In Vitro Effect of Different Airflow Rates on the Aerosol Properties of Nebulized Glycopyrrolate in the eFlow® Closed System and Tiotropium Delivered in the HandiHaler®

Chronic obstructive pulmonary disease (COPD) is one of the most common pulmonary diseases in the United States and globally [1‐3]. COPD is most commonly treated by inhalation of bronchodilators, with or without corticosteroids [1]. Inhalation is the preferred route of drug delivery in COPD, reducing the likelihood of adverse events due to lower systemic exposure to the active agents. Therapeutic agents may be delivered by a variety of inhalation devices/systems, including pressurized metered-dose inhalers (pMDI), dry powder inhalers (DPI), soft mist inhalers (SMI), or nebulizer systems [4, 5]. Recent treatment strategies have strongly suggested the need for personalized selection of drug-delivery devices based on individual patient characteristics, as well as appropriate patient training, to ensure optimal management of COPD [1, 4‐7]. Despite numerous advances in inhaler technologies, user error rates have remained high and unchanged over decades [8]. Incorrect use of inhaler devices can lead to errors that prevent effective drug delivery to the lungs, which is associated with non-adherence, poor disease management [9], and increased healthcare utilization cost [10]. Multiple factors have been identified that lead to errors in device use, some related to the device and some related to the patient [9, 11]. Further, patients are often not adequately trained by their healthcare providers in the correct use of their inhalation devices. In an online survey of 205 pulmonologists, only a small fraction were very knowledgeable in teaching patients how to use (43%) or clean and maintain (22%) inhaler devices [12].

Commonly used inhaler devices (pMDIs, SMIs, DPIs, and nebulizers) vary in their mechanisms of drug delivery and administration technique [4, 5]. DPIs require active, patient-dependent airflow generation to draw the powder out of the device and create a disaggregated, breathable aerosol plume that will enter the lungs rather than impact in the mouth and throat [4]. In contrast, drug delivery with a nebulizer is a relatively passive process from the patient’s perspective, as the energy required for aerosol generation comes from external sources such as compressed air or a vibrating membrane; it is important to note that nebulization still requires the patient to actively inhale, and thus the process can be considered somewhat active, depending on the nebulizer device and resistance [4, 13]. For effective DPI use, patients need to generate sufficient peak inspiratory flow (PIF) to overcome the unique internal resistance of the device in order to disaggregate and disperse the drug [14, 15]. Drug particle characteristics with a DPI are highly dependent on flow rate through the device, and even devices with low internal resistance, such as the Breezhaler® (Novartis, East Hanover, New Jersey), produce a reduced fine particle fraction (FPF) with low flow rates [16]. Many factors, including inability to breath hold for several seconds, physical or cognitive impairments and suboptimal PIF, may lead to reduced drug delivery and impaired treatment efficacy; all of which may be more common among elderly patients [4, 15, 17]. In such patients, SMIs, pMDI with spacers, and nebulizers are viable options; however, SMIs require some coordination between actuation and inhalation [4‐6] and error rates with pMDI actuation can reduce drug deposition despite the use of spacers [18]. Nebulizers are a good alternative in these patients as they produce a fine mist and use tidal breathing to deliver the medication, thereby circumventing PIF constraints [19].

Patient characteristics, such as tidal volume, PIF, anatomy of the lungs and inhalation pattern may affect drug deposition in the lower respiratory tract versus the upper airway and oropharyngeal cavity, which impacts treatment efficacy and safety [4‐6, 13]. In addition, aerosol properties such as particle size (assessed by mass median aerodynamic diameter [MMAD]: the diameter at which 50% of the particles by mass are larger and 50% are smaller) affect deposition. Aerosol particles < 5 µm have the greatest deposition in the lungs; particles > 5 µm are more likely to deposit in the oropharynx and are swallowed. Deposition is also a function of dispersion of particle diameter (assessed by geometric standard deviation [GSD]: the measure of the spread of the aerodynamic particle size distribution) and fine particle levels (assessed by fine particle dose [FPD]: the mass of particles < 5 µm in size within the total delivered dose; FPF: the FPD, expressed as a percentage of the delivered dose). A GSD ≥ 1.22 is ideal for delivery throughout the lungs; most therapeutic aerosols have a GSD between 2 and 3 [13, 20].

In light of the increase in handling errors with age and disease severity in patients using various devices [18, 21‐23], it is important to study the drug delivery properties of different devices under varying breathing conditions. Long-acting muscarinic antagonists (LAMAs) are bronchodilators that are widely used alone or in combination with long-acting β2-agonists, with or without inhaled corticosteroids. In this study, we compared the in vitro aerosol and drug-delivery properties of two LAMAs, delivered using different devices: tiotropium (TIO) delivered using the HandiHaler® DPI (18 μg powder in single-use capsules; SPIRIVA® HandiHaler®, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA), one of the most commonly prescribed DPIs, [24] and glycopyrrolate (GLY, 25 µg/ml in 1-ml single-use vials; LONHALA®, Sunovion Pharmaceuticals, Inc., Marlborough, MA, USA) delivered using the eFlow® Closed System (CS) (MAGNAIR®; PARI Pharma GmbH; Starnberg, Germany), a vibrating membrane nebulizer [25, 26]. It is to be noted that the HandiHaler® is a high-resistance device and may not be suited for patients who cannot generate high PIF (e.g., in cases of COPD); [14] GLY delivered by the eFlow® CS may be an alternative for patients with low PIF who prefer a LAMA-based inhalation therapy.

Prior comparisons of inhaler devices have been performed and showed differences between inhalers [27‐31], but comparisons of the aerosol performance and drug deposition with nebulizers are limited. In addition, the previous analysis of the aerosol performance and drug deposition of GLY delivered using the eFlow® CS nebulizer assessed characteristics at constant flow or a single tidal volume, consistent with normal patients [32]. The current in vitro study was designed to assess the differences between a DPI and a vibrating membrane nebulizer system, delivering two LAMAs, using different breathing patterns in a Next Generation cascade Impactor (NGI) system. The in vitro conditions tested in this study were designed to resemble breathing patterns or PIF variations frequently observed in patients with COPD. In addition, these analyses aimed to extend the observations on aerosol properties of GLY delivered using the eFlow® CS nebulizer, under simulated condition to mimic the range of breathing patterns observed among COPD patients.

Recent guidelines for the treatment of COPD recommend the personalization of therapeutic agent and delivery device, with the goal of optimal management of the disease. In this analysis, we assessed the impact of varying breathing patterns and inspiratory flow rates on drug delivery and pulmonary deposition with a vibrating membrane nebulizer and a DPI. The results show the majority of MMAD < 5 µm, high FPF, and, importantly, the majority of drug was within the respirable range, using the eFlow® CS nebulizer under all breathing patterns tested. We observed some variability in the MMAD of GLY under breathing pattern 1, in which the tidal volume was low (200 ml); this breathing pattern is representative of patients with severe COPD [36]. In contrast, the HandiHaler® DPI showed variations in the MMAD and FPF with different PIF, and a majority of drug deposition within the USP throat under all flow rates tested. These in vitro results support the use of the eFlow® CS nebulizer in patients with COPD with breathing patterns ranging from ‘normal’ to ‘severe’, although it must be noted that patients with very low tidal volumes (e.g., 200 ml) may experience reduced nebulizer performance, in terms of aerosol properties, which suggests that these patients require careful consideration regarding their treatment choice and attention to treatment outcomes. These results highlight the importance of device selection based on patient characteristics and needs. However, it is important to note that the testing of the eFlow® CS nebulizer and the HandiHaler® were performed under different conditions, with varying breathing patterns (including tidal volumes and PIF) for the nebulizer and varying PIF alone for the HandiHaler®. This is reflective of the variation in the drug deposition using these devices, whereby the nebulizer creates a mist that can be inhaled during normal tidal breathing whereas the HandiHaler® requires a sharp intake of breath representative of the PIF. Thus, while our results do not represent an exact comparison of the two devices, the data provide insight into the aerosol properties of both devices under conditions characteristic of COPD patients.

A previous analysis of the aerosol properties of GLY using the eFlow® CS nebulizer was performed with a generally accepted adult normal breathing pattern with 500 ml tidal volume [32]. The current analysis extends the available data and shows drug particle size distribution similar to the previously published data under breathing conditions consistent with COPD patients [32]. Whereas a previous study had shown that MMAD with an ultrasonic nebulizer was within the respirable range using tidal volumes between 300 and 500 ml but not at tidal volumes between 150 and 250 ml [36], our data show consistent MMAD within the respiratory range using the eFlow® CS vibrating membrane nebulizer across tidal volumes between 200 and 500 ml. The minimum PIF required for the HandiHaler® DPI is 20 l/min [34], whereas optimal PIF for other DPIs are between 30 and 60 l/min [37]. We tested the HandiHaler® at both the minimal and optimal PIF for DPIs, and observed PIF-dependent changes in MMAD, which was above or just at the respirable fraction size. These in vitro data suggest that drug deposition in the lungs may be compromised in patients who use DPIs and cannot generate and sustain the optimal PIF during the inspiratory maneuver.

In this study, use of the HandiHaler® DPI resulted in drug deposition in the USP throat, independent of inspiratory flow rate, whereas use of the eFlow® CS nebulizer led to drug deposition mostly in the later stages of the NGI, under all breathing patterns tested. The high in vitro deposition of GLY within the respirable range using the eFlow® CS nebulizer is consistent with previous analyses [32], and highlights the potential for efficient drug delivery to the lungs with this device. The in vitro deposition of TIO within the USP throat using the HandiHaler® DPI is consistent with a previous analysis, which showed that the HandiHaler® resulted in lower pulmonary drug deposition compared to other inhalers [27, 38]. These results provide support for benefits of nebulization in a wider set of patients who may show variable tidal volumes and breathing patterns, whereas DPIs may be more beneficial among patients who are capable of generating the required, device-specific PIF consistently. It is important to note that TIO is also available for delivery using an SMI, which may provide greater advantages for patients having similar breathing patterns to those tested in this study, as SMIs have been shown to have a higher in vitro deposition compared to other inhalers [29, 39, 40]. The timing of this study in the summer of 2019 coincided with a period in which the HandiHaler® was predominantly used for delivery of TIO, and as such led to the use of the HandiHaler® as a comparator device in the current analysis. However, clinical outcomes were similar with TIO delivered using the HandiHaler® and the Respimat® (5 µg dose), suggesting that patient-dependent factors are the key consideration for selection between the two devices [30]. While there are no direct comparisons of drug delivery by SMIs, DPIs, and nebulizers, drug aerosol properties and delivery tend to be improved with nebulizers and SMIs compared with DPIs [41].

The results of this analysis confirm the nebulization times of approximately 2 min using the eFlow® CS nebulizer, independent of breathing patterns assessed, and consistent with previous studies [13, 25, 32, 42]. In addition, the median residual dose of GLY in the nebulizer was markedly lower than that of TIO using the HandiHaler® DPI. These in vitro data further support the high efficiency of drug delivery with a vibrating membrane nebulizer, and highlight the dependence of drug delivery by DPI on patient PIF.

Proper and personalized device selection for patients with COPD is essential, as it is associated with optimal efficacy and importantly adherence to treatment [1]. Errors (being either patient- or device-related) associated with bronchodilators lead to poor disease control and clinical outcomes [17] and nonadherence to long-term therapy [4, 43, 44]. To date, there have been no head-to-head comparisons between DPIs and nebulizers with respect to patient adherence. Future studies in COPD are needed to assess patient adherence to DPI versus nebulizer therapy.

Personalization of therapy for patients with COPD can have a major impact on the success of treatment. However, there is limited guidance on prescribing devices [20], with selection largely driven by prescriber familiarity, rather than patient demographic and disease characteristics. Our analysis highlights potential differences in the two delivery systems tested, which may help inform clinicians on appropriate device selection for their COPD patients.