Numerical Model to Characterize the Size Increase of Combination Drug and Hygroscopic Excipient Nanoparticle Aerosols

Abstract

Enhanced excipient growth (EEG) is a newly proposed respiratory delivery strategy in which submicrometer or nanometer particles composed of a drug and hygroscopic excipient are delivered to the airways in order to minimize extrathoracic depositional losses and maximize lung retention. The objective of this study was to develop a validated mathematical model of aerosol size increase for hygroscopic excipients and combination excipient–drug particles and to apply this model to characterize growth under typical respiratory conditions. Compared with in vitro experiments, the droplet growth model accurately predicted the size increase of single component and combination drug and excipient particles. For typical respiratory drug delivery conditions, the model showed that the droplet size increase could be effectively correlated with the product of a newly defined hygroscopic parameter and initial volume fractions of the drug and excipient in the particle. A series of growth correlations was then developed that successively included the effects of initial drug and excipient mass loadings, initial aerosol size, and aerosol number concentrations. Considering EEG delivery, large diameter growth ratios (2.1–4.6) were observed for a range of hygroscopic excipients combined with both hygroscopic and nonhygroscopic drugs. These diameter growth ratios were achieved at excipient mass loadings of 50% and below and at realistic aerosol number concentrations. The developed correlations were then used for specifying the appropriate initial mass loadings of engineered insulin nanoparticles in order to achieve a predetermined size increase while maximizing drug payload and minimizing the amount of hygroscopic excipient.

Acknowledgments

This study was supported by Award Number R21 HL104319-01 from the National Heart, Lung, and Blood Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, And Blood Institute or the National Institutes of Health.