pegylation of protiens drugs
TRANSCRIPT
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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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1.ONCASPAR(l-asparaginase)
L-asparaginase-an enzyme anticancer Mechanism of action: described in 4
steps
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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