October 2009

932

Volume 8 • Issue 10

Copyright © 2009

Original Articles

Journal of Drugs in Dermatology

A Stabilized 0.1% Retinol Facial Moisturizer
Improves the Appearance of Photodamaged Skinin an Eight-Week, Double-Blind,
Vehicle-Controlled Study
Samantha Tucker-Samaras PhD,a Tara Zedayko,a Curtis Cole PhD,a Dara Miller,aWarren Wallo MS,a James J. Leyden MDb
Johnson & Johnson Consumer Companies, Inc., Skillman, NJ
b
University of Pennsylvania, Philadelphia, PA

aAbstract
Retinol is a cosmetic ingredient that is structurally similar to all-trans-retinoic acid, which has been shown to be effective in the treatment of photodamage. Since skin keratinocytes are reported to metabolize retinol to retinoic acid, investigators have hypothesizedthat retinol may also be helpful in improving skin photodamage. In this eight-week, double‑blind, split-face, randomized clinical study, astabilized 0.1% retinol-containing moisturizer was tested (36 subjects) against the vehicle (28 subjects) in women with moderate facial
photodamage. Each product was applied once daily to the designated half side of the face. Subjects were evaluated at baseline andafter four and eight weeks of treatment using a 0–9 scale for photoaging parameters. The results showed that, after eight weeks, theretinol moisturizer was significantly more efficacious than the vehicle in improving lines and wrinkles, pigmentation, elasticity, firmnessand overall photodamage. Many of these differences were significant at week 4, with a progressive improvement to week 8. This study
demonstrates that a formulation containing stabilized retinol is safe and effective to ameliorate the appearance of photoaged skin.

Introduction

Rlations has been chemical instability. Significant advances inthe stabilization and delivery of retinol have occurred and provide the opportunity for study of its clinical effects.13 Here, theauthors present a study evaluating the efficacy of a stabilized
0.1% retinol-containing moisturizer, which has been optimized
for topical delivery to improve the appearance of photodamaged skin on the face.

Do Not Copy
Penalties Applyetinol has a history of usage as an antioxidant in cosmetic products1 and has long been recognized as asafe cosmetic ingredient. Chemically, it is a precursorof retinaldehyde and retinoic acid (RA), the latter a topical drug
approved by the U.S. Food and Drug Administration (FDA) for
use in photodamaged skin. A multitude of studies have supported the efficacy of RA in improving facial wrinkles and hyperpigmentation.2–6 There is evidence that topical retinol penetrates
the skin when applied to test sites and that it is metabolizedby skin keratinocytes to RA.7,8 Studies have also shown thatwhile retinol may exert similar effects to RA, it has less irritancy
potential and it is safer to the skin.9 Intrinsically aged as well
as UV-damaged skin is characterized by increased synthesisof matrix metalloproteinases (MMPs), which mediate collagendestruction, and by decreased production of collagen.10,11 Human in vivo studies have described epidermal as well as dermal changes after retinol application: epidermal thickening,
decreased levels of MMPs, increased fibroblast growth and increased collagen synthesis have all been reported.9,10

Materials and Methods

Study Design and Formulations
This was an eight-week, double‑blind, split-face, vehicle‑controlled, randomized study conducted during the winter in the
Northeast region of the U.S. The study was approved by an
institutional review board and patients’ written informed consent was obtained prior to initiation of the investigation. A totalof 80 female subjects, aged 40–65, Fitzpatrick phototype I–III,
were enrolled in the study. To be included, subjects had to present with a moderate severity of: coarse wrinkles in crow’s feetand upper cheek areas; facial pigmentation; facial sagging; andoverall photodamage on both sides of the face. Subjects were
excluded if they had used topical anti-aging treatments and/or
topical retinoids within 30 days prior to study start.

Because of these retinoic acid-like effects but a higher skin tolerance, and because of its availability as a cosmetic ingredient,
topical retinol has been proposed as a potential agent to ameFour facial moisturizers and a vehicle were tested in a roundliorate the cutaneous changes associated with photoaging. Derobin randomization in a population of 80 subjects. Three moisspite these arguments, clinical studies on the efficacy of retinol
turizers included in this clinical study were of a proprietaryin photoaging are scant.12 A major problem with retinol formunature and cannot be disclosed in this publication. This manu© 2009-Journal of Drugs in Dermatology. All Rights Reserved.
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933
Journal of Drugs in Dermatology
October 2009 • Volume 8 • Issue 10

script will discuss only the comparison between a 0.1% retinolcontaining moisturizer and its vehicle. It should be noted thatwhile the efficacy of these other moisturizers will not be disclosed, the tolerance profile was comparable among all fiveproducts. Of the total study population, 37 subjects tested theactive retinol product and 29 subjects tested the vehicle. Eachsubject was assigned two formulations as per randomization.
Each product was applied to the designated half side of the facefor eight weeks. Applications were conducted once daily in themorning, and no other moisturizer was allowed for the durationof the study.
The novel active formulation discussed in this study has beendeveloped to deliver a stabilized form of retinol, significantly
reducing the issue of its chemical instability. Stabilization wasachieved by using a combination of a chelating agent, a hydrophilic antioxidant and a lipophilic antioxidant,13 and was assessed via HPLC analysis on unopened product samples stored
at room temperature and further characterized with analyticalstudies under accelerated conditions. The list of ingredients forthe active formulation is reported in Table 1.

S. Tucker-Samaras, T. Zedayko, C. Cole, et al.

Subjects’ self-evaluation for irritation and digital images were also
conducted at weeks 0, 4 and 8. Camera set-up, lighting conditions
and subject’s position were standardized during the study.

Statistical Analyses
Primary data for efficacy analysis was the data at week 8. Analysis data at week 4 was considered secondary. Dermatologist’s
evaluations were analyzed with multiple methods. A paired T
test was used to compare the individual scores at each time
point, relative to their respective baseline, within each treatment group. A student’s T test was used for each attribute foreach cell, for both the actual and net change scores at each time
point. Also, the net change scores for each attribute were converted to the number of panelists who showed “improvement”,“stayed the same” or “worsened”. For all analyses, a two-tailed
P<0.05 was used as the level of significance.

results
Thirty-six and 28 female subjects completed the applications of
the active and vehicle, respectively. Two subjects were discontinued for reasons unrelated to the study.

Evaluation

Efficacy

Efficacy was measured by clinical evaluations. Digital photography was conducted to document the results. Safety was measured by the incidence and severity of both cutaneous irritation
and adverse events.

The retinol group showed a significant and progressive improvement from baseline at weeks 4 and 8, in nearly all efficacy parameters. At week 8, the 0.1% retinol moisturizer was statistically

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Table 2.

Clinical evaluations were performed by the dermatologist atbaseline and at weeks 4 and 8 on each side of the face. Variables
were scored on a 0 (none) to 9 (severe) scale and included:
forehead wrinkles; crow’s feet wrinkles; crow’s feet fine lines;
cheek wrinkles; under eye wrinkles; mottled pigmentation; skinbrightness; skin firmness; skin lifting; sub-orbital elasticity (byskin pulling); elasticity at jaw line (jowl-visual sagging); overall sagging; overall forced choice (left versus right); and overall
photodamage severity. Overall cutaneous irritation was evaluated for safety, using a 0 (none) to 3 (severe) scale.

Table 1.

Net Improvement in Clinical Parameters From Baseline,
Based on a 0–9 Dermatologist Score
Week 4

Week 8Retinol

VehicleRetinol

VehicleCheek Wrinkles-0.7 √ *0-0.9 √ *-0.1

Under Eye Wrinkles-0.3 √-0.2 √-0.6 √ *-0.3 √

Crow’s Feet Lines-1.1 √ *-0.8 √-1.4 √ *-1.0 √

Crow’s Feet Wrinkles-0.4 √ *-0.1 √-0.7 √ *-0.1

Forehead Wrinkles-0.4 √ *0-0.5 √ *0

Mottled Pigmentation-1.2 √ *-0.3 √-1.7 √ *-0.9 √

Ingredient List of the 0.1% Retinol Moisturizer

Lack of Skin Brightness-1.5 √-1.3 √-1.8 √-1.7 √
Water, Dimethicone, Glycerin, Isodecyl Neopentanoate,
Overall Photodamage-0.8 √ *-0.3 √-1.0 √ *-0.5 √
Ethylhexyl Hydroxystearate, Dimethyl MEA, Cetearyl Alcohol,
Lack of Elasticity-0.2 √ *0-0.4 √ *0
Stearyl Alcohol, PEG 100 Stearate, Glyceryl Stearate, Ceteareth
Sub-Orbital
20, Steareth 10, Citric Acid, Glycolic Acid, Phenoxyethanol,
Lack of ElasticityHydroxyethyl Acrylate/Sodium Acryloyldimethyl Taurate
00-0.2 √ *0
Jaw Line
Copolymer, Methylmethacrylate Crosspolymer, Aluminum
Lack of Skin Firmness-0.7 √ *0-0.6 √ *0
Starch Octenylsuccinate, Squalane, Butyrospermum Parkii(Shea Butter), Fragrance, Methylparaben, Xanthan Gum,
Sagging
-0.1
0
-0.1
0
Propylparaben, Polysorbate 20, Polysorbate 60, Retinol, BHT,
For all parameters, improvement is shown by a decrease in severity
Disodium EDTA, Ascorbic Acid, Magnesium Aspartate, Zinc
(negative direction). (√) indicates significant improvement (P<0.05) frombaseline. (*) indicates significant improvement (P<0.05) of the retinol
Gluconate, Copper Gluconate.
© 2009-Journal of Drugs in Dermatology. All Rights Reserved.
formulation versus vehicle, from baseline.

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934

better than the vehicle (P<0.05) in the improvement of all wrinkle
parameters, pigmentation, elasticity, firmness and overall photodamage (Figure 1, Figure 2, Table 2). Particularly prominent were
the improvements from baseline in mottled pigmentation by
53%, crow’s feet lines by 39% (and crow’s feet wrinkles by 16%),cheek wrinkles by 20% and overall photodamage by 18% after
eight weeks of retinol applications (Figure 1). The vehicle group
showed also a few significant improvements from baseline, but
only for some of the surface parameters (Table 2).
Many parameters showed the superiority of retinol as early as
week 4 of treatment (Table 2). Additionally, in the dermatologist’s overall forced choice, where seven subjects received thesplit combination of retinol and vehicle, the side treated withretinol was more improved than the opposite side in 100% of
the subjects, both at four and at eight weeks.
At the end of the study, a high percentage of the subjects
using the retinol moisturizer showed improvement, with
86% showing an improvement in overall photodamage,100% showing improvement in mottled pigmentation, 64%
improving in crow’s feet wrinkles and 97% in lines, 75% showing
improvement in cheek wrinkles and 100% in skin brightness(Table 3). On the contrary, the vehicle group’s population
only demonstrated 54% of subjects showing improvement inoverall photodamage, 71% showing improvement in mottled
pigmentation, 86% improving for crow’s feet lines and 100%for skin brightness.

SafetyS. Tucker-Samaras, T. Zedayko, C. Cole, et al.

Discussion
Retinol is structurally similar to all-trans-retinoic acid (RA). It isreported that in keratinocytes, retinol is first converted to retinaldehyde, which is then irreversibly converted to RA.14 The skin has
all the enzymes required to convert retinol to RA and, therefore, it
has been suggested that once retinol is applied in stable form to
the skin, it can exert all the benefits of RA. Kurlandsky et al. haveshown that retinol is metabolized to RA by human keratinocytes.7
The effects of RA on photodamaged skin are well documented,
both clinically and histologically. Clinical studies have shownthat RA improves various parameters of photoaging skin, suchas wrinkles, mottled hyperpigmentation, roughness and laxity.2–6
In vivo human studies have also shown that RA significantly
increases epidermal thickness, decreases melanin content,4,15

Figure 1. Clinical efficacy parameters: Comparison in surface
parameters between 0.1% retinol-containing moisturizer and vehicle
at the end of the study.
% Improvement from baseline at week 8 (Mean), comparing active versus vehicle

Journal of Drugs in Dermatology
October 2009 • Volume 8 • Issue 10

DERMATOLOGIST ASSESSMENT Surface Parameters

60

Retinol

Vehicle

*

50

40

*

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Both agents were well tolerated, with only a few panelists
showing small areas of minor irritation in both cells. Throughout the study, there was no significant increase in erythema,
scaliness, and edema as evaluated by the dermatologist, and in
self-assessed itching and burning/stinging. No adverse events
related to the products occurred in the study.

Table 3.

Dermatologist Evaluations (0–9 scale).
Week 4Retinol Vehicle
Cheek Wrinkles
69
0
Under Eye Wrinkles
33
18
Crow’s Feet Lines
97
82
Crow’s Feet Wrinkles
42
14
Forehead Wrinkles
42
0
Mottled Pigmentation
92
32
Lack of Skin Brightness
100
96
Overall Photodamage81
32
Lack of Elasticity19
0
Sub-Orbital
Lack of Elasticity 00
Jaw Line
Lack of Skin Firmness
67
0
Sagging
60

Week 8Retinol Vehicle
75
11
56
25
97
86
64
18
47
3
100
71
100
100
86
54
36

3

22

0

58
8

3
0

30

20

*

10

0

Cheek
WrinklesUnder Eye
Wrinkles***Crow's Feet
Lines

*

Crow's Feet Forehead
MottledOverall
WrinklesWrinkles Pigmentation Photodamage* = Significant difference (P<0.05) against vehicle from baseline

At week 8, the retinol treated skin showed significant improvement(P<0.05) against vehicle (*) in all wrinkle parameters, pigmentation andoverall photodamage.

Figure 2. Improvement in wrinkle appearance.

Patient using the 0.1% retinol moisturizer at baseline (left) and at the end
Comparison between active (0.1% retinol moisturizer) and vehicle inof the study (right). After eight weeks, there is a visible improvement in thepercentage of subjects showing at least 1 point improvement fromappearanceskin wrinkling.
baseline. Data shown in percentages.
© 2009-Journal of Drugs in Dermatology.
AllofRights
Reserved.

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No reproduction or use of any portion of the contents of these materials may be made without the express written consent of JDD.
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935
Journal of Drugs in Dermatology
October 2009 • Volume 8 • Issue 10

increases deposition of collagen in the upper part of the dermis(papillary dermis)16,17 and improves the morphology of elastic
fibers.18 These histological effects may contribute to the clinicaleffacing of wrinkles and improved skin toning.
Notwithstanding these important benefits, the use of RA is
reduced by its availability by prescription and by reactionsof mild and moderate skin irritation4,5 in some patients. The
proposed use of retinol in ameliorating visible photodamage
has two major advantages over RA: it is a cosmetic ingredient,
therefore easily available to consumers, and it is far moretolerated by the skin.9 However, there are currently very few
published studies documenting the use of retinol in improving
photoaging.19 Histological in vivo human studies have shown
epidermal thickening, decreased levels of MMPs, increased
fibroblast growth and increased collagen synthesis after retinol
application.9,10 Clinically, Kafi et al. improved fine wrinkling,roughness and overall severity of intrinsically aged skin in
subjects over 80 years old, after 24 weeks of 0.4% retinol, withan average of 1.6 applications weekly.20
Here, the authors compared a stabilized 0.1% retinol moisturizer to the vehicle in a double-blind, split-face study on photodamaged women. The results support the efficacy of retinol inphotodamage with effects on parameters similar to those seen
in RA studies. In fact, after eight weeks of once a day application, the retinol treated side was significantly better than thevehicle side in lines and wrinkles, mottled pigmentation, elasticity, firmness and overall photodamage, with superiority as
early as four weeks in some parameters.

S. Tucker-Samaras, T. Zedayko, C. Cole, et al.

References
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Burgess C. Topical vitamins. J Drugs Dermatol. 2008;7(7 Suppl):s2s6.
Leyden JJ, Grove GL, Grove MJ, et al. Treatment of photodamaged
facial skin with topical tretinoin. J Am Acad Dermatol. 1989;21(3Pt 2):638-644.
Ellis CN, Weiss JS, Hamilton TA, et al. Sustained improvement withprolonged topical tretinoin (retinoic acid) for photoaged skin. J Am
Acad Dermatol. 1990;23(4 Pt 1):629-637.
Weinstein GD, Nigra TP, Pochi PE, et al. Topical tretinoin for treatment of photodamaged skin. A multicenter study. Arch Dermatol.
1991;127(5):659-665.
Olsen EA, Katz HI, Levine N, et al. Tretinoin emollient cream: A new
therapy for photodamaged skin. J Am Acad Dermatol. 1992;26(2Pt 1):215-224.
Kang S, Bergfeld W, Gottlieb AB, et al. Long-term efficacy andsafety of tretinoin emollient cream 0.05% in the treatment of photodamaged facial skin: A two-year, randomized, placebo-controlled
trial. Am J Clin Dermatol. 2005;6(2 Pt 1):245-253.
Kurlandsky SB, Xiao JH, Duell EA, et al. Biological activity of alltrans retinol requires metabolic conversion to all-trans retinoic acidand is mediated through activation of nuclear retinoid receptors inhuman keratinocytes. J Biol Chem. 1994;269(52):32821-32827.
Duell EA, Kang S, Voorhees JJ. Unoccluded retinol penetrates human skin in vivo more effectively than unoccluded retinyl palmitate
or retinoic acid. J Invest Dermatol. 1997;109:301-305.
Kang S, Duell EA, Fisher GJ, et al. Application of retinol to humanskin in vivo induces epidermal hyperplasia and cellular retinoid binding proteins characteristic of retinoic acid but without measurable
retinoic acid levels or irritation. J Invest Dermatol. 1995;105:549556.
Varani J, Warner RL, Gharaee-Kermani M, et al. Vitamin A antagonizes decreased cell growth and elevated collagen-degrading
matrix metalloproteinases and stimulates collagen accumulationin naturally aged human skin. J Invest Dermatol. 2000;114(3):480486.
Fisher GJ, Wang ZQ, Datta SC, et al. Pathophysiology of premature skin aging induced by ultraviolet light. N Engl J Med.
1997;337(20):1419-1428.
Leyden JJ, Grove G, Barkovic S, Appa Y. A double-blind controlled
evaluation of a stabilized retinol treatment with SPF15 on photoaged facial skin. Poster presented at the 57th AAD meeting, 1999.
United States Reissued Patent Number USRE38813E, as found at
http://patft.uspto.gov/.
Edwards H. Topical retinol and retinaldehyde in cosmetics as alternatives to retinoic acid: Evidence of efficacy. Retinoids & LipidSoluble Vitamins in Clinical Practice. 2001;17:98-102.
Bhawan J, Gonzalez-Serva A, Nehal K, et al. Effects of tretinoin on photodamaged skin. A histologic study. Arch Dermatol.
1991;127(5):666-672.
Yamamoto O, Bhawan J, Solares G, et al. Ultrastructural effects
of topical tretinoin on dermo-epidermal junction and papillary
dermis in photodamaged skin. A controlled study. Exp Dermatol.

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In the vehicle group there was also some improvement frombaseline, though far less than in the retinol group. It is likelythat these effects were promoted by both the moisturizing
properties of the vehicle, also containing glycerin, and by thepassive lightening of skin during winter months.

10.

11.

This study demonstrates that the stabilized 0.1% retinol moisturizer was efficacious in the improvement of the appearance ofphotodamage, with very low irritation potentials.

12.

Acknowledgements
The authors would like to thank Alessandra Pagnoni, MD forassistance in the preparation of the manuscript.

Disclosures

13.
14.

Samantha Tucker-Samaras PhD, Tara Zedayko, Curtis Cole15.
PhD, Dara Miller and Warren Wallo are employees of Johnson& Johnson Consumer Companies, Inc., the manufacturerof retinol-containing products. James J. Leyden MD is a16.
consultant for Johnson & Johnson Consumer Companies, Inc.
The preparation of this manuscript was sponsored in full byJohnson & Johnson Consumer Companies, Inc.
© 2009-Journal of Drugs in Dermatology. All Rights Reserved.
This document contains proprietary information, images and marks of Journal of Drugs in Dermatology (JDD).
No reproduction or use of any portion of the contents of these materials may be made without the express written consent of JDD.
If you feel you have obtained this copy illegally, please contact JDD immediately.

936
Journal of Drugs in Dermatology
October 2009 • Volume 8 • Issue 10

S. Tucker-Samaras, T. Zedayko, C. Cole, et al.

1995;4(3):146-154.
Cho S, Lowe L, Hamilton TA, et al. Long-term treatment of photoaged human skin with topical retinoic acid improves epidermal cellatypia and thickens the collagen band in papillary dermis. J Am
Acad Dermatol. 2005;53(5):769-774.
18. El-Domyati MM, Attia SK, Saleh FY, et al. Effect of topical tretinoin
on photoaged facial skin: A histometric, immunohistochemical andultrastructural study. J Cosmet Dermatol. 2004;3(4):191-201.
19. Bertin C, Zunino H, Lanctin M, et al. Combined retinol-lactoseglycolic acid effects on photoaged skin: A double-blind placebocontrolled study. Int J Cosmet Sci. 2008;30(3):175-182.
20. Kafi R, Kwak HS, Schumacher WE, et al. Improvement of naturally
aged skin with vitamin A (retinol). Arch Dermatol. 2007;143(5):606612.

Address for Correspondence

17.

Samantha Tucker-Samaras, PhD
Johnson & Johnson Consumer & Personal Products Worldwide
199 Grandview Road
Skillman, NJ 08558
Phone: .................................................................. (908) 904-3083

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