Sebum production regulator

Abstract

The present invention provides a novel sebum secretion regulator.

Description

[Technical Field]

[0001] The present invention relates to a compound of formula (I)

[0002] [ka]

[0003] (wherein R1 represents a hydrogen atom or a methyl group, and R2 represents a hydrogen atom or a methyl group) or a physiologically acceptable salt thereof. [Background technology]

[0004] Sebum protects the skin from dryness and external irritants and maintains its flexibility. Sebum is secreted by sebaceous glands, which are most developed during adolescence (twenties and twenties). These enlarged and developed sebaceous glands secrete excess sebum, which mixes with the dead stratum corneum of pores and forms keratin plugs, making the pores appear larger and becoming a cosmetic problem. Furthermore, excessive sebum secretion can lead to acne and other skin problems caused by the proliferation of acne bacteria. On the other hand, areas with low sebum secretion—i.e., areas with a low density of sebaceous glands—have a reduced ability to retain moisture, making the skin more susceptible to dryness and vulnerability to external irritants. For example, on the face, the areas around the eyes and mouth, cheeks, and neck have fewer sebaceous glands and therefore produce less sebum, making them prone to dryness. On the other hand, the forehead and nose have more sebaceous glands and are more prone to acne. Therefore, it was necessary to prevent excessive sebum secretion from the sebaceous glands in areas with many sebaceous glands, and to supplement the lack of sebum in areas with few sebaceous glands, thereby enhancing the skin's moisture retention function.

[0005] Compounds known to have a sebum secretion-suppressing effect include isoflavone compounds and matrix metalloproteinase inhibitors. On the other hand, compounds known to have a sebum secretion-promoting effect include γ-oryzanol. However, since areas with many sebaceous glands and areas with few sebaceous glands are adjacent to each other, particularly on the face, it is necessary to apply the appropriate agent to the appropriate area, which is cumbersome.

[0006] Oleanolic acid, a pentacyclic terpene, is a functional triterpene known to possess physiological activities such as anticancer, anti-inflammatory, antioxidant, and antihyperlipidemic effects. Oleanolic acid has already been reported as a hair growth or hair restoration agent (Patent Document 1), and derivatives of oleanolic acid and ursolic acid have been reported as anti-photoaging agents (Patent Document 2). However, the regulatory effect of oleanolic acid on sebum secretion has not been reported. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] Japanese Patent Application Publication No. 9-157139 [Patent Document 2] Japanese Patent Application Publication No. 9-140305 Summary of the Invention [Problem to be solved by the invention]

[0008] An object of the present invention is to provide a novel agent for regulating sebum secretion. [Means for solving the problem]

[0009] The present inventors have confirmed that treatment of sebaceous gland cells with oleanolic acid or ursolic acid in the absence of C. acnes resulted in a concentration-dependent increase in lipogenesis. However, in the presence of C. acnes, cells treated with DMSO exhibited significantly higher lipogenesis, whereas cells treated with oleanolic acid or ursolic acid suppressed the increase in lipogenesis induced by C. acnes. Furthermore, when C. acnes was injected into mouse skin, enlarged sebaceous glands and keratinocytes were observed in the injected skin, but treatment with 0.1% oleanolic acid suppressed these. Furthermore, when rabbit skin was treated with n-tetradecane and then oleanolic acid instead of n-tetradecane, the pore size enlarged by n-tetradecane was reduced by oleanolic acid. Furthermore, when rabbit skin was treated with n-tetradecane and then oleanolic acid was added to n-tetradecane, oleanolic acid suppressed the degree of pore size enlargement caused by n-tetradecane. In addition, oleanolic acid was applied to eight adult acne patients, and when evaluated one week later, improvement in symptoms was observed.

[0010] That is, the present invention provides: [1] Formula (I)

[0011] [ka]

[0012] (wherein R1 represents a hydrogen atom or a methyl group, and R2 represents a hydrogen atom or a methyl group) or a physiologically acceptable salt thereof. [2] The sebum production regulator according to [1], wherein the compound represented by 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, comprising the sebum production inhibitor in oily skin described in [3]. [5] The sebum production regulator according to [1] or [2], which is a sebum production promoter for dry skin. [6] A therapeutic agent for skin diseases caused by dry skin, comprising the sebum production promoter for dry skin described in [5]. [7] A therapeutic agent for a skin disease according to [6], wherein the skin disease caused by dry skin is adult acne. [8] Formula (I)

[0013] [ka]

[0014] (wherein R1 represents a hydrogen atom or a methyl group, and R2 represents a hydrogen atom or a methyl group) or a physiologically acceptable salt thereof to a subject. [9] A compound of formula (I) for use in treating skin diseases caused by dry skin or acne

[0015] [ka]

[0016] (wherein R1 represents a hydrogen atom or a methyl group, and R2 represents a hydrogen atom or a methyl group), or a physiologically acceptable salt thereof.

[10] A compound represented by formula (I) for producing a therapeutic agent for skin diseases or acne caused by dry skin.

[0017] [ka]

[0018] (wherein R1 represents a hydrogen atom or a methyl group, and R2 represents a hydrogen atom or a methyl group), or a physiologically acceptable salt thereof. to provide. [Effects of the Invention]

[0019] Formula (I)

[0020] [ka]

[0021] (wherein R1 represents a hydrogen atom or a methyl group, and R2 represents a hydrogen atom or a methyl group), or a physiologically acceptable salt thereof, can be provided as a sebum production regulator. [Brief explanation of the drawings]

[0022] [Figure 1] C. Graph showing relative fluorescence units (RFU) 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 Acne. n=6. *P<0.005, ***P<0.005 vs. control. Veh: DMSO control (0.1%). [Figure 2] C. A fluorescent stereomicroscope image of lipid droplets in mouse sebocytes treated with oleanolic acid in the presence of Acne. [Figure 3] C. HE staining of tissue containing mouse sebaceous gland cells treated with oleanolic acid in the presence of Acne. [Figure 4] FIG. 1 shows the administration schedule of n-tetradecane and test substances (oleanolic acid or petrolatum). [Figure 5] 1 is a graph showing the size of pore diameter after administration of n-tetradecane and a test substance (oleanolic acid or petrolatum). Black bar: Day 14, Gray bar: Day 22 [Figure 6] FIG. 1 shows HE staining images of tissues containing rabbit sebaceous gland cells treated with n-tetradecane and a test substance (oleanolic acid or petrolatum). DETAILED DESCRIPTION OF THE INVENTION

[0023] The present invention relates to a compound of formula (I)

[0024] [ka]

[0025] (wherein R1 represents a hydrogen atom or a methyl group, and R2 represents a hydrogen atom or a methyl group) (hereinafter referred to as the compound of the present invention) or a physiologically acceptable salt thereof.

[0026] In the compound of the present invention, the combination of R1 and R2 may be any combination, but when R1 is a hydrogen atom, R2 is preferably a methyl group, and when R1 is a methyl group, R2 is preferably a hydrogen atom. When R1 is a hydrogen atom and R2 is a methyl group, the compound of the present invention is represented by formula (II):

[0027] [ka]

[0028] When R1 is a methyl group and R2 is a hydrogen atom, the compound of the present invention is represented by the formula (III):

[0029] [ka]

[0030] Ursolic acid is expressed as follows:

[0031] The compound of the present invention may also be a physiologically acceptable salt thereof. The physiologically acceptable salt of the compound represented by formula (I) is not particularly limited as long as it is a salt that is usually used in pharmaceutical compositions, and examples thereof include alkali metal salts such as sodium and potassium; alkaline earth metal salts such as calcium and magnesium; organic amine salts such as triethylamine, piperazine, piperidine, and triethanolamine; and basic amino acid salts such as lysine and arginine.

[0032] As described in the Examples below, it has been confirmed that oleanolic acid and ursolic acid normally promote sebum production, but conversely suppress sebum production under conditions of excessive sebum secretion. Therefore, the compound of the present invention or a physiologically acceptable salt thereof can be provided as a sebum production regulator.

[0033] As used herein, 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. Thus, in one embodiment, the sebum production regulator of the present invention is provided as an agent for suppressing sebum production in oily skin.

[0034] Suppression of sebum production in oily skin refers to the suppression of sebum production by the compound of the present invention or a physiologically acceptable salt thereof when sebum is produced from sebaceous glands in excess of the normal amount. Causes of sebum production from sebaceous glands in excess of the normal amount include stimulation of sebaceous glands by Cutibacterium acnes, stress, and overexpression of hormones (e.g., testosterone, 5α-dihydrotestosterone). Suppression is sufficient as long as the amount of sebum production is reduced, and preferably reduced to a normal level.

[0035] In another embodiment, the sebum production regulator of the present invention is provided as a sebum production promoter in dry skin.

[0036] The promotion of sebum production in dry skin refers to the fact that when sebum is produced by sebaceous glands at a level lower than normal, the compound of the present invention or its physiologically acceptable salt promotes sebum production.The cause of sebum produced by sebaceous glands at a level lower than normal can be attributed to the insufficient secretion of sebum from sebaceous glands due to aging, the insufficient secretion of sebum due to the drop in winter temperature, etc.The promotion can be achieved only by increasing the amount of sebum produced, and preferably by increasing the amount of sebum produced to a normal level.

[0037] The sebum production regulator of the present invention can be applied to humans, non-human animals (e.g., non-human mammals (livestock such as pigs, cows, horses, dogs, and cats)), birds (poultry such as turkeys and chickens)), etc., and is preferably applied to humans.

[0038] The compound of the present invention or a physiologically acceptable salt thereof can be dissolved in ethanol, oils and fats such as camellia oil, cream, etc. and used as a sebum production regulator. The compound of the present invention is preferably blended in an amount of 0.001% (w / w) or more, preferably 0.01% (w / w) or more, more preferably 0.1% (w / w) or more of the total weight of the sebum production regulator. If the blending amount is too small, the sebum production regulation effect will not be sufficient, which is undesirable. The upper limit can be, for example, 10% (w / w) or less, preferably 5% (w / w) or less, and more preferably 2% (w / w) or less.

[0039] Other raw materials to be blended into the sebum production regulator may be those commonly used in sebum production regulators, such as hydrocarbons, waxes, oils and fats, esters, higher fatty acids, higher alcohols, surfactants, fragrances, colorants, preservatives, excipients, refreshing agents, humectants, antioxidants, UV protection agents, alcohols, and pH adjusters.

[0040] The sebum production regulator of the present invention may be in any form that allows for external application to the skin, such as in the form of a cream, ointment, or lotion as a pharmaceutical or quasi-drug.

[0041] 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 provides a therapeutic agent for acne comprising the sebum production inhibitor in oily skin. Acne is a chronic inflammatory disease of the sebaceous gland, and examples include acne vulgaris (acne, particularly adolescent acne) and seborrheic dermatitis. In addition, the therapeutic agent for acne of the present invention can be formulated with other auxiliary drugs such as keratolytic agents, bactericides, anti-inflammatory agents, antiseborrheic agents, and antipruritics.

[0042] When the sebum production regulator of the present invention is provided as a sebum production promoter for dry skin (the sebum production promoter of the present invention), the present invention provides a therapeutic agent for skin diseases caused by dry skin, comprising the sebum production promoter for dry skin. Skin diseases caused by dry skin are diseases caused by the loss of the skin's protective function provided by sebum, and examples include xerosis, adult acne, redness of adult acne, itchiness of adult acne, rough skin, dry skin, and rough skin.

[0043] Adult acne differs in many ways from acne that primarily affects teenagers, commonly known as "adolescent acne." For example, adult acne is known to be prone to recurrence and to leaving scars and blemishes. While adolescent acne is primarily caused by increased sebum secretion, adult acne can be caused by factors including, but not limited to, dryness, hormonal imbalance, an irregular lifestyle, lack of sleep, poor diet, overwork, and stress.

[0044] When the sebum production promoter of the present invention is applied to adult acne, from the viewpoint of being expected to have an effective therapeutic effect, its preferred application disease is adult acne caused by dryness or hormonal imbalance, more preferably adult acne caused by dryness. When the sebum production promoter of the present invention is applied to adult acne caused by dryness, the patient to whom it is administered often has dry skin. Examples of patients with dry skin include patients whose cheek moisture content measured with a Corneometer (trade name: Comeometer CM825, manufactured by Courage+Khazaka) is 72 or less. Patients whose cheek moisture content is 64 or less, preferably 60 or less, are more likely to be candidates for the sebum production promoter of the present invention.

[0045] The therapeutic agent for skin diseases caused by dry skin of the present invention may contain other auxiliary drugs such as moisturizers, disinfectants, anti-inflammatory agents, and antipruritics. [Example]

[0046] The present invention will be explained in more detail below with reference to examples, but the present invention is not limited to these examples.

[0047] material C. acnes (JCM6425, Riken Bioresource Center, Tsukuba, Japan) was cultured under strict anaerobic conditions from a stock solution of GMG broth (Nissui, Tokyo, Japan) at -85°C for 3-7 days until it reached stationary phase. In preliminary experiments, homogenates were used in the following examples because they were more efficient at sebum production than live C. acnes. 5 × 10 7 CFU of C. acnes were sonicated using a Branson Sonifier model 150 (Danbury, CT, USA) and aliquots were stored at 4°C until use. For the experimental purposes, protein was assayed and dissolved in medium and aliquots were added at 100 μg / ml.

[0048] culture SZ95 cells were kindly provided by Dr. Christos C. Zouboulis (Dessau Medical Center, Dessau, Germany). Immortalized human sebocytes, SZ95, were derived from human facial sebaceous glands and cultured in Sebomed® Basal Medium (Millipore, Billerica, MA, USA) supplemented with 10% fetal bovine serum (Thermo Fisher Scientific Inc., Waltham, MA, USA), 5 ng / ml human epidermal growth factor (hEGF) (PeproTech GmbH, Hamburg, Germany), 50 IU / ml penicillin, and 50 μg / ml streptomycin (Nacalai Tesque, Kyoto, Japan). The medium was changed every other day, and cells were subcultured at 60-70% confluence.

[0049] Intracellular lipid concentration For semiquantitative 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-indacene) (Thermo Fisher Scientific) stain was applied, while for quantitative measurements, fluorescent BODIPY stain was applied in 48-well plates. TM Cells stained with α-glucan were lysed in 55 μl of lysis buffer (25 mM Tris-phosphate [pH 7.8], 2 mM DTT, 2 mM EDTA, 10% glycerol, and 1% Triton X-100). 50 μl of the lysate was then placed in a well of a 96-well microplate, and fluorescence was measured using a microplate reader (Corona Electric; model: SH-8100lab; Ibaraki, Japan) (Ex = 493 nm / Em = 503 nm).

[0050] Example 1 Regulation of lipogenesis in sebocytes SZ95 by oleanolic acid and ursolic acid SZ95 cells were treated with oleanolic acid (0.1, 1, or 10 μM) or ursolic acid (0.1, 1, or 10 μM) in the absence or presence of C. acnes. After 1 day, cells were lysed and BODIPY TM The cells were stained with 493 / 503. The results are shown in Figure 1. Arbitrary relative fluorescence units (RFU) are presented as mean values ​​± standard error. When SZ95 cells were treated with oleanolic acid or ursolic acid in the absence of C. acnes, lipogenesis increased in a concentration-dependent manner. In contrast, in the presence of C. acnes, DMSO-treated cells produced significantly more lipogenetic activity, whereas oleanolic acid or ursolic acid-treated cells suppressed the C. acnes-induced increase in lipogenesis.

[0051] Example 2: Inhibitory effect of oleanolic acid on sebum secretion caused by C. Acne Ten-week-old male C57BL6 mice were intradermally injected into the cheeks with 100 μl of saline containing 100 μg of C. acnes suspension or with plain saline (saline on the right cheek, C. acnes on the left cheek). Additionally, 0.1% oleanolic acid dissolved in a 4:1 acetone:olive oil mixture was topically applied to the C. acnes-injected cheek. Two days after the first intradermal injection, mice were sacrificed and the cheeks were isolated. The tissues were stained with BODIPY. Macroscopic images were obtained from the reverse side of the skin using a LEICA MZ10F / DFC7000 T fluorescence stereomicroscope and analyzed using LAS V4.12 software (Leica microsystems, Wetzlar, Germany). The results are shown in Figure 2. Topical application of oleanolic acid inhibited the hypertrophy of sebaceous glands induced by P. acnes injection and significantly reduced BODIPY staining compared to the vehicle control. The tissues were fixed and embedded in 10% formalin. Paraffin sections were then prepared and stained with HE. The results are shown in Figure 3. HE staining of the paraffin sections revealed enlarged sebaceous glands (arrows) and keratin plugs (arrowheads) in the C. acnes-injected skin (CRL), but these were suppressed by treatment with 0.1% oleanolic acid.

[0052] Example 3: Inhibitory effect of oleanolic acid on sebum secretion promoted by n-tetradecane Test Method 1. Grouping rabbits The rabbits were divided into groups as shown in Table 1.

[0053] [Table 1]

[0054] 2. Administration of n-tetradecane and test substance The administration schedule of n-tetradecane and the test substance is shown in Figure 4. Before administration of n-tetradecane, the approximate area of ​​the inner ear of each rabbit was measured, and the dose was calculated to be 0.2 mL / 3 x 3 cm. The dose was administered to the entire inner ear of each rabbit. Administration was performed between 8:00 and 18:00. On test days 1-14, all groups received n-tetradecane once daily to both ears. On test days 15-21, Group I received n-tetradecane once daily to both ears. Group II received n-tetradecane once daily to both ears. Group III received n-tetradecane once daily to the right ear only, not to the left ear. A 3x3 cm area was created on the inside of the ear of rabbits treated with n-tetradecane, where comedones were fully formed, and 0.5 g of oleanolic acid (test substance A), a plant extract containing 0.1% oleanolic acid (test substance B), or petrolatum (base) was administered. A 3x3 cm area was also created in the right ear of the untreated group III for diameter measurement and excision. Treatment was administered to both ears of groups I and II and the left ear of group III for 7 days (once a day, 8:00-18:00) from test days 15 to 21; the right ear of group III was not treated.

[0055] 3. Pore diameter measurement Pore ​​diameter measurements were performed 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, pore diameter measurements were performed at 10 randomly selected pore areas at the administration sites of oleanolic acid (test substance A), plant extract containing 0.1% oleanolic acid (test substance B), or petrolatum (base) using a microscope (Dino-Lite Digital Microscope, model number: DILOTEPL, sold by Sanko). The average pore diameter and standard deviation were calculated. After 14 days of TD administration, the pore size increase was confirmed by applying test substance A or B for 7 days (Group III left ear vs. Group II right ear or left ear). Resistance to pore size increase when test substance A or B was applied in parallel with TD administration from day 14 to day 7 after TD administration was also confirmed (Group III right ear vs. Group I right ear or left ear). The percentage change in the pore size measured on each day relative to the pre-measurement value was calculated and a significant difference test was performed. Significance tests were performed using the F test to test for homogeneity of variance. In the case of homogeneity of variance, a Student's t-test was used. In the case of unequal variance, an Aspin-Welch t-test was used. The significance level for the F test was 5%, and for the t-test, the significance levels were 5% and 1%. The results are shown in Table 2 and Figure 5.

[0056] [Table 2]

[0057] In Study 1, when petrolatum (base) alone was administered after 14 days of n-tetradecane administration, the pore size on Day 22 was larger than that on Day 14 (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 14 days of n-tetradecane administration, the pore size on Day 22 was smaller than that on Day 14 (201 right ear, 201 left ear). In Study 2, when n-tetradecane administration was continued for 22 days, the pore size on Day 22 was larger than that on Day 14 (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, although the pore diameter on the 22nd day was still larger than the pore diameter on the 14th day, the degree of enlargement was reduced (101 right ear, 101 left ear).

[0058] 4. Histopathological Examination On test day 22, the rabbits were anesthetized with thiamylal sodium (0.5 g for injection, Nichi-Iko Pharmaceutical Co., Ltd.) and exsanguinated. After euthanasia, the injection sites of oleanolic acid, plant extract containing 0.1% oleanolic acid, or petrolatum were excised. The right ear of Group III was excised from the same area as the injection sites of the other groups. The excised area was divided in half, and the ear canal side was preserved in 10% neutral buffered formalin for pathological analysis. The remaining half was frozen and preserved for analysis. Paraffin sections of the excised area were prepared, stained with hematoxylin and eosin, and observed under a BHS binocular microscope. Representative findings are shown in Figure 6. Pore dilation was observed in the ear canal tissue of right ear 301 on day 22. In contrast, no pore dilation was observed in the stained images of ear canal tissue of right ears 101 and 201.

[0059] Example 4: Test of the effectiveness of oleanolic acid in treating adult acne Test Method The solutions shown in Table 3 were prepared using cetyl ethylhexanoate (trade name: NIKKOL CI0, Nikko Chemicals) as a solvent so that oleanolic acid (trade name: Oleanolic Acid, manufactured by Wako Pure Chemical Industries) was 1% (w / w).

[0060] [Table 3]

[0061] Eight subjects (3 men and 5 women) in their 20s and 30s with adult acne were given a solution containing the ingredients shown in Table 3 (1% by weight as oleanolic acid) twice a day after washing their faces. It is known that adult acne is caused by a partial decrease in skin moisture content. After washing their faces, the subjects with adult acne in this example were allowed to stabilize their skin in an environment at room temperature of 23°C and humidity of 50%, and then had the moisture content of their cheeks measured using a Corneometer (trade name: Comeometer CM825, manufactured by Courage+Khazaka). The subjects were those with a cheek moisture content of 72 or less, which is considered to be the level at which adult acne is likely to occur. The following items were evaluated the day before use of the solution and one week after use. 1: Adult acne is a concern 2: Redness from adult acne 3: Itching caused by adult acne 4: Rough skin 5: Sticky 6: Dry skin 7: Rough skin 8: Clogged pores 9: Size of adult acne The evaluation was done on a 5-point scale, and the average score for each item was calculated.

[0062] 1: Evaluation criteria for the degree to which adult acne is a concern 5 points: I don't mind 4 points: Neither 3 points: Somewhat annoying 2 points: I'm curious 1 point: Very interesting

[0063] 2: Evaluation criteria for redness of adult acne 5 points: No redness 4 points: Slight redness 3 points: Slight redness 2 points: redness 1 point: Very red

[0064] 3: Evaluation criteria for itching caused by adult acne 5 points: No itching 4 points: Not much itching 3 points: Slight itching 2 points: Itchy 1 point: Very itchy

[0065] 4: Evaluation criteria for skin roughness 5 points: No roughness 4 points: Not too rough 3 points: Slightly rough 2 points: Rough 1 point: Very rough

[0066] 5: Stickiness evaluation criteria 5 points: No stickiness 4 points: Not very sticky 3 points: Slightly sticky 2 points: Sticky 1 point: Very sticky

[0067] 6: Evaluation criteria for dryness 5 points: No dryness 4 points: Not too dry 3 points: Slightly dry 2 points: Dry 1 point: Very dry

[0068] 7: Evaluation criteria for rough skin 5 points: No skin irritation 4 points: Not too rough on the skin 3 points: Slightly rough skin 2 points: Rough skin 1 point: Very rough skin

[0069] 8: Evaluation criteria for clogged pores 5 points: No need to worry about clogged pores 4 points: I don't really notice clogged pores. 3 points: Pores are slightly clogged 2 points: I'm concerned about clogged pores 1 point: I'm very concerned about clogged pores

[0070] 9: Evaluation criteria for the size of adult acne 5 points: I don't mind the size of my acne. 4 points: I don't really care about the size of my acne. 3 points: I'm a little concerned about the size of my acne 2 points: I'm concerned about the size of my acne 1 point: I am very concerned about the size of my acne.

[0071] [Table 4]

[0072] The results are shown in Table 4. In the subjects who received the oleanolic acid solution, the scores for the degree of bother of adult acne, redness of adult acne, itchiness of adult acne, roughness of the skin, stickiness, dryness, rough skin, clogged pores, and size of adult acne all improved. In other words, these results indicate that oleanolic acid has an effect of improving adult acne. [Industrial Applicability]

[0073] Formula (I)

[0074] [ka]

[0075] (wherein R1 represents a hydrogen atom or a methyl group, and R2 represents a hydrogen atom or a methyl group), or a physiologically acceptable salt thereof, can be provided as a sebum production regulator. This application is based on Patent Application No. 2020-122251 filed in Japan (filing date: July 16, 2020), the contents of which are incorporated in their entirety herein.

Claims

1. Formula (I) 【Chemistry 1】 (wherein R1 represents a hydrogen atom or a methyl group, and R2 represents a hydrogen atom or a methyl group), or a physiologically acceptable salt thereof, When the subject has oily skin, it acts as a sebum production inhibitor, and A sebum production regulator that acts as a sebum production promoter when the subject has dry skin.

2. The sebum production regulator according to claim 1, wherein the compound represented by formula (I) is oleanolic acid or ursolic acid.

3. A therapeutic agent for acne, comprising the sebum production regulator according to claim 1.

4. A therapeutic agent for a skin disease caused by dry skin, comprising the sebum production regulator according to claim 1.

5. The therapeutic agent for a skin disease according to claim 4, wherein the skin disease caused by dry skin is adult acne.

6. A compound represented by formula (I) for producing a therapeutic agent for skin diseases caused by acne or dry skin. 【Chemistry 2】 (wherein R1 represents a hydrogen atom or a methyl group, and R2 represents a hydrogen atom or a methyl group), or a physiologically acceptable salt thereof, When the subject has oily skin, it acts as a sebum production inhibitor, and When the subject has dry skin, it acts as a sebum production promoter.

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