Composition containing 1-piperidinepropionic acid and geranium thunbergii

Abstract

Provided is a composition that has a favorable effect on the skin.　The present invention provides: a composition containing 1-piperidinepropionic acid and Geranium thunbergii; a composition for accelerating MSMO1 expression; and a composition for improving skin luster.

Description

Composition containing 1-piperidinepropionic acid and Geranium herb

[0001] The present invention provides compositions, particularly compositions comprising 1-piperidinepropionic acid and Geranium herb.

[0002] Maintaining healthy skin is important from the perspective of beauty and other aspects, but various skin problems can occur due to aging and various external factors. For example, it has been reported that skin cholesterol decreases due to aging, ultraviolet rays, etc. (Non-Patent Documents 1 and 2). These factors can impair moisture retention, barrier function, skin luster, etc. A wide variety of ingredients are being explored to address various skin problems.

[0003] For example, 1-piperidinepropionic acid is known to suppress the production of SCCA-1, which is frequently expressed in patients with psoriasis and atopy and is known to induce parakeratosis (Patent Document 1). 1-Piperidinepropionic acid is also known to have effects such as inhibiting matrix metalloproteinases (MMPs) and promoting the production of laminin 5 (Patent Document 2). Furthermore, it has been reported that 1-piperidinepropionic acid, when combined with pyridinecarboxamide, has a skin whitening effect (Patent Document 3).

[0004] Furthermore, Geraniol (Geranium thunbergii) is known to be effective in regulating the intestines, preventing diarrhea, and treating gastric weakness, loss of appetite, and indigestion when taken orally; to be effective in treating rashes, chilblains, swelling, and the like when applied topically; to have anti-photoaging properties, granzyme B inhibitory effects, and JAK (Janus kinase) inhibitory effects (Patent Documents 4 to 6).

[0005] Japanese Patent No. 5300302 Japanese Patent Application Laid-Open No. 2012-240911 Japanese Patent Publication No. 2020-529399 Japanese Patent No. 7040833 Japanese Patent Application Laid-Open No. 6988016 Japanese Patent Application Laid-Open No. 2022-41762

[0006] J Invest Dermatol. 2000 Feb;114(2):247-52. doi: 10.1046 / j.1523-1747.2000.00875.x.Skin Res Technol. 2014 Nov;20(4):409-15. doi: 10.1111 / srt.12132. Epub 2014 Feb 12.Sci Rep. 2016 Jun 23;6:28462. doi: 10.1038 / srep28462

[0007] The object of the present invention is to provide a composition that provides beneficial effects to the skin.

[0008] As a result of extensive research, the present inventors have found that combining 1-piperidinepropionic acid and Geranium Herbaceum promotes MSMO1 expression, synergistically enhancing effects not seen with either ingredient alone. Based on these discoveries, the present inventors have completed the following inventions: (1) A composition comprising 1-piperidinepropionic acid and Geranium Herbaceum. (2) A composition for promoting MSMO1 expression, comprising 1-piperidinepropionic acid and Geranium Herbaceum. (3) A composition for improving skin luster, comprising 1-piperidinepropionic acid and Geranium Herbaceum. (4) The composition according to any one of (1) to (3), which is a cosmetic composition.

[0009] The composition of the present invention can synergistically enhance the effects not seen with 1-piperidinepropionic acid or Geranium Herbaceum alone. Such a combination can synergistically promote MSMO1 expression. Promotion of MSMO1 expression is expected to increase skin cholesterol, thereby improving skin tone and other favorable effects on the skin.

[0010] FIG. 1 shows the expression level of MSMO1 mRNA in keratinocytes with or without the addition of 1-piperidinepropionic acid and Geranium herb, expressed as a relative value with the expression level of the control taken as 1.0.

[0011] The present inventors have discovered that combining 1-piperidinepropionic acid with Geranium Herbaceum enhances effects not seen with either ingredient alone, such as promoting MSMO1 expression. Therefore, the present invention provides a composition comprising 1-piperidinepropionic acid and Geranium Herbaceum. Furthermore, the composition of the present invention is expected to improve skin tone by promoting MSMO1 expression. Therefore, the present invention also provides a composition for promoting MSMO1 expression and a composition for improving skin tone, each comprising 1-piperidinepropionic acid and Geranium Herbaceum.

[0012] MSMO1 (Methylsterol Monooxygenase 1) is an enzyme involved in cholesterol production (Non-Patent Document 3). It is also known that skin cholesterol decreases due to aging, UV exposure, etc., which is thought to be one of the factors that weaken intercellular lipids and impair moisturizing and barrier function (Non-Patent Documents 1 and 2). Therefore, promoting MSMO1 expression increases the production of skin cholesterol, which decreases due to aging, UV exposure, etc., thereby strengthening intercellular lipids and improving moisturizing and barrier function, which is expected to improve skin radiance. For example, when the skin surface texture is improved by increasing intercellular lipids and improving moisturizing and barrier function, the surface reflected light is reflected evenly and the internal reflected light is also spread evenly, making the skin appear more radiant and improving skin radiance.

[0013] In this specification, improvement of skin gloss refers to improvement of skin gloss by promoting MSMO1 expression in skin cells such as keratinocytes, for example, improvement of skin gloss by promoting the production of skin cholesterol through promotion of MSMO1 expression in skin cells.

[0014] In the present invention, promotion of MSMO1 expression may mean, for example, that MSMO1 expression is enhanced when the composition of the present invention is administered compared to a state in which nothing is administered (a control). For example, this means that MSMO1 expression is enhanced with a statistically significant difference (e.g., Tukey's test), or that it is enhanced by, for example, 10% or more, 20% or more, 25% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 100% or more, 200% or more, 300% or more, 400% or more, or 500% or more.

[0015] Measurement of MSMO1 expression can be determined by measuring the amount of MSMO1 mRNA or protein in a biological sample. Measurement of mRNA level can be performed using techniques known in the art, such as quantitative PCR or Northern blotting. Measurement of protein level can be performed using any technique known in the art, such as Western blotting, immunostaining, or FACS.

[0016] The 1-piperidinepropionic acid (CAS number: 26371-07-3) according to the present invention is a compound of the following general formula (I).

[0017] The 1-piperidinepropionic acid represented by the general formula (I) according to the present invention is a known substance and can be easily synthesized by known methods, or can be easily purchased as a commercially available product.

[0018] Furthermore, the 1-piperidine-propionic acid used in the composition of the present invention may be in the form of a salt. The salt of 1-piperidine-propionic acid can be converted into an inorganic salt or an organic salt, for example, by a known method. The salt used in the present invention is not particularly limited, but examples of inorganic salts include hydrochloride, sulfate, phosphate, hydrobromide, sodium salt, potassium salt, magnesium salt, calcium salt, and ammonium salt. Examples of organic salts include acetate, lactate, maleate, fumarate, tartrate, citrate, methanesulfonate, p-toluenesulfonate, triethanolamine salt, diethanolamine salt, and amino acid salt.

[0019] Geraniol (Geraniol thunbergii), also known as "Gen (Experiment) no Shoko," "Gensou," "Roukakusou," "Mikoshigusa," and "Umezuru," is a perennial herb of the genus Geraniol in the family Geraniaceae, widely distributed throughout Japan, China, and other Asian regions. Geraniol is known for its oral effects in regulating the intestines, preventing diarrhea, treating gastric weakness, loss of appetite, and indigestion, its topical effects in treating rashes, chilblains, swelling, and other skin conditions, as well as its anti-photoaging effects, granzyme B inhibitory effects, and JAK (Janus kinase) inhibitory effects (Patent Documents 4 to 6). Geraniol may be used in the form of a Geraniol extract, which is an extract obtained from the plant body, such as leaves, stems, flowers, and roots of Geraniol, particularly the above-ground parts.

[0020] The extract may be commercially available as a cosmetic ingredient or health food ingredient, or may be obtained by conventional methods. The extraction method is not particularly limited, but extraction using a solvent is preferred. The plant material can be immersed or heated under reflux with the extraction solvent at room temperature or elevated temperatures, followed by filtration and concentration. While the plant material can be used as is, crushing it into granules or powder prior to extraction allows for more efficient extraction of active ingredients under milder conditions in a shorter time. The extraction temperature is not particularly limited and can be set appropriately depending on the particle size of the crushed material, the type of solvent, and other factors. It is typically set within the range from room temperature to the boiling point of the solvent. The extraction time is also not particularly limited and can be set appropriately depending on the particle size of the crushed material, the type of solvent, and the extraction temperature. Furthermore, the extraction may be performed with or without stirring, or ultrasonic waves may be applied.

[0021] As the extraction solvent, any solvent commonly used for extraction can be used, and for example, aqueous solvents such as water, physiological saline, phosphate buffer solution, borate buffer solution, etc.; alcohols such as ethanol, propylene glycol, 1,3-butylene glycol, glycerin, etc.; organic solvents such as chloroform, dichloroethane, carbon tetrachloride, acetone, ethyl acetate, hexane, etc.; and aqueous organic solvents such as aqueous alcohols such as aqueous ethanol, aqueous propylene glycol, aqueous 1,3-butylene glycol, and aqueous glycerin, can be used alone or in combination.

[0022] As an example of the aqueous organic solvent, an aqueous lower alcohol (e.g., C1 to C4) may be used, and in this case, the water content may be, for example, 0 to 10 v / v%, 10 to 40 v / v%, 20 to 30 v / v%, 30 to 40 v / v%, 30 to 50 v / v%, 60 to 70 v / v%, 50 to 80 v / v%, 80 to 99.5 v / v%, etc.

[0023] By such an extraction procedure, the active ingredient is extracted and dissolved in the solvent. The solvent containing the extract may be used as is, or may be subjected to conventional purification treatments such as sterilization, washing, filtration, bleaching, and deodorization before use. If necessary, the extract may be concentrated by drying treatment such as freeze-drying or diluted with an arbitrary solvent before use. Furthermore, the extract may be used after volatilizing the solvent completely to obtain a solid (dried product), or after redissolving the dried product in an arbitrary solvent.

[0024] In addition, the squeezed liquid obtained by squeezing the raw plant material also contains the same active ingredients as the extract, so the squeezed liquid can also be used instead of the extract.

[0025] The composition of the present invention, the composition for promoting MSMO1 expression, and the composition for improving skin tone (hereinafter, these may be collectively referred to as "the composition of the present invention") contain 1-piperidinepropionic acid and Geranium Herb, and may also be a composition in which one or more other ingredients, such as an excipient, a carrier, and / or a diluent, are further combined.

[0026] The amounts (dry mass) of 1-piperidinepropionic acid and Geranium Herbaceum in the composition of the present invention can be appropriately determined depending on their types, purposes, forms, methods of use, etc. For example, they may be added so as to yield about 0.0001 to 100 wt%, about 0.0001 to 90 wt%, about 0.001 to 50 wt%, about 0.001 to 5.0 wt%, about 0.001 to 1.0 wt%, about 0.01 to 1.0 wt%, about 0.001 to 0.1 wt%, about 0.1 to 0.5 wt%, or about 0.01 to 0.1 wt%, based on the total weight of the composition of the present invention.

[0027] The ratio of 1-piperidinepropionic acid to Geranium Herbaceum in the composition of the present invention is arbitrary, and examples thereof include, by weight, 1-50:1-50 (=1-piperidinepropionic acid:Geranium Herbaceum extract).Various ratios can also be employed, such as 1-20:1-20, 1-10:1-10, 1-5:1-5, and 1-3:1-3 (=1-piperidinepropionic acid:Geranium Herbaceum extract).

[0028] The composition and form of the composition are arbitrary and may be appropriately selected depending on the active ingredient, intended use, and other conditions. The composition can be prepared using conventional methods by appropriately combining excipients, carriers, and / or diluents, etc., and other ingredients depending on the dosage form. In addition to the above ingredients, if necessary, ingredients commonly used in skin topicals such as cosmetics, pharmaceuticals, and quasi-drugs, such as antioxidants, oils, UV protection agents, surfactants, thickeners, alcohols, powder ingredients, colorants, aqueous ingredients, water, various skin nutrients, etc., can be appropriately blended as needed within the scope that does not impair the effects of the present invention.

[0029] The composition of the present invention may be used by humans and animals in the form of cosmetics, pharmaceuticals, quasi-drugs, etc., or may be ingested by humans and animals in the form of various foods and beverages, for example, nutritional supplements such as supplements, or may be administered to humans and animals in the form of pharmaceutical preparations, etc. The composition of the present invention may be used orally or parenterally (transdermally, intravenously, intraperitoneally, etc.) as appropriate, and may be applied by any route. However, a topical composition that is applied transdermally so as to act directly on the skin is preferred. For example, the composition of the present invention may be used as a topical composition for skin application.

[0030] In the case of a composition for external use on the skin, it can be applied as a cosmetic, quasi-drug, or the like to be applied to the outer skin, and is particularly preferably applied as a cosmetic, and its dosage form is not limited as long as it can be applied to the skin, and any dosage form can be used, such as a solution system, a solubilized system, an emulsion system, a powder dispersion system, a water-oil two-layer system, a water-oil-powder three-layer system, an ointment, a lotion, a gel, or an aerosol.

[0031] When the composition of the present invention is used as a cosmetic product, it may be used in the form of, for example, face cream, massage cream, body cream, emulsion, lotion, beauty serum, gel, pack, cleansing cream, hand cream, skin lotion, foundation, lipstick, lip balm, hand powder, body shampoo, bath cosmetics, etc. When used as an external preparation, it may be used in various forms such as lotion, suspension / emulsion, liquid, ointment, patch, etc.

[0032] However, the forms that the agent of the present invention can take are not limited to those described above, and any form, such as oral solid preparations such as tablets, granules, powders, and capsules, oral liquid preparations such as oral liquids and syrups, or parenteral liquid preparations such as injections, can be appropriately prepared by known methods.

[0033] The present invention also relates to a method for improving moisturizing, barrier function, or skin radiance by, for example, increasing skin cholesterol, by administering a combination of 1-piperidinepropionic acid and Geranium Herbaceum to a subject in need thereof. Furthermore, the present invention also relates to a method for increasing skin cholesterol by administering a combination of 1-piperidinepropionic acid and Geranium Herbaceum to a subject in need thereof. One embodiment of these methods is a method for improving moisturizing, barrier function, or skin radiance by increasing skin cholesterol through promoting MSMO1 expression, by administering a combination of 1-piperidinepropionic acid and Geranium Herbaceum to a subject in need thereof. Subjects in need thereof include, for example, subjects experiencing decreased skin cholesterol, decreased MSMO1 expression, or decreased moisturizing, barrier function, or skin radiance. The methods described herein relate to cosmetic methods for cosmetic purposes and are distinguishable from medical procedures performed by doctors or medical professionals. Such cosmetic methods may be performed privately or at beauty salons, cosmetics stores, esthetic salons, etc.

[0034] Furthermore, the present invention provides use of a combination of 1-piperidinepropionic acid and Geranium Herbaceum in the manufacture of a medicament for increasing skin cholesterol or improving moisturizing, barrier function, or skin tone.The present invention also provides a combination of 1-piperidinepropionic acid and Geranium Herbaceum for use in increasing skin cholesterol or improving moisturizing, barrier function, or skin tone by promoting MSMO1 expression.

[0035] All documents mentioned herein are incorporated by reference in their entirety.

[0036] The following examples of the present invention are for illustrative purposes only and do not limit the technical scope of the present invention. The technical scope of the present invention is limited only by the claims. The present invention may be modified, for example, by adding, deleting, or substituting components of the present invention, provided that the modifications do not depart from the spirit of the present invention.

[0037] Experiment 1: Sample Preparation Geranium Herb extract was prepared by extracting the aerial parts of Geranium Herb. This Geranium Herb extract was added to the following medium to a final concentration of 0.1% (w / w). 1-Piperidinepropionic acid was a commercially available product (CAS number: 26371-07-3).

[0038] Experiment 2: Promotion of MSMO1 expression by the combination of 1-piperidinepropionic acid and Geranium Herb extract (Culture of epidermal keratinocytes) Commercially available normal neonatal skin-derived keratinocytes (NHEK (NB), Kurabo) were cultured at 5 x 10 ５ The cells were seeded into a T75 flask at 100 cells / flask and incubated at 37°C in 5% CO in a keratinocyte medium (Humedia-KG2, Kurabo). ２ The keratinocytes were cultured under atmospheric conditions until they reached semi-confluence and used as seed cells. The keratinocytes were harvested by trypsinization and placed in a 24-well plate at 12 × 10 ４ The cells were seeded at 100 cells / well and incubated at 37°C in 5% CO in a keratinocyte medium (Humedia-KG2, Kurabo). ２ The next day, the cells were cultured in a 1.8 mM CaCl ２The medium was replaced with a keratinocyte medium containing ２ The cells were cultured under atmospheric conditions for 2 days to induce cell differentiation.

[0039] (Sample addition) 1.8 mM CaCl ２ To a medium for keratinocytes containing 1-piperidinepropionic acid and / or Geranium Herbaceum extract from Experiment 1, 1 / 1000 (v / v) of the sample was added, either singly or together, to prepare media (mediums 1 to 3) so that the concentration of each sample in the medium was 0.1% by weight. Table 1 below shows the amount of 1-piperidinepropionic acid and Geranium Herbaceum extract added to each medium. These media were cultured at 37°C and 5% CO ２ The epidermal keratinocytes that had been subjected to the above-mentioned differentiation induction were continued to be cultured under the atmosphere.

[0040] (Extraction of RNA from Cells) Twenty-four hours after the addition of each sample, the medium was removed, and cells were lysed and RNA was extracted using a commercially available RNA extraction reagent (RNeasy Mini Kit, Qiagen).

[0041] (Evaluation of MSMO1 expression levels by quantitative PCR) Using the extracted RNA as a template, cDNA was synthesized using a commercially available cDNA synthesis reagent (SuperScript® VILO™ cDNA Synthesis Kit, Invitrogen). Then, quantitative PCR was performed using a PCR reagent (Platinum™ SYBR™ Green qPCR SuperMix-UDG w / ROX, Invitrogen) and a quantitative PCR device (StepOnePlus, Applied Biosystems) to measure the expression level of the MSMO1 gene. The expression level of the RPL13A gene, which has a nearly constant expression level as an internal standard, was also measured simultaneously. The MSMO1 expression level was normalized by dividing it by the expression level of the internal standard RPL13A.

[0042] The PCR primer sequences used are listed below: RPL13A-Fw: 5'-CCTGGAGGAGAAGAGGAAAGAGA-3' (SEQ ID NO: 1) RPL13A-Rv: 5'-TTGAGGACCTCTGTGTATTTGTCAA-3' (SEQ ID NO: 2) MSMO1-Fw: 5'-CGGCCGTTCAGGATAAGCC-3' (SEQ ID NO: 3) MSMO1-Rv: 5'-TGACTGCACAACCAAAGCATC-3' (SEQ ID NO: 4)

[0043] (Statistical Analysis) To verify the significance of the mean values ​​among the four groups, one-way analysis of variance was performed using the data obtained by quantitative PCR, followed by Tukey's test (n=5).

[0044] Results: The results are shown in Figure 1. The MSMO1 expression levels shown in Figure 1 are relative values, with the MSMO1 expression level when cultured in control medium being set at 1.0. As shown in Figure 1, in Medium 1 and Medium 2, which contained either 1-piperidinepropionic acid or Geranium Herbaceum extract alone, the MSMO1 expression level was almost unchanged compared to the control, but in Medium 3, which contained both 1-piperidinepropionic acid and Geranium Herbaceum extract, the expression level was 28.6% higher than the control, demonstrating a significant increase. This confirmed the synergistic effect of the combination of 1-piperidinepropionic acid and Geranium Herbaceum extract.

Claims

1. A composition comprising 1-piperidinepropionic acid and Geranium Herb.

2. A composition for promoting MSMO1 expression, comprising 1-piperidinepropionic acid and Geranium Herb.

3. A composition for improving skin tone, comprising 1-piperidinepropionic acid and Geranium Herb.

4. The composition according to any one of claims 1 to 3, which is a cosmetic composition.

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