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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 (DOC) has been used clinically in the treatment of non-small cell lung cancer, breast cancer and ovarian cancer. However, its water solubility is poor. Docetaxel (DOC) Ethanol solution as a mixed solvent, intravenous injection often lead to serious allergic reactions and limit its clinical use. This study investigated the preparation of DOC liposomes and investigated the pharmacokinetics of two liposomes in rabbits before and after modified with poly ethylene glycol-2000 (PEG-2000). Methods: The normal and PEG-2000 modified DOC liposomes were prepared by thin-film evaporation method, and the entrapment efficiency, particle size and surface potential were determined. After intravenous injection, the internal standard of diazepam was determined by solid-phase extraction- The content of the drug in plasma was determined by HPLC. The data of 3p87 program and SPSS13.0 statistical software were processed and analyzed to calculate the pharmacokinetic parameters. Results: The preparation of DOC liposomes encapsulation efficiency> 75%, the average particle size of about 150nm. Commonly available marketed docetaxel (M-DOC) and docetaxel liposome (L-DOC) and PEG-2000 modified long circulating liposomes (0.17 ± 0.04), (0.31 ± 0.11) and (0.32 ± 0.06) h respectively, and the elimination half-lives were (8.54 ± 1.05), (11.18 ± 1.33) and 10.51 ± 1.13 h, and the apparent volume of distribution were (13.66 ± 3.62), (8.65 ± 1.11) and (6.31 ± 0.55) L, respectively. The area under the curve of 0 ~ 24h were (13.45 ± 2.44) and (22.83 ± 3.57) And (29.31 ± 5.96) mg · (h · L) -1. The area under the curve from time zero to the time of eliminating all prototype drugs were (15.07 ± 2.76), (28.70 ± 4.95) and (36.95 ± 9.13) mg · (H · L) -1, the clearance rates were (1.10 ± 0.18), (0.54 ± 0.08) and (0.42 ± 0.07) L / h, respectively. CONCLUSION: The encapsulation efficiency of DOC liposomes prepared by the membrane dispersion method is high and the particle size is small. Both DOC liposomes can increase the area under the curve of DOC to some extent and reduce the apparent volume of distribution and clearance rate Prolonging its time in blood circulation, and using PEG modified DOC liposomes better.