Simultaneous Overcoming Approach for Poor Wettability and Low Stability in Stomach by Simple Methods; Formulation Design and Development of Monoacylglycerol Acyltransferase 2 Inhibitor, S-309309

Abstract

N-[(4R)-5,7-Difluoro-2′-(5-methylpyridin-2-yl)-4′-oxo-2,2′,3,4′,5′,7′-hexahydrospiro[1-benzopyran-4,6′-pyrazolo[4,3-c]pyridin]-3′-yl]-2-(methanesulfonyl)acetamide (S-309309) is an anti-obesity drug developed by Shionogi & Co., Ltd. that has a monoacylglycerol acyltransferase 2 inhibitory effect. S-309309 has poor wettability, and the amount of the degradation product (4R)-3′-amino-5,7-difluoro-2′-(5-methylpyridin-2-yl)-2,2′,3,7′-tetrahydrospiro[[1]benzopyran-4,6′-pyrazolo[4,3-c]pyridin]-4′(5′H)-one (compound 8) increases over time under acidic conditions. In this study, we have tried to improve S-309309 wettability and suppress the amount of degradation product increased under acidic conditions. As a result of the study, we found that by mixing with a water-soluble polymer, the wettability of S-309309 and its dissolved concentration in fluid were increased suggesting that its dissolution behavior should be enhanced. In addition, by encapsulating S-309309, the increase of degradation product amount was suppressed under acidic conditions, suggesting that the suppression of degradation product formation would be expected in the stomach after oral dosing. Overall, these results suggest that the drug property issues of S-309309 can be overcome by mixing S-309309 with a water-soluble polymer and encapsulation.