Cyclodextrins improve oral absorption of a novel factor Xa inhibitor by interfering with interaction between the drug and bile acids in rats.

Objectives: Poor oral absorption of a factor Xa inhibitor, DX-9065, is partly due to the interaction with bile acids in the gastrointestinal tract. The aim of this study is to improve the oral bioavailability of DX-9065 by cyclodextrins (CyDs) capable of interfering with such interaction.

Methods: The abilities of the CyDs to interfere with the interaction between DX-9065 and sodium chenodeoxycholate were evaluated using equilibrium dialysis. The interaction between DX-9065 and the CyDs was studied spectroscopically. Effects of the CyDs on the oral absorption of DX-9065 were examined in rats.

Key Findings: Hydroxypropyl-β-CyD and γ-CyD were effective in interfering with the interaction between DX-9065 and sodium chenodeoxycholate as a representative bile acid. Spectroscopic studies revealed that DX-9065 was included into the CyD cavity to form inclusion complexes in an acidic medium. With dissociation of the carboxyl group of DX-9065 in a neutral medium, the stability of the complexes was decreased to such an extent that DX-9065 in the cavity is replaced with co-existing bile acids. The average area under the plasma concentration-time curve value after oral administration of DX-9065 with hydroxypropyl-β-CyD was 2.5 times higher than that of DX-9065 alone with a statistical difference in rats.

Conclusions: We suggest that the CyDs are useful in designing oral formulations of DX-9065 with an improved bioavailability.