Study On Preparation Of Metoprolol Succinae Tablets Containing Sustained-release Pellets

Metoprolol succinate tablets containing sustained-release pellets as multiple unit pellets system,it has the advantages of less adverse reaction,high bioavailability and severability,this formulation can release metoprolol succinate can continuously within24 hours,which overcome the shortcomings of metoprolol ordinary formulation in clinical application.At present,the domestic market is only Toprol-XL developed by Astra Zeneca.This study will independently develop metoprolol succinate sustained-release tablets with the same quality as Toprol-XL in order to meet the needs of the domestic market and increase the availability of drugs.In this study we established content method by HPLC,release determination method by UV.In content determination methodology experiment,the peak area of metoprolol succinate in mobile phase had fine linear relation with concentration of metoprolol succinate solution in range of 19.22 ～ 115.32μg/m L,the linear coefficient was0.99995.The average recoveries in 80%,100% and 120% concentration of metoprolol succinate solution were 99.52%、99.76%、99.91% respectively;RSD(%)were0.42% 、 0.43% 、 0.47% respectively;in release determination experiment,the absorbance of metoprolol succinate in dissolution medium of in p H6.8 phosphate buffer had fine linear relation with concentration of metoprolol succinate solution in range of 9.57～114.86μg/m L,the linear coefficient was 0.99995.To use reverse engineering techniques,through the preparation of the reference formulation analysis,and to use of ion cutting,scanning electron microscope and other equipments,speculated the prescription formulation composition,key processes and the size of the sustained-release pellets.At the same time,using the free film technology,the different coating prescriptions were prepared into free film using the planar cast film method.With the mechanical properties as the inspection index,the appropriate prescription was applied to the coating prescription.The fluidized bed technique of preparing drug-loadede pellets,single factor experiments result show that the inlet air temperature,atomization pressure and supply rate were the key factors affect drug efficiency.On this basis,the orthogonal design optimization of the fluidized bed process,get the optimal formulation: feed volume300 g,fan frequency 16-20 Hz,inlet air temperature 70°C,material temperature 55°C,supply rate 15 rpm,atomization pressure 1.0 bar.The preparation of the three batch of drug-loaded pellets had drug efficiency of more than 90%,the yield reached 99.43%,and the drug-loaded pellets of roundness and friability are in compliance with the pharmacopoeia standards.The fluidized bed spray coating technique of preparing sustained-release pellets,and determine the parameters of the fluidized bed.To Eudragit NE30 D for sustained layer,the key factors affecting the rate of drug release: coating thickness,antisticking agent factors determine the optimal coating formulation: coating weigh reached 35%,talcum50%.To Surelease for sustained layer,single factor experiments result show that the coating weight and the proportion of porogrns were the key factors affecting the rate of drug release.The optimal formulation of coating carried out by central composite design-response surface methodology,which contained coating weight reached 43.39%,the proportion of porogrns 14.71%.Prescription validation test showed that the two kinds of sustained-release pellets prepared by different coating basically consistent with release curve of generic formulation and the prescription process were stable and highly reproducible.Through investigating the physical properties of different types of microcrystalline cellulose,PH200 MCC and UF711 MCC were selected as the main excipients of the filling layer.The prescription was further optimized,the ratio of that was 2:1,and the key factors affecting the rate of drug release,get the optimal formulation of metoprolol succinate tablets containing sustained release pellets for:metoprolol succinate sustained-release pellets 46.06%,PH200 MCC 31.33%,UF711 MCC 15.67%,sodium stearyl fumarate 0.94%,film coating 6%.Prescription validation test showed that the independently basically consistent with release curve of generic formulation.The in vitro release data of the metoprolol succinate tablets containing sustained-release pellets were fitted with the zero order equation,the first order equation and the Higuchi equation.The results showed that the data of metoprolol succinate tablets containing sustained-release pellets in vitro release could be well fitted with the first order equation.In this study,reverse engineering and free film technology were applied to the development of metoprolol succinate tablets containing sustained-release pellets,providing a new paradigm for the development and research of tablets containing sustained-release pellets.This study integrated use of the single factor investigation,orthogonal design and central composite design-respose surface methodology,independent research of metoprolol succinate tablets containing sustained-release pellets.Scanning electron microscopy showed that the morphology of the sustained-release pellets prepared with the two different coating formulations was well-rounded,the surface was smooth and there was no breakage and fusion after pressing.