Heterogeneous particle deaggregation and its implication for therapeutic aerosol performance

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  • March 22, 2019
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  • Xu, Zhen
    • Affiliation: Eshelman School of Pharmacy
Abstract
  • The delivery of aerosol drugs using dry powder inhalers (DPIs) greatly improves the treatment of diseases such as Asthma. The major hurdles for effective treatment using DPIs relate to the formulation performance efficiency and reproducibility. The relationship between the physicochemical nature of powder formulation and the behavior of particles in the aerosolization process are still poorly understood. In order to improve performance prediction and optimization of DPI formulation, we should have a comprehensive understanding of the physicochemical properties of the powders at rest and after being aerosolized. We hypothesize that: 1) The application of standardized entrainment tubes (SETs) for formulation performance evaluation can minimize the confounding factors caused by inhaler devices and reveal the relationship of airflow conditions and carrier-based dry powder formulation performance. 2) The models of molecular surface association described by adsorption expressions can be adapted to fit shear displacement observations. 3) The carrier surface treatment can reduce the surface heterogeneity and improve the performance efficiency of dry powder aerosol formulation. A set of SETs was used to allow focus on the relationship between formulation and their aerosolization performance. A novel interpretation using powder aerosol deaggregation equation (PADE) was developed based on comprehensive studies of carrier-based formulation performance. The PADE led to a fundamental understanding that the forces acting at the particle interface are analogous to those at the molecular level, and the models of molecular surface association described by the adsorption theory are analogous to shear displacement. The analogy from surface adsorption/desorption led to a completely novel way of looking at particle interactions. Several related surface phenomena were compared from their physical meanings to the fundamental theories. The PADE was further challenged by coating of lactose carrier particles with fatty acids. The coating was found to effectively improve the aerosolization performance, presumably by means of reducing surface heterogeneity and masking high surface energy density regions. Using SETs in which particle separation occurs in response to shear stress, we have developed a basic understanding of aerosolization performance described by PADE. This observation may serve as a link between macroscopic statistical thermodynamics and microscopic individual particle deaggregation.
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  • ... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the School of Pharmacy.
Advisor
  • Hickey, Anthony J.
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