| The research was aiming at the preparation of ondansetron 24h sustained-released pellets and validation in vivo, consisting of preparation methods for pellets, the sustained- release system of coated pellets, stability, pharmacokinetics. The results show: the sustained-release pellets exhibited a marked sustained-release property and the drug was released in vivo over 24h.Ondansetron (abbr. OND), a highly selective 5-HTj antagonist, has a good effect on prevention of nausea and vomiting induced by cyctotoxic drugs and high dose radiation. Preformulation studies illustrated that solubility of OND HC1 is highly dependent on pH values. In distilled water, simulated gastric liquid and simulated intestinal liquid, its solubility is 1.42, 0.50, 0.015g/l 00ml respectively, which directly leads its slow release in stimulated intestinal liquid. Considering this, different sustained-release oral ondansetron pellets were developed aiming to obtain the most constant and complete release of the drug during transit in gastrointestinal tract.By DSC, Glass transition temperature of different aqueous acrylic polymer dispersions such as Eudragit NE30D, Eudragit FS30D, Eudragit RS30D, Eudragit RL30D and their blends were tested. It illustrated that the formation of a heterogeneous film is possible either by increasing the drying temperatures above the film forming temperature of the blends or by adding effective plasticizers in order to decrease the Tg values of the hardest polymers.A Plackett-Burman screening design was employed to isolate critical parameters that influenced the yield of pellets bys Extrusion-spheronizationmethod. The result of this study found that amount of water, width of sieve and spheronization time had greater influences on the yield of pellets. Then, 23 full factorial design had been used to investigate the main effects and their interactive effects of amount of water, width of sieve and spheronization time on the yield, sphericity and friability. Pellets with good sphericity, high yield and appropriate hardness was produced.Pellets were coated with aqueous dispersion (Eudragit NE30D and Eudragit FS30D) using mini-fluidized bed spray coater. The effects of process variables and formulation variables on coating pellets preparation were investigated. The results showed: the coated pellets had a marked sustained release property. The coating level, the ratio of NE30D to FS30D and amount of pore-forming agent could alter the release rate of the drug. The stability of the preparation was investigated under 4500Lx light condition, 40 癈 and 75%RH, room temperature and 60%RH. The results showed that the preparation was stable.A reversed-phase HPLC method was established for determination of OND drug plasma concentration. Pharmacokinetics of ondansetron sustained-release capsule and conventional capsule was studied in three dogs. The AUC of conventional capsule (170mg) and sustained-release capsule(170mg) were 345. 51 34.10ng/ml h, 322.22 17.89ng/ml h respectively. The Cmax and Tmax of conventional capsule were 157.39 35.53ng/ml and 1.16?.14h. The sustained-release capsule had double peaks, Cmax1 and Tmax1 were 37.37.63 4.44ng/ml and 9h, Cmax2 and Tmax2 were 26.01 0.60ng/ml and 12h. The relative bioavailability of OND were 93.3% compared with conventional capsule. It was very significant between in vivo absorption and dissolution in vitro using Wagner-Nelson equation to calculate the in vivo absorption fraction.Consequently, sustained-release capsule dosed daily was expected to show amore efficiency than its reference dosed 3~4 times a day. |
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