Valved Holding Chambers and In Vitro Metered Dose Inhaler Performance: Effects of Flow Rate and Inhalation Delay.

BACKGROUND

Multiple factors may influence the performance of a metered dose inhaler (MDI) when used with a valved holding chamber (VHC or "spacer").

METHODS

Andersen Cascade Impactor measurements were conducted for three MDI products and two different VHCs using a specially designed system that accommodated variable delay times between MDI actuation and introduction of the aerosol into the impactor, and allowed reduced flow through the VHC while the impactor was operated at 28.3 L/min. Deposited drug mass and aerodynamic particle size distribution were determined using validated high-performance liquid chromatography (HPLC) methods. A two-level, three-factor full-factorial design of experiments (DOE) design was applied to assess the influences of VHC type, flow rate, and inhalation delay on a total of seven performance characteristics for each MDI product. An experiment without a VHC was added to assess the influence of VHC presence.

RESULTS

DOE study shows the presence and type of VHC are the major influences on emitted dose and respirable fraction. Following the VHC effect, the inhalation delay has the most significant influence on most MDI performance metrics-emitted dose, respirable particle dose and fraction (aerosols between 1.1 and 4.7 μm), and fine particle dose and fraction (aerosols under 4.7 μm).

CONCLUSION

This study illustrates the use of DOE analysis to effectively assess the effects of patient handling parameters (flow rate and inhalation delay) on the performance of MDI drugs when used with a VHC. The results of this study will inform Food and Drug Administration reviewers, the pharmaceutical industry, and healthcare practitioners as to safe and effective use of MDI products when used in conjunction with spacer devices.