Journal of Dermatological Treatment, 2013; 24: 122–125
© 2013 Informa Healthcare USA on behalf of Informa UK Ltd.
ISSN: 0954-6634 print / 1471-1753 online
DOI: 10.3109/09546634.2012.713461
ORIGINAL ARTICLE
Improvement of skin barrier function in atopic dermatitis patients with a
new moisturizer containing a ceramide precursor
Eric Simpson1, Arne Böhling2, Stephan Bielfeldt2, Catherine Bosc3 & Nabil Kerrouche3
1
Department of Dermatology, Oregon Health and Science University, Portland, Oregon, 2proDERM, Schenefeld/Hamburg, Germany and
3
Galderma R&D, Sophia Antipolis, France
Background: Atopic dermatitis (AD) is characterized by barrier
abnormalities, including insufficient ceramides in the stratum
corneum (SC). Objective: To measure the effects of a new
moisturizer (CRM) containing a ceramide precursor in improving
skin barrier function in patients with controlled atopic dermatitis.
Methods: In this randomized, intra-individual comparison,
investigator-blinded study, CRM was applied to the test area
of one lower leg for 27 days (the other leg remained as
untreated control). Evaluations at baseline and day 28 included
transepidermal water loss (TEWL), skin hydration by corneometry,
dryness severity, Raman spectroscopy, and collection of adverse
events. Results: After 4 weeks of treatment, results showed a
significantly greater reduction of TEWL and clinical dryness
scores, and increased skin hydration (all p < 01) in the CRM-
treated than untreated area. A significantly higher level of
ceramide (p < 05) and a trend toward increased water content
was observed with Raman in the SC for CRM than for the control.
There were no related AEs. Conclusion: Skin barrier function
and hydration were significantly improved after CRM treatment.
Key words: atopic dermatitis, ceramides, skin barrier, Raman
spectroscopy, transepidermal water loss, skin hydration
Introduction
Current prevalence estimates of atopic dermatitis (AD) range
between 9 and 18% in the U.S. pediatric population (1). Skin
barrier dysfunction represents a cardinal biophysical feature of
this common disease. It is currently accepted that AD results from
a series of gene–environment interactions (2). A theoretical
“outside-inside-outside” model of AD pathogenesis states that
skin inflammation results from a cycle of both inherited and
acquired skin barrier defects that lead to immune system activa-
tion, causing further deterioration of skin barrier homeostasis (3).
Experimental evidence demonstrates that AD lesional skin has
lower levels of ceramide (particularly ceramides 1 and 3) and
natural moisturizing factor (NMF), elevated pH, altered antimi-
crobial peptide production, reduced hydration, reduced cornified
envelop protein expression including filaggrin, and elevated
transepidermal water loss (TEWL) (2,4–9). As a consequence
of these abnormalities, lesional AD skin is characterized
by inflammation, xerosis, and a predisposition toward bacterial
infection (10).
Correspondence: Eric L. Simpson, MD, MCR, Oregon Health and Science University, Center for Health and Healing, Dermatology, 3303 SW Bond Ave, OR
97239-4501, Portland. Tel: +503 494 3968. Fax: +503 494 6907. E-mail: simpsone@ohsu.edu
(Received 4 June 2012; accepted 12 June 2012)
Findings from a recent study suggest a link between abnormal
ceramide/cholesterol ratio in the non-lesional skin of AD patients
and genotype (at least one filaggrin mutation) (11). Filaggrin loss-
of-function mutations represent a major heritable risk factor for
AD. Filaggrin deficiency may explain many of the barrier abnor-
malities seen in AD such as elevated pH, altered lipid profiles and
reduced natural moisturizing factor (12–14). Proteolytic cleavage
of filaggrin monomers yields hygroscopic amino acids such as
pyrolidine carboxylic acid (PCA) and arginine that are the key
components to natural moisturizing factor in the stratum cor-
neum (SC) (15).
With the new understanding of the molecular abnormalities
underlying AD skin, new emollients are emerging to address these
specific defects. Several over-the-counter emollients and prescrip-
tion devices have added ceramides species to their formulation in
order to improve barrier function (16–18). Other additives that
have shown improvement in AD skin include vitamin B12,
niacinamide, and urea (19,20). Insufficient data exist regarding
whether any of these additives actually penetrate the outer SC or
lead to measurable quantities in skin.
Cetaphil Restoraderm Body Moisturizer (CRM – Galderma
S.A.) is a new moisturizer designed to meet the specific needs of
children and adults with AD (21). Its ingredients include filaggrin
breakdown products (components of NMF), ceramide precursor,
and niacinamide (vitamin B3, which is important in ceramides
synthesis). The synthetic ceramide precursor, (22), pseudo-
ceramide 5 or N-(2-hydroxyhexadecanoyl) sphinganin, has
been shown in an in vitro skin model to increase endogenous
ceramide fractions 1, 2 and 3 (23). Our objective was to determine
whether this new formulation improved skin barrier function in
patients with controlled AD.
Methods
Study design
This was a randomized, intra-individual comparison (right/left),
investigator-blinded, single-center study carried out at the pro-
DERM Institute in Germany between December 2010 and Feb-
ruary 2011. Study visits were performed at screening (13–14 days
before baseline), baseline (day 1), and day 28.
Prior to the start of the study, a statistician generated a
randomization list and each bottle of product was identified by
a randomization number and was labeled with the side to be
treated. At the screening visit, the product was randomly assigned
 Moisturizer with ceramide precursor improves skin barrier 

to the right or left lower leg (for each subject, one 4  4 cm area Table I. Demographics and baseline clinical characteristics (ITT).
treated with CRM and one symmetric untreated control area) Demographics
with a block size of four subjects. The randomization list was kept
Sex
under restricted access until the study database was locked and
Males 4 (20%)
ready to be unblinded for statistical analyses. The investigator was
Females 16 (80%)
blinded to where the test product was applied.
Age (mean ± SD) 40.9 ± 6.6 years
This study was conducted in accordance with the ethical
principles derived from the Declaration of Helsinki and ICH Measurement CRM-treated area Untreated area
Good Clinical Practices and in compliance with local regulatory
requirements, and was reviewed and approved by an ethics Dryness scale (0–4) (mean ± SD) 2.05 ± 0.63 2.07 ± 0.63
committee. All subjects provided their written informed consent Skin hydration (I.U.) (mean ± SD) 17.77 ± 5.24 18.25 ± 5.91
before entering the study. TEWL [g/(m2h)] (mean ± SD) 5.15 ± 1.53 5.32 ± 1.73

Subjects
Enrolled subjects were male or female volunteers from 18 to
65 years old with controlled AD (without active lesions in the
target area). They also had to have clinically xerotic skin, corre-
sponding to a score of at least 1 on a dryness scale at inclusion
(mild dryness), and a corneometer value less than 30 (very dry
skin) at inclusion. Subjects were not allowed to use other topical
products on the target areas for the duration of the study.
Exclusion criteria included women who were pregnant or
breastfeeding.
Intervention
Starting at baseline (day 1), CRM was applied twice daily on
one leg for 27 days. Measurements were performed on day 28,
10–16 h after product application. CRM’s ingredients include
pseudoceramide-5 (a ceramide precursor which induces synthesis
of endogenous ceramides 1, 2 and 3), niacinamide (vitamin B3,
which is important in ceramides synthesis), fatty acids, filaggrin
breakdown products including pyrolidine carboxylic acid (PCA),
humectants, filmogenic substances, emollients, and shea butter.
CRM contains no fragrances and has a pH of approximately 5.5.
Assessments
During visits, subjects remained at least 30 m in a climatized room
(humidity and temperature controlled according to published
guidelines (24)). The following measurements were performed
at baseline and day 28: TEWL (Dermalab, Cortex), corneometry
(measurement of skin hydration; Corneometer CM825 Courage
& Khazaka), and clinical dryness evaluation. At baseline and day
28, three TEWL measurements per test area were performed in
order to assess the SC barrier function. A decrease in TEWL
signifies improvement in skin barrier function. Skin hydration
was evaluated using five measurements of corneometry in the test
area. Values less than 30 i.u. (instrumental units) usually represent
very dry skin, between 30 and 40 i.u. is considered dry skin, and
normal skin is typically ‡ 40 i.u., therefore an increase in
corneometry shows a skin-moisturizing effect (25). A blinded
assessor evaluated the level of skin dryness on a scale of 0 (no
dryness) to 4 (very severe dryness), and half-points were possible.
Raman spectroscopy, an established non-invasive method,
Safety was assessed through evaluation of the incidence of
adverse events (AEs).
Statistical methods
The ITT (intent to treat; all subjects enrolled and randomized)
and safety (all enrolled subjects who received the first dose of
study treatment) populations were analyzed. Subject disposition,
demographics, baseline characteristics, and adverse events were
summarized by descriptive statistics on the appropriate popula-
tion. Corneometry, TEWL, dryness measurements, and Raman
parameters were analyzed. The bilateral differences between
CRM-treated and non-treated areas for all assessments, in terms
of percent change from baseline, were analyzed using the paired t-
test (considered as statistically significant at the alpha level of
0.05).
Results
A total of 20 subjects with controlled AD were included and
completed the study without any major protocol deviations. The
majority of subjects (80%) were female, with a mean age of
40.9 ± 6.6 years (Table I). At baseline, the areas designated to be
treated or untreated had similar dry skin clinical scores (2.05 ±
0.63 and 2.07 ± 0.63, respectively), skin hydration (17.77 ± 5.24
and 18.25 ± 5.91 i.u., respectively), and TEWL (5.15 ± 1.53 and
5.32 ± 1.73 [g/(m2h)], respectively).
Clinical improvement was observed after 4 weeks of treatment
with CRM in terms of skin hydration and barrier function.
A significantly greater reduction of TEWL was observed in the
CRM-treated area [about sevenfold (-30% vs. -4%) change from
baseline for CRM and untreated area, respectively; p = 002],
indicating improved skin barrier function (Figure 1). Correspon-
dingly, a significantly increased SC hydration was measured
Day 28
Untreated CRM
–0
% change from baseline

–5
(26), was used to evaluate the changes in the stratum corneum –4.28
after the treatment with CRM. SC thickness ranges up to 20 mm as –10
measured by Raman (unpublished results), comparable with –15
previous findings of mean SC thickness (27). Total NMF, PCA,
and ceramide contents were measured at skin depths of 5 and –20
10 mm ± 1 mm from the skin surface, which represented superficial –25
vs. deeper layers of SC. For the measurement of water content, SC
was arbitrarily divided into three equally spaced compartments, –30
and change in water content within each SC compartment was –30.01
–35 * p = .002 vs. untreated
*
calculated according to area under the curve (AUC), (28), based
on the fact that water content in the outer SC is low and higher in Figure 1. Percentage change in TEWL from baseline (ITT). Note: A
the viable epidermis (29). reduction of TEWL represents an improvement in skin barrier function.
 E. Simpson et al.

140 * p<.001 vs. untreated * p<.05 Untreated

*
117.53 * CRM
120 60
% change from baseline
53.94
100

% change from baseline

50 *
80 39.62
40
60
30
40
25.42
20 20

0 10 8.05
Untreated CRM 4.28
Day 28 0
5 µm 10 µm
Figure 2. Percentage change in skin hydration from baseline (ITT). Depth

Figure 4. Percentage change in ceramide content from baseline (ITT).

by corneometry [over four times higher (118% vs. 25%) change
from baseline for CRM and untreated area, respectively;
p < 001; Figure 2]. In addition, the clinical observation of dryness
showed a significantly superior improvement for the CRM-
treated area (56% vs. 22% reduction of the dryness score for
CRM and untreated area, respectively, p < 001; Figure3): from an
average moderate dryness (score of 2.05) diagnosed at baseline to
an average light dryness (score of 0.90) after 28 days.
At day 28, results of Raman spectroscopy showed a signifi-
cantly higher level of ceramide content in the CRM-treated area
than the untreated area at both SC depths (both p < 05; Figure 4).
The mean percentage change of NMF levels from days 1 to 28 for
CRM and the untreated area was 4.14 vs. -.09 at 5 mm, respec-
tively. At 10 mm, the percentage change of NMF was 20.27
vs. -5.76, respectively. The mean percentage change of PCA levels
from days 1 to 28 for CRM and the untreated area was 6.38 vs.
1.89 at 5 mm, respectively. At 10 mm, the percentage change of
PCA was 8.30 vs. -2.83, respectively. These changes in NMF and
PCA were trends favoring CRM, but were not significant. In
addition, for the CRM-treated area, a higher level of water content
for the deepest layer of SC was measured (15.52 vs. -15.89 for the
untreated area in terms of mean AUC). Although this was not
significant, this trend was consistent with an increase in skin
hydration.
In terms of safety, no related adverse events were reported and
there were no serious adverse events.
Discussion
In this study, 28 days of CRM treatment improved skin barrier
function in AD skin as evidenced by the statistically significant
Day 28
Untreated CRM
0
% change from baseline
improvements in skin hydration, TEWL, and clinical dryness
scores observed in the CRM-treated vs. untreated areas.
Emollients are important in the long-term management of AD
and have been shown to improve clinical outcomes (30). They aim
to increase skin hydration and improve skin barrier function,
filling the gaps between desquamating corneocytes with lipids and
impacting eicosanoid production, membrane fluidity and cell
signaling (30). Our findings highlight the significant clinical
improvement that was observed after 4 weeks of treatment
with CRM in terms of TEWL, corneometry, and dryness severity
scores (all p < 01 compared to the untreated area). As shown by
the reduced TEWL (a seven times higher percent change for CRM
compared to the untreated area), skin barrier function was
improved. Skin hydration was also enhanced (a four times higher
percentage change for CRM). Additionally, the clinical assessment
of skin dryness was significantly improved, from an average
moderate dryness at baseline to light dryness after 4 weeks.
Though several studies of emollients have shown improvement
in TEWL, (31,32), the mechanism by which the products improve
barrier function is not well-characterized. Ceramides are typically
lacking in AD skin, which may help prevent water loss and
dispersion of water-soluble materials. Our findings showed a
higher level of ceramides and water content by Raman spectros-
copy after 4 weeks of treatment with CRM compared to the
untreated control. Therefore, the changes observed after CRM
appear to normalize xerotic AD skin.
A limitation of this study was that an untreated control was
used instead of a placebo, since there are several active ingredients
in CRM which makes it difficult to control. Another limitation
was that we did not evaluate subjects for FLG mutations, however
even non-FLG-mediated AD has been found to have lower NMF
(33). Nevertheless, our results were consistent as skin barrier
improvements and hydration favored CRM both according to
observed clinical improvement and instrumental measurements.

–10
Clinical trials are now needed to determine whether this improve-
–20 ment in skin barrier function translates to improved clinical
–22.17 outcomes such as flare-free days.
–30

–40 Conclusion
After 1 month of twice-daily treatment with CRM, statistically
–50 significant improvements in skin barrier function, hydration and
* p<.001 vs. untreated clinical dryness were observed in patients with controlled AD.
–60 –55.54
*
Improvement in barrier function may be mediated by the signifi-
cant increase in ceramide and a trend toward increased water
Figure 3. Percentage change in skin dryness from baseline (ITT). content of the stratum corneum observed with CRM treatment.
 Moisturizer with ceramide precursor improves skin barrier
Together, these results support the use of CRM as adjunctive
treatment in atopic dermatitis.
Acknowledgment
The authors would like to thank Galadriel Bonnel, MSN, for
editorial assistance.
Declaration of interest: Dr. Simpson is a consultant for Galderma,
and Dr. Böhling and Mr. Bielfeldt received investigator fees for
this research study. Ms. Bosc and Mr. Kerrouche are employees of
Galderma.
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