The Study On Consistency Assessment Of The Quality And The Curative Effect For Oral Solid Preparation Of Losartan Potassium Tablets

Developed by the Merck &CO.,Losartan potassium appeared on the Swedish market in 1994.It was officially launched in China in 1998 with the approval of CFDA.The chemical name of Losartan potassium is 2-butyl-4-chloride-1-[[2'-(1h-triazole-5-radical)[1,1'-biphenyl-]-4-radical]methyl-]-1h-imidazole-5-methanol-single potassium salt.The Losartan potassium tablet(trade name: COZAAR),developed by the Merck Sharp & Dohme Limited,is an oral tablet which applies in treating essential hypertension with the ratification of the FDA.It was the first listed oral non-peptide angiotensin II receptor antagonist(ARB)in the world,and has a good antihypertensive effect on blocking all kinds of pharmacological action caused by endogenous and exogenous angiotensin.This assay studied the dissolution behavior of the self-made preparation and the reference preparation COZAAR in the four different pH dissolution media to reach a similar dissolution performance with the reference preparation.By studying the plasma concentrations and main pharmacokinetic parameters of Losartan and its active metabolite EXP3174 in healthy human and evaluating its relative bioavailability and bioequivalence,this study provided the basis for the safe and rational use of the drug.1.The evaluation of existing processThis chapter included the study of dissolution method in vitro and the dissolution behavior between the self-made preparation and the reference preparation.The research of the reference preparation could ensure the accuracy of the evaluation and provide references for the study on formulation.The study of critical quality attributes of selfmade preparation and the reference preparation could help us to establish the quality standard methodology.2.The study on prescription and process(1)Pre-prescription researchThis part studied the API and excipients in the prescription.The physical and chemical properties and forced degradation test of API were studied to find out the impurity profile and degradation pathways,which could not only control the quality of API,but also guided the formulation and process research,and prevented the production of related impurities.(2)The research of prescription selection and process parameterBy analyzing the prescription composition of the reference preparation,pre experiment,screening the dosage of excipients,the optimized prescription was selected.The research of process and parameters ensured that the products with good quality uniformity and reproducibility could be produced under the determined process parameters.The dissolution behavior in 4 kinds of media of the Losartan Potassium tablets made of API,microcrystalline cellulose,lactose,pregelatinized starcha,magnesium stearate and coated with gastric dissolve type coating material Opadry,was studied using dissolution rate as the index and taking dissolution rate,related impurity,assay and other factors into account.The F2 similarity factor was used to evaluate the similarity of the dissolution curve with the reference preparation.The results of dissolution curve of three batches of pilot scale samples showed that the formulation and process of Losartan Potassium Tablets were reasonable,and the dissolution behavior of the self-made preparation and the reference preparation in 4 different pH dissolution media was similar.3.The study of quality standardA method for determining the dissolution rate of Losartan Potassium Tablets and a HPLC method for the determination of assay and related impurity were established.As a result,the quality standard of Losartan Potassium Tablets was confirmed by comparing the quality of the reference preparation with the self-made preparation.4.The investigation of stabilityThis part was to study the stability of the self-made preparation by stress test,accelerated test and long-term test.5.Bioequivalence experimentBy studying the plasma concentrations and main pharmacokinetic parameters of Losartan and its active metabolite EXP3174 in healthy human,and evaluating its relative bioavailability and bioequivalence,this study provided the basis for the safe and rational use of the drug.The results showed that both the 90% confidence interval of the metabolic prototype and active metabolites were in 80.00-125.00,which indicated the self-made preparation was bioequivalent to the reference preparation.