Advanced Drug Delivery Reviews: Cristina Loira-Pastoriza, Julie Todoroff, Rita Vanbever

Advanced Drug Delivery Reviews 75 (2014) 8191
Contents lists available at ScienceDirect
Advanced Drug Delivery Reviews

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Delivery strategies for sustained drug release in the lungs

Cristina Loira-Pastoriza 1, Julie Todoroff 1, Rita Vanbever
Advanced Drug Delivery and Biomaterials, Louvain Drug Research Institute, Universit Catholique de Louvain, Brussels, Belgium
a r t i c l e i n f o a b s t r a c t
Available online 8 June 2014 Drug delivery to the lungs by inhalation offers a targeted drug therapy for respiratory diseases. However, the
therapeutic efcacy of inhaled drugs is limited by their rapid clearance in the lungs. Carriers providing sustained
Keywords: drug release in the lungs can improve therapeutic outcomes of inhaled medicines because they can retain the
Pulmonary drug delivery drug load within the lungs and progressively release the drug locally at therapeutic levels. This review presents
Sustained release strategies the different formulation strategies developed to control drug release in the lungs including microparticles and
Polymeric carriers
the wide array of nanomedicines. Large and porous microparticles offer excellent aerodynamic properties.
Liposomes
PEGylation
Their large geometric size reduces their uptake by alveolar macrophages, making them a suitable carrier for
sustained drug release in the lungs. Similarly, nanocarriers present signicant potential for prolonged drug re-
lease in the lungs because they largely escape uptake by lung-surface macrophages and can remain in the pulmo-
nary tissue for weeks. They can be embedded in large and porous microparticles in order to facilitate their
delivery to the lungs. Conjugation of drugs to polymers as polyethylene glycol can be particularly benecial to
sustain the release of proteins in the lungs as it allows high protein loading. Drug conjugates can be readily de-
livered to respiratory airways by any current nebulizer device. Nonetheless, liposomes represent the formulation
most advanced in clinical development. Liposomes can be prepared with lipids endogenous to the lungs and are
particularly safe. Their composition can be adjusted to modulate drug release and they can encapsulate both hy-
drophilic and lipophilic compounds with high drug loading.
2014 Elsevier B.V. All rights reserved.
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
2. Factors affecting the local availability of inhaled compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
2.1. Mechanisms of particle deposition in the lungs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
2.2. Mechanisms of drug absorption from the lungs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
2.3. Clearance of carrier particles in the lungs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
3. Strategies for controlling drug release in the lungs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
3.1. Drug release mechanisms from carrier particles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
3.2. Poorly soluble drugs and coprecipitates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
3.3. Microparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
3.4. Nanomedicines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
3.4.1. Polymeric nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
3.4.2. Micelles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
3.4.3. Liposomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
3.4.4. Solid lipid nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
3.4.5. Dendrimers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
3.4.6. PEGylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
This review is part of the Advanced Drug Delivery Reviews theme issue on Improving the efcacy of inhaled drugs for severe lung diseases: emerging pulmonary delivery strategies.
Corresponding author at: Advanced Drug Delivery and Biomaterials, Louvain Drug Research Institute, Universit Catholique de Louvain, Avenue E. Mounier, 73 boite B1.73.12, 1200
Brussels, Belgium.
E-mail address: [email protected] (R. Vanbever).
1
C. Loira-Pastoriza and J. Todoroff contributed equally to this work.
http://dx.doi.org/10.1016/j.addr.2014.05.017
0169-409X/ 2014 Elsevier B.V. All rights reserved.
82 C. Loira-Pastoriza et al. / Advanced Drug Delivery Reviews 75 (2014) 8191
4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
1. Introduction therapeutic drug concentrations should improve local therapeutic efcacy

and further decrease systemic side effects as the biodistribution through-
Drug delivery to the lungs by inhalation offers a targeted drug out the systemic circulation is minimized. In addition, a sustained-release
therapy for respiratory diseases. The local route of drug administration inhaled formulation could avoid peaks in local drug concentrations that
allows one order of magnitude-lower drug doses to be delivered, com- could be toxic to the pulmonary tissue. This is particularly relevant for
pared to systemic administration by the oral route or by injection. The chemotherapeutic agents. Sustained drug release in the lungs could also
low dosing locally reduces systemic exposure to the drug, and thereby benet to systemically-acting drugs by controlling the rate of drug release
systemic side effects, and increases drug therapeutic index. In addition, and transport into the systemic circulation.
portable inhalers make this route of drug administration convenient for Although sustained-drug release in the lungs presents high potential
the patient. Inhalation aerosols are developed for drug administration to to improve the therapeutic efcacy and safety of inhaled drugs, there is
the systemic circulation as well. The large absorptive surface area of the not yet any sustained-release formulation available in the market. Only
alveoli, the very thin diffusion path from the airspaces into the blood a few sustained-release formulations are in clinical development and all
and the elevated blood ow make the lung a port of entry to the system- are in the form of liposomes (Table 1). In recent years, tremendous
ic circulation. Drug molecules are absorbed more efciently from the efforts in the area have focused on the development of new inhaler de-
lung than from any other non-invasive routes of drug administration. vices and new formulations with the goal to increase pulmonary deposi-
As a result, a continuously increasing number of inhaled drugs are be- tion and its reproducibility. However, a further degree of sophistication
coming available on the market to treat various diseases [1]. in inhalation aerosols could be reached through the development of
However, the therapeutic efcacy of inhaled drugs is limited by their controlled-release formulations.
rapid clearance in the lungs [2]. Small solutes delivered to the lungs This review will present the main parameters involved in the local
quickly diffuse across lung epithelia and penetrate the bloodstream availability of inhaled compounds as well as the different strategies
within minutes. Peptides are rapidly transported to the systemic circu- developed to control drug release in the lungs including microparticles,
lation as well, but are signicantly metabolized locally [3,4]. Although insolubilization and the wide array of nanomedicines.
macromolecules can be absorbed into the systemic circulation over sev-
eral hours, they can be rapidly taken up by alveolar macrophages, they
can be removed by the mucociliary escalator and they can be metabo- 2. Factors affecting the local availability of inhaled compounds
lized locally as well. For instance, recombinant human deoxyribonucle-
ase I is a 37 kDa glycoprotein which cleaves the DNA in respiratory Several factors affect the local availability of drugs following delivery
secretions of cystic brosis patients and thus, lowers their viscosity to the lungs. First, the ability of an aerosol particle to settle in one or an-
[5]. This glycoprotein is the mucolytic agent most widely used in the other region of the respiratory tract depends on its aerodynamic diam-
symptomatic treatment of cystic brosis. However, it is rapidly cleared eter. Second, the pulmonary fate and rate of clearance of a drug from the
from the human lungs: when the daily dose of 2.5 mg is inhaled, a lungs are determined by its physico-chemical and biological properties.
concentration of 3 g/ml is measured in sputum immediately after Third, if the drug formulation is not merely the drug molecule but in-
inhalation and it is reduced to 0.6 g/ml after 2 h. Therefore, its once volves a carrier, the latter must avoid its own pathways of clearance
to twice daily administration provides limited therapeutic coverage to within the lungs.
the patients. The short residence time of drugs within the lungs can
also imply frequent dosing and this can jeopardize patient compliance.
It is for instance recommended to inhale corticosteroids twice daily 2.1. Mechanisms of particle deposition in the lungs
and short-acting 2-agonists up to 4-times daily.
Carriers providing sustained drug release in the lungs could improve The site of deposition of an aerosol particle within the lungs depends
therapeutic outcomes of inhaled medicines. Their objectives are to re- on its aerodynamic diameter (daer) and on the breathing pattern of the
tain the drug load within the lungs for an extended period of time and patient. The aerodynamic diameter of a particle is equivalent to the di-
to progressively release the drug locally at therapeutic levels. Sustained ameter of a unit density (0) sphere that has the same terminal velocity
Table 1
Clinical status of liposome formulations for sustained drug release in the lungs.
Active, registered trade name if any Phase of clinical Indication Ref

development
Amikacine, Arikace III Cystic brosis patients with Pseudomonas lung infection [6,7]
Ciprooxacin, Pulmaquin Management of chronic lung infections with Pseudomonas aeruginosa in patients with non-cystic brosis bronchiectasie
Amphotericine B, Ambisome III Lung transplant recipients [8]
Amphotericine B, Ambisome IIIII Prophylaxis of invasive pulmonary aspergillosis in neutropenic hemato-oncologic patients [9]
Fentanyl, AeroLef II Moderate/severe acute pain in post-surgical setting in adults [10]
9-Nitro-20-S-camptothecin II Non-small cell lung cancer [11]
Ciclosporine I Chronic rejection in lung transplant recipients [12]

C. Loira-Pastoriza et al. / Advanced Drug Delivery Reviews 75 (2014) 8191 83
in still air as the particle: bloodstream within a few minutes following inhalation [22]. Peptides
and small proteins can be subject to local proteolysis and large macro-
r
molecules can be cleared by alveolar macrophages [2,23]. The
daer d
0 prolonged presence of macromolecules within the lungs can be utilized
to sustain drug presence within the respiratory tract by drug conjuga-
where d is the geometric diameter of the particle, is the particle den- tion to macromolecules [21].
sity and is the particle dynamic shape factor denoting deviation of The mechanisms of transport across respiratory epithelia depend on
shape from sphericity [13]. the physico-chemical and biological properties of the drug. Lipophilic
Filtering of large particles (daer N 5 m) occurs in the upper airways drugs are mainly absorbed by passive diffusion through the cells whereas
(mouth, trachea and main bronchi) by inertial impaction. 1 to 5 m daer hydrophilic drugs are absorbed by diffusion through tight junctions. Some
particles deposit by gravitational settling in the central and distal tracts. compounds have been shown to use drug transporters as active mecha-
Particles with daer between 0.1 and 1 m are mostly exhaled. Slow inha- nism of absorption. High levels of drug transporters are expressed in the
lation is generally preferred to minimize inertial impaction in upper air- lungs. Many efux transporters expressed in the intestine, liver, kidney
ways and to increase penetration into the lungs of large particles, or brain are also present in the lungs [24]. For instance, ipratropium bro-
whereas small particles are much less sensitive to fast/slow inhalation mide, an anticholinergic drug, is a substrate of the organic cation trans-
maneuvers [14]. A breath hold gives time to particles that have pene- porter Octn2 and is actively absorbed by this transporter within the
trated deep into the lungs to sediment on airway surfaces. Ultrane tracheal tissue [25]. Moreover, P-glycoprotein-mediated efux has been
(b 100 nm) particles efciently deposit by random Brownian motion shown to prevent pulmonary absorption of rhodamine 123 and
in the respiratory tract: particles b100 nm reach the alveolar region loperamide from the lung airways to the perfusate in an isolated perfused
while particles b 10 nm already deposit in the tracheo-bronchial region rat lung model [26]. Macromolecules can be transported by receptor-
due to their high diffusion coefcients [15]. mediated transcytosis, by para-cellular diffusion (b40 kDa) and/or by
As seen from the equation dening daer, other parameters than the non-specic pinocytosis (N40 kDa) [27].
geometric diameter of the particle are involved in lung deposition. Par- The amount of drug absorbed from the lung into the bloodstream is
ticle density is an important parameter that can adjust daer. Accordingly, generally higher following deposition of particle aerosols in the lung
large (N 5 m) particles can be successfully inhaled deep into the lungs periphery than after particle deposition in the central region of the
as far as their density is low [16]. Particle shape can be designed to target lungs [28]. However, drug transport can occur across both the airway
different regions of the respiratory tract. For instance, bers have an pseudostratied columnar epithelium and the thin alveolar epithelium
aerodynamic diameter few times smaller than their length, which per- [29]. Respiratory epithelia present a tighter barrier to the transport
mits deep lung deposition [17]. Unfortunately, a higher lung toxicity of compounds towards the bloodstream than does the capillary en-
has been reported for elongated particles, compared to spherical parti- dothelium [30].
cles [18]. Charged particles deposit more readily in the lungs than neu-
tral particles [19]. Moisture absorption may increase particle size, which 2.3. Clearance of carrier particles in the lungs
may shift pulmonary deposition upwards [20].
Two major mechanisms are involved in the clearance of particles in
2.2. Mechanisms of drug absorption from the lungs the lungs. Although these mechanisms protect the airways from disas-
trous exposure to foreign materials, they also represent barriers to pul-
It has been reported that lung epithelia are highly permeable to a monary drug delivery. Phagocytosis by lung-surface macrophages is the
wide range of drug types. Lipophilic and non-ionized compounds are main clearance mechanism of microparticles in the lungs. However, it is
transported across respiratory epithelia into the bloodstream more rap- inefcient to clear particles smaller than 200 nm. Semmler-Behnke et al.
idly and in larger amounts than hydrophilic compounds. In general, compared macrophages uptake of 18 nm iridium-192-radiolabeled par-
small hydrophilic compounds (log P b 0) have a mean half-life to ab- ticles and 2.1 m polystyrene particles after inhalation in rats. Twenty
sorption of around 1 h, whereas lipophilic small molecules (log P N 0) percent of the recovered radioactivity was associated with alveolar
are absorbed in approximately 1 min (Fig. 1) [21]. Furthermore, the macrophages over 3 weeks after nanoparticle delivery whereas 80% of
rate of macromolecule transport from the airway lumen into the sys- the recovered microparticles were retained within the alveolar macro-
temic circulation is inversely related to molecular weight. Macromole- phages over the same period [31]. Geiser et al. studied the role of lung
cules with a molecular weight above 40 kDa are absorbed over several surface macrophages in the clearance of inhaled 20 nm titanium dioxide
hours, in contrast to peptides or smaller proteins which reach the particles from rat lungs. They found an uptake of approximately 0.1% of
the inhaled dose by lung surface macrophages over 24 h [32].
The mucociliary escalator eliminates particles and solutes deposited
in the airways [2,33]. Mucociliary clearance velocities in respiratory air-
ways decrease with airway diameter [34]. The mucus velocity measured
in the human trachea is 5.5 mm/min and it is already decreased to
2.4 mm/min in the main bronchi [35]. Mller et al. targeted 100 nm
technetium 99 m-labeled carbon particles to the airways or lung periph-
ery using a bolus inhalation technique in healthy volunteers. A respiratory
aerosol probe allowed aerosol inhalation under controlled breathing con-
ditions and the application of an aerosol bolus to a predened lung depth.
Lung retention of the nanoparticles targeted to the airways and to the
lung periphery was 75% and 96%, respectively, after 24 h [36]. Mucociliary
clearance was the likely cause of the decreased retention following nano-
particle administration to the airways. The composition and clearance of
respiratory mucus are often altered in patients suffering from respiratory
Fig. 1. Drug absorption from the lungs is dependent on drug lipophilicity. The mean diseases and this may affect the fate of inhaled drug carriers. It has been
half-life to absorption is the time needed for half of the molecules deposited in the lungs
to disappear from the tissue. Log P represents the octanol/water partition coefcient.
reported that the thickness of the mucus layer increases from 2 to
Squares represent lipid insoluble molecules, triangles, lipid soluble molecules and inverted 30 m in healthy lungs to more than 250 m in cases of cystic brosis
triangles, molecules with active uptake [21]. and other obstructive airway diseases [37].
3. Strategies for controlling drug release in the lungs Another approach to modulate drug release consists of creating
an insoluble complex with the drug. Insulin forms an insoluble com-
Several formulation strategies have been developed to sustain drug plex with protamine and/or zinc chloride. Insoluble insulin was de-
release in the lungs and particulate carriers have been the most investi- livered as large porous particles to the lungs of rats and provided
gated approach. They allow the release of the drug in a controlled man- sustained plasma insulin levels for half a day, similarly as subcuta-
ner at a therapeutically optimal rate. These systems present several neous injection of the insoluble complex did [48]. Still another ap-
advantages over the soluble drugs namely i) an increased drug residence proach involves the agglomeration of nanoparticles. Nanometer-sized
time in the lungs, ii) a protection of the therapeutic agent against local drug particles can be assembled in micron-sized clusters with the de-
degradation, iii) the possibility to target drugs to specic cells, and iv) a sired aerodynamic diameter. For instance, nanoparticle agglomerates
stability against forces generated during aerosolization. of uticasone exhibited slower dissolution rate than single uticasone
The next paragraph will discuss the different mechanisms involved nanoparticles [49].
in drug release from carriers. Then, the various delivery strategies that
have been developed to control drug release in the lungs will be 3.3. Microparticles
presented.
Conventional inhaled particles with geometric sizes between 1 and
3 m and mass density near 1 g/cm3 are prone to particle aggregation
3.1. Drug release mechanisms from carrier particles
in the dry powder inhaler and to rapid clearance by macrophages in
the lung lumen [16]. The preparation of particles with large geometric
In order to become active locally, the drug should rst be released
size (N5 m) and low mass density (b0.4 g/cm3) may alleviate these
from its carrier. The drug release mechanism from any carrier particle
limitations [16]. The large geometric size of large porous particles
primarily involves drug diffusion through the carrier material. Addition-
(LPPs) leads to ease of particle dispersion. Their small aerodynamic
al mechanisms depend on the drug carrier considered [38].
size, resulting from their low particle density, allows large porous parti-
Drug release from polymeric carriers involves several mechanisms.
cles to effectively escape impaction in upper airways and penetrate
Depending on the polymeric structure, the drug might be released by
deep into the lungs. Apart from excellent ow properties, large porous
diffusion through the polymeric matrix or through pores present in
particles may more easily escape phagocytosis by alveolar macrophages
the carrier. Erosion of the carrier surface or bulk erosion can also lead
due to large geometric sizes and may therefore render the pulmonary
to drug release [33,39]. The high surface area to volume ratio of poly-
administration of sustained-release formulations attainable because of
meric carriers contributes to a rapid drug release from the matrix
diminished clearance of drug particles [16,50,51].
which is called a burst. This phenomenon can be reduced by drug
Poly(lactic-co-glycolic acid) (PLGA) represents the most investigat-
complexation with various agents before encapsulation as well as by
ed polymer for the preparation of sustained-release microspheres for
adding lipid aid excipients to the formulation [40]. Complexing agents
pulmonary administration [41,52]. PLGA is biocompatible and biode-
or lipid aid excipients interact with the encapsulated compound and
gradable. It is an excipient already found in several microsphere prod-
these interactions increase encapsulation efciency as they decrease
ucts for injection in the market. PLGA does not present toxicity toward
the burst [41].
several human airway cell lines in vitro and indication of safety follow-
Drug release from micelles or dendrimers involves drug diffusion
ing pulmonary delivery in vivo has been provided in the mice [41,53].
and micelle or dendrimer break-up. Drug release rate depends on the
However, the FDA has not yet approved PLGA as excipient for inhala-
rate of drug diffusion within the delivery system, the drug partition
tion. The degradation rate of PLGA can vary from 3 weeks to over a
coefcient, the stability of the micelles and the rate of polymer degrada-
year, depending on the polymer molecular weight and lactic acid to
tion [38].
glycolic acid mass ratio. Polymeric microparticles can encapsulate both
The most important mechanism of drug release from liposomes or
hydrophilic or lipophilic compounds, according to particle formulation
solid lipid nanoparticles is drug diffusion through the lipid bilayers or
method.
lipid matrix. Drug release may be modulated by the lipid composition,
In their initial work, Edwards et al. encapsulated insulin into large
the glass transition temperature of the phospholipids and the multi-
porous PLGA particles prepared by the double-emulsion solvent evapo-
lamellarity of the liposomes [38]. For instance, the presence of rigid
ration technique and obtained sustained serum insulin levels for 4 days
phospholipids or cholesterol decreases liposome membrane uidity,
following pulmonary delivery in rats. For comparison, small non-porous
which leads to a less permeable membrane [42].
insulin particles had high serum insulin levels for only 4 h [16]. Several
In addition, drug release from a carrier particle may be triggered by
other research groups have then prepared large porous PLGA particles
different stimuli such as temperature, ultrasounds and pH [43]. Howev-
(Fig. 2) [54,55]. Oh et al. prepared budesonide-loaded large porous
er, except for temperature, these mechanisms have not been reported
PLGA microparticles using the double-emulsion solvent evaporation
yet in pulmonary drug delivery research. Lipid microparticles loaded
method and ammonium bicarbonate as porogen. Budesonide was re-
with budesonide and superparamagnetic iron oxide nanoparticles
leased from the particles in a sustained-manner for 24 h in vitro and the
(SPIONs) presented both thermo-sensitive and magnetic characteristics
particles better reduced inammation in a murine model of ovalbumin-
in vitro suitable for controlled and targeted delivery, respectively. The
induced lung inammation than the free drug or budesonide-loaded
thermo-sensitive lipid system, based on the solid lipid glyceryl behenate,
non-porous particles [56].
allowed slow drug release at body temperature but fast release at hyper-
However, microparticles prepared with PLGA present inherent limi-
thermic temperature [44].
tations. These include the limited drug loading, the burst release of the
drug, the risk of polymer accumulation within the lungs and the core
3.2. Poorly soluble drugs and coprecipitates environment unfavorable to drug stability. Polymeric particles classical-
ly present a maximum drug loading of 10% [55,57], which means that
The intrinsic poor solubility of some drugs such as corticosteroids, they can only be applied to relatively low-dose drugs. In fact, mass
sex hormones and antifungals contributes to sustain drug release in loads that can be inhaled in one inhalation are limited to 25 or 50 mg,
the lungs [45]. For instance, uticasone presents a lower solubility depending on the dry powder inhaler device [58,59]. The initial burst re-
than budesonide and this lower solubility results in a slower absorption lease of the drug originates from drug diffusion from the particle surface
rate from the lungs following inhalation [46]. Estradiol formulated as and the subsequent sustained drug release from the hydrolytic degrada-
large and porous particles provided sustained systemic estradiol con- tion of the polymer mass. Particle porosity increases the particle surface
centrations for 5 days following inhalation in rats [47]. in immediate contact with the release medium and increases the initial
Fig. 2. Scanning electron microscopy images of large porous particles. A and B. PLGA microparticles of celecoxib [55]. C. Albuterol large porous particles [50]. D. Insulin/albumin/
dipalmitoylphosphatidylcholine 5/35/60 w/w/w large porous particles [48].
burst. More than 50% of the drug load can be released within a few PLGA microparticles also resulted in highly porous microparticles, owing
hours and this burst needs to be minimized through optimization of to an osmotic gradient between the particle core and the external aque-
the formulation [55,60]. Polymer accumulation within the lungs might ous phase [63].
arise as drug release proceeds over shorter periods than complete deg- Hydroxypropyl--cyclodextrin has been used as excipient in the
radation of the polymer. Bulk degradation of PLGA creates an acidic core preparation of large porous PLGA particles in order to slow insulin re-
which can damage pH sensitive drugs such as peptides or proteins [61]. lease from the microparticles as well as to optimize the aerodynam-
Osmotic agents have been used to create porosity in PLGA micropar- ic properties of the dry powder [60,64]. The formation of insulin/
ticles. For instance, bovine serum albumin dissolved in the internal hydroxypropyl--cyclodextrin complexes within the microspheres de-
water phase induced osmotic ow between the internal and external creased protein diffusivity in the polymer matrix and thereby decreased
water phases during the double emulsion process, resulting in the fabri- insulin burst and slowed overall insulin release. In addition, the incorpo-
cation of microspheres with controllable, uniform porous structures. ration of hydroxypropyl--cyclodextrin in the internal phase of the
In addition, bovine serum albumin reduced the initial burst of encapsulat- microspheres enabled the formation of porous microspheres due to
ed oppositely charged VEGF from the porous microspheres and sustained osmotic ow towards the internal phase [60]. Large porous particles of
VEGF release for 2 weeks [62]. The incorporation of polyethyleneimine in PLGA/hydroxylpropyl--cyclodextrin/insulin were able to reach the
Fig. 3. The different types of nanomedicines discussed in this review. A. Polymeric nanoparticles. B. Micelles. C. Liposomes. D Solid lipid nanoparticles. E. Dendrimers. F. PEGylated
conjugates.
deep lungs and to release insulin in the alveolar tissue. Insulin was then delivery is not recommended because chitosan opens tight junctions
rapidly absorbed systemically in bioactive form allowing a rapid onset of epithelia and may cause pulmonary edema [76].
of hypoglycaemic effect. The developed large porous particles were tested Coating nanoparticles with inert biocompatible polymers such as
in hyperglycemic rats and exerted a signicant and longer hypoglycemic polyethylene glycol (PEG) represents the most popular strategy of sur-
effect as compared with an insulin solution. face functionalization. Coating particles with PEG creates a hydrophilic
Other materials than PLGA have been used to prepare microparticles and neutral shell that minimizes adhesive interactions of the nano-
for prolonged drug release in the lungs. These include other polymers as particle core with mucus. Particles coated with 2 or 5 kDa PEG have
alginate, chitosan or poly(glycerol adipate-co--pentadecalactone), a been shown to present rapid mucus-penetrating properties whereas
biodegradable polyester, as well as lipids as dipalmitoylphosphatidyl- particles coated with 10 kDa PEG were trapped within the mucus
choline, tristearin, compritol and glyceryl behenate [50,6570]. Inhala- in vitro [77]. In addition, PEGylation of nanoparticle surface might further
tion of large porous particles made of albuterol, lactose, albumin and a safeguard them against clearance by lung surface macrophages [78].
high percentage of dipalmitoylphosphatidylcholine provided protection However, the impact of PEGylating the particle surface on the residence
against carbachol-induced bronchoconstriction for 16 h in guinea pigs time of carrier particles within the lungs has not been explored yet.
[50]. Budesonide release from solid lipid microparticles of compritol
was signicantly longer in vitro as compared to the release from 3.4.2. Micelles
crystalline or amorphous powder of budesonide. The slow release Micelles are colloidal particles formed of amphiphilic block copoly-
can be explained by the complex diffusion process in solid lipid mers or surface active agents [79]. In general, their size ranges from 5
microparticles [67]. to 100 nm. At low concentrations in aqueous medium, the amphiphiles
exist as monomers. Above the critical micelle concentration, the mono-
3.4. Nanomedicines mers self-assemble to form micelles characterized by a hydrophobic
core and a hydrophilic shell. Micelles are used as carriers of poorly sol-
Nanomedicines are a large eld of nanosized systems that can be uble compounds where solubilization occurs in the micelle core. The
divided in two categories: i) nanocarriers which include polymeric loading efcacy of micelles towards hydrophobic drugs ranges between
nanoparticles, micelles, liposomes, and solid lipid nanoparticles and 5 and 25% by weight. In addition, micelles can avoid alveolar macro-
ii) drug conjugates which include dendrimers and polymer conjugates phages uptake due to their small size and bulky hydrophilic outer
(Fig. 3). The sizes of these systems range from a few nanometers to shell and they can prolong drug release [22].
1 m [37]. Nanomedicines are of the same size as biological entities A variety of amphiphilic materials can be used to form polymeric mi-
and can readily interact with biomolecules on both the cell surface celles. The hydrophilic part of the micelles usually comprises PEG with a
and within the cell [2]. The combination of this attractive feature with molecular weight from 1 to 15 kDa. The hydrophobic part may be formed
interesting drug delivery properties has led to the development of a of phospholipids or hydrophobic polymers. Lipid moieties as hydrophobic
wide array of nanomedicines which will be reviewed below. blocks provide additional micelles stability compared to conventional
polymeric micelles: the two fatty acyls of phospholipids increase hydro-
3.4.1. Polymeric nanoparticles phobic interactions between chains in the core of the micelles [79]. Inter-
Nanoparticles are particularly interesting carriers for sustaining estingly, phospholipids that are endogenous to the lung can be selected in
drug release within the lungs because they largely escape uptake by order to create a carrier suitable for pulmonary drug delivery. This is the
lung-surface macrophages and can remain in the pulmonary tissue for case of diacylphosphatidylethanolamine, a constituent of the lung surfac-
weeks [2]. Polymers used to formulate nanoparticles are the same as tant, used to form PEG-diacylphosphatidylethanolamine micelles of size
those used to formulate microparticles and principally include PLGA from 5 to 35 nm [79].
but also poly--caprolactone, chitosan and alginate [71]. However, one Polyethylene glycol-distearoylphosphatidylethanolamine micelles
needs to keep in mind that the same limitations arise for PLGA nanopar- were investigated as carrier for pulmonary delivery of beclomethasone
ticles as for PLGA microparticles. dipropionate. The micelles increased the solubility of beclomethasone
Nanoaerosols require enormous energy for their creation and medi- dipropionate by 1300 times and prolonged its release in vitro. The
cal dry powder inhalers are not capable to disperse nanosized dry pow- drug release from the micelles occurred over 3 days whereas it occurred
der particles. Therefore, nanoparticle drug formulations are most often over a few hours from plain beclomethasone dipropionate. A signicant
delivered to the respiratory tract by nebulization of colloidal suspen- reduction in the inammatory cell counts in bronchoalveolar lavage
sions [72]. The incorporation of nanoparticles within large porous dry uid samples resulted from the intratracheal administration of the
powder particles is another way to administer nanoparticles to respira- beclomethasone dipropionate-loaded micelles, compared to free
tory airways [73]. Once deposited in the lungs, the microparticle carriers beclomethasone dipropionate, in an ovalbumin-induced inamma-
dissociate to yield the nanoparticles with their preserved release prop- tion rat model [80].
erties and inherent pulmonary persistence. Gill et al. loaded PEG-distearoylphosphatidylethanolamine micelles
Ungaro et al. prepared tobramycin PLGA nanoparticles by an with paclitaxel and studied their fate following pulmonary delivery in
emulsion/solvent diffusion technique and embedded the nanoparticles rats. The micelles retarded paclitaxel release over 8 h in vitro and better
in an inert microcarrier made of lactose. Different helper polymers retained paclitaxel within the lungs in vivo than paclitaxel formulated in
were added to PLGA in order to optimize the nanoparticle size, surface, cremophor and ethanol [81].
release properties and encapsulation efciency. Poly(vinyl alcohol) and Todoroff et al. showed that Poloxamer 407 micelles increased the
chitosan allowed to optimize the size and to modulate the surface prop- pulmonary residence time of the model antigen ovalbumin in mice
erties of the PLGA nanoparticles, whereas the use of alginate allowed ef- following their co-administration. The combination of P407 with the
cient tobramycin entrapment within the nanoparticles and its release vaccine adjuvant CpG oligonucleotide induced the highest Th-1 and
up to 1 month in vitro. Spray-drying of the nanoparticles with lactose Th-17 immune responses to M. tuberculosis antigen 85A compared to
led to dry powders presenting good aerosolization properties [74]. the adjuvants alone. The authors hypothesized that the increased vis-
Chitosan coating has been shown to increase the residence time of cosity of the P407 micelles allowed the copolymer solution to act as
PLGA nanoparticles in the lungs, probably due to its mucoadhesive an antigen depot [82].
properties [75]. The antidiabetic drug, palmitic acid-conjugated
exendin-4, was encapsulated in chitosan-coated PLGA nanoparticles. 3.4.3. Liposomes
The drug was released over 3 days in vitro and produced hypoglycemia Liposomes are the only sustained-release strategy for pulmonary de-
over 4 days in mice. However, the use of chitosan for pulmonary livery that has reached clinical development. Liposomes are articial
vesicles formed of lipid bilayers and can encapsulate both hydrophilic gel-to-liquid phase transition temperature resulted in an extended
and hydrophobic drugs. The lipid bilayers are basically composed of dye release prole. Nebulization with a vibrating-mesh nebulizer de-
phospholipids and cholesterol. The polar head and hydrophobic tail of creased the amount of encapsulated dye by 20%.
phospholipids allow the formation of lipid bilayers, whereas cholesterol Antibiotics have been successfully encapsulated in liposomes and
rigidies and stabilizes the liposome membrane. The lipid composition some liposomal antibiotics are in different stages of clinical development.
in liposomes may modulate drug release. For instance, rigid phospho- For instance, Arikace, a liposomal amikacin formulation is in phase III
lipids or cholesterol decrease membrane uidity and lead to a less per- clinical studies for the treatment of Pseudomonas aeruginosa infections
meable membrane for drugs to diffuse through [42]. Liposomes are a in patients with cystic brosis [101103] and in phase II clinical studies
particularly suitable drug delivery vehicle for pulmonary administration for the treatment of nontuberculous mycobacterial lung disease [104,
because liposomes are safe and well tolerated by the lungs. In particular, 105]. The liposomes are made with dipalmitoylphosphatidylcholine and
they can be prepared by using phospholipids and neutral lipids endog- cholesterol in a 2:1 weight ratio [106]. This composition confers a high
enous to the lungs such as dipalmitoylphosphatidylcholine, the major gel-to-liquid phase transition temperature and therefore a high degree
phospholipid of lung surfactant, and cholesterol [83]. In addition, the of membrane stability and reduced amikacin leakage. Amikacin is
versatility in composition can provide various fates of liposomes entrapped efciently in the aqueous core of the 250300 nm liposomes
in vivo [84]. and the overall lipid-to-drug weight ratio was 0.7:1. Liposomal amikacin
Liposomes can be classied in terms of size and number of lipid bi- provided slow sustained amikacin release in normal uninfected rat
layers. Multilamellar vesicles (MLVs) are made of multiple lipid bilayers lungs (Fig. 4). Free amikacin does not easily diffuse in mucus due to elec-
and present sizes from a few hundred nanometers to several microme- trostatic interactions with mucin bers. However, liposomal amikacin
ters. They have a moderate aqueous volume to lipid ratio (14 l/mol penetrates in sputum and biolm and attains access and close proximity
lipid) and better encapsulate lipophilic compounds than hydrophilic to bacteria. In addition, drug release is mediated by virulence factors
ones due to possible incorporation within each lipid bilayer. Large (the rhamnolipids) produced by biolm-localized P. aeruginosa. These
unilamelar vesicles (LUVs) and small unilamelar vesicles (SUVs) have properties make Arikace a therapeutic with reduced dosing frequency
a single lipid bilayer with an aqueous core suitable for encapsulating hy- (once-daily) and greater efcacy in man compared to free aminoglyco-
drophilic compounds. LUVs are larger than 100 nm with an aqueous side therapy (i.e., twice-daily tobramycin) [104,107].
volume to lipid ratio of 7 l/mol lipid. SUVs are smaller than 100 nm A dual release liposomal ciprooxacin formulation (Pulmaquin) is
and present an aqueous volume to lipid ratio of 0.21.5 l/mol lipid in phase III clinical studies by inhalation [108]. This formulation has
[83,84]. Drug release rate is faster from unilamellar liposomes than been developed in order to optimize drug delivery in the management
from multilamellar ones because the drug needs to cross only one bilay- of chronic lung infections with P. aeruginosa in patients with non-
er [38]. cystic brosis bronchiectasis. Although inhaled tobramycin presents
Many different drugs have been encapsulated in liposomes for microbiological efcacy in non-cystic brosis bronchiectasis, it also
sustaining their release in the lungs. These include antibiotics [85,86], increases respiratory adverse events and is poorly tolerated by the
bronchodilators [87,88], immunosuppressants [89,90], anticancer lungs. Pulmaquin is composed of a mixture of free and liposomal cip-
drugs [91], sex hormones [92,93], peptides [94], proteins [95] and oligo- rooxacin which provides an immediate release (free drug) followed by
nucleotides [96]. a sustained release over 24 h (liposomal ciprooxacin). In addition to
Liposomes can be delivered to the human lungs by nebulization of a providing sustained-release, Pulmaquin improves tolerability by min-
liposome suspension or as a dry powder [83,97]. However, nebulization imizing the amount of free irritant antibiotic in direct contact with the
can cause structural disruption of liposomes, which can result in the airway [7,108].
release of the encapsulated drug [98]. Dry powders of liposomes can
avoid stability issues seen with nebulized solutions. They can be pre- 3.4.4. Solid lipid nanoparticles
pared by spray-drying, spray-freeze-drying and freeze-drying followed Solid lipid nanoparticles are stable colloidal carriers made of lipids
by micronization [98100]. solid at both room and body temperatures [109]. They are formed of a
Beck-Broichsitter et al. prepared liposomes with different phospho- solid lipid core stabilized by a surfactant and containing the drug
lipids and cholesterol and adjusted their phase transition temperatures dissolved or dispersed. The rigidity of the lipid core is an important pa-
below and above body temperature [42]. The transition temperature rameter which determines the rate of drug release. Despite the diversity
from the gel to the liquid phase determines whether the liposome of compounds involved in the preparation of solid lipid nanoparticles,
membrane will be rigid or uid at body temperature. The amount of car- they are well tolerated by the lungs and are considered carriers of low
boxyuorescein released from the carboxyuorescein-loaded lipo- toxicity [110,111]. Compared to liposomes, solid lipid nanoparticles
somes correlated well with their membrane uidity and an increase in present the advantage of being more stable physically (e.g., during neb-
ulization) [109].
Solid lipid nanoparticles have been shown to sustain the release of dif-
ferent drugs in the lungs. Li et al. prepared microparticles containing
thymopentin-loaded solid lipid nanoparticles for pulmonary delivery.
The microparticles showed similar sustained release of the systemically-
acting peptide as free solid lipid nanoparticles in vitro. Following delivery
to the lungs in rats, the microparticles resulted in sustained plasma
concentrations of thymopentin over 48 h, whereas the unencapsulated
peptide was cleared from plasma within 1 h [112].
3.4.5. Dendrimers
Dendrimers are three-dimensional structures of hyperbranched ho-
mopolymers and form a tree structure. Dendrimers are composed of
four main regions: an initiator core, interior layers or generations
made of repeated units and attached to the core, terminal surface
groups and spaces in which the drug may be entrapped. Dendrimers
Fig. 4. Clearance of aminoglycosides in rat lungs after inhalation of liposomal amikacin are also called unimolecular micelles because they are formed of an
(75 mg/ml, diamonds) versus free tobramycin (60 mg/ml, squares) [107]. apolar core and a polar shell [38]. Dendrimers can be used as drug
carrier through different mechanisms such as encapsulation within Site-specic PEGylation of calcitonin by 1, 2 or 5 kDa linear PEG in-
dendrimeric cavities or binding to the dendrimer surface by electrostat- creased the peptide stability in rat lung homogenates by up to 3 orders
ic interactions or covalent linkage [113]. Dendrimers increase drug half- of magnitude. As a result, systemic bioavailabilities of the conjugates in-
life, can improve drug solubility and can protect biological tissues from creased up to 8-fold following pulmonary delivery. In addition, the con-
drug toxicity. In addition, the surface of the dendrimers can be modied jugates were much less rapidly removed from the systemic circulation.
by attaching antibodies and ligands and make dendrimers more specic A recent study demonstrated that the conjugation of antibody frag-
to certain tissues or organs [114]. ments to a large PEG greatly prolonged their residency within the
A few studies showed that dendrimers can prolong drug retention lungs. More specically, the coupling of a two-armed 40-kDa PEG
within the lungs. Inapagolla et al. conjugated methylprednisolone to a chain to anti-interleukin-17A (IL-17A) F(ab')2 and anti-IL-13 Fab'
polyamidoamine dendrimer, yielding 12 methyprednisolone molecules sustained their presence within the lungs for more than 2 days. In com-
per dendrimer molecule. The dendrimer was retained in the lungs for 7 parison, unconjugated counterparts were mostly cleared from the lungs
days and improved methylprednisolone efcacy in reducing allergen- within a day. The prolonged pulmonary residency of the anti-IL-17A
induced lung inammation in mice [115]. Ryan et al. showed that increas- PEG40-F(ab')2 translated into an improved efcacy in reducing markers
ing the size of dendrimers from 11 kDa to 78 kDa led to slower absorption of lung inammation in a murine model of house dust mite-induced
from the lungs into the bloodstream and to a more prolonged retention in lung inammation. PEGylated proteins were principally retained within
the lung tissue and airspaces. The largest dendrimers were retained in the the lung lumen rather than the nasal cavities or lung parenchyma. PEG
lungs for up to 7 days, providing potential for controlled drug delivery to increased pulmonary retention of antibody fragments through
the respiratory tissue or blood [116]. Kaminskas et al. conjugated a 56 kDa mucoadhesion and escape from alveolar macrophages rather than in-
PEGylated polylysine dendrimer to doxorubicin to promote the controlled creased hydrodynamic size or improved enzymatic stability [130]. Con-
and prolonged exposure of lung cancer cells to the cytotoxic drug. The jugation of antibody fragments to PEG allowed above 50% drug loading,
dendrimer sustained doxorubicin presence in the lungs for 7 days, which is advantageous for pulmonary delivery because high drug load-
whereas the free drug was rapidly cleared by absorption to the blood- ing limits the increase in mass load to be inhaled.
stream. Twice-weekly intratracheal instillation of the doxorubicin dendri- PEGylation has also been developed to prolong the retention of small
mer led to almost complete regression of lung tumor burden, whereas inhaled drugs in the lungs [131]. Hydrolysable ester conjugates of pred-
intratracheal instillation of the free drug led to extensive lung-related tox- nisolone and 2 kDa PEG reduced prednisolone absorption rate across
icity and death within several days of a single dose [117]. the pulmonary barrier by 7.7-fold following nebulization to the isolated
perfused rat lung. This strategy is based on the correlation between mo-
3.4.6. PEGylation lecular weight and pulmonary retention, as one increases, so does the
PEGylation is a common process used to improve the therapeutic other. This strategy has also been used for the preparation of cisplat-
value of a medicine by prolonging its body residence time. It involves inhyaluronan conjugates for the local treatment of lung cancer [132]
the attachment of one or more PEG chains on the entity and can be ap- and is similar to the dendrimer approach. Interestingly, the administra-
plied to proteins, peptides, particles, small molecules and cells [118]. tion of inactive prodrugs of corticosteroids as PEG ester of prednisolone
Several PEGylated proteins are approved for clinical use by injection. can reduce the incidence of local side effects in the mouth and orophar-
Polyethylene glycol is a neutral linear polyether with a wide range of ynx because inactive drugs deposited in that region will be swallowed
molecular weights. The repeated ethylene moiety along the PEG chain before activation occurs [133].
is responsible for hydrophobicity, whereas oxygen confers strong inter-
actions with water [119]. Consequently, PEG is soluble in both aqueous 4. Conclusion
and organic media. PEG has two important properties, the high exibil-
ity and the high hydration of its backbone. The carboncarbon and car- The strategies to control the release of drugs locally in the lungs
bonoxygen bonds offer extended exibility to the whole polymer, present both advantages and limitations. Large and porous microparti-
leading to a large exclusion volume of approaching molecules. Between cles are free-owing and are easily delivered to the lungs using a
two and three water molecules are bound per repeat monomer unit small breath-actuated dry powder inhaler. Compared to nanocarriers,
[120]. Consequently, the polymer has a hydrodynamic volume ve to the major drawback of microparticles is their greater vulnerability to
ten times higher than that of a globular protein of the equivalent molec- phagocytosis by alveolar macrophages. In contrast, nanocarriers escape
ular weight [121]. The large exibility and hydration of the polymer cre- more easily the clearance mechanisms in the lungs. In addition, their
ate steric hindrance [122]. Steric hindrance excludes proteases, surface can be functionalized in order to affect their interactions with
antibodies and opsonins from the vicinity of the medicine, thereby de- the lung environment and direct their fate in preferential pathways.
creasing degradation of proteins and phagocytosis of particles. In addition, Nanosystems offer wide possibilities in terms of structure and size.
the increased hydrodynamic volume of the PEGylated compound de- However, the increased surface area per unit volume of nanocarriers
creases its clearance by the kidney and contributes to the prolonged may increase the burst release of the drug and their tendency to aggre-
in vivo half-life of the conjugated moitie. PEG is safe, non-biodegradable gate diminishes the ease of their administration to the lungs. However,
and approved by the FDA for use by various routes including the inhala- to facilitate administration to the lungs, nanocarriers can be embedded
tion route in the case of small PEGs [123]. Its safety is assured by its in large porous microparticles.
established usage in foods, cosmetics and drugs [124]. Compared to carrier particles, drug conjugates avoid the need for ex-
PEGylated peptides and proteins have been delivered to the lungs tensive formulation work and can be readily delivered by any current
with different purposes. PEGylated rhG-CSF and PEGylated insulin nebulizer device. In addition, they allow high drug loading of proteins.
were delivered to the lungs in rats and/or dogs in order to test whether The drawback of drug conjugates is that they require a chemistry step.
PEGylated proteins could be absorbed systemically from the lungs The number of excipients approved for inhalation is currently limit-
[125127]. Once in the bloodstream, PEGylated proteins would provide ed. They include some sugars, some amino acids, some lipids and small
sustained plasma concentrations of the protein as they would have been size PEGs [123]. This low number of FDA-approved excipients for inha-
injected. PEGylated rhG-CSF and PEGylated insulin were both absorbed lation represents a limitation to the development of new sustained
from the lungs. However, the extent of systemic absorption decreased release formulations for pulmonary delivery and the use of any new ex-
following PEGylation on multi-protein sites and using large PEGs cipient will require extensive toxicity studies in rodents and non-
(512 kDa PEGs). PEGylation has also been used to protect peptides rodents. Because physiological lipids have little or no cytotoxicity, an
from local proteolysis in the lungs and thereby increase the systemic ab- improved toxicological prole is expected for lipid-based nanocarriers,
sorption of the intact molecule following pulmonary delivery [128,129]. compared to polymeric systems. Polymeric particles may cause lung
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Advanced Drug Delivery Reviews: Cristina Loira-Pastoriza, Julie Todoroff, Rita Vanbever

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Contents lists available at ScienceDirect

Advanced Drug Delivery Reviews

Delivery strategies for sustained drug release in the lungs

1. Introduction therapeutic drug concentrations should improve local therapeutic efcacy

Active, registered trade name if any Phase of clinical Indication Ref

Amphotericine B, Ambisome III Lung transplant recipients [8]

Fentanyl, AeroLef II Moderate/severe acute pain in post-surgical setting in adults [10]

9-Nitro-20-S-camptothecin II Non-small cell lung cancer [11]

Ciclosporine I Chronic rejection in lung transplant recipients [12]

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