LAUSR

Abstract Dimethyl fumarate (DMF) is used for the treatment of relapsing forms of multiple sclerosis and causes undesired adverse effects in patients such as gastroenteritis, dyspepsia, low bioavailability, gastritis, nausea and flushing. The aim of this study was to develop oral film containing biocompatible and biodegradable chitosan-alginate nanoparticles of DMF to improve oral bioavailability in multiple sclerosis treatment. The film formulations containing DMF were optimized through design of experiments using full factorial design, and impact of varying levels of independent factors on critical quality attributes of films were studied. The orodispersible film of chitosan-alginate core-shell-corona shaped nanoparticles of DMF was prepared by ionotropic pre-gelation of alginate core followed by chitosan polyelectrolyte complexation, the obtained colloidal nanosuspension was added to the optimized polymer matrix composition by simple process integration and then cast to films by solvent casting process. The films were characterized for their critical quality attributes like pH, tensile strength, disintegration time, in-vitro drug release, ex-vivo permeation study through porcine buccal mucosa and in-vivo pharmacokinetic study in wistar rats. The in-vitro drug release profile from chitosan-alginate core-shell-corona shaped nanoparticles evidenced a sustained release with initial 18.39% release in 30 minutes followed by sustained release up to 6 hours in compared to DMF oral film formulations which has released more than 80% drug within 15 minutes. The in-vivo pharmacokinetic study confirmed that nanoparticles of DMF in orodispersible films (DMF051) were 0.6-fold more bioavailable even at very low drug concentration (2 mg/film) in compared to conventional oral film formulation (DMF023) (30 mg of drug/film). The Cmax values obtained for DMF023 was 19.21 + 0.46 μg/ml in comparison to 21.90 + 0.38 μg/ml for DMF051 and 1.02 μg/ml for drug suspension, Tmax values obtained for DMF023 was 4.00h in comparison to 2.00 h for DMF051, t1/2 values 3.81 + 0.03 for DMF023 in comparison to 6.59 + 0.36 DMF051, AUC 0-t values for DMF023 was 142.02 + 1.17 μg/ml*h in comparison to 231.49 + 3.49 μg/ml*h for DMF051 and AUC 0-inf_obs values 153.67+1.27 μg/ml*h for DMF023 in comparison to 251.21+3.48 μg/ml*h for DMF051. The study indicates enhanced bioavailability from this promising dosage form, prompting dose reduction and reduced side effects.