索拉非尼衍生物CEP固体分散体的制备及大鼠体内生物利用度研究

Study on preparation of sorafenib derivative CEP solid dispersions and its bioavailability in rats

目的制备CEP-PVP K30固体分散体,考察其物相并提高其大鼠体内生物利用度。方法采用溶剂法制备CEP-PVP-K30固体分散体;利用溶出度法、差示扫描量热(DSC)、红外光谱(FTIR)等方法分析药物在载体中的存在状态;采用HPLC法测定大鼠血浆中药物浓度,与原料药比较,对CEP-PVP K30固体分散体进行大鼠体内生物利用度评价。结果物相分析结果表明,当药物与载体比例为1∶5时,固体分散体中CEP以非结晶态无定形存在。大鼠体内血药浓度-时间曲线表明,与原料药相比,CEP固体分散体达峰时间(tmax)相对不变,达峰浓度(ρmax)提高794%,相对生物利用度为1 572%。结论采用溶剂法制备CEP-PVP K30固体分散体,CEP以无定形存在,其体外溶出速率和大鼠体内吸收均有显著性提高。

Objective To prepare CEP solid dispersions with PVP K30 to investigate its phase and enhance CEP oral bioavailability in rats.Methods The solid dispersions of CEP were prepared by solvent evaporation method.The presence of drug in the carrier was analyzed by dissolution test,differential scanning calorimetry(DSC) and fourier transform infrared spectroscopy(FTIR).HPLC method was developed to determine the concentration of CEP in rats.in vivo bioavailability evaluation of rat CEP solid dispersions was performed compared to the drug substance.Results The results of phase analysis showed that when the ratio of drug to carrier was 1:5,CEP existed as amorphous form in the formulation.The plasma concentration-time curve in rats showed that the peak time(tmax) of the CEP solid dispersion was relatively unchanged compared to the drug substance,the peak concentration(ρmax) was increased by 794%,and the relative bioavailability was 1572%.Conclusion CEP exist amorphous in CEP solid dispersion prepared by solvent method.The in vitro dissolution rate and absorption in vivo of rats are significantly increased.