Effects of ramp-up of inspired airflow on in vitro aerosol dose delivery performance for certain dry powder inhalers

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Abstract

This study investigated the effect of airflow ramp-up on the dose delivery performance of seven dry powder inhalers, covering a broad range of powder formulations and powder dispersion mechanisms. In vitro performance tests were performed at a target pressure drop of 4 kPa, using two inspiratory flow ramp-up conditions, representing slow and fast ramp-up of airflow, respectively. The fluidization of bulk powder and aerosol clearance from the inhaler was assessed by laser photometer evaluation of aerosol emission kinetics and measurement of the delivered dose (DD). The quality of aerosol dispersion (i.e. de-agglomeration) and associated lung targeting performance was assessed by measuring the total lung dose (TLD) using the Alberta idealized mouth–throat model. The ratio of DD and TLD under slow/fast ramp conditions was used as a metric to rank-order flow ramp effects. Test results show that the delivered dose is relatively unaffected by flow ramp (DD ratio ~ 1 for all dry powder inhalers). In contrast, the total lung dose showed significantly more variation as a function of flow ramp and inhaler type. Engineered (spray dried) powder formulations were associated with relatively high TLD (> 50% of nominal dose) compared to lactose blend and agglomerate based formulations, which had a lower TLD (7–40% of nominal dose), indicative of less efficient targeting of the lung. The TLD for the Tobi Podhaler was the least influenced by flow ramp (TLD ratio ~ 1), while the TLD for the Asmanex Twisthaler was the most sensitive to flow ramp (TLD ratio ≪ 1). The relatively high sensitivity of the Asmanex Twisthaler to flow ramp is attributed to rapid aerosol clearance (from the inhaler) combined with a strong effect of flow-rate on particle de-agglomeration and resulting size distribution.

Graphical abstract

Effect of inhaler ramp-up flow on delivery of dry powder aerosols to the lungs depends on interplay between formulation and device.

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Introduction

There are many inhalation drug products currently available on the market that delivers an aerosolized medicine to the lung for treatment of respiratory diseases (e.g., asthma, COPD, and cystic fibrosis). Many of these are passive, breath-actuated dry powder inhalers (DPIs) relying on the patient's inspiratory breathing effort to deliver the drug dose for local or systemic effect. The total dose delivered to the lungs depends on product related factors such as the inhaler design and particle formulation characteristics, as well as patient related factors such as the airway geometry, and inspiratory flow characteristics (i.e., peak inspiratory flow-rate, PIF; ramp-up rate of inspired airflow, and inhalation volume) that vary from patient to patient.

DPIs of different designs rely on a variety of different working principles to fluidize and disperse bulk powder into respirable aerosol agglomerates. There have been several studies aimed to understand the dose delivery performance of different inhalers as a function of patient inspiratory flow parameters. Most prior studies on this subject have focused on the effect of patient PIF on dose delivery performance (Auty et al., 1987, Ramsgaard and Pedersen, 1989, Pedersen et al., 1990, Parry-Billings et al., 2003). There have been comparatively fewer studies on the effect of the ramp-up of flow-rate (De Boer et al., 1997, Everard et al., 1997, Chavan and Dalby, 2000, Beron et al., 2008). These studies have shown that for some passive DPIs, the ramp-up of airflow can adversely influence powder emptying and the respirable dose fraction delivered, especially if the aerosolization event duration is short and occurs within the ramp-up period. For some DPIs, such unfavorable airflow conditions could lead to high deposition in the oropharynx, resulting in unwanted oral absorption for some drugs, and in some instances may increases in both local and systemic side-effects (Newman and Clarke, 1983, Byron, 1986, Grim et al., 2001).

There have been recent attempts by DPI designers to address and mitigate the flow ramp-up effect on inhalation drug delivery. One approach has been to provide the inhaler with a breath-actuated-trigger to delay aerosol generation until a threshold flow-rate (or pressure drop) is achieved (Kohler, 2004). An alternative approach is to slow down the aerosol emission kinetics, such that the bulk of the aerosol emission occurs when the flow-rate is fully developed (Ung et al., 2012). Indeed, Coates et al. (2006) found that significant dispersion reductions may occur when a large amount of powder is released from the device before both the turbulence levels and particle impaction velocities were fully developed.

These recent innovations have stimulated an investigation of flow ramp effects in commonly available DPIs. This study investigates several different marketed oral inhalation products to assess sensitivity to flow ramp-up (or flow acceleration), and its impact on in vitro aerosol delivery performance. Experiments focused on testing inhaler dose delivery performance under two flow-ramp conditions (i.e., slow and fast ramp), using airflow profiles generated by a custom-designed breath-simulator. Measurements were focused on three dose delivery attributes; aerosol emission kinetics as measured by a custom-designed laser photometer, delivered dose (DD), and total lung dose (TLD) as measured by an anatomical mouth and throat model (the Alberta Idealized Throat model; DeHaan and Finlay, 2001). Results from the laser photometry, DD, and in vitro TLD tests will be used to assess the sensitivity of the inhalers to ramp-up of inspired airflow.

Section snippets

Dry powder inhalers and formulations

Table 1 summarizes the DPIs and formulations investigated in this study. Except for the first, all of the products listed in the table are commercially marketed and will not be described in detail here. The selection of the marketed dry powder inhalers is intended to cover different powder dispersion mechanisms, powder formulation technologies (e.g. spray dried powders versus micronized blends), drug package types (e.g., capsule, blister, or reservoir) and inhaler flow resistances, see Table 1,

Aerosol powder emission kinetics by laser photometry

Fig. 4 presents the applied flow-rate and resulting aerosol emission profiles as a function of flow-volume for each DPI for slow and fast ramp-up flows. In general, PulmoSphere formulations (i.e., Simoon — placebo & Tobi Podhaler) generated a higher aerosol signal obscuration than micronized lactose-based carrier formulations (e.g., OnBrez Breezhaler of 25 mg capsule fill mass) due to their low density (bulk powder density < 0.2 g·cm 3), which translates to a larger aerosol volume concentration

Conclusion

The results show that the effect of flow ramp on delivered dose (DD) is relatively small for all DPIs tested in the study. However, greater variation was observed in the TLD, with the Asmanex Twisthaler showing the greatest variation as a function of flow ramp. The flow ramp effect on TLD essentially reflect an underlying flow-rate dependence effect, since different ramp conditions lead to differences in the “effective” flow-rate during the aerosolization event. Historically, attention has been

Author disclosure statement

No conflicts of interest exist.

Acknowledgments

The authors thank Nagaraja Rao and Jeff Weers for their assistance in facilitating this research and Novartis Pharmaceuticals Corporation for providing test materials.

References (33)

  • S. Chodosh et al.

    Effective use of Handihaler dry powder inhalation system over a range of COPD severity

    J. Aerosol. Med.

    (2001)
  • A.R. Clark et al.

    The relationship between powder inhaler resistance and peak inspiratory conditions in healthy volunteers — implications for in vitro testing

    J. Aerosol Med.

    (1993)
  • W.H. DeHaan et al.

    In vitro monodisperse aerosol deposition in a mouth and throat with six different inhalation devices

    J. Aerosol Med.

    (2001)
  • R.R. Delvadia et al.

    In vitro tests for aerosol peposition II: IVIVCs for different dry powder inhalers in normal adults

    J. Aerosol Med. Pulm. Drug Deliv.

    (2013)
  • W.H. Finlay et al.

    Fluid mechanicals and particle deposition in the oropharynx: The factors that really matter

    Respiratory Drug Delivery VIII

    (2002)
  • W.H. Finlay et al.

    Choosing 3-D mouth-throat dimensions: a rational merging of medical imaging and aerodynamics

    Resp. Drug Delivery

    (2010)
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