注射用紫杉醇脂质纳米粒的制备、体外释放及体内药动学研究

Preparation,in Vitro Release and Pharmacokinetics of Paclitaxel Lipid Nanoparticles for Intravenous Injection

目的制备注射用紫杉醇脂质纳米粒,并考察其理化性质、体外释放及体内药动学性质。方法采用高压乳匀结合冷冻干燥工艺制备注射用紫杉醇脂质纳米粒;考察脂质纳米粒形态、粒径分布、载药量及超滤离心法测定包封率;考察了制剂的稳定性和安全性;以市售紫杉醇注射液为对照,考察其体外释放特性及大鼠体内药动学行为。结果注射用紫杉醇脂质纳米粒的平均粒径为25.6nm;包封率为(99.55±0.25)%,载药量为(1.37±0.78)%;与5%葡萄糖溶液或0.9%NaCl注射液配伍8h内稳定;安全性良好,无溶血现象;在0.8mol·L-1水杨酸钠溶液中24h的累积释放百分率分别为99.8%和99.9%,释放行为符合一级动力学方程;紫杉醇注射液与脂质纳米粒溶液在大鼠体内的平均滞留时间(mean residence time,MRT)分别为1.10和1.85h,两者24h内药-时曲线下面积(AUC)分别为6.78和33.6mg·h·L-1。结论采用高压乳匀-冷冻干燥工艺制备注射用紫杉醇脂质纳米粒,对纳米粒起到了很好的保护作用,避免了药物的渗漏;载药量和包封率较高,粒径分布均匀;与注射液相比,脂质纳米粒的体外释放显著慢于注射液,具有缓释效果。

OBJECTIVE To prepare paclitaxel lipid nanoparticles for intravenous injection and investigate its release characteristics in vitro and its pharmacokinetics in rats. METHODS Paclitaxel lipid nanoparticles for intravenous injection were prepared by high-pressure homogenization and lyophilization. The shape of lipid nanoparticles, particles size, drug-loading capability were evaluated. Entrapment efficiency was determined by filtration-centrifugal ultrafiltration. Stability and hemolysis reaction were evaluated. The in vitro release and its pharmacokinetics in rats were investigated by comparison with paclitaxel injection at the same time. RESULTS The mean particle size, entrapment efficiency and drug-loading capability were 25.6 am, （99.55 ±0.25 ） % and （ 1.37± 0.78） %, respectively. Paclitaxel lipid nanoparticles after being diluted by 5 % glucose solution and 0.9% NaC1 solution was stable within 8 h. It had no hemolysis reaction. The in vitro cumulative released in 0.8 mol-L-1 sodium salicylate solution reached about 99.8% and 99.9% in 24 h. The profile was described by first-class equation. The mean residence time and the area under the curve of concentration versus time from zero to the last time point of paclitaxel injection and lipid nanoparticles were 1.10 and 1.85 h, and 6.78 and 33.6 mg.h.L-1, respectively. CONCLUSION Paclitaxel lipid nanoparticles was prepared by high-pressure homogenization and lyophilization. It showed high drug-loading capability and high encapsulation efficiency. And lipid nanoparticles showed sustained release in vitro compared with injection.