| Objectives:Hypertension,angina,and arrhythmia has been a serious threat to human life and health,and the morbidity and mortality are increasing year by year.Metoprolol succinate is a selective ?1 receptor blocker,the desired concentration of effecting on cardiac ?1 receptor is less than the ?2 receptor on peripheral vascular and bronchial.Plasma concentration of sustained-release tablets is less than ordinary tablets,so the sustained-release tablets have a higher ?1 receptor selective.Now,Domestic listing sustained-release formulation is Betaloc,but also no imitation report.The purpose of this study is to prepare a metoprolol succinate multi-unit sustained-release formulation,which can be taken separately,each unit remains independent and similar release characteristic.Medication once a day you can get the smooth and effective plasma concentration for 24 hours to block ?1 receptor.For therapeutic purposes at the same time,reduce the incidence of adverse reactions.Methods:1 Preparation of sustained-release pellet tablets of metoprolol succinate: metoprolol succinate mixed with MCC,then used 10% WS-0314 as binder to make soft material,the cores were prepared by extrusion-spheronization.The coating material was ethyl cellulose aqueous dispersion,Containing triethyl citrate as a plasticizer.The sustained-release coated pellets were prepared by fluidized bed bottom-spray.The prescribed amount of glyceryl monostearate,PVPP,magnesium stearate,and sustained-release pellets were mixed uniformly,using the direct powder tabletting process to prepare sustained release tablets of metoprolol succinate.The prescription of cores was determined by a series of single factor experiments.The spherical(yield and roundness)of pellets was taken as a evaluation index.Extrusion speed,spheronization speed and the spheronization time were taken as the influential factors,through L9(33)orthogonal experimental design to screen the best preparation.At the same time,release as the indicator,the coating weight,the amount of plasticizer,tableting excipient and disintegrator were taken as the single factor to determine the best prescription and process.2 Research on quality control about metoprolol succinate extended-release pellet tablets :established UV spectrophotometric method for the determination of dissolution of metoprolol succinate extended-release pellet tablets;established HPLC method for the determination of content and content uniformity,both the methodological studies were carried out.Prepared metoprolol succinate extended-release pellet tablets in accordance with the best prescription,and studied the stability of the preparation with the evaluation indexes of appearance,dissolution and content.Stress testing and accelerated testing were also carried out.3 A fluorescence-HPLC method was developed for the determination of metoprolol succinate in Beagle dogs plasma.Betaloc was taken as the reference preparation,a single-dose,two-treatment,two-sequence and randomized crossover study was carried out on four adult beagle dogs,studying its pharmacokinetics,bioavailability and bioequivalence.Results:1 The best prescription and preparation process of the metoprolol succinate cores were selected through the single factor test and orthogonal test design.cores prescription: The metoprolol succinate(MS)100 g MCC 100 g 10% WS-0314 155 mL Process: MS and MCC mixed evenly,adding 10% WS-0314 to make soft material,the cores were prepared by extrusion spheronization(extrusion speed 40 r·min-1;spheronization speed 40 r·min-1;spheronization time 20 s).The cores were dried for 3 hours at 60°C,and sieved to 30~60 mesh pellets spare.The spheronization of pellets was good,the plane critical angle of pellets was 16.4°,the yield was 90.76%,the dissolution of the cores reached 100% in 10 min.The best prescription and preparation process of coating were selected through the single factor test.Coating liquid prescription: EC aqueous dispersion(surelease)100 g Distilled water 100 mL Triethyl citrate(based on EC solid content)15% Coating process parameters: inlet air temperature 45°C,the spray pressure 0.05 MP,spray liquid speed 0.7 mL·min-1,fluidized frequency of 30 Hz.The coating weight was 50%,the coated pellets were cured for 12 h at 40°C.The best prescription and preparation process of tablets were selected through the single factor test.Tablet prescription: Coated pellets 160 mg Glycerol monostearate 160 mg PVPP 1% Magnesium stearate 1% Tabletting process: the components were mixed uniformly.Direct powder tabletting.Die diameter was 10 mm,the tablet hardness was 1~2 kg.Tablet weight was 320 mg,and the unit was 47.5 mg.2 Established a UV spectrophotometric method for the determination of dissolution rate of metoprolol succinate extended-release pellet tablets.The detection wavelength was 274 nm with no interference of excipient,water as solvent.The methodological study results showed that within the concentration range of 6.34 ?g·mL-1~203 ?g·mL-1,the linear relationship between absorbance and concentration of metoprolol succinate was good.The regression equation was A=0.0036C+0.0142,correlation coefficient ?= 0.9997,RSD of precision value was 0.66%,low,medium,and high concentrations of recoveries mean of 100.7%.This method can be used for the determination of the dissolution of sustained-release pellet tablets of metoprolol succinate.Established a HPLC method for the determination of content of metoprolol succinate extended-release pellet tablets.The detection wavelength was 274 nm with no interference of excipient and mobile phase,water as the solvent.The methodological study results showed that within the concentration range of 12.56 ?g·mL-1~201.0 ?g·mL-1,the linear relationship between peak area and concentration of metoprolol succinate was good.The regression equation was A=4838.8C+295.69,correlation coefficient ?=1,RSD of precision value was 0.09%,low,medium,and high concentrations of recoveries mean of 99.55%.This method can be used for the determination of the content of sustained-release pellet tablets of metoprolol succinate.3 Study on stability of self-made tablets : Under the condition of high temperature(60?),the tablets would soon melt.Under the conditions of high temperature(40?),strong light(4500Lx)and accelerated testing,there was no significant change in the appearance,dissolution and content.However,under the conditions of wet RH92.5% and RH75%,the tablet surface was evidently wet,and the dissolution rate was significantly accelerated,but the content did not change significantly.The results showed that the tablets were stable to low temperature and light,but the preservation of the tablets should avoid high temperature and humidity.4 Established a fluorescent-HPLC method for the determination of metoprolol succinate blood drug concentration,Ex=285 nm,Em=316 nm,Blank plasma was no interference on Determination of main drugs.In range of 5 ng·mL-1~640 ng·mL-1,the linear relationship was good,the regression equation was A = 0.3489C+4.3399,?= 0.9998,extraction recovery rate was more than 90%.Relatively bioavailability of test preparation was 91.02%.Conclusions: The formulation and preparation of metoprolol succinate sustained-release pellet tablets was simple and feasible,with good reproducibility,and could be taken separately,the various parts of the tablet remained independent and similar release characteristics,and could achieve the effect of sustained-release.The methods were established for the determination of content and dissolution.Metoprolol succinate sustained-release pellet tablets should be protected from high temperature and humidity.Vivo pharmacokinetic studies had shown that self-preparation had relatively high bioavailability,and biological equivalent comparerd with reference preparation. |
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