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

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2-(N-Cyanoimino)-5-{(E)-4-styrylbenzylidene}-4-oxothiazolidine (FPFS-410) is a newly synthesized thiazoli-dine 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±0.0011μg/ml) in 1.0M phosphate buffer (pH 7.0) at 25℃). 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 stoi-chiometries were prepared by the spray drying and cogrinding methods, and confirmed by powder X-ray diffrac-tometry 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.
社団法人日本薬学会の論文
2006-03-01

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

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