1. DELIVERY OF PROTEINS USING BIODEGRADABLE POLYMERS Mahesh V. Chaubal Guilford Pharmaceuticals Inc. Baltimore, MD 21224 chaubal_m@guilfordpharm.com

2. PROTEIN THERAPEUTICS Increasing number of proteins being approved by FDA –Coagulation Factor IX –tissue plasminogen activator –Insulin Need for novel techniques to deliver proteins

3. DRUG DELIVERY Non-conventional way of administering drugs Conventional way Oral (Tablets, Capsules) Parenteral (IV injections)

4. 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

5. DRUG DELIVERY

6. Drug Delivery Useful for following types of drugs: –Short half-life Insulin t 1/2 < 25 min Growth hormone t 1/2 < 25 min –High systemic toxicity (causing side effects) Carmustinecauses nausea, hair loss –Frequent dosing Growth hormoneDaily dosage required –Expensive drugs

7. 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)

8. Polymeric Drug Delivery Controlled Release of drugs

9. Polymeric Drug Delivery Drug dispersed in a polymer matrix

10. Polymeric Drug Delivery Polymers should be: –Biodegradable –Bio-compatible –Non-toxic Examples: –Polylactides/glycolides –Polyanhydrides –Polyphosphoesters

11. Polymers Zero-order degrading polymers Temperature/pH sensitive polymers

12. 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

13. Polymeric Drug Delivery Drug Release by Polymer Degradation Polymer degradation by: Hydrolysis Enzymatic (Phosphotases; Proteases etc.)

14. 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

15. 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

16. Protein X Natural protein Specific enzymatic activity Negligible side effects Frequent injections (up to twice a day) Expensive

17. 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?

18. 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 doses

19. Potential sources of instability Interactions between protein and polymer Processing conditions (agitation, solvent exposure) Conditions inside the polymer matrix (low pH)