Evaluation Of Quality Consistency Of Tamsulosin Hydrochloride Sustained Release Capsules And Fenofibrate Tablets By Bioequivalence Test And In Vitro Simulation Technology

In order to comprehensively improve the quality of generic drugs and ensure their consistent therapeutic effects with the reference drugs,the Chinese pharmaceutical industry is focusing on the evaluation of quality consistency of generic drugs.Bioequivalence test is the gold standard for assessing the quality consistency of generic drugs,but it is time-consuming,laborious,costly and involving ethical issues.If the in vivo absorption characteristics of the drug can be accurately predicted through adequate in vitro simulation techniques,The bioequivalence test can be performed after optimizing the prescription through the software.the success rate of bioequivalence tests will be greatly increased,and even the drug can be recommended for a biowaiver.In this study,tamsulosin hydrochloride and fenofibrate were used as model drugs,and the bioequivalence tests of relevant preparations were conducted.Gastroplus software was used in combination with the basic physicochemical properties of drugs and in vitro dissolution results to simulate the in vivo absorption data and establish in vitro and in vivo correlation with measured data.Part one Bioequivalence study of tamsulosin hydrochloride sustained bioequivalence study by Gastroplus softwareObjective:It is to evaluate the bioequivalence of two tamsulosin hydrochloride sustained-release capsules in Chinese healthy adults,and to predict in vivo absorption by Gastroplus software combined with in vitro dissolution results and to explore the value of in vitro simulation techniques in predicting bioequivalence.Methods:1. The bioequivalence study was conducted in six healthy male volunteers after an oral dose of 0.2 mg tamsulosin hydrochloride sustained-release capsules in fed condiction according to a randomized,open,two-cycle,two-cross trial design.Plasma samples were extracted with methyl tert-butyl ether and analyzed by LC-MS/MS;pharmacokinetic parameters calculation and bioequivalence evaluation were performed with Winnolin 6.4software.2.In vitro release behaviors of tamsulosin hydrochloride sustained release capsules A and B were investigated by slurry method using p H 1.0hydrochloric acid（0-2 h）-p H 6.8 phosphate（2-24 h）as media.The similarity of dissolution curves was evaluated by similar f₂ factors.3.Gastroplus software based on the physiological pharmacokinetic model,combined with in vitro release results were used to simulate the absorption in vivo and establish in vitro and in vivo correlation.Results:1. The main pharmacokinetic parameters of 6 healthy subjects after an oral dose of 0.2 mg tamsulosin hydrochloride reference A and test B sustained-release capsules were as follows:t_max were（6.5±1.6）and（5.0±1.7）59.1)ng·h·m L^-1.The 90%confidence intervals for the geometric mean ratios of C_max and AUC_{0-48 h} were:138.2%to 157.1%and 100.1%to 125.5%.2.The in vitro release behavior of tamsulosin hydrochloride reference preparation A and test preparation B in p H 1.0 hydrochloric acid（0-2 h）-p H6.8 phosphate（2-24 h）medium were significantly different.The dissolution of tamsulosin hydrochloride A sustained-release capsules reached 90.4%of the labeled amount within 24 hours,and the dissolution of test B sustained-release capsules reached 97%of the labeled amount within 10 hours.3.A good correlation between the simulated in vivo absorption data and the measured in vivo data was developed by Gastroplus software.A good in vitro and in vivo correlation was established between the in vitro dissolution and in vivo dissolution data by the deconvolution integral method.The is in vivo release data.Part two Healthy adults bioequivalence test,in vitro dissolution test and in vivo and in vitro correlation of fenofibrate tabletsObjective:It is to evaluate the bioequivalence of two fenofibrate tablets in Chinese healthy adults,the quality consistency of the relevant formulations was evaluated.and to predict in vivo absorption by Gastroplus software combined with in vitro dissolution results and make a correlation study between the prediction data and the measured data to explore the value of in vitro simulation techniques in predicting bioequivalence.Methods:1. The bioequivalence of fenofibrate tablets was conducted in 24 healthy volunteers according to a randomized,open,two-cycle,two-cross trial design after an oral dose of 160 mg fenofibrate tablets in fasting and fed state,respectively.Plasma samples were processed by protein precipitation with methanol,then fenofibric acid was determined by LC-MS/MS;the pharmacokinetic parameter calculation and bioequivalence evaluation were completed by Winnolin 6.4 software.2. In vitro release behaviors of reference preparation R and five test preparations（T1-T5）in two dissolution media(2%Tween 80,0.025 mol·L^-1SDS)were investigated by slurry method.3. Gastroplus software were used to simulates the in vivo absorption characteristics of fenofibrate tablets based on physiological pharmacokinetic model and the food effect on the absorption of the preparations were investigated.Results:1.The main pharmacokinetic parameters of reference（R）and test（T1）fenofibrate tablets in 24 healthy volunteers after an oral dose of 160 mg inμg·h·m L^-1,The 90%confidence intervals for the geometric mean ratios C_maxand AUC_{0-96 h} were:121%-146.6%and 100.8%-118.9%,respectively.2.The main pharmacokinetic parameters of reference（R）and test（T1）fenofibrate tablets in 24 healthy volunteers after an oral dose of 160 mg in fed90%confidence intervals for geometric mean ratios of C_maxand AUC_{0-96 h}were:88.6%-104.1%and 96.0%-106.7%,respectively.3. When sampled at 60 min,two of the five test preparations（T1 and T2） showed similar dissolution to the reference preparation and were in compliance with the requirements of the Chinese Pharmacopoeia.While other three preparations（T3,T4 and T5）have poor dissolution rate in the above dissolution medias.The dissolution rate values at 60 min were 53.9%,58.7%and 74.62%in 0.025 mol·L^-1 SDS media,and 51.5%,50.6%and 56.52%in2%Tween 80 media,respectively.Conclusions:1.Tamsulosin hydrochloride sustained-release capsules A and B are not bioequivalent in healthy adult volunteers after an oral dose of 0.2 mg under feding state;The release behaviors of two tamsulosin hydrochloride sustained-release capsules are significantly different in p H 1.0 hydrochloric acid（0-2 h）-p H 6.8 phosphate（2-24 h）dissolution media.The dissolution rate of reference A is slower than test capsules B,which is consistent with the in vivo absorption characteristics.2.The in vitro dissolution results of tamsulosin hydrochloride sustained-release capsules in p H 1.0 hydrochloric acid（0-2 h）-p H 6.8phosphate（2-24 h）can accurately predict the in vivo absorption and virtual bioequivalence by Gastroplus software.The fit between the measured value and the predicted value is great.3. The tested（T1）and reference fenofibrate tablets are not bioequivalent in healthy adult volunteers after an oral dose of 160 mg under fasting state,but bioequivalent under feding state.The absorption of fenofibrate in healthy volunteers under the fed state is better than that under fasting state.4. The dissolution results in the media of 2%Tween 80 and 0.025 mol·L^-1SDS solution can reflect the quality of fenofibrate tablet to some extent.If two fenofibrate tablets dissolute completely within 60 min,they will have large possibility of bioequivalence.