ADR-12595; No of Pages 15

Advanced Drug Delivery Reviews xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Advanced Drug Delivery Reviews

journal homepage: www.elsevier.com/locate/addr

Emerging inhalation aerosol devices and strategies: Where are

we headed?☆
Qi (Tony) Zhou a, Patricia Tang a, Sharon Shui Yee Leung a, John Gar Yan Chan a,b, Hak-Kim Chan a,⁎
a
Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney, Sydney, 2006 NSW, Australia
b
Respiratory Technology, Woolcock Institute of Medical Research and Discipline of Pharmacology, Sydney Medical School, The University of Sydney, 2037 NSW. Australia

a r t i c l e i n f o a b s t r a c t

Article history: Novel inhaled therapeutics including antibiotics, vaccines and anti-hypertensives, have led to innovations in de-
Accepted 24 March 2014 signing suitable delivery systems. These emerging design technologies are in urgent demand to ensure high
Available online xxxx aerosolisation performance, consistent efficacy and satisfactory patient adherence. Recent vibrating-mesh and
software technologies have resulted in nebulisers that have remarkably accurate dosing and portability. Alterna-
Keywords:
tively, dry powder inhalers (DPIs) have become highly favourable for delivering high-dose and single-dose drugs
Inhalation therapy
Pulmonary drug delivery
with the aid of advanced particle engineering. In contrast, innovations are needed to overcome the technical con-
Nebuliser strains in drug–propellant incompatibility and delivering high-dose drugs with pressurised metered dose in-
Pressurised metered dose inhaler halers (pMDIs). This review discusses recent and emerging trends in pulmonary drug delivery systems.
Dry powder inhaler © 2014 Elsevier B.V. All rights reserved.
Computational modelling
Particle engineering
Patient adherence

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2. Nebulisers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.1. Integration of software control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3. Pressurised metered dose inhalers (pMDIs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.1. Addressing the poor patient adherence problem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.1.1. Breath-actuated devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.1.2. Add-on devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.1.3. Dose counter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.2. Exploring new therapeutics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.2.1. Combination formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.2.2. High dose antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
4. Dry powder inhalers (DPIs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
4.1. Innovation in DPI devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
4.1.1. Design modification and innovative concepts for passive devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
4.1.2. Active devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
4.1.3. Future directions in DPI design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
4.2. Computational modelling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
4.3. Emerging DPI approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
4.3.1. Reusable DPIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
4.3.2. Single-use DPIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
4.3.3. Formulation considerations for device-formulation compatibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
4.4. Device material . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

☆ This review is part of the Advanced Drug Delivery Reviews theme issue on “Improving the efficacy of inhaled drugs for severe lung diseases: Emerging pulmonary delivery strategies”.
⁎ Corresponding author.
E-mail address: kim.chan@sydney.edu.au (H.-K. Chan).

http://dx.doi.org/10.1016/j.addr.2014.03.006
0169-409X/© 2014 Elsevier B.V. All rights reserved.

Please cite this article as: Q.(T.) Zhou, et al., Emerging inhalation aerosol devices and strategies: Where are we headed?, Adv. Drug Deliv. Rev.
(2014), http://dx.doi.org/10.1016/j.addr.2014.03.006
2 Q.(T.) Zhou et al. / Advanced Drug Delivery Reviews xxx (2014) xxx–xxx

5. Emerging inhalation therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

5.1. Inhaled anti-pulmonary arterial hypertension agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
5.2. Inhaled antibiotics for respiratory bacterial infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
5.2.1. Pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
5.2.2. Tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
5.3. Inhaled neuraminidase inhibitor for influenza . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
5.4. Inhaled cyclosporine for transplant rejection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
5.5. Inhaled alpha 1 antitrypsin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
5.6. Inhaled cytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
5.7. Inhaled antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

1. Introduction
Therapeutic applications of respiratory drugs have rapidly expanded
beyond conventional indications such as asthma and chronic obstruc-
tive pulmonary diseases (COPDs), to include inhaled antimicrobials,
vaccines, and anti-hypertensives. The physico-chemical properties and
dose regimen of these newer therapies may vary significantly, thereby
necessitating new formulation techniques and device designs. As a
result, innovative technologies in aerosol medicine are emerging in
parallel with these new therapeutic indications to ensure optimal
aerosolisation performance, therapeutic efficacy and patient adherence.
This review covers emerging aerosol device innovations and the evolv-
ing roles of nebulisers, dry powder inhalers (DPIs) and pressurised
metered dose inhalers (pMDIs), as well as their impact on patient
adherence.
2. Nebulisers
Nebulisers generate an inhalable drug aerosol from a solution or sus-
pension. They are useful for treatment of respiratory diseases as asthma,
COPD and cystic fibrosis (CF) [1]. The most common nebuliser type is
the jet nebuliser, which generates aerosols from the liquid medicament
using a source of compressed gas. Although relatively inexpensive,
treatment with jet nebulisers has long treatment time, the air compres-
sors are bulky and noisy, and expensive medications are wasted in con-
siderable residual volumes [2]. Many of the pitfalls are addressed by
more recent vibrating-mesh nebulisers which have much greater porta-
bility and operate silently. The low velocity plume and minimal residual
volume greatly enhance drug delivery to the lungs [3,4]. However, these
new devices may have a much higher upfront cost and there is a lack of
open literature demonstrating equivalent dosing of existing products to
the more commonly used jet nebulisers. Other types of liquid aerosol
generation systems include the Respimat® SoftMist™ Inhaler and
AERx® systems, which generate liquid aerosol by mechanically forcing
a drug solution through a nozzle array [5,6].
Optimisation of this existing nebuliser technology has focused on
maximising aerosol lung deposition with each breath. Nebulisers typi-
cally generate aerosols throughout the entire respiratory cycle of the pa-
tients, leading to a significant loss during expiration. Thus mechanical
regulation of aerosol generation has been implemented in breath-
enhanced (Pari LC® Star) or breath-actuated (e.g. Trudell AeroEclipse®
II) jet nebulisers. These limit aerosol loss by mechanically restricting
the majority of aerosolisation to the inspiratory phase [1,7,8] and have
been shown to shorten treatment time whilst minimising wastage of
expensive medications [9,10]. However, these are relatively crude com-
pared to the more recent integration of digital control systems with
nebulisers, which provide much more precise regulation of aerosol de-
livery. These electronic systems further reduce treatment time by
personalising aerosolisation to an individual patient's breathing pattern,
thereby maximising lung drug deposition. Here we provide an update
on the Activaero AKITA® and Philips Respironics I-Neb® adaptive aero-
sol delivery (AAD) systems.
2.1. Integration of software control
Originally designed to be coupled with a jet nebuliser (AKITA® JET),
the AKITA® system – a stand-alone SmartCard electronic control unit
with an air compressor – can now also coordinate with newer mesh
nebulisers (AKITA® APIXNEB and AKITA2® APIXNEB) [4]. The software
directs the compressor unit which utilises positive air pressure to con-
trol the patient's entire inhalation manoeuvre [2]. By controlling the
aerosol flow rate, delivery volume and timing, the AKITA® system can
optimise aerosol release at specific periods of a patient's inspiratory
phase to target certain regions of the lungs and maximise aerosol deliv-
ery [11].
The AKITA® system has been particularly useful in gaining valuable
lung deposition and clinical trial data. To refine imaging techniques
used to assess lung deposition, Fleming et al. [12] used AKITA®
system-controlled mesh nebulisation to generate radiolabelled human
serum albumin with a variety of different lung deposition patterns.
These were used to show that the combination of single photon emis-
sion computed tomography and X-ray computed tomography was su-
perior to planar imaging, for the analysis of aerosol lung deposition.
With application to clinical efficacy, Bakkar et al. [13] demonstrated
that the AKITA® system can aid in determining optimal regional deposi-
tion profiles of inhaled drugs in specific disease states. Specifically,
nebulised dornase alpha was directed to either the smaller or larger air-
ways of patients with CF. Deposition in the smaller airways demonstrat-
ed greater improvement in therapeutic efficacy. Such data can allow
formulation and device improvements to enhance clinical response to
inhaled medications, and minimise unwanted side effects. The technol-
ogy also opens up new opportunities for efficacy testing and clinical tri-
als. For example, Moller et al. [14] showed that lung deposition of
lipopolysaccharide, an endotoxin that can trigger airway inflammation
and exacerbations in patients with COPD, can be well-controlled using
an AKITA® system coupled with jet nebulisation to limit the risk of ad-
verse effects. This could allow safe testing of new treatments for COPD
by using an AKITA® system controlled lipopolysaccharide challenge
test. Therefore, the AKITA® system has established new avenues in in-
haled delivery such as regional targeting of nebulised drugs and in refin-
ing clinical trials.
Similarly, the I-Neb® consists of an AAD software control unit and a
mesh nebuliser but combined into a single handheld device [15]. The
I-Neb® software has two modes of operation — a tidal breathing mode
and a targeted-inhalation mode. Whilst tidal breathing mode adapts
device aerosolisation to a patient's regular tidal breathing patterns, the
latter uses a unique vibratory feedback mechanism to guide the patient
towards an optimal breathing pattern that maximises aerosol deposi-
tion for a shorter treatment time.

Please cite this article as: Q.(T.) Zhou, et al., Emerging inhalation aerosol devices and strategies: Where are we headed?, Adv. Drug Deliv. Rev.
(2014), http://dx.doi.org/10.1016/j.addr.2014.03.006
 Q.(T.) Zhou et al. / Advanced Drug Delivery Reviews xxx (2014) xxx–xxx
Accurate and efficient dosing with the I-Neb® has made it increas-
ingly favourable for use with novel experimental therapies. Diaz et al.
[16] examined inhaled interferon gamma in the treatment of idiopathic
pulmonary fibrosis and found that total in vivo lung deposition was 65%
with the I-Neb®, compared to just 7% with a conventional jet nebuliser.
Importantly, interferon gamma was aerosolised without affecting the
efficacy of the protein. Patients used the I-Neb® three times a week,
for eight weeks, with adherence of approximately 97%, demonstrating
feasibility of the device for long term treatment. In a novel preliminary
trial of inhaled iloprost in patients with precapillary pulmonary hyper-
tension and right-side heart failure, Martischnig et al. [17] cited accurate
dosing and short treatment time for choosing the I-Neb® over jet and ul-
trasonic nebulisers. Finally, the I-Neb® might also be used to improve
clinical efficacy of existing treatments. In a group of patients with
COPD, Goodman et al. [18] asked patients to use the I-Neb® in lieu of
their existing nebuliser system for administration of bronchodilator
and/or corticosteroid therapy. This led to significant improvements in
dyspnea and fatigue, which may also have been associated with better
adherence or more correct use of the I-Neb® device. Thus the I-Neb®
system is establishing its advantage both for clinical trials, as well as en-
hanced delivery of current and future inhaled therapeutics.
The AKITA® and I-Neb® systems have potential to considerably im-
prove treatment times, aerosol deposition and patient adherence. In ad-
dition, they augment the scope and consistency of clinical trials with
more accurate dosing and adherence logging systems. Such digital
logging systems may allow telecommunication between patients and
healthcare professionals regarding treatment parameters and feed-
backs, which have a potential to increase treatment adherence and
reduce hospital visits [6,19]. Hence, we expect to see growing software
integration for nebulisers that evolve with future technological
advances. However, increased adoption of these newer technologies
desperately requires economic evaluation of these devices and im-
plementation of electronic technology advances to improve device
portability. Long-term clinical trials are also needed to determine
patient acceptance, optimal dosing regimens and to assess patient
outcomes [3].
The newer vibrating-mesh nebulisers have addressed many of the
concerns associated with previous nebuliser types and are unlikely to
be superseded soon. If cost-effectiveness of these devices can be demon-
strated in future studies, we anticipate an increased uptake of these
mesh devices by patients, particularly in the domiciliary setting. Whilst
in general, mesh devices will replace older nebulisers, the unique fea-
tures of the I-Neb® such as the individualised programming of device
settings to each drug, may continue to restrict its application to a limited
number of formulations. We anticipate growth in the number of clinical
studies with both the AKITA® and I-Neb® units, particularly those inves-
tigating regional lung deposition. Increased understanding of lung de-
position will see revisions and optimisation of their existing software,
and potentially an advent of other competing software-integrated
nebuliser devices. As electronic technology evolves, a reduction in the
physical size and weight of the software-controlled AKITA® and
I-Neb® units is envisaged, which should further aid acceptance by
patients.
3. Pressurised metered dose inhalers (pMDIs)
The pMDI has been favoured by patients and healthcare profes-
sionals for the treatment of asthma and COPD since its introduction
(Medihaler Epi™) in 1956 [20]. Whilst the basic designs remain rela-
tively unchanged, significant improvements in the sub-components of
pMDI were achieved in the past two decades, driven mainly by the
transition of the chlorofluorocarbons (CFCs) to the hydrofluoroalkanes
(HFAs) propellants (or the even more environmentally-friendly
hydrofluoroolefins (HFOs), although this is unlikely to occur in the
near future) and stringent regulations on dosing consistency. Facing
increasing competition from DPIs and novel soft-mist inhalers,
Please cite this article as: Q.(T.) Zhou, et al., Emerging inhalation aerosol devices and strategies: Where are we headed?, Adv. Drug Deliv. Rev.
(2014), http://dx.doi.org/10.1016/j.addr.2014.03.006
3
continuous efforts are required to advance pMDI technology in order
to retain its relevance in inhalation therapies. Thus the question is: in
shaping the next generation of pMDI use, what can we expect?
3.1. Addressing the poor patient adherence problem
Many patients experience difficulty in coordinating the actuation
and inhalation, leading to sub-optimal disease control and increased
risk of hospitalisation [21]. Two approaches, use of breath-actuated
pMDIs and add-on devices like spacers and valved holding chambers
have been implemented to overcome this problem. Another frequent
complaint from pMDI users is that it is very difficult to determine
when their pMDIs will be empty [22]. This has been addressed by the in-
corporation of a dose counter in the pMDI device.
3.1.1. Breath-actuated devices
The first breath-actuated pMDI was introduced by 3M in the
early 1970s (Autohaler™), and many other designs have been
marketed since [20]. Though improved treatment outcomes with
breath-actuated pMDI systems were reported for patients with
poor coordination [23,24], the increased device cost and complexity
have hindered a wider market adoption. Therefore, simpler and more
cost-effective breath-actuation and breath-coordination technologies
are necessary for realising their benefits to larger patient populations.
Recent development of the I-Breath coordination cap [25] is a good ex-
ample of attempts to improve breath-coordination. It contains a flexible
coordination cap designed to fit onto a conventional pMDI. In the rest-
ing mode, multiple airtight sealing slits made of deformable materials
are closed to prevent a patient from substantial inhalation prior to actu-
ation. When the canister is pressed, the slits in the coordination cap are
forced to open by compression, allowing airflow during patient inhala-
tion. The clinical study conducted by Azouz et al. [26] showed that the
patients' coordination between inhalation and actuation was signifi-
cantly improved when using the I-breath cap together with simple
instructions.
3.1.2. Add-on devices
Spacers and valved holding chambers are considered as add-on de-
vices for pMDIs. They increase the delay time between firing and inha-
lation, and allow patients to inhale the medication slowly and deeply,
to increase lung deposition [27,28]. They also help reduce the fraction
of large particles deposited in the oropharynx and hence minimise
local adverse effects [29,30]. The spacers and valved holding chambers
will continue its popularity among the young children and elderly pa-
tient groups who cannot coordinate their breathing with actuation
[31]. A drawback associated with the use of plastic is the build-up of
static charges on the spacer wall, decreasing the drug delivery efficien-
cy. This issue could be largely resolved by antistatic plastic spacers
(AeroChamber Plus®, Trudell) and metal valved holding chambers
(Vortex®, Pari) [32]. One direction for continuing spacer development
will be optimising spacer geometry and valve design [33], and applying
anti-static materials [34] to improve their performance.
3.1.3. Dose counter
The importance of integrated dose counters on the new pMDIs in
development was emphasised in guidelines (but not mandatory) issued
by the US Food and Drug Administration (FDA) [35]. Mechanical dose
counters are designed to rely on an active event of firing such as
sound, temperature or pressure change, with their reliability proven
clinically [36,37]. Electronic dose counters have also been developed
[38,39], but at a relatively higher cost and concerns remain regarding
the reliability of battery life. Nonetheless, the incorporation of dose
counters will become essential for pMDI development to improve
disease management, by preventing patients from using their inhalers
beyond the recommended number of doses and thus receiving subopti-
mal treatment [40].
4 Q.(T.) Zhou et al. / Advanced Drug Delivery Reviews xxx (2014) xxx–xxx
3.2. Exploring new therapeutics
3.2.1. Combination formulations
Clinical outcomes have proven the benefits of combination therapies
of long-acting β2 agonists (LABAs) and corticosteroids [41,42], as well
as LABAs and long-acting muscarinic antagonists (LAMAs) [43,44] for
the management of asthma or COPD. These findings have led to the
commercialisation of a number of combination formulations and more
are under development [45]. Recently, triple therapies combining
LBAB/LAMA/corticosteroids have also been proposed for the COPD pa-
tients with concomitant asthma and frequent exacerbations [46,47].
With the inhalation therapy moving towards combination products,
continual efforts are required to address the various technical chal-
lenges presented in combining multiple drug components in a single
pMDI canister.
Drugs in pMDIs can exist in either solution or suspension form. The
limitation of developing solution pMDI combination formulation falls
in the dissimilar solubilities of drug components in the HFA propellants.
Foster® (beclomethasone/formoterol fumarate) is the only pMDI of
combination solution in the market. The can-in-can pMDI design pro-
posed by Chiesi Farmaceutici S.p.A. [48], in which drugs are stored sep-
arately in two reservoirs (one within the other), offers a promising
approach for combination solution formulations. In such design, combi-
nation drugs are not dispensed concomitantly but sequentially upon
two actuations.
The majority of the commercial combination pMDI products are in
the suspension form [45]. Drug deposition on the canister and metering
valve surfaces used to be a problem for many suspension formulations.
The situation has been resolved to a large extent with advanced surface
coating technologies [49] and fast-fill fast-empty metering valves where
the metering chamber is open to the bulk formulation [50]. Therefore,
the biggest challenge for developing a combination product lies in en-
suring the suspension stability of individual drugs in the same canister.
One way to improve suspension stability is using HFA soluble polymers
(e.g. PEG and PVP) and ethanol-dissolved oleic acid, as suspension
stabilizers. This approach has been adopted in two commercial prod-
ucts Symbicort® (budesonide/formoterol fumarate) and Dulera®
(formoterol fumarate/mometasone furoate). However, the co-
formulation effect – apparent as individual drug components give
different aerosol performance due to drug–drug interactions and/
or different particle size distributions – has been reported for most
existing combination formulations [45,51], and will remain a key
technical challenge.
The established spray-drying-based PulmoSphere™ technology has
offered a promising potential to develop combination pMDI formula-
tions with minimum co-formulation effect [52]. Recently, Lechuga-
Ballesteros and co-workers proposed a novel extension of this approach
to minimise the co-formulation effect, by co-suspending drug micro-
crystals with spray dried porous phospholipid particles (PulmoSphere
™) [45,53]. Single, dual and triple formulations of formoterol fumarate,
glycopyrrolate and mometasone furoate were successfully produced,
with the aerosol performance (fine particle fraction (FPF) of 55%) de-
pending solely on the properties of porous particles, regardless of the
drugs and dose levels. This co-suspension technique provides a platform
to formulate a wide range of respiratory drugs, as well as using the same
device configuration to deliver different formulations.
3.2.2. High dose antibiotics
There is a clear trend towards the use of antiobiotics for respiratory
infections [54,55], with administration currently limited to DPIs and
nebulizers. The absence of antibiotic formulations in the pMDI form is
primarily due to the small dose range that can be afforded by pMDI
per actuation, generally 1 mg or less. To maintain the competitiveness
of pMDIs for pulmonary delivery, technologies to expand their dosing
range are necessary.
Please cite this article as: Q.(T.) Zhou, et al., Emerging inhalation aerosol devices and strategies: Where are we headed?, Adv. Drug Deliv. Rev.
(2014), http://dx.doi.org/10.1016/j.addr.2014.03.006
Typical pMDI valves are designed to deliver a volume ranging from
25 to 100 μL per actuation. A direct approach to deliver high doses of
drug is to utilise larger metering valve sizes. However, Stein et al. [56]
showed only a modest increase in respirable dose with increasing
valve size because of the decreased drug delivery efficiency. The pres-
sure generated from the propellant in the metering chamber decreases
as the formulation is being released, and eventually the pressure be-
comes too low to effectively drive out the residual contents, reducing
the overall drug delivery efficiency. This phenomenon becomes more
obvious for a larger valve size. To address this problem, a built-in
pressuriser was proposed by Alston et al. [57] to maintain the pressure
of the metering chamber at a certain level throughout the whole actua-
tion process. A metering valve size larger than 100 μL was shown to be
feasible with this design and the highest delivered dose achieved was
5 mg of insulin using a formulation described by Dellamary et al. [58].
Though this technique has been introduced for almost a decade, a
wide adoption in field has not been seen.
For solution formulation, the solubility of drugs in HFA is a major
limiting factor. Ethanol is generally employed as a co-solvent to improve
the solubility of polar drugs, but negative impacts on the aerosol perfor-
mance were reported [59]. It is not an easy task to develop high dose
suspension formulations either. The drug delivery efficiency was
found to decrease with increasing drug levels [56]. Stronger particle–
particle interactions are expected for formulations with high drug con-
centrations, leading to drug flocculation. Further advancements in for-
mulation technologies are essential for the realisation of high-dose
pMDIs.
4. Dry powder inhalers (DPIs)
4.1. Innovation in DPI devices
The amount of fine drug particles delivered to the lungs is governed
by the balance of varying forces including interparticulate forces within
powders, dispersion forces by airflow through an inhaler device and
deposition forces in airways. Fine powders generated through micro-
nisation generally have high surface energy hence are notoriously cohe-
sive. An inhaler device is necessary to disperse such powders into
inhalable aerosols. Aerosolisation behaviour of a DPI thus depends on
both the powder formulations and the inhaler devices. Whilst much ef-
forts have been focused on formulations in the past [60], there is a grow-
ing need to understand and improve the device design. Modification
and innovation on inhaler design can provide improvements in both
powder aerosolisation and patient adherence.
4.1.1. Design modification and innovative concepts for passive devices
The powder dispersion mechanisms in DPIs are complex, depending
on the specific device, and involving air turbulence [61,62] and impac-
tion [60,63]. Recent inhaler designs attempt to enhance powder de-
agglomeration or drug-carrier detachment by increasing air turbulence
and particulate collisions.
Addition of collision or turbulence enhancers in the airflowpath can
be a simple way to improve de-agglomeration. Such enhancers could be
in the form of a 3D array of rods [64], or an oscillating bead [65].
However, not all the modified designs can substantially improve
aerosolisation efficiency. For the Clickhaler®, the grid mesh did not sig-
nificantly increase the respirable doses of salbutamol sulphate or
beclometasone dipropionate [66]. This is because modifying grid affects
not only the impaction or turbulence, but also the flow trajectory [67,
68]. In contrast, a modified Handihaler® equipped with a 3D array of
rods in the mouthpiece improved the FPF5μm/ED (FPF of b5 μm relative
to the emitted dose) from 87.6 to 97.3% at a flow rate of 45 L/min for
a submicron excipient enhanced growth formulation [64]. Computa-
tional fluid dynamics (CFD) analysis revealed that a much higher non-
dimensional specific dissipation factor (a proposed parameter combin-
ing the effects of turbulence, eddy length scale, and particle exposure
 Q.(T.) Zhou et al. / Advanced Drug Delivery Reviews xxx (2014) xxx–xxx
time) contributed to the improved aerosolisation behaviour compared
to the 2D mesh device and unmodified device [64,69].
Conix™ is a passive DPI device utilising a reverse-flow cyclone tech-
nology [70] to generate a high velocity energised vortex to provide
shear and collision for de-agglomerating powders. An interesting device
feature is the retention of large carrier particles in the inhaler as a colli-
sion media to promote de-agglomeration [70].
Other innovative design concepts go beyond the conventional ap-
proaches of generating shear forces and/or impactions by inhalation to
disperse the powder. In a prototype flutter-aerodynamic device, an
aeroelastic film coated with drug particles was fluttered by the inspira-
tory flow and drug particles were dislodged from the film during oper-
ation [71]. For high dose drugs, it is crucial to ensure sufficient loading to
and consistent detachment of the particles from the film. A single-use
DPI based on the ActiveMesh™ technology was developed with a
mesh-sieving dispersion principle. Powder formulation is packed in a
mesh compartment inside the inhaler. Driven by the airflow during in-
halation, the mesh package vibrates and forces the powder agglomer-
ates through the mesh holes to promote de-agglomeration [72]. Since
the mesh vibration is a function of airflow rate, device emptying and
de-agglomeration may be a concern at low flow rates for cohesive pow-
ders which are difficult to be released from the small holes [72]. A 45 μm
size mesh plus a turbulence-generating insert were shown to signifi-
cantly improve the device performance [73]. In both the fluttering and
mesh-sieving designs, airflow is not the direct source for powder dis-
persion; whilst both de-agglomeration processes are still driven and af-
fected by the airflow rate. However, they provide new concepts for
dispersing drug powders, which could circumvent the patent issues of
traditional inhalers.
4.1.2. Active devices
Passive devices have been the mainstream for aerosolising powder
formulations. However, the dispersion performance of many passive
devices suffers from being airflow dependent. This problem is eliminat-
ed in the active devices which utilise the energy provided externally
such as compressed air (e.g. Exubera® and Aspirair®), electrical vibra-
tion (e.g. MicroDose), and heat (e.g. Staccato®). So far, active devices
are not as popular as passive ones due to higher cost and reduced
portability.
A multi-dose (up to 64) active device using compressed air has been
recently developed to deliver micro-doses of drug (b20 μg) [74]. Drug
powders are pre-filled in small pocket holes drilled through a rotating
disc, with only one drug pocket positioned in the air passage at a time.
Two different compressed airflows were applied with the primary
flow dispersing the drug powder from the pocket and the secondary
flow fluidising and pushing the powder into the primary flow path.
The FPF values of four tested powders (spray dried insulin, phenylala-
nine, nitrendipine and phenylalanine labelled fluorescein isothiocynate)
ranged from 50 to 70% measured by an Anderson Cascade Impactor at
28.3 L/min [74]. This active device has a potential to deliver expensive ac-
tive ingredients, although filling such small amount of cohesive drug
powders into the disc can be challenging.
A piezoelectric system has also been employed to actively aerosolise
drug powders [75]. In the MicroDose DPI, powders are stored in a blis-
ter. When the inhaler is activated by inspiration, the blister is opened
and powders are in contact with a piezo vibrator. In vitro results of an
atropine sulphate and lactose powder formulation aerosolised via the
MicroDose DPI showed a FPFtotal (b5.8 μm) of 57% at a flow rate of
28.3 L/min [75].
Instead of mechanically dispersing the powder, the Staccato® device
uses heat to vaporise drugs followed by condensation into inhalable
aerosols [76]. Drugs are coated on a metallic strip and vaporised with
a high temperature up to 400 °C within 0.2 s [77]. The drug vapour con-
denses quickly and generates solid aerosols. The emitted doses were
above 89% and FPFemitted (FPF b 6 μm relative to the emitted drug
mass) values were in the range of 80–93% at flow rates of 15, 30 and
Please cite this article as: Q.(T.) Zhou, et al., Emerging inhalation aerosol devices and strategies: Where are we headed?, Adv. Drug Deliv. Rev.
(2014), http://dx.doi.org/10.1016/j.addr.2014.03.006
5
45 L/min, demonstrating high aerosolisation efficiency. Surprisingly,
the drug degradation is less than 5% for the aerosols of 175 medications
[78], due to the extremely short exposure time of the drug to the hot
substrates [76].
It is worth noting that although the dispersion energy of active de-
vices does not rely on inspiration flow, throat deposition of drug aero-
sols could be dependent on the patient's inhalation pattern because
the main mechanism of throat deposition is inertial impaction. Thus,
drug deposition in the oropharynx may vary substantially for patients
with different inhalation capacities [79].
4.1.3. Future directions in DPI design
Passive devices based on traditional dispersion mechanisms will
continue to dominate the DPI markets in the near future. In past de-
cades, device efficiency has been less significant as the majority of med-
ications, such as those for asthma, only require low drug doses (b1 mg).
However, this has become a crucial aspect with the increasing interests
of delivering high dose active agents (N100 mg) such as antibiotics. It is
a challenge to deliver such large amounts of powder without
compromising the device portability and patient adherence. Further-
more, deposition of a high-dose powder in the oropharynx by a low-
efficiency inhaler could cause severe side effects such as coughing or
throat irritation, resulting in withdrawal of inhalation therapy.
Most passive DPIs are only prescribed to patients aged ≥ 6 years,
leaving nebulisation the only choice for the younger children. Active
DPIs can open a new window for the inhaled paediatric therapies. An-
other opportunity for active DPIs is in the delivery of dry powder aerosol
to the critically ill patients. In the past, DPIs were unsuitable for the in-
cubated patients because patients cannot generate the required airflow
to disperse the powder from passive inhalers. However, in a recent
study, Tang et al. [80] has developed a novel powder delivery system
suitable for incubated patients with the aid of a ventilation bag. This sys-
tem has been applied to deliver the mannitol powder to the distal end of
tracheal tubes in the critically ill patients (Fig. 1) [81].
4.2. Computational modelling
With the rapid advancements of the computational technologies,
CFD has become a useful tool for inhaler designs in providing informa-
tion on the air flow patterns, turbulence levels and particle trajectories
within and post device [82,83]. Different modelling approaches used
for pharmaceutical aerosol dispersion with corresponding advantages
and limitations were reviewed by Wong et al. [82] and Ruzycki et al.
[83]. Whilst few studies focusing on optimising the design variables
for pMDIs [84,85] and nebulizers [86,87], CFD modelling has been
most prevalent for DPIs. However, the complicated processes involved
in DPI dispersion have made it challenging to elucidate the underlying
powder de-agglomeration mechanisms by pure numerical analysis.
Therefore, using a combination of CFD simulations and in vitro ex-
periments is common for providing insights into the relative contribu-
tions of the various dispersion mechanisms on the aerosolisation
performance.
Coates et al. [61,67,88–90] were among the first to use coupled CFD
and in vitro experiments to study the Aerolizer® for a carrier-free
formulation. Results on the effects of the grid design, air inlet di-
mension, capsule size, mouthpiece dimension and air flow have
been summarised by Wong et al. [82] and de Boer et al. [91]. Jiang
et al. [92] further investigated the effect of extending the height of
the swirling chamber of the Aerolizer® and found improved aero-
solisation performance which was ascribed to a lengthened powder–
air interaction time.
The performance of the Aerolizer® and HandiHaler® for carrier-
based formulations was investigated by Donovan et al. [93]. CFD analy-
sis showed that the carrier particle–inhaler collision frequency was
increased with the carrier particle size in the Aerolizer®, but not in the
HandiHaler®. Therefore, they attributed the improved aerosol
6 Q.(T.) Zhou et al. / Advanced Drug Delivery Reviews xxx (2014) xxx–xxx

Fig. 1. A novel system delivering powders to the incubated patients. The schematic shows how to determine the dose and particle size distribution of mannitol aerosol coming out from this
system.
Reprint from Ref. [80] with kind permission from Mary Ann Liebert, Inc.

performance of the larger lactose carrier formulations in the Aerolizer® de-agglomeration on mechanical impaction [96]. They found that the
to the higher carrier–inhaler collision, and suggested impaction was a first impaction only broke the agglomerate into small fragments with
major de-agglomeration mechanism. Shur et al. [94] also computation- a weakened structure whilst the subsequent impaction disintegrated
ally studied the flow characteristics within the HandiHaler® and them into fine particles. They further proposed that the fine particle
Cyclohaler (same design as the Aerolizer®) to identify the key design fraction could be expressed as a unified error function of the ratio be-
features of inhalers. They fabricated two modified versions of the tween the impaction energy and agglomerate strength (Fig. 2).
Cyclohaler with the same specific resistances as the HandiHaler® to In their follow-up study [63], a fully coupled CFD–DEM model was
match the aerosol performance for the carrier-based Spiriva® formula- applied to study the dispersion of multiple agglomerates in the
tion. The two modified designs exhibited very different cyclonic flow Aerolizer® and identified the particle–wall impaction being the primary
behaviours and only the one with similar flow properties as that of de-agglomeration mechanism instead of the turbulence flow or
the HandiHaler® attained comparable performance. Longest et al. [64] particle–particle collisions. Sequential impactions of agglomerates
later utilised CFD to investigate the mouthpiece designs of HandiHaler®, with the inhaler base and grids led to a significant increase in the FPF.
as discussed in Section 4.1.1. Though the dispersion mechanisms were elucidated, Tong et al. [63]
With the increasing interests in developing high-dose DPI, de Boer emphasised that the information collected were specific for the formu-
et al. [91] evaluated computationally and experimentally the per- lation and device studied. Recently, they applied CFD–DEM analysis
formance of the high-dose disposable Twincer™ DPI to seek product
improvement. CFD results revealed that the flow split was independent
of pressure drop across the inhaler and the bypass channel had little
contribution to the swirl in the classifier. Therefore, they proposed
blocking the bypass channel to reduce the total flow rate to minimise
the mouth and throat deposition without affecting the dispersion
efficiency.
Whilst the aforementioned studies have provided considerable
insights in the mechanisms of powder de-agglomeration, the collected
data can only be treated qualitatively due to the lack of information
on particle interactions. To achieve quantitative analysis of the de-
agglomeration mechanisms, specific interests have been placed to cou-
ple the CFD with discrete element method (DEM) modelling which can
take into account the mechanics of particle–particle, particle–fluid and
particle–device interactions during powder dispersion.
A one-way coupled CFD–DEM approach was employed by Tong et al.
[95] to study the de-agglomeration of a single agglomerate comprising
particles of various sizes and poly-dispersities in a cyclonic flow model
similar to the Aerolizer®. They found that the breakup of agglomerate
into smaller fragments was governed by the particle–particle tensile Fig. 2. Correlation between FPF and the ratio between the impact energy and agglomerate
strength and particle–wall impact energy. Later, they used a two-way cohesion energy (ϕ).
coupled CFD–DEM model to investigate the mechanism of powder Reprint from Ref. [96] with kind permission from Elsevier.

Please cite this article as: Q.(T.) Zhou, et al., Emerging inhalation aerosol devices and strategies: Where are we headed?, Adv. Drug Deliv. Rev.
(2014), http://dx.doi.org/10.1016/j.addr.2014.03.006
 Q.(T.) Zhou et al. / Advanced Drug Delivery Reviews xxx (2014) xxx–xxx
coupled with in vitro experiments to identify the critical design features
of the Aerolizer® for carrier based formulations (Foradile®). CFD–DEM
analysis in the inhaler and USP induction port showed that high-
velocity particle–wall impactions in the inhaler dispersion chamber
contributed mainly to the detachment of fine drug particles from the
coarse carriers (Fig. 3) [68].
CFD–DEM modelling is more computationally time-consuming
compared with CFD alone. However, with the increase in the power of
advanced processors, it is envisaged that advanced computations will
play a more pivotal role in inhaler design in the near future.
4.3. Emerging DPI approaches
DPIs can be grouped into four classes: multi-unit, multi-dose reser-
voir, reusable single dose, and single-use devices. The choice of device
is dependent on dose, dosing frequency, and powder properties.
Multi-dose devices are popular for the frequently used medicines with
low doses such as anti-asthma drugs. There has been an increasing
emphasis on simplifying the operation procedure to reduce incorrect
device operation and improve patient adherence. For example,
NEXThaler® is a multi-dose inhaler designed with a simple operation
procedure: open the lid, inhale from the mouthpiece and close the lid.
A full dose feedback system was built into the NEXThaler® using a
breath-actuated mechanism [97]. The inhaler is activated only when a
certain inspiration flow rate is reached to avoid miscounting if the
Fig. 3. Spatial distribution of total carrier particle–wall collision in the inhaler and USP in-
duction port by CFD–DEM analysis of the (a) original Aerolizer; and (b) cross-gird
Aerolizer (colours represent impaction velocity between the particle and wall).
Reprint from Ref. [68] with kind permission from Springer.
Please cite this article as: Q.(T.) Zhou, et al., Emerging inhalation aerosol devices and strategies: Where are we headed?, Adv. Drug Deliv. Rev.
(2014), http://dx.doi.org/10.1016/j.addr.2014.03.006
7
dose is not inhaled [97]. In a randomised cross-over comparison clinical
study of NEXThaler®, Diskus®, and Turbuhaler® in 66 subjects, the
NEXThaler was rated as the easiest to use and most preferred inhaler
with a significantly lower number of using error [98]. Reloadable or re-
usable inhalers are favourable to administer frequently used medica-
tions. Most capsule-based DPIs belong to this group and are still active
in the DPI market. In the last five years, there is an increasing trend to
explore new applications of DPI to deliver antimicrobials, vaccines or
other single-dose active ingredients. As a result, single-use devices are
specially designed for the transient DPI therapies.
4.3.1. Reusable DPIs
In reusable DPIs, the powder formulation is prefilled in a capsule or
cartridge, which is then loaded into the inhaler device for use. With
the dose storage compartment being detached from the inhaler, reus-
able inhalers can come with smaller dimensions. Since the device can
be reused many times, the cost of medication per dose is significantly
reduced. In some cases, more than one dosing unit can be given, making
dosing more flexible.
Reusable devices are currently used for high dose antibiotics be-
cause a multi-dose inhaler will be too bulky for the many high-dose
units required. Both TOBI® Podhaler® (tobramycin) and Colobreathe
Turbospin® (colistimethate sodium) are capsule-based reusable DPI.
Passive reloadable devices can achieve satisfactory aerosol performance
with minimum flow rate dependence when drug powders are engi-
neered, which will be discussed in Section 4.3.3.
4.3.2. Single-use DPIs
Single-use DPIs provide an economical means for the pulmonary
drug delivery of less-frequent or single-dose applications, e.g. inhaled
vaccination. Design of disposable DPIs is quite different from that of
the multi-dose counterparts. Besides the general requirements of dose
consistency and dispersion efficiency, the single-use DPI products
should also incorporate the features of simple operation procedures
and low-costs. The TwinCaps® is a disposable passive DPI device for
delivery of laninamivir octanoate (Inavir®), long-acting neuraminidase
inhibitor prodrug, for the treatment of influenza. Unlike its short-
acting predecessor, zanamivir that requires administration twice daily
for five days, a single dose of 40 mg of inhaled laninamivir can be effec-
tive for a week, making it a perfect candidate for a disposable DPI. The
design of TwinCaps® is simple, with only two assembled plastic parts
consisting of a main inhaler body and a pre-filled powder reservoir
chamber. Since the Inavir® TwinCaps® has been approved for children
under 10 years old, a sufficient aerosolisation performance at lower
flow rates will be necessary [68].
Inhaler device contamination is a serious concern for nebulisation
treatments. It has been reported up to 65% of nebulisers were contami-
nated by microbes including pathogenic Pseudomonas aeruginosa after
home use by CF patients [99–101]. The use of DPIs as an alternative
may reduce the risk of retaining pathogenic bacteria because of dry con-
ditions in both the drug powder and inhaler. However, in a previous
study, Staphylcoccus aureus was still found in patient-returned DPI
devices (2 out of 11 DPIs) [102]. Therefore disposable devices go a
step further to mitigate the potential contamination due to inappropri-
ate cleaning and storage.
The Twincer™ is a disposable device used to deliver antibiotics of co-
listin for treatment of chronic infections in CF patients. It has three plas-
tic plate-like parts which can be easily assembled by stacking and
clicking three pieces together [103]. The powder formulation is packed
in a blister-like compartment [91]. The powders are dispersed through a
multiple air classifier technology [103]. Unlike Inavir® which requires
only a single administration, inhaled colistin therapy for CF patients
can be administered twice daily for at least 28 days, which makes the
cost issue more prominent. However, the disposable design is advanta-
geous for reducing the potential risk of bacterial contamination, an issue
8 Q.(T.) Zhou et al. / Advanced Drug Delivery Reviews xxx (2014) xxx–xxx
which is also critical for the treatment of highly contagious diseases
such as tuberculosis [104].
Aespira's resQhaler™ is a recently developed single-use disposable
DPI based on the ActiveMesh™ technology, as discussed in Section 4.1.1
[73]. The testing doses of resQhaler™ are up to 3 mg, which may limit
its use for high-dose drugs until further design improvements can accom-
modate more powder [72].
4.3.3. Formulation considerations for device-formulation compatibility
The compatibility between device design and formulation properties
should be considered carefully. There is no device which can fit all
formulations; in turn, no formulation is suitable for all devices. For
most DPIs, good flow and fluidisation properties are required for the
powder formulation with regard to manufacturing and drug release
[105]. In the traditional DPIs of asthma or COPD therapies, coarse carrier
(mostly lactose) is a common excipient to improve the flow and
fluidisation behaviour of powder formulations. Because of the low
doses of bronchodilator and corticosteroids (typically b1 mg), lactose
carriers are also functioning as diluents to facilitate the manufacturing.
However, for the high-dose antibiotic DPI formulations (N 100 mg), ad-
dition of lactose will increase the powder mass and volume excessively.
Therefore, particle engineering has been extensively explored to pro-
duce drug particles with satisfactory flow and fluidisation properties
without adding a carrier. Powders with superior flow and aerosolisation
performance will not only facilitate dose preparation during
manufacturing, but also reduce the airflow dependence of aerosol per-
formance. Porous tobramycin particles with demonstrated flowability
and aerosol performance in the TOBI® Podhaler® are produced by emul-
sion spray drying via the PulmoSphere™ technology [106]. Aerosol per-
formance of the PulmoSphere tobramycin formulations was consistent
in different temperatures (10–40 °C), relative humidities (10–65%)
and airflow rates (40–85 L/min) [107]. Colistin powders with corrugat-
ed surfaces and high aerosol performance (FPFtotal (b5 μm) N 80% via
the Aerolizer at 100 L/min and a pressure drop of 4 kPa) were prepared
by Zhou et al. using spray drying without adding any external excipient
[108]. Co-spray drying has also been employed to produce wrinkled
particles of a combination powder containing colistin and rifampicin
(Fig. 4), with combined characteristics of synergistic antimicrobial ac-
tivity, high aerosol efficiency (FPFtotal (b5 μm) N 90% via the Aerolizer
at 100 L/min and a pressure drop of 4 kPa) and moisture protection
[109]. Dry coating of drug particle surface with magnesium stearate
(MgSt) was also shown to be an effective approach to improve the
flowability and aerosolisation of cohesive jet-milled drug powders
[110]. Nanoparticle delivery for aerosol formulation is also an emerging
area [111]. It has been reviewed previously [112,113] and elsewhere in
other articles of this special issue.
Fig. 4. Scanning electron micrographs of the spray dried antibiotics particles of: (a) colistin sulphate; and (b) combination of colistin sulphate and rifampicin (with a high emitted dose of
96% and high FPFtotal of 92%). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Reprint from Ref. [109] with kind permission from Springer.
Please cite this article as: Q.(T.) Zhou, et al., Emerging inhalation aerosol devices and strategies: Where are we headed?, Adv. Drug Deliv. Rev.
(2014), http://dx.doi.org/10.1016/j.addr.2014.03.006
4.4. Device material
Powder retention in inhaler devices may be significant, and can
reach 20%–50% of the loaded doses for cohesive powders [114–116].
This can be due to mechanical impaction of the powder on the device
surface and/or electrostatic charge generated during powder dispersion.
Triboelectrification is an inevitable consequence of particle–particle or
particle–device contact or friction during the processing dispersion
[117]. As pharmaceutical solids and most DPI devices are insulative,
the generated electrostatic charge is difficult to dissipate [118]. Both im-
paction and charge depend on the surface roughness [119], contact area
[120] and particulate physico-chemical properties [121,122]. Hence,
modification of device surface characteristics may effectively reduce
the device retention by minimising attractive forces.
Pharmaceutical lubricants such as MgSt and leucine have a low sur-
face energy, which can reduce adhesion and friction between particle–
particle or particle–inhaler surface [105]. MgSt is a widely used lubri-
cant for tabletting, and is an approved excipient for inhalation products
by the US FDA (Foradil® Certihaler®) [123], UK Medicines and
Healthcare products Regulatory Agency (MHRA) (Pulmicort® CFC-free
Inhaler) [124] and many other countries. Given its established safety
profiles, coating of MgSt [110,125,126] and leucine [127–129] on
inhalable particles has been investigated extensively to improve device
retention and aerosolisation by decreasing particle surface energy and
powder cohesion [130]. Recently, Heng et al. have proposed a new
alternative strategy of coating the interior surfaces of capsules and DPI
devices (Rotahaler® and Aerolizer®) with MgSt, to reduce drug reten-
tion [115]. For the Aerolizer®, coating of capsules and inhalers at the
MgSt concentration of 0.3 mg/mL, significantly reduced capsule and in-
haler retentions by 79 and 69%, respectively, compared to the uncoated
counterparts. The Rotahaler®, which has a lower dispersion efficiency
than the Aerolizer®, also showed a substantial reduction in capsule
(by 73%) and device retention (by 53%). For both inhalers, reduced
capsule and device retentions translated to a significantly higher fine
particle doses [115].
In another study, the surface of a newly designed CC-3D resin inhaler
and HPMC capsules were coated with a low surface energy polytetra-
fluoroethylene suspension [131]. The capsule, capsule chamber and
mouthpiece retention were significantly reduced from 14.1 to 7.3%,
8.8 to 2.2% and 13.2 to 9.1%, respectively.
The above studies have shown the effectiveness of surface coating to
reduce powder retention in capsule and inhaler devices. Addition of an-
tistatic additives into these materials may further reduce the adhesive
forces. The lowest pull-off forces between insulin particles and polymer
surfaces measured by atomic force microscopy were achieved for the
material of polypropylene with addition of an antistatic additive (Dow
 Q.(T.) Zhou et al. / Advanced Drug Delivery Reviews xxx (2014) xxx–xxx
Entira™ AS) [132]. Future aerosolisation tests from the inhaler devices
made of these materials are necessary to confirm the correlation be-
tween the atomic force microscopy force measurement and device
retention.
5. Emerging inhalation therapies
5.1. Inhaled anti-pulmonary arterial hypertension agents
Nebulised iloprost is advantageous over the intravenous administra-
tion of epoprostenol as it avoids the occurrence of tachyphylaxis and
prevents complications caused by the use of a central-venous route
[133]. However, inhaled iloprost has a short half-life (approximately
2 h) which means that patients suffering from pulmonary arterial hy-
pertension have to administer the drug up to nine times a day. The com-
bination of inhaled iloprost and oral sildenafil was shown to be more
effective, and allowed reduction in the number of dose administrations
of iloprost alone, by prolonging the vasodilatory effect [133]. In a prom-
ising study, treprostinil, which has a long plasma half-life than iloprost
and is only administered up to a maximum of four times a day, was
prepared as a pMDI formulation [134]. Doses of 1 mg/mL (15 μg
treprostinil/puff) and 2 mg/mL (30 μ g treprostinil/puff) of treprostinil
sodium were prepared and 39 patients received 30, 45 or 60 μg of
treprostinil. Patients who received 45 μg (3 puffs of 1 mg/mL
treprostinil) or 60 μg (2 puffs of 2 mg/mL treprostinil) showed pulmo-
nary vasodilation surpassing the 120 min observation time which are
similar to the nebulised treprostinil (administered for 1 min). Further-
more, no side effects (e.g. nauseousness or dizziness) were observed,
proving that administering treprostinil using a pMDI was well-
tolerated by the patients.
Oral administration of nifedipine was shown to reduce pulmonary
arterial pressure [135,136] but no clinical study of inhaled nifedipine
has been reported. Several reports have shown success in preparing
spray-dried polymeric microparticles to control the release of sildenafil
[137] and nifedipine [138], aiming to further reduce the dosing frequen-
cy. However, the benefits of controlled-release characteristics of inhaled
nifedipine may need verification by clinical trials.
5.2. Inhaled antibiotics for respiratory bacterial infections
The TOBI® Podhaler® approved by FDA for cystic fibrosis treatment
may have higher treatment satisfaction contributing to ease of use and
treatment convenience [139]. TOBI® Podhaler® (Novartis AG, Basel,
Switzerland) delivers 112 mg tobramycin (from 4 capsules) as powder
aerosols twice a day. However, the repeat operation procedure “load,
pierce, inhale, check capsule if it has emptied properly and repeat
steps if not” for four capsules might be a tedious process.
The Turbospin® delivers 125 mg colistimethate sodium
(Colobreathe® , Forest Laboratories, Inc.) from a single capsule,
twice a day. Although dose preparation time is reduced, multiple inha-
lations may be necessary as a single inspiration may be insufficient to
empty the entire dose. With regard to operation convenience, multiple
inhalations of a single capsule have less repeated steps. However, when
a patient inhales too much powder from a single inhalation, side effects
such as coughing and chest tightness often occur [140]. A new high-
dose DPI Orbital®, which is able to deliver up to 400 mg of powder,
has a mechanism to control the dose of each inhalation. The dose con-
tainment chamber has an orifice that controls the release of the powder,
making it possible for patient to inhale a set dose per inhalation over
multiple inhalations [141].
In a thorough review by Cipolla and Chan on inhaled antibiotics
[142], most inhaled antibiotics have been prepared as nebulised formu-
lations — colistin (Colomycin® and Promixin®, approved in Europe for
CF); aztreonam (Cayston®, FDA approved for CF), liposomal amikacin
(ARIKACE™, phase III for CF in Europe, phase II for nontuberculosis
mycobacteria in USA, and completed phase II for non CF bronchiectasis),
Please cite this article as: Q.(T.) Zhou, et al., Emerging inhalation aerosol devices and strategies: Where are we headed?, Adv. Drug Deliv. Rev.
(2014), http://dx.doi.org/10.1016/j.addr.2014.03.006
9
fosfomycin/amikacin (completed phase I for ventilated-associated
pneumonia), fosfomycin/tobramycin (completed phase II for cystic fi-
brosis patients), liposomal ciprofloxacin (Lipoquin™ which has com-
pleted phase IIa for CF, Pulmaquin™ in phase III for non-cystic fibrosis
bronchiectasis), levofloxacin (Aeroquin™, completed phase III for CF).
The DPI is now another viable option to deliver these high dose antibi-
otics. For example, Bayer is developing a DPI of ciprofloxacin (1 capsule,
twice daily) for CF, which is also currently in phase III for non-CF bron-
chiectasis. Additionally, dry powder vancomycin (AeroVanc™, 2 or 4
capsules twice daily) is in phase IIa trial for CF.
5.2.1. Pneumonia
Oral and intravenous administered antibiotics commonly used in the
treatment of community-acquired and ventilated associated pneumo-
nia, respectively. However, these routes could produce systemic side ef-
fects since the drugs are distributed to various tissues via the blood
circulation following the administration [143]. The systemic side effects
can reduce patient adherence and therefore local pulmonary delivery is
advantageous. Furthermore, pulmonary drug delivery will result in high
antibiotic concentrations in the lungs and hence minimise the bacterial
resistance caused by insufficient local drug concentrations via systemic
delivery systems.
In a separate study, 400 mg of nebulised BAY41-6551 (Bayer
Schering Pharma/Nektar Therapeutics) containing amikacin, was ad-
ministered every 12 h using a proprietary gasless vibrating-mesh
nebuliser to the ventilated associated pneumonia patients. The patients
showed positive results with the maximum amikacin concentration in
tracheal aspirate found to be 25 times higher than the MIC (256 μg/mL)
in 50% of patients (6 out of 12 patients) [144]. In another study, amikacin
concentration in epithelial lining fluid (which reflects the condition of the
infection site more accurately than the amikacin concentration in the
suctioned tracheal aspirates) was found to be four times higher than the
MIC of 256 μg/mL threshold [145]. These studies indicate that local deliv-
ery to the lung is more efficacious than systemic administrations. The
BAY41-6551 is currently in phase III trials for approval in ventilated
associated pneumonia patients.
By administering aminoglycosides locally to the lung, the risks
of neuro-, nephro- and ototoxicity, which can be induced when the
drugs are administered through intravenous routes, can be minimised
[146]. Several in vitro works have reported successful preparation of
dry powder suitable for pulmonary delivery for treatment of pneumo-
nia, for example, DNase1 [147], fosfomycin [148], colistin [91,108] and
combination of ciprofloxacin hydrochloride plus gatifloxacin hydro-
chloride [149], and colistin plus rifampicin [150].
5.2.2. Tuberculosis
As shown above, inhaled antibiotics (particularly DPIs) have been
used extensively and have shown great success in treating pulmonary
infections by increasing local concentration, improving patient adher-
ence and decrease systemic effects. This has opened a window of oppor-
tunity to treat other infectious diseases, especially tuberculosis, where
multidrug resistance is common due to poor treatment efficacy and pa-
tient adherence [151].
Three first line antibiotics for tuberculosis, pyrazinamide, rifampicin
and isoniazid, were successfully combined as a single DPI formulation
with a FPFloaded (particlesb5.0 μm over the loaded dose) of 46 ± 3% pro-
duced by spray drying [152]. Delivering these three antibiotics in a sin-
gle administration may provide a more efficient and rapid approach to
treat local and systemic infections, which could potentially translate to
improvement in patient adherence. There are a number other studies
which have successfully prepared inhaled anti-tubercular formulations,
including a single powder formulation containing rifapentine,
moxifloxacin, and pyrainzamide (Fig. 5) [151] and a capreomycinoleate
powder having high efficacy against Mycobacterium tuberculosis and
low toxicity [153]. A recent novel approach to transport anti-tubercular
drugs into infected macrophages involves hydrolysed galactomannan-
10 Q.(T.) Zhou et al. / Advanced Drug Delivery Reviews xxx (2014) xxx–xxx
Fig. 5. Scanning electron micrographs of the spray dried particles containing rifapentine, moxifloxacin and pyrazinamide, (a) with and (b) without leucine. The powder formulation with
and without leucine had similar median aerodynamic diameters of 2.58 ± 0.08 μm and 2.51 ± 0.06 μm, with a relatively high FPF of 55.5 ± 1.9% and 63.6 ± 2.0%, respectively.
Reprint from ref. [151] with kind permission from Springer.
modified nanoparticles and flower-like polymeric micelles with high
loading of rifampicin [154].
5.3. Inhaled neuraminidase inhibitor for influenza
Laninamivir octanoate is the newest neuraminidase inhibitor for in-
fluenza treatment administrated by a DPI following the use of
oseltamivir (Tamiflu®, administered orally), zanamivir (Relenza®, by in-
halation) and peramivir (Rapiacta®, by single or multiple intravenous
administrations). Although the efficacy of oseltamivir decreased against
the oseltamivir-resistant H1N1/H275Y virus, it was still predominantly
prescribed by physicians during the 2008–2009 flu season in Japan
over zanamivir because of the simple oral administration proce-
dure [155]. In a survey (conducted in Okinawa during the 2010 flu sea-
son) comparing the ease of administration between oseltamivir,
zanamivir and laninamivir, the administration of zanamivir using
Diskhaler® was found to be the most difficult [156]. Laninamivir
(Inavir®) has been approved and prescribed more often than
oseltamivir and zanamivir in Japan since 2010 [156]. Biota Pharmaceu-
ticals is currently conducting a multinational phase II clinical trials of
laninamivir in USA [157] which likely to be followed by approval soon.
As a long-acting neuraminidase inhibitor, laninamivir remains in the
lungs for more than 5 days. Following a single dose of laninamivir, the
median duration for fever and flu symptoms to subside was three and
four days (including days of administration), respectively, in patients
having type A and B influenza. Thus only a single dose is necessary to
complete the treatment [157]. In contrast, oseltamivir and zanamivir
have to be administered twice daily for five days [155]. Absolute ad-
herence in these five-day therapies has to be ensured for complete clear-
ance of the virus. However, patients tend to stop taking the medications
once the flu symptoms have improved [157]. Thus the convenience of sin-
gle dose administration by laninamivir should considerable increase pa-
tient adherence.
Detailed information of the TwinCaps® device, which is used for pul-
monary delivery of laninamivir, is described in Section 4.3.2. Two dosing
chambers, each contains 10 mg of laninamivir octanoate powder, are
present in each TwinCaps® inhaler (Hovione FarmaCiencia, SA). Chil-
dren (b10 years old) are required to inhale from one device (total
dose of 20 mg) and adults from two devices (total dose of 40 mg). The
single administration of laninamivir is commonly done in front of the
health care professionals to ensure correct inhalation technique.
Laninamivir has proven to be effective to the H1N1/H275Y virus and
shown similar clinical efficacy to oseltamivir and zanamivir against
H1N1, H3N2 and influenza B viruses [158,159]. Alleviation time for chil-
dren was shorter with laninamivir compared to oseltamivir, whilst in
adults the alleviation time is similar [160]. Animal studies have further
shown the superior efficacy of laninamivir against the highly pathogenic
avian flu virus H5N1 [161].
Please cite this article as: Q.(T.) Zhou, et al., Emerging inhalation aerosol devices and strategies: Where are we headed?, Adv. Drug Deliv. Rev.
(2014), http://dx.doi.org/10.1016/j.addr.2014.03.006
5.4. Inhaled cyclosporine for transplant rejection
Cyclosporine A is a potent immunosuppressant drug used in long-
term to prevent allograft rejection in the lung transplant patients. How-
ever, oral and parenteral administrations induce substantial systemic
side effects which include renal toxicity and hypertension [162]. Provid-
ing high therapeutic concentration of cyclosporine A locally to the lungs
may reduce the drug dose and hence lower the incidence of the system-
ic side effects. In a single centre, double-blinded, placebo-controlled trial
comparing the nebulised cyclosporine A in propylene glycol to the aero-
sol placebo (three times a week for two years), the incidence of bronchi-
olitis obliterans syndrome in the patients receiving cyclosporine A was
reduced and positive improvements in pulmonary lung functions
were observed [163]. Unfortunately, the multi-centre phase III trial
(CYCLIST) showed no significant difference in delaying or preventing
the occurrence of bronchiolitis obliterans syndrome in lung transplanted
patients when they received nebulised cyclosporine A formulation
in propylene glycol (62.5 mg/mL cyclosporine A in propylene
glycol) [164].
Administration of nebulised cyclosporine A to these patients was
found to be challenging and claimed to influence the study outcome.
Various works have produced cyclosporine A formulations without
the inclusion of irritants such as ethanol and propylene glycol, which
are commonly used solvents to increase the dissolution of hydrophobic
cyclosporine A. Nebulised cyclosporine A encapsulated in liposomes
[165], as well as dry powders prepared by dry-emulsion [166], anti-
solvent precipitation [167] and spray drying [168,169] have successfully
been prepared. By removing the unsaturated fatty acids in the surfac-
tant of glycerol monooleate, the dissolution of cyclosporine A formed
by dry-emulsion was significantly enhanced and stable micelles (ap-
proximately 320 nm) were formed when resuspended in water [166].
With the absence of the unsaturated fatty acids, its oxidation to toxic
lipoperoxide during storage was avoided and greater chemical stability
was achieved. Animal studies showed that the powder could potentially
be used to treat respiratory inflammation.
The use of lung-surfactant mimic phospholipids 1,2-dipalmitoyl-
sn-glycero-3-phosphocholine and 1,2-dipalmitoyl-sn-glycero-3-
(phosphor-rac-1-glycerol) in cyclosporine A powder was found to in-
crease the powder dispersability, with the FPFTotal (b4.46 μm) of approx-
imately 50% measured by the next generation impactor at 60 L/min [168].
The bioavailability of hydrophobic cyclosporine A was increased by the in-
clusion of mannitol [167]. Porous microparticles (tap density of ≤about
0.3 g/cm3), suitable for nasal and pulmonary inhalation, containing an
immunosuppressant drug (e.g. cyclosporine A, everolimus, tacrolimus,
sirolimus and pimecrolimus) and excipient (e.g. saccharide, amino acid,
a sugar alcohol) without the use of surfactant have been reported [169].
The porous particles were prepared using spray drying and a blowing
agent such as ammonium carbonate and ammonium bicarbonate. Ad-
ministration of cyclosporine A using DPIs offers benefits which include
 Q.(T.) Zhou et al. / Advanced Drug Delivery Reviews xxx (2014) xxx–xxx
higher dose delivery with better control of aerosol properties and stability
[170]. Active DPIs, instead of passive DPIs, may be more suitable for these
patients and can increase adherence since they often have limited lung
function after the transplantation.
5.5. Inhaled alpha 1 antitrypsin
The current administration of alpha 1 antitrypsin (A1AT) in patients
is by intravenous infusion (60 mg/kg per dose [171]). Although inhala-
tion of A1AT has been shown to restore the protease–antiprotease im-
balance and anti-elastase activity in A1AT deficiency and CF patients
[172], no approved products are commercially available. When
radiolabelled A1AT (Prolastin®; α1-proteinase inhibitor (human);
TalecrisBiotherapeutics Inc., Research Triangle Park, NC, USA) was
nebulised with AKITA2® APIXNEB® (Activaero GmbH, Gemünden,
Germany) to the CF and A1AT deficiency patients, high lung deposition
(≥ 70% of loaded drugs) and high peripheral deposition (N 40%) were
achieved [173]. The lung and peripheral depositions were found to be
similar in the healthy patients, which showed that this nebuliser per-
formed similarly in patients despite the disease severity. Furthermore,
AKITA2® APIXNEB® nebuliser was well received by patients. The rela-
tively short time (7–13 min to administer 100 mg of A1AT) and ease
of administration were beneficial to improve patient acceptance. Anoth-
er smart nebuliser system, I-Neb® Adaptive Aerosol Delivery (I-Neb®
AAD, Philips Respironics, Parsippany, NJ) described in Section 2 has
shown high lung depositions in a relatively short administration time
to deliver 25 mg A1AT: 56.6% in 7.5 min (Tidal Breathing Mode) and
59.9% in 4.4 min (Target Inhalation Mode with inspiratory time set for
6 s) [174]. When the inspiratory time was increased to 9 s, 64.5% of
the total dose was successfully deposited in the lungs in 2.5 min. This
showed that slow and deep inspiration by patients can significantly re-
duce the administration time using the I-Neb® AAD system. This direct
administration of A1AT to the lungs will be more effective and reduce
the systematic effect than the intravenous administration. Additionally,
the low residual volume in the AKITA2® APIXNEB® and I-Neb® AAD sys-
tems means a more cost effective treatment compared to the intrave-
nous administration due to the high cost of A1AT.
5.6. Inhaled cytokines
Inhaled human granulocyte macrophage colony stimulating factor
(GM-CSF) is a promising therapy for pulmonary alveolar proteinosis
[175]. This rare lung disease is associated with high levels of neutralising
antibodies against GM-CSF, causing accumulation of lipoproteinaceous
material in the alveoli and consequent deterioration in gas exchange
[176]. Standard treatment involves whole-lung lavage, an invasive pro-
cedure that is repeated every 6–12 months [176]. Subcutaneous admin-
istration of GM-CSF has been reported as a safe and effective treatment.
However, exceptionally high incidences (in up to 85% of patients) of
systemic side effects such as rash, fever and bone pain have been report-
ed [177]. Aerosolised GM-CSF is proposed to mitigate these systemic ad-
verse effects. In a single-patient case study, a patient received nebulised
GM-CSF (sargramostim) treatment when marked deterioration in gas
exchange was observed after two lavages. A positive clinical response
and improvements in gas exchange were exhibited with no adverse ef-
fects after 1 year of treatment [176]. A multicentre, self-controlled phase
II trial conducted in Japan also found that nebulised GM-CSF (leukine)
therapy was safe and effective in treating pulmonary alveolar pro-
teinosis [175]. Additionally, the treatment provided a sustainable thera-
peutic effect, with more than 80% of the subjects remaining stable
without the need for further therapy for more than a year. Therefore
inhaled GM-CSF may be a viable therapeutic alternative to the current
invasive whole-lung lavage treatment.
Inhaled interferon beta (IFN-β) has been investigated for treatment
of asthmatic symptoms, COPD and infectious diseases. A Phase I study,
completed in 2009, demonstrated that inhaled IFN-β was well tolerated.
Please cite this article as: Q.(T.) Zhou, et al., Emerging inhalation aerosol devices and strategies: Where are we headed?, Adv. Drug Deliv. Rev.
(2014), http://dx.doi.org/10.1016/j.addr.2014.03.006
11
No adverse effects were found in terms of lung function and inflamma-
tion in asthmatic patients. Subsequently, a Phase II multi-centre,
randomised, double-blind, placebo-controlled trial was conducted on
147 adult asthmatic patients, who were taking inhaled corticosteroids
and had a history of worsening symptoms after contracting a common
cold [178]. The patients received either inhaled IFN-β or placebo for
14 days when cold symptoms appeared. Outcomes of this clinical trials
indicate that the severity of asthma symptoms were significantly re-
duced in patients who received inhaled IFN-β (patients on treatment
had a 65% reduction in moderate exacerbations). These patients also
demonstrated improved lung function as indicated by the steady in-
crease of morning peak expiratory flow. A constant increase of a bio-
marker indicator for anti-viral activity was observed for the IFN-β
patients group, whilst a rapid decrease was observed in patients treated
with placebo. Due to the positive outcome of IFN-β, a Phase II proof-of-
concept trial in COPD patients [179] and the preclinical development of
IFN-β for patients with other severe viral lung infection including pneu-
monia [180] are currently underway.
Interferon-γ (IFN-γ) is an immune-regulatory cytokine responsible
for the fibroblast proliferation and therefore has attracted interest for
treatment of idiopathic pulmonary fibrosis [181]. Subcutaneous injec-
tion of IFN-γ to 826 patients with idiopathic pulmonary fibrosis failed
to show a significant benefit in a randomised, double-blinded,
placebo-controlled trial [182]. However, it was suggested that local de-
livery of IFN-γ to the epithelial lining of lung might be more efficacious
[181]. Aerosol IFN-γ delivered by I-Neb® Adaptive Aerosol Delivery over
80 weeks (100 μg, 3 times/week) to 10 patients with idiopathic pulmo-
nary fibrosis showed efficient in vivo delivery to the lungs, with 65.4 ±
4.8% deposited in the parenchyma section determined by the scintigra-
phy method [16]. In this study, inhaled IFN-γ was well-tolerated with
no significant systemic side effects and patient adherence was as high
as 96.7 ± 4.81%. Further studies on inhaled IFN-γ for idiopathic pulmo-
nary fibrosis are anticipated.
Inhaled IFN-γ has also been investigated for the treatment of pulmo-
nary tuberculosis [183]. However, the verdict on treatment efficacy
from various studies is still inconclusive [184]. In an early open-label
clinical trial, 5 tuberculosis patients received aerosol interferon-γ
500 μg 3 times a week for 1 month. Results were promising, with spu-
tum smears returning negative [185]. However, these positive results
were not reproduced in the two subsequent clinical studies [186,187].
Another recent randomised, controlled 4-month trial of adjunctive in-
haled IFN-γ only showed a transient beneficial effect at the 4-week
timepoint [188]. Therefore, more rigorous clinical studies are necessary
to establish any potential clinical benefits of inhaled IFN-γ therapy
against pulmonary tuberculosis.
Inhaled Interleukin-2 alone or as combination therapies have
attracted interest for the treatment of pulmonary metastases of renal
cell carcinoma in the last two decades [189]. Previous clinical studies
have shown acceptable patient tolerance and proven efficacy, the
results of which have been reviewed previously [189,190]. A recent
clinical study in 20 patients has reported inhalation of low-dose
interleukin-2 (3 × 3 million IU once daily) in conjunction with monthly
dacarbazine bolus injections offered an effective and safe treatment
option for lung metastases in melanoma. In the study, the treatment
(inhaled interleukin-2 plus dacarbazine) exhibited clinical efficacy in 9
patients with partial regression (27%) or stable disease (33%). In the
prophylaxis group, newly developed lung metastases were not ob-
served during the inhaled interleukin-2 therapy [191]. These promising
results demonstrate the potential of inhaled cytokines for lung cancer-
related treatments.
5.7. Inhaled antibodies
Monoclonal antibody treatments may be effective in the manage-
ment and control of severe asthma [192]. However, clinical reports on
inhaled therapy of monoclonal antibodies are scarce. An early clinical
12 Q.(T.) Zhou et al. / Advanced Drug Delivery Reviews xxx (2014) xxx–xxx
study examined the attenuation efficacy of inhaled recombinant
humanised monoclonal antibody-E25 on the airway response to the al-
lergen in asthmatic patients [193]. In this randomised, double-blind,
three-group study in 33 subjects with mild allergic asthma, no signifi-
cant efficacy was found for the inhaled therapy compared to the placebo
groups. Recently, GSK has completed Phase I clinical trials on safety, tol-
erability, pharmacokinetics and pharmacodynamics of an inhaled fully
human, single domain antibody directed against the TNFR1 receptor
(GSK1995057) for the treatment of respiratory disorders. The results
showed significantly reduced pulmonary and systemic markers of in-
flammation and LPS-induced clinical symptoms (i.e. fever, nausea) for
the GSK1995057 treatment group compared to placebo group, with
no observed severe side events [194]. Further clinical studies are neces-
sary to elucidate the future role of monoclonal antibodies in pulmonary
diseases.
6. Conclusions
Inhaled pharmaceuticals have seen a number of innovations as they
evolve to accommodate novel medications and improve the efficacy of
existing treatments. In particular, targeted treatment and vaccination
of pulmonary infectious diseases are a growing area of interest, and in
turn the high-dose and disposable dry powder inhalers become increas-
ingly popular. pMDIs continue to encounter formulation challenges, al-
though device improvements, such as the relatively discrete electronic
dose counters, are more apparent. Meanwhile, software control units
for nebulisers have advanced treatment shortening and dosing accuracy
to a new level, and have appealing implications for enhancing clinical
trials. Whilst the DPI, pMDI and nebulizer fields are nearing maturity,
computational modelling of aerosol kinetics is a budding area. As the
cost of computing power reduces, new approaches such as CFD–DEM
promise to optimise device-formulation coupling, and will become inte-
gral in the future. Indeed, it appears that the explosive growth of global
digital technology has finally caught up with inhaled therapeutics. We
anticipate digital technology will define the next era of novel inhalation
devices and formulations, as well as delving into less traditional roles in-
volving improved patient interaction and adherence. Patient adherence
and treatment outcomes might also be improved by the application of
aerosol delivery to an increasing variety of pharmaceuticals.
Acknowledgement
The authors acknowledge the financial support from the Australian
Research Council's Discovery Projects funding scheme (DP120102778
& DP110105161) and the National Health and Medical Research
Council's (NHMRC) Project Grant funding scheme (APP1065046). Qi
Tony Zhou is a recipient of Early Career Fellowship from NHMRC
(APP1053528). John Chan is the recipient of the Australian Postgraduate
Award from the Australian Federal Government.
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