| Objectives : Hypertensive is the number one killer of death and disability of cardiovascular disease in Manipulation elderly, World Health Organization pointed that: it expects that by 2020, due to cardiovascular disease,,the number of the deaths caused by is high to 79% of the total, high blood pressure and its disease-induced seriously threat to human life and health. Metoprolol succinate is dose-dependent β1-blockers, The peak of plasma concentration of sustained release formulations is more lower than general formulation with the same dose, orally once each day you can get a day continuous β1 receptor blocker lag effect within 24 hours, so that β1 receptor selectivity of the dosage form has improved significantly. Currently the marketed sustained-release tablet is metoprolol of the Swedish Astra Zeneca. The purpose of this study is to develop a sustained-release metoprolol succinate capsules, due to eliminating the tedious process of tablet, compared with sustained-release tablets,it have a simpler preparation process, but also to prevent the process of sustained-release pellets from damaging. Increases the bioavailability of the drug, to reduce the incidence of adverse reactions and improve patient compliance.Methods:1 Preparation of a sustained-release metoprolol succinate capsules: Taking the druging loading rate as the index, investigate the effect of different binder, to determine the best prescription of drug layer coating solution. Taking the druging loading rate as the index, and observing the fluidized state of drug pellets,after repeated pre-experiment,to investigate the amount of wind, spray pressure, the material temperature and velocity of the liquid,to screen the best equipment parameters. Study and observe the releasing degree of the pellets,investigate the effect of different sustained-release coating material, porogen, and the type of plasticizer. Study and observe the releasing degree of the pellets, to determine the amount of plasticizer, the amount of porogen and sustained release coating weight gain though L9(33),and to screen the best formulation of the release layer coating solution and the sustained-release coating weight gain. Study and observe the releasing degree of the pellets, investigate the effect of different species of pareil and to choose the best.2 Research on quality control of metoprolol succinate extended- release capsules: established UV spectrophotometric method for the vitro releasing degree of metoprolol succinate extended- release capsules and to investigate the Methodology. established HPLC method for the determination of content and content uniformity and carried out the methodological studies. Prepared metoprolol succinate extended- release capsules in accordance with the best prescription, and studied the stability of the preparation with the evaluation indexes of appearance, content and dissolution. Both testing and accelerated testing were also carried out.3 Bioavailability studies: 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, A HPLC method was developed for the determination of metoprolol succinate in Beagle dog plasma. In this study, We study its pharmacokinetics, relatively bioavailability, bioequivalence and the in vitro-in vivo correlation(IVIVC).Results:1 The best prescription and preparation process of the coating liquid of drug loading layaer were selected through the single factor test and orthogonal test design.Coating liquid prescription:Blank MCC pellets 300gMS 300gHPMC E10 24gWater 1200gPreparation process: Dissolve HPMC E10 of the prescribed dose with theprescribed amount of water, make it though 100-mesh sieve,then add theprescribed amount of MS,and stir to dissolve.Screen the best formulation of the release layer coating solution thoughL9(33):Drug-containing pellets 150gEthyl cellulose 45gTriethylcitrate 9gHPMC E5 9g95% ethanol 1350gWater 270gPreparation process: Dissolve Ethyl cellulose and Triethylcitrate of the prescribed dose with 750ml95% ethanol, dissolve HPMC E5 with 375ml95% ethanol, mix the two solutions thoroughly and add the remaining 225ml95% ethanol, mix with a magnetic stirrer thoroughly.By examining the results of the analysis of sustained-release pellets releasing, select MCC pellets as pareil. Determine the parameters of the fluidized bed Through several preliminary experiments :Amount of wind 85m3.h-1Spray pressure, 1.4Kg/cm2Material temperature 35℃-36℃Velocity of the liquid 0.75ml/min2 Established a UV spectrophotometric method for the determination of dissolution rate of sustained-release capsules of metoprolol succinate. Select phosphate buffer of p H6.8 as releasing medium, The detection wavelength was 274 nm with no interference of excipients. The methodological study results showed that within the concentration range of 12.5 μg.ml-1-200μg.ml-1, he linear relationship between absorbance and concentration of metoprolol succinate was good, recovery and precision both meet the requirements, This method can be used for the determination of the dissolution rate of sustained-release capsules of metoprolol succinate.3 Established HPLC method for the determination of content of sustained-release capsules of metoprolol succinate. The detection wavelength was 274 nm with no interference of excipients and mobile phase. The methodological study results showed that within the concentration range of 12.5 μg.ml-1-200μg.ml-1, the linear relationship between peak area and concentration of metoprolol succinate was good. recovery and precision both meet the requirements, This method can be used for the determination of the content of sustained-release capsules of metoprolol succinate.4 Study on stability of self-made capsules:Under the conditions of high temperature(40℃), strong light( 4500Lx) and accelerating testing,there was no significant change in the appearance, content, and dissolution. Under the conditions of high temperature(60℃), there was no significant change in the appearance, content, but the eventual releaseing degree of the first 10 days reduced to the amount of about 85%, under the conditions of wet RH92.5% and RH75% for 5 days and 10 days, the capsules surface changed slightly wet and soft,but the moisture absorption is less than 1%, the releasing rate speed up,the cumulative releasing degree of 4h and 8h is overrun, but the content both meet the requirements, the capsules should avoid high temperature and humidity.5 Established a HPLC method for determination of metoprolol succinate blood drug concentration, wavelength was 274 nm, blank determination had no interference on mian drug. The linear relationship was good in range of 5 ng/m L ~ 160 ng/m L, recovery and precision both meet the requirements, Relatively bioavailability of test preparation was 92.55%, and there was a good correlation between absorption in vivo and drug release in vitro(γ=0.9678).Conclusions: The formulation and preparation of controlled release capsules of metoprolol succinate was simple and feasible, preventing the sustained-release pellets from destruction because of the process.Drug release in the form of more cells, it contact with the gastrointestinal tract broader, prevent high drug concentration form strongly stimulating the gastrointestinal tract. The methods were established for the determination of content and dissolution. Experiments show that sustained-release capsules of metoprolol succinate should be kept to avoid high temperature and the humidity. The vivo pharmacokinetic studies had shown that compare to reference preparation, self preparation had relatively high bioavailability(F=92.55%), and there was a good correlation between absorption in vivo and drug release in vitro(γ=0.9678). |
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