Modeling Deposition of Inhaled Particles - Aerosols: Measurement, Dosimetry, and Health Effects - page 115

exposure calculation module, but in this case the exposures are predicted not for a simulated population,
but rather for a targeted group of real individuals. The exposure module will be coupled with the MPPD
particle dosimetry model 301 and a particle clearance algorithm to estimate a time series of particle doses
for the individuals being studied. Both the exposure and dose estimates produced by EMI will then be
used in conjunction with epidemiological models to assess correlations with negative health outcomes.
5.6.2 d esign oF i nHaled P HarMaceuticals and d elivery s ysteMs
One of the most promising applications of aerosol deposition modeling is in the design of optimized
pharmaceutical aerosols and associated delivery systems. Computational models, especially CFPD
models, have the potential to predict the ideal particle properties, inhalation patterns, and aerosol
intake conditions (such as velocities or spatial distributions) for targeting the delivery of mass to the
therapeutically relevant portions of the respiratory system. Typically, this means reducing deposition
in the extrathoracic airways so that the drug can reach either the smooth muscle-lined airways of
the lungs (for asthma therapies) or the pulmonary region (for systemic treatments), although in the
case of some therapies (like nasal sprays) deposition in the extrathoracic region may be desirable.
In addition to their pure predictive power, deposition models can also be used to interpret observed
deposition patterns produced by drug delivery systems, such as dry powder inhalers (DPIs), nebulizers,
and pressured metered-dose inhalers (pMDIs). The use of models in conjunction with in vitro and
in vivo experiments can illuminate mechanistic reasons for differences in inhaler performance.
Martonen et al. 106 provide a review of the theoretical modeling issues relevant to assessing different
types of inhaled pharmaceuticals, and present a methodology for developing a physiologically based
model of the entire upper respiratory system for use in CFPD studies of inhaler performance. Other
CFPD models have recently been used to interpret human studies of dry powder inhalation, 302
compare deposition results among different pMDI formulations 303 and between an MDI and a
DPI, 304 evaluate different inhaler mouthpiece conigurations, 305-307 assess the inluence of spray
momentum on mouth and throat deposition, 308 and predict the deposition patterns of nasal sprays. 309
Recently, hygroscopicity has been proposed as the basis for a new method of improving deposition
of pharmaceutical aerosols. The method, called enhanced condensational growth (ECG), involves
inhaling a submicron-sized aerosolized medication in combination with water vapor. Ideally, the
initial small particle size would minimize extrathoracic deposition, while the hygroscopic growth of
the particle as it moves into the lung would provide enhanced deposition. Longest and coworkers 310,311
have developed CFPD models to explore the potential of this method.
5.7 SUMMARY
The modeling of particle deposition is of great use in both inhalation toxicology and inhalation
therapy. In particular, modeling provides a means of predicting total, regional, and local respira-
tory system concentrations of inhaled particles, and offers a foundation for the development of
targeted delivery protocols. In addition, modeling aids in interpreting experimental measurements
and advances the understanding of events and variables that cannot be experimentally quantiied.
Particle deposition in the human respiratory system is an extremely complex phenomenon, gov-
erned by a wide variety of overlapping and interacting factors. Development and validation of increas-
ingly sophisticated computational models that address particle deposition on local and regional scales,
and consider both biological variability and realism, will be instrumental in improving the prediction
of both the health effects of inhaled particles and the therapeutic value of inhaled pharmaceutics.
ACKNOWLEDGMENT
Kristin K. Isaacs was funded by the EPA/UNC DESE Cooperative Training Agreement CT827206,
with the Department of Environmental Sciences and Engineering, University of North Carolina at
Chapel Hill.