International Journal of Pharmaceutics 481 (2015) 97–103

Contents lists available at ScienceDirect

International Journal of Pharmaceutics

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

Pharmaceutical nanotechnology

Transdermal delivery of curcumin via microemulsion

Amnon C. Sintov *
Department of Biomedical Engineering, Faculty of Engineering Sciences, Ben Gurion University of the Negev, Be'er Sheva 84105, Israel

A R T I C L E I N F O A B S T R A C T

Article history: The objective of this study was to evaluate the transdermal delivery potential of a new curcumin-
Received 5 November 2014 containing microemulsion system. Three series of experiments were carried out to comprehend the
Accepted 1 February 2015 system characteristics: (a) examining the influence of water content on curcumin permeation, (b)
Available online 2 February 2015
studying the effect of curcumin loading on its permeability, and (c) assessing the contribution of the
vesicular nature of the microemulsion on permeability. The skin permeability of curcumin from
Keywords: microemulsions, which contained 5%, 10%, and 20% of water content (1% curcumin), was measured in vitro
Microemulsion
using excised rat skin. It has been shown that the permeability coefficient of CUR in a formulation
Curcumin
Transdermal drug delivery
containing 10% aqueous phase (ME-10) was twofold higher than the values obtained for formulations
Percutaneous penetration with 5% and 20% water (Papp = 0.116
103  0.052
103 vs. 0.043
103  0.022
103 and
0.047
103  0.025
103 cm/h, respectively. A reasonable explanation for this phenomenon may be
the reduction of both droplet size and droplets’ concentration in the microemulsion as the aqueous phase
decreased from 20% to 5%. It has also been shown that a linear correlation exists between the decrease in
droplet size and the increase of curcumin loading in the microemulsion. In addition, it has been
demonstrated that a micellar system, S/O-mix, and a plain solution of curcumin resulted in a significantly
lower curcumin permeation relative to that presented by the microemulsion, Papp = 0.018
103  0.011

103, 0.005
103  0.002
103, and 0.002
103  0.000
103 cm/h, respectively, vs. 0.110
103
 0.021
103 cm/h for the microemulsion. The enhancement ratio (ER = Jss-ME/Jss-solution) of CUR
permeated via 1% loaded microemulsion was 55.
ã 2015 Elsevier B.V. All rights reserved.

1. Introduction absorption and rapid metabolism, CUR is not chemically stable in

Curcumin (CUR; diferuloyl methane), a component of the
golden spice turmeric (Curcuma longa; family-Zingiberaceae), has
a variety of pharmacological activities. It has, just to name a few, an
anti-inflammatory effect in Crohn’s disease, ulcerative colitis,
rheumatoid arthritis, peptic and gastric ulcer, psoriasis, and
vitiligo, as well as anti-tumor, anti-diabetic, anti-oxidation, anti-
microbial and anti-viral actions (Anand et al., 2008; Gupta et al.,
2013). However, due to its low water solubility (maximum 11 ng/
ml in phosphate buffer, pH 5), CUR is slightly absorbed into the
body with a very low bioavailability (Yang et al., 2007; Tønnesen
et al., 2002; Tomren et al., 2007). Rapid metabolism and excretion
(t1/2 = 28.2 and 44.5 min after i.v. and oral curcumin in rats,
respectively) also curtails CUR bioavailability (Yang et al., 2007;
Anand et al., 2007; Metzler et al., 2013). In addition to its poor
* Correspondence at: Laboratory for Biopharmaceutics, E.D. Bergmann Campus,
Ben-Gurion University of the Negev, P.O. Box 653, Be'er Sheva 84105, Israel.
Tel.: +972 8 647 2709.
E-mail address: asintov@bgu.ac.il (A.C. Sintov).
physiological solutions. As reported by Wang et al. (1997), about
90% of CUR decomposed within 90 min when incubated in serum-
free phosphate buffer at pH 7.2. In more recent studies, the most
prevalent product of CUR was identified as the one formed by auto-
oxidative transformation, bicyclopentadione, and since it is also a
metabolic product catalyzed by lipoxygenase and cyclooxygenase
it has been proposed as a possible mediator of the biological
activity related to CUR (Griesser et al., 2011; Gordon and Schneider,
2012). Both high-rate chemical instability and the low solubility of
CUR are a major problem that limits its use in liquid formulations
and makes difficult for researchers to accomplish either in-vitro
evaluation or in vivo bioavailability studies. Several approaches has
been developed to improve CUR bioavailability and stability by
loading the agent into liposomes (Li et al., 2005, 2007; Kunwar
et al., 2006), nanoparticles (Bisht et al., 2007, 2010; Lim et al., 2011;
Chun et al., 2012), and microemulsions (Cui et al., 2009; Liu et al.,
2011; Liu and Chang, 2011; Hu et al., 2012). Further approaches
include derivatives and analogs (Mosley et al., 2007), and
phospholipid complexes (Liu et al., 2006; Maiti et al., 2007).
The vast majority of published studies aimed at improving
curcumin bioavailability have been focused on oral or injectable

http://dx.doi.org/10.1016/j.ijpharm.2015.02.005
0378-5173/ ã 2015 Elsevier B.V. All rights reserved.
98 A.C. Sintov / International Journal of Pharmaceutics 481 (2015) 97–103
delivery systems while transdermal delivery of curcumin has
received less attention so far. Patel et al. (2009) have developed a
dried polymeric film-type matrix containing curcumin, which its
in-vitro permeation followed Higuchi kinetics. In a series of three
publications dealing with microemulsion vehicles, the percutane-
ous delivery of 0.4% curcumin has been studied in terpene
microemulsions, such as eucalyptol and limonene combined with
polysorbate 80, ethanol and water (Liu and Chang, 2011; Liu et al.,
2011), and in microemulsions composed of Pluronic F127
(surfactant), isopropanol (co-surfactant), myristic acid (oil), and
water (Liu and Huang, 2012). Although microemulsions have not
been widely explored for transdermal curcumin they are
extensively utilized for a variety of pharmaceutical purposes
including transdermal and dermal drug delivery (Kreilgaard et al.,
2000; Alvarez-Figueroa and Blanco-Mendez, 2001; Kreilgaard,
2001; Kreilgaard et al., 2001; Rhee et al., 2001; Lee et al., 2003;
Sintov and Shapiro, 2004; Hua et al., 2004; Sintov and Botner,
2006; Sintov and Brandys-Sitton, 2006; Liu et al., 2007; Shevach-
man et al., 2008; Heuschkel et al., 2008; Gannu et al., 2010; Zhao
et al., 2011; Zhang et al., 2011; Zhang and Michniak-Kohn, 2011;
Sintov and Greenberg, 2014). Microemulsions, which are versatile
systems (oil-in-water, water-in-oil, or bi-continuous systems as
well as various structures and components), possess high
solubilizing capacity of diverse compounds and, in particular, is
capable of solubilizing poorly water-soluble drugs. The increase in
solute concentration and the tendency of the vehicle to favor
partitioning into the stratum corneum make microemulsions a
useful vehicle to enhance transdermal drug permeability.
In the present report, we describe an alcohol-free micro-
emulsion system for transdermal drug delivery with respect to its
contribution to percutaneous permeability of CUR. The micro-
emulsion system, which contains no chemical enhancers, is
composed of water, isopropyl palmitate, propylene carbonate,
and the commonly-used topical nonionic surfactants, PEG-
8 caprylic/capric glycerides (Labrasol1) and glyceryl oleate. We
studied the in vitro skin permeation of the microemulsions after we
had surmounted the technical difficulties of experimentation
regarding the high-rate of CUR degradability in aqueous solutions.
By using microemulsions as a vehicle, we have demonstrated an
increased solubilization as well as a significantly enhanced
permeability of the water insoluble and poorly absorbable
curcumin.
2. Materials and methods
2.1. Materials
Curcumin was obtained from Sigma, Rehovot, Israel. Labrasol1
(PEG-8 caprylic/capric glycerides) was purchased from Gattefosse
(Saint-Priest Cedex, France), and glyceryl oleate was obtained from
Croda Europe Ltd. (East Yorkshire, England). Isopropyl palmitate
and propylene carbonate were purchased from Sigma, Rehovot,
Israel. a-Tocopherol 1000 IU was obtained from BTSA Biotecno-
logias Aplicadas (Madrid, Spain). High-performance liquid chro-
matography (HPLC) grade water and solvents were obtained from J.
T. Baker (Mallinckrodt Baker, Inc., Phillipsburg, NJ).
2.2. Preparation of microemulsions
The formulation was prepared as previously published (Sintov
and Botner, 2006; Sintov et al., 2010; Sintov and Greenberg, 2014).
Shortly, water-in-oil (W/O) liquid microemulsions were prepared
by mixing Labrasol1 and glyceryl oleate (surfactants), propylene
carbonate (co-surfactant) and isopropyl palmitate (oil), followed
by gently titration of distilled water. The co-surfactant/surfactants
(CoS/S) weight ratio was 2:5, while the surfactants’ ratio was
1:3 glyceryl oleate/Labrasol1. The microemulsion formed sponta-
neously at room temperature as a clear monophasic liquid. The
loaded concentration of CUR in the microemulsions was by default
1.0 wt% but can be increased to 4.0 wt%. As a convenient method to
represent an increase of water content while decreasing CoS–S
levels, ‘water dilution lines’ were drawn from the water apex to the
opposite oil side of the phase diagram. The line was arbitrarily
denoted as the value of the line intersection with the oil scale (e.g.,
DL11 means line representing a surfactant-to-oil ratio of 89:11).
Formulations along a dilution line DL11 was prepared to contain
5%, 10%, and 20% (w/w) of aqueous phase. The stability of CUR in
10% water-containing microemulsion was tested at 4  C and at
ambient temperature, resulting in decrease of 5.9% and 8.9%,
respectively, after 7 days. However, no significant decrease in CUR
level has been noted when including 0.01% a-tocopherol in the
formulation.
2.3. Light scattering
The hydrodynamic diameter spectrum of microemulsion nano-
droplets was collected using CGS-3Compact Goniometer System
(ALV GmbH, Langen, Germany). The laser power was 20 mW at the
He–Ne laser line (633 nm). Correlograms were calculated by ALV/
LSE 5003 correlator during 10 s for 20 times at 25  C. Measure-
ments were performed at permanent angle of 60 . The droplet size
was calculated using the Stokes–Einstein relationship, and the
analysis was based on regularization method as described by
Provencher (1982).
2.4. Viscosity
The viscosity was measured by using a control stress rheometer
CSL 50 (TA Instruments Ltd., UK) at 25  C. Cone and plate geometry
was used.
2.5. In-vitro skin penetration study
The permeability of CUR through animal skin was determined
in vitro with a Franz diffusion cell system (Crown Bioscientific, Inc.,
Clinton, NJ). The diffusion area was 1.767 cm2 (15 mm diameter
orifice), and the receptor compartment volumes was from 12 ml.
The solutions in the water-jacketed cells were thermostated at
37  C and stirred by externally driven, Teflon-coated magnetic
bars. Each set of experiments was performed with at least four
diffusion cells (n  4), each containing skin from a different animal.
All animal procedures were performed in accordance with
protocols reviewed and approved by the Institutional & Use
Committee, Ben Gurion University of the Negev, which complies
with the Israeli Law of Human Care and Use of Laboratory Animals.
Sprague-Dawley rats (males, 300–350 g, Harlan Laboratories Ltd.,
Jerusalem, Israel) were euthanized by aspiration of CO2. The
abdominal hair was clipped carefully and sections of full-thickness
skin were excised from the fresh carcasses of animals and used
immediately. All skin sections were measured for transepidermal
water loss (TEWL) before mounted in the diffusion cells or stored
at lower temperatures until used. TEWL examinations were
performed on skin pieces using Dermalab1 Cortex Technology
instrument, (Hadsund, Denemark) and only those pieces that the
TEWL levels were less than 10 g/m2/h were introduced for testing.
The skin was placed on the receiver chambers with the stratum
corneum facing upwards, and the donor chambers were then
clamped in place. The excess skin was trimmed off, and the
receiver chamber, defined as the side facing the dermis, was filled
with 70:30 phosphate buffer (pH 7.4) – ethyl alcohol containing
a-tocopherol (0.01%). After 15 min of skin washing at 37  C, the
buffer was removed from the cells and the receiver chambers were
 A.C. Sintov / International Journal of Pharmaceutics 481 (2015) 97–103
refilled with fresh phosphate buffer–ethanol solution. Aliquots
(0.5 g each) of CUR-containing microemulsions or surfactant
mixtures were applied on the skin at time = 0. Samples (2 ml)
were withdrawn from the receiver solution at predetermined time
intervals, and the cells were replenished up to their marked
volumes with fresh buffer–ethanol solution each time. Addition of
buffer solution to the receiver compartment was performed with
great care to avoid trapping air beneath the dermis. After the 24-h
experimental period, each CUR-exposed skin tissue was washed
carefully in distilled water, wiped and tape-stripped (
15) to
remove the residues of curcumin adsorbed over the stratum
corneum. The tissue was then cut to small pieces and inserted into
2-ml vials. The skin pieces in each vial were extracted by 1-ml
ethyl alcohol. The extraction was performed by incubation in a
shaker (750 rpm) for 30 min. The receiver samples and the skin
extracts were taken into 1.5-ml vials and kept at 20  C until
analyzed by HPLC within two days.
2.6. HPLC analysis of samples from receiver solutions and skin extracts
Aliquots of 20 ml from each sample were injected into a HPLC
system, equipped with a prepacked column (ReproSil-Pur
300 ODS-3, 5 mm, 250 mm
4.6 mm, Dr. Maisch, Germany), which
was constantly maintained at 30  C. The HPLC system (Shimadzu
VP series) consisted of an auto-injector and a diode array detector.
The quantification of CUR was carried out at 425 nm. The samples
were chromatographed using an isocratic mobile phase consisting
of acetonitrile 0.2% acetic acid solution (80:20) at a flow rate of
1 ml/min.
2.7. Calculation of the in vitro data
A calibration curve (peak area versus drug concentration) was
constructed by running standard drug solutions in ethanol for each
series of chromatographed samples. As a result of the sampling of
large volumes from the receiver solution (and the replacement of
these amounts with equal volumes of buffer), the receiver solution
was constantly being diluted. Taking this process into account, the
cumulative drug permeation (Qt) was calculated from the
following equation:
Fig. 1. In vitro percutaneous permeation of curcumin through fresh rat skin after application of curcumin-loaded microemulsions containing various water contents. A
comparison was also made between 5% (diamonds), 10% (squares), and 20% aqueous phase (triangles) (n = 4).
99
X
t1
Qt ¼ Vr Ct þ Vs Ci
i¼0
where Ct is CUR concentration of the receiver solution at each
sampling timet, expressed by a running number (t = 1, 2, 3, ...tn). Ci
is CUR concentration of the ith sample, and Vr and Vs are the
volumes of the receiver solution and the sample, respectively. Data
were expressed as the cumulative curcumin permeation per unit of
skin surface area, Qt/S (S = 1.767 cm2). The steady-state fluxes (Jss)
were calculated by linear regression interpolation of the experi-
mental data at a steady state:
DQ t
Jss ¼
ðDt
SÞ
Apparent permeability coefficients (Papp) were calculated
according to the equation:
J ss
Papp ¼
Cd
where Cd is CUR concentration in the donor compartment (1.0 wt%
or 1.0
104 mg/ml), and it assumed that under sink conditions the
concentration of CUR in the receiver compartment is negligible
compared to that in the donor compartment.
2.8. Statistical analysis
The statistical differences between the skin permeation curves
of the formulations were analyzed employing the two-way ANOVA
test followed by Bonferroni’s multiple comparison t-test. The
differences among group means were considered significant when
p values < 0.05. The statistical differences between mean concen-
tration values of curcumin extracted from skin tissues were
assessed by using of Student’s t-test at p < 0.05. Data were
expressed as mean values (SD).
3. Results and discussion
3.1. Influence of water content
The permeability of curcumin from microemulsions containing
5%,10%, and 20% of water (dilution line DL11, CoS/S = 2:5,1% CUR) was
100 A.C. Sintov / International Journal of Pharmaceutics 481 (2015) 97–103

Table 1
Skin permeability parameters of various curcumin-loaded microemulsion (ME)
formulations as measured in vitro by using rat skin (n  4).

Formulation Papp
103 (cm h1) Q24 (mg cm2)

a
ME with 5% aqueous phase (ME-5) 0.043 (0.022) 6.53 (3.08)
ME with10% aqueous phasea (ME-10) 0.116 (0.052) 18.78 (8.68)
ME with 20% aqueous phasea (ME-20) 0.047 (0.025) 7.73 (4.37)
2% curcumin-loaded ME-10 0.233 (0.051) 39.10 (9.68)
3% curcumin-loaded ME-10 0.295 (0.050) 48.38 (8.39)
S/O-mix (surfactants–oil mixture)a 0.005 (0.002) 1.28 (0.49)
Micellar system (oil-free)a 0.018 (0.011) 3.40 (2.00)
1% curcumin in propylene carbonate 0.002 (0.000) 0.69 (0.06)
a
Loaded with 1% curcumin.

measured in vitro using excised rat skin. The cumulative percutane-

ous penetrating amounts of CUR from the three microemulsions are
illustrated in Fig. 1 and the permeation parameters are summarized
Fig. 3. Log–log plot of shear stress vs. shear rate and viscosity vs. shear rate showing
in Table 1. As seen, the cumulative permeating amount of CUR Newtonian fluid behavior related to 5% and 20% water-containing microemulsion,
following 24h-application (Q24) of a microemulsion containing 10% and a graph characteristic of a Bingham plastic that related to 10% water-containing
water fraction was about 3 times higher than those obtained by microemulsion.
application of microemulsions containing 5% or 20% aqueous
phases (Q24 = 18.78  8.68 vs. 6.53  3.08 and 7.73  4.37 mg/cm2,
size is not the only factor dictating the permeability of active
respectively; Student’s t-test, p < 0.05). The permeability coefficient
molecules and because a smaller fraction of inner phase in
of CUR in formulation containing 10% aqueous phase (ME-10) was
microemulsions naturally results in a lower density of the dispersed
twice higher than the values obtained for formulations with 5% and
droplets, it is reasonably conceived that the W/O formulation with
20% water (Papp = 0.116
103  0.052
103 vs. 0.043
103
5% water contains smaller number of droplets per unit volume than
 0.022
103 and 0.047
103  0.025
103 cm/h, respectively;
the formulation with 10% water. This conclusion was evidenced by
Student’s t-test, p < 0.05) (Table 1). The relatively high permeability
viscosity measurements as presented in Fig. 3. Unlike micro-
demonstrated by microemulsion ME-10 may be explained by the
emulsions containing relatively larger or smaller fractions of water
droplet size of the microemulsions. As measured by DLS (Fig. 2), the
phase, which have demonstrated a Newtonian fluid behavior, the
size of the nanodroplets in microemulsion containing 20% water
same microemulsion type with 10% water exhibited a typical
dropped from 5.95  0.21 nm (98% fraction by weight) to
Bingham plastic behavior. This type of fluid is characterized by a
2.53  0.90 nm (46% fraction) and 0.71  0.02 nm (48% fraction)
phenomenon, in which the shear stress (s ) must exceed a certain
when water content decreased to 10% and 5%, respectively. This
yield value, i.e., yield stress (s y), before the fluid deforms and flows
reduction in droplet size was accompanied by the appearance of an
as described by the following equation:
aggregate peak at approximately 150 nm diameter in both micro-
s
emulsions, however, approximately half of the nanodroplets were h ¼ h0 þ _y
much smaller in these formulations than in the microemulsion with g
20% water which contained almost no aggregates. Although when:
microemulsion with 5% water possessed the smallest droplet size,
s  sy
its CUR permeability was lower than that demonstrated by the h0 ¼
g_
microemulsion containing 10% water and was comparable to the
permeability of the microemulsion with 20% water, which where h is the apparent viscosity, h0 is the plastic viscosity, and g_ is
contained the largest droplet size. As it is obvious that the droplet the shear rate.

Fig. 2. Nanodroplet size (average diameter, nm) and their prevalence (percent of total droplets) in microemulsions containing 5%, 10%, and 20% aqueous phase.
 A.C. Sintov / International Journal of Pharmaceutics 481 (2015) 97–103 101

The physical behavior of Bingham fluids with a yield stress is

usually explained in terms of an internal structure in three
dimensions which is capable of preventing deformation for values
of the shear stress less than the yield value. This internal structure
could be flocculated particles in concentrated disperse systems or
designed microemulsions that generate high frictional forces
between the moving nanodroplets, forces that contribute to the
yield value.

3.2. Skin curcumin levels

Fig. 4 presents the extent of curcumin accumulation in rat skin

at 7 and 24 h of microemulsion application. In accordance with the
corresponding percutaneous permeation fluxes, skin accumulation
of CUR was significantly higher after administration of 10% water-
containing microemulsion (ME-10) than after 5% water-containing
system (ME-5) at either 7 or 24 h. Microemulsion ME-10 resulted in
twofold higher CUR concentration in the skin after 7 h compared
with microemulsion ME-5 (22.5  3.0 vs. 10.5  4.4 mg/g tissue),
and four times higher skin level of CUR after 24 h (331.3  38.4 vs.
83.5  11.8 mg/g tissue).
3.3. The effect of microemulsion nanostructure on curcumin
permeability
Fig. 5 shows the transdermal permeation profile of CUR applied
in a microemulsion (ME-10, 1% CUR concentration) in comparison
with permeation of CUR in oil-free micellar system, in a mixture of
the surfactants and oil (S/O-mix, water-free system), and in a plain
solution of 1% CUR in propylene carbonate. The CoS/S and the
surfactants ratios in the microemulsion as well as the micellar
system and the S/O-mix were kept constant. As seen in Fig. 5 and in
Table 1, the micellar system, the S/O-mix, and the plain solution
resulted in a significantly lower CUR permeation relative to that
presented by the microemulsion ME-10 (p < 0.05, ANOVA). The
permeability coefficients (Papp) of the micellar system, the S/O-
mix, and the plain solution were 0.018
103  0.011
103,
0.005
103  0.002
103, and 0.002
103  0.000
103 cm/
h, respectively, vs. 0.110
103  0.021
103 cm/h for ME-10. The
enhancement ratio (ER = Jss-ME/Jss-solution) of CUR permeated via 1%
Fig. 4. In vitro percutaneous penetration of curcumin to rat skin after application of
5% and 10% water-containing microemulsions. Skin retention of curcumin was
measured after 7 and 24 h microemulsion application (n = 6).
loaded microemulsion was 55. From this finding, it can be
summarized that: (a) the mechanism of CUR delivery through
the skin is based on the nature of microemulsion nanostructure
rather than on chemical enhancement driven by its ingredients, (b)
this is in agreement with our previous publications (Sintov and
Shapiro, 2004; Sintov and Greenberg, 2014), showing that micro-
emulsions are superior to micelles and S/O-mixtures in permeating
active substances through the skin, and (c) oil-free micelles
delivered more CUR across the skin than does S/O-mix, which is in
agreement with Sintov and Shapiro (2004) for lidocaine (as base),
but it is in contrast with Sintov and Greenberg (2014) for caffeine.
The latter argument indicates that unlike hydrophilic and water-
soluble molecules such as caffeine for which an oil additive is
crucial, the oil is redundant or less essential for the percutaneous
diffusion process of poorly soluble agents such as CUR.
3.4. Influence of curcumin loading
The in vitro percutaneous permeation profiles of 1–3% CUR
loaded in a microemulsion type ME-10 is illustrated in Fig. 6. As
shown, by increasing CUR concentration in the microemulsion,

Fig. 5. In vitro percutaneous permeation of curcumin using fresh rat skin after its application in a W/O microemulsion (10% aqueous phase), in micellar system, and in a water-
free surfactants and oil mixture (all formulations contained 1% curcumin, n = 4). Data were compared with 1% curcumin solution in propylene carbonate.
102 A.C. Sintov / International Journal of Pharmaceutics 481 (2015) 97–103

Fig. 6. In vitro percutaneous permeation of curcumin through fresh rat skin after application of curcumin-loaded microemulsions at various curcumin concentrations. A
comparison was also made between 1% (diamonds), 2% (squares), and 3% aqueous phase (triangles) (n = 10).
Average droplet size (nm in diameter)

4 3.65 nm 100

3.5 90
80

Percent of total droplets

3
70
2.5 2.36 nm
60
2 50

1.5 40
1.26 nm
0.80 nm 30
1
20
0.5 10
0 0
0.0 1.0 2.0 3.0
Curcumin concentraon (% wt/wt)
Fig. 7. Nanodroplet size (average diameter, nm) and their prevalence (percent of total droplets) in microemulsions containing 0–3% concentrations of curcumin.

its permeability coefficient increased from 0.116
103  0.052

103 cm/h in 1% CUR-loaded ME-10 to 0.233
103  0.051

103 cm/h and 0.295
103  0.050
103 cm/h in 2% CUR and
3% CUR-loaded ME-10, respectively (Table 1). It should be noted
that the Papp values for CUR permeation obtained in this study
are comparable with those previously published by Liu et al.
(2011), who used transdermal microemulsions composed of 20%
limonene (oil), 10% water, 35% polysorbate 80 (surfactant) and
35% ethanol (cosurfactant). There is no statistically significant
difference between the 2% and 3% CUR-loaded ME-10, however,
there is a significant difference between CUR permeability of
these high loaded formulations and 1% CUR-loaded micro-
emulsion (p < 0.05, ANOVA). It seems that although micro-
emulsion of the ME-10 type can be loaded up to 4% CUR, the
effect of loading on CUR permeation through the skin is
practically expressed from 1% to 2% CUR concentration. Fig. 7
presents the effect of CUR loading on droplet size, showing a
linear correlation between the decrease in droplet size and the
increase of CUR loading in the microemulsion. Although this
decrease was accompanied by increase in aggregation, the
diminution in size of more than 50% of the droplets may explain
the improvement in CUR permeability.
4. Conclusion
From the results presented in this paper, it has been concluded
that the W/O microemulsion vehicle for transdermal CUR
permeation is advantageous over a micellar system and a
surfactant-oil mixture, composed of the same proportions of
ingredient. This indicates that the mechanism of CUR delivery is
based on the nanostructural characteristics of the microemulsion.
In addition, it has been demonstrated that one of the mediating
factors of skin permeation and retention is the droplet size of the
microemulsion. One more important factor is apparently the
density of the dispersed droplets in the microemulsion, which
depends on both droplet size and the volume fraction of the inner
phase. Finally, this report joins to a series of studies demonstrating
the advantage of the microemulsion system in enhancement of
 A.C. Sintov / International Journal of Pharmaceutics 481 (2015) 97–103
percutaneous and cutaneous permeability of pharmacologically-
active agents.
Acknowledgment
The author is grateful for the professional assistance of Mr. Igor
Greenberg and Ms. Lillia Shapiro at the Laboratory for Biophar-
maceutics.
References
Alvarez-Figueroa, M.J., Blanco-Mendez, J., 2001. Transdermal delivery of
methotrexate: iontophoretic delivery from hydrogels and passive delivery from
microemulsions. Int. J. Pharm. 215, 57–65.
Anand, P., Kunnumakkara, A.B., Newman, R.A., Aggarwal, B.B., 2007. Bioavailability
of curcumin: problems and promises. Mol. Pharm. 4 (6), 807–818.
Anand, P., Thomas, S.G., Kunnumakkara, A.B., Sundaram, C., Harikumar, K.B., Sung,
B., Tharakan, S.T., Misra, K., Priyadarsini, I.K., Rajasekharan, K.N., Aggarwal, B.B.,
2008. Biological activities of curcumin and its analogues (congeners) made by
man and mother nature. Biochem. Pharmacol. 76 (11), 1590–1611.
Bisht, S., Feldmann, G., Soni, S., Ravi, R., Karikar, C., Maitra, A., Maitra, A., 2007.
Polymeric nanoparticle-encapsulated curcumin (nanocurcumin): a novel
strategy for human cancer therapy. J. Nanobiotechnol. 5, 3.
Bisht, S., Mizuma, M., Feldmann, G., Ottenhof, N.A., Hong, S.M., Pramanik, D.,
Chenna, V., Karikari, C., Sharma, R., Goggins, M.G., Rudek, M.A., Ravi, R., Maitra,
A., Maitra, A., 2010. Systemic administration of polymeric nanoparticle-
encapsulated curcumin (NanoCurc) blocks tumor growth and metastases in
preclinical models of pancreatic cancer. Mol. Cancer Ther. 9 (8), 2255–2264.
Chun, Y.S., Bisht, S., Chenna, V., Pramanik, D., Yoshida, T., Hong, S.M., de Wilde, R.F.,
Zhang, Z., Huso, D.L., Zhao, M., Rudek, M.A., Stearns, V., Maitra, A., Sukumar, S.,
2012. Intraductal administration of a polymeric nanoparticle formulation of
curcumin (NanoCurc) significantly attenuates incidence of mammary tumors in
a rodent chemical carcinogenesis model: implications for breast cancer
chemoprevention in at-risk populations. Carcinogenesis 33 (11), 2242–2249.
Cui, J., Yu, B., Zhao, Y., Zhu, W., Li, H., Lou, H., Zhai, G., 2009. Enhancement of oral
absorption of curcumin by self-microemulsifying drug delivery systems. Int. J.
Pharm. 371 (1–2), 148–155.
Gannu, R., Palem, C.R., Yamsani, V.V., Yamsani, S.K., Yamsani, M.R., 2010. Enhanced
bioavailability of lacidipine via microemulsion based transdermal gels:
formulation optimization ex vivo and in vivo characterization. Int. J. Pharm. 388,
231–241.
Gordon, O.N., Schneider, C., 2012. Vanillin and ferulic acid: not the major
degradation products of curcumin. Trends Mol. Med. 18 (7), 361–363.
Griesser, M., Pistis, V., Suzuki, T., Tejera, N., Pratt, D.A., Schneider, C., 2011.
Autoxidative and cyclooxygenase-2 catalyzed transformation of the dietary
chemopreventive agent curcumin. J. Biol. Chem. 286 (2), 1114–1124.
Gupta, S.C., Patchva, S., Aggarwal, B.B., 2013. Therapeutic roles of curcumin: lessons
learned from clinical trials. AAPS J. 15 (1), 195–218.
Heuschkel, S., Goebel, A., Neubert, R.H.H., 2008. Microemulsions—modern colloidal
carrier for dermal and transdermal drug delivery. J. Pharm. Sci. 97 (2), 603–631.
Hu, L., Jia, Y., Niu, F., Jia, Z., Yang, X., Jiao, K., 2012. Preparation and enhancement of
oral bioavailability of curcumin using microemulsions vehicle. J. Agric. Food
Chem. 60 (29), 7137–7141.
Hua, L., Weisan, P., Jiayu, L., Ying, Z., 2004. Preparation evaluation, and NMR
characterization of vinpocetine microemulsion for transdermal delivery. Drug
Dev. Ind. Pharm. 30 (6), 657–666.
Kreilgaard, M., Pedersen, E.J., Jaroszewski, J.W., 2000. NMR characterization and
transdermal drug delivery potential of microemulsion systems. J. Control.
Release 69, 421–433.
Kreilgaard, M., Kemme, M.J.B., Burggraaf, J., Schoemaker, R.C., Cohen, A.F., 2001.
Influence of a microemulsion vehicle on cutaneous bioequivalence of a
lipophilic model drug assessed by microdialysis and pharmacodynamics.
Pharm. Res. 18, 593–599.
Kreilgaard, M., 2001. Dermal pharmacokinetics of microemulsion formulations
determined by in vitro microdialysis. Pharm. Res. 18, 367–373.
Kunwar, A., Barik, A., Pandey, R., Priyadarsini, K.I., 2006. Transport of liposomal and
albumin loaded curcumin to living cells: an absorption and fluorescence
spectroscopic study. Biochim. Biophys. Acta 60 (10), 1513–1520.
Lee, P.J., Langer, R., Shastri, V.P., 2003. Novel microemulsion enhancer formulation
for simultaneous transdermal delivery of hydrophilic and hydrophobic drugs.
Pharm. Res. 20, 264–269.
Li, L., Braiteh, F.S., Kurzrock, R., 2005. Liposome-encapsulated curcumin: in vitro and
in vivo effects on proliferation, apoptosis, signaling, and angiogenesis. Cancer
104 (6), 1322–1331.
103
Li, L., Ahmed, B., Mehta, K., Kurzrock, R., 2007. Liposomal curcumin with and
without oxaliplatin: effects on cell growth, apoptosis, and angiogenesis in
colorectal cancer. Mol. Cancer Ther. 6 (4), 1276–1782.
Lim, K.J., Bisht, S., Bar, E.E., Maitra, A., Eberhart, C.G., 2011. A polymeric nanoparticle
formulation of curcumin inhibits growth, clonogenicity and stem-like fraction
in malignant brain tumors. Cancer Biol. Ther. 11 (5), 464–473.
Liu, A., Lou, H., Zhao, L., Fan, P., 2006. Validated LC/MS/MS assay for curcumin and
tetrahydrocurcumin in rat plasma and application to pharmacokinetic study of
phospholipid complex of curcumi. J. Pharm. Biomed. Anal. 40 (3), 720–727.
Liu, C.H., Chang, F.Y., 2011. Development and characterization of eucalyptol
microemulsions for topic delivery of curcumin. Chem. Pharm. Bull. (Tokyo) 59
(2), 172–178.
Liu, C.H., Chang, F.Y., Hung, D.K., 2011. Terpene microemulsions for transdermal
curcumin delivery: effects of terpenes and cosurfactants. Colloid Surf. B
Biointerfaces 82 (1), 63–70.
Liu, C.H., Huang, H.Y., 2012. Antimicrobial activity of curcumin-loaded myristic acid
microemulsions against Staphylococcus epidermidis. Chem. Pharm. Bull. 60 (9),
1118–1124.
Liu, H., Wang, Y., Han, F., Yao, H., Li, S., 2007. Gelatin-stabilized microemulsion-based
organogels facilitates percutaneous penetration of cyclosporine A in vitro and
dermal pharmacokinetics in vivo. J. Pharm. Sci. 96, 3000–3009.
Maiti, K., Mukherjee, K., Gantait, A., Saha, B.P., Mukherjee, P.K., 2007. Curcumin–
phospholipid complex: preparation, therapeutic evaluation and
pharmacokinetic study in rats. Int. J. Pharm. 330 (1–2), 155–163.
Metzler, M., Pfeiffer, E., Schulz, S.I., Dempe, J.S., 2013. Curcumin uptake and
metabolism. Biofactors 39 (1), 14–20.
Mosley, C.A., Liotta, D.C., Snyder, J.P., 2007. Highly active anticancer curcumin
analogues. Adv. Exp. Med. Biol. 595, 77–103.
Patel, N.A., Patel, N.J., Patel, R.P., 2009. Design and evaluation of transdermal drug
delivery system for curcumin as an anti-inflammatory drug. Drug Dev. Ind.
Pharm. 35 (2), 234–242.
Provencher, S.W., 1982. CONTIN: a general purpose constrained regularization
program for inverting noisy linear algebraic and integral equations. Comp. Phys.
Commun. 27, 229–242.
Rhee, Y.-S., Choi, J.-G., Park, E.-S., Chi, S.-C., 2001. Transdermal delivery of ketoprofen
using microemulsions. Int. J. Pharm. 228, 161–170.
Shevachman, M., Garti, N., Shani, A., Sintov, A.C., 2008. Enhanced percutaneous
permeability of diclofenac using a new U-type dilutable microemulsion. Drug
Dev. Ind. Pharm. 34, 403–412.
Sintov, A.C., Shapiro, L., 2004. New microemulsion vehicle facilitates percutaneous
penetration in vitro and cutaneous drug bioavailability in vivo. J. Control.
Release 95, 173–183.
Sintov, A.C., Botner, S., 2006. Transdermal drug delivery using microemulsion and
aqueous systems: influence of skin storage conditions on the in vitro
permeability of diclofenac from aqueous vehicle systems. Int. J. Pharm. 311,
55–62.
Sintov, A.C., Brandys-Sitton, R., 2006. Facilitated skin penetration of lidocaine by
using a combination of iontophoresis and microemulsion-based formulation.
Int. J. Pharm. 316, 58–67.
Sintov, A.C., Levy, H.V., Botner, S., 2010. Systemic delivery of insulin via the nasal
route using a new microemulsion system: in vitro and in vivo studies. J. Control.
Release 148, 168–176.
Sintov, A.C., Greenberg, I., 2014. Comparative percutaneous permeation study using
caffeine-loaded microemulsion showing low reliability of the frozen/thawed
skin models. Int. J. Pharm.. http://dx.doi.org/10.1016/j.ijpharm.2014.05.040.
Tomren, M.A., Másson, M., Loftsson, T., Tønnesen, H.H., 2007. Studies on curcumin
and curcuminoids XXXI. Symmetric and asymmetric curcuminoids: stability,
activity and complexation with cyclodextrin. Int. J. Pharm. 338 (1–2), 27–34.
Tønnesen, H.H., Másson, M., Loftsson, T., 2002. Studies of curcumin and
curcuminoids. XXVII. Cyclodextrin complexation: solubility, chemical and
photochemical stability. Int. J. Pharm. 244 (1–2), 127–135.
Wang, Y.J., Pan, M.H., Cheng, A.L., Lin, L.I., Ho, Y.S., Hsieh, C.Y., Lin, J.K., 1997. Stability
of curcumin in buffer solutions and characterization of its degradation products.
J. Pharm. Biomed. Anal. 15 (12), 1867–1876.
Yang, K.Y., Lin, L.C., Tseng, T.Y., Wang, S.C., Tsai, T.H., 2007. Oral bioavailability of
curcumin in rat and the herbal analysis from Curcuma longa by LC-MS/MS. J.
Chromatogr. B Analyt. Technol. Biomed. Life Sci. 853, 183–189.
Zhang, J., Michniak-Kohn, B., 2011. Investigation of microemulsion microstructures
and their relationship to transdermal permeation of model drugs: ketoprofen
lidocaine, and caffeine. Int. J. Pharm. 421, 34–44.
Zhang, Y.T., Zhao, J.H., Zhang, S.J., Zhong, Y.Z., Wang, Z., Liu, Y., Shi, F., Feng, N.P., 2011.
Enhanced transdermal delivery of evodiamine and rutaecarpine using
microemulsion. Int. J. Nanomed. 6, 2469–2482.
Zhao, J.H., Ji, L., Wang, H., Chen, Z.Q., Zhang, Y.T., Liu, Y., Feng, N.P., 2011.
Microemulsion-based novel transdermal delivery system of
tetramethylpyrazine: preparation and evaluation in vitro and in vivo. Int. J.
Nanomed. 6, 1611–1619.