| The cardiovascular diseases, known as diseases of the circulatory system, is a series of diseases related to the circulatory system, mainly involving the heart, blood vessels (arteries, veins, capillaries). The cardiovascular diseases, usually associated with atherosclerosis, can be subdivided into the acute type and the chronic type. These diseases have similar causes, disease process and treatment. The main symptoms include:heart palpitations, dyspnea, cyanosis, dizziness, fainting and fatigue. The common cardiovascular diseases include:coronary heart disease, hypertension, high cholesterol, exercise sudden death, acute myocardial infarction, and angina. Since the1980s, cardiovascular disease has become the number one human disease. What’s worse the hypertension and the disease caused by the hypertension have drawn growing attention.The report of the American Heart Association (AHA) in the year of2003especially emphasized that, β-blocker therapy is the most important part for the treatment of many patients with hypertension. The β-blocker owns the advantage of reducing stroke and slowing the progression of renal insufficiency the in treatment of hypertension. The β-blocker is suitable for acute myocardial infarction, diabetes, heart failure, peripheral vascular disease and coronary heart disease in hypertensive patients at high risk.Metoprolol, a specific β-blockers developed by the company of Astra in Swedish, has high selectivity to cardiac β1-adrenergic receptor, and can slow down the heart rate, decreased cardiac output, lower upright and supine blood pressure as well. Metoprolol fumarate, a fumarate of metoprolol, is widely used in the treatment of hypertension and ischemic heart disease, chronic stable heart failure, arrhythmias, and other medium.Metoprolol is now widely used as succinate and fumarate in the European countries. The pharmaceutical raw materials of metoprolol fumarate have been recorded in the United States Pharmacopoeia and European Pharmacopoeia. Metoprolol fumarate tablets have three specifications:95mg/tablet,190mg/tablet and285mg/tablet in clinical. However, the half-life of conventional tablets of metoprolol is only3～4h, which suggest that multiple doses a day is required. Based on domestic conditions and foreign clinical drug reference specifications, the sustained release tablets with a size of95mg/tablet was developed by our company to Extend dosing interval, reduce the frequency of administration and improve patient compliance.In this research, metoprolol fumarate was selected as the model drug to prepare the sustained release matrix tablets by the method of wet granulation with the main skeletal material HPMC and the blockers ethyl cellulose (EC). Analytical method, prescription design, preparation technology, quality standards as well as stability were investigated in this research.1. Establishment of analytical methodThe drug content of metoprolol fumarate and the in vitro drug release of the sustained release matrix tablets were determined by the method of ultraviolet spectrophotometry (UV). The related substances in the raw materials and the sustained release matrix tablets were determined by the method of HPLC. The UV and HPLC methodology were inspected.The methodological study results indicated that the established UV spectrophotometry has a high accuracy, high sensitivity and high precision. Three groups (40、100、200μg/ml) of metoprolol fumarate solution was determined and the RSD was1.466%,0.856%and0.590%, respectively. The UV spectrophotometry has a good linear relationship in the concentration range of20μg/ml-250μg/ml, and the standard equation was A=0.004149C+0.0135712(r=0.9999). The stability test suggested that the metoprolol fumarate solution was stable in24h. The extraction recovery of three groups (80、100、120mg) of metoprolol fumarate solution was larger than95%and the RSD was less than1%. The determined wavelength was274nm.The UV scanning spectrum of the sample solution, standard solutions and accessories solution in0.lmol/L hydrochloric acid, acetate buffer (pH4.5), water and phosphate buffer (pH6.8) showed that the excipients did not interfere with the determination in the wavelength of274nm±1nm. Water was selected to be the release media based on the structural features and release characteristics of the sustained-release tablets. The rotational speed was100rpm/min and the sampling time was determined to be1、6、16h. The in vitro drug release study revealed that the samples had a good uniformity of release. The degradation products in acid, alkali, high temperature and oxidant can be effectively separated with the established HPLC method. The linear relationship in the concentration range of50.72μg/ml～355.04μg/ml was good. The specific impurity was controlled by the method of the impurity reference. The impurity A should not be greater than0.3%, the impurity C should not be greater than0.3%, other single impurity should not be larger than0.3%, and total impurities should not exceed0.5%. The HPLC method owned a good precision, accuracy and recovery. The determination method of drug content and in vitro drug release was established to provide the basis for the optimization of prescription and preparation technology.2. Optimization of prescription and preparation technologyThe sustained release matrix tablets of metoprolol fumarate were prepared by the method of wet granulation with the main skeletal material HPMC and the blockers EC. With the index of release percentage in vitro, the optimal prescription and preparation technology was determined by single factor and orthogonal experiments. The feasibility of prescription and the stability of preparation technology were verified by the repeated experiment of three batches of samples. The results suggested that in vitro release rate of the two kinds of samples made from two different kinds of HPMC that had different viscosity had no significant difference. In vitro release rate of metoprolol fumarate decreased with the increase of HPMC. Three different blockers we used had no significantly different impact on the in vitro release rate. The blocker of EC had an optimum amount of12%.3. Quality criterion and stability researchFinally, three batches of samples prepared as the optimal prescription and preparation technology was characterized by the appearance, identification, weight variation, friability and other quality indicators. And the quality criterion was accordingly established. The cumulative release of1h,6h and16h was10%-30%,50%-70%and larger than75%. The drug content should be90-110%of the labeled amount. The impurity A, impurity C and other single impurity should not be greater than0.3%, and the total impurities should not exceed0.5%. Furthermore, the stability tests of the three batches of samples including the impact factor test, accelerated testing and long-term retention test, were conducted. The stability was evaluated by the traits, the release rate, the related materials and drug content. The study of preliminary stability showed that the sustained-release tablets showed stability in sunlight, high temperature, high humidity for10days, the accelerated test for six months, leaving samples at room temperature for24months. In consideration of the stability, the validity period is tentatively scheduled for24months.Conclusion:The method of UV showed good precision, accuracy and recovery, and can met the determination of the content of metoprolol fumarate. The UV spectrophotometry has a good linear relationship in the concentration range of20μg/ml-250μg/ml. The HPLC method for the related substances in the raw materials and the sustained release matrix tablets had a good specificity and high sensitivity.The sustained release matrix tablets of metoprolol fumarate with the hydrophilic gel filler of HPMC, the blockers of EC, the lubricant of talcum powder and magnesium stearate, showed a reasonable prescription and stable product process. So the sustained release matrix tablets may have the potential to extend the half-time of metoprolol fumarate in vivo, and improve the compliance of patients accordingly. |
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