D-最优混料设计优化格列吡嗪pH非依赖型缓释片的处方

Optimization the formulation of pH-independent sustained release tablets of glipizide using D-optimal mixture design

目的通过D-最优混料设计优化格列吡嗪pH非依赖型缓释片的处方。方法以HPMC K4M、HPMC K100LV、MgO、乳糖、无水Ca HPO4的用量为影响因素,分别以缓释片在2、8、24 h的药物累积释放率,在pH 6.8及pH 1.2溶出介质中释药行为的相似性(f2)为评价指标,选用最佳的数学模型定量描述评价指标和影响因素之间的关系;以设定的目标值,通过D-最优混料设计试验预测最优处方,再对最优处方进行验证。采用不同的释药模型对体外释药数据进行拟合,确定药物释放的机制;采用酸碱指示剂法表征缓释片内部pH值。结果数学模型拟合及回归分析结果表明,5个影响因素和4个指标之间存在可信的定量关系;优化处方的体外释放的实验值与预测值经验证非常接近,误差在可接受范围内(指标Y1除外)。优化处方制得的缓释片,药物释放不受pH影响;药物释放机制由扩散与骨架溶蚀共同作用;缓释片内部pH表征结果表明,缓释片内部能在较长时间保持pH>6.2的水平。结论 D-最优混料设计可用于格列吡嗪pH非依赖型缓释片处方的优化,所建立的数学模型具有准确的预测性。

Objective To optimize the formulation of pH-independent sustained release tablets of glipizide by D-optimal mixture design. Methods The content of HPMC K4M,HPMC K100LV,MgO,lactose and CaHPO 4 was the independent variances,and the cumulative drug release within 2,8,24 h and the similarity of drug release behaviors in pH 6.8 and pH 1.2 dissolution media were the dependent variances. Optimal mathematical models were chosen to estimate the relationship between the dependent and the independent variables. The optimal formulation was predicted by D-optimal mixture design with the target value of dependent variances. The drug release mechanism was confirmed by fitting the drug release data into different models. The inner pH of the tablets was characterized by pH indicator method. Results Reliable quantitative relationships between five factors and four evaluation indexes were found. There was high approximation between the predicted and experimental value of the in vitro release study of optimal formulation. The errors of four evaluation indexes were acceptable except Y 1 . The in vitro release of the optimal formulation was pH independent. The drug release mechanism was controlled by diffusion and erosion. The result of the characterization of the inner pH of the tablets indicated that the pH of the inner tablets was maintained at the level of greater than pH 6.2 within long time. Conclusion D-optimal mixture experimental design facilitated the optimization of pH independent sustained release tablet of glipizide. The models are proved to have the ability of high prognostic and feasible.