Aminoalkylmethacrylate copolymer E improves oral bioavailability of YM466 by suppressing drug-bile interaction

Shigeo Takemura, Hiromu Kondo, Shunsuke Watanabe, Kazuhiro Sako, Ken Ichi Ogawara, Kazutaka Higaki

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

The aim of this study was to find out polymeric compounds that can inhibit the interaction between YM466, a novel anticoagulant, and bile to improve its oral bioavailability. In vitro ultrafiltration method using extract gall powder was useful to detect the formation of insoluble complex of YM466 with bile and also used to select a polymer that can inhibit the interaction between YM466 and bile. The in vitro studies revealed that aminoalkylmethacrylate (AAM) copolymer E, a polymethacrylate, dose-dependently inhibited the interaction between YM466 and bile and that this polymer could interact with bile salt, but not with YM466, possibly by electrostatic and/or hydrophobic interactions. The coadministration of AAM copolymer E with YM466 to rats dose-dependently increased the plasma concentration of YM466 and it was found that the oral dose of the polymer three times of YM466 (polymer to drug ratio in weight, P-D ratio, 3) significantly increased AUC0-1 h of YM466 to 2.6-fold of that of YM466 alone. Considering the condition of therapeutic use of YM466 and the maximum tolerated dose of the polymer, the formulation of P-D ratio 3 would be clinically practical and promising from the viewpoint of safety.

Original languageEnglish
Pages (from-to)3128-3135
Number of pages8
JournalJournal of Pharmaceutical Sciences
Volume102
Issue number9
DOIs
Publication statusPublished - Sep 2013

Keywords

  • Aminoalkylmethacrylate copolymer E
  • Bile
  • Bioavailability
  • Excipients
  • Intestinal absorption
  • Oral anticoagulant
  • Passive diffusion/transport
  • Solubility
  • YM466

ASJC Scopus subject areas

  • Pharmaceutical Science

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