WO2023281657A1 - Oligopeptide ayant une activité favorisant le retrait du gel de collagène, et son utilisation - Google Patents
Oligopeptide ayant une activité favorisant le retrait du gel de collagène, et son utilisation Download PDFInfo
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- WO2023281657A1 WO2023281657A1 PCT/JP2021/025609 JP2021025609W WO2023281657A1 WO 2023281657 A1 WO2023281657 A1 WO 2023281657A1 JP 2021025609 W JP2021025609 W JP 2021025609W WO 2023281657 A1 WO2023281657 A1 WO 2023281657A1
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- WIPO (PCT)
- Prior art keywords
- oligopeptide
- amino acid
- skin
- collagen gel
- collagen
- Prior art date
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- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 230000002087 whitening effect Effects 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06104—Dipeptides with the first amino acid being acidic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
Definitions
- the present invention relates to oligopeptides and derivatives thereof that have collagen gel contraction-promoting action or fibroblast-activating action.
- the present invention also relates to an agent for preventing or improving wrinkles, sagging, sagging, reduced firmness, or reduced elasticity of the skin, an agent for promoting collagen gel contraction, and an agent for activating fibroblasts.
- Surgical treatment involves inserting ultra-fine absorbable thread into the subcutaneous fascia layer to lift up the skin and muscles.
- the burden on the patient is large.
- Hyaluronic acid is present in the skin as one of the extracellular matrices involved in water retention and viscosity.
- Hyaluronic acid has a water-retaining effect, and when applied to the skin, it increases the moisture content of the stratum corneum for a long time and improves the firmness of the skin. .
- hyaluronic acid is metabolized very quickly, and it is said that about half of hyaluronic acid is decomposed in the skin per day. Therefore, even if hyaluronic acid is applied to the skin every day, it is constantly metabolized, and it is not possible to fully realize the improvement in skin firmness.
- ingredients that promote the formation of extracellular matrices such as hyaluronic acid and collagen, and ingredients that suppress the degradation of elastin, which is an extracellular matrix, are added to external preparations to improve skin firmness. Although it is known to be compounded, these ingredients have the drawback of causing inflammation and stimulating the skin.
- peptides are desirable as active ingredients for external preparations because they are metabolized relatively slowly and do not irritate the skin.
- Bovine lactoferrin and its partial peptides are known as peptides expected to improve skin firmness.
- Non-Patent Document 1 reports that bovine lactoferrin enhances the phosphorylation of myosin light chain in fibroblasts and increases their collagen gel contractile activity.
- Lactoferrin is an iron-binding glycoprotein contained in exocrine fluids such as breast milk, tears, sweat, and saliva. After that, in 1960, it was purified from human and bovine milk, and the amino acid sequence was determined. It was found to have a structure in which two domains are linked by a single polypeptide, and each lobe strongly binds to one iron ion. Lactoferrin has been shown to have various functions such as anti-inflammatory, antioxidant, antibacterial, and cell proliferation-regulating effects, in addition to promoting collagen gel contraction.
- Non-Patent Document 2 discloses that a C-terminal fragment obtained by decomposing bovine lactoferrin with trypsin at a molar ratio of 1/200 for 45 minutes at 37° C. has significantly stronger collagen gel contraction-promoting activity than full-length lactoferrin, and fiber It has been reported to have pro-phosphorylation activity of myosin light chain in blast cells.
- the p44 fragment corresponds to the portion consisting of amino acids 341 to 689 of bovine lactoferrin
- the p36 fragment corresponds to the portion consisting of amino acids 1 to 284 of bovine lactoferrin
- the p51 fragment corresponds to It corresponds to the portion consisting of the 285th to 689th amino acids of bovine lactoferrin, and the molecular weights of these fragments are 44,000, 36,000 and 51,000, respectively.
- the skin is divided into epidermis, dermis, and subcutaneous tissue, of which 70% or more of the dermis is composed of collagen fibers, which are extremely important for maintaining skin structure, forming flexible and elastic dermal tissue.
- Fiber-constituting proteins such as collagen are produced by fibroblasts, and fibroblasts interact with collagen fibers to form flexible and elastic dermal tissue.
- Collagen gel contraction is a phenomenon in which fibroblasts pull and contract collagen fibers.
- Collagen fibers extracted from tissues are reconstituted into collagen fibers when placed at 37° C. under neutral and physiological ionic strength.
- Non-Patent Document 3 a contracted gel obtained by collagen gel contraction of fibroblasts is used as a model of dermal tissue.
- Non-Patent Document 4 It has been reported that fibroblasts derived from old people have lower collagen gel contractile activity than fibroblasts derived from young people.
- Non-Patent Document 4 This suggests that when the contractile activity of the collagen gel declines due to aging, the dermal tissue cannot be contracted and maintained in a tight state as it was when young (Patent Document 1).
- wrinkles, sagging, and lack of firmness of the skin associated with aging are caused by a decrease in the tissue contractile force of dermal fibroblasts, resulting in a loss of flexibility, elasticity, and strength. It is reported that by increasing the activity, it can be expected to improve wrinkles, sagging, and lack of firmness of the skin (Patent Document 2).
- both the bovine lactoferrin taught by Non-Patent Document 1 and the partial peptide of bovine lactoferrin taught by Non-Patent Document 2 are difficult to be percutaneously absorbed due to their large molecular weights, and may cause allergies due to their strong immunogenicity. Therefore, oligopeptides having a small molecular weight and having a collagen gel contraction action or a fibroblast activation action are desired as components of topical preparations.
- Takayama Y, Mizumachi K Effects of lactoferrin on collagen gel contractile activity and myosin light chain phosphorylation in human fibroblasts.
- Bell E Sher S, Hull B et al. The reconstitution of living skin. J Invest Dermatol. 1983, 81: 2s-10s.
- Yamato M Yamamoto K, Hayashi T. Age-related changes in collagen gel contraction by cultured human lung fibroblasts resulting in cross-over of contraction curves between young and aged cells. Mech Ageing Dev. 1993, 67(1-2): 149 -158.
- the present invention provides an oligopeptide and its derivatives having collagen gel contraction-promoting action, and an agent for preventing or improving skin wrinkles, sagging, sagging, loss of firmness, or loss of elasticity, containing the oligopeptide and its derivatives as active ingredients.
- the task is to
- the present inventor focused on lactoferrin, limitedly degraded bovine lactoferrin with trypsin, fractionated the limited decomposition product with a preparative ODS column, and had collagen gel contraction promoting activity.
- the fraction was further fractionated by gel filtration, and two oligopeptides consisting of 8 amino acids and one oligopeptide consisting of 5 amino acids were found to have collagen gel contraction-promoting action.
- each dipeptide of AV and DG was found to be the core amino acid sequence that promotes collagen gel contraction. This also suggests that any oligopeptide of up to 8 amino acids containing the amino acid sequence of AV or DG has a collagen gel contraction-promoting effect. Each oligopeptide from 2 to 10, and No. containing DG. It was confirmed that each of peptides 12 to 24 has collagen gel contraction-promoting action. Oligopeptides with respective numbers are as shown in the item "Oligopeptides" in "Mode for Carrying out the Invention". Furthermore, they have found that these oligopeptides do not lose their collagen gel contraction-promoting action even when modified forms such as esters are used.
- oligopeptides or derivatives thereof Any of the following (a), (b), (c) and (d) oligopeptides or derivatives thereof.
- an oligopeptide consisting of an amino acid sequence of DG, LLCLDGTR, LCLDGTR, CLDGTR, LDGTR, LDGT, DGTR, LDG, DGT, SVDGK, SVDG, VDGK, DGK, or VDG;
- (d) consists of an amino acid sequence in which one amino acid is substituted in DG, LLCLDGTR, LCLDGTR, CLDGTR, LDGTR, LDGT, DGTR, LDG, DGT, SVDGK, SVDG, VDGK, DGK, or VDG (including DG);
- the oligopeptide or derivative thereof according to [1], wherein the oligopeptide [2] derivative having collagen contraction-promoting activity is a modified N-terminal of the oligopeptide.
- the collagen gel contraction promoter of [5] which is a composition for external use or a food composition.
- An agent for activating fibroblasts comprising at least one of the oligopeptide and derivative thereof of [1] or [2].
- the fibroblast activator of [7] which is a composition for external use or a food composition.
- [9] Use of at least one of the oligopeptide and derivative thereof according to [1] or [2] for the production of an agent for preventing or improving skin wrinkles, sagging, sagging, reduced firmness, or reduced elasticity .
- the agent for preventing or improving wrinkles, sagging, sagging, reduced firmness, or reduced elasticity of the skin is a composition for external use or a food composition.
- the use of [11], wherein the collagen gel contraction promoting agent is a composition for external use or a food composition.
- [15] Use of a composition containing at least one of the oligopeptide and derivative thereof according to [1] or [2] as an agent for preventing or improving skin wrinkles, sagging, sagging, decreased firmness, or decreased elasticity
- Non-therapeutic use is a composition for external use or a food composition.
- the collagen gel contraction promoting agent is a composition for external use or a food composition.
- Non-therapeutic use of a composition comprising at least one of the oligopeptide and derivative thereof of [1] or [2] as an agent for activating fibroblasts.
- the composition is a composition for external use or a food composition.
- the oligopeptide or derivative thereof of [1] or [2] for use in preventing or improving wrinkles, sagging, sagging, reduced firmness, or reduced elasticity of the skin.
- the oligopeptide or derivative thereof of [1] or [2] for use in promoting collagen gel contraction.
- [24] Treatment of skin wrinkles, sagging, sagging, loss of firmness, or loss of elasticity, comprising the step of applying to humans an effective amount of at least one of the oligopeptides and derivatives thereof of [1] or [2]. Preventive or ameliorative methods. [25] The method of [24], wherein the application is application, rubbing, spraying, or sticking to the skin, or oral administration. [26] A method for promoting skin collagen contraction, which comprises the step of applying to a human an effective amount of at least one of the oligopeptide and its derivative of [1] or [2]. [27] The method of [26], wherein the application is application, rubbing, spraying, or sticking to the skin, or oral administration.
- a method for activating cutaneous fibroblasts comprising the step of applying an effective amount of at least one of the oligopeptide and derivative thereof of [1] or [2] to a human.
- the method of [28], wherein the application is application, rubbing, spraying, or sticking to the skin, or oral administration.
- the oligopeptide and derivatives thereof of the present invention have a collagen gel contraction promoting action or a fibroblast activating action.
- fibroblasts contract collagen fibers to keep them in a tight state. Therefore, when applied to human skin, the oligopeptides and derivatives thereof of the present invention are capable of producing collagen by fibroblasts in the dermis. It is believed that promoting contraction can prevent or improve wrinkles, sagging, sagging, loss of firmness, or loss of elasticity of the skin.
- the oligopeptide and its derivatives of the present invention have a small molecular weight, so they are easily absorbed through the skin, and when administered orally, are easily absorbed from the gastrointestinal tract.
- Human lactoferrin and bovine lactoferrin have molecular weights of about 83,000, respectively. Although the absorption efficiency is low, the oligopeptide and its derivative of the present invention have much higher penetration into the epidermis and dermis and absorption efficiency from the gastrointestinal tract than human lactoferrin and bovine lactoferrin. In addition, unlike proteins, the oligopeptides and derivatives thereof of the present invention have low immunogenicity, and thus are excellent in that they hardly cause allergies.
- the oligopeptide and its derivatives of the present invention are applied, rubbed, sprayed, or attached to the skin, It is difficult to be metabolized after being absorbed into the skin. Also, unlike conventional ingredients, there is no or little skin irritation. In these respects, the oligopeptide of the present invention is also superior to conventional ingredients used for improving skin wrinkles or firmness.
- Oligopeptide The oligopeptide of the present invention is any one of the following (a), (b), (c) and (d).
- d No. An oligopeptide consisting of an amino acid sequence in which one amino acid is substituted in the amino acid sequence of 12 to 24 (including DG) and having a collagen contraction-promoting effect
- No. 2 to 10, 12 to 24 amino acid substitutions of the oligopeptide can be made between amino acids having similar structures or properties, and it is reasonably expected that the substitution will have collagen gel contraction-promoting action.
- Examples of mutually substitutable amino acids include acidic amino acids E (Glu) and D (Asp), basic amino acids R (Arg), K (Lys) and H (His), and neutral amino acids with alkyl chains.
- G (Gly) and A (Ala) and V (Val) and L (Leu) and I (Ile) (among them, G (Gly) and A (Ala) with linear alkyl chains, V with branched alkyl chains (Val) and L (Leu) and I (Ile)), S (Ser) and T (Thr) having a hydroxy group, C (Cys) and M (Met) having a sulfur atom, N (Asn) having an amide group ) and Q (Gln), and F (Phe), Y (Tyr) and W (Trp) having an aromatic ring.
- HTAV has collagen gel contraction-promoting action
- HTAL also has collagen gel contraction-promoting action.
- the oligopeptide of the present invention was discovered based on the partial amino acid sequence of bovine lactoferrin, and the amino acid sequence (No. 2) of SCHTAVDR containing AV is 475 of bovine lactoferrin. In addition to being present at positions ⁇ 482, it was confirmed that it was present at positions 458-465 of human lactoferrin. Namely, No. 1-10 are amino acid sequences present in bovine lactoferrin and human lactoferrin. It was also confirmed that the amino acid sequence (No. 12) of LLCLDGTR containing DG is present in bovine lactoferrin at positions 590-597, but not in human lactoferrin. Namely, No.
- 11-19 are amino acid sequences present in bovine lactoferrin. It was also confirmed that the SVDGK amino acid sequence (No. 20) containing DG is present in bovine lactoferrin but not in human lactoferrin. Namely, No. 20-24 are amino acid sequences present in bovine lactoferrin. Therefore, among the oligopeptides of the present invention, those consisting of an amino acid sequence present in human or bovine lactoferrin can be prepared by digesting human or bovine lactoferrin with trypsin.
- an oligopeptide consisting of an amino acid sequence present in bovine lactoferrin may be obtained by tryptic digestion of milk, cheese, or yogurt, or milk whey, cheese whey, or yogurt. It may be obtained by digesting whey such as whey with trypsin.
- Each oligopeptide of the invention can also be prepared synthetically.
- oligopeptides of the present invention may be derivatives (modifications) such as salts.
- Salts include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; salts with metals such as zinc and aluminum; Examples thereof include salts of amines such as ethanolamine. It may also be a salt with an inorganic acid or an organic acid. Inorganic acid salts include salts of hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.
- Organic acid salts include acetic acid, propionic acid, butanoic acid (butyric acid), isobutanoic acid, 6-heptanoic acid, hexanoic acid (caproic acid), palmitic acid, stearic acid, myristic acid, lauric acid, oleic acid, linoleic acid, Salts of aliphatic monocarboxylic acids (fatty acid salts) such as octanoic acid (caprylic acid) and decanoic acid (capric acid), salts of aliphatic polycarboxylic acids such as fumaric acid, maleic acid, succinic acid and malonic acid salts of aliphatic oxycarboxylic acids such as lactic acid, tartaric acid and citric acid; salts of aromatic carboxylic acids such as nicotinic acid; Examples include salt.
- Derivatives may be those in which any of the N-terminus, C-terminus, or side chain of the oligopeptide of the present invention is modified, or two or more of these may be modified.
- Collagen gel contraction-promoting activity can be obtained regardless of which part is modified, but N-terminal modification is preferred in terms of good percutaneous absorbability.
- the oligopeptide and derivatives thereof of the composition of the present invention are agents for preventing or improving wrinkles, sagging, sagging, reduced firmness, or reduced elasticity of the skin, collagen gel contraction promoters, or fibroblast activators (hereinafter referred to as " may be abbreviated as "the agent of the present invention”).
- These agents can be external compositions (cosmetic compositions, quasi-drug compositions) or food compositions.
- the composition can be prepared by mixing the oligopeptide of the present invention and at least one of its derivatives with additives and other physiologically active or pharmacologically active ingredients blended as necessary.
- the concentration of the oligopeptide and/or derivative thereof of the present invention in the composition is 0.00001% by weight or more, 0.0001% by weight or more, 0.001% by weight or more, 0.01% by weight or more, relative to the total amount of the composition. It may be at least 10 wt%, at most 1 wt%, at most 0.1 wt%, or at most 0.01 wt%. Within this range, a sufficient collagen gel contraction-promoting action can be obtained.
- Topical Compositions can in particular be skin topical compositions.
- the skin also includes the scalp.
- mucous membranes are also included in the skin.
- the composition for external use may be solid or liquid.
- the solid state includes a state having plasticity such that it is deformed by applying a force, and a freeze-dried state.
- the liquid state also includes viscous properties such as fluidity. Dosage forms include lotions, creams, emulsions, gels, ointments, liquids, solutions, suspensions, sprays or nebulizers, foams, and patches obtained by impregnating or applying these to a base material. , powders, and solidified powders.
- Emulsified compositions such as creams, emulsions, etc. may be O/W type, W/O type, W/O/W type, O/W/O type, and the like.
- the composition for external use is a cosmetic product, in addition to basic cosmetics such as lotion, milky lotion, cream, gel, beauty essence, sunscreen cosmetic, mask, mask, hand cream, body lotion, body cream, foundation, lipstick , make-up cosmetics such as blush.
- Additives for the composition for external use include bases, surfactants, thickeners, antiseptics or preservatives, pH adjusters, stabilizers or chelating agents, UV absorbers or UV scattering agents, antioxidants, stimulants, Examples include emollients, colorants, perfumes, and the like. Additives can be used alone or in combination of two or more.
- ingredients other than the oligopeptide or derivative thereof of the present invention which improve skin firmness, can be preferably blended.
- Ingredients that improve skin elasticity include ingredients that promote collagen gel contraction, ingredients that promote the production of extracellular matrices (hyaluronic acid, collagen, elastin, glucosaminoglycan, etc.), and extracellular matrix. Examples include a component having a decomposition inhibitory action, a component having a fibroblast proliferation promoting action, a component having a keratinocyte turnover promoting action, and the like.
- Ingredients with such actions include lactoferrin, artichoke, argania spinosa, aloe vera, nettle, turmeric, prickly pear cactus, okra, panax ginseng, kakkon, birch, raspberry, snapper, kudzu, gardenia, mulberry, chlorella, Alpinia purpurata, and carambola.
- hyaluronic acid collagen, elastin, glucosaminoglycan, chondroitin sulfate, heparin-like substances, proteoglycans, and their decomposition products, derivatives, and salts can also be blended, and these can also improve skin firmness.
- bioactive or pharmacologically active ingredients whitening ingredients, immunostimulants, astringents, antioxidants, blood circulation promoters, antibacterial agents, warming agents, vitamins, amino acids, wound healing promoters, cell activators, enzymes And so on.
- Such ingredients include retinol, vitamin A and its derivatives, vitamin C and its derivatives, salicylic acid and its derivatives, resorcinol and its derivatives, phospholipids such as phosphatidylserine, phosphatidic acid, cyclic phosphatidic acid. , tranexamic acid and its derivatives, niacinamide, hydroquinone and its derivatives, trehalose, trehalose sulfate and the like.
- One or two or more physiologically active or pharmacologically active ingredients other than the oligopeptide or derivative thereof of the present invention can be blended.
- the food composition can be an orally administered preparation called a so-called supplement.
- Solid preparations for oral administration include tablets, powders, granules, fine granules, pills, capsules (soft capsules, hard capsules) and the like. Solid preparations contain one or more additives such as excipients, binders, disintegrants, lubricants, fluidizers, coloring agents, corrigents, sweeteners, flavoring agents, preservatives or preservatives. can be blended.
- Liquid formulations for oral administration include solutions, elixirs, suspensions, emulsions, limonades, syrups and the like.
- Liquid formulations contain one or more additives such as pH adjusters, buffers, thickeners, stabilizers, emulsifiers, dispersants, suspending agents, preservatives, coloring agents, and perfumes. be able to.
- one or more physiologically active or pharmacologically active ingredients other than the oligopeptide or derivative thereof of the present invention can be added to the oral administration formulation. Examples of such physiologically active or pharmacologically active ingredients include those exemplified for external compositions.
- the food composition may be a composition in which the oligopeptide and/or derivative thereof of the present invention is blended with general food.
- solid foods such as jelly, agar candy, gum, candy, baked goods (cookies, biscuits, etc.), drinks, tea drinks, coffee drinks, milk drinks, juices such as fruits and vegetables, and soft drinks
- the oligopeptide of the present invention and/or a derivative thereof can be mixed with liquid food, and the oligopeptide and/or derivative thereof of the present invention can be easily ingested.
- the food composition may be used as nutritional supplements, health supplements, nutritious foods, foods for specified health uses, foods with nutrient function claims, foods with function claims, and the like.
- the present invention includes the step of applying an effective amount of the oligopeptide and/or derivative thereof of the present invention described above to a human (i) to treat wrinkles, sagging, sagging, reduced firmness, or reduced elasticity of the skin. (ii) a method for promoting skin collagen contraction; and (iii) a method for activating skin fibroblasts.
- the effective amount is (i) prevention or improvement of skin wrinkles, sagging, sagging, loss of firmness, or loss of elasticity, (ii) promotion of skin collagen contraction, and (iii) activation of skin fibroblasts. effective amount.
- the oligopeptide and/or derivative thereof of the present invention may be applied to humans as the above-described agent of the present invention (composition for external use or food composition).
- “Applying” can be applying, rubbing, spraying, or sticking to the skin depending on the dosage form of the composition for external use.
- the targeted skin can be the face, neck, arms, fingers, feet, toes, torso, etc., among which wrinkles, sagging, sagging, loss of firmness, and/or loss of elasticity are occurring. It can be a part or an earlier part.
- “application” is oral administration or ingestion for food compositions.
- Humans to whom the agent of the present invention is applied include humans with skin wrinkles, sagging, sagging, reduced firmness and/or reduced elasticity, humans in the pre-stage thereof, and humans with healthy skin.
- the skin herein includes any of the face, neck, arms, fingers, feet, toes, and torso, but in particular, wrinkles, drooping, sagging, reduced firmness, and/or elasticity to the skin of the face and/or neck. Humans with hypogonadism and those with pre-existing conditions are preferred.
- the dose of the oligopeptide and/or derivative thereof of the present invention per day per 1 cm 2 of skin is 0.0001 mg or more, 0.001 mg or more, 0.01 mg or more
- the topical composition can be applied to the skin at 0.1 mg or more, or 1 mg or more, and 100 mg or less, 10 mg or less, 1 mg or less, or 0.1 mg or less.
- the daily administration or intake of the oligopeptide and/or derivative thereof of the present invention is 0.05 mg or more, 0.5 mg or more, 5 mg or more, 50 mg or more, or 500 mg or more.
- the food composition can be administered or ingested to 50000 mg or less, 5000 mg or less, 500 mg or less, or 50 mg or less.
- the daily application amount to the skin and the daily dosage or intake amount described above are (i) prevention or improvement of wrinkles, sagging, sagging, loss of elasticity, or loss of elasticity of the skin, and (ii) collagen contraction of the skin. and (iii) skin fibroblast activation, respectively.
- the number of applications per day can be 1-5 times, 1-4 times, 1-3 times, 1-2 times, or 1 time.
- Example 1 (Preparation of Oligopeptide/Evaluation of Collagen Gel Contraction Promotion Activity) (Preparation of trypsin-limited degradation product of bovine lactoferrin) 1 g of bovine lactoferrin and 0.01 g of trypsin were dissolved in 20 mL of a pH 8.0 buffer solution and allowed to stand at 50° C. for 16 hours for limited decomposition. This decomposition product was heated at 100° C. for 20 minutes to deactivate the enzyme to obtain a bovine lactoferrin decomposition product liquid.
- the bovine lactoferrin digest solution was fractionated by ODS column for 40 fractions and freeze-dried.
- a phosphate buffer (pH 7.4) solution with a concentration of 5 mg/mL of the lyophilized product of each fraction was prepared, and the collagen gel contraction promoting activity was evaluated.
- four candidate sequences (SCHTAVDR (No. 2), LLCLDGTR (No. 12), SVDGK (No. 20), DLLFK (No.
- a collagen gel The gel adhering to the walls of the well plate was peeled off and placed in the wells, and 500 ⁇ L of Dulbecco's Modified Eagle Medium (DMEM) containing 1% FBS containing the test sample adjusted to 5 mg/mL was added from above the gel. . Furthermore, this was cultured at 37° C., and the area of the gel 3 days after the start of culture was measured by measuring the diameter of the gel with a digital vernier caliper.
- DMEM Dulbecco's Modified Eagle Medium
- test sample culture and observation were performed in the same manner as described above, except that the solvent used for the preparation of the test sample was used instead of the test sample.
- Bovine lactoferrin was used as a positive control sample.
- Three gels were prepared and incubated for each sample (n 3), the gel area was measured, and the mean and standard deviation were determined. If the gel area of the test sample is smaller than that of the control, it is found that the test sample has collagen gel contraction-promoting activity for cultured human fibroblasts. Therefore, by measuring the gel area by the above method, it is possible to evaluate whether or not the test sample has an effect of improving wrinkles, sagging, and lack of firmness of the skin.
- Table 1 shows the results.
- the collagen gel area ratios in Table 1 are relative values when the collagen gel area of the control is set to 1.
- oligopeptides having amino acid sequences obtained by removing one amino acid from the N-terminus or C-terminus of each of the 12 oligopeptides significantly promoted collagen gel contraction compared to the control, but no significant collagen gel contraction was observed. Some had no promoting activity.
- the SVDGK (No. 20) oligopeptide promoted collagen gel contraction. Also, No. An oligopeptide having an amino acid sequence obtained by removing one amino acid from the N-terminus or C-terminus of 20 oligopeptides significantly promoted collagen gel contraction compared to the control.
- DLLFK (No. 25) consisting of the 316th to 320th amino acid sequences of bovine lactoferrin was not confirmed to have collagen gel contraction-promoting activity.
- Example 2 (effective concentration of collagen gel contraction-promoting activity of oligopeptide) Add 0.94 g of MEM, 500 ⁇ L of 1 mol/L NaHCO 3 , 29.2 mg of L-glutamine, and 1 mL of bovine serum to each well of a 24-well plate. Prepared to 20 mL ⁇ 100 ⁇ L, TAV (No. 9) oligopeptide 2.5 ⁇ L prepared to each concentration, type I collagen (IAC-30) 365 ⁇ L, 1 mol/L NaHCO 3 12.5 ⁇ L, human 20 ⁇ L of fibroblasts (2.5 million cells/mL) were added in this order. The well plate was then incubated at 37° C. for 1 hour to prepare a collagen gel.
- TAV No. 9
- the gel adhering to the walls of the well plate was peeled off and placed in the wells, and 500 ⁇ L of DMEM containing 1% FBS containing TAV oligopeptide prepared to each concentration was added onto the gel. Furthermore, this was cultured at 37° C., and the area of the gel 3 days after the start of culture was measured by measuring the diameter of the gel with a digital vernier caliper.
- test sample culture and observation were performed in the same manner as described above, except that the solvent used for the preparation of the test sample was used instead of the test sample.
- Bovine lactoferrin was used as a positive control sample.
- Three gels were prepared and incubated for each sample (n 3), the gel area was measured, and the mean and standard deviation were determined.
- Table 2 shows the results.
- the oligopeptide concentrations in Table 2 are the final concentrations of the medium in the wells.
- 0.1 ⁇ g/mL, 1 ⁇ g/mL, 10 ⁇ g/mL, 25 ⁇ g/mL, 50 ⁇ g/mL, and 100 ⁇ g/mL of TAV oligopeptides were added, respectively, a significant A reduction in the area of the collagen gel, that is, an effect of accelerating the contraction of the collagen gel was observed. It was confirmed that a composition containing this oligopeptide in a concentration range of 0.1 to 100 ⁇ g/mL has an effect of improving wrinkles, sagging and lack of firmness of the skin.
- Example 3 Evaluation of Collagen Gel Contraction Promotion Activity of Modified Oligopeptide
- the collagen gel contraction-promoting activity of the N-terminal acetyl-modified CHTAVDR (No. 3) oligopeptide, N-terminal succinyl-modified CHTAVDR (No. 3) oligopeptide, N-terminal succinyl-modified CHTAVDR (No. 3), and N-terminal palmitoyl-modified CHTAVDR (Biologica Inc.) were evaluated.
- Add 0.94 g of MEM, 500 ⁇ L of 1 mol/L NaHCO 3 , 29.2 mg of L-glutamine, and 1 mL of bovine serum to each well of a 24-well plate.
- Table 3 shows the results.
- Example 4 Comparison of Collagen Gel Contraction Promotion Activity with Other Agents for Improving Wrinkles, Sagging, and Elasticity
- Collagen gel contraction promoting activity of niacinamide (Sigma-Aldrich) and palmitoyl tripeptide-5 “(Pal)-Lys-Val-Lys-[OH]” (PH Japan Co., Ltd.)
- Collagen gel contraction-promoting activities of AVD (No. 10) oligopeptides were compared.
- Add 0.94 g of MEM, 500 ⁇ L of 1 mol/L NaHCO 3 , 29.2 mg of L-glutamine, and 1 mL of bovine serum to each well of a 24-well plate.
- test sample culture and observation were performed in the same manner as described above, except that the solvent used for the preparation of the test sample was used instead of the test sample.
- Bovine lactoferrin was used as a positive control sample.
- Three gels were prepared and incubated for each sample (n 3), the gel area was measured, and the mean and standard deviation were determined.
- Table 4 shows the results. Addition of the AVD oligopeptide at a final concentration of 100 ⁇ g/mL and the niacinamide at a final concentration of 100 ⁇ g/mL significantly reduced the area of the collagen gel compared to the control, that is, promoted contraction of the collagen gel. It was confirmed that it has the effect of improving wrinkles, sagging, and lack of firmness of the skin. In addition, there is a significant difference between the decrease in collagen gel area caused by the AVD oligopeptide and the decrease in collagen gel area caused by niacinamide. It was confirmed to be significantly greater than the contractile promoting effect of collagen gel. On the other hand, palmitoyl tripeptide-5 at a final concentration of 100 ⁇ g/mL was not found to promote collagen gel contraction.
- the oligopeptide and its derivatives of the present invention are excellent in percutaneous absorbability and are less irritating to the skin, and can effectively improve wrinkles, sagging, sagging, loss of firmness, and loss of elasticity of the skin. and is very useful.
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Abstract
L'un quelconque des oligopeptides (a), (b), (c) et (d) mentionné ci-dessous ou un dérivé de celui-ci a une activité favorisant le retrait du gel de collagène, et peut par conséquent empêcher ou améliorer de manière efficace le plissement, l'abaissement, l'affaissement, la détérioration de l'élasticité ou la détérioration de l'élasticité de la peau. L'invention concerne : (a) Un oligopeptide qui comprend la séquence d'acides aminés AV, SCHTAVDR, CHTAVDR, CHTAVD, HTAVD, CHTAV, TAVD, HTAV, TAV ou AVD ; (b) un oligopeptide qui comprend une séquence d'acides aminés ayant une telle structure qu'un résidu d'acide aminé est substitué dans la séquence d'acides aminés AV, SCHTAVDR, CHTAVDR, CHTAVD, HTAVD, CHTAV, TAVD, HTAV, TAV ou AVD (à condition que AV soit contenu) et a une activité favorisant le retrait du collagène ; (c) un oligopeptide qui comprend la séquence d'acides aminés DG, LLCLDGTR, LCLDGTR, CLDGTR, LDGTR, LDGT, DGTR, DLG, DGT, SVDGK, SVDG, VDGK, DGK ou VDG ; ou (d) un oligonucléotide qui comprend une séquence d'acides aminés ayant une telle structure qu'un résidu d'acide aminé est substitué dans la séquence d'acides aminés DG, LLCLDGTR, LCLDGTR, CLDGTR, LDGTR, LDGT, DGTR, LDG, DGT, SVDGK, SVDG, VDGK, DGK ou VDG (à condition que DG soit contenu) et a une activité favorisant le retrait du collagène.
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PCT/JP2021/025609 WO2023281657A1 (fr) | 2021-07-07 | 2021-07-07 | Oligopeptide ayant une activité favorisant le retrait du gel de collagène, et son utilisation |
JP2021544714A JPWO2023281657A1 (fr) | 2021-07-07 | 2021-07-07 | |
CN202180096074.8A CN117043175A (zh) | 2021-07-07 | 2021-07-07 | 具有胶原凝胶收缩促进作用的寡肽及其运用 |
JP2022033997A JP2023010554A (ja) | 2021-07-07 | 2022-03-06 | コラーゲンゲル収縮促進作用を有するオリゴペプチド及びその利用 |
JP2022033998A JP7329277B2 (ja) | 2021-07-07 | 2022-03-06 | コラーゲンゲル収縮促進作用を有するオリゴペプチド及びその利用 |
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KR20110083088A (ko) * | 2010-01-13 | 2011-07-20 | 주식회사 웰스킨 | 다이펩타이드를 유효성분으로 포함하는 섬유모세포 증식 조성물 및 상기 조성물을 포함하는 제품 |
JP2012522043A (ja) * | 2009-03-31 | 2012-09-20 | ウェルスキン カンパニー,リミテッド | ジペプチドを有効成分として含む紫外線による紅斑反応抑制組成物 |
JP2016193865A (ja) * | 2015-03-31 | 2016-11-17 | キリン株式会社 | ミクログリア貪食活性亢進のための組成物及びミクログリア貪食活性亢進作用の予測方法 |
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JP2004331564A (ja) * | 2003-05-07 | 2004-11-25 | Snow Brand Milk Prod Co Ltd | 皮膚コラーゲン産生促進剤 |
US8168586B1 (en) * | 2007-11-21 | 2012-05-01 | Celera Corporation | Cancer targets and uses thereof |
WO2010071132A1 (fr) * | 2008-12-15 | 2010-06-24 | カルピス株式会社 | Peptide destiné à l'inhibition du vieillissement cutané |
WO2013039056A1 (fr) * | 2011-09-12 | 2013-03-21 | ロート製薬株式会社 | Composition contenant un hydrolysat de protéines de soja |
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KR20110083088A (ko) * | 2010-01-13 | 2011-07-20 | 주식회사 웰스킨 | 다이펩타이드를 유효성분으로 포함하는 섬유모세포 증식 조성물 및 상기 조성물을 포함하는 제품 |
JP2016193865A (ja) * | 2015-03-31 | 2016-11-17 | キリン株式会社 | ミクログリア貪食活性亢進のための組成物及びミクログリア貪食活性亢進作用の予測方法 |
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