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AEROSOLS
S P Newman, Nottingham, UK
& 2006 Elsevier Ltd. All rights reserved.

Abstract
The inhaled route is used to deliver drugs as aerosols for the maintenance therapy of asthma, chronic obstructive pulmonary disease, and other conditions. The deposition of aerosol particles in the respiratory tract is an important prerequisite to obtaining a good clinical effect. Generally, inhaler devices should deliver particles smaller than approximately 5 mm in diameter in order to enter the lungs. A variety of inhaler devices are available for inhalation therapy. Pressurized metered dose inhalers (pMDIs) have been widely used for 50 years, but many patients have problems using them correctly. They are currently being reformulated with ozone-friendly propellants. Breath-actuated inhalers and spacer attachments may be useful supplements to pMDIs for some patients. Dry powder inhalers (DPIs) are easier to use correctly than pMDIs, and they do not require propellants. Many pharmaceutical companies seem to be prioritizing DPIs above pMDI reformulation, and they are also preferred by many patients. Nebulizers continue to be used widely, but the limitations of jet and ultrasonic nebulizers have led to the development of novel systems, sometimes involving vibrating meshes. Finally, a new class of inhalers (soft mist inhalers) is emerging, composed of multidose devices containing liquid formulations, some of which could challenge pMDIs and DPIs in the portable inhaler market.

Inhaled Drug Delivery

The pulmonary route may be used to deliver drugs for the maintenance therapy of some lung diseases, most notably asthma and chronic obstructive pulmonary disease (COPD). Drugs are also given by inhalation to treat other chest problems, including respiratory tract infections in cystic brosis. In addition, it is hoped that inhaled drugs intended to have a systemic action in the body (e.g., insulin) will soon be marketed. The potential benets of the inhaled route have long been recognized, but the importance of good quality inhaler devices that deliver drugs reliably to the lungs has only been appreciated during the past 25 years.

Aerosol Properties
An understanding of aerosol properties and aerosol deposition is an important prerequisite for optimizing inhalation therapy. Drugs are given by inhalation as aerosols of solid particles or liquid droplets, but for simplicity the term particle may be used to describe both solid and liquid dispersions. The most important property of an aerosol particle is its

size, and this is best expressed as the aerodynamic diameter, which also takes into account particle density and shape. For spherical particles, aerodynamic diameter (Da) and physical diameter (Dp) are related by the formula Da DpOr, where r is the specic gravity of the material from which the particles are made. In practice, aerosol particles are seldom spherical; for instance, micronized drug particles are often highly irregular in shape. Aerosol systems found in medicine are usually heterodisperse, indicating that the particles in a particular spray or cloud have a wide range of sizes. Monodisperse aerosols, in which all the particles have approximately the same size, are not normally found in pharmaceutical products, although they can be made using specialized equipment. It is preferable to describe the mass or volume distribution of an aerosol rather than the distribution of particles by number since many small particles may contain much less drug than a few large particles. In practice, particle size spectra from inhaler devices often approximate to log-normal distributions. The mass median aerodynamic diameter (MMAD) may be used to express the average aerosol size. This diameter is such that half the aerosol mass is contained in larger particles and half in smaller particles. The spread of particle sizes may be expressed as a geometric standard deviation (GSD), a dimensionless quantity. A perfectly monodisperse aerosol has a GSD of 1. A typical pharmaceutical aerosol may contain particles ranging in size from o0.5 to 410 mm, with an MMAD of 34 mm and a GSD of 2.02.5. As explained later, deposition of aerosols depends critically on particle size. The fraction of the aerosol mass contained in particles o5 mm in diameter is usually termed the respirable fraction or ne particle fraction (FPF). These are the particles with the greatest likelihood of reaching the lungs in adults, although even smaller particles may be needed for drug therapies in small children. In adults, particles o3 mm in diameter are needed in order to deliver drugs to the alveolated regions for instance, to deliver inhaled a1 antitrypsin to the alveoli of patients with emphysema. Particle size distributions of aerosols intended for pulmonary delivery may be quantied by several methods. The approach favored within the pharmaceutical industry is the cascade impactor, through which the aerosol is drawn by a vacuum pump, and particles of different sizes are collected on a series of stages. Each stage can be washed out with a solvent

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so that the amount of drug associated with different size bands may be quantied by an analytical technique. Supplementary particle size data may be provided by optical methods, the best known of which is laser diffraction. This involves passing the aerosol cloud through a laser beam, and the angle of diffraction of the laser light is inversely proportional to particle size. It is important to remember that these in vitro measurements are undertaken primarily for purposes of quality control and product release, and they may not predict accurately drug delivery to the lungs in vivo.

Deposition of Pharmaceutical Aerosols

Several mechanisms cause aerosol particles to deposit in the respiratory tract, but the two most important ones relating to pharmaceutical aerosols are inertial impaction and gravitational sedimentation. Inertial impaction takes place mainly in the oropharynx and at the bifurcations between major airways, when the aerosol particle has too much inertia to follow the air stream as it changes direction. The probability of inertial impaction occurring is proportional to D2Q, where Q is the inhaled ow a rate. Deposition in central lung regions may be enhanced by the effects of air turbulence, especially at fast inhaled ow rates. Gravitational sedimentation takes place mainly in smaller conducting airways and in the alveoli, when particles settle onto the airway surface under gravity either during slow steady breathing or during breath-holding. The probability of gravitational sedimentation occurring is proportional to D2T, where T is the residence time a of the particle in the airways. A third deposition mechanism (Brownian diffusion) is also important for aerosol particles o1 mm in diameter, which may be pushed in a random direction toward airway walls by collisions with gas molecules. Some particles (especially those o1 mm in diameter) are not deposited, and after inhalation they are simply exhaled. In addition to particle size, the patients inhalation also plays a major part in determining the site of aerosol deposition. The inhaled ow rate is particularly important, with slow inhalation usually being recommended in order to reduce impaction losses in the oropharynx. Deep inhalation and a period of breathholding help to increase gravitational sedimentation in the peripheral parts of the lungs. For most pharmaceutical aerosols, lung deposition is enhanced by a combination of aerosol particles o5 mm in diameter and a slow inhaled ow rate (2030 l min 1). As will be explained later, there is an exception to this rule for dry powder inhalers, where faster inhalation

may preferable. Particles are ltered efciently from the inhaled air by the nasal passages, so wherever practicable it is better to deliver an inhaled aerosol via a mouthpiece (with mouth breathing) than via a face mask (with nose breathing). The airways of the patient who inhales the aerosol particles also determine the site and extent of deposition in two major ways. First, random variations in airway geometry between different individuals will lead to random variations in the deposition pattern. Hence, for aerosols delivered from any inhaler device, considerable intersubject variability of deposition is to be expected. Second, in patients with asthma, COPD, and other obstructive conditions, the airways may be narrowed by bronchospasm, inammation, and mucus hypersecretion so that aerosol particles may deposit preferentially in the larger airways of the lungs, with less deposition in the peripheral airways. Both electrostatic charge and humidity affect aerosol deposition in a variety of ways. The most striking effect of humidity is that dry particles composed of water-soluble materials are likely to absorb water when they enter the respiratory tract and, hence, to increase in size. The deposition of pharmaceutical aerosols may be quantied by radionuclide imaging (gamma scintigraphy, single photon emission computed tomography (SPECT), and positron emission tomography (PET)). SPECT and PET are three-dimensional imaging methods and provide information about the distribution pattern within the lungs. However, PET is relatively complex and is probably not practical for use on a regular basis. Certain pharmacokinetic methods are also useful for assessing delivery of some drugs to the lungs. For instance, the plasma or urinary concentrations of albuterol in the rst 30 min after inhalation are considered to result solely from pulmonary absorption.

Pressurized Metered Dose Inhalers

The pressurized metered dose inhaler (pMDI) has been the backbone of inhalation therapy for asthma for approximately 50 years, since its introduction by 3 M Riker Laboratories in 1956. Patients and physicians recognized the convenience of the pMDI, which contains 100200 doses in a small portable device that is immediately ready for use (Figure 1). The pMDI consists of an aluminum can mounted in a plastic actuator. Individual doses (25100 ml) are delivered as a spray via a sophisticated metering valve. The drug is usually a micronized suspension of drug particles but may be a solution dissolved in propellants, ethanol, or another excipient as a co-solvent.

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Patient presses canister while breathing in Canister Actuator

Drug formulation in propellants

Metering valve Actuator nozzle

Spray plume

Figure 1 Design and operation of a typical pressurized metered dose inhaler.

The best known pMDI therapies include the b-agonists albuterol, terbutaline, and salmeterol and the glucocorticosteroids beclomethasone dipropionate, budesonide, and uticasone propionate. Successful pMDI therapy is highly dependent on the patients inhalation technique, and patient education about their use is essential. In most pMDI products, it is necessary for the patient to press the pMDI at the same time as inhaling. Failure to do this is sometimes described as poor coordination or handlung dyscoordination, and it is probably the most important problem patients have with pMDIs. A second major problem using pMDIs is the so-called cold Freon effect, where the patient stops inhaling when the cold propellant spray is felt on the back of the throat. Freon is one of the trade names of chlorouorocarbon (CFC) propellants. In order to optimize lung deposition from pMDIs, patients also need to inhale slowly and deeply and to hold the breath for several seconds. Even with perfect inhalation technique, no more than 1020% of the dose from a CFC pMDI is deposited in the lungs, with the majority of the dose being deposited in the oropharynx. However, the lung dose will vary from product to product according to the nature of the formulation and the diameter of the actuator orice. Until recently, all pMDIs were formulated in CFC propellants, giving the pMDI an internal pressure of approximately 300 kPa (3 atm) and a spray velocity at the nozzle exceeding 30 m s 1. However, it is possible to reduce the spray velocity by modications to the actuator design, for instance, in the Spacehaler device (formerly known as Gentlehaler). During the past few years, the pharmaceutical industry has been forced to start reformulating pMDIs in non-CFC propellants, consisting of one of two hydrouoroalkanes (HFA-134a or HFA-227). This challenge arose

following the discovery that the degradation of CFCs damages stratospheric ozone and has proved to be a major stimulus to the development of novel inhaler technologies. The switch to HFA-powered pMDIs is in progress and will take several more years to complete. In the meantime, CFCs have been granted an essential-use exemption in pMDIs under the Montreal Protocol of 1987, reecting their importance to the well-being of society. HFAs are greenhouse gases, and despite the fact that their contribution to global warming is small, this issue could restrict their future use. The development of novel HFA pMDI formulations has not been a simple manner, owing to a range of technical factors and the need to demonstrate clinical efcacy and safety for the reformulated products. Individual companies have adopted one of two strategies. One strategy involves making a product that is bioequivalent with the CFC pMDI that is to be replaced so that the HFA pMDI can be used in exactly the same doses as the CFC pMDI. The alternative strategy is to make a product that deposits drug in the lungs more efciently than a CFC pMDI. This usually involves formulating a corticosteroid product as a solution, enabling a very small particle size to be achieved as the propellant evaporates. With such a product, it is also possible to reduce the spray velocity and to deposit up to half the dose in the patients lung, with greatly reduced oropharyngeal deposition, so that asthma control may be achieved using only a fraction of the CFC pMDI dose. A formulation of beclomethasone dipropionate (Qvar) was the rst of these products to reach the market, and several similar products are either already marketed or in development. Breath-actuated pMDIs may be helpful in patients with poor coordination, who cannot actuate the pMDI at the same time as inhaling. These devices contain triggering mechanisms that are operated by the patients inhalation via the mouthpiece. However, it is unlikely that breath-actuated pMDIs confer any additional benet on patients who can use a conventional pMDI successfully.

pMDIs with Spacer Devices

Spacer devices are widely used with pMDIs. These vary greatly in size and shape, with volumes of commercially available models ranging from 50 to 750 ml. The concept of a spacer is to place some distance between the point at which the aerosol is generated and the patients mouth, allowing the propellant to evaporate and the rapidly moving aerosol cloud to slow down before it is inhaled (Figure 2). The most successful spacers have a one-way valve in

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Formulation: ordered mixture of drug and carrier

DPI device

Powder de-aggregated by patients inhalation

Figure 3 Principle of operation of a dry powder inhaler (DPI). The formulation most frequently consists of an ordered mixture of micronized drug and carrier lactose, which is de-aggregated by the patients inhalation through the device.

Figure 2 pMDI connected to a large volume spacer device.

the mouthpiece, which allows the pMDI to be actuated into the spacer, with a brief pause before the patient inhales so that it is not necessary to actuate and inhale simultaneously. Some spacers function effectively if the patient takes a series of relaxed tidal breaths from the device immediately after actuating a dose. Spacers reduce oropharyngeal deposition of drug and may increase lung deposition, but the majority of the dose is often deposited on the walls of the spacer. This may allow the reduction of the total body burden of inhaled corticosteroids compared with a standard pMDI. Large volume spacers, such as the Volumatic and Nebuhaler, have a well-accepted role in hospital emergency rooms for treating acute asthmatic attacks. Specially designed spacers with a volume of 200300 ml are available for treating young children. Most spacer devices are made of plastic, which may acquire a static charge during handling. This results in a suspended aerosol cloud being attracted to the spacer walls, with a marked reduction in the dose available for inhalation. Specic handling and washing techniques are usually recommended, and at least one lightweight metal spacer is available that is not susceptible to the effects of static charge. With correct use, including control over electrostatic charge effects, large volume (4500 ml) spacer devices may deposit more than 30% of the dose from a CFC pMDI in the patients lungs.

Dry Powder Inhalers

Dry powder inhalers (DPIs) have been available commercially since approximately 1970, although the earliest prototypes were described several decades earlier. DPIs contain a powder formulation, which most frequently consists of an ordered mixture of micronized drug (o5 mm in diameter) and larger

carrier lactose particles that are required to improve powder ow properties. The patients inhalation through the device is used to disperse the powder and to ensure that some of the dose is carried into the lungs (Figure 3). An alternative type of formulation used in some DPIs consists either of micronized drug particles alone loosely aggregated into small spherules or of cospheronized drug and lactose. DPIs are basically of three types: (1) unit-dose devices, in which an individual dose in a gelatin capsule or blister is loaded by the patient immediately before use; (2) multiple unit-dose devices, which contain a series of blisters or capsules; and (3) reservoir devices, in which powder is metered from a storage unit by the patient before inhalation. Unit-dose devices, including Spinhaler and Rotahaler, were the only DPIs available until the mid-1980s. Patients generally nd multiple unit-dose devices, such as the Diskus (Accuhaler), and reservoir DPIs, such as the Turbuhaler, to be more convenient than unit-dose DPIs since they provide several weeks treatment. DPIs tend to deposit a greater fraction of the dose in the lungs compared with CFC pMDIs, but in practice lung deposition varies widely between devices (Figure 4). Powder formulations are susceptible to the effects of moisture, and protecting the formulation against these effects is an important part of DPI design. By the end of 2004, at least 16 DPIs had been marketed in different areas of the world for asthma and COPD therapy, involving a range of unit-dose, multiple unit-dose, and reservoir systems. A further 2030 DPIs were also known to be in development. The anticipated expansion of the generics market for inhaled asthma and COPD drugs is likely to result in a number of these novel DPIs reaching the market. It is interesting to note that the major pharmaceutical companies with an interest in inhaled asthma and COPD drugs appear to be prioritizing the DPI over reformulated HFA pMDIs products. In particular,

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100 90 80 Percentage of dose 70 60 50 40 30 20 10 0
D is kh U ale ltr ah r al Pu er lv Sp inal in ha Ae ler ro liz e Ai r rm M AG ax Tu hal rb er uh Ea aler sy ha C lic ler kh al e N ov r ol iz e Ta r ifu Fl n ow ca p Ec s lip se

Figure 4 Mean percentage of the dose deposited in the lungs from 14 dry powder inhalers (DPIs), obtained in scintigraphic studies. The high lung deposition from the Flowcaps and Eclipse DPIs probably reects the properties of the formulation as much as the DPI.

combination products in DPIs containing a longacting b-agonist and a corticosteroid (e.g., Advair Diskus and Symbicort Turbuhaler) have been very successful. However, DPIs tend to be more expensive than pMDIs, and this may limit their use, especially in developing countries. DPIs have two major advantages over pMDIs. First, they do not contain propellants. Second, all currently marketed models are breath-actuated, and patients nd them easier to use correctly than pMDIs. However, this second advantage is closely linked to a disadvantage. In order to disperse the powder as efciently as possible, and hence to maximize lung deposition, it may be necessary for patients to inhale as forcefully as possible via the DPI, and some patients may be either unable or unwilling to do this. All DPIs exhibit some degree of inhaled ow rate dependence, with forceful (fast) inhalation tending to give higher lung deposition than more gentle (slow) inhalation. For instance, in the Turbuhaler DPI, a reduction in peak inhaled ow rate from 60 to 30 l min 1 was shown to result in a reduction in lung deposition from 27% to 14% of the dose. In this respect, DPIs present a paradox since fast inhalation per se is generally associated with enhanced deposition in the oropharynx, as described previously. Low inspiratory effort through a DPI may result in a reduced emitted dose and poor particle deaggregation. The actual magnitude of the peak inhaled ow rate associated with forceful inhalation will vary between devices from o30 to 4100 l min 1, according to the resistance to airow of each device. Not only the peak inhaled ow rate achieved through the DPI but

also the time taken to reach the peak ow will determine how efciently particles are deaggregated. In practice, it seems that almost all patients with stable asthma or COPD can inhale sufciently well via DPIs to benet from them. Several so-called active DPIs have been developed, in which the powder is dispersed by some mechanism other than the patients inhalation for instance, by an internal source of compressed air or by a fan driven by an electric motor. These active DPIs are generally more complex than breath-actuated DPIs and may come to be used primarily for therapies that require very efcient and reproducible targeting of drugs to specic lung regions, such as inhaled peptides for systemic therapy. Sophisticated formulations for use in DPIs are also in development. These include drug/lactose blends, in which the surface of the lactose particles has been smoothed in order to aid dispersion, or particles made by processes other than micronization. For instance, a spray-dried formulation of the antibiotic tobramycin is under development for the treatment and prevention of respiratory tract infections in patients with cystic brosis, consisting of low-density spherical particles that disperse efciently with minimal inspiratory effort. An advantage of these sophisticated formulations is that often they can be delivered efciently to the lungs using very simple and inexpensive DPI devices.

Nebulizers
Drugs may often be formulated as solutions in water or ethanol, and they may be delivered by nebulizers

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Signal from piezoelectric crystal Mouthpiece Baffle Venturi Drug formulation in nebulizer cup Mesh

Drug formulation in reservoir

Compressed air
Figure 5 Design and operation of a typical jet nebulizer.

To mouthpiece
Figure 6 Principle of operation of a mesh-based nebulizer system. A mesh or grid is vibrated by a piezoelectric crystal, and a dispersion of micron-sized liquid droplets is formed.

that convert the solution into a spray. A variety of devices may be used to form the spray, and the three most common are jet nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers. An important advantage of nebulizers is that they can be used with relaxed tidal breathing. This makes them attractive for delivering inhaled drugs to children, the elderly, and those undergoing acute asthmatic attacks, who may not be able to use pMDIs or DPIs successfully. Currently, nebulizers represent the most practical way to deliver very large drug doses (4100 mg) that are occasionally needed for some inhaled antibiotics. Jet nebulizers are operated by compressed air passing through a narrow constriction (a venturi). A single dose contained in a volume of typically 24 ml in a cup within the nebulizer is drawn up a feed tube and is fragmented into droplets (Figure 5). Only the smallest droplets are delivered directly to the patient; larger droplets impact on bafe structures situated close to the nozzle and are returned to the cup to be nebulized again. Several minutes are required to nebulize the entire dose, and even at completion of treatment the majority of the dose remains within the device as large droplets on internal walls. There are major differences in performance between different commercially available nebulizers, with lung deposition ranging from o2% to 20% of the dose. Jet nebulizers can also be used to aerosolize micronized suspensions of corticosteroids. Recent developments in technology have included breath-enhanced nebulizers, in which passage of inhaled air through the device is used to increase aerosol output, and adaptive aerosol delivery systems, in which aerosol generation is synchronized to coincide with the rst part of the patients inhalation. Adaptive aerosol delivery systems seem to be

able to reduce the intersubject variability of aerosol delivery. Ultrasonic nebulizers have many properties similar to jet nebulizers, but the aerosol is formed in a different way. A piezoelectric crystal is located beneath the cup, and a fountain of droplets is generated. Ultrasonic nebulizers are less popular now than a few years ago, possibly for several reasons. They may not handle either suspensions or viscous solutions well, and there is evidence that they damage some drug molecules, probably by heat generated during the nebulization process. Jet and ultrasonic nebulizers cannot compete with pMDIs and DPIs in the portable inhaler market, partly because they are singledose devices and partly because they generally need either a compressor or a power source in order to function. Several novel nebulizers are available in which the spray is formed by the passage of drug solution through a vibrating mesh or grid of micron-sized holes (Figure 6). The mesh is usually vibrated by a piezoelectric crystal, but unlike ultrasonic nebulizers, there is no evidence that this process damages drug molecules. Mesh-based systems deliver a higher proportion of the dose, and achieve higher lung deposition, compared to jet or ultrasonic nebulizers. A smaller percentage of the dose is retained in the device at the end of treatment, and this can result in less wastage for expensive drug substances. Nebulization time is short compared to that of jet and ultrasonic nebulizers, which should improve patient compliance. Some vibrating mesh nebulizers are small, compact, and battery operated, giving them practical advantages over jet and ultrasonic nebulizers. Careful cleaning of all nebulizers is essential in order to avoid bacterial contamination and to ensure that the working parts (particularly narrow nozzles) function correctly.

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Soft Mist Inhalers

A recent development in inhaler technology has been the development of low-velocity sprays known as soft mist inhalers. These devices represent a new class of multidose inhaler devices and contain liquid formulations similar to those in nebulizers. A variety of principles are utilized, including forcing liquid under pressure through a nozzle array, ultrasonics, vibrating meshes, and several novel approaches, such as condensation of vapors to form particle dispersions. Many of these devices are able to achieve extremely high lung deposition (450% of the dose), and they are capable of delivering drugs to the deepest parts of the lungs. This may allow them to play a major future role in inhalation therapy, particularly in situations in which precise aerosol targeting is needed. In 2004, one soft mist inhaler (Respimat) was launched in Europe for asthma and COPD therapy as a direct replacement for the same drugs given either in a CFC pMDI or in a DPI. The spray is formed by passing a metered dose (typically 15 ml) via a sophisticated nozzle system under pressure. The velocity of the spray is only a fraction of that found in a CFC pMDI. This device deposits a greater percentage of the drug in the lungs compared to a CFC pMDI (Figure 7), and it is clinically effective

using smaller doses. It is probable that other soft mist inhalers will be marketed in the relatively near future, and some could mount a significant challenge to pMDIs and DPIs in the portable inhaler market.
See also: Asthma: Overview. Bronchodilators: Anticholinergic Agents; Beta Agonists. Chronic Obstructive Pulmonary Disease: Overview: Emphysema, Alpha-1Antitrypsin Deciency. Corticosteroids: Therapy. Cystic Fibrosis: Overview. Particle Deposition in the Lung.

Further Reading
Adjei AL and Gupta PK (1997) Inhalation Delivery of Therapeutic Peptides and Proteins. New York: Dekker. Bisgaard H, OCallaghan C, and Smaldone GC (eds.) (2003) Drug Delivery to the Lung. New York: Dekker. Dalby RN, Byron PR, Peart J, and Farr SJ (eds.) (2002) Respiratory Drug Delivery VIII. Raleigh, NC: Davis Horwood. Dalby RN, Byron PR, Peart J, Suman JD, and Farr SJ (eds.) (2004) Respiratory Drug Delivery IX. River Grove, IL: Davis Healthcare. Dolovich M, MacIntyre NR, Dhand R, et al. (2000) Consensus conference on aerosols and delivery devices. Respiratory Care 45: 588776. Hickey AJ (ed.) 2003. Aerosol delivery and asthma therapy (theme issue). Advanced Drug Delivery Reviews 55, 777928. Mitchell JP and Nagel MW (2003) Cascade impactors for size characterization of aerosols from medical inhalers: their uses and limitations. Journal of Aerosol Medicine 16: 341377. Moren F, Dolovich MB, Newhouse MT, and Newman SP (eds.) (1993) Aerosols in Medicine: Principles, Diagnosis and Therapy. Amsterdam: Elsevier. Newman SP, et al. (1998) Lung deposition of fenoterol and unisolide delivered using a novel device for inhaled medicines. Chest 113: 957963. Newman SP and Newhouse MT (1996) Effect of add-on devices for aerosol drug delivery: deposition studies and clinical aspects. Journal of Aerosol Medicine 9: 5570. OCallaghan C and Barry PW (1997) The science of nebulised drug delivery. Thorax 52(supplement 2): S31S44. Pauwels R, Newman SP, and Borgstrom L (1997) Airway depo sition and airway effects of antiasthma drugs delivered from metered dose inhalers. European Respiratory Journal 10: 2127 2138. Smith IJ and Parry-Billings M (2003) The inhalers of the future? A review of dry powder devices on the market today. Pulmonary Pharmacology and Therapeutics 16: 7995.

100% 80% 60% 40% 20% 0% CFC pMDI Respimat

Exhaled Device Oropharynx Lungs

Figure 7 Fractionation of the dose from a novel Respimat soft mist inhaler compared to that from a pMDI formulated with chlorouorocarbon (CFC) propellants. Data from Newman SP et al. (1998) Lung deposition of fenoterol and unisolide delivered using a novel device for inhaled medicines. Chest 113: 957963.

Allergic Bronchopulmonary Aspergillosis see Asthma: Allergic Bronchopulmonary Aspergillosis.