title: Enhanced Brain Delivery of Dimethyl Fumarate Employing Tocopherol-Acetate-Based Nanolipidic Carriers: Evidence from Pharmacokinetic, Biodistribution, and Cellular Uptake Studies.
abstract: Dimethyl fumarate (DMF) is an approved drug for the management of relapsing multiple sclerosis. Despite efficacy, DMF is also reported to be a challenging drug owing to concerns like gastrointestinal tract flushing, multiple dosing, lower brain permeability, less patient compliance, and economic hurdles. The present study aims to develop DMF-tocopherol acetate nanolipidic carrier (NLCs) to enhance brain permeability and improve the gastric tolerance. The developed DMF-tocopherol acetate NLCs offered an average size of 69.70 nm, PDI of 0.317, and a zeta potential of -9.71 mV. Higher drug entrapment (90.12%) and drug loading (20.13%) assured controlled drug release behavior both in gastric and intestinal pH. Cellular uptake studies on Caco-2 and SH-SY5Y monolayers confirmed better intestinal absorption and neuronal uptake of the developed system, which was further corroborated by the pharmacokinetic and biodistribution studies. The oral bioavailability was enhanced by 4.09 times and brain availability was substantially improved vis-à-vis plain drug. The findings are promising and offer preclinical evidence for better brain availability of DMF, which can be exploited in the better management of diseases like multiple sclerosis.
authors.affiliation: Department of Pharmacy, School of Chemical Sciences and Pharmacy, Central University of Rajasthan , Bandar Sindri, Distt. Ajmer, Rajasthan, India -305817.
authors.forename: Pramod
authors.initials: P
authors.lastname: Kumar
authors.forename: Gajanand
authors.initials: G
authors.lastname: Sharma
authors.forename: Rajendra
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Department of Pharmacy, School of Chemical Sciences and Pharmacy, Central University of Rajasthan , Bandar Sindri, Distt. Ajmer, Rajasthan, India -305817.
authors.forename: Ruchi
authors.initials: R
authors.lastname: Malik
authors.forename: Bhupinder
authors.initials: B
authors.lastname: Singh
authors.forename: O P
authors.initials: OP
authors.lastname: Katare
authors.affiliation: Department of Pharmacy, School of Chemical Sciences and Pharmacy, Central University of Rajasthan , Bandar Sindri, Distt. Ajmer, Rajasthan, India -305817.
authors.forename: Kaisar
authors.identifier: 0000-0001-8159-8005
authors.initials: K
authors.lastname: Raza
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain; D018938:Caco-2 Cells; D002199:Capillary Permeability; D000069462:Dimethyl Fumarate / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D004337:Drug Carriers / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D008055:Lipids; D018613:Microscopy, Confocal; D049329:Nanostructures / Q000737:chemistry; D009474:Neurons / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution; D024502:alpha-Tocopherol
chemical_list: D004337:Drug Carriers; D007166:Immunosuppressive Agents; D008055:Lipids; D000069462:Dimethyl Fumarate; D024502:alpha-Tocopherol
keywords: Caco-2; NLCs; SH-SY5Y; SLNs; confocal laser scanning microscopy; drug delivery; vitamin E