ARDM Abstracts - The first, reporting morphine pharmacodynamics is the most important. The key to the success of this company is reproducibility of drug transfer to the plasma.
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Clin Pharmacol Ther 1997 Dec;62(6):596-609 Morphine pharmacokinetics after pulmonary administration from a novel aerosol delivery system. Ward ME, Woodhouse A, Mather LE, Farr SJ, Okikawa JK, Lloyd P, Schuster JA, Rubsamen RM Department of Anaesthesia and Pain Management, University of Sydney, Royal North Shore Hospital, Sydney, Australia.
BACKGROUND: 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. METHODS: 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. RESULTS: 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%). CONCLUSION: 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.
Eur J Nucl Med 1999 Apr;26(4):320-7 Deposition of aqueous aerosol of technetium-99m diethylene triamine penta-acetic acid generated and delivered by a novel system (AERx) in
healthy subjects. Chan HK, Daviskas E, Eberl S, Robinson M, Bautovich G, Young I Department of Pharmacy, University of Sydney, Australia.
Deposition of technetium-99m diethylene triamine penta-acetic acid aqueous radioaerosols generated by a novel aerosol delivery system (AERx) was studied in six healthy subjects using both planar and single-photon emission tomography (SPET) imaging. AERx is a microprocessor-controlled, bolus inhalation device that is actuated at pre-programmed values of inspiratory flow rate and volume. The aims of the study were to determine the effects of posture and inhaled volume upon deposition of the aerosol in the lungs. Each subject inhaled the radioaerosol in two positions (supine vs sitting) and with two inspiratory manoeuvres [vital capacity (VC) vs "fixed volume" of 1 l above functional residual capacity]. Simultaneous transmission-emission planar and tomographic images were acquired. The results showed diffuse deposition of the aerosol in the lung. Neither the breathing manoeuvre nor the posture was found to affect the distribution of the aerosol as measured by the ratio of the activity (counts per pixel) in the peripheral:central (penetration index, PI) or in the apex:base regions of the planar lung images (P>0.1). A small, albeit statistically significant, difference in PI (P<0.03) was found between VC and fixed volume sitting manoeuvres with SPET only. The PI values themselves indicate that the radioaerosol was well distributed in the lung, with the periphery having 45%-64% of the activity of the central region. Superposition of transmission SPET lung outline on emission SPET visually confirmed the excellent peripheral deposition of the aerosol. The AERx system showed high efficiency of delivery, with approximately 50% of the extruded dose in the device depositing in the lung. The uniformity of radioactivity distributed throughout the lung is attributed to the fine particle size (mass median aerodynamic diameter of 2 microm) of the aerosol and the electronic control of aerosol inhalation by the device. In conclusion, the AERx system can be ideal for diffuse aerosol deposition of therapeutic or diagnostic agents and is largely unaffected by inhaled volume and posture. The efficiency of the device device can limit the total radiation exposure of patients and staff administering the radioaerosols, and can make it suitable for delivery of expensive drugs.
Pharm Res 1997 Mar;14(3):354-7 The AERX aerosol delivery system.
Schuster J, Rubsamen R, Lloyd P, Lloyd J, Aradigm Corporation, Hayword, California 94545, USA. JSchuster@aol.com
PURPOSE: We describe the AERX aerosol delivery system, a new, bolus inhalation device that is actuated at preprogrammed values of inspiratory flow rate and inhaled volume. We report on its in vitro characterization using a particular set of conditions used in pharmacokinetic and scintigraphic studies. METHODS: Multiple doses of aerosol were delivered from single use
collapsible plastic containers containing liquid formulation. The aerosol was generated by forcing the formulation under pressure through an array of 2.5 micron holes. Air was drawn through the device at 70 LPM, and the aerosol was collected onto a filter or Andersen cascade impactor. The emitted dose was quantified from the filter collection data, and the particle size distribution was obtained from the best fit log-normal distribution to the impactor data. RESULTS: 57.0 +/- 5.9% of the dose of drug placed as an aqueous solution in the 45 microL collapsible container was delivered as an aerosol (n = 40). The best fit size distribution had an
MMAD = (2.95 +/- 0.06) microns and a geometric standard deviation sigma g = 1.24 +/- 0.01 (n = 6). CONCLUSIONS: The AERX aerosol delivery system generates a nearly monodisperse aerosol with the properties required for efficient and repeatable drug delivery to the lung. |
