Hara Takumi, Hirayama Fumitoshi, Arima Hidetoshi, Yamaguchi Yoshihiro, Uekama Kaneto
Graduate School of Pharmaceutical Sciences, Kumamoto University, Oe-honmachi, Japan.
Chem Pharm Bull (Tokyo). 2006 Mar;54(3):344-9. doi: 10.1248/cpb.54.344.
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) x 10(-8) M (0.0094+/-0.0011 microg/ml) in 1.0 M phosphate buffer (pH 7.0) at 25 degrees 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-beta-CyD (HP-beta-CyD) had the highest solubilizing ability to FPFS-410, e.g., the solubility of the compound was increased 200000-fold by the addition of 40 mM HP-beta-CyD, which was attributable to the formation of the 1 : 2 (guest : host) inclusion complexes. The interaction of HP-beta-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-beta-CyD forms a 1:2 (guest : host) inclusion complex with FPFS-410 by including both the stilbene and thiazolidine moieties. FPFS-410/HP-beta-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-beta-CyD. In vivo studies revealed that HP-beta-CyD markedly increases the bioavailability of FPFS-410 after oral administration in dogs. The present results suggest that HP-beta-CyD is useful for improvement of the extremely low bioavailability of FPFS-410.
2-(N-氰基亚氨基)-5-[(E)-4-苯乙烯基亚苄基]-4-氧代噻唑烷(FPFS-410)是一种新合成的噻唑烷衍生物，不仅具有抗糖尿病活性，还具有降血脂活性。然而，该化合物的水溶性极低(在25℃下，于1.0 M磷酸盐缓冲液(pH 7.0)中为2.8(±0.33)×10(-8) M(0.0094±0.0011 μg/ml))。在本研究中，我们研究了各种亲水性环糊精(CyDs)对FPFS-410溶解度的影响，以选择适合该化合物制剂的环糊精。在各种环糊精中，2-羟丙基-β-环糊精(HP-β-CyD)对FPFS-410的增溶能力最强，例如，加入40 mM HP-β-CyD后，该化合物的溶解度增加了200000倍，这归因于1:2(客体:主体)包合物的形成。使用包括ROESY光谱在内的1H-核磁共振(NMR)光谱和分子模型计算研究了HP-β-CyD与FPFS-410的相互作用。这些结果表明，HP-β-CyD通过包含芪和噻唑烷部分与FPFS-410形成1:2(客体:主体)包合物。通过喷雾干燥和共研磨方法制备了具有不同化学计量比的FPFS-410/HP-β-CyD固体复合物，并通过粉末X射线衍射法确认这些复合物为无定形状态。与HP-β-CyD络合显著加速了FPFS-410在水中的溶解。体内研究表明，HP-β-CyD在犬口服给药后显著提高了FPFS-410的生物利用度。目前的结果表明，HP-β-CyD有助于改善FPFS-410极低的生物利用度。
