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INTRODUCTION PROTEIN – Molecules composed of over 50 amino acid PEPTIDE- Molecules composed of less than 50 amino acid CHARACTERISTICS Protein structure 3

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Isoelectric point : The pH at which mean charges on the protein is zero Degradation through covalent bonds : 1 ) Peptide fragmentation 2) Deamination 3) Oxidation 4) Disulfide exchange 5) Racemization 6) Millard reaction 7) Dimerization & polymerization Denaturation It is a process of altering protein conformation 4

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Analytical methods UV Spectrometry 2) Protein assay 3) Thermal analysis 4) Electrophoresis 5) Liquid chromatography 5

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BIOMEDICAL IMPORTANCE Transport Metabolic control Structural function Hormones Serum protein Enzymes Neurotransmitters Antibiotics Sweetening agent in beverages 6

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CHALLENGES TO PROTEIN & PEPTIDE DELIVERY Proteins are relatively large molecule with complex architecture Degradation Drawbacks associated with their physicochemical & biological properties Short plasma half –life 7

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FORMULATION PRINCIPLES Ph At neutral pH ( 6-7 ) proteins undergo oxidation e.g. cysteine, methionine At pH above 8 protein & peptide shows degradation reaction At pH of isoelectric point protein solubility is minimal & it promote the formation of aggregates pH should be such that sum of various degradation reaction is at minimum Peptides are formulated at slightly acidic pH ( 3-5) but some of protein & peptide shows deamination & hydrolysis 9

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2 ) Effect of salt At low conc. of divalent ions ( Ca ++ , Mg ++ , Zn ++ ) thermal stability may enhanced At high salt conc. Protein solubility increases e.g. - (NH 4 ) 2 SO 4 is a strong stabilizer 10

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3) Common stabilizers Serum albumin -It can be withstand at 60 o C for 10 hr. -AT pH 1-2 albumin molecules expand & elongates reversibly -It has good solubility Stabilizing mechanism of albumin - Inhibition of surface adsorption - substitution for a nascen complex protein - dispersion in interstitial spaces - cryoprotection 11

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Amino acids -Reduces surface adsorption -Inhibit aggregate formation -stabilize against heat denaturation e.g . –Glycine, lycine Surfactants - Surfactant frequently causes denaturation of protein . - Strong interaction between surfactant & reactive site of protein, this interaction can stabilize protein against other denaturants - It reduces interfacial tension and increases the solubility 12

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Polyhydric alcohols & carbohydrates - It stabilizes protein against denaturation caused by - elevated temperature & freeze drying processes e.g . – manitol, sorbitol, glycol, PEGs Antioxidants & metal chelates - Prevents protein from oxidation. - Inhibit the disulfide bond formation e.g . – EDTA 13

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Miscellaneous - Formation of stable complex through hydrophobic interaction e.g .- heparin sulphate stabilize basic fibroblast growth factor - Excipients in an injectable formulation to a minimum Bridging function of Ca+ with polypeptide chain reduces flexibility of polypeptide backbone 14

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4 ) Aggregation • It is the phenomenon in which the protein molecule form aggregate ranging from 0.1-100 m and ppt. out of solution • It interferes with products desirable appearance • Reduction in biological potency • Blockage of tubing, membrane or pumps • Anaphylactic reaction • Aggregation is prominent when cause by heat, shaking, freezing or by freeze drying. • It is analyzed quantitatively by chromatographic technique • The aggregation effectively prevented by the addition of mild surfactant 15

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COMPATIBILITY WITH PACKAGING COMPONENTS In blood protein undergo rapid degradation, so not adm. By IV bolus Protein adsorbs to container, in-line filter, tubing & catheter The adsorption is maximum at the pH of its isoelectric point There is maximum loss of protein & peptide with plastic containers The most effective means of reducing adsorption is the addition of human serum albumin, at 10 times the amount of protein to be protected . 16

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VARIOUS Sustained RELEASE PROTEIN S& PEPTIDE PARENTRALS Biodegradable polymer based drug delivery system Liposomes Hydrogel Multiple emulsions Cellular carrier Self regulated devices ◘ competitive desorption ◘ Enzyme substrate reaction ◘ Membrane control release ◘ Erosion controlled release ◘ Temperature sensitive devices ◘ Magnetically controlled drug delivery systems 17

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ADVANTAGES OF PROTEIN & PEPTIDE SUSTAINed RELEASE PARENTRALS It provides maximum stability, activity & bioavailability of drug It provide reduced toxicity , improved efficiency & patient compliance It is delivery of drug at a rate or to a location determine by need of the body or disease state over a specific or extended period of time during drug therapy 18

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19 MARKETED PREPARATIONS PRODUCT ROUTE INDICATION LUPRON (Leuprolide acetate) i.m. Prostatic Cancer PITRESSIN TANNATE IN OIL (Vasopresisne tannate) i.m. Antidiuretic H.P.ACTHAR GEL (Adrenocorticoid in gelatin ) i.m.; s.c. Endocrine Cancer INSULIN Nasal; parentral ; transdermal D.M.

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20 REFERENCES: Yu- chang Jon Wang. Parentral products of Peptides & Proteins, Lachmann and Libberman series, pp- 283 to 314. R. D’Souza , S. Mutalik , S. Agarwal , N. Udupa . Protein and Peptides Drug Delivery : Recent Advances, pp: 184 to 205.

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Questions ? Loaded erythrocytes in parenterals Implants in sustained release parenterals Short note on insulin injection

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22 Thank You. Wish You Happy New Year