美沙拉秦缓释片中羧甲纤维素钠的关键质量属性辨识和控制

Identification and Control of Critical Quality Attributes of Carboxymethylcellulose Sodium in Mesalazine Sustained-release Tablets

本研究检测了4个厂家生产的羧甲纤维素钠(CMC-Na)的各项物理指标,再用其制备美沙拉秦缓释片,评价自制美沙拉秦缓释片与原研制剂体外释放曲线的相似因子(f2)。采用正交偏最小二乘(OPLS)法建立CMC-Na物理指标与f2值的关联模型。通过多变量统计建模方法,以变量投影重要性为指标筛选出CMC-Na潜在的关键质量属性(CQAs),并确定为松密度、重均分子量、振实密度、比表面积。通过绘制上述4个CQAs与f2值的响应面图,求得设计空间。结果表明,CMC-Na的松密度>0.51732 g/cm^3、重均分子量>644710 g/mol、振实密度>0.79387g/cm^3和比表面积>0.659 m^2/g时,自制美沙拉秦缓释片与原研制剂体外释放曲线的f2值可达到50,即体外释放行为相似。这为今后仿制药研发过程中辅料的筛选提供了依据,有助于使药物研发过程更加明确、可控。

In this paper,various physical parameters of carboxymethylcellulose sodium(CMC-Na)from four different manufacturers were investigated,and the mesalazine sustained-release tablets with CMC-Na from different manufacturers were prepared.The release similarity between the self-made sustained-release tablets and reference listed drug(RLD)were also evaluated by the similarity factor(f2)method.Then,orthogonal partial least squares(OPLS)was adopted to establish a correlation model between physical parameters of CMC-Na and f2 values.Thereby,the potential critical quality attributes(CQAs)for CMC-Na were screened by multivariate statistical modeling with variable importance in the projection(VIP)as the index.According to the results,the bulk density,weight-average molecular weight,tap density and specific surface area were identified as the CQAs for CMC-Na in mesalazine sustained-release tablets.Then,the response surface plots of f2 values versus above four CQAs were drawn to find the design space.The results showed that the f2 value between RLD and the self-made sustained-release tablets containing CMC-Na with bulk density>0.51732 g/cm^3,weight-average molecular weight>644710 g/mol,tap density>0.79387 g/cm^3 and specific surface area>0.659 m^2/g reached 50,indicating their release consistency in vitro.This study provides a basis for future research and development of generic drugs.The drug development process would be more clear and controllable.