自微乳化给药系统增加索拉非尼的口服吸收生物利用度

目的:为了增加难溶性药物索拉非尼(Sorafenib)的口服吸收,本研究制备索拉非尼自微乳化给药系统并测定其口服相对生物利用度。方法:以油酸乙酯(20%,w/w)为油相,聚山梨酯-80(48%,w/w)为主要乳化剂,聚乙二醇400(16%,w/w)和乙醇(16%,w/w)为助乳化剂制备索拉非尼自微乳化给药系统,以大鼠为实验动物测定其口服相对生物利用度。结果:自微乳化给药系统中索拉非尼的终浓度为20 mg.mL-1。该制剂乳化后粒径为20～25 nm,并可在去离子水,生理盐水及5%葡萄糖溶液中稳定存在8 h。与索拉非尼混悬液相比,自微乳化给药系统可以显著增加索拉非尼的血药浓度-时间曲线下面积(AUC0～72 h),峰浓度(Cmax)和平均滞留时间(MRT),降低清除率(CL)。尤其是与口服混悬液相比,其相对生物利用度提高约25倍。结论:索拉非尼自微乳化给药系统可以显著提高索拉非尼的口服吸收相对生物利用度,有望开发成为增加其口服吸收的药物制剂。

Self-microemulsifying drug delivery system used to improve the oral absorption of sorafenib

Objective: To improve the oral bioavailability of sorafenib,a poorly water-soluble drug,self-microemulsifying drug delivery system(SMEDDS) of sorafenib was prepared and its oral relative bioavailability in rats was evaluated.Methods: The SMEDDS was prepared from a mixture of ethyl oleate,Tween-80,PEG-400 and ethanol.The plasma concentration of sorafenib after oral administration to rats was determined by HPLC.Results: The particle size of emulsified sorafenib SMEDDS was 20~25 nm.The stability studies showed little changes in particle size and drug concentrations during 8 h after the forming of the microemulsions in saline or 5% glucose solution.Compared to sorafenib suspension,the SMEDDS significantly increased the area under the concentration-time curve(AUC0~72 h),maximal blood concentration(Cmax) and mean residence time(MRT) values.Most importantly,the oral relative bioavailability based on AUC0~72 h increased about 25 times after associating sorafenib to SMEDDS.Conclusion: SMEDDS may be a promising vesicle for sorafenib.