composition

Abstract

The present invention addresses the problem of providing: a composition which has excellent effects in the maintenance of muscle mass and muscle quality and in muscle activation; and a composition which has excellent effects in PGC-1α activation, Atrogin-1 expression suppression, or Myostatin expression suppression.　The present invention for solving the above-mentioned problem is a composition for muscle maintenance and / or muscle activation, the composition containing at least one compound selected from the group consisting of compounds represented by formula (I) and salts thereof. In formula (I), R1, R2, R3, R4, R5, and R6 each independently represent a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a cycloalkyl group, an aryl group, an acyl group, a heteroarylcarbonyl group, an alkoxycarbonyl group, -CHO, -COOH, or -OH.

Description

composition

[0001] The present invention relates to a composition.

[0002] In the formation of skeletal muscle (striated muscle), myoblasts first differentiate into myotubes, which then fuse to form muscle fibers (muscle cells). Muscle bundles are then formed by filling the spaces between the muscle fiber cells with connective tissue, and skeletal muscle is formed by the collection of muscle bundles. Skeletal muscle plays an important role in energy metabolism, the absorption of sugars and other substances into the body, daily movements such as walking and maintaining posture, and physical activities such as exercise. Skeletal muscle also has a significant impact on the impression of appearance. In particular, facial mimetic muscles have a significant impact on the impression of the face through the skin. It is known that skeletal muscle mass decreases with age, and maintaining and improving the quantity and quality of skeletal muscle is important from the perspectives of health promotion, motor function improvement, and beauty.

[0003] Compounds that activate muscles have been investigated to efficiently maintain and improve the quantity and quality of skeletal muscle. For example, a composition for activating PGC-1α containing compounds such as chalcones has been proposed (see Patent Document 1). According to this document, compounds such as chalcones are said to activate the PGC-1α gene and exhibit effects such as improved endurance and muscle hypertrophy. The expression level of the PGC-1α gene increases in skeletal muscle due to exercise, and the gene is involved in the increased expression of genes related to mitochondrial biogenesis and energy metabolism.

[0004] Another example is a proposed agent for suppressing the expression of genes that cause muscle atrophy, containing agarooligosaccharides as active ingredients (see Patent Document 2). According to this document, agarooligosaccharides suppress the expression of genes that cause muscle atrophy, such as atrogin-1 and myostatin, thereby promoting health, improving athletic function, muscle strength, and improving quality of life. Another example is a proposed athletic performance enhancer containing reishi mushrooms (see Patent Document 3). According to this document, reishi mushrooms suppress the expression of atrogin-1 and / or MuRF1 genes, which are involved in muscle atrophy suppression, thereby maintaining muscle mass.

[0005] As yet another example, a composition for preventing or treating a disease or symptom associated with decreased expression of PGC-1α has been proposed, which comprises a compound having a specific chemical structure, or a salt, hydrate, or solvate thereof (see Patent Document 4). According to this document, it is possible to increase the expression of the aforementioned PGC-1α by using a compound having a specific chemical structure.

[0006] However, the aforementioned compounds still have room for improvement in terms of muscle activation, and the aforementioned compounds have mainly focused on improving health and motor function, and their cosmetic effects have not been fully investigated.

[0007] JP 2022-130622 A JP 2020-079326 A JP 2020-005603 A JP 2022-166164 A

[0008] The present invention has been made under such circumstances, and an objective of the present invention is to provide a composition that has an excellent effect in maintaining and activating muscle quantity and quality, and a composition that has an excellent effect in activating PGC-1α, suppressing Atrogin-1 expression, or suppressing Myostatin expression.

[0009] The present inventors have found that the compound represented by formula (I) described below has excellent effects in maintaining and activating muscle quantity and quality. In particular, the present inventors have found that the compound represented by formula (I) has the effect of promoting PGC-1α expression, inhibiting atrogin 1 expression, and inhibiting myostatin expression in skeletal muscle-derived cells. Based on this, the present inventors have determined that the compound represented by formula (I) can be expected to have effects such as improving muscle endurance, improving muscle strength, increasing muscle hypertrophy, suppressing obesity, inhibiting muscle atrophy, and maintaining muscle. The present inventors have also determined that the compound represented by formula (I) can improve muscle-related diseases and symptoms, promote health, and achieve cosmetic effects via its action on facial muscles, and have completed the present invention.

[0010] That is, the gist of the present invention is as follows.

[0011] [1] A composition for maintaining and / or activating muscle, comprising at least one compound selected from the group consisting of compounds represented by the following formula (I) and salts thereof: (In the formula (I), R １ , R ２ , R ３ , R ４ , R ５ and R ６ each independently represent a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group having from 1 to 6 carbon atoms, a substituted or unsubstituted alkenyl group having from 2 to 6 carbon atoms, a substituted or unsubstituted alkynyl group having from 2 to 6 carbon atoms, a substituted or unsubstituted alkoxy group having from 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl group having from 3 to 8 carbon atoms, a substituted or unsubstituted aryl group having from 6 to 10 carbon atoms, a substituted or unsubstituted acyl group having from 2 to 21 carbon atoms, a substituted or unsubstituted heteroarylcarbonyl group, a substituted or unsubstituted alkoxycarbonyl group having from 2 to 7 carbon atoms, -CHO, -COOH, or -OH. [2] A composition for activating PGC-1α, for inhibiting the expression of atrogin-1, or for inhibiting the expression of myostatin, comprising at least one compound selected from the group consisting of compounds represented by the following formula (I) and salts thereof: (In the formula (I), R １ , R ２ , R ３ , R ４ , R ５ and R ６each independently represents a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group having from 1 to 6 carbon atoms, a substituted or unsubstituted alkenyl group having from 2 to 6 carbon atoms, a substituted or unsubstituted alkynyl group having from 2 to 6 carbon atoms, a substituted or unsubstituted alkoxy group having from 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl group having from 3 to 8 carbon atoms, a substituted or unsubstituted aryl group having from 6 to 10 carbon atoms, a substituted or unsubstituted acyl group having from 2 to 21 carbon atoms, a substituted or unsubstituted heteroarylcarbonyl group, a substituted or unsubstituted alkoxycarbonyl group having from 2 to 7 carbon atoms, -CHO, -COOH, or -OH. [3] In the formula (I), R １ represents an alkoxy group having 1 to 3 carbon atoms; R ２ and R ３ each independently represents a hydrogen atom or —CHO; ４ and R ５ each independently represents a hydrogen atom or an acyl group having from 2 to 4 carbon atoms; R ６ [4] The composition according to [1] or [2], wherein the compound represented by formula (I) is represented by the following formula (I-1): [5] The composition according to any one of [1] to [4], which is for improving muscle endurance, muscle hypertrophy, obesity prevention, muscle atrophy prevention, or muscle maintenance. [6] The composition according to any one of [1] to [5], which is for improving skin elasticity, wrinkle improvement, or anti-aging. [7] The composition according to any one of [1] to [6], which is an external composition or an oral composition.

[0012] According to the present invention, it is possible to provide a composition having excellent effects in maintaining and activating muscle quantity and quality, and a composition having excellent effects in activating PGC-1α, suppressing Atrogin-1 expression, or suppressing Myostatin expression.

[0013] Figure 1 shows the results of an in vitro study of the effect of the compound represented by formula (I-1) on the expression level of the PGC-1α gene in skeletal muscle-derived cells. Figure 2 shows the results of an in vitro study of the effect of the compound represented by formula (I-1) on the expression level of the myostatin gene in skeletal muscle-derived cells. Figure 3 shows the results of an in vitro study of the effect of the compound represented by formula (I-1) on the expression level of the atrogin 1 gene in skeletal muscle-derived cells. Figure 4 shows the results of an in vitro study of the effect of the compound represented by formula (I-1) on the expression level of the PGC-1α protein in skeletal muscle-derived cells. Figure 5 shows the results of an in vitro study of the effect of the compound represented by formula (I-1) on the secretion level of myostatin protein in skeletal muscle-derived cells. Figure 6 shows the results of an in vivo study of the effect of the compound represented by formula (I-1) on the width of human crow's feet wrinkles. Figure 7 is an image showing the change in crow's feet wrinkles in one of the subjects who used the compound represented by formula (I-1) (in vivo). Figure 8 is a diagram showing the results of examining the effect of the compound represented by formula (I-1) on the width of human nasolabial folds (in vivo). Figure 9 is an image showing the change in nasolabial folds in one of the subjects who used the compound represented by formula (I-1) (in vivo). Figure 10 is a diagram showing the results of examining the effect of the compound represented by formula (I-1) or (I-2) on the expression level of serotonin protein in a human neuronal cell model (in vitro).

[0014] The present invention will be described in detail below. Terms used in this specification are to be interpreted as meanings commonly used in the art unless otherwise specified. Furthermore, in this specification, the term "skeletal muscle" refers to a muscle that is histologically classified as a striated muscle, and includes the panniculus carnosus, typified by the orbicularis oculi muscle.

[0015] As used herein, "maintaining and activating muscle quantity and quality" broadly refers to having any of the effects of improving muscle endurance, improving muscle strength, muscle hypertrophy, suppressing obesity, suppressing muscle atrophy, or maintaining muscle; and narrowly refers to having at least one of the effects of promoting PGC-1α expression in skeletal muscle-derived cells, suppressing atrogin 1 expression, and suppressing myostatin expression. "Muscular endurance" refers to the stamina of muscles, measured by the number of times a certain load can be repeated. For example, in strength training, the number of times a certain movement can be continuously repeated to the limit (maximum number of repetitions) can be used as an indicator of muscle endurance. "Muscular strength" refers to the maximum force a muscle can exert in a single movement. For example, in strength training, the maximum weight that can be handled in a single movement (maximum lifted weight) can be used as an indicator of muscle strength. "Muscular hypertrophy" refers to an increase in muscle mass (specifically, muscle volume). "Obesity" refers to an increase in body fat percentage. "Muscle atrophy" refers to muscle thinning and is a concept that includes both atrophy caused by the muscle itself (myogenic muscular atrophy) and atrophy caused by motor nerve damage (neurogenic muscular atrophy). "Muscle maintenance" refers to maintaining a constant muscle mass and / or function.

[0016] [Composition] The composition according to the first embodiment of the present invention is a composition for maintaining and / or activating muscle, which contains at least one compound (hereinafter, sometimes referred to as a "specific compound") selected from the group consisting of compounds represented by the following formula (I) and salts thereof:

[0017]

[0018] In formula (I), R １ , R ２ , R ３ , R ４ , R ５ and R ６each independently represents a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group having from 1 to 6 carbon atoms, a substituted or unsubstituted alkenyl group having from 2 to 6 carbon atoms, a substituted or unsubstituted alkynyl group having from 2 to 6 carbon atoms, a substituted or unsubstituted alkoxy group having from 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl group having from 3 to 8 carbon atoms, a substituted or unsubstituted aryl group having from 6 to 10 carbon atoms, a substituted or unsubstituted acyl group having from 2 to 21 carbon atoms, a substituted or unsubstituted heteroarylcarbonyl group, a substituted or unsubstituted alkoxycarbonyl group having from 2 to 7 carbon atoms, -CHO, -COOH, or -OH.

[0019] A composition according to a second embodiment of the present invention is a composition for activating PGC-1α, for inhibiting the expression of atrogin-1, or for inhibiting the expression of myostatin, which contains at least one compound selected from the group consisting of compounds represented by the following formula (I) and salts thereof:

[0020]

[0021] In formula (I), R １ , R ２ , R ３ , R ４ , R ５ and R ６ each independently represents a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group having from 1 to 6 carbon atoms, a substituted or unsubstituted alkenyl group having from 2 to 6 carbon atoms, a substituted or unsubstituted alkynyl group having from 2 to 6 carbon atoms, a substituted or unsubstituted alkoxy group having from 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl group having from 3 to 8 carbon atoms, a substituted or unsubstituted aryl group having from 6 to 10 carbon atoms, a substituted or unsubstituted acyl group having from 2 to 21 carbon atoms, a substituted or unsubstituted heteroarylcarbonyl group, a substituted or unsubstituted alkoxycarbonyl group having from 2 to 7 carbon atoms, -CHO, -COOH, or -OH.

[0022] PGC-1α is an abbreviation for peroxisome proliferator-activated receptor gamma coactivator 1-alpha. PGC-1α is a protein whose expression level in skeletal muscle increases with exercise, and is involved in increased expression of genes related to mitochondrial biogenesis and energy metabolism. When PGC-1α is activated in skeletal muscle-derived cells, muscle mass increases and glucose metabolism in muscles is promoted during physical activity. For this reason, PGC-1α is believed to be involved in improving muscle endurance, muscle hypertrophy, obesity prevention, muscle atrophy prevention, and the like.

[0023] As shown in the Examples, the specific compound can activate PGC-1α in skeletal muscle-derived cells. When the composition according to the second embodiment of the present invention is used for activating PGC-1α, a high effect of improving muscle endurance, muscle hypertrophy, obesity prevention, or muscle atrophy prevention can be expected.

[0024] Atrogin-1 is a muscle atrophy-related gene whose expression level increases during muscle atrophy. Atrogin-1 is known to degrade nuclear transcription factors that promote muscle synthesis and differentiation, such as eukaryotic translation initiation factor 3 subunit F (eIF3-f) and MyoD.

[0025] Myostatin is a glycoprotein belonging to the TGF-β superfamily and is known as a negative regulator of muscle growth. Myostatin binds to ActR2B (Activin Receptor type 2B), suppresses the transcription of the myogenesis-promoting genes MyoD and myogenin, activates Smad2 / 3 and MAPK (Mitogen Activated Protein Kinase), and suppresses Akt-mTOR signaling. This inhibits muscle growth and causes muscle atrophy. Therefore, increased myostatin expression levels result in a loss or wasting of muscle mass. On the other hand, decreased myostatin expression levels result in an increase in muscle mass and a decrease in body fat.

[0026] As shown in the examples, the specific compound has an effect of suppressing atrogin 1 expression and / or myostatin expression in skeletal muscle-derived cells. When the composition according to the second embodiment of the present invention is used for suppressing atrogin 1 expression and / or myostatin expression, a high muscle-maintenance effect can be expected.

[0027] The composition according to the first embodiment of the present invention is substantially the same as the composition according to the second embodiment of the present invention, except for the different uses. Hereinafter, the composition according to the first embodiment of the present invention and the composition according to the second embodiment of the present invention may be collectively referred to as the "composition of the present invention." The composition of the present invention is effective as a composition for improving muscle endurance, muscle hypertrophy, obesity prevention, muscle atrophy prevention, or muscle maintenance.

[0028] The composition of the present invention can be used, for example, for the prevention and / or treatment of symptoms and diseases that result in a decrease in muscle mass or muscle strength (e.g., sarcopenia associated with aging, locomotive syndrome, physical frailty, muscular dystrophy, etc.), for the prevention and / or treatment of lifestyle-related diseases for which exercise therapy is effective (e.g., dyslipidemia, type 2 diabetes, hypertension, etc.), for supporting rehabilitation, and for the prevention and / or treatment of unpleasant symptoms caused by muscle tension or fatigue (e.g., lower back pain, stiff shoulders, eye strain, etc.). Furthermore, the composition of the present invention can be used for daily ingestion for the purpose of achieving a wide range of health-promoting effects (e.g., improvement of motor function, recovery from fatigue, maintenance or improvement of body shape and constitution, etc.). Thus, the composition of the present invention is suitable for use as a pharmaceutical, quasi-drug, cosmetic, food (functional food, supplement, etc.), etc.

[0029] Furthermore, since the specific compound in the composition of the present invention has a skeletal muscle activating effect, it can prevent and / or improve wrinkles and sagging through, for example, activating facial muscles (e.g., facial muscles) (e.g., muscle hypertrophy and improved function). That is, the composition of the present invention can be used for cosmetic and / or anti-aging purposes as a skin elasticity enhancer, wrinkle reducer, and anti-aging agent. When used for cosmetic and / or anti-aging purposes, the composition of the present invention can be used on any part of the body. However, the face is a part of the body that has a particularly large impact on the impression of appearance and is also a part whose appearance is prone to change with age, making it an important target site for the composition of the present invention. Among the face, the area around the eyes, where the skin is thin and the effects of aging are easily noticeable, can be a particularly important target site for the composition of the present invention. By applying the composition of the present invention to the face for cosmetic and / or anti-aging purposes, the facial muscles (particularly the orbicularis oculi muscle) are activated, and the effects of preventing and / or improving hollows in the eyelids, sagging and puffiness under the eyes (tear bags and eye bags), wrinkles and sagging at the corners of the eyes, wrinkles and sagging on the forehead, wrinkles and sagging around the mouth (including nasolabial folds) and sagging, wrinkles and sagging under the nose, wrinkles and sagging on the chin, etc. are expected.

[0030] The composition of the present invention can be preferably used on humans, with the above-mentioned effects expected. The composition of the present invention may also be used on animals other than humans. When the composition of the present invention is used on animals, it can be used for purposes such as improving the health of pet animals and improving the breeding efficiency of industrial animals. Examples of animals that can be used with the composition of the present invention include mammals (e.g., dogs, cats, pigs, cows, horses, sheep, etc.), birds (e.g., chickens, ducks, ostriches, etc.), reptiles, amphibians, and fish.

[0031] In this specification, a salt of a compound represented by formula (I) refers to a salt of a compound represented by formula (I) with an anion or a cation. Examples of anions include anions of inorganic acids (e.g., hydrochloric acid, phosphoric acid, etc.) and anions of organic acids (e.g., lactic acid, acetic acid, etc.). Examples of cations include ammonium cations and metal cations (e.g., lithium ion, sodium ion, potassium ion, magnesium ion, calcium ion, etc.).

[0032] In formula (I), examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc. The halogen atom is preferably a chlorine atom.

[0033] In formula (I), the alkyl group having 1 to 6 carbon atoms may be either a linear alkyl group or a branched alkyl group. Examples of the alkyl group having 1 to 6 carbon atoms include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexyl group. As the alkyl group having 1 to 6 carbon atoms, an alkyl group having 1 to 3 carbon atoms is preferred, and a methyl group or an ethyl group is more preferred.

[0034] In formula (I), the alkenyl group having from 2 to 6 carbon atoms may be either a linear alkenyl group or a branched alkenyl group. Examples of the alkenyl group having from 2 to 6 carbon atoms include a vinyl group, a propenyl group, a butenyl group, a pentenyl group, and a hexenyl group.

[0035] In formula (I), the alkynyl group having from 2 to 6 carbon atoms may be either a linear alkynyl group or a branched alkynyl group. Examples of the alkynyl group having from 2 to 6 carbon atoms include an ethynyl group, a propynyl group, a butynyl group, a pentynyl group, and a hexynyl group.

[0036] In formula (I), the alkoxy group having from 1 to 6 carbon atoms may be either a linear alkoxy group or a branched alkoxy group. Examples of the alkoxy group having from 1 to 6 carbon atoms include a methoxy group, an ethoxy group, a propoxy group, and a butoxy group. As the alkoxy group having from 1 to 6 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms is preferred, and a methoxy group or an ethoxy group is preferred.

[0037] In formula (I), the cycloalkyl group having from 3 to 8 carbon atoms may be either a monocyclic cycloalkyl group or a polycyclic cycloalkyl group. Examples of the cycloalkyl group having from 3 to 8 carbon atoms include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cycloheptyl group, and a cyclooctyl group.

[0038] In formula (I), the aryl group having 6 to 10 carbon atoms may be either a monocyclic aryl group or a polycyclic aryl group. Examples of the aryl group having 6 to 10 carbon atoms include a phenyl group and a naphthyl group.

[0039] In formula (I), the acyl group having from 2 to 21 carbon atoms is a group represented by R—(C═O)—. R is an alkyl group or an aryl group. Examples of the acyl group having from 2 to 21 carbon atoms include an acetyl group, a propionyl group, a butyryl group, a valeryl group, a pivaloyl group, a benzoyl group, and a naphthoyl group. As the acyl group having from 2 to 21 carbon atoms, an acyl group having from 2 to 7 carbon atoms is preferred, an acyl group having from 2 to 4 carbon atoms is more preferred, and an acetyl group is even more preferred.

[0040] In formula (I), the heteroarylcarbonyl group is a carbonyl group to which a heteroaryl group is bonded. Examples of the heteroarylcarbonyl group include a picolinoyl group, a nicotinoyl group, an isonicotinoyl group, and a pyrazine-2-carbonyl group.

[0041] In the formula (I), examples of the alkoxycarbonyl group having from 2 to 7 carbon atoms include a methoxycarbonyl group, an ethoxycarbonyl group, and a propyloxycarbonyl group.

[0042] In formula (I), examples of the substituent that substitutes the alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, aryl group, acyl group, heteroarylcarbonyl group, or alkoxycarbonyl group include a halogen atom (e.g., a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc.), —OH, —SH, a nitro group, a cyano group, —CHO, —COOH, an amino group, and a silyl group.

[0043] In formula (I), R １ R preferably represents an alkoxy group having 1 to 3 carbon atoms. ２ and R ３ Preferably, each independently represents a hydrogen atom or —CHO. ４ and R ５ Preferably, R each independently represents a hydrogen atom or an acyl group having 2 to 4 carbon atoms. ６ preferably represents a hydrogen atom.

[0044] Examples of the compound represented by formula (I) include a compound represented by the following formula (I-1) and a compound represented by the following formula (I-2). As the compound represented by formula (I), a compound represented by the following formula (I-1) is preferred.

[0045]

[0046]

[0047] The composition of the present invention can be used as a topical composition or an oral composition, and specifically, can be used in various forms, such as pharmaceuticals, quasi-drugs, topical or systemic skin cosmetics, various topical skin preparations including medicinal or cosmetic preparations for application to the scalp or hair, bath additives, oral pharmaceutical and quasi-drug compositions, general foods and beverages, supplements, energy drinks, and food compositions such as functional foods.

[0048] The content of the specific compound in the composition of the present invention may be adjusted appropriately depending on the dosage form and intended use, and is not particularly limited. When the composition of the present invention is a topical composition, the content of the specific compound in the composition of the present invention is, for example, 0.0001% by mass to 10.0% by mass, preferably 0.0005% by mass to 1.0% by mass, more preferably 0.0005% by mass to 0.5% by mass, and even more preferably 0.001% by mass. When the composition of the present invention is an oral composition, the amount of the specific compound contained in a daily dose of the composition of the present invention is, for example, 0.0001 mg / day to 10.0 mg / day, preferably 0.001 mg / day to 5.0 mg / day, and more preferably 0.003 mg / day to 3.0 mg / day. When the composition of the present invention is an oral composition, the recommended frequency of ingestion may be once a day, multiple times a day (e.g., 2 to 3 times a day), or once every several days.

[0049] The composition of the present invention may contain other ingredients in addition to the specific compound, which is an essential ingredient, as long as the ingredients do not impair the effects of the present invention. The composition of the present invention can be used in combination with, for example, drugs used in treating conventional external or internal use materials. Combinations with drugs that make the effects of the present invention more likely to be exhibited are particularly preferred.

[0050] Examples of these other components include anti-inflammatory agents, refreshing agents, disinfectants, vitamins, organic acids, moisturizing components, polyhydric alcohols, scrubbing agents, ultraviolet absorbing components, ultraviolet scattering components, astringent components, peptides or derivatives thereof, amino acids or derivatives thereof, cleansing components, keratin softening components, cell activating components, anti-aging components, anti-glycation components, blood circulation promoting components, whitening components, polyphenols, etc. In the composition of the present invention, these components may be used alone or in combination of two or more.

[0051] Examples of the anti-inflammatory agent include plant-derived components, allantoin and derivatives thereof, glycyrrhetinic acid and derivatives thereof, glycyrrhizinic acid and salts or derivatives thereof, salicylic acid derivatives, aminocaproic acid, azulene and derivatives thereof, zinc oxide, calamine, tocopherol acetate, hydrocortisone, prednisolone, and salts thereof.

[0052] Examples of the cooling agent include menthol and its derivatives, camphor, terpenes such as borneol, geraniol, cineole, anethole, limonene, and eugenol (which may be in the d-, l-, or dl-form); and essential oils such as eucalyptus oil, bergamot oil, peppermint oil, cool mint oil, spearmint oil, fennel oil, peppermint oil, cinnamon oil, rose oil, and turpentine.

[0053] Examples of the disinfectant include isopropylmethylphenol, chlorhexidine, salicylic acid, benzalkonium chloride, acrinol, ethanol, benzethonium chloride, cresol, gluconic acid and its derivatives, povidone-iodine, potassium iodide, iodine, triclocarban, triclosan, photosensitizer No. 101, photosensitizer No. 201, paraben, phenoxyethanol, 1,2-pentanediol, alkyldiaminoglycine hydrochloride, piroctoolamine, and miconazole.

[0054] The vitamins may be either water-soluble or oil-soluble, and examples thereof include vitamin B6s such as pyridoxine, pyridoxal, pyridoxamine, 5'-pyridoxal phosphate, and salts thereof (e.g., pyridoxine hydrochloride, pyridoxine acetate, pyridoxal hydrochloride, pyridoxamine hydrochloride); pantothenic acids such as pantothenic acid, calcium pantothenate, pantothenyl alcohol (panthenol), D-pantetheine, D-pantethine, coenzyme A, pantothenyl ethyl ether, and salts thereof; nicotinic acids such as nicotinic acid, dl-α-tocopherol nicotinate, benzyl nicotinate, methyl nicotinate, β-butoxyethyl nicotinate, 1-(4-methylphenyl)ethyl nicotinate, nicotinamide, and salts thereof; γ-oryzanol, thiamine, dibenzoylthiamine, thiamine cetyl, thiamine monophosphate, thiamine diphosphate, and thiamine triphosphate. Vitamin B1 compounds such as esters and salts thereof (e.g., dibenzoylthiamine hydrochloride, thiamine hydrochloride, thiamine cetyl hydrochloride, thiamine thiocyanate, thiamine lauryl hydrochloride, thiamine nitrate, thiamine monophosphate, thiamine lysine salt, thiamine triphosphate, thiamine monophosphate phosphate, thiamine diphosphate hydrochloride, thiamine triphosphate monophosphate); vitamin B2 compounds such as riboflavin, flavin mononucleotide, flavin adenine dinucleotide, riboflavin butyrate, riboflavin tetrabutyrate, riboflavin 5'-phosphate sodium, riboflavin tetranicotinate, and salts thereof; biotins such as biotin, biocytin, and salts thereof; folates such as folic acid, pteroylglutamic acid, and salts thereof; vitamin B12 compounds such as cyanocobalamin, hydroxocobalamin, deoxyadenosylcobalamin, and salts thereof;Water-soluble vitamin C compounds such as ascorbic acid, dehydroascorbic acid, ascorbic acid phosphate, ascorbic acid-2-glucoside, 2-O-ethyl ascorbic acid, 3-O-ethyl ascorbic acid, glyceryl ascorbic acid, bisglyceryl ascorbic acid, and alkylglyceryl ascorbic acid, and salts thereof (for example, sodium ascorbate, sodium ascorbyl phosphate, and magnesium ascorbyl phosphate); vitamin E compounds such as dl-α-tocopherol, dl-α-tocopherol acetate, dl-α-tocopherol succinate, dl-α-tocopherol calcium succinate, tocopherol linoleate, tocopherol (linoleate / oleate), tocopherol, and potassium (ascorbyl / tocopheryl) phosphate; ascorbigen-A, ascorbyl stearate, ascorbyl palmitate, dipotassium phosphate, hydroxybenzoate ... Oil-soluble vitamin C and its salts, such as L-ascorbyl lumitate and ascorbyl tetra-2-hexyldecanoate; vitamin Ds, such as ergocalciferol and cholecalciferol; vitamin Ks, such as phylloquinone and farnoquinone; vitamin A, such as retinol, retinal, retinoic acid, 3-dehydroretinol, 3-dehydroretinal, 3-dehydroretinoic acid, and hydrogenated retinol, and their derivatives, such as retinol palmitate and propionate. Vitamin A derivatives such as retinol phosphate, retinol linoleate, and retinol acetate; provitamin A such as α-carotene, β-carotene, γ-carotene, and cryptoxanthin; hesperidin derivatives such as ferulic acid, pyrroloquinoline quinone or a salt thereof, hesperidin and glucosyl herperidin; vitamin-like factors such as ubiquinone, glucurolactone, glucuronic acid amide, orotic acid, L-carnitine, α-lipoic acid, and orotic acid;

[0055] Examples of the organic acids include gluconic acid, aspartic acid, aminoethylsulfonic acid, citric acid, glutamic acid, succinic acid, oxalic acid, fumaric acid, malonic acid, maleic acid, propionic acid, malic acid, salicylic acid, glycolic acid, phytic acid, tartaric acid, acetic acid, lactic acid, pantothenic acid, glycyrrhetinic acid, alginic acid, ascorbic acid, benzoic acid, adipic acid, glutamic acid, azelaic acid, and salts thereof. Examples of the salts include salts of mineral acids such as sulfuric acid, hydrochloric acid, and phosphoric acid, salts of organic acids such as maleic acid and methanesulfonic acid, salts of alkali metals such as sodium and potassium, alkaline earth metal salts, ammonium salts, salts of basic amino acids, and amine salts such as triethanolamine.

[0056] Examples of the moisturizing components include diglycerin trehalose; mucopolysaccharides such as heparinoids and sodium chondroitin sulfate; MPC polymer; keratin, chitin, chitosan, etc. and their hydrolysates; amino acids such as glycine, aspartic acid, arginine, etc.; natural moisturizing factors such as sodium lactate, urea, and sodium pyrrolidone carboxylate; lipids such as ceramide, cholesterol, phytosterol, and phospholipid; glycerin, polyoxyalkylene alkyl glucoside, PEG / PPG / polybutylene glycol-8 / 5 / 3 glycerin, Examples include polyhydric alcohols or derivatives thereof such as glyceryl glucoside; 2-methacryloyloxyethyl phosphorylcholine-butyl methacrylate copolymer, 2-methacryloyloxyethyl phosphorylcholine-containing polymers such as polymethacryloyloxyethyl phosphorylcholine; alkylene oxides such as PPG-17 buteth-17, PPG-25 sorbitol, polyoxyalkylene alkyl glucoside, PEG / PPG / polybutylene glycol-8 / 5 / 3 glycerin, and polyoxyalkylene diglyceryl; and hydroxyethyl urea.

[0057] The polyhydric alcohol is preferably one having 2 to 10 carbon atoms, and examples thereof include glycerin, diglycerin, triglycerin, propylene glycol, dipropylene glycol, 1,3-propanediol, 1,3-butanediol, ethylene glycol, diethylene glycol, isoprene glycol, 1,3-butylene glycol, sorbitol, xylitol, erythritol, mannitol, pentanediol, hexanediol, octanediol, decanediol, and neopentyl glycol.

[0058] Examples of the scrubbing agent include apricot kernel powder, almond shell powder, apricot kernel powder, sodium chloride granules, olive kernel powder, seawater dried granules, candelilla wax, walnut shell powder, cherry kernel powder, coral powder, charcoal powder, hazelnut shell powder, polyethylene powder, and silicic anhydride.

[0059] Examples of the ultraviolet absorbing component include octocrylene, polysilicone, octyl triazone, dimethoxybenzylidene dioxoimidazolidine octyl propionate, 2-ethylhexyl paramethoxycinnamate, phenylbenzimidazole sulfonic acid, diethylaminohydroxybenzoyl hexyl benzoate, bisethylhexyloxyphenol methoxyphenyl triazine, trisethylhexyloxycarbonylanilinotriazine, t-butylmethoxydibenzoylmethane, paraaminobenzoic acid and derivatives thereof, octyl paradimethylaminobenzoate, dihydroxybenzophenone, and methylenebisbenzotriazolyltetramethylbutylphenol.

[0060] Examples of the ultraviolet scattering component include inorganic compounds such as hydrous silicic acid, zinc silicate, cerium silicate, titanium silicate, zirconium oxide, cerium oxide, titanium oxide, zinc oxide, iron oxide, and silicic anhydride; these inorganic compounds coated with inorganic powder such as hydrous silicic acid, aluminum hydroxide, mica, and talc; compounds composited with resin powder such as polyamide, polyethylene, polyester, polystyrene, and nylon; and compounds further treated with silicone oil, aluminum salt of a fatty acid, or the like.

[0061] Examples of the astringent component include metal salts such as ethanol, zinc sulfate, aluminum chloride, and zinc sulfocarbonate, and organic acids such as tannic acid.

[0062] Examples of the above peptides or derivatives thereof include keratin hydrolyzed peptides, hydrolyzed keratin, gelatin, conchiolin hydrolyzed peptides, hydrolyzed conchiolin, silk proteolytic peptides, hydrolyzed silk, sodium lauroyl hydrolyzed silk, wheat protein, wheat proteolytic peptides, hydrolyzed wheat protein, casein hydrolyzed peptides, acylated peptides (palmitoyl oligopeptide, palmitoyl pentapeptide, palmitoyl tetrapeptide, etc.), and the like.

[0063] Examples of the amino acids or derivatives thereof include betaine (trimethylglycine), proline, hydroxyproline, arginine, lysine, serine, glycine, alanine, phenylalanine, β-alanine, threonine, glutamic acid, glutamine, asparagine, aspartic acid, cysteine, cystine, methionine, leucine, isoleucine, valine, histidine, threonine, tyrosine, taurine, γ-aminobutyric acid, γ-amino-β-hydroxybutyric acid, carnitine, carnosine, creatine, epsilon-aminocaproic acid, tryptophan, ornithine, etc. Furthermore, these amino acids or derivatives thereof may be in the form of a solvate such as a hydrate, and may be in any of the d-, l-, or dl-forms.

[0064] Examples of the cleansing component include soaps selected from alkali metal salts such as potassium laurate, potassium myristate, potassium palmitate, and potassium stearate, alkanolamide salts, and amino acid salts; amino acid surfactants such as sodium cocoyl glutamate, sodium cocoyl methyl taurate, sodium cocoyl methyl taurate, and potassium cocoyl methyl glutamate; ether sulfate ester salts such as sodium laureth sulfate; ether carboxylate salts such as sodium lauryl ether acetate; sulfosuccinate ester salts such as sodium alkyl sulfosuccinate; and fatty acids such as coconut oil fatty acid monoethanolamide and coconut oil fatty acid diethanolamide. Examples of the surfactant include fatty acid alkanolamides; monoalkyl phosphate salts such as sodium lauryl phosphate and sodium polyoxyethylene lauryl ether phosphate; betaine-type amphoteric surfactants such as coconut oil fatty acid amidopropyl dimethylaminoacetic acid betaine, lauryl dimethylaminoacetic acid betaine, 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazolinium betaine, lauryl hydroxysulfobetaine, cocamidopropyl betaine, and lauroyl amidoethyl hydroxyethyl carboxymethyl betaine hydroxypropyl sodium phosphate; and amino acid-type amphoteric surfactants such as sodium lauryl aminopropionate.

[0065] Examples of the keratin softening ingredients include lanolin, lactic acid, salicylic acid, gluconic acid, glycolic acid, citric acid, malic acid, fruit acid, phytic acid, urea, sulfur, and the like.

[0066] Examples of the cell activating component include components derived from plants (for example, bilberry, etc.), amino acids such as γ-aminobutyric acid; vitamins such as retinol, thiamine, riboflavin, pyridoxine hydrochloride, pantothenic acids, etc.; α-hydroxy acids such as glycolic acid, lactic acid, etc.; tannin, flavonoid, saponin, photosensitizer No. 301, etc.

[0067] Examples of the anti-aging ingredients include retinoids (retinol and its derivatives, retinoic acid, retinal, etc.), pangamic acid, kinetin, ursolic acid, turmeric extract, sphingosine derivatives, silicon, silicic acid, N-methyl-L-serine, mevalonolactone, etc.

[0068] Examples of the anti-glycation component include plant extracts such as Budreja axillaris leaf extract, evening primrose oil, Amla fruit, fruit juice or extracts thereof, L-arginine, L-lysine, hydrolyzed casein, hydrolyzable tannin, carnosine, etc.

[0069] Examples of the blood circulation-promoting component include components derived from plants (e.g., ginseng, Angelica tree, arnica, ginkgo, fennel, emmeisou, Dutch oak, chamomile, Roman chamomile, carrot, gentian, burdock, rice, hawthorn, shiitake mushroom, ginger, European hawthorn, European juniper, cnidium rhizome, Swertia japonica, thyme, clove, tangerine peel, chili pepper, angelica acutiloba, peach kernel, spruce, carrot, garlic, butcher's broom, grape, peony, horse chestnut, melissa, yuzu, coix seed, ryokucha, rosemary, rose hip, tangerine peel, angelica acutiloba, spruce, peach, apricot, walnut, corn, golden chamomile, etc.); acetylcholine, ichthammol, cantharides tincture, gamma-oryzanol, cepharanthine, tolazoline, tocopherol nicotinate, glucosyl hesperidin, etc.).

[0070] Examples of the whitening ingredient include tocopherol, tranexamic acid, ascorbic acid and its salts, vitamin C such as ascorbic acid derivatives (such as sodium ascorbyl phosphate, magnesium ascorbyl phosphate, ascorbyl tetra-2-hexyldecanoate, 2-O-ethyl ascorbic acid, 3-O-ethyl ascorbic acid, and ascorbic acid glucoside), arbutin, kojic acid, placenta, ellagic acid, nicotinamide, hydroquinone, potassium 4-methoxysalicylate, and linoleic acid and derivatives thereof.

[0071] Examples of the polyphenols include flavonoid polyphenols such as curcuminoids, flavanones, stilpenoids, polymethoxyflavonoids, flavonols, xanthonoids, chalcones, lignoids, flavanols, and isoflavones, and phenolic acid polyphenols.

[0072] (pH) The pH of the composition of the present invention is usually 2.0 to 9.0, preferably 3.0 to 8.5, more preferably 3.5 to 8.0, and even more preferably 5.0 to 8.0. This pH can be adjusted by using a pH adjuster.

[0073] (Method for producing the composition of the present invention) The method for producing the composition of the present invention is not particularly limited, and the composition can be produced by a conventional method by appropriately selecting and mixing the specific compound, which is an essential component, with the other components described above that are mixed as needed, bases or carriers, additives, etc. that are necessary for producing various formulations. As the specific compound, a commercially available product or a synthetic product may be used.

[0074] The composition of the present invention can also be prepared into a topical composition in various formulations by mixing the specific compound and the other ingredients described above, if necessary, with a base or carrier commonly used in cosmetics, pharmaceuticals, quasi-drugs, foods, etc., and the additives described below, according to a conventional method, and emulsifying or solubilizing as necessary.

[0075] Examples of the base or carrier include hydrocarbons such as liquid paraffin, squalane, petrolatum, gelling hydrocarbons (such as Plastibase), ozokerite, α-olefin oligomer, polyethylene wax, and light liquid paraffin; silicone oils such as methylpolysiloxane, highly polymerized methylpolysiloxane, cyclic silicone, alkyl-modified silicone, amino-modified silicone, polyether-modified silicone, polyglycerin-modified silicone, silicone / alkyl chain co-modified polyether-modified silicone, silicone / alkyl chain co-modified polyglycerin-modified silicone, polyether-modified branched silicone, polyglycerin-modified branched silicone, acrylic silicone, phenyl-modified silicone, and silicone resin; fats and oils such as coconut oil, olive oil, rice bran oil, and shea butter; waxes such as jojoba oil, beaucoupon wax, candelilla wax, and lanolin; cetyl alcohol, cetostearyl alcohol, stearic acid, and the like. higher alcohols such as butyl alcohol, behenyl alcohol, octyldodecanol, isostearyl alcohol, phytosterol, and cholesterol; cellulose derivatives such as ethyl cellulose, hydroxypropyl cellulose, and hydroxypropylmethyl cellulose; polyvinylpyrrolidone; carrageenan; polyvinyl butyrate; polyethylene glycol; dioxane; butylene glycol adipate polyester; esters such as diisopropyl adipate, isopropyl myristate, octyldodecyl myristate, isopropyl palmitate, cetyl palmitate, isononyl isononanoate, pentaerythritol tetra-2-ethylhexanoate, and triethylhexanoin; polysaccharides such as dextrin and maltodextrin; vinyl polymers such as carboxyvinyl polymers and alkyl-modified carboxyvinyl polymers; lower alcohols such as ethanol and isopropanol;Examples of suitable bases or carriers include glycol ethers such as ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monopropyl ether, diethylene glycol monobutyl ether, propylene glycol monoethyl ether, propylene glycol monopropyl ether, dipropylene glycol monoethyl ether, dipropylene glycol monopropyl ether, and batyl alcohol; and water. The bases or carriers described above may be used alone or in combination of two or more. The amounts used may be appropriately selected from ranges known to those skilled in the art.

[0076] To the composition of the present invention, known additives added to cosmetics, pharmaceuticals, quasi-drugs, foods, etc., such as surfactants, stabilizers, antioxidants, colorants, pearlescent agents, dispersants, chelating agents, pH adjusters, preservatives (antiseptics), thickeners, irritation reducers, texture improvers, excipients, lubricants, binders, disintegrants, solvents, oils and fats, ester oils, emulsifiers, dispersants, suspending agents, stabilizers, thickeners, sweeteners, colorants, flavorings, antioxidants, acidulants, and food additives such as fruit juice, may be added, provided that the effects of the present invention are not impaired. These additives may be used alone or in combination of two or more.

[0077] The surfactant may be any of a nonionic surfactant, a cationic surfactant, an anionic surfactant, an amphoteric surfactant, and the like, and examples thereof include sorbitan fatty acid esters such as sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, diglycerol sorbitan penta-2-ethylhexylate, and diglycerol sorbitan tetra-2-ethylhexylate; propylene glycol fatty acid esters such as propylene glycol monostearate; hydrogenated castor oil derivatives such as polyoxyethylene hydrogenated castor oil 40 (HCO-40), polyoxyethylene hydrogenated castor oil 50 (HCO-50), polyoxyethylene hydrogenated castor oil 60 (HCO-60), and polyoxyethylene hydrogenated castor oil 80; polyoxyethylene (20) sorbitan monolaurate (polysorbate 20), and polyoxyethylene (20) monostearate. Examples of surfactants include polyoxyethylene sorbitan fatty acid esters such as sorbitan (polysorbate 60), polyoxyethylene (20) sorbitan monooleate (polysorbate 80), and polyoxyethylene (20) sorbitan isostearate; polyoxyethylene monococonut oil fatty acid glyceryl; glycerin alkyl ethers; lipophilic glyceryl monostearate; glyceryl isostearate; polyethylene glycol monostearate; alkyl glucosides; polyoxyalkylene alkyl ethers such as polyoxyethylene cetyl ether, polyoxyethylene lauryl ether, and PPG-13 decyltetradeceth-24; amines such as stearylamine and oleylamine; and silicone surfactants such as polyoxyethylene-methylpolysiloxane copolymer, lauryl PEG-9 polydimethylsiloxyethyl dimethicone, and PEG-9 polydimethylsiloxyethyl dimethicone.

[0078] Examples of the stabilizer include sodium polyacrylate, dibutylhydroxytoluene, and butylhydroxyanisole.

[0079] Examples of the antioxidant include dibutylhydroxytoluene, butylhydroxyanisole, sorbic acid, sodium sulfite, ascorbic acid, sodium ascorbate, ascorbyl stearate, ascorbyl sodium stearate, ascorbyl palmitate, tocopherol, tocopherol acetate, tocotrienol, bisulfite, sodium hyposulfite, sulfur dioxide, calcium disodium EDTA, erythorbic acid, sodium erythorbate, L-cysteine ​​hydrochloride, ubiquinones such as coenzyme Q10, lignans such as sesamin, curcumin, capsaicin, gingerol, resveratrol, anthocyanin, cyanidin, bilberry extract, and analogs or derivatives thereof. Of these, dibutylhydroxytoluene, ascorbic acid, ascorbyl palmitate, tocopherol, tocopherol acetate, coenzyme Q10, resveratrol, anthocyanin, sesamin, curcumin, capsaicin, gingerol, and bilberry extract are preferred.

[0080] Examples of the colorant include inorganic pigments and natural dyes.

[0081] Examples of the pearly luster imparting agent include ethylene glycol distearate, ethylene glycol monostearate, and triethylene glycol distearate.

[0082] Examples of the dispersant include sodium pyrophosphate, sodium hexametaphosphate, polyvinyl alcohol, polyvinylpyrrolidone, methyl vinyl ether / maleic anhydride crosslinked copolymer, and organic acids.

[0083] Examples of the chelating agent include EDTA disodium salt, EDTA calcium disodium salt, and caprylhydroxamic acid.

[0084] Examples of the pH adjuster include inorganic acids (phosphoric acid, hydrochloric acid, sulfuric acid, etc.), organic acids (lactic acid, sodium lactate, citric acid, sodium citrate, succinic acid, sodium succinate, gluconic acid, sodium malate, etc.), potassium carbonate, sodium bicarbonate, carbon dioxide, inorganic bases (potassium hydroxide, sodium hydroxide, etc.), and organic bases (triethanolamine, diisopropanolamine, triisopropanolamine, etc.).

[0085] Examples of the preservative (antiseptic) include benzoic acid, sodium benzoate, dehydroacetic acid, sodium dehydroacetate, isobutyl parahydroxybenzoate, isopropyl parahydroxybenzoate, butyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, benzyl parahydroxybenzoate, methyl parahydroxybenzoate (methylparaben), phenoxyethanol, chlorobutanol, benzyl alcohol, phenethyl alcohol, sorbic acid, and salts thereof.

[0086] Examples of the thickener include vinyl thickeners such as polyvinyl alcohol, polyvinylpyrrolidone, and carboxyvinyl polymers; cellulose thickeners such as methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, and carboxyethyl cellulose; guar gum, pectin, pullulan, gelatin, locust bean gum, carrageenan, agar, glucomannan, curdlan, gellan gum, xanthan gum, and acrylic and methacrylic acid alkyl esters. Examples of suitable acrylic acid copolymers include polyethylene glycol, bentonite, alginic acid, propylene glycol alginate, macrogol, sodium chondroitin sulfate, hyaluronic acid, sodium hyaluronate, (hydroxyethyl acrylate / sodium acryloyldimethyltaurate) copolymer, (ammonium acryloyldimethyltaurate / vinylpyrrolidone) copolymer, polyacrylic acid amide, polyethylene glycol-decyltetradeceth-20-hexamethylene diisocyanate copolymer ((PEG-240 / decyltetradeceth-20 / HDI) copolymer), and the like.

[0087] Examples of the irritation reducer include cellulose derivatives such as methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, and hydroxypropylmethyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, acrylic acid polymers, gelatin, gum arabic, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol alginate, licorice extract, and 2-methacryloyloxyethyl phosphorylcholine.

[0088] Examples of the feel improver include diisostearyl malate.

[0089] Examples of the excipient include lactose, sucrose, sodium chloride, glucose, starch, maltitol, calcium carbonate, kaolin, microcrystalline cellulose, and silicic acid.

[0090] Examples of the binder include polysaccharides such as refined sucrose, glucose, trehalose, lactose, maltose, saccharin sodium, aspartame, acesulfame potassium, and maltodextrin; corn starch, potato starch, wheat starch, and pregelatinized starches thereof; sugar alcohols such as mannitol, sorbitol, xylitol, erythritol, and sucralose; cellulose-based polymers such as crystalline cellulose, methyl cellulose, ethyl cellulose, hypromellose, hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carmellose calcium, hypromellose phthalate, and cellulose acetate phthalate; calcium phosphate; and polyvinylpyrrolidone.

[0091] Examples of the disintegrants include starch, low-substituted hydroxypropyl cellulose, carboxymethylcellulose calcium, croscarmellose sodium, hydroxypropyl starch, partially pregelatinized starch, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, monoglyceride stearate, and lactose.

[0092] Examples of the lubricant include stearic acid, magnesium stearate, calcium stearate, polyoxyl stearate, cetanol, talc, hydrogenated oil, sucrose fatty acid ester, dimethylpolysiloxane (dimethicone), beeswax, white beeswax, borax, polyethylene glycol, and silica.

[0093] Examples of the fats and oils include natural vegetable oils such as palm oil, palm kernel oil, coconut oil, corn oil, sunflower oil, safflower oil, peanut oil, cocoa butter, cottonseed oil, soybean oil, rapeseed oil, rice oil, rice germ oil, perilla oil, and linseed oil; animal fats and oils such as beef tallow, milk fat, lard, cacao butter, fish oil, whale oil, butter, and butter oil; and hardened oils thereof; glycerides (glycerides, diglycerides, triglycerides, etc.) of fatty acids (including medium-chain fatty acids); meadowfoam oil; and beeswax.

[0094] Examples of ester oils include isopropyl myristate, cetyl octanoate, octyldodecyl myristate, isopropyl palmitate, isopropyl isostearate, octyl palmitate, octyl isopalmitate, cetyl palmitate, butyl stearate, hexyl laurate, myristyl myristate, decyl oleate, isodecyl oleate, hexyldecyl dimethyloctanoate, diisopropyl sebacate, di-2-ethylhexyl sebacate, 2-hexyldecyl myristate, 2-hexyldecyl palmitate, diisopropyl adipate, L-pil, 2-hexyldecyl adipate, isononyl isononanoate, isotridecyl isononanoate, cetyl lactate, myristyl lactate, lanolin acetate, isocetyl stearate, isocetyl isostearate, isostearyl isostearate, cholesteryl 12-hydroxystearate, cholesteryl stearate, cholesteryl oleate, phytosteryl macadamiate, phytosteryl oleate, dextrin palmitate, inulin stearate, hydrogenated jojoba oil, ethylene glycol di-2-ethylhexylate, 2-ethylhexane Cetyl ester, dipentaerythritol fatty acid ester, N-alkyl glycol monoisostearate, neopentyl glycol dicaprate, diisostearyl malate, glycerin di-2-heptylundecanoate, tri-2-ethylhexyl trimellitate, tritridecyl trimellitate, trimethylolpropane tri-2-ethylhexylate, trimethylolpropane triisostearate, pentaerythritol tetra-2-ethylhexanoate, glycerin tri-2-ethylhexanoate, trimethylolpropane triisostearate, cetyl 2-ethyl Hexanoate, glycerin trimyristate, caprylic / capric triglyceride, caprylic / capric / myristic / stearic triglyceride, tri-2-heptylundecanoic acid glyceride, castor oil fatty acid methyl ester, oleyl oleate, 2-heptylundecyl palmitate, diisobutyl adipate, di-(phytosteryl / octyldodecyl) lauroyl glutamate, di-(octyldodecyl / phytosteryl / behenyl) lauroyl glutamate, di-2-heptylundecyl adipate, ethyl laurate,Bisethoxydiglycol Cyclohexane-1,4-dicarboxylate, 2-Ethylhexyl Succinate, Diethoxyethyl Succinate, Triethyl Citrate, Decaglyceryl Eicosandioate / Tetradecanedioate, Ethyl Acetate, Butyl Acetate, Amyl Acetate, Triethyl Citrate, Phytosteryl / Isostearyl / Cetyl / Stearyl / Behenyl Dimer Dilinoleate, Polyglyceryl-2 Triisostearate, Dimer Dilinoleyl Dimer Dilinoleate, Dipentaerythritol Tri-Polyhydroxystearate Examples of suitable glyceryl compounds include thrityl, tri(behenate / isostearate / eicosanedioate), polyglyceryl-10 (eicosanedioate / tetradecanedioate), bisethoxydiglycol cyclohexanedicarboxylate, bis(triethylene glycol monoethyl ether) 1,4-cyclohexanedicarboxylate, bis(diethylene glycol monoethyl ether) adipate, bis(triethylene glycol monoethyl ether) adipate, diethoxyethyl succinate, and diethylhexyl succinate.

[0095] Examples of the emulsifiers, dispersants, suspending agents, and stabilizers include polyhydric alcohols such as polyethylene glycol, propylene glycol, glycerin, and sorbitol; synthetic emulsifiers such as glycerin fatty acid esters, sucrose fatty acid esters, and polyglycerin fatty acid esters; natural emulsifiers such as lecithins, saponin, plant sterols, and milk fat globule membranes; and sodium carboxymethylcellulose, kaolin, xanthan gum, methylcellulose, tragacanth, and hydrogenated soybean phospholipid.

[0096] Examples of the sweetener include sucrose, fructose, maltose, trehalose, licorice extract, saccharin, saccharin sodium, sucralose, stevia processed sweetener, Monk fruit extract, aspartame, acesulfame potassium, erythritol, sorbitol, xylitol, maltitol, reduced starch syrup, and reduced maltose starch syrup.

[0097] Examples of the acidulant include adipic acid, itaconic acid, citric acid, potassium citrate, glucono-delta-lactone, gluconic acid, succinic acid, sodium succinate, sodium acetate, tartaric acid, sodium tartrate, carbon dioxide, lactic acid, sodium lactate, glacial acetic acid, phytic acid, fumaric acid, sodium fumarate, malic acid, and phosphoric acid.

[0098] Examples of the fruit juice include lemon juice, orange juice, berry juice, apple juice, banana juice, and the like.

[0099] The form of the composition of the present invention is not particularly limited, and examples thereof include ointments, liquids, suspensions, emulsions (milky lotions and creams), gels, liniments, lotions, patches, mists, foams, aerosols, sticks, powders, granules, tablets (including plain tablets, sugar-coated tablets, orally disintegrating tablets, chewable tablets, effervescent tablets, troches, and film-coated tablets), detergents, soaps, solids, capsules (e.g., soft capsules), films, confectioneries (including candies, gummies, and nougat), syrups, drinks, juices, soft drinks, and tea; solids such as biscuits, tablets, granular powders, powders, and capsules; and semi-liquid forms such as pastes, jellies, soups, seasonings, and dressings. These formulations can be produced by conventional methods, for example, the methods described in the General Provisions for Preparations of the Japanese Pharmacopoeia, 17th Edition.

[0100] When the composition of the present invention is in the form of a cosmetic, it can be used in the form of, for example, basic cosmetics such as creams, milky lotions, lotions, gels, serums, essences, facial cleansers, cleansing agents, packs, lip balms, etc., makeup cosmetics such as sunscreens, lipsticks, foundations, eye colors, etc., toiletries such as body soaps, soaps, shampoos, rinses, conditioners, etc., hair cosmetics such as hair styling agents, etc. The composition of the present invention can penetrate the skin and act on and activate muscles (for example, facial muscles, etc.), and is therefore suitable for use as an anti-aging cosmetic that improves wrinkles and sagging.

[0101] (Lotion) When the composition of the present invention is a lotion, for example, the lotion contains at least a specific compound and water. The specific compound is preferably the hydrochloride salt of the compound represented by formula (I-1). The content of the specific compound in the lotion is, for example, preferably 0.0005% by mass or more and 1.0% by mass or less, more preferably 0.0005% by mass or more and 0.5% by mass or less, and particularly preferably 0.001% by mass.

[0102] The lotion preferably contains, as optional ingredients, at least one of a moisturizing ingredient (e.g., glycerin, 1,3-butylene glycol, polyoxyalkylene alkyl glucoside, 2-methacryloyloxyethyl phosphorylcholine-butyl methacrylate copolymer, etc.), a thickener (e.g., xanthan gum, etc.), a preservative (e.g., methylparaben, etc.), a surfactant (e.g., PPG-13 decyltetradeceth-24, etc.), a pH adjuster (e.g., citric acid, trisodium citrate, etc.), and an ester oil (e.g., bisethoxydiglycol cyclohexane-1,4-dicarboxylate, etc.), and more preferably contains all of the above ingredients.

[0103] (Emulsion) When the composition of the present invention is an emulsion, for example, the emulsion contains at least a specific compound and water. The specific compound is preferably the hydrochloride salt of the compound represented by formula (I-1). The content of the specific compound in the emulsion is, for example, from 0.0001% by mass to 10.0% by mass, preferably from 0.01% by mass to 5.0% by mass, more preferably from 0.1% by mass to 2.0% by mass, and particularly preferably 1.0% by mass.

[0104] The emulsion preferably contains, as optional ingredients, at least one of a moisturizing ingredient (e.g., diglycerin, dipropylene glycol, 1,3-propanediol, PPG-17 buteth-17, etc.), a thickener (e.g., carboxyvinyl polymer, polyvinylpyrrolidone, etc.), a base or carrier (e.g., liquid paraffin, cetanol, dimethicone, etc.), a preservative (e.g., phenoxyethanol, etc.), a surfactant (e.g., sorbitan monostearate, polysorbate 60, etc.), a pH adjuster (e.g., triethanolamine), and vitamins (e.g., triferol, etc.), and more preferably contains all of the above ingredients.

[0105] (Cream) When the composition of the present invention is a cream, for example, the cream contains at least a specific compound and water. The specific compound is preferably the hydrochloride salt of the compound represented by formula (I-1). The content of the specific compound in the cream is, for example, from 0.0001% by mass to 10.0% by mass, preferably from 0.01% by mass to 5.0% by mass, more preferably from 0.05% by mass to 1.0% by mass, and particularly preferably 0.1% by mass.

[0106] The cream preferably contains, as optional ingredients, at least one of a moisturizing ingredient (e.g., glycerin, 1,3-butylene glycol, etc.), a thickener (e.g., agar, polyvinylpyrrolidone, pullulan, etc.), an oil (e.g., medium-chain fatty acid triglyceride, caprylic-capric-myristic-stearic triglyceride, meadowfoam oil, etc.), a base or carrier (e.g., cetanol, behenyl alcohol, shea butter, etc.), a preservative (e.g., sodium benzoate, phenoxyethanol, etc.), a surfactant (e.g., lipophilic glyceryl monostearate, polysorbate 60, etc.), and an emulsifier (e.g., hydrogenated soybean phospholipid, etc.), and more preferably contains all of the above ingredients.

[0107] (Gel) When the composition of the present invention is a gel, for example, the gel contains at least a specific compound and water. The specific compound is preferably the hydrochloride salt of the compound represented by formula (I-1). The content of the specific compound in the gel is, for example, 0.0001% by mass or more and 10.0% by mass or less, preferably 0.001% by mass or more and 1.0% by mass or less, more preferably 0.005% by mass or more and 0.1% by mass or less, and particularly preferably 0.01% by mass.

[0108] The gel preferably contains at least one optional ingredient selected from the group consisting of moisturizing ingredients (e.g., glycerin, diglycerin, dipropylene glycol, etc.), thickeners (e.g., xanthan gum, carboxyvinyl polymer, etc.), oils and fats (e.g., medium-chain fatty acid triglycerides, jojoba oil, meadowfoam oil, etc.), bases or carriers (e.g., squalane, stearyl alcohol, behenyl alcohol, etc.), preservatives (e.g., methylparaben, phenoxyethanol, etc.), surfactants (e.g., lipophilic glyceryl monostearate, etc.), and pH adjusters (e.g., sodium hydroxide, etc.), and more preferably contains all of the above ingredients.

[0109] (Sunscreen Cream) When the composition of the present invention is a sunscreen cream, for example, the sunscreen cream contains at least a specific compound, an ultraviolet absorbing component and / or an ultraviolet scattering component, and water. The specific compound is preferably the hydrochloride salt of the compound represented by formula (I-1). The content of the specific compound in the sunscreen cream is, for example, 0.0001% by mass or more and 10.0% by mass or less, preferably 0.001% by mass or more and 1.0% by mass or less, more preferably 0.001% by mass or more and 0.05% by mass or less, and particularly preferably 0.005% by mass. Examples of ultraviolet absorbers include octocrylene, polysilicone-15, and 4-tert-butyl-4'-methoxydibenzoylmethane. Examples of ultraviolet scattering agents include hydrophobized titanium oxide fine particles.

[0110] The sunscreen cream preferably contains, as optional ingredients, at least one of a moisturizing ingredient (e.g., polyoxybutylene polyoxyethylene polyoxypropylene glyceryl ether (3B.O.) (8E.O.) (5P.O.), 2-methacryloyloxyethyl phosphorylcholine-butyl methacrylate copolymer liquid, etc.), a thickener (e.g., gellan gum, carboxyvinyl polymer, etc.), a base or carrier (e.g., triethylhexanoin, stearyl alcohol, batyl alcohol, etc.), a lubricant (e.g., methylpolysiloxane, etc.), a preservative (e.g., phenoxyethanol, etc.), a surfactant (e.g., polyoxyethylene sorbitan isostearate, glyceryl isostearate, etc.), a pH adjuster (e.g., potassium hydroxide, etc.), and a chelating agent (e.g., edetate disodium, etc.), and more preferably contains all of the above ingredients.

[0111] (Sunscreen Gel) When the composition of the present invention is a sunscreen gel, for example, the sunscreen gel contains at least a specific compound, an ultraviolet absorbing component and / or an ultraviolet scattering component, and water. The specific compound is preferably the hydrochloride salt of the compound represented by formula (I-1). The content of the specific compound in the sunscreen gel is, for example, 0.0001% by mass or more and 10.0% by mass or less, preferably 0.01% by mass or more and 2.0% by mass or less, more preferably 0.1% by mass or more and 1.0% by mass or less, and particularly preferably 0.5% by mass. Examples of ultraviolet absorbers include 2-ethylhexyl paramethoxycinnamate, phenylbenzimidazole sulfonic acid, diethylaminohydroxybenzoylhexylbenzoate, bisethylhexyloxyphenol methoxyphenyl triazine, etc. Examples of ultraviolet scattering agents include hydrophobized zinc oxide fine particles, etc.

[0112] The sunscreen gel preferably contains, as optional ingredients, at least one of a moisturizing ingredient (e.g., 1,3-butylene glycol, pentanediol, 2-methacryloyloxyethyl phosphorylcholine-butyl methacrylate copolymer liquid, etc.), a thickener (e.g., polyacrylic acid amide, hydroxypropyl cellulose, etc.), an ester oil (e.g., isononyl isononanoate, etc.), a base or carrier (e.g., liquid paraffin, stearyl alcohol, etc.), a lubricant (e.g., methylpolysiloxane, etc.), a preservative (e.g., methylparaben, phenoxyethanol, etc.), a surfactant (e.g., sorbitan monostearate, polyoxyethylene sorbitan isostearate, polyoxyethylene lauryl ether (7E.O.), etc.), an antioxidant (e.g., dibutylhydroxytoluene, etc.), and a chelating agent (e.g., edetate disodium, etc.), and more preferably contains all of the above ingredients.

[0113] (Sunscreen BB Cream) When the composition of the present invention is a sunscreen BB (blemish balm) cream, for example, the sunscreen BB cream contains at least a specific compound, an ultraviolet absorbing component and / or an ultraviolet scattering component, and water. The specific compound is preferably the hydrochloride salt of the compound represented by formula (I-1). The content of the specific compound in the sunscreen BB cream is, for example, 0.0001% by mass or more and 10.0% by mass or less, preferably 0.01% by mass or more and 2.0% by mass or less, more preferably 0.1% by mass or more and 1.0% by mass or less, and particularly preferably 0.5% by mass. Examples of ultraviolet absorbers include 4-tert-butyl-4'-methoxydibenzoylmethane and diethylaminohydroxybenzoylhexyl benzoate. Examples of ultraviolet scattering agents include hydrophobized zinc oxide fine particles, hydrophilized pigment-grade titanium oxide, hydrophilized iron oxide, and titanium mica.

[0114] The sunscreen BB cream may optionally contain moisturizing ingredients (e.g., 1,3-butylene glycol, pentanediol, 2-methacryloyloxyethyl phosphorylcholine-butyl methacrylate copolymer liquid, etc.), thickeners (e.g., polyacrylic acid amide, hydroxypropyl cellulose, gellan gum, (PEG-240 / decyltetradeceth-20 / HDI) copolymer, etc.), ester oils (e.g., isononyl isononanoate, bisethoxydiglycol cyclohexanedicarboxylate, diethylhexyl succinate, etc.), bases or carriers (e.g., liquid paraffin, stearyl alcohol, cetanol, absolute ethanol, etc.), and lubricants (e.g., methylpolysiloxane It is preferable that the cosmetic composition contains at least one of an antioxidant (e.g., sorbitan monostearate, polyoxyethylene sorbitan isostearate, polyoxyethylene lauryl ether (7E.O.), glyceryl isostearate, polyethylene glycol monostearate, etc.), an antioxidant (e.g., dibutylhydroxytoluene, etc.), a chelating agent (e.g., caprylhydroxamic acid, edetate disodium, etc.), a pH adjuster (e.g., triethanolamine, etc.), and an anti-inflammatory agent (e.g., 2-ethylhexyl salicylate, etc.), and it is more preferable that the cosmetic composition contains all of the above-mentioned ingredients.

[0115] The present inventors have also found that the compound of formula (I) activates the secretion of serotonin in a human neuronal model. Serotonin is also known as the "happiness hormone," and is suggested to be involved in mental stability and skin condition.

[0116] Therefore, when the composition of the present invention is used as a cosmetic, it can be absorbed through the skin and reach serotonin-producing cells (e.g., the raphe nucleus of the brainstem) to activate the secretion of serotonin. This allows the composition of the present invention to be used as a so-called "neurocosmetics" that also provides cosmetic effects through the interaction between the skin and nerves.

[0117] (Tablets) When the composition of the present invention is in the form of a tablet, for example, the tablet contains at least a specific compound and an excipient. The specific compound is preferably the hydrochloride salt of the compound represented by formula (I-1). The amount of the specific compound contained in the daily dose of the tablet is, for example, 0.001 mg / day to 10.0 mg / day, preferably 0.001 mg / day to 5.0 mg / day, and more preferably 0.003 mg / day to 3.0 mg / day. Examples of excipients include maltitol and starch.

[0118] The tablet preferably contains at least one optional ingredient selected from the group consisting of a binder (e.g., crystalline cellulose, etc.) and a lubricant (e.g., calcium stearate, fine silicon dioxide, etc.), and more preferably contains all of the above ingredients.

[0119] (Soft Capsules) When the composition of the present invention is a soft capsule, for example, the soft capsule contains at least a specific compound, a base, and a coating component. The specific compound is preferably the hydrochloride salt of the compound represented by formula (I-1). The amount of the specific compound contained in a daily dose of the soft capsule is, for example, 0.001 mg / day or more and 10.0 mg / day or less, preferably 0.001 mg / day or more and 3.0 mg / day or less. Examples of the base include oils and fats (e.g., vegetable oils such as safflower oil, soybean oil, sunflower oil, and olive oil). Examples of the coating component include gelatin, glycerin, etc.

[0120] The soft capsule preferably contains at least one of an emulsifier and an antioxidant (e.g., vitamin E) as an optional ingredient, and more preferably contains all of the above ingredients.

[0121] (Granules) When the composition of the present invention is in the form of granules, for example, the granules contain at least a specific compound and an excipient. The specific compound is preferably the hydrochloride salt of the compound represented by formula (I-1). The amount of the specific compound contained in a daily dose of the granules is, for example, 0.001 mg / day or more and 10.0 mg / day or less, and preferably 0.001 mg / day or more and 3.0 mg / day or less. Examples of excipients include maltitol, xylitol, lactose, and modified starch.

[0122] The granules preferably contain at least one optional ingredient selected from the group consisting of a sweetener, a lubricant (calcium stearate), a base or carrier (e.g., hydroxypropyl methylcellulose, etc.), a flavoring, and a coloring (e.g., riboflavin, gardenia pigment, carotenoid pigment, etc.), and more preferably contain all of the above ingredients.

[0123] (Drinks) When the composition of the present invention is a drink, for example, the drink contains at least a specific compound and water. The specific compound is preferably the hydrochloride salt of the compound represented by formula (I-1). The amount of the specific compound contained in a daily dose of the drink is, for example, 0.001 mg / day or more and 10.0 mg / day or less, and preferably 0.001 mg / day or more and 3.0 mg / day or less.

[0124] The drink preferably contains at least one of the following optional ingredients: a sweetener (e.g., sugar, glucose, erythritol, etc.), a stabilizer (e.g., pectin, etc.), an acidulant, a flavoring, and a coloring (e.g., riboflavin, gardenia pigment, carotenoid pigment, etc.), and more preferably contains all of the above ingredients.

[0125] (Gummy Candy) When the composition of the present invention is a gummy candy, for example, the gummy candy contains at least a specific compound, sugar, starch syrup, and gelatin. The specific compound is preferably the hydrochloride salt of the compound represented by formula (I-1). The amount of the specific compound contained in a daily dose of the drink is, for example, 0.001 mg / day or more and 10.0 mg / day or less, and preferably 0.001 mg / day or more and 3.0 mg / day or less.

[0126] The gummy candy preferably contains at least one of the following optional ingredients: a stabilizer (e.g., pectin), a sweetener (e.g., sorbitol), glycerin, an acidulant, a flavoring, a glazing agent, an emulsifier, an oblate, and a coloring agent, and more preferably contains all of the above ingredients.

[0127] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0128] The present inventors conducted an in vitro test as described below to confirm the effect of the compound represented by formula (I-1) on skeletal muscle-derived cells.

[0129] (In vitro Test A) Human skeletal muscle myoblasts (HSMM CC-2580 #517047) were cultured in vitro in a medium containing the compound represented by formula (I-1) by the following method. The myoblasts were cultured in a 24-well plate at a density of 15 × 10 ４ The skeletal muscle-derived cells were then plated at a density of 100000000000 cells / well. Thereafter, the mRNA expression levels of the PGC-1α gene, the myostatin gene, and the atrogin 1 gene were measured.

[0130] The medium used for the maintenance culture of human skeletal muscle myoblasts (Human Skeletal Muscle Myoblasts (HSMM) manufactured by LONZA) is SkGM. ＴＭ -2 BulletKit ＴＭ The differentiation medium used was DMEM / F12-Dulbecco's Modified Eagle Medium (Thermo Fisher Scientific) supplemented with 2% horse serum (Thermo Fisher Scientific) and 1% antibiotics (Fujifilm Wako Pure Chemical Industries).

[0131] First, 1.5 x 10 ５HSMM cells were seeded into 24-well plates at 1 ml / well. Next, the HSMM cells were cultured in maintenance medium at 37°C under an environment of 5% carbon dioxide and 95% air for 24 hours. After confirming that the cells (HSMM) were growing normally by microscopic observation, the medium was replaced with differentiation medium, and the HSMM cells were cultured for an additional 3 days (these steps are referred to as "culture procedure A"). The medium was then replaced. The new differentiation medium used for this medium replacement contained the compound represented by formula (I-1) as a test substance, at the test concentrations shown in Tables 1 to 3 and Figures 1 to 3 . A control was prepared by using a normal differentiation medium without the test substance during the medium replacement. Thus, skeletal muscle-derived cells were treated with the test substance (48 hours for measuring the mRNA expression levels of the PGC-1α gene and atrogin 1 gene, and 24 hours for measuring the mRNA expression level of the myostatin gene).

[0132] Next, the treated cells (HSMM) were collected. Total RNA was extracted from the collected cells using an extraction kit (Maxwell RSC simplyRNA Tissue Kit: manufactured by Promega) and an automated extractor (Maxwell RSC48 Instrument: manufactured by Promega). The collected total RNA was then reverse transcribed using a reverse transcription kit (ReverTra Ace (registered trademark) qPCR RT Master Mix: manufactured by Toyobo Co., Ltd.) to synthesize cDNA. The obtained cDNA was then subjected to qPCR using a qPCR master mix (TaqMan Fast Advanced Master Mix: manufactured by ABI). The GAPDH (glyceraldehyde 3-phosphate dehydrogenase) gene was used as an internal standard. Myostatin and Atrogin-1, which are indicators of muscle atrophy, and PGC-1α, which is an indicator of metabolic control in skeletal muscle, were measured, and the mRNA expression level of the gene to be measured relative to the mRNA expression level of GAPDH (mRNA expression level of the gene to be measured / mRNA expression level of GAPDH) was evaluated.

[0133] The information on the primers used is shown below.

[0134]

[0135] The measurement results are shown in Tables 2 to 4 and Figures 1 to 3.

[0136]

[0137] As described above, it was confirmed that the compound represented by formula (I-1) activates the expression of the PGC-1α gene (FIG. 1).

[0138]

[0139] As described above, it was confirmed that the compound represented by formula (I-1) suppresses the expression of the myostatin gene (FIG. 2).

[0140]

[0141] As described above, it was confirmed that the compound represented by formula (I-1) suppresses the expression of the atrogin 1 gene (FIG. 3).

[0142] The above tests confirmed that the specific compound has excellent effects in activating PGC-1α, suppressing Atrogin-1 expression, and suppressing myostatin expression. Furthermore, the specific compound is considered to have excellent effects in maintaining and activating muscle quantity and quality by regulating these muscle-related genes.

[0143] (In Vitro Test B) The same procedure as in the culture procedure A described in In Vitro Test A was performed. Specifically, human-derived skeletal myoblasts (HSMM CC-2580 #517047) were cultured in a maintenance medium for 24 hours and then in a differentiation medium for 3 days. The medium was then replaced. The compound represented by formula (I-1) was added as a test substance to the new differentiation medium used for this medium replacement, at the test concentrations shown in Tables 5-6 and Figures 4-5. Meanwhile, a control (control) was prepared using a normal differentiation medium without the addition of the test substance during the medium replacement. Thus, skeletal muscle-derived cells were treated with the test substance. After 48 hours for measurement of PGC-1α protein expression levels and after 72 hours for measurement of myostatin gene secretion levels, skeletal muscle-derived cells and their culture supernatants were collected.

[0144] (PGC-1α protein and myostatin protein expression levels) The expression levels of PGC-1α protein in skeletal muscle-derived cells and the secretion levels of myostatin protein in the culture supernatant of skeletal muscle-derived cells were measured by ELISA. Specifically, the PGC-1α protein and myostatin protein were quantified using the kit shown below according to the standard protocol provided with the kit (n=2). PGC-1α kit: Human peroxisome proliferative activated receptor gama coactivator 1 alpha, PPARGC1 ELISA Kit CSB-E11761h (manufactured by CUSABIO Technology) Myostatin kit: Human Myostatin (GDF-8) ELISA Kit #DGDF80 (manufactured by R&D Systems)

[0145] The measurement results are shown in Tables 5 and 6 and FIGS.

[0146]

[0147] As described above, it was confirmed that the compound represented by formula (I-1) activates the expression of PGC-1α protein (Table 5, FIG. 4).

[0148]

[0149] As described above, it was confirmed that the compound represented by formula (I-1) inhibits the secretion of myostatin protein (Table 6, Figure 5).

[0150] (In vivo Study A) A placebo-controlled, randomized, single-blind, parallel-group comparative study was conducted on Japanese women aged 35 to 59. Specifically, subjects were administered a formulation containing the hydrochloride of the compound represented by formula (I-1) at a concentration of 0.001% (formulation group, 14 subjects) or a placebo formulation not containing the hydrochloride of the compound (placebo group, 14 subjects) for 8 weeks (twice daily, morning and evening). The widths of crow's feet and nasolabial folds were quantitatively measured before application (0W), 4 weeks after application (4W), and 8 weeks after application (8W) using the following method.

[0151] Details of the formulations used are as follows, where the numbers represent parts by mass. Water: 70.63362 Dimethicone: 11.7422 Butylene glycol (BG): 8.1 Ethanol: 5 PEG-11 methyl ether dimethicone: 1.5 Cyclopentasiloxane: 0.93 (Dimethicone / (PEG-10 / 15)) crosspolymer: 0.7578 Sodium chloride: 0.5 Phenoxyethanol: 0.305 Methylparaben: 0.2 EDTA-2Na: 0.1 Sodium citrate: 0.0758 (Dimethicone / vinyl dimethicone) crosspolymer: 0.07 TEA: 0.05 Glycerin: 0.03 Ethylhexylglycerin: 0.002 Citric acid: 0.0017 Hydrochloride of the compound represented by formula (I-1): 0.001 Potassium hydroxide: 0.00088

[0152] (Crow's feet wrinkles) The width of the crow's feet wrinkles was measured using the skin analyzer "Antera 3D ＴＭ (manufactured by Gadelius Medical Co., Ltd.) was used, and measurements were taken in accordance with the Guidelines for Evaluation of Anti-Wrinkle Products (Journal of the Japanese Society of Cosmetic Chemistry, Vol. 30, No. 4, pp. 316-332 (2006)). Note that "corner of the eye" refers to the outer corner of the eye (the point where the upper and lower eyelids meet), and corner of the eye wrinkles refer to the groove that runs linearly from the outer corner of the eye. In addition, for subjects with multiple corner of the eye wrinkles, the average width of each corner of the eye wrinkle was used as the measurement value. The measurement results are shown in Table 7 and Figure 6. For reference, images of corner of the eye wrinkles at 0W and 8W for one subject in the formulation group are shown in Figure 7.

[0153]

[0154] (Laugh lines) The width of laugh lines was measured using the skin analyzer described above. The measurement results are shown in Table 8 and Figure 8. For reference, images of laugh lines at 0W and 8W for one subject in the formulation group are shown in Figure 9.

[0155]

[0156] As is clear from Table 7, Figure 6, Table 8, and Figure 8, the formulation group to which the formulation containing the hydrochloride of the compound represented by formula (I-1) was applied showed a significant decrease in the width of crow's feet and the width of nasolabial folds in both intra-group comparisons and inter-group comparisons with the control group. From the above, it is presumed that the formulation containing the hydrochloride of the specific compound exhibits a high improvement effect on wrinkles and sagging by activating the subcutaneous facial muscles.

[0157] (In vitro Test C) According to the following method, a human neuronal cell model (human neuroblastoma cells (SH-SY5Y)) was cultured in vitro in a medium containing melatonin and a compound represented by formula (I-1) or (I-2). Then, the amount of serotonin protein secreted in the human neuroblastoma cells was measured.

[0158] The human neuroblastoma clone SH-SY5Y cell line was obtained from the American Type Culture Collection (ATCC®, Manassas, CA). The culture medium was prepared by adding 15% fetal bovine serum (FBS) (Corning), MEM non-essential amino acids (Fujifilm Wako Pure Chemical Industries, Ltd.), and 1% penicillin-streptomycin solution (Fujifilm Wako Pure Chemical Industries, Ltd.) to DMEM / F12 (Dulbecco's Modified Eagle Medium) (Thermo Fisher Scientific).

[0159] First, 4 x 10 ４ Cells (SH-SY5Y) were seeded in a 24-well plate at 500 μl / well under the conditions of 37°C, 5% CO ２SH-SY5Y cells were cultured for 24 hours under an environment of 0.1% CO₂ and 95% air. Microscopic observation confirmed that the cells (SH-SY5Y) were viable. The medium was then replaced. The new medium (A) used for this replacement (DMEM / F12 (Dulbecco's Modified Eagle Medium) (Thermo Fisher Scientific) supplemented with 1% penicillin-streptomycin solution (Fujifilm Wako Pure Chemical Industries)) was supplemented with a test compound at the test concentration shown in Table 9. Meanwhile, a control (control) was prepared by replacing the medium with normal medium (A) without the test substance. Thus, the cells were treated with the test substance. After 24 hours, the culture supernatant was collected.

[0160] The amount of serotonin protein secreted in the cell culture supernatant was measured by ELISA. Specifically, the serotonin protein was quantified using the kit shown below according to the standard protocol included with the kit. Serotonin kit: Serotonin ELISA kit (manufactured by Enzo Life Sciences).

[0161] The measurement results are shown in Table 9 and FIG.

[0162]

[0163] As is clear from Table 9 and Figure 10, it was revealed that the compound represented by formula (I-1) or (I-2) activates the secretion of serotonin in a human neuronal cell model. From the above, it is possible that a composition containing a specific compound may also have a positive effect on the mental state.

[0164] According to the present invention, it is possible to provide a composition having excellent effects in maintaining and activating muscle quantity and quality, and a composition having excellent effects in activating PGC-1α, suppressing Atrogin-1 expression, or suppressing Myostatin expression.

Claims

1. A composition for maintaining and / or activating muscle, comprising at least one compound selected from the group consisting of compounds represented by the following formula (I) and salts thereof: (In the formula (I), R １ , R ２ , R ３ , R ４ , R ５ and R ６ each independently represents a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group having from 1 to 6 carbon atoms, a substituted or unsubstituted alkenyl group having from 2 to 6 carbon atoms, a substituted or unsubstituted alkynyl group having from 2 to 6 carbon atoms, a substituted or unsubstituted alkoxy group having from 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl group having from 3 to 8 carbon atoms, a substituted or unsubstituted aryl group having from 6 to 10 carbon atoms, a substituted or unsubstituted acyl group having from 2 to 21 carbon atoms, a substituted or unsubstituted heteroarylcarbonyl group, a substituted or unsubstituted alkoxycarbonyl group having from 2 to 7 carbon atoms, -CHO, -COOH, or -OH).

2. A composition for activating PGC-1α, inhibiting the expression of atrogin-1, or inhibiting the expression of myostatin, comprising at least one compound selected from the group consisting of compounds represented by the following formula (I) and salts thereof: (In the formula (I), R １ , R ２ , R ３ , R ４ , R ５ and R ６ each independently represents a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group having from 1 to 6 carbon atoms, a substituted or unsubstituted alkenyl group having from 2 to 6 carbon atoms, a substituted or unsubstituted alkynyl group having from 2 to 6 carbon atoms, a substituted or unsubstituted alkoxy group having from 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl group having from 3 to 8 carbon atoms, a substituted or unsubstituted aryl group having from 6 to 10 carbon atoms, a substituted or unsubstituted acyl group having from 2 to 21 carbon atoms, a substituted or unsubstituted heteroarylcarbonyl group, a substituted or unsubstituted alkoxycarbonyl group having from 2 to 7 carbon atoms, -CHO, -COOH, or -OH).

3. In the formula (I), R １ represents an alkoxy group having 1 to 3 carbon atoms; R ２ and R ３ each independently represents a hydrogen atom or —CHO; ４ and R ５ each independently represents a hydrogen atom or an acyl group having from 2 to 4 carbon atoms; R ６ The composition according to claim 1 or 2, wherein represents a hydrogen atom.

4. The composition according to claim 1 or 2, wherein the compound represented by formula (I) is represented by the following formula (I-1):

5. A composition described in any one of claims 1 to 4, which is for improving muscle endurance, muscle hypertrophy, obesity prevention, muscle atrophy prevention, or muscle maintenance.

6. A composition according to any one of claims 1 to 5, which is used to improve skin elasticity, improve wrinkles or for anti-aging purposes.

7. A composition according to any one of claims 1 to 6, which is a topical or oral composition.

Images