EnvimnmemInternational,VoL20. No. 2, pp. 161-167,1994 CopyrightO1994ElsevierScienceLid Pfin~Ain the USA.Allrishtarelcece(i
SIZE DISTRIBUTIONS AND LUNG DEPOSITION OF SUBMICROMETER PARTICLES FROM METERED DOSE INHALERS Rong-Hwa Lin Graduate Institutes of Immunology and Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan, R.O.C.
Chrong-Reen Wang Division of Rheumatology and Immunology, Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan, R.O.C.
Chih-Shan Li Division of Environmental Health, College of Public Health, National Taiwan University,Taipei, Taiwan, R.O.C.
EI 9308-197 M (Received 19 August 1993; accepted 23 December 1993)
The size distributions of the submicrometer particles generated from ten metered dose inhalers (MDIs) were determined by a high resolution particle sizer, which could measure the particles in the size range of 0.01 ~m to 1 ~m. The particle sizer contains a differential mobility analyzer (TSI 307 I) and a condensation particle counter (TSI 3022). The median diameters ranged from 0.06 - 0.10 }.tmwith a geometric standard deviation of 2. In addition, the surface median diameters and volume median diameters were found to be 0.30 }.tm and 0.45 ~tm, respectively. Moreover, none of the size distributions of the generated submicrometer particles fits log-normal distributions. The deposition probabilities of the submicrometer particles in the airways were evaluated. It was observed that the average deposition percentages of the particles in the alveolar, tracheobronchial, and extrathoracic regions are 32%, 4%, and 4%, respectively. Understanding the deposition of submicrometer particles from MDIs should benefit the clinical practice in inhalation therapy.
the factors mentioned above, the aerodynamic size of the particles is the most important parameter to determine the site and deposition amount of the delivered drugs in the respiratory tracts. In general, the aerodynamic diameter of particle generally is used for describing the aerodynamic and deposition behaviors in the respiratutory tract. Practically, the. therapeutic drugs are expected to be carried by the aerosolized particles to the large or
The metered dose inhaler (MDI) is one of the most commonly used respiratorydrug delivery systems for therapy. It is found that the therapeutic efficiency of the drugs delivered by the inhalers depends on several important parameters, including the methods of aerosol generation, the size distributionsof the generated particles,the inhalation methods, and the types of the drugs (Bouchikli et al. 1988). Among all 161
even the small airway tract. It is noted that the particles larger than 10 I.tm traditionally have been excluded from the count because they are nonrespirable. Egan and coworkers (1989) investigated the transport and deposition behavior of the inhaled aerosols for the International Commission on Radiological Protection (ICRP) group. Their results demonstrated that the deposition of the submicrometer particles (smaller than 1 Ixm) and the ultrafine particles (smaller than 0.1 I.tm) dominate in the bronchial and alveolar regions. For instance, the deposition percentages of 0.02 Ixm aerosols are approximately 30% and 40% in the bronchial and alveolar regions, respectively. Furthermore, the submicrometer aerosols could be respired further into the pulmonary region and improve the delivery efficiency of the drugs to the small airways. Although, the mass of the submicrometer particles is much smaller than that of the larger particles, the submicrometer particles still play an important role in the therapeutic outcome. Many investigations were done on evaluating the size characteristics of the generated aerosols from MDIs in the different size ranges. For example, Hiller and colleagues (1978) evaluated the nine MDIs by an aerodymanic relaxation time analyzer which could measure particles in the 0.1 ~tm to 10 I.tm size range. The results suggested the count median diameters (CMD) ranged from 0.62 lxm to 0.82 ~tm and the aerodynamic mass median diameters (AMMD) were in the range of 2.8 ~tm to 4.3 I.tm with a relatively large geometric standard deviation (GSD) of 1.5 to 2.1. Besides, Ryan and coworkers (1981) determined the particle sizes of the nebulizers using a low-flowrate seven-stage cascade impactor (Mercer et al. 1970) by a trace technique. It was shown that the measured AMMD of the generated particles varied between 0.8 ~tm and 5.2 txm with a large GSD of 1.2 to 3.59. The particle sizes of the nine MDIs in the 0.5 Ixm to 15 ~tm size range by the use of a laser particle velocimeter were reported (Bouchikli et al. 1988). The measured CMD varied from 0.63 ~tm to 0.73 ~tm with a GSD between 1.2 and 1.8. Furthermore, the airway deposition probabilities of the aerosols were calculated by referring the lung deposition model made by Stahlhofen and his coworkers (Stahlhofen 1984; Stahlhofen et al. 1983). Recently, Dolovich (1991) evaluated the size characteristics of aerosols from beclomethasone MDI by the use of a laser particle sizing system. The AMMD and GSD were found to be 3.84 lxm and 1.46 I.tm, respectively. On the other hand, Suez and Gray recommended to use respirable mass, an alternative to the AMMD, as a characteristic value of the inhaler because of its consisten-
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cy by evaluating the respirable mass of the seven MDIs (Seuz and Gray 1990). From the previous investigations mentioned above, the size characteristics of the submicrometer acrosols (in the 0.01-1 I~m size range), with higher deposition probabilities from the inhalers and the corresponding lung deposition amounts, were not well characterized yet. The objective of this study was to investigate the size distributions and to calculate the deposition of the submicrometer aerosols generated from ten MDIS in the lung. The number, surface area, and volume (mass) size distributions of the produced aerosols within the 0.01 lxm to 1 lxm size range were determined by a high resolution particle sizer. Additionally, the deposition amounts of the submicrometer particles in the bronchial and alveolar regions were calculated using the most updated lung deposition model by Phalen and coworkers (1991). MATERIALS AND METHODS
Ten kinds of MDIs were investigated in this study, including six bronchodilator aerosols, three corticosteroid aerosols and one sodium cromoglycate aerosol. All of these pressured solution aerosols were prescribed in the treatment of patients with bronchial asthma at the National Taiwan University Hospital. The pharmacodynamic characteristics of the aerosols produced from the inhalers are detailed in Table 1. The parameters include therapeutic effects, expected deposited sites (Bames et al. 1983; Whelan and Hahn 1991), active substances, excipient, and number of the doses. The particle sizer used for determining the particle characteristics is a high resolution electrical mobility aerosol spectrometer, including a differential mobility particle sizer (DMPS, TSI 3932) and a condensation particle counter (CNC, TSI 3022). This particle detector could measure the concentrations of the acrosols within the size range of 0.017-0.886 txm (including 33 channels) at a sampling flowrate of 0.3 L/min. The mean median diameter of each channel for DMPS/CNC are described in Table 2. Before entering the DMPS/CNC, the aerosols larger than 1 lxm were removed by an impacter. The DMPS/CNC was used with a bipolar charger to charge aerosols to a known Boltzman distribution. The aerosols were then classified by their ability to traverse an electric field and counted by an optical detector after a supersaturated vapor was condensed onto the particles, causing them to grow into larger droplets. The experimental protocol was as follows: For each MDI, a puff of nebulization was directed into the inlet of the DMPS/CNC in which it was diluted with the ambient air. During the experiments, the
Aerosol characteristics of inhalers
Table 1. Pharmacodynamic properties of the ten tested aerosols. Aerosol Number
Expected Deposited Sites
Number of Doses
Anti-inflammationLargeand small airway Aiveoli
Anti-inflammationLargeand small airway Alveoli
Anti-inflammationLargeand small airway Alevoli
Large and small Airway
Mast cell stabilizer
Large, small airway alveoli
Large airway more than 2 mm in diameter; small airway less than 2 mm in diameter.
characteristics of the ambient air were assumed to be constant. The measurements of the size characteristics of the MDI were repeated three times to obtain the mean values. The surface and volume concentrations of the submicrometer particles as well as the median diameters with a standard deviation of the particle size distributions for each MDI were determined. The lung model used for estimating the aerosol respiratory deposition in this investigation was the newly proposed NCRP (National Council on Radiation Protection) respiratory tract model (Phalen et al. I991). The major differences between this updated model and the 1966 Task Group one are: inspiration is taken into consideration; the new subregions of the respiratory tract are counted; absorption of the materials by the blood is regarded in a more realistic way; and body size (related to age) is also considered. The calculated fraction deposition of unit density spheres from the proposed model are detailed elsewhere (Chang et al. 1991; Moss et al. 1991).
RESULTS AND DISCUSSION
The size of the inhaled particles is an important factor in determining their behavior in the respiratory tract, especially the deposition site and the deposited amounts in the lung. Generally, there are two most commonly used parameters for describing the size distributions of the particles, including the median diameter and standard deviation. The number-weighted size distributions of the submicrometer aerosols generated from the ten inhalers are shown in Fig. 1. During the experiments, it was found that the concentrations and size distributions of the ambient particles (background) were observed to be constant. It is demonstrated that some of the size distributions were close to monodispersed (unimodal). However, the minor peaks was also found to appear. In brief, the size distributions were regarded to be comparable for all of the ten investigated inhalers. The peaks of the size distributions of the inhalers were found to occur in the 0.06 ~tm to 0.11 ~tm size range. Moreover, the median diameter (NMD), surface
R.-H. Lin et al.
Table 2. The mean mediandiameters of the 32 channels for the DMPS/CNC. ChannelNumber
1 2 3 4 5 6 7 8 9 I0 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32
0.0107 0.0124 0.0143 0.0165 0.0191 0.o221 0.0255 0.0294 0.0340 0.0392 0.0453 0.0523 0.0604 0.0698 0.0806 0.0931 0.1075 0.1241 0.1433 0.1655 0.1911 0.2207 0.2548 0.2943 0.3398 0.3924 0.4532 0.5233 0.6043 0.6978 0.8058 0.9306
median diameter (SMD), and volume median diameter (VMD) with GSD for the submicrometer aerosols of the evaluated inhalers are presented in Table 3. Additionally, the NMDs of the MDIs were f o u n d to range from 0.06 I.tm to 0.10 I.tm. The GSD is regarded as a measure of the variability of the particle diameters. In general, a large GSD suggests a broad distribution of the particle diameters. The GSD for the number-weighted size distributions of MDIs was found to be approximately 2. Moreover, the cumulative distributions (number, surface, and mass) of all MDIs are similar to the example in Fig. 2. From
the cumulative number distributions of the MDIs, it is observed that none of the distributions fits a lognormal curve. For all particles sampled by the DMPS, which are less than 1 gm in diameter, due to the inclusion of a preseparator stage, it was found that approximately 70% to 80% of the particles were in the ultrafine size ranges. On the other hand, the peaks of the surface and volume distributions are observed to shift toward the larger particles because surface and volume are related to the square and cubic of the diameter, respectively. In regard to the surface-weighted size distributions, the SMDs were found to be in the size range of 0.20 gm to 0.35 gm with an average GSD of 2.00. Compared with NMDs and SMDs, VMDs were more variable and ranged from 0.30 gm to 0.50 gm with a smaller GSD of 1.80. In summary, the number, surface, and volume size distributions of the submicrometer aerosols from the evaluated inhalers were quite similar. The NMD, SMD, and VMD reported in this study are quite different from those observed in the previous investigations, because the size ranges of the generated particles from MDIs are different from those used in other investigations. In regard to the deposition behavior of the generated particles from MDIs, the probabilities of regional deposition as percentages by number are reported in Table 4 at a breathing rate of 300 cm3/s for the adult male at rest. The three major sites in the respiratory tract are the alveolar, tracheobronchial, and extrathoracic regions. The particle exposure rate (inhaled) with the deposition rates in the alveolar, tracheobronchial, and extrathoratic regions of all MDIs are similar to the example shown in Fig. 3. In summary, the mean deposition percentages of the particles in the alveolar, tracheobronchial, and extrathoracic regions are 32%, 4%, 4%, respectively. The dominant deposition region is the alveolar region, because of a large amount of submicrometer aerosol generation. The particle depositions in the alveolar region were much larger than those found by Bouchikhi and his coworkers (1988). The reason for these differences is that the size ranges of the detected particles are different. If the main target is the deep pulmonary level, the generations of the submicrometer particles are useful for carrying the drugs. Another important issue influencing the particle deposition is the hygroscopic growth of the inhaled particles. Any particle containing water-soluble components could absorb water vapor and increase in size as they are inhaled and exposed to the highly humid air in the respiratory tract. Therefore, the hygroscopic growth of the inhaled particles generated from
Aerosol characteristics of inhalers
-----o-- Aerosol Number 1
Aerosol Number 2 Aerosol Number 3
Aerosol Number 4 Aerosol Number 5
0.1 Particle Diameter (pm)
----o--- Aerosol Number 6
Aerosol Number 7
----o...- Aerosol Number 8 1500000
Aerosol Number 9 Aerosol Number 10
Particle Diameter ~ m ) Fig. 1. The number-weighted aerodynamic size distributions of submicrometer aerosols from the MDIs. Table 3. The summaries of the NMDs, SMDs, VMDs, and GSDs of the submicrometer aerosols from ten investigated MDIs. Aerosol Number
NMD GSDn (nm)
SMD GSDs (nm)
VMD GSDv (nm)
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100 -----o-= ._~
Particle Diameter 0um) Fig. 2. The cumulative number, surface, and volume distributions of aerosol number 4.
Table 4. The summaries of the percentage of regional deposition of submicrometer aerosols by number from ten investigated MDIs. Aerosol Number
MDIs is another important factor in determining the deposition of the carried drugs in the human lungs. However, this factor seems to be never considered in evaluating and improving the delivering efficiency of the drugs by MDIs. Furthermore, there is little information available on the hygroscopieity of the particles produced from MDIs. There are only several experiments to evaluate the hygroscopic growth of known compositions, such as sodium chloride (Tu and Knutson 1984; Li et al. 1992). Therefore, further work needs to be performed for the hygroscopic growth of the carried drugs of MDIs.
The evaluation of the submicrometer particles generated from ten MDIs were conducted in the size range of 0.017-0.886 ~tm. The deposition efficiency of the submicrometer particles is found to be larger than that of the micron ones. It was found that the NMDs of the MDIs ranged from 0.06 ~tm to 0.10 ~tm with a GSD of 2. Additionally, approximately 70% to 80% of the submicrometer particles were observed to be in the ultrafine size ranges. On the other hand, the average deposition percentages of the particles in the alveolar, tracheobronchial, and extrathoracic regions are 32%, 4%, and 4%, respectively. Moreover, the
Aerosol characteristics of inhalers
"~" Exposure 2.5
Channel Number Fig. 3. The exposure and deposition rates of aerosol number 4 in the respiratory tract.
hygroscopic growth of the inhaled particles from MDIs is an important factor which needs to be addressed for determining its influence on the deposition of the carried drugs in the human lungs. By further understanding the deposition of submicrometer particles from MDIs, clinicians could optimally utilize MDIs in the treatment of patients with bronchial asthma. REFERENCE Barnes, P.J.; Basbaum, C.B.; Nadel, J.A. Autoradiographic localization of autonomic receptors in airway smooth muscle. Am. Rev. Respir. Dis. 127:7 -762; 1983. Bouchikli, A.; Becquemin, M.H.; Bignon, J.; Roy, M.; Teillac, A. Particle size study of nine metered dose inhalers, and their deposition probabilities in the airways. Euro. Respir. J. 1: 547-552; 1988. Chang, I.Y.; Griffith, W.C.; Shyr, L.J.; Yeh, H.C.; Cuddihy, R.G.; Seiler, F.A. Software for NCRP respiratory tract dosimetry. Radiat. Prot. Desire. 38: 193-200; 1991. Dolovich, M. Clinical aspects of aerosol physics. Respir. Care 36: 931-935; 1991. Egan, MJ.; Nixon, W.; Robinson, N.I.; James, A.C.; Phalen, R.F. Inhaled aerosol transport and depostion calculations for the ICRP TASK group. J. Aerosol Sci. 20: 1301-1304;1989. Hiller, C.; Mazumder, M.; Wilson, D.; Roger, B. Aerodynamic size diatribution of metered-dose bronchodilator aerosols. Am. Rev. Respir. Dis. 118: 311-317; 1978.
Li, W.; Montassier, N.; Hopke, EK. A system to measure the hygroscopicity of aerosol particles. Aerosol Sci. Technol. 17: 25-35; 1992. Mercer, T.T.; Tillery, M.I.; Newton, G.J. A multistage low flow rate cascade impacter. J. Aerosol Sci. 1: 9; 1970. Moss, O.R.; Eckerman, K.R. Proposed NCRP respiratory tract model: geometric basis for estimating absorbed dose. Radiat. Prot. Desire. 38: 185-192; 1991. Phalen, R.E; Cuddihy, R.G.; Fisher, G.L.; Moss, O.R.; Schlesinger, R.B.; Swift, D.L.; Yeh, H.C. Main feature of the propsed NCRP respiratory tract model. Radiat. Prot. Desire. 38: 179-184; 1991. Ryan, G.; Dolovich, M.B.; Obminski, G.; Cockcroft, D.W.; Juniper, E.; Hargreav¢, F.E.; Nowhouse, M,T. Standardization of inhalation provocation tests: influence of nebulizer output, particle size and method of inhalation. J. Allergy Clin. Immunol. 67: 156-161; 1981. Seuz, D.; Gray, L.D. Evaluation of the respirable mass of commonly used metered dose inhalers.In: Masuda, S.; Takahashi, K., eds. Aerosols on science, industry, health, and environment, Vol. 2. New York: Pergamon Press; 1990: 1322-1325. Stahlhofen, W. Human data on deposition. In: Prec. of a joint meeting CEC/NRPB in Oxford. Smith. H.; Gerber, G., eds, Office of the European Communities, Luxembourg, 1984: 3962. Stahlhofen, W.; Gerhart, G.; Heyder, J.; Scheuch, G. New regional deposition data on the human respiratory tract. J. Aerosol Sci. 14: 186-188; 1983. Tu, K.W.; Knntson, E.O. Total deposition of uhrafine hydrophobic and hygroscopic aerosolsin the human respiratory system. Aerosol Sci. Technol. 3: 453-465; 1984. Whelan, A.M.; Hahn, N.W. Optimizing drug delivery from metereddose inhalers. Annal. Pharmac. 25: 638-645; 1991.