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Protein Delivery from Mechanical Devices Challenges and Opportunities

Protein Delivery from Mechanical Devices Challenges and Opportunities. Bill Van Antwerp and Poonam Gulati The Protein Formulation and Testing Group Medtronic Minimed. Why Protein Drugs in Devices. Protein/peptide drugs are increasingly important

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Protein Delivery from Mechanical Devices Challenges and Opportunities

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  1. Protein Delivery from Mechanical DevicesChallenges and Opportunities Bill Van Antwerp and Poonam Gulati The Protein Formulation and Testing Group Medtronic Minimed

  2. Why Protein Drugs in Devices • Protein/peptide drugs are increasingly important • Diabetes (Insulin, Symlin, Exendin, Somatokine) • Cancer (Interferon, Monoclonal Antibodies, Vaccines) • Cardiovascular Drugs (Natrecor, GPIIB receptor, Protein G receptor) • Inflammation (TNF-a, IL1-RA) • HIV/AIDS (Somatostatin, T20, T1249, IL-2, Interferon)

  3. Why Use Pumps? • Proteins and peptides need delivery • Poor oral bioavailability • Protein denaturation in the digestive system • Acid hydrolysis in the stomach • Enzymatic degradation • Poor adsorption due to size • Poor adsorption due to polar/charge distribution

  4. Advantages of Continuous Infusion for Protein Drugs 6 Side Effects Enzyme Activation P450 Activation 5 Wasted Drug 14 x CSI 4 Plasma Drug Concentration 3 2 1 Therapeutic Range Bolus Injection Continuous Infusion 0 0 4 8 12 16 20 24 Time (hours)

  5. Parenteral Delivery Today • IV administration • Subcutaneous injection • Continuous Subcutaneous Infusion (Pumps) • Continuous Intraperitoneal Infusion • Subcutaneous Depot (leuprolide etc) • PLGA microspheres • PEG attached peptides • Microemulsions • Intrathecal, Intraparenchymal

  6. Pump Challenges, Old and New • Formulation • Chemical Stability • Clearance • Physical Stability • PK/PD Therapeutic Range and Toxicity (localized site reactions)

  7. Regulatory Hurdles Let’s Not Re-invent the Wheel • Device Physics • Drug Chemistry • Drug Packaging • Pump/Drug Interactions (in-vitro) • Drug Physical Stability (in-vitro)

  8. Stability in Pumps • Chemical and physical stability can determine clinical efficacy • Physical stability is difficult to measure • Wide variety of measurements • Turbidity • Concentration Changes • Fluorescence • CD/Microcalorimetry/Denaturation Kinetics

  9. Chemical Stability • Chemical stability is determined by the molecule and by the formulation • Relatively simple formulation changes can affect stability • Pump chemical stability, in general, is the same as in primary packaging

  10. Physical Interactions • Protein physical stability in devices • Materials of contact • Teflon/Titanium/Polyolefin/Silicone Oil • Pumping mechanism physics, shear and compliance can lead to denaturation • Agitation in device • Body temperature storage

  11. Physical Interactions with Devices • Protein adsorption to the device • Protein denaturation after adsorption • Partially unfolded intermediates dominate physical stability of protein formulations • Protein aggregation on surface • Protein aggregation in solution Uversky, V. N. Lee , H. J., Li, J., Fink, A. L. & Lee, S. J. (2001)Stabilization of Partially Folded Conformation During a-Synuclein Oligomerization in Both Purified and Cytosolic Preparations. J. Biol. Chem. 276, 43495-43498.

  12. Proposed Aggregation Mechanism Surface P surf P2 2 P Psurf den Partially Unfolded Intermediate autocatalytic Pagg I + Pagg Psoln. den. P = Protein P soln. den. = denatured protein in solution P surf = surface bound protein P surf den= surface bound denatured protein P agg = Protein aggregates

  13. Curve Fit Results to Autocatalytic Model 800 700 600 500 400 300 200 100 0 -20 0 20 40 60 80 100 Time (hr) Value m1 734.57 m2 1.6383 m3 0.00016847 Chisq 4.5331e+05 R 0.99755

  14. Effect of Contact Material on Aggregation Rate (Insulin/Tris) 150 Glass Titanium Polyethylene 100 Teflon % survival 50 0 0 50 100 150 200 TimetoFixed Fluorescence

  15. Formulation and Drug Substance Effects GLP-1 100 75 Standard Drug Substance % survival 50 Standard Sub. Low pH New Drug Substance 25 New Drug Low pH 0 0 25 50 75 100 125 150 Time to Reach Fixed Fluorescence

  16. Proteins in Pumps • Formulation is the beginning of successful drug delivery • Multiple potential interactions between the protein and the pump • Control of the material interface is most important • Device design and formulation need to work together and be regulated together

  17. Conclusions • Pump/Drug interactions need to be managed and understood • Formulation and pump design need to work together • Combination product components can be evaluated separately and historical data used for regulatory approval with proper attention to drug/device interactions

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