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

• Published in: Journal of pharmaceutical sciences 2002-02, Vol.91 (2), p.362-370
• Main Authors: Kinoshita, Masahiro, Baba, Kazuhiko, Nagayasu, Atushi, Yamabe, Kanoo, Shimooka, Takashi, Takeichi, Yoh'ichiro, Azuma, Mami, Houchi, Hitoshi, Minakuchi, Kazuo
• Format: Article
• Language: English
• Subjects: Administration, Oral; Adsorption; amorphous; Animals; bioavailability; Biological and medical sciences; Biological Availability; Calcium Compounds - pharmacokinetics; Capsules; dissolution; Dogs; General pharmacology; Hot Temperature; Indoles - blood; Indoles - chemistry; Indoles - pharmacokinetics; Male; Medical sciences; melt adsorption; Pharmacology. Drug treatments; Physicochemical properties. Structure-activity relationships; porous calcium silicate; Powders; Silicates - pharmacokinetics; Solubility; twin screw extruder
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.10026

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‐2‐indolinone (TAS‐301), by its melt‐adsorption on a porous calcium silicate, Florite® 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 (60°C/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 (Cmax) values of the drug after dosing the melt‐adsorbed product were significantly greater than those after dosing the drug crystals. The solubility and bioavailability of TAS‐301 were improved by its melt‐adsorption on FLR. The present findings suggest melt‐adsorption is a useful technique for improving solubility and bioavailability of poorly water‐soluble drugs.