Predicting vapor transport and aerosol dynamics in the respiratory airways is important for analyzing both environmental exposure and respiratory drug delivery. A large number of analytical models, computational studies, and experiments on vapor and aerosol transport in the respiratory tract have been conducted previously. However, a number of critical questions remain unanswered. In this study, computational fluid dynamics (CFD) is primarily employed with frequent comparisons to existing and new experimental data sets to address previously unanswered issues related to the transport of vapors and aerosol in the respiratory tract. The three objectives of this study are further described below. Objective 1: A CFD model was developed to predict the transient absorption of inhaled vapors in the respiratory tract. Results indicated that transient absorption can significantly influence the transport and uptake of vapors in the walls of the conducting airways. Objective 2: The concept of enhanced condensational growth (ECG) applied to respiratory drug delivery was tested in a representative airway model extending from the oral cavity to the end of the tracheobronchial (TB) airways. Results indicated that ECG is an effective method to provide near full lung retention of the aerosol. The CFD results also indicated that the ECG delivery approach under transient inhalation conditions increased aerosol deposition in the TB airways by only a small amount, as compared with steady state conditions. Objective 3: The effect of transient waveforms on the transport and deposition of pharmaceutical aerosols from inhalers in the upper airways was considered. Results indicated that the CFD model predictions matched the in vitro experiments to a high degree. The CFD results also indicated that it was critical to consider transient inhalation effects when assessing aerosol deposition. The stochastic individual path (SIP) modeling approach was then introduced and implemented to evaluate the transport and deposition of pharmaceutical aerosols from inhalers in medium and small TB airways. Results indicated that steady state inhalation could be used to predict deposition efficiencies in the TB airways between the 4th branch (B4) and the bronchioles (B15).

An investigation into the factors affecting the metered atomisation of superheated liquids has been carried out. The investigation was aimed primarily at developing an understanding of the factors which affect the performance of. respiratory drug delivery systems (Suspension Pressurised Metered Dose Inhalers). Initial investigations used a semi-empirical sizing technique, representing the human airways, to identify the major variables (formulation and geometric) which affect the performance of the MDI system. Computer models were developed to describe both continuous and metered discharge from a superheated-liquid aerosol generator. These models were based on the concept of thermal and dynamic equilibrium, but they were improved and extended, to describe metered discharge, by including empirical corrections obtained from continuous discharge experiments. Experimental investigations using 'instrumented inhalers' were used to confirm the validity of the computer model. The experimental investigations encompassed the use of conventional CFC's and the new non-chlorinated propellants 134A and 227. The computer models and droplet correlation function developed during these investigations represent powerful tools for use in the design of both current and future HFC/HFA powered metered dose inhaler delivery systems.

The administration of pharmaceutical aerosols to infants on mechanical ventilation needs to be improved by increasing the efficiency of delivery devices and creating better ways of evaluating potential therapies. Aerosolized medicines such as surfactants have been administered to ventilated infants with mixed results, but studies have shown improvement in respiratory function with a much lower dose than with liquid instillation through an endotracheal tube (ETT). An aerosolized medicine must be transported through the ventilation tubing and deposit in the lungs to have the desired therapeutic response. This work has taken a systematic approach to (i) develop new devices for the efficient production of small sized charged pharmaceutical aerosols, (ii) adapt a lead device to an infant ventilation system, (iii) develop a novel breathing infant lung (BIL) in vitro model capable of capturing lung delivery efficiency in an infant without the need for human subjects testing, and (iv) evaluate the hypothesis that small sized charged pharmaceutical aerosols can improve drug delivery efficiency to the lungs of a ventilated infant. Three new devices were developed and screened for the efficient generation of small sized charged pharmaceutical aerosols, which were: wick electrospray, condensational vapor, and a modified vibrating mesh nebulizer in a streamlined low flow induction charger (LF-IC). Of these devices, only the LF-IC produced a small [mean(SD) = 1.6(0.1) micrometers] and charged (1/100 Rayleigh limit) aerosol at a pharmaceutically relevant production rate [mean(SD) = 183(9) micrograms per minute]. The LF-IC was selected as a lead device and adapted for use in an infant ventilation system, which produced an increase in in vitro lung filter deposition efficiency from 1.3% with the commercial system to 34% under cyclic ventilation conditions. The BIL model was first shown to produce a realistic pressure-volume response curve when exposed to mechanical ventilation. The optimized LF-IC was then implemented in the BIL model to demonstrate superior reduction in inspiratory resistance when surfactant was delivered as an aerosol compared to liquid instillation. For the delivery of an aerosolized medication, the lung deposition efficiency increased from a mean(SD) 0.4(0.1)% when using the conventional delivery system to 21.3(2.4)% using the LF-IC in the BIL model, a 59-fold increase. The charged aerosol produced by the LF-IC was shown to have more depositional loss in the LF-IC than an uncharged aerosol, but the charge decreased the exhaled fraction of aerosol by 17%, which needs additional study to achieve statistical significance. Completion of this work has produced a device that can achieve lung delivery efficiency that is 59-fold greater than aerosols from conventional vibrating mesh nebulizers in invasively ventilated infants using a combination of small particle size, synchronization with inspiration and appropriate charge. The BIL model produced in this work can be used to test clinically relevant methods of administering medications to infants and can be used to provide more accurate delivery estimates for development of new nebulizers and inhalers. The LF-IC developed in this work could be used for controlled and efficient delivery of aerosolized antibiotics, steroids, non-steroidal anti-inflammatories, surfactants, and vasodilators.

Dry powder inhalers (DPIs) are advantageous for delivering medication to the lungs for the treatment of respiratory diseases because of the stability of the powders, relative low cost, synchronization of inhalation and dose delivery, and many design options that can be used for optimization. However, currently marketed DPIs are very inefficient in delivering medications to the lungs. This study has developed multiple new high efficiency DPIs for use with spray dried excipient enhanced growth (EEG) powder formulations based on the following platforms: capsule-based for oral inhalation, high-dose for oral inhalation, inline with 3D rod array dispersion, and inline with capillary jet dispersion. The capsule-based DPIs for oral inhalation implemented a 3D rod array for aerosol dispersion with optimal designs producing mass median aerodynamic diameters (MMADs) in the range of 1.3-1.5 µm and emitted doses in the range of 79-81%. Keys to inhaler success were the orientation of the capsule and inclusion of the 3D rod array. For the high-dose oral inhaler, performance was similar to the optimized capsule-based devices, while aerosolizing a much larger mass of powder. Surprisingly, removal of the fluidized bed of spheres improved performance producing a simple high dose device containing only a single dose sphere. The inline device using the 3D rod array was effective in producing particles of approximately 1.5 µm, at flow rates consistent with high flow therapy using a 1 L ventilation bag as the delivery mechanism. Using a capillary jet as the dispersion mechanism, further advances were made to allow for both delivery using a low volume (LV) of air and delivery in low flow therapy. This easily adaptable platform was able to produce a high quality aerosol out of a nasal cannula with an ED greater than 60% and a size (~2 µm) that should produce minimal extrathoracic losses. In conclusion, this study demonstrates (i) the design and optimization of DPIs capable of delivering EEG aerosols to the lungs using oral inhalation, (ii) the ability to deliver EEG aerosols using N2L aerosol administration, and (iii) the design of a new flexible LV-DPI device that is easily adaptable to multiple patients and delivery platforms, which are greatly needed in clinical environments.