尼莫地平/川芎嗪双载药纳米粒的制备及脑内分布研究

Preparation and Brain Distribution of NMD /TMP-Loaded PLGA Nanoparticles

目的制备尼莫地平/川芎嗪聚乳酸-羟基乙酸共聚物[poly(lactic-co-glycolic acid),PLGA]双载药纳米粒(nimodipine/tetramethylpyrazine-PLGA-nanoparticles,NMD/TMP-PLGA-NPs),考察其体外释药特性和脑内分布情况。方法以聚乳酸-羟基乙酸共聚物为载体材料,采用改良的自乳化溶剂挥发法制备尼莫地平/川芎嗪聚乳酸-羟基乙酸共聚物双载药纳米粒,正交设计实验优化其处方工艺;透射电子显微镜观察纳米粒形态;激光粒度仪测定其粒径和Zeta电位;高速离心法测定其包封率及载药量;透析袋法考察其体外释药特性;以尼莫地平原料药和尼莫地平聚乳酸-羟基乙酸共聚物纳米粒为对照组,考察大鼠尾静脉注射尼莫地平/川芎嗪聚乳酸-羟基乙酸共聚物双载药纳米粒后尼莫地平的脑内分布情况。结果制备的尼莫地平/川芎嗪聚乳酸-羟基乙酸共聚物双载药纳米粒外观呈圆形或类圆形,平均粒径为(631.60±3.20)nm,PDI为(0.097±0.007),Zeta电位为(-29.25±1.87)mV,尼莫地平包封率和载药量为(76.25±1.18)%,(1.24±0.01)%,川芎嗪包封率和载药量为(39.30±1.00)%,(6.34±0.11)%;体外释药具有缓释特征;尼莫地平组、尼莫地平聚乳酸-羟基乙酸共聚物纳米粒组和尼莫地平/川芎嗪聚乳酸-羟基乙酸共聚物双载药纳米粒组中脑内AUC0→t分别为0.268 3,0.459 6,0.881 5μg·min·mL-1,且加入川芎嗪后尼莫地平更快达到脑内最高浓度。结论本实验成功制备了尼莫地平/川芎嗪聚乳酸-羟基乙酸共聚物双载药纳米粒,其体外释药具有明显缓释特征,加入川芎嗪制备纳米粒可显著提高尼莫地平脑内含量。

OBJECTIVE To prepare nimodipine/tetramethylpyrazine-loaded poly [ poly （ lactic-co-glycolic acid）, PLGA ] dualdrug nanoparticles （ nimodipine/tetramethylpyrazine-PLGA- nanoparticles, NMD/TMP-PLGA-NPs） , and investigate the in vitro release behavior and brain distribution. METHODS NMD/TMP-PLGA-NPs were prepared by optimized emulsion solvent evaporation method with PLGA as a carrier material ; the morphology of NMD/TMP-PLGA-NPs was observed by transmission electron microscope; the mean particle size, particle size distribution and Zeta potential were measured by laser particle size analyzer; the entrapment efficiency and drug loading were measured by uhracentrifugation; the in vitro release behavior was studied by dialysis; the brain distribution was com- pared with NMD-suspension and NMD-PLGA-NPs. RESULTS The NMD/TMP-PLGA-NPs were spherical; the mean particle size, particle size distribution and Zeta potential of NPs were （631.60± 3.20） nm, （0. 097 ±0. 007）, （ - 29. 25± 1.87 ） mV, respectively. The entrapment efficiency and drug loading of NMD were （76. 25 ± 1.18）% and （1.24± 0. 01 ）% , while those of TMP were （39. 30 ± 1.00 ） % and （ 6. 34 ± 0. 11 ） % , respectively. The profiles of in vitro release had the features of sustained release. The AUC0~, of NMD-suspension, NMD-PLGA-NPs and NMD/TMP-PLGA-NPs were 0. 268 3,0. 459 6 and 0. 881 5 Ixg ~ min ~ mL^-1, and the addition of TMP promoted the reach of highest brain concentration. CONCLUSION NMD/TMP-PLGA-NPs are prepared success- fully and show sustained-release in vitro, and the distribution of NMD into brain was increased significantly with the addition of TMP.