(Chest. 2001;120:89S-93S.)
© 2001
American College of Chest Physicians
Delivery Options and Devices for Aerosolized Therapeutics*
Paula J. Anderson, MD
*
From the University of Arkansas for Medical Sciences, Little Rock, AR.
Correspondence to: Paula J. Anderson, MD, University of Arkansas for Medical Sciences, 4301 W Markham, Slot 555, Little Rock, AR 72205; e-mail: AndersonPaulaJ{at}uams.edu
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Abstract
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Although inhalation is one of the oldest modes of drug delivery,
it is currently receiving renewed attention. Prior to 1987, aerosolized
therapeutics were delivered via systems that relied on
chlorofluorocarbon propellant systems. The subsequent ban on all
nonmedical uses of these inert gases stimulated pharmaceutical
companies to investigate other propellant systems. Two
hydrofluoroalkanes were effective. However, in some instances, the
change in propellant required reformulation of the drugs to be
delivered. In some cases, bioequivalence could be achieved at lower
doses with reduced toxicity. Pressurized metered-dose inhalers (pMDIs)
have been used to deliver many types of inhaled therapeutics since the
1960s. Their major limitation is that drug delivery and effectiveness
are affected by patient factors, including coordination difficulties
and problems related to breathing and breath holding in patients with
airway disease. Dry-powder inhalers are being developed to deliver
powdered formulations of drugs such as bronchodilators and
anti-inflammatory drugs for the treatment of asthma and COPD, and,
eventually, proteins, peptides, recombinant products, and gene
therapeutics. These devices have been proven to be as efficient as
pMDIs in clinical trials. In some cases, they deliver a greater amount
of the drug to the lungs. Percentages of the emitted dose deposited in
the lungs range from 15 to 40% with the current generation of these
devices. Finally, metered-dose liquid inhalers also are under
development. Drug deposition in the lung with devices that are
currently being tested ranges from 30 to 80% of the emitted dose. The
choice of delivery system depends on the effective dose, drug
deposition, patient ability, patient acceptance, and cost. Patient
education in the correct use of each device is essential to maximize
the therapeutic
benefit.
Key Words: aerosolized • chlorofluorocarbon propellant • dry-powder inhaler • emitted dose • hydrofluoroalkane • insulin • metered-dose inhaler • nebulizer • propellant
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Introduction
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Inhaled medications have been in clinical use since the
earliest days of medical history. Aerosolized medications were
particularly popular at the end of the 19th century. Medications were
added to boiling water for patients to breathe (Fig 1
). Asthma cigarettes, containing stramonium leaves with atropine-like
effects, were also widely used and quite effective. Since that time,
both the formulation and modes of delivery of medications for
inhalation have changed and evolved.
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Chlorofluorocarbon vs Hydrofluoroalkane Propellants
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One of the greatest impacts on the development of aerosolized
therapeutics resulted from the 1987 Montreal protocol banning
substances that depleted the ozone layer.1
This imposed
ban phased out the use of chlorofluorocarbons (CFCs), which had been
used as propellants in inhalers. Although medical devices were exempted
from the ban, many pharmaceutical companies began to investigate other
formulations and delivery systems for inhaled therapeutics. Two
propellants that were found to be effective substitutes for CFCs were
the hydrofluoroalkanes (HFAs), HFA 134a and HFA 227.
The substitution of HFA propellants for CFC propellants changed the
properties of some of the drugs delivered by CFC propellant systems and
required reformulation of the drugs. In general, the HFA-propelled
systems deliver a softer spray and alter the taste of the drug.
HFA-propelled beclomethasone, recently available in the United States
for the treatment of asthma (QVAR; 3M Pharmaceuticals; St. Paul, MN),
required reformulation as a solution rather than a suspension for
delivery via the HFA propellant. The reformulation resulted in an
increase in the fine-particle fraction and also reduced the velocity
with which particles exit the pressurized metered-dose inhaler (pMDI).
These changes caused increased drug delivery to the lungs and reduced
deposition in the oropharynx. As a result, the same degree of asthma
control could be obtained with half of the beclomethasone dose. Figure 2
shows radiolabeled lung scans of a healthy individual who inhaled equal
doses of either HFA-propelled or CFC-propelled
beclomethasone.2
It can be seen that HFA-propelled
formulations achieved greater lung deposition. The improved drug
deposition was of sufficient magnitude that the actual drug dose could
be reduced by 50%. Thus, the change from CFC to HFA propellant and the
subsequent reformulation of beclomethasone as a solution produced
equivalent pharmacokinetics at half the dose. Toxicity and adrenal
suppression were equal at equal doses. Figure 3
shows that an equivalent pharmacokinetic effect could be obtained with
200 µg HFA-propelled beclomethasone or 400 µg CFC-propelled
beclomethasone.3
HFA-propelled albuterol, which is
available both in the United States and Canada, appears to be
bioequivalent to the CFC-propelled formulation at the same dose.
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Figure 2. Gamma camera scanning of radiolabeled
beclomethasone (BDP) in a healthy subject showing differences in lung
deposition with different propellants. Right: BDP with
HFA propellant shows greater lung deposition and less oropharygeal
deposition than when the CFC propellant is used.2
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Figure 3. Pharmacokinetic profiles for beclomethasone with
HFA propellant ( ) vs CFC propellant (*). The HFA formulation
dose is half that of the CFC formulation (200 vs 400 µg), but because
of greater fine particle fraction, it results in similar blood levels
of the drug. Left: serum levels after one dose of the
drug are shown. Right: steady state after 14 days is
shown.3
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Dry-Powder Inhalers
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In addition to researching new propellants following the ban on
CFCs, pharmaceutical companies also began to develop inhalable drugs in
new forms such as dry powders. This was not entirely new territory.
Dry-powder inhalers (DPIs) such as the AeroHaler (Abbott Laboratories;
Abbott Park, IL) (Fig 4
), which was used principally for aerosolizing penicillin, had been in
existence for > 50 years. Clinical trials of these devices have shown
them to be equal to pMDIs4
; some studies5
6
have suggested that lower drug doses may be comparably as effective
when administered with a DPI device.
Several DPIs are available in the United States at present, but a
greater number of more sophisticated DPI devices are currently
available in Europe. They have a more stable aerosol and are activated
and driven by inspiratory flow. Their efficiency may vary according to
inspiratory flow rate as many are designed to maximize drug delivery at
a relatively high inspiratory flow rate. Thus, young children or
patients with severely compromised airways or pulmonary exacerbations
may have difficulty using DPI devices. It also is important for the
clinician to be aware that patients are not able to sense drug delivery
with these devices and, thus, may not realize that they are receiving
the medication.
Two DPIs in common use in the United States are the Diskus (Glaxo
SmithKline Inc; Research Triangle Park, NC) and the Turbuhaler (Astra
Zeneca Pharmaceuticals; Wilmington, DE). Currently, salmeterol and the
combination of salmeterol and fluticasone are available for delivery
via the Diskus. Drug dose is stable over flow rates ranging between 30
and 90 L/min. The Diskus inhaler contains multiple doses of the drug
sealed in blister packs, which confers better protection against
moisture. This device is recommended for use in patients 
4 years of
age for salmeterol and 12 years for the combination of salmeterol
and fluticasone.
The Turbuhaler, which has been available in Europe for a number of
years, has a drug reservoir. Each dose is sheared off by a cocking
mechanism. Use of this device results in relatively high drug
deposition in the lung, particularly in comparison with a pMDI. The
device output also is somewhat flow-dependent. It is optimally operated
at an inspiratory flow rate of 60 L/min. The Turbuhaler is recommended
for patients 6 years of age. Currently, in the United States, it is
available for use with budesonide. In Europe, it also is used to
deliver other bronchodilators and steroids.
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DPIs Currently in Development
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A large number of increasingly effective and sophisticated DPIs
are currently in development in the United States, Canada, and Europe.
Figure 5 shows the Spiros, currently under development by Dura Pharmaceuticals
(San Diego, CA).7
It is a small (approximately 6 x 10
cm), handheld, breath-actuated, battery-assisted device that contains
30 doses in a rotating cassette. When the patient initiates a breath, a
twin-bladed impeller aerosolizes the drug. It is optimally operated at
15 L/min. The fact that it is operated at such a low flow rate makes it
advantageous for use in pediatric patients and in those persons with
severe airflow obstruction or in those who suffer from periodic
pulmonary exacerbations that increase airflow obstruction. The
disposable device has a life span of 1,500 actuations.
The Clickhaler (ML Laboratories; Leicestershire, UK) (Fig 6
) is a multidose reservoir device that also is breath-actuated. It is
effective at flow rates from 15 to 60 L/min.8
Inhale Therapeutics Systems (San Carlos, CA) has developed a DPI
primarily for use with inhaled insulin. It generates compressed air to
release powder into a holding chamber. Other DPIs under development
include the EasyHaler from Finland (Orion Farmos; Kuopio, Finland), the
UltraHaler from Fisons (Loughborough, United Kingdom), and the Pulvinal
from Chiesi (Parma, Italy).9
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Drug Deposition in the Lung With DPIs
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The percentage of the emitted dose that is deposited in the lung
varies among the different DPI devices (Fig 7
).9
Lung deposition with the TurbuHaler is approximately
25%, and it is 15% with the Diskus DPI. The Spiros DPI delivers
approximately 40% of the emitted dose to the lungs. DPIs thus
represent a significant improvement over pMDIs, which deliver
approximately 10% of the emitted drug dose.
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Figure 7. Approximate percentage of the emitted drug dose
that is deposited in the lungs by different DPIs compared to a standard
pMDI (Turbuhaler, Diskus, Spiros, and Clickhaler). Data were taken from
Dolovich.9
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For most DPIs, drug deposition is greater at higher flow rates (Fig 8
).9
However, the Spiros DPI is an exception as it is meant
to operate optimally at 15 L/min. At 15 L/min, drug deposition is
approximately 40%. It decreases if the patient breathes faster.
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Figure 8. Lung deposition, as a percentage of the emitted
dose, from different DPIs at two different inspiratory flow rates
(IFRs). Most DPIs deliver lower amounts of aerosol to the lungs at less
than the optimal flow rates. From Dolovich.9
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Choice of Delivery System
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pMDIs, DPIs, and nebulizers all have advantages and disadvantages.
The pMDI is inexpensive and convenient but requires patient
coordination to operate effectively. Most pMDIs still use CFC
propellant systems.
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Nebulizer
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Air-jet and ultrasonic nebulizers are non-propellant-based
alternatives for the delivery of inhaled therapeutics that predate
metered-dose inhalers. These devices do not require a coordinated
breathing maneuver or a strong inspiratory effort, and so they have
received substantial use by pediatric, elderly, and hospitalized
patient populations. In particular, the simple nebulization of a
fast-acting bronchodilator is an effective way to treat an acute
bronchospasm attack without placing unreasonable demands on the
distressed patient. Nebulizers also have been the only method available
for delivering very high doses of some inhaled drugs, most notably
antibiotics and mucolytics for the treatment of cystic fibrosis. In
these special cases, the amount of drug that must be deposited in the
airways to achieve efficacy far exceeds the payload capabilities of
pMDIs and DPIs.
Numerous studies have shown that pMDIs with spacers are at least as
effective, if not more so, than nebulizers, or are more effective in
the hospital, in the emergency department, and at home. Nebulizers
continue to be used with great frequency, although they are cumbersome,
time-consuming, and relatively inefficient, because many clinicians
believe them to be superior to pMDIs. It should be noted that certain
drugs require a nebulizer for delivery. These include antibiotics and
rhDNase (Pulmozyme [dornase alfa] Recombinant Inhalation Solution;
Genentech, Inc; South San Francisco, CA). Nebulizers also may be
necessary for the delivery of recombinant products and gene
therapeutics. Except in those cases in which the type of therapeutic
agent dictates the delivery system, the choice of delivery system
depends first on clinical benefit. The efficiency of dose delivery,
upper and lower respiratory tract drug deposition, and toxicity all
must be considered. Cost also is an important consideration. Ease of
use and convenience should be considered. The optimal delivery
device is the one a given patient can and will use.
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Patient Education
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Metered-Dose Inhalers
With both pMDIs and DPIs, drug delivery and efficacy are affected
by patient factors. Numerous studies10
since the 1960s
have demonstrated rates of incorrect pMDI use ranging from 12 to 90%.
Patient problems may include difficulties with coordination, the
inability to breathe sufficiently slowly for drug delivery, and
difficulty in breath holding.
One way of improving drug delivery in patients who experience these
types of problems using a pMDI is to use a spacer or holding chamber.
The following are the three basic designs: the open tube; the holding
chamber; and the reverse-flow design. The holding chamber design
appears to function best for patients who are experiencing coordination
difficulties. Coordination is still required for both the open tube and
the reverse-flow design. Spacers and holding chambers decrease
oropharyngeal deposition and improve drug delivery to the lung in
patients experiencing difficulties using a pMDI effectively. They are
also important for decreasing oropharyngeal deposition of inhaled
steroids.
Although package inserts recommend the regular washing of spacers and
holding chambers, plastic spacers in particular often develop an
electrostatic charge that may attract significant amounts of drug
before it exits the spacer. Thus, with continued use, the drug coats
the spacer, decreasing electrostatic charge, and an increasing dose is
delivered to the patient. This problem can be exacerbated if the
patient washes the device frequently and rubs it dry, increasing the
electrostatic charge. Instead, patients should be instructed either to
dry the device with an antistatic cloth or to rinse it in a weak
detergent solution and let it air dry to avoid loss of drug in the
spacer or chamber.
Patients often ask whether it is acceptable to actuate multiple puffs
into a spacer prior to inhaling. They should be informed that even one
additional puff into the spacer would decrease the amount of drug that
is released. Only one puff should be actuated each time in order to
avoid adversely affecting medication delivery.
DPIs
DPIs are used differently from pMDIs, and patients must be
correctly instructed in their use. It is not necessary to shake the
device. The dose must be loaded, and loading is position-sensitive. The
device is held horizontally and placed on the lips; inhalation must be
forceful and deep. It is necessary to hold the breath, to increase lung
deposition by the settling of the drug particles. The patient should be
instructed not to exhale through the DPI, as it must be kept dry.
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Future Delivery Systems
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Several new products are in the research-and-development pipeline.
The Respimat (Fig 9
), which is being tested by Boehringer Ingelheim Pharmaceuticals,
Inc (Ridgefield, CT), is a metered-dose liquid inhaler (MDLI) that
employs a multidose reservoir.11
It functions similarly to
a pMDI, except that it delivers a stream of liquid. Like the pMDI, it
is mechanically actuated and requires patient coordination for
inhalation and effective drug delivery. Drug deposition in the lung
with this particular device is approximately 30 to 40% of the emitted
dose.12
Another device currently being tested is the AERx
Pulmonary Drug Delivery System (Aradigm; Haywood, CA).13
It, too, is a MDLI with a multidose reservoir. It has been developed
for topical drug delivery but also is being used with systemic drugs
like insulin analog and hematopoietic drugs. The drug is contained in
unit-dose blister packs. Delivery is computer-controlled. The liquid is
extruded under pressure through a nozzle. Drug deposition in the lung
is extremely high at approximately 80%. This fact would be
particularly advantageous when choosing a delivery device for expensive
medications such as gene therapeutics and recombinant products.
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Summary
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In summary, it is important for the clinician to be aware that
dose efficacy, deposition, and toxicity all can be influenced by the
drug formulation, the propellant, and/or the delivery device.
Therefore, a familiar drug in a new formulation or delivered using a
different device may not function as expected based on prior
experience.
pMDIs with a holding chamber are considered to be as effective as
nebulizers but are more convenient for patients to use. The
effectiveness of pMDIs can be influenced by patient education and
compliance. Electrostatic charge and the use of multiple puffs may
decrease the actual delivered dose. The use of spacers may help to
improve pMDI efficiency and decrease toxicity.
Many patients find DPI devices easier to use correctly than pMDIs.
However, DPIs are flow-dependent, and, therefore, effective use may be
difficult for patients with severe airway disease or frequent pulmonary
exacerbations that increase airflow obstruction.
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Footnotes
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Dr. Anderson is an investigator or subinvestigator for Astra Zeneca
Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals, Glaxo
SmithKline, TAP Holdings, 3M Pharmaceuticals, and Genentech.
Abbreviations:
CFC = chlorofluorocarbon; DPI = dry powder inhaler;
HFA = hydrofluoroalkane; MDLI = metered-dose liquid dose inhaler;
pMDI = pressurized metered-dose inhaler
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References
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Leach, CL (1998) Improved delivery of inhaled steroids to the large and small airways. Respir Med 92(suppl),3-8
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Seale, JP, Harrison, LI (1998) Effect of changing the fine particle mass of inhaled beclomethasone dipropionate of intrapulmonary deposition and pharmacokinetics. Respir Med 92(suppl),9-15
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Bronsky, E, Bucholtz, GA, Busse, WW, et al (1987) Comparison of inhaled albuterol powder and aerosol in asthma. J Allergy Clin Immunol 79,741-747[Medline]
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Borgström, L, Derom, E, Stahl, E, et al (1996) The inhalation device influences lung deposition and bronchodilating effect of terbutaline. Am J Respir Crit Care Med 153,1636-1640[Abstract]
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Toogood, JH, White, FA, Baskerville, JC, et al (1997) Comparison of the antiasthmatic, oropharyngeal, and systemic glucocorticoid effects of budesonide administered through a pressurized aerosol plus spacer or the Turbuhaler drug powder inhaler. J Allergy Clin Immunol 99,186-193[CrossRef][ISI][Medline]
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Newhouse, MT, Nantel, NP, Chambers, CB, et al (1999) Clickhaler (a novel drug powder inhaler) provides similar bronchodilation to pressurized metered-dose inhaler, even at low flow rates. Chest 115,952-956[Abstract/Free Full Text]
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Dolovich, M (1999) New propellant-free technologies under investigation. J Aerosol Med 12,S9-S17
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McFadden, ER (1995) Improper patient techniques with metered dose inhalers: clinical consequences and solutions to misuse. J Allergy Clin Immunol 96,273-283
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Abstract
Introduction
