Intracerebral delivery of the ionic liquid form of edaravone via nose-to-brain delivery route for treating cerebral ischemia/reperfusion injury

Abstract

Nose-to-brain drug delivery via intranasal administration is expected to be a promising route for efficient delivery to the central nervous system (CNS), as it allows for noninvasive and direct delivery of drugs to the CNS by avoiding the blood-brain barrier. However, the delivery efficiency of the administered drugs is still limited owing to poor mucosal epithelium permeation and mucociliary clearance. The use of ionic liquids (ILs) has garnered substantial attention in biomedical engineering for their potential to improve the physicochemical properties of active pharmaceutical ingredients and overcome biological barriers that impede drug delivery to the desired sites. We hypothesized that ILs are promising delivery platforms for achieving efficient permeation through the mucosal epithelium for nose-to-brain delivery. Herein, we newly developed IL forms of edaravone (edaravone-ILs), a clinically used cerebroprotectant, and applied them to nose-to-brain delivery to treat cerebral ischemia/reperfusion (I/R) injury. Through a series of in vitro studies, we found the biocompatible edaravone-IL which exhibits superior antioxidant activity and enhanced water solubility compared to that with native edaravone. Following intranasal administration, edaravone delivery to the brain was significantly more efficient with edaravone-IL than that with the edaravone solution. Moreover, the intranasal administration of edaravone-IL significantly ameliorated cerebral I/R injury in transient middle cerebral artery-occluded rats. These findings suggest that ILs offer a promising way for efficient intracerebral drug delivery via the nose-to-brain route and edaravone-IL could serve as a potential cerebroprotective agent for treating cerebral I/R injury.