Improvement of solubility and oral bioavailability of a poorly water-soluble drug, TAS-301, by its melt-adsorption on a porous calcium silicate

✍ Scribed by Masahiro Kinoshita; Kazuhiko Baba; Atushi Nagayasu; Kanoo Yamabe; Takashi Shimooka; Yoh'ichiro Takeichi; Mami Azuma; Hitoshi Houchi; Kazuo Minakuchi

• Publisher: John Wiley and Sons
• Year: 2002
• Tongue: English
• Weight: 131 KB
• Volume: 91
• Category: Article
• ISSN: 0022-3549
• DOI: 10.1002/jps.10026

✦ Synopsis

The aim of the present study was to improve the solubility and oral bioavailability of a poorly water-soluble drug, 3-bis(4-methoxyphenyl) methylene-2indolinone (TAS-301), by its melt-adsorption on a porous calcium silicate, Florite 1 RE (FLR), without any solvents. The melt-adsorbed products were prepared by two methods: the small-scale batch method and the twin screw extruder method. The drug was melted and adsorbed on FLR (i.e., ``melt-adsorption''), above its melting point. Crystallinity of the drug in the melt-adsorbed product was estimated by differential scanning calorimetry (DSC) and powder X-ray diffraction analysis. The dissolution test was conducted by the JP XIII paddle method. Oral absorption of the melt-adsorbed product was studied in fasted and fed dogs. The melt-adsorbed products prepared by the two methods were in powder forms. The drug existed in an amorphous state in the product and hardly recrystallized even after storing at a stressed condition (608C/80% RH for 3 days). The TAS-301 dissolution rate from the melt-adsorbed product was markedly enhanced compared with drug crystals. The area under the plasma concentration-time curve (AUC) and peak concentration (C max ) values of the drug after dosing the melt-adsorbed product were signi®cantly greater than those after dosing the drug crystals. The solubility and bioavailability of TAS-301 were improved by its meltadsorption on FLR. The present ®ndings suggest melt-adsorption is a useful technique for improving solubility and bioavailability of poorly water-soluble drugs.