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Enhanced bioavailability of a poorly soluble VR1 antagonist using an amorphous solid dispersion approach: a case
Michael Kennedy1, Jack Hu, Ping Gao
1Small Molecule Process & Product Development, Amgen Inc., Thousand Oaks, California 91320, USA. kennedy@amgen.com
Molecular Pharmaceutics
|May 13, 2009
Summary
Amorphous solid dispersions (ASDs) significantly enhance the physical stability and oral bioavailability of poorly soluble drugs like AMG 517. This approach improves drug delivery for development-stage molecules.
Area of Science:
- Pharmaceutical Sciences
- Drug Delivery
- Materials Science
Background:
- Poorly soluble drugs present significant formulation challenges.
- Improving physical stability and in vivo exposure is crucial for drug efficacy.
- Amorphous solid dispersions (ASDs) offer a promising strategy for enhancing solubility and bioavailability.
Purpose of the Study:
- To develop amorphous solid dispersions (ASDs) of a poorly soluble VR1 antagonist (AMG 517).
- To improve the physical stability and in vivo exposure of AMG 517.
- To evaluate the performance of ASDs compared to micronized drug formulations.
Main Methods:
- Spray-drying of AMG 517 with polymers (HPMCAS, HPMC) to create ASDs.
- Characterization using SEM, laser light scattering, TGA, modulated DSC, and XRPD.
- In vitro dissolution and supersaturation testing (USP-2 apparatus).
- In vivo pharmacokinetic (PK) studies in cynomolgus monkeys.
Main Results:
- Amorphous solid dispersions exhibited excellent physical stability for at least six months.
- ASDs demonstrated superior drug dissolution and supersaturation compared to micronized AMG 517.
- Oral administration of an ASD formulation in monkeys increased AUC by 163% and Cmax by 145%.
Conclusions:
- Amorphous solid dispersions effectively enhance the physical stability of poorly soluble drugs.
- The ASD approach significantly improves oral bioavailability and in vivo exposure.
- This strategy is valuable for developing poorly soluble, water-insoluble drug candidates.
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