Studies On Trimetazidine Hydrochloride Sustained Release Tablets

Cardiovascular and cerebrovascular diseases are frequently encountered,the incidence of which is increasing by year,a serious threat to human health and lives.Angina is a common-seen cardiovascular and cerebrovascular disease,one of coronary heart disease with highest incidence,and the study of sustained-release preparation of its curatives gets a lot of attention.Trimetazidine hydrochloride belonging to other kind of anti-angina drugs,is the first to act on the cardiac cell metabolism,playing a direct role in protecting cells by making the energy metabolism of the heart rational.Trimetazidine hydrochloride is widely used as anti-angina drug,and the research and development of its preparation has good market prospects and value.Trimetazidine hydrochloride was used as a model drug in this topic.Trimetazidine hydrochloride sustained-release tablets were prepared and turned into industrial production.Four aspects were included in the study:establishment of in vitro analysis methods,preparation and quality evaluation,in vitro release and stability studies,and in vivo kinetics study in beagles.1.Establishment of in vitro analysis methodsUV spectrophotometry was established for the release determination and formulation intermediates content determination and HPLC was established for the content determination and related substances determination.The methodology of UV spectrophotometry was validated by specificity,linearity and range,precision,accuracy,etc.The methodology of HPLC was validated by specificity,limit of detection and quantitation limit,linearity and range,precision,accuracy,durability,etc.The methods for determination of release,content and related substances and the corresponding quality requirements were also formulated.The results showed that UV spectrophotometry for release determination and intermediates content determination was specific with no interference of excipients,showing good linearity within the appropriate concentration range of four media(0.1 M HCl?pH4.5 PBS?pH6.8 PBS and water),with good precision of the reference or test solutions and high accuracy on the basis of recovery determination meeting with the requirements.HPLC for content determination and related substances determination was specific with good system suitability and durability,showing good linearity within the appropriate concentration range of each impurity and trimetazidine hydrochloride,with good precision of the reference or test solutions and high accuracy on the basis of recovery determination meeting with the requirements.In quality criteria,water was used as release medium,and the amount of drug released should be 20?40%?40?60%and over 80%of the labelled amount for 1h,2h and 8h,respectively.The content of tablets should be 95%-105%of the labelled amount.For related substances,impurity 1 and impurity 4 should no more than 0.2%,impurity 2 should no more than 0.5%,impurity 3 should no more than 1.0%,unknown single impurity should no more than 0.2%,total impurities should no more than 1.0%,all should meet with the requirement.Analytical methods validation results showed that the established analytical methods were suitable for the corresponding testing requirements.The formulated methods for determination of release,content and related substances and the corresponding quality requirements were scientific and rational,good for the quality evaluation of Trimetazidine hydrochloride sustained-release tablets.2.Preparation and quality evaluationThe dissolution profile similarity factor f2 of self-made tablets and marketed tablets was used as the evaluation index.The single factor test was performed on kind and content of HPMC,kind and content of blocking agents,kind and content of loading agent,adhesives,lubricants,etc.Content of HPMC,blocking agents and loading agent were selected as three factors in orthogonal experiment for the prescription optimization.The prescription was adjusted while turning to production process.The prescription suitable for industrial production was finally obtained.The tablets were pink with film-coated.Tablet weight difference complied with the limits of ±7.5%.The release profile in vitro of self-made tablets and marketed tablets was similar(f2>50),and the release curves of self-made tablets in four media were similar with each other.The release homogeneity of self-made tablets for one batch or between-batchs was good.The content for three batches were 98.55%?100.26%?99.90%,respectively.Impurity 1,impurity 2 and impurity 4 were not detected,and the content of impurity 3 was 0.010%?0.021%?0.011%,biggest single impurity 0.007%?0.008%?0.007%and total impurities 0.017%?0.029%?0.018%.All the determination results meet with the quality requirements.3.In vitro release and stability studiesZero-order model,first-order model,Higuchi model and Ritger-Peppas model were choosed to fit the release profile of trimetazidine hydrochloride sustained-release tablets in four medium to study the release feature and release mechanism.Influential factor tests were carried out under the following conditions:high temperature(60?),strong light(45001x)and high humidity(RH75%and RH92.5%).The stability studies of pro-commercially packaged formulations were conducted through accelerated test(temperature 40?,RH75%)and long-term test(temperature 25?,RH60%).Results showed that the in vitro release profile was fitted with first-order model,Higuchi model and Ritger-Peppas model well,and trimetazidine hydrochloride was released from sustained-release tablets by the synergistic effect of diffusion and erosion skeleton,with diffusion serving as the main release way.Results of influential factor tests showed that trimetazidine hydrochloride sustained-release tablets were sensitive to temperature,humidity and light,indicating that special attention should be paid to the moisture resistance and seal of the product packaging materials,and sustained-release tablets should be placed at dark,cool and dry place.The stability of accelerated test and long-term test of this product was good.4.In vivo kinetics study in beaglesMarketed tablets and self-made tablets were used as reference tablets and test tablets.Two-cycle two-preparation crossover design was conducted in beagles to study the drug kinetics.Results showed that compared with reference tablets,Cmax of test tablets was lower,tmex was longer,and MRT0?t was longer,but with no significant difference.Average of relative bioavailability was 102.52%based on AUC0?t and 109.27%for AUC0??.AUC0?t?Cmax could meet with the requirement for group bioequiavailability and tmax with no significant difference.All results showed that test tablets and reference tablets were bioequivalent.Conclusion:Scientific methods were established in this paper for the quality research of trimetazidine hydrochloride sustained-release tablets.Methods for determination were feasible and quality requirements were scientific and reasonable.Trimetazidine hydrochloride sustained-release tablets with acceptable qualities were successfully prepared,having been transformed into industrial production,which achieving the designed task.In vitro release feature was consistent with theoretical speculation.Influential factor tests provided references for the preparation,packaging and storage of the production,and accelerated test and long-term test provided a basis for the period of validity for the formulation.Test tablets and reference tablets were bioequivalent.This research could provide the basis for the development of other generic drugs for its good application and market prospects,with high theory and research value.