Studies On Isosorbide Dinitrate Sustained-release Pellets

Isosorbide Dinitrate(ISDN)was organic nitrate drug,it was used to treat and prevent angina and congestive cardiac failure(CCF)in clinical.It was absorbed completely after oral administration,but there was obvious first pass effect.The half-life in plasma was about 30-60min, so it was suitable to be made sustained-release preparation.The absorption phase of ISDN was delayed and peak time was significantly prolonged.The peak concentration was lower.The concentration of ISDN and its metabolites in plasma changed gradually with the time elapse.An HPLC method was set to assay the ISDN as well as to determine the release of ISDN in sustained release pellets.The preformulation results showed that ISDN was slightly soluble in pure water and various pH media(pH1.2,pH2.0,pH4.0,pH5.8,pH6.8 and pH7.8),the solubility was 538.6,557.7,554.6,486.3,506.4,502.6 and 514.2μg·mL^-1,respectively.The apparent partition coefficiency in n-octanol/aqueous system was 8.12～11.98.It showed that ISDN was a high lipophilic drug.ISDN pellets were prepared by powder superimpose with a domestic centrifugal granulation equipment.After the formulation screening and process evaluation,it was discovered that the yield of the objective pellets,24-28 mesh cut,was more than 90%and the average content of ISDN was about 9%.The results showed the preparation process and the content of ISDN pellets can reach the expected goals.The coating formula composed of Eudragit NE30D,Eudragit RL 30D and Eudragit RS 30D mixture,respectively,were adopted for the coating of the pellets(powder layering method)by a fluid-bed.The coating level,anti-static agent,pore-forming agent,anti-tacking agent,plasticizers and curing time,as well as proportion of Eudragit RL 30D to Eudragit RS 30D were studied. Eudragit RL 30D and Eudragit RS 30D was selected for the excellent drug release character and convenient progress.Thus,the ISDN formulation was as follows:the solid copolymer in the coating suspension was 15%,the ratio of Eudragit RS 30D to Eudragit RL 30D was 4:1.The amount of SDS was 0.5%,the amount of TEC was 20%.The final product was underwent a 24 h curing period in a 40℃oven.The results demonstrated that the coated pellets showed obviously sustained-release effect,and the drug release profiles in vitro followed Higuchi kinetics.The sustained-release pellets were also prepared by extrution-spheronization method.ISDN together with stearic acid,octadecyl alcohol,carbomer and HPMC(K4M)was investigated.The matrix pellets cannot reach the expected goalsAn HPLC -UV method was established to monitor the plasma concentration in dogs.The plasma concentration of ISDN in dogs were tested after a single oral administration of sustained-release pellets(T)and commercial tablets(5mg/tablet)as a reference preparation.The C_max,of T and commercial tablets were 2.74mg·L^-1and 4.21mg·L^-1;The T_maxof T and commercial tablets were 6 h and 3 h,respectively.Compared with commercial tablets,the relative bioavailability was 101.12%.The results showed that T and commercial tablets were bioequivalent.