Pulmonary aerosol delivery and the importance of growth dynamics

Abstract

Aerosols are dynamic systems, responding to variations in the surrounding environmental conditions by changing in size, composition and phase. Although, widely used in inhalation therapies, details of the processes occurring on aerosol generation and during inhalation have received little attention. Instead, research has focused on improvements to the formulation of the drug prior to aerosolization and the resulting clinical efficacy of the treatment. Here, we highlight the processes that occur during aerosol generation and inhalation, affecting aerosol disposition when deposited and, potentially, impacting total and regional doses. In particular, we examine the response of aerosol particles to the humid environment of the respiratory tract, considering both the capacity of particles to grow by absorbing moisture and the timescale for condensation to occur. [Formula: see text].

Keywords: aerosol microphysics; condensation; drug delivery to the lungs; inhalation; moisture.

Figure 1.. Aerosols can be formulated for a number of delivery modalities including metered dose inhalers and dry powder inhalers, producing solutions, suspensions or dry powders.

The outcome of the therapy can be dependent on the formulation. Aerosolization and aerosol processing are key intermediate steps that are often ignored when considering the delivery of drugs to the lungs but result in rapid changes in particle size, phase, morphology and composition, thereby affecting deposition pattern, disposition and, possibly, clinical efficacy.

Figure 2.. Particles respond to changes in the surrounding relative humidity of the gas phase by absorbing water and growing in size.

Here, the growth in size is represented as a diameter growth factor which reports the change in particle size relative to the dry particle as the relative humidity increases. Growth curves for particles of increasing hygroscopicity parameter (= 0.01, 0.12 and 1.27) are shown as examples of insoluble, low solubility and high solubility, respectively.

Figure 3.. Simulations of the response in size of sodium chloride droplets to a step change in the relative humidity surrounding for aerosol particles of varying initial size (note the log diameter axis).

Figure 4.. Dynamic behavior of pharmaceutical aerosol prior to, and during, inhalation.

(A) A simulation of the time-dependence of the size of particles of varying composition during condensation following a step change in relative humidity. (B) A comparison of the kinetics of particle size change during initial equilibration of an aqueous sodium chloride solution droplet following injection into a gas phase of lower RH than the starting water activity in the droplet, followed by condensation of water once the relative humidity is increased. The measurements were made with an EDB detailed in our previous work [10,34]. The model parameterization includes a quasi-steady analytical treatment of the coupling of heat and mass transport during water evaporation or condensation [34,39,41]. EDB: Electrodynamic balance; RH: Relative humidity.