Development of an in vitro model to assess deposition of aerosol particles in a representative replica of the rat's respiratory tract.

BACKGROUND: Small rodents continue to be the mainstay for the assessment of pharmacological and toxicological data of inhaled therapeutics. For meaningful interpretation of the results information about deposition of aerosol particles in the respiratory tract is warranted, but not trivial to obtain for animals with nose-only aerosol exposure. The purpose of this study was to develop and evaluate a general method to characterize the deposition of inhaled test particles in an in vitro model (IVR) of the rat's respiratory tract. METHODS: A highly detailed, realistic and representative image using micro-CT scanning technology was obtained and the generated morphological data was used to construct a plastic replica of the average rat respiratory tract. The model was connected to a rodent ventilator, which allowed the breathing frequency (f, min(-1)) and tidal volume (V(T), mL) to be varied as required. Polydisperse fluorescent microsphere particles with an average mass median aerodynamic diameter (MMAD) of 3.1 µm and geometric standard deviation (GSD) of 2.2 µm were used as model compound. RESULTS: Comparison of the experimental data for total and regional deposition levels with predicted outputs using the in silico MPPD model showed reasonably good relative agreement between the two models. The predictions were closest to the experimental values when default respiratory conditions of f=102 breaths/min and V(T) of 2.0 mL were used. Moreover, the IVR model revealed good correlation with published in vivo data. CONCLUSION: Using the IVR model allows an easy, fast and reasonably precise estimation of the inhaled dose in rodent inhalation studies. The IVR has the potential to be used along with live rats in inhalation exposure studies, and thus provides the unique possibility to run an internal standard for dose deposition in the respiratory tract in each inhalation experiment. This should contribute to enable a greater understanding of drug pharmacokinetics and dynamics in rats and may improve dose extrapolation from animals to humans.

Study of the variability in upper and lower airway morphology in Sprague-Dawley rats using modern micro-CT scan-based segmentation techniques.

Animal models are being used extensively in pre-clinical and safety assessment studies to assess the effectiveness and safety of new chemical entities and delivery systems. Although never entirely replacing the need for animal testing, the use of computer simulations could eventually reduce the amount of animals needed for research purposes and refine the data acquired from the animal studies. Computational fluid dynamics is a powerful tool that makes it possible to simulate flow and particle behavior in animal or patient-specific respiratory models, for purposes of inhaled delivery. This tool requires an accurate representation of the respiratory system, respiration and dose delivery attributes. The aim of this study is to develop a representative airway model of the Sprague-Dawley rat using static and dynamic micro-CT scans. The entire respiratory tract was modeled, from the snout and nares down to the central airways at the point where no distinction could be made between intraluminal air and the surrounding tissue. For the selection of the representative model, variables such as upper airway movement, segmentation length, airway volume and size are taken into account. Dynamic scans of the nostril region were used to illustrate the characteristic morphology of this region in anaesthetized animals. It could be concluded from this study that it was possible to construct a highly detailed representative model of a Sprague-Dawley rat based on imaging modalities such as micro-CT scans.

Studies of the human oropharyngeal airspaces using magnetic resonance imaging IV--the oropharyngeal retention effect for four inhalation delivery systems.

Magnetic resonance imaging (MRI) of the oropharyngeal region from 20 adult volunteers using four model inhalation devices (varying mouthpiece diameters, airflow resistances) and tidal breathing was carried out. Statistical analysis (convex hull method) selected 12 scans from 80 data sets representing the extremes of all dimensions in the population. Twelve physical mouth-throat models were made by stereolithography using the exact scan data. The aim was to produce models with varying dimensions to span the adult population, and to investigate if oropharyngeal dimensions affected throat retention for different delivery systems. In an in vitro analysis, the models were used to determine the retention effect of the oropharyngeal airspaces when drug aerosols were administered from four inhalation delivery systems: a pressurised metered dose inhaler (pMDI), two different dry powder inhalers (DPIs A and B), and a nebulizer. The aims of this work were to determine the key parameters governing mouth-throat retention and whether retention was dependent on the delivery system used. Characterizing the throat models by measuring 51 different dimensional variables enabled determination of the most influential variables for dose retention for each inhalation delivery system. Throat model retention was found to be dependent on the delivery system (pMDI approximately DPI(A) > DPI(B) > Neb.). The most influential variable was the total throat model volume. Throat models representing high, median, and low oropharyngeal filtration in healthy adults have been identified.