Protein glycation inhibitor

Abstract

To provide food compositions and the like for inhibiting protein glycation that exhibit excellent anti-glycation properties, particularly, protein glycation inhibitors that exhibit anti-glycation properties against a wide range of advanced glycation end products, have antioxidant properties, and are resistant to coloring when used in cosmetics and the like, and are highly safe and biocompatible.SOLUTION: Provided is a protein glycation inhibitor characterized in that the constituent amino acids are selected from the group consisting of acidic amino acids, basic amino acids, hydroxy amino acids, branched-chain amino acids, and antioxidant amino acids, and that the constituent amino acid on the C-terminus side contains a dipeptide or a salt thereof, which is an antioxidant amino acid, as an active ingredient.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a protein glycation inhibitor containing a neutral amino acid, a protein glycation inhibitor containing a dipeptide, etc. [Background technology]

[0002] As the skin ages, wrinkles, age spots, sagging skin, and dullness increase, while firmness and luster decrease. Therefore, preventing skin aging is extremely important for maintaining youthful, beautiful skin. It is known that skin aging is mainly related to two chemical reactions: glycation and oxidation.

[0003] A nonenzymatic 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 called a glycation reaction, but in a broad sense, 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 unknown. Various glycation reactions are known to contribute to skin aging. In the skin, for example, various proteins such as keratin in the stratum corneum (horny layer), collagen, elastin, and fibronectin in the dermis layer cause glycation reactions with sugars and highly reactive glycation reaction intermediates. The substances ultimately produced by glycation reactions are generally called advanced glycation end products (hereinafter also referred to as "AGEs") (Non-Patent Document 2).

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

[0005] For example, the generated advanced glycation end products are not metabolized in normal biological processes and accumulate in the skin, destroying healthy skin tissue through apoptosis of fibroblasts, induction of early degradation of normal collagen, and expression of toxicity, thereby causing wrinkles. In addition, browning of proteins due to glycation reactions and accumulation of advanced glycation end products over a long period of time can cause spots and dullness (Patent Document 1). In addition, cross-linked advanced glycation end products generated by glycation reactions cross-link and harden collagen, thereby reducing skin suppleness and elasticity.

[0006] For these reasons, in order to prevent and improve skin aging, it is important to inhibit the production of a wide variety of advanced glycation end products, regardless of the type of advanced glycation end products, such as fluorescent and non-fluorescent, cross-linked and non-cross-linked, etc.

[0007] So far, plant extracts have been known as components that exhibit anti-glycation properties (Patent Documents 2 and 3). However, impurities are inevitably mixed in during the extraction of the extract, which can cause problems with coloring and odor due to the impurities. In addition, there is a possibility that applying the extract to the skin may induce allergies, and so there are many problems.

[0008] Another well-known component that exhibits anti-glycation properties is aminoguanidine, which is free of impurities like plant extracts. However, side effects such as anemia, liver damage, and vitamin B6 deficiency have been reported, raising safety concerns.

[0009] As ingredients that exhibit a highly safe anti-glycation function, basic amino acids such as lysine and arginine have been found to have a collagen cross-linking inhibitory function (Patent Document 4), but the glycation inhibitory function is not sufficient, and it is not known that they are useful for inhibiting the production of a wide range of advanced glycation end products (e.g., fluorescent / cross-linked, non-fluorescent / cross-linked, non-fluorescent / non-cross-linked). For example, Nε-(carboxymethyl)lysine (CML), a non-fluorescent / non-cross-linked advanced glycation end product, is present in large amounts not only in the dermis but also in the stratum corneum, and it has been suggested that it is the cause of dullness of the stratum corneum, but there have been no reports that basic amino acids are useful for such advanced glycation end products. Furthermore, it is known that basic amino acids are prone to coloring when coexisting with polyhydric alcohols that are generally contained in cosmetics, etc., making it difficult to incorporate them into cosmetics, etc.

[0010] Insulin is known as a long-chain peptide that exhibits a highly safe anti-glycation function, but it is difficult to use it as a cosmetic or quasi-drug due to safety and cost considerations. In contrast, dipeptides are compounds in which two amino acids are bonded, and are also the decomposition products of proteins, so they exist in large quantities in the body. Carnosine, a type of dipeptide, exists in the body and is known to have high antioxidant and anti-glycation effects. Dipeptides are a combination of amino acids with a wide variety of functional groups, and the diversity expands due to differences in functional groups and stereochemical configurations, so there is a high possibility that they can control the substances produced in the skin that are related to aging.

[0011] On the other hand, it is known that active oxygen generated in the skin due to internal and external factors such as ultraviolet rays oxidizes the constituent factors of the skin, causing the loss or deterioration of the function of the constituent factors, and contributing to skin aging. In addition, active oxygen generates lipid peroxides, which are a cause of carbonylation, and promote the production of some advanced glycation end products. Therefore, if a component with excellent antioxidant function in addition to anti-glycation function is found, it is thought that skin aging can be further suppressed.

[0012] For these reasons, there is a demand for ingredients that suppress the production of a wide range of advanced glycation end products, have excellent antioxidant properties, and are highly safe and biocompatible so that they can be stably incorporated into cosmetics and other products.

[0013] On the other hand, the production and accumulation of advanced glycation end products is thought to cause neuropathy, retinopathy, nephropathy, microvascular disease, hypertension, heart failure, atherosclerosis, Alzheimer's disease, dermatological disorders, and the like (Patent Document 5).

[0014] On the other hand, it is known that collagen in the dermis turns yellow due to glycation and carbonylation (Patent Document 1), but it is difficult to inhibit the yellowing of collagen in the dermis due to the problem of percutaneous absorption. It is also known that advanced glycation end products accumulate in the stratum corneum, and yellowing of the stratum corneum due to glycation of keratin has been confirmed. It is believed that inhibiting the yellowing of the stratum corneum plays an important role in maintaining the transparency of the skin. [Prior art documents] [Patent documents]

[0015] [Patent Document 1] WO2012 / 014901 [Patent Document 2] WO2011 / 112799 [Patent Document 3] JP 2013-253072 A [Patent Document 4] JP 2001-39816 A [Patent Document 5] WO2010 / 128528 [Non-patent literature]

[0016] [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 Summary of the Invention [Problem to be solved by the invention]

[0017] The first object of the present invention is to provide a composition etc. that exhibits excellent anti-glycation function, in particular, a composition etc. that exhibits anti-glycation function against a wide range of advanced glycation endproducts, has antioxidant function, is unlikely to cause coloration when used in cosmetics etc., and contains a highly safe and biocompatible ingredient.

[0018] A second object of the present invention is to provide a composition or the like containing a component that exhibits a wide range of anti-glycation functions and further has antioxidant functions, while being highly stable, safe and biocompatible. [Means for solving the problem]

[0019] As a result of intensive research conducted in consideration of the above-mentioned first object of the present invention, the inventors have discovered that neutral amino acids having 3 or more carbon atoms exhibit superior anti-glycation function to basic amino acids, are capable of inhibiting the production of a wide range of advanced glycation end products, have excellent antioxidant function, and are less likely to cause coloration even when coexisting with polyhydric alcohols that are generally contained in cosmetics, etc., and have completed a first embodiment of the present invention.

[0020] That is, the first aspect of the present invention includes the following. [1] A protein glycation inhibitor comprising a neutral amino acid having 3 or more carbon atoms or a salt thereof as an active ingredient. [2] The protein glycation inhibitor according to [1] above, characterized in that the neutral amino acid having 3 or more carbon atoms is a neutral amino acid selected from the group consisting of aliphatic amino acids, aromatic amino acids, hydroxyamino acids, sulfur-containing amino acids, and imino acid amino acids. [3] The protein glycation inhibitor according to [1] or [2] above, characterized in that the neutral amino acid having 3 or more carbon atoms is selected from the group consisting of threonine, methionine, serine, cysteine, tryptophan, alanine, valine, phenylalanine, proline, and hydroxyproline. [4] The protein glycation inhibitor according to [3] above, wherein the neutral amino acid having 3 or more carbon atoms is selected from the group consisting of threonine, methionine, serine, and hydroxyproline. [5] The protein glycation inhibitor according to [4] above, wherein the neutral amino acid having 3 or more carbon atoms is selected from the group consisting of threonine and serine. [6] The protein glycation inhibitor according to any one of the above [1] to [5], characterized in that it contains two or more types of neutral amino acids having 3 or more carbon atoms or salts thereof as active ingredients. [7] A protein glycation inhibitor according to the above item [6], characterized in that it contains as active ingredients a combination of one or more hydroxyamino acids or salts thereof and one or more neutral amino acids or salts thereof. [8] (aa1) a combination of two or more hydroxyamino acids or salts thereof; (aa2) a combination of one or more hydroxyamino acids or salts thereof and one or more aliphatic amino acids or salts thereof; (aa3) a combination of one or more hydroxyamino acids or salts thereof and one or more aromatic amino acids or salts thereof; and (aa4) A combination of one or more hydroxyamino acids or their salts and one or more sulfur-containing amino acids or their salts The protein glycation inhibitor according to [7] above, characterized in that it contains as active ingredients a combination selected from the group consisting of: [9] (a1) a combination of threonine or a salt thereof and serine or a salt thereof; (a2) a combination of threonine or a salt thereof and alanine or a salt thereof; (a3) a combination of threonine or a salt thereof and valine or a salt thereof; (a4) a combination of threonine or a salt thereof and methionine or a salt thereof; (a5) a combination of threonine or a salt thereof and cysteine ​​or a salt thereof; (a6) a combination of threonine or a salt thereof and tryptophan or a salt thereof; (a7) a combination of threonine or a salt thereof and phenylalanine or a salt thereof; (a8) a combination of serine or a salt thereof and alanine or a salt thereof; (a9) a combination of serine or a salt thereof and valine or a salt thereof; (a10) a combination of serine or a salt thereof and methionine or a salt thereof; (a11) a combination of serine or a salt thereof and cysteine ​​or a salt thereof, and (a12) A combination of serine or a salt thereof and phenylalanine or a salt thereof The protein glycation inhibitor according to [8] above, characterized in that it contains as active ingredients a combination selected from the group consisting of:

[10] (a3) ​​A combination of threonine or a salt thereof and valine or a salt thereof. (a4) a combination of threonine or a salt thereof and methionine or a salt thereof, and (a7) A combination of threonine or a salt thereof and phenylalanine or a salt thereof The protein glycation inhibitor according to [9] above, characterized in that it contains as active ingredients a combination selected from the group consisting of:

[11] The protein glycation inhibitor according to any one of the above [1] to

[10] , further comprising a basic amino acid or a salt thereof as an active ingredient.

[12] (bb1) A combination of one or more hydroxyamino acids or salts thereof and one or more basic amino acids or salts thereof; (bb2) A combination of one or more sulfur-containing amino acids or their salts and one or more basic amino acids or their salts, and (bb3) A combination of one or more aromatic amino acids or their salts and one or more basic amino acids or their salts The protein glycation inhibitor according to

[11] above, characterized in that it contains as active ingredients a combination selected from the group consisting of:

[13] (b1) A combination of threonine or a salt thereof and arginine or a salt thereof. (b2) a combination of threonine or a salt thereof and lysine or a salt thereof; (b3) a combination of threonine or a salt thereof and histidine or a salt thereof; (b4) a combination of serine or a salt thereof and arginine or a salt thereof; (b5) a combination of serine or a salt thereof and lysine or a salt thereof; (b6) a combination of serine or a salt thereof and histidine or a salt thereof; (b7) a combination of methionine or a salt thereof and lysine or a salt thereof; (b8) a combination of cysteine ​​or a salt thereof and lysine or a salt thereof, and (b9) A combination of tryptophan or a salt thereof and lysine or a salt thereof The protein glycation inhibitor according to

[12] above, characterized in that it contains as active ingredients a combination selected from the group consisting of:

[14] (b1) A combination of threonine or a salt thereof and arginine or a salt thereof. (b3) a combination of threonine or a salt thereof and histidine or a salt thereof, and (b6) A combination of serine or a salt thereof and histidine or a salt thereof The protein glycation inhibitor according to

[13] above, characterized in that it contains as active ingredients a combination selected from the group consisting of:

[15] The protein glycation inhibitor according to any one of [1] to

[14] above, further comprising a polyhydric alcohol.

[16] The protein glycation inhibitor according to any one of [1] to

[15] above, which inhibits production of fluorescent advanced glycation end products.

[17] The protein glycation inhibitor according to any one of the above [1] to

[16] , characterized in that it inhibits the production of non-fluorescent advanced glycation end products.

[18] The protein glycation inhibitor according to the above

[17] , wherein the non-fluorescent advanced glycation end product comprises Nε-(carboxymethyl)lysine (CML).

[19] The protein glycation inhibitor according to any one of the above [1] to

[18] , wherein the protein is a protein in the skin.

[20] The protein glycation inhibitor according to any one of the above [1] to

[19] , wherein the protein is selected from the group consisting of collagen, elastin, fibronectin and keratin.

[21] A cosmetic preparation comprising the protein glycation inhibitor according to any one of [1] to

[20] above.

[22] A composition for preventing and / or improving skin aging, comprising as an active ingredient a neutral amino acid having 3 or more carbon atoms or a salt thereof.

[23] The composition described in

[22] above, wherein the skin aging is selected from the group consisting of the formation of wrinkles, the appearance of age spots, the appearance of sagging skin, and the appearance of dullness.

[24] A composition for treating and / or preventing a disease caused by the production and / or accumulation of advanced glycation end products, comprising a neutral amino acid having 3 or more carbon atoms or a salt thereof as an active ingredient.

[25] The composition described in

[24] above, wherein the disease is selected from the group consisting of neuropathy, retinopathy, nephropathy, microvascular disease, hypertension, heart failure, atherosclerosis, Alzheimer's disease, and dermatological disorders.

[26] A method for inhibiting protein glycation, comprising administering an effective amount of a composition containing a neutral amino acid having 3 or more carbon atoms or a salt thereof as an active ingredient to a human in need thereof.

[27] A method for preventing and / or improving skin aging, comprising administering an effective amount of a composition containing a neutral amino acid having 3 or more carbon atoms or a salt thereof as an active ingredient to a human in need thereof.

[28] A method for treating and / or preventing a disease caused by the production and / or accumulation of advanced glycation end products, comprising administering an effective amount of a composition containing as an active ingredient a neutral amino acid having 3 or more carbon atoms or a salt thereof to a human in need thereof.

[29] Use of a neutral amino acid having 3 or more carbon atoms or a salt thereof for producing a protein glycation inhibitor.

[30] Use of a neutral amino acid having 3 or more carbon atoms or a salt thereof for producing an agent for preventing and / or improving skin aging.

[31] Use of a neutral amino acid having 3 or more carbon atoms or a salt thereof for producing an agent for treating and / or preventing a disease caused by the production and / or accumulation of advanced glycation end products.

[0021] Furthermore, as a result of intensive research conducted by the inventors in consideration of the second object of the present invention, they discovered that a dipeptide whose constituent amino acids are selected from the group consisting of acidic amino acids, basic amino acids, hydroxyamino acids, branched-chain amino acids, and antioxidant amino acids, and whose constituent amino acid on the C-terminus side is an antioxidant amino acid, can inhibit the production of a wide range of advanced glycation end products, decompose the produced glycation reaction intermediates, and prevent or improve dull skin, and also has excellent antioxidant function and excellent stability, thereby completing a second form of the present invention.

[0022] That is, the second aspect of the present invention includes the following.

[32] A protein glycation inhibitor characterized in that its constituent amino acids are selected from the group consisting of acidic amino acids, basic amino acids, hydroxyamino acids, branched-chain amino acids, and antioxidant amino acids, and the constituent amino acid on the C-terminus side contains as an active ingredient a dipeptide or a salt thereof which is an antioxidant amino acid.

[33] The protein glycation inhibitor according to

[32] above, wherein the constituent amino acid on the C-terminal side of the dipeptide is selected from the group consisting of tryptophan, tyrosine, methionine, cysteine, and histidine.

[34] The protein glycation inhibitor according to

[32] or

[33] above, wherein the constituent amino acid on the N-terminal side of the dipeptide is selected from the group consisting of hydroxyamino acids, basic amino acids, and acidic amino acids.

[35] The protein glycation inhibitor according to any one of

[32] to

[34] above, wherein the constituent amino acid on the N-terminal side of the dipeptide is selected from the group consisting of serine, threonine, histidine, and glutamic acid.

[36] The protein glycation inhibitor according to any one of

[32] to

[35] above, characterized in that the dipeptide is selected from the group consisting of N-seryl tyrosine (Ser-Tyr), N-histidyl tryptophan (His-Trp), N-threonyl methionine (Thr-Met), N-seryl methionine (Ser-Met), and N-(α-glutamyl) tyrosine (Glu-Tyr).

[37] The protein glycation inhibitor according to any one of

[32] to

[36] above, characterized in that it inhibits production of fluorescent advanced glycation end products.

[38] The protein glycation inhibitor according to any one of

[32] to

[37] above, characterized in that it inhibits the production of non-fluorescent advanced glycation end products.

[39] The protein glycation inhibitor according to any one of

[32] to

[37] above, wherein the protein glycation inhibitor inhibits the production of both fluorescent and non-fluorescent advanced glycation endproducts.

[40] The protein glycation inhibitor according to

[37] or

[39] above, characterized in that the fluorescent advanced glycation end products include crosslin, pyrropyridine and / or pentosidine.

[41] The protein glycation inhibitor according to

[38] or

[39] above, wherein the non-fluorescent advanced glycation end product comprises Nε-(carboxymethyl)lysine (CML).

[42] The protein glycation inhibitor according to any one of

[32] to

[41] above, characterized by decomposing a glycation reaction intermediate.

[43] The protein glycation inhibitor according to any one of

[32] to

[42] above, which prevents or improves the occurrence of skin dullness.

[44] The protein glycation inhibitor according to any one of

[32] to

[43] above, wherein the protein is a protein in the skin.

[45] The protein glycation inhibitor according to any one of

[32] to

[44] above, wherein the protein is selected from the group consisting of collagen, elastin, fibronectin and keratin.

[46] An antioxidant characterized in that its constituent amino acids are selected from the group consisting of acidic amino acids, basic amino acids, hydroxyamino acids, branched-chain amino acids, and antioxidant amino acids, and the constituent amino acid on the C-terminus side contains a dipeptide or a salt thereof, which is an antioxidant amino acid, as an active ingredient.

[47] A cosmetic preparation comprising an amino acid selected from the group consisting of acidic amino acids, basic amino acids, hydroxyamino acids, branched-chain amino acids, and antioxidant amino acids, and wherein the C-terminal constituent amino acid contains a dipeptide or a salt thereof which is an antioxidant amino acid.

[48] ​​A food characterized in that its constituent amino acids are selected from the group consisting of acidic amino acids, basic amino acids, hydroxyamino acids, branched-chain amino acids, and antioxidant amino acids, and that the constituent amino acid on the C-terminal side contains a dipeptide or a salt thereof which is an antioxidant amino acid.

[49] A topical skin preparation characterized in that the constituent amino acids are selected from the group consisting of acidic amino acids, basic amino acids, hydroxyamino acids, branched-chain amino acids, and antioxidant amino acids, and the constituent amino acid on the C-terminus side contains a dipeptide or a salt thereof which is an antioxidant amino acid.

[50] A composition for preventing and / or improving skin aging, characterized in that the constituent amino acids are amino acids selected from the group consisting of acidic amino acids, basic amino acids, hydroxyamino acids, branched-chain amino acids, and antioxidant amino acids, and the constituent amino acid on the C-terminus side contains as an active ingredient a dipeptide or a salt thereof which is an antioxidant amino acid.

[51] The composition according to

[50] above, wherein the skin aging is selected from the group consisting of the formation of wrinkles, the appearance of age spots, the appearance of sagging skin, and the appearance of dullness.

[52] A composition for treating and / or preventing a disease caused by the production and / or accumulation of advanced glycation end products, characterized in that the constituent amino acids are amino acids selected from the group consisting of acidic amino acids, basic amino acids, hydroxyamino acids, branched-chain amino acids, and antioxidant amino acids, and the constituent amino acid on the C-terminus side contains as an active ingredient a dipeptide or a salt thereof which is an antioxidant amino acid.

[53] The composition according to

[52] above, wherein the disease is selected from the group consisting of neuropathy, retinopathy, nephropathy, microvascular disease, hypertension, heart failure, atherosclerosis, Alzheimer's disease, and dermatological disorders.

[54] A method for inhibiting protein glycation, comprising administering to a human in need thereof an effective amount of a composition comprising amino acids selected from the group consisting of acidic amino acids, basic amino acids, hydroxyamino acids, branched-chain amino acids, and antioxidant amino acids, and wherein the constituent amino acid on the C-terminus side contains as an active ingredient a dipeptide or a salt thereof which is an antioxidant amino acid.

[55] A method for preventing and / or improving skin aging, comprising administering to a human in need thereof an effective amount of a composition comprising amino acids selected from the group consisting of acidic amino acids, basic amino acids, hydroxyamino acids, branched-chain amino acids, and antioxidant amino acids, and wherein the constituent amino acid on the C-terminus side contains as an active ingredient a dipeptide or a salt thereof which is an antioxidant amino acid.

[56] A method for treating and / or preventing a disease caused by the production and / or accumulation of advanced glycation end products, comprising administering to a human in need thereof an effective amount of a composition comprising amino acids selected from the group consisting of acidic amino acids, basic amino acids, hydroxyamino acids, branched-chain amino acids, and antioxidant amino acids, and wherein the constituent amino acid on the C-terminus side contains as an active ingredient a dipeptide or a salt thereof which is an antioxidant amino acid.

[57] Use of a dipeptide or a salt thereof for producing a protein glycation inhibitor, wherein the dipeptide has constituent amino acids selected from the group consisting of acidic amino acids, basic amino acids, hydroxyamino acids, branched-chain amino acids, and antioxidant amino acids, and the constituent amino acid on the C-terminal side of the dipeptide is an antioxidant amino acid.

[58] Use of a dipeptide or a salt thereof for producing an agent for preventing and / or improving skin aging, wherein the dipeptide has constituent amino acids selected from the group consisting of acidic amino acids, basic amino acids, hydroxyamino acids, branched-chain amino acids, and antioxidant amino acids, and the constituent amino acid on the C-terminal side of the dipeptide is an antioxidant amino acid.

[59] Use of a dipeptide or a salt thereof for producing an agent for treating and / or preventing a disease caused by the production and / or accumulation of advanced glycation end products, wherein the dipeptide has constituent amino acids selected from the group consisting of acidic amino acids, basic amino acids, hydroxyamino acids, branched-chain amino acids, and antioxidant amino acids, and the constituent amino acid on the C-terminus of the dipeptide is an antioxidant amino acid. Effect of the Invention

[0023] According to the first embodiment of the present invention, it is possible to obtain a composition etc. that exhibits excellent anti-glycation function. In a specific embodiment, it is possible to obtain a composition etc. that exhibits anti-glycation function against a wide range of advanced glycation endproducts, has antioxidant function, is resistant to coloring even when used in cosmetics etc., and contains a component that is highly safe and biocompatible.

[0024] According to the second aspect of the present invention, it is possible to provide a composition or the like that contains a component that exhibits a wide range of anti-glycation functions and further has antioxidant functions, while being highly stable, safe, and biocompatible. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0025] The present invention will be described in detail below with reference to preferred embodiments. However, the present invention is not limited to the following embodiments and examples, and can be modified and implemented as desired without departing from the scope of the claims of the present invention and their equivalents.

[0026] (First aspect of the present invention) A first aspect of the present invention provides, in one embodiment, a protein glycation inhibitor comprising a neutral amino acid having 3 or more carbon atoms or a salt thereof as an active ingredient.

[0027] The protein glycation inhibitor of the first embodiment of the present invention contains a neutral amino acid having 3 or more carbon atoms or a salt thereof as an active ingredient, and therefore has superior anti-glycation function compared to basic amino acids, and in particular, is capable of inhibiting the production of a wide range of advanced glycation end products and also has excellent antioxidant function.

[0028] Therefore, in one embodiment, a first aspect of the present invention provides a method for inhibiting protein glycation, comprising administering an effective amount of a composition containing, as an active ingredient, a neutral amino acid having 3 or more carbon atoms or a salt thereof to a human in need thereof.

[0029] Furthermore, since the protein glycation inhibitor of the first form of the present invention has excellent function of inhibiting the formation of advanced glycation end products and antioxidant function, 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 occurrence of spots, the occurrence of sagging, the occurrence of dullness, etc.

[0030] Therefore, in one embodiment, a first aspect of the present invention provides a composition for preventing and / or improving skin aging caused by the production 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., characterized by containing a neutral amino acid having 3 or more carbon atoms or a salt thereof as an active ingredient.

[0031] Furthermore, in one embodiment, the first aspect of the present invention provides a method for preventing and / or ameliorating skin aging caused by the production and / or accumulation of advanced glycation end products, such as the formation of wrinkles, the occurrence of spots, the occurrence of sagging, the occurrence of dullness, etc., comprising administering an effective amount of a composition containing, as an active ingredient, a neutral amino acid having 3 or more carbon atoms or a salt thereof to a human in need thereof.

[0032] Furthermore, since the protein glycation inhibitor of the first form of the present invention has excellent inhibitory function for the production of advanced glycation end products and antioxidant function, it is useful for the treatment and / or prevention of diseases caused by the production and / or accumulation of advanced glycation end products, such as neuropathy, retinopathy, nephropathy, microvascular disorder, hypertension, heart failure, atherosclerosis, Alzheimer's disease, dermatological disorders, etc.

[0033] Therefore, in one embodiment, the first aspect of the present invention provides a composition for the treatment and / or prevention of diseases caused by the production and / or accumulation of advanced glycation end products, such as neuropathy, retinopathy, nephropathy, microvascular disease, hypertension, heart failure, atherosclerosis, Alzheimer's disease, dermatological disorders, etc., characterized by containing a neutral amino acid having 3 or more carbon atoms or a salt thereof as an active ingredient.

[0034] Furthermore, in one embodiment, the first aspect of the present invention provides a method for treating and / or preventing diseases caused by the production and accumulation of advanced glycation end products, such as neuropathy, retinopathy, nephropathy, microvascular disease, hypertension, heart failure, atherosclerosis, Alzheimer's disease, dermatological disorders, and the like, comprising administering an effective amount of a composition containing, as an active ingredient, a neutral amino acid having 3 or more carbon atoms or a salt thereof to a human in need thereof.

[0035] Hereinafter, the components contained in the protein glycation inhibitor or composition of the first embodiment of the present invention will be described.

[0036] (Neutral Amino Acids) The protein glycation inhibitor or composition of the first embodiment of the present invention contains a neutral amino acid having 3 or more carbon atoms or a salt thereof as an active ingredient.

[0037] A neutral amino acid having 3 or more carbon atoms means an amino acid having 3 or more carbon atoms and having the same number of acidic carboxyl groups and basic amino groups in the molecule. Here, the neutral amino acid may be D- or L-isomer, or may be a mixture thereof. In addition, the neutral amino acid includes not only protein-constituting amino acids but also non-protein-constituting amino acids. In addition, the neutral amino acid includes not only α-amino acids but also β-amino acids, γ-amino acids, δ-amino acids, etc. The neutral amino acid may be one type alone or two or more types in combination.

[0038] Examples of neutral amino acids having 3 or more carbon atoms as active ingredients include neutral amino acids such as aliphatic amino acids, aromatic amino acids, hydroxyamino acids, sulfur-containing amino acids, acid amide amino acids, and imino acid amino acids. Among these, neutral amino acids selected from aliphatic amino acids, aromatic amino acids, hydroxyamino acids, sulfur-containing amino acids, and imino acid amino acids are preferred, and neutral amino acids selected from aromatic amino acids, hydroxyamino acids, and sulfur-containing amino acids are more preferred.

[0039] An aliphatic amino acid means an amino acid having an alkyl group bound to the α-carbon atom, and examples thereof include alanine, α-aminobutyric acid, valine, norvaline, leucine, isoleucine, norleucine, and homonorleucine.

[0040] An aromatic amino acid means an amino acid in which an aromatic group is bound to an aliphatic amino acid, and examples thereof include tyrosine, tryptophan, phenylalanine, metatyrosine, thyronine, dopa, and thyroxine.

[0041] The hydroxyamino acid means an amino acid in which a hydroxy group is bound to an aliphatic amino acid, and examples thereof include serine, threonine, and homoserine.

[0042] The sulfur-containing amino acid refers to an amino acid in which any carbon atom in the side chain skeleton of an aliphatic amino acid is substituted with a sulfur atom, and examples thereof include cysteine, methionine, and homocysteine.

[0043] The acid amide amino acid refers to an amino acid in which the carboxy group in the side chain of an acidic amino acid is amidated, and examples thereof include asparagine, glutamine, and theanine.

[0044] The imino acid amino acid refers to an amino acid in which the side chain of an aliphatic amino acid is bonded to an α-amino group to form a ring, and examples of such amino acids include proline, hydroxyproline, and pipecolic acid.

[0045] The neutral amino acid having 3 or more carbon atoms is preferably selected from threonine, methionine, serine, cysteine, tryptophan, alanine, valine, phenylalanine, proline, and hydroxyproline, more preferably from threonine, methionine, serine, and hydroxyproline, and even more preferably from threonine and serine.

[0046] In one embodiment, the active ingredient of the protein glycation inhibitor or composition according to the first aspect of the present invention is preferably (A1) one or more aliphatic amino acids or salts thereof, (A2) one or more aromatic amino acids or salts thereof, (A3) one or more hydroxyamino acids or salts thereof, (A4) one or more sulfur-containing amino acids or salts thereof, (A5) one or more imino acid amino acids or salts thereof, (A6) A combination of one or more hydroxyamino acids or salts thereof and one or more aliphatic amino acids or salts thereof; (A7) A combination of one or more hydroxyamino acids or salts thereof and one or more aromatic amino acids or salts thereof, and (A8) A combination of one or more hydroxyamino acids or their salts with one or more sulfur-containing amino acids or their salts A combination selected from the group consisting of:

[0047] In one embodiment, when the active ingredient of the protein glycation inhibitor or composition according to the first aspect of the present invention is one type of neutral amino acid, preferably, (αα1) an aliphatic amino acid or a salt thereof, (αα2) an aromatic amino acid or a salt thereof, (αα3) hydroxyamino acid or a salt thereof, (αα4) sulfur-containing amino acid or its salt, and (αα5) Imino acid amino acid or its salt A neutral amino acid or a salt thereof selected from the group consisting of: (α1) threonine or a salt thereof, (α2) methionine or a salt thereof, (α3) serine or a salt thereof, (α4) cysteine ​​or a salt thereof, (α5) tryptophan or a salt thereof, (α6) alanine or a salt thereof, (α7) valine or a salt thereof, (α8) phenylalanine or a salt thereof, (α9) proline or a salt thereof, and (α10) Hydroxyproline or its salt or a salt thereof.

[0048] In one embodiment, when the active ingredient of the protein glycation inhibitor or composition of the first aspect of the present invention is two or more neutral amino acids, it is preferably a combination of one or more hydroxyamino acids or salts thereof and one or more neutral amino acids or salts thereof, more preferably (aa1) a combination of two or more hydroxyamino acids or salts thereof; (aa2) a combination of one or more hydroxyamino acids or salts thereof and one or more aliphatic amino acids or salts thereof; (aa3) a combination of one or more hydroxyamino acids or salts thereof and one or more aromatic amino acids or salts thereof; and (aa4) A combination of one or more hydroxyamino acids or their salts and one or more sulfur-containing amino acids or their salts and more preferably, (a1) a combination of threonine or a salt thereof and serine or a salt thereof; (a2) a combination of threonine or a salt thereof and alanine or a salt thereof; (a3) a combination of threonine or a salt thereof and valine or a salt thereof; (a4) a combination of threonine or a salt thereof and methionine or a salt thereof; (a5) a combination of threonine or a salt thereof and cysteine ​​or a salt thereof; (a6) a combination of threonine or a salt thereof and tryptophan or a salt thereof; (a7) a combination of threonine or a salt thereof and phenylalanine or a salt thereof; (a8) a combination of serine or a salt thereof and alanine or a salt thereof; (a9) a combination of serine or a salt thereof and valine or a salt thereof; (a10) a combination of serine or a salt thereof and methionine or a salt thereof; (a11) a combination of serine or a salt thereof and cysteine ​​or a salt thereof, and (a12) A combination of serine or a salt thereof and phenylalanine or a salt thereof From the viewpoint of obtaining a high synergistic effect of inhibiting the production of advanced glycation end products by the combination of active ingredients, it is particularly preferable to use a combination selected from the group consisting of: (a3) a combination of threonine or a salt thereof and valine or a salt thereof; (a4) a combination of threonine or a salt thereof and methionine or a salt thereof, and (a7) A combination of threonine or a salt thereof and phenylalanine or a salt thereof A combination selected from the group consisting of:

[0049] When the active ingredients are two or more types of neutral amino acids, the content of one of the neutral amino acids or a salt thereof as the active ingredients in the protein glycation inhibitor or composition is preferably 0.01 to 100, more preferably 0.1 to 10, in terms of weight ratio to the other neutral amino acid or a salt thereof as the active ingredient, and is preferably 0.01 to 100, more preferably 0.1 to 10, in terms of molar ratio to the other neutral amino acid or a salt thereof as the active ingredient.

[0050] The salt of a neutral amino acid having 3 or more carbon atoms may be any salt that is cosmetically and / or pharma- ceutically acceptable, and examples of such salts include, 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; salts with organic amines such as triethylamine, ethanolamine, morpholine, pyrrolidine, piperidine, piperazine, and dicyclohexylamine; and salts with arginine and lysine. For basic groups such as amino groups, examples of the salts 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.

[0051] For example, when a protein glycation inhibitor or composition is used in a topical composition such as a cosmetic for preventing and improving skin aging, the effective amount of a neutral amino acid having 3 or more carbon atoms or its salt in the topical composition is not particularly limited as long as it is a concentration that can inhibit protein glycation, but is preferably 0.001% by mass or more, more preferably 0.05% by mass or more, based on the total mass of the topical composition. The upper limit is not particularly limited as long as a topical composition such as a cosmetic can be produced, but 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 topical composition once to several times a day.

[0052] For example, when the protein glycation inhibitor or composition is used in an oral composition such as a processed food for the prevention and improvement of skin aging, the effective oral intake amount of a neutral amino acid having 3 or more carbon atoms or a salt thereof may be appropriately selected depending on the age, sex, body weight, degree of skin aging, and other conditions of the subject. In general, it is preferable to take 0.01 to 15 mg of a neutral amino acid having 3 or more carbon atoms or a salt thereof per kg of body weight per day, in one or several divided doses.

[0053] (Basic Amino Acids) The protein glycation inhibitor or composition of the first embodiment of the present invention may further contain a basic amino acid or a salt thereof as an active ingredient in addition to a neutral amino acid having 3 or more carbon atoms or a salt thereof. By including a basic amino acid or a salt thereof, the protein glycation inhibitory function can be further enhanced, and thus the effectiveness of preventing and improving skin aging can be further improved.

[0054] A basic amino acid means an amino acid having more basic amino groups than acidic carboxyl groups in the molecule. Here, the basic amino acid may be D- or L-isomer, or may be a mixture of them. In addition, basic amino acids include not only protein-constituting amino acids but also non-protein-constituting amino acids. In addition, basic amino acids include not only α-amino acids but also β-amino acids, γ-amino acids, δ-amino acids, etc. Basic amino acids may be one type alone or two or more types in combination.

[0055] Specific examples of basic amino acids include arginine, histidine, and lysine.

[0056] When the protein glycation inhibitor or composition according to the first aspect of the present invention contains a basic amino acid or a salt thereof as an active ingredient, in one embodiment, the combination of the active ingredients is (bb1) a combination of one or more hydroxyamino acids or salts thereof and one or more basic amino acids or salts thereof; (bb2) A combination of one or more sulfur-containing amino acids or their salts and one or more basic amino acids or their salts, and (bb3) A combination of one or more aromatic amino acids or their salts and one or more basic amino acids or their salts and more preferably selected from the group consisting of: (b1) a combination of threonine or a salt thereof and arginine or a salt thereof; (b2) a combination of threonine or a salt thereof and lysine or a salt thereof; (b3) a combination of threonine or a salt thereof and histidine or a salt thereof; (b4) a combination of serine or a salt thereof and arginine or a salt thereof; (b5) a combination of serine or a salt thereof and lysine or a salt thereof; (b6) a combination of serine or a salt thereof and histidine or a salt thereof; (b7) a combination of methionine or a salt thereof and lysine or a salt thereof; (b8) a combination of cysteine ​​or a salt thereof and lysine or a salt thereof, and (b9) A combination of tryptophan or a salt thereof and lysine or a salt thereof From the viewpoint of obtaining a high synergistic effect of inhibiting the production of advanced glycation end products by the combination of active ingredients, it is particularly preferable to select from the group consisting of (b1) a combination of threonine or a salt thereof and arginine or a salt thereof; (b3) a combination of threonine or a salt thereof and histidine or a salt thereof, and (b6) A combination of serine or a salt thereof and histidine or a salt thereof is selected from the group consisting of:

[0057] In the protein glycation inhibitor or composition, the content of the basic amino acid or a salt thereof as an active ingredient is preferably 0.01 to 100, more preferably 0.1 to 10, in terms of a weight ratio of the active ingredient to the neutral amino acid or a salt thereof (basic amino acid or a salt thereof / neutral amino acid or a salt thereof), and is preferably 0.01 to 100, more preferably 0.1 to 10, in terms of a molar ratio of the active ingredient to the neutral amino acid or a salt thereof (basic amino acid or a salt thereof / neutral amino acid or a salt thereof).

[0058] The salt of a basic amino acid may be any salt that is cosmetically and / or pharma- ceutically acceptable, and examples thereof 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.

[0059] (Polyhydric alcohol) The protein glycation inhibitor or composition of the first embodiment of the present invention may further contain a polyhydric alcohol as an optional component when used in, for example, cosmetics, pharmaceutical preparations, etc. The protein glycation inhibitor or composition of the first embodiment of the present invention contains a neutral amino acid having 3 or more carbon atoms or a salt thereof, so that it is difficult to color even in a form containing a polyhydric alcohol. In addition, it is generally known that coloring is generally likely to occur when a basic amino acid and a polyhydric alcohol coexist, but the protein glycation inhibitor or composition of the first embodiment of the present invention contains a neutral amino acid having 3 or more carbon atoms or a salt thereof, so that it is difficult to color even if a basic amino acid is contained. Therefore, the protein glycation inhibitor or composition of the first embodiment of the present invention is particularly useful for cosmetics containing a polyhydric alcohol.

[0060] In this specification, the term "polyhydric alcohol" refers to an alcohol having two or more hydroxy groups in one molecule. 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 decomposition sugar, maltose, xylitose, and starch decomposition sugar reduced alcohol. Among these, glycerin and 1,3-butylene glycol are preferred. These may be used alone or in combination of two or more.

[0061] The content of the polyhydric alcohol in the protein glycation inhibitor or composition is preferably 0.01 to 20,000, more preferably 0.05 to 400, and most preferably 0.5 to 40, as a weight ratio to the neutral amino acid or a salt thereof (polyhydric alcohol / neutral amino acid or a salt thereof).

[0062] (Second aspect of the present invention) The second aspect of the present invention provides, in one embodiment, a protein glycation inhibitor comprising, as an active ingredient, an amino acid selected from the group consisting of acidic amino acids, basic amino acids, hydroxyamino acids, branched-chain amino acids, and antioxidant amino acids, and wherein the constituent amino acid on the C-terminus side is a dipeptide or a salt thereof which is an antioxidant amino acid.

[0063] The protein glycation inhibitor of the second embodiment of the present invention contains the above-mentioned dipeptide or a salt thereof, and therefore can inhibit the production of a wide range of advanced glycation end products and also has excellent antioxidant function.

[0064] Therefore, in one embodiment, the second aspect of the present invention provides a method for inhibiting protein glycation, comprising administering an effective amount of a composition containing the above-mentioned dipeptide or a salt thereof as an active ingredient to a human in need thereof.

[0065] In addition, the second aspect of the present invention provides, in one embodiment, an antioxidant comprising the above dipeptide or a salt thereof as an active ingredient.

[0066] In addition, the protein glycation inhibitor of the second form of the present invention has a wide range of glycation inhibitory and antioxidant functions, and is therefore useful for preventing and / or improving aging caused by the production and / or accumulation of advanced glycation end products, particularly skin aging, such as the formation of wrinkles, the occurrence of age spots, the occurrence of sagging, and the occurrence of dullness.

[0067] Therefore, in one embodiment, the second aspect of the present invention provides a composition for preventing and / or improving aging, particularly skin aging, such as the formation of wrinkles, the appearance of age spots, the appearance of sagging skin, and the appearance of dullness, caused by the production and / or accumulation of advanced glycation end products, characterized by containing the above-mentioned dipeptide or a salt thereof as an active ingredient.

[0068] In addition, in one embodiment, the second aspect of the present invention provides a method for preventing and / or improving aging, particularly skin aging, such as the formation of wrinkles, the occurrence of spots, the occurrence of sagging, and the occurrence of dullness, caused by the production and / or accumulation of advanced glycation end products, comprising administering an effective amount of a composition containing the above-mentioned dipeptide or a salt thereof as an active ingredient to a human in need thereof.

[0069] In addition, the protein glycation inhibitor of the second form of the present invention has a function of inhibiting the production of advanced glycation end products and an antioxidant function, and is therefore useful for the treatment and / or prevention of diseases caused by the production and / or accumulation of advanced glycation end products, such as neuropathy, retinopathy, nephropathy, microvascular disease, hypertension, heart failure, atherosclerosis, Alzheimer's disease, and dermatological disorders.

[0070] Therefore, in one embodiment, the second aspect of the present invention provides a composition for the treatment and / or prevention of diseases caused by the production and / or accumulation of advanced glycation end products, such as neuropathy, retinopathy, nephropathy, microvascular disease, hypertension, heart failure, atherosclerosis, Alzheimer's disease, dermatological disorders, etc., characterized by containing the above-mentioned dipeptide or a salt thereof as an active ingredient.

[0071] In one embodiment, the second aspect of the present invention provides a method for treating and / or preventing diseases caused by the production and accumulation of advanced glycation end products, such as neuropathy, retinopathy, nephropathy, microvascular disease, hypertension, heart failure, atherosclerosis, Alzheimer's disease, dermatological disorders, etc., comprising administering an effective amount of a composition containing the above-mentioned dipeptide or a salt thereof as an active ingredient to a human in need thereof.

[0072] The above dipeptide or a salt thereof has an inhibitory function for the formation of advanced glycation end products and an antioxidant function, and is therefore useful for preventing and / or improving aging, particularly skin aging, caused by the formation and / or accumulation of advanced glycation end products. Therefore, in one embodiment, a second form of the present invention provides a skin topical agent, cosmetic, food, etc., characterized by containing the above dipeptide or a salt thereof.

[0073] The dipeptide or a salt thereof contained in the composition of the second embodiment of the present invention, the protein glycation inhibitor, the antioxidant, the cosmetic, the food, the topical skin preparation, and the pharmaceutical preparation (hereinafter, collectively referred to as "the composition of the second embodiment of the present invention, etc.") will be described below.

[0074] (Dipeptide) The dipeptide in the second embodiment of the present invention has as its constituent amino acids an amino acid selected from the group consisting of acidic amino acids, basic amino acids, hydroxyamino acids, branched-chain amino acids, and antioxidant amino acids, and the constituent amino acid at the C-terminus of the dipeptide is an antioxidant amino acid.

[0075] The constituent amino acids of a dipeptide may be D- or L-amino acids or a mixture thereof, but are preferably L-amino acids. The constituent amino acids may include not only α-amino acids but also β-amino acids, γ-amino acids, δ-amino acids, etc., but are preferably α-amino acids. The constituent amino acids may include not only proteinogenic amino acids but also non-proteinogenic amino acids, but are preferably proteinogenic amino acids.

[0076] The term "antioxidative amino acid" refers to an amino acid that has the ability to scavenge active oxygen. Examples of the antioxidant amino acid include, but are not limited to, tryptophan, tyrosine, methionine, cysteine, and histidine.

[0077] An acidic amino acid refers to an amino acid having more acidic carboxyl groups than basic amino groups in the molecule, and examples thereof include aspartic acid and glutamic acid.

[0078] The term "hydroxyamino acid" refers to an amino acid having a hydroxy group in the molecule, and examples thereof include tyrosine, serine, threonine, homoserine, and hydroxyproline.

[0079] The branched-chain amino acid refers to an amino acid whose side chain is a branched saturated hydrocarbon group, and examples thereof include valine, leucine, and isoleucine.

[0080] The dipeptide in the second form of the present invention is preferably a dipeptide whose constituent amino acids are α-amino acids and is obtained by a peptide bond between an amino group bonded to the α-carbon of one amino acid and a carboxy group bonded to the α-carbon of another amino acid.

[0081] The constituent amino acid on the C-terminal side of the dipeptide in the second embodiment of the present invention is preferably selected from the group consisting of tryptophan, tyrosine, methionine, cysteine, and histidine, and more preferably selected from the group consisting of tryptophan, tyrosine, and methionine.

[0082] The constituent amino acid on the N-terminus of the dipeptide in the second embodiment of the present invention is preferably selected from the group consisting of hydroxyamino acids, basic amino acids, and acidic amino acids, more preferably selected from the group consisting of tyrosine, serine, threonine, arginine, lysine, histidine, glutamic acid, and aspartic acid, and even more preferably selected from the group consisting of serine, threonine, histidine, and glutamic acid.

[0083] Specific examples of dipeptides in the second aspect of the present invention include N-arginyltryptophan (Arg-Trp), N-(α-aspartyl)tryptophan (Asp-Trp), N-cysteinyltryptophan (Cys-Trp), N-(α-glutamyl)tryptophan (Glu-Trp), N-histidyltryptophan (His-Trp), N-isoleucyltryptophan (Ile-Trp), N-leucyltryptophan (Leu-Trp), N-lysyltryptophan (Lys-Trp), N-methionyltryptophan (Met-Trp), N-seryltryptophan (Ser-Trp), N-threonyltryptophan (Thr-Trp), N-tryptophyltryptophan (Trp-Trp), N-tyrosyltryptophan (Tyr-Trp), N-valyltryptophan (Tyr ... Dipeptides with tryptophan at the C-terminus, such as tryptophan (Val-Trp); N-arginyl tyrosine (Arg-Tyr), N-(α-aspartyl) tyrosine (Asp-Tyr), N-cysteinyl tyrosine (Cys-Tyr), N-(α-glutamyl) tyrosine (Glu-Tyr), N-histidyl tyrosine (His-Tyr), N-isoleucyl tyrosine (Ile-Tyr), N- Dipeptides with tyrosine at the C-terminus, such as leucyltyrosine (Leu-Tyr), N-lysyltyrosine (Lys-Tyr), N-methionyltyrosine (Met-Tyr), N-seryltyrosine (Ser-Tyr), N-threonyltyrosine (Thr-Tyr), N-tryptophyltyrosine (Trp-Tyr), N-tyrosyltyrosine (Tyr-Tyr), and N-valyltyrosine (Val-Tyr);N-arginylmethionine (Arg-Met), N-(α-aspartyl)methionine (Asp-Met), N-cysteinylmethionine (Cys-Met), N-(α-glutamyl)methionine (Glu-Met), N-histidylmethionine (His-Met), N-isoleucylmethionine (Ile-Met), N-leucylmethionine (Leu-Met), N-lysylmethionine (Lys-Met), N-methionylmethionine (Met-Met), N-serylmethionine (Ser-Met), N-threonylmethionine (Thr-Met), N -Tryptophylmethionine (Trp-Met), N-tyrosylmethionine (Tyr-Met), N-valylmethionine (Val-Met), and other dipeptides with methionine at the C-terminus; N-arginylcysteine ​​(Arg-Cys), N-(α-aspartyl)cysteine ​​(Asp-Cys), N-cysteinylcysteine ​​(Cys-Cys), N-(α-glutamyl)cysteine ​​(Glu-Cys), N-histidylcysteine ​​(His-Cys), N-isoleucylcysteine ​​(Ile-Cys), N-leucylcysteine ​​(Leu-Cys), N-lysine Dipeptides with a cysteine ​​at the C-terminus, such as N-lysine (Lys-Cys), N-methionylcysteine ​​(Met-Cys), N-serylcysteine ​​(Ser-Cys), N-threonylcysteine ​​(Thr-Cys), N-tryptophylcysteine ​​(Trp-Cys), N-tyrosylcysteine ​​(Tyr-Cys), and N-valylcysteine ​​(Val-Cys); N-arginylhistidine (Arg-His), N-(α-aspartyl)histidine (Asp-His), N-cysteinylhistidine (Cys-His), and N-(α-glutamyl)histidine Examples of such dipeptides include dipeptides with histidine at the C-terminus, such as N-glucose (Glu-His), N-histidyl histidine (His-His), N-isoleucyl histidine (Ile-His), N-leucyl histidine (Leu-His), N-lysyl histidine (Lys-His), N-methionyl histidine (Met-His), N-seryl histidine (Ser-His), N-threonyl histidine (Thr-His), N-tryptophyl histidine (Trp-His), N-tyrosyl histidine (Tyr-His), and N-valyl histidine (Val-His);

[0084] The dipeptide in the second aspect of the present invention is preferably a dipeptide having a C-terminus of tryptophan, tyrosine, methionine, cysteine ​​or histidine and an N-terminus of tyrosine, serine, threonine, arginine, lysine, histidine, glutamic acid or aspartic acid, i.e., N-arginyltryptophan (Arg-Trp), N-(α-aspartyl)tryptophan (Asp-Trp), N-(α-glutamyl)tryptophan (Glu-Trp), N-histidyltryptophan (His-Trp), N-lysyltryptophan (Lys-Trp), ...arginyltryptophan (Arg-Trp), N-arginyltryptophan (Arg-Trp), N-arginyltryptophan (Arg-Trp), N-arginyltryptophan (Arg-Trp), N-arginyltryptophan (Arg-Trp), N-arginyltryptophan (Arg-Trp), N-arginyltryptophan (Arg-Trp), N-arginyltryptophan (Ar ys-Trp), N-seryltryptophan (Ser-Trp), N-threonyltryptophan (Thr-Trp), N-tyrosyltryptophan (Tyr-Trp), N-arginyltyrosine (Arg-Tyr), N-(α-aspartyl)tyrosine (Asp-Tyr), N-(α-glutamyl)tyrosine (Glu-Tyr), N-histidyltyrosine (His-Tyr), N-lysyltyrosine (Lys-Tyr), N-seryltyrosine (Ser-Tyr), N-threonyltyrosine (Thr-Tyr), N-tyrosyltyrosine (Tyr-Tyr), N-arginyl methionine (Arg-Met), N-(α-aspartyl) methionine (Asp-Met), N-(α-glutamyl) methionine (Glu-Met), N-histidyl methionine (His-Met), N-lysyl methionine (Lys-Met), N-seryl methionine (Ser-Met), N-threonyl methionine (Thr-Met), N-tyrosyl methionine (Tyr-Met), N-arginyl cysteine ​​(Arg-Cys), N-(α-aspartyl) cysteine ​​(Asp-Cys), N-(α-glutamyl) cysteine ​​(Glu-Met), u-Cys), N-histidyl cysteine ​​(His-Cys), N-lysyl cysteine ​​(Lys-Cys), N-seryl cysteine ​​(Ser-Cys), N-threonyl cysteine ​​(Thr-Cys), N-tyrosyl cysteine ​​(Tyr-Cys), N-arginyl histidine (Arg-His), N-(α-aspartyl) histidine (Asp-His), N-(α-glutamyl) histidine (Glu-His), N-histidyl histidine (His-His), N-lysyl histidine (Lys-His), N-seryl histidine (Ser-His),It is a dipeptide selected from the group consisting of N-threonylhistidine (Thr-His) and N-tyrosylhistidine (Tyr-His).

[0085] The dipeptide in the second embodiment of the present invention is more preferably a dipeptide having tryptophan, tyrosine, methionine, cysteine ​​or histidine at the C-terminus and serine, threonine, histidine or glutamic acid at the N-terminus, i.e., N-(α-glutamyl)tryptophan (Glu-Trp), N-histidyltryptophan (His-Trp), N-seryltryptophan (Ser-Trp), N-threonyltryptophan (Thr-Trp), N-(α-glutamyl)tyrosine (Glu-Tyr), N-histidyltyrosine (His-Tyr), N-seryltyrosine (Ser-Tyr), N-threonyltyrosine (Thr-Tyr), The dipeptide is selected from the group consisting of N-(α-glutamyl)methionine (Glu-Met), N-histidylmethionine (His-Met), N-serylmethionine (Ser-Met), N-threonylmethionine (Thr-Met), N-(α-glutamyl)cysteine ​​(Glu-Cys), N-histidylcysteine ​​(His-Cys), N-serylcysteine ​​(Ser-Cys), N-threonylcysteine ​​(Thr-Cys), N-(α-glutamyl)histidine (Glu-His), N-histidylhistidine (His-His), N-serylhistidine (Ser-His), and N-threonylhistidine (Thr-His).

[0086] The dipeptide in the second embodiment of the present invention is more preferably a dipeptide having tryptophan, tyrosine or methionine at the C-terminus and serine, threonine, histidine or glutamic acid at the N-terminus, i.e., N-(α-glutamyl)tryptophan (Glu-Trp), N-histidyltryptophan (His-Trp), N-seryltryptophan (Ser-Trp), N-threonyltryptophan (Thr-Trp), N and N-(α-glutamyl)tyrosine (Glu-Tyr), N-histidyltyrosine (His-Tyr), N-seryltyrosine (Ser-Tyr), N-threonyltyrosine (Thr-Tyr), N-(α-glutamyl)methionine (Glu-Met), N-histidylmethionine (His-Met), N-serylmethionine (Ser-Met), and N-threonylmethionine (Thr-Met).

[0087] The dipeptide in the second aspect of the present invention is particularly preferably a dipeptide selected from the group consisting of N-seryl tyrosine (Ser-Tyr), N-histidyl tryptophan (His-Trp), N-threonyl methionine (Thr-Met), N-seryl methionine (Ser-Met), and N-(α-glutamyl) tyrosine (Glu-Tyr).

[0088] The salt of the dipeptide in the second embodiment of the present invention may be any salt that is cosmetically and / or pharma- ceutically acceptable, and examples of such salts include, 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; salts with organic amines such as triethylamine, ethanolamine, morpholine, pyrrolidine, piperidine, piperazine, and dicyclohexylamine; salts with arginine, lysine, and the like; For basic groups such as amino groups, examples of the salts 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.

[0089] The content of the dipeptide or salt thereof in the second embodiment of the present invention in the composition etc. of the second embodiment of the present invention is preferably 0.0001% by mass or more, more preferably 0.001% by mass or more, even more preferably 0.01% by mass or more, even more preferably 0.05% by mass or more, and particularly preferably 0.1% by mass or more. The composition etc. of the present invention, by containing the dipeptide or salt thereof in the above content, may be effective in preventing and / or improving aging caused by the production and / or accumulation of advanced glycation end products, particularly skin aging. The upper limit of the content of the dipeptide or salt thereof is not particularly limited, and may be, for example, 100% by mass or less, 90% by mass or less, 80% by mass or less, 70% by mass or less, 60% by mass or less, 50% by mass or less, 40% by mass or less, 30% by mass or less, 20% by mass or less, 10% by mass or less, 5% by mass or less, 3% by mass or less, 2% by mass or less, 1% by mass or less, etc.

[0090] (Other anti-glycation ingredients, other antioxidant ingredients) The protein glycation inhibitor or composition of the present invention may further contain other anti-glycation components and / or other antioxidant components as optional components in addition to neutral amino acids and basic amino acids. By including other anti-glycation components and / or other antioxidant components, the protein glycation inhibitory function and / or antioxidant function can be further enhanced, and thus the effectiveness of preventing and improving skin aging can be further improved.

[0091] Other anti-glycation components include, for example, ascorbic acid, sodium ascorbate, benfotiamine, pyridoxamine, α-lipoic acid, taurine, aspirin, metformin, pioglitazone, pentoxifylline, carnosine, peony extract, mugwort extract, evening primrose extract, aminoguanidine, amla extract, hydrolyzed casein, hydrolyzable tannin, etc. These may be used alone or in combination of two or more.

[0092] Other antioxidant components include, for example, thiotaurine, hypotaurine, α-tocopherol, ascorbic acid, sodium ascorbate, catechin, albumin, ferritin, bilirubin, metallothionein, uric acid, black tea extract, green tea extract, thyme extract, myrtle extract, etc. These may be used alone or in combination of two or more.

[0093] (Cosmetics) In one embodiment, the protein glycation inhibitor or composition of the present invention can be processed into a cosmetic.

[0094] The cosmetic preparation of the first embodiment of the present invention includes the protein glycation inhibitor or composition of the first embodiment of the present invention. That is, the cosmetic preparation of the first embodiment of the present invention contains a neutral amino acid having 3 or more carbon atoms or a salt thereof as an active ingredient. Therefore, for example, by applying it to human skin, it is possible to prevent and / or improve skin aging caused by the production 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.

[0095] The cosmetic preparation of the second embodiment of the present invention contains a dipeptide or a salt thereof, the constituent amino acid of which is an amino acid selected from the group consisting of acidic amino acids, basic amino acids, hydroxyamino acids, branched-chain amino acids, and antioxidant amino acids, and the constituent amino acid on the C-terminus side is an antioxidant amino acid. Therefore, the cosmetic preparation of the second embodiment of the present invention has excellent advanced glycation endproduct formation inhibitory function and antioxidant function, and is therefore useful for preventing and / or improving aging, particularly skin aging, caused by the formation and / or accumulation of advanced glycation endproducts, such as the formation of wrinkles, the occurrence of age spots, the occurrence of sagging, and the occurrence of dullness.

[0096] The cosmetic preparation may be in the form of, for example, a paste, cream, lotion, gel, milky lotion, solution, suspension, oily liquid, etc. It may also be in the form of a powder, pack, mask, etc.

[0097] As the type of cosmetic, cosmetics for external use that come into direct contact with the skin are preferred, and examples thereof include lotions (including those for the face and hair), beauty serums, cosmetic creams, beauty gels, cosmetic emulsions, facial cleansers, cosmetic soaps, eye creams, eye shadows, eyeliners, makeup bases, BB creams, CC creams, powder foundations, liquid foundations, cream foundations, blushers, mascara, eyebrow ink, lipstick, lip balm, moisturizing creams, face powders, facial packs, shampoos, rinses, 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. Examples of methods for using the cosmetic include using the hands, cotton, puffs, etc., applying the cosmetic to nonwoven fabric, etc., and spraying the cosmetic from a spray container.

[0098] Cosmetics may contain any cosmetically acceptable ingredient as necessary. Examples of such optional ingredients include water, lower alcohols, surfactants, fragrances, colorants, preservatives, antioxidants, emulsifiers, oily ingredients, thickeners, sequestering agents, bactericides, 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, antiseborrheic agents, stabilizers, antioxidant ingredients, polyhydric alcohols, and other known ingredients, particularly known ingredients used in cosmetics. These may be used alone or in combination of two or more. Those skilled in the art can appropriately determine the amount of each ingredient.

[0099] Examples of the lower alcohol include ethanol, propanol, isopropanol, butanol, etc. Examples of the surfactant include sorbitan fatty acid esters such as sorbitan monoisostearate and sorbitan monolaurate, glycerin fatty acids such as glyceryl monostearate, polyglyceryl monostearate polyglycerin fatty acids, 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, silicone surfactants such as polyoxyethylene-methylpolysiloxane copolymers, etc.

[0100] Examples of the flavoring agent include limonene, orange flavor, lychee flavor, lemon flavor, lime flavor, strawberry flavor, pineapple flavor, mint flavor, grapefruit flavor, etc. Examples of the coloring agent include cochineal red A, patent blue, chlorophyllin, etc. Examples of the preservative include phenoxyethanol, paraben, sorbic acid, isopropylmethylphenol, benzalkonium chloride, benzoic acid, dehydroacetic acid, hexanediol, pentanediol, chlorhexidine sulfate, N-coconutoyl acyl-L-arginine ethyl·DL-pyrrolidone carboxylate, etc. Examples of the antioxidant include α-tocopherol, sodium sulfite, etc. Examples of the emulsifier include polyoxyl stearate, sorbitan sesquioleate, polysorbate, sodium lauryl sulfate, lauromacrogol, gum arabic, cholesterol, stearic acid, glycerin monostearate, povidone, etc.

[0101] 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 processed oils and fats thereof; fatty acids such as myristic acid, palmitic acid, isopalmitic acid, stearic acid, oleic acid, linoleic acid, and linolenic acid, and esters thereof; 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, carmellose sodium, carmellose calcium, povidone, and carboxyvinyl polymer. Examples of sequestering agents include disodium edetate, trisodium edetate, sodium citrate, sodium polyphosphate, sodium metaphosphate, and gluconic acid.

[0102] Examples of the disinfectant include 4-hydroxybenzoic acid and its salts and esters, triclosan, chlorhexidine, phenoxyethanol, menthol, mint oil, glyceryl caprate, glyceryl caprylate, salicylic acid-N-alkylamide, N-coconut oil fatty acid acyl-L-arginine ethyl-DL-pyrrolidone carboxylate, benzalkonium chloride, isopropyl methylphenol, etc. Examples of the deodorant include lauryl methacrylate, geranyl clotorate, acetophenone myristate, benzyl acetate, benzyl propionate, methyl benzoate, methyl phenylacetate, etc. Examples of the pH adjuster 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 such as retinol palmitate, collagen, elastin, allantoin, placenta extract, milk protein hydrolysate, bovine spleen extract, bovine blood hydrolysate, calf thymus extract, dialysate of young calf blood, yeast extract, etc.

[0103] Examples of moisturizing agents include polyethylene glycol, propylene glycol, glycerin, 1,3-butylene glycol, xylitol, sorbitol, maltitol, chondroitin sulfate, hyaluronic acid, mucoitin sulfate, caronic acid, atelocollagen, cholesteryl-12-hydroxystearate, sodium lactate, etc. Examples of blood circulation promoters include nonylic acid valerylamide, nicotinic acid benzyl ester, nicotinic acid β-butoxyethyl ester, capsaicin, zingerone, cantharides tincture, ichthammol, caffeine, tannic acid, α-borneol, nicotinic acid tocopherol, inositol hexanicotinate, cyclandelate, cinnarizine, tolazoline, acetylcholine, verapamil, cepharanthine, γ-oryzanol, etc. Examples of ultraviolet absorbing agents include para-aminobenzoic acid, homomenthyl-N-acetylanthranilate, amyl salicylate, octyl cinnamate, bisresorcinyl triazine, 3-(4'-methylbenzylidene)-d,l-camphor, 3-benzylidene-d,l-camphor, 2-phenyl-5-methylbenzoxazole, etc. Examples of ultraviolet scattering agents include fine particle titanium oxide, fine particle zinc oxide, etc.

[0104] 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, biotin, etc. Examples of plant extracts include extracts of turmeric, Phellodendron bark, Coptis japonica, Pueraria lobata, Lithospermum root, Peony root, Swertia japonica, Birch, Sage, Loquat, Carrot, Aloe, Mallow, Iris, Grape, Coix seed, Loofah, Lily, Saffron, Cnidium rhizome, Ginger, Hypericum perforatum, Rosemary, Garlic, Capsicum annuum, Scutellaria baicalensis, Citrus chinensis, and Angelica acutiloba. Examples of skin astringents include tannic acid, etc.

[0105] 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, salicylic acid, etc. Examples of whitening agents include arbutin, kojic acid, etc. Examples of sugars include glucose, fructose, mannose, sucrose, trehalose, etc. Examples of antiseborrheic agents include sulfur, thianthol, etc. Examples of stabilizers include sodium polyacrylate, dibutylhydroxytoluene, butylhydroxyanisole, etc. Examples of antioxidant components include those listed as other antioxidant components.

[0106] The amount of the neutral amino acid having 3 or more carbon atoms or its salt in the cosmetic of the first embodiment of the present invention may be appropriately set based on the effective amount etc. described above. The content of the dipeptide or its salt in the cosmetic of the second embodiment of the present invention is as described above.

[0107] The cosmetic composition of the present invention can be produced according to a conventional method.

[0108] (Processed foods and other foods) In one embodiment, the protein glycation inhibitor or composition of the present invention can be processed into a processed food.

[0109] The processed food of the first embodiment of the present invention contains the protein glycation inhibitor or composition of the first embodiment of the present invention. That is, the processed food of the first embodiment of the present invention contains a neutral amino acid having 3 or more carbon atoms or a salt thereof as an active ingredient. Therefore, by ingesting the processed food of the first embodiment of the present invention, skin aging caused by the production 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., can be prevented and / or improved.

[0110] The food (particularly processed food) of the second embodiment of the present invention contains a dipeptide or a salt thereof, the constituent amino acid of which is an amino acid selected from the group consisting of acidic amino acids, basic amino acids, hydroxyamino acids, branched-chain amino acids, and antioxidant amino acids, and the constituent amino acid on the C-terminal side is an antioxidant amino acid. Therefore, the food (particularly processed food) of the second embodiment of the present invention is excellent in the function of inhibiting the formation of advanced glycation end products and the antioxidant function, and is therefore useful for preventing and / or improving aging caused by the formation and / or accumulation of advanced glycation end products, particularly skin aging, such as wrinkle formation, age spots, sagging skin, and dullness. The food of the second embodiment of the present invention is preferably a food to which the above dipeptide or a salt thereof has been added or contained in an amount effective for preventing and / or improving aging caused by the formation and / or accumulation of advanced glycation end products, particularly skin aging.

[0111] In this specification, foods include general foods, health foods, functional foods (including foods for specified health uses, foods for conditional specified health uses, and foods with nutritional functions), foods for special dietary uses, dietary supplements, food additives, and the like.

[0112] In this specification, processed foods refer to foods that have been processed by adding any process to natural ingredients. Examples of processed foods include dairy products, flour products, confectioneries, pickles, simmered foods, dried foods, paste products (e.g., molded fish products), powders, canned foods, frozen foods, retort foods, instant foods (instant noodles, dry foods, powdered drinks, etc.), etc.

[0113] The amount of the neutral amino acid having 3 or more carbon atoms or a salt thereof in the processed food of the first embodiment of the present invention may be appropriately set based on the above-described effective oral intake amount, etc. The content of the dipeptide or a salt thereof in the food (particularly the processed food) of the second embodiment of the present invention is as described above.

[0114] The processed food can be produced according to a conventional method.

[0115] (Pharmaceutical preparations) In one embodiment, the protein glycation inhibitor or composition of the present invention may be formulated into a pharmaceutical preparation such as an ointment, liquid, suspension, emulsion, lotion, gel, tablet, pill, lozenge, powder, granule, capsule, suppository, injection (liquid, suspension, etc.), etc. It is preferably a skin external preparation in the form of an ointment, liquid, suspension, emulsion, lotion, gel, etc.

[0116] The pharmaceutical preparation of the first embodiment of the present invention includes the protein glycation inhibitor or composition of the first embodiment of the present invention. That is, the pharmaceutical preparation of the first embodiment of the present invention contains a neutral amino acid having 3 or more carbon atoms or a salt thereof as an active ingredient. Therefore, for example, by applying it to human skin, it is possible to prevent and / or improve skin aging caused by the production and / or accumulation of advanced glycation end products, such as wrinkle formation, age spots, sagging, dullness, etc. In addition, it is possible to treat and / or prevent diseases caused by the production and / or accumulation of advanced glycation end products, such as neuropathy, retinopathy, nephropathy, microvascular disorder, hypertension, heart failure, atherosclerosis, Alzheimer's disease, dermatological disorders, etc.

[0117] The pharmaceutical preparation of the second embodiment of the present invention contains a dipeptide or a salt thereof, the constituent amino acid of which is selected from the group consisting of acidic amino acids, basic amino acids, hydroxy amino acids, branched-chain amino acids, and antioxidant amino acids, and the constituent amino acid on the C-terminal side is an antioxidant amino acid. Thus, by administering to humans, aging caused by the production and / or accumulation of advanced glycation end products, particularly skin aging, such as wrinkle formation, age spots, sagging skin, and dull skin, can be prevented and / or improved. In addition, diseases caused by the production and / or accumulation of advanced glycation end products, such as neuropathy, retinopathy, nephropathy, microvascular disorder, hypertension, heart failure, atherosclerosis, Alzheimer's disease, dermatological disorders, etc. can be treated and / or prevented.

[0118] The pharmaceutical preparation of the first embodiment of the present invention is prepared using a neutral amino acid having 3 or more carbon atoms or a salt thereof and a cosmetically and / or pharma- ceutical acceptable carrier. The pharmaceutical preparation of the second embodiment of the present invention is prepared using a dipeptide or a salt thereof, the constituent amino acid of which is an antioxidant amino acid selected from the group consisting of acidic amino acids, basic amino acids, hydroxyamino acids, branched-chain amino acids, and antioxidant amino acids, and the constituent amino acid on the C-terminus side is a dipeptide or a salt thereof, and a cosmetically and / or pharma- ceutical acceptable carrier.

[0119] Carriers for ointments, liquids, suspensions, emulsions, lotions, gels, etc. include the same components as those for the cosmetics described above. Carriers for tablets, pills, lozenges, powders, granules, etc. include excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, hardened vegetable oil, kaolin, crystalline cellulose, talc, etc.; binders such as water, ethanol, propanol, gelatin, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, powdered gum arabic, powdered tragacanth, etc.; dry starch, sodium alginate, agar, laminaran, sodium bicarbonate, calcium carbonate, poly Examples of suitable disintegrants include disintegrants such as oxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, and lactose; disintegration inhibitors such as white sugar, stearin, cocoa butter, and hydrogenated oils; absorption promoters such as quaternary ammonium bases and sodium lauryl sulfate; moisturizers such as glycerin and starch; adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid, lubricants such as refined talc, stearates, boric acid powder, and polyethylene glycol; colorants; preservatives; fragrances; flavorings; and sweeteners.

[0120] The pharmaceutical preparations can be administered epicutaneously, transdermally, orally, intravenously, intraarterially, intramuscularly, subcutaneously, intraosseously, intraperitoneally, intradermally, by inhalation, enema, eye drop, ear drop, nasally, etc. In particular, epicutaneous administration by application to human skin as an ointment, solution, suspension, emulsion, lotion, or gel is preferred.

[0121] The dosage of the pharmaceutical preparation may be appropriately selected depending on the compounding amount, method of use, age, sex, weight, condition of the subject, and other conditions.

[0122] The amount of the neutral amino acid having 3 or more carbon atoms or a salt thereof in the pharmaceutical preparation of the first embodiment of the present invention may be appropriately set based on the effective amount of the topical composition or the effective oral intake amount of the oral composition, etc. The amount of the dipeptide or a salt thereof in the pharmaceutical preparation of the second embodiment of the present invention is as described above.

[0123] The pharmaceutical preparations can be manufactured in accordance with conventional methods.

[0124] (Proteins and their advanced glycation end products) The proteins that can be targets for glycation inhibition in the present invention and advanced glycation end products (AGEs) generated by glycation of these proteins will be described below.

[0125] In the present invention, glycation of a protein means a reaction of an amino acid residue of a protein with sugar or a glycation intermediate, and the reaction type is not particularly limited. Advanced glycation end products (AGEs) are generated by glycation of a protein. In the present invention, glycation includes both enzymatic and non-enzymatic glycation reactions, and is not limited to the Maillard reaction, which is a non-enzymatic glycation reaction, but in a preferred embodiment, it is the Maillard reaction.

[0126] Here, the amino acid residue of a protein that can be glycated can be, for example, a basic amino acid residue such as lysine or histidine, but is not particularly limited thereto. In the glycation of a protein, the basic amino acid residue can react, for example, at its amino group portion, but is not particularly limited thereto. In the glycation of a protein, sugar or a glycation reaction intermediate, for example, at its carbonyl portion, can react, but is not particularly limited thereto.

[0127] In the present invention, the protein that can be the target of glycation inhibition is not particularly limited as long as it is a known protein, but for example, when used in cosmetics, it can be a protein in the skin. Examples of the protein that can be the target of glycation inhibition include collagen, elastin, fibronectin, keratin, etc.

[0128] Examples of sugars that are substrates for the glycation of proteins include reducing sugars such as glucose, fructose, maltose, and arabinose. Examples of glycation intermediates include glyoxal, glycolaldehyde, methylglyoxal, 3-deoxyglucosone, and glyceraldehyde. It is known that the same substances as some of the glycation intermediates are also generated in vivo from metabolic pathways of lipids and amino acids, and in such cases, the glycation intermediates may be lipid metabolites, amino acid metabolites, and the source from which they originate is not limited. In addition, glycation intermediates also include sugar decomposition products generated in glycolysis and polyol metabolism.

[0129] Advanced glycation end products are generally classified into non-fluorescent advanced glycation end products and fluorescent advanced glycation end products. The protein glycation inhibitor according to the present invention can inhibit the production of both fluorescent advanced glycation end products and non-fluorescent advanced glycation end products (in the first embodiment of the present invention, it can inhibit the production of basic amino acids or more). In particular, it is excellent in the function of inhibiting the production of non-fluorescent, non-crosslinked advanced glycation end products and fluorescent advanced glycation end products.

[0130] Examples of fluorescent advanced glycation end products include fluorescent cross-linked advanced glycation end products containing pentosidine, crosslin, pyrropyridine, and the like.

[0131] Examples of non-fluorescent advanced glycation end products include non-fluorescent, non-crosslinked advanced glycation end products including Nε-(carboxymethyl)lysine (CML), Nε-(carboxyethyl)lysine (CEL), Nε-(carboxymethyl)arginine (CMA), pyrraline, argpyrimidine, etc.; and non-fluorescent, crosslinked advanced glycation end products including glyoxal-lysine dimer (GOLD), methylglyoxal-lysine dimer (MOLD), etc. The non-fluorescent advanced glycation end product preferably includes Nε-(carboxymethyl)lysine (CML).

[0132] For example, a glycation product containing Nε-(carboxymethyl)lysine (CML) may be, for example, (1) a glycation product generated when the carbonyl portion of a sugar such as glucose reacts directly with a lysine residue, followed by further transfer reaction, oxidation reaction, etc.; (2) a glycation product generated when glycolaldehyde, glyoxal, etc., which are decomposition products of a sugar such as glucose, reacts with a lysine residue, followed by further transfer reaction, oxidation reaction, etc.; or (3) a glycation product generated when the carbonyl portion of a sugar such as glucose reacts directly with a lysine residue, followed by further decomposition products such as glycolaldehyde, glyoxal, etc., which react with another lysine residue, followed by further transfer reaction, oxidation reaction, etc., but is not limited to these.

[0133] In one embodiment, the protein glycation inhibitor of the second embodiment of the present invention has a function of decomposing glycation intermediates, particularly a function of cleaving crosslinked structures of glycation intermediates. Examples of such crosslinked structures include C—C bonds of α-dicarbonyl structures. Such α-dicarbonyl structures are known to exist in glycation intermediates such as glyoxal, methylglyoxal, and 3-deoxyglucosone. In addition, crosslinked structures having α-dicarbonyl structures generated during the course of glycation can be targets for cleavage by the protein glycation inhibitor of the second embodiment of the present invention. In this embodiment, the protein glycation inhibitor of the second embodiment of the present invention can decompose glycation intermediates (including those crosslinked with proteins), particularly cleave the crosslinked structures, thereby suppressing the generation of advanced glycation end products and exhibiting excellent anti-glycation function.

[0134] (skin aging) The protein glycation inhibitor of the present invention can prevent and / or improve aging, particularly skin aging, caused by the generation and / or accumulation of advanced glycation end products. Aging can be aging of the skin, blood vessels, bones, organs, etc. For example, as a cosmetic, it can be useful for skin aging. Specific examples of skin aging include wrinkle formation, age spots, sagging, and dullness. Wrinkles refer to fine or deep grooves formed in the skin over time, and include dermal and epidermal wrinkles. Age spots refer to areas where melanin has accumulated in the skin, and include liver spots, senile pigmentation spots, and the like. Sagging refers to a state in which the skin sags under the influence of gravity due to reduced 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, and includes dullness (so-called yellowish dullness) of the dermis or epidermis (particularly the stratum corneum) of the skin. EXAMPLES

[0135] 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.

[0136] (Examples and Comparative Examples: Preparation of Sample Solutions) Each component such as amino acids shown in Tables 1 to 6 below was dissolved in 1x PBS (phosphate buffered saline) buffer at the predetermined concentration shown in Tables 1 to 6 below, and adjusted to pH 7.0 by adding 1M NaOH aqueous solution or 1M HCl to prepare a sample solution. All of the amino acids and pyrrolidone carboxylic acids used were in the L-form. However, in Test Example B4, a solution adjusted to pH 7.4 instead of pH 7.0 by adding 1M NaOH aqueous solution or 1M HCl was used, and in Test Example B7, a glyceraldehyde solution in which glyceraldehyde was dissolved in 1x PBS buffer at a concentration of 20 mM was used instead of 1x PBS buffer.

[0137] (Test Example A1-1: Measurement of non-fluorescent AGEs (CML)) 50 μL of sample solution of each Example and Comparative Example and 50 μL of 20 mM glyoxal solution were mixed per well of collagen solid-phase plate, and incubated at 37 ° C. under humid conditions for 24 hours. After the reaction, the solution was removed and washed, 200 μL of blocking solution was added to each well, and left at room temperature for 1 hour. The blocking solution was removed and washed, and 100 μL of primary antibody solution was added. After 1 hour, the solution was removed and washed, 100 μL of HRP-labeled secondary antibody was added, and left at rest for 1 hour. The solution was removed and washed, 100 μL of color development solution was added, and left at rest for 20 minutes. After the reaction, 100 μL of stop solution was added to stop the reaction. Immediately after stopping, the absorbance at 450 nm was measured with a plate reader. The CML generation rate when 1 × PBS (phosphate buffered saline) buffer (pH 7.0) was used instead of the sample solution was set to 100%, and the CML inhibition rate (%) of each sample solution was calculated using the following formula.

[0138] CML inhibition rate (%) = 100-100 x {absorbance (sample solution) / absorbance (1 x PBS buffer (pH 7.0))}

[0139] The CML suppression rate was evaluated according to the following criteria, and the results are shown in Table 1 below.

[0140] (Evaluation Criteria) A: CML suppression rate of 40% or more B: CML suppression rate is 25% or more but less than 40% C: CML suppression rate 0% to less than 25% D: CML suppression rate <0%

[0141] (Test Example A1-2: Measurement of non-fluorescent AGEs (CML)) For the combination of threonine and valine and the combination of threonine and arginine, tests were performed in the same manner as in Test Example A1-1 at the specific concentrations and concentration ratios shown in Table 2 below, and the CML inhibition rate (%) was calculated as the experimental value. Furthermore, the ratio of the experimental value to the calculated value was calculated using the following formula.

[0142] 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 during experiment (mM) / 20 (mM)) + (CML inhibition rate (%) of the other amino acid at 20 mM) × (concentration of the other amino acid during experiment (mM) / 20 (mM))}

[0143] The synergistic effect was evaluated according to the following evaluation criteria, and the results are shown in Table 2 below.

[0144] (Evaluation Criteria) +3: The ratio of experimental value to theoretical value is greater than 1.10. +2: The ratio of the experimental value to the theoretical value is greater than 1.05 and less than 1.10. +1: The ratio of the experimental value to the theoretical value is greater than 1.00 and less than 1.05.

[0145] (Test Example A2-1: Measurement of fluorescent AGEs (crosslin, pyrropyridine, etc.)) 50 μL of neutralized collagen solution was added per well to a 96-well plate and pre-incubated at 37°C. 10 μL of sample solution from each Example and Comparative Example and 50 μL of 200 mM fructose solution were mixed per well. The plates were incubated at 37°C for 35 days under humid conditions. Immediately after the reaction and after 35 days, the fluorescence intensity was measured using a plate reader at an excitation wavelength of 370 nm and a fluorescence wavelength of 440 nm. The fluorescent AGEs inhibition rate for each sample was calculated using the following formula, assuming that the fluorescent AGEs production rate was 100% when 1×PBS (phosphate buffered saline) buffer (pH 7.0) was used instead of the sample.

[0146] Fluorescent AGEs inhibition rate (%) = 100 - 100 x [{fluorescence intensity (sample solution, after incubation period) - fluorescence intensity (sample solution, 0 days)} / {fluorescence intensity (1 x PBS buffer (pH 7.0), after incubation period) - fluorescence intensity (1 x PBS buffer (pH 7.0), 0 days)}]

[0147] The fluorescent AGEs inhibition rate was evaluated according to the following evaluation criteria, and the results are shown in Table 1 below.

[0148] (Evaluation Criteria) A: Fluorescent AGEs suppression rate of 10% or more B: Fluorescent AGEs inhibition rate: 5% to less than 10% C: Fluorescent AGEs inhibition rate: 0% to less than 5% D: Fluorescent AGEs inhibition rate less than 0%

[0149] (Test Example A2-2: Measurement of fluorescent AGEs (crosslin, pyrropyridine, etc.)) The test was conducted in the same manner as Test Example A2-1, except that the incubation conditions were changed from 37°C for 35 days to 60°C for 6 days, and the fluorescent AGE inhibition rates of each sample were calculated using the formula in Test Example A2-1, and the fluorescent AGE inhibition rates were evaluated according to the following evaluation criteria. The results are shown in Table 3 below.

[0150] (Evaluation Criteria) A: Fluorescent AGEs suppression rate of 10% or more B: Fluorescent AGEs inhibition rate: 4% to less than 10% C: Fluorescent AGEs inhibition rate: 0% to less than 4% D: Fluorescent AGEs inhibition rate less than 0%

[0151] The fluorescent AGE inhibition rates (%) calculated above for Examples A25 to A27, A29, A32 to 34, and A36 were used as experimental values, and the ratios of the experimental values ​​to the calculated values ​​were calculated using the formula in Test Example A1-2 to evaluate the synergistic effect according to the following evaluation criteria. The results are shown in Table 4 below.

[0152] (Evaluation Criteria) +5: The ratio of experimental value to theoretical value is greater than 1.40. +4: The ratio of experimental value to theoretical value is greater than 1.30 and less than 1.40. +3: The ratio of the experimental value to the theoretical value is greater than 1.20 and less than 1.30. +2: The ratio of the experimental value to the theoretical value is greater than 1.10 and less than 1.20. +1: The ratio of the experimental value to the theoretical value is greater than 1.00 and less than 1.10. 0: The ratio of experimental value to theoretical value is 1.00 -1: The ratio of the experimental value to the theoretical value is 0.90 or more and less than 1.00 -2: The ratio of the experimental value to the theoretical value is 0.80 or more and less than 0.90 -3: The ratio of the experimental value to the theoretical value is 0.70 or more and less than 0.80. -4: The ratio of the experimental value to the theoretical value is 0.60 or more and less than 0.70 -5: The ratio of experimental value to theoretical value is less than 0.60

[0153] (Test Example A2-3: Measurement of the inhibition rate of fluorescent AGEs (pentosidine, etc.)) The test was conducted in the same manner as in Test Example A2-2, except that the fluorescence intensity was measured at an excitation wavelength of 335 nm and a fluorescence wavelength of 385 nm, and the fluorescent AGE inhibition rates of each sample were calculated using the formula in Test Example A2-1, and the fluorescent AGE inhibition rates were evaluated according to the following evaluation criteria. The results are shown in Table 3 below.

[0154] (Evaluation Criteria) A: Fluorescent AGEs suppression rate of 10% or more B: Fluorescent AGEs inhibition rate: 4% to less than 10% C: Fluorescent AGEs inhibition rate: 0% to less than 4% D: Fluorescent AGEs inhibition rate less than 0%

[0155] The fluorescent AGE inhibition rates (%) calculated above for Examples A24 to A28, A30 to A35, A37, and A38 were used as experimental values, and the ratios of the experimental values ​​to the calculated values ​​were calculated using the formula in Test Example A1-2 to evaluate the synergistic effect according to the following evaluation criteria. The results are shown in Table 4 below.

[0156] (Evaluation Criteria) +5: The ratio of experimental value to theoretical value is greater than 1.40. +4: The ratio of experimental value to theoretical value is greater than 1.30 and less than 1.40. +3: The ratio of the experimental value to the theoretical value is greater than 1.20 and less than 1.30. +2: The ratio of the experimental value to the theoretical value is greater than 1.10 and less than 1.20. +1: The ratio of the experimental value to the theoretical value is greater than 1.00 and less than 1.10. 0: The ratio of experimental value to theoretical value is 1.00 -1: The ratio of the experimental value to the theoretical value is 0.90 or more and less than 1.00 -2: The ratio of the experimental value to the theoretical value is 0.80 or more and less than 0.90 -3: The ratio of the experimental value to the theoretical value is 0.70 or more and less than 0.80. -4: The ratio of the experimental value to the theoretical value is 0.60 or more and less than 0.70 -5: The ratio of experimental value to theoretical value is less than 0.60

[0157] (Test Example A3-1: Measurement of absorbance change rate (350 nm) (absorbance with glycerin)) 100 μL of glycerin diluted 2-fold with 1×PBS (phosphate buffered saline) buffer was mixed with 70 μL of each sample solution of the Examples and Comparative Examples, and incubated at 70° C. for 9 days. After incubation, the absorbance at 350 nm was measured using a plate reader. 1×PBS (phosphate buffered saline) buffer (pH 7.0) was set as a negative control, and histidine was set as a positive control. The absorbance change rate of each sample was calculated using the following formula.

[0158] Absorbance change rate (%) = 100 x [{absorbance (sample solution) - absorbance (1 x PBS buffer (pH 7.0))} / {absorbance (positive control) - absorbance (1 x PBSS buffer (pH 7.0))}]

[0159] The rate of absorbance change was evaluated according to the following evaluation criteria, and the results are shown in Table 1 below.

[0160] (Evaluation Criteria) A: Absorbance change rate less than 60% B: Absorbance change rate 60% or more but less than 75% C: Absorbance change rate 75% or more but less than 90% D: Absorbance change rate 90% or more

[0161] (Test Example A3-2: Measurement of absorbance change rate (450 nm) (absorbance with glycerin)) The test was carried out in the same manner as in Test Example A3-1, except that the amount of glycerin used was changed from 100 μL to 500 μL, the amount of sample solution used was changed from 70 μL to 500 μL, and the absorbance at 450 nm was measured. The absorbance change rate of each sample was calculated using the formula in Test Example A3-1, and the absorbance change rate was evaluated according to the following evaluation criteria. The results are shown in Table 5 below.

[0162] (Evaluation Criteria) A: Absorbance change rate less than 10% B: Absorbance change rate 10% or more but less than 20% C: Absorbance change rate 20% or more but less than 50% D: Absorbance change rate 50% or more

[0163] (Test Example A3-3: Measurement of absorbance change rate (290 nm) (absorbance with butylene glycol)) The test was carried out in the same manner as in Test Example A3-2, except that glycerin was replaced with 1,3-butylene glycol and the absorbance at 290 nm was measured. The absorbance change rate of each sample was calculated using the formula in Test Example A3-1, and the absorbance change rate was evaluated according to the following evaluation criteria. The results are shown in Table 5 below.

[0164] (Evaluation Criteria) A: Absorbance change rate less than 25% B: Absorbance change rate 25% or more but less than 32% C: Absorbance change rate 32% or more but less than 70% D: Absorbance change rate 70% or more

[0165] (Test Example A3-4: Measurement of absorbance change rate (450 nm) (absorbance with butylene glycol)) Except for measuring the absorbance at 450 nm and setting tryptophan as the positive control, the test was performed in the same manner as in Test Example A3-3. The absorbance change rate of each sample was calculated using the formula in Test Example A3-1 and the following formula, and the absorbance change rate was evaluated according to the following evaluation criteria. The results are shown in Table 5 below.

[0166] (Evaluation Criteria) A: Absorbance change rate less than 2.5% B: Absorbance change rate 2.5% or more but less than 15% C: Absorbance change rate 15% or more but less than 25% D: Absorbance change rate 25% or more

[0167] (Test Example A4: Measurement of antioxidant capacity) Antioxidant Assay Kit (Cayman Chemical Company) was used to measure antioxidant capacity by the ABTS method. 10 μL of sample solution from each Example and Comparative Example, 10 μL of metmyoglobin solution, and 150 μL of chromogen solution were mixed per well. 40 μL of hydrogen peroxide solution (441 μM) was added to the mixture to start the reaction, and the mixture was shaken at room temperature for 5 minutes. After shaking, the absorbance at 750 nm was measured using a plate reader. 0.25 wt% sodium ascorbate (vitamin C) solution was used as a positive control, and 1×PBS (phosphate buffered saline) buffer (pH 7.0) was used as a negative control. The following formula was used to calculate antioxidant capacity.

[0168] Antioxidant capacity (%) = 100 - 100 x [{absorbance (sample solution) - absorbance (positive control (vitamin C))} / {absorbance (1XPBS buffer (pH 7.0)) - absorbance (positive control (vitamin C))}]

[0169] The antioxidant activity was evaluated according to the following evaluation criteria, and the results are shown in Table 1 below.

[0170] (Evaluation Criteria) A: Antioxidant capacity 10% or more B: Antioxidant capacity 5% or more and less than 10% C: Antioxidant capacity 0% or more and less than 5% D: Antioxidant capacity less than 0%

[0171] [Table 1]

[0172] [Table 2]

[0173] [Table 3]

[0174] [Table 4]

[0175] [Table 5]

[0176] The results of each of the test examples A1-1 to A4 show that when a neutral amino acid with 3 or more carbon atoms is contained, it has a wide range of excellent inhibitory function for the formation of advanced glycation end products and antioxidant capacity compared to when only other amino acids are contained, and furthermore, it is less likely to discolor even when coexisting with a polyhydric alcohol.

[0177] (Test Example B1: Measurement of non-fluorescent AGEs (CML)) 50 μL of sample solution of each Example and Comparative Example and 50 μL of 20 mM glyoxal solution were mixed per well of collagen solid-phase plate, and incubated at 37° C. for 24 hours under humid conditions. After the reaction, the solution was removed and washed, 200 μL of blocking solution was added to each well, and left at room temperature for 1 hour. The blocking solution was removed and washed, and 100 μL of primary antibody solution was added. After 1 hour, the solution was removed and washed, 100 μL of HRP-labeled secondary antibody was added, and left at rest for 1 hour. The solution was removed and washed, 100 μL of color development solution was added, and left at rest for 20 minutes. After the reaction, 100 μL of stop solution was added to stop the reaction. Immediately after stopping, the absorbance at 450 nm was measured with a plate reader. The CML generation rate when 1×PBS buffer (pH 7.0) was used instead of the sample solution was set to 100%, and the CML inhibition rate (%) of each sample solution was calculated using the following formula.

[0178] CML inhibition rate (%) = 100-100 x {absorbance (sample solution) / absorbance (1 x PBS buffer (pH 7.0))}

[0179] The CML suppression rate was evaluated according to the following criteria, and the results are shown in Table 6 below.

[0180] (Evaluation Criteria) A: CML suppression rate of 20% or more B: CML suppression rate 3% or more but less than 20% C: CML suppression rate - 50% or more but less than 3% D: CML suppression rate - less than 50%

[0181] (Test Example B2: Measurement of fluorescent non-crosslinked AGEs using glyceraldehyde) 50 μL of neutralized collagen was added per well, and after preincubation, 40 μL of sample solution from each Example and Comparative Example was mixed with 10 μL of 500 mM glyceraldehyde solution and incubated at 37°C for 24 hours under humid conditions. Immediately after the reaction and after 24 hours, the fluorescence intensity was measured using a plate reader at an excitation wavelength of 370 nm and a fluorescence wavelength of 440 nm. The production rate of fluorescent non-crosslinked AGEs when 1x PBS buffer (pH 7.0) was added instead of the sample was taken as 100%, and the fluorescent non-crosslinked AGE inhibition rate of each sample was calculated using the following formula.

[0182] Fluorescent non-crosslinking AGEs inhibition rate (%) = 100 - 100 x [{fluorescence intensity (sample solution, after 24 hours) - fluorescence intensity (sample solution, after 0 hours)} / {fluorescence intensity (1 x PBS buffer (pH 7.0), after 24 hours) - fluorescence intensity (1 x PBS buffer (pH 7.0), after 0 hours)}]

[0183] The fluorescent non-crosslinking AGEs inhibition rate was evaluated according to the following evaluation criteria, and the results are shown in Table 6 below.

[0184] (Evaluation Criteria) A: Fluorescent non-crosslinking AGEs inhibition rate of 20% or more B: Fluorescent non-crosslinked AGEs inhibition rate of 5% to less than 20% C: Fluorescent non-crosslinking AGEs inhibition rate -150% or more and less than 5% D: Fluorescent non-crosslinking AGEs inhibition rate - less than 150%

[0185] (Test Example B3: Measurement of fluorescent cross-linked AGEs using glyceraldehyde) 50 μL of neutralized collagen was added per well, and after preincubation, 40 μL of sample solution from each Example was mixed with 10 μL of 500 mM glyceraldehyde solution, and incubated at 37°C for 24 hours under humid conditions. Immediately after the reaction and after 24 hours, the fluorescence intensity was measured using a plate reader at an excitation wavelength of 335 nm and a fluorescence wavelength of 385 nm. The fluorescent crosslinking AGEs inhibition rate (%) of each sample was calculated using the following formula, assuming that the production rate of fluorescent crosslinking AGEs when 1x PBS buffer (pH 7.0) was added instead of the sample was 100%.

[0186] Fluorescent cross-linking AGEs inhibition rate (%) = 100 - 100 x [{fluorescence intensity (sample solution, after 24 hours) - fluorescence intensity (sample solution, after 0 hours)} / {fluorescence intensity (1 x PBS buffer (pH 7.0), after 24 hours) - fluorescence intensity (1 x PBS buffer (pH 7.0), after 0 hours)}]

[0187] The fluorescent cross-linking AGEs inhibition rate was evaluated according to the following evaluation criteria, and the results are shown in Table 6 below.

[0188] (Evaluation Criteria) A: Fluorescent cross-linking AGEs suppression rate of 20% or more B: Fluorescent cross-linking AGEs inhibition rate: 5% to less than 20% C: Inhibition rate of fluorescent cross-linking AGEs is 0% or more but less than 5% D: Fluorescent cross-linking AGEs inhibition rate less than 0%

[0189] (Test Example B4: Evaluation test of decomposition of intermediates in glycation reaction) As a model substrate, 1-phenyl-1,2-propanedione (PPD) was diluted to 4 mM with MeOH solution (MeOH:phosphate buffer = 1:4). The sample solution of each example (adjusted to pH 7.4) and PPD solution were mixed at 1:1 and incubated at 37°C for 12 hours. After incubation, hydrochloric acid was added to stop the reaction, and the generated benzoic acid was measured by HPLC. The crosslink cleavage rate when phosphate buffer was added instead of the sample was set to 0%, and the crosslink cleavage rate (%) was calculated using the following formula.

[0190] Glycation reaction intermediate cross-link cleavage rate (%) = 100 × [{benzoic acid amount (sample solution, 12 hours later) - benzoic acid amount (sample solution, 0 hours later)} - {benzoic acid amount (phosphate buffer, 12 hours later) - benzoic acid amount (phosphate buffer, 0 hours later)}] / benzoic acid amount (standard, 2 mM)

[0191] The glycation reaction intermediate crosslink cleavage rate was evaluated according to the following evaluation criteria, and the results are shown in Table 6 below.

[0192] (Evaluation Criteria) A: Glycation reaction intermediate cross-link cleavage rate 1% or more B: Glycation reaction intermediate cross-link cleavage rate: 0% to less than 1% C: Glycation reaction intermediate cross-link cleavage rate - 1% or more but less than 0% D: Glycation reaction intermediate cross-link cleavage rate - less than 1%

[0193] (Test Example B5: Measurement of antioxidant capacity) A 0.25% by weight sodium ascorbate (vitamin C) solution was used as a positive control, and 1x PBS buffer (pH 7.0) was used as a negative control. 10μL of sample solution from each Example and Comparative Example, 10μL of metmyoglobin solution, and 150μL of chromogen solution were mixed per well. 40μL of hydrogen peroxide solution was added to the mixture to start the reaction, and the mixture was shaken at room temperature for 5 minutes. After shaking, the absorbance at 750nm was measured using a plate reader. The following formula was used to calculate antioxidant capacity (%).

[0194] Antioxidant capacity (%) = 100 - 100 x [{absorbance (sample solution) - absorbance (positive control (vitamin C))} / {absorbance (1 x PBS buffer (pH 7.0)) - absorbance (positive control (vitamin C))}]

[0195] The antioxidant activity was evaluated according to the following evaluation criteria, and the results are shown in Table 6 below.

[0196] (Evaluation Criteria) A: Antioxidant capacity 10% or more B: Antioxidant capacity 5% or more and less than 10% C: Antioxidant capacity 0% or more and less than 5% D: Antioxidant capacity less than 0%

[0197] (Test Example B6: Stability test) The sample solutions of each Example and Comparative Example were incubated at 70°C for 5 days. After incubation, the absorbance at 350 nm was measured using a plate reader. 1x PBS buffer (pH 7.0) was used instead of the sample solution as a negative control, and L-histidine (His) (Comparative Example B7) was set as a positive control. The following formula was used to calculate the coloring rate (%). A lower coloring rate indicates higher stability.

[0198] Coloring rate (%) = 100 × [{Absorbance (sample solution) - Absorbance (1XPBS buffer (pH7.0))} / {Absorbance (His) - Absorbance (1XPBS buffer (pH7.0))}]

[0199] The coloring rate was evaluated according to the following evaluation criteria, and the results are shown in Table 6 below.

[0200] (Evaluation Criteria) A: Coloring rate less than 50% B: Coloring rate 50% or more but less than 65% C: Coloring rate 65% or more but less than 75% D: Coloring rate 75% or more

[0201] (Test Example B7: Yellowing (yellowing) inhibition test) The human excised stratum corneum skin was immersed in the sample solution (solution containing 20 mM glyceraldehyde) of each Example and Comparative Example and incubated at 37° C. for 7 days. After incubation, the human excised stratum corneum skin was washed with Milli-Q water and dried. The dried skin was measured using a spectrophotometric colorimeter to determine the yellowness index b ※ The b value of human excised stratum corneum skin immersed in a solution containing 20 mM glyceraldehyde was measured. ※ Yellow values ​​are the mutation inhibition rate of 0%, and the b values ​​are the mutation inhibition rate of excised human stratum corneum skin immersed in 1× PBS buffer. ※ The value was taken as 100% yellow mutation inhibition rate, and the yellow mutation inhibition rate (%) of each sample was calculated using the following formula.

[0202] Yellow Mutation suppression rate (%) = 100 × [{b ※ Value (20 mM glyceraldehyde)-b ※ value (sample solution, 20 mM glyceraldehyde)} / {b ※ Value (20 mM glyceraldehyde)-b ※ Value (1XPBS buffer)}]

[0203] The inhibition rate of yellow mutation was evaluated according to the following criteria, and the results are shown in Table 6 below.

[0204] A: Yellow mutation suppression rate 10% or more B: Yellow: Mutation suppression rate is 5% or more but less than 10% C: Yellow: Mutation suppression rate 0% to less than 5% D: Yellow: Mutation suppression rate is less than 0%

[0205] [Table 6]

[0206] From the above results, dipeptides (Examples B1 to B5) in which the constituent amino acids are selected from the group consisting of acidic amino acids, basic amino acids, hydroxy amino acids, branched-chain amino acids, and antioxidant amino acids and in which the constituent amino acid on the C-terminus side is an antioxidant amino acid, exhibit anti-glycation function against a wide range of advanced glycation end products (Test Examples B1 and B2), whereas commercially available known anti-glycation agents (Comparative Examples B1 and B2) did not exhibit anti-glycation function against a wide range of advanced glycation end products (Test Examples B1 and B2). In addition, dipeptides that do not have antioxidant amino acids at the C-terminus (Comparative Examples B3 and B4) and dipeptides with reversed sequences compared to the effective dipeptides (Examples B3 and B4) (Comparative Examples B5 and B6) did not exhibit anti-glycation function against a wide range of advanced glycation end products (Test Examples B1 and B2).

[0207] In addition, it was found that dipeptides (Examples B1 to B4) whose constituent amino acids are selected from the group consisting of acidic amino acids, basic amino acids, hydroxyamino acids, branched-chain amino acids, and antioxidant amino acids, and whose C-terminal constituent amino acid is an antioxidant amino acid, are excellent in the ability to decompose glycation reaction intermediates (Test Example B4), the ability to inhibit yellowing (Test Example B7), and the antioxidant ability (Test Example B5), and further have high stability (Test Example B6). [Industrial Applicability]

[0208] According to the first embodiment of the present invention, it is possible to obtain a composition or the like that contains a component that exhibits anti-glycation function against a wide range of advanced glycation endproducts, further has antioxidant function, is resistant to coloration when used in cosmetics, etc., and is highly safe and biocompatible. Therefore, it can be used in the production of cosmetics, processed foods, pharmaceutical preparations, etc., and is particularly useful for cosmetics containing polyhydric alcohols.

[0209] According to the second aspect of the present invention, it is possible to provide a composition or the like that contains a component that exhibits a wide range of anti-glycation functions and further has an antioxidant function, while being highly stable, safe, and biocompatible, and is therefore useful for cosmetics, foods, pharmaceutical preparations, etc.

Claims

1. A protein glycation inhibitor characterized in that the constituent amino acids are selected from the group consisting of acidic amino acids, basic amino acids, hydroxyamino acids, branched-chain amino acids, and antioxidant amino acids, and the constituent amino acid on the C-terminal side contains a dipeptide or a salt thereof, which is an antioxidant amino acid, as an active ingredient.

2. 2. The protein glycation inhibitor according to claim 1, wherein the constituent amino acid on the C-terminal side of the dipeptide is selected from the group consisting of tryptophan, tyrosine, methionine, cysteine, and histidine.

3. 3. The protein glycation inhibitor according to claim 1, wherein the constituent amino acid on the N-terminal side of the dipeptide is selected from the group consisting of hydroxyamino acids, basic amino acids, and acidic amino acids.

4. 4. The protein glycation inhibitor according to claim 1, wherein the constituent amino acid on the N-terminal side of the dipeptide is selected from the group consisting of serine, threonine, histidine, and glutamic acid.

5. The protein glycation inhibitor according to any one of claims 1 to 4, characterized in that the dipeptide is selected from the group consisting of N-seryl tyrosine (Ser-Tyr), N-histidyl tryptophan (His-Trp), N-threonyl methionine (Thr-Met), N-seryl methionine (Ser-Met), and N-(α-glutamyl) tyrosine (Glu-Tyr).

6. The protein glycation inhibitor according to any one of claims 1 to 5, characterized in that it inhibits the production of fluorescent advanced glycation end products.

7. The protein glycation inhibitor according to any one of claims 1 to 5, characterized in that it inhibits the production of non-fluorescent advanced glycation end products.

8. The protein glycation inhibitor according to any one of claims 1 to 5, characterized in that it inhibits the production of both fluorescent and non-fluorescent advanced glycation end products.

9. The protein glycation inhibitor according to claim 6 or 8, characterized in that the fluorescent advanced glycation end products include crosslin, pyrropyridine and / or pentosidine.

10. The protein glycation inhibitor according to claim 7 or 8, wherein the non-fluorescent advanced glycation end products include Nε-(carboxymethyl)lysine (CML).

11. The protein glycation inhibitor according to any one of claims 1 to 10, which decomposes a glycation reaction intermediate.

12. The protein glycation inhibitor according to any one of claims 1 to 11, characterized in that it prevents or improves the occurrence of dull skin.

13. The protein glycation inhibitor according to any one of claims 1 to 12, characterized in that the protein is a protein in the skin.

14. The protein glycation inhibitor according to any one of claims 1 to 13, characterized in that the protein is selected from the group consisting of collagen, elastin, fibronectin and keratin.

15. An antioxidant characterized in that its constituent amino acids are selected from the group consisting of acidic amino acids, basic amino acids, hydroxyamino acids, branched-chain amino acids, and antioxidant amino acids, and that the constituent amino acid on the C-terminal side contains a dipeptide or a salt thereof, which is an antioxidant amino acid, as an active ingredient.

16. A cosmetic preparation comprising an amino acid selected from the group consisting of acidic amino acids, basic amino acids, hydroxyamino acids, branched-chain amino acids, and antioxidant amino acids, and wherein the C-terminal constituent amino acid contains a dipeptide or a salt thereof which is an antioxidant amino acid.

17. A food characterized in that the constituent amino acids are selected from the group consisting of acidic amino acids, basic amino acids, hydroxyamino acids, branched-chain amino acids, and antioxidant amino acids, and the constituent amino acid on the C-terminal side contains a dipeptide or a salt thereof which is an antioxidant amino acid.

18. A skin topical preparation characterized in that the constituent amino acids are selected from the group consisting of acidic amino acids, basic amino acids, hydroxyamino acids, branched-chain amino acids, and antioxidant amino acids, and the constituent amino acid on the C-terminal side contains a dipeptide or a salt thereof which is an antioxidant amino acid.

19. A composition for preventing and / or improving skin aging, characterized in that the constituent amino acids are selected from the group consisting of acidic amino acids, basic amino acids, hydroxyamino acids, branched-chain amino acids, and antioxidant amino acids, and the constituent amino acid on the C-terminal side contains a dipeptide or a salt thereof as an active ingredient, the dipeptide being an antioxidant amino acid.

20. 20. The composition according to claim 19, wherein the skin aging is selected from the group consisting of the formation of wrinkles, the appearance of age spots, the appearance of sagging skin, and the appearance of dullness.

21. A composition for treating and / or preventing a disease caused by the production and / or accumulation of advanced glycation end products, characterized in that the composition contains, as an active ingredient, an amino acid selected from the group consisting of acidic amino acids, basic amino acids, hydroxyamino acids, branched-chain amino acids, and antioxidant amino acids, and the C-terminal constituent amino acid is an antioxidant amino acid, such as a dipeptide or a salt thereof.

22. 22. The composition of claim 21, wherein the disease is selected from the group consisting of neuropathy, retinopathy, nephropathy, microvascular disease, hypertension, heart failure, atherosclerosis, Alzheimer's disease, and dermatological disorders.

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