微型化介质研磨法制备延胡索乙素纳米混悬剂

Preparation of tetrahydropalmatine nanosuspensions by miniaturized media milling

目的制备延胡索乙素纳米混悬剂(tetrahydropalmatine nanosuspension,THP-NS),对其形态和晶型进行表征,并考察其体外溶出特性和制剂稳定性。方法以25 mL螺口玻璃瓶作为研磨室,以磁力搅拌装置作为动力来源,构建微型化介质研磨设备。采用单因素试验法对THP-NS的稳定剂的种类和用量进行优选,得到最佳制备处方:延胡索乙素固定为0.8 g,羟丙甲纤维素E5(hydroxypropyl methylcellulose E5,HPMC-E5)40 mg与十二烷基硫酸钠(sodium dodecyl sulfate SDS)10 mg作为THP-NS的稳定剂联合使用,蒸馏水0.01 L;采用正交试验法对其制备工艺中的研磨介质体积、研磨转速以及研磨时间进行优化,得到最优的制备工艺参数:研磨介质体积为10 mL,研磨转速为1600 r·min-1,研磨时间为4 h。结果以最优处方和工艺制备的3批THP-NS样品的粒径均在200 nm左右,多分散度指数(polydispersity index,PDI)均小于0.2,在稳定性考察中其平均粒径波动也均在30 nm内;而在其体外溶出考察中,THP-NS在磷酸盐缓冲液(pH 6.8)中,5 min即可溶出(95.91±2.09)%,体外溶出效果明显优于药物的粗混悬液。结论采用微型化介质研磨法制备THP-NS,为NS的研究发展提供了更多参考。

Objective To prepare tetrahydropalmatine nanosuspensions(THP-NS)by miniaturized media milling and characterize its morphology and crystal form and evaluate its in vitro dissolution characteristics and stability.Methods The miniaturized media milling method was constructed with 0.025 L glass bottle as the grinding chamber and the magnetic stirrer as the power plant.The formulation of THP-NS was optimized by a single factor test,and the process parameters were optimized by an orthogonal design test with the volume of milling media,milling speed and milling time as investigation factors.The optimal formulation was as follows:fixed main drug dosage of 0.8 g,40 mg HPMC-E5 and 10 mg SDS as the stabilizers of THP-NS,0.01 L distilled water;The optimal preparation process parameters are as follows:grinding media volume of 10 mL,grinding speed at 1600 r·min-1g and grinding time of 4 h.Results The particle size of three batches of THP-NS prepared by the optimal formulation and process was about 200 nm and the PDI was less than 0.2.The mean particle size fluctuation was also within 30 nm in the stability study.The results of in vitro dissolution study showed that THP-NS could dissolve(95.91±2.09)%within 5 min in phosphate buffered saline(pH 6.8),which was significantly higher than the crude drug suspension.Conclusion The results prove that the miniaturized media milling methods for preparation of THP-NS could provide more reference for the development of NS.