WO2022014660A1 - Sebum production regulator - Google Patents

Sebum production regulator Download PDF

Info

Publication number
WO2022014660A1
WO2022014660A1 PCT/JP2021/026544 JP2021026544W WO2022014660A1 WO 2022014660 A1 WO2022014660 A1 WO 2022014660A1 JP 2021026544 W JP2021026544 W JP 2021026544W WO 2022014660 A1 WO2022014660 A1 WO 2022014660A1
Authority
WO
WIPO (PCT)
Prior art keywords
skin
sebum production
acne
sebum
hydrogen atom
Prior art date
Application number
PCT/JP2021/026544
Other languages
French (fr)
Japanese (ja)
Inventor
隆司 藤田
Original Assignee
学校法人立命館
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 学校法人立命館 filed Critical 学校法人立命館
Priority to JP2022536434A priority Critical patent/JPWO2022014660A1/ja
Publication of WO2022014660A1 publication Critical patent/WO2022014660A1/en

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/08—Antiseborrheics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin

Definitions

  • the present invention is based on the formula (I).
  • R 1 represents a hydrogen atom or a methyl group
  • R 2 represents a hydrogen atom or a methyl group.
  • Sebum has the role of protecting the skin from dryness and external stimuli and keeping the skin soft. Sebum is secreted by the sebaceous glands, which develop most during puberty in the teens and twenties. The developed and enlarged sebaceous glands secrete excess sebum, mix with the old stratum corneum of the pores, and form keratin plugs in the pores to make the pores stand out, which is a cosmetic problem. In addition, excessively secreted sebum can cause acne and skin problems caused by the growth of P. acnes.
  • Isoflavone compounds, matrix metalloproteinase inhibitors and the like are known as compounds having a sebum secretion inhibitory effect.
  • examples of the compound having a sebum secretion promoting action include ⁇ -oryzanol.
  • the part with many sebaceous glands and the part with few sebaceous glands are adjacent to each other, it is necessary to apply an appropriate drug to the appropriate part, which is complicated.
  • Oleanolic acid which is one of the pentacyclic terpenes, is a functional triterpene and has been found to have physiological activities such as anticancer effect, anti-inflammatory effect, antioxidant effect, and antihyperlipidemic effect.
  • oleanolic acid has already been reported as a hair growth or hair growth agent (Patent Document 1), and derivatives of oleanolic acid and ursolic acid have been reported as photoaging inhibitors (Patent Document 2).
  • Patent Document 1 a hair growth or hair growth agent
  • Patent Document 2 derivatives of oleanolic acid and ursolic acid have been reported as photoaging inhibitors
  • no regulatory effect of oleanolic acid on sebum secretion has been reported so far.
  • An object of the present invention is to provide a novel agent for regulating sebum secretion.
  • the present inventor found that when sebaceous gland cells were treated with oleanolic acid or ursolic acid in the absence of C. Acne, lipogenesis increased in a treatment concentration-dependent manner, but DMSO-treated cells in the presence of C. Acne. Although the lipid production was very high, it was confirmed that the cells treated with oleanolic acid or ursolic acid suppressed the increase in the amount of lipid production induced by C. Acne. In addition, when C. Acne was injected into the skin of mice, enlarged sebaceous glands and keratin plugs were observed in the injected skin, but it was found that these were suppressed by treatment with 0.1% oleanolic acid.
  • R 1 represents a hydrogen atom or a methyl group
  • R 2 represents a hydrogen atom or a methyl group.
  • R 1 represents a hydrogen atom or a methyl group
  • R 2 represents a hydrogen atom or a methyl group.
  • the compound represented by the compound or a physiologically acceptable salt thereof should be administered to the subject.
  • Methods for regulating sebum production including. [9] Formula (I) for use in the treatment of skin disorders or acne caused by dry skin
  • R 1 represents a hydrogen atom or a methyl group
  • R 2 represents a hydrogen atom or a methyl group.
  • R 1 represents a hydrogen atom or a methyl group
  • R 2 represents a hydrogen atom or a methyl group.
  • R 1 represents a hydrogen atom or a methyl group
  • R 2 represents a hydrogen atom or a methyl group.
  • a compound represented by the compound or a physiologically acceptable salt thereof is used as a sebum production regulator. Can be provided.
  • the present invention is based on the formula (I).
  • R 1 represents a hydrogen atom or a methyl group
  • R 2 represents a hydrogen atom or a methyl group.
  • a sebum production regulator containing a salt is provided.
  • the combination of R 1 and R 2 may be any combination, but when R 1 is a hydrogen atom, R 2 is a methyl group, and when R 1 is a methyl group, R 2 is preferably a hydrogen atom.
  • R 1 is a hydrogen atom and R 2 is a methyl group
  • the compound of the present invention has the formula (II).
  • the compound of the present invention may be a physiologically acceptable salt thereof.
  • the physiologically acceptable salt of the compound represented by the formula (I) is not particularly limited as long as it is a salt usually used in a pharmaceutical composition, and is, for example, an alkali metal salt such as sodium or potassium.
  • Alkaline earth metal salts such as calcium and magnesium; organic amine salts such as triethylamine, piperazine, piperidine and triethanolamine; basic amino acid salts such as lysine and arginine; and the like can be exemplified.
  • the compounds of the present invention or physiologically acceptable salts thereof are provided as sebum production regulators.
  • the regulation of sebum production includes, but is not limited to, suppression of sebum production in oily skin or promotion of sebum production in dry skin. Therefore, in one embodiment, the sebum production regulator of the present invention is provided as a sebum production inhibitor in oily skin.
  • Suppression of sebum production in oily skin means that when sebum is produced from the sebaceous glands in excess of normal sebum production, the production of sebum is suppressed by the compound of the present invention or a physiologically acceptable salt thereof.
  • causes of sebum production from the sebaceous glands in excess of normal sebum production include sebaceous gland irritation by Cutibacterium acnes, stress, and overexpression of hormones (eg, testosterone, 5 ⁇ -dihydrotestosterone).
  • hormones eg, testosterone, 5 ⁇ -dihydrotestosterone
  • the amount of sebum produced may be reduced, and it is preferable that the amount of sebum produced is reduced to a normal level.
  • the sebum production regulator of the present invention is provided as a sebum production promoter in dry skin.
  • promotion of sebum production in dry skin means that when sebum is produced from the sebaceous glands below the normal amount of sebum produced, the compound of the present invention or a physiologically acceptable salt thereof promotes sebum production.
  • causes of sebum production from the sebaceous glands below the normal production amount include insufficient secretion of sebum from the sebaceous glands due to aging and insufficient secretion of sebum due to a decrease in temperature in winter.
  • the promotion may be as long as the amount of sebum produced is increased, and it is preferable that the amount of sebum produced is increased to a normal level.
  • the skin oil production regulator of the present invention is used for humans, non-human animals (for example, mammals other than humans (livestock such as pigs, cows, horses, dogs, cats), birds (poultry such as turkeys, chickens), etc.). It can be applied, preferably to humans.
  • non-human animals for example, mammals other than humans (livestock such as pigs, cows, horses, dogs, cats), birds (poultry such as turkeys, chickens), etc.
  • the compound of the present invention or a physiologically acceptable salt thereof can be dissolved in ethanol, oils and fats such as tea seed oil, cream and the like, and used as a sebum production regulator.
  • the compounding amount of the compound of the present invention is 0.001% (w / w) or more, preferably 0.01% (w / w) or more, and more preferably 0.1% (w / w) or more of the total weight of the sebum production regulator. It is preferable to mix in a ratio. If the blending amount is too small, the sebum production regulating effect cannot be sufficiently obtained, which is not preferable.
  • As the upper limit for example, 10% (w / w) or less, preferably 5% (w / w) or less, more preferably 2% (w / w) or less can be mentioned.
  • raw material components to be blended in the sebum production regulator those applied to a normal sebum production regulator can be used.
  • hydrocarbons, waxes, fats and oils, esters, higher fatty acids, higher alcohols, surfactants, fragrances, pigments, preservatives, preservatives, excipients, cooling agents, wetting agents, antioxidants. , UV protection agents, alcohols, pH adjusters, etc. can be blended.
  • the sebum production regulator of the present invention may be in any form as long as it can be applied externally to the skin.
  • it can be in the form of a cream, ointment, lotion or the like as a drug or quasi-drug.
  • the present invention is a therapeutic agent for sebum, which comprises a sebum production inhibitor in oily skin.
  • the sebum production inhibitor of the present invention is a therapeutic agent for sebum, which comprises a sebum production inhibitor in oily skin.
  • Acne is a chronic inflammatory disease of the sebaceous glands, and examples thereof include acne vulgaris (acne, especially adolescent acne) and seborrheic dermatitis.
  • the therapeutic agent for acne of the present invention may contain, as other auxiliary agents, a keratolytic agent, a bactericidal agent, an anti-inflammatory agent, an antiseborrheic agent, an antipruritic agent and the like.
  • the sebum production regulator of the present invention is provided as a sebum production promoter in dry skin (the sebum production promoter of the present invention)
  • the present invention is derived from dry skin, which comprises a sebum production promoter in dry skin.
  • Skin diseases caused by dry skin are diseases caused by the loss of the protective function of the skin due to sebum, such as xeroderma, adult acne, redness of adult acne, itching of adult acne, and roughness of the skin. Examples include dry skin or rough skin.
  • adolescent acne differs from acne that mainly affects teenagers, so-called “adolescent acne", in various respects.
  • adult acne is known to have problems such as easy recurrence, acne scars and spots.
  • adolescent acne is mainly caused by increased sebum secretion, whereas adult acne is not limited to them, but is dry, hormonal imbalance, irregular life, and lack of sleep. , Disordered eating habits, overwork, stress, etc. are cited as causes.
  • the preferred applicable disease thereof is adult acne due to dryness or imbalance of hormones, which is more preferable.
  • examples include adult acne due to dryness.
  • Patients with dry skin include patients with a water content of 72 or less when the water content of the cheeks of the face is measured with a corneometer (trade name: Comeometer CM825, manufacturer Courage + Khazaka).
  • Patients with a facial cheek moisture content of 64 or less, preferably 60 or less, can be expected to be more effective as a target for applying the sebum production promoter of the present invention.
  • the therapeutic agent for skin diseases caused by dry skin of the present invention may contain a moisturizer, a bactericidal agent, an anti-inflammatory agent, an antipruritic agent and the like as other auxiliary agents.
  • C. acnes JCM6425, Riken Bioresource Center, Tsukuba, Japan
  • GMG culture Nissui, Tokyo, Japan
  • sebum production was more efficient than live C. acnes, so homogenates were used in the following examples.
  • C. acnes of 5 ⁇ 10 7 CFU was sonicated with Branson Sonifier model 150 (Danbury, CT, USA) and aliquots were stored at 4 ° C until use.
  • protein quantification was performed and aliquots dissolved in the medium were added at 100 ⁇ g / ml.
  • SZ95 Immortalized human sebaceous gland cells SZ95 are derived from human facial sebaceous glands, 10% bovine fetal serum (Thermo Fisher Scientific Inc., Waltham, MA, USA), 5 ng / ml human epidermal growth factor (hEGF) (PeproTech GmbH,). It was cultured in Sebomed® Basal Medium (Millipore, Billerica, MA, USA) supplemented with Hamburg, Germany), 50 IU / ml penicillin, and 50 ⁇ g / ml streptomycin (Nacalai Tesque, Kyoto, Japan). Medium was changed every other day and cells were secondarily cultured at 60-70% confluence.
  • Intracellular lipid concentration For semi-quantitative detection of sebaceous lipids, 10 ⁇ g / ml BODIPY TM 493/503 (4,4-difluoro-1,3,5,7,8-pentamethyl-4-bora-3a) , 4a-Diaza-s-Indasen) (Thermo Fisher Scientific) stain v applied, while 55 ⁇ l lysis buffer of cells stained with fluorescent BODIPY TM in a 48-well plate for quantitative measurement. Lysis with (25 mM Triton phosphate [pH 7.8], 2 mM DTT, 2 mM EDTA, 10% glycerol, and 1% Triton X-100).
  • Tissues were stained with BODIPY, macroscopic images were obtained from the back of the skin with a fluorescent stereomicroscope LEICA MZ10F / DFC7000 T, and analyzed with software LAS V4.12 (Leica mycrosystems, Wetzlar, German). The results are shown in FIG. As a result, by applying oleanolic acid for external use, the enlargement of the sebaceous glands due to P. acnes injection was suppressed, and the stainability by BODIPY was reduced at the beginning compared to the solvent control. The tissue was fixed with 10% formalin and embedded. Paraffin sections were then prepared and stained with HE. The results are shown in FIG.
  • HE staining of paraffin sections showed enlarged sebaceous glands (arrows) and keratin plugs (arrowheads) in C. Acne-injected skin (CRL), which were suppressed by treatment with 0.1% oleanolic acid.
  • Example 3 Test method for suppressing the inhibitory effect of oleanolic acid on the promotion of sebum secretion by n-tetradecane 1. Rabbit grouping Rabbits were grouped as shown in Table 1.
  • n-tetradecane and test substance The administration schedule of n-tetradecane and test substance is shown in FIG. Before administration of n-tetradecane, the approximate area inside the auricle of both ears of each rabbit was determined, the dose was determined to be 0.2 mL / 3x3 cm, and the dose was administered to the entire inside of the auricle. Administration was performed between 8:00 and 18:00, and test days 1 to 14 were performed once / day in both ears of all groups. On test days 15-21, group I was performed once / day on both ears. Group II was not administered to both ears. In group III, only the right ear was performed once a day, and the left ear was not performed.
  • a plant extract containing oleanolic acid (test substance A) and 0.1% oleanolic acid (test substance) was provided at the site where petrolatum was sufficiently formed inside the auricle of rabbits treated with n-tetradecane.
  • B) or Vaseline (base) was administered in an amount of 0.5 g.
  • a 3x3 cm site for diameter measurement and excision was also set in the right ear of group III, which received no administration.
  • Administration was performed to both ears of groups I and II and the left ear of group III for 7 days (once / day, 8: 00-18: 00) on test days 15 to 21, and the right ear of group III was administered. I didn't.
  • Pore diameter measurement Pore diameter was measured before administration of n-tetradecane (TD) on test days 14 and 15, and the average value was used as the pre-value. On test days 16, 18, 20 and 22, optionally 10 pores at the administration site of oleanolic acid (test substance A), plant extract containing 0.1% oleanolic acid (test substance B) or petrolatum (base). The pore size was measured using a microscope (Dino-Lite Digital Microscope, model number: DILOTEPL, sold by Sanko). The average value and standard deviation of the pore diameter were calculated.
  • TD n-tetradecane
  • the significance test was performed by the F-test for homoscedasticity, the Student's t-test for homoscedasticity, and the Aspin-Welch's t-test for unequal dispersion.
  • the significance level was set to a risk rate of 5%
  • the significance level was set to a risk rate of 5% and 1%. The results are shown in Table 2 and FIG.
  • Test 1 when only petrolatum (base) was administered after administration of n-tetradecane for 14 days, the pore diameter on the 22nd day was even larger than the pore diameter on the 14th day (301 left ear). However, when oleanolic acid (test substance A) or a plant extract containing 0.1% oleanolic acid (test substance B) was administered after administration of n-tetradecane for 14 days, the pore diameter on the 22nd day was larger than the pore diameter on the 14th day. It was getting smaller (201 right ear, 201 left ear).
  • Test 2 when n-tetradecane was continuously administered for 22 days, the pore diameter on the 22nd day was even larger than the pore diameter on the 14th day (301 right ear). However, when oleanolic acid (test substance A) or a plant extract containing 0.1% oleanolic acid (test substance B) was administered together with n-tetradecane from the 15th day, the pore diameter on the 22nd day was the pore diameter on the 14th day. Although it was even larger, the degree could be suppressed (101 right ear, 101 left ear).
  • Paraffin sections at the excised site were prepared, stained with hematoxylin and eosin, and observed using a binocular microscope BHS.
  • a representative example of the findings is shown in FIG. In the ear canal tissue on day 22 in the 301 right ear, dilation of the pore diameter was confirmed. On the other hand, in the stained images of the external auditory canal tissue of the 101st right ear and the 201st right ear, no dilation of the pore diameter could be observed.
  • Example 4 Test method for treating adult acne using oleanolic acid Test method Setyl ethylcaproate (trade name: NIKKOL) so that oleanolic acid (trade name: Oleanolic Acid, manufactured by Wako Pure Chemical Industries, Ltd.) is 1% (w / w). CI0, Nikko Chemicals) was used as a solvent to prepare the solutions shown in Table 3.
  • R 1 represents a hydrogen atom or a methyl group
  • R 2 represents a hydrogen atom or a methyl group.
  • a compound represented by the compound or a physiologically acceptable salt thereof is used as a sebum production regulator. Can be provided. This application is based on Japanese Patent Application No. 2020-122251 (Filing date: July 16, 2nd year of Reiwa), the entire contents of which are incorporated herein by reference.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Dermatology (AREA)
  • Chemical & Material Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Emergency Medicine (AREA)
  • Birds (AREA)
  • Cosmetics (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The present invention provides a novel sebum secretion regulator.

Description

皮脂産生調節剤Sebum production regulator
　本発明は、式(I) The present invention is based on the formula (I).
Figure JPOXMLDOC01-appb-C000005
Figure JPOXMLDOC01-appb-C000005
（式中、R1は、水素原子またはメチル基を表し、R2は、水素原子またはメチル基を表す。）で表される化合物またはその生理的に許容される塩を含む、皮脂産生調節剤に関する。 (In the formula, R 1 represents a hydrogen atom or a methyl group, and R 2 represents a hydrogen atom or a methyl group.) A sebum production regulator containing a compound represented by the compound or a physiologically acceptable salt thereof. Regarding.
　皮脂は、皮膚を乾燥や外的刺激から守り、皮膚の柔軟性を保つ役割を持つ。皮脂は皮脂腺より分泌され、皮脂腺は１０～２０代の思春期に最も発達する。発達し肥大した皮脂腺は過剰に皮脂を分泌し、毛穴の古い角質層と混ざり、角栓が毛穴に形成されることによって毛穴の開きを目立たせ、美容上の問題となる。さらに、過剰に分泌される皮脂は、アクネ菌の増殖によって引き起こされるニキビや皮膚トラブルの原因にもなる。一方、皮脂の分泌が少ない部位、すなわち皮脂腺の密度が小さい部位では、皮膚の水分保持機能が低下し、乾燥肌になりやすく、外部からの刺激に弱くなる。例えば、顔の皮膚では、目や口の周り、頬、首は皮脂腺の数が少なく、皮脂分泌量が少ないため乾燥しやすい。一方、額や鼻は皮脂腺が多いため、ニキビなどが生じやすい。従って、皮脂腺の多い部分では皮脂腺からの過剰な皮脂の分泌を防止すると共に、皮脂腺の少ない部分では不足する皮脂を補い、皮膚の水分保持機能を高める必要があった。 Sebum has the role of protecting the skin from dryness and external stimuli and keeping the skin soft. Sebum is secreted by the sebaceous glands, which develop most during puberty in the teens and twenties. The developed and enlarged sebaceous glands secrete excess sebum, mix with the old stratum corneum of the pores, and form keratin plugs in the pores to make the pores stand out, which is a cosmetic problem. In addition, excessively secreted sebum can cause acne and skin problems caused by the growth of P. acnes. On the other hand, in a part where the secretion of sebum is low, that is, a part where the density of sebaceous glands is low, the water retention function of the skin is lowered, the skin tends to become dry, and it becomes vulnerable to external stimuli. For example, on the skin of the face, the eyes, around the mouth, cheeks, and neck have a small number of sebaceous glands, and the amount of sebum secreted is small, so that the skin tends to dry. On the other hand, since the forehead and nose have many sebaceous glands, acne is likely to occur. Therefore, it is necessary to prevent the secretion of excess sebum from the sebaceous glands in the portion having many sebaceous glands, and to supplement the insufficient sebum in the portion having few sebaceous glands to enhance the water retention function of the skin.
　皮脂分泌抑制作用を有する化合物として、イソフラボン化合物、マトリックスメタロプロテアーゼ阻害物質等が知られている。一方、皮脂分泌促進作用を有する化合物としては例えば、γ-オリザノールが挙げられる。しかし、特に顔の皮膚では皮脂腺の多い部分と少ない部分が互いに隣接するため、適切な部分に適切な薬剤を塗り分ける必要があり、煩雑であった。 Isoflavone compounds, matrix metalloproteinase inhibitors and the like are known as compounds having a sebum secretion inhibitory effect. On the other hand, examples of the compound having a sebum secretion promoting action include γ-oryzanol. However, especially on the skin of the face, since the part with many sebaceous glands and the part with few sebaceous glands are adjacent to each other, it is necessary to apply an appropriate drug to the appropriate part, which is complicated.
　五環性テルペンの１つであるオレアノール酸は機能性トリテルペンであり、抗がん作用、抗炎症作用、抗酸化作用、抗高脂血症効果などの生理活性を有していることが分かっている。また、オレアノール酸はすでに発毛または育毛剤として報告され（特許文献１）、オレアノール酸およびウルソール酸のそれぞれの誘導体は、光老化防止剤として報告されている（特許文献２）。しかし、これまでオレアノール酸による皮脂の分泌に対する調節効果は報告されていない。 Oleanolic acid, which is one of the pentacyclic terpenes, is a functional triterpene and has been found to have physiological activities such as anticancer effect, anti-inflammatory effect, antioxidant effect, and antihyperlipidemic effect. There is. In addition, oleanolic acid has already been reported as a hair growth or hair growth agent (Patent Document 1), and derivatives of oleanolic acid and ursolic acid have been reported as photoaging inhibitors (Patent Document 2). However, no regulatory effect of oleanolic acid on sebum secretion has been reported so far.
特開平9-157139号公報Japanese Unexamined Patent Publication No. 9-157139 特開平9-140305号公報Japanese Unexamined Patent Publication No. 9-140305
　本発明は、新規な皮脂分泌の調節剤を提供することを目的とする。 An object of the present invention is to provide a novel agent for regulating sebum secretion.
　本発明者は、C. Acneの非存在下、皮脂腺細胞をオレアノール酸またはウルソール酸で処理した場合、脂質生成は処理濃度依存的に増加したが、C. Acneの存在下、DMSO処理された細胞は脂質生成が非常に高いが、オレアノール酸またはウルソール酸で処理された細胞は、C. Acneによって誘導された脂質生成量の増加が抑制されることを確認した。また、マウスの皮膚にC. Acneを注射したところ、注射された皮膚では肥大した皮脂腺や角栓が観察されたが、0.1% オレアノール酸処理によってそれらが抑制されることを見出した。さらに、ウサギの皮膚をn-テトラデカンで処理し、その後、n-テトラデカンに代わってオレアノール酸で処理したところ、n-テトラデカンによって大きくなった毛孔径はオレアノール酸によって小さくなった。また、ウサギの皮膚をn-テトラデカンで処理し、さらに、n-テトラデカンにオレアノール酸を加えて処理したところ、オレアノール酸は、n-テトラデカンによる毛孔径の拡張の程度を抑えることができた。また、大人ニキビ患者８人に対してオレアノール酸を塗布し、１週間後の時点で評価したところ、症状の改善が見られた。 The present inventor found that when sebaceous gland cells were treated with oleanolic acid or ursolic acid in the absence of C. Acne, lipogenesis increased in a treatment concentration-dependent manner, but DMSO-treated cells in the presence of C. Acne. Although the lipid production was very high, it was confirmed that the cells treated with oleanolic acid or ursolic acid suppressed the increase in the amount of lipid production induced by C. Acne. In addition, when C. Acne was injected into the skin of mice, enlarged sebaceous glands and keratin plugs were observed in the injected skin, but it was found that these were suppressed by treatment with 0.1% oleanolic acid. Furthermore, when rabbit skin was treated with n-tetradecane and then with oleanolic acid instead of n-tetradecane, the pore diameter increased by n-tetradecane was reduced by oleanolic acid. Further, when the skin of the rabbit was treated with n-tetradecane and further treated with oleanolic acid added to n-tetradecane, oleanolic acid was able to suppress the degree of expansion of the pore diameter by n-tetradecane. In addition, when oleanolic acid was applied to 8 adult acne patients and evaluated one week later, improvement in symptoms was observed.
　すなわち、本発明は、
［１］式(I) That is, the present invention
[1] Equation (I)
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000006
（式中、R1は、水素原子またはメチル基を表し、R2は、水素原子またはメチル基を表す。）で表される化合物またはその生理的に許容される塩を含む、皮脂産生調節剤。
［２］式(I)で表される化合物が、オレアノール酸またはウルソール酸である、［１］に記載の皮脂産生調節剤。
［３］脂性肌における皮脂産生抑制剤である、［１］または［２］に記載の皮脂産生調節剤。
［４］［３］に記載の脂性肌における皮脂産生抑制剤を含む、ざ瘡の治療剤。
［５］乾燥肌における皮脂産生促進剤である、［１］または［２］に記載の皮脂産生調節剤。
［６］［５］に記載の乾燥肌における皮脂産生促進剤を含む、乾燥肌に起因する皮膚疾患の治療剤。
［７］乾燥肌に起因する皮膚疾患が大人ニキビである、［６］に記載の皮膚疾患の治療剤。
［８］式(I) (In the formula, R 1 represents a hydrogen atom or a methyl group, and R 2 represents a hydrogen atom or a methyl group.) A sebum production regulator containing a compound represented by the compound or a physiologically acceptable salt thereof. ..
[2] The sebum production regulator according to [1], wherein the compound represented by the formula (I) is oleanolic acid or ursolic acid.
[3] The sebum production regulator according to [1] or [2], which is a sebum production inhibitor in oily skin.
[4] A therapeutic agent for acne, which comprises the sebum production inhibitor in oily skin according to [3].
[5] The sebum production regulator according to [1] or [2], which is a sebum production promoter in dry skin.
[6] A therapeutic agent for a skin disease caused by dry skin, which comprises the sebum production promoter in dry skin according to [5].
[7] The therapeutic agent for a skin disease according to [6], wherein the skin disease caused by dry skin is adult acne.
[8] Equation (I)
Figure JPOXMLDOC01-appb-C000007
Figure JPOXMLDOC01-appb-C000007
（式中、R1は、水素原子またはメチル基を表し、R2は、水素原子またはメチル基を表す。）で表される化合物またはその生理的に許容される塩を対象に投与することを含む、皮脂産生調節方法。
［９］乾燥肌に起因する皮膚疾患またはざ瘡の治療における使用のための式(I) (In the formula, R 1 represents a hydrogen atom or a methyl group, and R 2 represents a hydrogen atom or a methyl group.) The compound represented by the compound or a physiologically acceptable salt thereof should be administered to the subject. Methods for regulating sebum production, including.
[9] Formula (I) for use in the treatment of skin disorders or acne caused by dry skin
Figure JPOXMLDOC01-appb-C000008
Figure JPOXMLDOC01-appb-C000008
（式中、R1は、水素原子またはメチル基を表し、R2は、水素原子またはメチル基を表す。）で表される化合物またはその生理的に許容される塩。
［１０］乾燥肌に起因する皮膚疾患またはざ瘡の治療剤を製造するための式(I) (In the formula, R 1 represents a hydrogen atom or a methyl group, and R 2 represents a hydrogen atom or a methyl group.) A compound represented by the compound or a physiologically acceptable salt thereof.
[10] Formula (I) for producing a therapeutic agent for skin diseases or acne caused by dry skin.
Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-C000009
（式中、R1は、水素原子またはメチル基を表し、R2は、水素原子またはメチル基を表す。）で表される化合物またはその生理的に許容される塩の使用。
を提供する。 (In the formula, R 1 represents a hydrogen atom or a methyl group, and R 2 represents a hydrogen atom or a methyl group.) Use of a compound represented by or a physiologically acceptable salt thereof.
I will provide a.
　式(I) Formula (I)
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000010
（式中、R1は、水素原子またはメチル基を表し、R2は、水素原子またはメチル基を表す。）で表される化合物またはその生理的に許容される塩を、皮脂産生調節剤として提供することができる。 (In the formula, R 1 represents a hydrogen atom or a methyl group, and R 2 represents a hydrogen atom or a methyl group.) A compound represented by the compound or a physiologically acceptable salt thereof is used as a sebum production regulator. Can be provided.
C. Acneの非存在下（上パネル）または存在下（下パネル）、オレアノール酸（OA:0.1、1または10μM）またはウルソール酸（UA:0.1、1または10μM）で処理したSZ95細胞の相対蛍光単位(RFU)を示すグラフである。n=6. *P<0.005, ***P<0.005 vs. control. Veh: DMSO control (0.1%).Relative fluorescence of SZ95 cells treated with oleanolic acid (OA: 0.1, 1 or 10 μM) or ursolic acid (UA: 0.1, 1 or 10 μM) in the absence (upper panel) or presence (lower panel) of C. Acne It is a graph which shows the unit (RFU). n = 6. * P <0.005, *** P <0.005 vs. control. Veh: DMSO control (0.1%). C. Acneの存在下、オレアノール酸で処理したマウス脂腺細胞の脂肪滴の蛍光実体顕微鏡像を示す図である。It is a figure which shows the fluorescent stereomicroscope image of the lipid droplet of the mouse fat gland cell treated with oleanolic acid in the presence of C. Acne. C. Acneの存在下、オレアノール酸で処理したマウス脂腺細胞を含む組織のHE染色像を示す図である。It is a figure which shows the HE staining image of the tissue containing the mouse fat gland cells treated with oleanolic acid in the presence of C. Acne. n-テトラデカンと被験物質（オレアノール酸またはワセリン）の投与スケジュールを示す図である。It is a figure which shows the administration schedule of n-tetradecane and a test substance (oleanolic acid or petrolatum). n-テトラデカンと被験物質（オレアノール酸またはワセリン）投与後の毛孔径のサイズを示すグラフである。黒色バー：14日目、灰色バー：22日目It is a graph which shows the size of the pore diameter after administration of n-tetradecane and a test substance (oleanolic acid or petrolatum). Black bar: 14th day, gray bar: 22nd day n-テトラデカンと被験物質（オレアノール酸またはワセリン）で処理したウサギ脂腺細胞を含む組織のHE染色像を示す図である。It is a figure which shows the HE staining image of the tissue containing the rabbit fat gland cell treated with n-tetradecane and a test substance (oleanolic acid or petrolatum).
　本発明は、式(I) The present invention is based on the formula (I).
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011
（式中、R1は、水素原子またはメチル基を表し、R2は、水素原子またはメチル基を表す。）で表される化合物（以下、本発明の化合物）またはその生理的に許容される塩を含む、皮脂産生調節剤を提供する。 (In the formula, R 1 represents a hydrogen atom or a methyl group, and R 2 represents a hydrogen atom or a methyl group.) A compound represented by a compound (hereinafter referred to as a compound of the present invention) or a physiologically acceptable compound thereof. Provided is a sebum production regulator containing a salt.
　本発明の化合物において、R1とR2の組み合わせは、どのような組み合わせであってもよいが、R1が水素原子の場合、R2はメチル基であり、R1がメチル基の場合、R2は水素原子であることが好ましい。R1が水素原子かつR2はメチル基である場合、本発明の化合物は式(II) In the compound of the present invention, the combination of R 1 and R 2 may be any combination, but when R 1 is a hydrogen atom, R 2 is a methyl group, and when R 1 is a methyl group, R 2 is preferably a hydrogen atom. When R 1 is a hydrogen atom and R 2 is a methyl group, the compound of the present invention has the formula (II).
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012
で表されるオレアノール酸である。また、R1がメチル基かつR2は水素原子である場合、本発明の化合物は式(III) It is an oleanolic acid represented by. Further, when R 1 is a methyl group and R 2 is a hydrogen atom, the compound of the present invention has the formula (III).
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
で表されるウルソール酸である。 Ursolic acid represented by.
　また、本発明の化合物は、その生理的に許容される塩であってもよい。式(I)で表される化合物の生理的に許容される塩としては、通常医薬組成物で用いられている塩であれば特段の限定はされず、例えば、ナトリウムやカリウム等のアルカリ金属塩；カルシウム、マグネシウム等のアルカリ土類金属塩；トリエチルアミン、ピペラジン、ピペリジン、トリエタノールアミン等の有機アミン塩；リジン、アルギニン等の塩基性アミノ酸塩；等を例示することができる。 Further, the compound of the present invention may be a physiologically acceptable salt thereof. The physiologically acceptable salt of the compound represented by the formula (I) is not particularly limited as long as it is a salt usually used in a pharmaceutical composition, and is, for example, an alkali metal salt such as sodium or potassium. Alkaline earth metal salts such as calcium and magnesium; organic amine salts such as triethylamine, piperazine, piperidine and triethanolamine; basic amino acid salts such as lysine and arginine; and the like can be exemplified.
　後述する実施例に記載の通り、オレアノール酸およびウルソール酸は、通常は皮脂産生を促進するが、皮脂産生が過剰に分泌される条件下では逆に皮脂の産生を抑制することが確認された。従って、本発明の化合物またはその生理的に許容される塩は皮脂産生調節剤として提供される。 As described in Examples described later, it was confirmed that oleanolic acid and ursolic acid normally promote sebum production, but conversely suppress sebum production under conditions where sebum production is excessively secreted. Therefore, the compounds of the present invention or physiologically acceptable salts thereof are provided as sebum production regulators.
　本明細書において皮脂産生調節とは、それに限定されるものではないが、脂性肌における皮脂産生の抑制または乾燥肌における皮脂産生の促進を包含する。従って、一実施態様として、本発明の皮脂産生調節剤は、脂性肌における皮脂産生抑制剤として提供される。 In the present specification, the regulation of sebum production includes, but is not limited to, suppression of sebum production in oily skin or promotion of sebum production in dry skin. Therefore, in one embodiment, the sebum production regulator of the present invention is provided as a sebum production inhibitor in oily skin.
　脂性肌における皮脂産生の抑制とは、正常な皮脂の産生量を超えて皮脂が皮脂腺から産生される場合、本発明の化合物またはその生理的に許容される塩によって、皮脂の産生が抑制されることをいう。正常な皮脂の産生量を超えて皮脂が皮脂腺から産生される原因としては、Cutibacterium acnesによる皮脂腺の刺激、ストレス、ホルモン（例えば、テストステロン、5α-ジヒドロテストステロン）の過剰発現などが挙げられる。抑制は、皮脂の生産量が減少すればよく、正常な水準の皮脂の産生量まで減少することが好ましい。 Suppression of sebum production in oily skin means that when sebum is produced from the sebaceous glands in excess of normal sebum production, the production of sebum is suppressed by the compound of the present invention or a physiologically acceptable salt thereof. Say that. Causes of sebum production from the sebaceous glands in excess of normal sebum production include sebaceous gland irritation by Cutibacterium acnes, stress, and overexpression of hormones (eg, testosterone, 5α-dihydrotestosterone). For suppression, the amount of sebum produced may be reduced, and it is preferable that the amount of sebum produced is reduced to a normal level.
　また、別の実施態様として、本発明の皮脂産生調節剤は、乾燥肌における皮脂産生促進剤として提供される。 Further, as another embodiment, the sebum production regulator of the present invention is provided as a sebum production promoter in dry skin.
　乾燥肌における皮脂産生の促進とは、皮脂が皮脂腺から正常な皮脂の産生量を下回って産生される場合、本発明の化合物またはその生理的に許容される塩によって、皮脂の産生が促進されることをいう。正常な皮脂の産生量を下回って皮脂が皮脂腺から産生される原因としては、老化による皮脂腺からの皮脂の分泌不足、冬季の気温の低下に伴う皮脂の分泌不足などが挙げられる。促進は、皮脂の生産量が増加すればよく、正常な水準の皮脂の産生量まで増加することが好ましい。 Promotion of sebum production in dry skin means that when sebum is produced from the sebaceous glands below the normal amount of sebum produced, the compound of the present invention or a physiologically acceptable salt thereof promotes sebum production. Say that. Causes of sebum production from the sebaceous glands below the normal production amount include insufficient secretion of sebum from the sebaceous glands due to aging and insufficient secretion of sebum due to a decrease in temperature in winter. The promotion may be as long as the amount of sebum produced is increased, and it is preferable that the amount of sebum produced is increased to a normal level.
　本発明の皮脂産生調節剤は、ヒト、ヒト以外の動物（例えば、ヒト以外の哺乳類（ブタ、ウシ、ウマ、イヌ、ネコ等の家畜）、鳥類（シチメンチョウ、ニワトリ等の家禽）等）等に適用することができ、好ましくはヒトに適用される。 The skin oil production regulator of the present invention is used for humans, non-human animals (for example, mammals other than humans (livestock such as pigs, cows, horses, dogs, cats), birds (poultry such as turkeys, chickens), etc.). It can be applied, preferably to humans.
　本発明の化合物またはその生理的に許容される塩は、エタノール、つばき油などの油脂類、クリームなどに溶解して、皮脂産生調節剤として使用することができる。
　本発明の化合物の配合量としては、皮脂産生調節剤重量の全体の0.001％(w/w)以上、好ましくは0.01％(w/w)以上、より好ましくは0.1％(w/w)以上の割合で配合することが好適である。配合量が少なすぎる場合、皮脂産生調節効果が十分に得られず好ましくない。
　上限としては、例えば、10％(w/w)以下、好ましくは5％(w/w)以下、より好ましくは2％(w/w)以下を挙げることができる。 The compound of the present invention or a physiologically acceptable salt thereof can be dissolved in ethanol, oils and fats such as tea seed oil, cream and the like, and used as a sebum production regulator.
The compounding amount of the compound of the present invention is 0.001% (w / w) or more, preferably 0.01% (w / w) or more, and more preferably 0.1% (w / w) or more of the total weight of the sebum production regulator. It is preferable to mix in a ratio. If the blending amount is too small, the sebum production regulating effect cannot be sufficiently obtained, which is not preferable.
As the upper limit, for example, 10% (w / w) or less, preferably 5% (w / w) or less, more preferably 2% (w / w) or less can be mentioned.
　また、当該皮脂産生調節剤に配合する他の原料成分としては、通常の皮脂産生調節剤に適用されるものを用いることができる。例えば、炭化水素類、ロウ類、油脂類、エステル類、高級脂肪酸類、高級アルコール類、界面活性剤、香料、色素、防腐剤、保存剤、賦形剤、清涼剤、湿潤剤、抗酸化剤、紫外線防御剤、アルコール類、pH調整剤などを配合することができる。 Further, as other raw material components to be blended in the sebum production regulator, those applied to a normal sebum production regulator can be used. For example, hydrocarbons, waxes, fats and oils, esters, higher fatty acids, higher alcohols, surfactants, fragrances, pigments, preservatives, preservatives, excipients, cooling agents, wetting agents, antioxidants. , UV protection agents, alcohols, pH adjusters, etc. can be blended.
　本発明の皮脂産生調節剤は、皮膚に対して外用塗布が可能な形態であれば如何なる形態であってもよい。例えば、医薬品または医薬部外品として、クリーム、軟膏、ローション等の形態とすることができる。 The sebum production regulator of the present invention may be in any form as long as it can be applied externally to the skin. For example, it can be in the form of a cream, ointment, lotion or the like as a drug or quasi-drug.
　本発明の皮脂産生調節剤が、脂性肌における皮脂産生抑制剤（本発明の皮脂産生抑制剤）として提供される場合、本発明は、脂性肌における皮脂産生抑制剤を含む、ざ瘡の治療剤を提供する。ざ瘡とは、脂腺の慢性炎症性疾患であり、例えば、尋常性ざ瘡（ニキビ、特に思春期ニキビ）、脂漏性皮膚炎などが挙げられる。また、本発明のざ瘡の治療剤は、他の補助的な薬剤として、角質溶解剤、殺菌剤、消炎剤、抗脂漏剤、止痒剤などを配合することができる。 When the sebum production regulator of the present invention is provided as a sebum production inhibitor in oily skin (the sebum production inhibitor of the present invention), the present invention is a therapeutic agent for sebum, which comprises a sebum production inhibitor in oily skin. I will provide a. Acne is a chronic inflammatory disease of the sebaceous glands, and examples thereof include acne vulgaris (acne, especially adolescent acne) and seborrheic dermatitis. In addition, the therapeutic agent for acne of the present invention may contain, as other auxiliary agents, a keratolytic agent, a bactericidal agent, an anti-inflammatory agent, an antiseborrheic agent, an antipruritic agent and the like.
　本発明の皮脂産生調節剤が、乾燥肌における皮脂産生促進剤（本発明の皮脂産生促進剤）として提供される場合、本発明は、乾燥肌における皮脂産生促進剤を含む、乾燥肌に起因する皮膚疾患の治療剤を提供する。乾燥肌に起因する皮膚疾患とは、皮脂による皮膚の保護機能が失われたことによって生じる疾患であり、例えば、乾皮症、大人ニキビ、大人ニキビの赤み、大人ニキビのかゆみ、皮膚のざらつき、皮膚のかさつきまたは肌荒れなどが挙げられる。 When the sebum production regulator of the present invention is provided as a sebum production promoter in dry skin (the sebum production promoter of the present invention), the present invention is derived from dry skin, which comprises a sebum production promoter in dry skin. Provide a therapeutic agent for skin diseases. Skin diseases caused by dry skin are diseases caused by the loss of the protective function of the skin due to sebum, such as xeroderma, adult acne, redness of adult acne, itching of adult acne, and roughness of the skin. Examples include dry skin or rough skin.
　大人ニキビとは、１０代のヒトが主に罹患するニキビ、所謂「思春期ニキビ」とは様々な点で異なる。例えば、大人ニキビは、再発しやすい、ニキビ跡やシミが残りやすいなどの問題があることが知られている。また、思春期ニキビは皮脂分泌の増大が主な原因とされているのに対し、大人ニキビは、それらに限定されるわけではないが、乾燥、ホルモンバランスの乱れ、不規則な生活、睡眠不足、食生活の乱れ、過労、ストレス等が原因として挙げられる。 Adult acne differs from acne that mainly affects teenagers, so-called "adolescent acne", in various respects. For example, adult acne is known to have problems such as easy recurrence, acne scars and spots. In addition, adolescent acne is mainly caused by increased sebum secretion, whereas adult acne is not limited to them, but is dry, hormonal imbalance, irregular life, and lack of sleep. , Disordered eating habits, overwork, stress, etc. are cited as causes.
　本発明の皮脂産生促進剤が、大人ニキビに適用される場合、効果的な治療効果を期待できるという観点から、その好ましい適用疾患として、乾燥またはホルモンバランスの乱れによる大人ニキビが挙げられ、より好ましくは、乾燥による大人ニキビが挙げられる。本発明の皮脂産生促進剤を乾燥による大人ニキビに適用する場合、投与される患者は乾燥肌であることが多い。乾燥肌の患者としては、コルネオメーター（商品名Comeometer CM825、製造元Courage+Khazaka社）で顔の頬の水分量を測定した際の水分量が、７２以下の患者が挙げられる。顔の頬の水分量が６４以下、好ましくは６０以下である患者であれば、本発明の皮脂産生促進剤の適用対象としてより効果が期待できる。 When the sebum production promoter of the present invention is applied to adult acne, from the viewpoint that an effective therapeutic effect can be expected, the preferred applicable disease thereof is adult acne due to dryness or imbalance of hormones, which is more preferable. Examples include adult acne due to dryness. When the sebum production promoter of the present invention is applied to adult acne due to dryness, the patient to which the present invention is administered often has dry skin. Patients with dry skin include patients with a water content of 72 or less when the water content of the cheeks of the face is measured with a corneometer (trade name: Comeometer CM825, manufacturer Courage + Khazaka). Patients with a facial cheek moisture content of 64 or less, preferably 60 or less, can be expected to be more effective as a target for applying the sebum production promoter of the present invention.
　本発明の乾燥肌に起因する皮膚疾患の治療剤は、他の補助的な薬剤として、保湿剤、殺菌剤、消炎剤、止痒剤などを配合することができる。 The therapeutic agent for skin diseases caused by dry skin of the present invention may contain a moisturizer, a bactericidal agent, an anti-inflammatory agent, an antipruritic agent and the like as other auxiliary agents.
　以下において、実施例により本発明をより具体的にするが、この発明はこれらに限定されるものではない。 Hereinafter, the present invention will be made more specific by way of examples, but the present invention is not limited thereto.
材料
　GMG培養液(Nissui, Tokyo, Japan)の－85℃のストック溶液からC. acnes (JCM6425, Riken Bioresource Center, Tsukuba, Japan)を静止期に達するまで3～7日間、厳密な嫌気条件下で培養した。予備実験では、生きたC. acnesよりも皮脂産生が効率的であったため、以下の実施例ではホモジネートを使用した。5×107 CFUのC. acnesをBranson Sonifier model 150 (Danbury, CT, USA)で超音波処理し、用時まで4℃でアリコートを保存した。実施例用に、タンパク質定量を行い、培地に溶解したアリコートを100 μg/mlで加えた。 Materials C. acnes (JCM6425, Riken Bioresource Center, Tsukuba, Japan) from -85 ° C stock solution of GMG culture (Nissui, Tokyo, Japan) for 3-7 days until quiescent conditions are reached under strict anaerobic conditions. It was cultured. In preliminary experiments, sebum production was more efficient than live C. acnes, so homogenates were used in the following examples. C. acnes of 5 × 10 7 CFU was sonicated with Branson Sonifier model 150 (Danbury, CT, USA) and aliquots were stored at 4 ° C until use. For the examples, protein quantification was performed and aliquots dissolved in the medium were added at 100 μg / ml.
培養
　Dr. Christos C. Zouboulis (Dessau Medical Center, Dessau, Germany)よりSZ95細胞をご提供いただいた。不死化したヒト脂腺細胞SZ95は、ヒト顔面皮脂腺に由来し、10%ウシ胎仔血清 (Thermo Fisher Scientific Inc., Waltham, MA, USA)、5 ng/mlヒト上皮増殖因子(hEGF) (PeproTech GmbH, Hamburg, Germany)、50 IU/ml ペニシリン、および50 μg/ml ストレプトマイシン(Nacalai Tesque, Kyoto, Japan)を補充したSebomed（登録商標）Basal Medium (Millipore, Billerica, MA, USA)中で培養した。培地を一日おきに交換し、60-70%のコンフレンスで細胞を二次培養した。 Cultured Dr. Christos C. Zouboulis (Dessau Medical Center, Dessau, Germany) provided SZ95 cells. Immortalized human sebaceous gland cells SZ95 are derived from human facial sebaceous glands, 10% bovine fetal serum (Thermo Fisher Scientific Inc., Waltham, MA, USA), 5 ng / ml human epidermal growth factor (hEGF) (PeproTech GmbH,). It was cultured in Sebomed® Basal Medium (Millipore, Billerica, MA, USA) supplemented with Hamburg, Germany), 50 IU / ml penicillin, and 50 μg / ml streptomycin (Nacalai Tesque, Kyoto, Japan). Medium was changed every other day and cells were secondarily cultured at 60-70% confluence.
細胞内脂質濃度
　脂腺性脂質の半定量的検出のために、10 μg/ml BODIPYTM 493/503 (4,4-ジフルオロ-1,3,5,7,8-ペンタメチル-4-ボラ-3a,4a-ジアザ-s-インダセン) (Thermo Fisher Scientific)染色をｖ適用し、一方で、定量的測定のために、48ウェルプレート中で蛍光BODIPYTMを用いて染色した細胞を55 μl の溶解バッファー(25 mM トリス-リン酸塩[pH 7.8]、2 mM DTT、2 mM EDTA、10% グリセロール、および1% Triton X-100)で溶解した。次いで、50 μlの溶解物を96ウェルマイクロプレートのウェル中に入れ、マイクロプレートリーダー(Corona Electric; model: SH-8100lab; Ibaraki, Japan) (Ex=493 nm/Em=503 nm)を用いて蛍光を測定した。 Intracellular lipid concentration For semi-quantitative detection of sebaceous lipids, 10 μg / ml BODIPY TM 493/503 (4,4-difluoro-1,3,5,7,8-pentamethyl-4-bora-3a) , 4a-Diaza-s-Indasen) (Thermo Fisher Scientific) stain v applied, while 55 μl lysis buffer of cells stained with fluorescent BODIPY TM in a 48-well plate for quantitative measurement. Lysis with (25 mM Triton phosphate [pH 7.8], 2 mM DTT, 2 mM EDTA, 10% glycerol, and 1% Triton X-100). Then, 50 μl of the lysate was placed in the well of a 96-well microplate and fluorescent using a microplate reader (Corona Electric; model: SH-8100lab; Ibaraki, Japan) (Ex = 493 nm / Em = 503 nm). Was measured.
実施例１　オレアノール酸およびウルソール酸による脂腺細胞SZ95における脂質生成の調節
　SZ95細胞を、C. Acneの非存在下または存在下、オレアノール酸（0.1、1または10μM）またはウルソール酸（0.1、1または10μM）で処理した。1日後、細胞を溶解し、BODIPYTM 493/503で染色した。結果を図１に示す。平均値±標準誤差として任意の相対蛍光単位(RFU)を示した。
　C. Acneの非存在下、SZ95細胞をオレアノール酸またはウルソール酸で処理した場合、脂質生成は処理濃度依存的に増加した。一方、C. Acneの存在下、DMSO処理された細胞は脂質生成が非常に高いが、オレアノール酸またはウルソール酸で処理された細胞は、C. Acneによって誘導された脂質生成量の増加が抑制された。 Example 1 Regulation of Lipogenesis in Fat Gland Cell SZ95 by Oleanolic Acid and Ursolic Acid SZ95 cells in the absence or presence of C. Acne with oleanolic acid (0.1, 1 or 10 μM) or ursolic acid (0.1, 1 or 10 μM). ). One day later, cells were lysed and stained with BODIPY TM 493/503. The results are shown in FIG. Any relative fluorescence unit (RFU) is shown as the mean ± standard error.
When SZ95 cells were treated with oleanolic acid or ursolic acid in the absence of C. Acne, lipogenesis increased in a treatment concentration-dependent manner. On the other hand, in the presence of C. Acne, DMSO-treated cells have very high lipid production, whereas cells treated with oleanolic acid or ursolic acid suppress the increase in lipid production induced by C. Acne. rice field.
実施例２　C. Acneによる皮脂分泌促進に対するオレアノール酸の抑制効果
　100 μg のC. Acne懸濁液を含む100μlの生理食塩水またはただの生理食塩水を10週齢の雄のC57BL6 マウスの頬に皮内注射した(右頬に生理食塩水、左頬にC. Acne)。また、0.1% オレアノール酸をアセトン：オリーブオイル＝4：1を溶媒として溶解し、C. Acneを注射した頬に外用塗布した。最初の皮内注射から2日後、マウスを犠死させ、頬を単離した。組織をBODIPYで染色し、蛍光実体顕微鏡LEICA MZ10F/DFC7000 Tで皮膚の裏側からマクロ像を得て、ソフトウェアLAS V4.12 (Leica mycrosystems, Wetzlar, German)で解析した。結果を図２に示す。その結果、外用でオレアノール酸を塗布することによって、アクネ菌注射による皮脂腺の肥大化が抑制され、BODIPYによる有染色性が溶媒コントロールに比べて、端緒に低下した。また、組織は10%ホルマリンで固定し、包埋した。次いで、パラフィン切片を調製し、HEで染色した。結果を図３に示す。パラフィン切片に対するHE染色によって、C. Acneを注射された皮膚(CRL)では肥大した皮脂腺（矢印）や角栓（矢頭）が観察されたが、0.1% オレアノール酸処理によってそれらが抑制された。 Example 2 Suppressive effect of oleanolic acid on the promotion of sebum secretion by C. Acne 100 μl saline containing 100 μg of C. Acne suspension or just saline was applied to the cheeks of a 10-week-old male C57BL6 mouse. Intracutaneous injection (saline on the right cheek, C. Acne on the left cheek). In addition, 0.1% oleanolic acid was dissolved in acetone: olive oil = 4: 1 as a solvent, and C. Acne was applied externally to the injected cheek. Two days after the first intradermal injection, mice were sacrificed and cheeks isolated. Tissues were stained with BODIPY, macroscopic images were obtained from the back of the skin with a fluorescent stereomicroscope LEICA MZ10F / DFC7000 T, and analyzed with software LAS V4.12 (Leica mycrosystems, Wetzlar, German). The results are shown in FIG. As a result, by applying oleanolic acid for external use, the enlargement of the sebaceous glands due to P. acnes injection was suppressed, and the stainability by BODIPY was reduced at the beginning compared to the solvent control. The tissue was fixed with 10% formalin and embedded. Paraffin sections were then prepared and stained with HE. The results are shown in FIG. HE staining of paraffin sections showed enlarged sebaceous glands (arrows) and keratin plugs (arrowheads) in C. Acne-injected skin (CRL), which were suppressed by treatment with 0.1% oleanolic acid.
実施例３　n-テトラデカンによる皮脂分泌促進に対するオレアノール酸の抑制効果
試験方法
１．ウサギの群分け
　ウサギを表１の通りに群分けした。 Example 3 Test method for suppressing the inhibitory effect of oleanolic acid on the promotion of sebum secretion by n-tetradecane 1. Rabbit grouping Rabbits were grouped as shown in Table 1.
Figure JPOXMLDOC01-appb-T000014
Figure JPOXMLDOC01-appb-T000014
２．n-テトラデカンと被験物質の投与
　n-テトラデカンと被験物質の投与スケジュールを図４に示す。
　n-テトラデカンの投与前に、各ウサギの両耳の耳介の内側のおおよその面積を求め、0.2mL/3x3 cmとなるように投与量を求め、耳介内側の全体に投与した。投与は8:00～18:00までの間に実施し、試験日1～14は全群の両耳に1回/日の頻度で実施した。試験日15～21は、I群は両耳に、1回/日の頻度で実施した。II群は両耳とも投与しなかった。III群は右耳のみ1回/日の頻度で実施し、左耳は実施しなかった。
　n-テトラデカンを投与されたウサギの耳介内側で面皰が十分に形成されている箇所で3x3 cmの部位を設け、オレアノール酸（被験物質A）、0.1%オレアノール酸を含む植物抽出液(被験物質B）またはワセリン（基剤）を0.5g投与した。何も投与しないIII群の右耳にも径測定及び摘出のための3x3 cmの部位を設定した。投与は、I、II群の両耳及びIII群の左耳に試験日15～21の7日間（1回/日、8:00～18:00）実施し、III群の右耳は投与しなかった。 2. 2. Administration of n-tetradecane and test substance The administration schedule of n-tetradecane and test substance is shown in FIG.
Before administration of n-tetradecane, the approximate area inside the auricle of both ears of each rabbit was determined, the dose was determined to be 0.2 mL / 3x3 cm, and the dose was administered to the entire inside of the auricle. Administration was performed between 8:00 and 18:00, and test days 1 to 14 were performed once / day in both ears of all groups. On test days 15-21, group I was performed once / day on both ears. Group II was not administered to both ears. In group III, only the right ear was performed once a day, and the left ear was not performed.
A plant extract containing oleanolic acid (test substance A) and 0.1% oleanolic acid (test substance) was provided at the site where petrolatum was sufficiently formed inside the auricle of rabbits treated with n-tetradecane. B) or Vaseline (base) was administered in an amount of 0.5 g. A 3x3 cm site for diameter measurement and excision was also set in the right ear of group III, which received no administration. Administration was performed to both ears of groups I and II and the left ear of group III for 7 days (once / day, 8: 00-18: 00) on test days 15 to 21, and the right ear of group III was administered. I didn't.
３．毛孔径測定
　試験日14及び15のn-テトラデカン(TD)投与前に毛孔径の測定を行い、その平均値をプレ値とした。試験日16、18、20及び22に、オレアノール酸（被験物質A）、0.1%オレアノール酸を含む植物抽出液(被験物質B）またはワセリン（基剤）の投与部位で任意に毛孔部10か所の毛孔径測定をマイクロスコープ(Dino-Lite Digital Microscope、型番:DILOTEPL、販売:サンコー)を用いて行った。なお、毛孔径は平均値と標準偏差を算出した。毛孔径の増大についてTDを14日間投与した後、7日間の被験物質AまたはBの塗布による増大した毛孔径の改善効果を確認したもの（III群左耳vsII群右耳、または左耳）と、TD投与14日目から7日後までTD投与と並行して被験物質AまたはBを塗布した場合の毛孔径増大の抵抗性を確認したもの（III群右耳vsI群右耳、または左耳）について、プレ値に対する各毛孔径測定日の測定値について変化率の算出と有意差検定を実施した。有意差検定はF検定により等分散性の検定を行い、等分散の場合はStudentのt検定、不等分散の場合はAspin-Welchのt検定により行った。F検定については有意水準を危険率5%、t検定については有意水準を危険率5%および1％とした。結果を表２および図５に示す。 3. 3. Pore diameter measurement Pore diameter was measured before administration of n-tetradecane (TD) on test days 14 and 15, and the average value was used as the pre-value. On test days 16, 18, 20 and 22, optionally 10 pores at the administration site of oleanolic acid (test substance A), plant extract containing 0.1% oleanolic acid (test substance B) or petrolatum (base). The pore size was measured using a microscope (Dino-Lite Digital Microscope, model number: DILOTEPL, sold by Sanko). The average value and standard deviation of the pore diameter were calculated. Regarding the increase in pore diameter After 14 days of administration of TD, the effect of improving the increased pore diameter by applying the test substance A or B for 7 days was confirmed (group III left ear vs. group II right ear or left ear). , The resistance to the increase in pore diameter when the test substance A or B was applied in parallel with the TD administration from the 14th day to the 7th day after the TD administration was confirmed (group III right ear vs. group I right ear or left ear). The rate of change was calculated and the significant difference test was performed for the measured values on each pore diameter measurement day with respect to the pre-values. The significance test was performed by the F-test for homoscedasticity, the Student's t-test for homoscedasticity, and the Aspin-Welch's t-test for unequal dispersion. For the F-test, the significance level was set to a risk rate of 5%, and for the t-test, the significance level was set to a risk rate of 5% and 1%. The results are shown in Table 2 and FIG.
Figure JPOXMLDOC01-appb-T000015
Figure JPOXMLDOC01-appb-T000015
　試験１では、14日間n-テトラデカン投与後にワセリン（基剤）のみを投与した場合、22日目の毛孔径は14日目の毛孔径よりさらに大きくなっていた（301左耳）。しかし、14日間n-テトラデカン投与後にオレアノール酸（被験物質A）または0.1%オレアノール酸を含む植物抽出液(被験物質B）を投与した場合、22日目の毛孔径は14日目の毛孔径より小さくなっていた（201右耳、201左耳）。また、試験２では、22日間n-テトラデカンの投与を継続した場合、22日目の毛孔径は14日目の毛孔径よりさらに大きくなっていた（301右耳）。しかし、15日目からn-テトラデカンと共にオレアノール酸（被験物質A）または0.1%オレアノール酸を含む植物抽出液(被験物質B）を投与した場合、22日目の毛孔径は14日目の毛孔径よりさらに大きくなっていたものの、その程度を抑えることができた（101右耳、101左耳）。 In Test 1, when only petrolatum (base) was administered after administration of n-tetradecane for 14 days, the pore diameter on the 22nd day was even larger than the pore diameter on the 14th day (301 left ear). However, when oleanolic acid (test substance A) or a plant extract containing 0.1% oleanolic acid (test substance B) was administered after administration of n-tetradecane for 14 days, the pore diameter on the 22nd day was larger than the pore diameter on the 14th day. It was getting smaller (201 right ear, 201 left ear). In Test 2, when n-tetradecane was continuously administered for 22 days, the pore diameter on the 22nd day was even larger than the pore diameter on the 14th day (301 right ear). However, when oleanolic acid (test substance A) or a plant extract containing 0.1% oleanolic acid (test substance B) was administered together with n-tetradecane from the 15th day, the pore diameter on the 22nd day was the pore diameter on the 14th day. Although it was even larger, the degree could be suppressed (101 right ear, 101 left ear).
４．病理組織学的検査
　試験日22にウサギをチアミラールナトリウム（イソゾール注射用0.5g、日医工（株））麻酔下で放血し、安楽死させた。安楽死後にオレアノール酸、0.1%オレアノール酸を含む植物抽出液またはワセリンの投与部位を摘出した。III群の右耳は、他の群の投与部位と同じ個所を摘出した、摘出部位を半分に分け、耳の外耳道側の部位を病理用として10％中性緩衝ホルマリン液に保存し、残りの部位を分析用として凍結保存した。摘出部位のパラフィン切片を作製し、ヘマトキシリンエオジン染色を施して、双眼顕微鏡BHSを用いて観察した。所見の代表例について、図６に示す。301右耳における22日目の外耳道組織は毛孔径の拡張が確認できた。一方、101右耳および201右耳の外耳道組織の染色像では、毛孔径の拡張は観察できなかった。 4. Histopathological examination On test day 22, rabbits were euthanized by bleeding under anesthesia under thiamiral sodium (0.5 g for isozole injection, Nichi-Iko Pharmaceutical Co., Ltd.). After euthanasia, the site of administration of oleanolic acid, a plant extract containing 0.1% oleanolic acid, or petrolatum was removed. For the right ear of group III, the same site as the administration site of the other groups was excised, the excised site was divided in half, and the site on the ear canal side of the ear was stored in 10% neutral buffered formalin solution for pathology, and the rest. The site was cryopreserved for analysis. Paraffin sections at the excised site were prepared, stained with hematoxylin and eosin, and observed using a binocular microscope BHS. A representative example of the findings is shown in FIG. In the ear canal tissue on day 22 in the 301 right ear, dilation of the pore diameter was confirmed. On the other hand, in the stained images of the external auditory canal tissue of the 101st right ear and the 201st right ear, no dilation of the pore diameter could be observed.
実施例４　オレアノール酸を用いた大人ニキビ治療効果試験
試験方法
　オレアノール酸（商品名：Oleanolic Acid、和光純薬製）を1%(w/w)になるようにエチルヘキサン酸セチル（商品名：NIKKOL CI0、日光ケミカルズ）を溶剤として用い、表３に示す溶液を作製した。 Example 4 Test method for treating adult acne using oleanolic acid Test method Setyl ethylcaproate (trade name: NIKKOL) so that oleanolic acid (trade name: Oleanolic Acid, manufactured by Wako Pure Chemical Industries, Ltd.) is 1% (w / w). CI0, Nikko Chemicals) was used as a solvent to prepare the solutions shown in Table 3.
Figure JPOXMLDOC01-appb-T000016
Figure JPOXMLDOC01-appb-T000016
　大人ニキビを有している20代から30代の被験者8名（男性3名、女性5名）に、表３に示す組成の内容物を含む溶液（オレアノール酸として１重量％）を1日2回洗顔した後に使用した。なお、大人ニキビは肌水分量の部分的な減少が原因であることが知られている。なお、本実施例における大人ニキビを有している被験者は、洗顔後、室温23℃湿度50%の環境で肌を安定させてからコルネオメーター（商品名Comeometer CM825、製造元Courage+Khazaka社）で顔の頬の水分量を測定し、大人ニキビができやすいといわれている頬の水分含有量が７２以下の人を対象にした。
　溶液の使用前の前日、および使用から１週間後の時点における、以下の項目について評価した。
１：大人ニキビが気になる程度
２：大人ニキビの赤み
３：大人ニキビのかゆみ
４：皮膚のざらつき
５：べたつき
６：かさつき
７：肌荒れ
８：毛穴詰まり
９：大人ニキビの大きさ
評価は、5段階で評価し、各項目の平均値を出した。 Eight subjects in their twenties to thirties (3 males and 5 females) with adult acne were given a solution containing the contents shown in Table 3 (1% by weight as oleanolic acid) 2 times a day. Used after washing the face. It is known that adult acne is caused by a partial decrease in skin moisture content. In this example, the subject having adult acne had a face with a corneometer (trade name: Comeometer CM825, manufacturer Courage + Khazaka) after washing the face and stabilizing the skin in an environment with a room temperature of 23 ° C and a humidity of 50%. The water content of the cheeks was measured, and the subjects were those with a water content of 72 or less on the cheeks, which is said to be prone to adult acne.
The following items were evaluated the day before the solution was used and one week after the use.
1: Degree of concern about adult acne 2: Redness of adult acne 3: Itching of adult acne 4: Rough skin 5: Stickiness 6: Rough skin 8: Clogged pores 9: Size evaluation of adult acne Evaluated on a 5-point scale, and the average value of each item was calculated.
１：大人ニキビが気になる程度の評価基準
５点：気にならない
４点：どちらともいえない
３点：やや気になる
２点：気になる
１点：非常に気になる 1: Evaluation criteria to the extent that adult acne is anxious 5 points: Not anxious 4 points: Neither can be said 3 points: Somewhat anxious 2 points: Anxious 1 point: Very anxious
２：大人ニキビの赤みの評価基準
５点：赤みがない
４点：わずかに赤みがある
３点：やや赤みがある
２点：赤みがある
１点：非常に赤みがある 2: Evaluation criteria for redness of adult acne 5 points: No redness 4 points: Slightly reddish 3 points: Slightly reddish 2 points: Reddish 1 point: Very reddish
３：大人ニキビのかゆみの評価基準
５点：かゆみはない
４点：あまりかゆみはない
３点：ややかゆみがある
２点：かゆみがある
１点：非常にかゆみがある 3: Evaluation criteria for itching of adult acne 5 points: No itching 4 points: Not very itchy 3 points: Slightly itchy 2 points: Itching 1 point: Very itchy
４：皮膚のざらつきの評価基準
５点：ざらつきはない
４点：あまりざらつきはない
３点：ややざらつきがある
２点：ざらつきがある
１点：非常にざらつきがある 4: Evaluation criteria for skin roughness 5 points: No roughness 4 points: Not very rough 3 points: Somewhat rough 2 points: Roughness 1 point: Very rough
５：べたつきの評価基準
５点：べたつきはない
４点：あまりべたつきはない
３点：ややべたつきがある
２点：べたつきがある
１点：非常にべたつきがある 5: Evaluation criteria for stickiness 5 points: No stickiness 4 points: Not very sticky 3 points: Slightly sticky 2 points: Sticky 1 point: Very sticky
６：かさつきの評価基準
５点：かさつきはない
４点：あまりかさつかない
３点：ややかさつく
２点：かさつく
１点：非常にかさつく 6: Evaluation criteria for dryness 5 points: No dryness 4 points: Not very dry 3 points: Slightly dry 2 points: Dry 1 point: Very dry
７：肌荒れの評価基準
５点：肌荒れはない
４点：あまり肌荒れはない
３点：やや肌荒れしている
２点：肌荒れしている
１点：非常に肌荒れしている 7: Rough skin evaluation criteria 5 points: No rough skin 4 points: Not very rough skin 3 points: Slightly rough skin 2 points: Rough skin 1 point: Very rough skin
８：毛穴詰まりの評価基準
５点：毛穴詰まりが気にならない
４点：あまり毛穴詰まりが気にならない
３点：やや毛穴詰まりが気になる
２点：毛穴詰まりが気になる
１点：毛穴詰まりが非常に気になる 8: Evaluation criteria for pore clogging 5 points: Pore clogging is not a concern 4 points: Pore clogging is not a concern 3 points: Pore clogging is a concern 2 points: Pore clogging is a concern 1 point: Pore clogging is a concern Is very worrisome
９：大人ニキビの大きさの評価基準
５点：ニキビの大きさが気にならない
４点：あまりニキビの大きさが気にならない
３点：ややニキビの大きさが気になる
２点：ニキビの大きさが気になる
１点：ニキビの大きさが非常に気になる 9: Evaluation criteria for adult acne size 5 points: I don't care about the size of acne 4 points: I don't care about the size of acne so much 3 points: I care about the size of acne 2 points: Acne One point to worry about the size: I am very concerned about the size of acne
Figure JPOXMLDOC01-appb-T000017
Figure JPOXMLDOC01-appb-T000017
　結果を表４に示す。オレアノール酸含溶液を投与した被験者において、大人ニキビが気になる程度、大人ニキビの赤み、大人ニキビのかゆみ、皮膚のざらつき、べたつき、かさつき、肌荒れ、毛穴詰まり及び大人ニキビの大きさについてすべてスコアが向上した。即ち、この結果は、オレアノール酸が大人ニキビの改善効果等を示している。 The results are shown in Table 4. In subjects who received the oleanolic acid-containing solution, all scores were given for the degree of concern for adult acne, redness of adult acne, itching of adult acne, rough skin, stickiness, dryness, rough skin, clogged pores, and size of adult acne. Has improved. That is, this result shows that oleanolic acid has an effect of improving adult acne and the like.
　式(I) Formula (I)
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
（式中、R1は、水素原子またはメチル基を表し、R2は、水素原子またはメチル基を表す。）で表される化合物またはその生理的に許容される塩を、皮脂産生調節剤として提供することができる。本出願は、日本で出願された特願2020-122251（出願日：令和2年7月16日）を基礎としており、その内容はすべて本明細書に包含されるものとする。 (In the formula, R 1 represents a hydrogen atom or a methyl group, and R 2 represents a hydrogen atom or a methyl group.) A compound represented by the compound or a physiologically acceptable salt thereof is used as a sebum production regulator. Can be provided. This application is based on Japanese Patent Application No. 2020-122251 (Filing date: July 16, 2nd year of Reiwa), the entire contents of which are incorporated herein by reference.

Claims (10)

  1. 　式(I)
    Figure JPOXMLDOC01-appb-C000001
     （式中、R1は、水素原子またはメチル基を表し、R2は、水素原子またはメチル基を表す。）で表される化合物またはその生理的に許容される塩を含む、皮脂産生調節剤。     Equation (I)
    Figure JPOXMLDOC01-appb-C000001
     (In the formula, R 1 represents a hydrogen atom or a methyl group, and R 2 represents a hydrogen atom or a methyl group.) A sebum production regulator containing a compound represented by the compound or a physiologically acceptable salt thereof. ..
  2. 　式(I)で表される化合物が、オレアノール酸またはウルソール酸である、請求項１に記載の皮脂産生調節剤。 The sebum production regulator according to claim 1, wherein the compound represented by the formula (I) is oleanolic acid or ursolic acid.
  3. 　脂性肌における皮脂産生抑制剤である、請求項１または２に記載の皮脂産生調節剤。 The sebum production regulator according to claim 1 or 2, which is a sebum production inhibitor for oily skin.
  4. 　請求項３に記載の脂性肌における皮脂産生抑制剤を含む、ざ瘡の治療剤。 A therapeutic agent for acne, which comprises the sebum production inhibitor for oily skin according to claim 3.
  5. 　乾燥肌における皮脂産生促進剤である、請求項１または２に記載の皮脂産生調節剤。 The sebum production regulator according to claim 1 or 2, which is a sebum production promoter for dry skin.
  6. 　請求項５に記載の乾燥肌における皮脂産生促進剤を含む、乾燥肌に起因する皮膚疾患の治療剤。 A therapeutic agent for skin diseases caused by dry skin, which comprises the sebum production promoter in dry skin according to claim 5.
  7. 乾燥肌に起因する皮膚疾患が大人ニキビである、請求項６に記載の皮膚疾患の治療剤。 The therapeutic agent for a skin disease according to claim 6, wherein the skin disease caused by dry skin is adult acne.
  8. 　式(I)
    Figure JPOXMLDOC01-appb-C000002
     （式中、R1は、水素原子またはメチル基を表し、R2は、水素原子またはメチル基を表す。）で表される化合物またはその生理的に許容される塩を対象に投与することを含む、皮脂産生調節方法。     Equation (I)
    Figure JPOXMLDOC01-appb-C000002
     (In the formula, R 1 represents a hydrogen atom or a methyl group, and R 2 represents a hydrogen atom or a methyl group.) The compound represented by the compound or a physiologically acceptable salt thereof should be administered to the subject. Methods for regulating sebum production, including.
  9. 　乾燥肌に起因する皮膚疾患またはざ瘡の治療における使用のための式(I)
    Figure JPOXMLDOC01-appb-C000003
     （式中、R1は、水素原子またはメチル基を表し、R2は、水素原子またはメチル基を表す。）で表される化合物またはその生理的に許容される塩。     Formula (I) for use in the treatment of skin disorders or acne caused by dry skin
    Figure JPOXMLDOC01-appb-C000003
     (In the formula, R 1 represents a hydrogen atom or a methyl group, and R 2 represents a hydrogen atom or a methyl group.) A compound represented by the compound or a physiologically acceptable salt thereof.
  10. 　乾燥肌に起因する皮膚疾患またはざ瘡の治療剤を製造するための式(I)
    Figure JPOXMLDOC01-appb-C000004
     （式中、R1は、水素原子またはメチル基を表し、R2は、水素原子またはメチル基を表す。）で表される化合物またはその生理的に許容される塩の使用。
          Formula (I) for producing a therapeutic agent for skin diseases or acne caused by dry skin
    Figure JPOXMLDOC01-appb-C000004
     (In the formula, R 1 represents a hydrogen atom or a methyl group, and R 2 represents a hydrogen atom or a methyl group.) Use of a compound represented by or a physiologically acceptable salt thereof.
PCT/JP2021/026544 2020-07-16 2021-07-15 Sebum production regulator WO2022014660A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2022536434A JPWO2022014660A1 (en) 2020-07-16 2021-07-15

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2020122251 2020-07-16
JP2020-122251 2020-07-16

Publications (1)

Publication Number Publication Date
WO2022014660A1 true WO2022014660A1 (en) 2022-01-20

Family

ID=79555643

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2021/026544 WO2022014660A1 (en) 2020-07-16 2021-07-15 Sebum production regulator

Country Status (3)

Country Link
JP (1) JPWO2022014660A1 (en)
TW (1) TW202216160A (en)
WO (1) WO2022014660A1 (en)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6293215A (en) * 1985-10-18 1987-04-28 Shiseido Co Ltd Hair tonic
JP2003508486A (en) * 1999-09-10 2003-03-04 アプライド・ジェネティクス・インコーポレーテッド・ダーマティクス Compositions and methods for improving skin lipid content
JP2003113069A (en) * 2001-10-03 2003-04-18 Sederma Sa External preparation for skin having acnegenic tendency
CN103222999A (en) * 2012-01-31 2013-07-31 财团法人工业技术研究院 Honeysuckle extract and preparation method and application thereof
JP2016132625A (en) * 2015-01-16 2016-07-25 株式会社マンダム Cosmetic method

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6293215A (en) * 1985-10-18 1987-04-28 Shiseido Co Ltd Hair tonic
JP2003508486A (en) * 1999-09-10 2003-03-04 アプライド・ジェネティクス・インコーポレーテッド・ダーマティクス Compositions and methods for improving skin lipid content
JP2003113069A (en) * 2001-10-03 2003-04-18 Sederma Sa External preparation for skin having acnegenic tendency
CN103222999A (en) * 2012-01-31 2013-07-31 财团法人工业技术研究院 Honeysuckle extract and preparation method and application thereof
JP2016132625A (en) * 2015-01-16 2016-07-25 株式会社マンダム Cosmetic method

Also Published As

Publication number Publication date
TW202216160A (en) 2022-05-01
JPWO2022014660A1 (en) 2022-01-20

Similar Documents

Publication Publication Date Title
CA2481499C (en) Use of cyclopamine in the treatment of psoriasis and other skin disorders
JP4152987B2 (en) Regulation of mammalian hair growth
KR100607438B1 (en) Skin disease treating agent containing sphingosine kinase activator
US7763288B2 (en) Skin care compositions and methods
US20220331389A1 (en) Skin composition
JP2011500597A (en) Method and composition for treating skin diseases or skin lesions
AU2014361780B2 (en) Exfoliative hair retention-promoting formulation
Lueangarun et al. The 24‐hr, 28‐day, and 7‐day post‐moisturizing efficacy of ceramides 1, 3, 6‐II containing moisturizing cream compared with hydrophilic cream on skin dryness and barrier disruption in senile xerosis treatment
CN101686957A (en) Combination comprising pyrrolidone-5-carboxylic acid and at least one compound from citrulline, arginine and asparagine, and use thereof in the treatment of atopic dermatitis
KR20020007207A (en) Topical treatment of skin
JP2024069595A (en) Composition for preventing hair loss or promoting hair growth
Brandner et al. Caffeine improves barrier function in male skin
Obagi The art of skin health restoration and rejuvenation
JPH1067648A (en) Novel topical composition containing extremely reduced dose of melatonin or its analogue and its use in cosmetic
WO2022014660A1 (en) Sebum production regulator
US20160220479A1 (en) Topical compounds containing adipose-derived hormones for the rejuvenation of skin
AU2019342136A1 (en) Iron chelating compounds for treating aesthetic skin conditions
JP2004277406A (en) USE OF 5-CHOLESTEN-3beta,25-DIOL-7-ONE FOR TREATMENT OF DRY SKIN OR DRY SCALP
KR20190024594A (en) A composition for preventing or treating for atopic dermatitis
JP2005519935A (en) Compositions and methods for the delivery of dermatological cosmetics
AU2013301601B2 (en) Eprotirome for use in the prevention and/or treatment of hair disorders and compositions thereof
Gołyński et al. Biophysical parameters of rats’ skin after the administration of methimazole
Maeda et al. Effect of facial application of essence containing royal jelly extract on stratum corneum moisture content: A placebo‐controlled, double‐blind, parallel‐group study
EP1900356A1 (en) Extract of fenugreek
Merja et al. Safety and efficacy of REGENDIL™ infused hair growth promoting product in adult human subject having hair fall complaints (alopecia)

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21842750

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2022536434

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21842750

Country of ref document: EP

Kind code of ref document: A1