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多西紫杉醇前体混合胶束的制备及体外评价

Preparation and in vitro evaluation of pro-mixed docetaxel micelles

  • 摘要: 研究制备经稀释可自发形成混合胶束的多西紫杉醇磷脂胆盐前体混合胶束。采用薄膜分散法制备多西紫杉醇磷脂胆盐前体混合胶束;通过高效液相色谱测定混合胶束的包封率;分别利用透射电镜、动态光散射法对混合胶束的形态、粒径进行了表征;采用透析法考察其体外释放行为;考察前体混合胶束与0.9%氯化钠注射液及5%葡萄糖注射液的配伍稳定性;通过家兔溶血试验、血管刺激性试验及小鼠异常毒性实验考察其安全性。结果表明,多西紫杉醇前体混合胶束稀释后自发形成圆盘状混合胶束,平均粒径为65 nm,粒度分布很窄,多分散系数为0.049,包封率为96%,24 h体外累积释药百分率为96.02%;与0.9%氯化钠注射液配伍稳定性较好;对家兔给予本注射液,滴注部位未出现刺激反应,对家兔红细胞未产生溶血和凝集作用;LD50大于20 mg/kg。综合上述研究可见,多西紫杉醇前体混合胶束具有良好的应用前景。

     

    Abstract: This paper prepared a pro-mixed docetaxel micelles(MM) formulation intended for the parenteral administration of docetaxel.Docetaxel bile salt(BS)/phospholipid(PC) pro-MM were prepared by thin-film dispersion and could be diluted to form MM spontaneously.Encapsulation efficiency was determined by HPLC.The morphology and diameter were characterized by transmission electron microscopy (TEM) and dynamic light scattering (DLS).In vitro release was observed by the dialysis.Compatibility with 0.9% saline and 5% glucose injections was assessed after dilution.Micelles stimulation to blood vessel and the potential of hemolysis relating to the micelles were evaluated in rabbits.Abnormal toxicity of the micelles was investigated using mice.The encapsulation efficiency of docetaxel MM after 50-fold dilution by saline was more than 96% with an average particle size of 65 nm.The accumulated release ratio was 96.02% in 24 h.The stability of docetaxel MM infusion solutions after dilution by normal saline was better than that by glucose injection.In rabbit vessel stimulation test,it showed that there were no obviously pathological changes in the injection site examined by naked eyes and microscope.There was no hemolysis or agglomeration on vitro-body red cells of rabbit.LD50 of MM was more than 20 mg/kg.Therefore,it could be concluded that pro-mixed docetaxel micelles has the potential of clinical applications.

     

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