DELIVERY OF PROTEINS USING BIODEGRADABLE POLYMERS Mahesh V. Chaubal Guilford Pharmaceuticals Inc....
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Transcript of DELIVERY OF PROTEINS USING BIODEGRADABLE POLYMERS Mahesh V. Chaubal Guilford Pharmaceuticals Inc....
DELIVERY OF PROTEINS USING BIODEGRADABLE POLYMERS
Mahesh V. Chaubal
Guilford Pharmaceuticals Inc.
Baltimore, MD 21224
PROTEIN THERAPEUTICS
• Increasing number of proteins being approved by FDA– Coagulation Factor IX– tissue plasminogen activator– Insulin
• Need for novel techniques to deliver proteins
DRUG DELIVERY
• Non-conventional way of administering drugs
• Conventional way • Oral (Tablets, Capsules)
• Parenteral (IV injections)
CONVENTIONAL
• ORAL– Ease of administration
– Patient Compliance
– Exposure to extremely acidic pH
– Poor absorption of larger drugs
– Degradation by enzymes
• INTRAVENOUS– Fast action
– No absorption issues
– Lesser patient compliance
– Fast clearance of drugs
DRUG DELIVERY
D R U G D E L IV E R Y C L A S S IF IC A T IO N
P u lm o n a ry P a re nte ral T ra n sd e rm al
Im p la n ts O c u lar N a sal
M isce lla ne o us O ra l
R o u te o f A dm in is tra tion
P E G y la tion P ro -d ru g P o ly m er d e p ot
D ru g M o d ific a tion
D ru g D e liv e ry
Drug Delivery
• Useful for following types of drugs:– Short half-life
• Insulin t1/2 < 25 min
• Growth hormone t1/2 < 25 min
– High systemic toxicity (causing side effects)• Carmustine causes nausea, hair loss
– Frequent dosing• Growth hormone Daily dosage required
– Expensive drugs
Drug Delivery
• Adverse Drug Effects – 15 % of hospital admissions
– 100,000 deaths
– $136 billion in health care costs
• Patient compliance– 10 % hospital admissions
• Drug delivery sales– $14 billion (1997)
Polymeric Drug Delivery
• Controlled Release of drugs
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Time
Pla
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Conventional
Controlled release
MEC
MTC
Polymeric Drug Delivery
• Drug dispersed in a polymer matrix
D iffu s io n
E n z y m a tic d e g rad a tion
B u lk e ro s ion S u rfa c e e ro s ion
H y d ro ly s i s C o m bin a tion
P o ly m e r D e g ra d a tion C o m bin a tion
D ru g R e le a se
Polymeric Drug Delivery
• Polymers should be:– Biodegradable– Bio-compatible– Non-toxic
• Examples:– Polylactides/glycolides– Polyanhydrides– Polyphosphoesters
Polymers
• Zero-order degrading polymers
• Temperature/pH sensitive polymers
Polymeric Drug Delivery
• Diffusion of drug out of the polymer• Governing equation: Fick’s laws of diffusion
• Drug release is concentration dependant
• Less applicable for large molecules
o o oo o oo o oo
o o oo o
Polymeric Drug Delivery
• Drug Release by Polymer Degradation
• Polymer degradation by:• Hydrolysis
• Enzymatic (Phosphotases; Proteases etc.)
Polymeric Drug Delivery
• Frequency of doses reduced
• Drug utilized more effectively
• Drug stabilized inside the polymer matrix
• Reduced side effects
• Possibility of dose-dumping
• De-activation of drug inside polymer
Role of a Chemical Engineer
• Modeling of drug delivery systems• Prediction of kinetics/thermodynamics
• Novel polymer research• Temperature sensitive polymers; pH sensitive polymers
• Development of new drug delivery techniques• Novel techniques for new therapies
• Development of purification processes • Solvent Removal; Removal of impurities etc.
• Process development• Design & Development of robust processes; GMP Validation
• Scale-up of processes
Protein X
• Natural protein
• Specific enzymatic activity
• Negligible side effects
• Frequent injections (up to twice a day)
• Expensive
Protein X delivery
• Applicable alternative techniques• Pulmonary delivery
• Non-invasive; Good patient compliance
• Poor efficiency; Requires patient training
• PEGylation• Improved stability; reduced frequency of injections
• Protein X activity?
• Polymeric delivery• Long-term delivery;improved patient compliance
• May improve protein X utilization
• Stability of protein X in polymer?
Protein X delivery
• Economical advantages• Improved protein utilization
– Less protein gets wasted
– Drives down product cost
• Improved patient compliance– Reduced frequency of dosing
– Improved patient compliance
– Less medical expenditure from
events due to missed doses0
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Time (days)
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Time (days)
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Conventional
Controlled release
MEC
Potential sources of instability
• Interactions between protein and polymer
• Processing conditions (agitation, solvent exposure)
• Conditions inside the polymer matrix (low pH)