Nasal Administration of Hyaluronic Acid-Based Hybrid Nanoparticles Loaded with Dimethyl Fumarate

Dimethyl fumarate (DMF) (Tecfidera®) is an oral treatment for relapsing-remitting multiple sclerosis but is often discontinued due to gastrointestinal issues. Intranasal delivery could improve DMF brain availability and reduce gastrointestinal side effects. This study developed hybrid nanoparticles (H-NPs) loaded with DMF using phosphatidylcholine, palmitoylethanolamide (PEA), cholesterol, poloxamer, and hyaluronic acid (HA). Various compositions of H-NPs (with and without PEA and HA) were prepared via a modified nanoprecipitation technique. The physical and chemical stability, size, zeta potential (ZP), morphology, viscosity, mucoadhesion and DMF release kinetics and permeation were studied. Results showed that HA and PEA significantly influenced H-NP properties, with particle sizes ranging from 119 nm to 254 nm and ZP from -2.3 mV to -29.9 mV. HA enhanced mucoadhesion and permeation, while PEA provided anti-inflammatory and neuroprotective benefits. The H- NPs remained stable over 30 days, with DMF amount around 60%. Cellular uptake studies indicated rapid absorption in cell lines, and in vitro permeation studies showed improved DMF delivery with HA. Compared to human blood, DMF degrades faster in rat blood. These findings suggest H-NPs are promising carriers for intranasal DMF delivery, with ongoing in vivo pharmacokinetic evaluations