Impact of co-administered stabilizers on the biopharmaceutical performance of regorafenib amorphous solid dispersions
Poor solubility of drug candidates is a well-known and thoroughly studied challenge in the development of oral dosage forms. One important approach to tackle this challenge is the formulation as an amorphous solid dispersion (ASD). To reach the desired biopharmaceutical improvement a high supersaturation has to be reached quickly and then be conserved long enough for absorption to take place. In the presented study, various formulations of regorafenib have been produced and characterized in biorelevant in-vitro experiments. Povidone-based formulations, which are equivalent to the marketed product Stivarga®, showed a fast drug release but limited stability and robustness after that.
Highlights
• Co-administration of external stabilizers to rapidly releasing ASDs studied in-vitro and in-vivo.
• Very promising in-vitro results did not translate to in-vivo performance.
• Exposure to gastric medium was identified as cause for the insufficient in-vivo performance.
• Bifunctional use of HPMCAS allowed tailored dissolution profiles an highest robustness
In contrast, HPMCAS-based formulations exhibited excellent stability of the supersaturated solution, but unacceptably slow drug release. The attempt to combine the desired attributes of both formulations by producing a ternary ASD failed. Only co-administration of HPMCAS as an external stabilizer to the rapidly releasing Povidone-based ASDs led to the desired dissolution profile and high robustness. This optimized formulation was tested in a pharmacokinetic animal model using Wistar rats. Despite the promising in-vitro results, the new formulation did not perform better in the animal model. No differences in AUC could be detected when compared to the conventional (marketed) formulation. These data represent to first in-vivo study of the new concept of external stabilization of ASDs.
Subsequent in-vitro studies revealed that temporary exposure of the ASD to gastric medium had a significant and long-lasting effect on the dissolution performance and externally administered stabilizer could not prevent this sufficiently. By applying the co-administered HPMCAS as an enteric coating onto Stivarga tablets, a new bi-functional approach was realized. This approach achieved the desired tailoring of the dissolution profile and high robustness against gastric medium as well as against seeding. Continue on Impact of co-administered stabilizers on the biopharmaceutical performance of regorafenib amorphous solid dispersions
Article information
Martin Müller, Raphael Wiedey, Werner Hoheisel, Peter Serno, Jörg Breitkreutz, Impact of co-administered stabilizers on the biopharmaceutical performance of regorafenib amorphous solid dispersions, European Journal of Pharmaceutics and Biopharmaceutics, Volume 169, 2021, Pages 189-199, ISSN 0939-6411, https://doi.org/10.1016/j.ejpb.2021.10.012.