Advances in soft mist inhalers

ABSTRACT

Introduction

Soft mist inhalers (SMIs) are propellant-free inhalers that utilize mechanical power to deliver single or multiple doses of inhalable drug aerosols in the form of a slow mist to patients. Compared to traditional inhalers, SMIs allow for a longer and slower release of aerosol with a smaller ballistic effect, leading to a limited loss in the oropharyngeal area, whilst requiring little coordination of actuation and inhalation by patients. Currently, the Respimat® is the only commercially available SMI, with several others in different stages of preclinical and clinical development.

Areas covered

The primary purpose of this review is to critically assess recent advances in SMIs for the delivery of inhaled therapeutics.

Expert opinion

Advanced particle formulations, such as nanoparticles which target specific areas of the lung, Biologics, such as vaccines, proteins, and antibodies (which are sensitive to aerosolization), are expected to be generally delivered by SMIs. Furthermore, repurposed drugs are expected to constitute a large share of future formulations to be delivered by SMIs. SMIs can also be employed for the delivery of formulations that target systemic diseases. Finally, digitalizing SMIs would improve patient adherence and provide clinicians with fundamental insights into patients’ treatment progress.

KEYWORDS:

• Soft mist inhaler
• aerosols
• inhalable formulations
• pulmonary drug delivery
• aqueous droplet inhaler
• non-pressurized metered-dose inhaler
• inhaled biologics

1. Introduction

The respiratory field is expanding, with pulmonary delivery being seen as a patient-friendly way of delivering biologic drugs. Dry powder inhalers and pMDIs require hand-breath co-ordination and inspiratory efforts for the efficient delivery of medication to lungs [1,2]. On the other hand, nebulizers are large, require electrical energy for nebulization, are not always efficient in the amount of drugs they deliver and require complicated cleaning procedures.

Innovations in inhaler technology have resulted in the development of low-velocity spray devices, called soft mist inhalers (SMIs). The SMI is a propellant-free multidose inhaler device that does not suffer from the ‘ballistic effects’ of aerosols created in pMDIs, thereby reducing the deposition of aerosol in the mouth-throat region [3]. In SMIs, the drug is present as a liquid formulation stored in an enclosed system, such as a pre-filled syringe or cartridge. Upon actuation, the formulation is released as a slow aerosol cloud using mechanical energy [4,5]. SMIs possess advantages of pMDIs and most of the DPIs, including high drug deposition (up to >50% of the dose) in the lungs, portability, and compactness, without the inconvenience of propellant usage or the necessity to formulate drugs as complicated dry powder formulations [6,7]. Moreover, the aerosol cloud produced by SMIs possesses a higher fraction of fine particles compared to most pMDIs and dry powder inhalers (DPIs), with an aerosol spray released from the inhaler that is slower and longer than that from pMDIs [8] and thereby minimizing the impact of errors in hand-lung coordination. The delivery of the drug as an aerosol mist eliminates the chilling sensation produced by evaporating gases experienced while using pMDIs [9]. Furthermore, SMIs tend to be more efficient in the percentage of total dose delivered into the lungs compared to nebulizers. These characteristics make the SMIs suitable to play a major role in inhalation therapies [5]. Some SMIs possess the capability to aerosolize sensitive lipid nano particle formulations (e.g. rhDNAse, mRNAs) which are not available as other inhalation dosage forms or are sensitive to current aerosolization methods [10,11]. Additionally, with the propellant free technology and the availability of reusable versions, SMIs contribute to low carbon emissions and environmental sustainability.

The objective of this review is to illustrate the mechanisms of soft mist formation, outline the main features of different SMI device types, and review their efficiency for respiratory drug delivery. This review also provides an overview of the SMI’s advantages and challenges while summarizing the recent progress and novel applications of current SMIs.

2. Characterization of soft mist inhaler

Identical to other inhalation products, the therapeutic efficacy of aerosolized drug droplets from SMI devices is dependent on the dose of the drug reaching the lungs [12]. The percentage of the emitted dose reaching the lung is dependent on particle size distribution (PSD) and breathing patterns. However, the functionality of the SMIs should not only be considered based on the above aerodynamic properties. Other performance indicators, such as inhaler design, airflow resistance, mechanism of aerosolization, spray velocity, spray duration, and physicochemical properties of the formulation should also be taken into consideration as they may affect the region of drug deposition [13,14]. These parameters are crucial for respiratory clinicians to prescribe the right inhaler and to offer appropriate administration advice to patients [15,16]. Moreover, it is important to tailor them for improved efficacy.

Some of the important characterization parameters for SMIs are discussed in the section below:

2.1. Spray velocity and duration

Spray velocity is one of the critical aerosol parameters affecting lung deposition, i.e. an increase in velocity increases throat deposition. The momentum of aerosol deposition is dependent on both the spray velocity and droplet mass [14]. Specifically, low-momentum drug delivery devices, such as SMIs have lower inertial impaction based on Newton’s second law, increasing the possibility of the emitted drug aerosol diverting in the mouth-throat region [14]. For the Respimat, the spray velocity of aerosol is greatly reduced to 0.8 m/s [17], which is approximately 3 to 10 times less than the aerosols from pMDIs. This makes the inhaler less prone to patient-device interference, such as variations in the inhaler insertion angle and the patient’s inspiratory effort [14]. The FPF produced by the Respimat SMI was shown to be highly reliant on aerosol velocity. For instance, for the Respimat, Zierenberg [18] reported FPFs of 66% for an aqueous fenoterol solution and 81% for an ethanol solution of flunisolide at a constant flow rate. This difference is explained by the low particle velocity recorded for ethanolic solution compared to aqueous, which led to a longer duration of dose release (1.2 s for aqueous solution vs 1.6 s for ethanolic solution) [3,18]. As opposed to Respimat SMI, pMDIs generate shorter spray plume duration ranging from 0.1 to 0.39 sec [17,19,20]. Moreover, the ability of SMIs to produce longer spray plume duration is responsible for maximizing lung deposition compared to most of the pMDIs.

2.2. Size distribution and deposition

Particle size distribution (PSD) is another critical parameter affecting lung deposition, there being an interplay between PSD, spray velocity, and inhalation flow rate. PSD is defined as the number of particles present within the certain size ranges in the form of distribution and the distribution is specified either by number of particles or particle mass [21]. Laser diffraction (LD) measurements are widely used for the analysis of droplet size distribution of aerosolized liquid formulations. LD provides information on the volume distribution of the geometric diameter of aerosolized particles [22–24]. For high inhalation flow rate devices, it is well-documented that drug aerosols with an Mass Median Aerodynamic Diameter (MMAD) defined as the median diameter of the aerosols based on the mass of particles in the aerodynamic size distribution, with 1–5 μm are more likely to be deposited in the peripheral airways and small bronchioles, whereas larger particles (≥6 μm) present no clinical benefits and tend to deposit in the upper airways (i.e. large conducting airways and oropharynx) [25,26]. A recent in-silico modeling study predicts a large lung deposition (66.97%), with an aerosol delivered using SMI with a relatively large volumetric mean diameter (VMD) of 6.07 µm and Geometric Standard Deviation (GSD) of 1.46, when inhalation takes place at a lower inhalation velocity [27,28]. This result is explained by the decrease in inertial impaction with these larger droplets and longer residence time, which is related to the lower inhalation velocity caused by inhalation flow resistance in these devices [29,30].

Ke et al. reported that the PSD from Respimat SMIs demonstrated a bimodal distribution with more than 50% of the atomized droplets falling within the 1–5 µm size range [16]. This phenomenon could be contributed to the generation of smaller satellite droplets in between the large droplets during drug–liquid collision within the converging jets of this SMI [16]. Using gamma scintigraphy, Newman et al. (Chest, 113: 957, 1997) reported lung deposition fractions of 39.2% and 44.6% for fenoterol and flunisolide, respectively, when administered from Respimat [29]. Recently, Erdelyi et al. modeled the deposition of Spiriva Respimat (tiotropium) based on breathing patterns of healthy subjects and COPD patients and achieved lung deposition between 30% and 50% [30]. Published distribution and deposition data for several SMIs are shown in Table 1.

Table 1. Example of deposition data reported for different SMIs.

SMIs	MMAD (µm)	GSD (-)	Fine Particle Fraction (< 5 µm)	References
Respimat	3.3–5.1	1.94	~30 —75%	[29–33]
Pulmospray	4.8–5.7	1.4	47.5% — 69.97%	[27,28]

In vitro cascade impactor methodologies (e.g. next-generation impactor (NGI), Anderson Cascade Impactor (ACI)) have been long used to investigate the aerodynamic properties and predicted in vivo lung deposition of inhaled therapies [33–35]. However, cascade impaction neglects the possibility of particle size evaporation prior to deposition in the impactor. SMI aerosols can undergo considerable changes in size if entrained with low water vapor content air, as it is found that the particle size distribution move toward larger aerosol diameters with increasing relative humidity as a result of different water evaporation rates [36]. Hence, there is a need to consider other characterization methods, such as laser diffraction, gamma scintigraphy, in silico modeling along with cascade impaction while investigating size distribution and deposition of SMIs.

2.3. Inhalation flow rate

As mentioned above, the inhalation flow rate is a critical parameter impacting lung deposition and consequently, the clinical performance of inhalation therapy. The impact of flow rate being device dependent. In a cross-over study with Respimat, untrained patients with a peak inspiratory flow rate (PIFR) of 146.9 L/min showed lower lung deposition (37% of delivered dose) compared to trained patients (53% of delivered dose) with a mean inspiratory flow rate of 67.9 L/min [37]. Similarly, another in vitro study using Respimat showed that an increase in flow rate from 15 to 45 L/min caused an increase in mouth/throat deposition from 9.8 to 14.2 μg [38]. Previously, several studies demonstrated that in the absence of a constant flow rate in the Respimat, an uneven aerosol plume is formed [39]. In another study, Muellinger et al. [28] demonstrated the effect of increasing inspiratory flow rate on lung deposition with the Pulmospray^TM device. Results from this study indicate that the single-use Pulmospray SMI is an efficient inhaler for delivery of drug products to the lungs at inspiratory flow rates of 15 and 30 L/min. Lung deposition is significantly higher (66.97% vs 57.10%) at a slow flow rate (15 L/min) although with a larger particle size (MMAD 6.07 μm) compared to a high flow rate (30 L/min) and a smaller particle size (MMAD 4.84 μm). These effects can be explained by deposition efficiency being attributed to inertial impaction, which is exponential to the flow rate to the power of 1 and particle size to the power of 2. Published data on the impact of inhalation flow rate on other SMIs is lacking and should be generated.

2.4. In vitro in vivo correlation (IVIVC)

Biorelevant in vitro testing is used to predict the in vivo deposition profiles of inhaled medications. Many parameters need to be included in the in vitro methods, such as the site of deposition in the lung, the dissolution rate, and respiratory clearance mechanisms. In vitro - in vivo correlations (IVIVC) have been performed using in vitro mouth-throat models, such as Virginia Commonwealth University (VCU), oropharyngeal consortium (OPC), Alberta Idealized Throat (AIT) and United States of Pharmacopoeia (USP) throat models. VCU, OPC, and AIT models achieved good IVIVC with Respimat SMIs at a high-flow rate (PIFR 147 L/min), as seen in untrained patients. However, at the low flow rates of 15–45 L/min as seen in trained patients, OPC_S showed a good correlation with the results reported in vivo [38]. Therefore, it is important to simulate mouth-throat models and inhalation profiles according to patients for successful IVIVCs. In vitro testing using mixing inlet, breath simulator, microfluidic platforms that incorporate cells in a chip, and 3D organoid models which simulate in vivo conditions are vital to understanding the realistic deposition profiles in vivo.

3. Mechanisms of soft-mist formation

The means of dispersing an aqueous drug formulation into a slow velocity mist for pulmonary drug delivery usually involves one of two different types of mechanisms. These mechanisms are i) colliding jets and ii) Rayleigh jets [7]. This section outlines the mechanisms of these soft mist formations.

3.1. Colliding jets

Colliding jets (also known as impinging jets) generate soft mists by the collision of two liquid jets.

This colliding jet approach is used in the Respimat (Boehringer, Ingelheim am Rhein, Germany), and involves forcing an aqueous-metered dose drug formulation through a uniblock, which consists of a compartment containing two-channel nozzles (5 × 8 µm²), at a pressure of around 250 bar (3600 psi). The two opposing liquid jets generated collide with each other at 25 µm from the SMI outlet at a controlled angle of 90º, as seen in Figure 1, creating a slow-moving fine ‘soft mist’ [3,12,13,17,40–42]. The mechanical energy is created from a 180º twist of the base (lower half) of the inhaler that increases the tension of a compressed spring and transfers a metered dose of the drug (10–15 μL) to the pump cylinder through a capillary tube. Once the dose-release button is pressed, the compressed spring pushes the drug through an uniblock and releases the drug [2,8,12,13,40].

Figure 1. Schematic diagram of the Respimat uniblock depicting the colliding jet mechanism of the soft mist droplet formation.

3.2. Rayleigh jets

Aerosolization by Rayleigh jet principle, a unique technology, has been developed by Medspray (Medspray BV, Enschede, Netherlands) employing Rayleigh breakup theory to produce extruded jets that result in the formation of a soft mist. In brief, the technology comprises a silicon-based spray nozzle chip with around 100 micro-nozzles of well-defined geometry (ranging from 1.7 to 10 µm, depending on application) (Figure 2a) [27]. Upon applying pressure in the liquid reservoir, each pore will extrude a Rayleigh jet that breaks into droplets of roughly twice the pore size, as shown in Figure 2b. This technique allows for the generation of mono-disperse droplets [43–47]. The SMIs designed by Resyca, Medspray, and Pharmaero deliver aqueous formulations utilizing this Raleigh Breakup Principle [43,48]. Technologies commonly used in semiconductor manufacturing have been adopted in the design and manufacturing of SMI spray nozzles. However, the chips being used in the SMI devices only possess mechanical functions, unlike computer chips which work electronically. This technique generates low shear forces upon aerosolization and is especially useful for sensitive biologic formulations (i.e. mRNA) [43–47,49]. Surface acoustic wave nebulizers produces fine mist suitable for inhalation and are efficient in delivering sensitive biologics, such as nucleic acids, peptides [50–52]; however, they operate by battery-powered circuit and hence cannot be categorized as soft mist inhalers.

Figure 2. a) Spray nozzle unit chip consisting of micro-nozzles, and b) Schematic representation of Rayleigh-breakup principle (Published with permission from Medspray).

4. SMI devices

Several SMI devices are discussed in this section, each of them listed according to their stage of development (preclinical and clinical). A list of their features and development status has been summarized in Table 2.

Table 2. List of Soft Mist Inhalers and their status in the clinical and commercial stages of development.

Soft Mist Inhaler	Company	Mechanism of soft mist formation	Formulations/Trade Name of Drug-Device combination	Current Status	References
Respimat®	Boehringer, Ingelheim am Rhein, Germany	Colliding Jet	Ipratropium/Albuterol (Combivent®)	Marketed	[12,53–56]
			Fenoterol hydrobromide and Ipratropium bromide (Berodual®)	Marketed
			Tiotropium bromide (Spiriva®)	Marketed
			Tiotropium bromide and Olodaterol (Stiolto®)	Marketed
			Olodaterol (Striverdi®)	Marketed
Softhale	Softhale N.V., Belgium	Colliding Jet	-	Preclinical	[57]
MRX004	Merxin Ltd, Norfolk, UK	Colliding Jet	Generic for Respimat®, Pulmozyme, Nicotine and Cannabidiol	Preclinical	[10]
AERx® essence	Aradigm Corporation, Hayward, CA	Rayleigh Jet	Nicotine	Phase 1 completed	[58]
Pulmospray^TM	Resyca BV, Enschede, Netherlands	Rayleigh Jet	Low Molecular Weight Heparin	CE registration as medical device under MDD	[59]
PFSI^TM	Resyca BV, Enschede, Netherlands	Pre-filled syringe inhaler; Rayleigh Jet	-	Preclinical	[11,44]
Aqueous Droplet Inhaler® (ADI)	Pharmaero, Copenhagen, Denmark	Rayleigh Jet	Tobramycin solution for inhalation (TobrAir®)	Phase 1 completed	[60]
Trachospray	Medspray, Enschede, Netherlands	Rayleigh Jet	Lidocaine	CE registration as medical device under MDD	[61,62]
Ecomyst90®	Aero Pump GmbH, Hochheim, Germany	Rayleigh Jet	-	Marketed	[61–63][(Internal information provided by Medspray]
SoftBreezer®	Ursatec GmbH, Tholey, Germany	Rayleigh Jet	-	CE registration under MDD to nebulise salt solutions to the respiratory tract.	[63]
AER-501; AER-601	Aerami Therapeutics		Insulin; Exenatide	Phase 3 and Phase 1/2a respectively	[64]

4.1. Respimat® SMI

The Respimat® is a convenient, pocket-sized, environmentally friendly SMI that can produce a patient-independent reproducible aerosol with high drug efficacy in the lungs [2,25,31,65]. To date, the marketed Respimat® is formulated with either ethanol or water or a combination of both. Preservatives (typically benzalkonium chloride (0.44 μg) and Ethylenediaminetetraacetic acid (2.2 μg)) are added to water-based formulations to maintain sterility of the formulations [2,40]. The drug solution is enclosed in a cartridge made of aluminum containing a double-walled, plastic, collapsible bag which contracts as the medication is used. Bacterial contamination is not seen after the patient’s use of the drug solution in the cartridge, as reported by several studies [8]. A dose indicator with 60–120 actuations (a monthly drug supply) is present to remind patients of the number of doses left and when a new drug cartridge is needed [2,40,53]. Additionally, the use of the empty device is prevented by locking the base of the device after finishing all the doses [8]. The soft mist generated by the Respimat® produces a perceptible taste, which is a crucial feedback mechanism to remind patients that the drug dose has been actuated [40]. Depending on the formulation being aerosolized using Respimat®, the MMAD of the aerosols range between 2 and 5 μm, with a significant fraction of the lung dose deposited in the lung periphery [32,66].

Respimat® is marketed with different APIs for the symptomatic treatment of asthma or Chronic obstructive pulmonary disease (COPD) [12,53,55]. In 2004, the first SMI was launched in Germany comprising a mixture of fenoterol hydrobromide and ipratropium bromide (Berodual® Respimat®) [8]. In 2011, the Respimat® SMI was approved for use with the combination of ipratropium/albuterol (Combivent® Respimat®) [53,54]. Recently, Tiotropium bromide (Spiriva® Respimat®) (Figure 3), olodaterol (Striverdi® Respimat®), a fixed combination of tiotropium bromide and olodaterol (Stiolto® Respimat®) have also become available [12,53,55,56]. Furthermore, an improved Respimat® that includes a simplified assembly, a better dose indicator, and is provided with six reusable cartridges, has been developed [67].

Figure 3. Spiriva® Respimat® SMI.

4.1.1. Respimat generic SMI

MRX004 (Merxin Ltd, Norfolk, UK) is an interchangeable AB-rated (FDA rating indicating that the approved application meets required bioequivalence criteria established through in vivo and/or in vitro studies compared to a currently approved reference product) SMI device initially established as a generic for Respimat® for delivering formulations of tiotropium and olodaterol for the treatment of COPD. Currently, MRX004 has been explored to deliver new and existing drugs. For instance, delivering Pulmozyme using the MRX004 achieved an FPF of 60% (≤5 µm), demonstrating the efficiency of MRX004 SMI for the delivery of biologics. Additionally, MRX004 is being investigated for the delivery of nicotine and cannabidiol [10]. The SoftHaler (Diepenbeek, Belgium) is another generic SMI that is currently in development.

4.2. AER_x®pulmonary drug delivery system

The AER_x® pulmonary delivery system is a novel inhalation device that delivers a single bolus of aerosolized medication during inspiration at a pre-programmed inspiratory flow rate and a fixed-inhaled volume. The device monitors the rate of inhalation and provides feedback on the flow rate. AER_x device flashes a red light when inhalation is inappropriate and a green light if the inhalation rate is optimal [68]. To deliver the formulation using the AER_x® system, a disposable three-layered unit dosage form has been developed. The bottom layer consists of four indexing holes and a liquid reservoir where 45 µL of the aqueous medical formulation is stored. The bottom layer is heat-sealed to the middle lid layer. In addition to four indexing holes like the bottom layer, the middle lid layer of the unit dosage form consists of a long oval hole. The top-nozzle layer made of polymer constitutes the third layer, where laser-drilled micrometer holes (nozzle array) are present that line up with the multilayer system. Under operation, a piston pushes the bottom layer of the strip toward the nozzle array. Eventually, the liquid breaks the middle layer and rapidly extrudes through the micro holes, leading to liquid breakup into slow velocity aerosol mist [68].

A temperature controller can also be accommodated in the AER_x® system to reduce the influence of external air conditions and generate aerosol droplets of a size range suitable for pulmonary targeting [69]. The AER_x® inhaler was initially battery-powered, relatively large and heavy. In contrast, the AER_x-Essence® device (Figure 4) is fully mechanical, portable, palm-sized, cheap, and follows the basic aerosolization principle of the AER_x® system [70]. AER_x® essence with breath control feature and consistent production of fine particles reduces inter- and intra-subject variability.

Figure 4. AER_x® Essence device with a zoomed-in figure denoting nicotine dosage form (Published with permission from Aradigm).

The AER_x® System has been evaluated for delivering different types of therapeutics, including morphine for pain management [71] and moderate-to-severe asthma [72]; and testosterone for postmenopausal women [73]. AER_x® system was able to generate a fine, reproducible and monodisperse aerosol when aerosolising the small organic prodrug ABT-431, with an emitted dose of 1.02 mg, MMAD of 2.9 ± 0.1 µm and GSD of 1.3 ± 0.1 [74]. Furthermore, protein solutions have also been aerosolized using the AER_x system, where an interleukin-4 receptor mixed with ^99mTechnetium diethylene triaminepentaacetic acid (99mTc-DTPA) radiolabelling compound in a saline solution demonstrated a higher peripheral deposition in comparison to the PARI LC STAR® air-jet nebulizer. The MMAD values were 2.0 μm (GSD 1.35) for AER_x and 3.5 μm (GSD 2.5) for the PARI® [75]. In another study by Geller et al., recombinant human deoxyribonuclease (rhDNase) at a single dose of 1.35 mg was delivered using three inhalations to Cystic Fibrosis (CF) patients [76]. After 2 weeks of treatment, there was a significant increase in lung function as indicated by a mean relative increase in FEV₁ (force expiratory volume) of 7.8%. Moreover, the dose used in this study was lower than the standard dose, demonstrating the improved drug deposition efficiency of the AER_x system even at a lower dose of rhDNase [76].

The newer AER_x® Essence was studied to deliver Nicotine [77] and Treprostinil [78]. In Phase I clinical trials inhaled Nicotine delivered using AER_x® Essence enabled users to achieve a quick and sustained reduction in cigarette craving score recorded for 2 h when compared to the Voke® inhaler and Nicorette® inhalator. The MMAD achieved was ~2.6 μm, with a GSD of 1.3 and FPF of 80%, ensuring maximum deposition of drugs into the lungs [77,79]. AER_x Essence® has its patent exclusivity until 2024 for drug/device combinations utilizing nicotine inhalable formulations [70,79].

Furthermore, the AER_x® insulin Diabetes Management System (iDMS) was developed as an inhalation insulin delivery system by Aradigm and Novo Nordisk for treating diabetic patients. This was discontinued due to a lack of clinical significance or patient acceptability over modern injectable insulin pen devices [80–85] (Clinical trial no. NCT00411892). Overall, the AER_x system has multiple advantages of being well tolerated, with a high lung deposition being achieved with lower doses of medications, while being apt for short-acting drugs [86].

4.2.1. Resyca SMI devices

Pulmospray^TM and the pre-filled syringe inhaler PFSI^TM are two SMI devices being developed by Resyca, a joint venture between Recipharm and Medspray.

4.2.1.1. Pulmospray

The Pulmospray is a single-use, fill-before-administration, disposable SMI (Figure 5a) that delivers up to 1 mL of inhalable medications to the lower respiratory tract. The device is used in combination with an off-the-shelf sterile plastic syringe, connected via a tube to the patient interface (mouthpiece). Prior to administration, the syringe is filled with the inhalation solution. Dosing is performed by manually actuating the Respi Lever Drive, synchronized with the patient’s inhalation. Upon actuation, the patient inhales deeply and slowly through the mouthpiece [27]. Pulmospray uses the Medspray spray nozzle unit to generate aerosol droplets, and the designed mouthpiece provides a controlled airflow pattern that enables the reliable deposition of the aerosols. Given the presence of a sterile syringe, Pulmospray is suitable for drug products requiring reconstitution before administration, and for single-dose applications. The Pulmospray demonstrates an advantage of high lung deposition and potential for clinical trials.

Figure 5. a) Pulmospray^TM, and b) PFSI^TM with permission from Resyca.

4.2.1.2. PFSI

The newer PFSI is a portable pen-shaped device (Figure 5b) containing drug solution in a pre-filled glass syringe and is designed for patient convenience. The device is purely mechanical and reusable by replacing pre-filled drug syringes. A high emitted dose is achieved with greater than 50% of the metered dose ending up in the lungs. Upon inhalation, up to 50 μL of the drug (equivalent to drug mass on a milligrams scale) can be delivered to the patient. Dosing may continue until the syringe is empty [11,44]. It possesses a dose indicator and a device lock-out when empty. Furthermore, with Alba® EZ®-fill finish glass syringes, coupled with soft mist nozzles, PFSI® is compatible with sensitive biologic formulations. It offers good stability, improved shelf-life and aseptic conditions, and low shear stress upon aerosolization for complex biologic products [11,44]. No device cleaning is required.Figure 6

Figure 6. Aqueous droplet inhaler® (ADI) with permission from Pharmaero.

4.3. Aqueous droplet inhaler

The Aqueous Droplet Inhaler® (ADI®) (PharmAero ApS, Copenhagen, Denmark) is an SMI made up of a reusable mechanical power pack powered by a clock spring, and a disposable mouthpiece/syringe assembly equipped with a spray nozzle unit [87]. Device cleaning after treatment is not needed as the mouthpiece of the device is disposable [56]. The ADI can deliver small or large volumes of medications at a low velocity in the form of aerosol mist without an electronic power source [60].

4.3.1. TobrAir®

Tobramycin solution for inhalation (TSI, TOBI®) is a high dose of tobramycin (an aminoglycoside antibiotic with antibacterial activity against Pseudomonas aeruginosa) being delivered to the lungs of CF patients [88]. PharmAero Aqueous droplet inhaler (ADI) formulated with Tobramycin solution (Tobr®Air®) is currently in early-stage clinical development [60]. TobrAir® is a new drug-device combination product made up of ADI® prefilled with 1 mL of a 15% sterile tobramycin sulfate solution designed to deliver 2 doses per day (i.e. 10 actuations per dose), which is equivalent to 7.5 mg of Tobramycin per actuation. In a Phase 1 study performed on 12 individuals, pharmacokinetic data revealed that the TobrAir® device achieved higher lung deposition with a mean ± S.D. value of 57.4% ± 12.9 when compared to TOBI®/PARI LC® PLUS nebulizer, which achieved 24.7% ± 3.5 lung deposition. It also significantly reduced the time for treatment (2 min vs 20 min) and less administered dose (75 mg vs 300 mg) than the conventional treatment. Relative bioavailability was greater for TobrAir® with a mean ± S.D. value of 271.0% ± 88.4 in comparison with TOBI® PARI LC® PLUS, and 111.1% ± 42 in comparison with TOBI® Podhaler™ DPI [60,87]. Therefore, ADI® is desirable for the administration of inhaled drugs as it delivers the same lung dose as conventional nebulizers in a shorter delivery time using only 20% of the drug to achieve similar efficacy. Additionally, it provides the advantage of multiple dosing and portability, thereby increasing patient usability [87]. Since the mouthpiece of the device is disposable, it avoids patient re-infection.

4.4. Medspray devices

The Trachospray (Medspray, Enschede, Netherlands) is an innovative SMI (Figure 7a) and is the only noninvasive method that is specifically designed for the application of local anesthesia (lidocaine) in targeted areas of the upper airways. Trachospray produced a good coverage of topical anesthesia with 67.23% ± 2.84 of the dose depositing in the mouth, 18.50% ± 2.48 in the pharynx and 13.35% ± 1.18 deposited in the lungs when evaluated in artificial idealized mouth and throat model using next-generation impactor (NGI) [61,62] (ClinicalTrials.gov Identifier: NCT05478122).

Figure 7. a) Trachospray, b) Ecomyst90® and c) SoftBreezer® (Published with permission from Medspray).

The Ecomyst90® (Figure 7b) and SoftBreezer® (Figure 7c) are other SMIs using Medspray’s nozzle technology. They are pump-based preservative free SMIs and their appearance is similar to a pMDI. Ecomyst90® is aimed at treating respiratory conditions such as asthma, and COPD using prescription products. Whereas SoftBreezer® has received CE registration to nebulize salt solutions to the respiratory tract [63].

5. Advantages of SMIs

SMIs offer a multitude of advantages for patients, including but not limited to ease-of-use, long shelf-life, and high deposition of drugs in the lungs. SMIs possess great potential as they produce aerosol in a size range suitable for inhalation without the need for propellants or external accessories/power sources. Some of the advantages of SMIs are listed below:

5.1. High lung deposition and delivery efficiency

SMIs can generate a long-lasting and slow-rate drug-containing soft mist that contributes to high drug deposition in the deep lung [12]. As discussed, the SMI devices can produce aerosol with low spray momentum and droplets with small particle sizes from either an aqueous or ethanolic-based system [3]. The size of the pores or channels in the SMI nozzle determines the droplet size, which will impact the region in the lung where the drug will be deposited. By means of in-silico modeling, Muellinger et al. [27,28] have shown high lung deposition in excess of 60% for the Pulmospray^TM device when compared to pMDIs or DPIs and a more consistent lung deposition profile and lung deposition rate which is relatively independent of the inspiratory flow rates. By synchronizing the patient’s breathing with the device actuation, the droplets can mix with the inhalation air stream to form a slow-moving cloud of soft mist. Inhalation of a slow-moving cloud means that less of the dose is deposited at the back of the throat, and a higher proportion of the drug is deposited in the lung. Unlike pMDIs, cumbersome spacer devices are not needed to reduce the spray velocity of the emitted aerosols from SMIs or minimize any unwanted drug loss in the mouth-throat region [12]. Moreover, compared to nebulizers, SMIs can deliver a high amount of the contained drug formulation in less inhaled volume [2,89–91].

5.2. Suitable for shear-sensitive drug formulations and products that require reconstitution before inhalation

Biologics are complex molecules derived from living organisms and are often not physiochemically stable, with stringent requirements for light exposure, buffer components, and temperature. Most biologics are available either in liquid form or in powders for reconstitution [92,93]. When delivered by inhalation, the biological activity of complex biologics is likely to diminish due to shear forces and heat generated during aerosolization. For instance, in a study investigating the delivery of interferon using an air-jet nebulizer, it was found that insoluble interferon aggregates were formed, with only ~25% of active monomeric protein remaining [94]. On the contrary, interferon aerosolized with the Respimat® SMI indicated a recovery of 47–98% of the immunologically active interferon, suggesting only a relatively small amount of loss in the drug’s biological activity [95].

Lipid-based nanoparticles are biocompatible carriers with enhanced membrane permeability and bioavailability. They have the potential for the controlled release of therapeutics and are widely studied for the delivery of biologics [96]. High shear stress may break lipid-based nanoparticles leading to the loss of the encapsulated active pharmaceutical ingredients during the nebulization process. In a study by Klein et al., three liposomal formulations made of Dipalmitoylphosphatidylcholine (DPPC), cholesterol-enriched dipalmitoyl-phosphatidylcholine (DPPC-CH), and sodium N-(carboyl-methoxypolyethylene glycol-2000)-1,2-distearoyl-sn-glycero-3-phosphoethanol-amine (DPPC‐DSPEPEG2K), respectively, were used to encapsulate calcein. Aerosolization with an SMI based on continuous Rayleigh jet atomization caused minimal breakage to liposomes when compared to a nebulizer, indicated by a lower amount of calcein release. For instance, calcein released from liposomes was less when delivered through the Pulmospray^TM (2.3—4.6%) compared to Pari eflow nebulizer (6.6—24%) [49]. In another study, aerosolization of a biologic (Low Molecular Weight Heparin) using Pulmospray^TM device demonstrated deposition of 57.08 ± 2.07% of the heparin, with a calculated FPF of 44.4% ± 2.3 µm and MMAD of 5.37 ± 0.11 µm [59]. Hence, SMIs have shown to be promising devices for the inhalation delivery of shear-sensitive drug formulations and biologics.

5.3. High spray content and delivered dose uniformity

The Respimat® SMI possesses high consistency in spray content uniformity throughout 120 actuations with no noticeable ‘tail-off’ effect, as seen with pMDIs when the reservoir is close to exhaustion. This has advantages for patients with chronic respiratory conditions requiring long-term treatment, especially since SMIs require minimal coordination between actuation and inspiration compared to pMDIs [9]. Respimat SMI contains a dose indicator similar to pMDIs but with a locking mechanism. The dose indicator allows patients to see the number of doses actuated and prompts the patient to fill up the prescription in good time. The presence of a locking mechanism prevents the usage of the device after the final dose is delivered.

5.4. Ease of use, high patient compliance and low risk of error in inhalation technique

SMI is a convenient, ‘user-friendly,’ and easy-to-operate device that suits a wide range of patients [12,97]. The inhaler cartridge of SMI does not need to be shaken before administration to release a homogenous drug aerosol as required by pMDIs [9,31]. SMI addresses the constraints of actuation-breath coordination faced by some pMDI users [8,9]. The most common errors made by pMDI users have been found to be device handling errors, lowering the therapeutic efficacy of inhaled drugs [98]. Ease of use, side effects, durability, and inhaler performance are recognized as key aspects for patients to comply with their treatment [31]. Patients, particularly those with co-morbidities, older age, cognitive impairment, or manual dexterity issues, can encounter difficulties in learning the correct inhalation technique or achieving the required peak inspiratory flow rate [31]. Indeed, improper use of inhalers has been recognized as the main contributing factor to poor therapeutic outcomes (e.g. more hospitalization) and increased severity of disease exacerbations [31,99,100]. Asynchronous actuation can result in a disparity in drug amounts reaching the lungs, lessening the clinical effect of inhalation therapies [8].

A recent study reported that perceived complexity (e.g. instructions for use, ease of holding) and confusion between required techniques can result in the intentional cessation of therapy [9]. SMIs do not have any difficult handling techniques [8,9], and their therapeutic efficacy is typically dependent upon the mechanical energy to aerosolise a slow-moving plume of drug solution instead of patients’ inhalation maneuver as required for some pMDIs [9,12,98,101,102]. The inspiratory force required to propel medication and de-agglomeration of powder from a DPI is often challenging in patients with advanced respiratory diseases [53]. While DPIs and pMDIs require propellants or inspiratory force to deliver a dose, only physical actuation is needed in SMIs to generate sufficient mechanical power in the dosing chamber that forces the release of the metered dose as a soft mist [53]. As the aerosol generated from SMI can travel at a slow velocity over a relatively long period, this feature could help patients achieve appropriate hand-inhalation coordination, which is crucial for the effective treatment of chronic respiratory conditions. Therefore, the dose and aerodynamic properties of the emitted aerosol from an SMI are independent of the inspiratory force of the patients [12]. Such a favorable feature allows the SMI device to play key roles in patient-oriented treatment, especially in chronic respiratory diseases that require fine aerosols to target the peripheral lung region.

SMI device requires minimal or less complicated education as the inhaler orientation and the insertion angle has less effect on drug deposition [31]. Several publications have evaluated patients’ experience and satisfaction using SMI as these are relevant to their compliance with therapeutic regimens [8,14]. In fact, most studies suggested that patients with COPD or asthma can acquire the correct inhaler technique of SMI more quickly than other inhalers, such as Genuair MDI and the Breezhaler DPI, which is beneficial to disease management [8,12,31,103–105]. Asakura et al. found that it was simple for patients to operate the device 12 weeks after switching the inhalation therapy from HandiHaler to Respimat [106]. Four recent studies suggested that the majority of the COPD or asthma patients preferred SMI devices over the conventional pMDIs and DPIs (e.g. HandiHaler, Breezhaler, Turbuhaler) [9,105,106,107]. The simplicity of SMI design also assists both pediatric (i.e. except for those aged <5 years who may need a valved holding chamber) and geriatric patients to actuate the device and achieve satisfactory lung dose, thereby improving treatment outcomes [9,107,108].

5.5. Propellant-free and sustainable

SMIs are designed to be propellant-free devices (i.e. without the need for hydrofluorocarbons), an environmentally friendly solution for generating drug aerosols from liquid formulations with minimal impact on global warming [109]. Their carbon footprint is mostly attributed to the raw materials and manufacturing process [110]. The transition of propellant-driven pMDIs to ‘low carbon alternative’ SMIs could potentially reduce annual carbon dioxide emissions by 64–71% [109]. Specifically, the Resyca pre-filled syringe inhaler PFSI offers improved sustainability as it possesses a replaceable drug cartridge similar to the Respimat device [11].

5.6. Less susceptible to moisture and long shelf life

Drugs in SMI devices are all delivered as liquid formulations and stored within a drug cartridge or syringe [12]. This offers advantages for APIs that are readily soluble. By formulating solutions, problems with moisture adsorption and subsequent drug agglomeration can be avoided. Therefore, these features assure that the delivered drug dose from each SMI spray is consistent. For instance, liquid formulations currently used with the Respimat have a long time-in-use shelf-life (3 months) and an unopened shelf-life of years, if the device is stored correctly as indicated by the manufacturer’s instructions [15].

6. SMIs challenges

Inhaled medication is the cornerstone of treatment for respiratory conditions [15]. Although SMIs have been on the market for a relatively short timeframe, it is expected that such devices will soon be more prevalent given their advantages such as high lung deposition and high satisfaction rate [31]. Regardless of the advantages offered by SMIs, some challenges surrounding formulation, device, inhalation pattern and technique still exist and need to be addressed to maximize the performance of SMIs. These are discussed in the sections below.

6.1. Formulation aspects

A key challenge in formulating therapeutics for SMIs is the effect of fundamental formulation parameters, such as solubility, viscosity, surface tension, density, and drug and ion concentrations on aerosol performance on SMIs aerosol performance. For instance, aerosolization efficiency using the AER_x device was significantly improved with the addition of 8.5 mM of sodium chloride (NaCl) (P value < .0025 vs lipoplex control). The addition of NaCl in concentrations 15 mM and 34 mM to lipoplexes containing DNA individually produced further improvement in aerosolization efficiency (P value < .03 vs lipoplex +8.5 mM NaCl) [111]. Hence, there is a need for studying the impact of the physical parameters of solutions to be delivered via SMIs.

High drug concentrations would also be needed as the inhaled volumes are small for SMIs (15 µL—1 mL) when compared with nebulizers (0.5—6 mL for nebulizer therapy) (excluding any potential increase in delivery efficiency) [2,90–92]. Moreover, in the case of antibiotics or mucolytics, high doses are needed to be delivered [112]. This is especially challenging for poorly water-soluble drugs, where a careful selection of excipients, such as solubilizing agents, surfactants, buffer salts, pH, cosolvents etc., must be made to ensure the safety and tolerability of solutions [113].

Additionally, the liquid formulation must be compatible with the SMI components [7]. The United States Food and Drug Administration (USFDA) mandates all aqueous-based inhalation products to be made sterile as mentioned in Section 21 CFR 200.51, Food and Drug Administration 2000. Consequently, sterility must be maintained during the preparation of liquid inhalable formulations and in the container closure systems. Proper microbiological quality must be guaranteed, especially with patients using SMIs that deliver multiple doses [7].

Ensuring dose uniformity (i.e. consistent release of a fixed volume drug formulation) is particularly challenging for suspension formulations (i.e. liposomal nanoparticles). Care must be taken to prevent any nozzle blockage of the SMI and ensure a uniform dose is being aerosolized [11,95].

6.2. Device considerations

It is important to engineer the nozzle pore size of the SMI to optimize particle size distribution for improved efficacy and regional targeting. For example, the Resyca Pulmospray^TM device with nozzle diameters of 1.7, 2.0, and 2.5 μm generated droplets with an MMAD of 4.03, 4.98, and 5.99 μm, respectively [27]. For all nozzle sizes tested, the aerosol clouded exhibits an approximated log-normal particle size distribution within a narrow band (GSD = 1.46–1.56) resulting in a fine-particle fraction of nearly 50%. The time to deliver 1 mL of inhalation solution with the Pulmospray^TM is between 1.5 and 2.3 min for the 1.9 and 1.6 μm micro-nozzle, respectively. Consequently, the combined results from narrow particle size distribution (GSD), small nozzle pore size (MMAD) and the built-in flow limitation of the device allows efficient delivery to the lungs. Further studies showed that larger droplets (6.0 μm) are more effective for improving pulmonary function in asthmatic patients [43]. While designing SMIs, it is important to consider the nozzle angle and position of SMIs as this would affect the site of particle deposition. For instance, in a study by Taha et al., a wrongly positioned nozzle in SMI resulted in high particle deposition in the mouth region [39].

Since maintaining a sterile environment is challenging when delivering multiple doses using SMI, Last et al., have developed a MEMS-based spray system comprising a slim silicon membrane with holes, which seals against the parylene valve by itself. This self-sealing mechanism blocked the SMI from getting contaminated by 70% when exposed directly to Citrobacter rodentium at a concentration of 10⁷ CFU/ml for 24 h in closed conditions [114]. This modification can be incorporated into the SMI devices to ensure a sterile environment, especially during the delivery of multiple doses.

6.3. Patient-related factors

The variations in breathing pattern, airway size, rate of respiration and lung volume from infants to geriatric patients cause substantial challenges for the effective delivery of drugs to the lungs. In a study by Kamin et al., the authors assessed the inhalation maneuvers (inspiratory flow rate, theoretical inhaled dose fraction, and estimated lung deposition of the aerosol cloud) among children aged 4–12 years using the Respimat SMI. Findings from the study demonstrate that children aged 5–8 years outperformed children aged 9–12 years by achieving greater estimated lung deposition values [115].

There is a lack of evidence on the assessment of inhalation maneuvers vs SMIs usage in older patients. Despite the multitude of advantages, SMIs need some degree of hand-breath coordination, which may be difficult for pediatric and geriatric patients with inspiration/coordination difficulties. Aerosol therapy using a face mask may be an attractive alternative for such a subset of the population. In a study by Amirav et al. infants had good intrapulmonary deposition using Respimat SMI while sleeping with the SootherMask coupled with a valved holding chamber, and the sleep was undisturbed by the procedure [93–95]. Similarly, using face masks and valve-holding chambers with SMIs is preferred in patients receiving mechanical ventilation. However, as previously mentioned by Oakes et al., inhaled particle sizes to be delivered by SMIs must be customized smaller for pediatric patients compared to adults to facilitate their chance to ‘go with flow’ and avoid losses in extra-thoracic and conducting airways due to differences in anatomy, physiology, and breathing pattern [116]. New users of SMI devices, including those who have a low educational background, low socioeconomic status, those on multiple types of inhalers, patients who are apprehensive to switch to an SMI device, and those with newly diagnosed COPD condition, usually require education for correct assembly of the cartridge before their first SMI use to promote effective drug delivery for their management of respiratory diseases [8,15,99,100,104,117]. Rossi et al. reported that only ~30% of patients possessed good inhalation techniques using the Respimat SMI in the absence of training [117], but training patients to actuate use and coordinate breathing increased lung deposition [118]. Overall, like other inhalation devices, there is a need to consider patient-related factors while delivering medications using SMIs.

7. Conclusions

Soft Mist Inhaler devices are a relatively new technology that are carving a market share for the delivery of drug formulations. Several studies have shown that SMIs can generate aerosol clouds, which are slower and of longer duration in comparison with standard inhaler devices, with higher fine particle fraction leading to high lung deposition. This specific characteristic of SMIs allows for a reduction in the dose while achieving similar therapeutic efficacy and improved safety.

Still, factors such as API-device compatibility, dose concentration, type, and physical properties of the formulation, sterility, and inhalation technique, are all factors that need to be considered when designing SMIs. Having major advantages at both the clinical and commercial stages of development, SMIs are ready to be game changers in the inhalation market for years to come.

8. Expert opinion

Even though soft mist inhalers have demonstrated many advantages in respiratory drug delivery as described in this review, improvements in many other areas are needed for unmet clinical needs, such as handling difficulties with inhalers for the vulnerable patient population, poor inhaler technique and adherence. Additionally, there exist significant opportunities to make advancements in disease treatment using SMIs.

Currently, soft mist inhalation technology is used to deliver bronchodilators for the treatment of COPD. With time, new drug-device combination products, prodrugs of existing drugs, and inhaled drug repurposing for new applications delivered through SMIs are expected to be seen. Therapeutics such as vaccines, small molecules (e.g. fentanyl, MW 336 Da), as well as some severe pain relievers, have already benefited from the pulmonary route and can be a new avenue for SMIs [119]. An increasing interest in the suitability of SMIs is anticipated to treat patients with systemic diseases, such as diabetes, pulmonary hypertension, psychiatric disorders, migraine, etc. Narrow therapeutic indexes drugs, such as opioids and anticancer drugs can potentially be delivered using SMIs as the spray duration is long and fewer doses would be needed to achieve enhanced efficacy.

In recent years, biological therapeutics that are protein-based, cell-based and nucleic acid-based have seen significant progress in the treatment of multiple diseases, but these biologics have been largely limited to the parenteral route of administration due to their sensitivity and lower stability in the gastric environment when delivered orally [120]. While inhaled drug delivery of biologics is a feasible alternative; hydrophilicity and sensitivity to various environmental stressors during inhalation delivery have limited their applications. The recombinant human DNase (Pulmozyme, Genentech, Inc.), was the first FDA-approved lyophilized biologic delivered through inhalation in 1993. Later, inhaled human insulin powder (Exubera, Pfizer) was approved in 2006 in the USA However, this product was complicated by protein stability issues, patient noncompliance, manufacturing costs and little dose flexibility which eventually led to the failure of Exubera.

Recent innovations in SMI technology and container closure of SMIs offer design advantages for both new biologics and reformulations of existing treatments There is the potential for SMIs to overcome some of the existing formulation challenges with the ability to deliver liquid solutions/suspensions, offering minimal shear stress during aerosolization, dose flexibility, and reduced cost of development and development timelines which can make SMI an attractive alternative delivery system for the clinical translation of biologics.

Viral pandemics like COVID-19 have also created several unmet clinical needs associated with inhalation devices. Inhaled vaccines and RNA therapeutics will continue to attract more attention in coming years and are expected to benefit from delivery via SMIs, which includes the convenience of self-administration [121,122]. Previous studies that evaluated the efficacy of vaccine delivery to the lower respiratory tract have demonstrated superior vaccine-induced immunity over the parenteral route [123,124]. Another important benefit of SMI is the lower risk spreading of infectious diseases. As the virus is known to be spread through droplet infection, there is an increased concern about the spread of disease from escaped aerosols during nebulized therapy for patients. Disposable soft mist inhalers can be considered for viral pandemics due to ease of use in hospital settings since they have a lower amount of escaped aerosols from the device during administration and can be easily and safely disposed of after use [125].

Another major area where innovation lies are in the advanced formulations that can be delivered using SMIs. Innovative particulate-based delivery systems, such as nanoparticles might extend lung residence time, improve pulmonary absorption, add cellular targeting, and resolve solubility as well as stability issues of hydrophobic drugs and protein therapeutics while decreasing dosing frequency. Specifically, nanoparticle platforms, such as liposomes and lipid particles, can facilitate drug delivery into the bloodstream and accumulation in tumors [126,127]. SMIs have already demonstrated minimal shear stress to nano-liposomes compared to nebulizers and hence, open up new opportunities for different formulations to be delivered using SMIs [49].

In terms of therapeutic efficacy and patient adherence, up to 60% of patients do not benefit from the medication prescribed due to improper inhaler techniques, which links to the number of practitioners who are not able to teach the patients the correct use of inhalers due to the sheer amount of inhalers currently available in the market and the complexities of operations [8,9,99]. Therefore, offering feedback and training to patients about their inhalation technique and supervising patient adherence to SMI therapy has become an important element in the development of novel aerosol technologies [56]. Technological advances have led to the development of several ‘digital inhalers’ that consist of sensors that are either attached to or embedded in the device and can record the timing of inhalation administered, prompting patients to take their medication, and providing feedback on the inhalation technique. These digital inhalers can be connected to the smartphone via Bluetooth and can concurrently provide information to both patients and physicians [128,129]. Digitalizing SMIs could be a new potential offering opening new opportunities for the development of the next generation of SMI inhaler technologies in the future.

Article highlights

• Recent advancements in soft mist inhaler (SMI) device technologies and formulation design have enabled reproducible drug administration even for challenging inhaled therapies.

• Understanding the parameters that impact the performance of SMIs – including but not limited to spray velocity, size distribution and deposition, inhalation flow rate, and in vitro in vivo correlation are important to optimize the performance of existing SMIs.

• Formulation, device characteristics, and patient-dependent factors need to be considered while designing the next-generation SMI devices.

• As liquid inhaler that produces a slow-moving aerosol cloud to enter the respiratory tract, SMIs optimize drug delivery while minimizing inspiratory effort on the part of the patients. Further design developments, such as new more targeted nozzle designs, make them ideal for the delivery of biologic formulations.

Declaration of interest

N Buchmann and I Sibum are full-time employees of Resyca, manufacturer of the Pulmospray and PFSI Soft mist inhalers. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This review was supported by funding from ARC LP190100917.