Sodium Cholate-Mediated Ion-Pairing for Skin Delivery of Methylene Blue: Physicochemical Characterization and Influence on Skin Barrier and Skin Penetration

Abstract

Methylene blue (MB)-based photodynamic therapy has proven to be effective and promising for the treatment of non-melanoma skin neoplasms. However, the topical application of MB has certain challenges. MB is a cationic and water-soluble molecule. These properties limit its partition and diffusion through the layers of the skin, limiting it from reaching the neoplastic cells at therapeutic concentration. Sodium cholate (CNa), a bile salt, enables ion-pairing with cationic drugs, such as MB, through electrostatic interactions. The complex formed modifies the physicochemical properties of MB, which may enable its partition and diffusion through the layers of the skin. Thus, we proposed to investigate the interaction between CNa and MB as a function of CNa concentration and its effect on the partition coefficient, solubility, skin barrier and skin delivery of MB. Spectroscopic and thermal studies of MB/CNa dispersions suggest intermolecular interactions between MB and CNa. CNa causes an increase in the partition coefficient of MB and reduces its solubility in water. CNa at the concentrations used does not cause significant changes in electrical resistance or the profile of FTIR spectra related to the lipids and the proteins of the stratum corneum. The use of CNa at the critical micelle concentration causes a reduction in the release and cutaneous delivery of MB; and, at a concentration below the critical micelle concentration, it does not significantly influence the release, but promotes the cutaneous delivery of MB.

Graphical Abstract