protein &peptide drug delivery system

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By - Bhimrao Rupnoor

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WEL-COME Proteins and Peptides drug delivery system

A Seminar on PROTEIN AND PEPTIDE DRUG DELIVERY SYSTEM : 

A Seminar on PROTEIN AND PEPTIDE DRUG DELIVERY SYSTEM By Bhimrao K. Rupnoor (M. Pharm., Sem. II) Under the guidance of Mr. K.K. Mali Asst. Professor, Satara College of Pharmacy, Satara.

CONTENTS : 

CONTENTS 3 Protein & Peptides Structure of protein Classification of protein Stability problems Formulation Aspects Parenteral delivery of protein and peptide Ocular delivery of protein & peptide Marketed formulations Conclusion References

Protein & Peptide : 

Protein & Peptide 4 . Proteins: These are large organic compounds made of amino acids arranged in a linear chain and joined together by peptide bonds. Protein > 50 amino acids Peptides: These are short polymers formed from the linking, in a defined order, of α-amino acids. peptide < 50 amino acids

STRUCTURE OF PROTEIN : 

STRUCTURE OF PROTEIN 5 There are four types. Primary structure- The amino acid sequence. Secondary structure- Regularly repeating local structures stabilized by hydrogen bond. Tertiary structure-Three dimensional structure of polypeptide Quaternary structure-The structure formed by several protein molecules (polypeptide chains).

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6

Protein Structure : 

Protein Structure 7 Lactate Dehydrogenase: Mixed α /β Immunoglobulin Fold: β Hemoglobin B Chain: α

Classification of Proteins : 

Classification of Proteins According to their biological roles Enzymes – Catalyses virtually all chemical reactions i.e. 6GDH Transport proteins i.e. Haemoglobin of erythrocytes Contractile or Motile proteins i.e. Actin and Myosin Structural proteins i.e.Collagen in bones Defense proteins i.e. Immunoglobulins and Antibodies Regulatory proteins i.e. insulin Nutrient and storage proteins i.e. Ovalbumin 8

FUNCTIONS : 

FUNCTIONS 9 Transport and storage of small molecules. Coordinated motion via muscle contraction. Mechanical support from fibrous protein. Generation and transmission of nerve impulses. Enzymatic catalysis. Immune protection through antibodies. Control of growth and differentiation via hormones.

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10 Advantages of protein and peptide drug delivery system Erythropoietin used for production of RBC. Tissue plasminogen activator is used for Heart attack, Stroke. Oxytocin maintain labor pain. Bradykinin increases the peripheral circulation. Somatostatin decrease bleeding in gastric ulcer. Gonadotropin induce ovulation. Insulin maintain blood sugar level.

Disadvantages : 

Disadvantages Very large and unstable molecules. Structure is held together by weak noncovalent forces. Easily destroyed by relatively mild storage conditions and gastric juices. Hard to obtain in large quantities.

Problem with Proteins (in vivo – in the body) : 

Problem with Proteins (in vivo – in the body) Elimination by B and T cells Proteolysis by endo/exo peptidases Small proteins filtered out by the kidneys very quickly Unwanted allergic reactions may develop (even toxicity) Loss due to insolubility/adsorption 12

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Problem with Proteins (in vitro – in the bottle) : 

Problem with Proteins (in vitro – in the bottle) Noncovalent Covalent Denaturation - Deamidation Aggregation - Oxidation Precipitation - Proteolysis Adsorption 14

Covalent processes : 

Covalent processes 15 Deamidation - conversion of Asn-Gly sequences to a-Asp-Gly or b-Asp-Gly Oxidation - conversion RSR’ to RSOR’, RSO2R’ or RSO3R’ (Met & Cys) Proteolysis - Asp-Pro, Trypsin (at Lys) or Chymotrypsin (at Phe/Tyr)

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16 How to Deal with These Problems Storage Formulation Delivery

Storage : 

Storage Refrigeration Packaging Additives Freeze-Drying 17

Commonly used excipients For solving physical and chemical stability problems : 

Commonly used excipients For solving physical and chemical stability problems 24 Jan. 2010 18 Modern College of Pharmacy, Pune

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19

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20 Protein Formulations

Site Directed Mutagenesis : 

Site Directed Mutagenesis 21 Allows amino acid substitutions at specific sites in a protein i.e. substituting a Met to a Leu will reduce likelihood of oxidation E343H

PEGylation : 

PEGylation 22 PEG is a non-toxic, hydrophilic, FDA approved, uncharged polymer Increases in vivo half life Decreases immunogenicity Increases protease resistance Increases stability

PEGylation : 

PEGylation 23 + CH-CH-CH-CH-CH-CH-CH-CH-CH-CH | | | | | | | | | | OH OH OH OH OH OH OH OH OH OH

Proteinylation : 

Proteinylation 24 Attachment of additional or secondary (nonimmunogenic) proteins for in vivo protection Cross-linking with Serum Albumin increases in vivo half life Cross-linking or connecting by protein engineering with antibody fragments

Proteinylation : 

Proteinylation 25 + Protein drug scfc (antibody)

Formulation with permeabilizers : 

Formulation with permeabilizers 26 Salicylates (aspirin) Fatty acids Metal chelators (EDTA)

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27 Drug Delivery

Parenteral Delivery of Proteins : 

Parenteral Delivery of Proteins 28 Intravenous Intramuscular Subcutaneous Intradermal

Advantages and Disadvantages : 

Advantages and Disadvantages 29

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30 Polymeric Drug Delivery Polymers should be: Biodegradable Bio-compatible Non-toxic Examples: Natural- Chitosan, Dextrin Synthetic- Polylactides/ glycolide Polyanhydrides Polyphosphoesters

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31 Release Mechanism Diffusion of drug out of the polymer Drug Release by Polymer Degradation Hydrolysis Enzymatic (Phosphotases; Proteases etc.)

Microsphere Drug delivery : 

Microsphere Drug delivery 32 Two types of microspheres Nonbiodegradable e.g, ceramic particles polyethylene co-vinyl acetate polymethacrylic acid/PEG Biodegradable (preferred) e.g, gelatin polylactic-co-glycolic acid (PLGA)

Magnetic Targeted Carriers (MTCs) : 

Magnetic Targeted Carriers (MTCs) 33 Founder of FeRx and pioneer of magnetic targeted drug delivery is Dr. Kenneth Widder Microparticles, composed of elemental iron and activated carbon Drug is adsorbed into the MTCs and transported The particles serve as delivery vehicles to the area of the tumor for site-specific targeting

Liposomal Drug Delivery : 

Liposomal Drug Delivery 34 Spherical vesicles with a phospholipid bilayer E.g, Bleomycin encapsulated in thermo sensitive liposome enhanced antitumor activity and reduced normal tissue toxicity Liposome have recently been used successfully as vehicles for vaccines

Hydrogel Based Drug Delivery : 

Hydrogel Based Drug Delivery 35 Hydrogels are three dimensional networks of hydrophilic polymers that are insoluble

Hydrogel Based Drug Delivery : 

Hydrogel Based Drug Delivery 36 e.g Insulin Hydrogels can swell as a result of changes in pH, Temperature.

Proteins in Pumps : 

Proteins in Pumps 37 Multiple potential interactions between the protein and the pump Infusaid Model 400 Implantable Pump Mechanical Insulin Pumps

Emulsion and Cellular carriers : 

Emulsion and Cellular carriers Emulsion : Emulsion can be used for parenteral delivery of protein and peptides. Multiple emulsion further prolong the release of drug. e.g. subcutaneous administration of muramyl dipeptide in a w/o emulsion Cellular carriers: Protein and peptides can be incorporated in erythrocytes to achieve the prolong release or targeting. Resealed erythrocytes as delivery system for c-reactive protein, and mainly used to target liver and spleen. 38

Ocular Delivery of Peptide & Protein : 

Ocular Delivery of Peptide & Protein 39 Relevant anatomy and Physiology of the Human eye Diameter of 23 mm Three layers Outermost coat : the clear, transparent cornea and the white, opaque sclera Middle layer : the iris anteriorly, the choroid posteriorly, and the ciliary body at the intermediate part Inner layer : retina

Peptides Useful in Ocular Pathology : 

Peptides Useful in Ocular Pathology 40 To treat infections and enzymes used to promote wound healing. a. Bacitracin The drug is applied topically to the eye for a variety of conditions, including eyelid burns and corneal superficial punctate keratits .It is also used to treat optic neuritis. Commercial bacitracin is a mixture of at least nine bacitracins, which is used for its antibacterial activity

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b. Chymotrypsin Chymotrypsin is used clinically in the eye for enzymatic intracarpsular lens extraction.  c. Cyclosporine Cyclosporine are a group of biologically active metabolites produced by Fungi. When cyclosporine A is administered by nonocular route in rats, it produces significant blood levels, but it can not be detected in tissues. 41

Advantages : 

Advantages 42 The mode of delivery is convenient, i.e., eye drops. Systemic absorption is extremely rapid. Avoid first-pass metabolism. The formulation can be designed to prolong drug action and/or reduce drug concentrations to achieve consistent drug action with least side effects. Drug delivery can be controlled precisely.

Marketed formulations : 

Marketed formulations

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44

45 Conclusion

REFERENCES : 

REFERENCES 46 Frokjaer, Hovgard,Pharmaceutical formulation development of peptides and proteins,2000 .29-32,41-60. Avis E. Kennith, Lieberman A, Herbert., Lachmam, Leon., Pharmaceutical dosage form: Parenteral Medication vol-1, Second edition, Mercel Dekker, USA, 284, 302, 312. Robinson, R. Joseph. Controlled Drug Delivery : Fundamental &application, Second edition, Mercel Dekkar, USA, 7-14.

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47 Mitra, K.Ashim, Opthalmic Drug delivery System, Second edition, Mercel Dekkar,464-73.  Jain N.K., Progress in Controlled & novel Drug delivery system. CBS publication; Delhi, 195. Gupta H, Sharma A. Recent trends in protein and peptide drug delivery systems. Asian J Pharm 2009;3:69-75.

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48 Thank you…