Journal
MOLECULAR PHARMACEUTICS
Volume 20, Issue 6, Pages 3115-3126Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.3c00103
Keywords
ionic liquid; edaravone; antioxidant; cerebroprotective agent; nanoparticles; cerebral ischemia; reperfusion injury
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Researchers have developed a new form of the antioxidant drug edaravone, called edaravone-IL, by using an ionic liquid (IL) preparation. The edaravone-IL demonstrated improved physicochemical properties and bioavailability, with increased water solubility and reduced distribution in the kidney. It also showed significant therapeutic effects against cerebral ischemia/reperfusion (I/R) injury.
Preparation of the ionic liquid (IL) form of active pharmaceutical ingredients (APIs), termed API-IL, has attracted attention because it can improve upon certain disadvantages of APIs, such as poor water solubility and low stability. Edaravone (3methyl-1-phenyl-2-pyrazolin-5-one) is a clinically approved cerebroprotective agent against ischemic stroke and amyotrophic lateral sclerosis, while new formulations that enable improvement of its physicochemical properties and biodistribution are desired. Herein, we report a newly developed API-IL of edaravone (edaravone-IL), in which edaravone is used as an anionic molecule. We investigated the physicochemical properties of edaravone-IL and its therapeutic effect against cerebral ischemia/reperfusion (I/R) injury, a secondary injury after an ischemic stroke. Among the cationic molecules used for edaravone-IL preparation, the IL prepared with tetrabutylphosphonium cation existed as a liquid at room temperature, and significantly increased the water solubility of edaravone without decreasing its antioxidative activity. Importantly, edaravone-IL formed negatively charged nanoparticles upon suspension in water. Intravenous administration of edaravone-IL showed significantly higher blood circulation time and lower distribution in the kidney compared with edaravone solution. Moreover, edaravone-IL significantly suppressed brain cell damage and motor functional deficits in model rats of cerebral I/R injury and showed comparable cerebroprotective effect to edaravone. Taken together, these results suggest that edaravone-IL could be a new form of edaravone with superior physicochemical properties and could be useful for the treatment of cerebral I/R injury.
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