卡巴他赛脂质体的制备及其大鼠药动学

Preparation and Pharmacokinetics in Rats of Cabazitaxel Liposomes by Film Dispersion Method

选用氢化大豆磷脂(HSPC)、胆固醇、二硬脂酰磷脂酰甘油(DSPG)为辅料,采用薄膜分散-高压均质法制备卡巴他赛脂质体。以透射电镜观察其形态、动态光散射法测定粒径分布及ζ电位、葡聚糖凝胶柱色谱法测定包封率;采用透析法测定脂质体在体外的释放行为、并测定脂质体在大鼠体内的药动学行为。结果显示,所制得的样品外观和形态较佳、平均粒径为(68.04±1.73)nm、多分散系数为0.213±0.015、ζ电位为(-57.7±1.2)mV、包封率为(86.7±1.5)%。卡巴他赛脂质体在0.05%Tween-80水溶液中的48 h累积释放率为74%,释放速率比注射液(20 h累积释放率为80%)缓慢。卡巴他赛注射液及其脂质体在大鼠体内的AUC_0→∞为(696.89±0.16)和(4 210.07±0.19)ng·ml^(-1)·h,t_(1/2)为(5.85±0.32)和(7.28±0.40)h,提示脂质体有延缓药物释放的作用。

Liposomes can be aggregated through the enhanced permeability and retention （EPR） effect in the target site, enhance the accumulation of drugs, so as to improve efficacy and reduce the side effects. Hydroxylated soybean phosphatidylcholine （HSPC）, cholesterol and distearoyl phosphatidylglycerol （DSPG） were used as raw materials to prepare the liposomes by film dispersion-high pressure homogenization method. The morphology of the liposomes was observed by transmission electron microscopy. The particle size and distribution were determined by laser scattering method. The encapsulation efficiency was determined by dextran gel column chromatography. The in vitro release behavior of liposomes was determined by dialysis method. The results showed that the average particle size, polydispersion index, ζ potential and entrapment efficiency of the liposomes were （68.04±1.73）nm, 0.213±0.015, （-57.7±1.2）mV and （86.7±1.5）%, respectively. The obtained negatively charged liposomes were able to avoid aggregation. In 0.05% Tween-80 solution, the cumulative amount at 48 h of cabazitaxel liposomes was 74%, while for its injection was 80% at 20 h. It demonstrated that the release rate of cabazitaxel liposomes was slower than that of its injection. Furthermore, the pharmacokinetic behaviors of the above two preparations were compared with male SD rats as the animal models. The results showed that the AUC0 → ∞ values for cabazitaxel injection group and cabazitaxel liposome group were （696.89±0.16） and （4 210.07±0.19）ng·ml-1·h, and t1/2 were （5.85±0.32） and （7.28±0.40）h, suggesting that liposomes had a role in delaying drug release.