Particle size inhalation aerosols

Site of deposition of tracer aerosol Particle size of aerosol Pattern of inhalation Airway caliber Lung capacity Mucus/cilia interaction Mucosal surface damage Spontaneous cough Exercise Disease Drugs... 

FIGURE 3.1.1.1 Ranges of Particles Sizes for Aerosols. Air can contain many sizes of particles that can be inhaled. There should be none of these in a laboratory. Any procedures that generate these aerosols should be conducted in chemical hoods. Industrial manufacturing facilities are a more likely site to encounter these particles. 

Pharmaceutical powder aerosols have more stringent requirements placed upon the formulation regarding moisture, particle size, and the valve. For metered-dose inhalers, the dispensed product must be deflvered as a spray having a relatively small (3—6 -lm) particle size so that the particles can be deposited at the proper site in the respiratory system. On the other hand, topical powders must be formulated to minimize the number of particles in the 3—6-p.m range because of the adverse effects on the body if these materials are accidently inhaled. 

As stated earlier, inhalation is the main route of absorption for occupational exposure to chemicals. Absorption of gaseous substances depends on solubility ifi blood and tissues (as presented in Sections 2.3.3-2.3.5), blood flow, and pulmonary ventilation. Particle size has an important influence on the absorption of aerosols (see Sections 2.3.7 and 3.1.1). 

Lung deposition patterns and the relative contributions of the fecal and urinary pathways vary with the aerosol particle size. Evidence for this is provided by a study in which dogs inhaled Am02 aerosols having... 

Subsequently, individual data on exposure are converted to dose by using conversion factors (OECD/NEA, 1983). The choice of the appropriate numerical value depends on physiological parameters (e.g. respiratory minute volume) as well as physical characteristics of the inhaled aerosol (e.g. particle size). Mean values range typically from about 5 mSv/WLM (non-occupational exposure) to about 10 mSv/WLM (occupational exposure). 

Metered-dose inhalation aerosols Delivered dose per actuation, number of metered doses, color, particle-size distribution, loss of propellant, pressure, valve corrosion, spray pattern, and absence of pathogenic microorganisms... 

Both from deposition studies and force balances it can be derived that the optimum (aerodynamic) particle size lies between 0.5 and 7.5 pm. Within this approximate range many different subranges have been presented as most favourable, e.g. 0.1 to 5 pm [24], 0.5 to 8.0 pm [25], 2 to 7 pm [26] and 1-5 pm [27-29]. Particles of 7.5 pm and larger mainly deposit in the oropharynx [30] whereas most particles smaller than 0.5 pm are exhaled again [31]. All inhalation systems for drug delivery to the respiratory tract produce polydisperse aerosols which can be characterized by their mass median aerodynamic diameter (MMAD) and geometric standard deviation (oq). The MMAD is the particle diameter at 50% of the cumulative mass curve. 

As described in Section 3.3 in more detah, particles in the aerosol cloud should preferably have an aerodynamic diameter between 0.5 and 7.5 pm. Currently three different types of devices are used to generate aerosol clouds for inhalation nebulizers (jet or ultrasonic), (pressurized) metered dose inhalers (pMDIs) and dry powder inhalers (DPIs). The basic function of these three completely different devices is to generate a drug-containing aerosol cloud that contains the highest possible fraction of particles in the desired size range. 

Laser diffraction is a fast alternative for analysis of the size distribution of particles in an aerosol cloud. The theory of laser diffraction is well understood [124,125]) but this technique requires special measures to test inhalation devices and to interpret the results correctly. One of the major problems is that flow adjustment through the inhaler is not possible. Furthermore, the presence of carrier particles from adhesive mixtures may disturb the measurement of the fine drug particles and the size distribution obtained is of an unknown dehvered mass fraction of the dose. These practical problems and limitations have been solved by the design of a new modular inhaler adapter for the Sympatec laser diffraction apparatus (Figure 3.6). 

The potential for liquid aerosols or finely divided powders to be inhaled will be determined by their particle size. Deposition patterns for dusts will depend not only on the particle size of the dust but also the hygroscopicity, electrostatic properties and shape of the particles, and the respiratory dynamics of the individual. Thus, it is only possible to make very general statements about sites of... 

A Guidance Document on Acute Inhalation Toxicity Testing is being developed and presently exists as a draft (OECD 2004b). The document recommends the Acute Toxic Class (ATC) Method with a group size of three animals per sex, if the objective of the test is solely related to hazard classification. Limits for particle-size distribution of aerosolized test substances are suggested. The preferred mode of exposure is the nose-only, head-only, or head/nose-only exposure technique, because this mode of exposure minimizes exposure or uptake by noninhalation routes. 

From a public health point of view, the concentration of nickel associated with small particles that can be inhaled into the lungs is of greatest concern. The nickel content of aerosols from power plant emissions is not strongly correlated with particle size (Hansen and Fisher 1980). In one modem coal plant, 53% and 32% of nickel in emissions were associated with particles <3 and <1.5 pm in diameter, respectively (Sabbioni et al. 1984). Other studies found that only 17-22% of nickel emissions from coal-fired power plants were associated with particles of >2 pm, and that the mass medium diameter (MMD) of nickel-containing particles from a plant with pollution control devices was 5. 4 pm (Gladney et al. 1978 Lee et al. 1975). In one study, 40% of the nickel in coal fly ash was adsorbed on the surface of the particles rather than being embedded in the aluminosilicate matrix (Hansen and Fisher 1980). Surface-adsorbed nickel would be more available than embedded nickel. 

An important aspect of inhalable PAHs is their distribution as a function of particle size in ambient aerosols since size is a key parameter in determining aerosol lung deposition efficiencies (see Chapter 2.A.5). 

Several portable inhalation devices have been developed and are being tested to determine whether they improve protein and peptide delivery via the airways. Aerosolized DNase has been shown in patients with cystic flbrosis to significantly reduce the buildup of mucus in the lung and the incidence of infections. Devices for delivery of therapeutic proteins to deep-lung alveoli to achieve systemic effects are also in development. These products are formulated so that the device aerosolizes the protein in a defined particle size range that cannot be easily achieved by means of conventional metered dose inhalers. 

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