Quality Consistency Evaluation Of Domestic Clarithromycin Sustained-release Tablets

Consistency evaluation of generic drugs is the current research focus,it is also the social hot spot,the quality of generic drugs has aroused widespread concern.The production of generic drugs in China is very large,but the quality of generic drugs is variable that affects greatly the drug's safety and efficacy,especially for the preparation process demanding an extended release formulation,the problem is even more pronounced.The topic selected domestic clarithromycin extended release tablets as a quality consistency evaluation study,looking for the fundamental reason which will result in the huge quality gap between the generic drugs and the original drug,seeking the critical to quality(CTQ)to help pharmaceutical manufacturers find and solve problems,improve generic drug's clinical safety and efficacy.The main contents are as follows:Clarithromycin(API + extended-release tablets)of the impurity profile has been studied,and the use of high-resolution mass spectrometer for the structural analysis of each impurity.The results show that the impurity profiles of different manufacturer's formulations have significant differences,including the type and content of impurities.In addition,the antibacterial activity and toxicity of the two impurities of N-oxidation impurity and acid degradation impurity(impurity I)were studied,preliminary results showed that the two no antibacterial activity,no cytotoxicity.From the angle of the prescription and technology to find reasons for the differences in the content of impurity I,the analysis and test results show that it is likely to be prescription acidic materials in the preparation or storage process,to clarithromycin occurs degradation,suggesting that it be prescription optimization.The release behavior of clarithromycin extended-release tablets in a variety of solvents were studied,and comparative analysis of the similarity of the domestic tablet's release profile with that of the original research pieces were performed,the results showed that each curve of domestic and original tablets was not exactly similar,in other words,in vitro release behavior was inconsistent,release mechanism similar inquiry results also draw the same conclusions.Combined with prescription information,the related experiments,found that the presence of acidic materials accelerated the dissolution of clarithromycin;homogeneity of HPMC will affect drug release.Using of Gastro Plus software,which can simulate in vivo absorption behavior of the drug,established clarithromycin intravenous,oral ordinary tablets,capsules,suspensions and other basic models by the physical and chemical parameters,PK parameters of the drug.Based on physiological parameters determined by the base model,successfully established in vivo PK model of clarithromycin extended-release tablets.By deconvolution calculation,got the release profile of clarithromycin extended release tablets in the human body.The curve tested dissolution methods in vitro,the correlation of A-level is poor,suggesting that in vitro dissolution methods need to be optimized.Further analysis of the results,suggesting increase speed or adding a surfactant can be used as the direction of improvement.