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Protein and Peptide drug delivery system.ppt

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Protein and Peptide drug delivery system.ppt

  1. 1. PROTEIN AND PEPTIDE DRUG DELIVERY SYSTEM 1 , By: Dr. Manish Kumar Professor, MM College of Pharmacy, MM (DU), Mullana. Ambala, Haryana
  2. 2. CONTENT S I. Protein & Peptides II. Structure of protein III. Classification of protein IV. Drug delivery system V. Stability testing VI. Conclusion VII. References 2
  3. 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. 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. 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. 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. 7. 2. STRUCTURE OF PROTEIN The structure of protein divided in to four types: 1. Primary structure : The amino acid sequence. 2. Secondary structure: Regularly repeating local structures stabilized by hydrogen bond. 3. Tertiary structure : Three dimensional structure of polypeptide. 4. Quaternary structure: The structure formed by several protein molecules (polypeptide chains). 7
  8. 8. CONTINUE… 8
  9. 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. 10. 4. DELIVERY OF PROTEINS DRUG DELIVERY CLASSIFICATION Pulmonary Parenteral Transdermal Implants Ocular Nasal Miscellaneous Oral Route of Administration PEGylation Pro-drug Polymer depot Drug Modification Drug Delivery 10
  11. 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. 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. 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. 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. 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. 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
  17. 17. 17
  18. 18. 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 18
  19. 19. • Route of delivery for 95% of proteins • Allows rapid and complete absorption . • Avoids first pass metabolism Advantages • Problems with overdosing, necrosis • Local tissue reactions/hypersensitivity • Everyone hates getting a needle Disadvantages 19
  20. 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. 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. 22. SUBCUTANEOUS 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. 23. 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 23
  24. 24. 24
  25. 25. POLYMER BASED DRUG DELIVERY SYSTEM polymers are used as carriers in this drug  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. 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 o o o o o o o o o o o o o o o
  27. 27. LIPOSOME 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. 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. 29. HYDROGEL 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. 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. 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. 32. NON PARENTERAL ROUTES OF ADMINISTRATION Parenteral route is not properly achievable, hence other routes are preferred.  Oral route.  Rectal route.  Nasal route.  Pulmonary route.  Buccal route.  Transdermal route.  Ocular route 32
  33. 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. 34. TRANSDERMAL 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. 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. 36. PULMONARY 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. 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. 38. RECTAL 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. 39. OCULAR ROUTE  In 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. 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. 41. NASAL 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. 42. PROTEIN FORMULATIONS 42 1 • Protein sequence modification (site directed mutagenisis) • PEGylation 2 • Proteinylation • Microsphere encapsulation 3 • Formulating with permeabilizers
  43. 43. PEGYLATION  PEG is a non-toxic, hydrophilic, FDA approved, uncharged polymer.  Increases in vivo half life.  Decreases immunogenicity.  Increases protease resistance.  Increases stability. 43 CH-CH-CH-CH-CH-CH-CH-CH-CH-CH | | | | | | | | | | OH OH OH OH OH OH OH OH OH OH +
  44. 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. 44 + Protein drug scfc (antibody)
  45. 45. FORMULATION WITH PERMEABILIZERS  Salicylates (aspirin)  Fatty acids  Metal chelators (EDTA) 45
  46. 46. STABILITY 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. 47. CONCLUSION  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. 48. REFERENCES  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. I nternational Journal of Current Pharmaceutical Research 48
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