星点设计-效应面法优化氢氯噻嗪盐酸可乐定复方缓释制剂处方

Optimization of compound hydrochlorothiazide/clonidine hydrochloride sustained-release preparation by central composite design/response surface methodology

目的:应用星点设计-效应面法优化氢氯噻嗪盐酸可乐定复方缓释制剂的处方。方法:以HPMC K100M和Carbopol 934的用量为考察因素,分别以氢氯噻嗪和盐酸可乐定在1,4,8,12h的累积释放度和黏附力为指标采用线性方程和二次、三次多项式分别描述各时间点累积释放度及黏附力与两个影响因素之间的数学关系,根据最佳数学模型绘制效应面图。各时间点的效应面二维等高线图最佳释放区域的重叠部分与黏附力的交集区域即为最佳处方区域,选择最佳处方,并进行预测分析。结果:采用二次、三次多项式拟合的相关系数优于线性方程,具有较高的可信度。最优处方为氢氯噻嗪片中HPMC K100M和Carbopol 934的含量分别为片重的17%和16%,盐酸可乐定片中上述两者的含量分别为片重的60%和18%。最佳处方在各时间点的释放度和黏附力的理论值与预测值的偏差均在±6%以内。结论:通过星点设计-效应面优化法建立的模型可以用于氢氯噻嗪盐酸可乐定复方缓释制剂处方的优化。

Aim： To optimize the formulation of compound hydrochlorothiazide/clonidine hydrochloride sustainedrelease preparation by central composite design/response surface methodology. Methods： The independent variables were the amount of HPMC KIOOM and Carbopol 934; and the dependent variables were the dissolution of hydrochlorothiazide and clonidine hydrochloride at 1 h, 4 h, 8 h, 12 h, and adhesive property of tablets. Linear or nonlinear mathematic models were used to estimate the relationship between the independent and the dependent variables. Response surface was delineated according to the best-fit mathematic models. The 2D-contour map of dissolution at each of intervals and adhesive property were overlapped, and the optimized formulations were selected from the overlap of the best release districts and adhesive property. Prediction was assessed by comparing the observed and predicted values. Results： Regression coefficients of second-order and third-order quadratic models were higher than first-order model. Optimized formulation of hydrochlorothiazide tablets was propose to consist of 17% HPMC K100M and 16% Carbopol 934; and clonidine hydrochloride tablets of 60% HPMC K100M and 18% Carbopol 934. Bias between the observed and predicted values was within ± 6%. Conclusion： It shows that the established model is suitable for compound hydrochlorothiazide/clonidine hydrochloride sustained-release preparation.