protein and peptide drug delivery system

1. PROTEIN AND PEPTIDE DRUG DELIVERY SYSTEM Presented By Brajesh kumar m. Pharm (1 st year) pharmaceutics Bbau lucknow , 1

2. Contents Protein & Peptides Structure of protein Classification of protein Drug delivery system Stability testing Conclusion References 2

3. 1. Protein & Peptides PROTEINS: Proteins are the 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 amino acids. peptide < 50 amino acids 3

4. Continue…. Why protein and peptide are used; The protein and peptides are very important in biological cells. Lack of proteins and peptides causes diseases like Diabetes mellitus. Diabetes mellitus is caused due to the lack of protein called INSULIN. Now a days R-DNA technology and hybridoma techniques also used in protein and peptide based pharmaceuticals. 4

5. Continue… ADVANTAGES 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. 5

6. Continue… FUNCTIONS 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 6

7. 2. Structure of protein The structure of protein divided in to four types: Primary structure : The amino acid sequence . Secondary structure: R egularly 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). 7

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9. 3. Classification of protein Depending on the number of amino acids they are classified as follows: Polypeptides protein Oligopeptides protein Fibrous proteins Globular proteins Oligo meric proteins 9

10. 4. Delivery of proteins 10

11. Continue… Parenteral routes of administration; Parenteral route is most efficient way for systemic delivery of proteins and peptides . This is the best choice to achieve therapeutic activity Mainly 3 routes of administration Intravascular Intramuscular Subcutaneous 11

12. Continue… Advantages Route of delivery for 95% of proteins Allows rapid and complete absorption . Avoids first pass metabolism Disadvantages Problems with overdosing, necrosis Local tissue reactions/hypersensitivity Everyone hates getting a needle 12

13. Continue… INTRAVENEOUS ROUTE: Excessively metabolized and tissue drug bound at the site of IM can be administered by this route such as Insulin , Interferon etc. DISADVANTAGES : Causes pain, tissue necrosis and thrombocytopenia. ADVANTAGES: Antibiotics can be administered. 13

14. Continue… INTRAMUSCULAR ROUTE: Gamma globulins given by this route are proved to have long-term protection from hepatic infection . some drugs given by this route include long acting insulin, GH. DISADVANTAGES: Not used for all proteins and peptide drugs because of metabolism of drugs at the site of injection . 14

15. Continue… SUBCUTANEOUS ROUTE; Controlled release is obtained from implantable polymeric devices . These are prepared from crossed linked polymers which are biocompatible and biodegradable e.g. Poly lactic acid. Release of Insulin, bovine serum albumin, LH was prolonged by this route. 15

16. 4. PARENTERAL DRUG DELIVERY SYSTEM Polymer based drug delivery system. Liposome based drug delivery system. Hydro gel based drug delivery system. Emulsion based drug delivery system. PUMPS: Implantable infusion pumps Mechanical pumps 16

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18. P arenteral routes of administration Parenteral route is most efficient way for systemic delivery of proteins and peptides. This is the best choice to achieve therapeutic activity . Mainly 3 routes of administration INTRAVASCULAR INTRAMUSCULAR SUBCUTANEOUS 18

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20. INTRAVENEOUS ROUTE Excessively metabolized and tissue drug bound at the site of IM can be administered by this route. EX: Insulin, Interferon . DISADVANTAGES : Causes pain, tissue necrosis and thrombopenia . ADVANTAGES : Antibiotics can be administered. 20

21. INTRAMUSCULAR ROUTE Gamma globulins given by this route are proved to have long-term protection from hepatic infection. some drugs given by this route include long acting insulin, GH. DISADVANTAGES : Not used for all proteins and peptide drugs because of metabolism of drugs at the site of injection. 21

22. S ubcutaneous route Controlled release is obtained from implantable polymeric devices. These are prepared from crossed linked polymers which are biocompatible and biodegradable. EX: polylactic acid Release of Insulin, bovine serum albumin, LH was prolonged by this route. 22

23. P arenteral drug delivery system Polymer based drug delivery system. Liposome based drug delivery system. Hydro gel based drug delivery system. Emulsion based drug delivery system. PUMPS : Implantable infusion pumps Mechanical pumps 23

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25. P olymer based drug delivery system polymers are used as carriers in this dr ug Pug delivery system . CHARACTERS OF POLYMERS It should be biodegradable. It should be bio compatible. And non-toxic . Two types of polymers are used widely natural polymers synthetic polymers 25

26. Natural polymers: Collagen , hemoglobin and gelatin. Synthetic polymers: mainly poly esters like PLA and PGA are used widely . Diffusion of drug out of the polymer Drug Release by Polymer Degradation 26

27. L iposome based drug delivery Spherical vesicles with a phospholipid bilayer Liposome's are microscopic vesicles composed of one or more aqueous compartments . Liposome’s in Proteins delivery : Example: Lecithin used in controlled drug release . Liposome’s in peptide drug delivery: Bleomycin : A peptide with anti tumor activity, reduces normal tissue toxicity . Negatively charged liposome's produces a prolonged hypoglycemic effect in diabetic drugs, which are injected by subcutaneous injection. 27

28. ADVANTAGES OF LIPOSOME DRUG DELIVERY Soluble in both organic and aqueous media . Liposome’s are important for targeting drugs directly to the liver, and brain. Lipsosomes easily crosses blood brain barrier. EXAMPLE : Dopamine converted to L-Dopa. Used as a vehicles for vaccines . DISADVANTAGES Less stable , easily susceptible to oxidation. Hence liposome’s are replaced by noisome an alternate for liposome’s. 28

29. H ydrogel based dds Hydrogels are three dimensional networks of hydrophilic polymers that are insoluble- Hydro gels are polymers which have the ability to swell in water . Biodegradable hydro gels are used, due to its biocompatibility . Examples : Hydroxymethylacrylate , used to minimize mechanical irritation to surrounding tissue . 29

30. EMULSION BASED DELIVERY Emulsions can be used for parenteral drug delivery of proteins and peptides used to prolong the release of drug. e.g. subcutaneous administration of muramyl dipeptide in a w/o emulsion. It is used to potentiate immune system. 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. 30

31. PUMPS Types of pumps : 1. IMPLANTABLE PUMPS Drug is implanted subcutaneously, and delivered by I.V infusion . Pumps are filled with drug through a septum with a needle . Pumps deliver drugs to central vein for 7-14 days a constant rate . 2. MECHANICAL PUMPS Easily manipulated to deliver protein and peptide drugs . Example : insulin has been successfully delivered by portable syringe. 31

32. NON PARENTERAL ROUTES OF ADMINISTRATION Parenteral route is not properly achievable, hence other routes are preferred . Oral route. Rectal route. Nasal route. P ulmonary route. Buccal route. Transdermal route. Ocular route 32

33. ORAL ROUTE Encapsulated peptides or proteins in amino acids with microsphere of approximately 10 micron in diameter , used for oral delivery. Example: Insulin and heparin . Orally administered insulin produces hypoglycemic effect . DISADVANTAGES: Acid catalyzed degradation in stomach . Proteolysis in GIT . 33

34. T ransdermal route of administration This is topical medication. Drug is absorbed through the skin. EX : Insulin, vasopressin ADVANTAGES: Controlled administration of drug is possible. Improved patient compliance. Drugs with short half lives can be administered . DISADVANTAGES : High intra and inter patient variability. Low permeation because of high molecular weight. Hydrophilicity and lipophilicity of stratum corneum . 34

35. Number of approaches are available for effective protein and peptide drug delivery . They are IONTOPHORESIS PHONOPHORESIS PENETRATION ENHANCERS PRODRUG Iontophoresis : Used for local and systemic delivery of proteins and peptides. In this an electric current is used to drive the molecules across the skin surface. Example : Transport of insulin using iontophoresis . Phonophoresis : The absorption is enhanced by thermal effect of ultrasonic waves and subsequent alteration of physical structure of skin surface. 35

36. P ulmonary route of administration Lungs are attractive site for systemic delivery of proteins and peptides because of their enormous surface area(70 sq.m ) Alveoli and lungs are the absorption sites . Drugs are absorbed through lungs by simple diffusion, carrier mediated transport 36

37. ADVANTAGES : Decrease in dose requirement. Fast absorption Increased patient compliance DISADVANTAGES: Inflammation may be observed in lungs. Degree of bioavailability was less due to hydrolytic enzymes present in lungs 37

38. R ectal route of administration Rectum is highly vascularised body cavity . Rectal mucosa is devoid of villi . Drugs are in form of suppositories, gel, dry powders. EX: Insulin, calcitonin ADVANTAGES: Reduced proteolytic degradation . Improved systemic bioavailability with co-administration of absorption enhancers. EX : surfactants Large dose can be administered. 38

39. OCULAR ROUTE I n this route enkephalins , thyrotrophin releasing hormones ,luteinizing hormones ,glucagon and insulin are administered BUCCAL ROUTE Mucoadhesive dosage forms can be used for buccal route . Adsorption enhancers like salicylates or a surfactant is used for protein and peptide delivery through buccal route . Example: Oxytocin , vasopressin , insulin, are reported to be absorbed through buccal mucosa . And adhesive gel, patches , tablets are used . Insulin is absorbed through buccal mucosa in the presence of sodium glycolate . 39

40. The drugs are absorbed through oral mucosa mainly through the non-keratinized regions . ADVANTAGES: It can be attached or removed without any discomfort and pain. Well acceptability by patients. Drugs are absorbed rapidly . DISADVANTAGES: Administration time is limited. Drug loss by accidental swallowing. 40

41. N asal route of administration The nasal route has been employed for producing local action on the mucosa which is more permeable compared to oral mucosa . Nasal absorption is through passive diffusion. EX : Insulin, human growth hormone . ADVANTAGES : Rapid onset of action First pass metabolism can be avoided Better drug absorption DISADVANTAGES: Long-term usage causes toxicity. Size of proteins and peptide drugs reduces systemic bioavailability. 41

42. PROTEIN FORMULATIONS 42

43. PEGYLATION PEG is a non-toxic, hydrophilic, FDA approved, uncharged polymer. Increases in vivo half life. Decreases immunogenicity. Increases protease resistance. Increases stability . CH-CH-CH-CH-CH-CH-CH-CH-CH-CH | | | | | | | | | | OH OH OH OH OH OH OH OH OH OH + 43

44. PROTEINYLATION Attachment of additional or secondary (non-immunogenic) 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. + Protein drug scfc (antibody) 44

45. FORMULATION WITH PERMEABILIZERS Salicylates (aspirin) Fatty acids Metal chelators (EDTA) 45

46. S tability testing The capability of a particular formulation in a specific container/closure system to remain within its physical,chemical,microbiological,toxicological and protective specifications. Evaluates the effect of environmental factors on the quality of the a drug substance or a formulated product which is utilized for prediction of its shelf life, determine proper storage conditions. General Selection of Batches Container Closure System Specification Testing Frequency Storage Conditions Stability Commitment Evaluation Statements/Labelling On-going Stability Studies   46

47. C onclusion Protein and peptide based pharmaceuticals are rapidly becoming a very important class of therapeutic agents and are likely to replace many existing organic based pharmaceuticals in the very near future . Peptide and protein drugs will be produced on a large scale by biotechnology processes and will become commercially available for therapeutic use . Their need in the clinical & therapeutic regions has intensified the investigation for their convenient & effective delivery through noninvasive system. 47

48. R eferences Controlled drug delivery concepts and advances by S.P vyas & Roop k.khar Understanding the Fundamentals of Peptides and Proteins By GARY HU (Bio processing journal -trends in development in bio process technology ) PEPTIDES AND PROTEINS IN PHARMACEUTICALS    RATNAPARKHI M.P.,* CHAUDHARI S.P., PANDYA V.A. International Journal of Current Pharmaceutical Research 48

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