Intranasal midazolam: A comparison of two delivery devices in human volunteers

Ola Dale, Turid Nilsen, Thorsteinn Loftsson, Hanne Hjorth Tønnesen, Pål Klepstad, Stein Kaasa, Trond Holand, Per G. Djupesland
Journal of Pharmacy and Pharmacology 58: 1311-18.


Bi-directional nasal drug delivery is a new administration principle with improved deposition pattern that may increase nasal drug uptake. Twelve healthy subjects were included in this open, non-randomized 3-way crossover study: midazolam (3.4 mg) intravenously (1 mg mL−1), or nasally by bi-directional or traditional spray (2 × 100 μL of a 17 mg mL−1 nasal midazolam formulation). The primary outcome was bioavailability. Blood samples were drawn for 6 h for determination (gas-chromatography-mass-spectrometry) of midazolam and 1-OH-midazolam. Pharmacokinetic calculations were based on non-compartmental modelling, sedation assessed by a subjective 0–10 NRS-scale, and nasal dimensions by non-invasive acoustic rhinometry. Mean bio-availabilities were 0.68-0.71, and Tmax 15 min for the sprays, which also were bioequivalent (ratio geometric means (90%) CI: 97.6% (90% CI 83.5; 113.9)). Sedation after bi-directional spray followed intravenous sedation closely, while sedation after the traditional spray was less pronounced. A negative correlation between Cmax and smallest cross-sectional area was seen. Adverse effects such as local irritation did not differ significantly between the sprays. Apparently bi-directional delivery did not increase systemic bio-availability of midazolam. We cannot disregard that only the traditional spray caused less sedation than intravenous administration. This finding needs to be confirmed in trials designed for this purpose.