Sub-micrometer particle production by pressurized metered dose inhalers

Evidence from both the air pollution and inhaled aerosol therapy fields suggests that the physiological impact of fine and ultrafine aerosols (defined as those below 1000 and 100 nm aerodynamic diameter, respectively) may be greater than their mass or volume of active agent alone might suggest. Traditionally, Andersen impactors and liquid impingers have been used for the sizing of particles produced by pressurized metered dose inhalers (pMDIs). However, these fail adequately to size particles in the ultrafine range (<100 nm aerodynamic diameter). In this paper, we report on a method of sizing pMDI particles down to 10 nm, using an electrical low pressure impactor (size range 30 nm to 10 microm) and a scanning mobility particle sizer (size range 3-150 nm). A range of pMDI drug formulations were assessed, including Flixotide (HFA-fluticasone propionate, GSK [Glaxo Smith Klein]), Salbulin (HFA-salbutamol sulphate, 3M), Qvar (HFA-beclomethasone dipropionate, 3M), Ventolin (HFA-salbutamol sulphate, GSK), Atrovent Forte (CFC-ipratropium bromide, Boehringer Ingelheim), Becotide (CFC-beclomethasone dipropionate, GSK), Pulmicort (CFC-budesonide, Astra Zeneca), and Serevent (CFC-Salmeterol xinafoate, GSK). All devices yielded high numbers of fine and ultrafine particles, with number median aerodynamic diameters (NMAD) of Qvar 68 nm, Becotide 73 nm, Salbulin 85 nm, and Pulmicort 89 nm, and %<100 nm Qvar 76%, Becotide 65%, Salbulin 61%, and Pulmicort 60%. We found a general trend of HFA-propelled pMDIs to produce smaller particles than the CFC units, but this trend was not statistically significant. These findings support previous published work, which suggests that significant bioactivity of pMDIs may reside in the ultrafine fraction.