Preparation And Bioequivalence Of Nitrendipine Tablets

Nitrendipine is a selective calcium channel antagonist,which is commonly used in the treatment of hypertension,and also in the treatment of coronary heart disease and congestive heart failure.The reference tablets used in this study is nitrendipine tablets produced by Bayer,Germany,with a content of 10 mg per tablet.It has not been listed in China at present,and there is no nitrendipine tablets that has passed the bioequivalence evaluation of generic drugs in China.Nitrendipine is BCS 2 class of drugs in the classification system of biopharmaceutics.It has the characteristics of low solubility and high intestinal permeability,and its release performance between in vivo and in vitro environments is poorly correlated.The purpose of this study is to evaluate the preparation in vitro and in vivo through an efficient quality evaluation method,and to screen high-quality prescriptions and preparation processes.Part ? Preparation of nitrendipine tablets and formulation of production processObjective: Analyze the formula of the reference drug.Select the appropriate formula and processes based on the similarity between the dissolution curve of self-made nitrendipine and the reference.At the same time,ensure that the content of impurity I in nitrendipine does not exceed the limit.Method:1.Determine the main ingredients,dosage and particle size of API in the prescription of reference preparation by pre-experiment.2.Nitrendipine tablets are prepared by wet granulation.Whether the reference preparation used co-grinding method or solid dispersion technology or not shell be verified by experiments.Results: According to the prescription selection,the optimal prescription of nitrendipine tablets is determined as follows:The process parameters is: drying temperature at 60?,drying time 4 h.The tablets weight is 82.6 mg,the pressure is 15 k N,the hardness of tablets is 4 6 kg / cm²,and the diameter is 6 mm.Conclusion: The appearance,microcosmic morphology and dissolution curve of self-made nitrendipine tablets are similar to reference.The preparation process of nitrendipine tablets is simple,stable and reliable.And the reproducibility of three batches of preparations are good.Part ?: Establishment of in vitro analytical method of nitrendipine tabletsObjective: According to the properties of nitrendipine and the data of previous studies,a simple and discriminative evaluation method of dissolution analysis in vitro should be established with good reproducibility and correlation in vitro and in vivo.Ensure the controllability of preparation quality on the premise to establish an appropriate analytical method for the content of impurity and content of drugs.Method:1.In vitro dissolution method: paddle method,100 RPM.Dissolution medium: 37?,900 ml.The four dissolution media are as follows:Aqueous solution containing 0.15% Tween 80Hydrochloric acid solution containing 0.15% Tween 80 at p H=1.2Phosphate buffer containing 0.15% Tween 80 at p H=6.8Acetate buffer containing 0.15% Tween 80 at p H=4.02.Analysis method of dissolution sample in vitro: UV-VIS method,? = 358 nm.3.Determination of drug content and related substances: HPLC-UV method,detection wavelength ? = 237 nm.Result:1.A method of dissolution of nitrendipine tablets in vitro is established.The method is simple and discrimination between the reference preparation and the self-made preparation is enough.It can be used for the prescription screening of the self-made nitrendipine tablets.2.A method for the detecting of nitrendipine tablets dissolution samples in vitro is established.The method is simple and rapid,and the adsorption,reproducibility,linearity,precision,stability and recovery are good.It can be used to detect the samples of nitrendipine tablets dissolution.3.A method for the detecting content of nitrendipine in nitrendipine tablets is established.The applicability,specificity,linearity,precision,repeatability,reproducibility,solution stability,durability and recovery of the method are good.It can be used to analyze the content of nitrendipine tablets.4.A method for the detecting of impurity in nitrendipine tablets is established.The system applicability,specificity,linearity,repeatability,solution stability and recovery of the method are all good and the detection limit is low.It can be used to analyze the content of related substances in nitrendipine tablets.Conclusion: The in vitro detection method of nitrendipine tablets established in this experiment is simple,rapid and reliable.The drug content and related substances of three batches of nitrendipine tablets meet the requirements of China Pharmacopoeia.The dissolution curve is similar to the reference preparation.Part ? Study on the stability of nitrendipine tabletsObjective: Study the change of dissolution curve and impurity with time under the influence of different temperature,humidity and light.It can provide reference for the production,packaging and storage of drugs.Methods: The influencing factors test and accelerated test are tested on the self-made tablets.Then the samples are evaluated in vitro.1.Influencing factor test:High temperature test: place the sample at the environment at 40? and 60?,and take samples on the 5th and 10 th day.High humidity test: put the sample in the environment at RH 92.5% and Rh 75%,and take samples on the 5th and 10 th day.Strong light exposure test: place the sample in 4500 lx light environment,and take samples on the 5th and 10 th day.2.Accelerated test: place at 40?,RH 75% for 6 months,and take samples at the first,second,third and sixth months.Result:1.The dissolution,drug content and impurity of nitrendipine tablets meet the requirements under high temperature.2.In high humidity environment,the dissolution of nitrendipine tablets decreased,but the dissolution,drug content and impurity still meet the requirements.3.The related substances of nitrendipine tablets does not meet the requirements under strong light irradiation,but there is no significant change in dissolution and drug content.4.After 6 months of accelerated test,the dissolution,drug content and related substances of nitrendipine tablets meet the requirements.Conclusion: Nitrendipine tablets should be light proof and moisture-proof packaged,stored in a cool and ventilated place.Part four: Pharmacokinetics of nitrendipine tablets in Beagle DogsObjective: Establish the analytical method of nitrendipine in Beagle dog plasma and study the bioequivalence of self-made nitrendipine tablets and of reference in Beagle dogs.Method:1.Test the measurement method of nitrendipine in Beagle dog plasma from the aspects of specificity,matrix effect,linearity,extraction recovery and sample stability.2.The animal experiment adopts the method of two preparation two cycle cross design.The concentration-time curves of the two preparations are determined and drawn.Finally,the pharmacokinetic parameters are calculated by Das software and thus bioequivalence is analyzed.Result:1.A method for the determination of nitrendipine in Beagle dog plasma is established.The method is cheap,simple and fast.Its specificity,matrix effect,linearity,extraction recovery and sample stability are all good.2.The AUC_0-t of self-made nitrendipine tablets and reference are?424.64±31.72?and?457.23±80.02?ng/ml*h.The AUC_0-? are?457.98±73.81?and?462.01±82.19?ng/ml*h.the C_max are?161.25±30.47?and?164.56±32.07?ng/ml.Tmax are?0.71±0.10?and?0.67±0.13?h.t_1/2 are?2.32±0.36?and?2.62±0.42?h.90%CI of ratio of geometric mean of AUC_0-t,AUC_0-? and C_max are not exceed 80% or 125%.ln(AUC_0-t),ln(AUC_0-?)and ln(C_max)passed the unilateral and bilateral t-test.Conclusion: The self-made nitrendipine tablet is bioequivalent to the reference nitrendipine tablet.