Dale Ola, Nilsen Turid, Loftsson Thorsteinn, Hjorth Tønnesen Hanne, Klepstad Pål, Kaasa Stein, Holand Trond, Djupesland Per G
Pain and Palliation Research Group, Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, 7489 Trondheim, Norway.
J Pharm Pharmacol. 2006 Oct;58(10):1311-8. doi: 10.1211/jpp.58.10.0003.
Bidirectional 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 bidirectional or traditional spray (2 x100 microL 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 bioavailabilities 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 bidirectional 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 bidirectional delivery did not increase systemic bioavailability 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.
双向鼻腔给药是一种新的给药原则，其沉积模式有所改善，可能会增加鼻腔药物吸收。12名健康受试者被纳入这项开放、非随机的三向交叉研究：静脉注射咪达唑仑（3.4mg，1mg/mL），或通过双向喷雾或传统喷雾鼻腔给药（2×100μL，17mg/mL的鼻腔咪达唑仑制剂）。主要结局是生物利用度。采集血样6小时，用于测定咪达唑仑和1-羟基咪达唑仑（气相色谱-质谱法）。药代动力学计算基于非房室模型，通过主观的0-10数字评定量表评估镇静情况，通过非侵入性鼻声反射法测量鼻腔尺寸。喷雾给药的平均生物利用度为0.68-0.71，达峰时间为15分钟，两者也具有生物等效性（几何均值比（90%）置信区间：97.6%（90%置信区间83.5；113.9））。双向喷雾后的镇静情况与静脉镇静密切相关，而传统喷雾后的镇静作用则较弱。观察到最大血药浓度与最小横截面积之间呈负相关。两种喷雾之间局部刺激等不良反应无显著差异。显然，双向给药并未增加咪达唑仑的全身生物利用度。我们不能忽视的是，只有传统喷雾引起的镇静作用比静脉给药弱。这一发现需要在为此目的设计的试验中得到证实。
