Nasal administration of microencapsulated dimeric conjugate of ferulic acid: towards a new approach for neurodegenerative diseases.

Ferulic acid (Fer) displays antioxidant/anti-inflammatory properties useful for neurodegenerative disease therapy. To increase Fer uptake and residence time in the central nervous system, a dimeric prodrug, optimizing the Fer loading on nasally administrable solid lipid microparticles (SLMs), was developed. The prodrug was synthesized as Fer dimeric conjugate, then methylated on the carboxylic moiety. Antioxidant/anti-inflammatory properties of the prodrug and its 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. The prodrug displayed by itself in vitro antioxidant/anti-inflammatory properties similar to those of Fer. Moreover, the prodrug ability to release Fer in physiologic environments, such as whole blood and brain homogenates, was demonstrated. Stearic acid SLMs exhibited the highest prodrug loading and dissolution rate and were selected as nasal formulation to rats for pharmacokinetic studies. Intranasal administration of SLMs allowed to obtain high prodrug bioavailability and prolonged residence in the cerebrospinal fluid of rats, showing values up to 30 times higher than that of Fer, following its intravenous/nasal administration at the same doses. Nasal administration of prodrug-loaded SLMs can be proposed as a non-invasive approach for neurodegenerative disease therapy.