Principles of Metered-Dose Inhaler Design
`
`Stephen P Newman PhD
`
`Introduction: Development of the Pressurized Metered-Dose Inhaler
`Component Parts of the pMDI
`Container
`Propellants
`Drug Formulation
`Metering Valve
`Actuator
`Designing pMDI products
`Advantages and Limitations of the pMDI
`Breath-Actuated pMDIs
`Autohaler
`Easibreathe
`K-Haler
`MD Turbo
`Xcelovent
`Smartmist
`Breath-Coordinated Devices
`Easidose
`Breath Coordinated Inhaler
`Other Novel Devices
`Spacehaler
`Tempo
`BronchoAir
`Spacer Devices
`Spacer Design
`Drug Delivery From Spacer Devices
`Summary
`
`The pressurized metered-dose inhaler (pMDI) was introduced to deliver asthma medications in a
`convenient and reliable multi-dose presentation. The key components of the pMDI device (propel-
`lants, formulation, metering valve, and actuator) all play roles in the formation of the spray, and
`in determining drug delivery to the lungs. Hence the opportunity exists to design a pMDI product
`by adjusting the formulation, metering-valve size, and actuator nozzle diameter in order to obtain
`the required spray characteristics and fine-particle dose. Breath-actuated pMDIs, breath-coordi-
`nated pMDIs, spray-velocity modifiers, and spacer devices may be useful for patients who cannot
`use a conventional press-and-breathe pMDI correctly. Modern pMDI devices, which contain non-
`ozone-depleting propellants, should allow inhalation therapy via pMDI to extend well into the 21st
`century for a variety of treatment indications. Key words: metered-dose inhaler, MDI, asthma, chronic
`[Respir Care 2005;50(9):1177–1188.
`obstructive pulmonary disease, spacer, aerosol, drug delivery.
`© 2005 Daedalus Enterprises]
`
`RESPIRATORY CARE • SEPTEMBER 2005 VOL 50 NO 9
`
`1177
`
`

`

`PRINCIPLES OF METERED-DOSE INHALER DESIGN
`
`Fig. 1. Schematic of typical pressurized metered-dose inhaler.
`
`Introduction: Development of the Pressurized
`Metered-Dose Inhaler
`
`In the first half of the 20th century, inhaled drugs for the
`treatment of asthma and chronic obstructive pulmonary
`disease (COPD) were mostly delivered via hand-held,
`squeeze-bulb nebulizers. These devices were fragile, and
`since the dose varied with hand pressure, they did not
`provide consistent drug delivery. As described in detail by
`Thiel,1 Riker Laboratories set out in the mid-1950s to
`develop formulations of bronchodilator drugs in pressur-
`ized containers, providing greater convenience and a more
`reliable dose. This development followed the introduction
`of proprietary cosmetic aerosols as pressure-packs, and
`coincided with the invention of a metering valve capable
`of providing the patient with at least 100 precise doses.
`The pressurized metered-dose inhaler (pMDI, Fig. 1)
`quickly became the most important device for delivering
`inhaled drugs, and today approximately 500 million are
`produced annually.2 Initially, they were given the acronym
`
`Stephen P Newman PhD is affiliated with Pharmaceutical Profiles Ltd,
`Nottingham, United Kingdom.
`
`Stephen P Newman PhD presented a version of this article at the 36th
`RESPIRATORY CARE Journal Conference, Metered-Dose Inhalers and Dry
`Powder Inhalers in Aerosol Therapy, held April 29 through May 1, 2005,
`in Los Cabos, Mexico.
`
`Pharmaceutical Profiles Ltd has received research grants directly related
`to the subject matter of this article from the following corporations:
`Altana Pharma, Aventis, Forest Laboratories, Fujisawa, Ivax, and Ot-
`suka.
`
`Correspondence: Stephen P Newman PhD. E-mail: steve.newman@
`physics.org.
`
`Fig. 2. The key component parts of the pressurized metered-dose
`inhaler.
`
`“MDI,” but the term “pMDI” is preferable, in order to
`distinguish them from dry powder inhalers (DPIs) and
`other nonpressurized devices, some of which also have a
`multi-dose capability. The pMDI was once termed “the
`most complex dosage form used in medicine today,”3 al-
`though with the development of increasingly sophisticated
`DPIs and microprocessor-controlled nebulizers, this may
`no longer be true.
`
`Component Parts of the pMDI
`
`The pMDI comprises several components (Fig. 2), each
`of which is important to the success of the whole device.
`These components are container, propellants, drug formu-
`lation, metering valve, and actuator. It was demonstrated
`many years ago that the aerosol size from a pMDI could be
`influenced by a variety of factors associated with these
`components,4 as listed in Table 1.
`
`Container
`
`The pMDI container must be able to withstand the high
`pressure generated by the propellant, it must be made of
`inert materials, and it must be sufficiently robust. The first
`prototype pMDI was formulated in a CocaCola bottle,1
`and smaller (10 mL) glass bottles were used in the earliest
`marketed pMDIs. Stainless steel has also been used as a
`pMDI container material. Aluminum is now preferred,
`since, compared to glass, it is lighter, more compact, less
`fragile, and light-proof. Coatings on the internal container
`surfaces may be useful to prevent adhesion of drug parti-
`cles and chemical degradation of drug.5
`
`1178
`
`RESPIRATORY CARE • SEPTEMBER 2005 VOL 50 NO 9
`
`

`

`PRINCIPLES OF METERED-DOSE INHALER DESIGN
`
`Table 1. Device and Formulation Variables That Influence Drug
`Delivery From Pressurized Metered-Dose Inhalers
`
`Details
`
`Internal coating
`Type and mixture
`Vapor pressure
`Ambient temperature
`Suspension versus solution
`Presence of surfactants
`Presence of ethanol and other excipients
`Drug concentration
`Drug particle size in suspension formulations
`Volume of metering chamber
`Valve design
`Elastomers
`Time since last actuation
`Orientation during storage
`Expansion chamber size and shape
`Nozzle diameter
`Nozzle path length
`Mouthpiece length and shape
`Breath-actuation/breath coordination
`Spray velocity modification
`Spacer attachments
`
`Component
`
`Container
`Propellants
`
`Formulation
`
`Metering Valve
`
`Actuator
`
`Propellants
`
`Propellants in pMDIs are liquefied compressed gases
`that are in the gaseous phase at atmospheric pressure, but
`form liquids when compressed. They are required to be
`nontoxic, nonflammable, compatible with drugs formu-
`lated either as suspensions or solutions, and to have ap-
`propriate boiling points and densities.6 To ensure consis-
`tent dosing, the vapor pressure must be constant throughout
`the product’s life, and this rules out the use of compressed
`gases such as carbon dioxide, the pressure of which would
`decrease as doses were emitted.
`Chlorofluorocarbons (CFCs) meet the required criteria,
`and pMDIs have traditionally been formulated with the
`highly volatile CFC-12 (dichlorodifluoromethane) as the
`major component. CFC-11 (trichlorofluoromethane) or
`CFC-114 (dichlorotetrafluoroethane), which have higher
`boiling points, may be used to modify the vapor pressure,
`and to facilitate preparation of the formulation. CFC-12
`may be added to the container either at low temperature,
`before the metering valve is crimped in place (cold-fill-
`ing), or via the metering valve after crimping (pressure-
`filling). A key property of CFCs is that within a closed
`container they form a 2-phase (liquid and saturated vapor)
`system, such that a dynamic equilibrium exists between
`liquid and vapor phases, giving a constant vapor pressure
`irrespective of whether the can is full or nearly empty. The
`vapor pressure inside a pMDI is typically 300 –500 kPa
`
`(3–5 atmospheres or 2,250 –3,750 mm Hg), depending on
`the propellant mixture, the presence of other excipients
`(surfactants and other inactive components of the formu-
`lation), and ambient temperature.
`Recently, the use of CFCs was banned under interna-
`tional agreement, because the release of chlorine during
`their degradation damages the ozone layer in the strato-
`sphere.7 Formulations containing one of 2 hydrofluoroal-
`kanes (tetrafluoroethane [HFA-134a] and heptafluoropro-
`pane [HFA-227]) are now appearing on the market.8
`Reformulation of pMDIs with HFA propellants has led to
`many challenges, often involving the development of new
`excipients and metering valves.9,10 HFA-134a and HFA-
`227 have broadly similar thermodynamic properties to
`CFC-12, but no HFA equivalent to CFC-11 or CFC-114 is
`available, so excipients with lower volatility may be re-
`quired to modify the vapor pressure. This issue also influ-
`ences the filling methods that are feasible for HFA prod-
`ucts, and has led to the development of novel pressure-
`filling processes.11 It has also been necessary to undertake
`extensive toxicity testing on the new propellants, and then
`to conduct clinical trials demonstrating safety and efficacy
`of new drug formulations. Taking into account the time
`required for reformulation, toxicity testing, and clinical
`testing, it has been estimated that development of a new
`HFA formulation of an inhaled drug takes about 10 years.8
`While CFC replacement continues, an essential-use ex-
`emption was granted for pulmonary inhalers, allowing the
`continued use of CFCs in recognition of the unique health
`benefits that pMDIs provide.12
`HFAs are “greenhouse gases,”6 which could lead to
`future restrictions on their use, although their contribution
`to global warming is likely to be very small.9 Dimethyl
`ether, propane, or butane could be considered as propel-
`lants,5 but propane and butane are likely to be ruled out
`because of their flammability.
`
`Drug Formulation
`
`Drugs in pMDIs take the form of either particulate sus-
`pensions or solutions. Suspensions are formed by microni-
`zation, usually in a fluid-energy mill.13 Suspensions have
`been widely used in pMDIs, because CFCs are nonpolar
`liquids in which many drugs have low solubility, and good
`chemical stability is achieved. Polar salts of drugs such as
`sulfates are sometimes used to further reduce solubility.
`Surfactants (usually sorbitan trioleate, oleic acid, or soya
`lecithin, in concentrations ranging from 0.1% to 2%) are
`used in CFC pMDIs to reduce particle aggregation and
`lubricate the valve mechanism. However, these surfactants
`are virtually insoluble in HFA-134a and HFA-227.10 The
`use of ethanol as a low-volatility co-solvent in HFA for-
`mulations has become widespread, initially to solubilize
`the surfactants approved for use in CFC formulations, but
`
`RESPIRATORY CARE • SEPTEMBER 2005 VOL 50 NO 9
`
`1179
`
`

`

`PRINCIPLES OF METERED-DOSE INHALER DESIGN
`
`Fig. 3. Effect of changes in (A) propellant vapor pressure, (B) mass median aerodynamic diameter (MMAD) of suspended drug particles, (C)
`actuator nozzle diameter, and (D) drug concentration, on the MMAD of the emitted aerosol from experimental pressurized metered-dose
`inhalers. (Adapted from Reference 4.)
`
`more recently to solubilize the drug itself.14 Solution for-
`mulations were used in many early CFC bronchodilator
`aerosols in the 1960s and 1970s, with anti-oxidants and
`flavoring agents added as excipients.
`The particle size distribution of a pMDI aerosol depends
`on the physicochemical properties of the formulation.5 For
`instance, work undertaken over 35 years ago by Polli et al4
`showed that the aerosol size for suspension formulations
`may be reduced if the formulation has a high vapor pres-
`sure, a small drug particle size, or a low drug concentra-
`tion (Fig. 3).
`Some companies have chosen to develop HFA pMDI
`products bioequivalent to the CFC pMDIs they replace,15
`while other companies have taken the opportunity afforded
`by the CFC ban to develop HFA products with solution
`formulations, which have better lung deposition than their
`CFC counterparts16 and which may be clinically effective
`in smaller doses.17 Recent data suggest that delivered dose
`and fine-particle dose from HFA pMDIs may be less de-
`pendent on ambient temperature than are their CFC coun-
`terparts.18
`A difference in density between the drug particles and
`the propellants will cause the drug particles either to rise to
`the liquid surface or to sink under the influence of gravi-
`ty.13 Patients are instructed to shake suspension-formula-
`tion pMDIs immediately prior to use, to ensure uniform
`dispersion of the drug particles in the propellants and,
`hence, that dosing is reproducible.19 A suspension of hol-
`low particles (PulmoSpheres, Nektar Therapeutics, San
`Carlos, California) was shown to form a homodispersion
`when mixed with propellant, which permeated the drug
`particles themselves, providing a more stable suspension.20
`
`Most pMDIs deliver only 100 –200 ␮g of drug per shot,
`partly because potential problems with valve clogging lim-
`its the quantity of drug that can be incorporated into a
`single dose of a suspension formulation.21 However, re-
`cent work suggests that higher doses are possible with
`solution formulations. Complexing excipients may be used
`to increase drug solubility in propellants while minimizing
`the quantity of ethanol in the formulation, offering the
`possibility of obtaining fine-particle doses of 1.0 –1.5 mg
`per shot with solution-formulation pMDIs.22
`
`Metering Valve
`
`The metering valve crimped onto the container is the
`most critical component of the pMDI, and has a volume
`ranging from 25 ␮L to 100 ␮L. While there are many
`designs of metering valve, they all operate on the same
`basic principle.23 Before firing, a channel between the body
`of the container and the metering chamber is open, but as
`the pMDI is fired, this channel closes, and another channel
`connecting the metering chamber to the atmosphere opens.
`The pressurized formulation is expelled rapidly into the
`valve stem, which, together with the actuator seating, forms
`an expansion chamber in which the propellant begins to
`boil (Fig. 4). The canister is used in the inverted position,
`with the valve below the container so that the valve will
`refill under gravity. Some valves are surrounded by a re-
`taining cup that contains the next few doses of drug (see
`Fig. 1). Several other valve designs aimed at improving
`the precision of dosing were recently described.23,24
`
`1180
`
`RESPIRATORY CARE • SEPTEMBER 2005 VOL 50 NO 9
`
`

`

`PRINCIPLES OF METERED-DOSE INHALER DESIGN
`
`Table 2.
`
`Comparison of the Albuterol Formulations* in CFC and
`HFA Propellants
`
`Active ingredient
`Formulation type
`Excipient
`Propellants
`
`CFC Ventolin
`
`HFA Ventolin
`
`Albuterol sulfate
`Suspension
`Oleic acid
`CFC-11/12
`
`Albuterol sulfate
`Suspension
`None
`HFA-134a
`
`*Ventolin, made by GlaxoSmithKline
`CFC ⫽ chlorofluorocarbon
`HFA ⫽ hydrofluoroalkane
`
`Fig. 5. Lung deposition and actuator retention with a hydroflu-
`oroalkane (HFA) solution formulation of fenoterol and ipratropium
`bromide delivered through actuator nozzles with diameters of 0.2
`mm, 0.25 mm, and 0.3 mm. The data are compared with values
`from a chlorofluorocarbon (CFC) formulation containing the same
`drugs. ⴱ indicates a statistically significant difference compared
`with HFA 0.3 mm. (Adapted from Reference 27.)
`
`gamma scintigraphy, increased step-wise, from 12.8% of
`the dose, to 15.2%, to 18.0%, as the actuator nozzle di-
`ameter was reduced from 0.3 mm to 0.25 mm to 0.2 mm.27
`However, the narrowest nozzle gave the greatest deposi-
`tion on the mouthpiece of the actuator, probably because
`of a wider spray-cone angle, and this observation was
`confirmed by the results of another study.28 Aerosol par-
`ticle size can also be modified by changing the length of
`the actuator nozzle path.10
`The actuator nozzle is critical to spray formation.29,30
`The final atomization process has been described as a
`2-phase gas/liquid air-blast.23 When the dose leaves the
`actuator nozzle, the liquid ligaments embedded in the pro-
`pellant vapor are pulled apart by aerodynamic forces to
`form a dispersion of liquid droplets (see Fig. 4). Evapo-
`ration of propellant, both in the initial flashing and as the
`droplets move away from the nozzle, cools the droplets, so
`the spray usually feels cold on the back of the throat.
`However, as shown in Table 3, both spray force and tem-
`perature reduction appear to be less marked with some
`HFA formulations.2,31 In one study, spray force was de-
`creased by reducing the actuator nozzle diameter from
`
`Fig. 4. How the spray from a pressurized metered-dose inhaler is
`formed.
`
`It is important to ensure that the emitted dose is as
`reproducible as possible, irrespective of when the pMDI
`was last actuated, and irrespective of the orientation of the
`pMDI during storage.23 When tested in vitro, pMDIs are
`usually “primed” by firing several times to waste, but this
`is seldom done in clinical practice. When CFC pMDIs are
`primed, stored valve-down for 3 hours, shaken, and then
`actuated, the drug content of the first dose may be errat-
`ic.25 Improvements in valve design may have largely elim-
`inated this problem, in addition to giving a more predict-
`able dose at the end of the canister’s life span, when the
`pMDI is almost empty.18
`Compatibility of the formulation with the valve compo-
`nents is essential. Elastomeric seals can swell because of
`solubility in CFCs, but this effect may be less marked in
`HFAs, so that the valve elastomers that function well with
`CFCs may not do so with HFAs. This has required the
`development of new elastomeric systems for use with
`HFAs. Valve elastomers must also be selected to ensure
`low concentrations of extractables and leachables into the
`formulation.26 Many newly designed valves appear to func-
`tion adequately without the need for surfactants to lubri-
`cate the valve stem.9 For instance, one HFA formulation of
`albuterol (HFA Ventolin, GlaxoSmithKline, Research Tri-
`angle Park, North Carolina) contains drug and HFA-134a
`only, without the use of any surfactant,23 while the equiv-
`alent CFC formulation also contains oleic acid as a sur-
`factant (Table 2).
`
`Actuator
`
`The complete pMDI canister is fitted into a plastic ac-
`tuator for use by the patient. The design of the actuator is
`important, particularly because the aerosol particle size is
`determined partly by the nozzle diameter, which ranges
`between 0.14 mm and 0.6 mm.14 Aerosol particle size
`varies directly with nozzle diameter,4,5 and particle size
`influences lung deposition. For one solution formulation
`containing the bronchodilators fenoterol and ipratropium
`bromide (Fig. 5), mean lung deposition, measured via
`
`RESPIRATORY CARE • SEPTEMBER 2005 VOL 50 NO 9
`
`1181
`
`

`

`PRINCIPLES OF METERED-DOSE INHALER DESIGN
`
`Table 3. Maximum Impact Force and Minimum Plume Temperature of CFC-Based and HFA-Based pMDI Products
`
`Product
`
`Manufacturer
`
`Maximum Impact
`Force (mN)*
`
`Minimum Plume
`Temperature (°C)*
`
`Formulation
`
`Qvar HFA
`Becotide CFC
`Proventil HFA
`Proventil CFC
`Flixotide HFA
`Flixotide CFC
`Ventolin CFC
`Maxair CFC
`
`3M
`GlaxoSmithKline
`Schering-Plough
`Schering-Plough
`GlaxoSmithKline
`GlaxoSmithKline
`GlaxoSmithKline
`3M
`
`34
`106
`29
`82
`117
`102
`95
`94
`
`⫹4
`⫺32
`⫹8
`⫺26
`⫺17
`⫺21
`⫺29
`⫺3
`
`Beclomethasone dipropionate solution, HFA-134a, ethanol
`Beclomethasone dipropionate suspension, oleic acid, CFC-11/12
`Albuterol suspension, oleic acid, HFA-134a, ethanol
`Albuterol suspension, oleic acid, CFC-11/12
`Fluticasone propionate suspension, HFA-134a
`Fluticasone propionate suspension, CFC-11/12
`Albuterol suspension, oleic acid, CFC-11/12
`Pirbuterol suspension, sorbitan trioleate, CFC-11/12
`
`CFC ⫽ chlorofluorocarbon
`HFA ⫽ hydrofluoroalkane
`pMDI ⫽ pressurized metered-dose inhaler
`*Measured a few centimeters from the actuator nozzle of various pressurized metered-dose inhaler (pMDI) products.
`mN ⫽ milliNewton
`(Adapted from Reference 31.)
`
`0.48 mm to 0.32 mm.31 For a CFC pMDI, the spray du-
`ration is typically 100 –200 ms, plume velocity at the ac-
`tuator nozzle is typically 30 m/s, and initial mean droplet
`diameter is 20 –30 ␮m.29,32 The combination of large drop-
`let size and high spray velocity cause high oropharyngeal
`deposition.27 The spray may initially be very turbulent,
`which may increase deposition in the front part of the
`mouth.33
`The first pMDI to reach the market, in 1956, had an
`elongated mouthpiece, about 8 cm in length,1 but currently
`marketed pMDIs almost all have much shorter mouth-
`pieces, only 2 to 3 cm, to improve convenience and port-
`ability.
`Since the patient cannot usually see the contents of the
`pMDI, the patient has no way to gauge effectively the
`fullness or emptiness of the inhaler.34 To overcome this
`problem, the Food and Drug Administration issued guid-
`ance to the effect that new pMDI actuators should be
`equipped with a dose counter that indicates the number of
`doses remaining.35 This measure is intended to prevent the
`inhaler from being either discarded prematurely or used
`beyond the recommended number of doses.
`
`Designing pMDI products
`
`As set out in Table 1, the actuator design, together with
`the properties of the formulation, determine the spray char-
`acteristics from HFA solution aerosols. Lewis et al14 de-
`scribed a series of empirical equations that allow the fine-
`particle fraction of HFA-134a systems to be predicted from
`knowledge of variables that include the actuator nozzle
`diameter (A, in mm), the metered volume size (V, in ␮L),
`and the HFA-134a content (C134, in percent). One of these
`equations predicts that the fine-particle fraction of a solu-
`tion formulation containing HFA-134a and ethanol can be
`expressed as follows:
`
`fine-particle fraction (%) ⫽
`
`2.1 ⫻ 10⫺5 ⫻ A–1.5 ⫻ V– 0.25 ⫻ C134
`
`3
`
`This formula is really the modern embodiment of the
`pioneering work of Polli et al,4 described earlier, and,
`importantly, it permits designing a pMDI with the desired
`spray characteristics and fine-particle dose by judicious
`selection of appropriate formulation and device variables.36
`
`Advantages and Limitations of the pMDI
`
`pMDIs have been favored by patients for almost 50
`years, because pMDIs combine the practical benefits of
`small size, portability, convenience, and unobtrusiveness,
`and are relatively inexpensive. The multi-dose capability
`means that a dose is immediately available when required
`to treat a wheezing attack. A dose can be delivered in a
`few seconds, unlike nebulizer therapy, which typically takes
`several minutes. Since the inhaler is pressurized, the con-
`tents are protected from the ingress of both moisture and
`pathogens. These factors provide powerful reasons why
`the pMDI has been successful for so long (Table 4).
`Conversely, the limitations of pMDIs have also been
`recognized for decades. Drug delivery is highly dependent
`on the patient’s inhaler technique. Reports of inhaler mis-
`use are commonplace in the literature, and failure to co-
`ordinate or synchronize actuation with inhalation is said to
`be the most important problem patients have with pMDIs.37
`Some patients suffer the so-called cold-Freon effect (Freon
`is the registered trademark of CFCs from DuPont), in which
`the arrival of the cold propellant spray on the back of the
`throat causes the patient to stop inhaling.37 The misuse of
`pMDIs can result in a suboptimal, or even zero, lung dep-
`
`1182
`
`RESPIRATORY CARE • SEPTEMBER 2005 VOL 50 NO 9
`
`

`

`PRINCIPLES OF METERED-DOSE INHALER DESIGN
`
`Table 4. Advantages and Disadvantages of Standard “Press and
`Breathe” pMDIs
`
`Autohaler
`
`Advantages
`
`Disadvantages
`
`Small size, portable, unobtrusive
`Quick to use
`Convenient
`More than 100 doses available
`Usually inexpensive
`Pressurization of contents protects
`against moisture and bacteria
`
`Require propellants
`Drug delivery highly dependent
`on good inhaler technique
`Possible to get no drug in lungs
`with very bad technique
`Most products have low lung
`deposition
`Most products have high
`oropharyngeal deposition
`Difficult to deliver high doses
`
`osition.38 Misuse of corticosteroid pMDIs is associated
`with decreased asthma stability, especially when misuse
`involves poor coordination.39
`Another problem with CFC pMDIs and some HFA
`pMDIs is that even with good inhaler technique they de-
`posit only 10 –20% of the dose in the lungs, with most of
`the dose being deposited in the oropharynx.38 High oro-
`pharyngeal deposition of glucocorticosteroids can cause
`localized adverse effects (dysphonia and candidiasis) and
`systemic adverse effects. Poor lung deposition and high
`oropharyngeal deposition have been partly addressed by
`some recent HFA pMDI products that better target inhaled
`drugs to the lower respiratory tract.16,17
`The drug-delivery characteristics of standard press-and-
`breathe pMDIs bear on the possible uses of pMDIs. Low
`lung deposition and dependence on inhaler technique can
`be accepted in the case of drugs for asthma and COPD,
`where the patient can simply take another dose as required.
`But those limitations may not be acceptable for targeted
`therapies that have narrow therapeutic windows, such as
`inhaled peptides for systemic action, where a very precise
`and reproducible dose may be needed.
`Some device technologies aimed at improving the ease
`of use of pMDIs and/or improving the efficiency of drug
`delivery will now be reviewed.
`
`Breath-Actuated pMDIs
`
`The concept of a breath-actuated pMDI is a good one,
`because it solves the problem of patient coordination of
`actuation with inhalation. Breath-actuated inhalers sense
`the patient’s inhalation through the actuator and fire the
`inhaler automatically in synchrony.23 Patients seem to find
`breath-actuated pMDIs easier to use than conventional
`pMDIs and may prefer them over other devices.40 Some
`breath-actuated inhalers are described below, and several
`others are currently in development.
`
`An early model of the Autohaler breath-actuated device
`was described over 30 years ago,41 but it operated noisily
`and some patients could not generate the necessary flow to
`trigger the device. The current Autohaler device (3M Phar-
`maceuticals, St Paul, Minnesota) overcomes these limita-
`tions, since it is quiet and can be triggered by a flow of
`only 30 L/min (Fig. 6). A lever on the top of the device is
`raised, and then inhalation triggers a vane mechanism,
`which results in the pMDI being actuated automatically by
`a spring. This device gave good lung deposition, even with
`patients who habitually exhaled immediately after firing a
`conventional pMDI.38
`
`Easibreathe
`
`The Easibreathe is a pMDI actuator, originally devel-
`oped by Norton Healthcare (London, United Kingdom).23
`In some ways it resembles the Autohaler, but is simpler to
`use because opening the mouthpiece automatically pre-
`pares the device for inhalation. The Easibreathe contains a
`pneumatic system, which restrains the operating spring.
`Actuation occurs in synchrony with inhalation at only 20
`L/min.
`
`K-Haler
`
`With the K-Haler breath-actuated device (Clinical De-
`signs, Aldsworth, United Kingdom), the dose is actuated
`into a kinked tube, which is straightened by a breath-
`operated lever, which releases the dose.42 Opening the
`device’s dust cap kinks the tube and depresses the pMDI
`valve stem.
`
`MD Turbo
`
`The MD Turbo (Respirics, Raleigh, North Carolina) is a
`breath-actuated inhaler that can accommodate various
`pMDI products. It incorporates “i-Point” technology, with
`which actuation only occurs at a pre-determined inspira-
`tory flow.
`
`Xcelovent
`
`Another breath-actuated pMDI device, the Xcelovent,
`designed by Meridica (Melbourn, United Kingdom), de-
`livers an HFA formulation containing budesonide and for-
`moterol. Xcelovent may in the future be developed by
`Pfizer (Sandwich, United Kingdom).
`
`RESPIRATORY CARE • SEPTEMBER 2005 VOL 50 NO 9
`
`1183
`
`

`

`PRINCIPLES OF METERED-DOSE INHALER DESIGN
`
`Fig. 6. Autohaler breath-actuated inhaler, at rest and during inhalation. The inhaler is primed by lifting the lever on the top of the device.
`(Courtesy 3M Pharmaceuticals, St Paul, Minnesota.)
`
`Smartmist
`
`A sophisticated microprocessor-controlled pMDI actua-
`tor device, the Smartmist (Aradigm, Hayward, Califor-
`nia),43 accommodates a standard pMDI canister. A pneu-
`motachograph reads the inhaled flow rate and volume, and
`a microprocessor actuates the pMDI only when a pre-
`programmed combination of flow and volume is achieved.
`While this device may be too complex and too expensive
`for routine pMDI use, it could provide a valuable function
`in controlled clinical trials by helping to ensure correct
`pMDI technique.
`
`Breath-Coordinated Devices
`
`Easidose
`
`The Easidose (Bespak, Milton Keynes, United King-
`dom) has been described as a breath-coordinated device,
`rather than a breath-actuated device.44 Inhaled air can pass
`through it only when the pMDI is depressed, so the pa-
`tient’s inhalation should be coordinated with actuation.
`
`Breath Coordinated Inhaler
`
`The Breath Coordinated Inhaler (Aeropharm, Edison,
`New Jersey)45 is designed to coordinate the inspiration
`with the release of the dose. The device controls the in-
`
`halation flow rate through the actuator, so the patient has
`more time to actuate the pMDI reliably during inhalation.
`
`Other Novel Devices
`
`Breath-actuated inhalers and breath-coordinated inhal-
`ers do not attempt to solve the cold-Freon effect prob-
`lem,37 but devices with slower spray velocity are likely to
`help. At least one device is already marketed, and several
`others are in development. In 1989, Byron et al46 reported
`that it is possible to reduce the nonrespirable fraction by
`placing baffles near the actuator nozzle, to intercept large,
`rapidly moving droplets. However, no devices based on
`this principle seem to be in development.
`
`Spacehaler
`
`The Spacehaler (Celltech Medeva, Slough, United King-
`dom), formerly known as the Gentlehaler (Schering-
`Plough, Kenilworth, New Jersey), is a compact, low-ve-
`locity-spray pMDI, 7.5 cm in length. The device produces
`a rapidly spinning vortex at the actuator nozzle, which
`reduces the initial spray velocity to approximately 2 m/s,
`which decreases oropharyngeal deposition and probably
`provides better lung deposition than a standard pMDI.47
`
`1184
`
`RESPIRATORY CARE • SEPTEMBER 2005 VOL 50 NO 9
`
`

`

`PRINCIPLES OF METERED-DOSE INHALER DESIGN
`
`Tempo
`
`The Tempo device, currently in development (Map Phar-
`maceuticals, Mountain View, California, formerly Shef-
`field Pharmaceuticals, St Louis, Missouri), contains a novel
`mechanism to manipulate the plume and reduce momen-
`tum of the spray. Some of the inhaled air is entrained to
`blow in the opposite direction to that of the spray plume.48
`Both in vitro and in vivo data show that the Tempo may be
`associated with less oropharyngeal deposition and better
`lung deposition than a standard pMDI. This device also
`includes a breath-actuated capability.
`
`BronchoAir
`
`BronchoAir (BronchoAir Medizintechnik, Munich, Ger-
`many), a novel actuator, has a series of air jets that sur-
`round the valve-stem induction port, but the effect of this
`device on fine-particle dose seemed to vary between pMDI
`formulations.49
`
`Spacer Devices
`
`Spacer Design
`
`Spacer devices are also known as add-on devices, ac-
`cessory devices, extension devices, and holding chambers.
`They are attachments to pMDI actuators, with volumes
`ranging from 20 mL to 750 mL in commercially available
`models. Spacers perform several functions. By placing
`some distance (and, thus, time) between the point of aero-
`sol generation and the patient’s mouth, they reduce oro-
`pharyngeal deposition and increase lung deposition. Spac-
`ers make pMDIs easier to use by reducing or eliminating
`the need for coordination between actuation and inhala-
`tion, and reducing the cold Freon effect.50,51 These bene-
`fits are achieved at the expense of making the pMDI sys-
`tem substantially larger and less convenient. Spacers can
`be grouped into 3 categories (Fig. 7): simple tube exten-
`sions to the actuator mouthpiece; holding chambers, which
`generally have a one-way valve in the mouthpiece to pre-
`vent the patient blowing the dose away; and reverse-flow
`devices, in which the spray is actuated away from the
`patient, into the spacer.
`The 8-cm long actuator mouthpiece to the first pMDI, in
`1956, was arguably the first tube spacer device, and 2
`years later Franklin et al52 described a 14-inch tube spacer
`for a hydrocortisone pMDI. At least 2 breath-actuated in-
`halers have been designed for use with short tube spacers
`to reduce oropharyngeal deposition.45,53 One tube spacer,
`Syncroner (Aventis, Bridgwater, New Jersey), had an open
`section in its upper surface,54 which served as a coordina-
`tion aid, because the patient could see the spray emerging
`from the open section if actuation and inhalation were not
`
`Fig. 7. Spacer devices used with pressurized metered-dose in-
`haler. Clockwise from top: InspirEase reverse-flow device, Azma-
`cort tube spacer, Volumatic large-volume holding chamber, Aero-
`chamber.
`
`correctly coordinated. This device was discontinued in Jan-
`uary 2004.
`Large-volume holding chambers include the Volumatic
`(GlaxoSmithKline) and Nebuhaler (AstraZeneca, Lough-
`brough, United Kingdom), and well as smaller devices
`such as Aerochamber (Trudell, London, Ontario, Canada)
`and Babyhaler (GlaxoSmithKline), which is specifically
`for use with infants. Both the Volumatic and Nebuhaler
`are pear-shaped, to match the shape of the expanding spray
`plume.50 Holding chambers have proven to be a viable
`alternative to nebulizers for delivering large bronchodila-
`tor doses to patients wit