Stabilizers of edaravone aqueous solution and their action mechanisms. 2. glutathione

Abstract

Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) has garnered attention since its approval for amyotrophic lateral sclerosis in Japan (2015) and the United States (2017). Edaravone is admin-istered intravenously, and as such, is distributed in the form of an aqueous solution. However, aqueous solutions of edaravone are very unstable because they present as edaravone anions, which become edaravone radicals when the anion donates an electron to free radicals including oxygen. In this study, glutathione (GSH) stabilized an aqueous edaravone solution during storage at 60: C for 4 weeks, and prevented the formation of potentially carcinogenic phenyihydrazine, while cysteine did not. One possible explanation is that GSH undergoes intermolecular hydrogen bonding with edaravone anions, while cysteine does not as it favors intramolecular hydrogen boding. The combination of GSH and sodium bisulfite (NaHSOj) stabilized aqueous edaravone at room temperature for more than 1 year even under aerobic conditions. However, the U.S. Food and Drug Administration cautioned that NaHS03 may cause allergic reactions. Therefore, we developed a stable edaravone aqueous solution without using NaHSOj, namely a combination of GSH with deoxygenation, which resulted in better stabilization of aqueous edaravone than the combination of GSH and NaHS03.