Strategies and Devices for Improving Respiratory Drug Delivery to Infants and Children with Cystic Fibrosis

Cystic Fibrosis (CF) is a degenerative disease, which causes thickening of the airway surface liquid and reduced mucociliary clearance, which provides an ideal habitat for bacterial infections. Early treatment of CF in children can prevent chronic infection, improve quality of life, and increase life expectancy. The most predominant bacteria found in CF-diseased lungs is Pseudomonas aeruginosa (Pa), which can be treated with inhaled tobramycin. Excipient enhanced growth (EEG) powder formulations are well suited for administering tobramycin to children, as the EEG approach provides minimal upper airway loss and targeted drug delivery. This method uses an initially small aerosol for high extrathroacic transmission, and includes hygroscopic excipients within the formulation that absorb moisture from the humid airways and increase lung retention of the aerosol. The overarching goal of this work was to develop delivery systems and strategies for improving respiratory drug delivery to children with CF, which was based on insights from computational fluid dynamics (CFD) simulations and in vitro models. The studies presented in this dissertation have three distinct and sequential phases: (i) CFD methods development; (ii) respiratory device design and optimization; and (iii) complete-airway modeling for aerosol delivery strategy development. The methods development phase produced meshing and solution guidelines that were computationally-efficient, accurate, and validated based on in vitro data. Results showed that the two-equation k-ω model, with near-wall corrections, was capable of matching experimental data across a range of Reynolds numbers and particle sizes that are specific to respiratory drug delivery. The guidelines also provided comparable accuracy to the more complex Large Eddy Simulation (LES) model, while providing multiple order-of-magnitude savings in computational time. The device optimization phase developed a highly efficient delivery system for tobramycin administration to pediatric CF patients. Correlations were developed, based on flow field quantities, that were predictive of aerosolization performance and depositional loss. Successful a priori validation with experimental testing highlighted the predictive capabilities of the correlations and CFD model accuracy. The best-case delivery system demonstrated an aerosol size of approximately 1.5 µm and expected lung dose of greater than 75% of loaded dose, which is a marked improvement compared to commercial devices. The delivery strategy development phase identified optimal EEG aerosol properties that better unify drug surface concentration. These studies present numerical models of a tobramycin EEG powder formulation for the first time, and provide the first instance of a complete-airway CFD model evaluating pediatric CF lungs. Results show that EEG aerosols are capable of delivering the drug above the minimum inhibitory concentration in all airway regions, reducing regional dose variability, and targeting the lower airways where infection is more predominant. In conclusion, results from this dissertation demonstrate: (i) accurate and efficient CFD models of respiratory drug delivery; (ii) optimized designs for respiratory delivery systems; and (iii) optimal delivery strategies for inhaled tobramycin to pediatric patients with CF