米托蒽醌长循环脂质体的制备及药代动力学的研究

目的研究米托蒽醌长循环脂质体的制备方法并考察其在家兔体内的驻留行为。方法用乙醇注入合并硫酸铵梯度法制备米托蒽醌长循环脂质体。用两亲性聚乙二醇2000-二硬脂酰磷脂乙醇胺(PEG-DSPE)修饰脂质体膜。以RP-HLPC柱切换方法测定家兔血浆中米托蒽醌药物浓度。结果长循环脂质体平均粒径为60 nm,药物包封率为93.6%。以相同剂量(2 mg·kg^-1)经iv分别给予家兔长循环脂质体和普通脂质体,前者平均驻留时间(MRT)为9.8 h,后者为3.6 h,长循环脂质体药时曲线下面积(AUC)提高了6.4倍。证明米托蒽醌长循环脂质体延长了在血液循环中的时间。结论用乙醇注入合并硫酸铵梯度法可制得包封率高、粒径小的脂质体,以PEG修饰磷脂膜可以增加长循环脂质体的AUC,并延长其在血液循环中的时间。

PREPARATION OF LONG CIRCULATING MITOXANTRONE LIPOSOMES AND ITS PHARMACOKINETICS

AIM: To prepare the mitoxantrone long circulating liposomes (LCL) and to observe the residence behavior of the mitoxantrone LCL in rabbits. METHODS: The long circulating mitoxantrone liposomes were prepared by ethanol injection combined with the ammonium sulphate gradients method. Amphipathic polyethylene glycol-distearoyl phosphatidylethanolamine (PEG-DSPE) was added to modify the membrane of the liposomes. The column-switching system of RP-HPLC was utilized to determine mitoxantrone concentration in rabbit plasma. RESULTS: The mean diameter of the long circulating mitoxantrone liposomes was 60 nm, with the entrapping efficiency of 93.6%. With the same dosage (2 mg.kg-1) i.v. in rabbits, the mean residence time (MRT) of the long circulating mitoxantrone liposomes was 9.8 h, while that of the normal liposomes was 3.6 h, and the AUC of the former is 6.4 fold greater than of the latter. It showed that the long circulating mitoxantrone liposomes prolonged the resident time of the drug in the blood circulating system and they reduced the uptake by the reticuloendothelial system, simultaneously. CONCLUSION: Liposomes with high entrapping efficiency and small particle size could be prepared by ethanol injection combined with the ammonium sulphate gradients method, and the liposomes modified by PEG-DSPE could raise the AUC and prolonged the resident time of the drug in the blood circulating system.