甲氨蝶呤/聚天冬氨酸衍生物-接枝-聚乙二醇共聚物胶束制备及其体内外释药考察

The preparation of methotrexate/ poly (aspartic acid) derivatives-graft-poly (ethylene glycol) copolymeric micelles and release in vitro and in vivo

目的:制备甲氨蝶呤/聚天冬氨酸衍生物-接枝-聚乙二醇共聚物胶束,考察该胶束的体内外释药情况。方法:以溶剂蒸发法制备甲氨蝶呤/共聚物胶束;以高效液相色谱法检测甲氨蝶呤;以动态透析法研究药物体外释放;以大鼠为实验动物进行体内药物分布研究。结果:共聚物胶束粒径为50nm左右,分布较窄;Zeta电位接近-30mV;甲氨蝶呤/共聚物胶束在pH7.4和pH5.5的介质中释药近似Weibull释药模型,但在pH5.5介质中释药较pH7.4介质中慢。胶束组甲氨蝶呤的血浆半衰期(t1/2)和药时曲线下面积(AUC)分别是溶液组的2.50和2.17倍。结论:甲氨蝶呤/聚天冬氨酸衍生物-接枝-聚乙二醇共聚物胶束能延长药物在血液循环中的滞留时间。

OBJECTIVE To prepare micelle of graft copolymer containing derivatives of poly （aspartic acid） as insoluble chain and monomethoxy poly （ethylene glycol） （mPEG） as hydrophilic segment loading methotrexate （MTX）, and explore its drug release in vitro and in vivo. METHODS The copolymeric micelle was prepared with solvent evaporation method; the content of drug was determined by HPLC; the rats were used as model animals to investigate the pharmacokinetics of MTX. RESULTS The size of micelle was about 50 nm with narrow distribution, the zeta potential was near 30 mV; drug release pro files of MTX/polymeric micelles nearly followed Weibull model. The drug release rate at pH 7. 4 was faster than that at pH 5.5. The first burst release can be seen at pH 7. 4. The t1/2 and AU（; of micelle group increased 2.45 and 2.22 times respectively, compared with MTX solution group. CONCLUSION Methotrexate/poly （aspartic acid） derivatives graft-poly （ethylene glycol） copolymeric micelles can prolong the drug retention time in blood circulation.