Improving Oral Bioavailability of Sorafenib by Optimizing the Spring and Parachute Based on Molecular Interaction Mechanisms

Sorafenib is a clinically important oral tyrosine kinase inhibitor for the treatment of various cancers. However, the oral bioavailability of sorafenib tablet (Nexavar) is merely 38-49% relative to the oral solution, due to the low aqueous solubility of sorafenib and its relatively high daily dose. It is desirable to improve the oral bioavailability of sorafenib to expand the therapeutic window, reduce the drug resistance, and enhance patient compliance. In this study, we observed that the solubility of sorafenib could be increased similar to 50-fold in the coexistence of poly(vinylpyrrolidone-vinyl acetate) (PVP-VA) and sodium lauryl sulfate (SLS), due to the formation of PVP-VA/SLS complexes at a lower critical aggregation concentration. The enhanced solubility provided a faster initial sorafenib dissolution rate, analogous to a forceful spring to release drug into solution, from tablets containing both PVPVA and SLS. However, SLS appears to impair the ability of PVP-VA to act as an efficient parachute to keep the drug in solution and maintain drug supersaturation. Using 2D (1)11 NMR, C-13 NMR, and FT-IR analysis, we concluded that the solubility enhancement and supersaturation of sorafenib were achieved by PVP-VA/SLS complexes and PVP-VA/sorafenib interaction, respectively, both through molecular interactions hinged on the PVP-VA VA groups. Therefore, a balance between spring and parachute must be carefully considered in formulation design. To confirm the in vivo relevance of these molecular interaction mechanisms, we prepared three tablet formulations containing PVP-VA alone, SLS alone, and PVP-VA/SLS in combination. The USP II in vitro dissolution and dog pharmacokinetic in vivo evaluation showed clear differentiation between these three formulations, and also good in vitro in vivo correlation. The formulation containing PVP-VA alone demonstrated the best bioavailability with 1.85-fold and 1.79-fold increases in C-max and AUC, respectively, compared with the formulation containing SLS only, the poorest performing one. Despite its forceful spring, the formulation containing both PVP-VA and SLS showed a moderate bioavailability enhancement, due to the lack of an efficient parachute.