Study And Industrial Investigation On Compound Ezetimibe And Atorvastatin Calcium

Objetive:Hyperlipidemia was caused by one or more kinds of plasma lipid structural imbalance due to systemic metabolism disorders of fat.Its diagnostic criteria were:total cholesterol（TC）>5.72 mmol·L^-1 and（or）low-density lipoprotein cholesterol（LDL-C）>3.12 mmol·L^-1,and（or）in serum triglyceride（TG）>1.70 mmol·L^-1.Drugs used to treat high cholesterol include statins,fibric acid,niacin,bile acid chelating agents,antioxidants,and ezetimibe.This project aimed to apply a combination into practice which was composed by atorvastatin calcium belonging to statins and ezetimibe,a new kind of anti-hyperlipidemic drug.And selecting an appropriate prescription to compress into tablets which will be coated in accordance with the relevant requirements.Establishing an accurate and reliable method for quality control of preparations,and conducting the relevant stability study simultaneously.Methods:In this study,the central composite design-response surface methodology and orthogonal experimental design with single factor method were applied to screen and optimize prescription.The use of single factor method was to determine the types and approximate amounts of certain materials used in the prescription.The single factor method was combined with the corresponding experimental design methods to make a systematic analysis of the point factors affecting prescription.In order to improve the water-solubility of ezetimibe,the main drug and lactose monohydrate were co-micronized.The disintegration and similarity factor f₂ values were as the evaluation criteria to optimize the amount of various pharmaceutical excipients of ezetimibe.The central composite design-response surface methodology was used to optimize the amount of various excipients of atorvastatin calcium and the content uniformity and similarity factor f₂ values were as its evaluation criteria.At the same time,an accurate,reliable quality control methods were established for the compound tablets of ezetimibe and atorvastatin calcium（Compound EACT）.While referring to"the State Food and Drug Administration guidelines for stability of new drug"and the actual situation,acids,alkalis,oxidizing destructive testing are conducted.Stress testing,accelerated testing and long-term tests were carried out in accordance with the optimal prescription to provide relevant data for prescription design,pharmaceutical process improvement,quality control,packaging,transportation and storage,etc.Results:The ultimate prescription were determined to be as follows.The part ofEzetimibe was consist of co-micronized Ezetimibe and lactose monohydrate（1:5）60mg;SDS 10 mg;PVP 40 mg;MCC 95 mg;anhydrous lactose 5 mg and CCNa 50mg.The part of atorvastatin calcium was composed by atorvastatin calcium 10.34 mg;NaHCO₃ 10 mg;HPC 40 mg;MCC 60 mg and lactose monohydrate 86.16 mg.While42 mg CCNa and 1.5 mg magnesium stearate were mixed out of above two parts.Chromatographic conditions of ezetimibe and atorvastatin calcium was determined as:a silica gel column Kromasil C18 reverse column（Ф200mm×4.6mm,5μm）was choiced,and mobile phase was methanol:0.05MKH2PO3（phosphoric acid to adjust the pH of 3.0）:acetonitrile（5:45:50）.The flow rate was 1.0 mL/min.Detection wavelength was set asλ=236 nm.Column temperature was 25℃.In this chromatographic conditions,concentration range of ezetimibe showed good linearity at 1.08²1.6μg/mL,while atorvastatin calcium was at 2.12⁴2.4μg/mL.The accuracy and precision was good.This method was accurate and with high specificity,which can effectively determine the content of the sample.Conclusion:This project screened the optimized prescription of compound EACT tablets.The tablets showed good traits and uniform content.Compared with the control formulation,dissolution behavior was similar.The HPLC method was special,simple,and can be used to determine the content of the two drugs and related inspection.