星点设计-效应面法优化盐酸氨溴索漂浮渗透泵给药系统及犬体内药动学

Optimization of a floating osmotic pump system of ambroxol hydrochloride using central composite design-response surface methodology and its pharmacokinetics in Beagle dogs

本文设计了具有漂浮特性的盐酸氨溴索渗透泵胶囊。采用中国药典(2010版)附录XD释放度测定法第三法装置同时评价制剂的体外释放和漂浮性能。以葡萄糖用量、致孔剂用量和包衣增重为自变量,自制处方释放曲线与目标释放曲线相比而得的相似因子(f2)为应变量,采用星点设计-效应面法优化系统。优化处方:葡萄糖100.99 mg,致孔剂用量11.70%,包衣增重4.21%。f2为89.14,高于市售胶囊(69.02)和自制片(72.15)。优化后零级释药明显(r=0.994 4),释药完全(>90%)。Beagle犬体内实验证明,自制胶囊Cmax、tmax低于市售胶囊、自制片,体内外相关性好(r=0.985 1),且生物利用度高(110.77%),说明自制胶囊有明显的控释特征。

This paper reported that a new type of floating osmotic pump of ambroxol hydrochloride was designed.Third method apparatus（Chinese Pharmacopeia 2010,appendix XD） was employed to simultaneously evaluate the release and floating behavior in vitro.The system was optimized using central composite design-response surface methodology.Similar factor（f2） between the release profile of self-made formulation and the target release profile was chosen as dependent factor.The amount of glucose（A,mg）,pore former（B,%） and weight of coating（C,%） were employed as independent factors.Optimized formulation was： A（100.99 mg）,B（1.70%）,C（4.21%）.The value of f2（89.14） was higher than that of market capsules（69.02） and self-made tablets（72.15）.It was showed that self-made capsules possessed character of zero-order release（r = 0.994 4） and drug release completely（90%）.It was showed in result of in vivo study that tmax and Cmax of self-made capsules were significantly lower than that of market capsules and self-made tablets.The correlation coefficient between the fraction of absorption in vivo and the release rate in vitro was 0.985 1,and relative bioequivalence of self-made capsules was 110.77%.Accordingly,self-made capsules displayed obviously characteristics of controlled release both in vivo and in vitro.