Propranolol is the first-line drug for managing migraine attacks. D-limonene is a citrus oil known for its neuroprotective mechanism. Thus, the current work aims to design a thermo-responsive intranasal limonene-based microemulsion mucoadhesive nanogel to improve propranolol efficacy. Microemulsion was fabricated using limonene and Gelucire® as the oily phase, Labrasol®, Labrafil®, and deionized water as the aqueous phase, and was characterized regarding its physicochemical features. The microemulsion was loaded in thermo-responsive nanogel and evaluated regarding its physical and chemical properties, in vitro release, and ex vivo permeability through sheep nasal tissues. Its safety profile was assessed via histopathological examination, and its capability to deliver propranolol effectively to rats' brains was examined using brain biodistribution analysis. Limonene-based microemulsion was of 133.7 ± 0.513 nm diametric size with unimodal size distribution and spheroidal shape. The nanogel showed ideal characteristics with good mucoadhesive properties and in vitro controlled release with 1.43-fold enhancement in ex vivo nasal permeability compared with the control gel. Furthermore, it displayed a safe profile as elucidated by the nasal histopathological features. The nanogel was able to improve propranolol brain availability with Cmax 970.3 ± 43.94 ng/g significantly higher than the control group (277.7 ± 29.71 ng/g) and with 382.4 % relative central availability, which confirms its potential for migraine management.
Keywords: BBB; brain distribution; limonene; microemulsion; mucoadhesion; nanocarriers; nanogel; propranolol; thermo-sensitive.