In situ nasal absorption of midazolam in rats

Intranasal (i.n.) midazolam (MDZ) administrations may be used successfully for preoperative sedation, especially in young patients. However, clinician s have to use the commercial parenteral formulation, the low pH of which (3 .3), necessary to solubilize MDZ (pK(n) 6.1), is probably responsible for t he signs of local irritation frequently reported. As a starting point to de sign a formulation suitable for the nasal route, MDZ nasal absorption was i nvestigated in rats. The effects of the MDZ solution concentration (10-100 mug/ml), osmolality (from less than 10 mOsm/kg up to 450 mOsm/kg) and pH (3 .3-7.4) were studied using an in situ perfusion technique. MDZ was determin ed by reversed-phase HPLC in the circulating solution and results were expr essed in clearance terms. MDZ absorption was independent of its concentrati on. The pH of the solutions was the key-parameter and only a pH above 4 all owed significant absorption. These results were consistent with a passive d iffusion absorption of MDZ and partly followed the pH partition theory. In conclusion, satisfactory MDZ absorption should be expected with a formulati on at a pH suitable for the nasal route in human (5.5-6.5). (C) 2001 Elsevi er Science B.V. All rights reserved.