Enhancement of dissolution rate and oral absorption of a poorly water-soluble drug, K-832, by adsorption onto porous silica using supercritical carbon dioxide.
The aim of this study was to enhance the dissolution rate and oral absorption of a poorly water-soluble drug, 2-benzyl-5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one (K-832) by adsorbing it onto the porous silica Sylysia 350 using supercritical CO(2) (scCO(2)) as a solvent. K-832-silica formulations were prepared using scCO(2) or dichloromethane (DCM) as the solvent (K-832-silica scCO(2) and K-832-silica DCM). Scanning electron microscopy, polarizing microscopy, differential scanning calorimetry, and powder X-ray diffraction observations revealed that in both formulations, K-832 existed mainly in an amorphous state. In a dissolution test, 70.2% and 13.3% of K-832 were released from K-832-silica scCO(2) and K-832-silica DCM, respectively, within 5min, whereas only 2.3% of K-832 was released from a physical mixture within 120min. Results of an in vivo absorption test showed that the area under the plasma concentration-time curve and peak concentration of K-832-silica scCO(2) were 8.3- and 13.3-fold greater than those of K-832 crystal, whereas the corresponding values of K-832-silica DCM were 5.0- and 8.3-fold greater than those of K-832 crystal. These results suggest that the method of using scCO(2) as the solvent is effective in enhancing the dissolution rate and oral absorption of poorly water-soluble drugs because it does not require a toxic solvent and surfactant.
Miura
Hiroshi
H
Fuji Research Laboratories, Pharmaceutical Division, Kowa Company, Ltd., Shizuoka, Japan. h-miura@kowa.co.jp
Kanebako
Makoto
M
Shirai
Hiroyuki
H
Nakao
Hiroshi
H
Inagi
Toshio
T
Terada
Katsuhide
K
D000284:Administration, Oral; D000327:Adsorption; D000818:Animals; D019540:Area Under Curve; D002152:Calorimetry, Differential Scanning; D002245:Carbon Dioxide / Q000737:chemistry*; D004285:Dogs; D004337:Drug Carriers / Q000737:chemistry*; D008297:Male; D008752:Methylene Chloride / Q000737:chemistry; D008853:Microscopy / Q000379:methods; D011724:Pyridazines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D012822:Silicon Dioxide / Q000737:chemistry*; D012995:Solubility; D012997:Solvents / Q000737:chemistry; D013440:Sulfides / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D014961:X-Ray Diffraction
C555018:2-benzyl-5-(4-chlorophenyl)-6-(4-(methylthio)phenyl)-2H-pyridazin-3-one; D004337:Drug Carriers; D011724:Pyridazines; D012997:Solvents; D013440:Sulfides; D002245:Carbon Dioxide; D008752:Methylene Chloride; D012822:Silicon Dioxide