Issues Related to the Formulation and Delivery of Pharmaceutical Proteins

Transcription

1 Issues Related to the Formulation and Delivery of Pharmaceutical Proteins Pretoria16 August Prof. dr. Daan J.A. Crommelin Dept. Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, UIPS Scientific Director of the Dutch Top Institute Pharma, Leiden Co-founder of OctoPlus, Leiden

2 Delivery of Proteins Are we stuck to the needle? Welcome to the kingdom of the needle?

3 Formulation: from raw material to final dosage form

4 Points to consider Route of administration Dose (conc. and volume) Temperature of storage Container and closure Exposure to light Exposure to air Compatibility of excipients Compatibility of ph Adsorption during delivery Shear sensitivity

5 Formulation principles Wang, Int. J. Pharmaceutics Functionality of excipients; they act as: Stabilizers Bulking agents Surfactants Isotonicity modifiers ph/buffering agents Preservatives

6 Points to consider Liquid versus freeze dried form Stability Costs of goods - Revenues of finished product Storage of finished product Convenience end user Wei Wang* International Journal of Pharmaceutics 203 (2000) 1 60 Lyophilization and development of solid protein pharmaceuticals

7 Why Parenteral Depot Formulations? Elimination half-life time is short Controlled release is required Site directed delivery is required (drug targeting)

8 PEGylated proteins PEG-Interferon alfa PEG-G-CSF.

9 Strategies for improved protein delivery PEGylation: coupling of PEG molecules to protein

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11 Modified Release Systems for Pharmaceutical Proteins Solid Complexes (insulin)(hours): Polymer solutions/hydrogels (days): Atrix, Macromed Microspheres from biodegradable polymers (0-1 month.)

12 Brange, 1987

13 Liquid/solid state hydrogels SABER Delivery System Sucrose Acetate IsoButyrate Extended Release High Viscosity Liquid (example SAIB) Hydrophobic Viscosity Drops with Addition of Solvent Biocompatible Biodegradable Established safety profile SAIB Only Strong patent position Low cost manufacturing Applications: 85/15 SAIB:Ethanol Parenteral depot DURECT Corp. 2005

14 In Vivo Protein Pharmacokinetics 1000 Protein Concentration (ng/ml) Commercial Depot SABER Formulation Time (days) >10x reduction in injection volume >10x reduction in burst DURECT Corp. 2005

15 In vitro release of MN rgp120 from PLGA microspheres Golden Standard technology From Cleland, 1997

16 Strategies for improved protein delivery Drug concentration microspheres Immediate release toxic therapeutic ineffective administration Approved microsphere products Lupron Depot, Trelstar Depot, Sandostatin LAR All based on PLGA

17 Biodegradable polymers for injectable depots Most systems are based on PLGA Drawbacks Hydrophobic Acid degradation products Use of organic solvents Consequences Protein stability problems Limited control over release kinetics Strong need for improved protein delivery systems

18 Degradation. In vitro Release of rhgh from PLGA microspheres (research stage) during 30 days. Composition of the released protein Monomer 74%; Dimer 26% Non-oxidixed 82% Non-deamidated 35% Cleland, Pharmaceutical Research

19 PolyActive TM Implants in over 20,000 patients (as of 2003) Device Master File present

20 PolyActive TM Microspheres Protein Incorporation homogenization solvent evaporation Lab scale: 1-5 g Scaled-up to g polymer solution aqueous protein solution aqueous phase Similar to well-established MS processes MS characteristics controlled by e.g. polymer type & concentration, stirring speed, aqueous phase. W/O emulsion W/O/W emulsion

21 PolyActive TM Microspheres Morphology Distribution of FITC labeled lysozyme µm

22 In vivo release from PolyActive TM microspheres Release of IFN from PolyActive TM microspheres, SC injected in rats 100 Free IFN 40 ug/rat PA IFN 40 ug/rat PA IFN 160 ug/rat Alfa-interferon ng/ml IFN in serum 10 1 PA IFN 640 ug/rat 0.1 Pharm.. Res Hours after injection

23 Pharmacokinetics, safety and biomarkers in man after administration of LocteronTM, alfa-interferon MS, a once every 2 weeks controlled release formulation of IFNa2b (Q4, 2005) Pharmacokinetics of Single Dose Locteron IFNa (pg/ml) Locteron 20 µg Locteron 80 µg Locteron 320 µg Time (days)

24 Reduced flu-like symptoms in Locteron (alfainterferon) groups 25 Average Duration 41 Hours Average Duration 19 Hours Ave. hours per subject doses of Locteron (n=3x4) compared to approved monotherapy dose of PEG-Intron (n=6) 80 ug 5 0 None None PEG-Intron Locteron 320 Locteron 80 Locteron 20 Severe Moderate Mild

25 Conclusion re Locteron Less side effects Dosing interval increased Efficacy? Phase II clinical study started Jan 2007 First results published of 12 weeks treatment on July Log 4+ viral reduction (360 and 480 microgram) with microsphere delivered interferon alfa

26 Dextran-Based Hydrogel: Alternative to PLGA technology Wim Hennink et al./uu/octoplus Why? dextran: non-toxic; used as plasma expander hydrogel: network of hydrophilic polymers good compatibility with protein possibilities to manipulate the release: cross-link density of the hydrogel degradation characteristics of the hydrogel

27 Derivatized Dextran Dextran-oligolactate-HydroxyEthyl Methacrylate (dex-lactate-hema) O HO O HO O O O O O O n O HO O HO O O O HO O HO HO O Hennink et al. HO O

28 Dextran Hydrogel Hydrogel formation polymerization Hennink et al.

29 Cross-linked dextran-based microspheres Schematic representation of the microsphere preparation process: NO ORGANIC SOLVENT protein DexHEMA + PEG PEG DexHEMA protein Aqueous solutions of Dex and PEG Phase Separation Stirring Radical Polymerization Water-in-water Emulsion

30 Liposome Release from dextran microspheres Cum. rel. (%) DexHEMA, DS 8, 70 % H2O, ph Time (days)

31 Conventional Vaccines: Multiple injections Antigen concentration Time

32 Single Shot Vaccines with OctoDEX TM Combining a priming dose with controlled release microspheres Japanese encephalitis vaccine Hepatitis B vaccine Antigen concentration Time

33 Why Parenteral Depot Formulations? Elimination half-life time is short Controlled release is required Options are now becoming available