Pharmaceutical Quality Evaluation And Pharmacokinetic Analysis In Human Of Losartan Potassium Of Different Formula Oral Preparations

Objective1.To establish and validate a HPLC method for simultaneous determination of dissolution and content of losartan potassium oral preparations.To comprehensively evaluate the pharmaceutical quality of losartan potassium oral preparations.2.To summarize the bioequivalence tests of different formulas of losartan potassium oral preparations and collect the human pharmacokinetics test data of losartan potassium oral preparations.To analyze the factors affecting the bioequivalence and the human pharmacokinetics parameters of losartan and E3174.Method1.HPLC methods:The chromatographic column was a CAPCELL PAK C8DD column（4.6mm× 150mm,5.0μm）,eluted with the mobile phase of acetonitrile 0.15%phosphoric acid solution（40:60,V/V）,at a flow rate of 1.0ml/min,and high performance liquid chromatograph was equipped with two-tube array detector（PDA）,detection wavelength was 220nm.The results were compared with that measured by the metheds provided by the pharmacopoeia.2.Different formulations of losartan potassium oral preparations were selected to test the key indicators of their quality by the metheds provided by the Chinese Pharmacopoeia.And the comprehensive scoring calculation table Ver2.02 software was used to comprehensively score the seven preparations according to the comprehensive scoring method described in Guiding Principles for Sampling Quality Analysis of National Drug Plan.3.The bioequivalence test datas of different formulations of losartan potassium oral preparations from the same new drug clinical research institute were summarized for significance analysis and multiple tests.The average pharmacokinetic parameters of different races of Cozaar were extracted to conduct the multifactor cluster analysis through searching CNKI and Pubmed.The average blood concentration datas of losartan and E3174 were extracted by the GetData Graph Digitizer software to make the blood concentration-time curve.Result1.The new HPLC method can detect the dissolution and content of different oral losartan potassium preparations at the same time,with high sensitivity,simple operation,good accuracy,reproducibility and stability.Compared with the results that that measured by the metheds provided by the pharmacopoeia,the relative average deviation of dissolution was more than 2.5%,and the relative average deviation of content was less than 1.0%.2.According to the quality standard of Chinese Pharmacopoeia,7 losartan potassium preparations on the market were tested,and the results were all qualified.Generic losartan potassium drugs that passed the conformance evaluation had a higher overall score.3.There was no significant difference in T_max of losartan and AUC_0-∞ of E3174 through comparing bioequivalence tests of different oral losartan potassium preparations;There were significant differences in test Ⅲ and Ⅰ、Ⅲ and Ⅱ,with C_max and AUC_0-∞ of losartan,t_1/2 and C_max of E3174.Cozaar’s PK parameters cluster analyses of losartan were divided into three subcategories,among which there were obvious ethnic differences.Han and Uighurs belonged to the same subgroup with population pharmacokinetic parameters AUC_0-∞（543.5±51.1）ng/ml·hper 50mg,T_max（1.24±.17）h,C_max（327.8±55.5）ng/ml per 50mg,t_1/2（2.95±3.12）h.Factors affecting cluster of E3174 PK parameter were complex,and the two groups of data of Chinese Han were clustered into different subcategories.CYP2C9 polymorphism had slightly different effects on PK parameters of Cozaar in different ethnic groups,and had a greater impact on t_1/2 of E3174.The mutation genes causing significant differences were CYP2C9^*3 and CYP2C9^*13.MR of Losartan was higher in Chinese Han,and lower in Chinese Hui and Swedish.Conclusions1.The HPLC method established in this study could simultaneously detect the dissolution and content of different formulations of losartan potassium oral preparations.It could improve the quality detection efficiency of losartan potassium oral preparations with the simple process and convenient operation.2.The pharmaceutical quality of domestic losartan potassium oral preparations was equivalent to that of the original preparation,especially for the drugs passde the consistency evaluation,with high comprehensive score.The drug comprehensive scoring method could be used for the daily supervision of the evaluated varieties after they were marketed.3.It wsa necessary to evaluate the bioequivalence of losartan and E3174.Compared with other preparations.The design of blood sampling time and the interaction between losartan potassium and amlodipine may be the influencing factors.Human pharmacokinetics of losartan has obvious ethnic characteristics,.Patients with genotype CPY2C9^*1^*1 of Han and Hui should pay attention to individualized dose adjustment when taking losartan potassium orally.