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Abstract Rationale Aerosol particle size influences the extent, distribution, and site of inhaled drug deposition within the airways. Objectives We hypothesized that targeting albuterol to regional airways by altering aerosol particle size could optimize inhaled bronchodilator delivery. Methods In a randomized, double-blind, placebo-controlled study, 12 subjects with asthma (FEV1, 76.8 ± 11.4% predicted) inhaled technetium-99m–labeled monodisperse albuterol aerosols (30-μg dose) of 1.5-, 3-, and 6-μm mass median aerodynamic diameter, at slow (30–60 L/min) and fast (> 60 L/min) inspiratory flows. Lung and extrathoracic radioaerosol deposition were quantified using planar γ-scintigraphy. Pulmonary function and tolerability measurements were simultaneously assessed. Clinical efficacy was also compared with unlabeled monodisperse albuterol (15-μg dose) and 200 μg metered-dose inhaler (MDI) albuterol. Results Smaller particles achieved greater total lung deposition (1.5 μm [56%], 3 μm [50%], and 6 μm [46%]), farther distal airways penetration (0.79, 0.60, and 0.36, respective penetration index), and more peripheral lung deposition (25, 17, and 10%, respectively). However, larger particles (30-μg dose) were more efficacious and achieved greater bronchodilation than 200 μg MDI albuterol (ΔFEV1[ml]: 6 μm [551], 3 μm [457], 1.5 μm [347], MDI [494]). Small particles were exhaled more (1.5 μm [22%], 3 μm [8%], 6 μm [2%]), whereas greater oropharyngeal deposition occurred with large particles (15, 31, and 43%, respectively). Faster inspiratory flows decreased total lung deposition and increased oropharyngeal deposition for the larger particles, with less bronchodilation. A shift in aerosol distribution to the proximal airways was observed for all particles. Conclusions Regional targeting of inhaled β2-agonist to the proximal airways is more important than distal alveolar deposition for bronchodilation. Altering intrapulmonary deposition through aerosol particle size can appreciably enhance inhaled drug therapy and may have implications for developing future inhaled treatments.

Background Our aim was to investigate total and regional lung delivery of salbutamol in subjects with idiopathic pulmonary fibrosis (IPF). Methods The TOPICAL study was a 4-period, partially-randomised, controlled, crossover study to investigate four aerosolised approaches in IPF subjects. Nine subjects were randomised to receive 99m Technetium-labelled monodisperse salbutamol (1.5 μm or 6 μm; periods 1 and 2). Subjects also received radio-labelled salbutamol using a polydisperse nebuliser (period 3) and unlabelled salbutamol (400 μg) using a polydisperse pressurized metered dose inhaler with volumatic spacer (pMDI; period 4). Results Small monodisperse particles (1.5 μm) achieved significantly better total lung deposition (TLD, mean % ± SD) than larger particles (6 μm), where polydisperse nebulisation was poor; (TLD, 64.93 ± 10.72; 50.46 ± 17.04; 8.19 ± 7.72, respectively). Small monodisperse particles (1.5 μm) achieved significantly better lung penetration (mean % ± SD) than larger particles (6 μm), and polydisperse nebulisation showed lung penetration similar to the small particles; PI (mean ± SD) 0.8 ± 0.16, 0.49 ± 0.21, and 0.73 ± 0.19, respectively. Higher dose-normalised plasma salbutamol levels were observed following monodisperse 1.5 μm and 6 μm particles, compared to polydisperse pMDI inhalation, while lowest plasma levels were observed following polydisperse nebulisation. Conclusion Our data is the first systematic investigation of inhaled drug delivery in fibrotic lung disease. We provide evidence that inhaled drugs can be optimised to reach the peripheral areas of the lung where active scarring occurs in IPF. Trial registration This trial was registered on clinicaltrials.gov ( NCT01457261 ).

Abstract Background: Two-dimensional gamma scintigraphy is an important technique used to evaluate the lung deposition from inhaled therapeutic aerosols. Images are divided into regions of interest and deposition indices are derived to quantify aerosol distribution within the intrapulmonary airways. In this article, we compared the different approaches that have been historically used between different laboratories for geometrically defining lung regions of interest. We evaluated the effect of these different approaches on the derived indices classically used to assess inhaled aerosol deposition in the lungs. Our primary intention was to assess the ability of different regional lung templates to discriminate between central and peripheral airway deposition patterns generated by inhaling aerosols of different particle sizes. Methods: We investigated six methods most commonly reported in the scientific literature to define lung regions of interest and assessed how different each of the derived regional lung indices were between the methods to quantify regional lung deposition. We used monodisperse albuterol aerosols of differing particle size (1.5, 3, and 6 μm) in five mild asthmatic subjects [forced expiratory volume in 1 sec (FEV1) 90% predicted] to test the different approaches of each laboratory. Results: We observed the areas of geometry used to delineate central (C) and peripheral (P) lung regions of interest varied markedly between different laboratories. There was greater similarity between methods in values of penetration index (PI), defined as P/C aerosol counts normalized by P/C krypton ventilation counts, compared to nonnormalized C/P or P/C aerosol count-ratios. Normalizing the aerosol deposition P/C count-ratios by the ventilation P/C count-ratios, reduced the variability of the data. There was dependence of the regional lung deposition indices on the size of the P region of interest in that, as P increased, C/P count-ratios decreased and P/C count-ratios increased, whereas PI was less affected by variations in the P area. We found particle size, itself, strongly influenced the indices of regional aerosol deposition such that C/P count-ratios increased with increasing particle size for each method and conversely, P/C count-ratios and PI decreased. Conclusions: Different approaches used to determine pulmonary regions of interest and quantify aerosol deposition produce different results. Our research highlights a genuine need for a consensus to standardize the methodology to facilitate data comparison between laboratories on aerosol deposition.

Abstract Background: While it is generally accepted that inertial impaction will lead to particle loss as aerosol is being carried into the pulmonary airways, most predictive aerosol deposition models adopt the hypothesis that the inhaled particles that remain airborne will distribute according to the gas flow distribution between airways downstream. Methods: Using a 3D printed cast of human airways, we quantified particle deposition and distribution and visualized their inhaled trajectory in the human lung. The human airway cast was exposed to 6 μm monodisperse, radiolabeled aerosol particles at distinct inhaled flow rates and imaged by scintigraphy in two perpendicular planes. In addition, we also imaged the distribution of aerosol beyond the airways into the five lung lobes. The experimental aerosol deposition patterns could be mimicked by computational fluid dynamic (CFD) simulation in the same 3D airway geometry. Results: It was shown that for particles with a diameter of 6 μm inhaled at flows up to 60 L/min, the aerosol distribution over both lungs and the individual five lung lobes roughly followed the corresponding distributions of gas flow. While aerosol deposition was greater in the main bronchi of the left versus right lung, distribution of deposited and suspended particles toward the right lung exceeded that of the left lung. The CFD simulations also predict that for both 3 and 6 μm particles, aerosol distribution between lung units subtending from airways in generation 5 did not match gas distribution between these units and that this effect was driven by inertial impaction. Conclusions: We showed combined imaging experiments and CFD simulations to systematically study aerosol deposition patterns in human airways down to generation 5, where particle deposition could be spatially linked to the airway geometry. As particles are negotiating an increasing number of airways in subsequent branching generations, CFD predicts marked deviations of aerosol distribution with respect to ventilation distribution, even in the normal human lung.

Inhaled radiolabeled aerosols provide invaluable information about in vivo drug deposition. Here, we report our methodology for radiolabeling and imaging monodisperse pharmacologic aerosols in order to study basic aerosol science concepts of drug delivery within the human airways. We used a spinning-top aerosol generator to produce (99m)Tc-labeled monodisperse albuterol sulfate aerosols of 1.5-, 3-, and 6- micro m mass median aerodynamic diameter. In vitro Andersen cascade validation data showed that technetium and albuterol were coassociated on each impactor stage for all 3 aerosols, and the radiolabeling process itself did not affect their particle size distributions. Good-quality gamma-camera scintigraphic images of lung and extrathoracic deposition were obtained within an asthmatic patient. We have successfully radiolabeled and imaged monodisperse albuterol aerosols within the human lungs. This novel technique provides an important tool to relate fundamental concepts of aerosol particle behavior, in vivo deposition, and therapeutic clinical response.

Aerosol particle size influences the extent, distribution, and site of inhaled drug deposition within the airways. We hypothesized that targeting albuterol to regional airways by altering aerosol particle size could optimize inhaled bronchodilator delivery. In a randomized, double-blind, placebo-controlled study, 12 subjects with asthma (FEV1, 76.8 +/- 11.4% predicted) inhaled technetium-99m-labeled monodisperse albuterol aerosols (30-microg dose) of 1.5-, 3-, and 6-microm mass median aerodynamic diameter, at slow (30-60 L/min) and fast (> 60 L/min) inspiratory flows. Lung and extrathoracic radioaerosol deposition were quantified using planar gamma-scintigraphy. Pulmonary function and tolerability measurements were simultaneously assessed. Clinical efficacy was also compared with unlabeled monodisperse albuterol (15-microg dose) and 200 microg metered-dose inhaler (MDI) albuterol. Smaller particles achieved greater total lung deposition (1.5 microm [56%], 3 microm [50%], and 6 microm [46%]), farther distal airways penetration (0.79, 0.60, and 0.36, respective penetration index), and more peripheral lung deposition (25, 17, and 10%, respectively). However, larger particles (30-microg dose) were more efficacious and achieved greater bronchodilation than 200 microg MDI albuterol (deltaFEV1 [ml]: 6 microm [551], 3 microm [457], 1.5 microm [347], MDI [494]). Small particles were exhaled more (1.5 microm [22%], 3 microm [8%], 6 microm [2%]), whereas greater oropharyngeal deposition occurred with large particles (15, 31, and 43%, respectively). Faster inspiratory flows decreased total lung deposition and increased oropharyngeal deposition for the larger particles, with less bronchodilation. A shift in aerosol distribution to the proximal airways was observed for all particles. Regional targeting of inhaled beta2-agonist to the proximal airways is more important than distal alveolar deposition for bronchodilation. Altering intrapulmonary deposition through aerosol particle size can appreciably enhance inhaled drug therapy and may have implications for developing future inhaled treatments.

Pharmacological aerosols of precisely controlled particle size and narrow dispersity can be generated using the spinning-top aerosol generator (STAG). The ability of the STAG to generate monodisperse aerosols from solutions of raw drug compounds makes it a valuable research instrument. In this paper, the versatility of this instrument has been further demonstrated by aerosolizing a range of commercially available nebulized pulmonary therapy preparations. Nebules of Flixotide® (fluticasone propionate), Pulmicort® (budesonide), Combivent ® (salbutamol sulphate and ipratropium bromide), Bricanyl® (terbutaline sulphate), Atrovent® (ipratropium bromide), and Salamol® (salbutamol sulphate) were each mixed with ethanol and delivered to the STAG. Monodisperse drug aerosol distributions were generated with MMADs of 0.95-6.7 µm. To achieve larger particle sizes from the nebulizer drug suspensions, the STAG formed compound particle agglomerates derived from the smaller insoluble drug particles. These compound agglomerates behaved aerodynamically as a single particle, and this was verified using an aerodynamic particle sizer and an Andersen Cascade Impactor. Scanning electron microscope images demonstrated their physical structure. On the other hand using the nebulizer drug solutions, spherical particles proportional to the original droplet diameter were generated. The aerosols generated by the STAG can allow investigators to study the scientific principles of inhaled drug deposition and lung physiology for a range of therapeutic agents.