`
`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 parti-
`cles 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 compa-
`nies seem to be prioritizing DPIs above pMDI reformu-
`lation, 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 pul-
`monary disease (COPD). Drugs are also given by in-
`halation to treat other chest problems,
`including
`respiratory tract infections in cystic fibrosis. In ad-
`dition, it is hoped that inhaled drugs intended to have
`a systemic action in the body (e.g., insulin) will soon
`be marketed. The potential benefits 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 opt-
`imizing inhalation therapy. Drugs are given by inha-
`lation 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 den-
`sity and shape. For spherical particles, aerodynamic
`diameter (Da) and physical diameter (Dp) are related
`by the formula Da¼ DpOr, where r is the specific
`gravity of the material from which the particles are
`made. In practice, aerosol particles are seldom spher-
`ical; for instance, micronized drug particles are often
`highly irregular in shape.
`Aerosol systems found in medicine are usually he-
`terodisperse, indicating that the particles in a par-
`ticular 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 pref-
`erable to describe the mass or volume distribu-
`tion of an aerosol rather than the distribution of
`particles by number since many small particles
`may contain much less drug than a few large parti-
`cles. In practice, particle size spectra from inhaler
`devices often approximate to log-normal distribu-
`tions. The mass median aerodynamic diameter
`(MMAD) may be used to express the average aero-
`sol 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 mono-
`disperse aerosol has a GSD of 1. A typical pharma-
`ceutical aerosol may contain particles ranging in size
`from o0.5 to 410 mm, with an MMAD of 3–4 mm
`and a GSD of 2.0–2.5.
`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 fine particle
`fraction (FPF). These are the particles with the great-
`est likelihood of reaching the lungs in adults, al-
`though 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 de-
`liver inhaled a1 antitrypsin to the alveoli of patients
`with emphysema.
`Particle size distributions of aerosols intended for
`pulmonary delivery may be quantified by several
`methods. The approach favored within the pharma-
`ceutical 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 quantified by an analytical tech-
`nique. Supplementary particle size data may be pro-
`vided 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 diffrac-
`tion of the laser light is inversely proportional to
`particle size. It is important to remember that these in
`vitro measurements are undertaken primarily for pur-
`poses 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 oro-
`pharynx and at
`the bifurcations between major
`airways, when the aerosol particle has too much in-
`ertia to follow the air stream as it changes direction.
`The probability of inertial impaction occurring is
`2Q, where Q is the inhaled flow
`proportional to Da
`rate. Deposition in central
`lung regions may be
`enhanced by the effects of air turbulence, especially
`at fast inhaled flow rates. Gravitational sedimenta-
`tion takes place mainly in smaller conducting air-
`ways and in the alveoli, when particles settle onto the
`airway surface under gravity either during slow
`steady breathing or during breath-holding. The prob-
`ability of gravitational sedimentation occurring is
`2T, where T is the residence time
`proportional to Da
`of
`the particle in the airways. A third deposi-
`tion mechanism (Brownian diffusion) is also impor-
`tant for aerosol particles o1 mm in diameter, which
`may be pushed in a random direction toward air-
`way 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 patient’s inhalation
`also plays a major part in determining the site of aero-
`sol deposition. The inhaled flow rate is particularly
`important, with slow inhalation usually being recom-
`mended in order to reduce impaction losses in the
`oropharynx. Deep inhalation and a period of breath-
`holding help to increase gravitational sedimentation in
`the peripheral parts of the lungs. For most pharma-
`ceutical aerosols, lung deposition is enhanced by a
`combination of aerosol particles o5 mm in diameter
` 1). As
`and a slow inhaled flow rate (20–30 l min
`will be explained later, there is an exception to this
`rule for dry powder inhalers, where faster inhalation
`
`AEROSOLS 59
`
`may preferable. Particles are filtered efficiently 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 depo-
`sition in two major ways. First, random variations
`in airway geometry between different individuals
`will lead to random variations in the deposition pat-
`tern. Hence, for aerosols delivered from any inhaler
`device, considerable intersubject variability of depo-
`sition is to be expected. Second, in patients with
`asthma, COPD, and other obstructive conditions, the
`airways may be narrowed by bronchospasm, inflam-
`mation, 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 aero-
`sol 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 quantified by radionuclide imaging (gamma sci-
`ntigraphy, single photon emission computed tomo-
`graphy (SPECT), and positron emission tomography
`(PET)). SPECT and PET are three-dimensional imag-
`ing methods and provide information about the dis-
`tribution 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 uri-
`nary concentrations of albuterol in the first 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 phy-
`sicians recognized the convenience of the pMDI,
`which contains 100–200 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 (25–100 ml) are de-
`livered 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 propel-
`lants, ethanol, or another excipient as a co-solvent.
`
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`60 AEROSOLS
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`Canister
`
`Drug formulation
`in propellants
`
`Metering
`valve
`
`Patient presses canister
`while breathing in
`
`Actuator
`
`Spray
`plume
`
`Actuator nozzle
`
`Figure 1 Design and operation of a typical pressurized me-
`tered dose inhaler.
`
`The best known pMDI therapies include the b-ago-
`nists albuterol, terbutaline, and salmeterol and the
`glucocorticosteroids beclomethasone dipropionate,
`budesonide, and fluticasone propionate.
`Successful pMDI therapy is highly dependent on
`the patient’s inhalation technique, and patient edu-
`cation 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 hand–lung 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 chlorofluorocarbon (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 10–20%
`of the dose from a CFC pMDI is deposited in
`the lungs, with the majority of the dose being de-
`posited 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 orifice.
`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
` 1. However,
`it is
`at the nozzle exceeding 30 m s
`possible to reduce the spray velocity by modifications
`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 pro-
`pellants, consisting of one of two hydrofluoroal-
`kanes (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 Mon-
`treal Protocol of 1987, reflecting 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 formula-
`tions has not been a simple manner, owing to a range
`of technical factors and the need to demonstrate
`clinical efficacy and safety for the reformulated prod-
`ucts. 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 ex-
`actly the same doses as the CFC pMDI. The alter-
`native strategy is to make a product that deposits
`drug in the lungs more efficiently 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
`patient’s lung, with greatly reduced oropharyngeal
`deposition, so that asthma control may be achieved
`using only a fraction of the CFC pMDI dose. A for-
`mulation of beclomethasone dipropionate (Qvar)
`was the first of these products to reach the market,
`and several similar products are either already mar-
`keted 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 patient’s inhalation via the mouthpiece. However,
`it is unlikely that breath-actuated pMDIs confer any
`additional benefit on patients who can use a con-
`ventional 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 patient’s mouth, allowing the pro-
`pellant 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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`AEROSOLS 61
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`Formulation:
`ordered mixture of
`drug and carrier
`
`DPI device
`
`Powder de-aggregated
`by patient’s 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 patient’s inhalation through the device.
`
`carrier lactose particles that are required to improve
`powder flow properties. The patient’s 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 sphe-
`rules or of cospheronized drug and lactose.
`DPIs are basically of three types: (1) unit-dose de-
`vices, 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 de-
`vices, 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
`find multiple unit-dose devices, such as the Diskus
`(Accuhaler), and reservoir DPIs, such as the Turbu-
`haler, 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 prac-
`tice lung deposition varies widely between devices
`(Figure 4). Powder formulations are susceptible to
`the effects of moisture, and protecting the formula-
`tion 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
`20–30 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,
`
`Figure 2 pMDI connected to a large volume spacer device.
`
`the mouthpiece, which allows the pMDI to be actu-
`ated 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 ef-
`fectively 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 200–300 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. Specific 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 de-
`vices may deposit more than 30% of the dose from a
`CFC pMDI in the patient’s lungs.
`
`Dry Powder Inhalers
`
`Dry powder inhalers (DPIs) have been available
`commercially since approximately 1970, although
`the earliest prototypes were described several dec-
`ades earlier. DPIs contain a powder formulation,
`which most frequently consists of an ordered mixture
`of micronized drug (o5 mm in diameter) and larger
`
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`100
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`Percentage of dose
`
`62 AEROSOLS
`
`0
`
`Flowcaps
`Easyhaler
`Eclipse
`Novolizer
`Spinhaler
`Diskhaler
`Aerolizer
`Clickhaler
`Turbuhaler
`Pulvinal
`M A G haler
`Ultrahaler
`Taifun
`Airm ax
`
`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 reflects the properties of the formulation as much as the DPI.
`
`combination products in DPIs containing a long-
`acting 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 find them easier to use correctly than
`pMDIs. However, this second advantage is closely
`linked to a disadvantage. In order to disperse the
`powder as efficiently as possible, and hence to maxi-
`mize lung deposition, it may be necessary for pa-
`tients 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
`flow rate dependence, with forceful (fast) inhalation
`tending to give higher lung deposition than more
`gentle (slow) inhalation. For instance, in the Turbu-
`haler DPI, a reduction in peak inhaled flow rate from
` 1 was shown to result in a reduction
`60 to 30 l min
`in lung deposition from 27% to 14% of the dose. In
`this respect, DPIs present a paradox since fast inha-
`lation per se is generally associated with enhanced
`deposition in the oropharynx, as described previ-
`ously. Low inspiratory effort through a DPI may re-
`sult in a reduced emitted dose and poor particle
`deaggregation.
`The actual magnitude of the peak inhaled flow rate
`associated with forceful inhalation will vary between
` 1, according to the
`devices from o30 to 4100 l min
`resistance to airflow of each device. Not only the
`peak inhaled flow rate achieved through the DPI but
`
`also the time taken to reach the peak flow will de-
`termine how efficiently particles are deaggregated. In
`practice, it seems that almost all patients with stable
`asthma or COPD can inhale sufficiently well via DPIs
`to benefit from them.
`Several so-called active DPIs have been developed,
`in which the powder is dispersed by some mechanism
`other than the patient’s 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 efficient and reproducible targeting of
`drugs to specific lung regions, such as inhaled pep-
`tides 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 in-
`stance, a spray-dried formulation of the antibiotic
`tobramycin is under development for the treatment
`and prevention of respiratory tract infections in pa-
`tients with cystic fibrosis, consisting of low-density
`spherical particles that disperse efficiently with min-
`imal inspiratory effort. An advantage of these so-
`phisticated formulations is that often they can be
`delivered efficiently 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
`
`Liquidia's Exhibit 1030
`Page 5
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`Mouthpiece
`
`Venturi
`
`Baffle
`
`Drug formulation
`in nebulizer cup
`
`Compressed air
`
`AEROSOLS 63
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`Signal from piezoelectric
`crystal
`
`Drug formulation
`in reservoir
`
`Mesh
`
`To mouthpiece
`
`Figure 5 Design and operation of a typical jet nebulizer.
`
`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 ne-
`bulizers, and vibrating mesh nebulizers. An impor-
`tant 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
`2–4 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 baffle struc-
`tures 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 per-
`formance 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 cortico-
`steroids. Recent developments in technology have
`included breath-enhanced nebulizers, in which pas-
`sage of inhaled air through the device is used to in-
`crease aerosol output, and adaptive aerosol delivery
`systems, in which aerosol generation is synchronized
`to coincide with the first part of the patient’s inha-
`lation. Adaptive aerosol delivery systems seem to be
`
`Figure 6 Principle of operation of a mesh-based nebulizer sys-
`tem. A mesh or grid is vibrated by a piezoelectric crystal, and a
`dispersion of micron-sized liquid droplets is formed.
`
`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 dif-
`ferent way. A piezoelectric crystal is located beneath
`the cup, and a fountain of droplets is generated. Ul-
`trasonic 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 port-
`able inhaler market, partly because they are single-
`dose 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 piezo-
`electric crystal, but unlike ultrasonic nebulizers, there
`is no evidence that this process damages drug mole-
`cules. Mesh-based systems deliver a higher proportion
`of the dose, and achieve higher lung deposition, com-
`pared to jet or ultrasonic nebulizers. A smaller per-
`centage 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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`64 AEROSOLS
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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 disper-
`sions. Many of these devices are able to achieve ex-
`tremely high lung deposition (450% of the dose),
`and they are capable of delivering drugs to the deep-
`est 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
`
`100%
`
`80%
`
`60%
`
`40%
`
`20%
`
`0%
`
`Exhaled
`Device
`Oropharynx
`Lungs
`
`CFC pMDI
`
`Respimat
`
`Figure 7 Fractionation of the dose from a novel Respimat soft
`mist
`inhaler compared to that
`from a pMDI
`formulated with
`chlorofluorocarbon (CFC) propellants. Data from Newman SP
`et al. (1998) Lung deposition of fenoterol and flunisolide delivered
`using a novel device for inhaled medicines. Chest 113: 957–963.
`
`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: Antic-
`holinergic Agents; Beta Agonists. Chronic Obstructive
`Pulmonary Disease: Overview: Emphysema, Alpha-1-
`Antitrypsin Deficiency. Corticosteroids: Therapy. Cys-
`tic 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, O’Callaghan 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) Respira-
`tory 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 Health-
`care.
`Dolovich M, MacIntyre NR, Dhand R, et al. (2000) Consensus
`conference on aerosols and delivery devices. Respiratory Care
`45: 588–776.
`Hickey AJ (ed.) 2003. Aerosol delivery and asthma therapy (theme
`issue). Advanced Drug Delivery Reviews 55, 777–928.
`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: 341–377.
`More´n 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 flu-
`nisolide delivered using a novel device for inhaled medicines.
`Chest 113: 957–963.
`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: 55–70.
`O’Callaghan C and Barry PW (1997) The science of nebulised drug
`delivery. Thorax 52(supplement 2): S31–S44.
`Pauwels R, Newman SP, and Borgstro¨ m 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: 79–95.
`
`Allergic Bronchopulmonary Aspergillosis see Asthma: Allergic Bronchopulmonary Aspergillosis.
`
`Liquidia's Exhibit 1030
`Page 7
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