Anti-rheumatic Drug Kirenol's Preparations And Research

ObjectiveResearch the physicochemical properties and absorption and metabolism and excretion of kirenol.Develop a variety of formulations of kirenol like tablet and matrix sustained release pellet.MethodsEstablish the method of the determination of kirenol to study its basic physical and chemical properties.The main absorption site,absorbing mechanism and the influencing factors of kirenol were studied by combining the methods in situ stomach perfusion and reversal intestinal sac in rats.The metabolic stability of kirenol was researched in human,rats,mice three liver microsomals with incubation in vitro system.Compared with LC-MS determination of the beagles' plasma levels of the kirenol,the pharmacokinetic parameters and excretion situation of the kirenol in the body were obtained.Preparing kirenol tablets with direct compression method and screening suitable materials.The kirenol matrix sustained release pellets were prepared by extrusion spheronization.The formulation and technology parameters were optimized according to in vitro release and the micromeritic properties of pellets.The relative bioavailability of kirenol formulations were investigated with beagles.Results:The results of the experiments in situ stomach perfusion and reversal intestinal sac in rats indicated that the absorption in rats intestinal was better and the absorption complied with the passive transport mechanism.The liver microsomal incubation in vitro experiments showed that the concentration of kirenol were unchanged basically before and after the response which concluded that kirenol was not metabolized by liver.The pharmacokinetics of kirenol in beagles showed that the T1/2a was 0.128±0.038 h,T1/2a was 0.309±0.137h,T1/2? was 1.694±0.506 h,Ka was 5.783±1.991 h-1,Cmax was 135.631±42.986 ng·mL-1,AUC was 205.669±39.96 ng·h-1·mL-1?The excretion experiment results showed that urine was the main way of kirenol discharge.The prepared kirenol tablets met required standards by the quality inspection.The prepared kirenol matrix sustained release pellets were in line with the requirements of controlled-release formulation.The pharmacokinetics of kirenol formulations in beagles showed that the AUC0-24,of pellets preparation were 560.274±37.395 ng·h-1·mL-1,Cmax were 103.609± 18.835 ng · mL-1,Tmax were 1h;the AUC0-24 of tablets preparation were 363.775±19.827 ng·h-1·mL-1,Cmax were 131.759±10.381ng·mL-1,Tmax were 0.5h.The relative bioavailability of kirenol matrix sustained-release pellets was 154.02%calculated as AUC0-24.The Tmax extended obviously and Cmax reduced and the drug consistence was in blood steady.Conclusion:Combined with rats' gastrointestinal absorption experiment and liver microsomal incubation in vitro experiment and beagle' s pharmacokinetic experiment,the absorption and metabolic mechanism and relevant pharmacokinetic parameters of kirenol were obtained.The kirenol matrix sustained-release pellets with high bioavailability and good stability were prepared successfully which can provide important theoretical foundation and experimental basis for research development and application of kirenol.