Lipid production inhibitor

Abstract

To provide a lipid production inhibitor that can efficiently control excessive lipid production on skin, and can improve an undesirable skin condition, and an external preparation containing the lipid production inhibitor.SOLUTION: Provided are: a lipid production inhibitor for inhibiting lipid production in which short-chain fatty acid is interposed, which contains at least one kind of component selected from the group consisting of (A) a specific phenol skeleton-containing compound or a pharmacologically acceptable salt thereof, (B) a plant extract containing the phenol skeleton-containing compound or the pharmacologically acceptable salt thereof, (C) a specific γ- butyrolactone skeleton-containing compound or a pharmacologically acceptable salt thereof, and (D) a plant extract containing the γ-butyrolactone skeleton-containing compound or the pharmacologically acceptable salt thereof; and an external preparation containing the lipid production inhibitor.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a lipid production inhibitor. More specifically, the present invention relates to a lipid production inhibitor useful for improving undesirable skin conditions caused by excessive lipid production in the skin and an external preparation containing the lipid production inhibitor.

Background Art

[0002] In human skin, when lipids are produced excessively, skin abnormalities may be caused. Therefore, in order to suppress excessive lipid production, for example, it has been proposed to use a lipid production inhibitor containing an extract of Pyracantha fortuneana (Maxim.) Li as an active ingredient (see Patent Document 1). However, since lipids are produced by various production mechanisms, even when the lipid production inhibitor is used, excessive lipid production may not be sufficiently suppressed.

[0003] Therefore, a new technology that can effectively suppress excessive lipid production in the skin and improve undesirable skin conditions is eagerly awaited.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0005] The present invention has been made in view of the above prior art, and an object thereof is to provide a lipid production inhibitor that can effectively suppress excessive lipid production in the skin and improve undesirable skin conditions, and an external preparation containing the lipid production inhibitor.

Means for Solving the Problems

[0006] The present invention is (1) A lipid production inhibitor for suppressing lipid production mediated by short-chain fatty acids, comprising (A) to (D): (A) Formula (I):

[0007] [Chemical formula]

[0008] [In the formula, R 1 represents a hydrogen atom, a hydroxyl group, a carboxyl group, a hydrocarbon group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, and R 2 represents a hydrogen atom, a hydroxyl group, a carboxyl group, or a hydrocarbon group having 1 to 4 carbon atoms, and R 3 represents a hydrogen atom or a hydrocarbon group having 1 to 20 carbon atoms, and R 4 represents a hydrogen atom, a hydrocarbon group having 1 to 4 carbon atoms, a group represented by formula (II):

[0009] [Chemical formula]

[0010] (wherein * represents a bond) or a group represented by formula (III):

[0011] [Chemical formula]

[0012] (wherein * represents a bond) and R 1 and R 2 at least one of the groups is a hydroxyl group), a phenol skeleton-containing compound represented by or a pharmacologically acceptable salt thereof, (B) a plant extract containing the phenol skeleton-containing compound or a pharmacologically acceptable salt thereof, (C) Formula (IV):

[0013] [Chemical formula]

[0014] (wherein, R 5 represents a hydrogen atom, a hydroxyl group, a carboxyl group, a hydrocarbon group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms, and R 6 represents a hydrogen atom or a hydrocarbon group having 1 to 4 carbon atoms), a γ-butyrolactone skeleton-containing compound represented thereby or a pharmacologically acceptable salt thereof, and (D) a plant extract containing the γ-butyrolactone skeleton-containing compound or a pharmacologically acceptable salt thereof A lipid production inhibitor characterized by containing at least one component selected from the group consisting of, and (2) An external preparation containing the lipid production inhibitor according to (1) above relates to. [Effect of the Invention]

[0015] According to the present invention, there is provided an excellent effect that a lipid production inhibitor capable of effectively suppressing excessive lipid production in the skin and improving an undesirable skin condition, and an external preparation containing the lipid production inhibitor are provided. [Brief Description of the Drawings]

[0016]

Figure 1

Figure 2

Figure 3

Figure 4

Mode for Carrying Out the Invention

[0017] (Lipid production inhibitor) As described above, the lipid production inhibitor of the present invention is a lipid production inhibitor for inhibiting short-chain fatty acid-mediated lipid production, and (A) to (D): (A) Formula (I):

[0018]

Chemical formula

[0019] [In the formula, R 1 represents a hydrogen atom, a hydroxyl group, a carboxyl group, a hydrocarbon group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, and R 2 represents a hydrogen atom, a hydroxyl group, a carboxyl group, or a hydrocarbon group having 1 to 4 carbon atoms, and R 3 represents a hydrogen atom or a hydrocarbon group having 1 to 20 carbon atoms, and R 4 represents a hydrogen atom, a hydrocarbon group having 1 to 4 carbon atoms, a group represented by formula (II):

[0020]

Chemical formula

[0021] (In the formula, * represents a bond) or a group represented by formula (III):

[0022]

Chemical formula

[0023] (In the formula, * represents a bond) and at least one of the groups of R 1 and R 2 is a hydroxyl group) A phenolic skeleton-containing compound represented by the formula or a pharmacologically acceptable salt thereof, (B) A plant extract containing the phenolic skeleton-containing compound or a pharmacologically acceptable salt thereof, (C) Formula (IV):

[0024] [Chemical formula]

[0025] (In the formula, R 5 represents a hydrogen atom, a hydroxyl group, a carboxyl group, a hydrocarbon group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms, and R 6 represents a hydrogen atom or a hydrocarbon group having 1 to 4 carbon atoms) A γ-butyrolactone skeleton-containing compound represented by the formula or a pharmacologically acceptable salt thereof, and (D) A plant extract containing the γ-butyrolactone skeleton-containing compound or a pharmacologically acceptable salt thereof characterized by containing at least one component selected from the group consisting of

[0026] The lipid production inhibitor of the present invention contains (A) the phenolic skeleton-containing compound or a pharmacologically acceptable salt thereof, (B) a plant extract containing the phenolic skeleton-containing compound or a pharmacologically acceptable salt thereof, (C) the γ-butyrolactone skeleton-containing compound or a pharmacologically acceptable salt thereof, and (D) a plant extract containing the γ-butyrolactone skeleton-containing compound or a pharmacologically acceptable salt thereof. Therefore, it can effectively inhibit lipid production mediated by the short-chain fatty acid.

[0027] In the present specification, (A) the phenolic skeleton-containing compound or a pharmacologically acceptable salt thereof, (B) a plant extract containing the phenolic skeleton-containing compound or a pharmacologically acceptable salt thereof, (C) the γ-butyrolactone skeleton-containing compound or a pharmacologically acceptable salt thereof, and (D) a plant extract containing the γ-butyrolactone skeleton-containing compound or a pharmacologically acceptable salt thereof are collectively referred to simply as the "active ingredient".

[0028] As used herein, the term "short-chain fatty acid" refers to a fatty acid having 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms. Examples of fatty acids having 2 to 6 carbon atoms include acetic acid, propionic acid, butyric acid, pentanoic acid, caproic acid, etc., but the present invention is not limited to such examples only. Among these short-chain fatty acids, propionic acid, butyric acid and acetic acid are preferred because they are greatly involved in lipid production, and propionic acid and butyric acid are more preferred. Therefore, according to the lipid production inhibitor of the present invention, among these short-chain fatty acids, at least one short-chain fatty acid selected from the group consisting of propionic acid, butyric acid and acetic acid, preferably at least one short-chain fatty acid selected from the group consisting of propionic acid and butyric acid can be suitably used for suppressing lipid production mediated thereby.

[0029] "Lipid production mediated by short-chain fatty acids" includes lipid production induced by at least one selected from the group consisting of the above short-chain fatty acids in lipid-producing cells present in the skin. As used herein, lipid production mediated by short-chain fatty acids is also referred to as "short-chain fatty acid-mediated lipid production". In addition, the concept of "skin" includes the scalp. Examples of the lipid-producing cells include sebaceous gland cells, etc., but the present invention is not limited to such examples only.

[0030] In the phenol skeleton-containing compound represented by formula (I), R 1 is a hydrogen atom, a hydroxyl group, a carboxyl group, a hydrocarbon group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms. Examples of the hydrocarbon group having 1 to 4 carbon atoms include linear or branched alkyl groups having 1 to 4 carbon atoms such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, etc.; alicyclic hydrocarbon groups having 3 or 4 carbon atoms such as cyclopropyl group, cyclobutyl group, etc., but the present invention is not limited to such examples only. Examples of the alkoxy group having 1 to 4 carbon atoms include methoxy group, ethoxy group, propoxy group, butoxy group, etc., but the present invention is not limited to such examples only. These R 1Among them, from the viewpoint of effectively suppressing lipid production mediated by short-chain fatty acids, a hydroxyl group and an alkoxy group having 1 to 4 carbon atoms are preferable, a hydroxyl group, a carboxyl group, a methoxy group and an ethoxy group are more preferable, and a hydroxyl group, a carboxyl group and a methoxy group are even more preferable.

[0031] R 2 is a hydrogen atom, a hydroxyl group, a carboxyl group or a hydrocarbon group having 1 to 4 carbon atoms. R 2 Examples of the hydrocarbon group having 1 to 4 carbon atoms used for R 1 can be the same hydrocarbon groups as those of the hydrocarbon group having 1 to 4 carbon atoms used for R 2 Among them, from the viewpoint of effectively suppressing lipid production mediated by short-chain fatty acids, a hydroxyl group and a carboxyl group are preferable.

[0032] R 3 is a hydrogen atom or a hydrocarbon group having 1 to 20 carbon atoms. Examples of the hydrocarbon group having 1 to 20 carbon atoms include linear or branched alkyl groups having 1 to 20 carbon atoms such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, 2-ethylhexyl group, heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group, tridecyl group, tetradecyl group, pentadecyl group, hexadecyl group, heptadecyl group, octadecyl group, nonadecyl group, icosyl group, etc.; alicyclic hydrocarbon groups having 3 to 20 carbon atoms such as cyclopropyl group, cyclopentyl group, cyclohexyl group, methylcyclohexyl group, cyclododecyl group, etc.; polycyclic hydrocarbon groups having 7 to 20 carbon atoms such as n-bornyl group, isobornyl group, etc.; aryl groups having 6 to 12 carbon atoms such as phenyl group, tolyl group, xylyl group, naphthyl group, etc.; aralkyl groups having 7 to 12 carbon atoms such as benzyl group, phenylethyl group, methylbenzyl group, etc., but the present invention is not limited only to such examples. These R 3Among them, from the viewpoint of effectively suppressing lipid production mediated by short-chain fatty acids, a hydrogen atom and a linear or branched alkyl group having 8 to 18 carbon atoms are preferable, a hydrogen atom and a linear or branched alkyl group having 10 to 18 carbon atoms are preferable, a hydrogen atom, a dodecyl group, a tridecyl group, a tetradecyl group, a pentadecyl group, a hexadecyl group, a heptadecyl group and an octadecyl group are more preferable, and a hydrogen atom and a pentadecyl group are even more preferable.

[0033] R 4 is a hydrogen atom, a hydrocarbon group having 1 to 4 carbon atoms or a group represented by the formula (II). The hydrocarbon group having 1 to 4 carbon atoms used for R 4 can be exemplified by the same hydrocarbon groups as those used for the hydrocarbon group having 1 to 4 carbon atoms used for R 1 and R 2 . Among these Rs 4 , from the viewpoint of effectively suppressing lipid production mediated by short-chain fatty acids, a hydrogen atom and a group represented by the formula (II) are preferable.

[0034] In the phenol skeleton-containing compound represented by the formula (I), at least one of R 1 and R 2 is a hydroxyl group.

[0035] The pharmacologically acceptable salt of the phenol skeleton-containing compound may be an inorganic salt or an organic salt. Examples of the inorganic salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; inorganic acid salts such as hydrochloride, but the present invention is not limited only to such examples. Examples of the organic salt include organic base salts such as trimethylamine salt, triethylamine salt and pyridine salt; organic acid salts such as acetate and maleate, but the present invention is not limited only to such examples.

[0036] The phenol skeleton-containing compound may further have a substituent in the formula (I) as long as it does not inhibit the object of the present invention.

[0037] Among the phenol skeleton-containing compounds represented by formula (I) or pharmacologically acceptable salts thereof, from the viewpoint of effectively suppressing lipid production mediated by short-chain fatty acids, · In formula (I), R 1 is a hydroxyl group, R 2 is a carboxyl group, R 3 and R 4 are hydrogen atoms (hereinafter also referred to as "Compound A"), · In formula (I), R 1 is a hydroxyl group, R 2 is a carboxyl group, R 3 is a pentadecyl group, R 4 is a hydrogen atom (hereinafter also referred to as "Compound B"), · In formula (I), R 1 is a hydroxyl group, R 2 is a hydroxyl group, R 3 is a hydrogen atom, R 4 is a group represented by formula (II) (hereinafter also referred to as "Compound C"), and · In formula (I), R 1 is a methoxy group, R 2 is a carboxyl group, R 3 is a hydrogen atom, R 4 is a group represented by formula (III) (hereinafter also referred to as "Compound D") are preferred, the Compound A, the Compound B and the Compound D are more preferred, and the Compound D is even more preferred.

[0038] Examples of the plant extract containing the phenol skeleton-containing compound or a pharmacologically acceptable salt thereof include extracts of Salicaceae plants, extracts of Ericaceae plants, extracts of Apocynaceae plants, extracts of Zingiberaceae plants, etc., but the present invention is not limited only to such examples. In addition, the plant extract containing the phenol skeleton-containing compound or a pharmacologically acceptable salt thereof may be a plant extract containing a precursor compound that is converted into the phenol skeleton-containing compound or a pharmacologically acceptable salt thereof when contacted with the skin.

[0039] Examples of the Salicaceae plants include, but are not limited to, plants of the genus Salix such as Salix alba and Salix gracilistyla. The extract of the Salicaceae plant can be produced, for example, by extracting from the plant body or organs of the Salicaceae plant by a conventional method using an extraction solvent. Examples of the organs of the Salicaceae plant include, but are not limited to, bark. Among the plant bodies and organs of the Salicaceae plant, organs are preferred, and bark is more preferred, from the viewpoint of effectively suppressing lipid production mediated by short-chain fatty acids. Examples of the extraction solvent used for producing the extract of the Salicaceae plant include water; lower alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, and 2-butanol; polyhydric alcohols such as 1,3-butylene glycol, propylene glycol, and glycerin; ketones such as acetone and methyl ethyl ketone, ester compounds such as ethyl acetate and butyl acetate; hydrocarbons such as hexane and heptane; ether compounds such as ethyl ether and propyl ether, but the present invention is not limited to such examples. These extraction solvents may be used alone or in combination of two or more. Among these extraction solvents, water and lower alcohols are preferred, and water and 1,3-butylene glycol are more preferred, from the viewpoint of effectively suppressing lipid production mediated by short-chain fatty acids. The extraction product obtained from the Salicaceae plant may be used as an extract in the form of a solution containing the extraction solvent, or a solution obtained by dissolving in an appropriate solvent the product obtained by subjecting to purification by filtration, concentration, column chromatography, etc. as necessary may be used as an extract. The obtained extract may be used in a liquid state, or may be used in a solid state by concentration to dryness, spray drying, vacuum drying, freeze drying, etc. Among the extracts of the Salicaceae plant, from the viewpoint of effectively suppressing lipid production mediated by short-chain fatty acids, an extract obtained by subjecting the ground bark of Salix alba to immersion extraction with 1,3-butylene glycol which may contain water, and an extract obtained by subjecting the ground bark of Salix gracilistyla to immersion extraction with 1,3-butylene glycol which may contain water are preferred.Extracts of plants in the Salicaceae family, such as extracts of willow bark and Michiyana willow bark, can be easily obtained commercially.

[0040] Examples of the Anacardiaceae plants include plants in the genus Anacardium such as cashew, etc., but the present invention is not limited to such examples only. The extract of the Anacardiaceae plant can be produced, for example, by extracting from the plant body or organs of the Anacardiaceae plant by a conventional method using an extraction solvent. Examples of the organs of the Anacardiaceae plant include seeds, fruits, husks, etc., but the present invention is not limited to such examples only. Among the plant bodies and organs of the Anacardiaceae plant, from the viewpoint of effectively suppressing lipid production mediated by short-chain fatty acids, organs are preferred, seeds, fruits and husks are more preferred, and husks are even more preferred. As the extraction solvent used for the production of the extract of the Anacardiaceae plant, the same solvents as those used for the production of the extract of the Salicaceae plant are exemplified. These extraction solvents may be used alone or in combination of two or more. Among these extraction solvents, from the viewpoint of effectively suppressing lipid production mediated by short-chain fatty acids, water and lower alcohols are preferred, and water and 1,3-butylene glycol are more preferred. Incidentally, the extraction product obtained from the Anacardiaceae plant may be used as an extract in the form of a solution containing the extraction solvent, or a solution obtained by subjecting it to purification by filtration, concentration, column chromatography, etc. as necessary and dissolving it in an appropriate solvent may be used as an extract. Also, the obtained extract may be used in a liquid state, or may be used in a solid state by concentration to dryness, spray drying, vacuum drying, freeze drying, etc. Among the extracts of the Anacardiaceae plant, from the viewpoint of effectively suppressing lipid production mediated by short-chain fatty acids, an extract obtained by subjecting the crushed cashew husk to immersion extraction with 1,3-butylene glycol which may contain water is preferred. Extracts of Anacardiaceae plants such as cashew husk extract can be easily obtained commercially.

[0041] Examples of the Zingiberaceae plants include, but are not limited to, plants of the genus Zingiber such as ginger. The extract of the Zingiberaceae plants can be produced, for example, by extracting from the plant body or organs of the Zingiberaceae plants by a conventional method using an extraction solvent. Examples of the organs of the Zingiberaceae plants include roots, stems, leaves, etc., but the present invention is not limited to such examples. Among the plant bodies and organs of the Zingiberaceae plants, organs are preferred, roots and stems are more preferred, and roots are even more preferred from the viewpoint of effectively suppressing lipid production mediated by short-chain fatty acids. As the extraction solvent used for producing the extract of the Zingiberaceae plants, the same solvents as those used for producing the extract of the Salicaceae plants are exemplified. These extraction solvents may be used alone or in combination of two or more. Among these extraction solvents, water and lower alcohols are preferred, and water and 1,3-butylene glycol are more preferred from the viewpoint of effectively suppressing lipid production mediated by short-chain fatty acids. The extraction product obtained from the Zingiberaceae plants may be used as an extract in the form of a solution containing the extraction solvent, or a solution obtained by dissolving in an appropriate solvent the product obtained by subjecting it to purification by filtration, concentration, column chromatography, etc. as necessary may be used as an extract. Further, the obtained extract may be used in a liquid state, or may be used in a solid state by concentration to dryness, spray drying, vacuum drying, freeze drying, etc. Among the extracts of the Zingiberaceae plants, from the viewpoint of effectively suppressing lipid production mediated by short-chain fatty acids, an extract obtained by subjecting the pulverized ginger root to immersion extraction with 1,3-butylene glycol which may contain water is preferred. Extracts of Zingiberaceae plants such as ginger root extract can be easily obtained commercially.

[0042] Examples of the Clusiaceae plants include, but are not limited to, Clusiaceae plants such as Garcinia cambogia and Garcinia indica. The extract of the Clusiaceae plant can be produced, for example, by extracting from the plant body or organs of the Clusiaceae plant by a conventional method using an extraction solvent. Examples of the organs of the Clusiaceae plant include, but are not limited to, pericarp, fruit, etc. Among the plant bodies and organs of the Clusiaceae plant, organs are preferred, pericarp and fruit are more preferred, fruit is more preferred, and nuts are even more preferred from the viewpoint of effectively suppressing lipid production mediated by short-chain fatty acids. Examples of the extraction solvent used for producing the extract of the Clusiaceae plant are the same solvents as those used for producing the extract of the Salicaceae plant. These extraction solvents may be used alone or in combination of two or more. Among these extraction solvents, water and lower alcohols are preferred, and water is more preferred from the viewpoint of effectively suppressing lipid production mediated by short-chain fatty acids. The extraction product obtained from the Clusiaceae plant may be used as an extract in the form of a solution containing the extraction solvent, or a solution obtained by dissolving in an appropriate solvent the product obtained by subjecting to purification by filtration, concentration, column chromatography, etc. as necessary may be used as an extract. The obtained extract may be used in a liquid state, or may be used in a solid state by concentration to dryness, spray drying, vacuum drying, freeze drying, etc. Among the extracts of the Clusiaceae plant, from the viewpoint of effectively suppressing lipid production mediated by short-chain fatty acids, an extract obtained by pulverizing the fruit or pericarp of Garcinia cambogia and then subjecting the obtained pulverized product to hot water extraction with water and an extract obtained by pulverizing the nuts of Garcinia indica and then subjecting the obtained pulverized product to hot water extraction with water are preferred. Extracts of Clusiaceae plants such as Garcinia cambogia fruit extract, Garcinia cambogia pericarp extract, and Garcinia indica nut extract can be easily obtained commercially.

[0043] In the γ-butyrolactone skeleton-containing compound represented by the formula (IV), R 5is a hydrogen atom, a hydroxyl group, a carboxyl group, a hydrocarbon group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms. R 5 Examples of the hydrocarbon group having 1 to 4 carbon atoms used for R 1 , R 2 and R 4 include the same hydrocarbon groups as those used for R 5 Examples of the alkoxy group having 1 to 4 carbon atoms used for R 1 include the same alkoxy groups having 1 to 4 carbon atoms as those used for R 5 Among these R

[0044] R 6 represents a hydrogen atom or a hydrocarbon group having 1 to 4 carbon atoms. R 6 Examples of the hydrocarbon group having 1 to 4 carbon atoms used for R 1 , R 2 , R 4 and R 5 include the same hydrocarbon groups as those used for R 6 Among these R

[0045] Examples of the pharmacologically acceptable salts of the γ-butyrolactone skeleton-containing compound include metal salts such as alkali metal salts, but the present invention is not limited only to such examples.

[0046] Among the γ-butyrolactone skeleton-containing compound or its pharmacologically acceptable salt, from the viewpoint of effectively suppressing lipid production mediated by short-chain fatty acids, in formula (IV), R 5 is a carboxyl group, and R 6 is a propyl group (hereinafter also referred to as "Compound E") is preferred.

[0047] The lipid production inhibitor of the present invention may contain components other than the active ingredient as necessary. Such components include, for example, water such as purified water, ion-exchanged water, pure water, and refined water; organic solvents such as monohydric aliphatic alcohols having 1 to 4 carbon atoms; stabilizers, etc. However, the present invention is not limited only to such examples. When the lipid production inhibitor of the present invention contains components other than the active ingredient, within a range that does not prevent the object of the present invention, in the lipid production inhibitor of the present invention, the active ingredient and other components may form a complex.

[0048] Since the content rate of the active ingredient in the lipid production inhibitor of the present invention varies depending on the type of the active ingredient, the use of the lipid production inhibitor of the present invention, etc., it cannot be determined unconditionally. Therefore, it is preferable to appropriately determine according to the type of the active ingredient, the use of the lipid production inhibitor of the present invention, etc. The content rate of the active ingredient in the lipid production inhibitor of the present invention (the content rate converted into the amount of the phenol skeleton-containing compound and / or the γ-butyrolactone skeleton-containing compound) is usually preferably 0.01% by mass or more, more preferably 0.05% by mass or more, still more preferably 0.1% by mass or more from the viewpoint of effectively suppressing lipid production in which short-chain fatty acids are involved, and preferably 5% by mass or less, more preferably 2% by mass or less, still more preferably 1% by mass or less from the viewpoint of suppressing the burden on the skin.

[0049] 1 cm of the skin surface area 2 Since the amount of the lipid production inhibitor of the present invention used per 1 cm of the skin surface area (the amount converted into the amount of the active ingredient) varies depending on the type of the active ingredient, the use of the lipid production inhibitor of the present invention, etc., it cannot be determined unconditionally. Therefore, it is preferable to appropriately determine according to the type of the active ingredient, the use of the lipid production inhibitor of the present invention, etc.

[0050] As described above, according to the lipid production inhibitor of the present invention, since lipid production mediated by short-chain fatty acids is effectively suppressed, the lipid production inhibitor of the present invention can be suitably used for applications such as improving undesirable skin conditions caused by excessive lipid production. Examples of undesirable skin conditions caused by excessive lipid production include, for example, acne, excessive shininess of the skin, seborrheic dermatitis, etc., but the present invention is not limited to such examples only.

[0051] (External preparation) The external preparation of the present invention is characterized by containing the lipid production inhibitor. Since the external preparation of the present invention contains the lipid production inhibitor, according to the external preparation of the present invention, excessive lipid production can be effectively suppressed. Therefore, the external preparation of the present invention can be suitably used for applications such as improving undesirable skin conditions caused by excessive lipid production. In this specification, the concept of "external preparation" includes cosmetics, quasi-drugs, and pharmaceuticals.

[0052] The external preparation of the present invention can be produced, for example, by mixing the lipid production inhibitor with components other than the lipid production inhibitor according to the use of the external preparation of the present invention, the dosage form of the external preparation of the present invention, etc.

[0053] The content rate of the lipid production inhibitor in the external preparation of the present invention varies depending on the type of active ingredient contained in the lipid production inhibitor, the use of the external preparation of the present invention, the dosage form of the external preparation of the present invention, etc., and thus cannot be determined unconditionally. Therefore, it is preferable to appropriately determine according to the type of active ingredient contained in the lipid production inhibitor, the use of the external preparation of the present invention, the dosage form of the external preparation of the present invention, etc. The content rate of the lipid production inhibitor in the external preparation of the present invention is usually, from the viewpoint of sufficiently expressing the effect of the active ingredient contained in the lipid production inhibitor, more preferably 0.01% by mass or more, still more preferably 0.1% by mass or more, and from the viewpoint of ensuring a feeling of use suitable for the external preparation, preferably 5% by mass or less, more preferably 1% by mass or less.

[0054] Examples of components other than the lipid production inhibitor include water such as purified water, ion-exchanged water, pure water, and refined water; organic solvents such as monohydric aliphatic alcohols having 1 to 4 carbon atoms; gelling agents; oil components such as waxes, hydrocarbon oils, fatty acids, fats and oils, ester oils, and silicone oils; surfactants such as anionic emulsifiers, cationic emulsifiers, nonionic emulsifiers, amphoteric emulsifiers, and polymer emulsifiers; humectants such as polyhydric alcohols and sugars (excluding the stabilizers); thickeners; antioxidants; chelating agents; fragrances; pigments; ultraviolet absorbers; ultraviolet scatterers; vitamins; amino acids (excluding the stabilizers); preservatives, etc. However, the present invention is not limited only to such examples.

[0055] Since the content of components other than the lipid production inhibitor in the external preparation of the present invention varies depending on the use of the external preparation of the present invention, the dosage form of the external preparation of the present invention, etc., and thus cannot be determined unconditionally, it is preferable to appropriately determine according to the use of the external preparation of the present invention, the dosage form of the external preparation of the present invention, etc.

[0056] Examples of the dosage form of the external preparation of the present invention include solutions, gels, ointments, creams, lotions, poultices, aerosol agents, etc. However, the present invention is not limited only to such examples.

[0057] As described above, according to the external preparation of the present invention, excessive lipid production can be effectively suppressed, so it can be suitably used for uses such as improving undesirable skin conditions caused by excessive lipid production.

Examples

[0058] Next, the present invention will be described in more detail based on examples, but the present invention is not limited only to such examples. In the following, the meanings of each abbreviation are as follows. <Explanation of Abbreviations> BSA: Bovine Serum Albumin FBS: Fetal Bovine Serum PBS: Phosphate Buffered Saline PBST: PBS solution containing polyoxyethylene sorbitan monolaurate (Tween 20) [Composition: 0.1% by volume Tween 20 and the balance PBS] PFA: Paraformaldehyde

[0059] Preparation Example 1 A neutral lipid staining reagent [manufactured by Wako Pure Chemical Industries, Ltd., trade name: Nile Red] was added to a PBS solution so that its concentration became 10 μg / mL to obtain a staining reagent A.

[0060] Preparation Example 2 Hoechst 33342 was added to a PBS solution so that its concentration became 10 μg / mL to obtain a staining reagent B.

[0061] Reference Example 1 Propionic acid was added to a medium for sebaceous gland cells [manufactured by CTI-Biotech, product number: CBSeb4Gln] so that its concentration became 0.01% by mass (Experiment No. 1) or 0.02% by mass (Experiment No. 2) to obtain a propionic acid-containing medium. In the following, the medium for sebaceous gland cells [manufactured by CTI-Biotech, product number: CBSeb4Gln] was used as the medium for Experiment No. 3 (control medium).

[0062] Sebaceous gland cells [manufactured by CTI-Biotech, product number: CTICC1.4.1] were seeded on a culture slide at a concentration of 5000 cells and cultured at 37°C for 24 hours under 5% by volume carbon dioxide. Then, the medium in the well was replaced with 0.5 mL of the medium of Experiment No. 1, Experiment No. 2, or Experiment No. 3, and the sebaceous gland cells were further cultured at 37°C for 48 hours under 5% by volume carbon dioxide. The medium was removed from the well containing the cultured sebaceous gland cells. Then, 0.5 mL of a PBS solution containing 4% by mass PFA was added to the well, and the sebaceous gland cells were fixed by incubating at room temperature (25°C) for 15 minutes to obtain a fixed sample.

[0063] The fixed sample was washed with PBST solution. 0.5 mL of staining reagent A of Preparation Example 1 was added to the well containing the washed fixed sample, and the neutral lipids were stained by incubating at room temperature for 30 minutes. The fixed sample after staining was washed with PBS solution.

[0064] 0.5 mL of staining reagent B of Preparation Example 2 was added to the well containing the washed fixed sample, and the nuclei were stained by incubating at room temperature (25 °C) for 30 minutes. The fixed sample after staining was washed with PBS solution.

[0065] The fixed sample after staining was observed using a confocal laser scanning microscope. The results are shown in Figure 1. In Figure 1, (A) shows the observation result of the stained image of sebaceous gland cells cultured in a medium containing 0.01% by mass of propionic acid (Experiment No. 1) in Reference Example 1, (B) shows the observation result of the stained image of sebaceous gland cells cultured in a medium containing 0.02% by mass of propionic acid (Experiment No. 2) in Reference Example 1, and (C) shows the observation result of the stained image of sebaceous gland cells cultured in a medium without propionic acid (Experiment No. 3) in Reference Example 1. In the figure, the scale bar indicates 100 μm.

[0066] From the results shown in Figure 1, it can be seen that in sebaceous gland cells cultured in the media of Experiment No. 1 and Experiment No. 2, the area of the part emitting fluorescence based on neutral lipids is increased compared with sebaceous gland cells cultured in the medium of Experiment No. 3. Also, it can be seen that in sebaceous gland cells cultured in the medium of Experiment No. 2, the area of the part emitting fluorescence based on neutral lipids is increased compared with sebaceous gland cells cultured in the medium of Experiment No. 1. From these results, it can be understood that in sebaceous gland cells, the amount of neutral lipids increases depending on the concentration of propionic acid.

[0067] Examples 1 and 2 Propionic acid and the compound A were added to a medium for sebaceous gland cells [manufactured by City Eye - Biotech, product number: CBSeb4Gln] so that the concentration of propionic acid was 0.02% by mass and the concentration of the compound A was 100 μg / mL (Example 1) or 200 μg / mL (Example 2) to obtain a medium. The compound A is, in formula (I), R1 is a hydroxyl group, R 2 is a carboxyl group, R 3 and R 4 is a compound in which is a hydrogen atom.

[0068] Examples 3 and 4 Propionic acid and the compound B were added to a medium for sebaceous gland cells [manufactured by City Cell - Biotech, product number: CBSeb4Gln] so that the concentration of propionic acid was 0.02% by mass and the concentration of the compound B was 12.5 μM (Example 3) or 25 μM (Example 4) to obtain a medium. The compound B is, in formula (I), R 1 is a hydroxyl group, R 2 is a carboxyl group, R 3 is a pentadecyl group, R 4 is a compound in which is a hydrogen atom.

[0069] Example 5 Propionic acid and turmeric extract [manufactured by Daiwa Kasei Co., Ltd., trade name: Curcumin GS] were added to a medium for sebaceous gland cells [manufactured by City Cell - Biotech, product number: CBSeb4Gln] so that the concentration of propionic acid was 0.02% by mass and the concentration of the turmeric extract [in terms of the phenolic - skeleton - containing compound] was 0.02% by mass to obtain a medium. The turmeric extract is a plant extract containing the compound D. Also, the compound D is, in formula (I), R 1 is a methoxy group, R 2 is a carboxyl group, R 3 is a hydrogen atom, R 4 is a compound in which is a group represented by formula (III).

[0070] Comparative Example 1 Hereinafter, the medium with experiment number: 3 [manufactured by City Cell - Biotech, product number: CBSeb4Gln] was used as the medium for Comparative Example 1.

[0071] Comparative Example 2 Hereinafter, the medium with experiment number: 2 (a medium containing 0.02% by mass propionic acid) was used as the medium for Comparative Example 2.

[0072] Test Example 1 In Reference Example 1, instead of using the media of Experiment Numbers 1 to 3, any one of the media of Examples 1 to 5 and Comparative Examples 1 and 2 was used; instead of seeding sebaceous gland cells on a culture slide at a concentration of 5000 cells, sebaceous gland cells were seeded in each well of a 96-well plate at a concentration of 20000 cells per well; and except for culturing the sebaceous gland cells for 4 days instead of culturing them for 48 hours after medium replacement, the same operations as in Reference Example 1 were performed, and the nuclei and neutral lipids in the sebaceous gland cells were stained. The cell count was determined based on the number of stained nuclei. Also, using a fluorescence measuring device, the fluorescence intensity based on Nile red bound to neutral lipids in the sebaceous gland cells was measured.

[0073] Next, the lipid amount index per unit cell was calculated by dividing the measured fluorescence intensity value by the cell count. The obtained lipid amount index per unit cell was used to evaluate the ability to suppress lipid production mediated by propionic acid. The results of examining the ability of Compound A, Compound B, or turmeric extract (plant extract containing Compound D) to suppress propionic acid-mediated lipid production are shown in FIGS. 2 to 4.

[0074] FIG. 2 shows the results of examining the ability of Compound A to suppress propionic acid-mediated lipid production. In FIG. 2, lane 1 represents the lipid amount index per unit cell when using the medium of Comparative Example 1, lane 2 represents the lipid amount index per unit cell when using the medium of Comparative Example 2, lane 3 represents the lipid amount index per unit cell when using the medium of Example 1, and lane 4 represents the lipid amount index per unit cell when using the medium of Example 2.

[0075] FIG. 3 shows the results of examining the ability of Compound B to suppress propionic acid-mediated lipid production. In FIG. 2, lane 1 represents the lipid amount index per unit cell when using the medium of Comparative Example 1, lane 2 represents the lipid amount index per unit cell when using the medium of Comparative Example 2, lane 3 represents the lipid amount index per unit cell when using the medium of Example 3, and lane 4 represents the lipid amount index per unit cell when using the medium of Example 4.

[0076] Figure 4 shows the results of examining the ability of the turmeric extract (plant extract containing compound D) to inhibit the production of propionate-mediated lipids. In Figure 2, lane 1 shows the lipid amount index per unit cell when the medium of Comparative Example 1 was used, lane 2 shows the lipid amount index per unit cell when the medium of Comparative Example 2 was used, and lane 4 shows the lipid amount index per unit cell when the medium of Example 5 was used.

[0077] From the results shown in Figures 2 to 4, when a medium containing compound A, compound B, or turmeric extract (plant extract containing compound D) was used (Examples 1 to 5), compared with the case of using a medium containing propionic acid and not containing any of compound A, compound B, and turmeric extract (plant extract containing compound D), it can be seen that the lipid amount index per unit cell decreased.

[0078] In addition, instead of using compound A, compound B, or turmeric extract (plant extract containing compound D), when using a phenolic skeleton-containing compound other than compounds A, B, and D, a plant extract containing a phenolic skeleton-containing compound other than compounds A, B, and D, the γ-butyrolactone skeleton-containing compound, or a plant extract containing the γ-butyrolactone skeleton-containing compound, a similar tendency to that when using compound A, compound B, or turmeric extract (plant extract containing compound D) is observed.

[0079] Also, when using other fatty acids having 2 to 6 carbon atoms (acetic acid, butyric acid, pentanoic acid, and caproic acid) instead of propionic acid, lipid production is observed, and when using the active ingredient, the lipid production tends to be suppressed.

[0080] As described above, since the lipid production inhibitor of the present invention contains the active ingredient, according to the lipid production inhibitor of the present invention, lipid production mediated by short-chain fatty acids is effectively suppressed. Therefore, the lipid production inhibitor of the present invention and the external preparation containing the lipid production inhibitor are expected to improve undesirable skin conditions.

Claims

1. A lipid production inhibitor for suppressing lipid production mediated by short-chain fatty acids, comprising (A) to (D): (A) Formula (I): 【Chemical 1】 [In the formula, R １ represents a hydrogen atom, a hydroxyl group, a carboxyl group, a hydrocarbon group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, and R ２ represents a hydrogen atom, a hydroxyl group, a carboxyl group, or a hydrocarbon group having 1 to 4 carbon atoms, and R ３ represents a hydrogen atom or a hydrocarbon group having 1 to 20 carbon atoms, and R ４ represents a hydrogen atom, a hydrocarbon group having 1 to 4 carbon atoms, formula (II): [Chemical Formula 2] (In the formula, * represents a bond) A phenol skeleton-containing compound represented by the group or formula (III): [Chemical Formula 3] (In the formula, * represents a bond) represents a group represented by, and R １ and R ２ at least one of the groups is a hydroxyl group) Or a pharmacologically acceptable salt thereof, (B) A plant extract containing the phenol skeleton-containing compound or a pharmacologically acceptable salt thereof, (C) Formula (IV): 【Chemical Formula 4】 (wherein, R ５ represents a hydrogen atom, a hydroxyl group, a carboxyl group, a hydrocarbon group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms, and R ６ represents a hydrogen atom or a hydrocarbon group having 1 to 4 carbon atoms), a γ-butyrolactone skeleton-containing compound represented thereby or a pharmacologically acceptable salt thereof, and (D) a plant extract containing the γ-butyrolactone skeleton-containing compound or a pharmacologically acceptable salt thereof A lipid production inhibitor characterized by containing at least one component selected from the group consisting of.

2. An external preparation containing the lipid production inhibitor according to Claim 1.

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