Evaluation and modification of commercial dry powder inhalers for the aerosolization of a submicrometer excipient enhanced growth (EEG) formulation

Eur J Pharm Sci. 2013 Jun 14;49(3):390-9. doi: 10.1016/j.ejps.2013.04.011. Epub 2013 Apr 19.


The aim of this study was to evaluate and modify commercial dry powder inhalers (DPIs) for the aerosolization of a submicrometer excipient enhanced growth (EEG) formulation. The optimized device and formulation combination was then tested in a realistic in vitro mouth-throat - tracheobronchial (MT-TB) model. An optimized EEG submicrometer powder formulation, consisting of albuterol sulfate (drug), mannitol (hygroscopic excipient), l-leucine (dispersion enhancer) and poloxamer 188 (surfactant) in a ratio of 30:48:20:2 was prepared using a Büchi Nano spray dryer. The aerosolization performance of the EEG formulation was evaluated with five conventional DPIs: Aerolizer, Novolizer, HandiHaler, Exubera and Spiros. To improve powder dispersion, the HandiHaler was modified with novel mouth piece (MP) designs. The aerosol performance of each device was assessed using a next generation impactor (NGI) at airflow rates generating a pressure drop of 4 kPa across the DPI. In silico and in vitro deposition and hygroscopic growth of formulations was studied using a MT-TB airway geometry model. Both HandiHaler and Aerolizer produced high emitted doses (EDs) together with a significant submicrometer aerosol fraction. A modified HandiHaler with a MP including a three-dimensional (3D) array of rods (HH-3D) produced a submicrometer particle fraction of 38.8% with a conventional fine particle fraction (%<5 μm) of 97.3%. The mass median diameter (MMD) of the aerosol was reduced below 1 μm using this HH-3D DPI. The aerosol generated from the modified HandiHaler increased to micrometer size (2.8 μm) suitable for pulmonary deposition, when exposed to simulated respiratory conditions, with negligible mouth-throat (MT) deposition (2.6%).

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aerosols
  • Albuterol / chemistry
  • Bronchodilator Agents / chemistry
  • Dry Powder Inhalers*
  • Excipients / chemistry*
  • Leucine / chemistry
  • Mannitol / chemistry*
  • Particle Size


  • Aerosols
  • Bronchodilator Agents
  • Excipients
  • Mannitol
  • Leucine
  • Albuterol