目的 提高盐酸青藤碱（sinomenine hydrochloride，SIN-HCl）脂质体的药物包封率，并阐明处方药量与脂质体粒径等因素对包封率的影响规律。方法 以离心沉淀-离心超滤法测定SIN-HCl脂质体的包封率；以包封率与成型性为主要指标筛选薄膜分散法（TFH）、逆相蒸发法（REV）与乙醚注入法（EI）3种制备方法；考察水化液的种类、pH值、离子浓度以及pH梯度载药、磷脂-胆固醇比例、药脂比对包封率的影响；以全面设计试验考察处方药量与粒径两因素对包封率的影响规律；考察代表性脂质体样品在4 ℃下的稳定性。结果 最适的制备工艺为薄膜分散法；最佳水化液为柠檬酸缓冲液（CBS）；随着水化液pH值的升高，包封率增加；当水化液的pH值相同时，脂质体包封率随着水化液离子浓度的降低而增加；pH梯度载药可提高脂质体的包封率，pH梯度载药脂质体的最适水化液为pH值2.5的CBS，最适大豆磷脂-胆固醇比例为6∶1，SIN-HCl与大豆磷脂的比例由1∶6增至6∶6，未经探针式超声处理的脂质体包封率略有下降；建立了药物包封率与处方药量和粒径之间的定量关系，一定粒径与处方药量的脂质体包封率大于80%；成品脂质体的稳定性良好。结论 pH梯度主动载药技术可以制备高包封率的SIN-HCl脂质体。

Objective To prepare sinomenine hydrochloride (SIN-HCl) liposomes with high entrapment efficiency (EE) and to illustrate the effects of drug quantity and particle size on EE. Methods Centrifugation sedimentation-centrifugation ultrafiltration was employed to determine EE of liposomes. Thin film hydration (TFH), reverse phase evaporation (REV), and ether injection (EI) were screened based on EE and formability of liposomes. The effects of water type, pH value, ion concentration of hydration liquid, pH gradient active drug loading, lecithin-cholesterol ratio, and drug-lipid ratio on EE of liposomes were investigated. The relationship between EE and the factors affecting the drug quantity and particle size was probed with a comprehensive design experiment. The stability of typical liposomes was evaluated at 4 ℃. Results The optimal preparation technology was TFH for SIN-HCl liposomes and citrate buffer solution (CBS) was the best hydration liquid. The liposome EE increased with the increase of pH values of CBS. When the pH value of CBS was fixed, the EE increased as a result of decrease in the ion concentration of CBS. pH gradient active drug loading led to increase of EE. The preferable hydration liquid for liposomes was CBS with pH value of 2.5. The optimal ratio of soybean lecithin to cholesterol was 6∶1. Increasing ratios of SIN-HCl to soybean lecithin from 1∶6 to 6∶6 led to a slight decrease in EE of liposomes without probe signification. A quantitative relationship was established between the EE and drug quantity and liposome size. The EE of SIN-HCl liposomes prepared by certain particle size and drug quantity could reach over 80%. The typical liposomes showed a good stability. Conclusion The technology of pH gradient active drug loading is able to prepare SIN-HCl liposomes with high EE.

教育部高等学校博士学科点专项科研基金项目（20123322120002）；上海市教委重点学科资助项目（J50302）