WO2014203885A1 - Promoteur de production de collagène - Google Patents

Promoteur de production de collagène Download PDF

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Publication number
WO2014203885A1
WO2014203885A1 PCT/JP2014/066004 JP2014066004W WO2014203885A1 WO 2014203885 A1 WO2014203885 A1 WO 2014203885A1 JP 2014066004 W JP2014066004 W JP 2014066004W WO 2014203885 A1 WO2014203885 A1 WO 2014203885A1
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WO
WIPO (PCT)
Prior art keywords
lipocalin
collagen production
production promoter
collagen
degradation product
Prior art date
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PCT/JP2014/066004
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English (en)
Japanese (ja)
Inventor
高野　義彦
晴彦 加藤
宏 上野
敏也 小林
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雪印メグミルク株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
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Publication of WO2014203885A1 publication Critical patent/WO2014203885A1/fr

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
    • A23L2/52—Adding ingredients
    • A23L2/66—Proteins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A61K38/1722—Plasma globulins, lactoglobulins
    • 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
    • A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
    • 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
    • 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
    • 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
    • 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

Definitions

  • the present invention relates to a collagen production promoter useful for preventing rough skin, wrinkles, reduced elasticity, reduced joint function, etc., a drink supplement for promoting collagen production, a food, and a cosmetic for promoting collagen production. More specifically, the present invention relates to a collagen production promoter comprising as an active ingredient a lipocalin family protein or a lipocalin family protein degradation product obtained by degrading the lipocalin family protein.
  • Macroscopic causes of dryness and rough skin include a decrease in metabolism due to aging.
  • actions such as sunlight (ultraviolet rays), drying, and oxidation are involved in complicated causes of dry skin and rough skin.
  • the tension retention mechanism such as the firmness and elasticity of the skin maintained by the collagen fibers is destroyed by the decrease of the collagen fibers, and the skin becomes wrinkled and sagging.
  • Collagen also has a function of retaining moisture, and helps to keep the skin moist. When collagen is destroyed by external factors, the skin becomes dry and rough.
  • OA osteoarthritis
  • the blood circulation around the joints deteriorates and the supply of oxygen decreases, thereby reducing the production of collagen and proteoglycans by chondrocytes, and dead chondrocytes stimulate the synovium and inflammation Cause pain in the joints.
  • the release of cytokines during inflammation induces chondrocyte death and intensifies pain symptoms.
  • Symptomatic treatment of OA includes administration of pain relievers and anti-inflammatory preparations, injection of high molecular hyaluronic acid (sodium hyaluronate) into the joint cavity, and the like.
  • Lipocalin 2 (LCN2) and ⁇ -lactoglobulin are proteins belonging to the lipocalin family having eight ⁇ -barrel structures.
  • Lipocalin 2 (LCN2) also called human neutrophil gelatinase-binding lipocalin (NGAL)
  • NGAL human neutrophil gelatinase-binding lipocalin
  • Lipocalin 2 secreted from the liver has an antibacterial action by selectively binding to diderophore-Fe3 + to inhibit bacterial iron utilization and growth.
  • lipocalin 2 in plasma and blood can be used as a marker for inflammation and infection
  • lipocalin 2 in urine can be used as a marker for malignant tumors such as breast cancer.
  • Lipocalin 2 is known to be also contained in milk, but it has been reported that it is more contained in colostrum than in mature milk.
  • ⁇ -lactoglobulin is the major whey protein in milk. It has the ability to bind hydrophobic substances such as retinol, which is a useful physiologically active substance, and has excellent functional properties (emulsifying property, gelling property, foaming property).
  • the present invention provides a collagen production promoter that can be easily ingested in daily life, and a collagen production promotion supplement, food and drink, and a cosmetic for promoting collagen acid production, containing such substances. It is an issue to provide.
  • the present inventors diligently searched for a substance exhibiting a skin collagen production promoting action, and found that the lipocalin family protein or a lipocalin family protein obtained by degrading the lipocalin family protein.
  • the degradation product has been found to increase the amount of collagen production in the skin, and the present invention has been completed. That is, the present invention includes the following aspects.
  • a collagen production promoter comprising a lipocalin family and / or a lipocalin family degradation product as an active ingredient.
  • the collagen production promoter according to (1), wherein the lipocalin family and / or lipocalin family degradation product is lipocalin 2 and / or lipocalin 2 degradation product.
  • a supplement containing the collagen production promoter according to any one of claims 1 to 6. A food or drink comprising the collagen production promoter according to any one of claims 1 to 6. (9) A cosmetic comprising the collagen production promoting agent according to any one of claims 1 to 6.
  • a collagen production promoter having improved safety can be provided by using a lipocalin family protein and / or a lipocalin family protein degradation product as an active ingredient.
  • the collagen production promoter of the present invention is characterized in that lipocalin 2 and / or lipocalin 2 degradation product obtained by degrading lipocalin 2 with a proteolytic enzyme is an active ingredient.
  • the lipocalin 2 of the present invention can be used from any origin.
  • the lipocalin 2 derived from human and bovine has already been clarified in gene sequence and can be produced by gene recombination, but in the present invention, lipocalin 2 produced by genetic engineering techniques can also be used.
  • cells derived from the cell culture medium can also be used. Lipocalin 2 is contained in bovine colostrum and may be recovered from milk.
  • the lipocalin 2 degradation product is a peptide mixture obtained by limiting degradation of lipocalin 2 with a proteolytic enzyme such as trypsin, pancreatin, chymotrypsin, pepsin, papain, kallikrein, cathepsin, thermolysin, and V8 protease to a molecular weight of 8,000 or less. It is possible to use. However, the lower limit of the molecular weight is preferably 300 or more.
  • the collagen production promoter of the present invention exhibits an effect of promoting collagen production by oral administration or application.
  • the active ingredient lipocalin 2 or lipocalin 2 degradation product can be used as it is, but in accordance with conventional methods, powders, granules, tablets, capsules In addition, it can be formulated into a drink or the like.
  • oral preparations such as powders, granules, tablets and capsules are formulated by conventional methods using excipients such as starch, lactose, sucrose, mannitol, carboxymethylcellulose, corn starch, and inorganic salts.
  • a binder a disintegrant, a surfactant, a lubricant, a fluidity promoter, a colorant, a fragrance, and the like may be used as appropriate in addition to the excipient.
  • the binder include starch, dextrin, gum arabic, gelatin, hydroxypropyl starch, sodium carboxymethylcellulose, methylcellulose, crystalline cellulose, ethylcellulose, and polyvinylpyrrolidone.
  • the disintegrant include , Starch, hydroxypropyl starch, carboxymethylcellulose, sodium carboxymethylcellulose, crosslinked sodium carboxymethylcellulose, crystalline cellulose and the like.
  • lipocalin 2 and lipocalin 2 degradation products can be blended in nutrients, foods and drinks, etc. as they are or after preparation. Since lipocalin 2 or a lipocalin 2 degradation product is relatively stable to heat, it is possible to heat sterilize the raw material containing the lipocalin 2 or the lipocalin 2 degradation product under conditions that are usually performed.
  • the collagen production promoter of the present invention When applying the collagen production promoter of the present invention, it can be prepared into various dosage forms such as liquids, solids and semi-solids by blending with commonly used known ingredients according to the purpose of use. Possible and preferred compositions include ointments, gels, creams, sprays, patches, lotions, powders and the like.
  • the collagen production promoter of the present invention is a hydrocarbon such as petrolatum, a higher fatty acid lower alkyl ester such as stearyl alcohol, isopropyl myristate, an animal fat such as lanolin, a polyhydric alcohol such as glycerin, a glycerin fatty acid ester, a monostearin
  • a hydrocarbon such as petrolatum, a higher fatty acid lower alkyl ester such as stearyl alcohol, isopropyl myristate, an animal fat such as lanolin, a polyhydric alcohol such as glycerin, a glycerin fatty acid ester, a monostearin
  • the effective amount of the collagen production promoter of the present invention by oral administration is appropriately defined according to the formulation form, administration method, purpose of use, and age, weight, and medical condition of the patient to which it is applied, but rats are used.
  • lipocalin 2 and / or lipocalin 2 degradation products show a collagen production promoting effect when ingested at least 10 ⁇ g per kg of rat body weight. Therefore, according to the extrapolation method, ingestion of lipocalin 2 and / or lipocalin 2 degradation product of 10 ⁇ g or more per adult per day can be expected to promote collagen production. What is necessary is just to mix
  • the effective amount by application of the collagen production promoter of the present invention varies depending on the dosage form, but is preferably lipocalin 2 and / or lipocalin so that it is preferably 0.001 to 2% by weight based on the total amount of the composition to be applied. What is necessary is just to mix
  • a column packed with 3,000 g of S Sepharose cake is thoroughly washed with deionized water, passed through 10,000 L of skimmed milk, washed thoroughly with deionized water, and then a straight line of 0.1 to 1.0 M sodium chloride. Elute with a gradient. Thereafter, the eluted fraction containing lipocalin 2 was fractionated again by phenyl S Sepharose hydrophobic column chromatography. Furthermore, this fraction was sequentially treated with C4 and C8 reverse phase chromatography and gel filtration chromatography using an HPLC system to obtain 2400 mg of lipocalin (fraction A). In addition, the lipocalin 2 obtained in this way can be used as a collagen production promoter as it is.
  • Example 1 Fraction A 25 mg obtained in Example 1 was suspended in 100 ml of water, pancreatin was added to a final concentration of 1%, and enzyme treatment was performed at 37 ° C. for 5 minutes to 6 hours. And after heat-processing at 90 degreeC for 5 minute (s), the enzyme was deactivated, it lyophilized
  • the average molecular weight of the lipocalin 2 degradation product thus obtained was about 8,000 for B, about 500 for C, and about 300 for D.
  • fraction A obtained in Example 1 25 mg was suspended in 100 ml of water, pepsin was added so that the final concentration was 0.01%, the pH was adjusted to 2 to 3, and then 12 ° C at 37 ° C. After carrying out enzyme treatment for a time and adjusting the pH to 8, trypsin was added so that the final concentration was 0.01%, and the enzyme treatment was carried out at 37 ° C. for 12 hours. And after heat-processing at 90 degreeC for 5 minute (s) and deactivating an enzyme, it lyophilized
  • Example 1 About the sample A obtained in Example 1, and the samples B thru
  • a 7-week-old Wistar male rat was obtained in the physiological saline-administered group (control group), the sample A obtained in Example 1 was administered in 10 ⁇ g per kg body weight of the rat (Group A-1), and in Example 1.
  • the amount of collagen in the skin was determined according to the following procedure. Rat dermis was treated according to the method of Nimni et al. (See Arch. Biochem.
  • hydroxyproline is a special amino acid contained only in collagen and accounts for about 10% of all amino acids constituting the collagen, so the amount of collagen was estimated (see Takashi Asano et al., Bio Industry, p. 12, 2001). The results are shown in Table 1.
  • Example 2 Experiments using sample A obtained in Example 1 and samples B, C, and D obtained in Example 2 using a normal human fibroblast cell line [CCD45SK (ATCCRL 1506) collected from white female skin] Thus, the collagen production promoting action was examined.
  • a modified Eagle's medium MEM, 10-101, manufactured by Dainippon Pharmaceutical Co., Ltd.
  • FBS fetal bovine serum
  • the amount of human procollagen type I C-terminal peptide (PIP) in the culture broth thus obtained was measured as a collagen amount using a measurement kit Procollagen Type I C-peptide (PIP) EIA kit (Takara Bio). The result is shown in FIG.
  • lipocalin 2 promotes collagen production in the sample to which NGAL was added as compared with the control because the amount of collagen was significantly increased.
  • a beverage for promoting collagen production having the composition shown in Table 3 was produced by a conventional method.
  • the flavor of the produced beverage was good and there were no problems such as precipitation.
  • a dough having the composition shown in Table 4 was prepared and molded by a conventional method, and then baked to produce a biscuit for promoting collagen production.
  • a collagen production promoter having the composition shown in Table 5 was produced by a conventional method.
  • a lotion having the composition shown in Table 6 was produced by a conventional method.
  • a cream having the composition shown in Table 7 was produced by a conventional method.
  • Example 4 Using the lotion obtained in Example 6 and the cream obtained in Example 7, an actual use test was conducted.
  • a comparative product the same formulation as in Examples 6 and 7 was used except that lipocalin 2 and / or lipocalin 2 degradation product was excluded.
  • the skin lotion of the present invention is significantly improved in dry feeling, rough skin, etc., and excellent in promoting collagen production, compared with the skin lotion of the comparative product.
  • the cream of the present invention also has an improvement in dry feeling and a marked improvement in rough skin, as compared with the comparative cream, and has been found to have an effect of suppressing natural deterioration such as rough skin.
  • Test Example 5 For 20 patients with mild pain due to osteoarthritis, 100 g of the beverage shown in Example 3 was drunk once a day, and a one-year clinical trial was conducted. Assess joint pain and function with the visual analog scale (VAS) for pain and the Western Ontario and McMaster Universities (WOMAC) index for pain, function and stiffness in arthritic joints It was. The results are shown in Table 9.
  • test food of the present invention is significantly improved in joint pain and function and superior in collagen production promoting effect as compared to the comparative test food.
  • the present invention relates to a collagen production promoter, a collagen production promotion supplement, a food and drink, and a collagen production promotion cosmetic useful for preventing rough skin, wrinkles, a decrease in elasticity, a decrease in joint function, and the like.

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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)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Dermatology (AREA)
  • Polymers & Plastics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nutrition Science (AREA)
  • Food Science & Technology (AREA)
  • Organic Chemistry (AREA)
  • Marine Sciences & Fisheries (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Birds (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Gerontology & Geriatric Medicine (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Cosmetics (AREA)
  • Non-Alcoholic Beverages (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)

Abstract

Dans la présente invention, une protéine de la famille de la lipocaline et/ou un produit protéolytique de la famille de la lipocaline obtenu à l'aide d'une protéase, telle que la pepsine ou la pancréatine, pour décomposer une protéine de la famille de la lipocaline est utilisée comme principe actif dans un promoteur de production d'acide hyaluronique, un promoteur de production de collagène, un aliment/boisson et un produit cosmétique favorisant la production de collagène. Cette protéine de la famille de la lipocaline et/ou ce produit protéolytique de la famille de la lipocaline a l'effet d'accroître la quantité de collagène.
PCT/JP2014/066004 2013-06-17 2014-06-17 Promoteur de production de collagène WO2014203885A1 (fr)

Applications Claiming Priority (2)

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JP2013126530A JP6259209B2 (ja) 2013-06-17 2013-06-17 コラーゲン産生促進剤
JP2013-126530 2013-06-17

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Families Citing this family (7)

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Publication number Priority date Publication date Assignee Title
JP6259208B2 (ja) * 2013-06-17 2018-01-10 雪印メグミルク株式会社 ヒアルロン酸産生促進剤
JP6259207B2 (ja) * 2013-06-17 2018-01-10 雪印メグミルク株式会社 エラスチン産生促進剤
WO2016147907A1 (fr) * 2015-03-13 2016-09-22 サントリーホールディングス株式会社 Boisson non alcoolisée ayant le goût de la bière
JP6647832B2 (ja) * 2015-03-13 2020-02-14 サントリーホールディングス株式会社 ノンアルコールのビールテイスト飲料
JP2016216436A (ja) * 2015-05-18 2016-12-22 株式会社ファンケル 皮膚粘弾性向上剤
JP6489486B2 (ja) * 2017-01-20 2019-03-27 富比積生物科技股▲分▼有限公司 ペンタペプチド／ヘキサペプチドにより変形性関節症を治療するための新規用途
JP6489487B2 (ja) * 2017-01-20 2019-03-27 富比積生物科技股▲分▼有限公司 テトラペプチド−３ ｇｅｋｇまたはペンタペプチド−３ ｇｅｋｇｆにより変形性関節症を治療するための新規用途

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JP2003533205A (ja) * 2000-05-12 2003-11-11 レキシコン・ジェネティクス・インコーポレーテッド 新規ヒトリポカリン相同体およびそれをコードするポリヌクレオチド
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WO2011144756A1 (fr) * 2010-05-21 2011-11-24 Xl-Protein Gmbh Polypeptides biosynthétiques en pelote statistique de proline/alanine et leurs utilisations
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JP6259208B2 (ja) * 2013-06-17 2018-01-10 雪印メグミルク株式会社 ヒアルロン酸産生促進剤
JP6259207B2 (ja) * 2013-06-17 2018-01-10 雪印メグミルク株式会社 エラスチン産生促進剤

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JP2003533205A (ja) * 2000-05-12 2003-11-11 レキシコン・ジェネティクス・インコーポレーテッド 新規ヒトリポカリン相同体およびそれをコードするポリヌクレオチド
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WO2011144756A1 (fr) * 2010-05-21 2011-11-24 Xl-Protein Gmbh Polypeptides biosynthétiques en pelote statistique de proline/alanine et leurs utilisations
WO2013080911A1 (fr) * 2011-11-30 2013-06-06 株式会社明治 Composition nutritionnelle pour améliorer la flore intestinale

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