多烯紫杉醇磷脂复合物亚微乳的制备与工艺优化

Preparation and characterization of docetaxel phospholipid complex submicron emulsion

目的为临床提供载药量高、稳定性好的静脉注射用多烯紫杉醇磷脂复合物亚微乳。方法采用高压均质法制备多烯紫杉醇磷脂复合物亚微乳;以离心稳定性常数(Ke)为评价指标,通过正交设计试验对处方进行优化;在最佳处方的基础上,考察工艺因素对亚微乳剂的性质及稳定性的影响。结果多烯紫杉醇磷脂复合物亚微乳的最佳处方与制备工艺为:中链脂肪酸甘油酯(油相)150g·L-1,乳化剂30g·L-1(大豆磷脂-Tween80质量比8:2),油酸4g·L-1,甘油22.5g·L-1;均质前调节pH6.0～6.5,以30MPa压力均质4次。多烯紫杉醇磷脂复合物亚微乳载药量为4g·L-1,粒径为(159±45)nm,含量质量分数为98.3%;与0.9%氯化钠和5%葡萄糖配伍后6h内使用安全;在(4±2)℃条件下,稳定性良好。结论该处方及工艺可行,所制备的多烯紫杉醇磷脂复合物亚微乳质量稳定,载药量高,具有临床使用意义。

objective To prepare docetaxel phospholipid complex submicron emulsion and investigate its physic-chemical properties.Methods High pressure homogenizer was utilized to prepare the submicro-emulsion.Orthogonal experiment was designed to optimize the formulation of docetaxel phosph-olipid complex submicron emulsion,using the stability index of centrifugation as the standard.And process parameters and sterilization conditions were optimized.Results The optimal formulation and preparation condition of docetaxel phospholipid complex submicro-emulsion were as follow:medium-chain triglyceride 100 g·L-1,phospholipids 240 g·L-1,Tween 80 6 g·L-1,oleic acid 4 g·L-1,glycerol 22.5 g·L-1,adjust pH to 6.0-6.5.The pressure of the homogenizer was set at 30 MPa and circled for 4 times.Docetaxel content in the final submicron emulsion was 4 g·L-1.The mean particle size of the submicron emulsion was (159±45) nm.Less than 2 % docetaxel was degraded after sterilization.The submicron emulsion showed good compatibility with 5 % glucose injection and 0.9 % sodium chloride injection,and was safe to use within 6 h.Accelerated test at (25±2) ℃ indicated that the appearance of the emulsion didn’t change,but the pH and the content of docetaxel decreased.In contrast,long-term test at (4±2) ℃ showed that there was no significant change with the appearance,the content of the drug and other parameters.Conclusions A stable and clinical applicable docetaxel phospholipid complex submicron emulsion was obtained and up to the standards of intravenous injection preparation.