Advanced Adv Pharm Bull, 2016, 6(1), 57-64

Pharmaceutical doi: 10.15171/apb.2016.009

Bulletin http://apb.tbzmed.ac.ir

Research Article

Aggregated Nanotransfersomal Dry Powder Inhalation of Itraconazole

for Pulmonary Drug Delivery
Mehdi Hassanpour Aghdam1, Saeed Ghanbarzadeh2,3, Yousef Javadzadeh4, Hamed Hamishehkar3*
1
Research Center for Pharmaceutical Nanotechnology, and Students’ Research Committee, Tabriz University of Medical Sciences,
Tabriz, Iran.
2
Zanjan Pharmaceutical Nanotechnology Research Center, and Department of Pharmaceutics, Faculty of Pharmacy, Zanjan
University of Medical Sciences, Zanjan, Iran.
3
Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
4
Biotechnology Research Center and Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences,
Tabriz, Iran.

Abstract
Article History: Purpose: Local therapy is a valuable and strategic approach in the treatment of lung
Received: 7 October 2015 associated diseases and dry powder inhalation (DPI) formulations play the key role in this
Revised: 23 November 2015 plan. Transfersome has been introduced as a novel biocompatible vesicular system with
Accepted: 17 January 2016 potential for administration in pulmonary drug delivery. The present study was designed to
ePublished: 17 March 2016 prepare Itraconazole-loaded nanotrantransfersomal DPI formulation.
Methods: Itraconazole-loaded nanotransfersomes with three different types of surfactant in
Keywords: varying concentrations were prepared and characterized in the point of particle size
 Pulmonary drug delivery distribution and morphology by laser light scattering and scanning electron microscopy
 Dry powder inhaler (SEM) methods. The optimized transferosomal formulations were co-spray dried with
 Transfersome mannitol and the aerosolization efficiency and aerodynamic properties of dry powders were
 Itraconazole determined by next generation impactor using a validated HPLC technique.
 DPI Results: The volume mean diameter of optimized nanotransfersomal formulation with
lecithin:Span® 60 in the ratio of 90:10 was 171 nm with narrow size distribution pattern
which increased up to 518 nm after drug loading. Different types of surfactant did not
influence the particle size significantly. SEM images confirmed the formation of aggregated
nanoparticles in the suitable range (1-5 µm) for the pulmonary drug delivery.
Aerosolization evaluation of co-spray dried formulations with different amounts of
mannitol indicated that 2:1 ratio of mannitol:transfersome (w:w) showed the best
aerosolization efficiency (fine particle fraction (FPF)=37%). Increasing of mannitol
significantly decreased the FPF of the optimized formulations.
Conclusion: The results of this study was introduced the potential application of
nanotransfersomes in the formulation of DPIs for lung delivery of various drugs.

Introduction
Itraconazole is a broad-spectrum synthetic triazole side effects, respectively.3-6 The use of liposomes as drug
antifungal agent which is active against a broad spectrum carriers for pulmonary delivery has been reported for
of fungal species including Cryptococcus, Candida, different kinds of therapeutics.7,8 The utilization of
Aspergillus, Blastomyces and Histoplasma capsulatum.1 lipidic vesicular systems for pulmonary drug delivery has
The lungs are suitable for both local and systemic drug many potential advantages over aerosol delivery of the
delivery due to the presence of a large alveolar surface corresponding non-encapsulated drug, including carrier
area with high permeability owing to their thin epithelial suitability for most lipophilic drugs, compatibility and
layer.2 Development of drug delivery systems for reducing local irritation of lung tissue, prolonging local
pulmonary application had received considerable and systemic therapeutic drug levels and finally
attention and high patient compliance in the last three facilitating intracellular drug delivery especially to
decades due to be a noninvasive method of drug alveolar macrophages, tumor cells or epithelial cells.9
administration. Furthermore, the possibility to locally Intensive research over the past 25 years led to the
and more site-specific drug delivery at high introduction and development of a new class of highly
concentrations into the diseased lung by avoiding the deformable liposomes resembling the natural cell vesicle,
first-pass metabolism and reduced systemic doses would named transferosomes.10-12 Transfersomes are composed
lead to maximum therapeutic efficiency and minimum of phospholipids like phosphatidylcholine and edge

*Corresponding author: Hamed Hamishehkar, Tel: +98 41 33355965, Fax: +98 41 33346977, Email: [email protected]
©
2016 The Authors. This is an Open Access article distributed under the terms of the Creative Commons Attribution (CC BY), which permits
unrestricted use, distribution, and reproduction in any medium, as long as the original authors and source are cited. No permission is required from
the authors or the publishers.
Hassanpour Aghdam et al.

activators which self assembles into lipid bilayer in Chemicals Co. (Germany). Soybean phosphatidylcholine
aqueous environment and closes to form a vesicle.13,14 (SPC, purity >99%) was purchased from Lipoid GmbH
An edge activator is often a single-chain surfactant with (Ludwigshafen, Germany). Itraconazole was supplied
a high radius of curvature that destabilizes the lipid from Cipla Company (India). Span® 60 and Span® 80
bilayers of the vesicles and increases the deformability of were supplied from Sigma Company (USA) and BDH
the bilayers.15 Spray drying has been considered as a laboratory (UK), respectively. D-Mannitol and ethyl
simple one-step process for producing small particles for alcohol were obtained from Fluka (Germany) and JATA
pulmonary administration, that can be easily scaled up.16- (Iran) Companies, respectively.
18
Pressurized metered-dose inhalers (MDI), nebulizers,
and dry powder inhalers (DPI) are the three main Methods
delivery systems used for aerosol inhalation in humans. Preparation of nanotransfersomes
Among these, DPI appears to be the most promising for Transfersomes were prepared by the thin film hydration
future use. They are propellant-free, portable, easy to method. Briefly, desired amounts of SPC (100 mg),
operate and low-cost devices with improved stability of Itraconazole (5 mg) and surfactant (5, 10, and 15 mg)
the formulation as a result of the dry state.19,20 According were dissolved in an appropriate volume of organic
to our literature review, there is no report about the solvent (Table 1). The container tightly closed, protected
application of nanotransfersomes in pulmonary drug from light and maintained at room temperature for one
delivery. Therefore, the primary aim of this study was to day to make sure of formation of complete and
introduce transfersomes as a carrier for pulmonary homogeneous solution. The mixture was transformed to
delivery in the form of dry powder inhalation a round-bottomed flask for solvent removal using a
formulation. rotary evaporator (Heidolph, Germany) at reduced
pressure and above phase transition temperature of
Materials and Methods lecithin (60 °C). The dried film was hydrated for one
Materials hour at 60 °C and then sonicated using a prob sonicator
Acetonitrile, Tween® 80, Ursodiol, Chloroform and (Sonix, Vibracell), with 0.5 sec on and 0.5 sec off
Ortho-phosphoric acid were purchased from Merck intervals, for a total period of 15 min.12,21
Table 1. Composition of various nanotransfersome formulations. Data was presented as mean ± standard deviation (n=3).
a
Formulation code Type of Surfactant Surfactant (mg) Itraconazole (mg) VMD (nm) Span
®
T1 Span 80 10 0 360 ± 21 1.18 ± 0.03
®
T2 Span 80 5 5 556 ± 29 1.44 ± 0.04
®
T3 Span 80 10 5 526 ± 31 1.74 ± 0.03
®
T4 Span 80 15 5 598 ± 34 1.70 ± 0.06
®
T5 Span 60 10 0 171 ± 28 1.03 ± 0.03
®
T6 Span 60 5 5 535 ± 22 1.33 ± 0.03
®
T7 Span 60 10 5 518 ± 23 1.07 ± 0.03
®
T8 Span 60 15 5 534 ± 30 2.16 ± 0.14
T9 Ursodiol 5 5 545 ± 22 1.17 ± 0.04
T10 Ursodiol 10 5 522 ± 27 1.04 ± 0.04
T11 Ursodiol 15 5 594 ± 41 1.66 ± 0.04
a
Volume median diameter

Spray drying process by particle size analyzer (Wing SALD 2101, Japan). The
For producing DPI formulations, different amounts of size distribution was expressed by the volume median
mannitol powder (100, 200, 300 and 600 mg named as diameter (VMD) and span value. The smaller span
F1, F2, F3 and F4, respectively) was co-spray dried with values correspond to narrower size distribution. Span
the nanotransfersomal dispersion (100 mg) with value calculated using following equation:
desired characteristics using a mini spray dryer at an ( ) ( )
inlet temperature of 100 ± 5 °C, outlet temperature of Span= ( )
60 ± 5 °C, aspiration setting of 90% and spray flow of
400 NL/h. Immediately after powder collection from the Where D(v,90), D(v,10) and D(v,50) are the equivalent
cyclone of spray dryer, spray-dried particles were packed volume diameters at 90, 10 and 50% cumulative volume,
into the tightly closed container wrapped in aluminum respectively.22,23
foil and desiccated over silica gel at room temperature
until further studies. Scanning electron microscopy (SEM)
The shape and surface morphology of the particles were
Particle size analysis studied by the scanning electron microscope (LEO 1430
The particle size and particle size distribution of VP, UK & Germany). Prior to scanning, the samples
prepared nanotransfersomal dispersions were determined

58 | Advanced Pharmaceutical Bulletin, 2016, 6(1), 57-64

Transferosomal Itraconazole for Lung Delivery

were coated with a thin layer of gold, using a direct The tubes were filled with certain amount of acetonitrile,
current sputter technique (Emitechk450X, England). vortexed and sonicated for a few minutes to dissolve the
extracted Itraconazole completely. 500 µl of acetonitrile
In vitro aerosolization assessment was moved into the micro tubes and centrifuged at 13000
The in vitro aerodynamic parameters including rpm for 10 minutes to separate the undissolved
aerodynamic diameter, aerosolization efficiency, transfersome compositions and capsule residuals to yield
dispersion and deposition characteristics of optimized a particle free solution suitable for HPLC analysis. After
Itraconazole-loaded nanotransfersomal dry powders were deposition onto the stages of the NGI, the mass deposited
assessed by an aerolizer connected to the next generation on each of the impactor pieces was collected and the
impactor (NGI) with pre-separator and USP induction total mass of drug was quantified by a validated HPLC
port (Copley Scientific, Nottingham, UK).24 The NGI system.
was assembled and operated in accordance with USP
General Chapter 601 to assess the drug delivered. An High performance liquid chromatography analysis
appropriate number of hard gelatin capsules (N = 3) were The Itraconazole content of each NGI stage was
filled with 10 mg of spray dried powder. To ensure analyzed using a Knauer apparatus HPLC system
efficient particle capture and prevent inter-stage losses (Germany) consisted of a model 1000 HPLC pump and a
due to particle bounce, the particle collection surface of model 2600 tunable absorbance detector, with the
each stage was coated with Tween® 80. For this purpose, following condition: Column: C-18 (150 × 4.6mm, 10
every eight collection cups of the NGI were soaked into µm, 125 A°) (Germany) protected by a C-18 guard
Tween® 80 ethanolic solution (1%) and placed under the column, mobile phase: acetonitrile: water (90:10), flow
fume hood until the complete evaporation of ethanol. rate: 1 mL/min, wave length: 263 nm and injection
The cups were placed into the apertures in the cup tray volume: 20 µl. The run time for Itraconazole appearance
and the cup tray was located into the bottom frame and following the sample injection was approximately 3 min.
lowered into place. The impactor lid was closed with the The area under the curve (AUC) that demonstrates the
sealed body attached and the handle was operated to lock Itraconazole concentration was calculated through the
the impactor together. Capsules were gathered after machine software (Chromgate® V3.3.1). An excess
actuation for the study of remained powder. The content amount of sample was injected into the injector to make
uniformity test was carried out for 10 mg of each sure that the loop has been completely filled with the
formulation in 5 repetitions. The coefficient variation sample. Calibration curve was leaner in the range of 1.25
percentage (CV%) were less than 6% for all spray-dried to 25 µg/mL (r2=0.997).
powders. The batches that showed CV% above 6% were
excluded from the study. The induction port was Statistical analysis
connected to the first stage of the NGI. The flow rate was Data are expressed as a mean value ± standard deviation
calibrated using a flow meter (DFM 2000, Copley (SD). Statistical analysis was performed using a one-way
Scientific, Nottingham, UK) and fixed at 60 L/min. Fine analysis of variance (ANOVA) with multiple
particle fraction (FPF), mass median aerodynamic comparisons between deposition data using a Tukey-
diameter (MMAD), and geometric standard deviation Kramer HSD test by SPSS software (version 13.0,
(GSD) indexes were calculated using the Copley Inhaler Chicago, IL, USA). A P value <0.05 was considered
Testing Data Analysis Software (CITDAS, version 3.10). statistically significant.
The MMAD is defined as the diameter at which 50% of
the particles by mass are larger and 50% are smaller. FPF Results
represents the percentage of emitted particles with an Preparation of Itraconazole-loaded nanotransfersomes
MMAD of 5 μm or less estimating the fraction of The effect of different kinds of surfactants and their
particles expected to deposit deep within the lungs. The concentration on the size of transfersomes are shown in
emission was defined as the mass of drug delivered from Table 1. The size of blank transfersomes (T1 and T5)
the inhaler (i.e., total amount excluding the inhaler were smaller than drug-loaded transfersomes (T3 and
device and capsule), expressed as a percentage of the T7) with the same compositions. Both drug free and
total amount of Itraconazole collected. Dispersibility was drug-loaded transfersomes showed relatively narrow size
defined as the ratio of FPF per emission. Each value was distribution pattern (Figure 1). Although there are no
expressed as the mean ± standard deviation.25 statistically difference among the formulations composed
Chloroform as a solvent that can dissolve both SPC and of different type and amount of surfactants, formulations
Itraconazole was used as the washing solvent to rupture containing 10 mg of Span® 60 (T7) was selected for
the transfersomes and extract Itraconazole. The whole further experiments due to its lowest size and narrowest
process of washing was performed under the fume hood. size distribution (Table 1). Results also showed that
The capsule shells, pre-separator, USP induction port and preparation of nanotransfersomal formulations with 10
NGI stages were washed with suitable amount of mg of all types of surfactants resulted in the lowest size
chloroform. Chloroform containing extracted drug was compared to using 5 and 15 mg of surfactant.
moved into the test tubes. The test tubes were kept under
nitrogen flow for complete removal of organic solvent.

Advanced Pharmaceutical Bulletin, 2016, 6(1), 57-64 | 59

Hassanpour Aghdam et al.

Figure 1. The size distribution pattern of a) drug free nanotransfersomes (T2) and b) drug loaded nanotransfersome (T7) formulations.

Preparation of DPI formulation nanoparticles in the suitable range for pulmonary drug
DPI formulations containing aggregated Itraconazol- delivery.
loaded nanotransfersomes were prepared by various
ratios of transfersomes to mannitol. The formulation F1 In vitro deposition
was not collected from the cyclone of the spray dryer The amount of Itraconazole in each stage of NGI device
and mostly adhered to the inner wall of heating was analyzed by HPLC method and illustrated in Figure
chamber. It was reported that lecithin forms a viscous 3. The in vitro parameters which were calculated
isotropic phase from 88 to 109 °C (the inlet temperature according to the results of Figure 3 including FPF,
of spray dryer in our experiment) which may be MMAD and GSD are shown in Table 2. F2 showed the
responsible for the formulation adhesion to the spray highest FPF and dispersibility, therefore, was selected
dryer's chamber. The rest of the formulations with as the optimized formulation. Although F4 had the best
higher amounts of mannitol provided the suitable emission and GSD indicating its suitable flowability
amounts of powder which were collected from the and aerodynamic size distribution, respectively, the
cyclone (yield value around 50 %) and assessed by NGI main aerosolization indexes (FPF and dispersibility) are
for determination of their aerosolization efficacy. lower than other formulations.
Figures 2a and 2b show SEM images of the spray- dried
particles (F2), confirmed the formation of aggregated

60 | Advanced Pharmaceutical Bulletin, 2016, 6(1), 57-64

Transferosomal Itraconazole for Lung Delivery

Discussion
Itraconazole is a poorly soluble drug that has displayed a
low and variable oral absorption following oral
administration. Absolute bioavailability of the oral
Itraconazole capsule is 40% lower in the non-fed state
compared to the fed state. To obtain a therapeutic level
of drug at the site of lung infections, a high oral or
intravenous dose must be administered which
consequently increases the incidence of unwanted side
effects associated with a high drug serum
concentration.26 In addition, gastrointestinal side effects
have been reported in recipients of the oral solution up to
25% in a randomized trial and are the major reason for
patient incompliance.27 Local targeting of the drug at the
usual site of infection (the lungs) means that less total
drug may be required for dosing and therefore, the
potential for side effects may be minimized due to a
much reduced systemic concentration.28 It has been
reported that pulmonary delivery of nanoparticulate
Itraconazole can achieve a significantly higher (more
than 10-fold) lung tissue concentrations compared to
conventional oral administration of Itraconazole.
Effective and sustained lung tissue concentrations were
achieved via inhalation of a nanoparticulate Itraconazole
formulation.29 Additionally, a targeted therapy may also
initiate a quicker therapeutic onset and ultimately reduce
the duration of treatment.28 The utilization of lipidic
vesicular systems for pulmonary drug delivery has many
Figure 2. Scanning electron micrographs of a) Itraconazole-loaded potential advantages over aerosol delivery of the
nanotransfersomes (formulation T7) and b) those co-spray dried corresponding nonencapsulated drug, including universal
with mannitol (formulation F2). carrier suitability for most lipophilic drugs, compatibility
and preventing local irritation of lung tissue, providing a
pulmonary sustained release reservoir prolonging local
and systemic therapeutic drug levels and facilitating
intracellular drug delivery especially to alveolar
macrophages, tumor cells or epithelial cells.9 The present
study explored a new idea for nanoparticle delivery to
the lower respiratory regions of the lung using
micrometer-sized carrier particles. In this investigation
Itraconazole-loaded nanotransfersomes were
incorporated as model drug delivery system by the lipid
film hydration technique followed by sonication for size
reduction. For the formulation of DPI, prepared
nanotransfersomes should have a mean size below 5µm30
to form inhalable carrier particles. This requirement was
Figure 3. The percentage of Itraconazole from formulations F2, F3 and F4, satisfied well when nanotransfersomes were co-spray
deposited in various stages of NGI. Data was presented as mean ± standard dried with mannitol, a regularly used inert excipient in
deviation (n=3).
pulmonary drug delivery. The administered excipients
Table 2. Aerosolization efficiency indexes of selected Itraconazole-loaded
(lecithin, mannitol, ursodiol, Span® 60 and Span® 80)
nanotransfersomal dry powders measured by the NGI (mean ± SD, n= 3). were used because of their biocompatibility and
d
Parameters F2 F3 F4 pharmaceutical acceptability. The particle size of the
a
FPF (%) 37.3 ± 3.1 17.8 ± 2.9 10.4 ± 1.4 transfersomes with different types of surfactant did not
b
MMAD (µm) 5.1 ± 0.7 6.5 ± 1 5.2 ± 0.9 show a significant difference. These results indicate that
c
GSD 2.1 ± 0.2 2.1 ± 0.1 1.9 ± 0.1 the particle size of the vesicles was not significantly
Emission (%) 82.7 ± 2.6 80.5 ± 3.1 94.8 ± 0.8 affected by the type of surfactant.31 Spray drying is a
Dispersibility 45.23 ± 2.9 22.11 ± 3.0 10.9 ± 1.1 low-cost, one-step pharmaceutical process that is widely
a
Fine Particle Fraction, b Mass Median Aerodynamic Diameter, used in the development of novel dry powder
c
Geometric Standard Deviation, d F2, F3 and F4 were prepared formulations.3 Spray drying technique offers a number of
by co-spray drying of 100 mg nanotransfersome and 200, 300 potential advantages over lyophilization technique. Spray
and 600 mg of mannitol, respectively

Advanced Pharmaceutical Bulletin, 2016, 6(1), 57-64 | 61

Hassanpour Aghdam et al.

drying technique was utilized for stabilization of mannitol as compared with F3 (300 mg of mannitol) of
nanoliposomes and development of uniform sized 17.8 ± 2.9% and F4 (600 mg of mannitol) of 10.4 ±
particles with desired aerosolization properties for 1.4%. Previous studies have indicated that increasing the
pulmonary administration to overcome constraints lipid concentration in the spray drying feeds can decrease
associated with lyophilization technique, such as the residual water content in the powder35 which
formation of hard cake, need of micronization, addition consequently may improve the aerodynamic properties
of coarse carriers for aersolization, and heterogeneous of the DPI formulation. Higher ratios of mannitol
size distribution pattern.32 Once the nanotransfersome improved emission of formulation F4 which may be
aggregates, with their large surface area, in the dry attributed to the powder flowability improvement by
powder formulation is deposited in the aqueous lining addition of carrier. The findings of this investigation
fluid in the lung, the mannitol may quickly dissolve, showed that dry powder inhalation formulation of
resulting in the dispersion of nanotransfersomes in the Itraconazole-loaded nanotransfersomes prepared by co-
respiratory tract fluids.33 Carriers form the backbone spray drying with mannitol possessed suitable
structure of the solid particles during the spray drying aerosolization performance. Therefore, this formulation
process and facilitate pulmonary delivery.32 The carrier may have a potential to deliver Itraconazole to the site of
of choice for DPI products is currently lactose infection in the lungs in the pulmonary aspergillosis. The
monohydrate and almost all DPI products already in results highlight the need to examine the enhanced in
market are using lactose as a carrier. The advantages of vivo therapeutic effects of pulmonary drug delivery via
lactose monohydrate are its well-investigated toxicity nanotransfersomal DPI formulations. The results of this
profile, its broad availability and its relatively low study was introduced the potential application of
price.19 However, it has some disadvantages that should nanotransfersomes in the formulation of DPIs for lung
be considered in its usage as carrier for DPIs. Lactose is delivery of various drugs.
incompatible with some drugs and compounds with a
primary amine group. Lactose may develop a yellow Acknowledgments
brown color with browning aging that is accelerated by This paper was extracted from Pharm.D. thesis No. 3662
the process of spray drying. Lactose monohydrate is that was submitted to the Faculty of Pharmacy of Tabriz
produced from bovine or with bovine-driven additives so University of Medical Sciences and financially supported
that the Transmissible Spongiform Encephalopathy by grant No. 90/92 from the Drug Applied Research
(TSE) discussion is still an issue for this compound. In Center of the same university.
addition, Lactose intolerance is a situation that requires a
solution. For overcoming the above mentioned Ethical Issues
drawbacks of lactose, mannitol is a suitable substitute Not applicable.
carrier that possesses further positive aspects.20 For these
reasons, mannitol was chosen as an excipient for co- Conflict of Interest
spray drying with nanotransfersomes. Once the The authors report no conflicts of interest.
nanotransfersomes aggregate, with their large surface
area, in the dry powder formulation is deposited in the References
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