PERMEATION OF WIN 55,212-2, A POTENT CANNABINOID RECEPTOR AGONIST, ACROSS HUMAN TRACHEO-BRONCHIAL TISSUE (EPIAIRWAY™) IN VITRO AND RAT NASAL EPITHELIUM IN VIVO.

• TR Number: 331
• Authors: Agu1, R.U., Valiveti1, S., Paudel1, K.S., Klausner2, M., Hayden2, P.J., Stinchcomb1, A.S. 1University of Kentucky College of Pharmacy, Lexington, KY, 2Mattek Corporation, Ashland, MA.
• Materials Tested: Dimethyl-beta-cyclodextrin (DM-beta-CD), Propyleneglycol (PG), Randomly methylated-beta-cyclodextrin (RAM-beta-CD), Trimethyl-beta- cyclodextrin (TM-beta-CD)

R-(+)-WIN 55,212-2 is prone to hepatic first-pass metabolism and variable bioavailability following oral administration. The aim of this study was to predict intranasal absorption of the compound using EpiAirway™ tissue culture. Permeation experiments of R-(+)-WIN 55,212-2 mesylate formulations with 2% dimethyl-β-cyclodextrin (DMβCD), 2% randomly methylated-β-cyclodextrin (RAMβCD), 1:1 propylene glycol:saline [PG:S (1:1)] and 1.5% propylene glycol + 3% Tween 80 (PG+TW80) were conducted in vitro and in vivo using EpiAirway™ tissue and an anesthetized rat nasal absorption model, respectively. Samples were analyzed by LC-MS and rat plasma data was analyzed with WinNonlin Pharmacokinetic software. Mucosal tolerance was screened using transepithelial electrical resistance (TEER), paracellular marker permeation, and tissue viability as indices. Relative to PG+TW80 (control), PG:S (1:1), RAMβCD, and DMβCD resulted in a 24-, 20-, and 17-fold WIN 55,212-2 permeation increase in vitro, respectively. Similarly, the in vivo absolute bioavailabilities were 0.61, 0.58, 0.64 and 0.1 for PG:S (1:1), RAMβCD, DMβCD, and PG+TW80, respectively. Although TEER was significantly reduced by all the formulations in vitro, the viability of the tissue was reduced only by the DMβCD formulation. Significant improvement in absorption of R-(+)-WIN 55,212-2 mesylate was achieved using methylated cyclodextrins and propylene glycol-based cosolvent. EpiAirway™ permeation of R-(+)-WIN 55,212-2 mesylate in vitro correlated well with its in vivo nasal bioavailability in the rat. This study confirms the relevance of the EpiAirway™ tissue system as a model for screening nasal drug absorption of pharmaceutical formulations. Acknowledgments: Mattek Corporation and American Cancer Society RPG-00-027-01-CDD.