本研究以"质量源于设计"(quality by design，QbD)理念为核心，优化氧化苦参碱-黄芪甲苷共载脂质体(oxymatrine-astragaloside Ⅳ liposomes，Om-As-Lip)的处方工艺并对其进行放大验证。采用乙醇注入联合pH梯度法制备Om-As-Lip，通过双重风险评估工具、Plackett-Burman设计和Box-Behnken响应面实验对其关键物料属性进行优化，建立设计空间;进一步考察Om-As-Lip的放大工艺，采用单因素试验优化高压匀质的关键工艺参数，并对其终产品进行质量评价。研究结果发现，黄芪甲苷药脂比、胆脂比和混合磷脂比例(氢化大豆卵磷脂:大豆卵磷脂)是影响Om-As-Lip质量的关键材料属性，Box-Behnken设计建立的回归模型具有良好的预测性，并确定Om-As-Lip的最佳处方为:黄芪甲苷药脂比为1∶40，胆脂比为1∶10，氢化大豆卵磷脂:大豆卵磷脂为51∶9。设计空间内的胆脂比可控制在1∶12～1∶5，氢化大豆卵磷脂:大豆卵磷脂比例可控制在1∶7～17∶3。Om-As-Lip高压匀质的最佳压力为600 bar，循环次数为6次，温度为4 ℃。基于QbD理念制备的Om-As-Lip质量评价符合预期，建立的处方工艺稳定可行，有望为其今后的开发应用奠定实验基础。
Formulation and technology of oxymatrine-astragaloside Ⅳ coloaded liposomes based on quality by design
To optimize the formulation and technology of oxymatrine-astragaloside Ⅳ coloaded liposomes(Om-As-Lip)based on quality by design(QbD)principles,and further to verify the feasibility of its amplification process,Om-As-Lip was prepared by ethanol injection combined with pH gradient method.The critical material attributions of Om-As-Lip were evaluated by dual-risk analysis tools and Plackett-Burman design(PBD).The formulation of Om-As-Lip was further optimized with the Box-Behnken design(BBD).The design space was also established based on the contour plots of BBD.In order to further investigate the amplification process of Om-As-Lip,the critical process parameters of high-pressure homogenization(HPH)were optimized by single-factor test,and the quality of the final product was also evaluated.The results of risk analysis and PBD confirmed that the astragaloside concentration,cholesterol concentration,and phospholipid ratio(HSPC∶SPC)were the ctitical material attributes.The model established by BBD had a good predictability,and the optimized mass ratio of As to phospholipids was 1∶40,cholesterol to phospholipids was 1∶10,HSPC to SPC was 51∶9.The design space of Om-As-Lip was as follows:the ratio of cholesterol to phospholipids was 1∶12-1∶5 and HSPC to SPC was 1∶7-17∶3.The optimized high-pressure homogenization pressure was 600 bar,temperature was 4 ℃,and cycle times was 6 times for HPH-Om-As-Lip.The quality of Om-As-Lip prepared based on the QbD concept can meet the expected CQAs,and the formulation and technology established can provide a reliable experimental basis for its future development and applications.
quality by designliposomehigh-pressure homogenizationastragaloside Ⅳoxymatrine
万方数据
维普
