Study On Stabilized Preparation And Pharmacokinetics Of Felodipine Sustained Release Tablets

Felodipine,a selective calcium channel antagonist,is mainly used for the treatment of mild to moderate essential hypertension.The reference preparation used in this study is the felodipine sustained-release tablets developed by Astra Zeneca UK,with a specification of 5 mg.At present,the reference preparation is not listed in China,and the same kind of medicine produced by domestic manufacturers has not passed the evaluation of generic medicine and efficacy consistency.From the pharmaceutical point of view,the most unsatisfactory characteristic of this drug is its high photochemistry sensitivity and is easy to produce photodegradable impurities,which leads to the reduction of therapeutic effect,and even some toxic and side effects after administration.The aim of this study is to prepare a sustained-release felodipine tablets with different prescriptions and Technology of stabilized preparation,conduct in vivo and in vitro tests and quality inspection in order to meet the requirements of quality control and to be consistent with the reference preparation in vivo and in vitro.Part one Preparation and Stabilization of Felodipine Sustained-release TabletsObjective:To optimize the formulation and process of felodipine sustained-release tablets so as to make the in vitro dissolution curve similar to the reference and optimize the production process to reduce and control the generation of photodegradation impurities.Methods:Felodipine sustained-release tablets were prepared by wet granulation with hydroxypropyl methylcellulose?HPMC?as the matrix material.On the basis of the existing core,a layer of light-shielding film is coated,and the finished tablet is finally obtained.Try Different antioxidants and optimize the prescription process with the content of main drugs and related substances as the index.Results:On the basis of single factor investigation,the best prescription was selected by similarity factor method with release factor as evaluation index.In the dark operation,a brown container is used in the preparation process.When the antioxidant is tocopherol,the content of the related substance is lower than that of the reference preparation,and the best effect of inhibiting the formation of photodegradation products is achieved.Conclusion:The preparation process of felodipine sustained-release tablets is simple,feasible and reproducible.The in vitro dissolution curve of the self-made tablet is similar to the reference tablet.Compared to the reference preparation,when the antioxidant is tocopherol,the content of photodegradable impurity I is the smallest.Part two Establishment of an in vitro analytical method for felodipine sustained-release tabletsObjective:To establish a simple and reliable in vitro analytical method based on the nature of felodipine,and to carry out quality control research on felodipine self-made sustained-release tablets to ensure its safety,effectiveness and quality control.Methods:The in vitro release,content and related substances of felodipine self-made sustained-release tablets are determined by HPLC.Results:Methodological findings showed good specificity,linearity,precision,repeatability and recovery.The relevant substances in the preparation were investigated and the results met the requirements.Conclusion:The established in vitro analytical method of felodipine is simple and durable.The determination of three batches of self-made preparations conforms to the requirements of this study.Part three Stability study of felodipine sustained-release tabletsObjective:To study the time-varying rule of self-made preparation under the influence of temperature,humidity and light,so as to provide evidence for the drug production,packaging and storage conditions.Methods:The stability test was carried out with the appearance of the preparation,the content of the principal agent and the content of the relevant substances as indicators.Results:The self-made preparation was placed under high temperature,high humidity and strong light for 5 and 10 days.Due to the coating of a layer of light-shielding film,the content of related substances increased,but did not exceed the impurity limit and met the quality requirements.Under the condition of high humidity of 90%,the dissolution rate of the principal agent is accelerated,and the release degree is different from that of the reference preparation,which affects the quality of the drug.The accelerated test and long-term test results show that the self-made preparation has better stability than the reference preparation according to the packaging conditions of the reference preparation.Conclusion:The preparation should be protected from moisture and light when storing tablets.Part four The pharmacokinetic study of felodipine sustained-release tablets in Beagle DogsObjective:To study the bioequivalence of self-made and reference preparations of felodipine sustained-release tablets in Beagle dogs.Methods:The two-formulation and two-cycle crossover design test method was used to determine and plot the drug-time curves of the two formulations by HPLC.Finally,the pharmacokinetic parameters were calculated by DAS software,and the bioequivalence was analyzed by 3P97 software.Results:The 90% confidence interval of the logarithmic ratio of AUC_0-? and Cmax of reference and self-made preparations was within the 80%¹25% confidence interval.The relative bioavailability of the self-made preparation for the reference preparation was 106.1%.Conclusion:The self-made preparation is bioequivalent to the reference preparation.