壳聚糖及其EDTA轭合物双层包覆胰岛素脂质体的处方工艺优化

Optimization of the formulation and process for the insulin liposome double-coated with chitosan and chitosan EDTA conjugates

目的：研究制剂因素对壳聚糖(CH)及其EDTA轭合物(CEC)双层包覆胰岛素脂质体降血糖作用的影响。方法：采用逆相蒸发法制得胰岛素脂质体，并用CH和CEC进行双层包覆。以小鼠口服降血糖效果作为实验指标，分别应用L16(215)和L8(27)正交实验设计优化CH-CEC双层包覆胰岛素脂质体的处方与工艺。结果：最佳处方组成为胰岛素．100IU，pH 7．4磷酸盐缓冲液，磷脂150mg，胆固醇25mg，维生素E 15mg，0．2％CH 1．5mL和1％CEC 1.5mL。最佳制备工艺为乙醚10mL，旋转蒸发温度20℃，探针式超声时间0．5min，加CH和CEC后的孵化时间30min，孵化温度10℃，CH要先于CEC加入。经优化得到的双层包覆胰岛素脂质体经糖尿病模型大鼠口服后，具有平稳持久的降血糖作用，以皮下注射胰岛素为对照，其相对药理生物利用度(PA)达14．78％。结论：CH-CEC双层包覆胰岛素脂质体的组成和制备因素的变化会影响降血糖效果，用CH-CEC双层包覆的胰岛素脂质体具有较好降血糖作用。

Objective:To explore the effects of the formulation and the coating process on the treatment of hyperglycemia with the double-coated insulin liposome. Methods: The insulin liposome through reverse-phase evaporation was double coated with chitosan and chitosan EDTA conjugates. The formulation and the coating process were optimized with orthogonal design L16(215) and L8(27) respectively. The anti-hyperglycemic efficacy was measured in mice model. Results:The optimized insulin liposome showed a flat and sustained hypoglycemic effect with a relative pharmacological bioavailability of 14.78% in mice that were orally administrated,compared with the one in mice that were injected. Conclusion: Both formulation and process of the double-coated insulin liposome have a significant impact on the hypoglycemic effect.