Azone® Decreases the Buccal Mucosal Permeation of Diazepam in a Concentration-Dependent Manner via a Reservoir Effect

The purpose of this study was to examine concentration-dependent effects of Azone® (AZ) on the buccal absorption of diazepam (DIAZ). Porcine buccal mucosa was placed in modified Ussing chambers and pretreated with 10 μL of 0%, 5%, 20%, and 50% (w/v) AZ in ethanol. DIAZ was administered to the donor chamber either in solution or a chitosan-based gel. The donor chamber disappearance, receptor chamber appearance, and tissue retention of DIAZ were monitored over 2 h by HPLC, with AZ tissue disposition also measured by liquid chromatography-mass spectrometry profiling of tissue cryosections. DIAZ steady-state flux values significantly (p < 0.05) decreased 1.4- and 2.4-fold in 20% and 50% AZ-pretreated tissues, respectively. Only 20% and 50% AZ-pretreated tissues were also accompanied by an increased loss of DIAZ from the donor chamber, suggesting DIAZ was forming a reservoir in the buccal mucosa with higher AZ concentrations. Indeed, the percentage of the initial DIAZ dose remaining in the mucosa following a 2 h experiment was increased 3.0-fold with a 50% AZ pretreatment compared with control. AZ provided a concentration-dependent reservoir for DIAZ in buccal mucosa, resulting in retarded release into the receptor chamber, an approach that may be exploited for controlled release of DIAZ. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:1133-1141, 2014