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 CO2 (scCO2) as a solvent. K-832-silica formulations were prepared using scCO2 or dichloromethane (DCM) as the solvent (K-832-silica scCO2 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 scCO2 and K-832-silica DCM, respectively, within 5 min, whereas only 2.3% of K-832 was released from a physical mixture within 120 min. Results of an in vivo absorption test showed that the area under the plasma concentration–time curve and peak concentration of K-832-silica scCO2 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 scCO2 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.

The investigation of a solid dispersion system using porous silica as a carrier and supercritical CO2 (scCO2) as a solvent revealed that with such a system, it is possible to achieve high solubility and good absorption in vivo of a poorly water-soluble drug.Figure optionsDownload as PowerPoint slide