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European
Respiratory Disease
Volume 8 • Issue 1 • Spring 2012 • Extract
Improved Localised
Lung Delivery Using
Smart Combination
Respiratory Medicines
Dipesh Parikh,1 John Burns,2
David Hipkiss,3 Omar Usmani4
and Rob Price5
1. Senior Scientist, Prosonix Ltd, Oxford; 2.
Engineering Manager, Prosonix Ltd, Oxford;
3. Chief Executive Officer, Prosonix Ltd,
Oxford; 4. Clinical Senior Lecturer and
Consultant Physician in Respiratory and
Internal Medicine, National Heart & Lung
Institute, Imperial College London;
5. Professor of Pharmaceutics, Department
of Pharmacy and Pharmacology, University
of Bath
www.touchrespiratory.com
Drug Delivery
Improved Localised Lung Delivery Using Smart Combination
Respiratory Medicines
Dipesh Parikh,1 John Burns,2 David Hipkiss,3 Omar Usmani4 and Rob Price5
1. Senior Scientist, Prosonix Ltd, Oxford; 2. Engineering Manager, Prosonix Ltd, Oxford; 3. Chief Executive Officer, Prosonix Ltd, Oxford;
4. Clinical Senior Lecturer and Consultant Physician in Respiratory and Internal Medicine, National Heart & Lung Institute, Imperial College London;
5. Professor of Pharmaceutics, Department of Pharmacy and Pharmacology, University of Bath
Abstract
combination therapies for the treatment of chronic obstructive pulmonary disease (coPD) have long been used to provide improved disease
management. current therapies aim to provide bronchodilatation and most of them are based on β-agonists or anticholinergics/muscarinics.
A widely used combination is an inhaled corticosteroid (ics) plus a long-acting β-agonist (LABA), which have shown an additive improvement
in lung function. however, for inhalation combination products, the most significant pharmaceutical challenge is to maintain a constant ratio
of drug components during various stages of drug formulation and drug delivery. Drug delivery to lungs with a consistent and predesigned
ratio of co-associated active components can help maximise the chance of co-location at the active site and hence increases the potential
of synergistic action from the solid. newer particle engineering-led approaches, such as constructive sonocrystallisation particle
engineering, can help design these smart medicines that can help achieve consistent localised delivery.
Keywords
Particle engineering, combination, budesonide, fluticasone, formoterol, salmeterol, synergy
Disclosure: Dipesh Parikh, John Burns and David hipkiss are all full time employees of Prosonix Ltd. omar usmani will be a principal investigator on an 18-month project
funded by Prosonix Ltd, due to start in April 2012. rob Price is a long-time paid consultant to Prosonix Ltd, and one of his PhD students is supported by Prosonix Ltd.
Acknowledgements: omar usmani is a recipient of an national institute of health research (nihr) uK career Development fellowship and supported by the nihr
respiratory Disease Biomedical research unit at the royal Brompton and harefield nhs foundation Trust and imperial college London.
Received: 10 february 2012 Accepted: 2 March 2012 Citation: European Respiratory Disease, 2012;8(1):40–5
Correspondence: Dipesh Parikh, Prosonix Ltd, The Magdalen centre, oxford science Park, oxford, oX4 4gA, uK. e: [email protected]
Support: The publication of this article was funded by Prosonix Ltd.
over the past 20 years, chronic obstructive pulmonary disease (coPD)
has emerged as a major public health problem and is a major cause
of chronic morbidity and mortality worldwide. The disease severity is
also known to increase with age. The key objectives with reference to
disease management are to prevent disease progression, provide
symptomatic relief and improve quality of life by providing treatment
for complications and exacerbations.
Current Practices and Development Pipeline
Bronchodilators (relievers) are normally used as first-line agents for
the symptomatic treatment of patients with coPD, whereas inhaled
glucocorticoids are the mainstay of long-term control therapy for
persistent disease.1 however, patients show variable responses to
inhaled glucocorticoids and some exhibit resistance to this drug
class.2 Although long-acting bronchodilators have been an important
advance in the management of coPD, these drugs do not interfere
with the underlying inflammatory process. however, the significance
of treatment is mainly judged by the adverse effects of the medication
and how these are prevented or minimised. no currently available
treatments reduce the progression of coPD or suppress the
inflammation in small airways and lung parenchyma.3 Towards this
end, guidelines provided by the uK national institute for health and
2
clinical excellence (nice) for the use of inhaled therapies give
better understanding of the disease stage and suggested treatment.4
As indicated by the nice guidelines (see Figure 1), with disease
progression, the treatment option requires incorporating
a progressive increase in the number of pharmaceutical agents, often
in combination, to provide the desired effect of symptomatic relief.
Two combination schemes widely used for the treatment of coPD are
a short-acting anticholinergic plus a short-acting β2-agonist (sABA)
and an inhaled corticosteroid (ics) plus a long-acting β2-agonist
(LABA). Among these, the use of the ics plus LABA combination has
shown an additive improvement in lung function. for example, since
its launch in 2001 the Advair®/seretide® (gsK) combination product
inhaler has been used as a very effective treatment of asthma. The
concurrent delivery of the ics fluticasone propionate (fP) and
the LABA salmeterol xinafoate (sX) is required for respective
treatment of the inflammatory and bronchoconstrictive elements of
asthma.5 The use of this combination and an extensive review of its
role in asthma management are provided elsewhere.6
symbicort® (AstraZeneca), a combination product containing the ics
budesonide (BDs) and the LABA formoterol fumarate was launched
© Touch Briefings 2012
Improved Localised Lung Delivery Using Smart Combination Respiratory Medicines
several years later and is another mainstay treatment for asthma and
coPD. formoterol has a rapid onset of bronchodilator action which is
mediated mainly by a relaxing effect on contracted airway smooth
muscle and, as a reliever, gives rapid and sustained relief of
symptoms during an exacerbation.7 A review of the use of BDs and
formoterol in asthma is provided elsewhere.8 Depending upon specific
country requirements and marketing/regulatory approval, both
Advair/seretide and symbicort combination drug products are
available as dry powder inhalation (DPi) or metered dose inhalation
(MDi) formulations in various ratios, with the ics being present in a
five- to ~30-fold mass excess compared with the LABA.
While anticholinergics and β-agonists reduce bronchoconstriction
through different mechanisms, there is also a long history
of combination therapy with these drug classes. The first inhaled
combination therapy introduced in the us was combivent ®
(Boehringer-ingelheim, ridgefield, cT), the combination of ipratropium
and albuterol.9 in a crossover study, combining the standard doses of
ipratropium and albuterol (40 μg and 200 μg, respectively) produced
greater bronchodilatation in 26 patients with stable coPD than did
doubling the standard dose of ipratropium.10
Based on these combination products, it is very clear that the current
therapies aim to provide bronchodilatation; most of them are based
on β-agonists or anticholinergics/muscarinics and are given by
inhalation. Theophylline (phosphodiesterase inhibitor) is the exception
and can be given orally. combinations of bronchodilators improve
effectiveness, improve compliance and reduce costs without
increasing adverse effects.11 The use of combination therapy for the
treatment of asthma and chronic inflammatory disease is now very
topical, with many new combinations of drugs either launched or
close to launch (see Table 1).
Figure 1: National Institute for Health and Clinical
Excellence Guidelines on Chronic Obstructive Pulmonary
Disease Management According to Disease Severity
Breathnessless
and exercise
limitations
FEV1≥50 %
Exacerbations
or persistent
breathnessless
Offer
FEV1<50 %
LAMA
Discontinue
SAMA
LABA + ICS in a
LAMA
combination
Discontinue
inhaler
SAMA
Consider LABA
Offer LAMA in
+ LAMA if ICS
preference to
declined or not regular SAMA
tolerated
four times a day
LAMA + LABA + ICS
in a combination inhaler
*SABAs (as required) may
continue at all stages
Consider
FEV1 = forced expiratory volume in one second; ICS = inhaled corticosteroid;
LABA = long-acting β2-agonist; LAMA = long-acting muscarinic antagonist;
SABA = short-acting β2-agonist; SAMA = short-acting muscarinic antagonist.
Table 1: A Selection of Combination Products for
Asthma and Chronic Obstructive Pulmonary Disease,
either Marketed or in Clinical Development
Company
gsK
Product
fluticasone propinate/
Product type Status
ics/LABA
Marketed
salmererol xinafoate;
Advair®/seretide®
AstraZeneca
Budesonide/formoterol
ics/LABA
Marketed
ics/LABA
Phase iii
ics/LABA
Phase iii (asthma)
fumarate; symbicort®
gsK
euroPeAn resPirATory DiseAse
LABA
LABA + ICS in a
combination
Persistent
inhaler
exacerbations or Consider LABA
breathnessless + LAMA if ICS
declined or not
tolerated
Combination Respiratory Medicines and
Mutual Synergy
Whilst corticosteroid therapy is an effective treatment for airway
inflammation, the use of an ics and an LABA together provides greater
asthma control along with a reduction in the frequency and severity of
exacerbations.12 This superior control is attributed to the complementary
actions of the drugs when taken together, including the activation of the
glucocorticosteroid receptor (gr) by salmeterol, and the effects of
the LABA on other cellular functions related to inflammation in
asthma.13,14 Moreover, it has been reported that clinical trials have shown
that the ‘as-required’, or pro re nata (Prn), use of inhaled combinations
as described above provides clinical advantages over the sole use of a
rapid-acting LABA.15 Whilst there is a rapid suppression of ics-induced
lower airway inflammation when the ics is combined with an LABA,
there is strong evidence that there are synergistic effects on both
inflammation and bronchodilatation. in principle, each drug enhances
the biochemical and pharmacological effects of the other. it is
postulated that, mechanistically, the synergy is related to the effects of
the LABA on the gr function by priming the gr for subsequent
corticosteroid binding.15 in a similar approach, product synergy has also
been demonstrated by using the long-acting muscarinic antagonist r,
r-glycopyrrolate combined with the phosphodiesterase-4 inhibitor
rolipram, the antihistamine azelastine and the corticosteroid BDs on the
release of tumour necrosis factor-α in lipopolysaccharide-stimulated
monocytes.16 interestingly, the use of theophylline in combination with
an ics has been reported to provide potent anti-inflammatory activity
without side effects associated with existing therapies.17
SABA or SAMA as required*
fluticasone furoate/
vilanteriol trifenatate;
horizon®
skye Pharma
fluticasone propionate/
formoterol fumarate;
flutiform®
Merck & co. inc. Mometasone furoate/
ics/LABA
formoterol fumarate;
Marketed
(coPD, asthma)
Dulera®
schering
Mometasone furoate/
Plough-Merck/
indacaterol maleate
ics/LABA
Phase ii (asthma)
ics/LABA
Marketed
ics/LABA
Phase ii (asthma)
novartis
chiesi
Beclomethasone
Pharmaceuticals dipropionate/formoterol
fumarate; fostair®
nycomed
ciclesonide/formoterol
fumarate
novartis
glycopyrronium bromide/ LAMA/LABA
Phase ii (coPD)
indacaterol maleate
Boehringer
ipratropium bromide/
ingelheim
albuterol; combivent®
Boehringer
Tiotropium bromide/
ingelheim
formoterol fumarate
LAMA/LABA
Marketed
LAMA/LABA
Phase ii
(coPD, asthma)
COPD = chronic obstructive pulmonary disease; ICS = inhaled corticosteroid;
LABA = long-acting β2-agonist; LAMA = long-acting muscarinic antagonist.
Thus, given the benefit of a mutual synergistic approach, these
products can demonstrate enhanced efficacy, which in turn can
clinically differentiate the combination product in comparison with
monotherapy. This can eventually lead to the development of a single
3
Drug Delivery
Figure 2: Scanning Electron Micrographs of Ultrasound-mediated Amorphous-to-crystalline Transition
Multi-component Particle (MCP ™ )
Fluticasone propionate/salmeterol xinafoate in 10:1 mass ratio (left); budesonide/formoterol fumarate dihydrate in 100:6 mass ratio (right).
inhaler that can deliver combination respiratory medicine. The
single-inhaler approach to treatment has also been reported to be very
effective in reducing asthma exacerbations7 and it is likely that this will
become widely used for asthma and coPD management in the future
for both children and adults. rather than using salmeterol, which has a
slower onset of action and prolonged systemic side effects, formoterol,
with a faster onset of action and reduced dose, can be used to facilitate
flexible dosing. in addition to using formoterol with BDs, other
combinations of an ics with formoterol are now in clinical development,
including those with beclomethasone dipropionate, fluticasone and
ciclesonide. An MDi formulation of beclomethasone dipropionate
and formoterol has been developed and, thus far, its efficacy as a
maintenance therapy is similar to other combination inhalers.18
furthermore, it has been reported that corticosteroids activate the
β2-receptor gene, increasing receptor density in the airway and
decreasing sensitisation.19 combination therapy for reducing airway
inflammation in patients with coPD is also very topical. it is known that
icss reduce coPD exacerbations, but their beneficial effects on airway
inflammation appear to be limited. The addition of an LABA, however,
not only reduces exacerbations but improves lung function and controls
symptoms to a greater extent than either component alone.20,21
it is worthy of mention that there are safety concerns with the use of
high-dose inhaled LABAs with respect to causing severe asthma
exacerbations and asthma-related deaths in patients who use these
drugs to treat the symptoms of asthma,22,23 although the mechanisms
by which these drugs cause such severe asthma exacerbations and
asthma-related deaths are not known.
Engineering Next-generation Combination
Respiratory Medicines
one important aspect of respiratory combination therapy is the clear
advantages it provides, such as delivering a synergistic effect at the
same target cell in the lung epithelia when the drugs are given
simultaneously.24 This, in turn, highlights the rationale for combining
both substances into one particle rather than having a combination
4
product containing both drugs but in a physical and mechanical
mixture. Whilst the intimate mixing of powdered drugs seems an
ideal way to formulate two or more active ingredients for dry
powder delivery to the lung, it can be difficult to achieve due to
complexities of material chemistry and possible interactions
between the active components. This can be very complicated when
dual and triple therapy options are considered.
With powder blends, the co-deposition of actives (ics and LABA) occurs
randomly when derived from the same aerosolised powder cloud.25 The
most significant challenge is to maintain the ratio of components during
the formulation stage and, importantly, upon re-dispersion and
deposition, although clearly if the particles separate (or are separated)
in the airstream there is little chance of co-deposition. The companies
responsible for multi-component products make every effort to
formulate their drug product with high precision in terms of maintaining
the ratio of individual actives; however, they cannot guarantee this ratio
when the dose is delivered to the actual lung. Despite the number of
publications that cite synergy and the usefulness of co-deposition when
referencing respiratory combination drugs, the data suggesting
consistency of dose and the ratio of actives from formulation to
re-dispersion to co-deposition are scarce or unavailable. This is mainly
because it is difficult to retain the ratios of actives, especially in the case
of inhalation products, when the selected drug substances are present
as micronised particles, in turn derived from mechanical milling.
The industrial practice of mechanically milling large particulate
material in order to produce particles suitable for inhalation can lead
to substantial problems with both the micronised material and its use
in inhaled drug product development. The high-energy process
causes poor chemical and physical stability, electrostatic charge, the
formation of amorphous domains, unwanted surface free energy and
polymorph transition. collectively, these deleterious effects bring
about variation and limitations in performance. 26,27 Micronised
particles can be very cohesive (auto-adhesion), which leads to
significant agglomeration due to higher surface free energy and
surface area per unit mass. in addition to this, the moisture sorption
euroPeAn resPirATory DiseAse
Improved Localised Lung Delivery Using Smart Combination Respiratory Medicines
profile of the material and cohesivity further influence the drug
product rheological properties. furthermore, the high heterogeneity
in particle–particle interaction intensifies the problems of maintaining
the ratio of actives at all stages of the drug delivery profile. This
ultimately affects the therapeutic efficiency and contributes to a
decreased level of drug product performance.
Figure 3: Formulation Performance of Fluticasone
Propionate–Salmeterol Xinafoate 10:1 (EF11162) and
Budesonide–Formoterol Fumarate Dihydrate 100:6
(EF11165) Following Aerosolisation of
Ultrasound-mediated Amorphous-to-crystalline
Transition Combination Particles
Deposition profile - FP:SX 10:1
sonocrystallisation involves the application of power ultrasound to a
processing medium, which in turn leads to the formation of energetic
cavitation bubbles, where crystal nucleation can take place.30,31 The
technology requires the use of a Prosonitron™ ultrasonic flow cell
operating at 20–100 khz. The more robust industrial variant of sAX,
ultrasound-mediated amorphous-to-crystalline transition (uMAX®),
can be used for the manufacture of combination particles with
optimal performance attributes for inhalation, including content
uniformity of the drugs, size, shape, surface rugosity, surface free
energy, crystallinity and stability; the particles being ultimately
designed for asthma and coPD structured drug products.32 uMAX
facilitates the preparation of both spheroidal and more regular
shaped particles for DPi or MDi.
100.0
Percentage
80.0
60.0
40.0
20.0
0.0
Actuator Throat 0
1
2
3
4
5
250 FP EF11162
6
7
Filter
25 SX EF11162
100.0
80.0
60.0
40.0
33.6
33.5
20.0
0.0
5.1
EF11162
FP
5.1
EF11162
SX
FPF (% ex-device), Stage 2-7
MMAD (microns)
Deposition profile - BDS:FFD 100:6
100.0
80.0
Percentage
in order to overcome the considerable problems in the delivery of two
or more micronised drug substances to the lung and ensure optimal
co-deposition and co-location of the molecules, particle engineering
technologies have been conceived to satisfy this unmet need. now
constructive sonocrystallisation particle engineering offers significant
benefits for the manufacture of inhalable drug powders. The solution
atomisation and crystallisation (sAX™) procedure was developed in
order to design respiratory particles with the optimal attributes for their
intended use and involves forming concentrated droplets of a drug
substance solution and treating with ultrasound in order to crystallise
as spheroidal particles.28 The processing of engineered combination
particles of fP–sX by this sonocrystallisation methodology with high
homogeneity and retention of ratio of actives, both in formulation and
deposition, along with analyses to establish the distribution of actives
within the given particles, is described elsewhere.29
60.0
40.0
20.0
0.0
Actuator Throat 0
1
2
3
4
125 BD5 EF11165
5
6
7
Filter
7.5 FFD EF11165
100.0
it is particularly important to consider ics/LABA formulations when
the LABA is low dose strength and is present in the powder blend in
a low concentration, perhaps as low as 1 % weight/weight. in this
instance it is extremely difficult to achieve suitable homogeneity in
the powder blend and, crucially, ensure consistency of the target
mass ratio in the final dosage form. for example, carmoterol
hydrochloride is a very low dosage LABA which is administered by
inhalation, at a very low daily therapeutic dose ranging from 1 to 4 μg,
concurrently with BDs in a mass ratio of up to 100:1. This combination
therapy is in clinical development. Trying to manufacture
compositions by dry powder blending and achieving constant ratio
with each delivered dose is fraught with problems.33 The uMAX
technique starts by preparing a solution of both actives which can be
established by precision weighing. subsequent processing yields
individual particles with the correct ratio of the two actives and with
extremely good blend content uniformity.
using the uMAX technology it is now possible to produce improved
combination products that will help deliver all active respiratory
molecules present in combination with increased airway co-location.
This improved co-location to targeted parts of the lung may help
achieve more pronounced synergy and additive efficacy on the key
target cells and pathologies of inflammation and bronchoconstriction,
euroPeAn resPirATory DiseAse
80.0
60.0
40.0
30.9
28.5
20.0
0.0
5.6
EF11165
BDS
5.3
EF11165
FFD
FPF (% ex-device), Stage 2-7
MMAD (microns)
BDS = budesonide; FFD = formoterol fumarate dehydrate; FP = fluticasone propionate;
FPF = fine particle fraction; MMAD = mass median aerodynamic diameter;
SX = salmeterol xinafoate.
in turn leading to lower doses and improved safety and adherence.34
highly crystalline inhalable-size combination particles of fP–sX
(10:1, PXLB043-112-D1-VD-3, formulation reference ef11162) and
BDs–formoterol fumarate dehydrate (ffD) (100:6, PXLB045-134-e1,
formulation reference ef11165) were manufactured by the uMAX
technology, demonstrating that novel dual therapy for both new
products and lifecycle management via appropriately engineered
multi-component particles can be leveraged successfully (see Figure 2).
The aerosolisation efficiency of the combination particles was
evaluated in MDi formulations using 1,1,1,2-tetrafluoroethane
(hfA134a) propellant. The blend strengths of the fP–sX (ef11162)
and BDs–ffD (ef11165) combination formulations equated to 250 μg
5
Drug Delivery
Figure 4: Multi-kilogram Ultrasound-mediated Amorphous-to-crystalline Transition Equipment – Mobile Minor ™
Spray Dryer (Left), Prosonitron ™ -based sonocrystallisation Module (Middle) and Prosonitron Reactor (Right)
fP/25 μg sX and 125 μg BDs/7.5 μg ffD per actuation, respectively.
Aerodynamic assessment was carried out using an Anderson
cascade impactor (Aci) calibrated at 28.5 l/min flow rate. The mass of
drug deposited on each part of the Aci was determined by
high-performance liquid chromatography (hPLc) and the mass
median aerodynamic diameter (MMAD) and fine particle fraction
(fPf) were determined.
in the design of respiratory combination particles one must consider
not only the total mass of drug deposited on the fine particle stages,
and stages iii–V in particular, of the impactor, but also the uniformity of
delivery of both drug substances. Figure 3 shows the comparison
of the Aci profile in percentage/target for both the combination
products. These data suggest that consistent deposition profiles were
seen for both fP–sX (ef11162) and BDs–ffD (ef11165), indicating
maintenance of co-deposition of both fP–sX and BDs–ffD on various
stages of the Aci. it is to be expected that the use of such engineered
particles will lead to near 100 % co-location and uniform delivery
throughout the full volume of the lung alongside an expected
enhanced synergistic action.
Process Scale-up
The manufacture of up to kilogram scale to current good
manufacturing practice (cgMP) has been demonstrated using a geA
niro Mobile Minor™ spray dryer (see Figure 4). This unit is one of the
smallest industrial spray dryers using either rotary or nozzle
atomisers. This type of system has a water evaporative capacity of up
to 7 kg/h, and 50–100 % greater when volatile solvents are used.
The part-amorphous particles containing both active ingredients in the
prescribed ratio are further ultrasonically treated in a selected
non-solvent (e.g., perfluorodecalin) until the resultant particles are stable
and appreciably crystalline. With respect to pilot scale operation, the
stage ii crystalline transition may be carried out using the Prosonitron
equipment (see Figure 4), using a diverse range of non-solvents
including hydrocarbons, water and fluorohydrocarbons.
actions of the drugs when taken together, including the activation of
the gr by the LABA and the effects of the ics on increasing the
number of β2-receptors. however, there are safety concerns with
the use of high-dose inhaled LABAs, with respect to causing severe
asthma-related exacerbations.
This article has focused on the rationale that improved topical
delivery for combination formulations can be expected if both
substances are co-associated with high homogeneity, rather than
using physical and mechanical mixtures that are not only difficult
to prepare with such homogeneity but are only very poorly
co-associated. Whilst physical mixture combination products offer a
solution to achieve the desired and targeted material mix, the
co-deposition of actives occurs randomly when derived from
the same aerosolised cloud and, as a result, there is inconsistency
in the ratio of deposition in various regions of the lung, despite the
use of a precise formulation mass ratio of the actives. Particle
engineering techniques involving the use of ultrasound can be used
to manufacture microcrystalline dual-component particles for
inhalation drug delivery with high homogeneity, and in particular
particles consisting of an ics and an LABA, as in this investigation.
in turn these particles should facilitate optimal and concurrent
delivery of both drugs to the lung. The uMAX sonocrystallisation
process used for manufacture of such particles circumvents the use
of mechanical milling and, in turn, avoidance of poor and variable
performance, and the effects of comminution on sensitive organic
crystals. These particles can have optimal performance attributes
for inhalation products designed for asthma and coPD.
Conclusions
Particles of BDs–ffD and fP–sX have been engineered and formulated
as an MDi. furthermore, aerosol performance has been assessed by
Aci to identify co-deposition of individual drug particles within the
impactor. The studies to date have shown that these combination
particle formulations are very consistent with respect to the delivery of
each active ingredient at each stage of the impactor, and presented
excellent content uniformity. These improved medicines could help
achieve acceptable efficacy at reduced dose, thus improving topical
delivery due to enhanced safety and mutual synergistic approach.
The use of combination therapy, and in particular the concurrent
delivery of an ics and an LABA, is a mainstay treatment of asthma and
coPD in order to treat inflammation and bronchodilatation in these
debilitating diseases. The Advair/seretide combination of fP and sX
and the symbicort combination of BDs and ffD have been used as
very effective treatments over a number of years. There is now very
compelling evidence for complementary and mutual synergistic
inhaled combination therapy is an exciting area of research in order
to develop improved respiratory medicines, and potentially offers
patients the best medication options for pulmonary disease.
co-associated drugs will not only improve any synergy of action but
may yield opportunities for dose sparing when designing new
ics/LABA structure drug products for respiratory disease. n
6
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Improved Localised Lung Delivery Using Smart Combination Respiratory Medicines
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