| Yinxintong is flavonoids which extracted from Hawthorm leaf,it's a kind of natural drugs which widely used with less adverse reaction.Traditional Chinese medicine believes it can active blood and resolves stasis,regulate "qi" and dredge the blood stasis.It has significant efficacy in treating cardiovascular diseases.According to the modem pharmacological researches and current events of its clinic applications show that Yixintong has the effects of lowering blood pressure?dilating coronary arteries and relieving myocardial ischemia.The conventional tablet-Yixintong tablet is recorded in Chinese Pharmacopoeia 2010 edition and it's one of national and traditional Chinese medicines.It is currently approved for the treatment of angina pectoris?hyperlipidemia and cerebral arterial insufficiency with proven clinical benefits.The mechanisms are as follow:?yixintong can Improve the microcirculation,outspread coronary artery,enhance the coronary blood flow and increase the perfusion in the ischemia area,all of these can alleviate the heart injury induced by ischemia;?it debases blood viscosity,speeds up blood flow,accelerates the development of coronary collateral circulation to improve myocardial ischemia and hypoxia and make a enhancement of blood circulation in the arteries and the capillaries;?it prevents the development of angina from reducing the content of serum lipids and preventing its deposition in the arterial wall and cells,which is the key step in forming atherosclerosis.?it can inhibit platelet adhesion by lowering the concentration of plasma fibrinogen,eliminating free radical and promoting fibrinolytic activity.Besides,yixintong can resist inflarmation,relieve pain,lower blood sugar and have excellent antioxidant activity,which has constructive and significant effects in certain diseases.The currently listed dosage forms includes Tablet,capsule,dispersible tablets and dropping pill,Although these formulations were proved to be effective,but the patients had to take high doses and repeated treatment with poor compliance,in the early medication,the administration made the blood concentration change enormously,which could probably cause toxic and side effects that was responsible for an instable efficacy.The two-layer osmotic pump delivery system is a solid preparation which includes drug layer?Push layer and a semi permeable coating layer,it can make the drug release curve followed the zero order equation and therefore a more stable blood drug concentration and a reductions of the frequency of drug administration.Compared with other dosages,it has these five advantages:?it can make the drug release curve followed the zero order equation and not to be influenced by physiological factors,such as medium,gastrointestinal peristalsis·?Blood-drug concentration is stable due to the constant release rate,which reduce drug adverse;?By reducing the frequency of drug administration,patients have a good compliance and the efficacy and safety of drug are increased obviously;? The film-coating technique can shield odor,which means it can improve the compliance of patients to some extent.;?osmotic pump formulations are high in technology,short development cycle and can be industrialized easily.Therefore,in this study,we prepare the yixintong two-layer osmotic pump tablets which is administered for two times per day and only one pill each time.It is in order to get an ideal preparation which has a more stable blood concentration,reductions of the peak and valley phenomenon and less frequency of drug administration,obviously an improved safety and compliance.In this article,we mainly study the preparation process,the prescription optimization,the quality standards and the stability of preparation.1.Quality standard research on yixintong two-layer osmotic pump controlled release tabletsThe quality control of yixintong two-layer osmotic pump tablets was researched.According to the character of two-layer osmotic pump tablets,a HPLC method was setup for determination and a ultraviolet spectrophotometry method was established for dissolution,both taking hyperoside as determining target.Chromatographic conditions for determination:a Yilite C18 column(250mm×4.6mm,5um);mobile phase:tetrahydrofuran-methanol-acetonitrile-0.5%acetic acid(19.4:1:1:78.6),detection wavelength:363nm,flow rate:1.0 ml·min-1,column temperature:30?.The results showed that the linear range of hyperoside was within 2-8.4 ug·ml-l,r=0.9999,the average recovery of hyperoside was 101.0%,RSD=0.95%(n=6).This illustrated that the HPLC method was specific,simple,rapid and accurate,and it could be used in the quality control of yixintong two-layer osmotic pump controlled release tablets.In vitro release test was performed in a dissolution apparatus using the third method that had been given by the CHP(Edition 2010).100ml degassing distilled water was chosen as release medium,the stirring rates in medium was 100rpm and the medium temperature was controlled at(37.0±0.5)?.At the predetermined intervals(2?4?6?8?10?12h),5ml samples were with drawn from each apparatus,filtered with a 0.45nm membrane,diluted 5-fold,and analyzed with UV method at 363nm detection wavelength.The same volume of fresh medium was replaced after sampling.As the result,it had a good linear within 0.2?g·ml-1-7.2?g·ml-1,r=0.9999,average recovery was 99.26%,RSD=1.460%(n=5).All of which indicated that UV method was specific,simple,rapid and accurate,and it could be used in determination of in vitro drug release.The research build up methods for determination and release rate in vitro,which were specific,simple,rapid and accurate,and provided basis for the establishment of its equality standard.2.Preparation process research on yixintong two-layer osmotic pump controlled release tabletsIn the study,we selected Polymer materials-PEO and sodium chloride as booster material and osmotic agents respectively,and used CA and PEG-4000 as the coating materials while the acetone was as the coating mudium.Similarity factors f2 which was recommended by the FDA were used as evaluation index to study the influence of factors which affected the drug release profiles.According to drug release mechanism of two-layer osmotic pump tablets,we studied several aspects:the drug layer formulation,the push layer formulation,the coating membrane formulation,preparation technology and the condition of drug release.Based on single factor experiments,we selected three important influential factors which affected the drug accumulative release percentage(R1)within 12h in vitro and drug release curve fitting(R2):the content of PEO(A)and sodium chioride(B)in push layer and film thickness(C).We used these three factors as dependent variable,and the drug accumulative release percentage(R1)and drug release curve fitting(R2)as variables in order to optimize the fornulation of yixintong two-layer osmotic pump controlled release tablets via three factors and three levels and Box-Behnken design-response surface method(BBD-RSM).According to the optimal results,we could test the forecasting result of the model by comparing the actual measured value with the optimized value.The test results indicated that the predicted value and the actual optimization value were basically same with a small deviation.It illustrated that BBD-RSM was highly accuracy in formulation optimization,and it could be popularized widely.The preparation technique and optimal formulation were described as follow:1)the drug layer:main drug 128mg?sodium chloride 8mg;2)the push layer:PEO-WSR303 128mg?sodium chloride 20mg;3)film thickness 10%of the weight of core tablets;4)tableting technology:diameter of core tablets 9mm?hardness:7-8kg?weight of core tablets 286mg;5)coating technology:pan diameter:10cm?bed temperature:35??fluid delivering rate 3 ml·min-1?pressure 0.4-0.6KPa?rotate speed 28 r·min-1.According to the optimal formulation,Yixintong Two-layer osmotic pump tablets were prepared with zero-order kinetics(R2=0.9863),and in line with controlled release.3.Stability research on yixintong two-layer osmotic pump controlled release tabletsAccording to the principles referring to the drug stability in the CHP and the quality standard,we investigated the stability of yixintong two-layer osmotic pump controlled release tablets,including stress testing,accelerated testing and long-term testing.1)Stress testing:stress testing last 10 days includes high temperature tests(60?)?high humidity test(RH=92.5%)and high-light exposure test(4500xl),at the predetermined intervals(0?5?10d),we investigated the properties of appearance?determination of main drug and accumulative release in 12 hours.10 days results showed that the samples were not stable and the drug out flowed from the drug release hole under the condition of relative humidity of 92.5%,while was stable under the condition of high temperature and high-light exposure,therefore the products should be kept in a sealed and dry condition.2)Accelerated testing:three batches of samples in commercial packaging were under the condition of 40? and RH=75%for 6 months.The results showed that three batch of samples had no change obviously in physic appearance?drug content and accumulative release in 12 hours,it indicated that the products were stable in commercial packaging condition.3)Long-term testing:three batches of samples in colmercial packaging are under the condition of 25?and RH=60%for 6 months.The results showed that the date of the simulation of three batches of samples were not significantly different from before,it indicated that the products had a good stability in commercial packaging conditions and the effective date could be tentatively scheduled for 6 months.Through the stability research,yixintong two-layer osmotic pump controlled release tablets was sensitive to high humidity circumstances,but it was stable under the condition of high temperature and high-light exposure,so it should be kept in sealed and dry condition... |
PDF Full Text Request