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.
Abstract
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.