Numerical study of effects of device design on drug delivery efficiency for an active dry powder inhaler

Highlights

• Piercing aperture location and inlet flow rate affect device emptying.

• Emitted dose fraction and CFD-based flow field parameters form strong correlations.

• Particle aerodynamic size and inhalation flow rate affect mouth-throat deposition.

• The reservoir can effectively decrease particle deposition in the mouth-throat.

Abstract

Active dry powder inhalers (DPIs) actuated by low air volume provide distinct advantages for delivering aerosols to patients with poor respiratory capacity. This work aims to investigate the effects of piercing aperture location and inlet flow rate on device-emptying, and to identify the mechanism of particle deposition in a realistic mouth-throat (MT) region. Computational fluid dynamics (CFD) is employed to predict dispersion parameters that measure turbulence intensity, and mono-sized particles are tracked by the discrete phase model (DPM). Results show that the piercing aperture location and the inlet flow rate both have significant impacts on device emptying. Strong correlations have been established between the emitted dose and flow field parameters. The pattern and distribution of the deposited particles in the realistic MT region are highly sensitive to particle size, flow rate and reservoir length. This work provides profound insights into the performance of the active DPIs and an additional perspective on device design.

Introduction

Dry powder inhalers (DPIs) are widely adopted to treat respiratory diseases for distinct advantages, such as the convenience of use, stable formulation and good coordination with patients. DPIs can be categorized into passive DPIs which are dependent on the patient's inhalation maneuver, and active DPIs actuated by external force (Daniher & Zhu, 2008; Islam & Gladki, 2008). Active DPIs become more acceptable in recent years for their unique mechanism, which is beneficial for respiratory treatment of patients with poor respiratory capacity, such as pediatric and geriatric patients (Laube et al., 2012), and also for nose-to-lung treatment (Golshahi et al., 2013; Longest et al., 2011). In addition, active DPIs are useful in evaluating the safety and efficiency of drug delivery in animal tests (Grainger et al., 2004).

The active DPIs have attracted increasing interest of researchers. Manion et al. (Manion et al., 2012) developed Puffhaler^TM which used a squeeze bulb as the external force source. When Puffhaler^TM was used for spray-dried formulations, the fine particle (particles with an aerodynamic diameter smaller than 5.8 μm) fractions (FPF) and emitted dose (ED) were 40–60% and 50%, respectively, and the reservoir bag accounted for most of the powder deposition. Exubera®, proposed by Pfizer company for delivering insulin, showed unsatisfactory market performance due to the oversized reservoir and difficulty in usage. Pohlmann et al. (Pohlmann et al., 2013) used 10–30 mL of air directly passing through a powder bed and found that the high mass of powder was aerosolized in the range of 3–3.5 μm.

Inspired by the experimental results from Pohlmann (Pohlmann et al., 2013), Behara et al. (Behara et al., 2014) presented a unique DPI actuated by a manual ventilation bag of 1 L for nose-to-lung aerosol delivery. This device generated a flow rate of approximately 10 L/min per actuation and achieved high aerosolization performance. Subsequently, Farkas et al. (Farkas et al., 2018) proposed a new inline DPI that required a lower air volume of 10 mL per actuation. It consists of a capsule chamber, orifice(s) for flow control and a 10 mL syringe. With the spray-dried excipient enhanced growth (EEG) formulation (Son et al., 2013) of albuterol sulfate (AS), the best case performance of the SS (Single-Side) device showed an ED higher than 84%, with MMAD of 2.13 μm. In addition, the best performing of the ST (Straight-Through) device generated aerosols with an ED of 61.9% and MMAD of 1.56 μm. Therefore, an active DPI that requires low air volume is feasible for aerosol delivery.

For a better understanding of the performance of active DPIs, the computational fluid dynamics (CFD) method has been applied to simulate the particle transport process in the device and massively used to study the mechanism of the particulate system in DPIs and respiratory tracts. Shur et al. (Shur et al., 2012) found that the airflow passing through the pierced capsule had a qualitative correlation with aerosolization performance. The research group also demonstrated how the CFD simulation of pressure drop, airflow field and particle trajectories could be used to investigate the aerosolization performance and to identify the key attributes of the device. Huang et al. (Huang et al., 2018) simulated the airflow and particle deposition patterns in three different mouth-throat (MT) models. Based on the device proposed by Farkas et al. (Farkas et al., 2018), Longest et al. (Longest et al., 2019; Longest & Farkas, 2019) conducted both simulation and in vitro experiments, and established quantitative correlations between predictive dispersion parameters and aerosolization performance. Practically, CFD simulation has not yet been developed to capture the breakup of the entire powder bed (Ariane et al., 2018; Longest & Farkas, 2019; Sommerfeld & Schmalfuβ, 2016; Wong et al., 2012). Considering the MMAD is highly sensitive to particle breakage, the CFD method is difficult to obtain an accurate prediction. Therefore, numerical investigation of the correlation between dispersion parameters and numerically predictive ED is more accessible. As a dominant role in evaluating the delivery performance of a DPI device, the factors affecting ED are complex. With the aid of the CFD method, the potentially predominant factors of flow field affecting ED are likely to be discovered.

Scientific measurements of predicting lung deposition and device function are essential for the design of novel inhaler devices. The MT region is the main obstacle for particles emitted from inhaler devices, directly affecting the lung deposition. The deposition efficiency in MT can effectively qualify the delivery performance of a DPI device. Thus the most common method to measure the delivery efficiency in the lung is in vitro experiments using idealized MT models with the hypothesis that particles deposit in the lung airways when exiting the MT region (DeHaan & Finlay, 2004; Delvadia et al., 2012). In order to make a more accurate prediction of the deposition process in the MT region, numerical simulation of MT models integrated with DPI devices has attracted much attention. For example, Renish et al. (Delvadia et al., 2013) constructed a geometrically realistic MT and tracheobronchial (TB) model connected with different inhalers to investigate the effect of the insertion angle using both experimental and CFD methods. The CFD simulation results were generally consistent with the experimental data. Previous studies (Delvadia et al., 2013; Dolovich et al., 2019; Ilie et al., 2008; Longest et al., 2015; Longest & Hindle, 2009) have demonstrated that integrating the inhaler into the delivery system was an effective method to investigate the realistic transport process and deposition distribution of particles emitted from the device.

While these previous in vitro and numerical analyses are useful for capsule-based DPIs, potentially different configurations are expected with the new device design. Besides, the external power magnitude plays a dominant role in affecting the particle emission of active DPI but few studies have made such investigation. There is also a lack of qualitative CFD-based correlations between flow field parameters and device emptying. Moreover, when the particles are discharged from the device, the subsequent transport process and deposition characteristics remain unclear. Therefore, a further investigation considering more potential factors affect device performance are conducted in this study.

The objective of this work is to investigate the effects of piercing aperture location and inhaler inlet flow rate on device emptying of an active DPI by simulating the transport process of the pharmaceutical aerosol. Based on the numerical results, the correlation between ED fraction and CFD-based flow field parameters has been developed. Furthermore, the active DPI model integrated into a realistic MT model is simulated to assess the attributes that affect particle deposition in the MT region when inhaling with an active DPI. Variables including particle size, inhalation flow rate and reservoir length have been investigated.