DELIVERY%20OF%20PROTEINS%20USING%20BIODEGRADABLE%20POLYMERS

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DELIVERY OF PROTEINS USING BIODEGRADABLE POLYMERS

• Mahesh V. Chaubal
• Guilford Pharmaceuticals Inc.
• Baltimore, MD 21224
• chaubal_m_at_guilfordpharm.com

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PROTEIN THERAPEUTICS

• Increasing number of proteins being approved by
  FDA
• Coagulation Factor IX
• tissue plasminogen activator
• Insulin
• Need for novel techniques to deliver proteins

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DRUG DELIVERY

• Non-conventional way of administering drugs
• Conventional way
• Oral (Tablets, Capsules)
• Parenteral (IV injections)

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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

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DRUG DELIVERY
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Drug Delivery

• Useful for following types of drugs
• Short half-life
• Insulin t1/2 lt 25 min
• Growth hormone t1/2 lt 25 min
• High systemic toxicity (causing side effects)
• Carmustine causes nausea, hair loss
• Frequent dosing
• Growth hormone Daily dosage required
• Expensive drugs

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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)

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Polymeric Drug Delivery

• Controlled Release of drugs

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Polymeric Drug Delivery

• Drug dispersed in a polymer matrix

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Polymeric Drug Delivery

• Polymers should be
• Biodegradable
• Bio-compatible
• Non-toxic
• Examples
• Polylactides/glycolides
• Polyanhydrides
• Polyphosphoesters

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Polymers

• Zero-order degrading polymers
• Temperature/pH sensitive polymers

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Polymeric Drug Delivery

• Diffusion of drug out of the polymer
• Governing equation Ficks laws of diffusion
• Drug release is concentration dependant
• Less applicable for large molecules

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Polymeric Drug Delivery

• Drug Release by Polymer Degradation
• Polymer degradation by
• Hydrolysis
• Enzymatic (Phosphotases Proteases etc.)

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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

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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

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Protein X

• Natural protein
• Specific enzymatic activity
• Negligible side effects
• Frequent injections (up to twice a day)
• Expensive

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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 deliveryimproved patient compliance
• May improve protein X utilization
• Stability of protein X in polymer?

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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

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Potential sources of instability

• Interactions between protein and polymer
• Processing conditions (agitation, solvent
  exposure)
• Conditions inside the polymer matrix (low pH)