多西紫杉醇脂质体的制备及其在家兔体内的药代动力学  

Preparation of Docetaxel Liposomes and Their Pharmacokinetics in Rabbits

作　　者：黄红兵[1] 刘韬[1] 林子超[1] 钟锦堂[1] 林沛亮[1] 刘金燕[1] 谭艳仪[1] 李苏[1] 廖海[1] 徐月红[2] 

机构地区：[1]华南肿瘤学国家重点实验室 [2]中山大学药学院,广东广州510080

出　　处：《癌症》2007年第12期1287-1291,共5页Chinese Journal of Cancer

基　　金：广东省科技计划项目(No.2005B30101004)~~

摘　　要：背景与目的:多西紫杉醇(Docetaxel,DOC)已在临床应用于非小细胞肺癌、乳腺癌、卵巢癌等的治疗,但其水溶性差,现临床使用的注射剂均采用吐温-80和13%乙醇溶液作为混合溶媒,静脉注射时常引发严重的过敏反应而限制了其临床使用。本课题研究DOC脂质体的制备方法,并考察用聚乙二醇2000(poly ethylene glycol-2000,PEG-2000)修饰前后的两种脂质体在家兔体内的药代动力学。方法:用薄膜蒸发法制备普通和PEG-2000修饰的DOC脂质体,测定其包封率、粒径和表面电位;静脉注射给药后,以地西泮为内标,采用固相萃取-高效液相色谱法测定血浆中药物含量;用3p87程序和SPSS13.0统计软件处理和分析数据,计算有关药代动力学参数。结果:制备的DOC脂质体包封率>75%,平均粒径在150nm左右。普通市售多西紫杉醇注射液(market docetaxel,M-DOC)和普通脂质体(docetaxel liposome,L-DOC)及PEG-2000修饰的长循环脂质体(PEG-2000-modified DOC long circulating liposome,PEG-DOC-LCL)的分布相半衰期分别为(0.17±0.04)、(0.31±0.11)和(0.32±0.06)h,消除相半衰期分别为(8.54±1.05)、(11.18±1.33)和(10.51±1.13)h,表观分布容积分别为(13.66±3.62)、(8.65±1.11)和(6.31±0.55)L,0～24h曲线下面积分别为(13.45±2.44)、(22.83±3.57)和(29.31±5.96)mg·(h·L)-1,零时间至所有原形药物全部消除时间内的曲线下面积分别为(15.07±2.76)、(28.70±4.95)和(36.95±9.13)mg·(h·L)-1,清除率分别为(1.10±0.18)、(0.54±0.08)和(0.42±0.07)L/h。结论:薄膜分散法制备的DOC脂质体包封率较高,粒径较小;两种DOC脂质体均可不同程度地增加DOC的曲线下面积,降低表观分布容积和清除率,从而延长其在血液循环中的时间,并以用PEG修饰的DOC脂质体效果更好。BACKGROUND ＆ OBJECTIVE： Docetaxel is used to treat non-small cell lung cancer, breast cancer and ovarian cancer. It is indissolvable and the solvent containing polysorbate-80 and 13% solution of ethanol is used for injections. Its clinical application is limited because of frequent severe hypersensitive responses. This study was to prepare docetaxel （DOC） liposomes and investigate their pharmacokinetics in rabbits after intravenous administration. METHODS： DOC liposomes, with or without modification of polyethylene glycol （PEG）, were prepared by thin-film ultrasonic dispersion method. The entrapment efficiency and mean diameter of the liposomes were measured. After intravenous administration in rabbits, plasma DOC concentration was detected by solid phase extraction high- performance liquid chromatography （SPE-HPLC）. The pharmacokinetic parameters were calculated and analyzed by 3p87 pharmacokinetic program. RESULTS, The entrapment efficiency of DOC liposomes was above 75%. The mean diameter was about 150 nm. The half-life of distribution （T1/2α） were （0.17±0.04） h for market docetaxel injection （M-DOC）, （0.31 ±0.11） h for common DOC liposome （L-DOC）, and （0.32±0.06） h for PEG-2000-modified DOC long circulating liposome （PEG-DOC-LCL）; the half-life of clearance （T1/2β） were （8.54±1.05）, （11.18±1.33）, and （10.51 ±1.13） h, respectively; the apparent volume of distribution （Vd） were （13.66±3.62）, （8.65±1.11）, and （6.31±0.55） L, respectively; the area under the concentration-time curve from 0 to 24 h （AUC0→24） were （13.45±2.44）, （22.83±3.57）, and （29.31±5.96） mg.（h·L）^-1, respectively; the area under the concentration-time curve from 0 to ∞ h （AUC0→∞） were （15.07±2,76）, （28.70±4.95）, and （36.95± 9.13） mg ·（h ·L）^-1, respectively; the clearance （CL） were （1.10±0.18）, （0.54±0.08）, and （0.42±0.07） L/h, respectively. CONCLUSION. The thinfilm prepared DOC lipo

关 键 词：多西紫杉醇 脂质体 药代动力学 高效液相色谱法 家兔 

分 类 号：R94[医药卫生—药剂学] R96[医药卫生—药学]