目的 制备延胡索乙素（dl-THP）醇质体（ETS），并初步阐明制剂的经皮吸收特性。方法 采用乙醇注入-pH梯度主动载药法制备dl-THP ETS，并对其形态、粒径、弹性与包封率等理化性质进行表征；以脂质体（LPS）与酊剂作为参比，采用Franz扩散池考察制剂的离体皮肤渗透特性。结果 按优选处方［dl-THP 100 mg，维生素E 1.3 mg，大豆卵磷脂1 200 mg，胆固醇120 mg，无水乙醇9 mL，柠檬酸缓冲液（pH 3.0）21 mL，0.1 mol/L NaOH溶液适量（调pH值至5.5）］制得的dl-THP ETS弹性指数为（20.1±1.1）mL，平均粒径为（85.8±0.9）nm，多分散指数为0.082±0.003，包封率为（81.7±3.2）%。dl-THP ETS 24 h的单位面积皮肤累积渗透药物量（Q_n）为（2 306.4±592.3）μg/cm²，与参比制剂LPS［（2 434.2±564.4）μg/cm²］无显著差异，但约为酊剂［（633.1±218.0）μg/cm²］的4倍（P<0.05）；ETS与LPS各时间点样品间的Q_n RSD的平均值分别为（28.4±10.9）%、（62.8±44.1）%（P<0.05），表明前者样品间的Q_n波动比后者小；ETS与LPS的24 h渗透曲线线性拟合的相关系数平均值分别为0.968±0.033与0.882±0.078（P<0.05），表明前者渗透过程更符合零级动力学。结论 所得的dl-THP ETS弹性高，粒径大小适宜，包封率高，药物经皮渗透速率高且稳定，并符合零级动力学。

Objective To prepare dl-tetrahydropalmatine (dl-THP) ethosomes (ETS) and elucidate their transdermal absorption properties. Methods Dl-tetrahydropalmatine ethosomes (dl-THP ETS) were prepared by ethanol injection combined with pH-gradient active drug-loading method. Their physicochemical properties including elasticity, vesicle size, morphology and entrapment efficiency were characterized. Franz diffusion cells were used to investigate the ex vivo skin permeation characteristics of the formulation with liposomes (LPS) and tinctures being used as reference preparations. Results According to a preferred formulation of dl-THP ETS[dl-THP 100 mg, vitamin E 1.3 mg, soybean lecithin 1 200 mg, cholesterol 120 mg, absolute ethanol 9 mL and cit-rate buffered saline (pH 3.0) 21 mL, 0.1 mol/L NaOH solution suitable quantity (to adjust the pH value to 5.5)], the obtained dl-THP ETS had an elasticity index of (20.1 ±1.1) mL, an average size of (85.8 ±0.9) nm with a polydispersity index of (0.082 ±0.003) and an entrapment efficiency of (81.7 ±3.2)%. The cumulative permeated drug quantity per unit area (Q_n) of dl-THP ETS in 24 h was (2 306.4 ±592.3) μg/cm² with no significant difference compared with the Q_n of the LPS[(2 434.2 ±564.4) μg/cm²] (P > 0.05) and about 4 times of that of the tincture[(633.1 ±218.0) μg/cm²] (P < 0.05). And the averages of RSD of the Q_n at each time point were (28.37 ±10.9)% and (62.83 ±44.1)% for the ETS and LPS, respectively, indicating that the Q_n fluctuation among samples of the ETS was smaller than that of the LPS (P < 0.05). Average correlation coefficients of (0.968 ±0.033) and (0.882 ±0.078) (P < 0.05) were obtained for the ETS and LPS respectively when their 24 h permeation curves were fitted to linear relationship, indicating the permeation of the former was closer to zero-order kinetics than that of the latter. Conclusion The dl-THP ETS have a high elasticity, a suitable size, a high entrapment efficiency, and enhanced and stable percutaneous absorption in line with zero-order kinetics.

浙江省大学生科技创新活动计划资助（2016R410023）；浙江省医药卫生科技计划项目基金（2015111458）