Preparation and characterization of a naringenin solubilizing glycyrrhizin nanomicelle ophthalmic solution for experimental dry eye disease

Abstract

An ophthalmic solution of naringenin (NAR) based on dipotassium glycyrrhizinate (DG) micelle solubilization, called DG-NAR, was prepared, and its effect on dry eye disease (DED) was evaluated. DG-NAR was a clear, colorless aqueous solution with small micelle size (24.75±0.52 nm), narrow size distribution of polydispersity index 0.273±0.160, and a high entrapment efficiency (99.67±0.51%). The solution also revealed good storage stability in a 12-week short-term storage evaluation; it also displayed good vivo ocular tolerance in rabbit eyes investigated via a slit lamp observation and histopathological examination. When observed under fluorescence microscopy, the solution further exhibited improved in vivo corneal permeation profiles in mice eyes. As expected, in a BAC-induced DED mouse model, ocular topical administration of DG-NAR achieved a remarkable efficacy against dry eye symptoms when compared to the DG&NAR physical mixture solution or free NAR solution; this included decreased rose bengal and fluorescein staining, increased tear volume and corneal sensitivities, alleviated histopathological symptoms, and reversed corneal epithelium and endothelium damages. Additionally, performance in some efficacy evaluation parameters were better than in the commercialized 0.1% hyaluronic acid sodium salt eye drops. This therapeutic effect can be attributed to the mechanisms regulating HMGB1 signaling and its related proinflammatory cytokines. Together, these in vitro/in vivo results suggested that this novel phytochemical-based nanoformulation of DG-NAR may be a promising candidate in the efficacious treatment of DED.