Development of a Nasal Drug Delivery System for Enhancement of Bioavailability of Ubrogepant

Abstract

Abstract newlineMigraine is a highly disabling neurological disorder characterized by recurrent newlineheadache and Sensory Hypersensitivities. Ubrogepant, a small molecule CGRP newlinereceptor antagonist, offers targeted therapy for migraine; however, its clinical newlineutility is limited by poor brain penetration and delayed onset via oral delivery. To newlineaddress this, a thermoresponsive intranasal gel of Ubrogepant-loaded nanoparticles newlinewas developed for enhanced nose-to-brain targeting. newlineNanoparticles were prepared using a emulsion solvent evaporation method and newlineoptimized for polymer content, surfactant levels, phase ratio, and stirring speed. newlineThe resulting formulation showed sub-200 nm particle size, low polydispersity, newlinenegative zeta potential, and high entrapment efficiency (~80%). Incorporation into newlinea poloxamer-carbopol-HPand#946;CD-based gel yielded a system with ~34 °C gelation newlinetemperature, suitable pH, and appropriate viscosity for nasal administration. newlineIn vitro and ex vivo studies confirmed sustained drug release and permeation. In newlinevivo pharmacokinetics in rats showed significantly improved brain delivery, rapid newlineonset and prolonged residence compared to oral solution. Pharmacodynamic newlineassessments in a nitroglycerin-induced model showed reduced neuroinflammation newline(TNF-and#945;, IL-6) and behavioural improvement. newlineThe results demonstrate that the optimized thermoresponsive nanoparticle gel is a newlinepromising non-invasive platform for rapid, sustained, and targeted delivery of newlineUbrogepant to the brain, potentially enhancing therapeutic outcomes in migraine newlinemanagement. newlineMr. Vignesh Mohan newline