Original Article

診療と新薬 2023; 60: 459‑470

Eﬀect of Continuous Ingestion of Pentadecyl-Containing
Aurantiochytrium Oil on Skin Condition:

診療と新薬 WebA Randomized, Double Blind, Placebo-Controlled Study

Takeshi KANEKO 1）／Akinobu MIYATA 2）／Makoto TSUBOI 3）／Yasuko SAKATA 3）● Abstract
Objective: The purpose of this study was to evaluate the eﬀects of 12 weeks of consumption of pentadecylcontaining orlan oil for healthy adult women aged 35 to 59 years with dry skin and sagging faces.
Methods: The study design was a randomised, double-blind, placebo-controlled study. Fifty trial participants
were randomly assigned to receive pentadecyl-containing orlane oil and placebo-controlled for 12 weeks. Skin
elasticity was the primary outcome, and collagen score and stratum corneum water and water transpiration
were secondary outcomes.
Results: In the test product group, there was a signiﬁcant improvement in elasticity R2 (left, average), R5(left), and R7 (left, right, mean) after 12 weeks compared to the control group. There was also a signiﬁcant
improvement in collagen score intensity (left, right, average), stratum corneum water content (left, right,
average), and water evaporation (left).
Conclusion: These results suggest that the 12-week intake of pentadecyl-containing orlan oil improves skinelasticity by increasing collagen density, which in turn improves skin moisture.
Keywords: Aurantiochytrium Oil, Pentadecyl, collagen, endoplasmic reticulum stress, pentadecanoic acid

INTRODUCTION
The skin that covers the human body is the largest organin the human body, accounting for about 16% of the bodyweight, and its structure is roughly divided into threelayers: epidermis, dermis, and subcutaneous tissue 1).
The skin functions as a barrier to protect the body fromexternal influences such as temperature, humidity,
ultraviolet rays, chemical substances, bacteria andviruses. Conversely, it also plays a role in preventing
water evaporation from inside the body 2). The epidermis,
the outermost layer of the skin, is divided into thestratum corneum, stratum granulosum, stratum
spinosum, and stratum basale. The dermis, which is thelower layer of the epidermis, is composed of extracellularmatrices such as collagen, elastin, and hyaluronic acid,and fibroblasts that produce them. The extracellularmatrix is highly elastic and ﬂexible, and is important as asupporting tissue that maintains the mechanical strengthof the skin 1). That is, each layer of the skin must be in ahealthy state in order for the skin, which serves as abarrier to the inside and outside of the body, to function
normally. However, it has been reported that the1) JACTA ( Japan Clinical Trial Association)2) Miyata Medical Clinic
3) Sea Act Co., LTD.

extracellular matrix decreases with aging 4) and also due
to endoplasmic reticulum stress due to UV exposure 5).
When the skin loses its flexibility and elasticity due tothese factors, its function as a barrier against the insideand outside of the body is also impaired.
The microalgae Aurantiochytrium has the characteristicof accumulating lipids as oil droplets in cells undernutrient-rich conditions. Fatty acids accumulated at thistime include not only even-numbered fatty acids such as
DHA and EPA, but also odd-numbered fatty acids 6)7).
Unlike even fatty acids, which are produced bycondensation of acetyl-CoA and malonyl-CoA, odd fatty
acids are synthesized by condensation of propionyl-CoA
and malonyl-CoA. In recent years, odd-numbered fatty
acids have been reported to have eﬀects on hair growth,
Alzheimer's disease, heart disease, cancer, and diabetes.
It is believed that this replenishment reaction of
propionyl-CoA is involved 8)9).
Auran oil is produced by separate extraction from
Aurantiochytrium and is mainly rich in odd-numberedfatty acids such as pentadecanoic acid. In particular, we
identified a C42-C48 pentadecanoic acid lipid aspentadecyl and focused on its bioactivity 10).
In a test in which pentadecyl was added to normal
human epidermal keratinocytes, the expression levels of
invocrine, transglutaminase 1, claudin 1, and filaggrin
were significantly increased. In addition, in a test in12 （460）

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Table 1-1 Raw materials for test products
Raw material nameamountAurantiochytrium Oil ＊30 mgtest article（Pentadecyl）
edible corn oil（6 mg）
120 mgcontrol

edible corn oil

150 mgCoating part (common to test
product and control product)

Gelatin (from pig)
glycerin (vegetable)
food additive glycerin
Fatty acid ester* Contains 0.3% tocopherol (Emix D: Mitsubishi Chemical Foods) as an antioxidant.

Table 1-2 Fatty acid content of Aurantiochytrium Oil

Table 1-3 Fatty acid composition of Pentadecyle

Fatty acids

Content (g/100 g oil)Fatty acids

C13
C14
C15
C16
C17
EPA
DPA
DHA
Others

1.1
1.7
30.5
9.4
4.3
0.5
4.1
31.8
2.8

C42
C43
C44
C45
C46
C47
C48

Total

86.2

which it was added to normal human dermal ﬁbroblasts, it
was conﬁrmed that the production of type I collagen was
signiﬁcantly increased 11).
Furthermore, a test in which pentadecyl was added tohuman fibroblasts under endoplasmic reticulum stressconﬁrmed an increase in collagen production due to therelaxation of endoplasmic reticulum stress 12). From this,
it is considered that one of the mechanisms of photoaging
is that the endoplasmic reticulum in the dermal ﬁbroblasts
is abnormal and collagen production is reduced by UV
exposure, so pentadecyl can be a strategy to suppress
collagen reduction (Five).
Based on the above, pentadecyl intake is expected tohave the function of keeping the skin in a healthy state,such as improving the skin's moisturizing function andmaintaining elasticity by preventing a decrease incollagen production due to endoplasmic reticulum stress.
A previous study in which pentadecyl-containing auranoil-containing food was continuously ingested for 6 weeks
suggested an improvement in skin moisture content in a
subgroup analysis based on skin moisture content. It is
possible that differences in skin condition between
subjects, due to whether or not they were aware ofdryness, aﬀected the results 13). Therefore, in this study,
we investigated the eﬀects on skin functions of subjects

Fatty acids composition
C15, C14, C13
C15, C15, C13
C15, C15, C14
C15, C15, C15
C15, C15, C16
C15, C15, C17
C15, C16, C17

C15, C14, C14

C15, C16, C16

C13 = Tridecanoic acid, C14 = Tetradecanoic acid,
C15 = Pentadecanoic acid, C16 = Hexadecanoic acid,
C17 = Heptadecanoic acid

Table 1-4 Nutritional composition of test product(per capsule)item

amountenergy1.8 kcal
0.1 g0.15 g
0g
0g
0g
0g

proteinlipid
carbohydrates
moisturecholesterol
dietary ﬁber

who were aware of their skin dryness when they
continuously ingested pentadecyl-containing auran oilcontaining food for 12 weeks.

1. SUBJECTS AND METHODS
1-1 Study design and ethics review committee
This study was a randomized, double-blind, placebocontrolled study with Akinobu Miyata (Director, Miyata
Medical Clinic) as the principal investigator. This trial
was previously registered in the UMIN Clinical Trials

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Table 2 Subject Background of Valid Analysis Subjects
Item

unit

Test product group

Control group(n = 24)(n = 25)

age *

age

51.9 ± 4.0

50.1 ± 5.1

elasticityR2̲leftelasticityR2̲right *elasticityR2̲average

index

0.645 ± 0.078

0.694 ± 0.052

index
index

0.658 ± 0.059
0.651 ± 0.061

elasticityR5̲left *elasticityR5̲right *elasticityR5̲average *elasticityR7̲left *elasticityR7̲right *elasticityR7̲average *

index
index
index
index
index
index

0.479 ± 0.088
0.497 ± 0.103
0.488 ± 0.092
0.301 ± 0.054
0.316 ± 0.053
0.309 ± 0.051

0.687 ± 0.054
0.691 ± 0.050
0.508 ± 0.085
0.506 ± 0.074
0.507 ± 0.073
0.329 ± 0.049
0.336 ± 0.051
0.333 ± 0.044

Intnsity̲left *Intnsity̲right *Intnsity̲average *LEB̲left
LEB̲right *LEB̲average
Thickness̲left *Thickness̲right *Thickness̲average *

index
index
index
μm
μm
μm
μm
μm
μm

43.78 ± 8.97
48.72 ± 10.08
46.25 ± 8.62
146.4 ± 109.7
120.1 ± 116.2
133.3 ± 101.0
1157.0 ± 159.0
1124.2 ± 177.1
1140.6 ± 145.5

43.12 ± 8.54
46.12 ± 8.89
44.62 ± 8.05
75.3 ± 90.9
66.3 ± 87.0
70.8 ± 71.6
1248.7 ± 209.2
1221.9 ± 220.9
1235.3 ± 203.5

stratum corneum water content̲left
stratum corneum water content̲rightstratum corneum water content̲averagewater loss̲left *water loss̲right *water loss̲average *

index
index
index
g/hm2

25.65 ± 6.03
26.23 ± 6.42
25.94 ± 6.20
11.51 ± 3.10
10.81 ± 2.82
11.16 ± 2.87

29.97 ± 7.06
30.36 ± 6.82
30.17 ± 6.63
10.38 ± 3.54
10.75 ± 3.22
10.57 ± 3.30

g/hm2
g/hm2

mean ± standard deviation* no signiﬁcant diﬀerence between groups

Registry (UMIN000050031) and is compliant with the
Declaration of Helsinki (Revised October 2013, Fortaleza)
and the Ethical Guidelines for Life Science and Medical
Research Involving Human Subjects (Effective March
2021), after obtaining approval from the Ethics Review
Committee of the Pharmaceutical Affairs Law Advisory
Council (Chairman: Toshio Houga, Attorney-at-Law)( January 4, 2023), the subject was given a written
informed consent, and the purpose and method of thisstudy were fully explained in writing and verbally. The
study was conducted with written informed consent fromthe subject.
1-2 Target person
JACTA conducted general recruitment through InchromeCo., Ltd. (Tokyo), and subjects were those who met thefollowing selection criteria, who did not meet theexclusion criteria, and who voluntarily wished to use thetest product.
1-2-1 Selection criteria① Healthy women aged from 35 to 59② Those with dry skin
③ Those who are concerned about facial sagging④ Subjects with a wrinkle grade of 2 to 4 on the left andright corners of the eyes
⑤ Subjects who have given written consent of their own
free will after fully understanding their participation inthis research
1-2-2 Exclusion criteria① Individuals with a history of food allergies② Those who are pregnant, breastfeeding, or planning to
do so during the test period③ Those who are currently going to the hospital orreceiving a doctor's prescription④ Those who have experience in aesthetic medicine on
the test site
⑤ Those who have inflammation or skin disease on theface⑥ Those who are receiving hormone replacement
therapy⑦ Subjects taking supplements or medicines that aﬀect
the eﬀects of the test product⑧ Subjects who are likely to show allergic symptoms to
drugs or food
⑨ Excessive smokers, regular alcohol users, and persons
with extremely irregular eating habits14 （462）

診療と新薬・第 60 巻

⑩ Subjects who have participated in other human clinical
trials within one month prior to obtaining informed
consent, and subjects who plan to participate in otherclinical trials during the study period⑪ Subjects deemed inappropriate by the study supervisor
1-2-3 Sample size
Based on the findings obtained from previous research,
the signiﬁcance level was set at 5%, the power was set at80%, and the sample size was set at 48 ± 2 cases.
1-3 Test product
The test product was pentadecyl-containing auran oil
provided by Sea Act Co., Ltd.
Subjects took 1 capsule each day for 12 weeks withwater or lukewarm water after breakfast for test or
control. The test product and the control product were
provided with an identification code after making themindistinguishable in terms of shape, color and taste.
Table 1-1 shows the raw materials of the test productand control product, Table 1-2 shows the Fatty acidcontent of auran oil, Table 1-3 shows the fatty acidcomposition of pentadecyle, and Table 1-4 shows thenutritional composition of the test product.
1-4 Randomization
Fifty applicants who met the inclusion criteria and did notmeet the exclusion criteria were selected and randomly
assigned by an allocator unrelated to the trial. In order toprevent bias, 25 people were divided into groups A and B,
taking age into consideration (see Table 2). Allotment
contents were kept strictly by the person in charge ofallotment and disclosed to the study site after data
fixation (key open). Group A took the test product andGroup B took the control product for 12 weeks.
1-5 Test schedule
The study period will be from January to April 2023, with
4 observation days before the start, 4 weeks, 8 weeks,and 12 weeks. They were aligned and the times were
almost the same. During the test period, instruct all
subjects not to start using or taking any medicines orhealth foods that affect the test site, and to maintain anormal life, and submit a diary to conﬁrm this point. (see1-7). Table 3 shows the test schedule.
1-6 Matters to be observed by subjects
All subjects were instructed to lead a normal life during
the test period and to comply with the following items.
(1) To maintain the lifestyle habits such as eating,exercising, drinking alcohol, smoking, sleeping
hours, etc. from before participating in the study
without changing them.
(2) Avoid excessive exercise, sleep deprivation,
excessive eating and drinking (banquets, all-you-caneat, buffets, etc.) and diets that deviate from your第 8 号（2023 年 8 月）

daily routine.
(3) It is prohibited to use pharmaceuticals, quasi-drugs,
health foods, etc. that claim or emphasize skinrelated effects, and to receive esthetics andtreatments.
(4) Do not take medicine unless it is unavoidable. Whentaking medicines, record the name of the medicine
and the amount taken in the diary.
(5) Subjects who have been taking quasi-drugs andhealth foods before participating in the study should
continue to take them without changing the intake
amount, intake frequency, or intake method. Intakeof new quasi-drugs and health foods is prohibited.
(6) Staying up late, staying up all night, and strenuous
exercise (breathtaking running, swimming, mountainclimbing, etc.) are prohibited for 3 days before themeasurement.
(7) Do not drink alcohol the day before your visit, getenough sleep, and keep yourself in good physicalcondition.

2. EVALUATION ITEM
On the 4 observation days, the subjects washed their facewith a commercially available cleansing agent to remove
makeup and cleanse their face, and then rested for 20
minutes in a room maintained at a temperature of 21 ±1℃ and a humidity of 50 ± 5RH% to acclimatize theirskin. After that, each measurement was performed.
Measurements were taken on the left and right sides ofthe face (once), and the values for each of the left andright sides and the average value for the left and rightsides were used.
2-1 Elasticity
Cutometer Ⓡ MPA580 (Courage+Khazaka electronicGmbH) was used to measure the intersection of a verticalline drawn from the outer corner of the eye and ahorizontal line drawn from the nostril of each subject. R2(total elasticity), R5 (net elasticity) and R7 (elasticity at
retraction) were obtained. Measurements were taken
once on each side. The unit is a percentage, and thecloser to 1.0, the higher the elasticity.
2-2 Collagen score
DermaLab (Cortex Technology) was used to measure theleft and right temple circumferences of the subjects.
Intensity represents the collagen density of the dermis,
and the higher the value, the better the condition. LEB
represents the width of the portion with less collagen in
μ m, and the smaller the LEB, the better the condition.
Thickness represents the thickness of the dermal
collagen, and the narrower it is (the smaller the value),the better the condition.

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Table 3 Test schedule
Main test
項目

consent

before

start

start
Test explanation

4weeks

8weeks12weeks

later

later

later

●

●

●

●

measurement●

Ingestion of test and control products
Diary● ：Conducted on measurement day：Every day during the period

Selected (n = 33; female 25)
Test product groupcontrol group

Assignment/Consent
Agree (n = 25)
Disagree (n = 0)

Agree (n = 25)
Disagree (n = 0)

FollowAborted (n = 1)

Aborted (n = 0)

Analysis

Number of analyzes (n = 24)

Number of analyzes (n = 25)

Figure 1

Analysis target decision process

2-3 Stratum corneum moisture content/moisture loss
The stratum corneum moisture content was measured
using a Corneometer Ⓡ CM825 (Courage+Khazaka
electronic GmbH). Measurements were taken at theintersection of a line drawn vertically from the outercorner of each eye of the subject and a line drawn
horizontally from the nostril. Measurements were taken
once on each side. The unit is an index, and the higher
the number, the higher the water content.
Water loss was measured using a Tewameter Ⓡ TM300(Courage+Khazaka electronic GmbH). A line drawn

vertically from the outer corner of each eye of the subject
and a line drawn horizontally from the nostril intersected,
and the value was obtained. The unit is g/h m2, and thesmaller the number, the less water transpiration.
2-4 Safety
The safety of the study article was assessed based ondiary surveys of lifestyle and adverse events during thestudy period. In addition, the principal investigator
evaluated and judged the relationship between adverse
events and the test product.

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Table 4 Changes in elasticity (1)Itempoint in time

Index
Control group (n=25) 1)

0.645 ± 0.078
0.697 ± 0.066
0.051 ± 0.093 *0.694 ± 0.052
0.672 ± 0.053− 0.022 ± 0.063 †0.002 ##

a before startb 4weeks later⊿a−belasticity R2̲leftcd

8weeks later⊿a−c0.631 ± 0.076− 0.015 ± 0.093

0.687 ± 0.067− 0.008 ± 0.070

0.767

12weeks later⊿a−d0.666 ± 0.075
0.021 ± 0.104

0.649 ± 0.077− 0.045 ± 0.078 **0.015 #

0.658 ± 0.059
0.690 ± 0.061
0.033 ± 0.072 *0.687 ± 0.054
0.669 ± 0.061− 0.018 ± 0.056

0.009 ##

a before startb 4weeks later⊿a−belasticity R2̲rightcd

8weeks later⊿a−c0.641 ± 0.057− 0.016 ± 0.069

0.668 ± 0.069− 0.019 ± 0.067

0.879

12weeks later⊿a−d0.654 ± 0.081− 0.003 ± 0.078

0.643 ± 0.076− 0.044 ± 0.064 **0.052 ‡

0.691 ± 0.050
0.670 ± 0.052− 0.020 ± 0.052 †0.001 ##

a before startb 4weeks later⊿a−belasticity R2̲averagecd0.651 ± 0.061
0.693 ± 0.058
0.042 ± 0.072 **8weeks later⊿a−c0.636 ± 0.060− 0.015 ± 0.075

0.677 ± 0.061− 0.013 ± 0.060

0.917

12weeks later⊿a−d0.660 ± 0.069
0.009 ± 0.082

0.646 ± 0.072− 0.045 ± 0.066 **0.016 #

0.479 ± 0.088
0.503 ± 0.092
0.025 ± 0.029 **0.508 ± 0.085
0.517 ± 0.093
0.009 ± 0.056

0.235

0.499 ± 0.095− 0.009 ± 0.093

0.941

a before startb 4weeks later⊿a−belasticity R5̲leftcdelasticity R5̲right

8weeks later⊿a−c0.472 ± 0.089− 0.007 ± 0.10412weeks later⊿a−d0.538 ± 0.073
0.059 ± 0.072 **0.501 ± 0.138− 0.007 ± 0.113

0.019 #

a before startb 4weeks later⊿a−b0.497 ± 0.103
0.528 ± 0.101
0.031 ± 0.031 **0.506 ± 0.074
0.510 ± 0.090
0.004 ± 0.062

0.060 ‡cd

8weeks later⊿a−c0.485 ± 0.075− 0.012 ± 0.096

0.506 ± 0.113− 0.000 ± 0.116

0.70412weeks later⊿a−d0.530 ± 0.072
0.033 ± 0.104

0.515 ± 0.118
0.009 ± 0.099

0.416

0.488 ± 0.092
0.516 ± 0.088
0.028 ± 0.023 **0.507 ± 0.073
0.513 ± 0.081
0.006 ± 0.057

0.095 ‡

0.502 ± 0.097− 0.005 ± 0.090

0.851

0.508 ± 0.120
0.001 ± 0.097

0.085 ‡

a before startb 4weeks later⊿a−belasticity R5̲averagep-value 2)

Test product group (n=24) 1)cd

8weeks later⊿a−c0.479 ± 0.069− 0.009 ± 0.08612weeks later⊿a−dmean ± standard deviation
1) † :p<0.1, * :p<0.05, ** :p<0.01 vs. before start2) ‡ :p<0.1, # :p<0.05, ## :p<0.01 vs. control group0.534 ± 0.060
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Table 4 Changes in elasticity (2)Itempoint in time

Index
Control group (n=25) 1)

0.301 ± 0.054
0.322 ± 0.056
0.021 ± 0.014 **0.329 ± 0.049
0.328 ± 0.056− 0.001 ± 0.033

0.005 ##

0.324 ± 0.059− 0.005 ± 0.055

0.794

a before startb 4weeks later⊿a−belasticityR7̲leftcdelasticityR7̲right

8weeks later⊿a−c0.301 ± 0.054− 0.000 ± 0.061

12weeks later⊿a−d0.332 ± 0.047
0.030 ± 0.051 **0.311 ± 0.072− 0.018 ± 0.053 †0.002 ##

a before startb 4weeks later⊿a−b0.316 ± 0.053
0.333 ± 0.062
0.018 ± 0.021 **0.336 ± 0.051
0.324 ± 0.060− 0.012 ± 0.036 †0.001 ##cd

8weeks later⊿a−c0.303 ± 0.044− 0.013 ± 0.051

0.330 ± 0.072− 0.006 ± 0.061

0.668

12weeks later⊿a−d0.335 ± 0.042
0.019 ± 0.063

0.315 ± 0.063− 0.021 ± 0.046 *0.015 #

0.309 ± 0.051
0.328 ± 0.055
0.019 ± 0.013 **0.333 ± 0.044
0.326 ± 0.052− 0.007 ± 0.032

0.001 ##

0.327 ± 0.061− 0.006 ± 0.046

0.924

0.313 ± 0.064− 0.020 ± 0.045 *0.002 ##

a before startb 4weeks later⊿a−belasticityR7̲averagep-value 2)

Test product group (n=24) 1)cd

8weeks later⊿a−c0.302 ± 0.041− 0.007 ± 0.04712weeks later⊿a−d0.333 ± 0.038
0.025 ± 0.051 *mean ± standard deviation
1) † :p<0.1, * :p<0.05, ** :p<0.01 vs. before start2) ‡ :p<0.1, # :p<0.05, ## :p<0.01 vs. control group

2-5 Statistical processing
Analysis adopted FAS. Measured values (scores) are
shown as mean ± standard deviation. A paired t-test was
performed for comparisons with before the start, andStudent's t-test was performed for comparisons between
groups and subject background bias. Data multiplicity
was not considered and there were no missing values. In
both cases, a signiﬁcant diﬀerence was judged to be lessthan 5% (p<0.05) in a two-sided test. Statcel 4 (Hisae
Yanai, 2015) was used as statistical analysis software.

3. RESULTS
3-1 Subject backgroundFifty started the study, one discontinued for personalreasons, and 49 completed the study. Forty-nine subjects(41-58 years old, 51.0 ± 4.6 years old) were included in
the analysis. Figure 1 shows the ﬂow up to the analysis,
and Table 3 shows the background of the subjects. The
intake rate of the test product group was 100% for 20
people, 99% for 3 people, and 94% for 1 person. % had
one and 89% had one.

3-2 Results of elasticity
Table 4 shows changes in measured values. In
comparison with the control group, there was asignificant difference in increase (improvement) in R2(left, right, left-right average) and R7 (left, right, leftright average) after 4 weeks, and R2 (left, left-rightaverage), R5 (left), and R7 (left, right, left-right average)
after 12 weeks.
Compared to before start R2 (left, right, left-rightaverage), R5 (left, right, left-right average) and R7 (left,right, left-right average) after 4 weeks, and R5 (left, leftright average) and R7 (left, left-right average) after 12
weeks showed a significant increase in test productgroup. In the control group, a significant decrease(exacerbation) was observed in R2 (left, right, left-rightaverage) and R7 (right, left-right average) after 12
weeks.
3-3 Collagen score results
Table 5 shows changes in measured values. In
comparison with the control group, there was asigniﬁcant decrease (improvement) in LEB after 8 weeks,18 （466）

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Table 5 Changes in Collagen Score (1)Item (unit)

Intensity̲left(index)point in time
before start

43.78 ± 8.97
46.05 ± 10.71
2.28 ± 7.80

43.1 ± 8.5
45.5 ± 11.4
2.4 ± 9.6

0.950

8weeks later⊿a−c45.12 ± 7.49
1.34 ± 7.17

40.8 ± 10.7
− 2.3 ± 10.9

0.17412weeks later⊿a−d47.29 ± 8.83
3.51 ± 7.32 *38.6 ± 9.2− 4.5 ± 8.6 *0.001 ##

a before startb 4weeks later⊿a−b48.72 ± 10.08
45.44 ± 9.05
− 3.28 ± 9.63

46.1 ± 8.9
41.7 ± 9.1− 4.5 ± 9.2 *

0.663

c

8weeks later⊿a−c

46.07 ± 7.35
− 2.65 ± 9.36

38.4 ± 8.5− 7.7 ± 9.5 **0.067 ‡

12weeks later⊿a−d47.60 ± 8.12
− 1.12 ± 8.61

37.9 ± 8.0− 8.2 ± 7.8 **0.004 ##

a before startb 4weeks later⊿a−b

46.25 ± 8.62
45.75 ± 8.93
− 0.50 ± 5.89

44.6 ± 8.0
43.6 ± 9.5− 1.0 ± 8.0

0.800

c

8weeks later⊿a−c45.60 ± 6.80
− 0.65 ± 6.75

39.6 ± 9.2− 5.0 ± 9.1 *0.064 ‡

12weeks later⊿a−d47.44 ± 7.92
1.20 ± 5.57

38.3 ± 8.2− 6.4 ± 6.8 **0.000 ##

a before startb 4weeks later⊿a−b146.4 ± 109.7
108.5 ± 119.8− 37.9 ± 141.9

75.3 ± 90.9
59.0 ± 93.8
− 16.3 ± 101.7

0.543

c

8weeks later⊿a−c96.2 ± 145.2− 50.3 ± 109.8 *95.8 ± 147.2
20.5 ± 131.3

0.047 #

12weeks later⊿a−d136.6 ± 134.4− 9.8 ± 96.1

51.6 ± 81.6
− 23.7 ± 89.1

0.601

66.3 ± 87.0
85.3 ± 125.5
19.0 ± 147.9

0.430

c

d

LEB̲right(μm)

a before startb 4weeks later⊿a−b120.1 ± 116.2
171.8 ± 141.7
51.7 ± 139.5 †c

8weeks later⊿a−c131.1 ± 145.9
11.0 ± 153.2

37.9 ± 81.4
− 28.4 ± 95.7

0.28412weeks later⊿a−d125.8 ± 109.4
5.6 ± 117.6

42.7 ± 79.1
− 23.6 ± 96.7

0.346

a before startb 4weeks later⊿a−b133.3 ± 101.0
140.2 ± 109.3
6.9 ± 98.5

70.8 ± 71.6
72.1 ± 91.2
1.3 ± 88.1

0.835

8weeks later⊿a−c113.6 ± 120.2− 19.6 ± 78.3

66.9 ± 94.3
− 3.9 ± 72.1

0.468

12weeks later⊿a−d131.2 ± 100.7− 2.1 ± 65.6

47.2 ± 68.1
− 23.7 ± 63.2 †

0.247

d

LEB̲average(μm)

p-value 2)

4weeks later⊿a−bdLEB̲left(μm)

Control group (n=25) 1)adIntensity̲average(index)

Test product group (n=24) 1)bdIntensity̲right(index)

Index

c
d

mean ± standard deviation
1) † :p<0.1, * :p<0.05, ** :p<0.01 vs. before start2) ‡ :p<0.1, # :p<0.05, ## :p<0.01 vs. control group

診療と新薬・第 60 巻

第 8 号（2023 年 8 月）

19 （467）

Table 5 Changes in Collagen Score (2)Item (unit)

Thickness̲left(μm)

point in time

Control group (n=25) 1)

p-value 2)abefore start
4weeks later⊿a−b1157.0 ± 159.0
1160.4 ± 202.4
3.4 ± 175.7

1248.7 ± 209.2
1213.9 ± 195.2− 34.8 ± 179.1

0.455

8weeks later⊿a−c1146.0 ± 217.3− 11.0 ± 202.5

1258.6 ± 235.8
9.9 ± 102.0

0.64812weeks later⊿a−d1198.3 ± 231.3
41.3 ± 212.6

1241.9 ± 194.1− 6.8 ± 149.5

0.363

a before startb 4weeks later⊿a−b1124.2 ± 177.1
1106.8 ± 195.7− 17.4 ± 216.1

1221.9 ± 220.9
1210.4 ± 218.9− 11.4 ± 149.1

0.910

c

8weeks later⊿a−c1155.4 ± 296.4
31.2 ± 310.1

1165.5 ± 157.7− 56.4 ± 210.0

0.251

12weeks later⊿a−d1095.0 ± 223.9− 29.2 ± 229.0

1209.4 ± 184.0− 12.5 ± 203.1

0.789

a

before start

1140.6 ± 145.5b4weeks later⊿a−b1133.6 ± 177.1− 7.0 ± 155.1

1235.3 ± 203.5
1212.2 ± 171.2− 23.1 ± 114.1

0.680

8weeks later⊿a−c1150.7 ± 234.2
10.1 ± 220.7

1212.0 ± 165.6− 23.3 ± 107.8

0.502

12weeks later⊿a−d1146.6 ± 213.9
6.0 ± 191.1

1225.6 ± 164.2− 9.7 ± 133.8

0.739

c

d

Thickness̲average(μm)

Test product group (n=24) 1)bd

Thickness̲right
(μm)

Index

c
d

mean ± standard deviation
1) † :p<0.1, * :p<0.05, ** :p<0.01 vs. before start2) ‡ :p<0.1, # :p<0.05, ## :p<0.01 vs. control group

and a signiﬁcant increase (improvement) in intensity (left,right, left-right average) after 12 weeks.
Compared to before the start of treatment, the test
product group showed a signiﬁcant decrease in LEB (left)
after 8 weeks and a signiﬁcant increase in intensity (left,right, average) after 12 weeks. In the control group, asignificant decrease in intensity was observed after 4
weeks (left), 8 weeks (right, average), and 12 weeks (left,right, average).

right, average). In the control product group, the stratum
corneum moisture content (right) after 4 weeks
significantly decreased (exacerbated), the moisture loss
(left, right, average) signiﬁcantly decreased (improved),
and the stratum corneum moisture content after 8 weeks.
(left, average), a signiﬁcant decrease in stratum corneum
water content (left, right, average) after 12 weeks, and asignificant increase (exacerbation) in water loss (left,
average).

3-4 Results of stratum corneum water content andwater loss
Table 6 shows changes in measured values. In
comparison with the control product group, the stratum
corneum water content signiﬁcantly increased (improved)
after 4 weeks, 8 weeks, and 12 weeks (all left, right,
average), and the amount of water loss was signiﬁcantly
increased after 12 weeks (left) showed a significant
decrease (improvement) diﬀerence.
Compared to before the start, the test product group
showed a signiﬁcant increase in stratum corneum watercontent after 4 weeks, 8 weeks, and 12 weeks (all left,

3-5 Safety
As a result of the adverse event survey by measurementand diary, no adverse events occurred in this study, andno clinical side effects caused by the test product wereobserved.

4. DISCUSSION
A test was conducted to evaluate changes in skinelasticity when pentadecyl-containing auran oil was
continuously ingested for 12 weeks. A randomized,
double-blind, placebo-controlled study was designed in20 （468）

診療と新薬・第 60 巻

第 8 号（2023 年 8 月）

Table 6 Changes in stratum corneum water content and water loss
Item (unit)

stratum corneum watercontent̲left(index)point in time

Control group (n=25) 1)

a before startb 4weeks later⊿a−b25.65 ± 6.03
31.42 ± 10.56
5.77 ± 5.82 **29.97 ± 7.06
29.96 ± 7.70
− 0.01 ± 1.70

0.000 ##c

8weeks later⊿a−c36.22 ± 8.24
10.57 ± 4.42 **27.31 ± 8.04
− 2.66 ± 4.50 **0.000 ##

12weeks later⊿a−d47.48 ± 6.20
21.83 ± 4.36 **26.15 ± 6.22
− 3.82 ± 3.98 **0.000 ##

a before startb 4weeks later⊿a−b

26.23 ± 6.42
31.55 ± 8.73
5.33 ± 4.50 **30.36 ± 6.82
29.34 ± 7.06
− 1.03 ± 2.07 *0.000 ##c

8weeks later⊿a−c37.02 ± 8.91
10.80 ± 5.92 **28.06 ± 8.53
− 2.30 ± 5.62 †0.000 ##

12weeks later⊿a−d47.31 ± 5.99
21.09 ± 4.90 **26.54 ± 6.26
− 3.83 ± 5.02 **0.000 ##

a before startb 4weeks later⊿a−b25.94 ± 6.20
31.49 ± 9.34
5.55 ± 4.51 **30.17 ± 6.63
29.65 ± 6.92
− 0.52 ± 1.37 †0.000 ##c

8weeks later⊿a−c36.62 ± 8.10
10.68 ± 4.40 **27.69 ± 7.70
− 2.48 ± 4.31 **0.000 ##

12weeks later⊿a−d47.40 ± 5.57
21.46 ± 3.84 **26.34 ± 5.72
− 3.82 ± 3.54 **0.000 ##

dstratum corneum watercontent̲average(index)dwater loss̲left(g/hm2)

a before startb 4weeks later⊿a−b

11.51 ± 3.10
10.50 ± 4.51
− 1.01 ± 2.94

10.38 ± 3.54
9.22 ± 3.89
− 1.16 ± 1.63 **

0.824

c

8weeks later⊿a−c10.23 ± 4.69
− 1.28 ± 5.67

11.66 ± 5.65
1.28 ± 4.41

0.083 ‡

12weeks later⊿a−d10.74 ± 4.04
− 0.77 ± 4.63

12.86 ± 5.99
2.47 ± 5.74 *0.035 #

a before startb 4weeks later⊿a−b

10.81 ± 2.82
10.14 ± 3.10
− 0.66 ± 2.24

10.75 ± 3.22
9.99 ± 3.02
− 0.76 ± 1.58 *

0.858

c

8weeks later⊿a−c10.23 ± 3.49
− 0.58 ± 4.33

11.24 ± 4.50
0.49 ± 3.120.32412weeks later⊿a−d10.51 ± 2.37
− 0.30 ± 3.49

11.81 ± 3.45
1.05 ± 2.79 †0.140

a before startb 4weeks later⊿a−b

11.16 ± 2.87
10.32 ± 3.72
− 0.84 ± 2.42

10.57 ± 3.30
9.60 ± 3.40
− 0.96 ± 1.47 **

0.827

c

8weeks later⊿a−c10.23 ± 4.05
− 0.93 ± 4.93

11.45 ± 5.04
0.89 ± 3.67

0.149

12weeks later⊿a−d10.63 ± 3.10
− 0.53 ± 3.86

12.33 ± 4.59
1.76 ± 4.13 *0.050 ‡dwater loss̲right(g/hm2)dwater loss̲average(g/hm2)p-value 2)

Test product group (n=24)1)d

stratum corneum watercontent̲right(index)Index

dmean ± standard deviation
1) † :p<0.1, * :p<0.05, ** :p<0.01 vs. before start2) ‡ :p<0.1, # :p<0.05, ## :p<0.01 vs. control group

診療と新薬・第 60 巻

women aged 35 to 59 who were concerned about dryness
and sagging skin.
The primary outcome was skin elasticity, and thesecondary outcomes were collagen score, stratum
corneum water content, and water loss. There was asigniﬁcant improvement diﬀerence in R2 (left, right, leftright average) and R7 (left, right, left-right average) after
4 weeks, and R2 (left, left-right average), R5 (left) andR7 (left, right, left-right average) after 12 weeks. As forsecondary outcomes, there was a signiﬁcant diﬀerence inimprovement after 12 weeks of collagen score intensity(left, right, left-right average) and after 8 weeks of LEB.
There was a significant improvement in the stratum
corneum water content after 4 weeks, 8 weeks, and 12
weeks (all left, right, average), and for water loss on theleft side after 12 weeks. Therefore, continuous intake ofpentadecyl for 12 weeks can be expected to improve skinelasticity and moisturizing function.
It has been conﬁrmed that pentadecyl increases collagenproduction in dermal ﬁbroblasts 11), and the collagen scoreafter 12 weeks was signiﬁcantly increased in this study as
well. Collagen is the main component of the dermis layer
and is important as a supporting tissue that maintains themechanical strength of the skin because it has strong
resistance to tension acting along the running of collagenfibers 1). It is considered that the skin elasticity wassigniﬁcantly improved due to the increase in the amountof collagen. Furthermore, since the dermis layer also
plays a role in supplying moisture to the epidermis 14), it isthought that the moisturizing and barrier functions of theepidermis were improved by the dermal layer maintaining
its elasticity and exerting suﬃcient functions. Apart from
this, pentadecyl has also been reported to have the eﬀectof activating epidermal keratinocytes 11) , and it isspeculated that it affected the moisturizing and barrier
functions.
Exposure to various stresses such as photoaging cancause fibroblasts and keratinocytes to produce unfolded
proteins in the endoplasmic reticulum. In particular, infibroblasts, collagen proteins are produced in theendoplasmic reticulum, but accumulation of unfolded
collagen proteins in the endoplasmic reticulum causes
endoplasmic reticulum stress, resulting in decrease innormal collagen production in ﬁbroblasts and exacerbationof the extracellular matrix of the skin. In humanfibroblasts under endoplasmic reticulum stress, anincrease in expression of XBP1S, an endoplasmic
reticulum stress marker gene, was observed, and the
addition of pentadecyl suppressed the increase in a dosedependent manner. Similarly, the decrease in collagenproduction in human fibroblasts under endoplasmic
reticulum stress was improved in a dose-dependent
manner with the addition of pentadecyl 12). Therefore, it issuggested that pentadecyl alleviates the endoplasmic
reticulum stress of fibroblasts and promotes the
production of normal collagen as a mechanism of action in

第 8 号（2023 年 8 月）

21 （469）

improving skin condition.
Although this study was conducted with only women
aged 35 to 59 as subjects, the mechanism of improving
the structure of the skin such as the epidermis anddermis, moisturizing function, and elasticity is common
to both men and women. For this reason, the effect ofcontinuous pentadecyl intake that was clarified in thisstudy can also be expected when targeting men.
We acknowledged that the results of previous studies
may have been aﬀected by seasonal variations, and that
subgroup analysis suggested an improvement inmoisturizing function for those with lower skin moisture
content 13). Since this test was conducted from January to
April, it is thought that the influence of seasonal
fluctuations was minimal. In addition, when the test
subjects had dry skin, the numerical values of many itemsin the effect index were significantly improved,
confirming the function of improving the elasticity andmoisturizing function of the skin.
In addition, while the previous study involved
continuous intake for 6 weeks, this study confirmed
signiﬁcant improvement in multiple eﬀect indicators withc o n t i n u o u s i n t a k e f o r 1 2 w e e k s . I n t h i s s t u d y,
improvements were seen in some eﬃcacy measures evenat week 4, but more eﬃcacy measures were improved at
12 weeks. These ﬁndings suggest that continuous intake
over a certain period of time is desirable.
A limitation to mention in this study is that the test dose
was only 6.0 mg/day. Therefore, it is unclear if similar
efficacy can be observed even at lower doses, or if
stronger eﬀect can be obtained at higher doses. Further
research is required to determine the optimal dose.
There were no adverse events or side effects in thisstudy, and it was considered that there was no problem
with the safety of the test product.

5. SUMMARY
To evaluate the eﬀects of 12-week intake of pentadecylcontaining orlan oil on skin condition, the study was
conducted in healthy adult women aged 35 to 59 years
with dry skin and concern about facial sagging. In thisstudy, the test food group showed significant
improvement in elasticity R2 (left, average), R5 (left),and R7 (left, right, average) after 12 weeks compared tothe control group. There were also signiﬁcant diﬀerencesin improvement of collagen score intensity (left, right,
average), stratum corneum water content (left, right,
average), and water loss (left). These results suggestthat the 12-week intake of pentadecyl-containing orlan oil
improves skin elasticity by increasing collagen density,
which in turn improves skin moisture. During the study,no adverse events were observed that were attributed tothe intake of test product.

22 （470）

診療と新薬・第 60 巻

Conﬂict of Interest
This research has received financial support and a manuscript requestfrom Sea Act Co., Ltd.

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