Review

Nebulizers for drug delivery to the lungs

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Andrew R Martin & Warren H Finlay† 1.

Introduction

University of Alberta, Department of Mechanical Engineering, Edmonton, Alberta, Canada

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Fundamental aspects of nebulizers

3.

Use of nebulizers

4.

Conclusions

5.

Expert opinion

Introduction: Nebulizers are the oldest modern method of delivering aerosols to the lungs for the purpose of respiratory drug delivery. While use of nebulizers remains widespread in the hospital and home setting, certain newer nebulization technologies have enabled more portable use. Varied fundamental processes of droplet formation and breakup are used in modern nebulizers, and these processes impact device performance and suitability for nebulization of various formulations. Areas covered: This review first describes basic aspects of nebulization technologies, including jet nebulizers, various high-frequency vibration techniques, and the use of colliding liquid jets. Nebulizer use in hospital and home settings is discussed next. Complications in aerosol droplet size measurement owing to the changes in nebulized droplet diameters due to evaporation or condensation are discussed, as is nebulization during mechanical ventilation. Expert opinion: While the limelight may often appear to be focused on other delivery devices, such as pressurized metered dose and dry powder inhalers, the ease of formulating many drugs in water and delivering them as aqueous aerosols ensures that nebulizers will remain as a viable and relevant method of respiratory drug delivery. This is particularly true given recent improvements in nebulizer droplet production technology. Keywords: droplet formation, droplet sizing, inhalation drug delivery, jet nebulizers, nebulizers, respiratory drug delivery, vibrating membrane, vibrating mesh Expert Opin. Drug Deliv. [Early Online]

1.

Introduction

Respiratory drug delivery of pharmaceutical aerosols is commonplace in the treatment of a variety of pulmonary diseases, including, but not limited to, asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis. In this context, local delivery of drug to the lungs reduces required doses and side effects as compared to other routes of delivery. The inhalation delivery route has also itself been explored for systemic drug delivery, where the large alveolar epithelial surface can result in rapid drug absorption. Aerosol drug delivery devices are commonly sorted into three categories: pressurized metered dose inhalers (pMDIs), for which drug is formulated in suspension or solution under pressure in a liquid propellant, which is subsequently released through an orifice as a spray upon device actuation; dry powder inhalers (DPIs), for which drug is formulated as a powder that is fluidized and entrained as aerosol particles by the patient’s own inspiratory effort; and nebulizers, for which drug is formulated in aqueous solution or suspension and then atomized into droplets produced through one of several fundamental processes described in this review. Use of nebulizers is well-entrenched in respiratory drug delivery. Traditionally, nebulizers have been used in hospital and home, or domiciliary, settings, primarily due to the requirement of a source of compressed gas or electrical power to drive nebulization, and the time required to administer a dose. Both the power requirement and administration time are generally viewed as limitations of nebulizers as 10.1517/17425247.2015.995087 © 2014 Informa UK, Ltd. ISSN 1742-5247, e-ISSN 1744-7593 All rights reserved: reproduction in whole or in part not permitted

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While nebulizers have traditionally been used in the hospital or home, newer nebulization technologies have expanded application of some nebulizers to more portable use. The ability of certain nebulizers to be used with tidal breathing, rather than a specific single breath maneuver, can be an attractive aspect for acute exacerbated and very young patients. Nebulizers more readily deliver much larger drug doses than other respiratory drug delivery device types. Use of electronic monitoring of patient breathing with some nebulizers, with feedback to aerosol production, may allow for improved adherence and monitoring of drug delivery. With recent improvements in nebulizer droplet production technology, nebulizers are expected to remain as a viable and relevant method of respiratory drug delivery.

This box summarizes key points contained in the article.

compared to pMDIs and DPIs. However, newer nebulization technologies developed over the past two decades have expanded application of some nebulizers to portable use outside the home, where pMDIs and DPIs have long been preferred. In addition, nebulizers are well suited for incorporation into aerosol delivery systems that aim to optimize administration of drug to the lungs by controlling, or measuring and adapting to, patient breathing patterns. As new nebulization technologies have been developed, the role of nebulizers in respiratory drug delivery continues to adapt. Several recent reviews examine the role of nebulizers in treating specific illnesses, conditions or symptoms of illness, for example, cystic fibrosis [1], acute lung injury [2], ventilatorassociated pneumonia [3], dyspnea [4] and acute asthma [5]. The suitability of nebulizers, as well as pMDIs and DPIs, for systemic administration of macromolecules has also been reviewed [6]. In the present review, we first describe various fundamental droplet formation processes used in both traditional and newer nebulizers, before considering use of nebulizers in various settings. In so doing, we aim to link nebulization fundamentals and device design to applications and limitations of current nebulizer use.

2.

Fundamental aspects of nebulizers

The process of dispersing a drug-containing aqueous formulation into aerosol droplets for the purpose of respiratory drug delivery normally involves one of three different types of mechanical breakup methods [7]. These methods are: i) air-blast atomization; ii) high-frequency vibration; and iii) colliding liquid jets. Before examining the merits and use of each method, it is worthwhile to briefly consider the fundamental aspects of each as follows. 2

Air-blast atomization (jet nebulization) The oldest of the currently used nebulization methods, airblast atomization, is the purview of jet nebulizers. With this approach, compressed air flows through a nozzle and accelerates to high speed before then coming into contact with the liquid to be dispersed. The large speed of the compressed air relative to the bulk drug-containing liquid in the nebulizer results in liquid breakup and droplet formation, with the newly created droplets entrained in the high-speed air. While the details of droplet production depend on the nebulizer design, an instability associated with the difference in viscosity between the high-speed air and the underlying liquid has been hypothesized as a fundamental driving mechanism for the primary production of droplets [8]. The extreme difference in velocity between the air and liquid in the primary droplet production region causes intense shear in the liquid. While this shearing is necessary for droplet production, exposure of large molecules, such as proteins or DNA, to such shear may be partly responsible for drug degradation seen by some authors [9,10]. Albasarah et al. [11], among others, have seen a reduction in such drug degradation with the addition of protective agents. Droplet sizes in the primary droplet production region of jet nebulizers are typically too large for inhalation into the lungs. For this reason, the primary spray from a jet nebulizer normally impacts immediately onto a baffle that causes further breakup by splashing [12]. Subsequent impaction on secondary baffles and the nebulizer walls causes further size selection of the aerosol, such that the final aerosol leaving the nebulizer is only a small fraction of the original spray produced in the primary droplet region [13]. As a result, material in the nebulizer cycles through the spray-impaction process many times before finally leaving the nebulizer as an aerosol. The repeated stresses associated with repeated exposure to droplet formation, breakup and impaction can make jet nebulization unsuitable for certain easily degraded large molecules and liposomes [14]. The process of production of droplets in a jet nebulizer can produce electrostatic charge on the resulting droplets. However, these charge levels have been found to be lower than would be expected to significantly affect deposition in the lungs [15]. While most nebulized drugs are formulated as solutions, it is possible to deliver aqueous suspensions via nebulization. Jet nebulization is in fact the preferred method of nebulization for such formulations, since other methods are prone to producing drugfree droplets [16]. However, it should be noted that while jet nebulizers are well suited to aerosolizing suspension formulations, suspension particle diameters should be much smaller than aerosol droplet diameters, otherwise the drug may be preferentially contained within the larger droplets [17]. 2.1

Article highlights.

High-frequency vibration To remove the need for a compressed air source, highfrequency vibration can instead be used as the droplet 2.2

Expert Opin. Drug Deliv. (2014) 12(4)

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Nebulizers for drug delivery to the lungs

generation mechanism. There are several approaches used in this regard. The oldest approach relies on vibration of a bulk piezoelectric head immersed in liquid to create pressure waves that propagate to the air--liquid interface and cause droplets to break from the surface. These devices are often termed ultrasonic nebulizers. The underlying physical mechanism of droplet production with such traditional ultrasonic remains a topic of discussion in the literature [18]. However, difficulties with nebulizing high-viscosity liquids [19], suspensions [16], as well as significant heating of the nebulizer solution [20], which can be problematic for heat-sensitive drugs like rhDNase [21], limits their generality. A higher frequency, lower power, more recent ultrasonic approach instead uses surface acoustic waves (SAWs) induced on a piezoelectric crystal to produce aerosol droplets (Figure 1) [22,23]. SAW nebulization has been shown to aerosolize plasmid DNA with little degradation [22]. In addition, SAW nebulization is able to nebulize a higher fraction of the presented material compared with traditional ultrasonic nebulizers. Another alternative approach involves the extrusion of droplets through a thin plate, membrane or mesh filled with many micrometer-sized holes (Figure 2). Two subcategories of this approach exist, one involving vibration of the mesh [24] and the other involving oscillatory forcing of fluid through a stationary mesh [25]. It should be noted that the latter approach, that is, extrusion of liquid through tiny holes in a fixed plate, can also be enacted with constant, nonoscillatory forcing of fluid through the holes and instead relies on Rayleigh breakup to produce droplets [26]. Naturally, all such hole-filled plate methods, either with or without vibration, are prone to clogging by suspended microparticulates, an issue that can be a concern with suspension formulations, or even dried drug and excipients. Colliding jets A rather unique approach to aerosol droplet production involves extruding an aqueous formulation under very high pressure (i.e., hundreds of atmospheres) through tiny opposing nozzles such that opposing liquid jets collide with each other [27]. Using silicon chip etching methods, nozzle blocks containing many hundreds of such nozzles can be built, allowing aerosolization of a 100 µl liquid volume during a single breath. Boehringer’s Respimat device, shown schematically in Figure 3, is based on this technology. Because of the need for very high pressures, the drug is contained in solution within a sealed reservoir, which for the Respimat device is pressurized by the action of a spring [28]. 2.3

Droplet evaporation and sizing The purpose of all of the aforementioned methods is to produce aqueous aerosol droplets with diameters in the range appropriate for drug delivery to the lungs. For typical breathing patterns that are used with nebulizers, this means particle diameters of a few micrometers. However, an undeniable aspect of aqueous aerosol droplets is their ability to evaporate

or condense water at their surface. Such evaporation or condensation can result in significant changes in droplet diameter, which in turn can affect the fraction of inhaled droplets that deposit in the lungs. For example, droplets that are too large will deposit mostly in the extrathoracic region. However, if these droplets are immediately exposed to low-humidity air before being inhaled, they may evaporate and shrink to smaller diameters before passing through the extrathoracic airways and thereby avoid the expected high extrathoracic deposition losses. Because of the possibility of diameter changes with nebulized aerosols, care should be taken to understand whether such effects may occur and what their implications may be on drug delivery [29]. One of the most commonly seen effects in this regard is droplet evaporation prior to particle size measurement. Particle size is one of the most important criteria in assessing a nebulizer’s potential ability to deliver drugs to the lungs. However, because of the aforementioned ability of nebulized aerosols to change diameter, caution must be used when sizing nebulized aerosols in order to avoid underestimating particle diameters. An important determinant of whether such effects may be an issue is the mass fraction of the nebulized aerosol, since nebulizers that produce dense aerosols may humidify any entrained ambient air with little change in particle diameter. However, less-dense (low aerosol mass fraction) nebulized aerosols are more prone to diameter changes upon exposure to low-humidity entrained air [29]. Because jet nebulizers produce aerosol that is cooler than ambient temperatures, heat transfer to the aerosol can also cause particle size changes with such nebulizers even when the aerosol is not exposed to any ambient air [30]. Such heat transfer can cause evaporation of droplets and subsequent particle shrinkage [31]. Cascade impactors are notoriously difficult to use correctly in the measurement of nebulized aerosols for these reasons. If the cascade impactor flow rate is higher than that supplied by the nebulizer, the resulting exposure of the aerosol to ambient makeup air can result in unexpected, and ambient conditiondependent, droplet size changes. Even if the nebulizer can supply the entire cascade impactor flow rate, heating of aerosol in transit through the impactor can result in spurious changes in particle size if the impactor is not cooled to match the temperature of the aerosol exiting the nebulizer [31]. The use of cooled impactors [31-33] and low flow rate impactors [34] may partially address some of these issues. An alternative approach is to use optical sizing methods such as phase Doppler anemometry [35,36] or laser diffraction [37,38], which if used properly can avoid such particle sizing errors.

2.4

3.

Use of nebulizers

In the hospital Nebulizers find wide use in the hospital environment for several reasons. First, they do not require specialized inhalation maneuvers that deviate from the patient’s spontaneous 3.1

Expert Opin. Drug Deliv. (2014) 12(4)

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Figure 1. (A) A SAW device shown schematically, with IDTs patterned on a piezoelectric substrate. Atomization is driven by a sinusoidal excitation signal provided by the RF input. (B) An enlargement of the SAW substrate showing the IDTs. (C) Interaction between a SAW and a fluid drop placed on the substrate as shown in (A). Capillary waves are induced on the free surface of the drop, destabilizing the interface and resulting in atomization of the drop through capillary wave breakup. Images reproduced from [23] with permission of The Royal Society of Chemistry. IDT: Interdigital transducers; RF: Radio frequency; SAW: Surface acoustic wave.

breathing; therefore, in contrast to pMDIs or DPIs, they can be used in emergency settings or for patients who are unable to control their breathing or consciously follow instruction. Second, nebulizers can be used to deliver relatively high doses continuously over extended time periods, as may be required, for example, in delivering bronchodilators in cases of acute severe asthma. Third, the requirement of a source of compressed gas to power a jet nebulizer, or an electrical outlet to power or recharge a vibrating mesh nebulizer, is readily met in the hospital, where patients are commonly sedentary. Fourth, some inhaled antibiotics and biotherapeutics are only available as solutions for nebulization. Finally, nebulizers are widely used in critical care in combination with positive pressure ventilation. Many newer mechanical ventilators include means to power a nebulizer, along with controls to coordinate nebulization with the breathing cycle. 3.2 In the hospital -- spontaneously breathing patients

For spontaneously breathing patients, nebulizers are frequently used in the hospital, either with a mouthpiece or an oro-nasal facemask. Concerning the delivery of inhaled b-agonists for treatment of acute asthma in emergency departments, a recent systematic review concluded that outcomes 4

using nebulizers versus pMDI--spacer combinations were not significantly different in adults [5]. The same review found evidence to suggest that for children, time spent in the emergency department, oxygenation and observable side effects (pulse rate and tremor) were more favorable for patients treated with pMDI--spacer combinations [5]. It should be noted that the reviewed studies excluded life-threatening asthma, where the ability of patients to use MDI--spacer combinations is unknown [5]. For nebulizers, the choice of mouthpiece or mask depends primarily on the age and status of the patient. A mouthpiece should in theory deliver more medication to the lungs due to the lower particle filtration efficiency of the mouth compared to the nose in adults (but not in infants [39]), and due to avoidance of aerosol deposition on the face; however, clinical studies have not consistently found improved efficacy with mouthpieces versus facemasks [40-42]. In some cases, theoretical advantages of using a mouthpiece may be countered by the tendency of patients experiencing shortness of breath to mouth-breathe using facemasks [43]. In the absence of a tight seal between mask cuff and face, facemasks have been shown to permit deposition of aerosol in and around patients’ eyes [44,45], which may be reason enough to prefer a mouthpiece when administering certain nebulized medications [43]. For young infants, nebulization hoods or tents have also been explored as alternatives to

Expert Opin. Drug Deliv. (2014) 12(4)

Nebulizers for drug delivery to the lungs

measured nebulizer output and droplet size distributions for 19 different nebulizers delivering salbutamol sulfate, and estimated lung dose to range from 3.1 to 23.4% of the nominal dose placed in the nebulizer. Clearly, not all nebulizers are created equal. One significant variation in jet nebulizer design is between vented and non-vented nebulizers. The latter, and most common nebulizer design found in the hospital environment, is shown schematically in Figure 4. The nonvented design permits room air to be entrained during inhalation through a T-piece connecting the nebulized droplet stream to the patient interface (e.g., mouthpiece). During exhalation, continuously produced droplets mix with exhalation flow in the T-piece and are expelled to the room. If desired, a filter or exhaust system can be coupled to the T-piece to avoid contamination of room air with nebulized drugs. Regardless, loss of nebulized drug during exhalation presents a significant inefficiency. Vented nebulizers, also called breath-enhanced nebulizers or active venturi nebulizers, aim to reduce these losses using two one-way valves. A schematic representation of a vented nebulizer is provided in Figure 5. During inhalation, an inspiratory valve opens to permit room air to be entrained through the main body of the nebulizer. During exhalation, this valve closes, and an expiratory valve on or near the mouthpiece opens, permitting flow of exhaled gas to bypass the droplet production region of the nebulizer and exit directly to the room environment. Accordingly, a greater fraction of nebulized drug produced during exhalation is retained in the nebulizer and available for the subsequent inhalation. As might be expected, in the study by Finlay et al. [50], some of the highest estimated lung doses for jet nebulizers were achieved by vented nebulizers; however, as an aggregate class, vented nebulizers did not outperform non-vented nebulizers. Evidently, even within a subclass of nebulizers, specific designs have profound impact on performance. Unfortunately, direct comparison of nebulizer performance based on manufacturer claims or measurements performed between different laboratories have historically been made difficult by the complexities of nebulizer droplet sizing described above. Significant efforts have been made by industry groups and standards organizations over the past decade to improve reproducibility of nebulizer testing between laboratories [51,52]. When using jet nebulizers in the hospital, the default driving gas is pressurized medical air, or filtered room air from a compressor. Alternatively, oxygen may be used to drive nebulization of bronchodilators in acute cases of asthma. The physical properties of oxygen are sufficiently close to those of air that nebulization efficiency and produced droplet sizes can be considered approximately equivalent between oxygen and air. In contrast, helium/oxygen mixtures (heliox) are in some cases used to reduce patient airway resistance, primarily during severe acute asthma [53], and hypothetically deliver a greater amount of aerosol to obstructed airways [54-58]. When helium/oxygen mixtures are used to drive jet nebulizers at equivalent flow rates as used for air, nebulizer output and [50]

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50 mm

Figure 2. Perforated membranes or meshes used in commercial high-frequency nebulizer devices: from top to bottom are images from Omron, Aerogen, and TouchSpray (Pari) devices, respectively. Reproduced from [104] with permission from Wiley-Liss, Inc.  2008.

facemasks and mouthpieces, primarily for the purpose of alleviating patient discomfort [46-49]. In addition to the choice of interface, the selection of the nebulizer itself can have profound impact on efficiency of drug delivery to the lungs. The European Respiratory Society Guidelines on use of nebulizers estimated > 10-fold differences in the amount of aerosol delivered from different nebulizer systems in use throughout Europe [43]. Similarly, Finlay et al.

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Figure 3. Schematic view of the Respimat device, including a close-up of the nozzle block. Reproduced from [100] with permission from Elsevier.  2004.

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Figure 4. Schematic of a conventional, non-vented jet nebulizer. Room air is entrained during inhalation through a T-piece connecting the nebulized droplet stream to the patient interface (mouthpiece). During exhalation, continuously produced droplets mix with exhalation flow in the T-piece and are expelled to the room. Reprinted from [105] with permission from BMJ Publishing Group Ltd.

droplet sizes change significantly [59,60], owing to the low density of helium/oxygen as compared with air. Accordingly, in this case it is important to evaluate effects of the driving gas on nebulizer performance. One way to circumvent these issues when delivering nebulized drugs in combination with helium/ oxygen is to use high-frequency vibrating mesh nebulizers, which are much less affected by carrier gas properties [61,62]. In the hospital -- ventilated patients Patients in critical care receiving mechanical ventilation are commonly administered inhaled bronchodilators. Both nebulizers and pMDI/holding chamber combinations are used for 3.3

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this purpose; a recent Cochrane review concluded that there is currently not sufficient evidence to support either delivery method over the other [63]. Nebulized antibiotics have also been widely studied for treatment of pneumonia in ventilated patients [64-68]. When jet nebulizers are used with ventilator breathing circuits, there exists potential for the additional flow output from the nebulizer to interfere with operation of the ventilator [69], and for nebulizer drug to simply be swept from the inspiratory to expiratory circuit along with bias flow [67,70]. For this reason, some commercial ventilators include controls and a gas supply line to drive jet nebulizers. Alternatively, vibrating mesh nebulizers are attractive for use

Expert Opin. Drug Deliv. (2014) 12(4)

Nebulizers for drug delivery to the lungs

Air sucked through vent on inspiration Patient

Feeding tube

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Air from compressor Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Trent University on 01/06/15 For personal use only.

Vent closed on expiration

Air from compressor

Figure 5. Schematic of a vented jet nebulizer design. Room air is drawn through the main body of the device during inhalation (left). Exhalation flow (right), passes through a one-way valve on the mouthpiece such that the majority of nebulized drug produced during exhalation is retained in the nebulizer and available for the subsequent inhalation. Reprinted from [105] with permission from BMJ Publishing Group Ltd.

with ventilators because they deliver negligible accompanying gas flow with their droplet output into breathing circuits. A number of newer ventilator models include controls to operate specific vibrating mesh nebulizers. Regardless of the nebulizer type employed, the efficiency of delivery to the patient depends on myriad factors [71,72], including the position of the nebulizer in the breathing circuit [73-75], coordination of nebulization with inhalation [74], continuation or interruption of humidification during nebulization [75-77], ventilator settings [73,78,79], and the patient interface [80]. The droplet size distribution produced by the nebulizer is also an important determinant of aerosol losses in the breathing circuit [64,81]. For intubated adult patients, in vivo measurements indicate that as little as a few percent of the nominal dose placed in a jet nebulizer reach the patient’s lungs [72]. Optimized configurations using vibrating mesh nebulizers designed for incorporation into ventilator circuits may improve on this significantly [64,82]. Similarly, improvements in efficiency of delivery for vibrating mesh compared with jet nebulizers have been noted for ventilation of children and infants [83,84]. Delivery of nebulized drugs during ventilation using noninvasive patient interfaces has received considerable recent attention [85,86]. As with invasive ventilation, the specifics of the nebulizer used, configuration of the breathing circuit and ventilator settings have large impact on the amount of drug delivered to the patient’s lungs [87-90]. Accordingly, for nebulizer use during both invasive and noninvasive ventilation, it is recommended that delivery efficiency be carefully evaluated for a given nebulizer/circuit/ventilator combination under anticipated settings of use. In the home Aerosol drug delivery is standard in long-term management of asthma, COPD, and other lung diseases. Use of nebulizers in 3.4

patient’s homes or other domiciliary settings is common, though selection of nebulizers in place of pMDIs or DPIs in many cases follows local prescribing habits, rather than published guidelines or evidence [43,91]. Generally, home use of nebulizers may be deemed appropriate for patients incapable of performing acceptable inhalation maneuvers with pMDIs or DPIs, for patients with severe lung disease or with frequent acute airflow obstruction that interferes with pMDI or DPI use, or for patients requiring medications or doses that are not available from a pMDI or DPI [92]. Technical considerations for home use of nebulizers are largely similar to those for use in the hospital by spontaneously breathing patients. Again, wide variation in drug delivery from different nebulizers can be expected. Air compressors are used in the home to generate supply of pressurized gas required to drive jet nebulizers. The performance of the nebulizer will depend on the pressure and flow rate of air supplied by the compressor; therefore, manufacturers should specify which compressor or compressors are to be used with a given nebulizer. Likewise, nebulizer/compressor combinations used in establishing the safety and efficacy of a drug product are frequently required to be identified in drug product labeling. Such labeling requirements are important in encouraging use of the drug product as tested and approved. However, if the nebulizer or compressor model becomes unavailable at a later date, the drug can no longer be used as approved by regulators. Efforts mentioned above to standardize nebulizer testing procedures [51,52] may help in defining processes through which a replacement delivery system can be identified and established with limited additional clinical testing requirements. While cost considerations typically favor use of jet nebulizers over high-frequency vibrating mesh nebulizers for administration of bronchodilators, at least one inhaled antibiotic is approved for use by cystic fibrosis patients only with a specific vibrating mesh device [93]. Similar devices have reportedly been used off-label to deliver other inhaled antibiotics, owing to their reduced nebulization time and easier handling as compared with jet nebulizers [94]. Vibrating mesh nebulizers have been, and are currently, employed in several drug and drug-device development programs. For proprietary drug formulations, vibrating mesh devices are attractive in that they may be used to offer faster treatment times and increased nebulization efficiency (less drug left in the nebulizer after treatment) than conventional jet nebulizers. Both jet nebulizers and vibrating mesh technologies have been incorporated into software-driven aerosol delivery systems that aim to optimize administration of drug to the lungs by controlling or measuring and adapting to patient breathing patterns. Such systems include Activaero’s Akita and Philips’ i-neb [95-99]. These systems can improve efficiency of aerosol delivery and, as a further advantage, can enable logging of dosing and patient breathing parameters for monitoring adherence rates. The latter is particularly useful during clinical evaluation of drugs in development.

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3.5

Outside the home

Traditionally, nebulizers have found limited use outside the home or domiciliary environment owing to their lack of portability. New nebulization technologies have challenged this status over the past decade. One marketed device incorporating vibrating mesh technology, Philips’ i-neb [96,99], is intended for use as a portable device that can be carried outside the home. In addition, the colliding jet approach to droplet production described above has been incorporated into a commercial inhaler device, Boehringer’s Respimat [100]. This inhaler has similar portability as a pMDI or DPI, and in this regard is suitable for use by ambulatory patients with COPD or asthma. In comparison to pMDIs, the cloud of aerosol produced by the Respimat is slow-moving [101], which may aid in reducing mouth-throat deposition and increasing lung deposition, especially for patients who have difficulty coordinating their inhalation with pMDI actuation. A recently completed, large-scale randomized clinical trial found no difference in safety or efficacy between tiotropium delivered to COPD patients via Respimat versus the HandiHaler DPI (Boehringer Ingelheim) [102]. Aggregate results of smaller studies indicate that both asthma and COPD patients generally prefer the Respimat device to pMDIs and to at least one common DPI [103]. 4.

Conclusions

Use of nebulizers for respiratory drug delivery is widespread in hospital and domiciliary settings. Newer nebulization technologies have also found application for portable use, where pMDIs and DPIs have traditionally been preferred. Understanding fundamental nebulization processes is important in selecting the most appropriate nebulizer for a given formulation and intended use. Considerations such as nebulization efficiency, output rate, delivery efficiency, potential drug degradation and challenges associated with nebulizing high viscosity or suspension formulations all may have substantial impact on device performance. As new and emerging technologies continue to expand applications of nebulizers in respiratory drug delivery, nebulization is expected to remain a relevant option for delivery of inhaled medications for years to come. 5.

Expert opinion

Nebulizers are the oldest modern method of delivering aerosols to the lungs for the purpose of respiratory drug delivery.

8

While other devices, such as pMDIs and DPIs, occupy a larger market share, nebulizers remain an attractive method of aerosol drug delivery for certain applications. In particular, they are the only device type that is readily amenable to offlabel use of solutions. They can also more readily deliver much larger drug doses than other device types. While older nebulizer designs suffer from relatively low drug delivery efficiencies, several more recent designs are competitive with other device types in this regard. The ability of certain nebulizers to be used with tidal breathing, rather than a specific single breath maneuver, can be an attractive aspect for acute exacerbated and very young patients. In addition, the use of electronic monitoring of patient breathing with some nebulizers, with feedback to aerosol production, may allow for improved adherence and monitoring of drug delivery. Because nebulizers produce aqueous droplets that can evaporate or condense water vapor, nebulizer particle sizes can be unstable and give unexpectedly dynamic aerosol behavior. This is of considerable concern when using particle sizing methods to measure droplet sizes of nebulized aerosols, with many cascade impactor experiments suffering from unintended droplet shrinkage and undersizing of nebulized droplets. However, it can also cause unexpected differences in delivery between different ambient environments, as well as different nebulizer configurations within mechanical ventilation breathing circuits. Such effects are reduced for high output rate devices, but should be kept in mind in general when using nebulizers. While ongoing attention by the aerosol community may often appear to be focused on other delivery devices, such as pressurized metered dose and DPIs, the ease of formulating many drugs in water and delivering them as aqueous aerosols ensures that nebulizers will remain as a viable and relevant method of respiratory drug delivery. This is particularly true given recent improvements in nebulizer droplet production technology.

Declaration of interest The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Nebulizers for drug delivery to the lungs

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Affiliation

Andrew R Martin & Warren H Finlay† † Author for correspondence University of Alberta, Department of Mechanical Engineering, Edmonton, Alberta, T6G 2G8, Canada E-mail: [email protected]

Nebulizers for drug delivery to the lungs.

Nebulizers are the oldest modern method of delivering aerosols to the lungs for the purpose of respiratory drug delivery. While use of nebulizers rema...
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