Skin Research and Technology 2014; 20: 208–212
Printed in Singapore
All rights reserved
doi: 10.1111/srt.12107
Reduction in facial hyperpigmentation after treatment
with a combination of topical niacinamide and
tranexamic acid: a randomized, double-blind,
vehicle-controlled trial
Do Hyun Lee1, In Young Oh2, Kyo Tan Koo1, Jang Mi Suk3, Sang Wook Jung3,
Jin Oh Park4, Beom Joon Kim2 and Yoo Mi Choi5
1
Nutrex technology R&D center, Seoul, South Korea,
2
Department of Dermatology, Chung-Ang University College of Medicine, Seoul, South Korea,
3
P&K Skin Research Center, Seoul, South Korea,
4
Daebong LS, Incheon, South Korea and 5Pacificpharma, Seoul, South Korea
Background: Facial hyperpigmentation occurs in multiple con-
ditions. In addition, many Asian women desire a lighter skin
color. Thus, there is a need for the development of skin light-
ening agents, and niacinamide and tranexamic acid (TXA) are
promising candidates.
Objective: To assess the effectiveness of a combination of
niacinamide and TXA as a topical moisturizing formulation for
treatment of irregular facial pigmentation.
Materials and Methods: A total of 42 Korean women (age
range: 30–60 years) who were not pregnant, nursing, or
undergoing any concurrent therapy were enrolled in this study
for 8 weeks. Subjects used a twice-daily regimen of either a
moisturizing cream containing 2% niacinamide + 2% TXA (test
formulation; n = 21) or cream vehicles (vehicle control;
n = 21) in addition to an assigned sunscreen each morning.
Pigmentation was measured objectively using a mexameter
hyperpigmentation is a sub-
I RREGULAR FACIAL
stantial contributor to the aged appearance of
skin (1). As a result, technology that can effec-
tively address pigment appearance is of interest,
especially given proposed regulatory changes
limiting the use of hydroquinone (2). Niacin-
amide is a member of the vitamin B3 family and
can be used as an ingredient in cosmetic mois-
turizers. It is a precursor to a group of enzyme
cofactors: nicotinamide adenine dinucleotide
(NAD), nicotinamide adenine dinucleotide
phosphate (NADP), and their reduced forms
(NADH and NADPH). These cofactors are
involved in many reactions in the body, includ-
ing several in the skin which appear to contrib-
ute to a reduction in the appearance of
208
© 2013 John Wiley & Sons A/S.
Published by John Wiley & Sons Ltd
Skin Research and Technology
and chromameter, in addition to physicians’ assessment using
clinical photographs.
Results: The niacinamide + TXA formulation regimen was sig-
nificantly (P < 0.05) more effective than the vehicle control for-
mulation regimen in reducing the appearance of pigmentation.
Conclusion: A formulation containing the combination of nia-
cinamide + TXA reduced the appearance of irregular pigmenta-
tion, providing an effect beyond that achieved with sunscreen.
Key words: facial hyperpigmentation – niacinamide – tranexa-
mic acid
Ó 2013 John Wiley & Sons A/S. Published by John
Wiley & Sons Ltd
Accepted for publication 18 July 2013
hyperpigmentation (3). The results of in vitro cell
coculture suggest that a relevant mechanism of
this effect is the inhibition of melanosome trans-
fer from melanocytes to keratinocytes by niacin-
amide (4,5).
Tranexamic acid (TXA) is a lysine analog
known to have antiplasmin activity that has
been shown to prevent UV-induced pigmenta-
tion. TXA decreases melanocyte tyrosinase
activity by preventing the binding of plasmino-
gen to keratinocytes, which results in the
reduction in prostaglandins and arachidonic
acid, which are inflammatory mediators
involved in melanogenesis (6). Localized intra-
dermal injection of TXA reportedly improves
melasma (7).
 Niacinamide and tranexamic acid for pigmentation reduction
Because niacinamide and TXA have different
mechanisms of action, it was proposed that their
combination could be more effective than each
individual treatment in reducing hyperpigmen-
tation. We conducted this clinical trial to evalu-
ate and compare the effects of a topical facial
regimen containing niacinamide in combination
with TXA on the appearance of facial hyperpig-
mentation and uneven skin tone in female sub-
jects with that of a vehicle control regimen.
Materials and Methods
Subjects
Forty-two female Korean volunteers aged 30–
60 years with moderate to moderately severe
irregular hyperpigmentation were enrolled.
Subjects were randomly assigned to receive the
niacinamide plus TXA (n = 21) or vehicle con-
trol (n = 21) regimen; study groups were bal-
anced with respect to hyperpigmentation and
age (30–45 and 46–60 years) at baseline. The
study was approved by the relevant institu-
tional review boards. All subjects signed
informed consent forms, and the study protocol
conformed to the principles set forth by the
Declaration of Helsinki and Korean Good Clini-
cal Practice guidelines.
Study design
This was an 8 week, prospective, randomized,
double-blind, vehicle-controlled clinical study.
During the study, subjects were permitted to
apply their usual brand of foundation, blushers,
and eye and lip makeup provided these prod-
ucts did not contain any ingredients known to
affect skin pigmentation.
Subjects in the experimental group received a
topical cream formulation containing 2% niacin-
amide plus 2% TXA (Regederm RX White Pro-
jectâ; Aestura, Seoul, Korea) and sun protection
factor (SPF) 15 sunscreen agents. Subjects in the
control group received a cream vehicle with the
same sunscreen agents. The vehicle control and
niacinamide plus TXA formulations were pack-
aged in identical 50-g blind-coded pump jars
labeled with the subject number.
In the morning and evening, each subject
applied approximately 1.0 g of her assigned test
formulation to her entire face (total daily prod-
uct usage ~2 g). Subjects received the containers
of test formulation at the beginning of the study
and returned the used containers at week 8.
Subjects recorded each application of the test
formulation in a diary. Compliance with the
product use regimen was assessed on the basis
of diary records and the weight of returned
containers.
Efficacy and safety assessments
Subjects were assessed at baseline, week 4, and
week 8 of the study. The severity of facial
hyperpigmentation was determined at each visit
using a mexameter (Courage-Khazaka Elec-
tronic, K€
oln, Germany) and by two blinded
expert graders using high-quality clinical photo-
graphs. The graders viewed and compared
blind-coded images taken at baseline, week 4,
and week 8. Each image was graded according
to a pigment intensity score (1–10 scale). In
addition, skin lightness was assessed with a
chromameter (Konica Minolta, Inc., Tokyo,
Japan) using L-value.
At each visit, subjects were queried about
adverse events, such as pain, itching, and red-
ness.
Statistical analysis
All data were statistically analyzed using the
paired t-test with SPSS version 19.0 (SPSS, Inc.,
Chicago, IL, USA). In all cases, differences
were considered statistically significant when
P < 0.05.
Results
All 42 subjects completed the study. No subjects
discontinued their participation due to lack of
effectiveness or adverse events. On average, the
subjects used 85–98% of the amount of test for-
mulation expected.
The mean melanin index (MI) scores are
shown in Fig. 1. In the experimental group, MI
scores were decreased significantly from base-
line at both 4 and 8 weeks, from 131.16
to 126.97 (P < 0.001) and 119.62 (P < 0.001),
respectively. MI scores in the control group
revealed slight but insignificant decreases from
132.03 at baseline to 130.24 at 4 weeks
(P = 0.454) and 129.70 at 8 weeks (P = 0.380).
The mean scores of two blinded expert grad-
ers at 4 weeks and 8 weeks after treatment
showed significantly greater improvement in
209
Lee et al.

140 ascorbic acid, azelaic acid, kojic acid, licorice,

Control group niacinamide, resveratrol, various peptides, and
Experimental group
soy have skin lightening properties. However,
135
while proof-of-principle approaches have been
conducted at the in vitro level for most of these
Melanin index

130
125
120
115
Baseline 4 w eek
Fig. 1. Change in melanin index (MI) after treatment. The MI of
the experimental group decreased significantly, whereas the MI of
the control group had a slight, but insignificant decrease.
the experimental group compared with the con-
trol group (Table 1). Clinical photographs of
facial hyperpigmentation in the experimental
group before and after treatment are presented
in Fig. 2.
Skin lightening effects, as measured by
chromameter, were significantly higher in the
experimental group compared with the control
group (2.02% vs. 0.25% at week 8; P = 0.018).
Both product regimens were well tolerated by
study subjects. None of the participants
reported any serious adverse events.
Discussion
There is a high demand for safe and effective
skin lightening agents to target various skin
conditions. The previously accepted ‘gold stan-
dard’ of skin lightening, hydroquinone, has a
number of reported side effects (8,9). Due to
these potential health risks, hydroquinone was
banned in 2001 from cosmetic usage, and safer
alternatives have been proposed (10). Among
them, it is generally acknowledged that arbutin,
TABLE 1. Mean pigment intensity score (1–10 scale), according to two
blinded expert graders
Control group Experimental group
(mean  SD) (mean  SD)
Baseline 5.35  0.48 5.29  0.64
4 weeks 5.16  0.62 4.76  0.54
8 weeks 5.25  0.60 4.48  0.60
*P < 0.05.
agents, there is still no vehicle-controlled clini-
cal data. Recently, variable combinations of top-
ical agents have been researched and developed
to treat hyperpigmentation disorders (11, 12).
In this study, a formulation containing the
combination of niacinamide and TXA was eval-
uated. The combined formulation performed
significantly better than the vehicle control, as
evaluated by all measures. This advantage may
8 w eek arise from the inhibition of two different mecha-
nisms of pigmentation. Topical niacinamide
does not inhibit melanin production, but instead
blocks the transfer of melanosomes to the sur-
rounding cells (4). On the other hand, topical
TXA inhibits UV-induced hyperpigmentation by
reducing UV-induced plasmin activity and sub-
sequent free arachidonic acid release (6).
The safety of a formulation containing the
combination of niacinamide and TXA was also
confirmed in this study. None of the partici-
pants reported any adverse effects after 8 weeks
of use; thus, as a cosmetic, it showed great
safety in vivo. This formulation may be an excel-
lent candidate for pigmentation control without
the negative side effects commonly associated
with many other skin lightening agents.
Niacinamide is stable in heat and light, and
remains efficacious in formulated products. In
addition, it is better tolerated than its counter-
part niacin and does not produce the well-
known ‘niacin flush’ (13). TXA is also very stable
to light, temperature, pH, and oxygen, and no
special protections are needed to maintain its
effectiveness unlike many other agents. Thus, it
seems an ideal choice for use in skin lightening
creams. The newer topical preparation of tra-
nexamic acid cetyl ester hydrochloride is already
available in cosmetic formulations (14).
This study was designed to evaluate the clini-
cal efficacy and safety of a formulation contain-
ing a combination of niacinamide and TXA for
facial hyperpigmentation. According to our lit-
erature search using PubMed, this is the first
P-value publication addressing the effects of this combi-
0.922 nation on pigmentation and skin lightness. A
0.042* similar study using a formulation containing
0.015* the combination of niacinamide and N-acetyl
glucosamine was previously reported (12).

210
 Niacinamide and tranexamic acid for pigmentation reduction

(a)

(b)

Fig. 2. Clinical photographs of facial hyperpigmentation in the experimental group before and after 8 weeks of treatment. Improvement of pigmen-
tation after treatment (a, b) is noticeable.

Because this study was not designed as a
split face study due to ethical issues, it is
impossible to assess intra-individual variation.
In addition, the epidermal and dermal concen-
tration of melanin was not examined before or
after the treatment. In spite of these limitations,
the results of this study suggest that this
formulation, containing a combination of 2%
niacinamide plus 2% TXA, reduced the appear-
ance of irregular hyperpigmentation, providing
an effect beyond that achieved with sunscreen
alone. This study demonstrates the importance
of careful selection of ingredients when
formulating cosmetic products to improve the
appearance of facial hyperpigmentation.
Acknowledgements
This research was financially supported by the
Ministry of Knowledge Economy (MKE), Korea
Institute for Advancement of Technology (KIAT),
through the Inter-ER Cooperation Projects.
Conflict of Interest
None declared.

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Address:
Beom Joon Kim
Department of Dermatology, Chung-Ang
University Hospital
224-1 Heukseok-dong, Dongjak-gu, Seoul
156-755
South Korea
Tel: +82 2 6299 1525
Fax: +82 2 823 1049
e-mail: beomjoon@unitel.co.kr