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, clinicians have to use the commercial parenteral formulation, the low pH of which (3.3), necessary to solubilize MDZ (pK(a) 6.1), is probably responsible for the signs of local irritation frequently reported. As a starting point to design a formulation suitable for the nasal route, MDZ nasal absorption was investigated in rats. The effects of the MDZ solution concentration (10--100 microg/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 determined by reversed-phase HPLC in the circulating solution and results were expressed in clearance terms. MDZ absorption was independent of its concentration. The pH of the solutions was the key-parameter and only a pH above 4 allowed significant absorption. These results were consistent with a passive diffusion absorption of MDZ and partly followed the pH partition theory. In conclusion, satisfactory MDZ absorption should be expected with a formulation at a pH suitable for the nasal route in human (5.5--6.5).
Olivier
J C
JC
Equipe émergente Medicaments et Barrière Hématoencéphalique, Laboratoire de Pharmacie Galénique et Biopharmacie, Faculté de Médecine et Pharmacie, 34, rue du Jardin des Plantes, 86005 Poitiers Cedex, France.
Djilani
M
M
Fahmy
S
S
Couet
W
W
D000042:Absorption; D000281:Administration, Intranasal; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D006863:Hydrogen-Ion Concentration; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000493:pharmacokinetics*; D009297:Nasal Mucosa / Q000378:metabolism*; D009994:Osmolar Concentration; D051381:Rats; D017207:Rats, Sprague-Dawley
D006993:Hypnotics and Sedatives; D008874:Midazolam