Development of an Injectable Formulation of a Water-Insoluble Glycyrrhizin Derivative That Potently Inhibits High-Mobility Group Box 1 in Murine Intracerebral Hemorrhage

High-mobility group box (HMGB) 1, a nuclear protein that acts as an inflammatory mediator, exacerbates injury following intracerebral hemorrhage (ICH). Glycyrrhizin, a natural HMGB1 inhibitor derived from licorice, alleviates ICH-induced inflammatory responses, including brain edema formation. In our previous study, inspired by the bioconversion of endophytes living symbiotically in licorice, we discovered a glycyrrhizin derivative with more potent anti-HMGB1 activity than glycyrrhizin. However, this derivative is poorly soluble in water, and some issues remain to be resolved when applying it to treat ICH. The aim of this study was to develop an injectable formulation of a water-insoluble glycyrrhizin derivative (WIGLD) to treat acute ICH. Screening of Pluronic surfactants revealed that Pluronic P103 significantly improved the solubility of WIGLD. The micelles had a particle size of approximately 20 nm; therefore, this formulation was considered suitable for intravenous injection. Thus, we investigated the therapeutic efficacy of an intravenously injected solubilized WIGLD formulation in a murine model of ICH induced by intrastriatal collagenase injection. The injected WIGLD formulation increased brain penetration compared to that after oral administration. Additionally, it inhibited microglial activation by HMGB1, decreased brain edema, and ameliorated neurological deficits. These findings suggested that the injectable WIGLD formulation, with its potent anti-HMGB1 activity, represents a promising therapeutic strategy for managing ICH-related brain edema and associated injuries.