Ward M E, Woodhouse A, Mather L E, Farr S J, Okikawa J K, Lloyd P, Schuster J A, Rubsamen R M
Department of Anaesthesia and Pain Management, University of Sydney, Royal North Shore Hospital, Sydney, Australia.
Clin Pharmacol Ther. 1997 Dec;62(6):596-609. doi: 10.1016/S0009-9236(97)90079-5.
Successful pharmacotherapy of pain often depends on the mode of drug delivery. A novel, unit dose, aqueous aerosol delivery system (AERx Pulmonary Drug Delivery System) was used to examine the feasibility of the pulmonary route for the noninvasive systemic administration of morphine.
The study had two parts: (1) a dose-ranging study in four subjects with three consecutive aerosolized doses of 2.2, 4.4, and 8.8 mg (nominal) morphine sulfate pentahydrate at 40-minute intervals, and (2) a crossover study, on separate days, in six subjects with 4.4 mg (nominal) aerosolized morphine sulfate administered over 2.1 minutes on three occasions and intravenous infusions of 2 and 4 mg over 3 minutes. Subjects were healthy volunteers from 19 to 34 years old. Arterial blood was sampled for a total of 6 hours and plasma morphine concentrations were measured by gas chromatography-mass spectrometry.
In part 1, plasma morphine concentrations were proportional to dose. In part 2, the mean +/- SD peak plasma concentration (Cmax) occurred at 2.7 +/- 0.8 minutes after the aerosol dose, with mean values for Cmax of 109 +/- 85, 165 +/- 22, and 273 +/- 114 ng/ml for the aerosol and 2 and 4 mg intravenous doses, respectively. The bioavailability [AUC(0-360 min)] of aerosol-delivered morphine was approximately 100% relative to intravenous infusion, with similar intersubject variability in AUC for both routes (coefficient of variation < 30%).
The time courses of plasma morphine concentrations after pulmonary delivery by the AERx system and by intravenous infusions were similar. This shows the utility of the pulmonary route in providing a noninvasive method for the rapid and reproducible systemic administration of morphine if an appropriate aerosol drug delivery system is used.
疼痛的成功药物治疗通常取决于给药方式。一种新型的单位剂量水性气雾剂给药系统（AERx肺部药物递送系统）被用于研究肺部途径用于吗啡无创全身给药的可行性。
该研究分为两部分：（1）在4名受试者中进行剂量范围研究，以40分钟的间隔连续给予三剂雾化的2.2、4.4和8.8毫克（标称）五水合硫酸吗啡；（2）在不同日期对6名受试者进行交叉研究，分三次在2.1分钟内给予4.4毫克（标称）雾化硫酸吗啡，并在3分钟内静脉输注2毫克和4毫克。受试者为19至34岁的健康志愿者。共采集6小时动脉血样，采用气相色谱-质谱法测定血浆吗啡浓度。
在第1部分中，血浆吗啡浓度与剂量成正比。在第2部分中，气雾剂给药后平均±标准差的血浆峰浓度（Cmax）出现在2.7±0.8分钟，气雾剂、2毫克和4毫克静脉注射剂量的Cmax平均值分别为109±85、165±22和273±114纳克/毫升。气雾剂递送的吗啡的生物利用度[AUC(0 - 360分钟)]相对于静脉输注约为100%，两种途径的AUC在受试者间的变异性相似（变异系数<30%）。
通过AERx系统肺部给药和静脉输注后血浆吗啡浓度的时间过程相似。这表明如果使用合适的气雾剂药物递送系统，肺部途径可用于提供一种无创方法来快速且可重复地进行吗啡的全身给药。
