马西替坦片剂的研制及质量评价

Preparation and Evaluation of Macitentan Tablets

以自制马西替坦片和原研制剂(Opsumit)在含0.1%十六烷基三甲基溴化铵(CTAB)的pH 6.8磷酸盐缓冲液中溶出曲线的相似因子f_2为主要考察指标,片剂的性质(如颗粒流动性、崩解时间等)为辅助指标,采用单因素试验和正交设计筛选了马西替坦片片芯的最优处方,即过200目筛的原料药30 g,一水乳糖116.9 g,聚维酮K30 6.6 g,微晶纤维素和羧甲淀粉钠在制湿颗粒前加入11.7和4.2g,在整粒后加入剩余的35.1和4.2 g,黏合剂采用0.2%Tween-80溶液。经包薄膜衣后得到3批优化自制片,与原研制剂相比,在pH 1.0盐酸、pH 4.5乙酸盐缓冲液、pH 6.8磷酸盐缓冲液及水中溶出曲线的相似因子(f_2)值均大于65。影响因素试验结果显示自制片具有较好的稳定性。

The formulation of macitentan tablets was optimized by single factor test and orthogonal design with the similarity between the dissolution curves of the self-made tablets and the reference listed drug （Opsumit） in pH 6.8 phosphate buffer containing 0.1% cetyltrimethyl ammonium bromide as the main index, and the qualities of tablets, such as flowability of particles and disintegration time, as the auxiliary indexes. The optimal formulation of core tablets were as follows： the active pharmaceutical ingredient （API） should be pretreated by passing through 200-mesh sieve and its amount was 30 g; the amounts of lactose monohydrate and povidone K30 were 117 and 6.6 g; microcrystalline cellulose and sodium carboxymethyl starch were added partly prior to wet granulation （11.7 and 4.2 g） and partly after size stabilization process （35.1 and 4.2 g） ; the adhesive was 0.2 % Tween-80 solution. After a thin-layer coating, three batches of self-made tablets were obtained. The similarities of dissolution curves between the self-made tablets and Opsumit in pH 1.0 hydrochloric acid, pH 4.5 acetate buffer, pH 6.8 phosphate buffer and water were evaluated, and the calculated similarity factor （f2） values were all above 65. The results of stress test showed that the product was rather stable.