A silica-supported solid dispersion of bifendate using supercritical carbon dioxide method with enhanced dissolution rate and oral bioavailability

In this study, to enhance the dissolution rate and oral bioavailability of bifendate, a silica-supported solid dispersion (SD) of bifendate was prepared using supercritical carbon dioxide (ScCO2) technology. The properties of bifendate-silica SD were characterized by differential scanning calorimetry (DSC), X-ray diffraction (X-RD) and scanning electron microscopy. The pharmacokinetic study was carried out in beagle dogs using commercial bifendate dropping pills as a reference which is a conventional SD formulation of bifendate and PEG6000. A novel method of Ultra Performance Convergence Chromatography-tandem mass spectrometry (UPC2-MS/MS) method was applied to determine bifendate concentration in plasma. The amorphous state of bifendate in bifendate-silica SD was revealed in X-RD and DSC when the ratios of bifendate and silica were 1:15 and 1:19, respectively. In vitro dissolution rate was significantly improved with cumulative release of 67% within 20min relative to 8% for the physical mixture of bifendate and silica, and which was also higher than the commercial dropping pill of 52%. After storage at 75% relative humidity (RH) for 10d, no recrystallization was found and reduced dissolution rate was obtained due to the absorption of moisture. In pharmacokinetic study, C-max and AUC(0-t) for bifendate-silica SD were 153.1ng/ml and 979.8ngh/ml, respectively. AUC(0-t) of bifendate-silica SDs was approximate to 1.6-fold higher than that of the commercial dropping pills. These results suggest that adsorbing bifendate onto porous silica via ScCO2 technique could be a feasible method to enhance oral bioavailability together with a higher dissolution rate.