Box-Behnken法优化盐酸氨溴索夹芯渗透泵片的处方

Optimization of Prescription of Ambroxol Hydrochloride Sandwich Osmotic Pump Tablets by Box-Behnken Design-Response Surface Method

目的采用Box-Behnken法优化盐酸氨溴索夹芯渗透泵片的处方。方法通过单因素实验,确定渗透物质葡萄糖的含量、包衣膜致孔剂的用量、包衣膜的增重为重要影响因素,对三因素采用Box-Behnken法设计实验,以相似因子f2为评价指标建立多元线性/二次多项式考察各因素对处方释药行为的影响及夹芯渗透泵片渗透机制的考察。结果二次多项式为理想的释药模型,依据Design-Expert8.0.5软件得出最佳处方:葡萄糖:50 mg,致孔剂:8%,包衣增重:9%。优化后3批药物释放曲线相似因子f2为89.33(与设定的理想曲线比较),与模型预测值88.89接近。渗透机制考察发现,以恒定渗透压为释药动力,释药过程中水分通过包衣致孔剂形成的孔道进入片芯内部。结论用Box-Behnken设计法可以优化夹芯渗透泵片的处方。

OBJECTIVE To optimize the formulation of ambroxol hydrochloride sandwich osmotic pump tablets using Box-Behnken design response surface method.METHODS Firstly,significant factors,including amount of glucose,ratio of pore former to weight of coating,and thicknesss of coating,were chosen carefully by single-factor methods,then Box-Behnken design-response surface method was adopted to understand the effects of these factors on the drug release by using similarity factor f_2 as evaluation index.And multiple linear regression model and quadratic polynomial equation were established to evaluate the relationship between these factors and similarity factor f_2.Secondly,the permeation mechanism of sandwich osmotic pump was studied carefully by SEM and drug release behavior investigation.RESULTS The quadratic polynomial equation was ideal to fit the prediction result of drug release;the optimal formulation according to Design-Expert8.0.5 software was established as follows：50 mg of glucose,8% of pore former,9% of coating weight.The f_2 was approximate 89.33 compared with ideal drug release curve,which was relatively close to the model-predicted f_2value（88.89）.Through investigation of permeation mechanism,it was found that the drug release from this delivery system was driven by osmotic pressure difference between the interior of tablets and the release medium.By means of SEM observation,it was shown that some pores on the coating surface were produced after drug release in the medium,but few before drug release,which cued that a lot of medium got into the interior of tablets through the tunnels formed by the porogen in the coating.CONCLUSION Box-Behnken design method can be used to optimize the formulation of sandwich osmotic pump tablets.