Content uploaded by Akkarach Bumrungpert
Author content
All content in this area was uploaded by Akkarach Bumrungpert on Jul 26, 2021
Content may be subject to copyright.
Available via license: CC BY-NC
Content may be subject to copyright.
J Cosmet Dermatol. 2020;00:1–6. wileyonlinelibrary.com/journal/jocd
|
1© 2020 Wiley Periodicals, Inc.
Received: 4 Januar y 2020
|
Accepted: 9 January 2020
DOI: 10.1111/jocd.13305
ORIGINAL CONTRIBUTION
Anti-aging and brightening effects of a topical treatment
containing vitamin C, vitamin E, and raspberry leaf cell culture
extract: A split-face, randomized controlled trial
Pattarawan Rattanawiwatpong MD1 | Rungsima Wanitphakdeedecha MD, MA, MSc2 |
Akkarach Bumrungpert PhD1 | Mart Maiprasert MD1
1Master of S cience Program i n Anti-A ging
& Regener ative Me dicine, College of
Integrative Medicine, D hurak ij Pundit
University, Bang kok, Tha iland
2Depar tment of Dermatology, Faculty
of Medicine Sirir aj Hospital, Mahidol
University, Bang kok, Tha iland
Correspondence
Rungsim a Wanitph akdeed echa, D epar tment
of Dermatology, Faculty of Me dicine S iriraj
Hospit al, Mahidol Universit y, Bangkok
10700, Thailand.
Email: rungsima.wan@mahidol.ac.th
Funding information
This stu dy was funded by Ma x Biocare Pt y
Ltd, Australia .
Abstract
Background: Skin aging has many manifestations such as wrinkles, uneven skin tone,
and dryness. Both intrinsic and extrinsic factors, especially ultraviolet light-induced
oxidative radicals, contribute to the etiology of aging. Human skin requires both
water- and lipid-soluble nutrient components, including hydrophilic and lipophilic an-
tioxidants. Vitamins C and E have important protective effects in the aging process
and require exogenous supply. Raspberry leaf extracts contain botanical actives that
have the potential to hydrating and moisturizing skin. Topical products with these in-
gredients may therefore combine to provide improved anti-aging effects over single
ingredients.
Objectives: To evaluate the anti-aging and brightening effects of an encapsulated
serum containing vitamin C (20% w/w), vitamin E, and European raspberry (Rubus
idaeus) leaf cell culture extract.
Methods: Fifty female volunteers aged 30-65 years were allocated one capsule
of serum for topical application on one side of the face for 2 months, in addition
to self-use of facial skin products. Both test (treated) and contralateral (untreated)
sides were dermatologically assessed after 4 and 8 weeks. Skin color (melanin index),
elasticity, radiance, moisture, and water evaporation were measured by Mexameter
MX18®, Cutometer®, Glossymeter GL200®, Corneometer CM825®, and Tewameter
TM300® instruments, respectively (Courage + Khazaka Electronic GmbH). Skin mi-
crotopography parameters, smoothness (SEsm), roughness (SEr), scaliness (SEsc),
and wrinkles (SEw), were measured by Visioscan® VC98 USB (Courage + Khazaka
Electronic GmbH), and gross lifting effects were measured by VECTRA® H1 (Canfield
Scientific), and adverse reactions and satisfaction were also assessed.
Results: Skin color, elasticity, and radiance were significantly improved. The smooth-
ness, scaliness, and wrinkles were also revealed significant improvement. Mild ad-
verse reactions were tingling and tightness.
Conclusions: The vitamin C, vitamin E, and raspberry leaf cell culture extract serum
has anti-aging and brightening effects of skin.
KEY WORDS
antioxidant, raspberr y leaf cell culture ex trac t, skin aging, skin radiance, vitamin C, vitamin E
2
|
RATTANAWIWATPONG eT Al.
1 | INTRODUCTION
Facial skin aging is one of the most prevalent cosmetic concerns to
women. The many noticeable manifestations such as wrinkles, sag-
ging, uneven skin tone, and dull and dry skin can significantly impact
self-esteem and social relations.1 Both intrinsic and extrinsic fac-
tors are involved in skin aging; however, photoaging is an import-
ant cumulative factor.2 Nowadays, there are many modalities that
can improve the condition of aging skin and address the underly-
ing mechanisms of cellular and molecular damage. Treatment with
topical antioxidants represents a noninvasive approach that treats
the underlying mechanisms of cellular and molecular damage from
oxidative free radicals. Other agents include topical cell growth reg-
ulators and retinoids, which are used alongside the more invasive
procedures such as chemical peeling, ablative and nonablative laser
photo-rejuvenation, radiofrequency (RF) therapy, dermal fillers, and
botulinum toxin.3
Human skin has both water- and lipid-soluble compartments
with their respective bioactive antioxidants. Many of these, includ-
ing vitamins C and E, are not able to be produced endogenously
and so must be provided externally or through diet. L-ascorbic
acid is the most abundant antioxidant in the skin and is the bi-
ologically active form of vitamin C. The maximum concentration
of topical L-ascorbic acid for percutaneous absorption is 20%.4
Vitamin C has many anti-aging skin effec ts, not only as a potent
antioxidant and mediator of photo-damage and melanogenesis,
but also through its roles in supporting collagen biosynthesis and
stability, which provide renewal and anti-inflammatory effects.5-7
The lipid-soluble properties of vitamin E, which suppor ts skin lev-
els of tocopherols, allow it to pass down to the deepest layers of
the stratum corneum via sebaceous gland secretions, to reside
within cell membranes and protect them from oxidative stress.8
Furthermore, vitamin E can reduce hyperpigmentation induced by
ultraviolet light.9
Vitamins C and E work synergistically in quenching free radicals.
Vitamin C regenerates the oxidized form of vitamin E to its reduced
form. Topi cal use of 15% L-asco rbic acid combined with 1% alpha-to-
copherol has been shown to provide significantly more protection
against sunburn cell formation compared with either L-ascorbic acid
or 1% alpha-tocopherol alone.10
Raspberry (Rubus ideaus) leaf cell culture extract has many po-
tent antioxidants able to protect cells from oxidative stress. The ex-
tract also has important lipid component of epidermal hydrolipidic
film, which can protect skin from transepidermal water loss and in-
duce the expression of genes involved in molecular pathways that
support skin hydration and moisturization, such as hyaluronic acid
synthesis.11,12
To provide maximal anti-aging and brightening effects to facial
skin, topical products may combine more than one active ingredi-
ent in one formulation. The aim of this study was to evaluate the
synergistic anti-aging and brightening effects of topical vit amin C,
vitamin E, and raspberry leaf cell culture extract on aging facial skin
in women. There have been no previous published studies that have
assessed the synergistic effect of these three compounds in an Asian
population.
2 | MATERIALS AND METHODS
The study was conducted in a group of 50 Thai women with
Fitzpat rick sk in typ e III or IV, mea n age 47 year s, re cru ited throu gh
advertising and electronic media. Women showing the presence
of facial wrinkles, skin sagging, skin dryness, or uneven skin color
were included in the study. Subjec ts were excluded if they were
under a physician's care or were taking any medication that might
interfere with the test results; were using nonsteroidal anti-in-
flammatory drugs; had a histor y of hypersensitivit y to cosmetics;
showed signs of skin infection or inflammation; or suffered from
diseases that would increase the risk associated with participa-
tion or that would interfere with the results. Women who were
pregnant and lactating or intending to become pregnant during the
study period were also excluded. Fur ther exclusion criteria related
to skin treatments included the use of oral retinoids, dermal fill-
ers, RF therapy, micro-focused ultrasound therapy (in the previous
year); botulinum toxin injections (in the previous 8 months); had
laser resurfacing (in the previous 6 weeks); or chemical peels or
dermabrasion (in the previous 2 weeks). Subjects were asked to
abs tain from changi ng any f ac ial skin p roduct s for at least 2 we ek s
prior to the study and nu tr it io na l su pp le me nt s for at le as t 1 month
prior to the study.
The treatment serum (Rejuvenating Capsules, Antioxidant and
Collagen Booster Serum; supplied by Belmarama, a Division of Max
Bioc ar e Pty Ltd .; man uf act ur ed by Catal en t In c) conta in ed the ascor-
bic acid 20%, tocopher yl acetate 1%, and Rubus idaeus leaf cell cul-
ture 0.0005%. Subjects were advised to apply one capsule to the
random side of the face every night for 8 weeks. The contralateral
side of the face was left untreated (control side). Facial skin products
based on participants’ daily self-use were allowed on both sides, and
per their usual routine.
Skin parameters were measured at baseline and after 4 and
8 weeks of test product use by the dermatologist in a single-blinded
fashion. Subject s were required to rinse their face thoroughly with
a neutral lotion and acclimatized to the ambient environment for at
least 15 minutes before measurements.
In vivo skin parameters were evaluated as following methods:
• Cutometer® dual MPA 580 (Courage + Khazaka Electronic
GmbH) to determine skin color using melanin index parameter
(Mexameter MX18®), elasticity using R2 parameter (Cutometer®),
rad iance usin g gloss DSC va lue param eter (Glossy meter GL200®),
moisture (Corneometer CM825®), and transepidermal water loss,
TEWL, (Tewameter TM300®) on both upper cheeks in well-de-
fined measurement locations.
• Visioscan® VC98 USB (Courage + Khazaka Electronic GmbH)
to determine skin microtopography using the SELS (Surface
Evaluation of the Living Skin) parameters—smoothness (SEsm),
|
3
RATTANAWIWATPONG e T Al.
roughness (SEr), scaliness (SEsc), and wrinkles (SEw) on both outer
corner of the eyes in well-defined measurement locations.
• VECTR A® H1 (C anf iel d Sci ent ifi c) to det erm ine gros s/ vis ual lif ting
effect by measuring the distance between the upper and lower
part of the face (from the hairline to the lower limit of the face
corresponding to the mandible) in two points on both sides: me-
dial and lateral canthus.
In addition, after 4 and 8 weeks of product use, the volunteers
were assessed the adverse reactions by the physician and were
asked to do satisfaction questionnaire regarding the anti-aging ef-
fects and the serum itself.
Statistical analysis was performed using GraphPad Prism
v8.3.0 and SPSS v26. The Shapiro-Wilk test was used to deter-
mine the normality of the data distribution. The repeated mea-
sures ANOVA with Bonferroni correction and Friedman's multiple
comparisons test was used to assess changes of normally distrib-
uted variables and non-normally distributed groups, respectively.
Sample comparisons for TEWL were performed using the Kruskal-
Wallis rank sum test, as the data were unable to be adjusted for
multiple comparisons. Differences between treatment and non-
treatment groups were considered biologically significant for P-
values of .05 or less.
This study was approved by the Ethical Review Committee for
Human Research, College of Integrative Medicine, Dhurakij Pundit
University (003/62EX), and research protocols were conducted in
agreement with the Declaration of Helsinki on human subjects. All
subjects were informed and gave their consent before enrollment
(clinical trial registration: TCTR20190418004, www.clini caltr ials.in.th).
3 | RESULTS
Skin was found to be significantly lighter in color and higher in elas-
ticity on the treated side, compared to the untreated side, after
8 weeks of product use (Figure 1A,B), whereas skin radiance im-
proved significantly after both 4 and 8 weeks of use (Figure 1C).
No significant changes in skin moisture level (P > .9999) or TEWL
(P > .9999) between treatment or control sides were observed
(Table 1).
Skin topography assessment s revealed statistically significant
improvements in skin smoothness, scaliness, and wrinkles after both
4 and 8 weeks of use (Figure 2A-C). However, skin roughness was
higher on the treated side compared to the untreated side on the 8th
week (Figure 2D). There was no significant improvement on gross
lifting effect (P > .9999, Table 1).
The serum was well tolerated after application. No adverse reac-
tion in the form of redness, swelling, dryness, desquamation, itching,
or burning was observed. Eight percent of subjects reported mild
tightness (n = 4) in the 4th week, which decreased to four percent
(n = 2) in the 8th week. Thirty-eight (76%) subjects had mild and
transient tingling (mostly <1 minute) in the 4th week and reduced to
twenty-five (50%) in the 8th week.
4 | DISCUSSION
Skin aging, one of the most concerned problem in women, can
be noticed as wrinkles, sagging, uneven skin tone, and dull or dry
skin.1 The causes of skin aging can be categorized into intrinsic/
chronological and extrinsic factors. Extrinsic factors especially
ultraviolet are superimposed on intrinsic factors and account for
most age-associated changes in skin appearance. Ultraviolet irra-
diation causes the aging skin by producing free radicals and re-
active oxygen species (ROS), which interferes collagen synthesis,
degrades collagen and elastin, and damages lipid component of
membranes leading to ceramide and arachidonic acid release caus-
ing more water loss and more inflammation, respectively.13 There
was previous study showed that topical antioxidants reduce oxida-
tive damages, the cause of aging skin.8-10,12,14,1 5 To provide maxi-
mum anti-aging ef fect to the skin, topical products may combine
various ingredients. The present evaluation revealed improve-
ments in skin aging, pigment appearance, and skin integrity that
were in agreement with the synergistic, anti-aging effects of topi-
cal vitamin C, vitamin E, and raspberry leaf cell culture extract on
Asian skin types.
The product was found to have a measurable reduction in mela-
nin index. Vitamin C is known to decrease melanin production5 and
topical vitamin E is effective in reducing UV-induced hyperpigmen-
tation,9 with the combination of both being more pronounced.10 An
in vivo study by Espinal-Perez et al16 found that topical L-ascorbic
acid (5%) decreased the melanin index after 3 months of treatment,
whereas a study by Xu et al17 involving Chinese women found that
topical L–ascorbic acid (23.8%) combined with a chemical penetration
enhancer with iontophor esi s improve d skin lightness from the se con d
week. This study confirmed the whitening effect of the serum. There
was improvement in the melanin index at the 8th week after serum
use which was earlier than the effect seen by Espinal-Perez et al, but
later than that of Xu et al Because of dif ferent parameters used, we
can not dire ct ly compare the results. But , the reason might be that the
form er use d lowe r concent ration of as corbi c ac id while the latt er used
iontophoresis for enhancing penetration of vitamin C into the skin.
The present study found increased R2 ratio, representing increased
skin ela stici ty, which is in acc ordan ce wit h ot her stu di es.1 2,14,18,19 Three
active ingredients of the serum are antioxidants, so to some degree,
this serum can protect collagen and elastin degradation from gener-
ated reac tive oxygen species, and therefore, the increased elasticity
may represent a preservation effect. Furthermore, vit amin C is also
necessary for collagen biosynthesis and stability,4,6 and raspberry
(Rubus ideaus) leaf cell culture extract can induce the expression of
genes involved in collagen and elastin.12 All of these effects together
improve skin elasticity. Both the lightening effect and the elasticity ef-
fect of the serum may have also combined to improve the surface in-
tegrity of skin and its ability to reflect white light, which would explain
the increase in the gloss DSC value.
We obser ved no significant improvement of skin moisture or
TEWL. This is consistent with the in vivo study by Xu et al and
Campos et al17, 20 This might have been due to the acidity of
4
|
RATTANAWIWATPONG eT Al.
ascorbic acid, which may have caused some shedding of epidermal
cells and loss of skin surface moisture. Tito et al12 found that an
oil-soluble extract of Rubus idaeus leaves enhanced skin moisture
measured by Corneometer CM850® but the concentration of the
extract was much higher than that in our study. Moreover, Tito et
al12 studied in women with dry to very dry skin who applied the
extract twice a day, whereas the subjects in our study had suf-
ficiently moisturized skin (due to additional self-use of standard
topical products), live in a tropical climate with high humidity, and
applied the serum once a day.
Skin topography parameters of skin smoothness, scaliness, and
wrinkles in our study showed significant improvement s. These are in
agreement with the skin elasticity and DSC gloss values. However,
skin roughness gave the opposite result, which was unexpected. A
possible explanation for this might be that the SEr parameter is cal-
culated from the number of pixels which have a smaller gray level
than the threshold of SEr, average number of wrinkles, and width
and height of the histogram of gray level distribution. SEr is inversely
propor tional to number of wrinkles but direc tly propor tional to the
number of pixels which have a smaller gray level than the threshold.
FIGURE 1 Mean melanin index (A),
R2 ratio (B), and gloss DSC value (C)
at baseline, 4, and 8 wk. P-value < .05,
determined as significant value
150
170
190
210
230
250
270
290
Baseline 4 weeks8 weeks
Melanin index (AU)
Treated side Untreated side
0.5
0.6
0.7
0.8
Baseline 4 weeks8 weeks
R2 ratio
Treated side Untreated side
2
3
4
5
6
7
Baseline 4 weeks8 weeks
Gloss DSC value (AU)
Treated side Untreated side
**
* P = 0.02
(A)
***
*** P < 0.0001
***
*** P < 0.0001
(B)
(C)
TABLE 1 The results of skin parameters
Parameters
Treated side Untreated side
P1P2Baseline 4 wk 8 wk Baseline 4 wk 8 wk
R2 ratio 0.63 ± 0.06 0.68 ± 0.07 0.72 ± 0.06 0.65 ± 0.10 0.64 ± 0.10 0.64 ± 0.10 .07 <.0001
Melanin index 226.7 ± 42.4 213.7 ± 39.4 209.3 ± 41.2 223.1 ± 42.6 222.3 ± 44.9 225.4 ± 46.6 .557 <.0001
Gloss DSC value 4.09 ± 1.52 4.90 ± 1.65 5.08 ± 1.61 4.41 ± 1.58 4. 31 ± 1.49 4.41 ± 1.71 .0221 .0201
Moisture level 73.04 ± 9.35 74.33 ± 8.46 73.77 ± 9.75 72.09 ± 9.29 73.77 ± 8.13 73.62 ± 10.06 >.9999 >.9999
TEWL (g /h/m2) 11.48 ± 2.38 12.45 ± 2.05 11.79 ± 2.15 11.10 ± 2.04 12.87 ± 2.09 11.66 ± 2.45 >.9999 >.9999
SELS parameters
SEsm 178.7 ± 28.2 160.9 ± 24.2 154.4 ± 23.8 171.3 ± 30.4 173.0 ± 34.5 171.8 ± 31.3 .0233 <.0001
SEr 2.98 ± 1.02 2.51 ± 0.80 2.27 ± 0.78 2.69 ± 0.90 2 .74 ± 0.93 2.82 ± 0.92 .206 <.0001
SEsc 0.67 ± 0.11 0.58 ± 0.12 0.55 ± 0.11 0.67 ± 0.13 0.66 ± 0.12 0.68 ± 0.13 .0317 <.0001
SEw 67.96 ± 15.64 58.46 ± 13.41 57.21 ± 12.79 64.82 ± 14.66 65.59 ± 14.93 66.39 ± 14.77 .001 <.0001
Gross lif ting effect
Medial canthus 164.5 ± 7.4 164.7 ± 7.1 164.7 ± 6.6 164.7 ± 7.3 164.8 ± 7.2 16 4.6 ± 6.7 >.9999 >.9999
Lateral canthus 153.9 ± 7.3 154.1 ± 7.4 153. 3 ± 6.5 153. 6 ± 7.3 153.7 ± 7.2 153.4 ± 6.2 >.9999 >.9999
Abbreviations: P1, P-value at 4 wk (comparison to control); P2, P-value at 8 wk (comparison to control); P value < .05 considered significant; R2 ratio,
skin elas ticit y; SEr, skin roughness; SEsc , skin sc aliness; SEsm, skin smoothness; Sew, wrinkles; TE WL, transepidermal water loss (g/h/m2).
|
5
RATTANAWIWATPONG e T Al.
So, it might be that the elasticity improvement had more effect than
the number of wrinkles, such as a tightening effect. However, the
elasticity improvement of skin was not sufficient to see a gross con-
tour lifting effect.
In relation to tolerability, the present study showed that the ad-
verse effects of the serum were relatively mild and more tolerable
after 1 month. Regarding this limitation, this study may be yet be
inferred to middle-aged Thai or Asian women with Fitzpatrick skin
type III or IV.
5 | CONCLUSIONS
This present study demonstrated that an encapsulated serum con-
taining vitamin C, vitamin E, and raspberr y leaf cell culture extract
can improve most signs of aging skin, namely skin darkening, elas-
ticity, radiance, smoothness, scaliness, and wrinkles. However, the
elasticity improvement was not sufficient to cause gross lifting ef-
fects. Furthermore, the serum was well tolerated.
ACKNOWLEDGMENT
We would like to express appreciation to all volunteers, who
kindly gave excellent cooperation. Special thanks to Ms Phassara
Klamsawat, Ms Phonsuk Yamlexnoi, and Mr Panyawat Wongjaruwat
for their assistance in recruiting subjects and managing the
database.
CONFLICT OF INTERESTS
No conflict of interests has been declared.
ORCID
Rungsima Wanitphakdeedecha https://orcid.
org/0000-0002-3926-2193
REFERENCES
1. Gupta M, G ilchrest B. Psychosocial aspects of aging skin. Clin
Dermatol. 2005;23(4):6 43-648.
2. Debacq-Chainiaux F, Leduc C , Verbeke A, Toussaint O. UV, stress
and aging. Dermatoendocrinol. 2012;4(3):236-240.
3. Ganceviciene R, Liakou A , Theodoridis A, Makrantonaki E,
Zouboulis C. Skin anti-aging strategies. Dermatoendocrinol.
2012;4(3):308-319.
4. Pinnell S, Yang H, Omar M, et al. Topical L-ascorbic acid: percut ane-
ous absorption studies . Dermatol Surg. 2001;27(2):137-142.
5. Al-Niaimi F, Chiang NYZ. Topical vitamin C and the skin: mecha-
nisms of action and clinical applications. J Clin Aesthet Dermatol.
2017;10 (7 ):14-17.
6. Matsuda S, Shibayama H, Hisama M, Ohtsuki M, Iwaki M. Inhibitory
effects of a novel ascorbic derivative, disodium isostearyl 2-O-L-
ascorbyl phosphate on melanogenesis. Chem Pharm Bull (Tokyo).
2008;56(3):292-297.
7. Telang PS. Vitamin C in dermatology. Indian Dermatol Online J.
2013 ;4 (2) :143-146 .
8. Chen L, Hu J, Wang S. The role of antioxidants in photoprotection:
a critical review. J Am Acad Dermatol. 2012;67(5):1013-1024.
9. Burke K, Clive J, Combs G, Commisso J, Keen C, Nakamura R.
Effects of topical and oral vitamin E on pigmentation and skin can-
cer induced by ultraviolet irradiation in Skh:2 hairless mice. Nutr
Cancer. 2000;3 8(1):87-97.
10. Lin J, Selim M, Shea C , et al. UV photoprotec tion by combination
topical antioxidants vitamin C and vitamin E. J Am Acad Dermatol.
2003;48(6):866-874.
11. Barbulova A, A pone F, Colucci G. Plant cell cultures as source of
cosmetic active ingredients. Cosmetics. 2014;1(2):94-104.
FIGURE 2 Mean SEsm (A), SEsc (B),
SEw (C), and SEr (D) values at baseline,
4, and 8 wk. SEsm and SEr values are
inversely propor tional to skin smoothness
and skin roughness, respectively. P-
value < .05, determined as significant
value
100
120
140
160
180
200
220
Baseline 4 weeks8 weeks
SEsm
Treated side Untreated side
(A)
***
0.3
0.4
0.5
0.6
0.7
0.8
0.9
Baseline 4 weeks8 weeks
SEsc
Treated side Untreated side
(B)
***
30
40
50
60
70
80
90
Baseline 4 weeks8 weeks
SEw
Treated side Untreated side
(C)
***
1
2
3
4
Baseline 4 weeks8 weeks
SEr
Treated side Untreated side
***
(D)
** P = 0.02
*** P < 0.0001
**
** P = 0.03
*** P < 0.0001
**
** P = 0.001
*** P < 0.0001
*** P < 0.0001
**
6
|
RATTANAWIWATPONG eT Al.
12. Tito A, Bimonte M , Carola A, et al. An oil-soluble extract of Rubus
idaeus cells enh ances hydr ation and wate r homeo st asis in skin cells.
Int J Cosmet Sci. 2015;37(6):58 8-594.
13. Yaar M, Gilchrest B. Photoageing: mechanism, prevention and ther-
apy. Br J Dermatol. 20 07;157(5):874-887.
14. Traikovich S. Use of topical ascorbic acid and its effect s on pho-
todamaged skin topography. Arch Otolaryngol Head Neck Surg.
1999;125(10):1091-1098.
15. Lopez-Torres M, Thiele JJ, Shindo Y, Han D, Packer L. Topical ap-
plication of α-tocopherol modulates the antioxidant network and
diminishes ultraviolet-induced oxidative damage in murine skin. Br J
Dermatol. 1998;138(2):207-215.
16. Espinal-Perez L, Moncada B, Castanedo- Cazares J. A double-blind
randomized trial of 5% ascorbic acid vs. 4% hydroquinone in me-
lasma. Int J Dermatol. 200 4;43(8):604-607.
17. Xu T, Chen JZ, Li YH , et al. Split-face study of topical 23.8%
L-ascorbic acid serum in treating photo-aged skin. J Drugs Dermatol.
2012;11(1):51-56.
18. Humbert P, Haf tek M, Creidi P, et al. Topic al ascorbic acid on pho-
toaged skin. Clinical, topographical and ultrastructural evaluation:
double-blind study vs. placebo. Exp Dermatol. 2003;12(3):237-244.
19. Jurkiewicz B, Bissett D, Buettner G. Effect of topically applied to-
copherol on ultraviolet radiation-mediated free radical damage in
skin. J Invest Dermatol. 1995;104(4):484-488.
20. Maia C ampos P, Gonalves G, Gaspar L. In vitro antioxidant activity
and in vivo efficacy of topical formulations containing vitamin C and
its derivatives studied by non-invasive methods. Skin Res Technol.
2008;14(3):376-380.
How to cite this article: Rattanawiwatpong P,
Wanitphakdeedecha R, Bumrungpert A, Maiprasert M.
Anti-aging and brightening effects of a topical treatment
containing vitamin C, vitamin E, and raspberry leaf cell
culture ex trac t: A split-face, randomized controlled trial.
J Cosmet Dermatol. 2020;00:1–6. https ://doi.org/10.1111 /
jocd.13305