Dimeric ferulic acid conjugate as a prodrug for brain targeting after nasal administration of loaded solid lipid microparticles

Abstract

ABSTRACT Objective Ferulic acid (Fer) displays antioxidant/anti-inflammatory properties useful against neurodegenerative diseases. To increase Fer uptake and its central nervous system residence time, a dimeric prodrug, optimizing the Fer loading on nasally administrable solid lipid microparticles (SLMs), was developed. Methods The prodrug was synthesized as Fer dimeric conjugate methylated on the carboxylic moiety. Prodrug antioxidant/anti-inflammatory properties and ability to release Fer in physiologic environments were evaluated. Tristearin or stearic acid SLMs were obtained by hot emulsion technique. In vivo pharmacokinetics were quantified by HPLC. Results The prodrug was able to release Fer in physiologic environments (whole blood and brain homogenates) and induce in vitro antioxidant/anti-inflammatory effects. Its half-life in rats was 18.0 ± 1.9 min. Stearic acid SLMs, exhibiting the highest prodrug loading and dissolution rate, were selected for nasal administration to rats (1 mg/kg dose), allowing to obtain high prodrug bioavailability and prolonged residence in the cerebrospinal fluid, showing AUC (Area Under Concentration) values (108.5 ± 3.9 μg∙mL−1∙min) up to 30 times over those of Fer free drug, after its intravenous/nasal administration (3.3 ± 0.3/5.16 ± 0.20 μg∙mL−1∙min, respectively) at the same dose. Chitosan presence further improved the prodrug brain uptake. Conclusions Nasal administration of prodrug-loaded SLMs can be proposed as a noninvasive approach for neurodegenerative disease therapy.