Study On Compound Metolazone Tablets

With the development of social economic and the way of life,hypertension has become one of the chronic diseases with higher prevalence,and the state of hypertension in China is extremely grim.Single drug can't control the blood pressure ideally,the patient needs to use two or more antihypertensive drugs for combination treatment.The monolithic compound preparation not only posses the advantages of combination treatment,but also can reduce the frequency of administration,greatly improved patient compliance.This paper selected metolazone?quinazoline diuretic?and valsartan?the leading drug of angiotensin receptor blockers?as the model drugs,to form a new antihypertensive drug combinations,and preparae compound metolazone tablets so as to provide a new choice for clinical medication requirements.First,the paper selected and determined the reference preparations.According to the principles of choosing and determining reference preparation for the common oral solid preparation,it finally choosed Mycros?of Porient Pharma CO.,Ltd for metolazone and Diovan?of Novartis Co.,Ltd for valsartan by comparing the in vitro dissolution differences in valsartan with different batches.Then dissolution method referred to Chinese Pharmacopoeia were choosed and the four dissolution curves were obtained for the preparation prescription screening and evaluation in the development process.Second,the paper established and verified a detection method of the related substances in compound metolazone tablets.In this paper,with reference to the physical and chemical properties of drugs and related requirements in pharmacopoeia,a kind of HPLC assay with great sensitivity,specificity and accuracy were established and an Agilent Eclipse SB-C18 column?4.6 mm×250 mm,5?m?was used with 0.01 mol·L^-1KH₂PO₄ buffer?pH 3.5?–acetonitrile as the mobile phase with gradient elution.The results showed that metolazone,valsartan and releated substance B of valsartan were separated completely.The calibration curves were linear within the range of 3³0?g·mL^-1for metolazone,0.1².0?g·mL^-1for valsartan and 0.08².0?g·mL^-1for releated resource B of valsartan.The average recoveries of them were 102.97%,100.81%and100.44%,respectively.The repeatability and intermediate precision met with requirements.The test solution was stable within 24 h.Thereby,the method was accurate and reliable.Third,the paper researched the non-clinical pharmacokinetic of compound metolazone tablets.In vivo analytical method based on series triple level 4 pole mass spectrometer was established to simultaneously determine the concentrations of metolazone and valsartan in beagle plasmas.It drawed the concentration-time curve and simulated the main pharmacokinetic parameters.Results displayed that after taking the homemade compound metolazone tablets and marked preparations?Mycros?and Diovan??,they were eliminated fast in the body without time-lag,and the main pharmacokinetic parameters such as t_1/2?MRT_0-t?C_max?T_max?AUC_0-t of both the trial preparations and reference preparations have no significant differences?p>0.05?,showing that two kinds of preparations of drugs have similar pharmacokinetic properties.In summary,the qualities and bioequivalence of compound metoprolol tablets were controllable and achievable by in vivo and in vitro analysis method.Thus,it is the ideal antihypertensive drug.