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Clinical, Cosmetic and Investigational Dermatology 2018:11 21–28
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CLINICAL TRIAL REPORT
open access to scientific and medical research
Open Access Full Text Article
http://dx.doi.org/10.2147/CCID.S145561
Comparison of linoleic acid-containing water-
in-oil emulsion with urea-containing water-in-oil
emulsion in the treatment of atopic dermatitis:
a randomized clinical trial
Saman Ahmad Nasrollahi1
Azin Ayatollahi1
Taraneh Yazdanparast1,2
Aniseh Samadi1
Hamed Hosseini3
Mansour Shamsipour4
Ali Asghar Akhlaghi5
Somayeh Yadangi1
Christoph Abels6
Alireza Firooz1,2
1Center for Research and Training
in Skin Diseases and Leprosy,
2Telemedicine Research Center,
National Research Institute of
Tuberculosis and Lung Diseases
(NRITLD), Shahid Beheshti University
of Medical Sciences, 3Clinical Trial
Center, 4Department of Research
Methodology and Data Analysis,
Institute for Environmental Research,
Tehran University of Medical Sciences,
5Department of Epidemiology and
Reproductive Health, Reproductive
Epidemiology Research Center,
Royan Institute for Reproductive
Biomedicine, ACECR, Tehran, Iran;
6Dr. August Wolff GmbH & Co. KG
Arzneimittel, Bielefeld, Germany
Background: Application of topical moisturizers is an essential part of the management of
atopic dermatitis (AD). Linoleic acid (LA), the most abundant fatty acid in the epidermis, and
its derivatives have an essential role in the structure and function of the epidermal barrier, and
their defects are prominent in AD. The aim of this study was to compare the efficacy and safety
of two cosmetic products containing either LA or urea in patients with AD.
Patients and methods: A total of 20 patients with AD who met the eligibility criteria and
provided written informed consents were enrolled in this randomized, intra-individual split-body,
single-center trial. Symmetrical lesions of patients were randomized for treatment with LA- or
urea-containing water-in-oil (w/o) emulsions applied two to three times daily for 4 weeks. The
efficacy of the two products was evaluated by local Scoring Atopic Dermatitis (SCORAD) of
both lesions and also patient (or guardian) satisfaction. In addition, trans-epidermal water loss
(TEWL), stratum corneum (SC) hydration, pH, sebum, temperature, erythema, melanin content,
and ultrasonographic thickness and echo density of epidermis and dermis were measured before,
and 2 and 4 weeks after, treatment.
Results: Four weeks of treatment with the LA-containing product resulted in a significant
decrease in local SCORAD, TEWL, erythema, and echo density of dermis, as well as an increase
in SC hydration compared to baseline. The urea-containing product also reduced the local SCO-
RAD and echo density of dermis and increased SC hydration. In contrast to the LA-containing
product, changes in TEWL and erythema were not significant. Moreover, the reduction of
erythema was significantly higher in the LA-containing product-treated side compared to the
urea-containing product-treated side (p = 0.006).
Conclusion: Both LA- or urea-containing w/o emulsions can significantly improve barrier
dysfunction and clinical severity of AD. In agreement with literature, it was confirmed that an
LA-containing w/o emulsion exhibited erythema-reducing effects. Since emollients should be
used on a regular basis, patients should choose a product by individual preference following
recommendation by their dermatologists.
Keywords: emollient, moisturizer, humectants, epidermal barrier, erythema
Introduction
Atopic dermatitis (AD) is a chronic inflammatory pruritic skin disorder characterized
by increased trans-epidermal water loss (TEWL) which requires appropriate skin care
on a regular basis.1–3
The first line of skin protection against the environmental hazardous effects, water
loss, and conservation of electrolyte balance is the epidermal barrier (EB). The stratum
Correspondence: Alireza Firooz
Center for Research and Training in Skin
Diseases and Leprosy, Tehran University
of Medical Sciences, # 415 Taleqani
Avenue, Tehran 1416613675, Iran
Tel/fax +98 21 8896 3804
Email rozali@tums.ac.ir
Journal name: Clinical, Cosmetic and Investigational Dermatology
Article Designation: CLINICAL TRIAL REPORT
Year: 2018
Volume: 11
Running head verso: Nasrollahi et al
Running head recto: Comparison of LA- with a urea-containing w/o emulsion
DOI: http://dx.doi.org/10.2147/CCID.S145561
This article was published in the following Dove Press journal:
Clinical, Cosmetic and Investigational Dermatology
Clinical, Cosmetic and Investigational Dermatology 2018:11
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22
Nasrollahi et al
corneum (SC), a unique differentiation end product of the
epidermis, produces a set of protective/defensive functions.4
Inherited barrier abnormalities, exogenous and endog-
enous stressors with additional exacerbation of barrier
dysfunction, and compromised antimicrobial defense with
further impairment of barrier function are the main causes
of barrier dysfunction in AD.4–6
One of the most important clinical features of AD which
results from a dysfunctional EB is very dry skin (xerosis).
Moisturizers with different agents containing varying
amounts of emollients, occlusives, and/or humectants are
used to reduce TEWL, increase skin hydration, and thus
improve xerosis in AD patients.7 Emollients soften and
smooth the skin by filling the spaces between desquamating
corneocytes and provide increased cohesion leading to a
smoother surface with less friction.8
Occlusive agents (such as petrolatum, mineral oil, and
lanolin) retard evaporation of water by coating the SC. By
decreasing TEWL, these agents are one of the best choices
for treating xerosis.9
Humectants (such as glycerol, lactic acid, and urea) are
water-soluble agents with the capacity to complex and hold
water.10 Urea, as a humectant, decreases TEWL in normal
skin and dry skin of patients with AD.11–14
Linoleic acid (LA), the most abundant fatty acid in the
epidermis, and its derivatives have an essential role in the
structure and function of the SC permeability barrier, and
their defects are most prominent in AD.15,16 Moreover, it has
also been shown that LA has anti-inflammatory effects.17,18
In this study, we compared the efficacy and safety of a
water-in-oil (w/o) emulsion containing 1.5% LA with a dif-
ferent w/o emulsion containing 5% urea in patients with AD.
Patients and methods
This study was an open, randomized, intra-individual split-body,
single-center trial. The study protocol as well as other essential
documents was approved by the Ethics Committee of Tehran
University of Medical Sciences and was registered in Iran
Randomized Controlled Trial (IRCT; IR.TUMS.REC.1394.32)
Registry with registration number IRCT2015062017994N1.
A total of 20 patients with AD who were referred to the
outpatient skin clinic of the Center for Research and Train-
ing in Skin Diseases and Leprosy, met the eligibility criteria,
and provided written informed consent were enrolled in this
study. The inclusion criteria were female or male patients at
least 2 years old and with mild-to-moderate AD (defined as
Scoring Atopic Dermatitis [SCORAD] between 4 and 12,
erythema and pruritus score of at least 1) without any signs
of infection having at least two symmetrical lesions on arms
or legs with similar local SCORAD.
Patients with severe AD (SCORAD > 12), pregnancy
or lactation, drug addiction and alcoholism, AIDS or other
infectious diseases (such as hepatitis), active skin disease
(other than AD) at test area, documented allergies to any
ingredients of study products, use of other skin care prod-
ucts (e.g., creams, lotions, and sunscreens) at the treatment
areas throughout the course of the study, poor compliance,
or enrollment in any clinical trial within the past 3 months
were excluded from our study.
Symmetrical lesions of patients were randomized using
a software generated randomization list for treatment with a
1.5% LA-containing w/o emulsion (aluminum stearate, aqua,
beta-carotene, canola oil, cera alba, cetearyl alcohol, decyl
oleate, Helianthus annuus, hydrogenated coco-glycerides,
lanolin, lanolin alcohol, isomerized safflower acid, magne-
sium stearate, paraffin, paraffinum liquidum, petrolatum,
sorbitan stearate; “Linola-F” cream; Dr. August Wolff GmbH
& Co. KG Arzneimittel, Bielefeld, Germany) or a 5% urea-
containing eucerin (cetylstearyl alcohol, white vaseline, and
wool wax alcohols), purified water, and urea in w/o emulsion
system (Samin Co., Tehran, Iran) applied two to three times
daily for 4 weeks.
The efficacy of the products was evaluated by local
SCORAD of both lesions and, in addition, by patient (or
guardian) satisfaction. Moreover, TEWL, SC hydration,
pH, sebum, temperature, erythema, melanin content, and
ultrasonographic characteristics of skin (thickness and echo
density of epidermis and dermis) were measured using the
corresponding probes of Tewameter, Corneometer, pH meter,
Sebumeter, Thermometer, and Mexameter of Cutometer®
MPA 580 (CK Company, Cologne, Germany) and 22 MHz
probe of high-frequency skin ultrasonography (DUB Skin
Scanner; TPM, Luneburg, Germany) in standardized condi-
tions of temperature and humidity. All the assessments were
performed at baseline and 2 and 4 weeks after beginning the
treatment.
Furthermore, any local adverse events at the site of
applications were recorde, and the participants answered a
questionnaire regarding tolerability and acceptance of each
product (Figure S1).
Each subject was asked to rate the severity of itching and
burning in both treatment areas from 0 (none) to 5 (severe).
Patients were also asked to rate the level of satisfaction from
treatment, on a 5-grade scale (5 = very satisfied, 4 = somewhat
satisfied, 3 = indifferent, 2 = somewhat dissatisfied, 1 = very
dissatisfied). In case of younger children and infants who
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23
Comparison of LA- with a urea-containing w/o emulsion
were not capable of answering/filling the questionnaire,
patients’ parents were asked to fill it.
Results were presented as median (quartile 1 – quartile 3),
and differences were compared between two treatment groups
using Wilcoxon signed-rank test.
The SPSS software version 18 (SPSS Inc., Chicago, IL,
USA) was used for statistical analyses. Data are presented as
mean ± SD or median (quartile 1 – quartile 3) unless stated
otherwise and analyzed by the Wilcoxon signed-rank test.
The statistical significance level was defined as p < 0.05.
Results
In this pilot study, 20 patients (12 females and 8 males) with a
mean age of 16.75 years (SD = 13.67, range 2–45 years) and
a mean SCORAD of 10.46 (SD = 1.02, range 8.7–11.9) were
included, and 16 patients completed the study. The local SCO-
RAD and the biophysical measurements at baseline and after 2
and 4 weeks of treatment on both sides are shown in Figure 1.
At baseline, there was no significant difference in local
SCORAD and in any of the measured variables, except for
the mean erythema level which was significantly higher in
site designated to be treated by LA-containing product.
There was no significant differences between the two
treated sides in any parameter, except for a higher pH in LA-
containing product-treated side after 2 weeks of treatment
(p-value = 0.003).
Four weeks of treatment with a LA-containing product
resulted in a significant decrease in local SCORAD, TEWL,
and erythema as well as an increase in SC hydration compared
to baseline (Figure 1).
Treatment with a urea-containing product cream resulted
in a significant decrease in local SCORAD and an increase
in SC hydration. TEWL and erythema reduction after appli-
cation of the urea-containing product, however, was not
significant. The erythema was significantly reduced after
the application of the LA-containing product-treated side
compared to the side treated with the urea-containing product
(p = 0.006). There was a clear, but not statistically significant
trend (p = 0.098) regarding the reduction in skin melanin
content in the LA-containing product-treated side, whereas
skin melanin content even increased in the urea-containing
product-treated side (Figure 1).
The ultrasonographic measurements showed a decrease at
week 4 for both products; however, there was no statistically
significant difference (Table 1).
Moreover, patients’ satisfaction with treatment was higher
for the LA-containing product, and this difference was sta-
tistically significant (p = 0.046).
No statistically significant differences were found in the
severity of itching and burning between two groups (p-value=
0.912 and 0.961, respectively). No other adverse reactions
were reported or observed in any of the two treatment groups.
Discussion
It is well known to dermatologists and just recently confirmed
by a Cochrane Review that topical application of emulsions
prolongs the time to flare, decrease the number of flares,
and reduce the amounts of topical corticosteroids needed.19
Therefore, the current available guidelines recommend the
use of emulsions as a key and basic step in the treatment of
AD, 20–23 in particular, since several recent studies showed that
preventing degradation and repairing the barrier dysfunc-
tions are critical strategies for reducing the risk of relapse
in AD.4,24,25
In this study, we assessed the effects of two w/o emulsions
in AD lesions in a randomized, intra-individual, controlled
clinical trial. One of the products contained 1.5% LA as cos-
metic active ingredient, whereas the other one contained 5%
urea. After 4 weeks of treatment, both products significantly
decreased local SCORAD and significantly increased SC
hydration, although reduction in skin erythema and TEWL
was only significant in the lesions treated with the LA-
containing product. An impaired skin barrier function and
clinical signs of dryness are usually expected to be improved
after use of the appropriate topical emulsion. Unfortunately,
clinical improvement in xerosis and eczematous lesions may
not necessarily induce normalization of TEWL.26
The beneficial effects of the two products, both w/o emul-
sions (appropriate pharmaceutical formulation for xerosis),
can be explained by the measured increase in skin hydration
and through possible effects on the barrier function, although
only for the LA-containing product, a statistically significant
change was observed for the TEWL. Components of the
LA-containing product, such as complex mixture of esters,
diesters and hydroxy esters of high molecular weight, lanolin
alcohols, and lanolin acids, form an inert layer on the skin
and can also penetrate the damaged skin and repair the EB
leading to a reduction in TEWL.27–31 Thus, occlusion is the
most predictable mechanism by which water loss is reduced
from the skin.32 However, since the two products tested in
this clinical study are not identical in their composition, they
exhibit different effects on the skin (as shown).
Moreover, different effects of products used for the
treatment of xerosis in AD patients are well described in the
literature.12,33–35 Patients with similar disease characteristics
have been considered to benefit from different topically
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24
Nasrollahi et al
applied emulsions with different ingredients.36 Unfortunately,
up to now, there is no unifying clinical classification system
available to decide which type of products are best suited for
different degrees of xerosis due to different AD phenotypes.36
Humectants such as urea in emulsions are absorbed into
the SC and can increase skin hydration by attracting water.
Although, in our study, the TEWL following application
of urea-containing product decreased from baseline, the
Figure 1 The local SCORAD (A), hydration (B), melanin content (C), erythema level (D), TEWL (E), temperature (F), pH (G), and sebum content (H) at baseline and after
2 and 4 weeks in LA- and urea-containing products. *p<0.05.
Abbreviations: LA, linoleic acid; SCORAD, Scoring Atopic Dermatitis; TEWL, trans-epidermal water loss.
Linola-F Urea 5% Linola-F Urea 5%
Linola-F
175
0
3
4
5
6
7
6.04
6.36
5.98 5.89 5.79 5.84
5
10
15
20
25
20.2
13.63
17.41
22.19 20.69
15.55
30.48 30.57
31.25
30.82
30.68
31.17
30
30.2
30.4
30.6
30.8
31
31.2
31.4
0
50
100
150
200
250
300
350
400 372.17
292.05 309.31
*
*
324.27315.88 321.63
180
206.58
196.45
189.42
199.27 201.14
211.76
Before
2 weeks
after
4 weeks
after
Before
2 weeks
after
4 weeks
after
Before
2 weeks
after
4 weeks
after
Before
2 weeks
after
4 weeks
after
Before
2 weeks
after
4 weeks
after
Before
2 weeks
after
4 weeks
after
185
190
195
200
205
210
215
Urea 5%
Linola-F
Linola-F
Urea 5%
Urea 5% Linola-F
0
2
4
6
8
4.9
10.57
14.75
1.85
3.64
6.67
10
12
14
16
Urea 5%
Linola-F Urea 5%
Linola-F Urea 5%
Local SCORAD
Melanin content (AU)
TEWL (g/(h.m2))
pH
Temperature (ºC)
Sebum (µg/cm2)Erythema level (AU) Hydration (AU)
0.5
0
1
1.5
22
1.5
0.5
2
11
50
45
40
35
30 28.04
40.05 43.18
29.6
41.3 42.9
25
30
15
10
5
0
Before
2 weeks
after
4 weeks
after
Before
2 weeks
after
4 weeks
after
2.5
AB
CD
EF
GH
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25
Comparison of LA- with a urea-containing w/o emulsion
difference was not statistically significant, whereas skin
hydration increased, which can be explained by the same
mechanism mentioned earlier.
Essential fatty acids (EFAs) such as LA are necessary
for the synthesis of ceramides, e.g., CER[EOH], CER[EOS]
and CER[EOP], which play a critical role in barrier func-
tion of the epidermis.14,15 In contrast to the urea-containing
product, the LA-containing product significantly decreased
erythema (one of the signs of inflammation) in this clini-
cal study. According to the experimental literature, this
is not surprising knowing that LA has anti-inflammatory
effects.17,18,37 Since LA is a potent naturally occurring ligand
and activator of PPRAα,38 skin inflammation of irritant
contact dermatitis is reduced by the topical application of
LA in a mice model.39 Moreover, an erythema-reducing
effect was already reported in a previous clinical study in
an irritative contact dermatitis model using a different LA-
containing product. The effect of LA-containing product
in that study was comparable to a 0.25% hydrocortisone-
containing formulation.40
Although skin pigmentation was not in the focus of our
study, a clear trend toward a reduction in the melanin content
in the LA-containing product-treated side was observed.
This effect of the LA-containing product on melanin content
may be explained via the abovementioned anti-inflammatory
properties of LA leading to a reduction in post-inflammatory
hyperpigmentation.41 Of course, anti-pigmentary effect of other
components in the LA-containing product cannot be ruled out.
Furthermore, unsaturated fatty acids such as oleic acid
and LA can decrease tyrosinase activity (via posttranscrip-
tional events and acceleration of the proteolysis of tyrosinase)
and thus subsequently reduce melanin synthesis.42
In this study, we also used high-frequency ultrasonogra-
phy to assess dermal changes after treatment with the w/o
emulsions. Both creams decreased dermal echo density
significantly, which might be the result of a decrease in
inflammation in the dermis. In contrast to another study that
compared the results of ultrasound images with pathologic
findings in AD, the echogenicity of dermis had a strong nega-
tive correlation with the intensity of inflammation.43
It is worth to mention that, in this study, patients were more
satisfied using the LA-containing w/o emulsion compared to
the urea-containing product. This may be explained by the
stinging and burning sensation of urea immediately after its
application, which has been reported in previous studies.14,44
Finally, we are aware of limitations of our study. First,
this study was a small pilot study and exploratory in nature
with low number of patients (n = 20). Second, we used split-
body design to compare two products. Third, although we
focused on urea and LA, we cannot and are not excluding the
effect of whole product on seen clinical improvements. On
the other hand, strengths of this study are direct comparison
of products with objective as well as subjective assessment
of efficacy.
Conclusion
Both products, the LA- and the urea-containing w/o emul-
sion, increased skin hydration and thus improved the clini-
cal severity of AD in this clinical study. However, only the
LA-containing product due to the known anti-inflammatory
effects of LA reduced erythema significantly after treatment.
In general, the choice of moisturizers can be determined by
individual preference, safety, and efficacy, and the absence
of fragrances, additives, or other sensitizing agents.45
Acknowledgments
This study was supported by research grant from Sina Tejarat
Pishgam Co., Tehran, Iran.
Table 1 Comparison of high-frequency ultrasonography (22 MHz) parameters at visit 0 (day 0), visit 1 (day 14 + 2), and visit 2 (day
28 + 4) between treatment groups
p-valueControlLinola-FOutcome measurement#
Visit no.
0.114138.81 (23.61)151.44 (32.28)Epidermis thicknessVisit 0
0.637131.02 (24.04)134.29 (33.80)Epidermis density
0.9051310.62 (385.94)1319.25 (392.00)Dermis thickness
0.24626.86 (13.89)31.79 (21.35)Dermis density
0.844134.17 (29.23)141.17 (37.62)Epidermis thicknessVisit 1
0.814137.95 (29.71)131.53 (31.67)Epidermis density
0.9691255.58 (259.63)1227.25 (332.52)Dermis thickness
0.81474.38 (136.27)38.52 (25.51)Dermis density
0.240150.7 (40.91)143.10 (52.01)Epidermis thicknessVisit 2
0.721143.76 (29.76)139.10 (45.86)Epidermis density
0.8781281.40 (324.67)1254.30 (444.93)Dermis thickness
0.61042.25 (29.20)49.74 (35.80)Dermis density
Note: #Data are shown as mean (SD) and analyzed by Wilcoxon signed-rank test.
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Nasrollahi et al
Disclosure
Christoph Abels, MD, PhD, a board-certified dermatologist,
is an employee of Dr. August Wolff GmbH & Co. KG Arz-
neimittel, Bielefeld, Germany. The other authors report no
conflicts of interest in this work.
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Nasrollahi et al
Supplementary material
Patient questionnaire
Please mark on the lines below the severity of the following symptoms:
Itching None(0)_____________________2.5_____________________ (5)Very strong
Burning None(0)_____________________2.5_____________________ (5)Very strong
Satisfaction with the routine moisturizer: Very satised□ Somewhat satised□ Indifferent□
Somewhat dissatised□ Very dissatised□
Figure S1 Patient questionnaire.
Available via license: CC BY-NC 4.0
Content may be subject to copyright.
