Box-Behnken效应面法优化盐酸普拉克索缓释片处方及体外释放机制

通过单因素试验筛选盐酸普拉克索缓释片处方，采用Box-Behnken效应面法优化处方并制备盐酸普拉克索缓释片。单因素试验考察羟丙基甲基纤维素(HPMC)不同型号、不同用量及与不溶性缓释材料组合使用对盐酸普拉克索缓释片体外释放度的影响。确定以HPMC K100M、Eudragit RSPO、Eudragit L100为主要考察因素，以不同时间的累积释放度为评价指标。Box-Behnken效应面法优化处方得出三者的最优范围，以其中优选处方HPMC K100M 101.5 mg、Eudragit RSPO 98 mg和Eudragit L100 13.7 mg和其他辅料制备盐酸普拉克索缓释片并考察释放度。通过相似因子计算，优选处方的体外累积释放度预测值和实测值相似度均大于80。对体外释药数据进行方程拟合，探讨其释药机制，Eudragit RSPO促进盐酸普拉克索的释放，Eudragit L100阻滞盐酸普拉克索的释放，二者互为拮抗作用。结果表明，该处方制备的普拉克索缓释片pH依赖性小，体外释放行为稳定，实现了该缓释片的处方优化。

Optimization of pramipexole hydrochloride sustained-release tablets using Box-Behnken design and mechanism of in vitro drug release

The formulations of pramipexole hydrochloride sustained-release tablets were screened by single factor test and optimized by Box-Behnken design. The effects of the viscosity and content of hydroxypropyl methyl cellulose, as well as the insoluble sustained-release material combined with HPMC K100M on the in vitro release behavior were investigated. After single factor screening, a three-factor, three-level Box-Behnken design was used for optimization using the contents of HPMC K100, Eudragit RSPO and Eudragit L100 as independent variables, and the cumulative release at different time as responses. The optimal range of the three-factor optimized by Box-Behnken design, one of the optimized formulations was achieved with HPMC K100M of 101. 5 mg, Eudragit RSPO of 98 mg, and Eudragit L100 of 13. 7 mg, and the observed responses of the optimized formulation were very close to the predicted values. The in vitro drug release mechanism of the tablet was studied by drug released model fitted with different equations. The results explained that Eudragit RSPO promoted the release of the pramipexole hydrochloride, while Eudragit L100 blocked the release, and there was an antagonism between them. In conclusion, the drug release behavior of optimized formulations prepared by Eudragit RSPO/L100 was stable, less pH-dependent, which improved the drug bioavailability in vivo.