Oral Mucosal Absorption of Midazolam in Dogs is Strongly pH Dependent

A significant amount of orally administered midazolam, an anxiolytic and sedative, may be absorbed by the mucosal membranes in the oral cavity, esophagus, and the stomach. The pH dependence of the opening or closure of a ring in midazolam's molecular structure suggests a pH dependence of the mucosal absorption, which was evaluated using a dog model. Five milliliters of 5 mg/mL midazolam solution, with a pH of 2.8, 3.2, or 3.9, was placed on the buccal mucosa of seven anesthetized dogs for 15 min. The same dogs were also infused intravenously (iv) with midazolam on separate days. Mean serum Cmax were 92.3±42.5 (mean±SD), 274.3±150.8, 377.1±211.3, and 2552.4±1305.3 ng/mL for pH 2.8, 3.2, 3.9 solutions and iv infusion, respectively. Mean tmax for all buccal solutions and iv infusion was 15 min. Bioavailability for the pH 2.8, 3.2, and 3.9 solutions were 6.2, 18.7, and 22.6%, respectively. Because the commercially available midazolam syrup and the midazolam–fruit juice blends for oral administration have a pH of 2.8 to 3, these results suggest that the absorption from the blends or syrup may be significantly improved by slightly increasing the pH. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:980–982, 2002