Inhaled aerosol dose distribution between proximal bronchi and lung periphery

Abstract

Modern inhaled drug discovery programs assess dose delivery to proximal and distal airways using rudimentary imaging indices, where relative deposition is estimated by generically defined ‘central’ and ‘peripheral’ lung regions. Utilizing recent data linking the proximal airway topology to a characteristic pattern of aerosol lung deposition, we provide a direct measure of dose distribution between the proximal bronchi and the distal lung. We analyzed scintigraphic lung images of twelve asthma patients following inhalation of 1.5-, 3- and 6-µm monodisperse drug particles at breathing flows of 30- and 60-L/min. We explicitly used the central hot-spots associated with each patient’s specific bronchial topology to obtain a direct measure of aerosol deposition in the proximal bronchi, rather than applying standard templates of lung boundaries. Maximum deposition in the central bronchi (as % of lung deposition) was 52 ± 10(SD)% (6 µm;60 L/min). Minimum central deposition was 17 ± 2(SD)% (1.5 µm;30 L/min) where the 83% aerosol ‘escaping’ deposition in the central bronchi reached 75 ± 17(SD)% of the lung area that could be reached by Krypton gas. For all particle sizes, hot-spots appeared in the same patient-specific central airway location, with greatest intensity at 60 L/min. For a range of respirable aerosol sizes and breathing flows, we have quantified deposited dose in the proximal bronchi and their distal lung reach, constituting a platform to support therapeutic inhaled aerosol drug development.