7-乙基-10-羟基喜树碱长循环脂质体的制备及药动学研究

Preparation of long-circulated liposome containing 7-ethyl-10-hydroxycamptothecin and its pharmacokinetic study

目的:研究7-乙基-10-羟基喜树碱长循环脂质体(Lip-SN38)的制备方法以及在大鼠体内的药动学。方法:采用两步合成法制备脂质体空间稳定膜材甲氧基聚乙二醇-磷脂酰乙醇胺(mPEG-PE);同时采用薄膜分散法制备Lip-SN38;用阳离子交换树脂微型小柱层析法分离游离药物和脂质体,紫外分光光度法测定包封率;HPLC法测定大鼠血浆中药物浓度。结果:Lip-SN38平均粒径<200 nm,药物包封率>90%;48 h只有<30%的药物体外释放;大鼠尾静脉注射Lip-SN38,剂量为10 mg.kg-1,与SN3-8溶液剂相比,t1/2β增加4.61倍。结论:采用薄膜分散法可制得包封率高、粒径小的脂质体,mPEG-PE修饰磷脂膜可增加Lip-SN38的t1/2β,延长药物在血中的循环时间。

Objective：To investigate the preparation of long-circulated liposome containing 7-ethyl-10- hydroxycamptothecin （Lip-SN38） and to observe its pharmacokinetics in rats. Methods： Methoxy-poly （ethylene glycol）-phosphatidylethanolamine was synthesized by a two-step process. Lip-SN38 was prepared by thin-film dis- persion method. Free drugs and liposomes were separated by cation exchange resin column chromatograph and drug entrapment efficiency was determined by ultraviolet-visible spectrophotometry （UV）. HPLC method was established for the determination of SN38 concentration in plasma of rats. Results： Mean size of Lip-SN38 was 〈 200 nm and drug entrapment efficiency was 〉 90%. Drug released from Lip-SN38 in vitro was less than 30% within 48 h. Lip- SN38 was given to rats at 10 mg·kg^-1 by iv injection, t1/2β was 4.61 fold higher than SN-38 solution. Conclusion： By thin-film dispersion method,liposomes had been prepared with high entrapment efficiency and nanometer size. t1/2β of Lip-SN38 was increased and long circulation effects could be reached after modification of lipid membrane with mPEG-PE.