Composition

Abstract

To provide a composition having excellent action of inhibiting a decrease in MITOL and or promoting its production.MEANS FOR SOLVING THE PROBLEM: A composition contains moutan bark and taurine. Combinational use of moutan bark and taurine can markedly enhance the action of moutan bark to promote MITOL production.SELECTED DRAWING: Figure 2

Description

[Technical Field]

[0001] The present invention relates to a composition comprising Moutan Pea and taurine. [Background technology]

[0002] Mitochondria are intracellular organelles whose primary function is to produce the energy ATP. Therefore, maintaining mitochondrial function contributes to maintaining cellular and ultimately bodily functions. It has been discovered that mitochondrial function is regulated by mitochondrial fusion and fission, also known as mitochondrial dynamics, and interactions with other intracellular organelles. MITOL, a ubiquitin ligase localized in the outer mitochondrial membrane, has been reported to be involved in mitochondrial dynamics and the regulation of mitochondrial-endoplasmic reticulum adhesion (Non-Patent Document 1). Mice with cardiac-specific MITOL deficiency exhibited reduced cardiac function, as well as increased lipofuscin deposition and SA-β-gal expression, both of which are signs of cardiac aging (Non-Patent Document 2). Furthermore, mice lacking MITOL specifically in the epidermis exhibited hair follicle aging symptoms such as graying and hair loss, as well as skin aging-like findings such as epidermal thickening (Non-Patent Document 3). Furthermore, Alzheimer's disease model mice lacking MITOL specifically in the nerves exhibited worsening Alzheimer's disease pathology (Non-Patent Document 2). These findings suggest that MITOL loss is involved in the promotion of a wide range of aging symptoms, including cardiac aging, hair follicle aging, skin aging, and brain aging. Furthermore, it has been reported that MITOL knockdown in HELA cells elevated the expression of the senescence marker SA-β-gal, which was rescued by MITOL knock-in (Non-Patent Document 4). These findings suggest that MITOL loss accelerates aging, and that restoring the reduced MITOL level reverses aging. Based on these findings, approaches that increase or activate MITOL production are considered useful for anti-aging.

[0003] To date, plant extracts such as those from Coptis japonica and Moutanga pisum (Patent Document 1) and berberine (Patent Document 2) are known to increase MITOL production, but there is a demand for materials that exhibit even stronger effects.

[0004] Increasing the concentration of each ingredient can be expected to produce a proportionally stronger effect, but if plant extracts and other ingredients are used in too high a concentration, formulation issues such as discoloration, stability, and reduced usability may arise, and safety issues such as skin irritation may also arise, so simply increasing the amount used may not be desirable. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Nagashima Shun et al. (2014) Biochemistry, 86(1):63-67 [Non-patent document 2] Nagashima Shun et al. (2017) Japanese Pharmacological Journal, 149(6):254-259 [Non-patent document 3] Shigeru Yanagi (2016) Cosmetology Research Report, 24:149-152 [Non-patent document 4] Park et al. J Cell Sci. 2010;123:619-26. [Patent documents]

[0006] [Patent Document 1] Japanese Patent Application Publication No. 2019-52145 [Patent Document 2] Japanese Patent Application Publication No. 2019-178070 Summary of the Invention [Problem to be solved by the invention]

[0007] An object of the present invention is to provide a composition that has an excellent effect of inhibiting MITOL decrease or promoting MITOL production. [Means for solving the problem]

[0008] As a result of extensive research, the inventors discovered that the MITOL production-promoting effect of Moutanga pisi can be enhanced by combining it with taurine, leading to the completion of the present invention.

[0009] That is, the present invention provides: (1) A composition comprising moutan pith and taurine, (2) The composition according to (1), which is for external use on the skin. (3) The composition according to (1) or (2), which is used to inhibit MITOL reduction or promote MITOL production. [Effects of the Invention]

[0010] By inhibiting MITOL reduction or promoting MITOL production, the composition of the present invention can prevent or improve aging symptoms, such as hair follicle aging symptoms such as graying and hair loss, and skin aging symptoms such as decreased skin barrier function and age spots and wrinkles. It can also be used to prevent or improve cardiac aging symptoms such as cardiac decline and brain aging symptoms such as Alzheimer's disease. Furthermore, it can be used as a reagent for promoting MITOL production, and is preferably used as a positive control drug when conducting material screening, etc. [Brief explanation of the drawings]

[0011] [Figure 1] FIG. 1 is a graph showing the results of a test evaluating the MITOL production-promoting effect of Moutan Pea extract. [Figure 2] FIG. 2 is a graph showing the results of a test example in which the MITOL production-promoting effect was evaluated when either Peony extract or taurine (20 mM) was used alone and when they were used in combination. DETAILED DESCRIPTION OF THE INVENTION

[0012] The moutan peel in the present invention is the root bark of the peony (scientific names: Paeonia suffruticosa, Paeonia moutan) of the Paeoniaceae family. Moutan Pea is used in the form of a herbal powder or herbal extract. The herbal powder used in the present invention may be, for example, a dried product obtained by further pulverizing a dried, chopped product into a powder. The Moutan Pea extract used in the present invention can be extracted with a solvent such as water, lower aliphatic alcohols (e.g., methanol, ethanol, isopropyl alcohol), polyhydric alcohols (e.g., propylene glycol, 1,3-butylene glycol, glycerin, dipropylene glycol), or lower aliphatic ketones (e.g., acetone). However, extraction with a mixture of ethanol and water or a mixture of polyhydric alcohols and water is preferred, with a mixture of ethanol and water being most preferred. When extracting with a solvent consisting of water and ethanol, the ethanol content in the solvent is preferably 50-95% by volume. The extract form is not particularly limited; it can be prepared into a dried extract powder, extract powder, soft extract, or liquid extract by heat treatment, freeze-drying, or vacuum drying. It is also possible to use extracts purchased from various reagent and raw material manufacturers. Commercially available products of this type of extract include "Moutan Peony Extract" and "Moutan Peony Extract BG" from Maruzen Pharmaceuticals, and "Falcorex (registered trademark) Moutan Peony B" and "Falcorex Moutan Peony E" from Ichimaru Falcos. The label name for quasi-drugs and cosmetics is "peony extract" or "peony extract."

[0013] The amount of Moutan Pea in the composition of the present invention is not particularly limited, but is preferably 0.00000003 to 0.3 mass %, more preferably 0.000003 to 0.2 mass %, and even more preferably 0.00003 to 0.03 mass %, calculated on solids.

[0014] Taurine (also known as aminoethylsulfonic acid or 2-aminoethanesulfonic acid) in the present invention is a compound specified by Cas No. 107-35-7. Taurine can be produced by general chemical synthesis or by extraction from seafood, particularly mollusks (octopus and squid). It can also be purchased from various reagent and raw material manufacturers.

[0015] The amount of taurine contained in the composition of the present invention is not particularly limited, but is preferably 0.0001 to 10% by mass, and more preferably 0.001 to 5% by mass.

[0016] In the composition of the present invention, the mass ratio of the content of moutan pith to taurine (moutan pith (solid equivalent): taurine) is not particularly limited, but from the viewpoint of the effect of inhibiting MITOL reduction or promoting MITOL production, it is preferably 1:0.3 to 1:30000, more preferably 1:3 to 1:300, and even more preferably in the range of 1:50 to 1:300.

[0017] The compositions of the present invention include pharmaceuticals, quasi-drugs, cosmetics, foods and beverages, reagents, etc. The dosage form is not particularly limited, but includes topical and oral administration, preferably topical application to the skin, including the scalp, and / or hair. When the present invention is applied topically to the skin, examples of dosage forms include lotions, liquids, creams, ointments, gels, sprays, shampoos, conditioners, and soaps. When the present invention is applied orally, examples of dosage forms include tablets, powders, granules, liquids, capsules, dry syrups, jellies, liquid foods, semi-solid foods, and solid foods.

[0018] These can be produced by known methods. During production, various additives that can be contained in cosmetics, quasi-drugs, pharmaceuticals, foods and beverages, or reagents can be blended within a range that does not impair the effects of the present invention.

[0019] The composition of the present invention containing Moutan Peony and taurine has the effect of inhibiting MITOL reduction or promoting MITOL production, and based on this effect, it can be effective in preventing or ameliorating aging symptoms such as hair follicle aging symptoms such as gray hair and hair loss, and skin aging symptoms such as impaired skin barrier function, age spots, and wrinkles. It can also be used to prevent or ameliorate cardiac aging symptoms such as cardiac decline and brain aging symptoms such as Alzheimer's disease.

[0020] Mice lacking MITOL specifically in the skin epidermis have been observed to exhibit symptoms of hair follicle aging, such as increased gray hair, hair loss, and increased hair follicle cell death (Non-Patent Document 3). Hair pigment is produced by melanocytes present in the hair bulb of the hair follicle, which is hair tissue. Hair follicle keratinocytes, such as hair matrix cells, are supplied with this pigment to form pigmented hair. When hair is replaced, the area below the bulge region of the hair follicle, such as the old hair bulb, disappears, and the melanocytes in the hair bulb disappear as well. When a new hair cycle begins and new hair is generated, melanocytes are supplied from melanocyte stem cells present in the bulge region of the hair follicle, resulting in the regeneration of pigmented hair. Aging and various stresses can cause a decrease or depletion of melanocyte stem cells, or problems with the melanocyte supply process, resulting in an inadequate supply of melanocytes, resulting in the development of pigment-depleted gray hair.

[0021] In the bulge region, hair follicle epithelial stem cells (hereafter referred to as "hair follicle stem cells") reside adjacent to melanocyte stem cells. When body hair grows out, hair follicle stem cells supply hair matrix cells, which are epithelial cells of the hair follicle, and these cells form new hair follicle tissue. Furthermore, it has been revealed that hair follicle stem cells not only have the function of reconstructing the epithelial cells of the hair follicle, but also have the function of forming a microenvironment (hereafter referred to as "niche function") to maintain the adjacent melanocyte stem cells (Tanimura S et al (2011) Cell Stem Cell., 6(2):130-40.). Hair follicle stem cells maintain the undifferentiated state of melanocyte stem cells by controlling their activation and maintenance through TGFβ signaling and WNT signaling. Based on this, it is thought that the decline in melanocyte stem cells is caused by the loss of hair follicle stem cell niche function as a result of accumulated damage to hair follicle stem cells due to aging and various stresses (Aoki H et al (2013) J Invest Dermatol., 133(9):2143-51.).

[0022] It has been elucidated that type XVII collagen plays an important role in maintaining hair follicle stem cells. Type XVII collagen is a bell-shaped collagen that constitutes the hemidesmosomes (hemidesmosomes) that anchor epithelial cells to the basement membrane, and the α-chain component is COL17A1. Hair follicle stem cells are also anchored to the basement membrane by this hemidesmosome structure. Loss of type XVII collagen leads to hair loss due to impaired hair follicle stem cell maintenance. This results in the loss of melanocyte stem cells and the graying of body hair. Furthermore, it has recently been elucidated that type XVII collagen is degraded with age, leading to the loss of hair follicle stem cells and hair loss (Matsumura H et al. (2016) Science., 351 (6273): aad4395.). Based on these findings, promoting the production of COL17A1, a component of the α-chain of type XVII collagen, and increasing the expression of type XVII collagen can prevent and improve hair loss and graying.

[0023] Mice that overexpress SCF in epithelial cells, including hair follicle stem cells, have been found to be resistant to the stress that causes hair to turn gray. This suggests that increasing SCF expression in epithelial cells leads to the maintenance of melanocyte stem cells, resulting in the prevention and improvement of hair turning gray (Aoki H et al. (2011) J Invest Dermatol. 131(9):1906-15.).

[0024] WNT7A, a type of WNT ligand, is strongly expressed in hair follicles during the hair cycle. Hair regenerated after wound healing is usually white and lacks pigment. However, if the wound occurs during the anagen phase, when epithelial cells strongly express WNT7A, colored hair regenerates. This is due to WNT7A activating melanocyte stem cells. Therefore, increasing WNT7A expression can prevent and improve gray hair (Yuriguchi M et al (2016) J Dermatol Sci., 84(1):80-87.).

[0025] Hair loss and graying can also occur due to the decline in function or cell death of hair follicle keratinocytes, hair follicle stem cells, melanocyte stem cells, etc. Cell proliferation markers such as the cell cycle-related nuclear protein KI67 and the protein PCNA, which controls the cell cycle, serve as indicators of the activation of these cells, so increasing the expression of KI67, PCNA, etc. can prevent and improve hair loss and graying.

[0026] It has been confirmed that MITOL is involved in the proliferation of hair follicle stem cells and hair follicle keratinocytes via the expression of MKI67 and PCNA, in the expression of type XVII collagen via the expression of COL17A1, and in the maintenance of melanocyte stem cells via the expression of WNT7A, TGFβ2, and SCF (Patent Document 1). Therefore, components that promote MITOL production or that suppress the decrease of MITOL have the effects of suppressing the decrease, promoting the proliferation, and activating hair follicle stem cells, melanocyte stem cells, and hair follicle keratinocytes, and based on these effects, can provide effects of preventing and improving hair loss and graying (Patent Document 1).

[0027] Skin is broadly divided into three layers: the epidermis, dermis, and subcutaneous tissue. The main constituent cells of the epidermis are keratinocytes, which undergo four morphological stages during differentiation. Basal cells in the lowest layer contact the basement membrane, synthesize DNA, and divide and proliferate. These divided cells migrate upward and become spinous cells. Further differentiation leads to granular cells, which ultimately differentiate into corneocytes, forming the stratum corneum (stratum corneum). Keratinocytes at these stages of differentiation are layered within the epidermis. The stratum corneum formed in this way functions as a barrier to prevent various external stimuli from penetrating the body (skin barrier function). The keratinocytes that make up the stratum corneum are adhered to each other by desmosomes. However, in healthy skin, this adhesion mechanism gradually weakens, leading to spontaneous detachment of the stratum corneum in response to physical stimuli (stratum corneum desquamation). In this way, the epidermis undergoes a rhythmic cycle of proliferation, differentiation, and exfoliation (epidermal turnover). In addition to keratinocytes, the epidermis also contains pigment cells, which produce melanin. Normally, melanin is transferred to keratinocytes and excreted with the stratum corneum peeling during the process of epidermal turnover. However, if there is an abnormality in epidermal turnover, such as a decrease in differentiation and proliferation from basal cells, the melanin is not excreted and accumulates in the epidermis, resulting in the formation of age spots.

[0028] Below the basal cells of the epidermis is the dermis, which consists of three layers: the papillary layer, the subpapillary layer, and the reticular layer. Fibroblasts are present in the dermis and synthesize extracellular matrix materials such as collagen fibers (collagenous fibers), elastin fibers (elastic fibers), and hyaluronic acid. Collagen fibers form thick fiber bundles in the reticular layer, constituting the support tissue of the skin. Elastin fibers exist mixed with collagen fibers, giving the tissue elasticity. Hyaluronic acid has excellent moisture retention properties and provides flexibility to the skin.

[0029] As we age, the proliferation function of basal cells in the epidermis declines, resulting in thinning of the epidermis and a longer turnover time. In the dermis, the proliferation function of fibroblasts also declines, and the ability to synthesize extracellular matrix components also declines. As a result, the overall volume of collagen fibers decreases, becoming thinner and the gaps between fibers becoming larger. Furthermore, elastin fibers denature, losing elasticity, and the amount of hyaluronic acid decreases, resulting in a decrease in moisture retention. As a result, skin atrophy and loss of firmness occur, leading to wrinkles, sagging, and other problems. Furthermore, abnormalities in epidermal turnover can lead to the formation of age spots.

[0030] It has been confirmed that MITOL is involved in the proliferation of epidermal keratinocytes, dermal fibroblasts, hair follicle keratinocytes, etc., through the expression of MKI67, PCNA, CDC25C, etc. in these cells (Patent Document 1). Therefore, components that promote MITOL production or that suppress the reduction of MITOL have the effect of suppressing the reduction, promoting the proliferation, and activating epidermal keratinocytes, dermal fibroblasts, and hair follicle keratinocytes, thereby achieving the effects of preventing and improving skin barrier function deterioration and skin aging symptoms such as blemishes and wrinkles (Patent Document 1).

[0031] It is also known that the influence of external factors such as ultraviolet rays can cause symptoms similar to chronological aging, also known as photoaging. UV rays and other factors increase reactive oxygen species (ROS) in epidermal cells, denaturing or cross-linking extracellular matrix components, resulting in decreased skin elasticity and inducing abnormal melanin pigment deposition, resulting in age spots and freckles. Mitochondria are the main source of ROS in the body, and it has been reported that increased ROS levels due to mitochondrial damage accelerate skin aging. Epidermis-specific MITOL knockout mice exhibit skin abnormalities, such as increased cell death in the epidermis, which has been suggested to be caused by increased ROS levels in epidermal keratinocytes (Non-Patent Document 3). Therefore, ingredients that promote MITOL production or inhibit MITOL reduction can prevent or ameliorate skin aging by preventing increased ROS levels in epidermal cells.

[0032] The composition of the present invention containing Moutan Peony and taurine has the effect of inhibiting MITOL loss or promoting MITOL production. This can prevent or improve symptoms of hair follicle aging, such as graying and hair loss, and symptoms of skin aging, such as impaired skin barrier function, age spots, and wrinkles. It can also be used to prevent or improve symptoms of cardiac aging, such as cardiac dysfunction, and symptoms of brain aging, such as Alzheimer's disease. Furthermore, it can be used as a reagent to promote MITOL production, and is suitable as a positive control for material screening and other purposes.

[0033] The composition of the present invention and its instructions may be labeled, for example, that it is used to inhibit the decrease or promote the production of MITOL, that it is used to prevent or improve hair follicle aging, that it is used to prevent or improve gray hair, that it is used to prevent or improve hair loss, that it is used to prevent or improve skin aging, that it is used to prevent or improve a decrease in skin barrier function, that it is used to prevent or improve wrinkles, that it is used to prevent or improve spots, or that it is used for anti-aging. Here, "labeled" includes being labeled on the body, container, packaging, etc. of a product containing the composition of the present invention, being labeled in documents such as instructions, package inserts, pamphlets, and other printed materials disclosing product information, and being labeled in various flyers and advertisements used for promotion, including on the Internet. [Example]

[0034] The present invention will be explained in more detail below with reference to examples and test examples, but the present invention is not limited to these examples.

[0035] (Test Example) Evaluation of the MITOL production promoting effect of Moutan Pea and taurine Human hair follicle keratinocytes (ScienCell Research Laboratories) were seeded in Humedia-KG2 medium (Kurashiki Boseki, supplemented with the attached supplements) onto 24-well plates and cultured for several days in an incubator set at 37°C and 5% CO2. When the appropriate cell density was reached, the medium was replaced with medium containing the test substance and cultured for an additional 48 hours. After culture, the medium was removed, and cells were lysed by adding lysate buffer to recover the cell lysate. RNA was extracted from the cell lysate using an RNeasy Mini Kit (Qiagen) according to the attached protocol. Using this as a template, cDNA was synthesized by reverse transcription using Prime Script RT Master mix (Takara Bio). The mRNA expression levels of RPLP2 and MITOL were measured (SYBR Green method) from the synthesized cDNA using a real-time PCR system (Step One Plus, Thermo Fisher Scientific). MITOL expression levels were normalized by the expression level of the internal control gene, RPLP2. The following primers were used: RPLP2: HA067804, MITOL: HA192576 (both Takara Bio). The measured mRNA expression levels were compared with those of a control group (medium not containing the test substance) to evaluate the MITOL production-promoting effect of the test substance.

[0036] <Test Results> The results of evaluating Moutan Pea extract (extract extracted with a mixture of ethanol and water containing approximately 3% solids by mass) at various concentrations are shown in Figure 1. Moutan Pea exhibited the effect of promoting MITOL production, and this effect increased in a concentration-dependent manner. Next, the results of using Moutan Pea in combination with taurine are shown in Figure 2. As with the results shown in Figure 1, under these test conditions, the MITOL production-promoting effect of Moutan Pea at a concentration of 0.1% by mass (approximately 0.003% by mass in terms of solid matter) was weak, but by using it in combination with taurine, the MITOL production-promoting effect was synergistically enhanced. This indicates that taurine enhances the MITOL production-promoting effect of Moutan Pea.

[0037] <Production Example: Cleaning Composition> A cleaning composition having a pH of 6.0 was obtained by dissolving 7 g of sodium tetradecene sulfonate solution, 3 g of sodium methyl taurate of coconut oil fatty acid, 3 g of coconut oil fatty acid amidopropyl betaine solution, 2 g of coconut oil fatty acid N-methylethanolamide, 1 g of polyoxyethylene sorbitan monolaurate, 1 g of polyoxypropylene coconut oil fatty acid monoisopropanolamide (1P.O.), 0.3 g of O-[2-hydroxy-3-(trimethylammonio)propyl]hydroxyethyl cellulose chloride, 0.1 g of dipotassium glycyrrhizinate, 0.1 g of salicylic acid, 0.1 g of l-menthol, 0.5 g of methyl parahydroxybenzoate, 0.2 g of sodium benzoate, 0.05 g of Moutan Pea Extract, 0.03 g of taurine, 0.01 g of Coptis Rhizome Extract, 0.02 g of Phellodendron Bark Extract, an appropriate amount of fragrance, an appropriate amount of citric acid, an appropriate amount of sodium citrate, and purified water to a total volume of 100 g.

[0038] <Production example: hair composition> A hair composition having a pH of 4.3 was obtained by adding 2 g of alkyltrimethylammonium chloride, 1.5 g of hydrogenated rapeseed oil alcohol, 2.5 g of cetanol, 2 g of liquid paraffin, 0.3 g of O-[2-hydroxy-3-(trimethylammonio)propyl]guar gum chloride, 3 g of concentrated glycerin, 3 g of 1,3-butylene glycol, 0.5 g of l-menthol, 0.1 g of dipotassium glycyrrhizinate, 0.1 g of salicylic acid, 0.2 g of methyl parahydroxybenzoate, 0.1 g of moutan peel extract, 0.01 g of taurine, 0.05 g of coptis japonica extract, 0.05 g of Phellodendron Bark extract, an appropriate amount of fragrance, an appropriate amount of citric acid, an appropriate amount of L-arginine, and purified water to a total volume of 100 g.

[0039] <Production Example: Hair Growth Composition> A hair growth composition with a pH of 6.0 was obtained by adding 50 g of ethanol, 2 g of concentrated glycerin, 2 g of 1,3-butylene glycol, 0.5 g of polyoxyethylene hydrogenated castor oil, 1 g of l-menthol, 0.3 g of moutan pisa extract, 0.05 g of taurine, 0.3 g of coptis japonica extract, 0.3 g of phellodendron bark extract, an appropriate amount of fragrance, an appropriate amount of citric acid, an appropriate amount of sodium citrate, and purified water to a total volume of 100 g. [Industrial Applicability]

[0040] The composition of the present invention, characterized by containing Moutanga pisi and taurine, inhibits MITOL loss or promotes MITOL production, and is therefore expected to prevent or improve, for example, hair follicle aging symptoms such as graying and hair loss, and skin aging symptoms such as impaired skin barrier function, age spots, and wrinkles. It can also be used to prevent or improve cardiac aging symptoms such as cardiac dysfunction and brain aging symptoms such as Alzheimer's disease. Alternatively, it can be used as a reagent to promote MITOL production, and is preferably utilized as a positive control agent in material screening, etc.

Claims

1. A composition for preventing or improving gray hair, comprising Peony root extract and taurine, wherein the mass ratio of Peony root extract to taurine (Peony root extract (solid content): taurine) is 1:50 to 1:

300.

2. A composition for preventing or improving hair loss, comprising Peony Fruit and taurine, wherein the mass ratio of Peony Fruit to taurine (Peony Fruit (solid equivalent): taurine) is 1:50 to 1:300.

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