Predicting Lung Deposition

This approach has been taken by Clark et al. (3), and the correlation plots are shown in Figs. 8 and 9. Fig. 8 presents a compilation of the available data relat- 

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Peripheral airway deposition Total body deposition 

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Martonen TB, Katz I, Fults K, et al. Use of analytically defined estimates of aerosol respirable fraction to predict lung deposition patterns. Pharm Res 1992 9 1634-1639. 

In Vitro Testing of Pharmaceutical Aerosols and Predicting Lung Deposition from In Vitro Measurements... 

Beyond their potential value in predicting lung deposition, in vitro laboratory tests are a major component of the quality-control and product-release process for pharmaceutical aerosol products. In this context they are not required to have any in vivo predictive power. Danonstrating that different batches of product possess the same physical characteristics is all that is needed. However, understanding a test s relevance to clinical performance is important. 

The pnrpose of this chapter has been to review the literature and data that are available in relation to predicting lung deposition from in vitro measurements of pharmaceutical aerosols. In vitro test methods where described and discussed in the context of the dynamic behavior of inhalation aerosols, the issue being that an understanding of the behavior of the aerosol, coupled to and an understanding of the principles of operation of the sizing instruments, leads to a more detailed appreciation of the value and limitations of the correlations between in vitro and in vivo data. 

A number of models have been developed to attempt to predict respiratory deposition, especially in the lower airways—the alveolar region. Experimental studies have tended to confirm the validity of the models, recognizing that there is much individual variation and thus a great spread in the results. The results have been clear enough, however, to indicate that till else being equal, deposition of particles in the lungs is greatly influenced by particle size and particle density. 

Pinlay, W.H. Stapleton, W.K. Zuberbuhler, P. Variations in predicted regional lung deposition of salbutamol sulphate between 19 nebulizer types. J. Aerosol Med. 1998, 11 (2), 65-80. 

Finlay WH, Stapleton KW, Zuberbuhler P. Errors in regional lung deposition predictions of nebulized salbutamol sulphate due to neglect or partial inclusion of hygroscopic effects. Int J Pharm 1997 149 63-72. 

Hashish AH, Fleming JS, Conway J, Halson P, Moore E, Williams TJ, Bailey AG, Nassim MN, Holgate ST. Lung deposition of particles by airway generation in healthy subjects three-dimensional radionuclide imaging and numerical model prediction. J Aerosol Sci 1998 29 205-215. 

Physical size is a parameter that helps predict particle deposition in the deep lung. Differentiate the accumulation fraction of fine particles from ultrahne particles describe where in the lung they are most likely to deposit. 

It can be seen that Newman s approach improves the agreement and results in a slope of approximately 1, but fails to improve variability. Olsson s method on the other hand reduces variability, but it continues to overestimate lung deposition by a factor of 1.7. From the deposition data presented in earlier chapters this overestimate of lung deposition when using FTF would seem quite logical in that none of the deposition models predict complete deposition of this size fraction. It would also be expected that an oropharyngeal model would bring pMDI data more in line with DPI data and reduce scatter since it deals more correctly... 

A number of attempts have been made to use lung deposition models and in vitro size distributions to predict deposition profiles for both DPIs and pMDls. These studies have always been performed in hind sight and are limited in extent because of the expense of performing lung deposition studies in human volunteers. 

The data reported in the sections above may, if viewed in a favorable light, lead to the conclusion that there are reasonable correlations between in vitro sizing data and mean lung deposition determined in vivo. (The predictive power of these correlations is discussed in more detail below.) However, one of the other factors that determines the suitability of an inhalation product for use with a particular drug is variability of deposition. As one would perhaps expect a pri-... 

For extrathoracic deposition of particles, the model uses measured airway diameters and experimental data, where deposition is related to particle size and airflow parameters, and scales deposition for women and children from adult male data. Similar to the extrathoracic region, experimental data served as the basis for lung (bronchi, bronchioles, and alveoli) aerosol transport and deposition. A theoretical model of gas transport and particle deposition was used to interpret data and to predict deposition for compartments and subpopulations other than adult males. Table 3-4 provides reference respiratory values for the general Caucasian population during various intensities of physical exertion. 

The deposition model used here includes expressions for diffusion (Ingham, 1975) sedimentation (Pich, 1972) and impaction (Egan and Nixon, 1985) and a realistic treatment of lung ventilation. It can be shown that this predicts the aerosol deposition measured in the lungs of human subjects (summarised by Rudolf (1986)) over the range of aerosol size from 5 nm to 5 pm diameter, and for all breathing conditions tested, to within 207o of measured values. 

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