WO2014175001A1 - 美白促進剤またはアトピー性皮膚炎改善剤 - Google Patents
美白促進剤またはアトピー性皮膚炎改善剤 Download PDFInfo
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- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
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- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
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- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
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Classifications
-
- 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
- A61K38/39—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K20/00—Accessory food factors for animal feeding-stuffs
- A23K20/10—Organic substances
- A23K20/142—Amino acids; Derivatives thereof
- A23K20/147—Polymeric derivatives, e.g. peptides or proteins
-
- 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
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- 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
- A61Q19/007—Preparations for dry 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
- A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/4702—Regulators; Modulating activity
- C07K14/4703—Inhibitors; Suppressors
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/78—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin or cold insoluble globulin [CIG]
Definitions
- the present invention relates to a whitening accelerator or atopic dermatitis improving agent containing a peptide or the like.
- UV rays are thought to cause skin spots and freckles.
- the process of pigmentation formation by ultraviolet rays can be roughly divided into three processes: melanocyte growth, synthesis and activation of tyrosinase, the rate-limiting enzyme of melanin synthesis, and melanosome transport from melanocytes to keratinocytes.
- cytokines that act on melanocytes in a paracrine manner from epidermal keratinocytes after UVB irradiation have contributed greatly, and so far endothelin-1 (ET-1), basic fibroblast growth factor (BFGF), ⁇ -melanocyte stimulating hormone ( ⁇ MSH), membrane-bound stem cell growth factor (SCF), nitric oxide (NO) and the like have been reported. Therefore, pigmentation can be suppressed by suppressing these cytokines, for example, by suppressing the expression of endothelin-1 (Non-patent Document 1).
- the skin is composed of the stratum corneum and the dermis layer.
- the conifer envelope which is a marginal structure, also plays an important role in the barrier function.
- the precursor protein constituting CE is expressed from the upper spinous layer to the granular layer.
- an isopeptide bond is formed between the lysine residue and glutamine residue of these proteins, thereby cross-linking and insolubilizing CE.
- existence of a pseudoisopeptide bond in which glutamine residues are formed by the interposition of polyamine is also known.
- transglutaminase transglutaminase
- TGase transglutaminase
- isozymes in TGase, and it is considered that TGase3 present in the cytoplasm and membrane-bound TGase1 play important roles in CE formation.
- Transglutaminase is responsible for cross-linking of structural proteins, and has no function of adhering proteins to each other in an undifferentiated stage where the epidermis is still deep. Therefore, there is a clever mechanism in which precursors with low activity begin to become active and work as the epidermis matures.
- Precursor proteins constituting CE include involucrin, loricrin, small proline rich protein (SPR, cornifine), cystatin A, elafin, filaggrin, keratin, emboplatin, desmosome constituent protein, skielin, annexin I, PAI-2, and the like. If these precursor proteins increase, CE also increases, and the barrier function is improved accordingly.
- filaggrin is a kind of basic protein produced in the epithelial granule cells, and improves the barrier function by forming a stratum corneum indispensable for the atopic dermatitis improving function. It plays a role in suppressing the immune response to.
- the profilagrin phosphate undergoes dephosphorylation and limited hydrolysis and is degraded to produce filaggrin.
- filaggrin is degraded to form natural moisturizing factor (NMF). Drying is also a factor that exacerbates atopic dermatitis.
- NMF moisturizing factor
- Increased filaggrin, the source of NMF, and promotion of hyaluronic acid production in the epidermis also improve moisturizing properties and improve atopic dermatitis by improving skin dryness like NMF. It is considered possible.
- transglutaminase 1 TGM1
- involucrin ivl
- keratin 10 K10
- filaggrin FLG
- filaggrin protein and moisturizing properties decrease, and therefore, the increase in filaggrin gene expression and the increase in hyaluronic acid synthase 2 gene expression contribute to the improvement of atopic dermatitis.
- Non-patent document 2 discloses that collagen synthesis is recovered to 98% and skin turnover is accelerated by about 20% by orally administering collagen to pseudo-aged mice whose collagen synthesis is suppressed to 40% of normal mice. It has been described. The result of this experiment is that collagen synthesis in the dermis layer that supports the basal layer of the skin was promoted, and the epidermal metabolism was activated in conjunction with this.
- Non-Patent Document 2 does not describe a collagen peptide mixture or the like, and does not show a whitening promoting action because it is a test using a pseudo-aged mouse in which collagen synthesis is abnormally decreased.
- Non-Patent Document 3 describes that a jellyfish-derived collagen peptide mixture has an antioxidant action and has reduced the amount of melanin.
- Non-Patent Document 3 since the experimental system of Non-Patent Document 3 was different from the test system of the present specification and the effect of the present invention could not be compared, a collagen peptide mixture of Non-Patent Document 3 was prepared as Comparative Example 24 described later. When an evaluation test was performed, it was confirmed that the test was far inferior to the effect of the present invention.
- Non-Patent Document 4 describes that deer glue has the ability to promote filaggrin expression. However, as shown in Comparative Example 26 described later, when an evaluation test was performed by purchasing deer glue, it was confirmed that the effect was far inferior to the effect of the present invention.
- Non-Patent Document 5 reports that scab-derived collagen peptides show improvement in atopic dermatitis due to the cervical dorsal score. However, as described in Comparative Example 27 described later, when a marine collagen peptide was purchased and subjected to an evaluation test, it was confirmed that it was far inferior to the effect of the present invention.
- Patent Document 1 describes an external preparation for improving skin pruritus caused by atopic dermatitis caused by a tripeptide.
- the peptide related to Patent Document 1 has a sequence different from that of the peptide related to the present invention, and the improvement of the pruritic sensation caused by atopic dermatitis, which is the application thereof, improves the essence of the atopic dermatitis itself of the present invention. Is different.
- Patent Document 2 the same collagen peptide as in Patent Document 1 is used, and itching of skin caused by atopic dermatitis, measurement of total IgE in blood, transdermal water loss (TEWL), favorable in skin The number of eosinophils and the number of mast cells are shown, and there was no significant difference in all measurement items. Moreover, as a result of purchasing these collagen peptides and simultaneously comparing them in Comparative Example 25 described later, it was confirmed that the effects were far inferior to the effects of the present invention.
- the problem to be solved by the present invention is to provide an excellent whitening promoter or atopic dermatitis remedy.
- the present inventors have found that peptides Hyp-Gly, Pro-Ala-Gly, Gly-Pro, Glu-Hyp-Gly, (Pro-Hyp-Gly) 5 , (Pro-Hyp-Gly) 2 , a peptide selected from the group consisting of Pro-Hyp-Gly, Glu-Hyp, Ala-Hyp-Gly, Ser-Hyp-Gly and Phe-Hyp has an excellent endothelin-1 expression inhibitory action, The present inventors have found that it also has an action of promoting the expression of transglutaminase 1, involucrin, keratin 10, filaggrin and hyaluronic acid synthase 2, and the present inventors have completed the present invention. That is, the present invention is as follows.
- the whitening accelerator or the atopic dermatitis improving agent according to [1] which contains a collagen peptide mixture that is contained in an amount of not less than% by weight.
- a whitening enhancer according to [1] comprising a collagen peptide mixture containing a pharmaceutically acceptable salt thereof such that the total of these peptides or pharmaceutically acceptable salts is 1.6% by weight or more.
- atopic dermatitis improving agent [4] The whitening enhancer or atopic dermatitis ameliorating agent according to any one of [1] to [3], which is administered orally or transdermally.
- these peptides promote the expression of transglutaminase 1, involucrin, keratin 10 and filaggrin, thereby promoting epidermal metabolism, promoting skin turnover, and making melanin pigments (stains) in the skin more Discharge quickly. Whitening is promoted by the above two actions.
- NMF natural moisturizing ingredient
- atopic dermatitis is a decrease in in vivo immunity.
- a collagen peptide mixture containing these peptides at a high concentration is ingested, the IgE value in the body is significantly suppressed and allergic immunity is decreased. It was observed. Atopic dermatitis is improved by the above two actions.
- Peptides used in the present invention are Hyp-Gly, Pro-Ala-Gly, Gly-Pro, Glu-Hyp-Gly, (Pro-Hyp-Gly) 5 , (Pro-Hyp-Gly) 2 , Pro-Hyp -Gly, Glu-Hyp, Ala-Hyp-Gly, Ser-Hyp-Gly and Phe-Hyp (hereinafter also referred to as the present peptide), and the peptide can be a pharmaceutically acceptable salt.
- Preferred peptides include Hyp-Gly, Pro-Ala-Gly, Gly-Pro, Glu-Hyp-Gly, (Pro-Hyp-Gly) 5 and (Pro-Hyp-Gly) 2 , more preferably Hyp- Gly and Pro-Ala-Gly. Moreover, it is also preferable to use this peptide in combination of 2 or more. It can also be used as a collagen peptide mixture containing these peptides or pharmaceutically acceptable salts thereof. In that case, those containing a total of these peptides or pharmaceutically acceptable salts thereof at 1.6% by weight or more are mentioned, preferably those containing 1.8% by weight or more, more preferably 2.0% by weight or more.
- the pharmaceutically acceptable salt of these peptides or the pharmaceutically acceptable salt thereof is 1.6% by weight or more, preferably 1.8% by weight or more, more preferably 2.0% by weight or more, further preferably
- a collagen peptide mixture containing not less than 2.3% by weight, particularly preferably not less than 2.6% by weight.
- Preferable examples include, for example, a collagen peptide mixture “Type-S” (made by Nitta Gelatin) containing 2.94% by weight of these peptides.
- Examples of the “pharmaceutically acceptable salt” include inorganic acid salts such as hydrochloride, sulfate, phosphate and hydrobromide, acetate, methanesulfonate, benzenesulfonate, and p-toluene.
- examples include organic acid salts such as sulfonate, succinate, oxalate, fumarate and maleate, inorganic base salts such as sodium salt, potassium salt and calcium salt, and organic base salts such as triethylammonium salt. It is done.
- a specific peptide can be converted into a pharmaceutically acceptable salt.
- the peptide can be synthesized from amino acids using, for example, a solid phase synthesis method or a liquid phase synthesis method (for example, JP-A No. 2003-183298).
- a solid phase synthesis method methods of Fmoc method and Boc method are further known, and this peptide may be synthesized by any method.
- An example of the solid phase synthesis method will be specifically described below.
- a polystyrene polymer gel bead having a diameter of about 0.1 mm whose surface is modified with an amino group is used as a solid phase, and diisopropylcarbodiimide is used as a condensing agent.
- the amino group of the C-terminal amino acid is protected with an Fmoc group or a Boc group to form a peptide bond with the amino group of the polystyrene polymer gel.
- the solid phase is thoroughly washed with a solvent, the remaining reagent and amino acid are washed away, and then the amino group protecting group of the amino acid bonded to the solid phase is removed.
- a peptide is synthesized on a solid phase by sequentially repeating the same reaction using an amino acid with an amino group protected.
- the peptide can be synthesized by digesting the solid phase with trifluoroacetic acid to separate the peptide from the solid phase.
- the present peptide can also be produced by hydrolyzing gelatin with a combination of two or more of endo-type protease and exo-type protease.
- the hydrolyzed collagen peptide mixture or a partially purified mixture thereof can also be used. Hydrolysis combining these two or more types, purification thereof, and the like can be performed with reference to, for example, the methods described in WO2012 / 081531, WO2012 / 102308, and the like.
- the peptide may be chemically modified.
- Chemical modification can be performed in amino acid units, and examples thereof include a hydroxyl group of hydroxyproline, an amino group of an N-terminal amino acid, and a carboxyl group of a C-terminal amino acid.
- examples of the chemical modification of the hydroxyl group of hydroxyproline include O-acetylation.
- Examples of chemical modification of the amino group of the N-terminal amino acid include polypeptidylation, succinylation, maleylation, acetylation, deamination, benzoylation, alkylsulfonylation, allylsulfonylation, dinitrophenylation, trinitrophenylation, Examples thereof include carbamylation, phenylcarbamylation, and thiolation.
- Examples of the chemical modification of the carboxyl group of the C-terminal amino acid include esterification and amidation.
- the present peptide is cationized, it can be subjected to ethylenediamine formation, spermination or the like.
- ⁇ Normal peptide chemical modification technology is applied to specific means and processing conditions for chemical modification.
- O-acetylation of the hydroxyl group of hydroxyproline can be performed by the action of acetic anhydride in an aqueous solvent or a non-aqueous solvent.
- esterification of the carboxyl group of the C-terminal amino acid can be performed by passing dry hydrogen chloride gas after suspension in methanol and the amidation can be performed by acting carbodiimide or the like.
- the chemical modification techniques described in Japanese Patent Publication No. 62-44522 and Japanese Patent Publication No. 5-79046 can be applied.
- Whitening accelerating agent or atopic dermatitis improving agent This peptide has an inhibitory action on endothelin-1 expression as described in Test Examples described later. It also has an action of promoting the expression of transglutaminase 1, involucrin, keratin 10, filaggrin and hyaluronic acid synthase 2 in the epidermis. By these two actions, melanin pigment production can be suppressed and the melanin pigment in the skin can be discharged more quickly, and can be used as a whitening promoter or an atopic dermatitis amelioration agent. As a specific application, it can be administered to subjects such as humans and mammals as pharmaceuticals, cosmetics, foods for specified health use, health foods, or contained in various foods.
- the whitening enhancer or the atopic dermatitis ameliorating agent of the present invention can be administered orally or parenterally in various forms.
- a tablet, a granule, a capsule, a powder, a liquid agent, a suspension formulation, an emulsion formulation etc. are mentioned, for example, It can also mix with food-drinks.
- parenteral administration for example, application to skin, injection, transdermal agent, suppository, nasal drop, inhalant and the like can be mentioned.
- Preferable examples include tablets, granules, capsules, liquids directly applied to the skin, films, ointments, creams, poultices and the like.
- this peptide hardly decomposes into amino acids in the digestive tract and is rapidly absorbed in the intestinal tract, it is also suitable for ingestion by oral administration. It is also preferable to ingest the peptide by mixing it with food or beverages.
- the dose of this peptide varies depending on the condition and body weight of the subject, the type of compound, the route of administration, etc., but in the case of oral administration per day for adults, for example, about 0.1 to 2000 mg, preferably about 1 to 1000 mg, The amount is preferably about 5 to 500 mg, particularly preferably about 10 to 200 mg.
- the content of the present peptide relative to the whole transdermal agent is, for example, about 0.00001 to 20% by weight, preferably about 0.0001 to 10% by weight, more preferably about 0.001 to 5%. % By weight.
- Formulations in other forms can be appropriately determined with reference to these dosages. These preparations can be administered 1 to several times a day, or can be administered once to several days a day.
- the whitening accelerator or the atopic dermatitis ameliorating agent of the present invention may contain other active ingredients and ingredients for preparations as appropriate as long as the effects of the present invention are not impaired.
- examples of other active ingredients include hyaluronic acid.
- the blending amount of other active ingredients can be appropriately changed according to each action.
- Pharmaceutically acceptable carriers used in formulating pharmaceutical preparations include diluents, binders (syrup, gum arabic, gelatin, sorbit, tragacanth, polyvinylpyrrolidone), excipients (lactose, sucrose, corn starch, Examples include potassium phosphate, sorbit, glycine), lubricants (magnesium stearate, talc, polyethylene glycol, silica), disintegrants (potato starch), wetting agents (sodium lauryl sulfate), and the like.
- the pharmaceutical preparation can be produced by mixing the peptide, other active ingredients, a pharmaceutically acceptable carrier and the like according to a conventionally known method.
- Example 1 (Pro-Hyp-Gly) 5 [(POG) 5 ]
- Example 2 (Pro-Hyp-Gly) 2 [(POG) 2 ]
- Example 3 Gly-Pro [GP]
- Example 4 Pro-Ala-Gly [PAG]
- Example 5 Pro-Hyp-Gly [POG] (Example 6)
- Glu-Hyp [EO] Example 7
- Example 8 Glu-Hyp-Gly [EOG]
- Example 9 Hyp-Gly [OG]
- Example 10 Ser-Hyp-Gly [SOG]
- Example 11 Phe-Hyp [FO]
- Example 12 Collagen peptide mixture “Type-S” (manufactured by Nitta Gelatin). When analyzed by LC-MS / MS, the collagen peptide mixture contained the following peptides, respectively. GP: 672 ppm, PAG: 12520 ppm, POG: 340 ppm, EO: 58 ppm, AOG: 331 ppm, EOG: 308 ppm, OG: 14581 ppm, SOG: 283 ppm, FO: 283 ppm.
- Example 13 Collagen peptide mixture “LCP” (manufactured by Nitta Gelatin). When analyzed by LC-MS / MS, the collagen peptide mixture contained the following peptides, respectively. GP: 249 ppm, PAG: 15568 ppm, POG: not detected, EO: 14 ppm, AOG: 29 ppm, EOG: 126 ppm, OG: 545 ppm, SOG: 3 ppm, FO: not detected.
- Comparative Examples 1-6 The following peptides were synthesized using the peptide solid phase synthesis method described above.
- Comparative Example 1 Gly-Pro-Hyp [GPO] (Comparative Example 2) Ala-Hyp [AO] (Comparative Example 3) Leu-Hyp [LO] (Comparative Example 4) Pro-Gly [PG] (Comparative Example 5) Pro-Pro [PP] (Comparative Example 6) Pro-Ala [PA]
- a jellyfish-derived collagen peptide mixture was prepared. Specifically, gelatin was thermally extracted from jellyfish according to a conventional method, trypsin (manufactured by Sigma) was added at a ratio of 1/100 to the substrate, and reacted at 45 ° C. for 3 hours (pH 7.0). Further, Properase E (manufactured by Genencor Kyowa) was added at a ratio of 1/50 to the substrate, reacted at 50 ° C. for 3 hours (pH 7.5), kept at 95 ° C. for 5 minutes to inactivate the enzyme.
- trypsin manufactured by Sigma
- Properase E manufactured by Genencor Kyowa
- the collagen peptide mixture contained the following peptides, respectively.
- GP 5 ppm, PAG: 2 ppm, POG: 7 ppm, EO: not detected, AOG: 2 ppm, EOG: 2 ppm, OG: 10 ppm, SOG: 1 ppm, FO: not detected.
- Comparative Example 25 Collagen peptide mixture “HACP (derived from pig)” (manufactured by Zerais). When analyzed by LC-MS / MS, the collagen peptide mixture contained the following peptides, respectively. GP: 359 ppm, PAG: 761 ppm, POG: 14 ppm, EO: 271 ppm, AOG: 25 ppm, EOG: not detected, OG: 75 ppm, SOG: not detected, FO: not detected.
- Comparative Example 26 Deer square glue is available from Siwon Herbal Medicine Co. We purchased more. As a result of LC-MS / MS analysis, none of the present peptides were detected in the keratin glue of Comparative Example 26.
- Comparative Example 27 Marine collagen peptide was purchased from Ihara Suisan. When analyzed by LC-MS / MS, the collagen peptide mixture of Comparative Example 27 contained the following peptides, respectively. GP: not detected, PAG: 58 ppm, POG: 15 ppm, EO: 128 ppm, AOG: 34 ppm, EOG: 104 ppm, OG: 378 ppm, SOG: not detected, FO: not detected.
- Test example 1 ET-1 expression suppression test / K10, TGM1, ivl, FLG and HAS2 expression promotion test
- Human normal epidermal keratinocytes NHEK (NB) (manufactured by Kurabo Industries) were used. The cells were pre-cultured with HuMedia-KG2 (manufactured by Kurabo Industries) and cultured in a 60 mm dish at 1.5 ⁇ 10 4 cells / ml ⁇ 5 ml (7.5 ⁇ 10 4 cells / dish) for 2 days. After confirming that the cells were subconfluent, the cells were replaced with 5 ml of HuMedia-KB2 (Kurabo).
- endothelin-1 (ET-1; Hs00174961_m1), keratin 10 (K10; Hs01043114_g1), transglutaminase 1 (TGM1; Hs01070310_m1), involucrin (ivl; Hs00846307_s1), filaggrin (FLG; Hs00856927_g1) Acid synthase 2 (HAS2; Hs00193435_m1) was measured.
- the correction gene was GAPDH.
- a calibration curve method was used, and for the primer and probe, a FAM dye of TaqMan Gene Expression was used.
- Test example 2 Tests with dry skin model mice Male hairless mice (HOS: HR-1) at 5 weeks of age are divided into 3 groups, a group to which normal feed is administered (group N), and a special feed for inducing dry skin (HR-AD, A control group (Group C) administered with Nippon Agricultural Industry Co., Ltd., and a group (CP group) administered with HR-AD mixed with 1% by weight of collagen peptide as a collagen peptide were provided. Five weeks after the start of feed administration, the moisture content of the back skin was measured with a Corneometer. The results are shown in Table 13. At the same time, transdermal moisture transpiration (TWEL) was measured with a Tewameter. The results are shown in Table 14. The values in each table represent mean values ⁇ standard deviation. *, ** and *** are P ⁇ 0.05 and P ⁇ 0.01, respectively, with respect to the control group (Group C) in the Paired-t-test. Indicates significant.
- Test example 3 Measurement of blood IgE concentration in ovalbumin (OVA) sensitized mice 6 weeks old BALB / c male mice were sensitized by intraperitoneal administration of 20 ⁇ g / animal OVA. After sensitization, the mice were divided into 7 groups, and a control sample and Examples 12, 13, and Comparative Examples 24, 25, 26 or 27 were each administered with an experimental sample containing 1% by weight as a collagen peptide in the control sample. did. The amount of IgE in the blood was detected with an ELISA kit (E99-115 manufactured by Funakoshi). The procedure followed the protocol. The results are shown in Table 15. The values in each table indicate mean ⁇ standard deviation, and *, ** and *** are significant in the Paired-t-test with P ⁇ 0.05 and P ⁇ 0.01, respectively, with respect to the control. Show.
- OVA ovalbumin
- this peptide suppressed the expression of endothelin-1.
- melanin pigment production from melanocytes can be suppressed and pigmentation can be suppressed.
- these peptides promoted the expression of transglutaminase 1, involucrin, keratin 10, filaggrin and hyaluronic acid synthase 2.
- epidermal metabolism is thereby promoted, skin turnover is promoted, and melanin pigments (stains) in the skin can be discharged more quickly.
- transglutaminase 1 involucrin, keratin 10, filaggrin and hyaluronic acid synthase 2
- the skin barrier function and moisturizing properties are improved, and the amount of IgE in blood is further reduced, thereby reducing atopic skin. Can improve the flame.
- the mixture “Type-S” (manufactured by Nitta Gelatin Co., Ltd .: Example 12) exhibits both an endothelin-1 expression inhibitory action and an expression promoting action of transglutaminase 1, involucrin, keratin 10, filaggrin and hyaluronic acid synthase 2. It was shown that.
- Example 14 in “LCP” of Example 13 and “Type-S” of Example 12, it is shown that the TWEL value is improved to a normal value. Similarly, from Table 15, in Example 12 and Example 13, the blood IgE value was significantly reduced, indicating that the allergic reaction was suppressed.
- an excellent whitening accelerator or atopic dermatitis improving agent containing a peptide or the like can be provided.
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Abstract
Description
非特許文献3には、クラゲ由来のコラーゲンペプチド混合物が抗酸化作用を有しており、またメラニン量を低下させたことが記載されている。しかし、非特許文献3の実験系は本明細書の試験系と異なり、本発明と効果の比較ができなかったため、後述の比較例24の通り、非特許文献3のコラーゲンペプチド混合物を調製して評価試験を行ったところ、本発明の効果よりも遥かに劣ることが確認された。
非特許文献5には、鮭皮由来コラーゲンペプチドが頸背部スコアによるアトピー性皮膚炎の改善が見られることを報告している。しかし、後述の比較例27の通り、マリンコラーゲンペプチドを購入し、評価試験を行ったところ、本発明の効果よりも遥かに劣ることが確認された。
特許文献1には、トリペプチドによるアトピー性皮膚炎による皮膚掻痒感の改善用外用剤が記載されている。なお、特許文献1に関するペプチドは、本発明に関するペプチドとは配列が異なり、またその用途であるアトピー性皮膚炎による皮膚掻痒感の改善は、本発明のアトピー性皮膚炎そのものの本質を改善するものとは異なる。また、特許文献2でも特許文献1のコラーゲンペプチドと同様のものを用いてアトピー性皮膚炎による皮膚掻痒感および血中の総IgE量の測定、経皮水分損失量(TEWL)、皮膚中の好酸球数と肥満細胞数を示し、すべての測定項目において、有意な差はなかったとしている。また、これらのコラーゲンペプチドを購入し、後述の比較例25で同時比較した結果、本発明の効果よりも遥かに劣ることが確認された。
[2] Hyp-Gly、Pro-Ala-Gly、Gly-Pro、Glu-Hyp-Gly、(Pro-Hyp-Gly)5、(Pro-Hyp-Gly)2、Pro-Hyp-Gly、Glu-Hyp、Ala-Hyp-Gly、Ser-Hyp-GlyおよびPhe-Hypからなる群から選択されるペプチドまたはその薬学上許容される塩をこれらのペプチドまたはその薬学上許容される塩の合計が1.6重量%以上となるように含むコラーゲンペプチド混合物を含有する、[1]に記載の美白促進剤またはアトピー性皮膚炎改善剤。
[3] Hyp-Gly、Pro-Ala-Gly、Gly-Pro、Glu-Hyp-Gly、Glu-Hyp、Ala-Hyp-Gly、Ser-Hyp-GlyおよびPhe-Hypからなる群から選択されるペプチドまたはその薬学上許容される塩をこれらのペプチドまたはその薬学上許容される塩の合計が1.6重量%以上となるように含むコラーゲンペプチド混合物を含有する、[1]に記載の美白促進剤またはアトピー性皮膚炎改善剤。
[4] 経口的または経皮的に投与される、[1]~[3]のいずれかに記載の美白促進剤またはアトピー性皮膚炎改善剤。
[6] Hyp-Gly、Pro-Ala-Gly、Gly-Pro、Glu-Hyp-Gly、(Pro-Hyp-Gly)5、(Pro-Hyp-Gly)2、Pro-Hyp-Gly、Glu-Hyp、Ala-Hyp-Gly、Ser-Hyp-GlyおよびPhe-Hypからなる群から選択されるペプチドまたはその薬学上許容される塩を含有する、フィラグリン発現促進剤。
[7] Hyp-Gly、Pro-Ala-Gly、Gly-Pro、Glu-Hyp-Gly、(Pro-Hyp-Gly)5、(Pro-Hyp-Gly)2、Pro-Hyp-Gly、Glu-Hyp、Ala-Hyp-Gly、Ser-Hyp-GlyおよびPhe-Hypからなる群から選択されるペプチドまたはその薬学上許容される塩を、それを必要とする対象に適用することによる、美白の促進方法またはアトピー性皮膚炎の改善方法。
[8] Hyp-Gly、Pro-Ala-Gly、Gly-Pro、Glu-Hyp-Gly、(Pro-Hyp-Gly)5、(Pro-Hyp-Gly)2、Pro-Hyp-Gly、Glu-Hyp、Ala-Hyp-Gly、Ser-Hyp-GlyおよびPhe-Hypからなる群から選択されるペプチドまたはその薬学上許容される塩を、それを必要とする対象に適用することによる、エンドセリン-1の発現抑制方法またはフィラグリンの発現促進方法。
1.ペプチド
本発明に用いられるペプチドは、Hyp-Gly、Pro-Ala-Gly、Gly-Pro、Glu-Hyp-Gly、(Pro-Hyp-Gly)5、(Pro-Hyp-Gly)2、Pro-Hyp-Gly、Glu-Hyp、Ala-Hyp-Gly、Ser-Hyp-GlyおよびPhe-Hyp(以下、本ペプチドとも言う)であり、本ペプチドは薬学上許容される塩とすることができる。好ましいペプチドとして、Hyp-Gly、Pro-Ala-Gly、Gly-Pro、Glu-Hyp-Gly、(Pro-Hyp-Gly)5および(Pro-Hyp-Gly)2が挙げられ、より好ましくはHyp-GlyおよびPro-Ala-Glyが挙げられる。また、本ペプチドは、2つ以上を組み合わせて用いることも好ましい。これらペプチドまたはその薬学上許容される塩を含むコラーゲンペプチド混合物として用いることもできる。その場合、これらペプチドまたはその薬学上許容される塩の合計が1.6重量%以上で含むものが挙げられ、好ましくは1.8重量%以上で含むもの、より好ましくは2.0重量%以上で含むもの、さらに好ましくは2.3重量%以上で含むもの、特に好ましくは2.6重量%以上で含むものが挙げられる。また、Hyp-Gly、Pro-Ala-Gly、Gly-Pro、Glu-Hyp-Gly、Glu-Hyp、Ala-Hyp-Gly、Ser-Hyp-GlyおよびPhe-Hypからなる群から選択されるペプチドまたはその薬学上許容される塩をこれらのペプチドまたはその薬学上許容される塩の合計が1.6重量%以上、好ましくは1.8重量%以上、より好ましくは2.0重量%以上、さらに好ましくは2.3重量%以上、特に好ましくは2.6重量%以上となるように含むコラーゲンペプチド混合物も好ましい。好ましい例としては、例えば、これらペプチドを2.94重量%含むコラーゲンペプチド混合物「Type-S」(新田ゼラチン製)が挙げられる。
具体的には、ヒドロキシプロリンの水酸基の化学修飾としては、例えばO-アセチル化等が挙げられる。N末アミノ酸のアミノ基の化学修飾としては、例えばポリペプチジル化、スクシニル化、マレイル化、アセチル化、脱アミノ化、ベンゾイル化、アルキルスルホニル化、アリルスルホニル化、ジニトロフェニル化、トリニトロフェニル化、カルバミル化、フェニルカルバミル化、チオール化等が挙げられる。C末アミノ酸のカルボキシル基の化学修飾としては、例えばエステル化、アミド化等が挙げられる。さらに、本ペプチドをカチオン化する場合は、エチレンジアミン化、スペルミン化などを行うことができる。
本ペプチドは、後述の試験例に記載の通り、エンドセリン-1発現抑制作用を有する。また、表皮のトランスグルタミナーゼ1、インボルクリン、ケラチン10、フィラグリンおよびヒアルロン酸合成酵素2の発現促進作用をも有する。この2つの作用によって、メラニン色素生成を抑制し、皮膚中のメラニン色素をより早く排出させることができ、美白促進剤またはアトピー性皮膚炎改善剤として用いることができる。具体的な適用としては、医薬品、化粧料、特定保健用食品、健康食品として、あるいは色々な食材に含有させて、ヒト、哺乳動物等の対象に投与することができる。
本発明の美白促進剤またはアトピー性皮膚炎改善剤は、経口的にまたは非経口的に種々の形態で投与することができる。その形態としては、経口的に投与する場合は、例えば、錠剤、顆粒剤、カプセル剤、粉剤、液剤、懸濁製剤、乳化製剤等が挙げられ、または飲食品に混合することもできる。非経口的に投与する場合は、例えば、皮膚への塗布、注射剤、経皮剤、坐剤、点鼻剤および吸入剤等が挙げられる。好ましくは、錠剤、顆粒剤、カプセル剤、皮膚への直接塗布する液剤、フィルム剤、軟膏、クリーム剤、パップ剤等が挙げられる。なお、本ペプチドは、消化管でアミノ酸への分解もほとんど起こらず、腸管で迅速に吸収されるため、経口投与による摂取にも適している。本ペプチドは食事または飲料に混ぜて摂取させることも好ましい。
本発明の美白促進剤またはアトピー性皮膚炎改善剤は、本発明の効果を害しない範囲で、適宜他の有効成分や製剤用の成分を含有させても良い。他の有効成分として、例えばヒアルロン酸等が挙げられる。他の有効成分の配合量としては、各々の作用に応じて適宜、変更することができる。
実施例1~11
前記のペプチド固相合成法を用いて、以下のペプチドを合成した。
(実施例1)(Pro-Hyp-Gly)5[(POG)5]
(実施例2)(Pro-Hyp-Gly)2[(POG)2]
(実施例3) Gly-Pro[GP]
(実施例4) Pro-Ala-Gly[PAG]
(実施例5) Pro-Hyp-Gly[POG]
(実施例6) Glu-Hyp[EO]
(実施例7) Ala-Hyp-Gly[AOG]
(実施例8) Glu-Hyp-Gly[EOG]
(実施例9) Hyp-Gly[OG]
(実施例10) Ser-Hyp-Gly[SOG]
(実施例11) Phe-Hyp[FO]
コラーゲンペプチド混合物「Type-S」(新田ゼラチン製)。
LC-MS/MSで分析したところ、本コラーゲンペプチド混合物には以下のペプチドがそれぞれ含まれていた。
GP:672ppm,PAG:12520ppm,POG:340ppm,EO:58ppm,AOG:331ppm,EOG:308ppm,OG:14581ppm,SOG:283ppm,FO:283ppm。
コラーゲンペプチド混合物「LCP」(新田ゼラチン社製)。
LC-MS/MSで分析したところ、本コラーゲンペプチド混合物には以下のペプチドがそれぞれ含まれていた。
GP:249ppm,PAG:15568ppm,POG:不検出,EO:14ppm,AOG:29ppm,EOG:126ppm,OG:545ppm,SOG:3ppm,FO:不検出。
前記のペプチド固相合成法を用いて、以下のペプチドを合成した。
(比較例1) Gly-Pro-Hyp[GPO]
(比較例2) Ala-Hyp[AO]
(比較例3) Leu-Hyp[LO]
(比較例4) Pro-Gly[PG]
(比較例5) Pro-Pro[PP]
(比較例6) Pro-Ala[PA]
(比較例7) L-プロリン(和光純薬製)
(比較例8) L-ヒドロキシプロリン(東京化成工業製)
(比較例9) L-グリシン(関東化学製)
(比較例10) L-ロイシン(関東化学製)
(比較例11) L-グルタミン酸(関東化学製)
(比較例12) L-アラニン(関東化学製)
(比較例13) L-セリン(和光純薬製)
(比較例14) L-フェニルアラニン(和光純薬製)
(比較例15) L-グリシン(関東化学製)+ヒドロキシプロリン(東京化成工業製)
(比較例16) L-プロリン(和光純薬製)+L-アラニン(関東化学製)+L-グリシン(関東化学製)
(比較例17) L-プロリン(和光純薬製)+L-ヒドロキシプロリン(東京化成工業製)+L-グリシン(関東化学製)
(比較例18) L-グルタミン酸(関東化学製)+L-ヒドロキシプロリン(東京化成工業製)
(比較例19) L-アラニン(関東化学製)+L-ヒドロキシプロリン(東京化成工業製)+L-グリシン(関東化学製)
(比較例20) L-グルタミン酸(関東化学製)+L-ヒドロキシプロリン(東京化成工業製)+L-グリシン(関東化学製)
(比較例21) L-ヒドロキシプロリン(東京化成工業製)+L-グリシン(関東化学製)
(比較例22) L-セリン(和光純薬製)+L-ヒドロキシプロリン(東京化成工業製)+L-グリシン(関東化学製)
(比較例23) L-フェニルアラニン(和光純薬製)+L-ヒドロキシプロリン(東京化成工業製)
非特許文献3に記載の方法に従って、クラゲ由来のコラーゲンペプチド混合物を調製した。具体的には、クラゲからゼラチンを常法に従って熱抽出し、トリプシン(Sigma社製)を基質に対して1/100の割合で添加し、45℃で3時間反応させた(pH7.0)。さらにプロペラーゼE(Genencor協和製)を基質に対して1/50の割合で添加し、50℃で3時間反応させ(pH7.5)、5分間95℃に保温して酵素を失活させた。次に、遠心(5000g×15分間)し、上清を回収して、コラーゲンペプチド混合物を得た。LC-MS/MSで分析したところ、本コラーゲンペプチド混合物には以下のペプチドがそれぞれ含まれていた。
GP:5ppm,PAG:2ppm,POG:7ppm,EO:不検出,AOG:2ppm,EOG:2ppm,OG:10ppm,SOG:1ppm,FO:不検出。
コラーゲンペプチド混合物「HACP(豚由来)」(ゼライス社製)。
LC-MS/MSで分析したところ、本コラーゲンペプチド混合物には以下のペプチドがそれぞれ含まれていた。
GP:359ppm,PAG:761ppm,POG:14ppm,EO:271ppm,AOG:25ppm,EOG:不検出,OG:75ppm,SOG:不検出,FO:不検出。
鹿角膠はSiwon Herbal Medicine Co.より購入した。LC-MS/MSで分析したところ、比較例26の鹿角膠中には、本ペプチドのいずれもが不検出であった。
マリンコラーゲンペプチドを井原水産より購入した。LC-MS/MSで分析したところ、比較例27のコラーゲンペプチド混合物には以下のペプチドがそれぞれ含まれていた。
GP:不検出,PAG:58ppm,POG:15ppm,EO:128ppm,AOG:34ppm,EOG:104ppm,OG:378ppm,SOG:不検出,FO:不検出。
ET-1発現抑制試験/K10,TGM1,ivl,FLGおよびHAS2発現促進試験
ヒト正常表皮角化細胞NHEK(NB)(クラボウ社製)を用いた。HuMedia-KG2(クラボウ社製)で前培養し、60mmシャーレに1.5×104細胞/ml×5ml(7.5×104細胞/皿)で2日培養した。細胞がサブコンフルエントになっていることを確認後、HuMedia-KB2(クラボウ社製)5mlに置き換えた。サンプルを各濃度となるように添加し、24時間(ET-1,K10)、48時間(TGM1,ivl,HAS2)、72時間(FLG)反応させた。細胞より全RNAを抽出し、逆転写を行い、リアルタイムPCRにかけた。リアルタイムPCRでは標的遺伝子として、エンドセリン-1(ET-1;Hs00174961_m1)、ケラチン10(K10;Hs01043114_g1)、トランスグルタミナーゼ1(TGM1;Hs01070310_m1)、インボルクリン(ivl;Hs00846307_s1)、フィラグリン(FLG;Hs00856927_g1)およびヒアルロン酸合成酵素2(HAS2;Hs00193435_m1)を測定した。補正遺伝子はGAPDHで行った。計算は検量線法を用い、プライマー&プローブはTaqMan Gene ExpressionのFAM色素を用いた。
乾燥肌モデルマウスによる試験
5週齢の雄性へアレスマウス(HOS:HR-1)を3群に分け、通常飼料を投与する群(N群)、乾燥肌を誘導する特殊飼料(HR-AD,日本農業工業株式会社製)を投与するコントロール群(C群)、HR-ADにコラーゲンペプチドとして1重量%となるように配合した飼料を投与する群(CP群)をそれぞれ設けた。飼料投与開始から5週間後、背部皮膚の水分量をCorneometerによって測定した。その結果を表13に示す。同時に経皮膚水分蒸散量(TWEL)をTewameterにより測定した。その結果を表14に示す。各表中の値は平均値±標準偏差を示し、*、**および***は、Paired-t-testにおいて、コントロール群(C群)に対してそれぞれP<0.05、P<0.01で有意であることを示す。
オボアルブミン(OVA)感作マウスにおける血中IgE濃度測定
6週齢のBALB/c系雄性マウスに、20μg/匹のOVAを腹腔内投与することにより感作した。感作後、マウスを7群に分け、対照試料と実施例12、13、比較例24、25、26または27をそれぞれ対照試料にコラーゲンペプチドとして1重量%となるように配合した実験試料を投与した。血中のIgE量に関しては、ELISAキット(フナコシ製E99-115)によって検出した。手順はプロトコールに従った。その結果を表15に示す。各表中の値は平均値±標準偏差を示し、*、**および***は、Paired-t-testにおいて、コントロールに対してそれぞれP<0.05、P<0.01で有意であることを示す。
以上より、本ペプチド等は、美白促進剤またはアトピー性皮膚炎改善剤として有用である。
Claims (6)
- Hyp-Gly、Pro-Ala-Gly、Gly-Pro、Glu-Hyp-Gly、(Pro-Hyp-Gly)5、(Pro-Hyp-Gly)2、Pro-Hyp-Gly、Glu-Hyp、Ala-Hyp-Gly、Ser-Hyp-GlyおよびPhe-Hypからなる群から選択されるペプチドまたはその薬学上許容される塩を含有する、美白促進剤またはアトピー性皮膚炎改善剤。
- Hyp-Gly、Pro-Ala-Gly、Gly-Pro、Glu-Hyp-Gly、(Pro-Hyp-Gly)5、(Pro-Hyp-Gly)2、Pro-Hyp-Gly、Glu-Hyp、Ala-Hyp-Gly、Ser-Hyp-GlyおよびPhe-Hypからなる群から選択されるペプチドまたはその薬学上許容される塩をこれらのペプチドまたはその薬学上許容される塩の合計が1.6重量%以上となるように含むコラーゲンペプチド混合物を含有する、請求項1に記載の美白促進剤またはアトピー性皮膚炎改善剤。
- Hyp-Gly、Pro-Ala-Gly、Gly-Pro、Glu-Hyp-Gly、Glu-Hyp、Ala-Hyp-Gly、Ser-Hyp-GlyおよびPhe-Hypからなる群から選択されるペプチドまたはその薬学上許容される塩をこれらのペプチドまたはその薬学上許容される塩の合計が1.6重量%以上となるように含むコラーゲンペプチド混合物を含有する、請求項1に記載の美白促進剤およびアトピー性皮膚炎改善剤。
- 経口的または経皮的に投与される、請求項1~3のいずれかに記載の美白促進剤またはアトピー性皮膚炎改善剤。
- Hyp-Gly、Pro-Ala-Gly、Gly-Pro、Glu-Hyp-Gly、(Pro-Hyp-Gly)5、(Pro-Hyp-Gly)2、Pro-Hyp-Gly、Glu-Hyp、Ala-Hyp-Gly、Ser-Hyp-GlyおよびPhe-Hypからなる群から選択されるペプチドまたはその薬学上許容される塩を含有する、エンドセリン-1発現抑制剤。
- Hyp-Gly、Pro-Ala-Gly、Gly-Pro、Glu-Hyp-Gly、(Pro-Hyp-Gly)5、(Pro-Hyp-Gly)2、Pro-Hyp-Gly、Glu-Hyp、Ala-Hyp-Gly、Ser-Hyp-GlyおよびPhe-Hypからなる群から選択されるペプチドまたはその薬学上許容される塩を含有する、フィラグリン発現促進剤。
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CN201480023474.6A CN105188727A (zh) | 2013-04-26 | 2014-03-31 | 美白促进剂或特应性皮炎改善剂 |
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JP2016155785A (ja) * | 2015-02-25 | 2016-09-01 | 株式会社ニッピ | 環状ジペプチドの製造方法 |
JP2016185909A (ja) * | 2015-03-27 | 2016-10-27 | 株式会社ファンケル | 美白用組成物 |
JP2016185908A (ja) * | 2015-03-27 | 2016-10-27 | 株式会社ファンケル | メラニン産生抑制剤 |
JP2018039751A (ja) * | 2016-09-07 | 2018-03-15 | 新田ゼラチン株式会社 | 表皮細胞間機能強化剤 |
JP2018039737A (ja) * | 2016-09-05 | 2018-03-15 | 株式会社ファンケル | キマーゼ阻害用組成物 |
WO2018174286A1 (ja) | 2017-03-24 | 2018-09-27 | 味の素株式会社 | 角層機能改善剤 |
JP2018177767A (ja) * | 2017-04-04 | 2018-11-15 | 味の素株式会社 | 保湿剤 |
JP2019085380A (ja) * | 2017-11-09 | 2019-06-06 | 株式会社ファーマフーズ | ヒアルロン酸産生促進剤 |
JP2019131531A (ja) * | 2018-01-29 | 2019-08-08 | 日本メナード化粧品株式会社 | ガレクチン−9産生促進剤 |
US10406086B2 (en) | 2015-10-19 | 2019-09-10 | Ajinomoto Co., Inc. | Moisturizer and cosmetic including the same |
JP2020196738A (ja) * | 2020-08-20 | 2020-12-10 | 株式会社ファーマフーズ | ヒアルロン酸産生促進剤 |
WO2021015041A1 (ja) * | 2019-07-25 | 2021-01-28 | 新田ゼラチン株式会社 | 老化の進行抑制剤、およびこれを含む飲食品 |
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CN114032269B (zh) * | 2021-10-19 | 2023-08-04 | 华南理工大学 | 一种富含二肽Hyp-Gly的胶原小分子肽及其制备方法和用途 |
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JPWO2014175001A1 (ja) | 2017-02-23 |
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