WO2020246468A1 - 動物細胞の細胞賦活剤 - Google Patents
動物細胞の細胞賦活剤 Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
- A61K8/4966—Triazines or their condensed derivatives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/16—Emollients or protectives, e.g. against radiation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/18—Antioxidants, e.g. antiradicals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/007—Preparations for dry skin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/08—Anti-ageing preparations
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/0018—Culture media for cell or tissue culture
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0625—Epidermal cells, skin cells; Cells of the oral mucosa
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- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0625—Epidermal cells, skin cells; Cells of the oral mucosa
- C12N5/0629—Keratinocytes; Whole skin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/74—Biological properties of particular ingredients
- A61K2800/78—Enzyme modulators, e.g. Enzyme agonists
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/74—Biological properties of particular ingredients
- A61K2800/78—Enzyme modulators, e.g. Enzyme agonists
- A61K2800/782—Enzyme inhibitors; Enzyme antagonists
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- C12N2500/00—Specific components of cell culture medium
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- C12N2501/00—Active agents used in cell culture processes, e.g. differentation
- C12N2501/999—Small molecules not provided for elsewhere
Definitions
- the present invention relates to a cell activator for animal cells.
- the skin is a tissue composed of the epidermis and dermis, and functions as a barrier to protect the body from physical and chemical stress from the outside world.
- the epidermis and dermis are separated by the basement membrane, and the epidermis is in contact with the outside world.
- the epidermis is composed of four layers, a basal layer, a spinous layer, a stratum granulosum, and a stratum corneum, from the basement membrane side, and is mainly composed of epidermal keratinocytes (keratinocytes). Epidermal keratinocytes that have divided in the basal layer migrate to the outer layer through differentiation and maturation, reach the outermost stratum corneum, then shed and repeat turnover.
- the epidermis has a barrier function due to the outermost stratum corneum and a barrier function due to the tight junction of the stratum granulosum inside the stratum corneum.
- Epidermal turnover is involved in the barrier function of the skin and the retention of water content. Therefore, if the turnover of epidermal keratinocytes differentiation, maturation, migration, and shedding is delayed due to aging or external stress, it causes rough skin and dry skin.
- the dermis inside the epidermis has capillaries, secretory glands (sweat glands, sebaceous glands), hair follicles, and nerves, and plays a role of nourishing the epidermis and receiving information from the epidermis.
- the dermis is divided into a papillary layer and a reticular layer.
- collagen fibers form dense stitches, accompanied by an elastic fiber network.
- the combination of collagen fibers and elastic fibers gives the skin strength, stretchability and elasticity. Between the fiber bundles, there are fibroblasts, macrophages, mast cells, plasma cells, dermal dendritic cells, etc. that produce collagen fibers and elastic fibers.
- the dermis contains a gel-like substrate containing proteoglycans (hyaluronic acid, chondroitin sulfate, dermatan sulfate, etc.), proteins, and minerals.
- proteoglycans hyaluronic acid, chondroitin sulfate, dermatan sulfate, etc.
- proteins and minerals.
- Proteoglycans have the ability to bind to water.
- Patent Documents 1 to 4 Conventionally, in the fields of skin cosmetics and skin medicines, many studies have been conducted to activate skin cells themselves to produce improvement of skin symptoms, anti-inflammatory effect or wound healing effect, and various skin cell activators have been used. It is provided (for example, Patent Documents 1 to 4).
- Japanese Unexamined Patent Publication No. 2011-148742 Japanese Unexamined Patent Publication No. 2013-194008 International Publication No. 2015/015816 Japanese Unexamined Patent Publication No. 2016-37470
- An object of the present invention is to provide a new cell activator capable of activating animal cells, particularly skin cells.
- 3H-imidazo [4,5-d] [1,2,3] triazine-4,6 (5H, 7H) -dione (also known as: It has been found that 2-aza-8-oxo-hypoxanthine (hereinafter, sometimes referred to as "AOH”) has an action of activating animal cells, particularly skin cells.
- the present invention is as follows.
- [1] A cell activator for animal cells containing 3H-imidazole [4,5-d] [1,2,3] triazine-4,6 (5H, 7H) -dione.
- [2] The cell activator according to [1], wherein the animal cell is a skin cell.
- [3] Skin metabolism promoter, skin wound healing promoter, skin anti-aging agent, skin anti-aging agent, skin anti-wrinkle agent, skin barrier function improving agent, skin moisturizing agent, skin elasticity improving agent, skin
- the cell activator according to [2] which is at least one selected from the group consisting of a dullness improving agent, a rough skin improving agent and a skin whitening agent, preferably a skin moisturizing agent.
- a method for culturing an animal cell or tissue which comprises a step of adding the cell activator according to claim [8] to the cultured cell or tissue.
- a method for activating animal cells which comprises administering 3H-imidazole [4,5-d] [1,2,3] triazine-4,6 (5H, 7H) -dione to a subject.
- the method according to [10] which is a method for activating skin cells.
- 3H-Imidazo [4,5-d] [1,2,3] Triazine-4,6 (5H, 7H) -Dione, including administration of skin metabolism promoting method, skin wound healing promoting method, Skin aging prevention method, skin aging improvement method, skin wrinkle prevention method, skin barrier function improvement method, skin moisturizing method, skin elasticity improvement method, skin dullness improvement method, skin roughness improvement method or skin whitening method , Preferably a method of moisturizing the skin.
- animal cells particularly skin cells
- skin cells can be activated.
- the cell growth promoter of the animal cells of the present invention includes AOH, that is, 3H-imidazole [4,5-d] [1,2,3] triazine-4,6 (5H, 7H) -dione (also known as: 2). -Aza-8-oxo-hypoxanthine) is contained.
- AOH is a compound represented by the following formula (I).
- AOH is a compound known to have a plant growth-regulating effect (International Publication No. 2012/147750, hereinafter referred to as "Reference 1").
- AOH can be produced, for example, by the method described in Reference 1.
- a plant hormone that is a precursor of AOH 7H-imidazole [4,5-d] [1,2,3] triazine-4 (3H) -one (also known as 2-azahypoxanthine, in the following cases)
- AOH can be obtained by allowing xanthine oxidase to act on (referred to as "AHX").
- AHX xanthine oxidase to act on
- AOH can also be obtained by applying AHX to a plant and isolating the AOH produced as an AHX metabolite from the plant body.
- the cells targeted by the cell activator of the present invention are animal cells.
- the cell activator of the present invention is preferably applied directly to living animals. Examples of the target animal include humans and mammals other than humans, but humans are preferable. Mammals other than humans include, for example, mice, rats, guinea pigs, hamsters, rabbits, cats, dogs, sheep, pigs, cows, horses, goats, and monkeys.
- the tissues or organs in which animal cells are present include, for example, skin, muscle, bone, joint, fat, brain, spinal cord, digestive organ, reproductive organ, endocrine organ, respiratory organ, circulatory system, immune system, bone, joint and Examples thereof include adipose tissue, and among these, skin is preferable.
- the cell activator of the present invention exerts an effect on skin cells.
- the cells of the skin include cells constituting the epidermis and the dermis, and among these, cells constituting the epidermis are preferable.
- Examples of cells constituting the epidermis include epidermal keratinocytes (keratinocytes), pigment cells (melanocytes), Langerhans cells, and Merkel cells, and among these, epidermal keratinocytes are preferable.
- the cells constituting the epidermis are preferably cells existing in the basal layer, the spinous layer, the stratum granulosum or the stratum corneum of the epidermis.
- Examples of cells constituting the dermis include fibroblasts, macrophages, mast cells, plasma cells, and dermis dendritic cells, and among these, fibroblasts are preferable.
- the cells constituting the dermis are preferably cells existing in the papillary layer or the reticular layer of the dermis.
- the application sites include, for example, the scalp, face (forehead, cheeks, lips, nose, ears), neck, shoulders, back, chest, abdomen, genitals, arms, It can be applied to any surface of the body, including hands, lower limbs, feet, nails and hair.
- the cell activating agent of the present invention has a cell activating effect by containing AOH. That is, the active ingredient of the cell activator of the present invention is AOH. Specific examples of the cell activating effect of the cell activating agent of the present invention include a cell proliferation effect and an effect of enhancing expression of various genes. On the other hand, the cell activator of the present invention has low cytotoxicity. Therefore, the cell activator of the present invention is highly safe and suitable for application to a living body.
- the cell activator of the present invention When applied to the skin of animals, the cell activator of the present invention acts on the cells constituting the epidermis and / or the dermis, and exhibits a cell proliferation effect and various gene expression enhancing effects.
- genes related to cell-cell adhesion function, barrier function, stratum corneum exfoliation function, differentiation function, moisturizing function, and whitening function are included in the gene group whose expression is enhanced. Is included. Therefore, the cell activator of the present invention promotes skin metabolism, promotes skin wound healing, prevents skin aging, improves skin aging, prevents skin wrinkles, improves skin barrier function, moisturizes skin, and improves skin elasticity.
- the cell activator of the present invention is a skin metabolism promoter, a skin wound healing promoter, a skin antiaging agent, a skin antiaging agent, a skin wrinkle inhibitor, a skin barrier function improving agent, and a skin moisturizing agent. It can be used as at least one selected from the group consisting of a skin elasticity improving agent, a skin dullness improving agent, a rough skin improving agent and a skin whitening agent.
- the shape of the cell activator of the present invention is not particularly limited, and may be any shape such as solid, liquid (solution or suspension), emulsified form such as emulsion or cream, paste, gel, mousse form or the like. ..
- the cell activator of the present invention can be used as a cosmetic, a pharmaceutical product, or a quasi-drug.
- the dosage form of the cell activator as a pharmaceutical product is not particularly limited, and for example, an aerosol agent, a liquid agent, a suspension agent, an emulsion, a cream agent, an ointment agent, a gel agent, a liniment agent, a lotion agent, a pap agent, a tape agent, and an eye drop.
- an aerosol agent for example, an aerosol agent, a liquid agent, a suspension agent, an emulsion, a cream agent, an ointment agent, a gel agent, a liniment agent, a lotion agent, a pap agent, a tape agent, and an eye drop.
- examples thereof include agents, nasal drops, ear drops, suppositories, elixirs, capsules, granules, pills, scattered, tablets, syrups, injections, troches and the like.
- When used as a drug for the skin it is preferably an external preparation.
- the dosage form is an aerosol agent, a liquid agent, a suspension agent, an emulsion, a cream agent, an ointment agent, a gel agent, a liniment agent, a lotion agent, a poultice agent, a tape agent or the like.
- the form of the cell activator as a non-medicinal product or cosmetic is not particularly limited, and for example, lotion, milky lotion, cream, gel, beauty liquid, sunscreen cosmetic, pack, hand cream, foot cream, body lotion, etc.
- Basic cosmetics such as body cream; cleaning cosmetics such as wash pigments, makeup removers, soaps, body shampoos, shampoos, rinses, conditioners, and light removers; foundations, makeup bases, lip creams, lipsticks, teak colors, eye colors , Makeup cosmetics such as eyebrows, manicure, hair color; antiperspirants; bathing agents; perfume; nutritional functional foods, foods with functional claims, foods for specified health use, foods and drinks such as special purpose foods.
- the quasi-drugs or cosmetics as external preparations are preferably quasi-drugs and cosmetics in the form excluding foods and drinks among the above.
- the cell activator of the present invention may contain a base or carrier usually used in cosmetics, pharmaceuticals or quasi-drugs, and various additives as necessary.
- Additives include, for example, excipients, oils, powders, buffers, solubilizers, antioxidants, surfactants, thickeners, preservatives, pH regulators, chelating agents, stabilizers. , Irritation reducing agents, preservatives, pigments, coloring agents, fragrances, gloss-imparting agents, gelling agents, alcohols, water-soluble polymers, film-forming agents, resins, keratolytic agents and the like.
- the base, carrier and various additives can be used alone or in combination of two or more, if necessary.
- the cell activator of the present invention may contain an active ingredient other than AOH as long as the effect as the cell activator is not impaired.
- active ingredients other than AOH include moisturizing ingredients, anti-inflammatory ingredients, antibacterial ingredients, cell activating ingredients, antiaging ingredients, blood circulation promoting ingredients, UV protection ingredients, whitening ingredients, vitamins, proteins, peptides, etc. Examples include amino acids and alcohols. These active ingredients may be used alone or in combination of two or more, if necessary.
- the cell activator of the present invention can be produced by a method well known to those skilled in the art by blending AOH and, if necessary, other components described above. Further, the concentration and content of AOH contained in the cell activator of the present invention can be appropriately set by those skilled in the art according to the administration target, dosage form, use, desired effect and the like of the cell activator. For example, the cell activator of the present invention may contain 0.0001 to 5% by mass, preferably 0.001 to 1% by mass, and more preferably 0.01 to 0.5% by mass of AOH.
- the number of administrations, the dose, and the administration method of the cell activator of the present invention can be appropriately set by those skilled in the art according to the administration target, dosage form, use, target effect, and the like of the cell activator.
- the administration method is preferably skin administration such as application or affixing to the skin.
- the cell activator of the present invention may be used as a cosmetic, a drug or a quasi drug having a cell activating effect by itself, but the cell activator of the present invention may be applied to a cosmetic, a drug or a quasi drug. It may be added for the purpose of adding the function of the cell activator. That is, the cell activator of the present invention can also be used as a raw material for cosmetics, pharmaceuticals or quasi-drugs. For example, the cell activator of the present invention may be blended with an external preparation applied directly to the skin, for example, an insect repellent.
- the cell activator of the present invention may be a reagent. Since the cell activator of the present invention can effectively activate animal cells, it can be used as a reagent for experiments or studies using animal cells. Such experiments or studies may be in vitro or in vivo.
- a reagent for cell culture or a reagent for tissue culture can be mentioned.
- the cells targeted by the cell culture reagent include the animal cells described above in the same manner.
- the tissue or organ targeted by the tissue culture reagent the tissue or organ in which animal cells are present as described above can be similarly mentioned.
- the cell activator of the present invention may be applied directly to a living animal, or may be applied in vitro to cells isolated from an animal or cultured cells derived from an animal. it can. Such cells may be fusion cells such as normal cells, cancer cells, stem cells, hybridomas and the like. These cells can be activated by the cell proliferation action and the gene expression enhancing action of the cell activator of the present invention.
- the present invention also provides a method for culturing an animal cell or tissue, which comprises the step of adding the above-mentioned cell activator to the cultured cell or tissue.
- a method for culturing an animal cell or tissue which comprises the step of adding the above-mentioned cell activator to the cultured cell or tissue.
- Example 1 Skin irritation test
- the skin irritation test is a protocol published by the OECD Test Guidelines (No. 439) and the European Center for the Validation of Alternate Methods (ECVAM). It was carried out according to CHEMICALS.
- This skin irritation test uses a regenerated human epidermal (RhE) model (human-derived non-transformed epidermal keratinocytes as a cell source) designed to closely resemble biochemical and physiological properties in human epidermis.
- RhE human epidermal
- the cell viability of the RhE model to which the test substance was locally applied using the organized basal layer, spinous layer, granular layer, and stratum corneum was determined by the skin irritation of the test substance. It is an index.
- the cell viability of the RhE model was measured by the MTT method.
- the vital dye MTT (3- (4,5-dimethylthiazole-2-yl) -2,5-diphenyltetrazolium bromide, thiazolyl blue) is reduced to blue formazan by an enzymatic reaction of living cells.
- the cell viability is measured by quantifying blue formazan using. If the cell viability of the RhE model is higher than a predetermined value, the applied test substance can be judged to be non-irritating.
- SkinEthic TM- RHE was incubated in growth medium for 24 hours and transferred to maintenance medium. 10 ⁇ L of sterile purified water was added dropwise from the epidermis side to homogenize, and then 16 mg of a test sample was added from above. Further, PBS ( ⁇ ) was used as a negative (non-irritating) control, and a 5% SDS aqueous solution was used as a positive (irritating) control, and 16 ⁇ L was exposed from the epidermis side and a nylon film was applied from above.
- the test sample was immediately removed from the epidermis model by a washing operation and cultured in a fresh growth medium for another 42 hours. After culturing, the epidermis model was transferred to a maintenance medium containing 1.0 mg / mL MTT and cultured for 3 hours. Then, the epidermis model was immersed in isopropanol for 2 hours to extract blue formazan in the epidermis model, and the absorbance of the extract at 570 nm was measured with a microplate reader. The same treatment was performed on the epidermis model exposed to the negative control and the positive control, and the absorbance was measured.
- Example 2 Epidermal cell activating action
- HuMedia KG2 medium HuMedia KB2 medium
- KB2 HuMedia KB2 medium
- AOH and AHX (2-azahypoxanthine) were used as test samples
- KG2 was treated instead of the test sample as a positive control (PC) for cell activation
- untreated sample cells were used as a negative control. ..
- the cells were replaced with KB2 containing 0.2 mg / mL MTT and cultured for 1 hour.
- the absorbance at 550 nm and 650 nm of the cell lysate in which 2-propanol was added to lyse the cells was measured.
- the amount of MTT reduced to blue formazan was determined by subtracting the absorbance at 650 nm, which is derived from cell turbidity, from the absorbance at 550 nm.
- the epidermal keratinocyte activation effect was shown as Index (%), which is a percentage of the absorbance of the test sample-treated cells to the absorbance of the sample-untreated cells (negative control), using the amount of MTT reduction as an index.
- Example 3 Microarray test
- AOH was found to be less toxic to cells than AHX, but rather to promote cell proliferation. Therefore, in Example 3, the factors that promote cell proliferation were verified by microarray. did.
- Table 2 shows typical changes in gene expression in the microarray analysis results.
- Table 2 if the value is larger than 1, gene expression is increased, and if the p value is smaller than 0.05, it can be determined that there is a significant change with respect to the control (indicated by * in the table).
- AOH treatment varied the expression of some genes in a concentration-dependent manner. It showed a significant increase in gene expression of claudin 1 (CLDN1), desmocollin 1 (DSC1), desmoglein 1 (DSG1) and E-cadherin (CDH1) involved in cell-cell adhesion / barrier function.
- CLDN1 claudin 1
- DSC1 desmocollin 1
- DSG1 desmoglein 1
- CDH1 E-cadherin
- FN1 fibronectin
- the raw materials of component A in Table 3 were mixed and dissolved.
- the raw materials of component B were mixed, heated and dispersed, and added to component C.
- the C component to which the B component was added and the A component were mixed to prepare a lotion.
- Example 5 Long-term continuous use test
- a test double blind test was performed to evaluate the amount of keratin water and the amount of transepidermal water evaporation (TEWL). Twenty-two subjects (female, average age 48.4 ⁇ 4.68 years old) were asked to apply Toner A on half face and Toner B on half face after washing their faces twice in the morning and evening. I continued for 8 weeks. At the start of the test, 4 weeks and 8 weeks later, the keratin water content and TEWL were measured.
- the water content of the stratum corneum and TEWL in the left and right cheeks of the subject were measured using SKICON-200EX (Yayoi Co., Ltd.) and Cyclone Moisture Evaporator AS-CT1 (Nippon Ash Co., Ltd.), respectively. Two subjects whose left-right difference in keratin water content at the start of the test was 150 ⁇ S or more were excluded, and 20 subjects were used as effective subjects to analyze the test results.
- Table 4 shows the average value of the relative values after 4 weeks and 8 weeks, assuming that the keratin water content and TEWL before the start of use are 100.
- the keratin water content after 4 weeks was significantly increased in the keratin water content before the start of use in the group to which the lotion containing AOH was applied (p ⁇ 0.05)
- the TEWL after 8 weeks was significantly reduced as compared with the TEWL before the start of use (p ⁇ 0.05). From these results, it was confirmed that AOH has a moisturizing effect on the skin.
Abstract
Description
[1]
3H-イミダゾ[4,5-d][1,2,3]トリアジン-4,6(5H,7H)-ジオンを含有する、動物細胞の細胞賦活剤。
[2]
動物細胞が皮膚の細胞である、[1]に記載の細胞賦活剤。
[3]
皮膚の新陳代謝促進剤、皮膚創傷治癒促進剤、皮膚の老化防止剤、皮膚の老化改善剤、皮膚のしわ防止剤、皮膚のバリア機能改善剤、皮膚用保湿剤、皮膚の弾力改善剤、皮膚のくすみ改善剤、肌荒れ改善剤及び皮膚用美白剤からなる群から選択される少なくとも一種、好ましくは皮膚用保湿剤である、[2]に記載の細胞賦活剤。
[4]
化粧品である、[1]~[3]のいずれかに記載の細胞賦活剤。
[5]
医薬品又は医薬部外品である、[1]~[3]のいずれかに記載の細胞賦活剤。
[6]
外用剤である、[1]~[5]のいずれかに記載の細胞賦活剤。
[7]
試薬である、[1]又は[2]に記載の細胞賦活剤。
[8]
細胞培養用又は組織培養用の試薬である、[7]に記載の細胞賦活剤。
[9]
請求項[8]に記載の細胞賦活剤を培養細胞又は培養組織に添加する工程を含む、動物細胞又は動物組織の培養方法。
[10]
3H-イミダゾ[4,5-d][1,2,3]トリアジン-4,6(5H,7H)-ジオンを対象に投与することを含む、動物細胞の賦活方法。
[11]
皮膚の細胞の賦活方法である、[10]に記載の方法。
[12]
3H-イミダゾ[4,5-d][1,2,3]トリアジン-4,6(5H,7H)-ジオンを対象に投与することを含む、皮膚の新陳代謝促進方法、皮膚創傷治癒促進方法、皮膚の老化防止方法、皮膚の老化改善方法、皮膚のしわ防止方法、皮膚のバリア機能改善方法、皮膚の保湿方法、皮膚の弾力改善方法、皮膚のくすみ改善方法、肌荒れ改善方法又は皮膚の美白方法、好ましくは皮膚の保湿方法。
[13]
動物細胞の細胞賦活剤の製造における、3H-イミダゾ[4,5-d][1,2,3]トリアジン-4,6(5H,7H)-ジオンの使用。
[14]
動物細胞が皮膚の細胞である、[13]に記載の使用。
[15]
皮膚の新陳代謝促進剤、皮膚創傷治癒促進剤、皮膚の老化防止剤、皮膚の老化改善剤、皮膚のしわ防止剤、皮膚のバリア機能改善剤、皮膚用保湿剤、皮膚の弾力改善剤、皮膚のくすみ改善剤、肌荒れ改善剤及び皮膚用美白剤からなる群から選択される少なくとも一種、好ましくは皮膚用保湿剤の製造における、3H-イミダゾ[4,5-d][1,2,3]トリアジン-4,6(5H,7H)-ジオンの使用。
[16]
動物細胞の賦活方法に使用するための、3H-イミダゾ[4,5-d][1,2,3]トリアジン-4,6(5H,7H)-ジオン。
[17]
動物細胞が皮膚の細胞である、[16]に記載の3H-イミダゾ[4,5-d][1,2,3]トリアジン-4,6(5H,7H)-ジオン。
[18]
皮膚の新陳代謝促進方法、皮膚創傷治癒促進方法、皮膚の老化防止方法、皮膚の老化改善方法、皮膚のしわ防止方法、皮膚のバリア機能改善方法、皮膚の保湿方法、皮膚の弾力改善方法、皮膚のくすみ改善方法、肌荒れ改善方法又は皮膚の美白方法、好ましくは皮膚の保湿方法に使用するための、3H-イミダゾ[4,5-d][1,2,3]トリアジン-4,6(5H,7H)-ジオン。
本発明の動物細胞の細胞増殖促進剤には、AOH、すなわち、3H-イミダゾ[4,5-d][1,2,3]トリアジン-4,6(5H,7H)-ジオン(別名:2-アザ-8-オキソ-ヒポキサンチン)が含有される。AOHは、下記式(I)で表される化合物である。
本発明の細胞賦活剤が対象とする細胞は、動物細胞である。本発明の細胞賦活剤は、生きている動物に対して直接適用することが好ましい。対象となる動物としては、ヒト及びヒト以外の哺乳類を挙げることができるが、ヒトが好ましい。ヒト以外の哺乳類としては、例えば、マウス、ラット、モルモット、ハムスター、ウサギ、ネコ、イヌ、ヒツジ、ブタ、ウシ、ウマ、ヤギ、サルが挙げられる。
真皮を構成する細胞としては、例えば、繊維芽細胞、マクロファージ、肥満細胞、形質細胞、真皮樹状細胞が挙げられ、この中でも繊維芽細胞であることが好ましい。真皮を構成する細胞は、真皮の乳頭層又は網状層に存在する細胞であることが好ましい。
本発明の細胞賦活剤は、AOHを含有することにより、細胞賦活作用を有する。すなわち、本発明の細胞賦活剤の有効成分はAOHである。本発明の細胞賦活剤の細胞賦活作用として具体的には、細胞増殖作用及び各種遺伝子発現の増強作用が挙げられる。一方で、本発明の細胞賦活剤は、細胞毒性が低い。したがって、本発明の細胞賦活剤は、安全性が高く、生体への適用にも適している。
医薬品としての細胞賦活剤の剤型は特に限定されず、例えば、エアゾール剤、液剤、懸濁剤、乳剤、クリーム剤、軟膏剤、ゲル剤、リニメント剤、ローション剤、パップ剤、テープ剤、点眼剤、点鼻剤、点耳剤、坐剤、エリキシル剤、カプセル剤、顆粒剤、丸剤、散在、錠剤、シロップ剤、注射剤、トローチ剤等が挙げられる。皮膚用の医薬品として用いる場合は、外用剤であることが好ましい。外用剤とすることにより、皮膚の細胞にAOHが直接作用し、より強く効果を発揮することができる。外用剤としては、エアゾール剤、液剤、懸濁剤、乳剤、クリーム剤、軟膏剤、ゲル剤、リニメント剤、ローション剤、パップ剤、テープ剤等の剤型であることが好ましい。
医薬部外品又は化粧品としての細胞賦活剤の形態は特に限定されず、例えば、化粧水、乳液、クリーム、ジェル、美容液、日焼け止め用化粧料、パック、ハンドクリーム、フットクリーム、ボディローション、ボディークリーム等の基礎化粧料;洗顔料、メイク落とし、石鹸、ボディーシャンプー、シャンプー、リンス、コンディショナー、除光液等の洗浄用化粧料;ファンデーション、化粧下地、リップクリーム、口紅、チークカラー、アイカラー、眉墨、マニキュア、ヘアカラー等のメークアップ化粧料;制汗剤;入浴剤;香水;栄養機能食品、機能性表示食品、特定保健用食品、特別用途食品等の飲食品等が挙げられる。皮膚用の医薬部外品又は化粧品として用いる場合も、医薬品同様、外用剤であることが好ましい。外用剤とすることにより、皮膚の細胞にAOHが直接作用し、より強く効果を発揮することができる。外用剤としての医薬部外品又は化粧品は、上記挙げた中で飲食品を除く形態の医薬部外品及び化粧品であることが好ましい。
本発明の細胞賦活剤には、化粧品、医薬品又は医薬部外品に通常使用される基剤又は担体、及び必要に応じて各種添加剤が含まれていてもよい。添加剤としては、例えば、賦形剤、油剤類、粉体類、緩衝材、溶解補助剤、酸化防止剤、界面活性剤、増粘剤、保存剤、pH調整剤、キレート剤、安定化剤、刺激軽減剤、防腐剤、顔料、着色剤、香料、光沢付与剤、ゲル化剤、アルコール類、水溶性高分子、皮膜形成剤、樹脂、角質溶解剤等を挙げることができる。基剤、担体及び各種添加剤は、必要に応じて、一種又は複数種を組み合わせて用いることができる。
本発明の細胞賦活剤は、細胞賦活剤としての効果を損なわない範囲で、AOH以外の有効成分を含むことができる。AOH以外の有効成分の具体例としては、例えば、保湿成分、抗炎症成分、抗菌成分、細胞賦活化成分、老化防止成分、血行促進成分、紫外線防御成分、美白成分、ビタミン類、タンパク質、ペプチド、アミノ酸、アルコール類等が挙げられる。これらの有効成分は必要に応じて、一種又は複数種を組み合わせて用いることができる。
皮膚刺激性試験を、OECDテストガイドライン(No.439)及びEuropean Centre for the Validation of Alternative Methods(ECVAM)により公開されているプロトコルである、SKINETHIC SKIN IRRITATION TEST、TEST METHOD FOR THE PREDICTION OF ACUTE SKIN IRRITATION OF CHEMICALSに準じて実施した。この皮膚刺激性試験は、ヒトの表皮に、生化学的・生理学的特性に極めて類似するよう設計された再生ヒト表皮(RhE)モデル(ヒト由来の非形質転換表皮角化細胞を細胞源として使用し、組織化された基底層、有棘層、顆粒層、角質層から構成される。)を用い、被検物質を局所塗布したRhEモデルの細胞生存率を、被検物質の皮膚刺激性の指標とするものである。RhEモデルの細胞生存率は、MTT法により測定した。MTT法では、生体染色色素であるMTT(3-(4,5-ジメチルチアゾール-2-イル)-2,5-ジフェニルテトラゾリウムブロミド、チアゾリルブルー)が生細胞の酵素反応によりブルーホルマザンへ還元される性質を利用して、ブルーホルマザンを定量することにより細胞生存率を測定する。RhEモデルの細胞生存率が所定の値より高ければ、塗布した被検物質は非刺激性と判断できる。
また、陰性(非刺激性)コントロールとしてPBS(-)、陽性(刺激性)コントロールとして5%SDS水溶液を用い、それぞれ表皮側から16μLを暴露し、上からナイロン膜を適用した。
細胞生存率は、陰性コントロールを暴露した皮膚モデルの吸光度に対する試験試料を曝露した皮膚モデルの吸光度の百分率で表した。結果は、陰性コントロールであるPBS(-)を処理した皮膚モデルの細胞生存率を100%として、陽性コントロールである5%SDSを処理した皮膚モデルの細胞生存率が1.2%、AOHを処理した皮膚モデルの細胞生存率は100%であった。したがって、AOHは非刺激性と判定された。
正常ヒト表皮角化細胞をHuMedia KG2培地(KG2)を用いて、5.0×103細胞/ウェルの密度にて96穴プレートに播種した。播種24時間後、試験試料を含有するHuMedia KB2培地(KB2)に交換した。試験試料として、AOH及びAHX(2-アザヒポキサンチン)を用い、細胞賦活作用の陽性コントロール(P.C.)として試験試料の代わりにKG2を処理し、陰性コントロールとして試料未処理細胞を用いた。48時間培養後、0.2mg/mLのMTTを含有するKB2に交換し、1時間培養した。培地を除去したのち、2-プロパノールを添加して細胞を溶解させた細胞溶解液の550nmおよび650nmにおける吸光度を測定した。550nmにおける吸光度から細胞濁度に由来する650nmにおける吸光度を差し引き、MTTがブルーホルマザンへ還元される量を求めた。表皮角化細胞賦活作用を、MTT還元量を指標とし、試料未処理細胞(陰性コントロール)の吸光度に対する試験試料処理細胞の吸光度の百分率、Index(%)として示した。
試験結果を表1に示した。表1中、AOH処理細胞は、7.8から31.3μg/mLの濃度において、Indexの有意な増加を示し、生細胞が増殖することが示唆された。一方、AHX処理細胞は、AOH処理細胞のような増殖効果がなく、31.3μg/mL以上の濃度においては有意に減少し、Indexの減少の割合もAOH処理細胞に比べて大きかった。これらの結果より、AOHはAHXより細胞毒性が低く、細胞賦活作用があることが判明した。
実施例1及び2から、AOHがAHXとは異なり、細胞に対して毒性が低く、むしろ細胞増殖を促進する効果が認められたことから、実施例3ではマイクロアレイにて細胞増殖を促す要因を検証した。
マイクロアレイの解析結果において、遺伝子発現の変化を示した代表的なものを表2に示した。表2中、値が1より大きければ遺伝子発現が上昇しており、p値が0.05より小さければコントロールに対して有意な変化があると判定できる(表中に*で示した。)。AOH処理により、いくつかの遺伝子発現が濃度依存的に変動した。細胞間接着・バリア機能に関わるクローディン1(CLDN1)、デスモコリン1(DSC1)、デスモグレイン1(DSG1)及びEカドヘリン(CDH1)の有意な遺伝子発現の上昇を示した。
また、角質層剥離に関わるプロテアーゼカリクレイン5(KLK5)及びカリクレイン7(KLK7)並びにその制御剤であるセリンプロテアーゼインヒビター(SPIMK5)の有意な遺伝子発現の上昇を示した。
また、一般的な分化指標とされるケラチン1(KRT1)、ケラチン10(KRT10)、トランスグルタミナーゼ1(TGM1)及びインボルクリン(IVL)、並びにコーニファイドエンベロープ(角質細胞膜)構成タンパクであるSPRR1Bの有意な遺伝子発現の上昇を示した。
また、ヒアルロン酸合成酵素(HAS3)遺伝子発現の有意な上昇が確認された。
細胞外マトリックス関連の遺伝子群においては、フィブロネクチン(FN1)遺伝子発現の軽微な上昇が認められた。
これらの結果から、細胞へのAOH処理は、表皮のターンオーバーを促進し、分化・成熟を促し、古い角質の新陳代謝を促進し、保湿作用を高める等、広く表皮機能に作用する可能性が示唆された。
表3の組成で、以下のとおりに化粧水を作製した。
実施例4の0.1重量%のAOHを含む化粧水(化粧水B)及びAOHを含まない以外は実施例4の化粧水と同じ組成のプラセボ化粧水(化粧水A)を用いて長期連用試験(ダブルブラインド試験)を行い、角質水分量及び経表皮水分蒸散量(TEWL)の評価を行った。22名の被験者(女性、平均年齢48.4±4.68歳)に対して、朝晩2回の洗顔後に、半顔に化粧水Aを、半顔に化粧水Bを塗布してもらうことを8週間続けた。試験開始時、4週間後及び8週間後に角質水分量及びTEWLを測定した。被験者の左右頬部の角層水分量及びTEWLは、それぞれ、SKICON-200EX(株式会社ヤヨイ)及びサイクロン水分蒸散計AS-CT1(日本アッシュ株式会社)を用いて測定した。試験開始時の角質水分量の左右差が150μS以上であった2名の被験者を除外し、20名を有効被験者として試験結果の解析を行った。
AOHに関して以下の安全性試験を行ったところ、いずれも毒性は認められなかった。
変異原性試験(Ames試験)(OECD TG471)
インビトロ皮膚感作性試験(DPRA法)(OECD TG442C)
インビトロ光毒性試験(OECD TG432)
ヒトパッチテスト
Claims (10)
- 3H-イミダゾ[4,5-d][1,2,3]トリアジン-4,6(5H,7H)-ジオンを含有する、動物細胞の細胞賦活剤。
- 動物細胞が皮膚の細胞である、請求項1に記載の細胞賦活剤。
- 皮膚の新陳代謝促進剤、皮膚創傷治癒促進剤、皮膚の老化防止剤、皮膚の老化改善剤、皮膚のしわ防止剤、皮膚のバリア機能改善剤、皮膚用保湿剤、皮膚の弾力改善剤、皮膚のくすみ改善剤、肌荒れ改善剤及び皮膚用美白剤からなる群から選択される少なくとも一種である、請求項2に記載の細胞賦活剤。
- 皮膚用保湿剤である、請求項2に記載の細胞賦活剤。
- 化粧品である、請求項1~4のいずれか一項に記載の細胞賦活剤。
- 医薬品又は医薬部外品である、請求項1~4のいずれか一項に記載の細胞賦活剤。
- 外用剤である、請求項1~6のいずれか一項に記載の細胞賦活剤。
- 試薬である、請求項1又は2に記載の細胞賦活剤。
- 細胞培養用又は組織培養用の試薬である、請求項8に記載の細胞賦活剤。
- 請求項9に記載の細胞賦活剤を培養細胞又は培養組織に添加する工程を含む、動物細胞又は動物組織の培養方法。
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JP2011148742A (ja) | 2010-01-22 | 2011-08-04 | Noevir Co Ltd | 細胞賦活剤及び皮膚外用剤 |
WO2012147750A1 (ja) | 2011-04-27 | 2012-11-01 | 国立大学法人静岡大学 | イミダゾール誘導体 |
JP2013194008A (ja) | 2012-03-21 | 2013-09-30 | Cci Corp | 細胞賦活剤およびその用途 |
WO2015015816A1 (ja) | 2013-07-30 | 2015-02-05 | 森永乳業株式会社 | 繊維芽細胞賦活剤 |
JP2016037470A (ja) | 2014-08-07 | 2016-03-22 | 株式会社 資生堂 | Orai3遺伝子発現抑制剤又はORAI3タンパク質の機能抑制剤を含む細胞賦活剤 |
WO2016136508A1 (ja) * | 2015-02-23 | 2016-09-01 | 国立大学法人静岡大学 | 2-アザ-8オキソヒポキサンチンの製造方法 |
WO2019172268A1 (ja) * | 2018-03-05 | 2019-09-12 | 国立大学法人静岡大学 | 植物病害防除剤 |
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- 2020-06-02 JP JP2021524859A patent/JP7341438B2/ja active Active
- 2020-06-02 KR KR1020217038943A patent/KR20220003051A/ko not_active Application Discontinuation
- 2020-06-02 WO PCT/JP2020/021787 patent/WO2020246468A1/ja unknown
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JP2011148742A (ja) | 2010-01-22 | 2011-08-04 | Noevir Co Ltd | 細胞賦活剤及び皮膚外用剤 |
WO2012147750A1 (ja) | 2011-04-27 | 2012-11-01 | 国立大学法人静岡大学 | イミダゾール誘導体 |
JP2013194008A (ja) | 2012-03-21 | 2013-09-30 | Cci Corp | 細胞賦活剤およびその用途 |
WO2015015816A1 (ja) | 2013-07-30 | 2015-02-05 | 森永乳業株式会社 | 繊維芽細胞賦活剤 |
JP2016037470A (ja) | 2014-08-07 | 2016-03-22 | 株式会社 資生堂 | Orai3遺伝子発現抑制剤又はORAI3タンパク質の機能抑制剤を含む細胞賦活剤 |
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SUZUKI TOMOHIRO, YAMAMOTO NAOKI, CHOI JAE-HOON, TAKANO TOMOYUKI, SASAKI YOHEI, TERASHIMA YURIKA, ITO AKINOBU, DOHRA HIDEO, HIRAI H: "The biosynthetic pathway of 2-azahypoxanthine in fairy-ring forming fungus", SCIENTIFIC REPORTS, vol. 6, no. 39087, 19 December 2016 (2016-12-19), pages 1 - 10, XP055772500, DOI: 10.1038/srep39087 * |
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Publication number | Publication date |
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US20220233547A1 (en) | 2022-07-28 |
CN112955116B (zh) | 2023-10-27 |
KR20220003051A (ko) | 2022-01-07 |
JP7341438B2 (ja) | 2023-09-11 |
CN112955116A (zh) | 2021-06-11 |
EP3960244A1 (en) | 2022-03-02 |
EP3960244A4 (en) | 2023-01-25 |
JPWO2020246468A1 (ja) | 2020-12-10 |
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