Permeation of WIN 55,212-2, a potent cannabinoid receptor agonist, across human tracheo-bronchial tissue in vitro and rat nasal epithelium in vivo

The aim of this study was to investigate the intranasal absorption of R-(+)-WIN 55,212-2 mesylate in vivo and in vitro. Permeation experiments of R-(+)-WIN 55,212-2 formulations with 2% dimethyl-beta-cycloclextrin (DM beta CD), 2% trimethyl-o-cyclodextrin (TM beta CD) or 2% randomly methylated-beta-cycloclextrin (RAM beta CD) in 1:1 propylene glycol/saline and 1.5% propylene glycol + 3% Tween 80 in saline were conducted using EpiAirway (TM) tissue and an anesthetized rat nasal absorption model, respectively. Samples were analysed by liquid chromatography-mass spectrometry. Mucosal tolerance was screened using paracellular marker permeation and tissue viability as indices. Nasal absorption of WIN 55,212-2 was rapid, with a tax (time of peak concentration) of 0.17 to 0.35 h in vivo. Relative to 1.5% propylene glycol+3% Tween 80 (control), 1:1 propylene glycol/saline, RAM beta CD, DM beta CD and TM beta CD resulted in 24-, 20-, 17- and 10-fold WIN 55,212-2 permeation increases in vitro, respectively. The in vivo absolute bioavailabilities were also increased with 1:1 propylene glycol/saline, RAM beta CD, DM beta CD and TM beta CD compared to 1.5% propylene glycol+3% Tween 80 (0.15 vs. 0.660.77). The viability of the EpiAirway (TM) tissues was significantly reduced by DM beta CD and TM beta CD formulations. This study showed that WIN 55,212-2 mesylate can be delivered via the nasal route. Absorption of R-(+)-WIN 55,212-2 was rapid and bioavailability was significantly improved using methylated cycloclextrins and propylene glycol-based cosolvent.