西尼地平缓释片的处方优化及释药机制研究

Study on Formulation Optimization and Drug-release Mechanism of Cilnidipine Sustained-release Tablet

目的:优化西尼地平缓释片处方,研究其释药机制。方法:采用溶剂法制备西尼地平固体分散体,再以羟丙甲纤维素K4M(HPMC K4M)为缓释材料制备西尼地平缓释片。利用单因素法和Box-Behnken响应面法,以2、6、12 h累积释放度的综合评分为指标,筛选西尼地平缓释片处方中HPMC K4M用量、乙基纤维素(EC)用量、乳糖-微晶纤维素(MCC)比例,并进行验证。通过模型拟合的方式考察西尼地平缓释片的释药机制。结果:最优处方为西尼地平固体分散体25%、HPMC K4M 30%、EC 10%、乳糖-MCC(1∶1,m/m),黏合剂为5%的聚乙烯吡咯烷酮乙醇溶液,润滑剂为0.5%的硬脂酸镁。所制缓释片2、6、12 h时的累积释放度分别为(21.4±3.3)%、(62.9±2.8)%、(85.4±0.5)%(n=3),与预期值25%、60%、90%的相对误差分别为14.4%、4.8%、5.1%;释放曲线与一级释药模型拟合度最高,符合non-Fick扩散机制。结论:按优化后的处方成功制得具有缓释作用的西尼地平缓释片。

OBJECTIVE： To optimize the formulation of Cilnidipine sustained-release tablet, and study its drug-release mecha- nism. METHODS： Solvent method was adopted to prepare the cilnidipine solid dispersion, then Cilnidipine sustained-release tablet was prepared by using hypromellose K4M （HPMC K4M） as release material. Using comprehensive scores of cumulative release degree in 2, 6, 12 h as indexes, single factor method and Box-Behnken response surface method were used to screen the amounts of HPMC K4M and ethyl cellulose （EC）, lactose-microcrystalline cellulose （MCC） ratio in formulation of Cilnidipine sustained-release tablet, and verification test was conducted. The drug-release mechanism of Cilnidipine sustained-release tablet was investigat- ed by model fitting way. RESULTS： The optimal formulation was as follow as 25% of cilnidipine solid dispersion, 30% of HPMC K4M, 10% of EC, lactose-MCC ratio of 1 ： 1 （m/m）. The adhesive was 5% PVPP ethanol solution and the lubricant was 0.5% magnesium stearate. The cumulative release degrees of prepared sustained-release tablet in 2, 6, 12 h were （21.4± 3.3）%, （62.9 ± 2.8）%, （85.4± 0.5）% （n=3）, relative error of which to predicted value 25%, 60%, 90% were 14.4%, 4.8% and 5.1%. Release curve showed the highest fitting degree with the first-order release model, conforming to non-Fick diffusion, CONCLUSIONS： Cilnidipine sustained-release tablet with sustained-release effect is successfully prepared by optimized formulation.