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Drug Dev Ind Pharm, Early Online: 1–7

! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/03639045.2014.884127

RESEARCH ARTICLE

Curcumin nanoemulsion for transdermal application: formulation and

evaluation
Heni Rachmawati, Dewa Ken Budiputra, and Rachmat Mauludin
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Department of Pharmacy, Bandung Institute of Technology, Bandung, Indonesia

Abstract Keywords
The aim of this work is to develop a curcumin nanoemulsion for transdermal delivery. The Curcumin, Higuchi release profile, self
incorporation of curcumin inside a nanoglobul should improve curcumin stability and assembly nanoemulsion, shed snake skin,
permeability. A nanoemulsion was prepared by the self-nanoemulsification method, using an transdermal
oil phase of glyceryl monooleate, Cremophor RH40 and polyethylene glycol 400. Evaluation of
the nanoemulsion included analysis of particle size, polydispersity index, zeta potential, History
physical stability, Raman spectrum and morphology. In addition, the physical performance of
the nanoemulsion in Viscolam AT 100P gel was studied. A modified vertical diffusion cell and Received 14 October 2013
shed snake skin of Python reticulatus were used to study the in vitro permeation of curcumin. Revised 15 December 2013
A spontaneously formed stable nanoemulsion has a loading capacity of 350 mg curcumin/10 g Accepted 9 January 2014
of oil phase. The mean droplet diameter, polydispersity index and zeta potential of optimized Published online 7 February 2014
For personal use only.

nanoemulsion were 85.0 ± 1.5 nm, 0.18 ± 0.0 and 5.9 ± 0.3 mV, respectively. Curcumin in a
nanoemulsion was more stable than unencapsulated curcumin. Furthermore, nanoemulsifica-
tion significantly improved the permeation flux of curcumin from the hydrophilic matrix gel;
the release kinetic of curcumin changed from zero order to a Higuchi release profile. Overall,
the developed nanoemulsion system not only improved curcumin permeability but also
protected the curcumin from chemical degradation.

Introduction Curcumin oil-in-water nanoemulsions, with a mean droplet size

ranging from 79.5 nm to 618.6 nm, have been proven to enhance
Curcumin is a natural polyphenolic compound, usually derived
anti-inflammatory activity of curcumin. In addition, the stability
from Curcuma longa Linn. and possess potent anti-inflammatory
of curcumin can be maintained9. However, none of them aimed
properties following oral or topical administration1–3. Curcumin
for transdermal application.
was found to inhibit arachidonic acid metabolism, cyclooxygen-
Transdermal delivery in the form of a gel or patch is an
ase, lipoxygenase, pro inflammatory cytokines and activation of
interesting alternative for topical route to give local or systemic
nuclear factor-kB. It has very low intrinsic toxicity, even at very
effects. It can improve patient compliance and also has some
high doses. Curcumin has poor solubility in water at acidic
benefits for curcumin, such as avoiding first-pass metabolism,
or neutral pH and is degraded extensively in an alkaline
decreasing side or unwanted effects and enabling constant blood
environment, thus limiting its use4. Curcumin also undergoes
levels over longer periods of time. However, curcumin exhibits
rapid first-pass metabolism into inactive metabolites, causing
low skin penetration resulting in poor efficacy. Recently, a stable
low bioavailability in systemic circulation5. Therefore, several
curcumin gel has been produced using 15% alcohol (to dissolve
approaches have been investigated to increase curcumin bio-
curcumin in the gel). Dimethylsulfoxide (DMSO) is also needed
logical efficacy, including chemical derivatization, complex
to improve curcumin release from the gel9. In contrast to common
formation or interaction with macromolecules and using nano-
chemical skin penetration (using enhancers such as organic
scale drug delivery systems6.
solvents, which are generally associated with skin irritation,
In the past few years, application of nanotechnology in
toxicity and sensitization), a solvent-free topical vehicle based on
curcumin formulation has been tried by many researchers because
drug entrapment in oil/water emulsion droplets of submicron
of its potential to improve curcumin efficacy7. Encapsulation of
particle is more efficacious in terms of percutaneous absorption
curcumin in nanoscale carrier systems, such as nanoemulsion, has
and is possibly devoid of adverse effects. In addition, the
shown significant improvement of its bioavailability.
uniqueness of the large internal hydrophobic core of oil/water
Nanoemulsion possess high kinetic stability and can act as a
submicronized emulsion droplets allows high solubility for water
carrier to protect active compounds against extreme conditions8.
insoluble topically active ingredients and also improves on
carrying water, an excellent softener, to the skin.
Address for correspondence: Heni Rachmawati, Department of Pharmacy, This report describes a more effective and efficient strategy to
Bandung Institute of Technology, Ganesha 10, Bandung 40132, deliver curcumin via the transdermal route. This work is not only
Indonesia. E-mail: hrachma@yahoo.com focused on a better release of curcumin from a gel matrix but also
 2 H. Rachmawati et al.
on enhancing skin permeation as well as on the stability of the
curcumin to obtain better bioavailability.
Materials and methods
Materials
Curcumin was obtained from PT. Phytochemindo Lestari (Bogor,
Indonesia). Glyceryl monooleate (GMO) was purchased from PT.
Tritunggal (Jakarta, Indonesia). Polyoxyl 40 hydrogenated castor
oil (Cremophor RH40) was purchased from BASF
(Ludwigshafen, Germany). Polyethylene glycol 400 (PEG 400),
DMSO, triethanolamine (TEA) and potassium dihydrogen
phosphate were purchased from Merck (Darmstadt, Germany).
Glycerine, propylene glycol, methylparaben and propylparaben
were from Brataco (Jakarta, Indonesia). Viscolam AT 100 P was
purchased from Nardev Chemie (Singapore). Methanol and
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acetonitrile were of analytical grade and purchased from J.T.
Baker (Phillipsburg, NJ). Deionized water was obtained from the
School of Life Sciences and Technology (Bandung Institute of
Technology, Bandung, Indonesia). Double distilled water was
purchased from Ippha Laboratories (Bandung, Indonesia). Shed
snake skin of Python reticulatus was obtained from Bandung Zoo
(Bandung, Indonesia).
Methods
Preparation of emulsion and nanoemulsion
A conventional emulsion was prepared using GMO (16% w/v) and
Cremophor RH40 (4% w/v). Curcumin (0.25% w/v) was added
under stirring to GMO and Cremophor RH40. The mixture was
For personal use only.
then dispersed in water under stirring for 30 min to form an
emulsion. This emulsion was used for comparison.
A nanoemulsion of curcumin formed spontaneously in an oil
phase of GMO, Cremophor RH40 and PEG 400 (1:8:1). Various
amounts of curcumin (10, 25, 50, 100, 250, 350, 500 and 750 mg)
were added to 10 gram of oil phase. Curcumin, oil, surfactant and
co-surfactant were stirred at 100 rpm for 2 h. Further sonication
for 1 h using a bath sonicator (Nagoya S Ultrasonic Cleaner GB-
928) was applied to complete the mixing process. To obtain
nanoemulsion, deionized water was added to the oil phase at a
ratio of 5:1 and stirred gently.
Particle size and zeta potential measurement
The particle size, polydispersity index and zeta potential of
nanoemulsion were determined using a particle size and zeta
potential analyzer (DelsaTM Nano, Beckman Coulter, Brea, CA).
Determination of incorporation efficiency of curcumin in
nanoemulsion
The calculation of the incorporation efficiency (IE) of curcumin in
nanoemulsions was performed by a direct method. The nanoemul-
sion was centrifuged at 14 000 rpm for 20 min to break up the
nanoemulsion and 5 mL of DMSO was added to 10 mL of
supernatant to extract the curcumin. The curcumin concentration
in the DMSO phase was determined using a UV-visible spectro-
photometer (Beckman DU 7500i, Brea, CA). The %IE of curcumin
in the nanoemulsion was calculated using the following equation:
%IE ¼
amount of curcumin encapsulated in nano oil globule
100
amount of curcumin added into formula
Raman spectroscopy of nanoemulsion
To measure the incorporation of curcumin in the nanodroplets,
Raman spectra were obtained and recorded on a Bruker Senterra
Drug Dev Ind Pharm, Early Online: 1–7
Raman spectrometer (Ettlingen, Germany) using a diode pump
laser with an excitation wavelength of 785 nm. Spectra were taken
with a laser power of 10 mW for 60 s (curcumin powder), 10 mW
for 180 s (curcumin diluted in GMO) and 50 mW for 180 s (GMO,
Cremophor RH40, PEG 400, blank nanoemulsion and curcumin
nanoemulsion). Data were acquired between 2200 and 700 cm1.
Morphology of nanoemulsion
The morphology of nanoemulsion was observed using a
transmission electron microscope (TEM; JEM 1400, JEOL,
Tokyo, Japan). About 10 mL of sample was dropped in the
specimen place and covered with a 400 mesh grid. After 1 min,
10 mL of uranyl acetate was dropped on top of the grid, and this
sample was allowed to dry for 30 min before observation under
the electron microscope. This procedure was used to confirm the
particle size in the nanoemulsion as measured using the particle
size analyzer.
Stability study of nanoemulsion
The chemical and physical stabilities of the nanoemulsion were
studied by observation of phase separation, determination of
particle size, polydispersity index, zeta potential and analysis of
curcumin content using a UV-visible spectrophotometer. Samples
were kept at room temperature, and evaluation was performed at
day 0 (day of production), day 2, day 5, day 7, day 9, day 12 and
day 28. Gravitational tests were also performed to assess the
physical stability of nanoemulsions compared with a conventional
emulsion. Emulsion and nanoemulsion were centrifuged for
15 min at 12 000 rpm.
UV-visible spectrophotometric analysis
Quantification of curcumin content in emulsions and nanoemul-
sions was carried out using a UV-visible spectrophotometer
(Beckman DU 7500i, USA). A calibration curve was prepared
using curcumin diluted in DMSO. The calibration curve was
linear in a range of 1–8 ppm (R2 ¼ 0.999).
Preparation of curcumin gel
A gel was formulated using Viscolam AT 100P (5% w/v) as the
gel matrix. About 0.01% w/v of curcumin powder or curcumin
nanoemulsion were dispersed in water first, then mixed with the
gel whilst stirring (IKA RW 20 Digital, Wurttemberg, Germany)
at 500 rpm for 10 min). A mixture of methylparaben (0.2% w/v),
propylparaben (0.05% w/v), glycerine (5% w/v) and propylene
glycol (15% w/v) was added, and the mixture was stirred for 5 min
at 500 rpm. TEA was then added dropwise to the formulation with
continuous stirring (500 rpm, 5 min) to adjust the pH to 6–7 and to
produce proper consistency of the gel.
Characterization of gel
Evaluation of the gel was carried out by visual observation, and
measuring pH, viscosity and curcumin content. The curcumin
content in the gel was measured using high-performance liquid
chromatography (HPLC, Agilent, Santa Clara, CA) with a
Phenomenex Luna C-18 column (Phenomenex, Torrance, CA)
as previously reported10. The mobile phase consisted of
acetonitrile and phosphate buffer pH 4.5 (55:45 v/v) at a flow
rate of 1.0 mL/minute. Fifty microliters of sample was injected
into the system and curcumin content was determined using an
UV detector at max of 425 nm. A calibration curve was prepared
using curcumin diluted in the mobile phase. The calibration curve
was linear in a range of 0.625–10 ppm (R2 ¼ 0.999). Prior to
HPLC analysis, curcumin contained in gel was extracted with
 DOI: 10.3109/03639045.2014.884127 Curcumin nanoemulsion for transdermal application 3

acetonitrile and phosphate buffer pH 4.5 (55:45 v/v) using

forceful stirring on a vortex (IKA Genius 3, Staufen, Germany)
and then filtered over a 0.22 mm membrane (Sartorius, Göttingen,
Germany).

Stability study of gel

Stability of the gel during storage was evaluated over 28 d both at
room temperature and at 40  C, 75% RH. Samples were taken
every day and evaluated for physical alteration by visual
observation, and measuring pH and viscosity. The changes in
the content of curcumin were also determined.

In vitro diffusion test

A modified vertical diffusion cell and shed snake skin of
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P. reticulatus were used to study the permeation of curcumin as

previously reported10. Prior to the procedure, the shed snake skin
was hydrated and mounted between the donor and receptor
compartments. The system consisted of a donor compartment
with one gram gel containing curcumin powder or nanoemulsion,
Figure 1. Physical appearance of nanoemulsion (left) and conventional
and the receptor compartment contained 6 mL of phosphate buffer emulsion (right) with same curcumin concentration.
pH 7.4, at a temperature of 37  C and slow stirring at 100 rpm.
The available diffusion area between the compartments was
0.951 cm2. About 1 mL samples were withdrawn through the
sampling port of the diffusion cell at predetermined time intervals
over a period of 24 h (5, 10, 15, 30 and 45 min and 1, 1.5, 2, 3, 4,
5, 6, 7, 8 and 24 h). The buffer was immediately replenished with
1 mL of fresh buffer. The permeated amount of curcumin was
determined by HPLC as described previously. These tests were
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done in triplicate for each gel containing either unencapsulated

curcumin or curcumin in a nanoemulsion. The cumulative amount
of curcumin, which crossed the shed snake skin was plotted
against time. The transdermal drug flux was calculated from the
slope of the linear portion of the plot. The permeation kinetics
were determined (zero order, first order, Higuchi and Kors Meyer-
Peppas).

Data analysis
All experiments were done in triplicate, and the data were
expressed as mean value ± standard deviation. Statistical data
analyses were performed using Student’s t-test and one-way
ANOVA. A value of p50.05 was considered statistically
significant.
Figure 2. Influence of curcumin amount to particle size and poly-
dispersity index of nanoemulsion (mean + SD, n ¼ 3).
Table 1. Permeation flux of gel containing unencapsulated curcumin and
curcumin nanoemulsion (mean ± SD, n ¼ 3).

Sample Flux (mg/(cm2.h))

Results
Formulation and characterization of nanoemulsion
The potential of curcumin encapsulated and delivered as a
nanoemulsion for transdermal delivery was evaluated with respect
to monodispersity, physical stability, in vitro stability and
effectiveness in skin permeability. The visualization of curcumin
emulsion versus curcumin nanoemulsion with the same concen-
tration is presented in Figure 1. Nanoemulsions have some
interesting physical properties, which distinguish them from
microscale emulsions. Microscale emulsions typically exhibit
strong scattering of visible light, and, as a result, have a white
appearance. In contrast, the structures in nanoemulsions are much
smaller than the wavelengths in visible light, so most nanoemul-
sions appear optically transparent.
We determined whether any relationship existed between
transparency and the amount of the curcumin loaded inside the
globules. As shown in Figure 2, the droplet size of nanoemulsion
increased with the increase of the amount of curcumin added.
Increments of the amount of curcumin up to 750 mg resulted
Gel containing unencapsulated curcumin 0.836 ± 0.004
Gel containing curcumin nanoemulsion 1.699 ± 0.050
in opaque nanoemulsions, followed by phase separation after a
few hours. This indicated that the maximum IE of curcumin had
been reached (Table 1) at 750 mg. The droplet size in the
emulsion is a crucial factor in self-emulsification because it
determines the rate and extent of drug release, as well as the
absorption.
The successful incorporation of curcumin in the oil droplets
was supported by Raman spectra (Figure 3). Marked structural
differences between pure curcumin, excipients and curcumin
nanoemulsion were observed. As indicated, the peaks of
curcumin powder in the Raman spectra were similar to those of
curcumin diluted in GMO. Both showed bands at 1626, 1601,
1430, 1320, 1250, 1184, 1151 and 962 cm1. However, the
intensity of the peaks decreased, probably due to reduction in
crystallinity of curcumin in oil. Peaks in blank nanoemulsion
 4 H. Rachmawati et al. Drug Dev Ind Pharm, Early Online: 1–7

Figure 3. Raman spectra of (a) curcumin

powder, (b) GMO, (c) Cremophor RH40, (d)
PEG 400, (e) curcumin diluted in GMO, (f)
blank nanoemulsion and (g) curcumin
nanoemulsion.
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For personal use only.

(1475, 1442, 1287, 1143, 844 and 807 cm1) corresponded to

some peaks in GMO, Cremophor RH40 and PEG 400, with a
minor shift. This might suggest that some interactions occurred
between nanoemulsion components and water, causing a shift in
and broadening of the peaks, as shown in Figure 3(f).
The morphology of curcumin nanoemulsions was analyzed
using TEM and is presented in Figure 4. Visualization of
nanoemulsion using transmission electron microscopy (TEM)
imaging is likely the most powerful and accurate technique to
determine a specimens’ morphology, purity and particle size
distribution. As shown in Figure 4, the droplets were distributed
evenly and the particle size was uniform, confirming the particle
size measurements as determined with photon correlation
spectrophotometer.

Stability study of nanoemulsion

Nanoemulsions have many interesting physical properties, which
are different from, or are more extreme, than those of microscale
emulsions. We examined the (enhanced) shelf stability of
nanoemulsions and monitored physical alterations as well as the
chemical degradation of curcumin. We found that particle size,
polydispersity index, zeta potential and %IE of nanoemulsion
were relatively stable over 14 d of storage. No agglomeration was Figure 4. Transmission electron microscopy (TEM) image of curcumin
nanoemulsion. (magnification: 10 000).
observed as confirmed by the constant particle size and particle
distribution.
 DOI: 10.3109/03639045.2014.884127 Curcumin nanoemulsion for transdermal application 5

Formulation and stability study of curcumin gel resembles the stratum corneum of the human skin. The vascular
structures and collageneous connective tissues found in snake and
Stability study of gel were established over 28 d at room
human skin are also similar11. There is also similarity of thickness
temperature and 45  C, 75% RH. We followed the appearance
between shed skin of P. reticulatus and the stratum corneum of
by eye and measured pH, viscosity and curcumin concentration in
human skin, which approximately lie in the range of 11–16 mm
the gel. The formation of curcumin crystals was only observed in
and 15 mm, respectively12,13. Permeation of curcumin through the
gels containing curcumin powder and not in gels containing
skin of P. reticulatus is shown in Figure 7.
curcumin nanoemulsions (figure not shown). Crystallization
occurred due to the limited solubility of curcumin in the
Discussion
hydrophilic matrix gel. Curcumin nanoemulsions could be
easily dispersed preventing physical and chemical problems Formulation and characterization of nanoemulsion
with the curcumin. Curcumin nanoemulsions enhanced the
Nanoemulsion using our established composition formed sponta-
solubility of curcumin in aqueous gels, and at the same time,
neously after water addition. Self nanoemulsification is only
protected curcumin from degradation, as can be seen in the
achieved with some oils, surfactants and co-surfactants at a
stability profile as depicted in Figure 6.
certain ratio. Selection of an appropriate oily phase is very
important as it influences the selection of other ingredients in
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In vitro diffusion test

In vitro diffusion test for all gels were performed using a modified
vertical diffusion cell and shed snake skin of P. reticulatus
as a membrane. Shed snake skin is easily available without
causing harm to the snake, as a relatively large amount of skin
is periodically shed by each snake. Shed snake skin closely
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oil/water nanoemulsions. Usually, the oil with the maximum
solubility for the selected drug is chosen as the oily phase for the
formulation of nanoemulsions. This helps to achieve maximum
drug loading14. Generally, surfactant alone cannot lower the oil–
water interfacial tension sufficiently to yield a nanoemulsion; this
necessitates the addition of an amphiphilic short chain molecule

Figure 7. Permeation profiles of curcumin through shed snake skin from

Figure 5. Influence of curcumin concentration on the incorporation gel containing curcumin nanoemulsion and gel containing unencapsulated
efficiency of curcumin nanoemulsion (mean + SD, n ¼ 3). curcumin (mean + SD, n ¼ 3).

Figure 6. (A) Degradation profile of curcumin from gel containing curcumin nanoemulsion and gel containing unencapsulated curcumin, stored for
28 d at room temperature (A) and in climatic chamber (B) (mean + SD, n ¼ 3).
 6 H. Rachmawati et al.
Table 2. In vitro permeation kinetics of gel containing unencapsulated curcumin and curcumin nanoemulsion.
Sample
Gel containing unencapsulated curcumin Zero order
First order
Higuchi
Kors Meyer-Peppas
Gel containing curcumin nanoemulsion Zero order
First order
Higuchi
Kors Meyer-Peppas
or cosurfactant to lower the surface tension close to zero.
Cosurfactants penetrate into the surfactant monolayer, providing
additional fluidity to the interfacial film and thus disrupting the
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liquid crystalline phases, which are formed when the surfactant
film is too rigid14.
Figure 3 shows a transmission electron micrograph of a
curcumin nanoemulsion (formula F6). The droplets are spheric
and nearly monodisperse in accordance with the data presented in
Table 1.
Different amounts of curcumin loaded in the oil droplets did
not significantly impact the zeta potential of nanoemulsions, as
listed in Table 2. Distinct from other colloidal systems, the
physical stability of nanoemulsions does not depend on zeta
potential. High amounts of surfactant formed rigid films covering
the surface of oil droplets, maintaining sufficient distance
between droplets. The use of the non-ionic surfactant,
Cremophor RH40, in high amounts might be responsible for the
For personal use only.
low value of zeta potential found in this study. Cremophor
contains a fatty acid ester15, which was dissociated, forming a
negatively charged free fatty acid that contributed to the negative
value of the zeta potential. Different zeta potential values at
different amounts of curcumin in nanoemulsion might be
attributed to the interaction of the functional groups in curcumin
with functional groups of other component in the formula. Zhang
et al.16 also found that blank nanoemulsion and nanoemulsion
containing curcumin have different zeta potentials. This might be
due to an alteration on the surface electrostatic double layer of
droplets, because of the formation of intermolecular hydrogen
bonds among the hydroxyl groups in curcumin and some related
groups containing oxygen or nitrogen atoms in the surfactant,
cosurfactant and oil16.
Raman spectrophotometer showed some interesting spectra in
curcumin nanoemulsions. The peak at 1626 cm1, which is
attributed to carbonyl groups, shifted to 1635 cm1. Moreover, the
intensity of the symmetric aromatic ring stretching vibrations of
curcumin in 1601 cm1 was reduced. The ratio of intensity at
1626 and 1601 cm1 in curcumin powder was 0.67. The ratio of
intensity of curcumin nanoemulsion at 1635 and 1601 cm1 was
found to be 1.03. This showed the presence of a surrounding
obstacle opposing the Raman active vibrational mode17. The
excipient molecules surrounding the curcumin used in the formula
reduced the intensity of the curcumin peak and shifted the spectra.
Some peaks of the excipients were seen as weak bands at 1130
and 849 cm1.
Figure 5 gives information about %IE of nanoemulsion. It is
assumed that the amount of oil influences the IE of a compound in
a nanoemulsion system. At low amounts of oil curcumin cannot
be dissolved and incorporated completely. As a result, unencap-
sulated curcumin was still present outside the nanoemulsion
droplets, and the IE of nanoemulsion decreased. Based on these
preliminary results, we chose a formulation composed of 350 mg
curcumin in 10 gram of oil. This formula was then tested for
stability and incorporated into gel.
Drug Dev Ind Pharm, Early Online: 1–7
Model r2 Equation
0.995 y ¼ 0.835x + 1.440
0.989 y ¼ 0.067x + 0.392
0.976 y ¼ 3.537x  2.117
0.985 y ¼ 0.678x + 0.282
0.954 y ¼ 1.162x + 5.220
0.893 y ¼ 0.057x + 0.741
0.991 y ¼ 4.097x + 2.252
0.971 y ¼ 0.340x + 0.816
Stability study of nanoemulsion
The physical stability of nanoemulsion can easily deducted from
the value of the zeta potential. A zeta potential of nearly 30 mV
ensures a high energy barrier toward coalescence of dispersed
droplets. However, this value is based on experiments and not the
only indicator to predict nanoemulsion stability18. Conventional
emulsions show low stability as indicated by sedimentation of
curcumin at storage at room temperature. Nanoemulsion often
results in better physical stability7. Curcumin, which is incorpo-
rated in an oily phase in a nanoemulsion, does not come in contact
with the water in the external phase. It is likely that a
nanoemulsion thus provides an inert environment for curcumin.
Curcumin in nanoemulsions was effectively protected from
degradation19.
Formulation and stability study of curcumin gel
The viscosity and pH of all gels tested in this study were relatively
stable after storage for 28 d at room temperature or at 40  C.
Viscosity of gels ranged between 2000 and 2700 cps, which
means that the gels are relatively easy to pour, but viscous enough
to stick to the skin and to remain physically stable over time. The
pH for all gels tested was in an acceptable range of 6.2–6.9.
Although the surface of the human skin has a pH between 5.5 and
5.9, application of gels with a pH up to neutral did not cause
irritation20.
Compared to gels containing unencapsulated curcumin, gels
with curcumin nanoemulsions were more stable at both room
temperature and 40  C, in terms of curcumin content in gel
(Figure 6). There was a 3-fold (room temperature) and 4.6-fold
(climatic chamber) improvement in stability of nanoemulsion gels
over unencapsulated curcumin gels. These improvements were
statistically significant (p50.05). This suggests that surfactant
and co-surfactant in nanoemulsions play an important role in
improving curcumin stability in gels.
In vitro diffusion test
Water, the main component in gels, hydrates the skin and causes
the cells in the stratum corneum to swell, thus making drug
channels wide, resulting in improved cumulative permeation21.
This study shows a significant improvement (1.6-fold, p50.05) of
cumulative curcumin permeated from nanoemulsion gels com-
pared to gel containing unencapsulated curcumin (Figure 7). The
permeation flux was calculated from the curve of cumulative
amounts of curcumin permeated versus time. Statistical compar-
ison of the flux in a 24-h experiment shows that nanoemulsion
gels provide a flux (p50.05), which is higher than from
conventional curcumin gel, as seen in Table 1. This is in
agreement with previous data, which showed a significant
improvement of cumulative curcumin permeated from nanoemul-
sion gel. Nanoemulsion interact with the stratum corneum,
altering both the lipophilic and polar pathways, resulting in
 DOI: 10.3109/03639045.2014.884127
increased permeation rates. Alterations in the tight junction
properties of the stratum corneum also provide improved
permeation by increased solubilization or extraction of lipids
present in the stratum corneum, as well as increased membrane
fluidity. Another possible mechanism is direct permeation of
loaded drug from the nanoemulsion droplets to the stratum
corneum. We suggest that nanosized droplets in nanoemulsions in
the continuous phase can carry the drug through the skin barrier
and can move easily into the stratum corneum, resulting in
enhancement transfer of the drug from nanoemulsion as also
reported by other groups21–23. Figure 7 also shows a burst in the
initial release of curcumin from the gel. Due to the hydrophilic
nature of the polymer used, the polymeric matrix of the gel
forms loose channels within the network, causing fast initial
release of drug.
Based on the cumulative amount of curcumin permeated
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through the shed snake skin membrane, the permeation kinetics
were determined. Four kinetic equations are appropriate
for transdermal delivery kinetics: zero order, first order, Higuchi
and Kors Meyer-Peppas24. Curves were plotted from
cumulative curcumin permeated versus time (zero order),
log cumulative curcumin permeated versus time (first order),
cumulative curcumin permeated versus the square root of time
(Higuchi) and log cumulative curcumin permeated versus log time
(Kors Meyer-Peppas), respectively. The correlation coefficient of
each of these permeation kinetics was calculated and compared
(Table 2). The permeation kinetic best fitted was indicated by value
of correlation coefficient. As shown in Table 2, the permeation
profiles of free and nanoemulsion of curcumin followed zero-order
and Higuchi release kinetic, respectively. The difference in
For personal use only.
permeation kinetics of active compound was influenced by the
concentration of both the polymer used and the active compound25.
However, as the gel composition containing unencapsulated
curcumin and curcumin nanoemulsion were similar, the observed
difference in kinetics in this study can only due to the form of
curcumin, i.e. in dissolved or in crystalline states.
Conclusions
Curcumin is widely used as a potent anti-inflammatory herbal
drug. Its activity is similar to the NSAIDs in inflammatory pain
management. An early study pointed out that the hydroxyphenyl
unit in curcumin confers anti-inflammatory activity. Some
problems are related to the oral administration of curcumin, and
topical application is difficult due to its low permeability through
the skin. Our gel-containing nanoemulsion of curcumin seems to
be promising as a transdermal delivery system for curcumin.
Mixing of GMO:Chremophor RH40:PEG 400 (1:8:1) resulted in
the spontaneous formation of nanoemulsion, and successfully
encapsulated curcumin with better physicochemical stability,
prolonged shelf life and enhanced skin permeability. As
transdermal delivery requires this permeability to provide the
required therapeutic dose, encapsulation of curcumin into
nanoemulsion seems to be promising for transdermal delivery
of curcumin.
Aknowledgements
We thank to JICA (Japan International Cooperation Agency) for
financially supporting this work. An appreciation was also conveyed to
Dr. H. J. Doddema and Dr. Wangsa Tirta Ismaya for careful grammatical
correction.
Declaration of interest
The authors report no declarations of interest.
Curcumin nanoemulsion for transdermal application 7
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