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

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Time

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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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Controlled release

MEC

Potential sources of instability

• Interactions between protein and polymer

• Processing conditions (agitation, solvent exposure)

• Conditions inside the polymer matrix (low pH)