PROTEINS & PEPTIDE DRUG DELIVERY SYSTEMS Presented By K.Bhavya M.

Pharmacy(1st year) CONTENTS : CONTENTS Introduction Advantages Routes of administrations Parenteral Non Parenteral Development of delivery systems Conclusion References INTRODUCTION : INTRODUCTION Proteins and peptides are most abundant components of biological cells not only structural components but also functional moieties. Amino acid linked together in a sequential manner by peptide bond resulting the formation of peptides. Slide 4: PEPTIDE BOND FORMATION: TYPES OFPROTEINS & PEPTIDES : TYPES OFPROTEINS & PEPTIDES Depend on number of amino acids classified as follows: Poly peptides Oligopeptide Protein Fibrous proteins Globular proteins Oligomeric protein Slide 6: POLYPEPTIDES: COLLAGEN INSULIN Slide 7: Depend upon spatial arrangement of amino acid in proteins causes following structure to proteins: Slide 8: ADVANTAGES OF PROTEINS&PEPTIDE DRUGS: Tissue plasminogen activator used for heart attacks, strokes. Speroxide dismutage is an enzyme used for treatment of heart attacks. Erythropoietin used for production of red blood cells. Bradikinins increase peripheral circulation. Oxytosine maintain labor pains. Slide 9: Encephalin stimulate lymphocyte blastogenisis. Gonadotropins induce ovulation. Vasopressin treat diabetisisipidus. Cyclosporine inhibit function of T-lymphocytes. Somatostatins decrease bleeding of gastric ulcer. LHRH induce ovulation. Slide 10: ROUTES OF ADMINISTRATIONS PARENTERAL NONPARENTERAL INTRMSCULAR ORAL INTRAVASCULAR BUCCAL SUBCUTANIOUS NASAL RECTAL TRANSDERMAL PULMONARY PARENTERAL ROUTE OF ADMINISTRATIONS : PARENTERAL ROUTE OF ADMINISTRATIONS For the systemic delivery of proteins and peptide drugs through parenteral route is the most efficient route. And this is the best choice to achieve therapeutic activity. Mainly 3 types of administrations are used. Those are: INTRAVASCULAR INTRMSCULAR SUBCUTANIOUS Slide 12: ADVANTAGES: Fast absorption. Avoid first pass effect, proteolytic degradation. DISADVANTAGES: Short duration of their biological action. Stimulate immunogenic response. Inability to transport. Slide 13: INTRVENOUS ROUTE: Excessively metabolized and tissue bound drugs at the site of IM can be administered by this route. Ex: Insulin, interferon But causes pain, tissue necrosis, thrambopenia. Antibiotics are also administered Slide 14: INTRAMUSCULAR ROUTE: Gamma globulins has been beneficial to prove long term protection from hepatic infection. Not used for all proteins & peptide drugs because of metabolism of drugs at injection site. Adjutants, electrical current improve the bioavailability. Ex: Polymers Some of the drugs given by this route are LHRH, GH & long acting insulin.

Slide 15: SUBCUTANIOUS ROUTE: Implanted polymeric device: These are prepared by cross linked polymers. And these polymers must be biocompatible and biodegradable. Ex: Poly(d,l-lactide co-glycoside), Poly lactic acid. Some of the drugs are ACTH, insulin, bovin, calcitonin. Slide 16: In parenteral route Proteins & peptide drugs can be administered in this dosage forms LIPOSOMES HYDROGELS PUMPS EMULSIONS CELLULAR CARRIERS SELF REGULATED DEVICES AQUEOUS DRUG LIPID LAYER DRUG ENCLOSED IN GELLING POLYMERS HYDROPHILIC/ LIPOPHLIC DRUG ENCLOSED IN ERYTHROSYTES ENZYME SBSTRATE REACTION COMPETITIVE DESORPTION EROSSION CONTROLLED CONTROLLED RELEASE MECHANICAL IMPLANTABLE TEMPERATURE SENSITIVE Slide 17: ENZYME SBSTRATEREACTION COMPETITIVE DESORPTION Glucose concanavalin Insulin SELF REGULATED DEVICE NR2 NR2 NH R2 NH R2 INSULIN SWOLLEN MEMBRANE GLUCOSE OXIDASE ENZYME GLUCOSE ENTRY Slide 18: EROSION CONTROLLED: HYDROCARTISONE U U U U U U U U U U U U U U U U HYDROCARTISONE Poly vinyl methyl ether Urease Alkaline pH TEMPERATURE SENSITIVE: Myoglobin Myoglobin Myoglobin N- isopropyl acryl amide Slide 19: PUMPS MECHANICAL PUMPS 1 Automated cannula insertion system 2 Water tight housing 3 Insulin reservoir (capacity of 85 to 200 deliverable units) 4 Adhesive 5 Drive mechanism 6 Angled infusion set 7 Electronic circuitry for programming insulin delivery and enabling wireless communications 8 Power supply (batteries) IMPLANTABLE PUMPS NONPARENTERAL ROUTE OF ADMINISTRATIONS : NONPARENTERAL ROUTE OF ADMINISTRATIONS ORAL ROUTE OF ADMINISTRATION: Oral route is most popular route of delivery from patients point of view. Advantages : convenience, acceptability and high patient compliance. Slide 21: DISADVANTAGES: The systemic bioavailability of protein peptide drug by this route was generally less than 2% Very less permeability through oral mucosa. Potential degradation by strong acids, proteolytic enzymes. Slide 22: Various strategies have been attempted for effective delivery of proteins & peptide drugs through oral route. Some of them are as follows: Modification by chemical synthesis: This modification assist in manipulating the pharmacokinetic parameters to improve the therapeutic value of parent drug. This can be done by 1) Irreversible (Analogue) 2) Reversible (prodrug) Slide 23: Enzyme inhibitor: Ex: aprotine, camostatt mesilate, bacitracine. Penetration enhancer: Ex: Salicylic acid, Acrylitine Carrier systems: This strategy is particularly applicable in case of poorly absorbed, the drugs which are unstable in G.I lumen. Ex: liposome, sub micron emulsion BUCCAL ROUTE OF ADMINISTRATIONS : BUCCAL ROUTE OF ADMINISTRATIONS The drugs are absorbed through oral mucosa i.e. reportedly occour in the non-keratinized sections. ADVANTAGES: It is close resemblance to oral route seems well acceptable to the patients. It can attached and remove without any pain or discomfort. It is worth considerations when penetration enhancers are to be used. Slide 25: The inherent problem with these dosage forms is the risk of drug loss by accidental swallowing administration time is limited. Example of protein and peptide drugs administered by this route are: insulin, oxytosine, vasopressin. Insulin drug delivery: Medicated core salivary activation Gelation & adhesion Adhesive dome

NASAL ROUTE OF ADMINISTRATIONS : NASAL ROUTE OF ADMINISTRATIONS The nasal route has been chiefly employed for producing local action on the mucosa. This mucosa is more permeable compare to oral mucosa. Nasal absorption of protein and peptide drugs can be via passive diffusion or by special targeted mechanism. That is 1-20%. Ex: Insulin, Human growth hormone Slide 27: ADVANTAGES: Convenient, simple and practical way of drug administrations. The high vascular permits better drug absorption. First pass metabolism can be avoided. Rapid onset of action. DISADVANTAGES: Long term usage causes toxicity. Enzymatic barrier, size of proteins& peptide drugs reduce the systemic bioavailability Slide 28: Number approaches are available for achieving effective delivery of protein and peptide drugs. Those are: VISCOSITY MODIFICATION: Ex: Hydroxy propyl methyl cellulose REVERSEMICELLA FORMATION: Ex: Bile salts MEMBRANE TRANSPORTORS: Ex: Surfactant (SLS) ENZYME INHIBITORS: Ex: Bestatin, Amastatin TRANSDERMAL ROUTE OF ADMINISTRATIONS : TRANSDERMAL ROUTE OF ADMINISTRATIONS This is a topical medication. In this the drug was absorbed through skin. Ex: Insulin, vasopressin, TRH ADVANTAGES: Better and improved patient compliance. Drug with short half life also administered. Administration of drugs with low therapeutics index. Controlled administration was possible. Slide 30: DISADVANTAGES: High intra and inter patient variability. Low rate of permeation for these drugs because of large molecular weight. And hydrophilicity and lipophylisity of stratum cranium of skin. Slide 31: Number approaches are available for achieving effective delivery of protein and peptide drugs. Those are: IONOPHORESIS: PHONOPHORESIS: PENETRATION ENHANCERS: PRODRUG: PULMONARY ROUTE OF ADMINISTRATIONS : PULMONARY ROUTE OF ADMINISTRATIONS Respiratory track offers an alternative site for systemic non invasive delivery of protein and peptide drugs. Alveoli, lungs are the absorption sites(90%). Drugs are absorbed through lungs by simple diffusion, carrier mediated transport. Slide 33: ADVANTAGES: Provide a direct route into systemic circulation. Safe route even in patient with lung disease. Decrease in dose requirement. Fast absorption. Increase patient compliance. Slide 34: DISADVANTAGES: Only small amount of drug was administered. Inflammation, edema was observed in lungs. Degree of bioavailability was less due to hydrolytic enzymes present in lungs. Most of the drugs are delivered at the upper part of lung area with low systemic circulation. Slide 35: Insulin inhalers Insulin nebulisers RECTAL ROUTE OF ADMINISTRATIONS : RECTAL ROUTE OF ADMINISTRATIONS Rectum is highly vascularised body cavity. The rectal mucosa is devoid of any villi. These drugs are in a suppository dosage form, gel, dry powders. Ex: insulin, Gastrin, Calcitonin. Slide 37: ADVANTAGES: Large dose can be administered. Avoid first pass metabolism. Drugs can be targeted to the lymphatic system. In case of drug overdo drug absorption can be terminated. Reduce proteolytic degradation, the improved systemic bioavailability of protein and peptide drugs was observed with co administration of absorption enhancers. Ex: Surfactant, EDTA, Salicylates. DEVELOPMENT OF DELIVERY SYSTEMS :

DEVELOPMENT OF DELIVERY SYSTEMS FORMULATION CONSIDIRATIONS: Preformulation considerations. Surface adsorption behavior Stability profiles PHARMACOKINETIC CONSIDERATIONS ANALYTICA CONSIDERATIONS REGULATORY CONSIDIRATIONS FORMULATION CONSIDIRATIONS : FORMULATION CONSIDIRATIONS The development of delivery systems for therapeutic proteins and peptides & their evaluation depend on the biophysical, chemical, physical characters of proteins & peptides include their molecular size,t1/2,immunogenisitry. Preformulation studies Surface absorption behavior Slide 40: STABILITY PROFILE PHYSICAL CHEMICAL DENATURATION DEAMIDATION ABSORPTION PROTEOLYSIS AGGREGATION RACEMISATION PRECIPITATION OXIDATION & REDUCTION PHARMACOKINETIC CONSIDERATIONS : PHARMACOKINETIC CONSIDERATIONS Pharmacokinetic considerations of protein and peptide drugs are same as that of other drugs. But having some problems. Those are: Less biological half life. Instability at the absorption site. Endogenous compounds interact at absorption site. Sampling errors. Presence of binding proteins. ANALYTICA CONSIDERATIONS : ANALYTICA CONSIDERATIONS High resolution power. Sensitivity can be improved by adding reagents. EXTERNAL PHOTOGRAPH INTERNAL CONNECTIONS 1)RADIOIMMUNO ASSAY 2)HPLC REGULATORY CONSIDIRATIONS : REGULATORY CONSIDIRATIONS Unlike the conventional organic based pharmaceutical protein and peptide pharmaceutical have its structure, identification, quality, potency and purity. The main regulatorities are FDA,EPA,USDA FDA Food & Drug administrations EPA Environmental protection agency USDA US Department of agriculture CONCLUSION : CONCLUSION Protein and peptide pharmaceuticals are very important class of therapeutic agents. Their emergencies on the clinical& therapeutic horizon has intensified the investigation for their convenient & effective delivery through noninvasive route. The additional challenges for the pharmacist is designing & development of viable delivery system for non parenteral administration of peptide and proteins drugs. REFERENCES : REFERENCES Controlled Drug Delivery Concepts And Advances By S.P Vyas&Roop.K.Khar Page no: 503 Novel Drug Delivery systems By yie .W. Chien Second Edition Page no :631 Progress in controlled & novel drug delivery systems By N.K.Jain Page. no 184 Slide 46: Any Queries Slide 47: THANKING U