Studies On Metoprolol Succinate Sustained Release Pellets Coated With Ethylcellulose And The Model Drug Itself As A Pore Former

Metoprolol Succinate （MS）, a β-blocker clinically used to treat hypertension, angina pectoris andarrhythmia, has a relatively short plasma half-life （t1/2） of3-4h. The absorption of MS is rapid andcomplete throughout most of the gastrointestinal tract. It is therefore a logical candidate for thedevelopment of a controlled release formulation in order to provide an even effect over24h inhypertension and coronary heart disease with convenient once-day treatment. Compared to conventionaloral controlled-release drug delivery systems（OCDDS）, a multiple-unit pellet system （MUPS） providesmany advantages, such as better statistical assurance of drug release, less potential for dose dumping tominimize the local concentration of drug, less in-vivo and in-vitro subject variability, allowing the drug tospread throughout the gastrointestinal track more evenly and thus providing a more predictable gastrictransit time and drug absorption and gastric emptying that is independent of the nutrition state. At present,there are not any kind of independent research and development of products to market in our country, andsome foreign reports on the study of metoprolol succinate with the problem of zero release in prophase andburst release at late stage. This topic is based on the principle of the osmotic pump and coated pelletsrelease mechanism, the high-water-soluble model drug metoprolol succinate is selected as a pore former,added into a coating material which, by a fluidized bed coating technology, the use of reasonable theexperimental design and optimization program, preparing metoprolol succinate sustained-release coatedpellets with no zero-release or late burst release problem.In-vitro assay development and prescription of metoprolol succinate is studied at first, it has themaximum absorption in the274nm wavelength; solubility tests showed that metoprolol succinate is highlywater-soluble drugs; solution stability test shows it is stable in water,0.1mol L^-1hydrochloric acid solutionand pH6.8phosphate buffer solution for24hours for metoprolol succinate; thermodynamic analysis andX-ray powder diffraction analysis showed that metoprolol succinate is substance and no interaction with theexcipients. UV-visible spectrophotometry determination of content and in vitro release for metoprololsuccinate is builded in this article. It has a good linear correlation at40¹80μg ml^-1. The average recoverywas101.25%, and the relative standard error of0.5%. The relative standard error of within-day and day to day precision are less than2%. The article also examines the Influence of the medium and the impact ofspeed on the in-vitro release of metoprolol succinate.Metoprolol Succinate’s physicochemical properties such as ultraviolet absorption spectrum, stabilityin solution and pre-formulation were studied at first. The objective of this study was to develop MS pelletscoated with a novel, controlled-release membrane consisting of ethylcellulose （ethocel, standard10premium） and the model drug itself to overcome the lag phase associated with drug release. MS-loadedcores （drug loading,80%w/w） were prepared by layering the drug solution onto Non-pareil and thencoating the drug solution with bends of ethocel and the model drug itself （used as a pore former）. Atwo-factor, five-level central composite design and response surface methodology （CCD-RSM） wasemployed to optimize and explore the effect of pore former level （X1） and coating weight gain （X2） on therelease rate of the drug from the pellets. The percentage of drug released at given times （Y1, Y2, Y3, Y4andY5） was selected as a dependent variable. The level of X1and X2of the optimized formulation were17%and23%, respectively. A model was fit to the data that explained90%of the response variability, and therelease profile was optimized to a first-order model. Interestingly, the lag phase of the drug release profilewas absent, and the cumulative percent of MS released within1h was up to9.15%. Additionally, the drugrelease profiles of the obtained pellets were not changed by variations in pH within the simulativephysiological range and were independent of variations in peristalsis, as simulated by agitation in vitro.Furthermore, the optimized product was characterized by thermal, X-ray, and SEM analyses. Thermal andX-ray analyses suggested the absence of any significant interaction between the drug and the excipientsincorporated in the formulation. Meanwhile, the coated drug （pore former） was present in both itscrystalline form and in a drug layer. SEM photographs showed the integrity of the coating layer, with athickness of34-37μm. Thus, MS controlled release pellets coated with ethocel and the model drug itselfwere successfully designed and demonstrated advantageous features.