Mechanism study on ion-pair complexes controlling skin permeability: Effect of ion-pair dissociation in the viable epidermis on transdermal permeation of bisoprolol

Abstract Though ion-pair strategy has been widely used in transdermal drug delivery system, knowledge about the molecular mechanisms involved in the skin permeation processes of ion-pair complexes is still limited. In the present study, a homologous series of fatty acids were chosen to form model ion-pair complexes with bisoprolol (BSP) to rule out the influence of functional groups on polar surface area, stability and other physicochemical properties of ion-pair complexes. The ion-pair complexes were characterized by FTIR, thermal analysis, and 1 H NMR. The skin permeability of BSP as well as its ion-pair complexes was investigated by in vitro skin permeation experiments then visualized by CLSM. The skin permeability coefficient ( k p ) of BSP ion-pair complex was negatively related to its n -octanol/water apparent partition coefficient ( P’ o/w ) in the hydrophobic vehicle caprylic/capric triglyceride, (log k p  = −1.657 − 1.229 log P’ o/w ), suggesting that the instability of ion-pair complexes due to their dissociation in the viable epidermis (VED) played an important role in controlling the skin permeability of BSP, which was further proved by 1 H NMR and molecular docking. These findings broadened our understanding about the molecular mechanisms involved in the skin permeation processes of ion-pair complexes.