Studies with Stable Monodisperse Aerosols

Much of our early understanding of deposition of inhaled particles in the human respiratory tract as a function of aerodynamic diameters and breathing parameters comes from experiments conducted with monodisperse, stable aerosols (i.e., systems with a well-characterized size that does not change between the point of generation and deposition) under carefully controlled breathing conditions [31,32]. Experimental data in normal adults breathing such aerosols by mouth have been obtained by numerous investigators (see reviews in Refs. 8, 26, 32, and 34). In these experiments, the particle velocity is controlled by the subjects' inspiratory flow rate. Steady breathing with moderate inspiratory flow rates and inspired volumes, coupled with a brief respiratory pause, was typically employed in these studies. (This should be contrasted with special breathing maneuvers employed with most therapeutic delivery systems.) There is a general agreement from these studies that particles with aerodynamic diameters greater than about 15 mm deposit entirely in the head region. The maximum tracheobronchial deposition of about 20% occurs for aerodynamic diameters of 5-10 mm. Above ~ 1 mm, there is a maximum in alveolar deposition of about 60% for aerodynamic diameters of about 3 mm. However, it should be appreciated that at this optimum size for alveolar deposition, a significant amount of material also deposits in the tracheobronchial (~ 10%) and extrathoracic (~ 10%) regions, which renders this size range somewhat nonselective if the aerosol cloud is generated and inhaled continuously.

Under normal breathing, submicronic particles are exhaled [unless they are of ultrafine sizes (< 0.01 mm), in which case they can deposit sufficiently rapidly by diffusion]. However, breath holding allows more time for small particles to deposit by sedimentation and diffusion [43].

There is a substantial intersubject variation observed in the previously mentioned studies, despite the restrictive selection of the subjects (mostly normal nonsmoking adult males) and the control of breathing conditions. Reduction in the deposition in the head region, which shows large variability, could result in more predictable deposition in the distal parts of the respiratory tract. More information is required on intrasubject and intersubject variability in subjects with respiratory diseases. Experimental studies in patients with airway obstructions indicate that there is more deposition in the central, large airways than in the peripheral regions containing small airways and alveoli [44,45]. There is likely to be more deposition in the vicinity of the obstruction [46]. In an in vitro model, the deposition downstream from a flow-limiting element was shown to increase as the aerodynamic diameter was increased from 1.2 to 4 mm [46].

Several theoretical models exist describing the regional deposition of aerosols [47-50]. These models are in reasonable agreement with experimental data and therefore can be used to understand and design the delivery of therapeutic substances. They can reduce the number of in vivo experiments and enable investigations to be performed that would be difficult or even impossible experimentally. One particularly interesting and important aspect of modeling is the estimation of the effects of age, body size, and sex on deposition [51,52].

There is an important aspect of the deposition patterns that often escapes the unwary reader, who may be getting the impression that the three "compartments" can be treated as homogeneous. In fact, it is expected and observed experimentally that the deposition in the upper respiratory tract and central airways, which is primarily by impaction, tends to take place at the bifurcations. It would be expected, however, that in the lower part of the respiratory tract, where sedimentation and diffusion dominate and the gas flow should be essentially laminar, the deposited material would be evenly spread on the surface. Evidence from studies of experimental animals indicates that this is not so [53,54]. Even material that passes all the way through the small airways tends to deposit at the alveolar duct bifurcations, instead of covering evenly the alveolar spaces.

Indirect evidence indicates that droplets of solutions administered to human volunteers do not spread too rapidly on the surfaces of the respiratory tract, suggesting that even liquids will form deposits of hot spots of material that may never spread uniformly over the surfaces. This affects the clearance rate [55], and it may also modulate the magnitude of the local biological (i.e., both therapeutic and toxic) effects.

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