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 ?L 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.