Quercetin and 3‐ O ‐methylquercetin in vitro skin layers permeation/retention from hydrogels: why only a methoxy group difference determines different behaviors?

Abstract Objectives The present study was designed to verify if quercetin (QCT), a flavonoid with antioxidant and antiviral activity, and 3‐ O ‐methylquercetin (3 O MQ), a quercetin C3‐methoxylated derivative, present differences in their behavior against complexation with β‐cyclodextrin (β‐CD) and the corresponding permeation/retention trhough porcine ear skin, when incorporated into hydroxypropyl methylcellulose (HPMC) or chitosan (CS) hydrogels. Methods The influence of β‐CD on the skin permeation/retention of QCT and 3 O MQ from hydrogels is comparatively evaluated for both flavonoids using porcine ear skin in Franz cells model. The properties of the two flavonoids using the semi‐empirical method Recife Model was studied. Key findings Quercetin presented higher skin retention compared with its C3‐methoxy derivative 3 O MQ. The best permeation/retention of QCT was observed when it was incorporated into CS hydrogel containing 5% β‐CD, whereas, for 3 O MQ, the HPMC hydrogel containing 5% β‐CD was the best formulation. The flavonoids complexation with β‐CD in water occurred preferentially with the insertion of the B ring through the secondary OH rim. Conclusions The dynamic molecular modeling revealed that the methyl group at C3 in 3 O MQ molecule determined significant difference in its complexation with β‐CD, in comparison to its analogous QCT and that difference is coincident with the permeation behavior of these flavonoids, denoting a possible relationship with their molecular dynamics.