Improvement of solubility and oral bioavailability of a poorly water-soluble drug, TAS-301, by its melt-adsorption on a porous calcium silicate.
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 degrees 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 (C(max)) 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.
Kinoshita
Masahiro
M
Pharmaceutical Research Laboratory, Taiho Pharmaceutical Co., Ltd., 224-2, Ebisuno, Hiraishi, Kawauchi-cho, Tokushima 771-0194, Japan. m-kinoshita@taiho.co.jp
Baba
Kazuhiko
K
Nagayasu
Atushi
A
Yamabe
Kanoo
K
Shimooka
Takashi
T
Takeichi
Yoh'ichiro
Y
Azuma
Mami
M
Houchi
Hitoshi
H
Minakuchi
Kazuo
K
D000284:Administration, Oral; D000327:Adsorption; D000818:Animals; D001682:Biological Availability; D017610:Calcium Compounds / Q000493:pharmacokinetics*; D002214:Capsules; D004285:Dogs; D006358:Hot Temperature; D007211:Indoles / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D011208:Powders; D017640:Silicates / Q000493:pharmacokinetics*; D012995:Solubility
D017610:Calcium Compounds; D002214:Capsules; D007211:Indoles; D011208:Powders; D017640:Silicates; C112781:TAS 301; C031293:calcium silicate