Reid M. Rubsamen

Morphine pharmacokinetics after pulmonary administration from a novel aerosol delivery system

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.

Pulmonary Insulin Administration Using the AERx® System: Physiological and Physicochemical Factors Influencing Insulin Effectiveness in Healthy Fasting Subjects

BACKGROUND Orally inhaled insulin may provide a convenient and effective therapy for prandial glucose control in patients with diabetes. This study evaluated the influence of formulation pH and concentration and different respiratory maneuvers on pharmacokinetic and pharmacodynamic properties of inhaled insulin. METHODS Three, open-label crossover studies in a total of 23 healthy subjects were conducted in which the safety, pharmacokinetics, and pharmacodynamics of insulin inhalation were compared to subcutaneous (SC) injection into the abdomen of commercially available regular insulin. A novel, aerosol generating system (AERx Diabetes Management System, Aradigm Corporation, Hayward, CA) was used to deliver aqueous insulin bolus aerosols to the lower respiratory tract from formulations at pH 3.5 or 7.4 and concentrations of U250 (250 U/mL) or U500 (500 U/mL). RESULTS Time to maximum insulin concentration in serum (Tmax) after SC dosing occurred approximately 50-60 minutes with the time to minimum plasma glucose concentration (i.e., maximum hypoglycemic effect), (TGmin), occurring later, at around 100-120 minutes. In contrast, pulmonary delivery led to a significantly earlier Tmax (7-20 minutes) and TGmin (60-70 minutes), parameters that were shown to be largely unaffected by changing the pH or concentration of the insulin. However, investigation of changes in inhaled volume (achieved by different programming of the AERx system) for administration of the same sized aerosol bolus revealed significant effects. Significantly slower absorption and time to peak hypoglycemic activity occurred when aerosol delivery of insulin occurred during a shallow (approximately 40% vital capacity) as opposed to a deep (approximately 80% vital capacity) inspiration. In addition, it was shown that serum concentration of insulin increased immediately after a series of forced expiraratory maneuvers 30 minutes after inhaled delivery. CONCLUSIONS Pulmonary delivery of aqueous bolus aerosols of insulin in healthy subjects resulted in rapid absorption with an associated hypoglycemic effect quicker than is achieved after subcutaneous dosing of regular insulin. Inhaled insulin pharmacokinetics and pharmacodynamics were independent of formulation variables (pH, concentration) but affected by certain respiratory maneuvers.

Aerosol deposition in the human lung following administration from a microprocessor controlled pressurised metered dose inhaler.

BACKGROUND--Gamma scintigraphy was employed to assess the deposition of aerosols emitted from a pressurised metered dose inhaler (MDI) contained in a microprocessor controlled device (SmartMist), a system which analyses an inspiratory flow profile and automatically actuates the MDI when predefined conditions of flow rate and cumulative inspired volume coincide. METHODS--Micronised salbutamol particles contained in a commercial MDI (Ventolin) were labelled with 99m-technetium using a method validated by the determination of (1) aerosol size characteristics of the drug and radiotracer following actuation into an eight stage cascade impactor and (2) shot potencies of these non-volatile components as a function of actuation number. Using nine healthy volunteers in a randomised factorial interaction design the effect of inspiratory flow rate (slow, 30 l/min; medium, 90 l/min; fast, 270 l/min) combined with cumulative inspired volume (early, 300 ml; late, 3000 ml) was determined on total and regional aerosol lung deposition using the technique of gamma scintigraphy. RESULTS--The SmartMist firing at the medium/early setting (medium flow and early in the cumulative inspired volume) resulted in the highest lung deposition at 18.6 (1.42)%. The slow/early setting gave the second highest deposition at 14.1 (2.06)% with the fast/late setting resulting in the lowest (7.6 (1.15)%). Peripheral lung deposition obtained for the medium/early (9.1 (0.9)%) and slow/early (7.5 (1.06)%) settings were equivalent but higher than those obtained with the other treatments. This reflected the lower total lung deposition at these other settings as no difference in regional deposition, expressed as a volume corrected central zone:peripheral zone ratio, was apparent for all modes of inhalation studied. CONCLUSIONS--The SmartMist device allowed reproducible actuation of an MDI at a preprogrammed point during inspiration. The extent of aerosol deposition in the lung is affected by a change in firing point and is promoted by an inhaled flow rate of up to 90 l/min-that is, the slow and medium setting used in these studies.

The AERX aerosol delivery system

AbstractPurpose. 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 μL collapsible container was delivered as an aerosol (n = 40). The best fit size distribution had an MMAD = (2.95 ± 0.06) μm and a geometric standard deviation σg = 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.

Comparison of in vitro and in vivo efficiencies of a novel unit-dose liquid aerosol generator and a pressurized metered dose inhaler

Gamma scintigraphic imaging was employed in 10 healthy volunteers to compare the total and regional lung deposition of aerosols generated by two delivery platforms that permitted microprocessor-controlled actuation at an optimal point during inhalation. An aqueous solution containing 99mTc-DTPA was used to assess the deposition of aerosols delivered by inhalation from two successive unit-dosage forms (44 microl volume) using a prototype of a novel liquid aerosol system (AERx Pulmonary Delivery System). This was compared with aerosol deposition after inhalation of two 50 microl puffs of a 99mTc-HMPAO-labeled solution formulation from a pressurized metered dose inhaler (MDI). The in vitro size characteristics of the radiolabeled aerosols were determined by cascade impaction. For the AERx system, the predicted lung delivery efficiency based on the product of emitted dose (60.8%, coefficient of variation (CV)=12%) and fine particle fraction (% by mass of aerosol particles <5.7 microm in diameter) was 53.3% (CV=13%). For the solution MDI, the emitted dose was 62.9% (CV=13%) and the predicted lung dose was 44. 9% (CV=15%). The AERx system demonstrated efficient and reproducible dosing characteristics in vivo. Of the dose loaded into the device, the mean percent reaching the lungs was 53.3% (CV=10%), with only 6. 9% located in the oropharynx/stomach. In contrast, the lung deposition from the solution MDI was significantly less (21.7%) and more variable (CV=31%), with 42.0% of the radiolabel detected in the oropharynx/stomach. Analysis of the regional deposition of the radioaerosol indicated a homogeneous pattern of deposition after delivery from the AERx system. A predominantly central pattern of distribution occurred after MDI delivery, where the pattern of deposition was biased towards a central zone depicting the conducting airways. The AERx system, in contrast to MDIs, seems highly suited to the delivery of systemically active agents via pulmonary administration.

Evaluation of the AERx Pulmonary Delivery System for Systemic Delivery of a Poorly Soluble Selective D-1 Agonist, ABT-431

AbstractPurpose. ABT-431 is a chemically stable, poorly soluble prodrug that rapidly converts in vivo to A-86929, a selective dopamine D-1 receptor agonist. This study was designed to evaluate the ability of the AERx™ pulmonary delivery system to deliver ABT-431 to the systemic circulation via the lung. Methods. A 60% ethanol formulation of 50 mg/mL ABT-431 was used to prepare unit dosage forms containing 40 μL of formulation. The AERx system was used to generate a fine aerosol bolus from each unit dose that was collected either onto a filter assembly to chemically assay for the emitted dose or in an Andersen cascade impactor for particle size analysis. Plasma samples were obtained for pharmacokinetic analysis after pulmonary delivery and IV dosing of ABT-431 to nine healthy male volunteers. Doses from the AERx system were delivered as a bolus inhalation(s) (1, 2, 4, and 8 mg) and intravenous infusions were given over 1hr (5 mg). Pharmacokinetic parameters of A-86929 were estimated using noncompartmental analysis. Results. The emitted dose was 1.02 mg (%RSD = 11.0, n = 48). The mass median aerodynamic diameter of the aerosol was 2.9 ± 0.1 μm with a geometric standard deviation of 1.3 ± 0.1 (n = 15). Tmax (mean ± SD) after inhalation ranged from 0.9 ± 0.6 to 11.5 ± 2.5. The mean absolute pulmonary bioavailibility (as A-86929) based on emitted dose ranged from 81.9% to 107.4%. Conclusions. This study demonstrated that the AERx pulmonary delivery system is capable of reproducibly generating fine nearly monodisperse aerosols of a small organic molecule. Aerosol inhalation utilizing the AERx pulmonary delivery system may be an efficient means for systemic delivery of small organic molecules such as ABT-431.