| Edaravone(3-methyl-1-phenyl-2-pyrazolin-5-one)is the world' s first neuroprotective agent,developed by Mitsubishi Pharma Corp.in 2001.It has been widely used in clinical,specially in the treatment of nervous system symptom,daily life movement disorders and dysfunction caused by acute cere bral infarction.The purpose of this research is to develop an oral drug delivery system.This study include three parts.Firstly,obvious,the oral absorption mechanism of edaravone should be in-depth study in order to definite the best absorption site and to investigate the factors affecting the absorption.Furthermore,the pharmaceutical preparation of edaravone can go on wheels according to the result of the oral absorption mechanism.Certainly,the formulation,preparation technology,the release behavior and the pharmacokinetics in vivo have been investigated to clear and definite the absorption,distribution and metabolism of preparation in vivo.Simultaneously,the results provide basic data and the development basis for future clinical application,and finally help develop an oral preparation of edaravone with high bioavailability and high compliance.To provide a good quantitative method,chromatographic conditions for content determination are obtained through some experiments and the methodology study is carried on to validate the feasibility and the veracity of this HPLC method.In the research on basic physical and chemical properties of edaravone,we find that sodium hydrogen sulfite can prevent oxidation of edaravone and increase the solubility of edaravone in fluid of Taiwan' s.The absorption,absorption mechanism and factors affecting absorption are investigated through Valgus gut sac model.Results show that edaravone is absorbed by duodenum,jejunum and ileum with the absorption rate constant Ka of 0.0171 ± 0.0082,0.0348 ± 0.0.0026,0.0183 ± 0.0017 min-1(n=3),respectively.This indicates that jejunal absorption is better than that of duodenum and ileum,and colon were little absorption.Different concentration and pH of Tyrodecan affect the absorption of edaravone.With the increase of concentration,the uptake of edaravone is increase but the absorption rate constant is almost the same,which indicates the intestinal absorption of edaravone is passive diffusion.Edaravone gets better absorption at pH6.0 in jejunum.The gastric absorption is studied through In situ stomach absorption method.Results show the absorption percentage in stomach 2h after administration is 38.29±5.17%,79.63±4.45%(n=3)4h after administration and the absorption rate constant Ka is 0.2344 ± 0.0372h-1(n=3).Here is the conclusion the gastric absorption of edaravone is better than the intestinal absorption,which gives a good reason to develop the gastric retention preparation of edaravone.After optimization of formulation and preparation technology,the optimal formulation is obtained which includes microcrystalline cellulose 29%,edaravone 30%,Glyceryl Behenate 30%,lactose 10%,and sodium bisulfite 1%.The optimal preparation technology is:extruded velocity 27rpm,rolling speed 504rpm,rolling time 6min.After preparation,the pellets are put in oven drying for 12 h at 37?,then elevate the oven drying temperature to 75? and maintain it for 3h.The pellets sieved from 16-30 mesh are coated with mixture of HPMC:MCC(1:1)to the coating level of 20%.Finally,the pellets coated with adhesive layer are tableted with optimal adjuvants.The gastric adhesive pellets tablet of edaravone is obtained.The adhesion behavior and drug release behavior are evaluated by determinating the drug release amount in vitro and gastrointestinal adhesion rate in rats.The pharmacokinetics of stomach adhesive pellets tablet in rats in vivo is evaluated and the determination method of edaravone concentration in rat plasma is established.To compare with edaravone in physiological saline solution,the relative bioavailability of this preparation is 165%,whichindicates that the preparation improve the oral bioavailability of edaravone. |
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