doi: 10.1111/j.1346-8138.2009.00716.

x Journal of Dermatology 2009; 36: 583–586

ORIGINAL ARTICLE

Evaluation of anti-wrinkle effects of a novel cosmetic

containing retinol using the guideline of the Japan
Cosmetic Industry Association
Akira KAWADA,1 Natsuko KONISHI,1 Tomoyuki MOMMA,2 Naoki OISO,1
Shigeru KAWARA1
1
Department of Dermatology, Kinki University School of Medicine Osaka, and 2Inforward, Tokyo, Japan

ABSTRACT
Retinol is known to be effective in the treatment of sallowness, wrinkling, red blotchiness and hyperpigmented spots
in aging skin. In this study, we have evaluated the anti-wrinkle effects of a new cosmetic containing retinol. An open
study was performed in 30 healthy Japanese women who had wrinkles at the corners of the eyes. The tested lotion,
Retin-OX+ (RoC SA, Colombes, France), was applied on wrinkles of one side of the face for 8 weeks, and not on
the other site as a control. Anti-wrinkle effects were evaluated by two methods: (i) doctors’ observation and photos
based on the guideline of the Japan Cosmetic Industry Association; and (ii) the Robo Skin Analyzer. This lotion
showed marked and moderate improvement in 34% of the subjects with a significant difference as compared with
the control sites (P < 0.05). Moreover, the length and area decreased in the applied site more than the control site
with a significant difference (P < 0.01). All the patients completed the study without significant adverse reactions.
The tested lotion was well tolerated and may be an optional preparation for the treatment of wrinkles at the corner
of the eyes.
Key words: anti-wrinkle effects, cosmeceutical, photoaging, retinol.

INTRODUCTION stress; (iv) controlling cutaneous bacterial flora; and

(v) improving skin aging and photoaging.3
Recently, numerous cosmeceutical products have In this study, we investigated anti-wrinkle effects of
been focused on various clinical signs on photoaging a novel cosmetic containing retinol in healthy Japa-
skin including dyspigmentation, fine wrinkles and nese women according to the guideline of the Japan
roughness. Retinoids, vitamin C, a-hydroxy acids, Cosmetic Industry Association (JCIA).4
niacinamide and topical growth factors have been
added to cosmeceuticals that could stimulate repair
METHODS
mechanisms resulting in improvements in photodam-
aged skin.1,2 In retinoids, tretinoin and isotretinoin are Subjects
used as therapeutic preparations, while retinol (vita- Thirty Japanese female subjects aged 35–59 years
min A), retinalaldehyde and retinyl esters are used as (mean, 50.4) participated in a split face study with
cosmeceuticals. These retinoids are expected to be left–right randomization that was carried out between
helpful in: (i) renewing epidermal cells; (ii) acting April and July 2006. Subjects having fine wrinkles
as ultraviolet (UV) filters; (iii) preventing oxidative in the eye area were investigated. Recreational sun

Correspondence: A. Kawada, M.D., Ph.D., Department of Dermatology, Kinki University School of Medicine, 377-2 Ohno-Higashi, Osaka-
Sayama City, Osaka 589-8511, Japan. Email: [email protected]
Received 9 January 2009; accepted 13 July 2009.

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A. Kawada et al.

exposure was prohibited. Daily cosmetics that had adaptive binarization process was performed to
continued before the test were permitted, while reveal pixels with weaker intensity. Wrinkles were
anti-wrinkle cosmetics, pharmaceuticals or aesthetic defined as lines or lesions of which pixels varied to
modalities were prohibited. Informed consent was some degrees from surrounding pixels of wrinkle-free
obtained. There were no conflicts of interest. lesions in a captured image. For wrinkles, total area
of wrinkles on the eye area (30 · 30 mm2) and maxi-
Testing substance mum length of wrinkles from the corner of the eye
A novel cosmetic, Retin-OX+ (Roc SA, Colombes, were calculated.
France), was evaluated compared with a control with-
out application. Retin-OX+ is an anti-wrinkle cream
RESULTS
that contains retinol as a main constituent and ‘‘Colla-
gen Ox’’. Collagen Ox is a mixture of magnesium The combination of observations and photographs
asparaginate, zinc gluconate and copper gluconate. indicated clinical improvement of wrinkles of the
A dose of 0.3 g Retin-OX+ was applied for a half of the tested substance Retin-OX+. Thirty-four percent of
face twice a day after washing the face for 8 weeks. subjects showed marked or moderate improvement
at 8 weeks in the tested site, whereas 16% did in the
Evaluation of wrinkles in the eye area unapplied control site (Table 1). These effects were
First, evaluation was conducted by the combination statistically significant (P < 0.005). A representative
of observation and photographs by two investigators case with marked response is shown in Figure 1.
(A. K. and N. K.) based on the guideline of the JCIA.4 Reduction rates of total area of wrinkles in CS50 at
The evaluation was conducted based on the condi- 8 weeks were 13% on the tested site and 6% in the
tion of the eyes when opened and closed. This guide- control site with a significant difference (P < 0.01).
line classifies conditions of wrinkles as 8 grades, 0–7. There was a significant difference (P < 0.01) of reduc-
The physicians’ overall assessments of the extent tion of maximum length of the wrinkles between the
of improvement ⁄ worsening were graded as ‘‘wors- tested (12%) and control site (7%). A representative
ened’’, ‘‘no change’’, ‘‘slight improvement’’, ‘‘moder- case with marked response in the digital image is
ate’’ and ‘‘marked’’ (Table 1). shown in Figure 2.
For the second, the Robo Skin Analyzer CS50 All the subjects completed the 8-week study.
(Inforward, Tokyo, Japan)5,6 was used for the evalua- Seven subjects complained of a burning sensation
tion when the eyes were opened. The skin images with faint erythema on the applied site, that dis-
were taken with a 3CCD digital video camera. This appeared in a few weeks without any medication.
device was connected to a Windows-based personal
computer system through a digital video unit and an
DISCUSSION
image acquisition PC card. The software analysis in
CS50 calculates the area of wrinkles and pigmentary This study revealed the efficacy for wrinkles and toler-
lesions and measures brightness. Briefly described, ability of a cosmetic containing retinol, Retin-OX+, in
blue signals are extracted from a digital image that Japanese women. Overall, 34% of subjects showed
is composed of red, green and blue signals. An marked or moderate improvement with the combina-
tion of observation and photographs. Retin-OX+ also
Table 1. Overall ratings for the response of wrinkles showed reduction in both the total area and maxi-
mum length of wrinkles using computer analysis of
Tested Control
Rating site (%) site (%) the video-captured image. Significant improvements
Worsened (0 > change in grades) 0 (0) 0 (0)
in the combination of observation and photographs
No change (no change in grades) 17 (56) 22 (74) and analysis of digital image based on the JCIA’s
Slight (0.5 > change in grades ‡ 0) 3 (10) 3 (10) guideline imply that Retin-OX+ has anti-wrinkle
Moderate (1.5 > change in grades ‡ 0.5) 5 (17) 4 (13)
effects as a cosmetic. Retin-OX+ contains retinol as a
Marked (change in grades ‡ 1.5) 5 (17) 1 (3)
main constituent and a mixture of magnesium aspar-
P < 0.005 compared with the control site in Wilcoxon’s rank sum test. aginate, zinc gluconate and copper gluconate. All of

584  2009 Japanese Dermatological Association

 Anti-wrinkle effects of a novel cosmetic

(a) (a)

(b)

(b)

Figure 2. A 58-year-old woman (a) before and (b) 8 weeks

after the treatment. Total area of wrinkles in the eye area and
maximum length of wrinkles from the corner of the eye
reduced.

been reported to improve fine wrinkles associated

with photoaging or natural aging for the skin of white
subjects.7 Our study demonstrated reduction of wrin-
kles with a cosmetic containing retinol in Japanese
female skin. Thus, topical retinol may have anti-
wrinkle effects both on white and Mongoloid skin.
Retinoic acid (tretinoin), widely used for topical
therapy of several skin diseases, improves aging skin
with significant biological activity and induces
irritation of skin.3 Tretinoin causes severe irritation of
Japanese photodamaged skin and is not officially
approved in Japan. Therefore, topical retinol with low
Figure 1. A 52-year-old woman (a) before and (b) 8 weeks irritative potential may be more appropriate than treti-
after the treatment. Marked improvement was seen.
noin for Japanese skin.
In human keratinocytes and mouse skin, retinoic
these constituents may have contributed to the acid is thought to be formed enzymatically from all-
improvement. The combination of observations, trans-retinol by a two-step oxidation process in which
photographs and CS50 analysis showed some retinal is the intermediate metabolite.8–10 When
improvements in the unapplied control site. Protec- applied to human skin, retinol penetrates and is
tion against UV may affect this improvement because sequentially oxidized to retinoic acid, enhancing
recreational sun exposure was prohibited in this expression of cellular retinoid binding protein
study. mRNA and causing some effects of retinoic acid.11
Although retinol is contained in many cosmetics, The ranking order of retinoid-like activity following
few studies have demonstrated clinical improvement topical application is as follows: retinoic acid >
for aging and photoaging skin. Topical retinol has retinaldehyde > retinol >> retinyl esters.3 Similar

 2009 Japanese Dermatological Association 585

A. Kawada et al.

mechanisms to retinoic acid12 may be involved in the 5 Kawada A, Kameyama H, Asai M et al. A new approach
improvement of wrinkles with topical retinol. First, to the evaluation of whitening effect of a cosmetic using
computer analysis of video-captured image. J Dermatol
increase in collagen production with retinol may
Sci 2002; 29: 10–18.
cause wrinkle reduction. Topical retinol increases 6 Kawada A, Kawara S, Oiso N et al. (2008) An evaluation
fibroblast growth and collagen synthesis, and con- of whitening effect of an intense pulsed light source
comitantly reduces the levels of collagen-degrading using computer analysis of the video-captured digital
matrix metalloproteinases in naturally aged human image. Arch Dermatol Res 2008; 300(Suppl 1): S39–
skin.13 Topical retinol also increases protein expres- S41.
7 Kafi R, Kwak HSR, Schumacher WE et al. Improvement
sion of type I procollagen in chronologically aged
of naturally ages skin with vitamin A (retinol). Arch
skin.7 These findings suggest that retinol could sti- Dermatol 2007; 143: 606–612.
mulate fibroblast growth, collagen production and 8 Strickland S, Mahdavi V. The induction of differentiation
reduce degradation of collagen, leading to the in teratocarcinoma stem cells by retinoic acid. Cell
improvement of wrinkles. Second, retinol induces epi- 1978; 15: 393–403.
9 Siegenthaler G, Saurat JH, Ponec M. Retinol and retinal
dermal hyperplasia11,14 and increase in epidermal
metabolism: relationship to the state of differentiation of
glycosaminoglycan skin7 that has the capacity to bind cultured human keratinocytes. Biochem J 1990; 268:
water. We hypothesized that epidermal thickening 371–378.
and increase of glycosaminoglycan may lead to the 10 Connor MJ, Smit MH. Terminal-group oxidation of reti-
improvement of roughness and fine lines. nol by mouse epidermis. Biochem J 1987; 244: 489–
In conclusion, our study indicated that the topical 492.
11 Kang S, Duell EA, Fisher GJ et al. Application of reti-
retinol-containing cosmetic reduced wrinkles in the
nol to human skin in vivo induces epidermal hyperpla-
eye area of Japanese women and was well tolerated. sia and cellular retinoid binding proteins characteristic
Further study is needed to reveal the precise mecha- of retinoic acid but without measurable retinoic acid
nism of anti-wrinkle effects of retinol. levels or irritation. J Invest Dermatol 1995; 105: 549–
556.
12 Cho S, Lowe L, Hamilton TA, Fisher GJ, Voorhees JJ,
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586  2009 Japanese Dermatological Association