title: 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-beta-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) 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.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kumamoto University, Oe-honmachi, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Hara
authors.forename: Fumitoshi
authors.initials: F
authors.lastname: Hirayama
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Arima
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Kaneto
authors.initials: K
authors.lastname: Uekama
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000465:Algorithms; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D004285:Dogs; D005079:Excipients / Q000737:chemistry*; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D000960:Hypolipidemic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D008297:Male; D008958:Models, Molecular; D012995:Solubility; D013844:Thiazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D014961:X-Ray Diffraction; D047392:beta-Cyclodextrins / Q000737:chemistry*
chemical_list: D005079:Excipients; C497430:FPFS-410; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D013844:Thiazoles; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin