Evolving In Vitro and In Silico Methods for Predicting Performance in Respiratory Drug Delivery Applications

The overarching theme of this work is the investigation and development of in vitro and in silico methods used to characterize inhaled pharmaceutical aerosols. The ultimate aim is to expand and strengthen the links between applied science and clinical practice for inhaled medications. Chapter 1 introduces the structure of the thesis. Chapter 2 consists of a review of literature. Relevant metrics used in the characterization of inhaled therapies are discussed, together with advanced in vitro and in silico methods for characterizing respiratory tract deposition and drug disposition. Chapter 3 describes an in vitro study on deposition from commercially available pharmaceutical inhalers in the Alberta Idealized Throat. This mouth-throat geometry has been used to accurately characterize aerosol deposition in terms of extrathoracic and total lung doses, though its ability to replicate in vivo deposition from some inhalers requires careful consideration of the underlying aerosol mechanics. We hypothesized that differences between in vitro and in vivo data may be partly caused by variations in factors not typically considered during in vitro testing, primarily the insertion angle of the inhaler into the mouth-throat geometry itself. Three of six examined inhalers showed sensitivity to the angle of insertion. For DPIs, this sensitivity may be reduced using larger diameter mouthpieces and smaller particle sizes in powder formulations. For pMDIs, lower momentum sprays demonstrated more consistent performance. Consideration of these factors in future devices and formulations may improve the consistency of dosing during real-world use. Chapter 4 describes a combined in vitro – in silico methodology to predict systemic exposure of budesonide from dry powder inhalers, incorporating in vitro measurements of intrathoracic particle size distributions, regional lung deposition modeling, and pharmacokinetics. Good agreement between predictions and in vivo data were obtained without the requirement of extraneous fit factors, suggesting the model is robust for well-characterized therapeutic agents like budesonide. Comparatively modest deposition in the small conducting airways was predicted to occur with each dry powder inhaler despite large in vitro differences in performance. Tracheobronchial deposition was predicted to correlate poorly with systemic drug concentrations, suggesting that overt reliance on systemic exposure data in establishing bioequivalence of locally acting inhaled therapies may not properly elucidate differences between formulations. Rather, a combination of methods like that proposed in the present work may aid in better predicting bioequivalence. In Chapter 5, a novel in vitro – in silico methodology was developed to characterize nebulizer performance in the context of methacholine challenge testing. The incorporation of experimental methods with hygroscopic theory and lung deposition modeling allowed for the quantification of regional deposition of methacholine and better estimation of the provocative dose than is provided by existing methods, which likely overestimate the relevant dose by considerable and device-dependent margins. Measurements of airstream conditions suggested that droplets exiting nebulizer mouthpieces exist in highly concentrated states compared to stock solutions, and upon inhalation these droplets can be expected to undergo significant hygroscopic growth. The procedure outlined in Chapter 5 may serve as step towards standardizing the determination of provocative doses obtained with methacholine challenge testing, which could improve the translatability of results currently obtained with disparate methods and protocols. Finally, Chapter 6 summarizes major conclusions, identifies contributions to knowledge, and proposes potential avenues for future work. Methods described in this thesis provide a framework for improving upon the standard pharmacopeial methods used to characterize pharmaceutical aerosols. With increased focus on the use of inhaled aerosols as a vehicle for both local and systemic delivery of medication, such methods are of interest in streamlining the drug development process and in optimizing future devices and formulations.

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