Quality Consistency Evaluation Of Cefaclor Extended-release Tablets

The consistency evaluation of the quality and efficacy of generic drugs is a research hotspot in the domestic pharmaceutical industry at the current stage,and it is also a focus of attention in the entire society.China is a big country of generic drugs,but it is not powerful.The quality of generic drugs is uneven,which seriously affects the safety and efficacy of drugs.For the extended-release preparations with higher requirements for prescription technology,the quality problems are more prominent.This study selects cefaclor extended-release tablets as the object of quality consistency evaluation,looking for the possible causes of differences in the efficacy of generic drugs and original drugs,seeking to control key quality attributes,helping production companies to identify problems,solve problems,and improve the clinical safety and efficacy of generic drugs.The main research content is as follows:On the basis of investigating the national pharmacopoeia methods,a new method for the inspection of related substances with better resolution was established and a methodological validation was conducted.UPLC-QTOF method was used to isolate and identify the 11 impurities that were produced under strong degradation condition,and speculate its fragmentation pathways and chemical structure.In addition,the compatibility between API and excipients,and pharmaceutical packaging materials were investigated.The results showed that the compatibility between API and excipients is good.The pharmaceutical packaging materials play an indispensable role in reducing the generation of impurities,impurities increased by average of 0.5%over10 days without avoiding light,the increase is significant.It is recommended to use light-proof packaging materials.A discriminative release method was developed for cefaclor extended-release tablets.It provided a very important in vitro release condition for the production companies to screen out the formulation preparation method which conformed to the requirements of national generic drug quality and conformance standard.In addition,the release behavior of cefaclor extended-release tablets was studied in a variety of pH release media,comparative analysis of the similarity of the generic cefaclor extended-release tablets'release curve with that of the original research pieces was performed,screening out the new process drug of company A which is similar to the original drug in vitro release behavior,f₂ ware 63?75?81 in three media.Simultaneous analysis of cefaclor extended-release tablets from other companies was performed.The results show that the f₂ factor of the three enterprises is less than 50,which is not similar to the original drug.Through the GastroPlus^TM simulation software,using literature data,a series of in vivo absorption of cefaclor model was established,and through the verification.Screening out the release method that may be related with the release curve in vivo.And based on the release curve determined in this release conditions and GastroPlus^TM model with cefaclor extended-release tablets speculating bioequivalence between original drug and generic drug and predicting the absorption of them.The computer obtained that the fitting results?R²?of prediction results and actual measurement results of A company's new process drugs and B companies'drugs were0.98 and 0.96,the fitting error?RMSE?was 0.27 and 0.40.To further verify both A company's new process drugs and B companies'drugs were likely to be bioequivalent with original drugs.At the same time,the simulation results show that the main absorption site of cefaclor is the intestinal tract,and its absorption value accounts for about 43.2%.According to the results of computer simulations and related literature,the main absorption of cefaclor extended-release tablets was intestinal,therefore,the release status of cefaclor extended-release tablets in the intestinal environment?pH 6.8?was studied and compared with the release status of the original drug.The results showed that both the new process drug of company A and original drug can maintain a high drug concentration in the medium with a pH value of 6.8,and further verify that the new processs drug of company A and the original drug may be bioequivalent.It is suggested that the formulation process has a great influence on drug release and drug efficacy.Each generic company needs to strengthen the research on the original drug technology and improve the quality and efficacy of generic drugs.Finally,by examining the pharmacokinetic characteristics of the new process drug of company A and original drug in beagle dogs,the bioequivalence was evaluated,the results of A company's new process drugs ware:T_max=?3.7±1.2?h,C_max=?17.6±5.2??g/mL,AUC_last=?71242.7±16503.0??g/L·h;The results of B company'sdrugsware:T_max=?3.2±0.8?h,C_max=?19.1±6.4??g/mL,AUC_last=?70839.9±16832.5??g/L·h,the confidence interval of each parameter is within the equivalent range of 80.00%-125.00%.Results once again verified that the new process drug of company A was equivalent to the original drug from the animal's body perspective.Through the comparison of impurity spectrum,in vitro release,computer simulation,and bioequivalence in animal body,evaluating the quality consistency of a company's new process drug and original drug comprehensively,and providing a fast,effective and economical technical means and important guarantee for improving the clinical human body bioequivalence test pass rate.