Pegylation

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PEGYLATION BY MS. SEEMA B. INGLE M.PHARM

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Pegylation refers to Chemically attachment of PEG to Drug Peptide Drug delivery system

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ADVANTAGES OF PEG MOLECULE Amphipathic in nature. High mobility in solution Lack of toxicity and immunogenicity Readily cleared from the body

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PEG SYNTHESIS PEG is formed by a process of linking repeated units of ethylene glycol to form linear or branched polymers. HOCH2CH2OH + n (CH2CH2O) →(HOCH2CH2O)n+1 Most useful polymer is monomethoxy PEG. Monomethoxy PEG (CH3 O–(CH2 CH2 O)n–CH2 CH 2–OH) is synthesized by anionic ring opening polymerization initiated by methoxy ions.

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USES OF PEG Low molecular weight PEG Binding agent :tablets, cosmetic creams, suppositories. Oligomer in polyurethane manufacturing. Production of non ionic surfactants. High molecular weight PEG. Pegylation process (lower immunogenicity and lower toxicity) Manufacturing suppositories Lubricant in tablet manufacturing

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ADVANTAGES OF PEGYLATION REDUCED TOXICITYAND IMMUNOGENICITY. PROLONGED CIRCULATION TIME REDUCED PROTEOLYSIS. INCREASED CHEMICAL STABILITY. IMPROVED SOLUBILITY.

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TYPES OF PEGYLATION FIRST GERENERATION SECOND GENERATION

FIRST GENERATION PEGYLATION : 

FIRST GENERATION PEGYLATION Linear and relatively low molecular weight PEG molecule are used. These PEG derivatives are usually synthesized from mono methoxypolyethylene glycol (mPEG) which has hydroxyl group at one end of the molecule available for manipulation.

1.1 AMINO GROUP CONJUGATION : 

1.1 AMINO GROUP CONJUGATION PEG derivatives are prepared by reacting the PEG polymer or m-PEG with a group which conjugates with drug molecule. e.g. PEG dichlorotriazine PEG tresylate PEG succinimidylcarbonate

EXAMPLES OF FIRST GENERATION PEGYLATION : 

EXAMPLES OF FIRST GENERATION PEGYLATION PEGADEMASE (Adagen). Adenosine deaminase, Severe combined immunodeficiency disease (SCID) PEGASPARGINASE (Ancaspar). Asparaginase Acute lymphocytic leukemia and chronic myelogenous leukemia. PEGINTRONα2b (Pegintron). Interferonα2b Hepatitis C

LIMITATIONS OF FIRST GENERATION PEGYLATION : 

LIMITATIONS OF FIRST GENERATION PEGYLATION Linear PEG molecule with molecular masses 12kDa or less forms unstable bond between drug and PEG molecule, leading to degradation of PEG during manufacturing and injection. Diols from mPEG cross link with each other to form inactive aggregates.

SECOND GENERATION PEGYLATION : 

SECOND GENERATION PEGYLATION Second generation pegylation is done to avoid pitfalls associated with diol contamination, unstable bond and low molecular masses m-PEG. Second generation pegylation uses branched PEG molecule.

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Approaches of second generation pegylation 1. Site specific pegylation. 2. Branched derivatives.

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1. SITE SPECIFIC 1.1 CYSTEINE MODIFICATION Pegylation of free cysteine residues at –SH bond in proteins is the main approach of site specific drug delivery. e.g. 1. PEG-vinylsulfone (PEG-VS). 2. PEG-maleimide (PEG-MAL)

1.2 N-TERMINAL MODIFICATION OF GLYCOPROTEINS : 

1.2 N-TERMINAL MODIFICATION OF GLYCOPROTEINS Oxidation of carbohydrate residues on N-terminal serine or threonine is an alternative method for site-directed pegylation of glycoproteins. This modification produces multiple site for attachment on PEG molecule.

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EXAMPLES OF SECOND GENERATION PEGYLATION PEGINTERFERON α2a (Pegasys) Interferon α2a Hepatitis C PEGVISOMANT (Somavert) Growth hormone antagonist Acromegaly

PHARMACOKINETIC AND PHARMACODYNAMIC PARAMETERS FOR PEGYLATED MOLECULE AND THEIR UNMODIFIEDE DRUGS : 

PHARMACOKINETIC AND PHARMACODYNAMIC PARAMETERS FOR PEGYLATED MOLECULE AND THEIR UNMODIFIEDE DRUGS

PEGYLATION OF DIFFERENT DRUG MOLECULES : 

PEGYLATION OF DIFFERENT DRUG MOLECULES 1. POLYPEPTIDE HORMONES

2.NUCLEIC ACIDS : 

2.NUCLEIC ACIDS

3.CYTOKINES : 

3.CYTOKINES

4.ENZYMES : 

4.ENZYMES

CASE STUDY : 

CASE STUDY PEGASYS (Peginterferonα2a) The altered PK profile of PEG-IFN-a2a.

PEGYLATION OF FINISHED PRODUCTS : 

PEGYLATION OF FINISHED PRODUCTS PEGYLATED LIPOSOMES e.g. Pegylated liposomes of Doxorubicin. PEGYLATED NANOPARTICLES

PEGYLATED DRUG AND DRUG FORMULATIONS HAVE FOLLOWING COMMERCIAL ADVANTAGES : 

PEGYLATED DRUG AND DRUG FORMULATIONS HAVE FOLLOWING COMMERCIAL ADVANTAGES Opportunities for new delivery formats and dosing regimen. Extended patent life of previously approved drugs.

REFERENCES : 

REFERENCES J. Milton Harris, R. B. Chess, Effect of Pegylation on pharmaceuticals, review article, Drug Discovery, vol. 2,(2003),214-226. Y. Kodera, A. Matsushima ,M. Hiroto, H. Nishimura, A. Ishi , T. Ueno, Y.Inada, Pegylation of proteins and bioactive substances for medical and technical applications, Programmed Polymer Sciences,vol.23,1233-1271. F. M.Veronese, Peptide and protein Pegylation; a review problem and solutions, Biomaterials, vol 22,(2001) .405-417. R. B.Greenwald, PEG drugs; an overview, Journal Of Controlled Release, vol 74, (2001) 159-171. P. Bailon and W. Berthold, Polyethylene glycol-conjugated Pharmaceutical proteins International Journal of Pharmaceutics Vol. 53(1998) 88-110.

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THANK YOU

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