Abstract
The size of aerosol particles prior to, and during, inhalation influences the site of deposition within the lung. As such, a detailed understanding of the hygroscopic growth of an aerosol during inhalation is necessary to accurately model the deposited dose. In the first part of this study, it is demonstrated that the aerosol produced by a nebulizer, depending on the airflows rates, may experience a (predictable) wide range of relative humidity prior to inhalation and undergo dramatic changes in both size and solute concentration. A series of sensitive single aerosol analysis techniques are then used to make measurements of the relative humidity dependent thermodynamic equilibrium properties of aerosol generated from four common nebulizer formulations. Measurements are also reported of the kinetics of mass transport during the evaporation or condensation of water from the aerosol. Combined, these measurements allow accurate prediction of the temporal response of the aerosol size prior to and during inhalation. Specifically, we compare aerosol composed of pure saline (150 mM sodium chloride solution in ultrapure water) with two commercially available nebulizer products containing relatively low compound doses: Breath®, consisting of a simple salbutamol sulfate solution (5 mg/2.5 mL; 1.7 mM) in saline, and Flixotide® Nebules, consisting of a more complex stabilized fluticasone propionate suspension (0.25 mg/mL; 0.5 mM in saline. A mimic of the commercial product Tobi© (60 mg/mL tobramycin and 2.25 mg/mL NaCl, pH 5.5-6.5) is also studied, which was prepared in house. In all cases, the presence of the pharmaceutical was shown to have a profound effect on the magnitude, and in some cases the rate, of the mass flux of water to and from the aerosol as compared to saline. These findings provide physical chemical evidence supporting observations from human inhalation studies, and suggest that using the growth dynamics of a pure saline aerosol in a lung inhalation model to represent nebulizer formulations may not be representative of the actual behavior of the aerosolized drug solutions.
Highlights
For nearly a century, nebulizers have been used to administer medication to the lungs and account for ∼13% of all inhaler retail sales in Europe as of 2008 (Lavorini et al, 2011)
In order to predict the relative humidity (RH) within a nebulizer airflow as a function of ambient RH and device construction, the amount of water nebulized was first measured as a function of the airflow by weighing the mass of water in the reservoir of the nebulizer before and after a set period of time of nebulization
When a secondary airflow was added through a T-junction, the humidity of the airflow downstream of the T-junction followed a similar trend as those predicted in Fig. 2B, but at much lower total flow rates with values that are readily achieved during inhalation
Summary
Nebulizers have been used to administer medication to the lungs and account for ∼13% of all inhaler retail sales in Europe as of 2008 (Lavorini et al, 2011). During this time, the use of the respiratory tract for drug delivery has proven highly successful for treating diseases of the lung, such as delivering bronchodilators to treat asthma (Johnson, 1989), and in the treatment of systemic diseases, such as delivering insulin to treat diabetes (Dubus and Luc, 2003; Watts et al, 2008). Given that the aerosol generated by many nebulizers has an aerodynamic size distribution
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