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Effect of particle size of dry powder mannitol on the lung deposition in healthy volunteers

https://doi.org/10.1016/j.ijpharm.2007.08.013Get rights and content

Abstract

There is a lack of in vivo studies focusing on the effect of particle size of dry powder aerosols on lung deposition and distribution. We investigated the dose and distribution of radiolabelled powder aerosols of mannitol in the lungs using single photon emission tomography (SPECT). Three different sized radiolabelled powders were produced by co-spray drying mannitol with 99mTc-DTPA. The primary particle size distribution of the powders measured by laser diffraction showed a volume median diameter of 2, 3 and 4 μm with span 2.3, 2.0 and 2.1, respectively, which corresponded to an aerodynamic diameter of 2.7, 3.6, 5.4 μm and geometric standard deviation of 2.6, 2.4 and 2.7 when the powders were dispersed using an Aeroliser® dry powder inhaler. Three capsules each containing approximately 20 mg (i.e. a total of 60 mg containing 60–90 MBq) of each of the radiolabelled powders were inhaled by eight healthy volunteers using the Aeroliser® inhaler. Images of aerosol deposition in the lungs were acquired using fast, multi-bed position SPECT. The lung dose markedly decreased with increasing aerosol particle size (mean ± S.E.M.: 44.8 ± 2.4, 38.9 ± 0.9, 20.6 ± 1.6% for 2.7, 3.6, 5.4 μm, respectively, p < 0.0001). The sites of deposition of the 2.7 and 3.6 μm aerosols were similar (penetration index, PI = 0.63 ± 0.05, 0.60 ± 0.03, respectively, p > 0.3), but different to the 5.4 μm aerosols (PI = 0.52 ± 0.04, p < 0.02). The lung dose followed the in vitro powder dispersion performance, with the % lung dose being related to fine particle fraction by a slope of 0.8 for a regression with intercepts forced through the origin. The SPECT results provide direct evidence that the lung deposition of dry powder aerosols depends on the particle size. The lung dose of the 2.7 and 3.6 μm aerosols using the Aeroliser® was double compared to that of the 5.4 μm aerosols and the deposition of the smaller particles was more peripheral.

Introduction

Particle size is an important determinant of in vitro aerosol performance for dry powder aerosols (Louey et al., 2004). Studies using mannitol and disodium cromoglycate have shown that as the particle size of powders is decreased, the fine particle fraction (FPF, i.e. % mass of particles <5 μm in the aerosol) measured by cascade impaction is increased (Chew and Chan, 1999, Chew et al., 2000). While particles of small size are expected to be more difficult to disperse into aerosols due to increased cohesion (Zimon, 1969), increasing the inhaler dispersion efficiency and air flow improves deagglomeration, leading to a larger FPF (Chew et al., 2000). Particle size is also known to affect deposition of dry powder aerosols in the lungs as well as therapeutic response (Zanen et al., 1994, Zanen et al., 1995).

There have been many in vivo deposition studies using dry powder inhalers (DPIs). The focus of these studies has been on comparing DPI performance at different air flow rates (Newman et al., 1994, Meyer et al., 2004) or comparison with other DPIs, or with metered dose inhalers or nebulisers (Thorsson et al., 1998, Ball et al., 2002, Rohatagi et al., 2004). Most studies have used commercial DPI products where the particle size distributions of the powders were already fixed. Few studies have addressed the relationship between the physical or aerodynamic particle size distribution (APSD) of pharmaceutical aerosols and lung deposition. This is likely due to the need for using imaging techniques to study lung deposition that are less readily available (Chan et al., 2006). Thus, it remains unclear just how in vitro dispersion performance translates to in vivo deposition in the lung (Newman, 1998).

The purpose of the present study was to link changes in the in vitro particle size of a DPI to the in vivo lung deposition using SPECT and mannitol as the dry powder with different particle sizes. Mannitol is a sugar alcohol, and is used as a dry powder by inhalation for diagnosis of bronchial hyperresponsiveness (Anderson et al., 1997, Brannan et al., 2005). Being an osmotic agent, mannitol is also used for enhancing clearance of mucus in people with bronchiectasis and cystic fibroses (Daviskas et al., 1997, Daviskas et al., 1999, Daviskas et al., 2001, Daviskas et al., 2005, Robinson et al., 1999). Mannitol was primarily chosen as a model in this study because its particle size can be readily controlled by spray drying (Chew and Chan, 1999) and the spray-dried powder is crystalline and physically stable (Rowe et al., 2001).

Section snippets

Human subjects

Eight human subjects (three male, five female) aged between 20 and 29 (mean ± standard error of the mean: 22.3 ± 1.1) with height 156–180 cm (165.9 ± 3.1) were recruited for the study. All subjects were healthy, non-smokers and had a forced expiratory volume in 1 s (FEV1) > 98% predicted (110.6 ± 3.1). All subjects had no significant reactivity to mannitol in response to inhaling increasing doses of mannitol up to 75 mg on the screening visit (% fall in FEV1 was <3%).

The study was approved by the Ethics

Radiolabelling validation and chemical assay

Initially the spray-drying techniques used to radiolabel the mannitol powders were validated by performing in vitro powder dispersions and chemical assays. The chemical assay results followed the radioactivity distribution for the mannitol powders of all three-particle sizes (Fig. 1). The aerosol particle size distributions of the radiolabelled and control (non-radiolabelled) powders were also similar, indicating that the radiolabelling method did not alter the aerosol performance of the

Lung dose

Overall the lung dose (i.e. radioactivity in the lungs) of the dry powder mannitol, inhaled using the low resistance DPI (Aeroliser®), increased as the primary particle size of the mannitol powder was decreased (Fig. 2). Fig. 3 illustrates the results showing coronal slices of SPECT images of a subject (no. 7). The mean ± S.E.M. doses expressed as a percentage of the loaded dose were 44.7 ± 2.4, 38.9 ± 0.9 and 20.6 ± 1.6% for the 2.7, 3.6 and 5.4 μm aerosols, respectively (p < 0.0001). These percentages

Discussion

Mannitol powders with primary particle size 2.1, 2.9 and 4.0 μm (VMD) and similar polydispersity (span: 2.3, 2.0 and 2.1 respectively), corresponding to 2.7, 3.6 and 5.4 μm MMAD (GSD: 2.5, 2.2 and 2.7 respectively), when dispersed by the dry powder inhaler Aeroliser® were used in the study. The unimodal size distributions with a similar polydispersity, but different only in the median particle size for the powders made it feasible to use the median size for comparing the deposition behaviour.

Conclusion

In conclusion, SPECT has been used to establish the particle size dependence of in vivo lung deposition of mannitol aerosols. The dose delivered to the lung with the 2.7 and 3.6 μm aerosols was double compared to the dose with the 5.4 μm aerosol delivered using the low resistance device Aeroliser®. This increase in lung dose also follows the increase in cascade impactor-measured aerosol performance with decreasing particle size. Deposition of the inhaled powder was increased in the lung periphery

Acknowledgements

The authors would like to thank the following: Dr. Sandra Anderson for her valuable suggestions to the manuscript, Drs. Iven Young and Michael J. Fulham for their supports, all of the volunteers who participated in this study, the University of Sydney for the Sesqui Research Grant and the Australian Research Council for funding the scholarship held by W. Glover.

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