| Objective: Coronary heart disease,which is mainly caused by the dangerous factor of dyslipidemia,has been a crucial threat to life of human with rapidly developing society. Statins are widely used to clinical treatment of coronary heart disease due to their function of lipid metabolism’s regulation. However,their dose-dependence,which means using high dose to achieve a good treatment result also bring a serious problem of high risk for adverse reaction. Ezetimibe,a cholesterol absorption inhibitor,has complementary mechanism for Statins so that their combination may attain outstanding effect of lipid metabolism’s regulation and reliable safety. This study is aimed to research the combination of Atorvastatin and Ezetimibe,find an appropriate prescription and a preparation process to produce compound capsules of both, establish an accurate and reliable method for quality control of made preparations and conduct the relevant stability study simultaneously.Methods: In this study,we granulated two medicines individually. At first,single factor method was applied to determine types and approximate amounts of some materials used in the prescription,then orthogonal experimental design and central composite design-response surface methodology were used to screen and optimize the prescription and the preparation process by the evaluation criteria of two medicines’ dissolutions in medium of aqueous and sodium acetate 4.5. At the same time, a series of accurate, reliable quality control methods are established for the compound capsules of ezetimibe and atorvastatin calcium. 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 are carried out in accordance with the best 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 of Ezetimibe is consist of ezetimibe 10 mg; sodium lauryl sulfate 10 mg; povidone 40 mg; microcrystalline cellulose 70 mg;croscarmellose sodium 50 mg. The part of atorvastatin calcium is composed by atorvastatin calcium 10 mg; Na HCO3 10 mg; hydroxypropyl cellulose 50 mg; microcrystalline cellulose 28.2 mg and lactose monohydrate 80 mg. Besides, 1.8 mg magnesium stearate is mixed out of above two parts. Chromatographic conditions of ezetimibe and atorvastatin calcium is determined as: mobile phase is acetonitrile-0.05 M KH2PO4(phosphoric acid to adjust p H of 3.0)-methanol(50:45:5). Detection wavelength is set as λ=236 nm. Column temperature is 25 ℃. The flow rate is 1.0 m L/min. In this chromatographic conditions, concentration range of atorvastatin calcium showed good linearity at 1.12 ~ 16.8 μg/ m L, while ezetimibe was at 1.14 ~ 17.1 μg/m L. The accuracy and precision is good. This method is accurate and with high specificity, which can effectively determine the content of the sample easily. Through the study of the impact factor test, the preparation should be stored in a cool, dry place; long-term trials to nine months, during this period, the preparation of the items of the indexes are in line with the requirements. The expiration period is to be tested further to complete.Conclusion: This project screened optimized prescription of the compound capsules of ezetimibe and atorvastatin calcium. Capsules showed good traits and uniform content. Compared with the control formulation, dissolution behavior is similar. HPLC method is special, simple, and can be used to determine the content of the two drugs and related inspection. |
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