盐酸阿霉素聚乳酸纳米粒的制备及大鼠体内药动学研究

Preparation of Doxorubicin-loaded PLA Nanoparticles and Study Their Pharmacokinetics in Rats

关键词:  盐酸阿霉素  聚乳酸纳米粒  体外释放  药动学

Key words:  doxorubicin  PLA nanoparticles  in vitro release  pharmacokinetics

摘要:

目的 优化盐酸阿霉素聚乳酸纳米粒（DOX-PLA-NPs）的制备工艺，并对其理化性质、体外释放及大鼠体内药动学进行研究。方法 采用改良的复乳-溶剂挥发法制备DOX-PLA-NPs，正交设计优化其处方工艺，对其纳米粒形态、粒径、Zeta电位、包封率与载药量进行测定。以DOX原药为对照组，考察DOX-PLA-NPs的体外释药特性及大鼠尾静脉给药后的体内药动学参数。结果 DOX-PLA-NPs外观圆整，平均粒径为（125.67±3.80） nm、Zeta电位为（-35.97±1.58） mV、包封率和载药量分别为（81.23±1.46）%，（10.29±0.63）%。体外释放结果显示，DOX经纳米粒包裹后，具明显的缓释作用。DOX原药和纳米粒的体内药动学过程均符合开放式二室模型，t_1/2β分别为（1.15±0.175） h、（6.43±2.12） h，CL分别为（174.76±47.22） h·L^-1、（30.68±11.86） h·L^-1，AUC_0→t分别为（6.01±1.61）μg·h·L^-1、（36.04±13.72）μg·h·L^-1。结论 制备的盐酸阿霉素聚乳酸纳米粒粒径较小、包封率较高，具明显的缓释作用，并能提高药物的生物利用度。

Abstract:

OBJECTIVE To optimize the preparation of doxorubicin-loaded PLA nanoparticles (DOX-PLA-NPs), and evaluate their physicochemical properties, release behavior in vitro and study their pharmacokinetics in rats. METHODS The DOX-PLA-NPs were prepared by modified double emulsification(W/O/W) solvent evaporation method. Orthogonal test was used to optimize the preparation procedure. The morphology, size distribution, Zeta potential, encapsulation efficiency, and drug loading of DOX-PLA-NPs were characterized. The drug release behavior in vitro and pharmacokinetics behavior in vivo was investigated in comparison with DOX-sol. RESULTS The optimized nanoparticles were spherical in shape with the mean particle size of (125.67±3.80)nm and the Zeta potential of (-35.97±1.58)mV. The encapsulation efficiency and drug loading were (81.23±1.46)%, (10.29±0.63)%, respectively. In vitro drug release results showed DOX-PLA-NPs had a sustained release character. In in vivo study, the pharmacokinetic behavior of DOX-sol and DOX-PLA-NPs were best fitted to two-compartment model and the parameters were as follows:t_1/2β (1.15±0.175)h, (6.43±2.12)h, CL(174.76±47.22) h·L^-1, (30.68±11.86)h·L^-1, AUC_0→t(6.01±1.61)μg·h·L^-1, (36.04±13.72)μg·h·L^-1. CONCLUSION The optimized DOX-PLA-NPs is practicable with small particle size, high encapsulation efficiency, a certain sustained release characteristic and can significantly improve the bioavailability after vein injection.