Study On Isosorbi Dedinitrate Sustained-release Pellets

Isosorbide Dinitrate（ISDN）was organic nitrate drug.It was used to prevent andtreat angina andeo ngestive eardiac failure in clinieal.it was absorbed completely afteroral administration, but there was a obvious first pass effect.the half-time in plasmawas about30-60min,acause of short half-time and obvious first pass effect, so it wassuitable to be made into sustained-release preparation. The peak time of ISDNsustained-releas preparation was significantly prolonged and absorption phase wasdelayed. The concentration of ISDN and its metabolites in plasma changed graduallywith the time elapse.An HPLC method was set to assay the content as well as to determine the releaseof ISDN in sustained release pellets.The method is easy to operate,results isaccurate,reproducibility and stability is high.The method can be used for the analysisand control of isosorbide dinitrate in vitro quality.The preformulation study showedthat:the ISDN had a low solubility in various physiological pH medium,it stanble inwater and methanol can meet the demand of operation time.ISDN pellets were prepared with the centrifugal granulatim equipment.After theformulation screening and process evalution by Orthogonal experiment design,thequality and yield of the objective pellets were improved.The fluid-bed spray proessor was adopted for coating of the pellets withEudragitRLPO and EudragitNE30D as sustained release coating material.The coatingprocess variables were determined by single factor examination,The effects ofanti-tacking agents,static electricity-proof,coating level and curing time,etc.on drugrelease of pellets were studied.Coating solution formulation and technology processwere optimized by orthogonal experiment design and central composition design.Afteroptimized,similarity factor was used to evaluate the suatained release pellets and had asimilar in vitro release behavior to reference,the f2=69.9.The pellets were coated by centrifugal method with alcohol solvent coatingfluid,the result showed that:compared with the fluid-bed coating this method had theadvantages of large capacity, easy to operate and the parameters are easy to control.The matrix sustained release pellets were prepared by centrifugal granulation method with blank MCC pellets as core,orthogonal experiment design was used tooptimized Process parameters.Compared with other methods, the method has theadvantages of fast molding, high yield, good flatness, particle sizedistribution.Compared with the coated pellets,there are advantages as simple process,low cost and so on.based on the research of drug release mechanism it showed that themechanism of self-made ISDN sustained release pellets beonged to non-Fickianrelease kinetics.Stability test showed:ISDN sustained release pellets were stable when exposed tolight and temperature,but not high moisture,so avoid moisture storage is necessry.An HPLC method was established to monitor the plasma concentration inrabbit.Pharmacokinetics studies of ISDN sustained pellets in rabbits were performedby two-treatment,two-period randomized crossover design.The result showed that: thepharmacokinetics parameters of test and reference formulations were calculated withCmaxas536ng/ml and569ng/ml,Tmaxas6.5h and6.8h.Correlation between in vitro andin vivo was calculated by Wagner-Nelson method,it showed that:absorption percent invivo(Fa) and accumulative release percent in vitro(Fd) had good linear correlation.