Bioequivalence Study Of Isosorbide Mononitrate,Difenidol And Ambroxol Hydrochloride

The evaluation of generic drug conformity refers to the evaluation of the quality consistency of the generic drugs that have been approved for marketing,in accordance with the principle of the quality and efficacy of the original drug,and the generic drug needs to be consistent with the original drug in terms of quality and efficacy.Level.The consistency evaluation of generic drugs plays an irreplaceable positive role in safeguarding the safety of public drug use,improving the quality of generic drugs in China,improving the overall level of the industry,and enhancing the international competition in the pharmaceutical industry.The bioequivalence test is an important indicator for evaluating the consistency of the quality and efficacy of generic drugs and original drugs.The bioequivalence test refers to the method of bioavailability research,using pharmacokinetic parameters as indicators to compare the absorption and speed of active ingredients in the same or different dosage forms of the same drug under the same test conditions.There are no statistically significant human trials.Common biological samples include whole blood,serum,plasma,urine,etc.The matrix components are more complex,and the biological sample analysis has the following characteristics:less sample volume;low analyte concentration;endogenous substance interference;individual differences.The LC-MS/MS method has the advantages of higher sensitivity and selectivity,high quantitative accuracy,simple pretreatment method and good reproducibility,and has become the first choice for bioequivalence test.The first chapter of this paper is the introduction part,which mainly introduces the three drugs of this topic:isosorbide mononitrate,physicochemical properties,pharmacological effects and pharmacokinetics of difenidol and ambroxol hydrochloride,and its biological analysis The method is summarized,the advantages and disadvantages of its common methods are summarized,and its regularity and application trend are explored.Finally,the bioequivalence study was introduced,its important role in the evaluation of generic drug consistency,and its experimental characteristics and difficulties were introduced.The second chapter of this paper describes the determination of isosorbide mononitrate in human plasma by LC-MS/MS,including method development and method validation.The method pretreatment uses protein precipitation method,with isosorbide mononitrate-13C6 as internal standard,linear range is 20-2000 ng/mL?r =0.9996?,analysis time is 5 minutes,intra-batch/batch accuracy range For the range of 86.9%to 110.7%,the intra-assay/inter-assay precision is in the range of 1.1%to 11.1%.The method used less plasma,only 50 ?L,which greatly improved the clinical applicability and provided an effective method for bioequivalence testing.The third chapter of this paper describes the determination of difenidol in human plasma by LC-MS/MS,including method development and method validation.The method uses the isotope of the Finistero-d10 as an internal standard,and the protein is precipitated with acetonitrile for 4 minutes,the linear range is 1 to 500 ng/mL?r=0.9982?,and the intra-batch/batch accuracy range is 86.3%?104.2%,intra-batch/inter-assay precision is in the range of 0.0%?7.4%.The method has the advantages of rapid,sensitive,high selectivity and low plasma consumption.Compared with the published literature,the lower limit of quantitation of this method is reduced from 4 ng/mL to 1 ng/mL,and the pretreatment method is simplified,the analysis time is shortened,and the requirements for high through-put sample analysis in the bioequivalence test are met.Moreover,the plasma dosage in the method is reduced to 50 ?L,which reduces the blood collection burden of the subject and improves the clinical applicability,and provides an important method reference for future bioequivalence studiesThe fourth chapter of this paper introduces the LC-MS/MS method for the determination of ambroxol hydrochloride in human plasma and its bioequivalence,including method development,method validation and sample determination.The results showed that ambroxol hydrochloride had a good linearity in the range of 2-400 ng/mL?r=0.9993?.The intra-and inter-batch accuracy deviations were less than 10.0%,the precision was less than 6.0%,and the matrix effect was 96.3%.In the existing method,the minimum amount of plasma is also required to be 100 ?L,and the plasma dosage is low in this method,which greatly improves the clinical applicability.The method was applied to the human bioequivalence test to determine the plasma concentration of the oral test preparation and the reference preparation in 6 healthy volunteers.The results showed that the 90%confidence intervals of AUCo-t,AUC_0-? and C_max were in the range of 80.0%?125.0%,indicating that the two preparations were bioequivalent.The method is sensitive and rapid,laying the foundation for its bioequivalence study.