Famotidine Oral Pulse Study Of Controlled-release Pellets

With the development of chronobiology ,it is realized that many physiological phenomena such as blood pressure ,heart-beating rate, gastric acid secretion and many disease symptoms such as hypertension, asthma, rheumatic arthritis exhibit circadian rhythms. Time-controlled delivery system releases drug and achieves an effective drug level at the required time so that optimum therapy can be obtained.According to the fact that gastric acid secretion reaches its climax at 21:00?2:00 in the evening, we prepared an orally applicable time-controlled release capsule(TRC)using famotidine as the model drug, which was administered in the morning while reaching plasma concentration climax in the evening. At the same time, we prepared normal pellets which released drug immediately after administration. The two types of pellets were put into one capsule together in proportion in order to prepare famotidine pulsed release capsule(PRC)which released drug two times a day while being administered only once.Ultraviolet spectrophotomatry method was developed for assay during the study of physicochemical properties, content and drug release. Some physicochemical properties of famotidine were investigated, which were connected closely with phannaceutic form design. In order to increase extraction recovery, we use solid phase extraction (SPE)to extract famotidine from human plasma. Precise and reliable HPLC method was developed for in vivo assay.To clarify the absorption of famotidine from gastrointestine, the absorption was studied by utilizing the rat intestinal absorption recirculating method in situ. No significant difference of value of Ka was absorbed among duodenum, jejunum, ileum and colon. The mechanism of intestinal absorption was studied with different drug concentrations, which suggested that the intestinal absorption of famotidine was via passive transport mechanism.The pharmaceutic form design was devided into two parts. Nomal pellets3ABSTRACTwere prepared by extrusion-spheronization. Time-controlled release pellets were 搊rganic acid-induced type drug delivery system? The core pellets, which contained organic acid, were prepared by extrusion-spheronization also and the coating process was performed on a mini-fluidized bed spray coater. Because the drug release behavior was dependent on both organic acid and the polymer, orthogonal design test was used to obtain optimal formulation. We also studied some factors which affected the release of the drug from the time-controlled release pellets.The release profile of TRC pellets in vitro complied with zero order kinetics. The coated pellets were film-controlled release sysf em. The organic acidinduced drug delivery system has a typical sigmodical release profile which achieved a prolonged lag time, followed by rapid release. We studied the drug release mechanism on the basis of lots of experiment results.Plasma concentration-time profiles in three healthy volunteers after oral administration of TRC, PRC and normal pellets were determined by HPLC and the pharinacokinetic parameters of the three types of formulations were calculated. The lag time of TRC was dramatically prolonged and t~ was obviously delayed, indicating that TRC had positive effect of time-controlled release system. The plasma concentration-time profiles of PRC had two peaks. T,~1 and tm~2 were 1.5h and 12h. Cmaxi and Cm~ were 82.1 ng/ml and 44.3 nglml. The comparative bioavailabiity were 95.22% and 93.83% .Obvious correlation (r=O.9869) existed between absorption fraction in vivo and the release percentage in vitro.