依托泊苷隐形前体脂质体的构建及家兔体内药动学研究

构建依托泊苷隐形前体脂质体，并考察其在家兔体内的药动学。采用薄膜分散法构建窄白隐形脂质体；硫酸铵梯度法包封依托泊苷；结合真空冷冻干燥技术构建依托泊苷隐形前体脂质体。采用凝胶色谱法测定脂质体包封率；透射电镜观察脂质体的形态；电泳光散射技术测定Zeta电位与粒径分布；以市售依托泊苷注射液和普通脂质体为参比制剂，评价其在家兔体内药动学特点。脂质体平均包封率为83．92％±3．65％，粒径为（124．5±26．9）nm，Zeta电位为（-39．50±1．04）mV，家兔单剂量静脉注射1．5mg／kg依托泊苷制剂后呈二室模型特征，依托泊苷隐形前体脂质体的T1/2β为（19．26±3．16）h，AUC为（26．04±3．53）μg／h／mL；注射液的T1/2β为（0．94±0．21）h，AUC为（0．98±0．26）μg／h／mL；普通脂质体的T1/2β为（7．99±1．36）h,AUC为（11．65±1．70）μg/mL。构建的隐形前体脂质体包封率高，且延长了依托泊苷在血液中的循环时间。

Preparation of stealthy etoposide proliposomes and the pharmacokinetics in rabbits

The objectives of the present study were to prepare stealthy etoposide proliposomes and study the pharmacokinetics in rabbits. Blank stealthy liposomes were prepared by film dispersion method. Stealthy etoposide liposomes were prepared by using the ammonium sulfate gradient loading procedure. Vacuum freeze-drying technique was used to dry stealthy etoposide liposomes. Encapsulation efficiency of stealthy etoposide proliposomes was determined by Sephadex chromatography. The morphology was observed by transmission electronic microscope. The particle size and zeta potential were measured by using electrophoretic light scattering technology. The pharmacokinetics in rabbits was evaluated by comparison with etoposide injection and conventional liposomes, respectively. Mean encapsulation efficiency of stealthy etoposide proliposomes was 83.92% ± 3.65% （n = 3）. The liposomes were round or oval. Mean particle size was （124.5 ±26.9） nm, and zeta potential was （-39.50 ±1.04） mV. Following intravenous injection administration at a dose of 1.5 mg/kg etoposide, the three kinds of etoposide preparations were fitted with the two-compartment model. T1/2 β and A UC values of stealthy etoposide proliposomes were （19.26 ± 3.16） h and （26.04 ±3.53） μg/h/mL, respectively. T1/2 β and AUC values of etoposide injection were （0.94 ± 0.21） h and （0.98 ± 0.26） μg/h/mL, respectively. T1/2β and AUC values of conventional liposomes were （7.99 ± 1.36） h and （11.65 ± 1.70） μg/h/mL, respectively. Results indicated that the stealthy etoposide proliposomes could significantly extend the duration of etoposide in blood circulation.