Characterization of a Microprocessor-Controlled Tubular Multiple Metered Dose Inhaler Aerosol Generator for Inhalation Exposures of Pharmaceuticals

Abstract

A microprocessor-controlled tubular multiple metered dose inhaler (MDI) aerosol generator was constructed for the delivery of pharmaceutical aerosols to inhalation chambers. The MDIs were mounted in four cassettes containing one to four MDIs on a stepped end plate. The MDIs in each cassette were pneumatically activated at intervals that were controlled by the microprocessor. The cassettes permitted easy replacement of each set of MDIs with a fresh set of MDIs whenever necessary. Aerosol concentration was controlled by varying the number of active MDIs in each cassette and the frequency of activations per minute of each row. Aerosol from the MDIs flowed along the long axis of the tube, which provided a path length sufficient to diminish impaction losses. Using a light-scattering device to monitor the aerosol concentration, the pulsatile output from the MDIs in the cassettes was demonstrated to be adequately damped out provided that the dilution/mixing/aging chamber exceeded 3 ft in length. The tube diameter selected was the minimum compatible with mounting the required number of MDIs so that the linear velocity of the aerosol was adequate to efficiently transport the aerosol out of the dilution chamber. Aerosol concentration and particle size data were recorded for a nose-only rodent exposure chamber. Reproducible aerosol concentrations ranging from 0.03 to 0.6 mg/L were generated. Particle sizes ranged from 2- to 3-microm mass median aerodynamic diameter. Thus, the aerosol generated was within the size range suitable for inhalation exposures.

Toxicology Studies for Inhaled and Nasal Delivery

“…Some rodent systems have been designed using metered dose inhalers (MDIs). 22 Also, because rodents are obligate nose breathers, nasal deposition is a significant issue; keeping particle size as small as possible can be an approach to minimize nasal deposition. However, particle size reduction can be difficult since the clinical formulation should be used for the toxicology studies.…”

“…Using metered dose inhalers (MDIs) as aerosol generation devices for nonclinical toxicology studies 22 can be done when this is the clinical device. One of the goals of toxicology studies is to expose animals to a range of doses.…”

“…Given these constraints, careful consideration of aerosol science and electromechanical challenges in setting up such systems needs to be considered, as described by Rothenberg et al 22 At the high exposure concentrations required for rodent studies, it is often necessary to use multiple MDIs actuating into a plenum and then to deliver the resultant aerosol to an exposure chamber. Usually, several MDIs are fired simultaneously into a plenum that is sufficiently large to avoid impaction of the aerosol plume on the plenum walls.…”

“…Use of a plenum also allows sufficient time for reasonably complete evaporation of the CFCs or HFAs to minimize particle size and provides mixing of the aerosol to promote uniformity of the aerosol's distribution in the exposure chamber. Use of tubular plenums over 60 cm long have demonstrated less concentration variation, and a fairly steady concentration can be obtained (Rothenberg et al 22 ). The MDI banks are activated at intervals ranging from every 5 s to once per minute, with the aerosol concentration controlled by the number of MDIs activated in each bank or row and the frequency of activation.…”

“…One challenge is, in some cases, to attempt to use human inhalers for much smaller rodents. Some rodent systems have been designed using metered dose inhalers (MDIs) . Also, because rodents are obligate nose breathers, nasal deposition is a significant issue; keeping particle size as small as possible can be an approach to minimize nasal deposition.…”