Carvacrol-based nanoemulsions loaded with dimethyl fumarate intended for nose to brain delivery for treatment of multiple sclerosis.

Dimethyl fumarate (DMF) is a first-line oral medication for the treatment of multiple sclerosis (MS), unfortunately associated with several adverse events, mainly affecting the gastrointestinal tract. Intranasal drug delivery could potentially alleviate these adverse events enhancing the therapeutic efficacy. This study aims to formulate an oil-in-water (o/w) nanoemulsion (NE) encapsulating DMF solubilized in carvacrol (CV), a neuroprotective essential oil component, for a possibly synergistic therapeutic effect. Chitosan oleate as amphiphilic polymer has been selected as a surfactant, owing to its mucoadhesive and permeation enhancement properties. Spectrophotometric (FT-IR) and thermogravimetric analyses used to characterize the DMF-CV combination, revealed an increased stability of DMF due to the presence of CV. Response surface methodology was used for the optimization of NE formulations by applying the Central Composite Design model. The final optimized formulation showed a mean size of around 200 nm, a polydispersity index of about 0.3, a positive zeta potential (about + 30 mV) as attended and a drug content of about 70%. Moreover, NEs demonstrated good cell viability and permeability on RPMI 2650 nasal cell lines. DMF-CV NEs are a promising tool to further studies to verify nose-to-brain efficacy of DMF and therapeutic synergism with CV, in the perspective to reduce the adverse events related to DMF, enhancing therapeutic efficacy as well as patient compliance and medication adherence.