Improvement of solubility and oral bioavailability of 2-(N-Cyanoimino)-5- {(E)-4-styrylbenzylidene}-4-oxothiazolidine (FPFS-410) with antidiabetic and lipid-lowering activities in dogs by 2-hydroxypropyl-β-cyclodextrin

Abstract

2-(N-Cyanoimino)-5-{(E)-4-styrylbenzylidene}-4-oxothiazolidine (FPFS-410) is a newly synthesized thiazolidine derivative having not only antidiabetic but also lipid-lowering activities. However, this compound has an extremely low aqueous solubility (2.8(±0.33) × 10-8 M (0.0094 ± 0.0011 μg/ml) in 1.0 M phosphate buffer (pH 7.0) at 25°C). In this study, we investigated the effect of various hydrophilic cyclodextrins (CyDs) on the solubility of FPFS-410 to select a CyD suitable for formulations of the compound. Among various CyDs, 2-hydroxypropyl-β-CyD (HP-β-CyD) had the highest solubilizing ability to FPFS-410, e.g., the solubility of the compound was increased 200000-fold by the addition of 40mM HP-β-CyD, which was attributable to the formation of the 1:2 (guest:host) inclusion complexes. The interaction of HP-β-CyD with FPFS-410 was studied using 1H-nuclear magnetic resonance (NMR) spectroscopies including ROESY spectroscopy and a molecular modeling calculation. These results suggested that HP-β-CyD forms a 1:2 (guest:host) inclusion complex with FPFS-410 by including both the stilbene and thiazolidine moieties. FPFS-410/HP-β-CyD solid complexes with various stoichiometries were prepared by the spray drying and cogrinding methods, and confirmed by powder X-ray diffractometry that these complexes are in an amorphous state. The dissolution of FPFS-410 in water was significantly accelerated by the complexation with HP-β-CyD. In vivo studies revealed that HP-β-CyD markedly increases the bioavailability of FPFS-410 after oral administration in dogs. The present results suggest that HP-β-CyD is useful for improvement of the extremely low bioavailability of FPFS-410. © 2006 Pharmaceutical Society of Japan.