Original Contribution

Sodium L-ascorbyl-2-phosphate 5% lotion for the treatment

of acne vulgaris: a randomized, double-blind, controlled trial
Heather Woolery-Lloyd, MD,1 Leslie Baumann, MD,2 & Hiroshi Ikeno, MD3
1
Voluntary Assistant Professor, University of Miami Department of Dermatology and Cutaneous Surgery, Miami, FL, USA
2
Director, Baumann Cosmetic and Research Institute, Miami Beach, FL, USA
3
Director, Ikeno Clinic of Dermatology and Dermatologic Surgery, Tokyo, Japan

Summary Background Antioxidants are becoming increasingly important in the treatment of skin
disease. In addition to their known anti-inflammatory effects, antioxidants may act to
prevent the oxidation of sebum which has been proposed to be comedogenic in acne
patients. Sodium L-ascorbyl-2-phosphate (APS) is a stable vitamin C derivative and
highly effective antioxidant that has demonstrated efficacy in acne in open label studies.
Objective To evaluate the efficacy and safety of APS 5% lotion for the treatment of acne
in a blinded controlled study.
Methods A total of 50 subjects were randomized in a double-blind controlled trial to
receive APS 5% lotion or vehicle for 12 weeks. Evaluation included an Investigator’s
Global Assessment Score, a Subjects’ Global Assessment Score, lesion counts, cutaneous
tolerability, and adverse events.
Results APS 5% lotion demonstrated statistically significant improvement when com-
pared to vehicle in all of the parameters measured. The adverse event frequency and
cutaneous tolerability profile for APS 5% lotion were similar to vehicle.
Limitations Adjunctive topical or oral agents and their impact on acne were not studied
in this trial.
Conclusions This study demonstrates that 5% sodium L-ascorbyl-2-phosphate is effica-
cious as monotherapy for the treatment of acne. APS 5% lotion offers a novel addition to
our current acne armamentarium.
Keywords: acne, acne vulgaris, vitamin C, ascorbic acid, sodium L-ascorbyl-2-
phosphate, antioxidant

pathogenesis include follicular hyperkeratinization,

Introduction
Acne is a common dermatologic disorder affecting up to
85% of individuals in their lifetime. The etiology of acne
is multifactorial. The main factors implicated in acne
Correspondence: Heather Woolery-Lloyd, MD, Voluntary Assistant Professor,
University of Miami Department of Dermatology and Cutaneous Surgery,
Cosmetic Medicine and Research Institute, 4701 North Meridian Avenue,
Nichol Building Suite 7450, Miami Beach, FL 33140, USA. E-mail:
woolerylloyd@yahoo.com
Accepted for publication September 27, 2009
excessive sebum production, presence and activity of
Proprionibacterium acnes, and inflammation. Most acne
treatments in the past have targeted these proposed
mechanisms. Few treatments have focused on the other
factors implicated in acne.
Antioxidants are becoming increasingly important in
understanding and treating skin disease. There are two
mechanisms by which antioxidants may be useful in
acne. Firstly, thin layer chromatography of skin surface
lipids revealed that patients with acne have a higher
concentration of polar lipids on their skin surface than

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 Sodium L-ascorbyl-2-phosphate 5% lotion for acne
control subjects without acne. Further analysis revealed
that these polar lipids were by-products of squalene
oxidation, also known as squalene oxides. Squalene is
the most abundant lipid in the skin and is a highly
effective oxygen-scavenging agent. It is a lipid of
sebaceous origin that is highly susceptible to oxidation
due to the presence of six carbon double bonds which
can bind atmospheric oxygen. Squalene can bind up to
25% of its molecular weight in oxygen. Porphyrins
produced by Proprionibacterium acnes potentiate the
squalene oxidation process. In the rabbit ear model of
comedogenicity, squalene oxides proved to be highly
comedogenic. Thus, antioxidants could be useful in acne
to combat the oxidation of sebum and comedogenesis.1,2
Another mechanism by which antioxidants may be
useful in acne is to decrease inflammation. Once the
neutrophils arrive at the site, they cause inflammation
by producing lysosomal enzymes and reactive oxygen
species. Tetracycline, doxycycline, and erythromycin
inhibit the release of reactive oxygen species from
neutrophils and are well established in the treatment
of acne.3,4 Other antioxidants may be similarly useful in
acne by reducing the production of reactive oxygen
species by neutrophils and, thus, inflammatory lesions.
Vitamin C, also known as ascorbic acid, is a potent
antioxidant that has been utilized extensively in cos-
metic dermatology. Sodium L-ascorbyl-2-phosphate
(APS) is a stable vitamin C derivative generated by the
introduction of a phosphate group into the second
position of the cyclic ring.5 APS is absorbed in the skin
and enzymatically converted into ascorbic acid. It is also
continuously taken up into the cells and increases the
intracellular concentration of ascorbic acid.6 The effi-
cacy of topical APS in the treatment of acne has been
demonstrated in open label studies as both monotherapy
and in combination with other therapies.7–11 In this
study, we examined 5% APS in a double-blinded
placebo-controlled trial as a novel treatment for acne
based on its potent antioxidant activity.
Materials and methods
Subjects
This study was a 3-month randomized, double-blinded,
vehicle-controlled study. Fifty adult subjects with acne
ages 18–39 were enrolled in this study. Acne was graded
on a six-point scale. Subjects were rated as clear (0),
almost clear (1), mild (2), moderate (3), severe (4), and
very severe (5). Subjects with mild to severe acne were
eligible to enroll in the study. Female subjects who
were pregnant, nursing, or planning to get pregnant
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• H Woolery-Lloyd et al.
were excluded from the study. Subjects who were on
systemic antibiotics or any other treatment, which in the
opinion of the investigator could influence the results
of the study, were excluded from the study. Enrolled
subjects who were on acne therapy prior to enrollment
were required to complete a 2-week washout period prior
to beginning treatment. The appropriate institutional
review boards approved the study protocol. Written
informed consent was obtained from all subjects.
Treatments
Once enrolled, and after the specified washout period,
study subjects were randomized to receive APS lotion or
vehicle lotion. Randomization was by individual in a 1:1
ratio in blocks of six. The randomization code was
inaccessible to the investigator throughout the study.
The APS lotion and vehicle lotion were prepared by
Showa Denko Inc. (Tokyo, Japan). Both study medica-
tions had identical texture and color, and were provided
in identical containers. Study subjects were instructed to
apply a quarter-sized amount of the provided lotion
evenly onto the affected area twice daily for the entire
trial period. Subjects were provided with a gentle
cleanser to cleanse with twice daily. Subjects were
instructed to avoid excessive sun exposure during the
course of the trial. Additionally, they were instructed to
apply the provided moisturizer with sunscreen as needed
for dryness and ⁄ or sun protection.
Assessments
Subjects were evaluated at week 4, week 8, and week
12. At each visit, photographs were taken, a Subject
Global Assessment Score was obtained, and an Investi-
gator Global Assessment Score was obtained. In addi-
tion, at each visit, the investigator performed an
inflammatory and noninflammatory acne lesion count.
Primary efficacy endpoints were defined as follows:
• At least a one-step reduction in the Investigator’s
Global Assessment Score.
• A decrease in inflammatory lesion count as measured
by the investigator.
• A decrease in noninflammatory lesion count as
measured by the investigator.
Secondary endpoints included:
• At least a one-step decrease in Subjects’ Global
Assessment Score.
• Evaluation of cutaneous side effects.
One single investigator performed all evaluations at
each time point for each subject to optimize the
consistency of the evaluations. In addition, the
23
Sodium L-ascorbyl-2-phosphate 5% lotion for acne • H Woolery-Lloyd et al.

investigator and subjects were provided with a set of

detailed descriptive guidelines for reporting the Global
Assessment Score.

Statistical evaluations

As a result of the sample size of the active and vehicle

groups, the Friedman nonparametric test was chosen to
analyze the overall statistical significance of the primary
and secondary efficacy endpoints. The Friedman test is
commonly used when study participants are assessed on
two or more occasions. This test was utilized to
determine if there was a statistically significant decrease
in the Investigator’s Global Assessment Score, the
Subjects’ Global Assessment Score, the Investigator’s
inflammatory lesion count, and the Investigator’s non-
inflammatory lesion count. A Wilcoxon-Signed Ranks
test was used to confirm statistical significance of the
Investigator’s and Subjects’ Global Assessment Scores.

Results

Subjects

A total of 50 subjects enrolled in the study. The

investigational site was an academic research center
and enrollment was from private patients within the
academic practice or individuals that responded to
advertisements. Of the 50 subjects enrolled in the study,
25 subjects received the APS lotion and 25 subjects
received the vehicle lotion. Baseline demographics in the Figure 1 Trial profile.
two groups are described in Table 1.
At baseline, the average Investigators Global Assess- inflammatory lesion count was 4.71 for the active group
ment Score was 2.71 for the active group and 2.60 for and 4.56 for the vehicle group. At baseline, the average
the vehicle group. At baseline, the average Subjects noninflammatory lesion count was 18.63 for the active
Global Assessment Score was 2.88 for the active group group and 18.04 for the vehicle group.
and 2.92 for the vehicle group. At baseline, the average Thirty-seven subjects (74%) completed the study. Five
subjects did not complete the study in the active group.
Table 1 Subject demographics Four subjects were lost to follow up and one subject
withdrew from the study. Eight subjects did not complete
Skin type Active Vehicle the study in the vehicle group. Three subjects withdrew
and five were lost to follow up. Protocol deviations were
I 0 1
limited and included late subject visits and missed
II 3 2
III 8 4 product applications. The randomization code was not
IV 9 4 broken prematurely for any subject. The trial profile is
V 2 7 summarized in Fig. 1.
VI 3 7
Ethnicity
Caucasian 4 4
Efficacy evaluations
Hispanic 13 7
Black 8 10 Overall efficacy
Asian 0 3
Other 0 1
The active group showed statistically significant
decreases in the Investigator’s Global Assessment Score

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 Sodium L-ascorbyl-2-phosphate 5% lotion for acne • H Woolery-Lloyd et al.

Figure 3 Subject after 8 weeks of therapy with APS 5% lotion.

Figure 2 Subject at baseline.

(P = 0.001), Subjects’ Global Assessment Score (P =
0.001), Investigator’s inflammatory lesion counts (P =
0.029), and Investigator’s noninflammatory lesion
counts (P = 0.037).
Investigator’s Global Assessment Score
Thirteen of twenty-one subjects (61%) improved in the
active group as measured by the Investigator’s Global
Assessment Score at week 12 (exit visit). Improvement
in the Investigator’s Global Assessment Score in the
active group was statistically significant at week 8
(P = 0.006) and week 12 (P = 0.007). Figs 2 and 3
demonstrate a subject in the active group at baseline and
after 8 weeks of therapy.
Seven of eighteen (38%) subjects improved in the
vehicle group at week 12. Improvement in Investigator’s
Global Assessment Score in the vehicle group was not
statistically significant at any time point.
in Subjects Global Assessment Score in the vehicle group
was not statistically significant at any time point.
Lesion Counts
Results of the Friedman test showed a statistically
significant decrease in lesion counts over time in the
active group.
A summary of the day 0 and week 12 data is described
in Table 2.
Tolerability
Adverse events considered to be possibly, probably, or
definitely related to treatment were reported in both
treatment groups. Four subjects in the active group
reported adverse events that were possibly, probably, or
Table 2 Summary of day 0 and week 12 data
Average Active* Vehicle

Subjects’ Global Assessment Score IGA Day 0 2.71 2.60

IGA Week 12 1.90 2.18
Fifteen of twenty-one subjects (71%) improved in the SGA Day 0 2.88 2.92
active group as measured by the Subjects’ Global SGA Week 12 1.95 2.44
Assessment Score at week 12. Improvement in Subjects’ Inflammatory lesion count day 0 4.71 4.56
Global Assessment Score in the active group was Inflammatory lesion count week 12 3.70 4.24
Noninflammatory lesion count day 0 18.63 18.04
statistically significant at week 8 (P = 0.039) and week Noninflammatory lesion count week 12 13.35 10.24
12 (P = 0.008). Nine of seventeen subjects (52%)
improved in the vehicle group at week 12. Improvement *Statistically significant reduction (P < 0.05).

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Sodium L-ascorbyl-2-phosphate 5% lotion for acne • H Woolery-Lloyd et al.
definitely related to treatment. Two subjects reported dry
skin. One subject reported scale. One subject reported
mild erythema.
Four subjects in the vehicle group reported adverse
events that were possibly, probably, or definitely related
to treatment. One subject reported peeling. One subject
reported itching. One subject reported a sunburn. One
subject reported worsening of the acne. All of the
mentioned adverse events were reported as mild in both
treatment groups.
Discussion
The use of vitamin C in acne vulgaris was first reported
in 1954.12 However, this report was based on the oral
administration of nonderivative vitamin C and citrus
juice. When nonderivative vitamin C is digested and
transported to peripheral tissues, its stability is compro-
mised. Additionally, cutaneous levels of orally adminis-
tered vitamin C may be inadequate to achieve clinically
significant antioxidant activity.13
Ikeno first reported topical vitamin C for the treatment
of acne in 1998.11 This open label study demonstrated
efficacy of topical vitamin C in combination with
clindamycin lotion. Additional open label studies have
supported the efficacy of APS in the treatment of acne as
both monotherapy and in combination with other
agents.7–10
Vitamin C, also known as ascorbic acid, is the most
abundant antioxidant in the skin.14 Topical formula-
tions of vitamin C are typically modified to improve
stability. Ascorbyl phosphate salts, including sodium
and magnesium, are among the most stable ascorbic
acid derivatives.5 The increased stability of these salts
are due to the introduction of the phosphate group in the
second position of the cyclic ring, which protects the
enediol system of the molecule against oxidation in
topical formulations.15 Once applied topically, sodium L-
ascorbyl-2-phosphate is converted into free ascorbic acid
by enzymes present in the skin to achieve cutaneous
antioxidant activity.5
Sodium ascorbyl phosphate has been extensively used
in cosmetic products in concentrations ranging from
0.01% to 3%.16 In cosmetic products, sodium ascorbyl
phosphate is used as an antioxidant to treat and protect
against UV induced photoaging. An in vitro study has
examined the protective effects of sodium-L-ascorbyl-2
phosphate on the development of UVB-induced damage
in cultured mouse skin. This study demonstrated
prevention of sunburn cell formation, DNA fragmenta-
tion, and lipid peroxidation in treated skin after UVB
irradiation.5 The role of vitamin C and its derivatives are
26
well established as antioxidants in the treatment and
prevention of photoaging.17
Although antioxidants are not typically used to treat
acne, studies suggest that antioxidants may be useful as
acne therapy. Subjects with acne have a higher
concentration of polar lipids on their skin surface than
control subjects.2 These polar lipids are squalene oxides
which proved to be highly comedogenic in the rabbit ear
model.1 Based on this data, treatment of acne with
antioxidants could help to prevent comedogenesis.
Interestingly, statistically significant improvement with
5% APS was first observed at week 8. Clinically, this
time frame suggests that APS may act via prevention of
comedogenesis.
An additional role of antioxidants in acne is to treat
the neutrophil production of reactive oxygen species in
inflammatory lesions. The role of the antioxidative
defense system has been examined in papulopustular
acne. Impaired antioxidative defense enzymes have been
observed in the leukocytes of subjects with papulopust-
ular acne.18 Tetracycline, doxycycline, and erythromy-
cin, typically used for acne, have been shown to have
significant antioxidant activity.3,4 Prevention of reactive
oxygen species via topical antioxidants should act
similarly to treat inflammatory acne.
Five percent APS demonstrated a statistically signifi-
cant decrease in both inflammatory and noninflamma-
tory acne lesions. As a result of the small sample size,
more stringent statistical analysis could not quantify the
percent reduction in each of these groups. A larger study
would be helpful to determine if APS has a greater effect
on inflammatory lesions than noninflammatory lesions.
A study of systemic vitamin C in rats demonstrated
prevention of minocycline-induced pigmentation of the
thyroid gland.19 In our study, postinflammatory hyper-
pigmentation was not specifically assessed; however,
vitamin C has been demonstrated to have skin bleaching
properties.20 This feature of vitamin C may further
support its use in acne associated with hyperpigmenta-
tion.
In conclusion, vitamin C derivatives are not widely
utilized in the treatment of acne and there are no blinded
controlled clinical trials in the peer-reviewed literature
examining the role of vitamin C in acne. Previous open
label studies have demonstrated the efficacy of APS in
acne vulgaris.7–11 We present the first double-blinded,
vehicle-controlled study to demonstrate the efficacy of
vitamin C in acne vulgaris. This study demonstrates that
5% APS is efficacious as monotherapy for the treatment
of acne. Despite the small sample size, statistically
significant improvement was demonstrated in all of the
parameters measured. This study showed improvement
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 Sodium L-ascorbyl-2-phosphate 5% lotion for acne
of acne in 61% of subjects based on the investigator’s
scores and 71% of subjects based on subjects’ scores.
Additionally, this unique acne therapy demonstrated
minimal irritation, which is frequently observed with
conventional acne treatments. APS may offer an ideal
adjunct therapy to common acne regimens. Further
studies will be helpful to clarify the role of APS as a novel
addition to our current acne armamentarium.
Acknowledgment
We would like to acknowledge Deborah Biele for
assistance with statistical analysis.
Funding ⁄ support: This study was funded by an
unrestricted research grant from the Ikeno Clinic of
Dermatology & Dermatologic Surgery.
Role of sponsor: The sponsors had no role in the
design and conduct of the study; in the collection,
analysis, and interpretation of data; or in the prepara-
tion, review, or approval of the manuscript.
Financial disclosure: Heather Woolery-Lloyd, MD:
None reported
Leslie Baumann, MD: None reported
Hiroshi Ikeno, MD: Director, Ikeno Clinic of Derma-
tology and Dermatologic Surgery
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