Aerosol Delivery Devices for Obstructive Lung Diseases

History of Modern Aerosol Devices

Commercial availability of modern day inhalers began in the 1950s with the pressurized metered-dose inhaler (pMDI).¹ Although available since the 1970s, development of the dry powder inhaler was expanded by the 1987 Montreal Protocol eliminating chlorofluorocarbons (CFCs) in pMDIs. In the late 1970s, spacers and valved holding chambers were developed for patients with poor coordination and to decrease oropharyngeal deposition by slowing aerosol velocity and decreasing the number of large particles. Nebulizers have been available for centuries, but they can be less convenient, more time-consuming, more expensive, and thus have a secondary role in the out-patient setting. In the early 21st century, the soft mist inhaler became available. Sanchis et al² evaluated improper inhaler techniques and reported that many problems with the proper use of these devices still exist.

Definition of Terms

Deposition is a function of particle size, shape, and density, as well as anatomy of the lungs and breathing parameters (eg, flow and inhaled volume).³ The labeled dose (nominal dose) is the mass of drug that is available within the aerosol generator per actuation or inhalation; for example, for the albuterol pMDI, the labeled dose is 90 μg per puff. The total emitted dose or delivered dose is the mass of drug emitted per actuation that is available for inhalation at the mouth, which is lower than the labeled dose. The fine-particle dose is the mass of particles < 5 μm within the emitted dose. Fine-particle fraction is the fine-particle dose divided by the emitted dose. Mass median aerodynamic diameter (MMAD) is the diameter at which 50% of the particles of an aerosol by mass are larger and 50% are smaller. The optimal MMAD for obstructive lung disease is 1–5 μm; this is also referred to as the respirable particle range (or fraction). The geometric standard deviation (GSD) measures the dispersion of particle diameter. GSD is the ratio of the MMAD to the diameter at 15.9% of the probability scale, or the ratio of the diameter at 84.1% on the probability scale to the MMAD. Aerosols with a GSD > 1.15 are considered polydisperse. A perfectly monodisperse aerosol (ie, one in which all aerosol particles have exactly the same size) has a GSD = 1. Most therapeutic aerosols are polydisperse and have a GSD in the range of 2–3. There are rationales for both monodiperse and polydisperse aerosols relative to delivery throughout the airways.

Methods to Measure Aerosol Delivery and Deposition

There are a number of methods to measure aerosol characteristics and delivery in the human lungs.^4,5 Cascade impactors are often used to estimate MMAD and fine-particle dose of aerosol formulations. However, such in vitro measurements are limited in their ability to fully mimic the upper and lower respiratory tract and breathing pattern. Regulators require in vitro measurements, and in some cases in vivo measurements such as drug blood levels, to determine bioavailability of a new inhalational product.

In vivo methodologies that image drug particles in humans include gamma scintigraphy, computed tomography, magnetic resonance imaging (MRI), and fluorescence imaging. In vivo methods that use isotopes are limited by high cost, high radiation doses, safety hazards, and training required for handling of radiolabeled isotopes.^4,5 Gamma scintigraphy labels formulations with gamma ray-emitting radioisotopes and thus measures particle deposition and mucociliary clearance. There are limitations in the ability to label some inhalational products. Radio-scintigraphy uses radionuclides as an in vivo imaging technique to measure oropharyngeal and total lung deposition of particles. Figure 1 shows the use of radio-scintigraphy to evaluate aerosol deposition with different methods of delivery.⁶ MRI and fluorescent imaging are considered the safest. In addition to measurement of ventilation, MRI with gas provides measurements of parenchyma microstructures, including the alveoli and acini.⁷ A study using MRI in subjects with COPD reported that spirometry was unable to detect changes in flow in the small airways, whereas MRI could.⁸ MRI will likely provide a much better understanding of the pharmacology of inhaled medicines, but it is in the early stages of application. In vivo imaging techniques are preferred over in vitro techniques because these can provide an image of regional deposition in the lungs.

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Fig. 1.

Aerosol deposition with a pressurized metered-dose inhaler without a spacer (A), and with a spacer (B), compared to the soft mist inhaler (C) using radio scintigraphy. From Reference 7, with permission.

Pharmacokinetic studies are also used to assess pulmonary deposition and systemic delivery of inhaled medications. The inhaled dose that reaches the lungs eventually diffuses into the systemic circulation, excluding the small portion of the inhaled drug that is exhaled or expectorated.^9,10 Although blood levels of inhaled drug do not necessarily correlate with therapeutic effects in the lungs, they do reflect lung deposition and potential for systemic effects, and they can be used to compare lung deposition between 2 inhaled formulations. Combined with the formulation's aerosol particle size and respirable fraction, pharmacokinetic data provides a more complete understanding of inhaled medication disposition. Manufacturers report pharmacokinetic data in the package insert. Aerosol particle size (MMAD) and fine-particle measures are typically reported in the literature and may be available from the manufacturer.

Aerosol Deposition in the Airways

Inhaled medications pass through the conducting and respiratory zones.⁴ The large airways, medium airways, and small airways (generations from 8 to 23 with < 2 mm internal diameter) are affected in asthma and COPD. Therefore, aerosol delivery throughout the airways is desirable.¹¹ Muscarinic receptors are mostly in the medium and large airways, although muscarinic antagonist effects also occur in the small airways. The β adrenoreceptors and corticosteroid receptors are distributed throughout the airways.³ Airway smooth muscle, which is affected by inhaled bronchodilators, is distributed in the non-cartilaginous portion of the airways, is denser in medium and larger airways, and is least dense in the terminal and respiratory bronchioles.

Size is an important determinant of particle deposition in the lungs (Fig. 2). There are 3 processes that affect aerosol deposition: inertial impaction, sedimentation, and diffusion.^3,12 Larger particles tend to deposit by impaction in the oropharynx and larger conducting airways, whereas the smallest particles tend to deposit in the smaller conducting airways and in the distal airways, including the alveoli and terminal bronchioles.^3,13,14 Each deposition process occurs rapidly, allowing the drug to exert its effects within minutes and before entering the systemic circulation. The tremors and relief of shortness of breath that occur within moments after albuterol inhalation are a reflection of how quickly the receptors in the lung respond and how rapidly a drug can reach the bloodstream and tissue receptors (skeletal muscle). The lung is the major route by which inhaled drugs reach the systemic circulation, as most agents have relatively poor systemic bioavailability through the gastrointestinal tract (eg, for beclomethasone, ∼ 20% of swallowed drug reaches the systemic circulation).

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Fig. 2.

The adult lung with dimensions and generations of the airways with predicted aerosol deposition. BSM = bronchial smooth muscle. From Reference 4, with permission.

The high relative humidity of the airway affects particle deposition due to hygroscopic growth, contributing to deposition of drug on the respiratory epithelium.¹⁴ Impaction and sedimentation of aerosols are the dominant mechanisms of deposition of most inhaled medications.^3,14 Inertial impaction occurs more in the oropharynx and upper airways, particularly at airway bifurcations and areas of obstruction. Depending on the characteristics of the drug, device, and patient, some portion of the drug is swallowed and absorbed into the systemic circulation from the gastrointestinal tract and/or is excreted through the gastrointestinal tract. Sedimentation of aerosolized particles depends on gravity, residence time in airway (eg, breath-hold time), airway dimensions, and patient position.

The inhaled drugs most likely to reach the airways, and thus exert local clinical effects, are aerosol particles in the fine-particle fraction of 1–5 μm. The fine-particle fraction varies widely among inhalers, with 12–35% for DPI, 10–50% for pMDI, and 30–50% for the soft mist inhaler (SMI). Deposition of particles 3–7 μm in diameter occurs largely in the conducting airways, whereas particles < 2–3 μm in diameter can reach the alveoli, particularly those < 1 μm (see Fig. 2).^3,13,14 Particles < 0.5–1 μm undergo Brownian motion, settle very slowly, and may be exhaled like a gas or may diffuse into the pulmonary capillaries after impaction. Diffusion of inhaled medications may be altered in smokers, where the tight junctions of the epithelium are damaged, allowing for more transport across the membranes.¹⁵ Air-flow obstruction and restriction can also determine in which parts of the lungs aerosol particles are deposited. There has been interest in the potential clinical benefits of delivering drug to the small airways.^10,11

Clearance of drugs from the lungs is influenced by pharmacokinetic properties, including half-life, and physicochemical properties, such as molecular weight, lipophilicity, solubility, protein binding, and charge.¹⁴ Lipophilic molecules cross the airway epithelium by passive transport and hydrophilic molecules via extracellular pathways. Inhaled medications are often intentionally lipophilic to promote slow clearance from the lungs and thus exert a long duration of effect. Drug particles with a low dissolution rate that reach the alveolar space can be phagocytized by alveolar macrophages or absorbed into the pulmonary circulation.¹⁴ Particles deposited in the airways that are not absorbed are cleared by mucociliary transport and cough. Some inhaled medications can undergo metabolism in the lungs, such as the inhaled corticosteroid (ICS) beclomethasone dipropionate, whose metabolites diffuse into the bloodstream.¹⁶

Inhaler Devices

Table 1 shows advantages and disadvantages of aerosol delivery devices. In addition to the characteristics of each device, ultimately the choice is often made by the health care provider, the patient, and availability based on issues such as the formulary. In individual patients, one device may better suit their preference than another.

Pressurized Metered-Dose Inhalers

The pMDI was the first widely used multi-dose portable inhalational device.^1,17,18 Virtually every patient with COPD and asthma either uses or has used a pMDI, most often as albuterol and/or ipratropium. All inhaled drug classes for obstructive lung diseases are available in a pMDI as single or combination products. Yet the pMDI is one of the most challenging devices for patients to use correctly. The pMDI has evolved over the decades, with one of the most significant changes being the switch of propellant from CFC to hydrofluoroalkane (HFA).¹

The pMDI is a multi-dose, pressurized, aluminum canister that, when actuated, delivers drug through a metering valve and orifice (Fig. 3).^3,17,18,20 The formulation is either solution, suspension, or co-suspension and contains other components such as propellant, suspending agents, co-solvents, and surfactants (eg, lecithin or oleic acid, which are soy derivatives).²⁰ Excipients infrequently cause adverse effects. Surfactants aid in decreasing particle crystal agglomeration. The interior wall of the canister is coated to decrease adhesion and potential for interaction with components in the formulation. Drug crystals in some pMDIs flocculate, leading to sedimentation. A new formulation, a co-suspension technology, represents a significant advance. It uses phospholipid particles to reversibly attach to drug molecules to provide more uniform suspension, facilitate pharmaceutical compatibility of drug combinations, and provide more consistent drug delivery as well as relying less on the need for shaking prior to use.²¹ Due to differences in boiling temperatures between the drug formulation and room air, when drug reaches the air, it immediately evaporates and aerosolizes small droplets. The aerosol particle size varies among products. Solutions typically have a smaller MMAD than suspensions.

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Fig. 3.

Components of a pressurized metered-dose inhaler. From Reference 19.

Soft Mist Inhalers

The SMI (Respimat, Boehringer Ingelheim, Ingelheim am Rhein, Germany) is the newest type of inhaler, initially marketed with ipratropium/albuterol and more recently with long-acting bronchodilators (Fig. 4).^22,23 The Respimat does not use propellants, as the drug is released via a compressed spring inside the inhaler that pushes drug through a membrane, emitting a small-particle aerosol.²² The medication canister is inserted into the inhaler, and both are discarded after all doses are used. It is the only liquid aerosol inhaler that stops emitting doses when the stated number of puffs are reached. Shaking is not necessary prior to using the device.

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Fig. 4.

Soft mist inhaler showing the internal components as well as an enlargement of the uniblock, which helps aerosolize the drug solution from the medication cartridge. From Reference 17.

The MMAD for the Respimat is ∼ 2 μm.¹¹ The aerosol is released slowly compared to current pMDIs and yields a homogeneous composition.^22,23 The greater stability of cloud emission from the Respimat is likely to contribute to easier and more convenient use for patients.²² Additionally, the relatively long duration over which the dose is released from the Respimat (∼ 1.2 s compared with < 0.5 s from pMDIs) may reduce the coordination required for actuation and inspiration, thus improving the likelihood for greater lung deposition. Based on scintigraphy data, the slower velocity of the Respimat reduces the potential for drug impaction in the oropharyngeal cavity, so that lung deposition is higher (nearly 50%) and oropharyngeal deposition is lower than that with a pMDI or a pMDI with a spacer.²⁴ Although not commonly used, data are now available for administration of the SMI with a valved holding chamber (VHC) with a face mask for use in children.²⁵

Spacers and Holding Chambers

VHCs and spacer devices are used to overcome some of the limitations of pMDIs.^17,18,26,27 A spacer is a simple tube or extension with no valves to contain the aerosol, whereas a VHC is an extension device with a 1-way valve that, when the attached pMDI is actuated, holds the aerosol until inhalation, although impaction on the inner walls occurs shortly after actuation. Spacers and VHCs allow deceleration of the aerosol plume and, in the case of the latter, trap the aerosol cloud until the patient inhales. However, their availability and coverage by payers is suboptimal in some settings. Although the word spacer is often used for all types of extension add-on devices, these devices are best categorized as either as a spacer or a VHC (Fig. 5). Most VHCs available in the United States are ∼ 200 mL.

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Fig. 5.

Spacer (top) and valved holding chamber (bottom). From Reference 17.

Use of these devices can decrease oropharyngeal deposition by ∼ 80–90% by slowing particle speed and retention of large aerosol particles within the holding chamber.¹⁷ Compared to a pMDI alone, lung deposition with a spacer is either increased or unchanged, depending on the patients' inhaler technique as well as the particle size. Lung deposition may be increased with large particles via a VHC, but this is less likely with small-particle aerosols, depending on the delay time for inhalation after actuation. Oropharyngeal adverse effects can be decreased with a VHC. This is most important for ICS administered via pMDI, but it is also relevant when the patient does not like the taste of an inhaled medication.

A number of studies have evaluated clinical aspects of the use of a VHC with a pMDI.^28–31 In one study, single puffs of albuterol through a spacer produced higher plasma levels and greater systemic β-2 responses than either multiple puffs or single puffs with delayed inhalation through the spacer.²⁸ The peak blood level of albuterol, reflecting greater lung bioavailability, was ∼ 2-fold greater for single puffs than for multiple puffs and 1.80-fold greater lung for single puffs without a delay than for single puffs with a 20-s delay between actuation and inhalation.²⁸ However, one in vitro study of a small-particle albuterol pMDI suggested a 10-s delay was acceptable.²⁹

A study by Leach and Colice³⁰ provides insight into the effects of a VHC with pMDIs of different aerosol particle size. In 10 healthy volunteers, radiolabeled beclomethasone dipropionate (BDP) was administered as 2 different products: HFA with smaller aerosol particles, and CFC with larger particles. For both products, the drug was administered with and without a VHC and assessed the effect of breath-hold time and delay of inhalation from the VHC. As shown in Figure 6, the small particle HFA-BDP lung deposition averaged ∼ 50% and was affected less by the use of a VHC with or without a delay in inhalation. However, oropharyngeal deposition of HFA-BDP was reduced from 28% to 4% with the VHC. Lung deposition with the large particle CFC-BDP was 7% and was unchanged with the VHC without a delay. A 2-s delay between actuation and inspiration with the spacer reduced lung deposition slightly but reduced oropharyngeal deposition substantially (84% to 3%–20%) for the large-particle aerosol using the VHC with and without a delay. HFA-BDP lung deposition was dependent on breath-hold because lung deposition with HFA-BDP was reduced by 16% with a 1-s breath-hold versus a 10-s breath-hold. The difference was measured in the increased exhaled fraction, confirming that smaller particles need time to deposit and are exhaled if there is a reduced breath-hold. The large particle CFC-BDP lung deposition was less affected by breath-hold. Similarly, another study in healthy volunteers found that adding a VHC to an HFA pMDI delivering small-particle beclomethasone and formoterol aerosol did not affect the systemic exposure of these drugs compared with pMDI alone.³¹ However, the VHC is still useful with small-particle pMDI to decrease the risk of adverse oropharyngeal effects, at least in the susceptible patient, and to also improve technique such as timing of actuation and inhalation. It appears that a slight delay with large aerosol particles through a VHC may decrease oropharyngeal deposition, which is most relevant for ICS.

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Fig. 6.

Delivery of BDP as a small aerosol particle size (QVAR) and as a larger aerosol particle size (BDP) via a CFC inhaler with spacer as well as with a spacer and without a 2-s delay. QVAR = hydrofluoroalkane-beclomethasone dipropionate; CFC = chlorofluorocarbon; BDP = beclomethasone dipropionate. Data from Reference 29.

Aerosol drug particles discharged into a VHC or spacer can be lost to the chamber walls by inertial impaction, gravitational sedimentation, and electrostatic attraction to the interior wall of the device.^3,27 Devices like the Aerochamber Plus (Monaghan, Plattsburgh, New York) and Vortex (Pari Respiratory, Midlothian, Virginia) are antistatic VHCs. In addition to using an antistatic device, other ways to overcome this problem are to actuate multiple doses into the spacer when new (expensive) and washing in detergent to decrease the static charge. A comparison of normal and ant-static spacers showed differences in albuterol³² blood levels and clinical response to albuterol.³³

In vitro data are also available describing the use of a VHC with a mask with the SMI in children.²⁵ Inspiratory flows of 4.9, 8.0, and 12.0 L/min in combination with holding times of 0, 2, 5, and 10 s were tested. The flows were selected to be representative of inspiratory flows of children from 6 m > 5 y old, respectively. There was a modest reduction in absolute delivered dose through a VHC. According to the manufacturer, the dose per kilogram of body weight suggested that the dose of tiotropium Respimat delivered by the AeroChamber Plus Flow-Vu VHC with a mask led to dosing comparable to that of adults without use of a VHC and mask. The fine-particle fraction (< 5 μm) across the flows was 69–89% of the delivered dose through the VHC, consistent with the removal of the coarser fraction by the VHC. In contrast, the fine-particle fraction for tiotropium Respimat delivered without a holding chamber typically represents ∼ 50–60% of the delivered dose. Although not studied in adults, sometimes patients cough with the prolonged aerosol plume with the Respimat, and the use of VHC might decrease that effect. It may also be helpful to decrease oropharyngeal deposition in a patient complaining of dry mouth with the tiotropium Respimat, as well as improve delivery in patients with suboptimal technique.

Dry Powder Inhalers

DPIs have become very popular in recent years, due in part to the ban on CFCs, which has facilitated the development of new formulations, and they are user-friendly¹ (Fig. 7). DPI formulations often have excipients because of pharmaceutical formulation issues, and some patients perceive they are not receiving any drug if they do not taste it (eg, lactose excipient). Breath-actuated DPIs may overcome the difficulties with coordination of inhaler actuation and inspiration, but errors still exist, such as inadequate effort.^3,17,18,34 The DPI requires each dose to be loaded, whether as a separate capsule or by advancing powder into position by some steps.

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Fig. 7.

Examples of dry powder inhalers. Handihaler (A); Ellipta (B).

DPIs derive the energy for drug delivery by the patient's inspiratory effort, which is greater than that required for a medication administered as a liquid aerosol.^35,36 As DPI device technologies have evolved, so have the different approaches to de-agglomerate the powder. Components of the DPI that facilitate de-agglomeration induced by the patient's inspiration include a manifold (eg, Ellipta [GlaxoSmithKline, Brentford, United Kingdom]), cylone (Respiclick [Teva Pharmaceuticals, Petach Tikva, Israel]), mesh (Handihaler [Boehringer Ingelheim] and Neohaler [Sunovion, Marlborough, Massachusetts]), and a spiral chamber (Flexhaler [AstraZeneca, Cambridge, United Kingdom]). To produce the optimal MMAD, the drug and excipient agglomerate must be de-aggregated during a forceful inhalation against the internal resistance of the inhaler.^35,36

The inspiratory effort required to adequately deliver medication varies among DPIs. Some require more effort than others, and some are more susceptible to variations in flow than others.^35,36 Failure to exhale to functional residual capacity, but not residual volume, before inhaling through a DPI and failure to use a forceful, deep inhalation were 2 of the most common problems with DPIs. The recommended minimum inspiratory effort among different DPI manufacturers has a range of 30–60 L/min.^35,36

Nebulizers

A variety of nebulizers are available to generate aerosols for inhaled drug delivery. There has recently been increased interest in the use of nebulizers due to the high cost of HFA formulations. A liquid solution or suspension is added to the nebulizer for each treatment. Traditionally, nebulizers and the drug formulation are marketed separately. Increasingly, formulations introduced to the market are intended for use with a specific nebulizer. Moreover, a variety of nebulizer designs are now available.

Jet Nebulizers

A jet nebulizer delivers compressed gas through a jet (Fig. 8)¹⁷ This causes a region of negative pressure, in which a solution or suspension is entrained into the gas stream and is sheared into a liquid film. This film is unstable and breaks into droplets due to surface tension forces. A baffle in the aerosol stream produces smaller particles, and it is further conditioned by factors such as the relative humidity of the carrier gas.

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Fig. 8.

Drawing of the function of a pneumatic jet nebulizer. From Reference 17.

The volume of solution that is trapped inside the nebulizer's dead volume is typically 0.5–1 mL. To reduce dead volume, clinicians and patients commonly tap the nebulizer cup in an effort to increase nebulizer output, but therapy continued past the point of sputtering in an attempt to decrease the dead volume is unproductive and is not recommended.^47,48 Due to evaporative losses within the nebulizer, the solution becomes increasingly concentrated and cools during nebulization.

An important characteristic of nebulizer performance is its respirable dose, which is the output of droplets from a nebulizer in the respirable range of 1–5 μm.¹⁷ Other characteristics of nebulizer performance include nebulization time, ease of use, ease of cleaning and sterilization, and cost. A short nebulization time that delivers an effective dose is desirable.

Unless designed for a smaller or larger fill volume, the nebulizer should be filled to 4–5 mL.^17,49 Because the volume of some unit-dose medications is suboptimal, the formulation should be diluted to a volume to 4–5 mL. The increased nebulization time associated with a greater fill volume can be offset by increasing the flow used to power the nebulizer. Increased flow also decreases the droplet size produced by nebulizers. A flow of 6–8 L/min is recommended unless the nebulizer is designed specifically for a flow other than this. Performance differences between nebulizers of different manufacturers and among nebulizers of the same manufacturer has been reported.^49–51

In the home setting, jet nebulizers are used with a compressor. Often the nebulizer and compressor are provided as a unit, both from the same manufacturer. The flow and pressure characteristics of compressor/nebulizer units affect nebulizer output. For reasons such as cost, clinicians and patients might not follow recommendations to use compressor/nebulizer combinations. Awad and Berlinski⁵² reported that replacing the nebulizer or compressor with a different brand changed the flow-pressure and aerosol characteristics, with greater effect when the nebulizer was replaced than when the compressor was changed. In another study by Awad et al,⁵³ the performance of compressor/nebulizer units was found to deteriorate over time, with some units affected more than others. Others have also reported suboptimal performance of nebulizer compressors.^50,54,55 Thus, it is important for clinicians to consider compressor performance when assessing patient response to aerosol therapy.

Designs to Decrease Aerosol Waste During Exhalation

The traditional jet nebulizer has a constant output during the inspiratory and expiratory phases. This results in drug loss during exhalation, and several designs can be used to minimize this loss. An inexpensive approach is to attach corrugated tubing to the nebulizer T-piece as a reservoir (Fig. 9).^69,70 Another approach uses a bag to store aerosol during exhalation.^71–76 Breath-enhanced nebulizers use a mainstream or open-vent design to boost nebulizer output during inhalation. Several studies reported greater pulmonary deposition and shorter treatment time with this design compared with a conventional nebulizer.^77–82

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Fig. 9.

Nebulizer designs. A: Jet nebulizer with reservoir tube. B: Nebulizer with aerosol collection bag. C: Breath-enhanced nebulizer. D: Breath-actuated nebulizer. In each case, the aerosol output of the device is indicated by the striped area. From Reference 17.

Aerosol waste during the expiratory phase can be eliminated with the breath-actuated dosimetric design.⁸³ Several studies have reported reduced drug waste with this nebulizer design.^{57,76,80,84–86} Arunthari et al⁸⁶ reported better subject and respiratory therapist satisfaction with the use of a breath-actuated nebulizer. Sabato et al⁸⁷ reported that, although use of a breath-actuated nebulizer did not reduce the time in the emergency department for pediatric subjects with asthma, it was associated with a significantly improved clinical asthma score, decreased admissions, and decreased breathing frequency.

Mesh Nebulizers

Mesh nebulizers use a mesh or plate with multiple apertures to produce an aerosol (Fig. 10).^88–90 Mesh nebulizers have very low residual volume, fast treatment time, and the ability to nebulize a variety of solutions and suspensions. These devices are powered by batteries or electricity, and an external gas flow is not required.

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Fig. 10.

Mesh nebulizer. Top: Principle of operation of the device. Bottom: Representative of commercially available devices. From Reference 17.

With active mesh nebulizers (vibrating mesh), a vibrational element contracts and expands, moving a domed aperture plate with > 1,000 tapered holes.⁹¹ The holes are larger on the liquid side and smaller on the side from which the droplets emerge. Passive mesh nebulizers use a piezoelectric crystal that vibrates a transducer horn interacting with the liquid formulation and a static aperture plate, which pushes fluid through the mesh.⁹¹ For both active and passive designs, the drug is placed in the reservoir of the nebulizer above the aperture plate. Particle size and aerosol flow are determined by the exit diameter of the holes on the aperture plate. There is the potential for the pores of the nebulizer to become clogged with some suspensions or viscous drugs. The reliability of vibrating mesh nebulizers has also been questioned, with one report finding that nebulization was often randomly interrupted with a wide range of retained volumes.⁹²

Aerosol delivery from a mesh nebulizer has been reported to be greater than that of a jet nebulizer.^79,93,94 Delivery efficiency of a mesh nebulizer may be > 3 times that of jet nebulizers, and thus drug doses may need to be adjusted.⁹⁴ A holding chamber can be used with the mesh nebulizer to collect aerosol during exhalation, further increasing the dose on the subsequent inhalation.⁹⁴ Mesh nebulizers are more expensive than jet nebulizer/compressor systems. Mesh nebulizers are available for use by ambulatory patients, and systems are also available for use during invasive and noninvasive ventilation. Aztreonam (an antibiotic for cystic fibrosis) and glycopyrrolate (a long-acting muscarinic antagonist for COPD) are examples of FDA-cleared drugs for inhalation using a mesh nebulizer.

Ultrasonic Nebulizers

Ultrasonic nebulizers convert electrical energy to high-frequency ultrasonic waves. The ultrasonic waves are transferred to the surface of a liquid, thus producing an aerosol (Fig. 11). Small-volume ultrasonic nebulizers are commercially available for delivery of inhaled bronchodilators. Their cost is greater than that of jet nebulizer/compressor systems but comparable to that of mesh nebulizers. A drug/device combination that uses an ultrasonic nebulizer is the treprostinil/Tyvaso system.⁹⁵ Use of these devices has been hampered by their tendency for mechanical malfunction. A potential issue with the use of ultrasonic nebulizers is the possibility for drug inactivation by the ultrasonic waves, although this has not been shown to occur with common aerosol medications. The ultrasonic nebulizer is inefficient in nebulizing a suspension.⁹⁶

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Fig. 11.

Function of an ultrasonic nebulizer. From Reference 168.

Smart Nebulizers

Smart nebulizers have recently become available for individualized controlled inhalation, which allows a bolus aerosol inhalation technique adjusted to the patient's breathing pattern or lung function.^97,98 These systems combine nebulizer technology, flow and/or pressure sensors, and a microprocessor.

One type of smart nebulizer is adaptive aerosol delivery (I-neb, Philips, Murraysville, Pennsylvania).^99–103 This device analyzes the patient's breathing pattern to determine the timing of the aerosol pulse during inhalation (Fig. 12). An aerosol is generated using a mesh nebulizer. The pressure changes of the initial breaths are used to determine the starting point for aerosol delivery during inhalation. Monitoring of the preceding 3 breaths continues throughout the treatment, and the device continually adapts to the patient's breathing pattern. The adaptive aerosol delivery system can be operated in either the tidal breathing mode or the target inhalation mode. The breathing mode is selected by using a specific mouthpiece, which is detected by the electronics in the device. In the tidal breathing mode, the patient breathes tidally though the mouthpiece. In the target inhalation mode, the patient is provided feedback to take a slow and deep breaths. There are several potential benefits of adaptive aerosol delivery. The aerosol is frontloaded in the breath, which should maximize parenchymal deposition and minimize dead-space deposition. The device is breath-actuated, which eliminates drug waste during the expiratory phase.

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Fig. 12.

A schematic representation of flow and inspiration/expiration ratios of 4 different types of nebulizer. The drug available for inhalation is indicated by the dark shaded areas, whereas the lightly shaded areas indicate losses to the surrounding air.

The AKITA (Vectura, Chippenham, United Kingdom) is another smart nebulizer system. It can be used with either a jet nebulizer of a mesh nebulizer. For the jet nebulizer, it controls a compressor so that the dose delivery is targeted to a specific region of the lungs. Information about the patient's lung function information can be entered into the system and used to individualize drug delivery. When used with a mesh nebulizer, this system deposits ∼ 70% of the nominal nebulizer fill to the lungs.^97,98

Clinical Studies Supporting the Impact of Aerosols

Factors that influence optimal delivery of inhaled drug therapy in subjects with obstructive lung diseases include the device, drug formulation, and patient characteristics such as cognition, disease severity, and clinical status of the patient, all of which can influence patient outcomes.^3,17,18 In patients with asthma or COPD, incorrect pMDI technique has been associated with a 50% increased risk of hospitalization as well as increased emergency department visits and oral corticosteroid use.¹¹⁸ Clinical and real-world studies in subjects with obstructive lung disease show differences in outcomes and adverse effects associated with less efficient DPIs.^119–124 When compared to the same drug administered with a pMDI, the Seretide Accuhaler (GlaxoSmithKline) was shown to have a higher risk of exacerbations in subjects with asthma and COPD as well as oropharyngeal adverse effects, presumably related to differences in lung and oropharyngeal deposition between the less efficient Accuhaler and pMDI.^120–122

In a study of pediatric subjects with asthma, it was found that formoterol DPI achieved a greater increase in FEV₁ post-exercise when inhaled at a higher inspiratory flow.¹²⁴ Another study evaluated the effect of beclomethasone HFA (smaller MMAD) on spirometry and computed tomography in adult asthmatics. There was less air trapping in subjects receiving the smaller MMAD, whereas symptoms and FEV₁ were not different between the formulations with different MMAD.¹²³

Several studies have found that impaired peak inspiratory flow (ie, below the minimum necessary for DPI) occurred in a third or more of subjects with COPD exacerbations requiring hospitalization. Loh et al¹²⁵ reported that subjects with impaired peak inspiratory flow were at a greater risk of all-cause 90-d re-hospitalization, whereas this was not found in the study by Sharma.¹²⁶ The decrease in inspiratory flow persists after exacerbations, where it was reported the post-bronchodilator inspiratory capacity and inspiratory reserve volume was increased by 20% and 37%, respectively, between day 2 after hospital admission and 6 weeks later in subjects with COPD exacerbations.¹²⁷ Broeders et al¹²⁸ reported that peak inspiratory flow measured with the InCheck DIAL (Alliance Tech Medical, Granbury, Texas) increased between 17% and 22% between hospital admission and 5 weeks later when subjects were clinically stable in the out-patient setting.

Small particle size decreases oropharyngeal deposition and local adverse effects compared to the same drug with a larger aerosol size.^6,122,129 Studies in subjects with asthma and COPD indicate greater improvements in small-airway function with small-particle aerosols, which lends support to this benefit.^130–135 However, it is possible that particles that are too small (ie, < 1 μm) may be less efficacious than particles of a medium size. Two studies reported that FEV₁ improved to a greater extent with particle sizes of ∼ 3 μm than with particles ∼ 1.5 μm.^136,137 It is important to recognize that spirometry does not precisely measure function in the small airways, which means spirometry is not a good estimate of the effects of small-particle aerosols in the respiratory zone. MRI with hyperpolarized gas might provide a better scientific understanding in this area, but this is largely in early stages of clinical research application.⁸

Increased lung deposition might be expected to be associated with greater systemic effects, such as the suppression of cortisol production with ICS. However, short-term clinical trials have not documented increased risk of systemic effects with a small-particle ICS,^129–131 or with a small-particle ICS/long-acting β agonist (LABA) combination formulation.¹³³ Treatment with small-particle HFA-pMDI, ICS/LABA, and nebulizer-based aerosols has resulted in less suppression of the hypothalamic-pituitary-adrenal axis than has treatment with an equipotent dose of large-particle ICS/LABA pMDI.¹³³ However, long-term studies are needed to better understand the potential risks for systemic adverse effects that may occur with increased lung deposition achieved with small particle sizes. The use of small-particle aerosol therapy may decrease the need for a VHC or spacer because of the reduced impaction of particles in the oropharynx.

Inhalation Device Selection

There are many challenges with the use of inhalers and nebulizers, and no one device suits all patients.^3,17,18 Challenges range from difficulties related to lung disease severity to physical impediments. In terms of device selection and adherence, patient engagement and satisfaction are important to consider. Each device has different technical properties, so a personalized approach to the selection of the most appropriate device is recommended to achieve desired clinical outcomes for each patient. If an inhaler does not produce optimal results, the patient may become non-adherent. Furthermore, the use of multiple types of devices can present challenges to patients. Some strengths and weaknesses of different inhalation devices are shown in Table 1.

Patient factors to consider in device selection include disease status, physical and mental capabilities, past experiences with inhalers, preferences and satisfaction with their inhalers. Disease-related factors include respiratory muscle weakness, air trapping, airway narrowing, and worsening symptoms such as during an exacerbation.^3,17,18 Elderly patients are more likely to have physical impediments such as arthritis or cognitive impairments such as dementia. Patient preferences for different inhaler types include ease of use, portability, compact design of the device, noise, taste, treatment time, and convenience. A real-world observational study reported that the higher the satisfaction level of the subject with their device, the more likely they were to adhere to therapy and have better outcomes (eg, improved quality of life, fewer acute care visits).¹³⁸

In addition to patient factors, choice of inhaler depends on other factors, such as medication(s) availability in particular inhalers, the need for use of a spacer or VHC, required inhaler technique, and health insurance coverage. The first step in device selection may be to determine the formulary status of the medication prescribed. If not, this could lead to the first inhalational technique error the patient can make, which is not acquiring the inhaler.

Of the multi-dose inhalers, the pMDI is the most difficult to use correctly, particularly for the elderly patient with COPD. DPI breath-activated devices tend to be easier to use. Multiple-step DPIs, such as those requiring insertion of capsules, are slightly more complicated than those with doses already loaded. The target inspiratory flow for the pMDI and SMI is approximately 30 L/min, with a slow inhalation over 3–5 s, and the majority of patients are able to achieve this. Due to technique differences with the SMI compared to other inhalers, it should be determined whether the patient is able to properly use the device.

Although DPIs are relatively simple to use, adequate inspiratory flow is important. The minimum peak inspiratory flow ranges from 30 L/min for the Handihaler and Breezhaler (Novartis, Basel, Switzerland) to 60 L/min for the Diskus and Ellipta.^35,36 The Handihaler is a high-resistance DPI, whereas the Ellipta, Turbuhaler (AstraZeneca), and Diskus are medium-resistance DPI, and the Breezhaler is a low-resistance DPI. Patient-related impediments to achieving adequate inspiratory flow in patients with COPD include elderly age, female gender, and stature.^42,139,140 Ideally, the peak inspiratory flow can be measured to ensure the patient achieves an acceptable value, recognizing that this measure may drop with worsening symptoms.

Some in vitro studies indicate that the fine-particle dose from DPIs is reduced when inspiratory flow is < 60 L/min,^141–144 whereas other studies show little effect of flow.^145,146 Diskus lung delivery may be suboptimal with a peak inspiratory flow < 60 L/min. In a study of healthy volunteers, a decrease in the peak inspiratory flow from 60 L/min to 30 L/min resulted in a 30% decrease in blood levels of albuterol and fluticasone,⁴³ suggesting decreased lung delivery.⁹ In a study conducted in an out-patient research setting, using an instrumented Ellipta inhaler, severe to very severe subjects with COPD had shorter inspiratory times and tended to have impaired inspiratory flow (< 60 L/min).¹⁴⁴ Decreased inspiratory flow has been observed when patients with COPD are clinically stable^{36,140,143,147} and during exacerbations requiring hospitalization.^125,126,128 One study in subjects with COPD recently discharged from the hospital were instructed in the use of a Diskus inhaler with the INCA smart inhaler device.⁴⁵ The most common subject error with the DPI was an inadequate inspiratory flow. Notably, 20% of the subjects had a zero inspiratory flow, as they never used the device over the 1-month study period.

Another factor that might affect inspiratory flow in the patient with COPD is the position of the patient when using the DPI (standing, sitting, supine). Air-flow obstruction in COPD increases resistance to air flow during expiration and inspiration, although it is more evident during expiration.¹⁴⁸ It has also been shown that functional residual capacity was lower in a supine position than in a standing position.¹⁴⁹ A study in subjects with COPD and air trapping showed that the inspiratory flow was reduced.¹⁵⁰ Therefore, it is possible that, under certain conditions, lung deposition that depends on a strong inspiratory effort could be altered by the physical position and impaired inspiratory capacity of the patient with COPD. Using γ-scintigraphy in healthy volunteers, it was found that inhalation in a supine posture shifts relative deposition from the alveolar to the bronchial airways compared to the seated posture.¹⁵¹ This was suggested to be due to changes in functional residual capacity, airway size, and changes in the regional distribution of ventilation between postures. Additional research is needed to better understand this issue.

DPIs have greater susceptibility to environmental humidity, ie, some products under certain circumstances can be affected.^152–154 If moisture gets into the powder, it decreases de-agglomeration and therefore increases MMAD as well as decreases fine-particle fraction and fine-particle dose. The excess moisture in the aerosol powder does not affect the total dose delivered by the DPI; rather, it affects the fine-particle dose. From the time that the drug is manufactured and stored, then dispensed, and during the variable usage and storage by the patient, the dry powder may be exposed to excessive humidity. If everything is done correctly, the exposure to moisture is usually minimal. Some products are sold in foil packaging with desiccants (eg, Ellipta),¹⁵⁵ and others may not, depending on the country of origin (Accuhaler).¹⁵⁶ The FDA requires testing under certain temperatures, humidity, and time periods for all inhalers, and this is especially relevant for DPIs.

Storage of fluticasone propionate/salmeterol Accuhaler (not in foil pack) and budesonide/formoterol Turbuhaler at 40° C and 75% relative humidity over 3 months led to a 42% decrease in the in vitro fine-particle dose of fluticasone propionate for the Accuhaler, with only minimal change for the Turbuhaler.¹⁵³ Storage of the Accuhaler device at 25°C/30% relative humidity over 3 months led to a 10% decrease in fine-particle dose of fluticasone propionate. Corroborating the in vitro findings, at 40° C and 75% relative humidity, the area-under-the-serum-concentration curve after fluticasone propionate/salmeterol administration in healthy volunteers decreased by ∼ 40% for the 2 ingredients for the Accuhaler and changed minimally for the Turbuhaler. A study evaluating the effects of humidity and temperature on the fluticasone propionate/salmeterol Spiromax and budesonide/formoterol Turbuhaler reported a slight decrease (9.3% and 10.3%, respectively) in fine-particle dose of the steroid components in vitro after 1.5 months of storage at 40°C/75% relative humidity.¹⁵⁴ The fine-particle dose of budesonide from budesonide/formoterol Easyhaler (available in Europe) decreased by 59% at 40°C/75% relative humidity and by 38% at 25°C/75% relative humidity, suggesting that excess moisture alone can affect fine-particle dose. Non-adherent patients are the ones most apt to encounter problems with moisture as they use their inhalers for longer than the recommended usage period (eg, the Twisthaler [Merck, Kenilworth, New Jersey] is to be discarded 45 d after removing from the foil pack). DPIs that use a capsule inserted into the device are less susceptible; however, if the patient removes the capsule from the foil packaging and does not use it within a short time period, moisture starts penetrating the capsule.¹⁵⁷

Patient Education

Among the most common chronic diseases, arguably the most complicated types of drug therapies for patients to self-administer are injectables for diabetes mellitus and inhaled medications for obstructive lung diseases. Whereas diabetics are taught how to administer injectables, such education is often lacking for inhaled medications in patients with asthma and COPD. There are numerous reasons for this, including a lack of well-established mechanisms to reimburse health care providers for this teaching, a lack of providers being adequately trained, and it does not appear to be complicated. Recently, a survey of pulmonologists and patients found that the minority of subjects received education from providers and that providers were not highly comfortable with their knowledge with certain devices.¹⁵⁸ Only 40% of pulmonologists reported that device characteristics influenced their prescribing of inhalers. Part of the problem is the lack of incorporating inhalation therapy training in pulmonary and other specialty fellowship training programs.

Health care professionals are central to the management of patients with COPD and asthma, whether it is the physician, respiratory therapist, nurse, pharmacist, or other provider. The wide range of drug and inhaler combinations increases the complexity of inhaler choice for providers and patients. Many providers cannot describe all of the steps involved or demonstrate correct inhaler use for all of the inhalers they prescribe.^159,160

The most effective patient training technique has been established as verbal instruction combined with a demonstration by the provider and then a reciprocal demonstation by the patient. This is challenging due to the lack of an available device that the patient can use to demonstrate adequate technique. Repetitive instruction over time increases the proportion of patients who maintain the correct technique at follow-up visits.^161,162 If a patient is unable to use one device, perhaps another should be chosen. But there are limits, such as how to teach a patient with major cognitive impairment to use an inhaler. If poor technique persists, it is essential to elucidate from the patient the challenges they are experiencing and then address any potential lack of understanding around the need for medication and adherence. A review evaluated a range of interventions and determined that, although many studies demonstrate a post-intervention improvement in the number of individuals with correct inhaler technique, it could not be confirmed whether this translated into clinical benefits.¹⁶² A selection of educational aids has been developed and are reviewed elsewhere.¹⁶³ National Jewish Health has a Web site with videos on proper inhaler instruction.¹⁶⁴

Melani and colleagues reported that the strongest associations with inhaler misuse were older age, lower education level, and lack of proper instruction.¹¹⁸ Even the most user-friendly devices require education and demonstration, and all patients should, as early as possible, be given proper instruction. There are situations where it may be more important, such as initiating therapy or when disease control is not being achieved.

In one study, health care providers watched tablet-based multimedia educational videos that demonstrated correct inhaler technique by a clinical pharmacist with teach-back from the patient before being re-evaluated.¹⁶⁵ Correct inhaler technique was significantly increased among all health care professionals after the training, with the largest increase for the Respimat device; 32% versus 93% demonstrated the correct steps for usage before and after training, respectively. Takaku et al¹⁶¹ evaluated the number of instructions necessary to minimize errors in using pMDI, DPI, and SMI and concluded that, for every device, at least 3 instructions were required to achieve an error rate < 10%.

Proper Inhalation Techniques

The pMDI is a commonly used device because of the many medications that can be delivered, as well as provider and patient familiarity. Instructions are shown in Table 3. Patients should be instructed to rinse their mouth after use, regardless of the medication, because all medications contribute to tooth decay, and ICS can cause thrush and dysphonia.¹⁶⁶ Many of the inhaled drugs are not very water-soluble (lipophilic), so an alcohol-based mouthwash might remove more drug from the oropharyngeal cavity.

Some pMDIs are stored and dispensed in foil packages with desiccants to minimize exposure to moisture. Drug degradation occurs slowly, although this can occur more rapidly at high temperatures, so adherence to the expiration date is warranted. Storage of the pMDI where the mouthpiece is kept downward can decrease consistency of doses, and thus this is not recommended. Priming with new use or re-priming if not used for a specified time period is recommended to avoid incomplete doses. Most pMDIs now have dose counters, and in the United States this is the case for all devices except for one brand of albuterol (Proventil). Notably, more puffs can be actuated from the pMDI after the labeled number of maximum puffs is reached. However, drug delivery becomes variable and eventually minimal as largely only propellant is being released. Many patients use their albuterol pMDI until nothing comes out, eventually wondering why it is not working as well, which is not a good situation for a patient in respiratory distress.

Clogging of HFA pMDI albuterol actuators has been reported. pMDIs should be cleaned at least once a week by removing the metal canister, running warm water through the actuator, shaking the actuator to remove water, and then drying the device per manufacturer's instructions.

Common user errors with pMDIs include not shaking vigorously before each inhalation, failure to empty lungs prior to inhalation (eg, the breath mint technique, where the aerosol pours out of the mouth), failure to tilt head to the correct position, inhaling too fast (and thus not slowly and deeply over 3–5 s), and failure to hold the breath after inhalation for at least 5 s. The patient can repeat the steps when they are ready, and do not have to wait any specific time. Occasionally, patients actuate 2 puffs into their mouth at the same time and then inhale, which is a waste of the first actuation.

After inserting the pMDI into the VHC, similar steps are followed as for the pMDI alone, except that the patient can wait 1–2 s to inhale the dose. For VHCs that have an audible warning for inhalation that is too fast, the patient should breathe in so slowly as to make little or no sound, then hold the breath for 5–10 s.

DPIs like Ellipta involve preparing the dose by moving the cover to the side to expose the mouthpiece, whereas for the Turbuhaler the bottom is turned and a cover is taken off. For the Handihaler and Breezhaler, a capsule is inserted and punctured (Table 4). The patient should ensure that his or her lips or fingers do not cover the air inlets on the DPI during inhalation. Common errors for DPIs include not keeping the device in the correct position while loading the dose (eg, Turbuhaler needs to be held vertically when loading a dose), failure to tilt the head to the correct position, not emptying the lungs before inhalation, insufficient inspiratory effort, and no breath-hold. Accidentally closing the mouthpiece of the Ellipta prior to inhalation causes the dose to be lost.¹⁵⁵ Failure to achieve a forceful inspiratory flow is the most common error with DPIs, occurring in 26–29% of cases.¹¹⁸ Sulaiman et al⁴⁴ reported that an inadequate inspiratory flow for a DPI was common among subjects with COPD recently discharged from the hospital. An inadequate inspiratory effort may be related to the patient's impaired respiratory function; alternatively, perhaps they just do not take a rapid deep breath for some reason.

The Respimat requires a slow, deep inhalation similar to that required by the pMDI (Table 5). Notably, for the Combivent Respimat, the full dose is 1 puff, whereas for the Striverdi, Stiolto, and Spiriva the dose is 2 puffs. While turning the base of the device to load a dose, 1 puff is wasted if it is turned past the click. Once the medication canister is inserted, it should not be removed as drug will be lost. Common errors are similar to those found with the pMDI, except that the slow, prolonged actuation allows for some patient error.

Summary

This review supplements published guidelines for aerosol delivery.^3,18,167 Correct use of inhalation devices and adherence to prescribed therapy are key aspects to achieve better clinical control, improved quality of life, and fewer adverse effects. However, a wide range of factors are known to present challenges to patients with respect to inhaler use, including inhalation technique and pulmonary function. Using aerosol delivery devices correctly requires interaction between providers and patients to assure correct use and adherence. This responsibility is shared by physicians, respiratory therapists, pharmacists, nurses, and others involved in the care of the patient.