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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