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ADR-12687; No of Pages 17
Advanced Drug Delivery Reviews xxx (2014) xxxxxx

Contents lists available at ScienceDirect

Advanced Drug Delivery Reviews

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

Inhaled formulations and pulmonary drug delivery systems for

respiratory infections
Qi (Tony) Zhou a, Sharon Shui Yee Leung a, Patricia Tang a, Thaigarajan Parumasivam a,
Zhi Hui Loh b, Hak-Kim Chan a,
a
Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney, Sydney, NSW 2006, Australia
b
GEA-NUS Pharmaceutical Processing Research Laboratory, Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore

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

Available online xxxx Respiratory infections represent a major global health problem. They are often treated by parenteral administra-
tions of antimicrobials. Unfortunately, systemic therapies of high-dose antimicrobials can lead to severe adverse
Keywords: effects and this calls for a need to develop inhaled formulations that enable targeted drug delivery to the airways
Inhaled antibiotics with minimal systemic drug exposure. Recent technological advances facilitate the development of inhaled
Pharmaceutical aerosol anti-microbial therapies. The newer mesh nebulisers have achieved minimal drug residue, higher aerosolisation
Nebulisation
efciencies and rapid administration compared to traditional jet nebulisers. Novel particle engineering and
Dry powder inhaler
Particle engineering
intelligent device design also make dry powder inhalers appealing for the delivery of high-dose antibiotics. In
Nanoparticles view of the fact that no new antibiotic entities against multi-drug resistant bacteria have come close to
Liposomes commercialisation, advanced formulation strategies are in high demand for combating respiratory super bugs.
Polymeric particles 2014 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2. Inhaled anti-bacterial formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.1. Wet aerosol formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.2. Dry powder formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.2.1. Powder production and particle engineering . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.2.2. Stability of spray-dried powders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.3. Liposomal formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.3.1. Amikacin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.3.2. Ciprooxacin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.3.3. Polymyxins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.3.4. Proliposomes for anti-tuberculosis agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.4. Polymeric formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.4.1. Ciprooxacin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.4.2. Levooxacin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.4.3. Tobramycin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.4.4. Anti-tuberculosis agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.5. Nanoparticle formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.5.1. Amikacin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.5.2. Ciprooxacin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.5.3. Tobramycin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.5.4. Vancomycin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

This review is part of the Advanced Drug Delivery Reviews theme issue on Inhaled antimicrobial chemotherapy for respiratory tract infections: Successes, challenges and the road
ahead.
Corresponding author. Tel.: +61 2 9351 3054; fax: +61 2 9351 4391.
E-mail address: kim.chan@sydney.edu.au (H.-K. Chan).

http://dx.doi.org/10.1016/j.addr.2014.10.022
0169-409X/ 2014 Elsevier B.V. All rights reserved.

Please cite this article as: Q.(T.) Zhou, et al., Inhaled formulations and pulmonary drug delivery systems for respiratory infections, Adv. Drug Deliv.
Rev. (2014), http://dx.doi.org/10.1016/j.addr.2014.10.022
2 Q.(T.) Zhou et al. / Advanced Drug Delivery Reviews xxx (2014) xxxxxx

2.6. Combination formulations of antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

2.6.1. Liquid formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.6.2. Powder formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.7. Combination formulations containing non-antibiotic adjuvants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.8. Bacteriophage formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3. Inhaled antiviral formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.1. Zanamivir . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.2. Laninamivir . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.3. Anti-inuenza drugs under development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
4. Inhaled anti-fungal formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
4.1. Amphotericin B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
4.2. Itraconazole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
4.3. Voriconazole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

1. Introduction Most inhaled antibiotic products focus on the treatment of chronic

Lower respiratory infections are particularly problematic [1], being
the top leading cause of death in the developing countries and the
third leading cause of death world-wide [2]. Apart from the high
mortality and morbidity rates, respiratory infections are also causing
an escalating nancial burden to the global healthcare system.
In general, respiratory infections are difcult to treat because microbes
reside deep in the airways where only a small proportion of drug can ac-
cess after traditional oral or parenteral administration. Consequently, high
doses of drugs are required to maintain drug levels above their minimum
inhibitory concentrations (MIC) at the infection sites [3]. It has been re-
ported that less than 4% of colistin methanesulfonate, an inactive prodrug
of colistin, was converted to its active form after intravenous administra-
tion [4]. To achieve colistin concentrations above its MIC at the site of in-
fection in airways, high doses of colistin methanesulfonate would have to
be administered parenterally to patients. Unfortunately, systemic expo-
sure of high dose colistin can cause severe neurotoxicity and nephrotoxi-
city in up to 60% of treated patients [5]. Delivery of antibiotics directly to
the respiratory tract provides an attractive solution in such situations be-
cause it allows higher drug concentrations to be achieved at the target
site with lower systemic exposures [6]. A pharmacokinetic study involv-
ing the nebulisation of colistin methanesulfonate solution (2 million IU)
in cystic brosis patients clearly demonstrated that high drug concentra-
tions could be achieved in the sputum (Cmax 6 mg/l) and maintained
above MIC90 for a prolonged period (e.g. 12 h) with negligible systemic
drug exposure (Cmax b0.3 mg/l) [7].
In this review, innovative formulation strategies of inhaled drug ther-
apies for the treatment of respiratory infections are discussed. As devices
for inhaled formulations have been reviewed previously [8] and clinical
indications of inhaled anti-microbials are discussed in another article of
this issue [9], they are only briey described here wherein it is relevant
to the formulation design.
2. Inhaled anti-bacterial formulations
To date, only tobramycin and aztreonam solutions have been
approved for nebulisation in USA. Nebulised colistin methanesulfonate
solution (also known as colistimethate sodium, CMS) has been
approved only in some European countries. Other nebulised antibiotics
include amikacin, ciprooxacin and levooxacin, all of which are under-
going clinical trials. For dry powder formulations, only tobramycin
(TOBI podhaler) and colistin methanesulfonate (Colobreathe)
have been approved in USA and Europe, respectively. Dry powder
formulations of ciprooxacin and vancomycin are in the advanced
development stage [10].
respiratory infections such as those in cystic brosis (CF) patients, an
autosomal recessive multi-system condition characterized by recurrent
respiratory infections [11]. Clinical in vivo data have shown that inhaled
antibiotics can decrease the colonisation of Gram-negative bacteria such
as Pseudomonas aeruginosa and delay the onset of infections [12]. Conse-
quently, improved lung function and quality of life can be achieved
along with reduced morbidities and hospital admissions. Nebulised
antibiotics can also be used for non-CF bronchiectasis although no
product has yet been approved for this indication. Compared to CF
patients, the nebulisation of antibiotics may cause more severe local
irritation, including bronchospasm, coughing and wheezing in patients
with non-CF bronchiectasis. Pre-treatment with bronchodilators or
encapsulation of drugs in liposomes may reduce the occurrences or
severity of these adverse events [10].
2.1. Wet aerosol formulations
Nebulisation of antibiotic solutions or suspensions is commonly
employed for the treatment of respiratory infections in both adult and
children [9,13]. During nebulisation, antibiotic liquid aerosols are
generated by mechanical or electrical mechanisms. Recent advances in
nebuliser design have been reviewed elsewhere [9]. Briey, convention-
al jet nebulisers are bulky and generally have low drug delivery efcien-
cies [14], whilst vibrating mesh nebulisers exhibit minimal residual
volume, rapid output and improved drug delivery efciencies despite
its higher purchase price. Other emerging technologies for nebulisation
include surface acoustic wave microuidic atomisation, which
was shown to have a high delivery efciency, with FPF ranging from
7080% [15]. This new technology causes minimal damage to shear-
sensitive biomolecules of plasmid DNA and antibodies [16], thus solving
the problem of drug loss during high shear nebulisation. Today, drug
delivery by nebulisation can also be optimised by digital software
control and performance feedback systems. For example, the
nebulisation of a solution of diethylenetriaminepentaacetic acid in
saline using the I-neb nebuliser equipped with the Adaptive Aerosol
Delivery system resulted in a reasonably high FPF emitted (b4.6 m)
of 56.8% [17].
2.2. Dry powder formulations
Dry powder inhaler (DPI) devices are generally small and portable.
The duration of treatment for DPIs is also short [1820] and this results
in improved patient compliance [21]. Dry powder mixtures of drugs
and/or excipients may also be chemically more stable and less suscepti-
ble to microbial contamination than corresponding liquid formulations

Please cite this article as: Q.(T.) Zhou, et al., Inhaled formulations and pulmonary drug delivery systems for respiratory infections, Adv. Drug Deliv.
Rev. (2014), http://dx.doi.org/10.1016/j.addr.2014.10.022
 Q.(T.) Zhou et al. / Advanced Drug Delivery Reviews xxx (2014) xxxxxx
[2224]. These advantages contribute to the superior treatment ef-
ciencies and patient adherence of DPIs as exemplied by the colistin
methanesulfonate and tobramycin DPIs [19]. However, some powder
formulations may be physically unstable at under conditions of high hu-
midity, which is discussed in Section 2.2.2.
2.2.1. Powder production and particle engineering
Drug particles with aerodynamic diameters ranging from 15 m are
optimal for lung deposition. To obtain ne drug powders in this size
range, jet milling is traditionally adopted by the pharmaceutical indus-
try. However, jet-milled powder is notoriously cohesive because of the
high surface energies of the milled particles [25]. For low-dose drugs
used for the treatment of asthma or chronic obstructive pulmonary dis-
ease, coarse carrier particles are often added to improve powder ow.
However, this approach is unfavourable for high-dose antibiotics as ad-
ditional excipients will increase powder volume which may necessitate
an excessive number of inhalation manoeuvres or makes the multi-dose
inhaler bulky. Therefore, particle engineering becomes an attractive so-
lution for the production of carrier-free (or with minimum carrier)
inhalable powders of antibiotics with good owability and superior
aerosolisation properties [26].
Spray drying is a prime example of a particle engineering technique
suitable for the efcient production of inhalable particles with scale-up
capability. It has been used for the manufacturing of inhaled insulin
(Exubera, Pzer), tobramycin (TOBI podhaler, Novartis) and man-
nitol (Aridol, Pharmaxis).
Leucine is a recognised dispersibility enhancer that is commonly
added into spray-drying feed solution or suspension [27,28]. Weaker
particulate interactions are achieved with low surface-energy leucine
forming a rough shell or coating on the outer surface of spray-dried par-
ticles [2931]. Porous particles of tobramycin and ciprooxacin pro-
duced by spray drying emulsion formulations of these drugs via the
PulmoSphere technology have demonstrated satisfactory ow and
aerosolisation performance [3234]. The PulmoSphere technology in-
volves the preparation of stable emulsions of peruorooctyl bromide
(Perubron) in water containing a pre-dissolved drug by high-
pressure homogenisation, followed by spray drying the emulsion.
Aerosolisation performances of PulmoSphere tobramycin formula-
tions were consistent at different temperatures (1040 C), relative hu-
midities (1065%) and airow rates (4085 l/min) [35]. Such high
aerosolisation efciencies translate to consistent drug deposition pat-
terns in patients with varying inhalation abilities [36]. Additionally,
the good powder owability of the spherical and porous spray-dried
particles reduced the need for carriers to aid manufacturing and
dispersion.
Hollow particles of capreomycin (a second-line anti-tuberculosis
drug) with corrugated surfaces have been produced by spray drying a
feed containing 80% capreomycin and 20% leucine in a co-solvent of
ethanol and water (1:1) [37]. The powder formulation was stable at
4 C for three months, but physically and chemically unstable after
one month of storage under accelerated conditions of 40 C and 75%
relative humidity. This was attributed to the absorption of signicant
amounts of water during storage [37]. In a Phase I clinical study,
administration of the highest dose (300 mg) of inhaled capreomycin
was found to provide a serum concentration of drug above MIC against
Mycobacterium tuberculosis (2 mg/l) for only a short period of approxi-
mately 2 h, with a T1/2 of 4.8 h [38]. In this study, drug concentration in
local airways or in sputum was not measured. Inhaled therapy might
generate a high concentration of capreomycin in respiratory tracts
although systemic drug concentration was low, which deserves
further investigation. Stable, inhalable porous para-aminosalicylic
acid particles have also been produced by spray drying with 1,2-
dipalmitoyl-sn-glycero-3-phosphocholine in ethanol [39] or with
ammonium carbonate [40].
Re-crystallisation enables the production of inhalable crystalline
drug powders that are otherwise unstable in their amorphous forms
Please cite this article as: Q.(T.) Zhou, et al., Inhaled formulations and pulmonary drug delivery systems for respiratory infections, Adv. Drug Deliv.
Rev. (2014), http://dx.doi.org/10.1016/j.addr.2014.10.022
3
after spray drying or milling. McConville and Son developed a novel
dry powder formulation of rifampicin by recrystallising the drug into a
ake-like crystal hydrate using anhydrous ethanol [41]. This formula-
tion was chemically stable for up to nine months under ambient condi-
tions, unlike amorphous rifampicin which underwent approximately
26% degradation during storage. Chan et al. also developed inhalable,
elongated crystals of rifapentine, a long-acting derivative of rifampicin
[42]. The crystalline particles exhibited a high FPF of 83.2% determined
via the Aerolizer device at a ow rate of 100 l/min, and were also
chemically more stable than its amorphous counterpart [42].
Surface coating of cohesive ne particles with force control agents
(e.g. magnesium stearate or sodium stearate) can potentially improve
powder owability and aerosolisation [43,44]. Magnesium stearate
has been approved for inhalation by FDA (Foradil Certihaler,
BREO ELLIPTA and ANORO ELLIPTA) and UK (Pulmicort CFC-
free Inhaler). Qualitative and quantitative data from surface chemistry
measurements have demonstrated that the deposition of an ultra-thin
coating layer (in the nanometer-scale) of magnesium stearate on jet-
milled drug powders by mechanical dry coating can bring a substantial
reduction in their cohesiveness [4346]. Tobramycin powders coated
with 1% w/w of sodium stearate via spray drying also achieved a high
FPF total (particles b5 m over the recovered dose) of 84.3 2.0%
compared to 27.1 1.9% for pure spray-dried tobramycin, measured
via the Aerolizer device at a ow rate of 60 l/min [47]. It is noteworthy
that the choice of excipient is critical to the aerosolisation performance
of coated powders. Belotti et al. showed that the addition of PEG-32
stearate, a surface-active excipient, decreased the FPD of spray-dried
amikacin powder [48].
Advanced particle engineering techniques and intelligent device
designs have contributed to much improved DPI therapies of antibiotics.
However, adverse events of cough and throat irritation are common for
inhaled therapy of high-dose antibiotics in either wet or dry form. There
is a long-term argument on whether wet form is more tolerable by the
patients; however, to date there is no sufcient data from well-designed
clinical studies to conclude. On the other hand, the nature of drug plays
a more important role in the severity of local side effects. This topic has
been discussed in detail in other articles of this issue [9,49].
2.2.2. Stability of spray-dried powders
Amorphous or partly amorphous forms of many small molecule
drugs produced in the spray drying process may be unstable [5052].
Thereby one of concerns on spray-dried drug powders pertains to
their physical and chemical instabilities, particularly for the reservoir-
type inhalers. In an early study, Adi et al. reported that spray-dried cip-
rooxacin powders were amorphous and absorbed signicant amounts
of water of up to 7.9% w/w when exposed to a relative humidity of 50%
[53]. Re-crystallisation occurred at a higher relative humidity of 70%,
demonstrating moisture-induced instability. Co-spray-dried combina-
tion powders of ciprooxacin with 50% w/w mannitol reduced drug
hygroscopicity and prevented the re-crystallisation of amorphous
ciprooxacin [53]. However, the ip side of this is that the addition of
50% excipients would signicantly increase the total amount of powder
required for inhalation and thus may impact convenience.
Recently, Zhou et al. produced carrier-free colistin powders (a
polypeptide) by spray drying. The powders exhibited high FPF total
(b5 m over the recovered dose) values of N 80%, determined via the
Aerolizer at a ow rate of 100 l/min [54]. The superior aerosolisation
performance of the spray-dried colistin powders is attributed to their
rough particle surfaces (Fig. 1a) and low surface energies [55]. It is
noted that unlike many small molecule drugs that may re-crystallise
during storage, the spray-dried amorphous colistin powders remained
stable under ambient conditions, indicating that spray drying was suit-
able for the production of stable, inhalable colistin powder. It was also
found that both the supplied and spray-dried colistin powders absorbed
up to 30% water when exposed to an elevated relative humidity of 90%.
Airtight packaging for each individual dose is highly recommended to
4 Q.(T.) Zhou et al. / Advanced Drug Delivery Reviews xxx (2014) xxxxxx

Fig. 1. SEM micrographs of spray-dried antibiotic powder formulations of: (a) pure colistin (reprint from [54] with permission from John Wiley and Sons); (b) combination of colistin and
rifampicin (reprint from [56] with permission from Springer); (c) combination of ciprooxacin hydrochloride, gatioxacin hydrochloride and lysozyme (reprint from [137] with permis-
sion from Elsevier); (d) combination of moxioxacin, rifapentine, pyrazinamide and leucine (reprint from [144] with permission from Elsevier).

avoid moisture induced instability [54]. In a subsequent study, by coat-
ing the hygroscopic colistin particle surfaces with hydrophobic rifampi-
cin, moisture-induced deterioration in aerosolisation performance of
colistin could be circumvented [56]. Interestingly, data obtained from
time-of-ight secondary ion mass spectrometry and X-ray photoelec-
tron spectroscopy showed that the surfaces of the composite drug par-
ticles were dominated by hydrophobic rifampicin although equivalent
ratios of two drugs were used [56].
2.3. Liposomal formulations
Many inhaled antibiotics are water-soluble and can be absorbed
readily into the systemic circulation, which are consequently cleared.
To maintain drug concentrations above their MICs in the respiratory
tract, liposomal formulations of inhaled drugs are exploited to sustain
drug release, prolong the action of drug in the infection sites and en-
hance bacterial killing. Sustained-release of antibiotics reduces dosing
frequency and improves patient compliance. In addition, liposomal for-
mulations could potentially enable targeted delivery of antibiotics [57].
When delivered to the respiratory tract, liposomes are engulfed and de-
graded by the macrophages with subsequent release of the antibiotics
within them [58] and this mechanism can be exploited to target intra-
cellular infections [59]. Modication of liposomes with mannose could
facilitate active targeting of macrophages with mannose receptors [60,
61]. Some liposomal formulations have been shown tolerated by inhala-
tion and have a good safety prole, which has been discussed in a recent
review of the topic [62]. Table 1 summarises the key studies on inhaled
liposomal formulations of anti-microbials.
2.3.1. Amikacin
Arikace is an inhaled liposomal formulation of amikacin, comprising
the drug encapsulated in neutral liposomes composed of dipalmitoyl-
phosphatidylcholine and cholesterol. In a Phase II clinical trial, Arikace
(280 mg or 560 mg) was nebulised once-daily to cystic brosis patients
infected by P. aeruginosa for 28 days using the eFlow nebuliser [63].
The outcomes of the study conrmed the acute tolerability, safety, biolog-
ical activity and efcacy of the inhaled therapy. Using the same nebuliser,
Li et al. reported a 3035% loss of entrapped amikacin with a FPF of 32.5%
upon nebulisation of Arikace [64]. The loss of encapsulated drug from
liposomes deserves further investigations with other nebuliser devices
in order to understand the role of nebuliser on the performance of liposo-
mal formulations.
2.3.2. Ciprooxacin
Liposomal formulations enable sustained-release of ciprooxacin
[65,66] leading to reduced dosing frequencies and improved treatment
convenience [67]. Clinical data have shown that a nebulised liposomal
formulation of ciprooxacin (Lipoquin) [68] and a combination of
liposomal and free ciprooxacin (Pulmaquin) [67] were both efca-
cious with well-accepted tolerability in CF and non-CF bronchitis pa-
tients. In vitro characterization of these liposomal ciprooxacin
formulations has demonstrated liposome integrity following jet nebuliza-
tion as measured by drug encapsulation, mean vesicle size distribution
[69], and in vitro release prole [70]. The addition of surfactant (0.4%
polysorbate 20) to these formulations resulted in a faster in vitro release
rate [66,71]. In contrast, other conventional liposomal preparations may
have signicantly larger loss of drug encapsulation [64,72]. Additionally,
the physicochemical properties of the liposomal formulations remained
unchanged after storage at 28 C for up to two years [71].
A facile method was developed to produce inhaled liposomal formu-
lations of ciprooxacin by dispersing a powder mixture of micronised
drug and excipients in saline [73,74]. Upon dispersed, over 90% of
drug was encapsulated in the liposomes for the optimised formulations
but the encapsulation was reduced to approximately 50 to 55%
after nebulisation [73]. Such micronised powder exhibited relatively
high FPF of N50% when it was aerosolised by a deagglomeration rig at

Please cite this article as: Q.(T.) Zhou, et al., Inhaled formulations and pulmonary drug delivery systems for respiratory infections, Adv. Drug Deliv.
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 Q.(T.) Zhou et al. / Advanced Drug Delivery Reviews xxx (2014) xxxxxx 5

60 l/min. The encapsulation efciency of aerosolised powder was

Drug encapsulation, vesicle size and in vitro [2,3]

Ref

[1]

[4]

[5]

[6]

[7]

[8]
approximately 35% for ciprooxacin [75]. In a subsequent study, the
encapsulation efciency of reconstituted formulation was improved to
93.5% in isotonic saline, 80% in bovine mucin, 75% in porcine mucus
and 73% in ve-fold-diluted ex vivo human cystic brosis patient

release are stable upon nebulization

24 times lower MICs against many

3035% loss of entrapped amikacin

Pseudomonas aeruginosa, Klebsiella

sputum [76].

Fast release with 50% of colistin

pneumoniae and Escherichia coli
reference and clinical strains of
In addition to sustained-drug release, liposomal ciprooxacin has
also demonstrated enhanced anti-microbial activity [77]. Gubernator
et al. reported that cationic liposomal ciprooxacin formulations

dissolved in 10 min
Faster release rate possessed 24 times lower MICs against most reference and clinical
after nebulisation

strains of P. aeruginosa, Klebsiella pneumoniae and Escherichia coli,

including a two-fold decrease in MIC against resistant strains of
Comments

High FPF
Low FPF
P. aeruginosa [78]. Enhanced anti-microbial effects of the cationic liposo-
mal formulation were attributed to the interaction of positively-charged
liposomes with the negatively-charged bacterial cell membrane [79].
Testing ow
rate (l/min)

Consequently, antibiotics in the liposomes accumulated in the

periplasm, leading to more anti-microbial molecules diffusing into the
cytoplasm [78,79].
12.5

12.5
N/A

N/A

N/A

60

60
63.5 (of the emitted

2.3.3. Polymyxins
aerosol, b4.95 m)

1535% (b4.4 m)
VMD of 3.74 m

Desai and co-workers have produced liposomal formulations of

polymyxin B by a thin-lm hydration technique, with dimyristoyl
phosphatidylglycerol and surfactants of Tween 80 and Span 20 [80].
32.5%

92.5%

The optimised formulation achieved an exceptionally high encapsula-

N/A

N/A
FPF

tion efciency of 100% even after nebulisation. However, it is interesting

to note the liposomal formulation had a much higher MIC (31.3 g/l)
Dispersion device
made in-house
Testing device

against P. aeruginosa (ATCC 27853) than pure polymyxin B (3.9

7.8 g/l) [80]. The possible reason for the reduced antimicrobial activity
Pari eFlow

Pari eFlow

Rotahaler

could be the negative particle surface charge of the liposomes. The

eFlow

N/A

N/A

consensus bactericidal mechanism of polymyxins is that: positively

charged drug molecules bind to negatively charged lipopolysaccharide
(DOTAP), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine

of bacterial outer membrane and cause the rupture of bacterial cells

[81]. The binding to the lipopolysaccharide could be compromised for
negatively charged liposomes, leading to reduced antimicrobial activity.
1,2-Dioleoyloxy-3-trimethylammonium-propane

(DOPE), phosphatidyl-choline (PC), cholesterol

Further investigations are warranted to understand this issue by

Membrane extrusion Polysorbate 20, 0.4% (w/v), hydrogenated soy

comparing positively and negatively charged liposomes.

Membrane extrusion Hydrogenated soy phosphatidylcholine,

l- soybean phosphatidylcholine (SPC),

Using a dry lm method, Wallace et al. encapsulated colistin

sulphate and colistin methanesulfonate in dioleoylphosphatidylcholine
cholesterol from lanolin, mannitol
phosphatidylcholine, cholesterol

liposomes of approximately 180 nm in size and achieved encapsulation

Dioleoylphosphatidylcholine

efciencies of around 50% [82]. Contrary to expectations, the release of

Soya phosphatidylcholine

colistin from the liposomes was rapid, with 50% of colistin dissolved in
10 min and no further release was observed in 72 h. These ndings
differed from the sustained-release proles of colistin liposomes
Major excipient

reported by Wang et al. [83]. Wallace hypothesised that unlike typical

cholesterol

hydrophilic drugs, amphipathic colistin may have increased the

permeability of the liposomal bilayer, enabling more rapid release of
N/A

encapsulated colistin from the core of the liposomes. In a subsequent

study, incorporating colistin in liposomes of azithromycin also
Production method

enhanced the in vitro release of azithromycin and this was attributed

Thin lm method

Dry lm method
Summary of key liposomal formulations of inhaled antibiotics.

by spray drying

by spray drying

to the increased permeability of liposomes by colistin [84]. This study

Proliposomes

Proliposomes

opens up new research opportunities in the application of liposomal

formulations for the delivery of combination antibiotics to the lungs.
Nebulisation (Arikace) N/Aa

2.3.4. Proliposomes for anti-tuberculosis agents

Proliposomes are dry powders which can form liposomes upon
contact with water either before or after administration into the body
[85,86]. Rojanarat et al. developed spray-dried proliposomes of
isoniazid [87]. Data showed the proliposomes possessed a low FPF of
Ciprooxacin Nebulisation

Ciprooxacin Nebulisation
Formulation

Dry powder

Dry powder

1535% (b 4.4 m) due to particle agglomeration [87]. A recent study

showed that soya phosphatidylcholine proliposomes of rifapentine
N/A: not available.
Ciprooxacin Wet

Wet

produced using single-step spray drying, possessed mass median

aerodynamic diameters of 1.56 0.16 m and exhibited surprisingly
Rifapentine

good aerosolisation performance with FPF of 92.5 1.5% measured

Amikacin

Isoniazid
Colistin

via a low-efciency Rotahaler device at 60 l/min [88]. Hence, the choice

Table 1

Drug

of proliposome materials affects not just the drug release prole but also
a

aerosolisation performance.

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6 Q.(T.) Zhou et al. / Advanced Drug Delivery Reviews xxx (2014) xxxxxx

One critical challenge in the assessment of inhaled sustained-release
formulations pertains to the selection of an appropriate in vitro
dissolution method. To date, there is neither regulatory guidelines on
the dissolution testing of inhaled products nor any conclusive answers
to what constitutes the best dissolution medium capable of mimicking
the pulmonary environment [89]. This creates a barrier for quick
prediction of formulation performance and development of generic
liposomal products. In May of 2014, FDA has called research grant
applications to evaluate different in vitro release assays in terms of
their capacity in detecting formulation differences and predicting
in vivo release of liposomal drug products. Recently, Cipolla developed
a dissolution method to evaluate the in vitro dissolution of inhaled
liposomal ciprooxacin formulations in the lungs [90]. Bovine serum
was selected as the release agent that would trigger the release of
drug from the liposomes. The method was robust over a range of release
parameters including release agent, liposomal concentration, incuba-
tion temperature, and buffer pH [90]. An in vitro air-interface Calu-3
cell model was also developed by Ong et al. to evaluate drug release
and intracellular drug transport of liposomal ciprooxacin formulations
on the human epithelium cell lines [91]. Other challenges for the evalu-
ation of liposomal formulations include damage of liposome integrity
upon nebulisation [92] and differentiation of released and encapsulated
drug in vivo. Further fundamental studies are warranted to understand
the drug delivery and therapeutic actions of liposomal formulations.
of many water-soluble antibiotics. Although polyvinyl alcohol (PVA)
and poly (lactide-co-glycolide) (PLGA) have been examined as
polymeric sustained-release agents in many studies in view of their
biocompatibilities and minimal toxicities in in vitro and in vivo studies
[9395], the long-term persistence of these undissolved particles in
the lungs remains a concern as they may trigger pulmonary inamma-
tion and brosis [96]. Furthermore, as foreign particles in the lung
would be removed either by mucociliary clearance or macrophage
uptake, prolonged drug release exceeding i.e. 24 h by means of
polymeric particles is extremely challenging in vivo; however, these
may allow treatment that is targeting pulmonary macrophage (i.e. for
treatment of latent tuberculosis). Hence, in vivo and clinical studies on
the safety and efcacy of inhaled polymeric formulations are needed
to ll this knowledge gap. Key studies on polymeric formulations of
inhaled antibiotics are listed in Table 2.
2.4.1. Ciprooxacin
Sustained-released powders of ciprooxacin and doxycycline have
been prepared by co-spray drying hydrochloride salts of both drugs
with PVA [97]. It was found that the incorporation of PVA slowed
down the release of both hydrophilic antibiotics, with less than 50% of
the drugs dissolved in the pH 7.4 phosphate buffer for the PVA formula-
tion in 6 h compared to more than 90% dissolved for the pure drugs,
measured by a modied Franz diffusion cell [97].

2.4. Polymeric formulations 2.4.2. Levooxacin

Sustained-release of levooxacin has also been achieved by encap-
Investigations into polymeric formulations of antibiotics for inhala- sulating the antibiotic in poly(caprolactone) and PLGA nanoparticles
tion have been conducted to address the rapid-release characteristics via an emulsicationsolvent-evaporation method [98]. Gradual release

Table 2
Summary of key polymeric formulations of inhaled antibiotics.

Drug Formulation Production method Major excipient Testing device FPF Testing Reference
ow rate
(l/min)

Ciprooxacin Dry powder Co-spray drying PVA Aerolizer 25.9% for 60 [9]
and ciprooxacin and
doxycycline 25.8% for
doxycycline
Levooxacin Dry powder Lipid-coated nanoparticles via an emulsication- PLGA, PVA, N/A N/A N/A [10,11]
solvent-evaporation method followed by spray drying phosphatidylcholine, L-
leucine
Tobramycin Dry powder Nanoparticle suspension by the emulsion/solvent PLGA, PVA, chitosan, Turbospin 3852% 60 [12]
diffusion method followed by spray drying alginate, lactose
Isoniazid Dry powder Chitosan microspheres followed by spray drying Chitosan, Cyclohaler 6070% 28.3 [13]
tripoliphosphate, lactose,
L-leucine
Isoniazid Dry powder Chitosan nanoparticles by ionic gelation method Chitosan, Cyclohaler 745% (b5.8 m), 60 [14]
followed by spray drying tripolyphosphate, lactose, 7.811%
mannitol or maldextrose, (b3.3 m)
L-leucine
Rifampicin Dry powder Recrystallization and coating with PLGA/PLA followed PLGA/PLA Aerolizer 2645% 60 [15]
by spray coating
Rifampicin Dry powder Amorphous matrix followed by spray drying PLGA/PLA Aerolizer 2333% 60 [15]
Rifampicin Dry powder Poly-(ethylene oxide)-block-distearoyl phoaphatidyl- mPEG-DSPE w/v) Pari LC Plus 40% 30 [16]
ethanolamine (mPEG-DSPE) nanoparticles followed by nebulizer
lyophilization for rehydration and nebulisation
Rifampicin Dry powder Solvent evaporation of single (w/o) and double PLGA, PVA A model DP-4 3370% 30 [17]
emulsion (w/o/w) with premix membrane dry powder
homogenization followed by freeze-drying insufator
Rifampicin Dry powder Microspheres using single emulsion (o/w) followed by PLGA, sucrose palmitate A model DP-4 52% 30 [18]
freeze-drying dry powder
insufator
Rifampicin Dry powder PLGA nanoparticle containing mannitol microspheres PLGA, mannitol Jethaler dual 35% 28.3 [19]
followed by four-uid nozzle spray drying chamber type
inhalation
device
Rifampicin Dry powder Spray drying PLGA-drug solution PLGA Cyclohaler 2232% 28.3 [20]
Rifampicin Dry powder Spray drying PLA-drug solution PLA Cyclohaler 5570% 28.3 [20]

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 Q.(T.) Zhou et al. / Advanced Drug Delivery Reviews xxx (2014) xxxxxx
of levooxacin-loaded poly(caprolactone) nanoparticles was main-
tained for 6 days whilst the PLGA nanoparticles released approximately
80% of the loaded drug in one day. Lipid-coated polymeric nanoparticles
of levooxacin demonstrated improved biolm afnity and conse-
quently, more superior anti-biolm activity than the pure drugs [99].
2.4.3. Tobramycin
A chitosan-modied PLGA nanoparticle suspension of tobramycin
was prepared by the emulsion/solvent diffusion method [100].
Sustained drug release was achieved in vitro in the pH 7.2 phosphate
buffer for up to 30 days. The MIC of the nanoparticle suspension against
P. aeruginosa was ten-fold higher than pure tobramycin, and severe
in vitro cytotoxicity of the nanosuspension on human alveolar epithelial
cells (A549) was observed. Based on results obtained from the MTT
assay, an approximate 82% reduction in cell viability was observed for
the blank chitosan-modied nanoparticle suspension compared to
50% reduction for the tobramycin-loaded nanoparticles at a concentra-
tion of 1 mg/ml [100]. In the light of these ndings, caution should be
exercised when developing drug-loaded polymeric nanoparticles for
pulmonary delivery.
2.4.4. Anti-tuberculosis agents
Micro- and nano-sized polymeric particles containing encapsulated ri-
fampicin, a rst-line anti-tuberculosis drug, have been investigated exten-
sively. The ake-like dihydrate particles of rifampicin were coated with
PLGA or polylactide (PLA) using a spray dryer equipped with a multi-
channel nozzle to reduce the initial drug release and protect the micro-
crystals from chemical decomposition [101]. The emulsionsolvent-evap-
oration method has also been used to produce PLGA-rifampicin particles
[102105]. Drug loading efciencies and particle size were found to be
highly dependent on the shear forces and formulation parameters such
as aqueous phase volume and polymer concentration [106].
Pre-mix membrane emulsication has also been employed [102,
104,107]. In this technique, a polymer emulsion with narrow particle
distribution is generated through a Shirasu Porous Glass membrane
with known pore sizes into a continuous phase containing surfactants.
Hu et al. showed that the initial burst release of rifampicin from PLGA
microparticles produced by this method could be avoided by coating
with sodium alginate [108]. Other production methods include the
electrostatic drop generation approach for the preparation of sodium
alginate microparticles loaded with 22% rifapentine [109] and an ionic
gelation method for the production of isoniazid-loaded chitosan/
tripolyphosphate nanoparticles [110].
2.5. Nanoparticle formulations
Inhalable nanoparticle formulations are advantageous for the
purposes of improving the solubility and dissolution rates of water-
insoluble drugs as well as minimising premature mucociliary clearance
of drugs [111]. Inhaled nanoparticles could be exhaled during DPI
administration due to their extremely low mass. This problem has
been solved by formulating nanoparticles into inhalable micro-
aggregates via spray drying [112114] or spray-freeze-drying [115,
116] with mannitol [113,116], PVA, or leucine as matrix materials. The
micro-sized aggregates generated by spray-freeze drying exhibited
superior aerosolisation performance compared to those produced by
spray drying [112] and this was attributed to the porous structure and
low density of the particles [116,117]. However, the toxicities of inhaled
nanoparticles deserve further investigations. Key studies on nanoparti-
cle formulations of inhaled antibiotics are listed in Table 3.
2.5.1. Amikacin
Varshosaz and co-workers optimised a solvent diffusion technique
for the production of solid lipid nanoparticles of approximately
150 nm in size with a high drug loading efciency of 88% [118]. Freeze
drying was employed to improve the long-term stability of the
Please cite this article as: Q.(T.) Zhou, et al., Inhaled formulations and pulmonary drug delivery systems for respiratory infections, Adv. Drug Deliv.
Rev. (2014), http://dx.doi.org/10.1016/j.addr.2014.10.022
7
nanoparticles [119,120]. Results showed that the MIC and minimum bac-
teriostatic concentration of amikacin nanoparticles against P. aeruginosa
was less than half of the values for free amikacin, indicating enhanced
anti-microbial activity [119,120].
2.5.2. Ciprooxacin
Nanoparticle suspensions of ciprooxacin base were produced by
sonicating a colloidal dispersion of drug in acetone with L-leucine
added into the suspension as a matrix material. The inhalable aggre-
gates subsequently produced by freeze-drying were characterized by a
high FPF total (b5.8 m) of 81% measured via a Monodose inhaler at a
ow rate of 30 l/min [121]. Furthermore, the nanoparticle agglomerates
exhibited an accelerated dissolution prole compared to the supplied
ciprooxacin base powder [121].
2.5.3. Tobramycin
Nanoparticles of tobramycin were prepared by the conventional
high-pressure homogenisation approach in the presence of a surfactant
(sodium glycocholate) to improve its dispersion [122]. The agglomer-
ates formed by spray drying the drug nanosuspension, exhibited an
FPF (b 5 m relative to the loaded dose) of 61% when determined
using the Aerolizer at a ow rate of 100 l/min [122]. This was signi-
cantly higher than that of micronized tobramycin which was found to
be 36%.
2.5.4. Vancomycin
Savara Pharmaceuticals has developed an inhalable dry powder
form of vancomycin hydrochloride (AeroVanc) [123125]. The
formulation of AeroVanc has not been disclosed but data from a
Phase I clinical study in healthy volunteers reported excellent tolerability
and favourable pharmacokinetic proles [126].
2.6. Combination formulations of antibiotics
Mono-therapy of antibiotics may lead to the development of
antibiotic resistance [127]. Hence, combination therapies containing
different types of antibiotics have been extensively used clinically to
prevent the emergence of drug resistance [128]. Drug combinations
should be carefully selected to exploit any potential synergism or even
antagonism in their anti-bacterial activities. An early study of the anti-
microbial activity of a co-spray-dried combination of ciprooxacin and
doxycycline hydrochloride (1:1) carried out based on the disc diffusion
method revealed minimal changes in the inhibition zone diameter
of the combination against Staphylococcus aureus, P. aeruginosa and
Streptococcus pyrogenes [129]. However, suppressive effects have been
reported for this combination against E. coli [130]. Therefore, both the
measurement method and the target bacterial strain are critical in the
selection of synergistic combinations of antibiotics.
2.6.1. Liquid formulations
The combination of tobramycin with other antibiotics such as
fosfomycin has resulted in synergistic anti-bacterial effects against
S. aureus and P. aeruginosa in both in vitro and in vivo models [131].
MacLeod et al. discovered that fosfomycin enhanced the uptake of
tobramycin in P. aeruginosa in a dose-dependent manner [132].
Co-administration of tobramycin with clarithromycin [133,134] and
colistin [135] also exhibited enhanced anti-biolm activities. Results
of a Phase II clinical trial on nebulised tobramycin/fosfomycin in CF pa-
tients conrmed the clinical anti-microbial efcacy against P. aeruginosa
[136].
2.6.2. Powder formulations
Lee et al. developed a binary formulation comprising hydrochloride
salts of ciprooxacin and gatioxacin as well as a ternary (binary plus
lysozyme) combination of powders via spray drying (Fig. 1c) [137].
The binary combination showed a synergistic anti-microbial effect
8 Q.(T.) Zhou et al. / Advanced Drug Delivery Reviews xxx (2014) xxxxxx
against P. aeruginosa in a time-kill model [137]. The ternary combination
resulted in an indifference interaction against P. aeruginosa, S. aureus,
K. pneumoniae, and Acinetobacter baumannii but may have potential
mucolytic effects [138] in CF patients which deserve further investigation.
Combination powder formulations consisting of tobramycin and other
antibiotics including azithromycin, ceftazidime [139] or clarithromycin,
were also produced by spray drying. Inhalable powders of tobramycin
and ceftazidime were spray-dried with dipalmitoylphosphatidylcholine,
albumin, and lactose with the purpose of producing highly dispersible
porous particles [139]. Contrary to expectations, the spray-dried
combination particles were not porous, possessed relatively low FPF
values (b 4.7 m over the nominal dose) of 2030% and displayed no
synergistic anti-microbial action [139]. Spray drying suspended
tobramycin in clarithromycin solution resulted in powders with
improved aerosolisation performance compared to the corresponding
physical mixture [140]. The FPF (b4.7 m over the nominal dose),
measured via the Axahaler at a ow rate of 100 l/min, increased from
35% (tobramycin) and 31% (clarithromycin) for the physical mixture to
65% and 63% for tobramycin and clarithromycin, respectively, in the
combination formulation [140].
Selective combination powders of colistin and rifampicin were
developed by co-spray drying based on apparent synergistic anti-
microbial activities against A. baumannii [56] and P. aeruginosa. A high
aerosolisation efciency was achieved with an emitted dose of 96%
and FPF total of 92% measured via an Aerolizer device at 100 l/min
[56]. This was attributed to the wrinkled particle shape (Fig. 1b) and
surface coating of rifampicin. The FPF total of pure colistin powder
decreased from 80% to 63.2% when storage humidity increased from
60 to 75%. In strong contrast, the FPF total of the combination powder
was unchanged when relative humidity was increased. It was postulat-
ed that the hydrophobic rifampicin precipitated earlier than colistin on
the particle surfaces during spray drying and this resulted in rifampicin
dominating the surface composition of the particles and providing
moisture protection for the combination powders. This was conrmed
by surface chemistry measurements using X-ray photoelectron
spectroscopy and time-of-ight secondary ion mass spectrometry [56].
Inhalable formulations consisting of rst-line, second-line or a
combination of both classes of anti-tuberculosis drugs have been well
studied to reect current treatment regimens [137,141144]. Advanced
formulations of polymeric particles have been extensively explored for
anti-tuberculosis drugs [141143,145]. In terms of maximising the
delivered dose to the patients, pure drug combinations are preferred.
A key concern in the development of combination formulations pertains
to their physiochemical stabilities. For example, when rifampicin is
combined with either isoniazid, pyrazinamide or both, degradation of
one or more drugs [146] was observed due to the formation of
adduct-rifamycin isonicotinyl hydrazone [145]. A similar phenomenon
was reported in the polymeric particles [145]. In a subsequent study
by Chan, isoniazid and rifampicin were replaced by moxioxacin and
rifapentine [137] and the powder formulation comprising this triple-
combination of the anti-tuberculosis agents was prepared by co-spray
drying (Fig. 1d) [137]. Addition of 10% w/w leucine was found to be
essential to prevent overt crystallisation of pyrazinamide after
long-term storage [137].
2.7. Combination formulations containing non-antibiotic adjuvants
Besides the combination of various antibiotics, the incorporation of
non-antibiotic adjuvants in antibiotic formulations may potentially
enhance their anti-microbial effects. Metallic cations (e.g. iron, calcium
and magnesium) are essential for bacterial growth, microbial adherence
and biolm formation. Metal-ion chelators are hence useful for
combating multi-drug resistant bacteria by binding to these ions [147]
. A combination formulation consisting of an ion chelator, citrate and
taurolidine was shown to inhibit the growth of P. aeruginosa biolms
Please cite this article as: Q.(T.) Zhou, et al., Inhaled formulations and pulmonary drug delivery systems for respiratory infections, Adv. Drug Deliv.
Rev. (2014), http://dx.doi.org/10.1016/j.addr.2014.10.022
[148]. Another ion chelator, lactoferrin, was reported to block biolm
development of P. aeruginosa [149].
Osmotic agents such as mannitol may also be added as adjuvants. In
CF patients, pathogens can reside in the thick mucus which forms an
impenetrable boundary preventing the entry of antibiotics. Using an
in vitro articial mucus model, Yang et al. reported that the combination
of mannitol with ciprooxacin enhanced its anti-microbial effects
against P. aeruginosa [150]. Such effects were attributed to the presence
of mannitol which increased water inux to the articial mucus and
subsequently improved ciprooxacin penetration through the mucus
layer [150]. However, the dose of ciprooxacin in the proportion (5%
w/w) that was investigated in combination with mannitol was low. If
the actual dose of ciprooxacin as used in previous clinical trials
(32.5 mg) [151] was combined with mannitol in a similar ratio, the
total powder mass of each dose could amount up to a total of 650 mg.
Further optimisation in the formulation may reduce the dose of total
powder. Other potential benets of adding mannitol to the inhaled
antibiotic formulation include eradication of bacterial persistent cells
[152,153], improved airway clearance associated with CF [154] and
non-CF bronchiectasis [155].
Other reported non-antibiotic components include deoxyribonu-
clease (DNase, a mucolytic) with enhanced anti-microbial effects on
P. aeruginosa in articial sputum [156] and beclomethasone dipropi-
onate for the treatment of respiratory infections in patients with
chronic obstructive pulmonary diseases [157]. Nitric oxide donors
[158160] and D-amino acids [161] have also been shown in vitro
biolm-dispersal effects.
2.8. Bacteriophage formulations
Phage therapy represents a unique approach for the treatment of
infections based on an anti-bacterial mechanism that is entirely
different from the traditional antibiotics. Bacteriophage is a type of
virus that infects and replicates itself inside bacterial cells. Phages
have also acquired mechanisms to counter bacterial defences [162].
Furthermore, in many cases bacteria at the infection sites are protected
from antibiotic penetration by a biolm barrier. Phages are able to
penetrate the biolm, replicate locally to kill bacteria and can also
potentially restore antibiotic efcacy [163165].
Formulating bacteriophages as inhalable dry powders is generally
preferred to improve patient adherence and product stability. Making
biologically stable phages as dry powders is critical as stability impacts
on the cost and efcacy of treatment. Conventional powder technologies
such as mechanical milling are unsuitable as the energy and stresses
produced are known to cause damage to biopharmaceuticals such as
proteins [166180]. A Canadian aerosol research group led by Finlay
and Vehring has undertaken pioneering studies on the formulation of
phages as powders for inhalation [181,182]. Inhalable powders of
bacteriophage KS4-M and KZ with lactose/lactoferrin (60:40, w/w)
were generated by lyophilisation followed by milling [182]. The
lyophilisation process exhibited an acceptable loss of titre with c. 2
log10s for KS4-M (from 2.3 0.5 1010 to 1.1 0.5 108) and c. 1
log10 for KZ (from 1.7 0.4 109 to 7.8 3.3 108). However, the
FPF total measured at 60 l/min via the Aerolizer was relatively low, in
the range of 3234% over the loaded dose.
Improvements in the loss of titre and aerosolisation have been
achieved by low-temperature spray drying with protective excipients.
Dry powder formulations of bacteriophage KS4-M, KS14 and cocktails
of phages KZ/D3 and KZ/D3/KS4-M, have been produced via spray
drying at an inlet temperature of 75 C and outlet temperatures ranging
from 4045 C [181]. Casein sodium salt and -trehalose were added as
protective agents, surfactants like Tyloxapol and Pluronic F68 as wet
dispersing agents and L-leucine as a powder aerosolisation enhancer.
The optimised formulation had a total lung mass of approximately
70% determined via the Aerolizer at 90 l/min and the titre loss was
 Q.(T.) Zhou et al. / Advanced Drug Delivery Reviews xxx (2014) xxxxxx
Table 3
Key nanoparticle formulations for inhaled antibiotics.
Drug Formulation Production method Major
excipient
Amikacin Dry powder Lipid nanoparticles by solvent Sucrose,
diffusion technique followed by dextrose,
freeze-drying mannitol
Ciprooxacin Dry powder Sonicating a colloidal dispersion of L-leucine
drug in acetone followed by freeze-
drying
Tobramycin Dry powder High-pressure homogenisation Sodium
followed by spray drying glycocholate
Vancomycin Dry powder Low density nanoparticle-clusters N/A
with rough and porous surfaces
less than 0.5 log. Future in vivo studies are needed to further conrm the
efcacies of these new inhaled anti-microbial therapies.
3. Inhaled antiviral formulations
3.1. Zanamivir
Only zanamivir is approved for inhalation use in US (Relenza,
GlaxoSmithKline, Middlesex, UK). In Relenza Rotadisk, each blister
contains a mixture of 5 mg zanamivir and 20 mg lactose [183]. Patients
are to inhale the contents of two blisters, twice a day for ve days.
Signicant reductions in the median time to relieve the symptoms
were reported to be 1.25 days in inuenza positive patients (512
years old) [184]. The Diskhaler is a low resistance device
(0.022 kPa1/2/(l/min)) which generates a ow rate of 90 l/min at a
4 kPa pressure drop across the inhaler [185]. An in vitro study using
the Next Generation Impactor revealed FPF less than 30% even at a
high ow rate of 90 l/min with most of powder retentions found in
the pre-separator (45.4 5.0%) and the device (20.9 5.2%) [185].
Using a breath simulator, generating a peak inspiratory ow of 84 l/
min and 2.78 L of air and a realistic physical airway model instead of a
USP throat, a similar lung dose was obtained [186]. Data obtained
from atomic force microscopy has additionally uncovered doubling
increase of adhesion force (240 nN to 582 nN) between spray-dried
lactose (dv, 0.5 = 150 m with geometric standard deviation of 1.8)
and micronized zanamivir (dv, 0.5 = 2.5 m with geometric standard
deviation of 1.5) when the relative humidity was increased from 32%
to 85% [187]. This nding indicated that the already low FPF could be
further decreased in high humidity.
The low lung dose could be one of the reasons why Relenza gained
poor acceptance in the market. Relenza only managed to dominate
25% of anti-inuenza market in USA when it was rst marketed in
1999/2000 [188]. In addition, worldwide safety warning involving risk
of bronchospasm was then issued which triggered GSK to reduce
marketing for Relenza and further caused the sales to drop even
more [188]. Another reason for the poor acceptance is the difculty in
using the Diskhaler. A survey, conducted in Okinawa during the
2010 u season, found the administration of zanamivir using
Diskhaler to be the most difcult compared with the administration
of oseltamivir (oral tablet) and laninamivir (powder inhaler) [188]. A
randomised controlled trial found that elderly people (N65 years old.),
where 80% of inuenza related death occurs, cannot use the Diskhaler
correctly [189]. Even directly after training, 50% (19 out of 38 elderly
patients) of the subjects failed to load and prime the device correctly.
This number increased to 65% after 24 h of training. Loading and
priming the device consist of too many steps, starting with the
squeezing of the side of the tray to remove it from the device, placing
the Rotadisk in the tray, inserting the tray back into the device and
puncturing the blister. Unless the inhaler is improved, the delivery of
zanamivir to treat inuenza in elderly patients is unlikely to be efcient.
Please cite this article as: Q.(T.) Zhou, et al., Inhaled formulations and pulmonary drug delivery systems for respiratory infections, Adv. Drug Deliv.
Rev. (2014), http://dx.doi.org/10.1016/j.addr.2014.10.022
9
Testing device FPF Testing Comments Reference
ow rate
(l/min)
N/A N/A N/A Enhanced antimicrobial effects [2123]
against Pseudomonas aeruginosa
compared to pure drug
Monodose inhaler 81% 30 Accelerated dissolution prole [24]
Aerolizer 61% 100 Improved dispersion compared to [25]
micronised drug
A capsule-based 80% N/A N/A [2628]
device similar to
Aerolizer
Relenza is a formulation strictly for inhalation. One fatal incident
occurred when Relenza was nebulised and given to a mechanically
ventilated adult patient suffering from severe H1N1 inuenza A. The lac-
tose in Relenza formulation triggered ventilator occlusion causing the
patient to have severe hypoxemia (SpO2 dropped to 7178%) and bilater-
al pneumothoraces [190]. The Relenza manufacturer, GlaxoSmithKline,
further claried that this formulation is not to be reconstituted in any
liquid formulation for nebulisation [191]. The aqueous saline solution of
zanamivir that has been used for nebulisation does not contain lactose
[192].
3.2. Laninamivir
Laninamivir octanoate (LANI) is the newest neuraminidase inhibi-
tors currently only approved in Japan (Inavir, Daiichi Sankyo Company
Ltd, Tokyo, Japan and Biota Pharmaceuticals, Alpharetta, USA). It is an
antiviral drug that has long retention in the lungs and is able to remain
for more than 5 days and hence requires only a single inhalation as
opposed to the twice daily ve days treatment course for zanamivir
[193]. In an animal study, t1/2 (time to half the concentration of LANI
soon after administration) was 41.4 h and even at 120 h post-dose,
concentration of LANI in the lung was considerable higher than IC50
(50% inhibitory concentration) [194]. The median duration required
for fever and u symptoms to disappear was three to four days
(including days of administration) in patients having type A and B inu-
enza, respectively [195].
Patients need to inhale the required dose from a single-use disposable
TwinCaps inhaler (Hovione Farmaciencia, SA, Portugal). TwinCaps is a
high resistance device (0.057 kPa1/2/(l/min)) which generates a ow rate
of 35 l/min at a pressure drop of 4 kPa across the device [196]. A low
ow of 20 l/min was claimed to be sufcient to achieve effective delivery
[196]. Inavir manufacturer, Daiichi Sankyo, further claimed that the
FPF is consistent in the range of 1.2 kPa (corresponding to 19 l/min)
4 kPa and therefore suitable for patients with weak inhalation strength
[197]. However, the FPF values and device retention were not available
in the open literature. Post-marketing surveillance conducted by the
company reported that more that 90% patients, ranging from 2 to
94 years old, were able to achieve sufcient inhalation required for
therapeutic delivery. Children (b 10 years old) are required to inhale a
total dose of 20 mg whilst 40 mg doses are to be inhaled for adults.
The single administration of LANI is commonly done under the supervi-
sion of health care professionals who ensure that the correct inhalation
technique is adhered by the patients. Laninamivir has proven to be
effective to the H1N1/H275Y virus and shown similar clinical efcacy
to zanamivir and oseltamivir against H1N1, H3N2 and inuenza B
viruses [198,199]. Alleviation time for children was shorter with
laninamivir compared to oseltamivir, whilst in adults the alleviation
time is similar [200]. Moreover, animal studies have shown the superior
efcacy of laninamivir against the highly pathogenic avian u virus
H5N1 [201].
10 Q.(T.) Zhou et al. / Advanced Drug Delivery Reviews xxx (2014) xxxxxx

A rotating brush, with a precise speed rate, picks up the particles from the surface of compacted powder and release them at uniform dosing speed into air stream to form aerosol. Varying the reservoir diameter, where powder is loaded, and the
LANI has just completed a randomised, double-blind, placebo-

57 and 59 year old men and

controlled, parallel-arm Phase 2 clinical trial comparing the safety and

18 month old infant [29]

64 year old woman [29]

47 year old female [29]
Model and reference efcacy of a 40 mg and a 80 mg dose to placebo in 639 patients. Interest-
ingly, the study demonstrated a statistically signicant reduction in viral

Rabbit model [32].

Mice model [31].
Mice model [30]
shedding on day 3 for those patients in both the 40 mg and 80 mg
cohorts compared to placebo; however, neither two doses achieved a
statistically signicant reduction in the median time to alleviation of
inuenza symptoms as measured by the Flu-iiQ patient-recorded
outcome questionnaire [202]. The median time to alleviation of inuenza

Corresponding survival rate: 50, 83, 100%

symptoms was 102.3 h for the 40 mg cohort and 103.2 h for the 80 mg
Once daily for 5 days. Nebulisation time:

Once daily for 5 days. Nebulisation time:

cohort, as compared to 104.1 h for the placebo cohort [202]. The reason

Once daily for 3 days. Three different

One capsule daily for 5 days. 10 mg

Once daily for 4 days. Nebulisation

4 min (1st day), 7 min (2nd day),

is unclear that virus shedding did not translate into the alleviation of

doses: 0.5, 1.0, and 1.75 mg/kg.

inuenza symptoms. Therefore, full analysis and understanding of all
the clinical data are essential prior to the further development of inhaled
714 min (3rd5th days)

DAS181 in each capsule

LANI.
Twice a day for 4 days

3.3. Anti-inuenza drugs under development

Dose 1.5 ml/kg
Dosing regime

time: 30 min

It is only a matter of time before a mutated strain(s) emerged

8 min

triggering resistance to the available antiviral drugs that targets the

viral genes which encode the proteins that are susceptible to mutation
deposited = 6.1 mg

deposited = 7.9 mg
Deposited lung dose

[203,204]. Broad spectrum antiviral drugs that do not target these

20.4 mg ribavirin/

viral proteins will then be more valid since it will still be efcacious
kg body weight
5 m) = 68.2%

5 m) = 68.2%
Total DAS181

Total DAS181

despite gene mutations of these viruses. Inhaled anti-inuenza drugs

under development but yet approved are listed in Table 4 including
6570%
FPF (1

FPF (1

DAS181 [205], ribavirin [206], recombinant human catalase [207] and

N/A

N/A

Cidovir [208].
Nebulised (type of nebuliser is not

Rotating brush powder generator

4. Inhaled anti-fungal formulations

Nebulised with Aerotech II (CIS-
Nebulised with Aerogen Pro X

(Palas, Karlsruhe, Germany)a

Immunocompromised patients with malignancy, hematologic

disease, HIV, cancer and organ transplantation are highly susceptible
USA, Bedford, MA)

to invasive pulmonary fungal infections. These infections cause

Delivery method

unacceptably high mortality and morbidity rates (4090%) and become

an alarming healthcare problem [209,210]. A vast majority of the
Aerolizer

specied)

infected cases are caused by Candida spp. and Aspergillus spp. [211].
Oral and/or intravenous administrations of anti-fungal drugs, such as
amphotericin B, ucytosine and a handful of clinically available azole
Stock solution of 10.0 mg DAS181/ml water is

agents, are the mainstay in the treatment of pulmonary fungal

infections [212]. However, these traditional treatments are unavoidably
Dry powder composition is not specied.

associated with different degree of systemic toxicities which often lead

diluted in saline to give 1.3 mg/ml

to early discontinuation of treatments, and hence have poor therapeutic

outcomes. In the last two decades, increasing attention has been drawn
RHC in saline (33,000 U/ml).

to pulmonary delivery of anti-fungal agents for the prevention of inva-

100 mg ribavirin/ml water
1.0 mg DAS181/ml water

piston speed, to change the compaction strength, will give different aerosol sizes.

sive pulmonary fungal infections [213]. Yet, the administration of

Inhaled anti-viral drugs that showed efcacy against different types of virus.

aerosolised antifungal agents is limited to case studies due to the lack

Micronised Cidovir

of sufcient clinical data on their efcacy and safety proles [213,214].

Whilst further well-designed clinical trials are required to establish
Formulation

their therapeutic roles and risks, here we will provide an update on

the recent developments of anti-fungals designed for aerosol delivery
(Table 5).
H3N2 inuenza

H1N1 inuenza

Smallpox virus
parainuenza

4.1. Amphotericin B
Target virus

Human

virus 3

Amphotericin B, which is a membrane-active polyene macrolide

virus

virus

antifungal agent, has been the most commonly used therapy for the
treatment of life-threatening pulmonary fungal infections and the
protein with sialidase activity)

High dose ribavirin to shorten

Recombinant human catalase

most thoroughly studied agent for inhalation administration [215].

Liposomal amphotericin B dry powder inhaler formulation was
DAS181 (a recombinant

developed by Shah and Misra [216]. However, majority of the studies

are intended to demonstrate the feasibility of nebulising commercially
treatment time

available formulations, including Fungizone (a deoxycholate formula-

tion), Ambisome (liposome-based formulation), Abelect and
Amphotec (lipid-based formulations). The corresponding pharmaco-
Cidovir
(RHC)
Table 4

kinetics properties and safety proles have been summarised in Kuiper

API

and Ruijgrok [217]. In brief, the liposomal and lipid-based formulations

Please cite this article as: Q.(T.) Zhou, et al., Inhaled formulations and pulmonary drug delivery systems for respiratory infections, Adv. Drug Deliv.
Rev. (2014), http://dx.doi.org/10.1016/j.addr.2014.10.022
 Q.(T.) Zhou et al. / Advanced Drug Delivery Reviews xxx (2014) xxxxxx 11

Table 5
Formulations of inhaled anti-fungal drugs.

Drug Formulation Production method Major excipient FPF Device Test Reference
ow
rate (l/
min)

Amphotericin Liposomal Commercially available as Hydrogenated soy 18.5% Atomiser NL9M 15 [33]
B formulation for AmBisome for injection phosphatidylcholine
nebulisation (48%), cholesterol (24%),
distearoylphosphatidylglycerol
(19%)
Suspension for Chitosanstearic acid conjugate Chitosanstearic acid with 17 4052% Air-jet nebuliser 60 [34]
nebulisation nanomicelles by solvent evaporation or 60% substitution degree
(6095% w/w)
Suspension for Non-ionic surfactant vesicles Hydroxypropyl-- 421% Buxco nebulisation 60 [35]
nebulization cyclodextrin: system
amphotericin B = 100:1 w/w,
lipids including
Mono-n-hexadecyl
ether tetraethylene glycol,
cholesterol, and dicetyl
phosphate (30 and 150 mM)
Itraconazole Suspension for Crystalline nanoparticles Mannitol (30%), leucine (12%) 4754% Aeroneb 28.3 [36]
nebulisation by wet-milling and
amorphous nanostructured
aggregated by ultra-rapid freezing
Suspension for Crystalline nanoparticles Polysorbate 80 (14%) N/A Pari LC Plus, Medel N/A [37]
nebulisation by wet-milling Jet Basic, Multisonic
and Pari eFlow
Dry powder Chitosan-based nanoparticle Lactose (2.520% w/w), 1643% Cyclohaler 60 [38]
by ionic gelation, then mannitol (2.520% w/w),
spray drying nanosuspension leucine (010% w/w)
Dry powder Crystalline nanoparticles by TPGS (3.2%), mannitol (64.5%), 4663% Axahaler 100 [39]
high-pressure homogenization, sodium taurocholate
then spray drying nanosuspension (0.30.9%)
Dry powder Spray drying drug solution with excipients Mannitol (6190%), 4767% Axahaler 100 [40]
phospholipid (0.363.47%)
Voriconazole Dry powder by spray Crystalline microparticles in the PVP K12 (33%), PVP K30 543% Handihaler 60 [41]
drying micro-nano- absence of excipients and amorphous (2533%)
suspensions nanostructured aggregated in the presence of
excipients by thin lm freezing

were nebulised better with higher local drug concentration and no
negative effect on pulmonary surfactant when compared with the
deoxycholate formulation. It is believed that the detrimental effect on
lung function may be related to the deoxycholate component.
Therefore, the recent work has been focused on studying the liposomal
or other encapsulated formulations.
Fauvel et al. [218] investigated the in vitro aerosol performance of
liposomal amphotericin B delivered by a Atomiser NL9M nebuliser
with an AOBOX compressor and conrmed the ability to deliver the
liposomal formulation to the alveolar compartment. They also tested
the drug uptake and toxicity of drug at concentrations achievable by
nebulisation on the A549 human lung epithelial cell line. Drug
concentrations above the MIC of most Aspergillus species were reported,
but amphotericin B approached levels potentially being cytotoxic to the
cells. Their ndings could possibly explain the inconsistency in the
safety prole observed in various clinical studies [217] when different
nebulisation set-ups and/or protocol were used.
Gilani et al. [219] specically formulated amphotericin B for jet
nebulisation using chitosanstearic acid conjugate nanomicelles as the
carrier. A solvent evaporation technique was used to incorporate the
drug into nanomicelles in a size range of 101248 nm with encapsula-
tion efciency up to 97%. They found that the micelle size was decreased
with increasing drug loading, which was attributed to the enhanced
hydrophobic interaction between adjacent drug and stearic acid
molecules. Whilst comparable antifungal activities were obtained
between the micelle formulations and Fungizone, the micelles
possessed less aggregated amphotericin B which is responsible for
systemic toxicity. The air-jet nebulised nanomicelle formulation
showed a FPF (b6.4 m) of 52% without compromising on drug
stability after nebulisation. Alsaadi et al. [220] formulated amphotericin
B-hydroxypropyl-g-cyclodextrin (1:100 w/w with 1 mg/ml amphotericin
B) complex into non-ionic surfactant vesicles which was composed of
mono-n-hexadecyl ether tetraethylene glycol, cholesterol, and dicetyl
phosphate in a 3:3:1 molar ratio (30 or 150 mM lipid). The formulations
were freeze-dried to extend the shelf-life and then rehydrated with water
for nebulisation using a Buxco nebulisation system to treat leishmania-
sis. A treatment with 5 doses of aerosolised non-ionic surfactant vesicle
formulation (once daily for 5 consecutive days with a total dose of
12.65 mg drug/kg) exhibited enhanced anti-fungal performance com-
pared with treatment using amphotericin B-dextrin solution in a mice
model.
4.2. Itraconazole
Itraconazole is a highly hydrophobic and weakly basic broad spec-
trum anti-fungal azole available as oral and intravenous formulations
(e.g. Sporanox). There are strong interests to develop inhalable formu-
lations of itraconazole because of its low aqueous solubility (1 ng/ml at
pH 7), coupled with the requirement of a high therapeutic concentra-
tion (0.5 g/g lung tissue or 0.5 g/ml blood), as well as its poor and
erratic absorption characteristics [221]. Even so, improving drug disso-
lution and/or solubility remains a challenge for pulmonary delivery of
itraconazole to treat invasive pulmonary aspergillosis. A common
strategy to enhance the dissolution rate of poorly water-soluble drugs
is to reduce the drug particle size to the nanometer scale, which results
in very large specic surface area for dissolution [222,223]. Particle en-
gineering techniques, including evaporative precipitation of aqueous
solution (100500 nm), spray freezing into liquid (2050 nm) and

Please cite this article as: Q.(T.) Zhou, et al., Inhaled formulations and pulmonary drug delivery systems for respiratory infections, Adv. Drug Deliv.
Rev. (2014), http://dx.doi.org/10.1016/j.addr.2014.10.022
12 Q.(T.) Zhou et al. / Advanced Drug Delivery Reviews xxx (2014) xxxxxx
ultra-rapid freezing (2050 nm), have been used in the past decade to
prepare nanostructured itraconazole dispersions for nebulisation.
Major ndings are summarised in Yang et al. [224]. Briey, nebulised
itraconazole nanoparticle formulations were able to deliver the drug
to the alveoli; improved bioavailability and in-vivo prophylactic effects
of inhaled itraconazole formulations were achieved compared with the
Sporanox oral formulation [224].
Whilst particle size reduction signicantly enhances the dissolution
rate of itraconazole, the potential impact of polymorphs on the solubil-
ity of drug was also recognised. Yang et al. [225] compared the bioavail-
ability of nano-crystalline and amorphous itraconazole formulations,
which were prepared by wet-milling and ultra-rapid freezing
techniques, respectively. Single-dose (20 mg/ml in 5 ml suspension)
was nebulised to SpragueDawley rats using a nose-only dosing
apparatus. They found that the systemic bioavailability of the amorphous
formulation (peak concentration of 180 ng/ml at 4 h after dosing) was 3.8
times higher than that of the crystalline counterpart, despite similar aero-
dynamic performance and lung deposition of the two formulations. This
was attributed to the rapid dissolution of the amorphous nanoparticles
and higher levels of supersaturation which was dened as the ratio of
drug concentration to the equilibrium solubility (4.7 times of the crystal-
line formulation). A wet-milled itraconazole nanosuspension containing
polysorbate 80 (itraconazole: polysorbate 80 = 86:14, 10% total solid
content) was shown to improve bioavailability in a rat model [221]. A
dose of 22.5 mg/kg was nebulised and a systemic peak concentration of
104 ng/ml 4 h after dosing was reached. This formulation could result
in longer exposure of the lung tissue to itraconazole (14.3 g/g lung tissue
24 h after dosing). Such features are important for a poorly water-soluble
drug to enhance its efcacy, but drug dosing should be carefully consid-
ered to avoid systemic toxicity.
For the development of DPI formulations, Jafarinejad et al. [226]
employed a modied ionic gelation approach to encapsulate itraconazole
into chitosan-based nanoparticle (190240 nm) with an encapsulation
efciency of up to 55%. The nanosuspension was then spray dried with
and without excipients (lactose, mannitol and leucine) to produce
inhalable microparticles. The highest FPF obtained was 43% for a formula-
tion containing 10% mannitol and 10% leucine using a Cyclohaler at
60 l/min for 4 s. A nanoparticle-based dry powder formulation was also
proposed by Duret et al. [227]. Itraconazole suspensions were produced
by high-pressure homogenization and stabilised by 10% tocopherol
polyethylene 1000 (10% w/w), then co-spray dried with mannitol and/
or sodium taurocholate. They found that the nanoparticle formulation
has a much higher FPF (46.263.2%) and solubility (5896 ng/ml)
compared to the microparticle-based itraconazole formulations
(23.1% and b10 ng/ml). Amorphous dry powder formulations were
prepared by spray drying itraconazole solution with mannitol and/
or hydrogenated soy-lecithin (phospholipid) as excipients. High
FPF (46.967.0%) was obtained and the addition of phospholipid
(10%) resulted in a signicantly higher dissolution rate [227]. Duret
et al. [228] compared the bioavailabilities of three itraconazole-
containing dry powder formulations: micronized crystalline powder,
amorphous powders with and without phospholipid. A single dose
(0.5 mg/kg) of each of the powders was endotracheally insufated
into mice. The amorphous formulations had a higher systemic
bioavailability (plasmatic AUC 024 h of 491.5 ng/ml without
phospholipid and 376.8 ng/ml with phospholipid) compared with
the micronized crystalline itraconazole formulation (182 ng/ml).
Though the addition of phospholipid increased the wetting and
absorption of the itraconazole powders, a faster elimination rate from
the lung tissue was also observed (elimination half-life of 4.1 h). On
the other hand, amorphous powders without phospholipid had an
extended pulmonary retention (elimination half-life of 14.7 h), even
higher than the crystalline formulation (elimination half-life of 6.5 h).
With the improved local bioavailability, careful dosing of the dry
powder formulations may achieve sufcient anti-fungal activity with
minimum systemic toxicity.
Please cite this article as: Q.(T.) Zhou, et al., Inhaled formulations and pulmonary drug delivery systems for respiratory infections, Adv. Drug Deliv.
Rev. (2014), http://dx.doi.org/10.1016/j.addr.2014.10.022
4.3. Voriconazole
Voriconazole is a broad-spectrum anti-fungal agent and available as
oral and intravenous products (e.g. Vfend and Captisol). Though it is
700 times more soluble than itraconazole, its low aqueous solubility
(0.61 mg/ml at pH 7) remains a challenge in formulation design. The
efcacy of inhaled voriconazole therapy was demonstrated in three life-
threatening invasive aspergillosis cases when systemic voriconazole
treatments were withdrawn due to severe adverse effects [214].
Intravenous formulation was nebulised to introduce 40 mg voriconazole
to patients without attempts to control their respiratory pattern. After a
3 month treatment, all patients were reported to return to good
conditions with minimal or no adverse effects reported during and
6 months after the therapy.
Dry powder-based inhalation formulations of voriconazole were
developed by Beinborn and co-workers using a thin lm freezing
technique [229]. Various process parameters, type/grade of stabilising
excipient, drug to excipient ratio, solvents and solid contents were
examined [229]. Whilst microstructure low density crystalline aggre-
gates (specic surface area = 10 m2/g) were produced in the absence
of excipients, addition of PVP as a stabilising agent produced low density
amorphous nanostructure voriconazole aggregates (specic surface
area = 15180 m2/g). When the powders were assessed using a
Handihaler at 60 l/min, the highest ne particle fraction was obtained
in an excipient-free formulation (42.4%) and a formulation stabilised by
PVP K12 at a drug to excipient ratio of 1:2 (43.1%). In a follow up study
[229], the microstructure crystalline voriconazole gave more favourable
pharmacokinetics in lung tissues (AUC024 h = 452.6 g h/g) compared
with the amorphous nanostructure aggregates formulation (AUC0
24 h = 232.1 g h/g) after a 10 mg/kg insufated dose. The low retention
of voriconazole in the lung tissue for the amorphous nanostructure ag-
gregates was attributed to its faster dissolution rate, similar to the nd-
ing of adding phospholipid to the amorphous microparticle itraconazole
formulation [228]. In such case, the benets brought by faster dissolu-
tion were out-weighed by the rapid elimination of drugs from the
lungs as well as the potential risk of getting plasma peak
concentration related side effects.
5. Conclusions
Inhaled anti-microbial therapy is an emerging and rapidly expanding
area. As systemic exposure of many high-dose anti-microbials can cause
severe adverse effects, inhalation therapy provides an attractive solution
that allows the establishment of high localized drug concentrations in the
respiratory tract with minimal systemic drug exposure. In reality, it is
challenging to formulate high-dose anti-microbial agents into inhaled
dosage forms as the dose, dosing frequency and site of action of inhaled
antibiotics are substantially different from those for asthma and chronic
obstructive pulmonary disease. Delivery of high-dose drugs via tradition-
al nebulisation may require lengthy treatment durations. High drug doses
in a DPI also preclude or limit the use of carriers or other functional
excipients as these would signicantly increase the bulk volume of total
dose and necessitate a bulkier device or a larger number of doses. Techno-
logical advances are essential to maximise drug delivery efciencies and
convenience of use.
Nebulisation is still the mainstay of inhaled therapy for the treat-
ment of respiratory infections. However, traditional jet nebulisers,
with their long administration times and low delivery efciencies, do
not meet the stringent requirements of inhaled high-dose antibiotics.
These problems have been largely solved by the development of mesh
nebulisers. Apart from nebulisers, DPIs are also becoming popular and
have attracted rising interest in recent years for the delivery of inhaled
high-dose antibiotics. Their popularity stems from their enhanced sta-
bilities, the ability to administer high drug doses within relatively
shorter durations of time and ease of use. Cough and throat irritation
are some common problems caused by the inhalation of high-dose of
 Q.(T.) Zhou et al. / Advanced Drug Delivery Reviews xxx (2014) xxxxxx
antibiotics in both liquid and powder forms, which can be minimised.
With advanced particle engineering techniques and intelligent inhaler
designs, it is expected that the delivery performance and patient adher-
ence of antibiotic DPIs would improve further.
Liposomal, polymeric and nanoparticle formulations of inhaled
antibiotics are advanced drug delivery systems designed for the
purposes of targeting drug delivery, sustaining drug release and
enhancing the anti-microbial activities of antibiotics in the lungs. In
vivo safety and efcacy evaluations particularly clinical studies are
essential to the further development of such advanced formulations.
Given that no new antibiotics are in the advanced development stage
against Gram-negative multi-drug resistant bacteria, innovative
formulations of existing antibiotics are of paramount importance to
win the long-term war against the respiratory super bugs.
Acknowledgement
The authors acknowledge the nancial support from the Australian
Research Councils Discovery Projects funding scheme (DP120102778)
and the National Health and Medical Research Council's (NHMRC)
Project Grant funding scheme (APP1065046). Qi Tony Zhou is an
NHMRC Early Career Fellow (APP1053528). Thaigarajan Parumasivam
is a recipient of Malaysian Government scholarship.
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