Hybrid Nanoparticles for Intranasal delivery of Dimethyl Fumarate

Introduction: Dimethylfumarate (DMF) (Tecfidera®) is a first-line oral therapy for relapsing-remitting multiple sclerosis. After oral administration, DMF is rapidly metabolized to monomethylfumarate (MMF). Gastrointestinal discomfort was indicated in patients, with withdrawal of treatment in the first 3 months. Nose-to-brain drug delivery could be advantageous in increasing DMF brain availability, avoiding gastrointestinal exposure Hybrid nanoparticles loaded with DMF (H-NPs) were prepared using at different ratios phosphatidylcholine, cholesterol, poloxamers (P) with (LH and LHD) or without (L and LD) hyaluronic acid (HA), which has an excellent mucoadhesive capacity and can specifically bind RHAMM receptors overexpressed in many forms of inflammation. Method: H-NPs were made by a modified nanoprecipitation technique. Size, zeta potential (ZP), morphology, total drug in dispersion, viscosity and thermal properties were studied. For 30 days, the physical stability of all H-NPs, as well as the chemical stability of DMF in the H-NPs were investigated. In-vitro DMF permeation studies were carried out . The stability of DMF in human and rat blood was determined by setting appropriate extraction and HPLC procedures. Results: H-NPs had a mean size from 209 nm (LD) to 230 nm (LHD) and the ZP was from 0.28 of LD to -19.6 mV of LHD, thus HA influenced the physical properties of H-NPs. TEM images proved that H-NPs were spherical but with irregular surfaces. Results of thermal analyses evidenced that DMF was encapsulated in the formulations. The formulations showed good chemical-physical stability along 30 days. The total amount of DMF in dispersion was about 63%, equal to 2.8 mg/ml. H-NPs showed viscosity suitable for nasal admistration regardless HA presence. In-vitro permeation studies indicated that LHD increased the amount of DMF permeated with respect to free-DMF evidencing the influence of HA on H-NPs performance. In comparison to human blood, DMF appears immediately and totally degraded in rat blood, where it is partially hydrolyzed to MMF. Conclusion: Theseresults suggest that H-NPs could be successfully used as nanocarrier candidates for DMF encapsulation aimed at intranasal delivery and support the work in progress aimed to in vivo pharmacokinetic evaluation.