Consistency Evaluation Of The Dissolution Of Candesartan Cilexetil Tablets And Its Virtual Bioequivalence Study

Objective:Candesartan cilexetil is a diphenyltetrazolium angiotensin II receptor antagonist and is a new antihypertensive drugs following angiotensin converting enzyme inhibitors.Candesartan cilexetil is a prodrug of candesartan,which is hydrolyzed during the absorption of the gastrointestinal tract to get candesartan.Candesartan acts on the renin-aldosterone system,which has a strong affinity for the angiotensin II type receptor and has the effect of selectively blocking the receptor,thus blocking the angiotensin vasoconstriction and reducing aldosterone secretion,to achieve antihypertensive effect.The indications for candesartan cilexetil tablets include atherosclerosis,myocardial infarction,congestive heart failure,left ventricular hypertrophy,essential hypertension,diabetic nephropathy,and metabolic syndrome.Since candesartan cilexetil has a good antihypertensive effect,few adverse reactions,and long-lasting effects,it is already the winner in the list of angiotensin II receptor antagonists.The original manufacturer of candesartan cilexetil tablets is Takeda Pharmaceutical Industry Co.,Ltd.in Japan,and there are 11 generic tablet manufacturers in China.However,there has been no research on the consistency evaluation of candesartan cilexetil tablets.Clinical verification is the"gold standard"for the consistency evaluation,but it is often very difficult.For oral solid preparations,the comparison of the dissolution profiles under various media is mainly chosen to evaluate whether it is consistent with the brand name drug.This is because the comparison of the dissolution curves under various media can better reflect the therapeutic effect in vivo and can be used for the consistency evaluation of solid formulations.In this article,Candesartan cilexetil tablets produced by Takeda Pharmaceutical Industry Co.,Ltd.of Japan were used as the brand name drug,and candesartan cilexetil tablets produced by seven domestic manufacturers were selected as generic drugs.Four different media were used to investigate and compare the dissolving curve of brand name drug and generic drugs whether the quality was consistent.Gastro Plus software was used to establish the in vitro and in vivo correlations of candesartan cilexetil tablets,it was inferred whether the brand name drug and the generic drug were bioequivalent.The purpose of this study was to establish a method for the determination of the dissolution of candesartan cilexetil tablets,which laid the experimental basis and scientific guidance for the consistency evaluation of candesartan cilexetil tablets,and provided strong support for safe,effective and reasonable clinical application.Methods:In this paper,the dissolution rate was measured by the“paddle method”in the dissolution rate and release rate determination method of the 4th part of the Chinese Pharmacopoeia 2015 Edition No.0931,and the candesartan cilexetil were quantitatively analyzed by HPLC.Four different media were selected?pH was1.0,4.5,6.5 and water?were used as drug dissolution media,and surfactant Tween 20was added to the media for comparison.The in vitro dissolution of candesartan cilexetil was compared between different brands Tween 20;and study for its solubility and stability in media?representing digestive fluids in different parts of the body's gastrointestinal tract?;make dissolution profiles of brand name drug and generic candesartan cilexetil tablet,then using the f₂ factor method to evaluate the similarity of the dissolution profile between the brand name drug and eight generic drugs;Gastro Plus software was used to establish a drug prediction model in vivo and correlation in vivo and in vitro to evaluate the bioequivalence of the generic candesartan cilexetil tablet and the brand name drug.Results:The HPLC quantitative analysis method of candesartan cilexetil determined in this study has high sensitivity,less interference,and can effectively achieve the quantitative analysis of candesartan cilexetil;screening and optimization of the dissolution method of candesartan cilexetil tablets,four different media were used as the dissolution media of candesartan cilexetil by comparing and studing the dissolution methods of the three countries which were the United States,Japan and China,the surfactant Tween 20 was added and determined 0.05%as the optimal concentration;the dissolution behavior in medium pH 6.5 can better reflect the pros and cons of its release in vivo;the similarity of the dissolution curves shows that there is one manufacturer's generic drug that exhibits similar dissolution curve from the brand name drug in three dissolution media.?f₂ is bigger than 50?,there are four manufacturers in only one kind of dissolution medium behaves like the dissolution curve of the brand name drug?f₂ is bigger than 50?,and the other manufacturer's products have no similarity with the brand name drug.Gastro Plus software simulation predicted that candesartan cilexetil oral main absorption site was the colon,drugs generally reach the site after 5h;permeability and dose are not major factors affecting candesartan cilexetil's absorption,its in vivo absorption is mainly affected by its effective particle radius and particle density.The simulation and prediction results showed that when C_max and AUC were used as indexes,candesartan cilexetil tablets with different dissolution characteristics had poor bioequivalence in vivo.At present,only one kind of candesartan cilexetil tablet made in China is bioequivalent with the brand name drug.Conclusion:The consistency evaluation of Candesartan Cilexetil tablets and Japan Takeda Pharmaceutical's original research tablets was performed for the first time.In this study,the dissolution method of candesartan cilexetil tablets was optimized,and the dissolution rate of candesartan cilexetil tablets was determined by high performance liquid chromatography.The dissolution curves in four different media were evaluated by the similarity factor?f₂?method.Using Gastro Plus software with C_max and AUC as indicators,the bioequivalence of candesartan cilexetil formulations in vivo was predicted.This study has important theoretical and practical significance for improving the quality of domestic generic drugs.