目的 运用Box-Behnken设计-效应面法（Box-Behnken design-response surface method，BBD-RSM）优化小白菊内酯脂质体（parthenolide liposomes，Par-Lips）处方，并对其进行质量表征及初步体外药效评价。方法 采用薄膜分散法制备Par-Lips，以包封率、载药量、ζ电位、粒径和PDI为考察指标，通过单因素考察和BBD-RSM优化Par-Lips处方，并对其进行制剂学评价，同时采用CCK-8法考察其对胆管癌TFK-1细胞的体外药效作用。结果 Par-Lips最佳处方工艺：二硬脂酰基磷脂酰乙醇胺-聚乙二醇2000（DSPE-PEG₂₀₀₀）用量为68.68 mg，膜材比为150∶1，药脂比为1∶10.15。Par-Lips包封率为（83.18±0.90）%，载药量为（5.87±0.06）%，ζ电位为（−7.36±0.02）mV、粒径为（67.38±0.33）nm、PDI为0.200±0.003。Par-Lips体外释放相较于小白菊内酯原料药具有一定的缓释效果；体外抗肿瘤活性实验表明，相对于小白菊内酯原料药溶液，Par-Lips体外抑制胆管癌TFK-1细胞生长效果显著（P＜0.001）。结论 经BBD-RSM筛选获得Par-Lips的最佳处方工艺，该制剂粒径均一、稳定性较好，具有一定缓释作用，且能显著抑制胆管癌TFK-1细胞生长。

Objective To optimize the formulation of parthenolide liposomes (Par-Lips) by Box-Behnken design-response surface method (BBD-RSM), and to characterize its quality and evaluate its efficacy in vitro. Methods Par-Lips was prepared by the thin-film hydration method. The encapsulation efficiency, drug loading, ζ potential, particle size and PDI were investigated. The formulation of Par-Lips was optimized through single factor and BBD-RSM, and the formulation of Par-Lips was evaluated. At the same time, CCK-8 assay was used to investigate its in vitro efficacy on bile duct cancer TFK-1 cells. Results The optimum formulation of Par-Lips was 68.68 mg of DSPE-PEG₂₀₀₀, the ratio of membrane to material was 150:1 and the ratio of drug to lipid was 1:10.15. The encapsulation efficiency of Par-Lips was (83.18 ±0.90) %, the drug loading was (5.87 ±0.06) %, the ζ potential was (−7.36 ±0.02) mV, the particle size was (67.38 ±0.33) nm, and the PDI was 0.200 ±0.003. The release of Par-Lips in vitro has a certain sustained release effect compared with parthenolide. The results of antitumor activity in vitro showed that compared with parthenolide solution, Par-Lips significantly inhibited the growth of bile duct cancer TFK-1 cells in vitro (P < 0.001). Conclusion The optimal formulation process of Par-Lips was obtained by BBD-RSM. The preparation has uniform particle size, good stability, sustained release and can significantly inhibit the growth of bile duct cancer TFK-1 cells.

R283.6

国家自然科学基金面上项目（82473885）