In vitro bioaccessibility and intestinal transport of retinoic acid in ethyl cellulose-based microparticles and impact of meal co-ingestion.

ABSTRACT

The development of carrier-based delivery systems for oral administration of retinoic acid (RA), that provides its release and absorption at intestinal level, is of major relevance in the treatment of acute promyelocytic leukemia. The aim of this work was to evaluate RA bioaccessibility and intestinal transport on ethyl cellulose (EC)- and EC + polyethylene glycol (ECP)-based microparticles and to understand the impact of meal co-ingestion by applying in vitro assays. RA-loaded microparticles were produced by spray-drying with an encapsulation efficiency higher than 90 % for both formulations. The gastric bioaccessibility of RA (after in vitro static digestion of RA-loaded particles) was lower than 3 % for both types of microparticles, with and without meal co-ingestion. Whereas after intestinal digestion, RA bioaccessibility was significantly higher and affected by the type of microparticles and the presence of meal. The digestion of EC- and ECP-based microparticles without diet enabled a significantly higher bioaccessibility of RA when compared to the one recorded for the co-digestion of these microparticles with diet. Herein, RA bioaccessibility decreased from 84 ± 1 to 24 ± 6 % (p < 0.0001) for microparticles EC and 54 ± 4 to 25 ± 5 % (p < 0.001) for microparticles ECP. Moreover, comparing both types of microparticles, RA bioaccessibility was significantly higher for EC-based microparticles digested without diet (p < 0.0001). At last, the bioaccessibility of RA was similar among EC- and ECP-based microparticles when co-digested with diet. Intestinal transport experiments performed in Caco-2 monolayers evidenced that after 2 h of transport the amount of RA retained in the apical compartment was higher than the amount that reached the basolateral compartment evidencing a slow transport at intestinal level that was higher when RA is spiked in the blank of digestion and the meal digestion samples compared to RA dissolved in HBSS (44 ± 6 (p < 0.01) and 38 ± 1 (p < 0.05) vs 26 ± 2 %, respectively).