Mucoadhesive Nanoemulsions for Nose-to-Brain Delivery of Dimethyl Fumarate: Development, Characterization and Proof-of-Concept In Vivo Evaluation
TL;DR
These findings provide pharmacokinetic proof-of-concept supporting further investigation of this intranasal formulation for CNS delivery of DMF, and show high biocompatibility and reciprocal enhancement of stability.
Abstract
Background: Dimethyl fumarate (DMF) is an approved therapeutic agent for the treatment of multiple sclerosis, known for its anti-inflammatory and neuroprotective properties. However, its oral administration is often accompanied by gastrointestinal side effects, limiting its therapeutic potential. In the present study, a novel nanoemulsion (NE) formulation was developed and characterized with the aim of enhancing DMF exposure in the cerebrospinal fluid (CSF) following intranasal administration. Methods: The formulation was prepared via a self-emulsification method using geraniol (GER) as the oil phase, selected for its antioxidant properties, and chitosan oleate as a mucoadhesive stabilizer and absorption promoter. Physicochemical characterization, in vitro release, RPMI 2650 cell cytotoxicity, and permeability were evaluated. Finally, an optimized NE (1.08 ± 0.02 mg/mL DMF and 0.28 ± 0.01 mg/mL GER) was administered intranasally to adult male Sprague–Dawley rats to assess DMF and GER exposure in the CSF. Results: The NEs exhibited optimal physicochemical properties: a mean particle size of approximately 170 nm, a polydispersity index below 0.3, and a positive zeta potential (above 20 mV). Spectroscopic and thermal analyses confirmed GER and DMF compatibility and a reciprocal enhancement of stability. In vitro drug release studies revealed a fast release profile, with 81% of DMF released within 2 h, aligning with the rapid absorption expected from nasal administration. Cytotoxicity assays showed high biocompatibility (>86% viability up to 50 µM DMF), while permeability studies demonstrated significant absorption, with 60% of DMF and 90% of GER absorbed within 2–3 h, favored by smaller droplet size. In rats, intranasal delivery achieved maximum CSF concentrations of ~8 µg/mL for DMF and ~1.5 µg/mL for GER within 2 h. Conclusions: These findings provide pharmacokinetic proof-of-concept supporting further investigation of this intranasal formulation for CNS delivery of DMF.