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

• Hara Takumi

  Graduate School of Pharmaceutical Sciences, Kumamoto University

• Hirayama Fumitoshi

  Graduate School of Pharmaceutical Sciences, Kumamoto University

• Arima Hidetoshi

  Graduate School of Pharmaceutical Sciences, Kumamoto University

• Yamaguchi Yoshihiro

  Graduate School of Pharmaceutical Sciences, Kumamoto University

• Uekama Kaneto

  Graduate School of Pharmaceutical Sciences, Kumamoto University

Bibliographic Information

Other 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-β-cyclodextrin
• 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 ベータ 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 40 mM 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.

Journal

• Chemical and Pharmaceutical Bulletin

  Chemical and Pharmaceutical Bulletin 54 (3), 344-349, 2006

  The Pharmaceutical Society of Japan

Keywords

• 2-hydroxypropyl-β-cyclodextrin
• FPFS-410
• inclusion complex
• solubility
• dissolution
• bioavailability

Details

• CRID: 1390282679148095360
• NII Article ID: 110004820390
• NII Book ID: AA00602100
• DOI: 10.1248/cpb.54.344
• ISSN: 13475223
• ISSN: 00092363
• NDL BIB ID: 7830118
• Web Site: https://ndlsearch.ndl.go.jp/books/R000000004-I7830118
• Web Site: http://www.jstage.jst.go.jp/article/cpb/54/3/54_3_344/_pdf
• Text Lang: en
• Data Source:
  • JaLC
  • NDL
  • Crossref
  • CiNii Articles
• Abstract License Flag: Disallowed