug delivery : recent advances. In : Jain NK, editor. Progress in Controlled and novel drug delivery systems. 1st ed. Delhi : CBS Publishers; 2004.p.184-204

3) Erb RJ. Protein and Peptide therapeutics in the eye.In : Mitra AK editor. Ophthalmic Drug Delivery Systems. Volume 58. New York : Marcel Dekker Inc.p.437-440

4) Krishnamoorthy R. Ocular Delivery of Peptides and Proteins.In : Mitra AK,editor. Ophthalmic Drug Delivery Systems. Volume 58. New York : Marcel Dekker Inc.p.455-465

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THANK YOU!

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