Gastric retention pellets of edaravone with enhanced oral bioavailability: Absorption mechanism, development, and in vitro/in vivo evaluation

摘要

Absorption mechanism of edaravone (EDR) was studied to inform the preparation of gastric retention pellets with the aim to enhance its oral bioavailability. Three different models, namely, Caco-2 cells model, in situ single-pass intestinal perfusion model, and everted gut sac model in rats, were employed to characterize the gastrointestinal absorption kinetics of EDR. And it was found that passive transfer plays a vital role for the transport of EDR, and acidic condition is preferable for EDR absorption. Further, it is likely that EDR acts as a substrate for P-glycoprotein and multidrug-resistance protein. And hence, an orally available gastric retention pellets were developed accordingly. Pharmacokinetic experiments performed with rats and beagles showed that the absolute bioavailability of EDR solution and enteric-coated pellets following oral administration were 33.85% +/- 2.45% and 7.64% +/- 1.03%, indicating that stomach absorption is better than intestinal adsorption for EDR. However, the gastric retention pellets resulted in 68.96% absolute bioavailability and about 200% relative bioavailability in comparison to EDR solution, which was 9 times that of enteric-coated pellets. The present work demonstrates that gastric retention pellets has excellent potential as oral administration route for EDR.