The Preparation Of SK Sustained-Release Tablets And In Vitro And In Vivo Evaluation

SK is a dihydropyridine calcium ion antagonist with low solubility and high permeability.It belongs to BCS class II drugs.Its release rate is a key factor affecting its absorption.SK sustained-release tablets were first developed and marketed by Bayer,Germany.After years of clinical application,it had became one of the preferred drugs for the treatment of hypertension and various types of angina.With the development of the consistency assessment,the aim of this study was to prepare SK sustained-release tablets with the same active ingredients,dosage forms,routes of administration and clinical efficacy as the reference standard by pre-prescription,formulation,quality and stability,and in vivo pharmacokinetic studies.This study can provides support for the development of generic drugs.Part one Pre-prescription study of SK sustained-release tabletsObjective:To determine the composition and content of the main excipients in the reference standard and examine the physical and chemical properties of the APIs,which laid a foundation for the research of the prescription process of test solution.Methods:Through reverse engineering research on the reference standard,determined the amount of each auxiliary ingredient;studied the physical and chemical properties of the APIs and the compatibility of APIs and excipients to investigate whether there is interference between them.Results:The main excipients in the reference standard were microcrystalline cellulose,A,B,and C,which were 34.8,10,14,and 1 mg,respectively.Through the compatibility test of the APIs and excipients,the results showed that the compatibility was good.Conclusion:This section determined the amount of the main components in the prescription.Through the investigation of the drug substance,the results showed that the drug substance was sensitive to light and need to be protected from light during the test.Part two Study on the prescription process of SK sustained-release tabletsObjective:To screen the optimal formulation and process of SK sustained-release tablets with release curve as an indicator.Methods:The optimal formulation of the core is determined by screening the type,amount,viscosity and concentration of the adhesive in the prescription;The optimum preparation process of the preparation is determined by examining the size of the granulation,the hardness of the tablet,and the weight gain of the coating.Three batches of test solution were prepared by wet granulation tableting and coating technology to verify the best prescription and process.The microscopic morphology and the distribution of the prescription components of the reference standard and the test solution were investigated by scanning electron microscopy and raman spectroscopy.Results:According to the prescription screening,the optimal prescription for determining SK core is:SK 20 mg MCC 34.8 mg A 10 mg B 14 mg C 1 mg MS 0.2 mgTableting parameters:the oretical weight 80 mg,punch of ?6 mm,hardness of 5?6 kg/cm2.The best parameters for the coating process:Tablet 200g Opadry concentration 8%Coating weight 5%The best parameters for the coating process:Inlet temperature 80?Pot body temperature 3 5?40?Pot rotation speed 11 rpm Coating liquid pump speed 1.5?3 rpm Spray pressure 1 kg Fan speed 1500 rpmConclusion:The preparation process of SK sustained-release tablets was simple and feasible,and the reproducibility of the three batches of test solution was good.The microscopic morphology and the distribution of the prescription components of the reference standard and the test solution were consistent.Part three Study on quality and stability of SK sustained-release tabletsObjective:To evaluate the consistency of the in vitro release and quality study of the test solution and reference standard.Investigate the changes of test solutions under the influence of high temperature,high humidity and strong light irradiation,and provide basis for drug production,packaging and storage.Methods:In this part of the experiment,the method for determining the release and content of SK was established.The appearance of the preparation,the content of the main drug and related substances were used as indicators to investigate the stability of the preparation by influencing factors and accelerated tests.Results:A method for the determination of the content and release of SK sustained-release tablets by HPLC was established.The results of the two methods showed that the system suitability,linearity,precision,repeatability and recovery rate met the requirements.The similarity factors of the four release curves of the test solution and reference standard wer all greater than 50;The influencing factors and accelerated tests were carried out on the test solution.The results showed that the preparation was stable to high temperature and high humidity and extremely unstable to light.Conclusion:The established method for determination of SK content was simple and convenient,and had good durability.The content of the three batches of test solution met the requirements and the content was uniform.The test solution was consistent with the in vitro release profile of the reference standard.SK was extremely sensitive to light.During production,packaging,storage and transportation,it must be protected from light and improve the stability of the preparation.Part four Study on pharmacokinetics of SK sustained-release tabletsObjective:To study the bioequivalence of test solutions and reference standard in Beagle dogs.Methods:The Beagle dog was used as a test animal,and the HPLC method was used to determine the content of SK in plasma.Pharmacokinetic tests were performed using a two-period dual-cycle crossover design,and drug-time curves for the two formulations were recorded and plotted.Finally,the pharmacokinetic parameters were calculated using DAS software,and bioequivalence analysis was performed using 3P97 software.Results:The HPLC method for the determination of SK in plasma was established.The pretreatment of blood samples was simple and feasible.The AUC0?? of SK in the test solution and reference standard were(599.28±68.20)and(693.42±221.74)mg/L·h,and the Cmax was(97.54±21.33)and(106.16±21.82)?g/mL,The Tmax was(2.92±0.20)and(2.75±0.27)h.The 90% confidence intervals for the log ratios of AUC0-? and Cmax for SK in the reference standard and test preparations were within 80%to 125%confidence intervals;In(AUC0?)and In(Cmax)After two one side t-tsst,t1?t1-?(v)and t2?t1-?(v)are established at the same time.Conclusion:The test solutions of SK sustained-release tablets is bioequivalent to the reference standard.