European Journal of Pharmaceutical Sciences 75 (2015) 101–113

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European Journal of Pharmaceutical Sciences

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

Electrospun polycaprolactone nanofibers as a potential oromucosal

delivery system for poorly water-soluble drugs
Tanja Potrč, Saša Baumgartner, Robert Roškar, Odon Planinšek, Zoran Lavrič, Julijana Kristl,
Petra Kocbek ⇑
University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia

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

Article history: The number of poorly water-soluble drug candidates is rapidly increasing; this represents a major chal-
Received 4 February 2015 lenge for the pharmaceutical industry. As a consequence, novel formulation approaches are required.
Received in revised form 3 April 2015 Furthermore, if such a drug candidate is intended for the therapy of a specific group of the population,
Accepted 5 April 2015
such as geriatric or pediatric, the formulation challenge is even greater, with the need to produce a
Available online 21 April 2015
dosage form that is acceptable for specific patients. Therefore, the goal of our study was to explore elec-
trospun polycaprolactone (PCL) nanofibers as a novel nanodelivery system adopted for the oromucosal
Keywords:
administration of poorly water-soluble drugs. The nanofibers were evaluated in comparison with poly-
Electrospinning
Nanofibers
mer films loaded with ibuprofen or carvedilol as the model drugs. Scanning electron microscopy revealed
Polycaprolactone that the amount of incorporated drug affects the diameter and the morphology of the nanofibers. The
Poorly soluble drugs average fiber diameter increased with a higher drug loading, whereas the morphology of the nanofibers
Oromucosal drug delivery was noticeably changed in the case of nanofibers with 50% and 60% ibuprofen. The incorporation of drugs
into the electrospun PCL nanofibers was observed to reduce their crystallinity. Based on the morphology
of the nanofibers and the films, and the differential scanning calorimetry results obtained in this study, it
can be assumed that the drugs incorporated into the nanofibers were partially molecularly dispersed in
the PCL matrix and partially in the form of dispersed nanocrystals. The incorporation of both model drugs
into the PCL nanofibers significantly improved their dissolution rates. The PCL nanofibers released almost
100% of the incorporated ibuprofen in 4 h, whereas only up to 77% of the incorporated carvedilol was
released during the same time period, indicating the influence of the drug’s properties, such as molecular
weight and solubility, on its release from the PCL matrix. The obtained results clearly demonstrated the
advantages of the new nanodelivery system compared to the drug-loaded polymer films that were used
as the reference formulation. As a result, electrospinning was shown to be a very promising nanotechnol-
ogy-based approach to the formulation of poorly water-soluble drugs in order to enhance their dissolu-
tion. In addition, the great potential of the produced drug-loaded PCL nanofiber mats for subsequent
formulation as oromucosal drug delivery systems for children and the elderly was confirmed.
Ó 2015 Elsevier B.V. All rights reserved.

1. Introduction
The development of novel formulations and delivery
approaches for poorly water-soluble drugs is a common challenge
with modern pharmaceuticals. The main reason for this is the large
proportion of drug candidates that are poorly water soluble.
However, when these drugs need to be administered to specific
populations, e.g., paediatric or geriatric, the technological
⇑ Corresponding author at: University of Ljubljana, Faculty of Pharmacy,
Aškerčeva cesta 7, 1000 Ljubljana, Slovenia. Tel.: +386 1 47 69 620; fax: +386 1
42 58 031.
E-mail address: petra.kocbek@ffa.uni-lj.si (P. Kocbek).
challenges associated with their poor water solubility are accom-
panied by additional challenges associated with the acceptability
of the final dosage form with these patients.
Nanofibers represent one of the newest and very promising
nanomaterials for a number of applications. They have already
demonstrated important applicability in biomedicine, where
numerous studies have already described in the field of tissue engi-
neering, wound healing as well as drug delivery (Rošic et al., 2013).
Immediate or modified drug release can be achieved by the selec-
tion of a polymer for nanofiber production and the manner of the
drug loading. The drug can be either incorporated into the polymer
matrix of the nanofibers or bound to their surfaces (Huang et al.,
2003; Meinel et al., 2012; Rošic et al., 2012). Both biodegradable

http://dx.doi.org/10.1016/j.ejps.2015.04.004
0928-0987/Ó 2015 Elsevier B.V. All rights reserved.
102 T. Potrč et al. / European Journal of Pharmaceutical Sciences 75 (2015) 101–113
and non-degradable, either natural or synthetic, polymers can be
used to control the drug release via diffusion alone or by a
combination of diffusion and fiber degradation. Furthermore, the
proper selection of the polymer can ensure the optimal combina-
tion of mechanical and biomimetic properties for the nanofibers
(Pelipenko et al., 2013a; Sill and von Recum, 2008). The special
characteristics of nanofibers, in addition to their very small diame-
ters, include a high surface-to-volume ratio, a very high porosity, a
small pore size, a good mechanical strength and a diversity in the
surface functionalities (Huang et al., 2003; Pelipenko et al., 2013b).
The drug release can be tuned for a specific application by chang-
ing the fiber’s composition, production technology or the process
parameters, resulting in a different fiber diameter and/or porosity
(Bertoncelj et al., 2014; Sill and von Recum, 2008). The application
of nanofiber mats on mucosa results in fluid absorption, due to the
presence of numerous nanometer-sized interfibrillar pores. This is,
in addition to the large surface area of the nanofibers available to
interact with the biosurface, the main mechanism for the adhesion
of the nanofibers to the biosurfaces, making them one of the
promising mucoadhesive drug delivery systems (Sill and von
Recum, 2008).
Electrospinning is the most common method for the production
of fibers with diameters ranging from a few nanometers to a few
micrometers from polymer solutions or melts (Frenot and
Chronakis, 2003; Huang et al., 2003). This method is applicable
to virtually any soluble or fusible polymer (Bhardwaj and Kundu,
2010; Sill and von Recum, 2008). Biodegradable and biocompatible
polymers, such as polycaprolactone (PCL) (Fig. 1a), are good
candidates for the preparation of nanofibers for applications in bio-
medicine. Such nanofibers represent a novel class of nanomaterials
that is currently being investigated for drug-delivery applications
(Dash and Konkimalla, 2012; Woodruff and Hutmacher, 2010).
The oral mucosa is very interesting for the purposes of drug
delivery. It provides a much more constant environment for
drug absorption than the gastrointestinal environment, where
the drug is not exposed to the harsh conditions in the gastrointesti-
nal tract and the absorption across the oral mucosa can bypass the
hepatic first-pass effect. Even though the permeability of the oral
Fig. 1. Chemical structure of polycaprolactone (a), ibuprofen (b) and carvedilol (c).
mucosa is lower than the intestinal mucosa, the rich blood supply
enables an effective drug absorption (Hearnden et al., 2012; Shakya
et al., 2011). Oromucosal formulations are, due to their simple use
and non-invasive application, widely accepted by patients (Lam
et al., 2014). They are especially suitable for pediatric (Lam et al.,
2014; Sattar et al., 2014) and geriatric patients (Illangakoon
et al., 2014; Sattar et al., 2014), as well as for any other patient with
swallowing or digestion difficulties (Illangakoon et al., 2014). The
buccal and sublingual dosage forms are among the most com-
monly used oromucosal delivery systems (Lam et al., 2014; Patel
et al., 2011). However, for the drug to be a suitable candidate for
the formulation of an oromucosal delivery system it has to satisfy
some key criteria that relate to the drug’s molecular weight,
potency and water solubility. The molecular weight of drug candi-
dates that are appropriate for oromucosal delivery should not
exceed 800 Da (Lam et al., 2014) and the drug potency should be
relatively high due the limited surface area that is available for
the drug absorption. Usually, only doses up to a few milligrams
can be efficiently absorbed through the oral mucosa. In addition,
the dissolved drug might be washed away with saliva before it
permeates through the mucosal membrane (Lam et al., 2014;
Patel et al., 2011); therefore, an intense contact between the
dosage form and the mucosa is highly advantageous for reducing
the possibility of drug washout by the saliva. A drug delivered
via the oromucosal route should not cause any local irritation at
the application site, i.e., the oral mucosa (Lam et al., 2014).
Furthermore, a sufficient aqueous solubility is necessary to allow
the drug to diffuse through the mucus layer. The number of poorly
water-soluble drug candidates has been increasing rapidly over
recent years (Kawabata et al., 2011; Pouton, 2006); however, they
are not usually suitable for the formulation of oromucosal drug
delivery systems. The preparation of salts usually improves their
solubility; however, drug molecules are better absorbed through
the oral mucosa if they are in unionized form (Lam et al., 2014).
Therefore, a nanotechnology-based approach, which would
improve the dissolution rate and the solubility of such drugs, and
would not affect their chemical properties, would be advanta-
geous. The formulation of nanofibers represents one possible route
to achieving these goals.
During the electrospinning of a polymer solution the rapid
evaporation of the solvent results in the instant formation of nano-
fibers and the entrapment of the drug in the polymer matrix or its
deposition onto the nanofiber surface (Seif et al., 2015; Yu et al.,
2010), resulting in a decreased drug mobility (Yu et al., 2010).
The drugs are usually randomly encapsulated within ultrathin
and flexible polymer nanofibers with a very high surface area
available for contact with the application site. All these character-
istics of nanofibers have a significant influence on the drug’s
bioavailability (Yu et al., 2010).
The aim of our research was to explore electrospun PCL nanofi-
bers as a novel nanodelivery system intended for the oromucosal
administration of poorly water-soluble drugs and to determine
their potential advantages over polymer films. We chose two
model drugs with similar hydro-lipophilic properties, but differing
in their molecular weights, and investigated their influence on the
nanofiber’s physical properties and drug release profiles, aiming to
establish a correlation between the drug’s properties and the
release characteristics of a PCL nanofiber-based delivery system.
2. Materials and methods
2.1. Materials
The polycaprolactone (PCL) Mw 70,000–90,000 g/mol was pur-
chased from Sigma–Aldrich, Germany. The sodium iodide
 T. Potrč et al. / European Journal of Pharmaceutical Sciences 75 (2015) 101–113 103

Table 1 to determine the average diameter of the nanofibers. Between

The process parameters optimized for preparation of electrospun drug loaded PCL thirty and forty, randomly selected, nanofibers were measured
nanofibers.
using ImageJ 1.44p software (NIH, USA), and based on the mea-
Polymer solution Flow Tip to collector Voltage surements the average fiber diameter and its standard deviation
rate (ml/h) distance (cm) (kV) (SD) were determined.
10% PCL/10%a ibuprofen 1.63 15 15.0
10% PCL/15%a ibuprofen 1.98 15 15.0 2.2.5. Preparation of buffer solutions
10% PCL/30%a ibuprofen 1.98 15 15.0
10% PCL/40%a ibuprofen 1.98 15 17.5
A phosphate buffer with a pH of 7.4 was prepared by dissolving
10% PCL/50%a ibuprofen 1.63 15 17.5 8.00 g of sodium chloride, 0.20 g of potassium chloride, 1.44 g of
10% PCL/60%a ibuprofen 1.63 15 17.5 disodium hydrogen phosphate and 0.24 g of potassium dihydrogen
10% PCL/10%a carvedilol 1.63 15 15.0 phosphate in distilled water, after which the pH was adjusted to
10% PCL/15%a carvedilol 1.63 15 15.0
pH 7.4 with 0.1 M sodium hydroxide and the distilled water was
10% PCL/30%a carvedilol 1.63 15 17.5
10% PCL/40%a carvedilol 1.63 15 17.5 added up to 1000 ml.
10% PCL/50%a carvedilol 1.63 15 17.5 A phosphate buffer of pH 7.6 was prepared by mixing 250 ml of
10% PCL/60%a carvedilol 1.63 15 17.5 0.2 M potassium dihydrogen phosphate and 200 ml of 0.2 M NaOH.
a
Based on the dry weight of polymer.
The pH was adjusted to pH 7.6 with 1 M NaOH, after which dis-
tilled water was added up to 1000 ml.

2.2.6. Differential scanning calorimetry (DSC)

(P99.5%), chloroform, acetone (P99.5%), methanol (P99.8%),
dichloromethane (P99.8%), sodium chloride (P99.5%), sodium
hydroxide (P99.5%), potassium chloride (P99.5%), potassium
dihydrogen phosphate (P99.5%), di-sodium hydrogen phosphate
(P99.0%) and ortho-phosphoric acid (98%) were all obtained from
Merck, Germany. The acetonitrile (P99.5%) was purchased from
J.T. Baker, Netherlands. The ibuprofen and carvedilol were obtained
from Sigma–Aldrich, Germany. The water was purified by reverse
osmosis.
2.2. Methods
2.2.1. Preparations of polymer solutions
The PCL solutions (10%, w/w) were prepared by dissolving the
PCL in a mixture of chloroform and acetone in the weight ratio
75:25, then 0.03% (w/w) of sodium iodide was added and stirred
with a magnetic stirrer for 3–4 h at room temperature. The ibupro-
fen and carvedilol were then added (10%, 15%, 30%, 40%, 50% or 60%
w/w, based on the dry weight of the polymer) and the solutions
were stirred for an additional 2–3 h prior to the electrospinning
or film-casting process.
2.2.2. Electrospinning process
The solution was placed in a plastic syringe fitted with a metal
needle that had an inner diameter of 0.8 mm. A high voltage was
applied between the needle and the collector using a high-voltage
generator (model HVG-P60-R-EU, Linari Engineering s.r.l., Italy) to
initiate the jet of the polymer solution, which was fed with a con-
trolled rate by the syringe pump (model R-99E, Razel Scientific,
USA). A grounded, aluminum-foil-covered screen was used as the
collector. The process parameters used in the current study are
shown in Table 1.
2.2.3. Film casting
The film casting was performed using polymer solutions pre-
pared according to the method described in Section 2.2.1. Each
polymer solution (4 ml) was pipetted into a Petri dish and left in
a fume hood at room temperature for at least 24 h, allowing the
solvents to evaporate and the polymer film to dry.
2.2.4. Scanning electron microscopy (SEM)
The electrospun product or polymer film was fixed onto metal-
lic studs with double-sided conductive tape (diameter 12 mm,
Oxford instruments, Oxon, UK). The morphology of the sample
was observed with a scanning electron microscope (Supra35 VP,
Carl Zeiss, Oberkochen, Germany), using an accelerating voltage
of 1 kV and a secondary-electron detector. SEM images were used
The crystallinity of the drug in the nanofibers and the polymer
films was assessed by DSC. Pure ibuprofen, pure carvedilol, pure
PCL, a physical mixture of PCL and ibuprofen (weight ratio 5:2),
ibuprofen-loaded nanofibers and films, a physical mixture of PCL
and carvedilol (weight ratio 5:2), carvedilol-loaded nanofibers
and films were analyzed. The DSC analyses were performed using
a Mettler Toledo, STARe System. Accurately weighed samples (3–
5 mg) were sealed in 40 ll, non-hermetically sealed, aluminum
pans. The heating rate was 5 K/min and the nitrogen purge rate
was 50 ml/min. All the samples were analyzed in the temperature
range from 50 to 130 °C. All the DSC curves were normalized to
the sample mass.
2.2.7. Determination of the drug content in the nanofibers and polymer
films
An Agilent 1290 Infinity liquid chromatograph coupled to an
Agilent 6460 triple quadrupole mass spectrometer (Agilent
Technologies, USA) was used for a determination of the total carve-
dilol content in the fibers and polymer films. A known amount of
sample (about 13 mg) was dissolved in 5 ml of dichloromethane
(DCM). The obtained solution was diluted 250 times with metha-
nol and then analyzed. The sample (0.1 ll) was injected onto a
100  3.0 mm, 2.7 lm Poroshell EC-C18 column (Agilent
Technologies, USA) at 50 °C using 0.1% formic acid and acetonitrile
(50:50, v/v) as the mobile phase at a flow rate of 0.4 ml/min. The
retention time of the carvedilol was approximately 1.2 min and
the run time was 1.7 min. After each injection, the sampling needle
was washed with a washing solvent composed of methanol and
water in the ratio 80:20 (v/v). The detection was performed using
a JetStreamÒ electrospray source operated in the positive mode.
The mass spectrometer parameters were set as follows: drying
gas temperature, 275 °C; drying gas flow, 5 l/min; nebulizer,
45 psi; sheath gas temperature, 320 °C; sheath gas flow, 11 l/min;
capillary entrance voltage, 4000 V; and nozzle voltage, 1000 V.
Both quadrupoles Q1 and Q3 were set at a unit mass resolution.
The MRM m/z transitions and collision-energy characteristics for
optimal quantification were 407 ? 100, 28 eV (quantifier ion)
and 407 ? 222, 16 eV (qualifier ion), respectively. The instrument
control, data acquisition and quantification were performed with
MassHunter Workstation software. All the analyses were per-
formed at least in triplicate.
The ibuprofen content in the nanofibers and polymer films was
determined based on the results of the dissolution studies
described in Section 2.2.8. The drug concentration in the medium
reached a plateau during the time period of the dissolution study,
and this maximum concentration was used to calculate the drug
content in the sample.
104 T. Potrč et al. / European Journal of Pharmaceutical Sciences 75 (2015) 101–113
The drug entrapment efficiency (EE) was calculated according
to the ratio of the actual to the theoretical drug content in the
nanofibers (Eq. (1)).
wd
EE ½% ¼  100
wt
where wd represents the amount of drug, which was determined in
100 mg of prepared nanofibers, and wt is the weight of the drug
used for the preparation of 100 mg of nanofibers.
2.2.8. Dissolution studies
The PCL nanofibers (80 mg of ibuprofen-loaded nanofibers or
10 mg of carvedilol-loaded nanofibers) were gently rolled on a
glass carrier and placed in 250 ml of phosphate buffer, pH 7.4, used
as a dissolution medium. The sample was stirred on a magnetic
stirrer at room temperature. At the predetermined time points
1 ml of ibuprofen- or 2 ml of carvedilol-containing sample was
withdrawn and replaced with fresh phosphate buffer. The sample
was then filtered through a 0.45-lm filter (Agilent Technologies,
Germany) and analyzed by HPLC. The dissolution studies were per-
formed in triplicate.
The ibuprofen and carvedilol were quantified using an HPLC
analysis (Agilent 1100 Series, Hewlett Packard, Waldbron,
Germany) using the drug-adjusted conditions, as follows. The
ibuprofen was analyzed using an ODS Nucleosil C18 column
(5 lm, 250 mm  4 mm; Thermo Scientific) at 35 °C. The mobile
phase consisted of a mixture of acetonitrile and phosphate buffer
(pH 7.6) in the ratio 28.5:71.5 (v/v). A constant flow rate of
1.2 ml/min was used and the drug was monitored using a diode
array detector at 225 nm.
The carvedilol was determined using a Beta Basic C8 column
(3 lm, 150 mm  4.6 mm; Thermo Scientific) at 35 °C. The mobile
phase was a mixture of 0.02 M potassium dihydrogen phosphate
and acetonitrile in the ratio 6.5:3.5 (v/v) adjusted to pH 2.0 with
phosphoric acid R. The flow rate of the mobile phase was 1.0 ml/
min and the drug was monitored using a diode array detector at
241 nm.
3. Results and discussion
3.1. Preparation of drug-loaded PCL nanofiber mats
A polymer solution suitable for the preparation of electrospun
nanofibers should exhibit good spinnability; therefore, the selec-
tion of the right combination of polymer and solvent is crucial. In
the present study PCL was chosen for the preparation of drug-
loaded nanofiber mats, since it exhibits good compatibility with
many drugs and can be used in various formulations intended for
controlled drug delivery or tissue engineering (Dash and
Konkimalla, 2012; Woodruff and Hutmacher, 2010). PCL has pre-
viously been reported as a main building block of different PCL-
based formulations, e.g., micro and nanospheres (Sinha et al.,
2004), films, micelles, scaffolds, and fibers (Dash and Konkimalla,
2012; Woodruff and Hutmacher, 2010). It has also been success-
fully electrospun in previous studies (Canbolat et al., 2014;
Fujihara et al., 2005; Karuppuswamy et al., 2015; Kenawy et al.,
2009; Kim et al., 2012; Kouhi et al., 2013; Li et al., 2005; Luong-
Van et al., 2006; Madhaiyan et al., 2013; Reneker et al., 2002;
Seif et al., 2015; Shin et al., 2004; Srikar et al., 2007; Valarezo
et al., 2013; Vrbata et al., 2013; Yoshimoto et al., 2003; Zamani
et al., 2010).
The solvent mixture composed of 75% (w/w) chloroform, being
a very good solvent for PCL, and 25% (w/w) acetone, being less
favorable for PCL dissolution (Sinha et al., 2004; Woodruff and
Hutmacher, 2010), and optimized regarding the processability
and morphology of the obtained electrospun product, was selected
for the preparation of the PCL nanofibers in the current study. If the
percentage of acetone in the solvent mixture was above 50%, the
drying of the polymer solution was very fast, causing needle clog-
ging and hindering the electrospinning process. Increasing the per-
ð1Þ centage of chloroform in the solvent mixture reduced the volatility
and prolonged the drying time of the polymer solution, enabling
the continuous production of nanofibers. Furthermore, the mixture
of chloroform and acetone was chosen to balance the low dielectric
constant of the chloroform (e = 4.75) (Horváth and Szalai, 2014)
and the high dielectric constant of the acetone (e = 19.10)
(Akerlof, 1932). It is well known that the high electrical conductiv-
ity of the solution generally results in thinner, smoother nanofibers
with fewer beads (Bhardwaj and Kundu, 2010). Although the
obtained PCL solution in the mixture of chloroform and acetone
was spinnabile, 0.03% (w/w) sodium iodide was additionally added
to further increase the solution’s conductivity and enable the for-
mation of fibers in the nanometer size range (Lalia et al., 2013;
Zong et al., 2002).
The polymer concentration has a significant influence on the
fiber diameter. The starting concentration of the PCL solution used
in our research was chosen on the basis of the literature data. It
was later optimized experimentally, depending on the solvent
mixture being used. The optimal concentration of PCL solution
for electrospinning was shown to be 10% (w/w). Higher polymer
concentrations caused problems with needle clogging, whereas
lower concentrations resulted in the solution dripping. Similar
observations were reported by other authors (Frenot and
Chronakis, 2003; Zong et al., 2002). The concentration of PCL solu-
tion used in this study is thus similar to previously published data,
reporting the electrospinning of PCL solutions with concentrations
from 7.5% (w/w) in a mixture of chloroform and methanol (1:1, 2:1,
3:1 and 4:1 (v/v) (Kouhi et al., 2013), 3:1 (w/w) (Fujihara et al.,
2005) up to 18% (w/v) in pure acetone (Reneker et al., 2002).
The starting point for the optimization of the process parame-
ters in our study was the results of the previous studies on the
electrospinning of PCL solutions. The optimal distance between
the needle and the collector was shown to be 15 cm, the flow rate
1.63–1.98 ml/h, and the voltage necessary to obtain smooth, bead-
less nanofibers from all the investigated polymer solutions was set
to 15.0–17.5 kV (Table 1).
Two poorly water-soluble model drugs were incorporated into
the PCL nanofibers in the scope of the present study, i.e., ibuprofen
(Fig. 1b) and carvedilol (Fig. 1c). The aqueous solubilities of the
ibuprofen and carvedilol at room temperature are 0.056 mg/ml
(Kocbek et al., 2006) and 0.020 mg/ml (Loftsson et al., 2008),
respectively. Both drugs belong to the class II drugs, according to
the biopharmaceutical classification system (BCS) (Lindenberg
et al., 2004; Loftsson et al., 2008). They are soluble in the solvent
mixture used for the preparation of the PCL solution; therefore,
they readily dissolved in the PCL solution prior to the
electrospinning.
3.2. Morphology of the electrospun products and polymer films
The electrospinning of PCL solutions under optimal process
parameters (Table 1) enabled the preparation of beadless, ran-
domly oriented, continuous ibuprofen- and carvedilol-loaded
nanofibers (Figs. 2 and 3). In this study nanofibers with a very high
drug loading were successfully prepared. The theoretical drug
loading in the nanofibers reached up to 37.5% (w/w) (Table 2) in
the case of nanofibers with 60% of drug based on the dry weight
of the polymer. The achieved drug loading was higher than all
the available previously published data, where the drug loading
did not exceed about 30% (w/w) (based on the dry weight of the
polymer) (Vrbata et al., 2013). A high drug loading can significantly
affect the electrospun product’s morphology, as shown in Fig. 2 and
 T. Potrč et al. / European Journal of Pharmaceutical Sciences 75 (2015) 101–113
Fig. 2. SEM images of electrospun PCL nanofibers loaded with 10% (A and B), 15% (C
and D), 30% (E and F), 40% (G and H), 50% (I and J) and 60% (K and L) ibuprofen
(based on the weight of dry polymer). The nanofibers were visualized at low (A, C, E,
G, I and K) and high (B, D, F, H, J and L) magnification.
reported also by Karuppuswamy et al. (2015) and Shen et al.
(2011). SEM imaging of the prepared electrospun products with
10%, 15%, 30% and 40% of incorporated drug revealed nanofibers
with a smooth surface, i.e., without any visible drug crystals
(Figs. 2 and 3). This observation indicates that the ibuprofen and
carvedilol were fully embedded in the nanofibers. In the case of
ibuprofen-loaded electrospun products with 50% and 60% of incor-
porated drug the morphology is distinctly different (Fig. 2J and L),
105
Fig. 3. SEM images of electrospun PCL nanofibers loaded with 10% (A and B), 15% (C
and D), 30% (E and F), 40% (G and H), 50% (I and J) and 60% (K and L) carvedilol
(based on the weight of dry polymer). The nanofibers were visualized at low (A, C, E,
G, I and K) and high (B, D, F, H, J and L) magnification.
whereas the SEM images of the electrospun product with a similar
loading of carvedilol do not show any evident changes in the fiber
morphology (Fig. 3J and L). The individual fibers loaded with larger
amounts of ibuprofen are flattened, fused together and highly per-
forated, in contrast to the smooth, rounded, individual nanofibers
loaded with smaller amounts of the drug. Their average diameters
range from 465 ± 88 nm (10% ibuprofen) to 686 ± 196 nm (60%
ibuprofen), and in the case of the carvedilol-loaded PCL nanofibers
106 T. Potrč et al. / European Journal of Pharmaceutical Sciences 75 (2015) 101–113

Table 2
Comparison of the average diameters of electrospun ibuprofen and carvedilol loaded PCL nanofibers.

Nanofiber sample Drug loading Average diameter Nanofiber sample Drug loading Average diameter
(%, w/w) (nm) (%, w/w) (nm)
10%a ibuprofen 9.1 465 ± 88 10%a carvedilol 9.1 418 ± 76
15%a ibuprofen 13.0 454 ± 83 15%a carvedilol 13.0 530 ± 102
30%a ibuprofen 23.1 593 ± 105 30%a carvedilol 23.1 539 ± 80
40%a ibuprofen 28.6 568 ± 97 40%a carvedilol 28.6 603 ± 113
50%a ibuprofen 33.3 582 ± 109 50%a carvedilol 33.3 639 ± 121
60%a ibuprofen 37.5 686 ± 196 60%a carvedilol 37.5 756 ± 139
a
Based on the dry weight of polymer.

from 418 ± 76 nm (10% carvedilol) to 756 ± 139 nm (60% carvedi-

lol) (Table 2). The average fiber diameter increased with the
amount of incorporated drug, being in line with the previous stud-
ies (Karuppuswamy et al., 2015; Shen et al., 2011).
To evaluate the advantages of nanofibers, polymer films with
the same qualitative and quantitative composition were prepared
as a reference material. The polymer films were prepared from
the same solutions as the nanofibers by drying the solution at room
temperature in a fume hood. The SEM images of the ibuprofen-
loaded films captured at a lower magnification revealed the pres-
ence of some rounded pores in the films with 10% to 40% of drug,
whereas a higher magnification also showed the presence of smal-
ler pores in the films with 50% and 60% of ibuprofen (Fig. 4). Some
films were composed of differently sized, irregular, pentagonal
segments, most probably indicating the crystallization of the poly-
mer, while the others did not show any regular pattern. A signifi-
cant difference in the morphology is visible in the case of films
with 50% and 60% ibuprofen, which is in good correlation with
the changes in the morphology of the electrospun nanofibers.
The carvedilol-containing polymer films, except the film with
10% carvedilol, exhibited a patterned structure that was clearly
visible at higher magnification. These films seem denser than the
ibuprofen-loaded films, but without the presence of rounded pores
in their structure (Fig. 5). The presence of pores most probably
results from the solvent evaporation during the drying. None of
the films exhibited visible drug crystals on their surface, indicating
the drug’s incorporation into the film. However, the crystallinity of
the drugs was further investigated using DSC studies, as described
in the following section.

3.3. Evaluation of the drug’s crystallinity

The preparation of drug-loaded nanofibers involves drug

dissolution and a subsequent solidification, which can cause
changes in its crystal structure. The DSC studies were therefore
performed to evaluate any changes in the drug crystallinity during
the preparation of the nanofibers or polymer films. Pure PCL, pure
ibuprofen, pure carvedilol, physical mixtures of the drugs and PCL,
nanofibers and films containing different amounts of drug were
analyzed and the results are shown in Figs. 6–8. The DSC curves
of the pure ibuprofen and carvedilol show endothermic peaks at
79.3 °C and 118.1 °C (Fig. 6A and B), indicating the melting points
of the ibuprofen and carvedilol, according to the literature data
(Planinšek et al., 2011; Xu et al., 2004). The endothermic peak
observed on the DSC curve of the pure PCL at 59.8 °C indicates its
melting (Fig. 6C). The determined melting point is in line with
the literature data, reporting that the PCL’s melting point is in
the range from 59 to 64 °C, (Sinha et al., 2004; Woodruff and Fig. 4. SEM images of PCL films loaded with 10% (A and B), 15% (C and D), 30% (E
and F), 40% (G and H), 50% (I and J) 60% (K and L) ibuprofen (based on the weight of
Hutmacher, 2010). The endothermic peak at a temperature of
dry polymer). The films were visualized at low (A, C, E, G, I and K) and high (B, D, F,
around 60 °C is visible on the DSC curves of all the samples con- H, J and L) magnification.
taining PCL (Figs. 6–8), indicating its crystalline structure. The
DSC curves of the physical mixtures show two endothermic peaks, mixture the peaks are at 59.6 °C and 76.1 °C (Fig 6D), whereas
corresponding to the melting points of both components in the the PCL/carvedilol physical mixture shows peaks at 59.7 °C and
mixture (Fig. 6D and E). In the case of the PCL/ibuprofen physical 117.3 °C (Fig. 6E). These results revealed that both drugs and the
 T. Potrč et al. / European Journal of Pharmaceutical Sciences 75 (2015) 101–113
Fig. 5. SEM images of PCL films loaded with 10% (A and B), 15% (C and D), 30% (E
and F), 40% (G and H), 50% (I and J) 60% (K and L) carvedilol (based on the weight of
dry polymer). The films were visualized at low (A, C, E, G, I and K) and high (B, D, F,
H, J and L) magnification.
polymer were crystalline in the studied PCL/drug physical mix-
tures. In contrast to the DSC curves of the physical mixtures, DSC
curves of prepared nanofibers show only a single endothermic
peak in the temperature range from 53.5 to 57.5 °C, indicating
melting of the PCL (Fig. 7). The peak is slightly shifted to lower
temperatures, compared to the pure PCL, indicating the reduction
in the polymer’s crystallinity and the size of its crystals. The shift
of the PCL melting peaks in the DSC curves of the carvedilol
107
nanofibers with up to 40% of carvedilol correlates well with the
increasing amount of drug in the nanofibers (Fig. 7b).
The melting point of PCL in the form of plain PCL nanofibers
(Fig. 7) is the same as the melting point of pure PCL, i.e., 59.8 °C
(Fig. 6). In the DSC curves of all the drug-loaded nanofibers the
endothermic peak, which would indicate melting of the drug, is
absent. This finding suggests that the ibuprofen and carvedilol
were molecularly dispersed in the polymer matrix, indicating the
formation of a solid solution (Bodmeier and Chen, 1989; Kouhi
et al., 2013; Seif et al., 2015; Vrbata et al., 2013; Zamani et al.,
2010) or the drugs were amorphous (Kouhi et al., 2013; Vrbata
et al., 2013). However, the glass transition temperatures were
not observed for any sample of drug-loaded nanofibers or films
in the scope of our study. The magnitude of the PCL melting enthal-
pies (which is equal to the area under the peak, or in other words,
to the size of the melting peak) revealed an unexpectedly minor
decrease, when the amount of carvedilol in the sample was
increased, whereas in the case of the samples with ibuprofen the
values were increased even above the value that is characteristic
for the melting of the plain PCL nanofibers (Fig. 7). This observation
suggests that a part of the drug in both types of nanofibers was
present in nanocrystalline form and thus the melting or dissolution
(in PCL melt) of such a nanosized crystal nuclei overlaps with the
melting of the PCL, thereby increasing the total melting enthalpy
in this temperature interval.
It needs to be pointed out that the DSC measurements were
very challenging, because PCL has a lower melting temperature
than either of the two drugs, thus it melts first and the drug
nanocrystals can dissolve in the PCL melt during the DSC analysis,
which could also contribute to the absence of the drug’s melting
peaks on the DSC curves, as previously reported also by
Bodmeier and Chen (1989). The SEM images did not show any visi-
ble crystals on the surface of the nanofibers, but they can still be
present in the polymer matrix.
In the scope of this research the polymer films were prepared as
a reference for the polymer nanofibers. The results of the DSC
analysis of the films (Fig. 8) are very similar to the results of the
nanofiber samples (Fig. 7). The endothermic peaks representing
the melting of the PCL are visible, whereas the melting peaks of
the ibuprofen and carvedilol are absent. The assessment of the
melting enthalpies of the films also revealed increased values com-
pared to the pure PCL. The comparison between the melting
enthalpies of the nanofiber and the film samples of both investi-
gated drugs suggests a decreased crystallinity of the drugs in the
nanofibers, with 10–15% of ibuprofen and 10–40% of carvedilol.
The changes in the drug’s crystallinity due to the electrospin-
ning of the PCL solution were already reported in previous studies
(Kouhi et al., 2013; Seif et al., 2015; Valarezo et al., 2013; Vrbata
et al., 2013; Zamani et al., 2010). The group of Vrbata confirmed
the changed crystalline structure of naproxen and sumatriptan
succinate when incorporated into PCL nanofibers (Vrbata et al.,
2013). Based on the DSC measurements they concluded that the
produced fibers contained the drug in a non-crystalline form,
either in the amorphous state or, which is more likely, homoge-
nously dispersed in the polymer matrix of the fibers. The reduction
in the PCL’s crystallinity with an increasing amount of loaded
metronidazole benzoate and the absence of a crystalline form of
the drug in nanofibers was reported by Zamani et al. (2010).
They assumed that the drug was molecularly dispersed in a poly-
meric matrix. Similar results were also reported by Kouhi et al.,
who investigated the incorporation of simvastatin in PCL nanofi-
bers (Kouhi et al., 2013).
To sum up, the incorporation of drugs in electrospun PCL nano-
fibers reduced their crystallinity. Based on the morphology of the
nanofibers and the films, and the DSC results obtained in the pre-
sent study, it can be assumed that the drugs incorporated into the
108 T. Potrč et al. / European Journal of Pharmaceutical Sciences 75 (2015) 101–113

Fig. 6. DSC curves of pure ibuprofen (A), pure carvedilol (B), pure PCL (C), PCL/ibuprofen (D) and PCL/carvedilol physical mixture (E).

Fig. 7. DSC curves (a) of pure ibuprofen (A), plain PCL nanofibers (B) and PCL nanofibers with 10% (C), 15% (D), 30% (E), 40% (F), 50% (G) and 60% (H) of ibuprofen and DSC
curves and (b) of pure carvedilol (A), plain PCL nanofibers (B) and PCL nanofibers with 10% (C), 15% (D), 30% (E), 40% (F), 50% (G) and 60% (H) of carvedilol.

nanofibers were partially molecularly dispersed in the polymer
matrix and partially in the form of dispersed nanocrystals.
3.4. Entrapment efficacy and dissolution studies
The drug entrapment efficiency can usually be determined on
the basis of results from a dissolution study, which was also the
case in the analysis of the ibuprofen-loaded samples. The
determination of the entrapment efficacy was much more chal-
lenging in the case of the carvedilol-loaded samples, where the
amount of drug released from some samples differed a great deal
from the theoretical drug loading. Therefore, a completely new
method was developed. Based on the obtained results the entrap-
ment efficiency of carvedilol in the electrospun PCL nanofibers was
 T. Potrč et al. / European Journal of Pharmaceutical Sciences 75 (2015) 101–113 109

Fig. 8. DSC curves (a) of pure ibuprofen (A), PCL films (B) and PCL films with 10% (C), 15% (D), 30% (E), 40% (F), 50% (G) and 60% (H) of ibuprofen and DSC curves and (b) of pure
carvedilol (A), PCL films (B) and PCL films with 10% (C), 15% (D), 30% (E), 40% (F), 50% (G) and 60% (H) of carvedilol.

between 91% and 100% for the nanofibers with 10%, 15%, 30% and
40% of carvedilol, and about 86% for the samples with 50% and 60%
of carvedilol. This high entrapment efficacy in the nanofibers was
expected, since the solution of the drug and the PCL is solidified
during the electrospinning and the drug is entrapped in the poly-
mer matrix. The risk of drug loss during this process is low.
However, when the amount of drug in the polymer solution was
high, the entrapment efficiency decreased. It needs to be pointed
out that the entrapment efficiency of all the drug-loaded PCL nano-
fibers was significantly higher than the drug-loaded PCL films
(Fig. 9), where the entrapment efficiency was lower than 87%,
but still above 74%. The most probable reason for the determined
lower drug entrapment efficiency was the drug’s inhomogeneity
in the film, resulting from the procedure of the film’s preparation.
Some parts of the film were firmly adsorbed to the bottom of the
Petri dish and could not be removed from it. Since the drug could
have been predominantly deposited on the surface of the Petri
dish, it remained there after the film’s removal and the determined
drug content was, consequently, much lower than expected.
Based on the experimental results it can be concluded that the
drug entrapment efficiency was higher than 86% for the nanofibers
and generally lower for the drug-loaded films. The entrapment effi-
ciency of ibuprofen in the nanofibers and the films was determined
on the basis of the dissolution studies. The comparison of the total
amount of the drug released and the theoretical drug loading
showed that the entrapment efficiency of the ibuprofen was
100%. The overall results demonstrated that the efficiency of the
drug loading achieved by the electrospinning is very high.
When developing a dosage form for oromucosal drug delivery,
the drug release profile from the formulation is of crucial impor-
tance. In our study the drug release from nanofiber mats was
determined in vitro and compared to the drug release from poly-
mer films with the same qualitative and quantitative composition.
The influences of the drug loading and the molecular weight of the
incorporated drug on the drug release profiles were also evaluated.
The release profiles revealed that the ibuprofen-loaded nanofi-
ber mats released the drug faster than the ibuprofen-loaded PCL
films. This makes them a very promising system for the oromuco-
sal delivery of poorly water-soluble drugs. The release of ibuprofen
from all the nanofiber mats was fast (Fig. 10a), reaching about 96%
of the total drug release in the first 4 h from the PCL nanofibers.
Similar results were already reported previously (Karavasili et al.,
2014). The drug release rates from the fibers loaded with different
amounts of ibuprofen were not significantly different, indicating
that the differences in the fiber diameters and the surface mor-
phology did not influence the release of the ibuprofen. In contrast
to the release of the ibuprofen from the nanofibers, the release of
the carvedilol from the PCL nanofibers was slower (Fig. 10b). In
the first 4 h some 77% of the drug was released from the nanofibers
with 30% of carvedilol, whereas only 56–62% of the drug was
released from other samples of nanofibers. Furthermore, in 120 h
the PCL nanofibers released only 89% of the carvedilol in the case
110 T. Potrč et al. / European Journal of Pharmaceutical Sciences 75 (2015) 101–113

Fig. 9. Carvedilol entrapment efficiency in PCL nanofibers (a) and films (b).

Fig. 10. Release profiles of ibuprofen (a) and carvedilol (b) from electrospun PCL nanofibers. The data points represent the means ± SD of three measurements.

of the nanofibers with 30% of the drug and between 73% and 79% of
carvedilol in the case of the nanofibers with 10%, 15% and 40% of
the drug. The slowest drug release was observed in the case of
the nanofibers with 50% and 60% of carvedilol, where only 49–
56% of the drug was released in 120 h. The observed differences
in the release rates of the ibuprofen and carvedilol are not the
result of different drug crystallinity or different nanofiber mor-
phologies, but can be attributed to the differences in the drug solu-
bility and/or molecular weight. The ibuprofen has an almost two
times smaller molecular weight than the carvedilol and its release
is faster compared with the carvedilol. It is known from the litera-
ture that the drug can be released from the PCL matrix by a diffu-
sion process (Dash and Konkimalla, 2012; Kenawy et al., 2009),
where the molecular weight is a limiting factor.
Since the nanofibers are characterized by their very large sur-
face-to-volume ratio and the short diffusion distance for the incor-
porated drug, the drug release profiles of the electrospun
nanofibers are very different to those of the polymer films. The
results showed that 63–83% of the ibuprofen was released in the
first 4 h from the PCL films with 10–50% of drug and only about
38% from the PCL film with 60% of ibuprofen (Fig. 11a). The total
drug release in the first 4 h from the PCL films was about 13–58%
smaller than the ibuprofen release from the drug-loaded PCL nano-
fibers (Fig. 10a). After 20 h the PCL films with 10–50% of ibuprofen
released about 100% and the PCL film with 60% of drug released
only about 74% of the theoretical amount of ibuprofen in the film.
The comparison between the release profiles of the carvedilol-
loaded PCL films and the nanofibers showed a similar relationship
to that observed for the ibuprofen samples. The carvedilol release
was much faster from the PCL nanofibers (Fig. 10b) than from
the PCL films (Fig. 11b). The PCL films released only from 10%
(PCL film with 60% of carvedilol) to 43% (PCL film with 10% of car-
vedilol) of the carvedilol in the first 4 h and from 52% (PCL film
with 60% of carvedilol) to 96% (PCL film with 10% of carvedilol)
 T. Potrč et al. / European Journal of Pharmaceutical Sciences 75 (2015) 101–113 111

Fig. 11. Release profiles of ibuprofen (a) and carvedilol (b) from PCL films. The data points represent the means ± SD of three measurements.

of the incorporated carvedilol in the first 120 h (Fig. 11b). The
results are in line with the literature data reporting an initially fas-
ter release of the incorporated drug within the first few hours, fol-
lowed by the second slow release phase from the electrospun mat
and the thin film (Kenawy et al., 2009). As was already observed,
the drug’s properties, especially its molecular weight and water
solubility, could also explain the differences in the obtained release
rates.
After the dissolution tests were finished it was observed that
the amount of released drug from the carvedilol-loaded nanofibers
differed from the total drug loading, since the determined drug
concentration in the dissolution medium was lower than expected,
which should be close to the theoretical. This observation was
much more pronounced in the case of the carvedilol-loaded nano-
fibers than the ibuprofen-loaded nanofibers, where only 52–89% of
the drug was detected. Therefore, additional experiments to deter-
mine the carvedilol loading were performed.
Because the release profiles reached the plateau in a time period
of 120 h, it was concluded that the drug cannot be completely
released from the nondegraded PCL matrix, which starts to
degrade, according to the literature, after 9 weeks (Dash and
Konkimalla, 2012) and can to run for more than one year, depend-
ing on its molecular weight (Sinha et al., 2004; Woodruff and
Hutmacher, 2010). The amount of drug remaining entrapped in
the polymer increased with the drug loading, reaching 27% in the
case of the nanofibers with 60% of carvedilol. Similar results were
reported by Srikar et al. (2007) and Vrbata et al. (2013). Both
groups assumed that only the compound localized on the surface
of the fibers and within their pores can be released, whereas the
drug encapsulated in the bulk of the polymer matrix cannot be
released (Srikar et al., 2007). In our study it was observed that
the amount of drug remaining in the nanofibers also depends on
its molecular weight. Smaller drug molecules, e.g., ibuprofen, could
be released more easily than the higher-molecular-weight drug

Fig. 12. The amount of the drug ((a) ibuprofen and (b) carvedilol) that remained in nanofibers after the dissolution test was finished.
112 T. Potrč et al. / European Journal of Pharmaceutical Sciences 75 (2015) 101–113
molecules, e.g., carvedilol. Besides the molecular weight, the inter-
actions between the drug and the polymer can also influence the
amount of unreleased drug. Since the amount of carvedilol remain-
ing unreleased was much higher than the amount of ibuprofen
(Fig. 12), stronger hydrophobic–hydrophobic interactions between
the polymer and the drug exist (Tarafder et al., 2013). The interac-
tions between the PCL and the drug also influence the drug release
rates; therefore, the ibuprofen release was faster than the carvedi-
lol release from the nanofibers.
As expected, the incorporation of the poorly soluble drugs in the
PCL nanofibers improved their release rates, nevertheless, the
release rate also depends on the drug’s properties, most impor-
tantly the drug’s molecular weight.
4. Conclusion
The results obtained in this study demonstrated that electro-
spinning can be used for the preparation of highly drug-loaded
PCL nanofibers. The incorporation of poorly water-soluble drugs
in such a nanomaterial significantly enhances their dissolution
rate. However, the release rate from the nanofibers was shown to
be drug dependent. The release of ibuprofen, having a smaller
molecular weight and a better aqueous solubility, was shown to
be faster than the carvedilol. In the first 4 h up to 96% of ibuprofen
and only up to 77% of carvedilol was released during the same time
period. Furthermore, electrospinning decreased the drug’s crys-
tallinity, and thus the drugs in the nanofibers were partially
molecularly dispersed or present in an amorphous state and par-
tially in the form of nanocrystals.
To conclude, electrospinning was shown to be very promising
nanotechnology-based approach to the formulation of poorly
water-soluble drugs in order to enhance their release.
Specifically, the drug-loaded PCL nanofiber mats show great poten-
tial for further formulation as oromucosal drug delivery systems.
Acknowledgements
The authors gratefully acknowledge the financial support pro-
vided by the Slovenian Research Agency (Programme Code P1-
0189 and Research Projects J1-4236, J1-6746).
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