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Sultan UllahMedicinal chemistry labCollege of Pharmacy, PNU

(Pharmaceutical Dosage Form)Seminar on

Pegylation a Potential Technique for Protein Drug Delivery

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Contents

What is Pegylation?Comparison with other technologiesStructures of PEG Common Pegylation approachesProteins propertiesWhy pegylated proteins? Products on market Oncaspar PEG-Intron • Limitations • Future perspectives

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WHAT IS PEGYLATION?

Most widely used in delivering anticancer drugs clinically.

Biopharmaceutical, Dr Frank Leenders JUNE 2006,39-40

PEGylation is the covalent coupling of non-toxic, hydrophilic polyethylene glycol (PEG) to active pharmaceutical ingredients(API).

The technology was developed in the 1950s and 1960s working on the coupling of polymers to proteins, Later on in 1970s Frank F. Davis used PEG for protein modifications.

The first PEG-protein company Enzon, founded in 1981, and the first PEG-drug product was PEG-adenosine deaminase, approved in 1990. Nowadays, PEGylated proteins represent a significant therapeutic and business importance: worldwide sales of PEGylated drugs total about $6 billion annually.

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Comparison with other Technologies

Pegylation Other delivery systems

In PEGylated products, API is chemically modified in a durable fashion, and the drug is not released from a formulation but has a permanent action

and is in fact classed as a new API.

Other formulated products such as

tablets, liquids and capsules, the

formulation process is reversible, the drug

becomes active after its release from the

formulation and the API remains unchanged

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Structures of PEG1. Linear shape PEG: 1st generation

2. Branched shape PEG: 2nd generation

3. Hyper branched shape PEG:3rd generation

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Common approaches for PEG conjugation with proteins

PEG is modified by functionalization through the use of

Cyanuric chloride, PEG-succinimidyl

succinate, and Imidazolyl formate.

nature reviews | drug discovery, (2) (2003 )215

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Properties of PROTEIN DRUGS

High molecular

weightGreat instability

Relatively short half lifeEasily

eliminated

Wild tissue distribution

Potential for immunogenici

ty

Frequent dosing is required

Complicated dosing

regimen

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WHY PEGYLATED PROTEINS ?

• Improve stability and solubility

• Reduce immunogenicity and proteolysis

• Improve clinical effects

• Prolong patent protection

• More competitive in market with an increase commercial opportunity

• Slow clearance from the body

• Less frequent dosing

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COMMERCIAL DRUGS

ONCASPAR*PEG-INTRON*1

.

2.

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1.ONCASPAR(l-asparaginase)

L-asparaginase-an enzyme anticancer Mechanism of action: described in 4

steps

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EE

Effect of Pegylation on L-Asparaginase1st generation technology used(linear PEG)

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2.PEG-Intron (Interferon alpha-2)

An-enzyme Anti-HCV Mechanism of actions:

complex

Binds with receptors and activate and modulate the immune system of the body against HCV.

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Antiviral activity increased from 12- to 135-times

Anti tumor activity increases 18-times

Half-life increases (from 3–8 h to 65 h)

Volume of distribution decreases (from 31–73 l to 8–12 l)

Improved sustained response to chronic hepatitis C

Decreased systemic clearance (from 6.6–29.2 to 0.06–0.10 l/h)

Effect of Pegylation on Interferon α2a:2nd generation technology used (branch PEG)

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Limitation of PEGylation

PEG has limited conjugation capacitypossibility of side products due to chemical reactions.Loss of activity Require specific enzyme for processing Each drug require separate Pegylation Cost benefit ratio

Biopharmaceutical, Dr Frank Leenders JUNE 2006,39-40.

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Future perspectives

The primary use of Pegylation: Large molecules,however the successful entry for large molecules leads to Pegylation of Small molecules. Three PEGylated small molecules drugs are in clinical trial (NKTR-102, EZN-2208 and NKTR-105).

Progress in Polymer Science 38 (2013) 421–444

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Thanks