Amino acid-containing protein glycation inhibitor

Abstract

To provide compositions showing an excellent anti-glycation function and the like.SOLUTION: Provided is a protein glycation inhibitor containing as an active ingredient a combination selected from the group consisting of: (A) a combination of an imino acid-based amino acid or a salt thereof and a neutral amino acid or a salt thereof; (B) a combination of an imino acid-based amino acid or a salt thereof and a basic amino acid or a salt thereof; (C) a combination of an acidic amino acid or a salt thereof and a neutral amino acid or a salt thereof; (D) a combination of an acidic amino acid or a salt thereof and a basic amino acid or a salt thereof; (E) a combination of a lactam carboxylic acid or a salt thereof and a neutral amino acid or a salt thereof; (F) a combination of a lactam carboxylic acid or a salt thereof and a basic amino acid or a salt thereof; and (G) a combination of a lactam carboxylic acid or a salt thereof and an acidic amino acid or a salt thereof.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a protein glycation inhibitor containing an amino acid, etc.

Background Art

[0002] As the skin ages, wrinkles, spots, sagging, and dullness increase, while firmness and elasticity decrease. Therefore, suppression of skin aging is very important for maintaining a youthful and beautiful skin. It is known that skin aging mainly involves two chemical reactions: glycation reaction and oxidation reaction.

[0003] The non-enzymatic reaction between the amino group of an amino acid or protein and the carbonyl group of a sugar is called the Maillard reaction (Non-Patent Document 1). The Maillard reaction is sometimes also called the glycation reaction, but the broad sense of the glycation reaction refers to complex reactions such as non-enzymatic reactions, enzymatic reactions, oxidation, decomposition, and transfer that occur between sugars or glycation reaction intermediates, and the exact mechanism is not known. Various glycation reactions that contribute to skin aging are known. In the skin, for example, various proteins such as keratin in the stratum corneum, collagen, elastin, and fibronectin in the dermis layer cause glycation reactions with sugars and highly reactive glycation reaction intermediates. The substance finally produced by the glycation reaction is generally called an advanced glycation end product (hereinafter also referred to as "AGEs") (Non-Patent Document 2).

[0004] Since the glycation reaction has various adverse effects on the living body, research on inhibiting the glycation reaction plays a very important role in the field of anti-aging. In particular, in recent years, research on the glycation reaction in the skin has been actively carried out, and the effects of the glycation reaction on the skin have become clear.

[0005] For example, advanced glycation end products (AGEs) produced are not metabolized through normal biological processes and accumulate in the skin, causing wrinkles by destroying healthy skin tissue through mechanisms such as fibroblast apoptosis, premature degradation of normal collagen, and toxicity. Furthermore, the browning of proteins due to glycation reactions and the long-term accumulation of AGEs can cause age spots and dullness (Patent Document 1). In addition, cross-linkable AGEs produced by glycation reactions cross-link collagen fibers and harden them, reducing skin suppleness and elasticity.

[0006] For these reasons, suppressing the production of advanced glycation end products (AGEs) is important for preventing and improving skin aging.

[0007] To date, plant extracts have been known as components that exhibit anti-glycation functions (Patent Documents 2 and 3). However, impurities are inevitably introduced during the extraction process, leading to problems such as discoloration and odor caused by these impurities. Furthermore, there is a possibility of inducing allergies when applied to the skin, resulting in numerous problems.

[0008] While aminoguanidine, which is free of impurities and exhibits other anti-glycation properties, such as plant extracts, is well-known, it has been reported to have side effects such as anemia, liver damage, and vitamin B6 deficiency, raising safety concerns.

[0009] While basic amino acids such as lysine and arginine have been found to inhibit collagen cross-linking as safe anti-glycation ingredients (Patent Document 4), their effectiveness is not considered sufficient. Furthermore, basic amino acids tend to discolor when coexisting with polyhydric alcohols commonly found in cosmetics, making them difficult to incorporate into cosmetics.

[0010] On the other hand, the formation and accumulation of advanced glycation end products (AGEs) are thought to be causes of neuropathy, retinopathy, renal impairment, microvascular disorders, hypertension, heart failure, atherosclerosis, Alzheimer's disease, and dermatological disorders (Patent Document 5). [Prior art documents] [Patent Documents]

[0011] [Patent Document 1] WO2012 / 014901 [Patent Document 2] WO2011 / 112799 [Patent Document 3] Japanese Patent Publication No. 2013-253072 [Patent Document 4] Japanese Patent Publication No. 2001-39816 [Patent Document 5] WO2010 / 128528 [Non-patent literature]

[0012] [Non-Patent Document 1] Mauron Prog.Fd.Nutur.Sci.,5:5-35,1981 [Non-Patent Document 2] M.Ichihashi,Anti-Aging Medicine,8,23-29,2011 [Overview of the Initiative] [Problems that the invention aims to solve]

[0013] The object of the present invention is to provide a composition or the like that exhibits excellent anti-glycation function. [Means for solving the problem]

[0014] In view of the above problems, the present inventors conducted diligent research and found that by using a specific combination of amino acids, a high synergistic effect between the amino acids can be obtained, resulting in a composition that exhibits excellent anti-glycation function, thus completing the present invention.

[0015] [1] (A) combinations of imino acid amino acids or salts thereof and neutral amino acids or salts thereof, (B) A combination of an imino acid amino acid or a salt thereof and a basic amino acid or a salt thereof, (C) A combination of an acidic amino acid or its salt and a neutral amino acid or its salt, (D) A combination of an acidic amino acid or its salt and a basic amino acid or its salt, (E) A combination of a lactam carboxylic acid or its salt and a neutral amino acid or its salt, (F) A combination of a lactam carboxylic acid or its salt and a basic amino acid or its salt, and (G) A combination of a lactam carboxylic acid or its salt and an acidic amino acid or its salt <9>A protein glycation inhibitor characterized by containing, as an active ingredient, a combination selected from the group consisting of [2] (A-a) A combination of two imino acid-based amino acids or their salts, (A-b) A combination of an imino acid-based amino acid or its salt and a hydroxy amino acid or its salt, (A-c) A combination of an imino acid-based amino acid or its salt and an aliphatic amino acid or its salt, (A-d) A combination of an imino acid-based amino acid or its salt and an aromatic amino acid or its salt, (A-e) A combination of an imino acid-based amino acid or its salt and a sulfur-containing amino acid or its salt, (B) A combination of an imino acid-based amino acid or its salt and a basic amino acid or its salt, (C-a) A combination of an acidic amino acid or its salt and an imino acid-based amino acid or its salt, (C-b) A combination of an acidic amino acid or its salt and a hydroxy amino acid or its salt, (C-c) A combination of an acidic amino acid or its salt and an aromatic amino acid or its salt, (C-d) A combination of an acidic amino acid or its salt and a sulfur-containing amino acid or its salt, ) A combination of an acidic amino acid or its salt and a basic amino acid or its salt, (E-a) A combination of a lactam carboxylic acid or its salt and an imino acid-based amino acid or its salt, (E-b) A combination of a lactam carboxylic acid or its salt and a hydroxy amino acid or its salt, (F) A combination of a lactam carboxylic acid or its salt and a basic amino acid or its salt, and (G) A combination selected from the group consisting of lactam carboxylic acid or a salt thereof and an acidic amino acid or a salt thereof The protein glycation inhibitor according to [1] above, characterized by containing, as an active ingredient, a combination selected from the group consisting of [3] (A-1) A combination of proline or a salt thereof and alanine or a salt thereof, (A-2) A combination of proline or a salt thereof and valine or a salt thereof, (A-3) A combination of proline or a salt thereof and methionine or a salt thereof, (A-4) A combination of proline or a salt thereof and phenylalanine or a salt thereof, (A-5) A combination of proline or a salt thereof and serine or a salt thereof, (A-6) A combination of proline or a salt thereof and hydroxyproline or a salt thereof, (A-7) A combination of hydroxyproline or a salt thereof and alanine or a salt thereof, (A-8) A combination of hydroxyproline or a salt thereof and methionine or a salt thereof, (A-9) A combination of hydroxyproline or a salt thereof and taurine or a salt thereof, (A-10) A combination of hydroxyproline or a salt thereof and phenylalanine or a salt thereof, (A-11) A combination of hydroxyproline or a salt thereof and serine or a salt thereof, (B-1) A combination of proline or a salt thereof and lysine or a salt thereof, (B-2) A combination of proline or a salt thereof and histidine or a salt thereof, (B-3) A combination of hydroxyproline or a salt thereof and lysine or a salt thereof, (B-4) A combination of hydroxyproline or a salt thereof and histidine or a salt thereof, (C-1) A combination of aspartic acid or a salt thereof and taurine or a salt thereof, (C-2) A combination of aspartic acid or a salt thereof and tryptophan or a salt thereof, (C-3) A combination of aspartic acid or a salt thereof and threonine or a salt thereof, (C-4) A combination of aspartic acid or a salt thereof and serine or a salt thereof, (C-5) A combination of aspartic acid or a salt thereof and proline or a salt thereof, (C-6) A combination of aspartic acid or a salt thereof and hydroxyproline or a salt thereof, (C-7) A combination of glutamic acid or a salt thereof and threonine or a salt thereof, (C-8) A combination of glutamic acid or a salt thereof and proline or a salt thereof, (C-9) A combination of glutamic acid or a salt thereof and hydroxyproline or a salt thereof, (D-1) A combination of aspartic acid or a salt thereof and arginine or a salt thereof, (D-2) A combination of aspartic acid or a salt thereof and lysine or a salt thereof, (D-3) A combination of aspartic acid or a salt thereof and histidine or a salt thereof. (E-1) A combination of pyrrolidone carboxylic acid or a salt thereof and hydroxyproline or a salt thereof, (E-2) A combination of pyrrolidone carboxylic acid or a salt thereof and serine or a salt thereof, (F-1) A combination of pyrrolidone carboxylic acid or a salt thereof and lysine or a salt thereof. (F-2) Pyrrolidone carboxylic acid or a salt thereof and histidine or a salt thereof, and (G-1) Combination of pyrrolidone carboxylic acid or its salt and aspartic acid or its salt The protein glycation inhibitor described in [2] above, characterized by containing a combination selected from the group consisting of the above as an active ingredient. [4] A protein glycation inhibitor according to any one of [1] to [3] above, characterized by suppressing the formation of fluorescent advanced glycation end products. [5] A protein glycation inhibitor according to any one of [1] to [4] above, characterized in that the protein is a protein found in the skin. [6] A protein glycation inhibitor according to any one of [1] to [5] above, characterized in that the protein is selected from the group consisting of collagen, elastin, fibronectin, and keratin. [7] A cosmetic composition characterized by containing any of the protein glycation inhibitors described in [1] to [6] above. [8] (A) combinations of imino acid amino acids or salts thereof and neutral amino acids or salts thereof, (B) A combination of an imino acid amino acid or a salt thereof and a basic amino acid or a salt thereof, (C) A combination of an acidic amino acid or its salt and a neutral amino acid or its salt. (D) A combination of an acidic amino acid or its salt and a basic amino acid or its salt, (E) A combination of lactam carboxylic acid or a salt thereof and a neutral amino acid or a salt thereof. (F) A combination of lactam carboxylic acid or a salt thereof and a basic amino acid or a salt thereof, (G) A combination of lactam carboxylic acid or a salt thereof and an acidic amino acid or a salt thereof. A composition for preventing and / or improving skin aging, characterized by containing a combination selected from the group consisting of the following as an active ingredient. [9] The composition according to [8] above, characterized in that skin aging is selected from the group consisting of wrinkle formation, age spot formation, sagging, and dullness.

[10] (A) combinations of imino acid amino acids or salts thereof and neutral amino acids or salts thereof (B) A combination of an imino acid amino acid or a salt thereof and a basic amino acid or a salt thereof, (C) A combination of an acidic amino acid or its salt and a neutral amino acid or its salt. (D) A combination of an acidic amino acid or its salt and a basic amino acid or its salt, (E) A combination of lactam carboxylic acid or a salt thereof and a neutral amino acid or a salt thereof. (F) A combination of lactam carboxylic acid or a salt thereof and a basic amino acid or a salt thereof, (G) A combination of lactam carboxylic acid or a salt thereof and an acidic amino acid or a salt thereof. A composition for the treatment and / or prevention of diseases caused by the formation and / or accumulation of advanced glycation end products, characterized by containing a combination selected from the group consisting of the above as an active ingredient.

[11] The composition according to

[10] above, characterized in that the disease is selected from the group consisting of neuropathy, retinopathy, renal impairment, microvascular disorders, hypertension, heart failure, atherosclerosis, Alzheimer's disease, and dermatological disorders.

[12] (A) combinations of imino acid amino acids or salts thereof and neutral amino acids or salts thereof, (B) A combination of an imino acid amino acid or a salt thereof and a basic amino acid or a salt thereof, (C) A combination of an acidic amino acid or its salt and a neutral amino acid or its salt. (D) A combination of an acidic amino acid or its salt and a basic amino acid or its salt, (E) A combination of lactam carboxylic acid or a salt thereof and a neutral amino acid or a salt thereof. (F) A combination of lactam carboxylic acid or a salt thereof and a basic amino acid or a salt thereof, (G) A combination of lactam carboxylic acid or a salt thereof and an acidic amino acid or a salt thereof. A method for inhibiting protein glycation, comprising administering an effective amount of a composition, characterized by containing a combination selected from the group consisting of the following as an active ingredient, to a person in need of it.

[13] (A) combinations of imino acid amino acids or salts thereof and neutral amino acids or salts thereof, (B) A combination of an imino acid amino acid or a salt thereof and a basic amino acid or a salt thereof, (C) A combination of an acidic amino acid or its salt and a neutral amino acid or its salt. (D) A combination of an acidic amino acid or its salt and a basic amino acid or its salt, (E) A combination of lactam carboxylic acid or a salt thereof and a neutral amino acid or a salt thereof. (F) A combination of lactam carboxylic acid or a salt thereof and a basic amino acid or a salt thereof, (G) A combination of lactam carboxylic acid or a salt thereof and an acidic amino acid or a salt thereof. A method for preventing and / or improving skin aging, comprising administering an effective amount of a composition containing a combination selected from the group consisting of the following as an active ingredient to a person in need of it.

[14] (A) combinations of imino acid amino acids or salts thereof and neutral amino acids or salts thereof, (B) A combination of an imino acid amino acid or a salt thereof and a basic amino acid or a salt thereof, (C) A combination of an acidic amino acid or its salt and a neutral amino acid or its salt. (D) A combination of an acidic amino acid or its salt and a basic amino acid or its salt, (E) A combination of lactam carboxylic acid or a salt thereof and a neutral amino acid or a salt thereof. (F) A combination of lactam carboxylic acid or a salt thereof and a basic amino acid or a salt thereof, (G) A combination of lactam carboxylic acid or a salt thereof and an acidic amino acid or a salt thereof. A method for treating and / or preventing diseases caused by the formation and / or accumulation of advanced glycation end products, comprising administering an effective amount of a composition containing a combination selected from the group consisting of the above as an active ingredient to a person in need thereof.

[15] For the manufacture of protein glycation inhibitors (A) A combination of an imino acid amino acid or a salt thereof and a neutral amino acid or a salt thereof, (B) A combination of an imino acid amino acid or a salt thereof and a basic amino acid or a salt thereof, (C) A combination of an acidic amino acid or its salt and a neutral amino acid or its salt. (D) A combination of an acidic amino acid or its salt and a basic amino acid or its salt, (E) A combination of lactam carboxylic acid or a salt thereof and a neutral amino acid or a salt thereof. (F) A combination of lactam carboxylic acid or a salt thereof and a basic amino acid or a salt thereof, (G) A combination of lactam carboxylic acid or a salt thereof and an acidic amino acid or a salt thereof. The use of combinations selected from a group consisting of [the specified elements].

[16] For the manufacture of agents for the prevention and / or improvement of skin aging (A) A combination of an imino acid amino acid or a salt thereof and a neutral amino acid or a salt thereof, (B) A combination of an imino acid amino acid or a salt thereof and a basic amino acid or a salt thereof, (C) A combination of an acidic amino acid or its salt and a neutral amino acid or its salt. (D) A combination of an acidic amino acid or its salt and a basic amino acid or its salt, (E) A combination of lactam carboxylic acid or a salt thereof and a neutral amino acid or a salt thereof. (F) A combination of lactam carboxylic acid or a salt thereof and a basic amino acid or a salt thereof, (G) A combination of lactam carboxylic acid or a salt thereof and an acidic amino acid or a salt thereof. The use of combinations selected from a group consisting of [the specified elements].

[17] For the manufacture of therapeutic and / or prophylactic agents for diseases caused by the formation and / or accumulation of advanced glycation end products (A) A combination of an imino acid amino acid or a salt thereof and a neutral amino acid or a salt thereof, (B) A combination of an imino acid amino acid or a salt thereof and a basic amino acid or a salt thereof, (C) A combination of an acidic amino acid or its salt and a neutral amino acid or its salt. (D) A combination of an acidic amino acid or its salt and a basic amino acid or its salt, (E) A combination of lactam carboxylic acid or a salt thereof and a neutral amino acid or a salt thereof. (F) A combination of lactam carboxylic acid or a salt thereof and a basic amino acid or a salt thereof, (G) A combination of lactam carboxylic acid or a salt thereof and an acidic amino acid or a salt thereof. The use of combinations selected from a group consisting of [the specified elements]. [Effects of the Invention]

[0016] According to the present invention, it is possible to obtain compositions that exhibit excellent anti-glycation function through the synergistic effect of specific amino acid combinations. [Modes for carrying out the invention]

[0017] The present invention will be described in detail below with reference to its preferred embodiments. However, the present invention is not limited to the embodiments and examples described below, and can be implemented with modifications as appropriate without departing from the scope of the claims and equivalents of the present invention.

[0018] In one embodiment, the present invention provides a protein glycation inhibitor characterized by containing as an active ingredient a combination selected from the group consisting of (A) an imino acid amino acid or a salt thereof and a neutral amino acid or a salt thereof, (B) an imino acid amino acid or a salt thereof and a basic amino acid or a salt thereof, (C) an acidic amino acid or a salt thereof and a neutral amino acid or a salt thereof, (D) an acidic amino acid or a salt thereof and a basic amino acid or a salt thereof, (E) a lactam carboxylic acid or a salt thereof and a neutral amino acid or a salt thereof, (F) a lactam carboxylic acid or a salt thereof and a basic amino acid or a salt thereof, and (G) a lactam carboxylic acid or a salt thereof and an acidic amino acid or a salt thereof (which may be referred to as a "specific amino acid combination" in this specification).

[0019] Because the protein glycation inhibitor of the present invention contains a specific combination of amino acids as an active ingredient, a high synergistic effect is obtained, and therefore it can suppress the formation of advanced glycation end products more effectively than when a single amino acid is used alone.

[0020] Therefore, in one embodiment, the present invention provides a method for inhibiting protein glycation, which includes administering an effective amount of a composition containing a specific combination of amino acids as an active ingredient to a person in need of it.

[0021] Furthermore, since the protein glycation inhibitor of the present invention has the function of suppressing the formation of advanced glycation end products, it is useful for preventing and / or improving skin aging caused by the formation and / or accumulation of advanced glycation end products, such as the formation of wrinkles, the appearance of age spots, the appearance of sagging skin, and the appearance of dullness.

[0022] Accordingly, in one embodiment, the present invention provides a composition for preventing and / or improving skin aging caused by the formation and / or accumulation of advanced glycation end products, such as the formation of wrinkles, the appearance of age spots, the appearance of sagging skin, and the appearance of dullness, characterized by containing a specific combination of amino acids as an active ingredient.

[0023] Furthermore, in one embodiment, the present invention provides a method for preventing and / or improving skin aging caused by the formation and / or accumulation of advanced glycation end products, such as the formation of wrinkles, the appearance of age spots, the appearance of sagging skin, and the appearance of dullness, by administering an effective amount of a composition containing a specific combination of amino acids as an active ingredient to a person in need thereof.

[0024] Furthermore, since the protein glycation inhibitor of the present invention has the function of suppressing the formation of advanced glycation end products, it is useful for the treatment and / or prevention of diseases caused by the formation and / or accumulation of advanced glycation end products, such as neuropathy, retinopathy, renal impairment, microvascular disorders, hypertension, heart failure, atherosclerosis, Alzheimer's disease, and dermatological disorders.

[0025] Accordingly, in one embodiment, the present invention provides a composition for the treatment and / or prevention of diseases caused by the formation and / or accumulation of advanced glycation end products, such as neuropathy, retinopathy, renal impairment, microvascular disorders, hypertension, heart failure, atherosclerosis, Alzheimer's disease, and dermatological disorders, characterized by containing a specific combination of amino acids as an active ingredient.

[0026] Furthermore, in one embodiment, the present invention provides a method for treating and / or preventing diseases caused by the formation and accumulation of advanced glycation end products, such as neuropathy, retinopathy, renal impairment, microvascular disorders, hypertension, heart failure, atherosclerosis, Alzheimer's disease, and dermatological disorders, which involves administering an effective amount of a composition containing a specific combination of amino acids as an active ingredient to a person in need thereof.

[0027] The following describes the components contained in the protein glycation inhibitor or composition of the present invention.

[0028] (Active ingredients) The protein glycation inhibitor or composition of the present invention contains, as an active ingredient, a combination selected from the group consisting of (A) a combination of an imino acid amino acid or a salt thereof and a neutral amino acid or a salt thereof, (B) a combination of an imino acid amino acid or a salt thereof and a basic amino acid or a salt thereof, (C) a combination of an acidic amino acid or a salt thereof and a neutral amino acid or a salt thereof, (D) a combination of an acidic amino acid or a salt thereof and a basic amino acid or a salt thereof, (E) a combination of a lactam carboxylic acid or a salt thereof and a neutral amino acid or a salt thereof, (F) a combination of a lactam carboxylic acid or a salt thereof and a basic amino acid or a salt thereof, and (G) a combination of a lactam carboxylic acid or a salt thereof and an acidic amino acid or a salt thereof.

[0029] Neutral amino acids are defined as amino acids in which the number of acidic carboxyl groups and basic amino groups in the molecule is equal. Neutral amino acids may be D-forms, L-forms, or mixtures thereof. Furthermore, neutral amino acids include not only amino acids that make up proteins, but also amino acids that do not make up proteins. In addition, neutral amino acids include not only α-amino acids, but also β-amino acids, γ-amino acids, δ-amino acids, etc. These may be individual amino acids or combinations of two or more.

[0030] Examples of neutral amino acids include glycine, aliphatic amino acids, aromatic amino acids, hydroxy amino acids, sulfur-containing amino acids, imino acid amino acids, and acid amide amino acids.

[0031] Aliphatic amino acids are amino acids in which an alkyl group is bonded to an α-carbon atom. Examples include alanine, α-aminobutyric acid, valine, norvaline, leucine, isoleucine, norleucine, and homonorleucine.

[0032] Aromatic amino acids are amino acids in which an aromatic group is bonded to an aliphatic amino acid. Examples include tyrosine, tryptophan, phenylalanine, metatyrosine, thyronine, dopa, and thyroxine.

[0033] Hydroxy amino acids are amino acids in which a hydroxyl group is attached to an aliphatic amino acid, and examples include serine, threonine, and homoserine.

[0034] Sulfur-containing amino acids refer to amino acids in which any carbon atom is replaced by a sulfur atom, and include amino acids in which a carboxyl group is replaced by a sulfo group. Examples include cysteine, methionine, homocysteine, and taurine.

[0035] Imino acid amino acids refer to amino acids in which the side chain of an aliphatic amino acid is bonded to an α-amino group to form a ring. Examples include proline, hydroxyproline, and pipecolic acid.

[0036] Acid amide amino acids refer to amino acids in which the carboxyl group of the side chain of an acidic amino acid is amidated. Examples include asparagine, glutamine, and theanine.

[0037] Basic amino acids are defined as amino acids in which the number of basic amino groups is greater than the number of acidic carboxyl groups in the molecule. Here, basic amino acids may be D-forms, L-forms, or mixtures thereof. Furthermore, basic amino acids include not only amino acids that constitute proteins, but also those that do not. Basic amino acids also include not only α-amino acids, but also β-amino acids, γ-amino acids, δ-amino acids, etc. These may be individual amino acids or combinations of two or more.

[0038] Examples of basic amino acids include arginine, histidine, and lysine.

[0039] Acidic amino acids refer to amino acids in which the number of acidic carboxyl groups is greater than the number of basic amino groups in the molecule. Here, acidic amino acids may be D-forms, L-forms, or mixtures thereof. Furthermore, acidic amino acids include not only amino acids that make up proteins, but also amino acids that do not make up proteins. In addition, acidic amino acids include not only α-amino acids, but also β-amino acids, γ-amino acids, δ-amino acids, etc. These may be individual or in combination of two or more types.

[0040] Examples of acidic amino acids include aspartic acid and glutamic acid.

[0041] Lactam carboxylic acid refers to a carboxyl group-containing lactam compound formed by the condensation of a carboxyl group and an α-amino group of an acidic amino acid side chain to form a lactam ring. Here, the lactam carboxylic acid may be the D-isomer, the L-isomer, or a mixture thereof. These may be a single compound or a combination of two or more compounds.

[0042] Examples of lactam carboxylic acids include pyroglutamic acid (pyrrolidone carboxylic acid), 4-hydroxypyroglutamic acid, and 6-oxopiperidine-2-carboxylic acid.

[0043] The active ingredient of the protein glycation inhibitor or composition of the present invention is preferably, (Aa) A combination of two imino acid amino acids or their salts, (Ab) A combination of an imino acid amino acid or a salt thereof and a hydroxy amino acid or a salt thereof, (Ac) A combination of an imino acid amino acid or its salt and an aliphatic amino acid or its salt, (Ad) Combinations of imino acid amino acids or their salts and aromatic amino acids or their salts, (Ae) A combination of imino acid amino acids or their salts and sulfur-containing amino acids or their salts, (B) A combination of an imino acid amino acid or a salt thereof and a basic amino acid or a salt thereof, (Ca) combination of an acidic amino acid or its salt and an imino acid amino acid or its salt, (Cb) A combination of an acidic amino acid or its salt and a hydroxyamino acid or its salt, (Cc) A combination of an acidic amino acid or its salt and an aromatic amino acid or its salt, (Cd) A combination of an acidic amino acid or its salt and a sulfur-containing amino acid or its salt, (D) A combination of an acidic amino acid or its salt and a basic amino acid or its salt, (Ea) A combination of lactam carboxylic acid or a salt thereof and an imino acid amino acid or a salt thereof, (Eb) A combination of lactam carboxylic acid or a salt thereof and a hydroxyamino acid or a salt thereof, (F) A combination of lactam carboxylic acid or a salt thereof and a basic amino acid or a salt thereof, (G) Selected from the group consisting of a combination of a lactam carboxylic acid or a salt thereof and an acidic amino acid or a salt thereof.

[0044] The active ingredient of the protein glycation inhibitor or composition of the present invention is more preferably, (A-1) A combination of proline or a salt thereof and alanine or a salt thereof, (A-2) A combination of proline or a salt thereof and valine or a salt thereof, (A-3) A combination of proline or a salt thereof and methionine or a salt thereof, (A-4) A combination of proline or a salt thereof and phenylalanine or a salt thereof, (A-5) A combination of proline or a salt thereof and serine or a salt thereof, (A-6) A combination of proline or a salt thereof and hydroxyproline or a salt thereof, (A-7) A combination of hydroxyproline or a salt thereof and alanine or a salt thereof, (A-8) A combination of hydroxyproline or a salt thereof and methionine or a salt thereof, (A-9) A combination of hydroxyproline or a salt thereof and taurine or a salt thereof, (A-10) A combination of hydroxyproline or a salt thereof and phenylalanine or a salt thereof, (A-11) A combination of hydroxyproline or a salt thereof and serine or a salt thereof, (B-1) A combination of proline or a salt thereof and lysine or a salt thereof, (B-2) A combination of proline or a salt thereof and histidine or a salt thereof, (B-3) A combination of hydroxyproline or a salt thereof and lysine or a salt thereof, (B-4) A combination of hydroxyproline or a salt thereof and histidine or a salt thereof, (C-1) A combination of aspartic acid or a salt thereof and taurine or a salt thereof, (C-2) A combination of aspartic acid or a salt thereof and tryptophan or a salt thereof (C-3) A combination of aspartic acid or a salt thereof and threonine or a salt thereof, (C-4) A combination of aspartic acid or a salt thereof and serine or a salt thereof, (C-5) A combination of aspartic acid or a salt thereof and proline or a salt thereof, (C-6) A combination of aspartic acid or a salt thereof and hydroxyproline or a salt thereof, (C-7) A combination of glutamic acid or a salt thereof and threonine or a salt thereof, (C-8) A combination of glutamic acid or a salt thereof and proline or a salt thereof, (C-9) A combination of glutamic acid or a salt thereof and hydroxyproline or a salt thereof, (D-1) A combination of aspartic acid or a salt thereof and arginine or a salt thereof, (D-2) A combination of aspartic acid or a salt thereof and lysine or a salt thereof, (D-3) A combination of aspartic acid or a salt thereof and histidine or a salt thereof. (E-1) A combination of pyrrolidone carboxylic acid or a salt thereof and hydroxyproline or a salt thereof, (E-2) A combination of pyrrolidone carboxylic acid or a salt thereof and serine or a salt thereof, (F-1) A combination of pyrrolidone carboxylic acid or a salt thereof and lysine or a salt thereof. (F-2) Pyrrolidone carboxylic acid or a salt thereof and histidine or a salt thereof, and (G-1) Combination of pyrrolidone carboxylic acid or its salt and aspartic acid or its salt It is selected from the group consisting of the following.

[0045] The active ingredient of the protein glycation inhibitor or composition of the present invention is more preferably, (A-1) A combination of proline or a salt thereof and alanine or a salt thereof, (A-4) A combination of proline or a salt thereof and phenylalanine or a salt thereof, (A-6) A combination of proline or a salt thereof and hydroxyproline or a salt thereof, (A-9) A combination of hydroxyproline or a salt thereof and taurine or a salt thereof, (A-10) A combination of hydroxyproline or a salt thereof and phenylalanine or a salt thereof, (B-2) A combination of proline or a salt thereof and histidine or a salt thereof, (B-4) A combination of hydroxyproline or a salt thereof and histidine or a salt thereof, (C-1) A combination of aspartic acid or a salt thereof and taurine or a salt thereof, (C-2) A combination of aspartic acid or a salt thereof and tryptophan or a salt thereof (C-5) A combination of aspartic acid or a salt thereof and proline or a salt thereof, (C-7) A combination of glutamic acid or a salt thereof and threonine or a salt thereof, (C-8) A combination of glutamic acid or a salt thereof and proline or a salt thereof, (C-9) A combination of glutamic acid or a salt thereof and hydroxyproline or a salt thereof, (D-1) A combination of aspartic acid or a salt thereof and arginine or a salt thereof, (D-3) A combination of aspartic acid or a salt thereof and histidine or a salt thereof, (G-1) Combination of pyrrolidone carboxylic acid or its salt and aspartic acid or its salt It is selected from the group consisting of the following. Depending on the combination of these amino acids, a higher synergistic effect can be obtained in suppressing glycation.

[0046] The active ingredient of the protein glycation inhibitor or composition of the present invention is, particularly preferably, (A-1) A combination of proline or a salt thereof and alanine or a salt thereof, (A-4) A combination of proline or a salt thereof and phenylalanine or a salt thereof, (A-6) A combination of proline or a salt thereof and hydroxyproline or a salt thereof, (A-9) A combination of hydroxyproline or a salt thereof and taurine or a salt thereof, (C-1) A combination of aspartic acid or a salt thereof and taurine or a salt thereof, (C-2) A combination of aspartic acid or a salt thereof and tryptophan or a salt thereof (C-5) A combination of aspartic acid or a salt thereof and proline or a salt thereof, (C-7) A combination of glutamic acid or a salt thereof and threonine or a salt thereof, (C-8) A combination of glutamic acid or a salt thereof and proline or a salt thereof, (C-9) A combination of glutamic acid or a salt thereof and hydroxyproline or a salt thereof, (D-1) A combination of aspartic acid or a salt thereof and arginine or a salt thereof, (G-1) Combination of pyrrolidone carboxylic acid or its salt and aspartic acid or its salt It is selected from a group consisting of the following. These amino acid combinations can yield a very high synergistic effect in inhibiting glycation.

[0047] The active ingredient salts in this invention, which are neutral amino acids, acidic amino acids, basic amino acids, or pyrrolidone carboxylic acids (hereinafter collectively referred to as "active amino acids"), may be any salts that are cosmetically and / or pharmaceutically acceptable. For example, for acidic groups such as carboxyl groups, salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; aluminum salts; zinc salts; triethylamine, ethanolamine, morpholine, pyrrolidine, piperidine, pipe Examples include salts with radins and organic amines such as dicyclohexylamine. For basic groups such as amino groups, examples include salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, and hydrobromic acid; salts with organic carboxylic acids such as formic acid, acetic acid, propionic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, butyric acid, pamoic acid, enanthic acid, decanoic acid, salicylic acid, lactic acid, oxalic acid, mandelic acid, and malic acid; and salts with organic sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

[0048] In a protein glycation inhibitor or composition, the content of one effective amino acid or its salt in a combination of effective amino acids is preferably 0.01 to 100 by weight relative to the other effective amino acid or its salt, more preferably 0.1 to 10, and the molar ratio is preferably 0.01 to 100, more preferably 0.1 to 10.

[0049] For example, when using a protein glycation inhibitor or composition in an external composition such as a cosmetic for the prevention or improvement of skin aging, the effective amount of the specific amino acid combination of the present invention in the external composition is not particularly limited as long as it is at a concentration that can suppress protein glycation. However, it is preferably 0.001% by mass or more, more preferably 0.05% by mass or more, and even more preferably 0.1% by mass or more, based on the total mass of the external composition in terms of total effective amino acids. Furthermore, the upper limit is not particularly limited as long as it is possible to manufacture an external composition such as a cosmetic, but it is preferably 50% by mass or less, more preferably 5% by mass or less, and even more preferably 1% by mass or less. In this case, it is preferable to use the external composition once to several times a day.

[0050] For example, when using a protein glycation inhibitor or composition in an oral composition such as a processed food to prevent or improve skin aging, the effective oral intake amount of the specific amino acid combination of the present invention can be appropriately selected according to the age, sex, weight, degree of skin aging, and other conditions of the subject. Typically, it is preferable to take an amount equivalent to 0.01 to 15 mg of total effective amino acids per kg of body weight per day, divided into one to several doses.

[0051] (Other anti-glycation ingredients) The protein glycation inhibitor or composition of the present invention may contain other anti-glycation components in addition to the specific amino acid combination of the present invention. By including other anti-glycation components, the protein glycation inhibitory function can be further enhanced, thereby further improving the effectiveness of preventing and improving skin aging.

[0052] Other anti-glycation components include, for example, ascorbic acid, sodium ascorbate, benfotiamine, pyridoxamine, alpha-lipoic acid, taurine, aspirin, metformin, pioglitazone, pentoxifylline, carnosine, peony extract, mugwort extract, evening primrose extract, aminoguanidine, amla extract, hydrolyzed casein, and hydrolyzed tannins. These may be used individually or in combination of two or more.

[0053] (Cosmetics) In one embodiment, the protein glycation inhibitor or composition of the present invention can be processed into a cosmetic.

[0054] The cosmetic composition of the present invention comprises the protein glycation inhibitor or composition of the present invention. Therefore, by applying it to human skin, for example, it is possible to prevent and / or improve skin aging caused by the generation and / or accumulation of advanced glycation end products, such as the formation of wrinkles, the appearance of age spots, the appearance of sagging, the appearance of dullness, etc.

[0055] The form of the cosmetic may be, for example, a paste, cream, lotion, gel, emulsion, solution, suspension, or oil. It may also be in the form of a powder, pack, or mask.

[0056] Preferred types of cosmetics include external cosmetics that come into direct contact with the skin, such as lotions (including those for the face and hair), serums, cosmetic creams, cosmetic gels, cosmetic emulsions, facial cleansers, cosmetic soaps, eye creams, eyeshadows, eyeliners, makeup bases, BB creams, CC creams, powder foundations, liquid foundations, cream foundations, blushes, mascaras, eyebrow pencils, lipsticks, lip balms, moisturizing creams, face powders, face masks, shampoos, conditioners, liquid body soaps, solid body soaps, liquid hand soaps, solid hand soaps, hand creams, body creams, hair dyes, baby oils, shaving creams, shaving lotions, shaving gels, concealers, bath cosmetics, suntan oils, sunscreen oils, suntan lotions, sunscreen lotions, suntan creams, sunscreen creams, massage creams, massage lotions, ointments, and the like. Methods of using cosmetics include, for example, applying them with your hands, cotton pads, or puffs; applying them to non-woven fabrics; or spraying them from a spray bottle.

[0057] Cosmetics may contain any cosmetically acceptable ingredients as needed. Examples of such optional ingredients include various known ingredients, particularly those known to be used in cosmetics, such as water, lower alcohols, polyhydric alcohols, surfactants, fragrances, pigments, preservatives, antioxidants, emulsifiers, oily components, thickeners, chelating agents, disinfectants, deodorants, pH adjusters, cell activators, moisturizers, blood circulation promoters, UV absorbers, UV scattering agents, vitamins, plant extracts, skin astringents, anti-inflammatory agents, whitening agents, sugars, anti-seborrheic agents, stabilizers, antioxidants, and polyhydric alcohols. These may be used individually or in combination of two or more. The amount of each ingredient can be appropriately determined by those skilled in the art.

[0058] Examples of lower alcohols include ethanol, propanol, isopropanol, and butanol. Examples of polyhydric alcohols include dihydric alcohols such as ethylene glycol, propylene glycol, trimethylene glycol, 1,2-butylene glycol, 1,3-butylene glycol, tetramethylene glycol, 2,3-butylene glycol, pentamethylene glycol, 2-butene-1,4-diol, hexylene glycol, and octylene glycol; trihydric alcohols such as glycerin, trimethylolpropane, and 1,2,6-hexanetriol; tetrahydric alcohols such as pentaerythritol; pentahydric alcohols such as xylitol; hexahydric alcohols such as sorbitol and mannitol; polyhydric alcohol polymers such as diethylene glycol, dipropylene glycol, triethylene glycol, polypropylene glycol, tetraethylene glycol, diglycerin, polyethylene glycol, triglycerin, tetraglycerin, and polyglycerin; and sugars such as maltitol, maltotriose, sucrose, erythritol, glucose, fructose, starch-derived sugars, maltose, xylitol, and starch-derived sugar-reduced alcohols.

[0059] Examples of surfactants include sorbitan fatty acid esters such as sorbitan monoisostearate and sorbitan monolaurate; glycerin fatty acids such as glyceryl monostearate; polyglyceryl monostearate; propylene glycol fatty acid esters such as propylene glycol monostearate; hydrogenated castor oil derivatives such as polyoxyethylene hydrogenated castor oil; polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monolaurate; polyoxyethylene monococonut oil fatty acid glyceryl; glycerin alkyl ethers; alkyl glucosides; polyoxyalkylene alkyl ethers such as polyoxyethylene cetyl ether; amines such as stearylamine and oleylamine; and silicone-based surfactants such as polyoxyethylene methylpolysiloxane copolymers.

[0060] Examples of flavorings include limonene, orange flavor, lychee flavor, lemon flavor, lime flavor, strawberry flavor, pineapple flavor, mint flavor, and grapefruit flavor. Examples of colorants include cochineal red A, patent blue, and chlorophyllin. Examples of preservatives include phenoxyethanol, parabens, sorbic acid, isopropylmethylphenol, benzalkonium chloride, benzoic acid, dehydroacetic acid, hexanediol, pentanediol, chlorhexidine sulfate, and N-coconut oil fatty acid acyl-L-arginine ethyl DL-pyrrolidone carboxylate. Examples of antioxidants include α-tocopherol and sodium sulfite. Examples of emulsifiers include polyoxyl stearate, sorbitan sesquioleate, polysorbate, sodium lauryl sulfate, lauromacrogol, acacia gum, cholesterol, stearic acid, glyceryl monostearate, and povidone.

[0061] Examples of oily components include animal and vegetable oils and fats such as soybean oil, corn oil, cottonseed oil, rapeseed oil, sesame oil, and perilla oil, and their processed oils; fatty acids such as myristic acid, palmitic acid, isopalmitic acid, stearic acid, oleic acid, linoleic acid, and linolenic acid, and their esters; paraffins such as light liquid paraffin and heavy liquid paraffin; higher alcohols such as lauryl alcohol, myristyl alcohol, cetanol, and stearyl alcohol; and waxes such as jojoba oil, rice wax, and propolis. Examples of thickeners include gum arabic, aluminum monostearate, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carmellose, sodium carmellose, calcium carmellose, povidone, and carboxyvinyl polymer. Examples of chelating agents include disodium edetate, trisodium edetate, sodium citrate, sodium polyphosphate, sodium metaphosphate, and gluconic acid.

[0062] Examples of disinfectants include 4-hydroxybenzoic acid and its salts and esters, triclosan, chlorhexidine, phenoxyethanol, menthol, mint oil, glyceryl caprate, glyceryl caprylate, N-alkyl salicylate, N-coconut oil fatty acid acyl-L-arginine ethyl / DL-pyrrolidone carboxylate, benzalkonium chloride, isopropylmethylphenol, etc. Examples of deodorants include lauryl methacrylate, geranyl chloride, acetophenone myristate, benzyl acetate, benzyl propionate, methyl benzoate, methyl phenylacetate, etc. Examples of pH adjusters include citric acid, adipic acid, phosphoric acid, glutamic acid, lactic acid, sulfuric acid, hydrochloric acid, ammonium, sodium citrate, sodium hydroxide, potassium hydroxide, arginine, γ-oryzanol, etc. Examples of cell activators include vitamin A compounds such as retinyl palmitate, collagen, elastin, allantoin, placenta extract, milk protein hydrolysate, bovine spleen extract, bovine blood hydrolysate, calf thymus extract, calf blood dialysis product, and yeast extract.

[0063] Examples of moisturizing agents include polyethylene glycol, propylene glycol, glycerin, 1,3-butylene glycol, xylitol, sorbitol, maltitol, chondroitin sulfate, hyaluronic acid, mucoitin sulfate, carotenoid acid, atelocollagen, cholesteryl-12-hydroxystearate, and sodium lactate. Examples of blood circulation promoting agents include nonyl valerylamide, benzyl nicotinate, β-butoxyethyl nicotinate, capsaicin, gingerol, cantharis tincture, ichthammol, caffeine, tannic acid, α-borneol, tocopherol nicotinate, inositol hexanicotinate, cyclandelate, cinnarizine, trazoline, acetylcholine, verapamil, cepharanthine, and γ-oryzanol. Examples of UV absorbers include para-aminobenzoic acid, homomenthyl-N-acetylanthranilate, amyl salicylate, octyl cinnamate, bisresorcinyl triazine, 3-(4'-methylbenzylidene)-d,l-camphor, 3-benzylidene-d,l-camphor, and 2-phenyl-5-methylbenzoxazole. Examples of UV scattering agents include fine particle titanium dioxide and fine particle zinc oxide.

[0064] Examples of vitamins include vitamin A such as retinol, vitamin B2 such as riboflavin, vitamin B6 such as pyridoxine hydrochloride, vitamin C such as L-ascorbic acid, pantothenic acids such as calcium pantothenate, vitamin D such as cholecalciferol, nicotinic acids such as nicotinic acid, vitamin E such as α-tocopherol, vitamin P, and biotin. Examples of plant extracts include extracts of turmeric, Phellodendron amurense, Coptis japonica, Pueraria lobata, Lithospermum erythrorhizon, Peony, Swertia japonica, Birch, Sage, Loquat, Carrot, Aloe vera, Malva sylvestris, Iris, Grape, Coix lacryma-jobi, Luffa gourd, Lily, Saffron, Cnidium officinale, Ginger, St. John's wort, Rosemary, Garlic, Chili pepper, Sanguisorba officinalis, Citrus unshiu peel, and Angelica acutiloba. Examples of skin astringents include tannic acid.

[0065] Examples of anti-inflammatory agents include allantoin, calamine, dipotassium glycyrrhizinate, sodium glycyrrhizinate, stearyl glycyrrhetinate, 18α-hydroxyglycyrrhetinic acid, guaiazulene, pyridoxine hydrochloride, menthol, camphor, turpentine oil, indomethacin, and salicylic acid. Examples of whitening agents include arbutin and kojic acid. Examples of sugars include glucose, fructose, mannose, sucrose, and trehalose. Examples of anti-seborrheic agents include sulfur and thianthol. Examples of stabilizers include sodium polyacrylate, dibutylhydroxytoluene, and butylhydroxyanisole. Examples of antioxidants include thiotaurine, hypotaurine, α-tocopherol, ascorbic acid, sodium ascorbate, catechin, albumin, ferritin, bilirubin, metallothionein, uric acid, black tea extract, green tea extract, thyme extract, and myrtle extract.

[0066] The amount of the specific amino acid combination of the present invention incorporated into the cosmetic composition may be appropriately determined based on the effective amount and other factors described above.

[0067] The cosmetic composition of the present invention can be manufactured according to conventional methods.

[0068] (processed food) In one embodiment, the protein glycation inhibitor or composition of the present invention can be processed into processed foods.

[0069] The processed food of the present invention contains the protein glycation inhibitor or composition of the present invention. Therefore, for example, by ingesting the processed food, it is possible to prevent and / or improve skin aging caused by the generation and / or accumulation of advanced glycation end products, such as the formation of wrinkles, the appearance of age spots, the appearance of sagging skin, the appearance of dullness, etc.

[0070] Processed foods are foods that have undergone any kind of processing on natural ingredients.

[0071] Foods include general foods, health foods, functional foods (including Foods for Specified Health Uses, Foods for Specified Health Uses with Conditional Approval, and Foods with Nutrient Function Claims), foods for special dietary uses, health supplements, and food additives. Examples of general foods include dairy products, wheat flour products, confectionery, pickles, boiled foods, dried foods, processed foods (such as fish paste products), flours, canned goods, frozen foods, retort foods, and instant foods (such as instant noodles, dry foods, and powdered beverages).

[0072] The amount of the specific amino acid combination of the present invention incorporated into processed foods may be appropriately determined based on the effective oral intake amount described above.

[0073] Processed foods can be manufactured in accordance with conventional laws.

[0074] (Pharmaceutical preparations) In one embodiment, the protein glycation inhibitor or composition of the present invention may be formulated into pharmaceutical preparations such as ointments, liquids, suspensions, emulsions, lotions, gels, tablets, pills, lozenges, powders, granules, capsules, suppositories, and injections (liquids, suspensions, etc.).

[0075] The pharmaceutical formulation of the present invention comprises the protein glycation inhibitor or composition of the present invention. Therefore, by applying it to human skin, for example, it is possible to prevent and / or improve skin aging caused by the generation and / or accumulation of advanced glycation end products, such as the formation of wrinkles, the occurrence of age spots, the occurrence of sagging, the occurrence of dullness, etc. Furthermore, it is possible to treat and / or prevent diseases caused by the generation and / or accumulation of advanced glycation end products, such as neuropathy, retinopathy, renal impairment, microvascular disorders, hypertension, heart failure, atherosclerosis, Alzheimer's disease, dermatological disorders, etc.

[0076] Pharmaceutical formulations are prepared using a specific combination of amino acids of the present invention and a cosmetically and / or pharmaceutically acceptable carrier.

[0077] For ointments, liquids, suspensions, emulsions, lotions, gels, etc., the carriers can be the same ingredients as those described above for cosmetics. For tablets, pills, lozenges, powders, granules, etc., the carriers can be excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, hydrogenated vegetable oil, kaolin, crystalline cellulose, talc, etc.; binders such as water, ethanol, propanol, gelatin, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, acacia powder, tragacanth powder, etc.; dried starch, sodium alginate, agar, laminaran, sodium bicarbonate, calcium carbonate, poly Examples of additives include: disintegrants such as oxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, monoglyceride stearate, starch, and lactose; disintegration inhibitors such as sucrose, stearin, cocoa butter, and hydrogenated oil; absorption enhancers such as quaternary ammonium bases and sodium lauryl sulfate; humectants such as glycerin and starch; adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid; lubricants such as refined talc, stearate, boric acid powder, and polyethylene glycol; colorants; preservatives; fragrances; flavorings; and sweeteners.

[0078] Pharmaceutical preparations can be administered by means of the skin, transderm, oral, intravenous, intraarterial, intramuscular, subcutaneous, intraosseous, intraperitoneal, intradermal, inhalation, enema, eye drops, ear drops, nasal administration, etc. In particular, it is preferable to administer them by applying them to human skin as ointments, liquids, suspensions, emulsions, lotions, or gels.

[0079] The dosage of a pharmaceutical preparation should be appropriately selected according to the amount of ingredients, method of use, the age, sex, weight, condition of the subject, and other conditions.

[0080] The amount of the specific amino acid combination of the present invention incorporated into the pharmaceutical formulation may be appropriately determined based on the effective amount of the topical composition or the effective oral intake amount of the oral composition as described above.

[0081] Pharmaceutical preparations can be manufactured in accordance with conventional laws.

[0082] (Proteins and their advanced glycation end products) The following describes proteins that can be targeted for glycation inhibition in this invention, and advanced glycation end products (AGEs) that are produced when these proteins undergo glycation.

[0083] In this invention, protein glycation refers to the result of a reaction between amino acid residues of a protein and sugars or glycation reaction intermediates, and the reaction mode is not particularly limited. Protein glycation produces advanced glycation end products (AGEs). In this invention, glycation includes both enzymatic and non-enzymatic glycation reactions and is not limited to the Maillard reaction of non-enzymatic glycation reactions, but in one preferred embodiment, it is the Maillard reaction.

[0084] Here, the amino acid residues of proteins that can be glycated may be, for example, basic amino acid residues such as lysine and histidine, but are not particularly limited to these. In protein glycation, basic amino acid residues may react, for example, only the amino group portion, but are not particularly limited to these. In protein glycation, sugars or glycation reaction intermediates, for example, the carbonyl portion, may react, but are not particularly limited to these.

[0085] In the present invention, the proteins that may be targeted for glycation inhibition are not particularly limited as long as they are known proteins, but for example, when used in cosmetics, they may be proteins in the skin. Examples of proteins that may be targeted for glycation inhibition include collagen, elastin, fibronectin, or keratin.

[0086] Examples of sugars that serve as substrates for protein glycation include reducing sugars such as glucose, fructose, maltose, and arabinose. Examples of glycation reaction intermediates include glyoxal, glycolaldehyde, methylglyoxal, 3-deoxyglucosone, and glyceraldehyde. It is known that some glycation reaction intermediates are also produced in vivo from lipid and amino acid metabolic pathways, but in such cases, the glycation reaction intermediate may be a lipid metabolite, an amino acid metabolite, etc., and its origin is not limited. Furthermore, glycation reaction intermediates also include sugar breakdown products produced in glycolysis and polyol metabolism.

[0087] Advanced glycation end products (AGEs) are generally classified into non-fluorescent AGEs and fluorescent AGEs. The protein glycation inhibitor according to the present invention can particularly effectively suppress the formation of fluorescent AGEs.

[0088] Examples of fluorescent advanced glycation end products include fluorescent and crosslinkable advanced glycation end products such as pentosidine, crossrin, and pyropyridine.

[0089] Examples of non-fluorescent advanced glycation end products include non-fluorescent, non-crosslinking advanced glycation end products containing Nε-(carboxymethyl)lysine (CML), Nε-(carboxyethyl)lysine (CEL), Nε-(carboxymethyl)arginine (CMA), pyralin, argupyrimidine, etc.; and non-fluorescent, crosslinking advanced glycation end products containing glyoxal-lysine dimer (GOLD), methylglyoxal-lysine dimer (MOLD), etc.

[0090] (skin aging) The protein glycation inhibitor of the present invention can prevent and / or improve skin aging caused by the generation and / or accumulation of advanced glycation end products. Specific examples of skin aging include, for example, the formation of wrinkles, the appearance of age spots, the appearance of sagging, and the appearance of dullness. Wrinkles refer to fine or deep grooves that form on the skin over time, including dermal and epidermal wrinkles. Age spots refer to areas where melanin has accumulated in the skin, including melasma and senile lentigines. Sagging refers to a condition in which the skin sags due to the effects of gravity, caused by decreased muscle strength or loss of skin elasticity. Dullness refers to a skin condition in which transparency has decreased and brightness and luster have been lost, including dullness of the dermis or epidermis (especially the stratum corneum) of the skin (so-called yellowish dullness). [Examples]

[0091] The present invention will now be described in more detail with reference to examples, comparative examples, and test examples, but the present invention is not limited to the following examples.

[0092] (Examples and Comparative Examples: Preparation of Sample Solutions) Each amino acid component shown in Table 1 was dissolved in 1×PBS (phosphate-buffered saline) buffer at the specified concentrations listed in Table 1, and the pH was adjusted to 7.0 by adding 1M NaOH aqueous solution or 1M HCl to prepare the sample solution. L-isomers were used for all amino acids and pyrrolidone carboxylic acids.

[0093] (Test Example 1: Measurement of fluorescent AGEs (crossrin, pyrropyridine, etc.)) 50 μL of neutralized collagen solution was added to each well of a 96-well plate and pre-incubated at 37°C. 10 μL of the sample solution for each example and comparative example was mixed with 50 μL of 200 mM fructose solution in each well. The mixture was incubated at 60°C for 6 days under humid conditions. Fluorescence intensity at excitation wavelength 370 nm and fluorescence wavelength 440 nm was measured using a plate reader immediately after the reaction and after 6 days. The generation rate of fluorescent AGEs when 1×PBS (phosphate-buffered saline) buffer (pH 7.0) was used instead of the sample was set to 100%, and the inhibition rate of fluorescent AGEs for each sample was calculated using the following formula. The inhibition rate of fluorescent AGEs was then evaluated according to the following evaluation criteria.

[0094] Fluorescent AGEs inhibition rate (%) = 100 - 100 × [{fluorescence intensity (sample solution, after 6 days) - fluorescence intensity (sample solution, day 0)} / {fluorescence intensity (1 × PBS buffer (pH 7.0), after 6 days) - fluorescence intensity (1 × PBS buffer (pH 7.0), day 0)}]

[0095] (Evaluation Criteria) AAA: Fluorescent AGEs suppression rate of 20% or more AA: Fluorescent AGEs inhibition rate 15% to less than 20% A: Fluorescent AGEs suppression rate 10% to less than 15% B: Fluorescent AGEs inhibition rate 4% to less than 10% C: Fluorescence AGEs suppression rate 0% to less than 4% D: Fluorescent AGEs inhibition rate less than 0%

[0096] Furthermore, the fluorescence AGEs inhibition rate (%) calculated above was used as the experimental value, and the ratio of the experimental value to the calculated value was calculated using the following formula. The synergistic effect was then evaluated according to the evaluation criteria below.

[0097] Ratio of experimental value to theoretical value = Experimental value of CML inhibition rate (%) / {(CML inhibition rate of one amino acid at 20 mM (%)) × (concentration of one amino acid in the experiment (mM) / 20 (mM)) + (CML inhibition rate of the other amino acid at 20 mM (%)) × (concentration of the other amino acid in the experiment (mM) / 20 (mM))}

[0098] (Evaluation Criteria) ++: Theoretical value is negative, experimental value is positive +5: The ratio of experimental value to theoretical value is 10.00 or higher. +4: The ratio of experimental value to theoretical value is between 6.00 and 10.00. +3: The ratio of experimental value to theoretical value is between 4.00 and 6.00. +2: The ratio of experimental value to theoretical value is between 2.00 and 4.00. +1: The ratio of experimental value to theoretical value is greater than 1.00 and less than 2.00.

[0099] (Test Example 2: Measurement of the inhibition rate of fluorescent AGEs (pentosidine, etc.)) The experiment was conducted in the same manner as in Test Example 1, except that the fluorescence intensity was measured at an excitation wavelength of 335 nm and an emission wavelength of 385 nm. The fluorescence AGEs suppression rate of each sample was calculated using the formula in Test Example 1, and the fluorescence AGEs suppression rate was evaluated according to the evaluation criteria in Test Example 1. Furthermore, the calculated fluorescence AGEs suppression rate (%) was used as the experimental value, and the ratio of the experimental value to the calculated value was calculated using the formula in Test Example 1, and the synergistic effect was evaluated according to the evaluation criteria in Test Example 1.

[0100] The results of the evaluation of the fluorescence AGEs inhibition rate and synergistic effect in Test Examples 1 and 2 are summarized in Table 1 below.

[0101] [Table 1]

[0102] From these results, it was found that when a composition contains a specific combination of amino acids, a high synergistic effect is obtained, and it exhibits superior anti-glycation function compared to a single amino acid or a combination of basic amino acids. [Industrial applicability]

[0103] According to the present invention, compositions exhibiting excellent anti-glycation functions can be obtained. Therefore, they can be used in the manufacture of cosmetics, processed foods, pharmaceutical preparations, and the like.

Claims

1. (A-1) A combination of proline or a salt thereof and alanine or a salt thereof, (A-2) A combination of proline or a salt thereof and valine or a salt thereof, (A-3) A combination of proline or a salt thereof and methionine or a salt thereof, (A-4) A combination of proline or a salt thereof and phenylalanine or a salt thereof, (A-6) A combination of proline or a salt thereof and hydroxyproline or a salt thereof, (A-8) A combination of hydroxyproline or a salt thereof and methionine or a salt thereof, (A-9) A combination of hydroxyproline or a salt thereof and taurine or a salt thereof, (A-10) A combination of hydroxyproline or a salt thereof and phenylalanine or a salt thereof, and (A-11) A combination of hydroxyproline or a salt thereof and serine or a salt thereof, A protein glycation inhibitor characterized by containing an active ingredient consisting of a combination selected from the group comprising the following (excluding those containing fermented ginger).

2. The protein glycation inhibitor according to claim 1, characterized by suppressing the generation of fluorescent advanced glycation end products.

3. The protein glycation inhibitor according to claim 1 or 2, characterized in that the protein is a protein found in the skin.

4. A protein glycation inhibitor according to any one of claims 1 to 3, characterized in that the protein is selected from the group consisting of collagen, elastin, fibronectin, and keratin.

5. A cosmetic composition for inhibiting protein glycation, characterized by containing the protein glycation inhibitor described in any one of claims 1 to 4 (excluding those containing fermented ginger).

6. (A-1) A combination of proline or a salt thereof and alanine or a salt thereof, (A-2) A combination of proline or a salt thereof and valine or a salt thereof, (A-3) A combination of proline or a salt thereof and methionine or a salt thereof, (A-4) A combination of proline or a salt thereof and phenylalanine or a salt thereof, (A-6) A combination of proline or a salt thereof and hydroxyproline or a salt thereof, (A-8) A combination of hydroxyproline or a salt thereof and methionine or a salt thereof, (A-9) A combination of hydroxyproline or a salt thereof and taurine or a salt thereof, (A-10) A combination of hydroxyproline or a salt thereof and phenylalanine or a salt thereof, and (A-11) A combination of hydroxyproline or a salt thereof and serine or a salt thereof, A protein glycation inhibitor for preventing and / or improving skin aging selected from the group consisting of the occurrence of blemishes, sagging, and dullness (excluding those containing fermented ginger), characterized by containing an active ingredient consisting of a combination selected from the group consisting of the following.

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