Post on 05-Jan-2016
DELIVERY OF PROTEINS USING BIODEGRADABLE POLYMERS
Mahesh V. Chaubal
Guilford Pharmaceuticals Inc.
Baltimore, MD 21224
chaubal_m@guilfordpharm.com
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
0
10
20
30
40
50
60
0 1 2 3 4 5 6 7 8
Time
Pla
sma
con
cen
trat
ion
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
10
20
30
40
50
60
0 1 2 3 4 5 6 7 8
Time (days)
Pla
sma
con
cen
trat
ion
0
10
20
30
40
50
60
0 1 2 3 4 5 6 7 8
Time (days)
Pla
sma
con
cen
trat
ion
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)