WO2013132873A1 - ヒアルロン酸合成酵素遺伝子の発現促進剤 - Google Patents
ヒアルロン酸合成酵素遺伝子の発現促進剤 Download PDFInfo
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- WO2013132873A1 WO2013132873A1 PCT/JP2013/001531 JP2013001531W WO2013132873A1 WO 2013132873 A1 WO2013132873 A1 WO 2013132873A1 JP 2013001531 W JP2013001531 W JP 2013001531W WO 2013132873 A1 WO2013132873 A1 WO 2013132873A1
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- WO
- WIPO (PCT)
- Prior art keywords
- hyaluronic acid
- acid synthase
- synthase gene
- gene expression
- present
- Prior art date
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- 230000035945 sensitivity Effects 0.000 description 1
- 239000000344 soap Substances 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
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- 239000004299 sodium benzoate Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
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- 239000004328 sodium tetraborate Substances 0.000 description 1
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- 238000005063 solubilization Methods 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
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- 210000000434 stratum corneum Anatomy 0.000 description 1
- 235000019408 sucralose Nutrition 0.000 description 1
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 description 1
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- 229940099259 vaseline Drugs 0.000 description 1
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Images
Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/01—Hydrocarbons
- A61K31/015—Hydrocarbons carbocyclic
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
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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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
- A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
- A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/336—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having three-membered rings, e.g. oxirane, fumagillin
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- A—HUMAN NECESSITIES
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- 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
- A61K8/31—Hydrocarbons
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- A—HUMAN NECESSITIES
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- 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
- A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
- A61K8/37—Esters of carboxylic acids
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- A—HUMAN NECESSITIES
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- 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
- A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
- A61K8/41—Amines
- A61K8/411—Aromatic amines, i.e. where the amino group is directly linked to the aromatic nucleus
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- A—HUMAN NECESSITIES
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- 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
- A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
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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
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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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
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K2800/74—Biological properties of particular ingredients
- A61K2800/78—Enzyme modulators, e.g. Enzyme agonists
Definitions
- the present invention relates to a hyaluronic acid synthase gene expression promoter.
- Hyaluronic acid is a high-molecular polysaccharide present in the skin (epidermis and dermis), cartilage, joint fluid, etc., retains moisture in the cell gap, and retains cells based on the formation of a jelly-like matrix in the tissue. It has many functions such as maintaining the lubricity and flexibility of tissues, resistance to external forces such as mechanical failure, and prevention of bacterial infection.
- Hyaluronic acid is present in large amounts in the skin and has a very high ability to retain moisture, and is deeply involved in the freshness, firmness and elasticity of the skin. As the amount of hyaluronic acid decreases with age, the skin It is said that skin aging phenomena such as wrinkles and sagging appear.
- hyaluronic acid is blended into cosmetics and the like to maintain moisture and tension skin, and hyaluronic acid is replenished from the outside.
- hyaluronic acid is given from the surface of the skin, The development of drugs that promote hyaluronic acid synthesis in the skin is drawing attention.
- hyaluronic acid In the healing process after burn injury, hyaluronic acid is known to increase significantly in the granulation during the period from the beginning of the granulation tissue growing from below the necrotic tissue until the entire tissue is replaced with granulation tissue. (Non-patent Document 1), hyaluronic acid production promoters are also expected as an early treatment for burns.
- Cactus fruit juice obtained from fruits of plants belonging to the genus Opuntia, plant of Amla (Phyllanthus emblica) or extract thereof, plant of Manga ginger (Curcuma amada ROXB.) Or extract thereof Have been reported to promote hyaluronic acid production in human dermal fibroblasts (Patent Documents 1 and 2).
- Hyaluronic acid is contained in the stratum corneum, epidermis and dermis in the skin, and three types of hyaluronic acid synthases (HAS1, HAS2, HAS3) have been reported as enzymes involved in human hyaluronic acid synthesis. ing.
- hyaluronic acid produced by these hyaluronic acid synthases has various molecular weights ranging from about 10 3 Da to 10 7 Da, and exhibits various biological or physical properties depending on the molecular weight. It has been known.
- hyaluronic acid synthase 2 HAS2
- HAS2 hyaluronic acid synthase 2
- hyaluronic acid synthase gene especially hyaluronic acid synthase 2 gene (Has2), which contributes to the production of high molecular hyaluronic acid, thereby preventing skin aging (retaining skin elasticity and elasticity) ), Prevention and improvement of moisturization, arthritis, etc., early treatment of burns, etc. It is possible to effectively prevent or ameliorate various symptoms, illnesses, etc. that benefit from the promotion of hyaluronic acid production. Accordingly, there is still a strong demand for the development of a new drug that can be used in a wide range of applications and can effectively promote the expression of the hyaluronic acid synthase gene.
- Has2 hyaluronic acid synthase 2 gene
- an object of the present invention is to provide a novel drug that can promote the expression of a hyaluronic acid synthase gene.
- the present inventor succeeded in inducing a circadian rhythm of expression of a hyaluronic acid synthase gene in cultured human skin fibroblasts, and further evaluated in the system at a time when the gene expression level is high.
- the hyaluronic acid synthase gene expression promoting effect of substances can be evaluated with high sensitivity.
- the present inventors have found that ⁇ -caryophyllene, caryophyllene oxide, and methyl benzoate (methylbenzoate) derivatives can promote the expression of hyaluronic acid synthase gene, and have completed the present invention. It was.
- the hyaluronic acid synthase gene expression promoter of the present invention contains, as an active ingredient, one or more selected from the group consisting of ⁇ -caryophyllene, caryophyllene oxide, and a compound having the following structural formula: X is CH 3 , NH 2 or NHCH 3 .
- HAS1, HAS2, and HAS3 exist as human hyaluronic acid synthase, but high molecular hyaluronic acid with high moisturizing power is mainly produced by HAS2. Therefore, the hyaluronic acid synthase gene expression promoter of the present invention is HAS2. It is preferable to promote the expression of the gene (Has2).
- the hyaluronic acid synthase gene expression promoter of the present invention can be used in various forms such as pharmaceuticals, quasi-drugs, cosmetics, foods, miscellaneous goods, clothing, etc., and enhances hyaluronic acid synthase gene expression safely and effectively.
- Various symptoms that benefit from the promotion of hyaluronic acid production such as prevention of skin aging (retention of skin elasticity and elasticity), moisturizing, moisturizing, prevention and improvement of arthritis, etc., as well as early treatment of burns Alternatively, the disease can be treated or improved.
- the hyaluronic acid synthase gene expression promoter of the present invention contains ⁇ -caryophyllene, caryophyllene oxide, or the above methyl benzoate (methylbenzoate) derivative as an active ingredient. These compounds are all known compounds, but will be briefly described below.
- ⁇ -caryophyllene (4, 11, 11-trimethyl-8-methylene bicyclo [7.2.0] undecene) is a sesquiterpene having a molecular weight of 204.36 represented by the following structural formula. It has been separated. Naturally, it is known to exist in clove oil, copaiba oil, lavender oil and the like.
- Caryophyllene oxide ((1R, 4R, 6R, 10S) -4,12,12-trimethyl-9-methylene-5-oxatricyclo [8.2.0.04,6] dodecane) has a molecular weight of 220.
- 35 sesquiterpenes can be synthesized by monoepoxidation of ⁇ -caryophyllene with peracid. It is known to exist naturally in clove oil, lavender oil and the like.
- methyl 2-methylbenzoate which is a methyl benzoate derivative used in the present invention, is a colorless liquid having a molecular weight of 150.18.
- Methyl 2-aminobenzoate is a liquid having a molecular weight of 151.17.
- Methyl 2-methylaminobenzoate is a colorless liquid having a molecular weight of 165.2 and is known to exist naturally in orange peel, mandarin oil, and the like.
- the hyaluronic acid synthase gene expression promoter of the present invention contains one or more of the above compounds.
- the compound may be naturally derived or synthesized.
- the hyaluronic acid synthase gene expression promoter of the present invention may be used alone or in combination with other agents having a hyaluronic acid synthase gene expression promoting action.
- hyaluronic acid synthase gene expression promoter of the present invention may be used alone, but can be included in various objects. Depending on the type of the object, optional components can be further included in addition to the essential components.
- the object when the object is an external preparation for skin, its dosage form (for example, liquid, powder, granule, aerosol, solid, gel, patch, suppository, etc.) or product form (for example, Depending on cosmetics, pharmaceuticals, quasi drugs, etc., any component usually contained in such an external preparation for skin may be included together with the hyaluronic acid synthase gene expression promoter.
- the topical skin preparation is a concept that encompasses all compositions applied to the skin (including the scalp, hair, and nails). For example, basic cosmetics, makeup cosmetics, hair cosmetics, skin or hair cleansing agents, etc. Cosmetics, ointments, patches, suppositories, various drugs such as dentifrices and quasi drugs.
- the dosage form is not particularly limited.
- an aqueous solution system a solubilization system, an emulsification system, an oil liquid system, a gel system, a paste system, an ointment system, an aerosol system, a water-oil two-layer system, a water-oil-powder 3
- the skin external preparation is a cosmetic, for example, perfume, eau de toilette, eau de cologne, cream, milky lotion, lotion, foundations, powdered white powder, lipstick, soap, shampoo / rinse, body shampoo, body rinse, body powder And bath agents.
- any miscellaneous goods such as fragrance, deodorant, aroma candle, incense, stationery, wallet, bag, shoes, etc.
- any clothing such as underwear, clothes, hats, stockings, socks, etc.
- the hyaluronic acid synthase gene expression promoter of the present invention can be included in any form of supplements (nutritional supplements) such as powders, granules, tablets, capsules, confectionery, beverages, etc., and inhalation It may be used in inhalation products such as pharmaceuticals and space sprays.
- hyaluronic acid synthase gene expression promoter of this invention is not limited to these, As long as the effect of this invention can be achieved, it can be used in arbitrary aspects.
- other drugs having a hyaluronic acid production promoting action can be added according to specific embodiments as long as the effects of the present invention are not impaired. .
- the amount of the hyaluronic acid synthase gene expression promoter of the present invention in the object can be appropriately selected depending on the type and form of the compound used, the object, etc., and is not particularly limited.
- the total mass of the object On the other hand, it is 0.00001 to 100% by mass, more preferably 0.0001 to 50% by mass, and still more preferably 0.0001 to 20% by mass.
- the specific application of the hyaluronic acid synthase gene expression promoter of the present invention and the object containing the hyaluronic acid synthase gene expression promoter is not particularly limited.
- skin aging prevention skin elasticity and elasticity retention
- moisturizing it can be used for prevention and improvement of various symptoms and diseases that can benefit from promotion of hyaluronic acid production, such as prevention and improvement of arthritis, early treatment of burns, etc.
- circadian rhythm of hyaluronic acid synthase gene expression was confirmed that circadian rhythm of hyaluronic acid synthase gene (hHas2) expression can be induced in cultured human skin fibroblasts .
- glucocorticoids such as cortisol are involved in the regulation of biological clocks in peripheral tissues and the like, and it is considered that cortisol blood concentration rises when waking up in the morning and resets the biological clock.
- cortisol blood concentration rises when waking up in the morning and resets the biological clock.
- individual cells usually have rhythms at different timings, but circadian rhythm can also be induced in cultured cells by stimulation with a signal stimulating factor such as cortisol.
- FIG. 2 shows the relative expression level of the hHas2 gene 16 hours after the addition of the test substance.
- Table 1 below shows the relative expression level of the hHas2 gene after 16 hours.
- ⁇ -caryophyllene, caryophyllene oxide, methyl 2-methylbenzoate, methyl 2-methylaminobenzoate, and methyl aminobenzoate both significantly increased the expression level of the hHas2 gene compared to the control It was shown that these compounds can promote the expression of the hyaluronic acid synthase gene.
- Aromatic fiber A microcapsule (particle diameter of 50 ⁇ m or less, microcapsule containing a Has gene expression promoter of the present invention in a cupro ammonium cellulose solution (cellulose concentration 10% by weight, ammonium concentration 7% by weight, copper concentration 3.6% by weight). (The ratio of the compound in the capsule is 50% by weight) within a range of 0.1 to 20% by weight with respect to the cellulose weight, and after mixing, spinning according to the usual wet spinning method, through the refining process and the drying process Obtained aromatic fiber.
- Granule (1) Sucralose 0.1 (2) Has gene expression promoter of the present invention: ⁇ -caryophyllene 0.1 (3) Has gene expression promoter of the present invention: methyl 2-methylbenzoate 0.1 (3) Flavoring 5.0 (4) Excipient (Theolus) 10.0 (5) Maltitol residual
- the products of these formulation examples can enhance the production of hyaluronic acid by promoting the expression of the hyaluronic acid synthase gene by a use test in a typical usage mode of each product form.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Birds (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Emergency Medicine (AREA)
- Dermatology (AREA)
- Immunology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Rheumatology (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cosmetics (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2012053460A JP5487227B2 (ja) | 2012-03-09 | 2012-03-09 | ヒアルロン酸合成酵素遺伝子の発現促進剤 |
| JP2012-053460 | 2012-03-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2013132873A1 true WO2013132873A1 (ja) | 2013-09-12 |
Family
ID=49116362
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/JP2013/001531 WO2013132873A1 (ja) | 2012-03-09 | 2013-03-08 | ヒアルロン酸合成酵素遺伝子の発現促進剤 |
Country Status (3)
| Country | Link |
|---|---|
| JP (1) | JP5487227B2 (ja") |
| TW (1) | TW201340987A (ja") |
| WO (1) | WO2013132873A1 (ja") |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP4241768A4 (en) * | 2020-11-06 | 2024-10-09 | Kinki University | COMPOSITION FOR THE TREATMENT OF VASCULAR DISEASE, COMPOSITION FOR THE PREVENTION OF VASCULAR DISEASE, COMPOSITION FOR THE TREATMENT OF HYPERTENSION AND COMPOSITION FOR THE PREVENTION OF HYPERTENSION |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112107563B (zh) * | 2020-10-19 | 2021-07-23 | 中国科学院动物研究所 | 一种影响人和动物对冷感知的化合物及其应用 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011122041A1 (ja) * | 2010-03-31 | 2011-10-06 | 株式会社 資生堂 | 時計遺伝子Periodの発現調節剤 |
-
2012
- 2012-03-09 JP JP2012053460A patent/JP5487227B2/ja active Active
-
2013
- 2013-03-08 TW TW102108386A patent/TW201340987A/zh unknown
- 2013-03-08 WO PCT/JP2013/001531 patent/WO2013132873A1/ja active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011122041A1 (ja) * | 2010-03-31 | 2011-10-06 | 株式会社 資生堂 | 時計遺伝子Periodの発現調節剤 |
Non-Patent Citations (1)
| Title |
|---|
| YOKO AIZU ET AL.: "Hito Hifu Baiyo Saibo o Mochiita Tokei Idenshi Sayo Busshitsu no Tansaku", ABSTRACTS OF 132TH ANNUAL MEETING OF PHARMACEUTICAL SOCIETY OF JAPAN, vol. 3, 5 March 2012 (2012-03-05), pages 93 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP4241768A4 (en) * | 2020-11-06 | 2024-10-09 | Kinki University | COMPOSITION FOR THE TREATMENT OF VASCULAR DISEASE, COMPOSITION FOR THE PREVENTION OF VASCULAR DISEASE, COMPOSITION FOR THE TREATMENT OF HYPERTENSION AND COMPOSITION FOR THE PREVENTION OF HYPERTENSION |
Also Published As
| Publication number | Publication date |
|---|---|
| JP5487227B2 (ja) | 2014-05-07 |
| TW201340987A (zh) | 2013-10-16 |
| JP2013184953A (ja) | 2013-09-19 |
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