See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/236249499

The application of nanoemulsion in dermatology: An overview

Article  in  Journal of Drug Targeting · April 2013

DOI: 10.3109/1061186X.2013.765442 · Source: PubMed

CITATIONS READS

24 707

4 authors, including:

Yuan-Hong Li Xing-Hua Gao

43 PUBLICATIONS   514 CITATIONS   
China Medical University (PRC)
287 PUBLICATIONS   3,127 CITATIONS   
SEE PROFILE
SEE PROFILE

Hong-Duo Chen

252 PUBLICATIONS   2,159 CITATIONS   

SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Poxviruses View project

All content following this page was uploaded by Yuan-Hong Li on 16 May 2014.

The user has requested enhancement of the downloaded file.

 http://informahealthcare.com/drt
ISSN: 1061-186X (print), 1029-2330 (electronic)

J Drug Target, 2013; 21(4): 321–327

! 2013 Informa UK Ltd. DOI: 10.3109/1061186X.2013.765442

REVIEW

The application of nanoemulsion in dermatology: an overview

Yan Wu, Yuan-Hong Li, Xing-Hua Gao, and Hong-Duo Chen

Department of Dermatology, No.1 Hospital of China Medical University, Shenyang, China

Abstract Keywords
Nanotechnology has been introduced into dermatology for years. Nanoemulsions (NEs) are Drug delivery, drug targeting, nanoemulsion,
promising drug delivery systems with practical applications for pharmaceutical, cosmetic and nanoparticles, nanotechnology
chemical industry applications. Herein, we provide an overview of the application of NEs in
dermatology during the latest 5 years. We reviewed the antioxidants in NEs form, non-steroidal History
anti-inflammatory drug loaded by NE, NEs in photodynamic therapy, NEs in decontamination of
radionuclides, antimicrobial NEs, NEs carrying lipids, NEs containing Octyl Methoxycinnamate, Received 23 October 2012
et al. NEs demonstrate good stability, stable physical and chemical properties. NEs are able to Revised 24 December 2012
enhance the functionality and efficacy of active chemicals and natural ingredients. NEs exhibit Accepted 6 January 2013
great application potential in the field of dermatology. Published online 19 April 2013

Introduction offer advantages in thermodynamic stability to unstable

suspensions [5]. The nanometer-size and polydispersity
Nanotechnology has been introduced into dermatology for
affectEM’s properties such as particle stability, rheology,
years. Owing to the small size, nanomaterials are able to
appearance, color, texture and shelf life and produce
‘‘connect’’ more substances with their large surface area and
improvement of pharmacological effects of drugs [6].
easy transport ability. Furthermore, facilitated by surface
NEs are promising drug delivery systems with practical
drainage, nanomaterials can remain and accumulate prefer-
applications for pharmaceutical, cosmetic and chemical
entially at skin level [1].
industry applications. Herein, we provide an overview of the
In nanotechnology, one critical factor is carrier system,
application of NEs in dermatology during the latest 5 years
which can load the active ingredients (the other critical factor)
(Table 1).
into nanoparticles (NPs). The carrier system includes nano-
lipid delivery system such as solid lipid NPs (SLN) and
nanostructured lipid carriers (NLC), nanoemulsions (NEs), Antioxidants in NEs form
NP suspension, polymer NPs, and magnetic NPs.
Many cellular components are targeted by reactive oxygen
NEs are broadly emulsions (EMs) in combination with
species (ROS) generated by ultraviolet (UV) irradiation.
lipid, and primarily produced by high-energy or low-energy
Pharmaceutical and cosmetics industries have launched a
emulsification [2]. NEs can also be defined as ‘‘ultrafine
wide range of substances to protect against ROS attack.
EMs’’ because of the formation of droplets in the submicron
Antioxidants in NEs form were evaluated recently. NEs-based
range. The average droplet size of NEs has been defined
broadly from 50 to 500 nm and typically in the range of
aqueous extract of propolis and lycopene were studied by 13
20
Butnariu and Giuchici [7]. Their results showed that NEs
200–300 nm. This is smaller than the usual 1–100 mm range
provided a sustained drug release in vitro for a period of 8 h
for the droplet size in macroemulsions [3]. The small droplet
and had a high kinetic stability. The NEs, without any
size can resist the physical destabilization caused by gravi-
irritation, induced a reduction in the activity of collagenase
tational separation, flocculation and/or coalescence [4,5].
and produced inflammation decreased by 75–100%. Local
Furthermore, NEs are thermodynamically stable transparent
application of the experimental NEs (propolis and lycopene)
(translucent) dispersions of oil and water stabilized by an
conferred potiential high therapeutic effects and safety profile
interfacial film of surfactant and cosurfactant molecules.
[7]. NE of liquid-lipid type has a smaller particle size
There are three types of NEs, i.e. oil-in-water (o/w) type,
compared to SLN and NLC. When lutein (a natural antioxi-
water-in-oil (w/o) type, bio-continuous type and NEs can help
dant) was encapsulated in this kind of NE, it showed a high
delivery of both hydrophilic and lipophilic drugs [4].
release profile (19.5%) and a good penetration profile (60%)
NEs have greater capacity for micellar solubilization and
in 24 h. The NE was also able to protect lutein against UV
degradation (14%), thus exhibited a good enhancement in the
Address for correspondence: Hong-Duo Chen, Department of Dermatol- lutein photostability [8]. Rice bran oil contains high levels of
ogy, No.1 Hospital of China Medical University, 155N. Nanjing Street,
Shenyang 110001, P.R. China. Tel: þ86-24-83282642. Fax: þ86-24- antioxidant-rich components, such as tocopherols/tocotrienols
83282633. E-mail: chenhd@cae.cn and gamma-oryzanol [9]. Cosmetic industries use rice bran
322 Y. Wu et al. J Drug Target, 2013; 21(4): 321–327

Table 1. Composition and function of NEs.

Sources Composition Advantages

Antioxidants in NEs form
Butnariu and Giuchici [7] NE1: 28% lycopene, 27% propolis, 53%
water vol/vol;
NE2: 35% lycopene, 35% propolis, 30%
water vol/vol
Mitri et al. [8] 1.0% (w/w) lutein corn oil,
9% (w/w) Miglyol 812,
1.5% (w/w) Plantacare 810
Bernardi et al. [10] 10% rice bran oil, 10% surfactant blend, 80%
water, 0.05% antioxidants, 0.5%
preservatives
NSAID loaded by NE
Sakeena et al. [12,13] 2.5% ketoprofen, 3% limonene, 23.6% POEs,
35% distilled water, 35.9% Tween 80
Kim et al. [14] NE1: ketoprofen, 4% benzyl alcohol;
NE2: ketoprofen, 1% Solutol(R) HS 15
Shakeel et al. [15] NE1: Indomethacin F6;
NE2: Indomethacin F7
Shakeel et al. [16,17] C2: 2% w/w Celecoxib, 15% w/w Sefsol-218
and Triacetin (1:1), 35% w/w Cremophor-
EL and Transcutol-P (1:1), distilled water
to 100% w/w;
NGC2: 2% w/w Celecoxib,15% w/w Sefsol-
218 and Triacetin (1:1), 35% w/w
Cremophor-EL and Transcutol-P (1:1), 1%
w/w Carbopol-940, 0.5% w/w triethano-
lamine, distilled water to 100% w/w.
Shakeel et al. [18] 2% w/w aceclofenac, 10% w/w Labrafil, 5%
w/w Triacetin, 35.33% w/w Tween 80,
17.66% w/w Transcutol P, 32% w/w
distilled water.
NEs in PDT
Maisch et al. [19]; Szeimies et al. [20]; BF-200 ALA: lecithin, 10% 5-aminolevulinic
Dirschka et al. [21] acid-hydrochloride
Primo et al. [22] Foscan, aqueous solution, nonionic surfac-
tants and oil
NEs in decontamination of radionuclides
Spagnul et al. [23–26] 2 mg/g calixarene, 20% paraffin oil, 5%
nonionic surfactants, 75% water (w/w)
Antimicrobial NEs
Hemmila et al. [27] 10% NB-201: benzalkonium chloride, super-
refined soybean oil, surfactants, alcohol,
water
1. High kinetic stability;
2. Sustain drug release for a period of 8 h;
3. Reduce collagenase activity in guinea pigs
skin
1. Stable lutein-loaded lipid nanocarriers;
2. High release profile;
3. Good in vitro penetration of dermis pig ear
skin;
4. Phtoprotection
1. Stable during the period of study;
2. Increase the relative hydration of human skin,
the skin oiliness and maintained normal skin
pH values
1. Increase permeation rate through rat skin;
2. Anti-inflammatory effects in carrageenan-
induced rat hind paw edema study;
3. Analgestic effects in carrageenan-induced
hyperalgesia pain threshold study
Enhanced in vitro permeation rate through
mouse skins
1. High inhibition value on carrageenan-induced
paw edema in rats,
2. Decreased activation energy across rat skin
1. Decreased activation energy for permeation
across rat skin;
2. Increased absorption of celecoxib;
3. High % inhibition value in carrageenan-
induced paw edema in rats
Decreased activation energy for permeation
across rat skin
1. Significant increasing in the fluorescence
signals of metabolite PpIX in full-thickness
porcine skin model;
2. High patient complete clearance rate and
lesion complete clearance rate of AK patients
1. An adequate profile for the interaction in
different skin layers with an ideal time lag in
the skin animal model;
2. Increase the diffusion flux of Foscan
1. Extract and retain enough free uranium from
contamination solution;
2. Rapid response with uranium-contaminated
solution;
3. Effect maintained in case of small-contami-
nated volumes;
4. Uranium extraction rate significantly
improved in case of acidification of the
contaminated medium;
5. Significant decrease of a uranium transcuta-
neous diffusion in Franz diffusion cells of pig
ear skin explants
1. Antimicrobial effect: significantly reduce
bacterial growth in a partial thickness burn
rats model;
2. Anti-inflammatory effects: attenuate neutro-
phil sequestration, diminish levels of pro-
inflammatory cytokines (IL-1b and IL-6),

(continued )
DOI: 10.3109/1061186X.2013.765442 Application of nanoemulsion in dermatology 323
Table 1. Continued

Sources Composition Advantages

reduce the degree of hair follicle cell apop-
tosis in rat skin
Pannu et al. [28] NB-002: purified oil, ethanol, polysorbate 20, 1. Fungicidal activity against both microconidial
cetylpyridinium chloride, cationic surfac- spore and mycelial forms of dermatophytes;
tant, water 2. Activity against both azole-susceptible and
-resistant Candida albicans yeast
NEs carrying lipids
Yilmaz and Borchert [29] PN: 20.8% eutanol G, 2% lipoid E-80, 0.6% Increase skin hydration and elasticity
phytosphingosine, 0.03% vitamin E, 2%
Tween 80, 2.5% glycerol, 0.1% potassium
sorbate, water to 100%;
PNSC: PN, 0.2% ceramide 3B, 0.2% cer-
amide 3, 0.2% palmitic acid, 0.2% chol-
esterol, water to 100%;
NNSC: PNSC (not include 0.6% phyto-
sphingosine), 0.6% myristic acid, 2%
ethanol, water to 100%;
Zhou et al. [30] F1-12: 15% snake oil, 2.5-7.5% soybean 1. Significantly improved the skin hydration;
lecithin, 0-82.5 glycerol, 0-82.5% water 2. Strengthened the penetrability of Nile red dye
into the dermis layer in rat model
NEs containing OMC
Olvera-Martı́nez et al. [31] 0.5 ml OMC, 80 ml 5% poly(vinyl alcohol) 1. Increase the extent of OMC penetration;
aqueous solution 2. Improve the accumulation in the skin of OMC
Calderilla-Fajardo et al. [32] OMC, sucrose laureate 1. High penetration in the SC;
2. Increase OMC skin deposition

oil in sunscreen formulations, anti ageing products and in
treatments for skin diseases. A rice bran oil NEs created by
low energy emulsification methods was evaluated by Bernardi
et al. The NE formulation composing of 10% rice bran oil,
10% surfactant blend, 80% water and supplemented with
0.05% antioxidants and 0.5% preservatives, was proved to be
stable for up to 90 d without irritating. When NE was applied
to human skin, the NE increased the moisture variance by
about 38% in normal skin volunteers and by 30% in volunteers
with atopic dermatitis or psoriasis [10]. The pH value is
important for determining EMs’ stability because pH changes
can compromise the quality of the product. EMs produced
with vegetable oils may experience a decrease in pH due to
the hydrolysis of fatty acid esters into free fatty acid
degradation products. The rice bran oil NEs maintained skin
pH values within the accepted PH range of 4.9–5.2 [10].
Non-steroidal anti-inflammatory drug loaded by NE
Non-steroidal anti-inflammatory drug (NSAID) is widely
used for releasing pain and usually administered orally with
unacceptable adverse effects such as nausea, dyspepsia and
gastrointestinal bleeding. Topical dosage form of NSAIDs
gained great interests and NEs have been used as potential
vehicle to enhance skin permeation and improve the anti-
inflammatory effects of NSAIDs [11–18].
In 2010, topically applied 2.5% ketoprofen entrapped palm
oil esters (POEs)-based NE was evaluated by Sakeena et al.
and series studies were reported. The small size of the NE
droplets leads to the increase in total surface area for release,
transfer and absorption of the drug [11]. The in-vitro release
studies through rat skin showed that the POEs NE formulation
containing 3% limonene (a skin penetration enhancer)
produced similar skin permeation with marketed formulation
(containing 2.5% ketoprofen). The results of the skin irritation
studies based on the visual observation score suggested that
the formulation was safe to be applied on the skin [12].
Carrageenans are a complex group of polysaccharides made
up of repeating galactose-related monomers. Inflammation
induced by carrageenan is acute, nonimmune, well-researched
and highly reproducible. This model has long been used to
assess the anti-inflammatory properties of agents such as
NSAIDs. In in-vivo carrageenan-induced rat hind paw edema
study and carrageenan-induced hyperalgesia pain threshold
study, the prepared POEs NE product showed comparably
anti-inflammatory and analgesic properties with market
ketoprofen gel [13]. The developed NE has great potential
for topical application of ketoprofen and POEs were revealed
to be suitable as an ingredient to deliver ketoprofen by
transdermal rout. In other study of Kim et al., NEs system
with benzyl alcohol/ethanol/Solutol/smash(R) HS 15/water
was prepared to deliver ketoprofen. The NE containing 4%
benzyl alcohol presented a permeation rate higher than NEs
containing 1% or 2% ones, in contrast to the NE containing
1% Solutol(R) HS 15 providing a higher permeation rate than
NEs with 2% or 4% Solutol. Whatever, all ketoprofen-loaded
NEs showed enhanced in vitro permeation rate through mouse
skins comparing to the control [14].
Oil-in-water NEs including ‘‘true NEs’’ are different from
lipid NEs in terms of thermodynamic stability [15].
Indomethacin, also a potent NSAID, was loaded with a true
NE and evaluated by Shakeel et al. in 2009. After 12 h
application, the % inhibition value (a index that indicates
inhibition degree) on carrageenan-induced paw edema in rats
was found to be highest for optimized formulation F6 (85%)
and intermediate for F7 (69.7%) as compared to marketed
indomethacin gel (IndobeneÕ , Benghazi, Libya) (32.1%). The
values in formulation F6 and F7 significantly enhanced after 6
and 12 h, indicating the sustained type of anti-inflammatory
effects [15]. The activation energy is an index that can reflect
324 Y. Wu et al.
the diffusion of a drug molecule across skin and depends on
its route of diffusion and physicochemical properties. NEs can
change this value to greater extent by their action on stratum
corneum (SC) lipids. In the study of Shakeel et al. [15], the
activation energy (1.396 kcal/mol) across rat skin signifi-
cantly decreased, indicating a significant disruption of the SC
lipid bilayers and thus suggesting the used NE can be
successfully used for enhancement of skin permeation as well
as bioavailability of poorly soluble drugs.
Celecoxib is a selective cyclo-oxygenase-2 inhibitor
belonging to NSAIDs. A study conducted by Shakeel et al.
assessed the skin permeation mechanism and bioavailability
of celecoxib by transdermally applied NE formulation. The
activation energy for permeation across rat skin obviously
decreased to 2.373 kcal/mol. The absorption of celecoxib
through transdermally applied NE resulted in about three-fold
increase in bioavailability [16]. Another study compared the
anti-inflammatory effects of an optimized NE formulation of
celecoxib with conventional celecoxib gel and NE gel on
carrageenan-induced paw edema in rats. The % inhibition
value after 24 h application was significantly high for
optimized formulation (85.4%) compared with celecoxib gel
and NE gel [17].
The rate limiting step for transdermal drug delivery is
lipophilic part of SC in which lipids (ceramides) are tightly
packed as bilayers due to the high degree of hydrogen
bonding. When skin was treated with NE formulation,
ceramides got loosened due to penetration of NE into the
lipid bilayers of SC. The skin permeation mechanism of an
optimized o/w NE of aceclofenac was investigated by Shakeel
et al., using FTIR spectroscopy, DSC thermography, activa-
tion energy measurement and histopathological examination.
The results indicated that the hydrogen bond network at the
head of ceramides was broken by the NE formulation and
intracellular transport could be a possible mechanism of
permeation enhancement due to the extraction of SC lipids by
the NE. Like indomethacin and celecoxib, the activation
energy for aceclofenac permeation across rat skin was also
significantly decreased, and the disruption and extraction of
lipid bilayers as distinct voids and empty spaces were visible
in the epidermal region. These observations support the
in vitro skin permeation of NSAIDs [18].
NEs in photodynamic therapy
Photodynamic therapy (PDT) with 5-aminolaevulinic acid
(ALA) was recently ranked as first-line therapy for the
treatment of actinic keratosis (AK). As previous ALA has the
problems of instability and low skin penetration, a gel
formulation of ALA with NE (BF-200 ALA) has been
introduced recently. In 2010, Maisch et al. utilized an ex vivo
porcine skin model to analyse the penetration of BF-200 ALA
(10% 5-ALAhydrochloride) versus 16% aminolevulinate
methyl esterhydrochloride in a commercially cream (MAL
cream). At 8 and 12 h, the fluorescence signals of metabolite
protoporphyrin IX (PpIX) were 4.8- and 5.0-fold higher and
almost two times deeper than those measured after MAL
cream application [19]. In 2010, Szeimies et al. used BF-200
ALA versus placebo to treat a total of 122 patients with AK
lesions. After one and two PDT with BF-200 ALA, the
J Drug Target, 2013; 21(4): 321–327
patient complete clearance rate and lesion complete clearance
rate reached 64% and 81%, respectively, superior to
those of placebo PDT (11% and 22%, respectively) [20].
Another report made by Dirschka et al. showed that 248
patients were treated with 1 or 2 PDT with BF-200 ALA. The
results revealed higher patient complete clearance rate
(78.2%) and lesion complete clearance rate (90.4%), compar-
ing to placebo PDT (17.1% and 37.1%) [21]. These
results indicated PDT-ALA with NE is a promising medica-
tion for AK.
Topical photosensitizer drugs such as Foscan used in PDT
can also be incorporated into NE. A colloidal vehicle of the
oil/water (o/w) type NE was obtained based on the mixture,
an aqueous solution and an organic medium consisting of
nonionic surfactants and oil. The photophysical properties of
Foscan, which was incorporated into NE were maintained
compared with homogeneous organic medium. In vitro assays
showed an adequate profile for the interaction of this system
in the different skin layers with an ideal time lag of 6 h after
topical administration in the skin animal model, and the
diffusion flux of Foscan (J) was increased compared with its
flux in physiological medium [22].
NEs in decontamination of radionuclides
Cutaneous contamination by radionuclides-uranium is diffi-
cult to be treated, because no efficient emergency treatment is
available to remove the actinide from the skin. An o/w NE
containing a tricarboxylic calixarene was developed. The
calixarene molecules were located at the surface of the
dispersed oil droplets of the NE, being thus potentially
available for its high affinity and selectivity of uranium
chelation. In vitro experiments by using an adapted ultrafil-
tration method revealed that the calixarene NE was able to
extract and retain up to 80% of free uranium from an aqueous
uranyl nitrate contamination solution [23,24]. The calixarene
NE effect can be observed after a very short time of contact
with uranium-contaminated solution (5 min) and the effect
is maintained in case of small-contaminated volumes.
Contaminated solution PH was found to be the most
important parameter affecting the calixarene NE efficiency.
In case of acidification of the contaminated medium, the
uranium extraction rate could be dramatically improved [25].
Ex vivo experiments in Franz diffusion cells of pig ear skin
explants during 24 h showed that the immediate application of
the calixarene NE on the skin contaminated by a uranyl nitrate
solution allowed a uranium transcutaneous diffusion decrease
of about 98% through both intact and excoriated skin [24,26].
Even delayed application up to 30 min since the 24 h-uranium
transfer through excoriated skin allowed 71% reduction [26].
These results reveal that calixarene NE can be regarded as a
promising treatment for uranium cutaneous contamination.
Antimicrobial NEs
Antimicrobial NEs are highly stable o/w EMs composed of
nanometer-sized droplets that have broad-spectrum activity
against enveloped microbes. NB-201 is an antimicrobial NE
consisting of emulsification of vegetable oil and water with
surfactants and alcohol. Topical NB-201 significantly reduced
bacterial growth in a partial thickness burn model by a
DOI: 10.3109/1061186X.2013.765442
thousand fold. It can attenuate neutrophil sequestration,
diminish levels of pro-inflammatory cytokines (IL-1b and
IL-6), and reduce the degree of hair follicle cell apoptosis in
skin. Topical NE therapy with NB-201 showed great
antimicrobial and anti-inflammatory effects [27]. NB-002 is
a NE designed for the use of either fungistatic or fungicidal.
Recent results showed that NB-002 has fungicidal activity
against both microconidial spore and mycelial forms of
dermatophytes. For filamentous nondermatophyte fungi, the
MIC range of NB-002 varied from 0.06 to 0.5 mg/ml for
Alternaria spp. and from 2 to 8 mg/ml for Paecilomyes spp.
NB-002 also had activity against both azole-susceptible
and -resistant Candida albicans yeast isolates with MIC90s
of 2 mg/ml, and minimum fungicidal concentrations at
which 90% of isolates are inhibited of 4 and 8 mg/ml,
respectively [28].
NEs carrying lipids
Some skin disorders are characterized by impaired SC barrier
function and by increase in transepidermal water loss
(TEWL) leading to a decrease in skin hydration. Products
containing SC lipids could restore the disturbed skin barrier
function. Furthermore, a positively charged delivery system
might enhance the permeability of a poorly soluble drug, due
to the strong interaction between epithelial membranes with
positively charged solutes. The development of positively
charged NE for the skin penetration enhancement of low
soluble biological active compounds such as ceramides. In
2006, a positively charged oil/water NE (PN) containing
ceramide 3B and naturally found SC lipids (PNSC) such as
ceramide 3, cholesterol and palmitic acid was evaluated,
compared with PNSC and a cream with negatively charged
o/w NE and SC lipids (NNSC) by Yilmaz and Borchert [29].
The study was carried out on three groups, each with 14
healthy female test subjects between 25 and 50 years of age.
The results indicated that all formulations (PN, PNSC and
NNSC) increased skin hydration and elasticity, and phyto-
sphingosine induced positive charge, SC lipids and ceramide
3B are crucial for the enhanced effect on skin hydration and
viscoelasticity [29]. In another study, a lecithin NE (LNE)
system without any synthetic surfactant was determined to
evaluate its topical delivery potential for lipophilic com-
pounds. The LNE, composed of snake oil, soybean lecithin,
glycerol and water, was incorporated into o/w cream. Topical
LNE in 10% concentration significantly improved the skin
hydration about 2.5-fold and strengthened the penetrability of
Nile red dye into the dermis layer 9.9-fold in rat model. The
observation suggest that LNE could be used as a promising
topical delivery vehicle for lipophilic compounds [30].
NEs containing octyl methoxycinnamate
Octyl methoxycinnamate (OMC) absorbs radiation in the
290–320 nm region of the UV spectrum and represents one of
the most common liposoluble absorbers incorporated in
sunscreen preparations. NEs and polymeric nanocapsules
(NCs) all belong to colloidal carriers that have been proposed
to improve topical administration, based on their capacity to
encapsulate highly lipophilic pharmaceutical and cosmetic
active compounds. The total amount of OMC detected in the
Application of nanoemulsion in dermatology 325
SC and the penetration depth are strongly dependent upon the
formulation’s nature, the particle size and the type of
enhancer. One study compared the NE containing OMC and
NCs containing OMC on their distribution profile through SC.
In vivo percutaneous penetration demonstrated that NE
increased the extent of OMC penetration relative to the
penetration achieved by NCs or a conventional o/w EM, with
relative penetration depths through the SC of 0.86  0.1,
0.64  0.11 and 0.57  0.08, respectively. In the same
manner, the accumulation in the skin of OMC was signifi-
cantly greater with NE than with EM or NCs [31]. Among all
formulations, the size of NE was the smallest (161.7 nm), with
EM being the largest (2814.0 nm) and NCs being intermedi-
ate. These may partly contribute to the different distribution
and penetration profiles of the particles. In 2006, in vivo
percutaneous penetration of OMC in NEs and NCs formulated
with sucrose laureate was evaluated by Calderilla-Fajardo.
NEs containing sucrose laureate exhibited the highest pene-
tration in the SC compared to the NCs and conventional o/w
EMs, and a two-fold increase in OMC skin deposition
compared to the control [32].
Application of NEs in other respects
Hyperpigmentation predominantly affects the female popula-
tion. A study observed the depigmenting efficacy of topical
NEs containing heartwood extract of Artocarpus incisus on
UVB-stimulated hyperpigmented dorsal skin of C57BL/6
mice. The NE containing extract exhibited melanogenesis
inhibition with an IC(50) value of 30.2  2.4 mg/ml, in
contrast to 51.4  5.1 mg/ml of kojic acid (a well known
lightening agent). The formulated NE showed strong reduc-
tion of hyperpigmentation after 6 week treatment, with the
degree of 84  4 units in contrast to 51  3 units of control
extract [33]. 3,5-Dihydroxy-4-isopropylstilbene (DHPS) has
attracted much attention for its diversified pharmacological
activities and was developed as a new drug for chronic skin
diseases caused by disorder of the autoimmune system.
However, the drug’s instability and insolubility in water
resulted in the alteration of properties and poor skin
permeability. To overcome the problem, Zhang et al. prepared
a kind of DHPS NE using a low-energy emulsification
method. The DHPS NE was characteristic of transparent
appearance, low viscosity, spherically uniform distribution,
and had good stability, and stable physical and chemical
properties. The formulation dramatically improved the DHPS
transdermal release from 8.02 to 273.15 mg cm2 [34].
Dacarbazine (DAC) is an anticancer drug. The efficacy of
water-soluble NEs of the highly lipid-soluble DAC was
observed in a xenograft model using a human melanoma cell
line. The NEs DAC presented mean particle sizes of 131 nm
in contrast to suspensions DAC with a mean particle size of
5470 nm. Compared to the suspension preparation of DAC,
topical application of NEs DAC produced up to 10-fold
greater percent (%) reductions of tumor size. The reduction in
tumor size by the intramuscular injection (61%) appeared to
be greater than by topical preparations (49%). Twelve weeks
after NEs DAC treatment cessation, 98% of the animals
treated by intramuscular injection remained tumor-free
compared to the untreated animals and NEs DAC showed
326 Y. Wu et al.
five-fold greater efficacies (73%) in preventing tumor growth
versus 14% of the suspension preparations. In this xenograft
mouse model of melanoma, NEs of DAC were shown to be
very efficacious in the treatment and prevention of tumor
growth [35].
Although NEs have many obvious advantages, some
problems are needed to be concerned. Firstly, the storage
time at different temperatures may influence the stability of
NE. In Mitri’s study, although the NE product remained stable
at both 4  C and room temperature, clear particle aggregations
with very big size were noticed at 40  C after 1 month [8].
Sufficient quantity of stabilizer in a NE formulation is helpful
to maintain stability. Secondly, the surfactant amount affects
the stabilization and size of the EM droplets. However,
according to Bernardi et al. [10], the surfactant concentration
of 5% is not sufficient to form a NE. An ideal NE formulation
is suggested to be the lowest possible surfactant concentration
while maintaining thermal stability, centrifugal stability and
small droplet size [10]. Thirdly, a NE formulation in the same
concentration of surfactant will definitely not present the
same stability. In Bernardi’s study, two NEs which were
composed of the lowest surfactant (10%) showed different
stability, i.e. the NE composed of 10% oil and 70% water
showed signs of instability at high temperatures (70  C) in
contrast to the NE composed of 10% oil and 80% water being
very stable [10]. Lastly, the effectiveness of transdermal drug
delivery depends on the drug’s ability to penetrate the skin
sufficiently to reach therapeutic level. Sometime, skin pene-
tration enhancers such as limonene are needed to enhance the
skin permeation of NE products. Sakeena et al. [12] found
that 3% limonene significantly enhanced the permeation of
ketoprofen NE comparing to the NE containing 0%, 1% or 2%
limonene.
In summary, nano-structured ingredients have gained great
scientific interests in many fields as well as in human health
and medicine. Amongst, NEs demonstrate good stability,
stable physical and chemical properties. NEs are able to
enhance the functionality, and efficacy of active chemicals
and natural ingredients. NEs exhibit great application poten-
tial in the field of dermatology. With some problems in the
NE formulations needed to be determined, there is a long way
to go to develop optimal NEs that can be used in marketed
products.
Declaration of interest
The authors report no conflicts of interest. The authors alone are
responsible for the content and writing of the article.
References
1. Goel RK, Singh A, Mahajan MP, et al. Evaluation of anti-
inflammatory and antihyperalgesic activity of some novel
monocyclic b-lactam compounds in rats. Indian J Pharm Sci
2004; 66:87–91.
2. Solans C, Esquena J, Forgiarini A, et al. Surfactants in solution:
fundamentals and applications. In: Mittal KL, Shah D, eds.
Surfactant science series. New York: Marcel Dekker; 2002:487–96.
3. Guglielmini G. Nanostructured novel carrier for topical application.
Clin Dermatol 2008;26:341–6.
4. Shafiq-un-Nabi S, Shakeel F, Talegaonkar S, et al. Formulation
development and optimization using nanoemulsion technique: a
technical note. AAPS PharmSciTech 2007;8:E12–17.
J Drug Target, 2013; 21(4): 321–327
5. Thadros T, Izquierdo P, Esquena J, et al. Formation and stability of
nanoemulsions. Adv Colloid Interface Sci 2004;108–9:303–18.
6. Becher P. Emulsions: theory and pratice. Oxford: Oxford University
Press; 2001.
7. Butnariu MV, Giuchici CV. The use of some nanoemulsions
based on aqueous propolis and lycopene extract in the skin’s
protective mechanisms against UVA radiation. J Nanobiotechnol
2011;9:3.
8. Mitri K, Shegokar R, Gohla S, et al. Lipid nanocarriers for dermal
delivery of lutein: preparation, characterization, stability and
performance. Int J Pharm 2011;414:267–75.
9. Lilitchan S, Tangprawat C, Aryusuk K, et al. Partial extraction
method for the rapid analysis of total lipids and gamma-oryzanol
contents in rice bran. Food Chem 2008;106:752–9.
10. Bernardi DS, Pereira TA, Maciel NR, et al. Formation and stability
of oil-in-water nanoemulsions containing rice bran oil: in vitro and
in vivo assessments. J Nanobiotechnol 2011;9:44.
11. Sakeena MH, Muthanna FA, Ghassan ZA, et al. Formulation and
in-vitro evaluation of palm oil esters nanoemulsion for topical
delivery. J Oleo Sci 2010;59:223–8.
12. Sakeena MH, Elrashid SM, Muthanna FA, et al. Effect of limonene
on permeation enhancement of ketoprofen in palm oil esters
nanoemulsion. J Oleo Sci 2010;59:395–400.
13. Sakeena MH, Yam MF, Elrashid SM, et al. Anti-inflammatory and
analgesic effects of ketoprofen in palm oil esters nanoemulsion.
J Oleo Sci 2010;59:667–71.
14. Kim BS, Won M, Lee KM, et al. In vitro permeation studies of
nanoemulsions containing ketoprofen as a model drug. Drug Deliv
2008;15:465–9.
15. Shakeel F, Ramadan W, Ahmed MA. Investigation of true
nanoemulsions for transdermal potential of indomethacin: charac-
terization rheological characteristics and ex vivo skin permeation
studies. J Drug Target 2009;17:435–41.
16. Shakeel F, Baboota S, Ahuja A, et al. Celecoxib nanoemulsion: skin
permeation mechanism and bioavailability assessment. J Drug
Target 2008;16:733–40.
17. Shakeel F, Baboota S, Ahuja A, et al. Enhanced anti-inflammatory
effects of celecoxib from a transdermally applied nanoemulsion.
Pharmazie 2009;64:258–9.
18. Shakeel F, Baboota S, Ahuja A, et al. Skin permeation mechanism
of aceclofenac using novel nanoemulsion formulation. Pharmazie
2008;63:580–4.
19. Maisch T, Santarelli F, Schreml S, et al. Fluorescence induction of
protoporphyrin IX by a new 5-aminolevulinic acid nanoemulsion
used for photodynamic therapy in a full-thickness ex vivo skin
model. Exp Dermatol 2010;19:e302–5.
20. Szeimies RM, Radny P, Sebastian M, et al. Photodynamic therapy
with BF-200 ALA for the treatment of actinic keratosis: results of a
prospective, randomized, double-blind, placebo-controlled phase
III study. Br J Dermatol 2010;163:386–94.
21. Dirschka T, Radny P, Dominicus R, et al. Photodynamic therapy
with BF-200 ALA for the treatment of actinic keratosis: results of a
multicentre, randomized, observer-blind phase III study in com-
parison to a registered methyl-aminolaevulinic acid cream and
placebo. Br J Dermatol 2012;166:137–46.
22. Primo FL, Bentley MV, Tedesco AC. Photophysical studies and
in vitro skin permeation/retention of Foscan/nanoemulsion (NE)
applicable to photodynamic therapy skin cancer treatment.
J Nanosci Nanotechnol 2008;8:340–7.
23. Spagnul A, Bouvier-Capely C, Phan G, et al. Calixarene-entrapped
nanoemulsion for uranium extraction from contaminated solutions.
J Pharm Sci 2009;99:1375–83.
24. Spagnul A, Bouvier-Capely C, Phan G, et al. A new formulation
containing calixarene molecules as an emergency treatment of
uranium skin contamination. Health Phys 2010;99:430–4.
25. Spagnul A, Bouvier-Capelyb C, Adam M, et al. Quick and efficient
extraction of uranium from a contaminated solution by a calixarene
nanoemulsion. Int J Pharm 2010;398:179–84.
26. Spagnul A, Bouvier-Capely C, Phan G, et al. Ex vivo decrease
in uranium diffusion through intact and excoriated pig ear skin
by a calixarene nanoemulsion. Eur J Pharm Biopharm 2011;79:
258–67.
27. Hemmila MR, Mattar A, Taddonio MA, et al. Topical nanoemul-
sion therapy reduces bacterial wound infection and inflammation
following burn injury. Surgery 2010;148:499–509.
DOI: 10.3109/1061186X.2013.765442
28. Pannu J, McCarthy A, Martin A, et al. NB-002, a novel
nanoemulsion with broad antifungal activity against dermatophytes,
other filamentous fungi, and candida albicans. Antimicrob Agents
Chemother 2009;53:3273–9.
29. Yilmaz E, Borchert HH. Effect of lipid-containing, positively
charged nanoemulsions on skin hydration, elasticity and erythema-
an in vivo study. Int J Pharm 2006;307:232–8.
30. Zhou H, Yue Y, Liu G, et al. Preparation and characterization of a
lecithin nanoemulsion as a topical delivery system. Nanoscale Res
Lett 2009;5:224–30.
31. Olvera-Martı́nez BI, Cázares-Delgadillo J, Calderilla-Fajardo SB,
et al. Preparation of polymeric nanocapsules containing octyl
methoxycinnamate by the emulsification-diffusion technique:
penetration across the stratum corneum. J Pharm Sci 2005;
94:1552–9.
View publication stats
Application of nanoemulsion in dermatology 327
32. Calderilla-Fajardo SB, Cázares-Delgadillo J, Villalobos-Garcı́a R,
et al. Influence of sucrose esters on the in vivo percutaneous
penetration of octyl methoxycinnamate formulated in nanocapsules,
nanoemulsion, and emulsion. Drug Dev Ind Pharm 2006;32:107–13.
33. Buranajaree S, Donsing P, Jeenapongsa R, et al. Depigmenting
action of a nanoemulsion containing heartwood extract of
Artocarpus incisus on UVB-induced hyperpigmentation in
C57BL/6 mice. J Cosmet Sci 2011;62:1–14.
34. Zhang Y, Gao J, Zheng H, et al. The preparation of 3,5-dihydroxy-
4-isopropylstilbene nanoemulsion and in vitro release. Int J
Nanomed 2011;6:649–57.
35. Tagne JB, Kakumanu S, Nicolosi RJ. Nanoemulsion preparations
of the anticancer drug dacarbazine significantly increase its
efficacy in a xenograft mouse melanoma model. Mol Pharm
2008;5:1055–63.