JP2022183036A - Antiglycative agent, and use thereof - Google Patents

Abstract

To provide an antiglycative agent having high antiglycative activity.SOLUTION: An antiglycative agent contains dihydroxybenzalacetone or a salt thereof as an active ingredient.SELECTED DRAWING: None

Description

There is an application for exception to loss of novelty

The present invention relates to anti-glycation agents and uses thereof.

Glycation is a series of chemical reactions starting from the non-enzymatic binding of carbonyl groups of reducing sugars to amino groups of proteins or amino acids, and advanced glycation endproducts (hereinafter also referred to as "AGEs"). ) is generated. AGEs produced by in vivo glycation cause various age-related diseases, diabetic complications, inflammation, and the like.

Aminoguanidine and the like are known as typical AGE production inhibitors that suppress the production of AGEs. Aminoguanidine inhibits the accumulation of AGEs in living tissues and may have a protective effect against age-related decline in cardiovascular and renal function.

In addition, as an anti-glycation agent that suppresses saccharification, for example, Patent Document 1 discloses an anti-glycation agent containing an extract of Betula anatake.

Japanese Patent Application Laid-Open No. 2019-43887

However, aminoguanidine and the anti-glycation agent disclosed in Patent Document 1 are not sufficient from the viewpoint of high anti-glycation activity and the like, and there is room for further improvement.

One embodiment of the present invention has been made in view of the above problems, and an object thereof is to provide an anti-glycation agent having high anti-glycation activity.

The present inventor has completed the present invention as a result of intensive studies to solve the above problems. That is, one embodiment of the present invention includes the following configurations.

[1] An anti-glycation agent containing dihydroxybenzalacetone or a salt thereof as an active ingredient. [2] The anti-glycation agent of [1] above, which is for suppressing glycation of collagen or elastin.
[3] The anti-glycation agent of [1] or [2] above, which is for suppressing saccharification by glucose, fructose, xylose, arabinose, galactose, lactose or glyceraldehyde.
[4] A food, drink, feed, cosmetic or pharmaceutical containing the anti-glycation agent according to any one of [1] to [3] above.

According to one aspect of the present invention, an anti-glycation agent having high anti-glycation activity can be provided.

1 is a graph showing anti-glycation activity against glycation of BSA by glucose. 1 is a graph showing anti-glycation activity against glycation of BSA by fructose. 4 is a graph showing the anti-glycation activity against glycation of collagen by glyceraldehyde. 1 is a graph showing anti-glycation activity against glycation of elastin by glyceraldehyde.

An embodiment of the invention will be described below, but the invention is not limited thereto. The present invention is not limited to each configuration described below, and various modifications are possible within the scope of the claims. Further, embodiments or examples obtained by appropriately combining technical means disclosed in different embodiments or examples are also included in the technical scope of the present invention. Furthermore, new technical features can be formed by combining the technical means disclosed in each embodiment. In addition, all the scientific literatures and patent documents described in this specification are used as references in this specification. In addition, unless otherwise specified in this specification, "A to B" representing a numerical range means "A or more (including A and greater than A) and B or less (including B and less than B)".

[1. Definition of terms〕
As used herein, "anti-glycation agent" intends an agent having anti-glycation activity. In addition, "anti-glycation" refers to the action of inhibiting glycation and suppressing the production of advanced glycation end products (AGEs) (hereinafter also referred to as "glycation inhibitory action" or "AGEs production inhibitory action"); It includes an action of suppressing accumulation (hereinafter also referred to as "ages accumulation suppressing action") and an action of promoting degradation of AGEs (hereinafter also referred to as "AGEs degradation promoting action"). Therefore, in the present specification, the anti-glycation agent can also be referred to as "glycation inhibitor", "AGEs production inhibitor", "AGEs accumulation inhibitor" or "AGEs degradation promoter".

Methods for examining the anti-glycation activity include a method of measuring fluorescence spectra from fluorescent AGEs in a reaction solution containing a sample, protein and reducing sugar. Fluorescent AGEs have the property of emitting fluorescence when excited by a wavelength of about 370 nm or its vicinity. Glycation activity can be examined.

"Advanced glycation end-products (AGEs)" is a generic term for products resulting from saccharification (also called "Maillard reaction"). AGEs are known to be involved in various diseases (eg, aging-related conditions and diseases (hereinafter also referred to as “aging-related diseases”), diabetic complications, inflammation, and the like).

AGEs include Nε-carboxymethyllysine (CML), Nε-carboxyethyllysine (CEL), argupyrimidine, pentosidine, pyrarin, crossrin, GA-pyridine, Nω-carboxymethylarginine (CMA), furoylfuranylimidazole, and , glucospan and the like.

[2. anti-glycation agent]
An anti-glycation agent according to one embodiment of the present invention contains dihydroxybenzalacetone represented by the following formula (1) or a salt thereof as an active ingredient. The anti-glycation agent according to one embodiment of the present invention may be hereinafter referred to as "the present anti-glycation agent".

Aminoguanidine, which has hitherto been known as an AGE production inhibitor, has room for improvement in terms of the strength of its anti-glycation activity. In addition, it has been reported that aminoguanidine may cause side effects such as liver damage. In contrast, dihydroxybenzalacetone and its salts discovered by the present inventors have higher antiglycation activity than aminoguanidine. Therefore, the present antiglycation agent has the advantage of exhibiting a higher antiglycation activity than aminoguanidine by containing dihydroxybenzalacetone or a salt thereof as an active ingredient.

As used herein, the term "active ingredient" means a substance having anti-glycation activity or a substance that increases the anti-glycation activity of the composition.

Dihydroxybenzalacetone is also called 4-dihydroxyphenyl-but-3-en-2-one, or dihydroxybenzylideneacetone.

The action mechanism by which the present anti-glycation agent exerts anti-glycation activity is presumed to be any of the following (i) to (iii) or a combination thereof, but the present invention is not limited to such conjecture: ( i) suppressing the production of AGEs by inhibiting glycation of the target protein; (ii) suppressing the in vivo accumulation of AGEs produced by glycation of the target protein; and (iii) producing by glycation of the target protein. The amount of AGEs is reduced by promoting the decomposition of AGEs.

The present antiglycation agent has antiglycation activity against glycation of various substances such as proteins. Among these, the present antiglycation agent exhibits high antiglycation activity against glycation of collagen or elastin. In particular, by appropriately adjusting the dosage of the active ingredient (dihydroxybenzalacetone or its salt) during the present antiglycation activity, the antiglycation activity is significantly superior to that of aminoguanidine, which is typically used as a positive control. Exhibits anti-glycation activity. Since saccharification of collagen and elastin has been reported to be highly associated with skin aging, arteriosclerosis, osteoporosis, etc., this effect is very important.

Therefore, the present anti-glycation agent can be suitably used as a collagen glycation inhibitor for inhibiting glycation of collagen or as an elastin glycation inhibitor for inhibiting glycation of elastin. . In other words, the present invention provides collagen glycation inhibitors and elastin glycation inhibitors containing dihydroxybenzalacetone or a salt thereof as an active ingredient. The collagen glycation inhibitor and elastin glycation inhibitor according to one embodiment of the present invention can be suitably used, for example, in cosmetics for improving skin conditions related to AGEs.

The anti-glycation agent has anti-glycation activity against glycation caused by various reducing sugars. Examples of reducing sugars include all simple sugars (eg, glucose, fructose, xylose, arabinose, and galactose), lactose, glyceraldehyde, and the like. Among these reducing sugars, glucose and fructose are abundant in vivo. In addition, AGEs produced by saccharification by glyceraldehyde are reported to be highly related to the onset of diseases and the like.

The present antiglycation agent exhibits excellent antiglycation activity against saccharification by glucose, fructose, xylose, arabinose, galactose, lactose, and glyceraldehyde among these reducing sugars. In other words, the anti-glycation agent can be suitably used to suppress saccharification by glucose, fructose, xylose, arabinose, galactose, lactose and glyceraldehyde.

(2-1. Active ingredient)
It has been reported that dihydroxybenzalacetone or its salt, which is the active ingredient of this antiglycation agent, suppresses inflammation and generation of reactive oxygen species (W. Chao, et al., Int. Immunopharmacol., 50, 77-86 (2017) and Y. Nakajima, et al.,: Free Radic. Biol. Med., 47, 1154-1161 (2009)). However, no report has been made so far regarding the relationship between dihydroxybenzalacetone or a salt thereof and saccharification or AGEs. The present inventors for the first time focused on the relationship between dihydroxybenzalacetone or a salt thereof, glycation and AGEs, and found that the compound exhibits high anti-glycation activity.

Dihydroxybenzalacetone or a salt thereof may be cis, trans, or a mixture of cis and trans. The trans form is more preferable because it has excellent anti-glycation activity.

特に好ましい実施形態において、ジヒドロキシベンザルアセトンは、（Ｅ）－３，４－ジヒドロキシベンザルアセトンである。（Ｅ）－３，４－ジヒドロキシベンザルアセトンのＩＵＰＡＣ名は、（Ｅ）－４－（３，４－ジヒドロキシフェニル）－ブタ－３－エン－２－オン（ＣＡＳ番号：１２３６９４－０３－１）である。 In a preferred embodiment, dihydroxybenzalacetone is 3,4-dihydroxybenzalacetone represented by formula (2) below. The IUPAC name for 3,4-dihydroxybenzalacetone is 4-(3,4-dihydroxyphenyl)-but-3-en-2-one.

In a particularly preferred embodiment, the dihydroxybenzalacetone is (E)-3,4-dihydroxybenzalacetone. The IUPAC name for (E)-3,4-dihydroxybenzalacetone is (E)-4-(3,4-dihydroxyphenyl)-but-3-en-2-one (CAS number: 123694-03-1 ).

Dihydroxybenzalacetone or a salt thereof may be a commercial product from a supplier (for example, Fuji Film Wako Chemical Co., Ltd. or Alpha Acer Co., Ltd.), or chemically synthesized according to a known method. , may be derived from natural sources (eg, plant extracts, etc.). In addition, dihydroxybenzalacetone may be purified by purification or may contain impurities.

In one embodiment, the dihydroxybenzalacetone may be a derivative of the substances mentioned above. As used herein, the term "derivative" refers to a group of compounds produced by substituting a part of the molecule of a specific compound with another functional group or another atom.

Examples of the other functional groups include alkyl groups, alkoxy groups, alkylthio groups, aryl groups, aryloxy groups, arylthio groups, arylalkyl groups, arylalkoxy groups, arylalkylthio groups, arylalkenyl groups, arylalkynyl groups, and allyl. group, amino group, substituted amino group, silyl group, substituted silyl group, silyloxy group, substituted silyloxy group, arylsulfonyloxy group, alkylsulfonyloxy group, nitro group and the like. Examples of the other atoms include carbon atoms, hydrogen atoms, oxygen atoms, nitrogen atoms, sulfur atoms, phosphorus atoms, halogen atoms and the like.

As used herein, the term "salt" is not limited as long as it is a salt that is physiologically acceptable for administration to a subject as a pharmaceutical. Examples of salts include alkali metal salts (sodium salts, potassium salts, etc.), alkaline earth metal salts (calcium salts, magnesium salts, etc.), ammonium salts, organic base salts (trimethylamine salts, triethylamine salts, pyridine salts, picoline salts, etc.). , dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.), organic acid salts (acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, tri fluoroacetate, etc.), and inorganic acid salts (hydrochloride, hydrobromide, sulfate, phosphate, etc.). "Salts" have advantages such as being easily soluble in water and being easy to administer.

Derivatives or salts of dihydroxybenzalacetone can be produced by known techniques. Of course, it is also possible to use commercially available derivatives or salts.

(2-2. Other components)
The anti-glycation agent may be dihydroxybenzalacetone or its salt itself, or may be in the form of a composition containing other ingredients. Other ingredients in the present anti-glycation agent when it is a composition are described in [3. Food and drink], [4. Feed], [5. Cosmetics] and [6. Drugs], which will be described later can be applied. Therefore, the description is omitted here.

(2-3. Content of active ingredients and other ingredients)
The amount of the active ingredient (dihydroxybenzalacetone or salt thereof) contained in the present antiglycation agent is not particularly limited as long as the desired effect is obtained. A suitable amount of the active ingredient varies depending on the administration subject, dosage form, etc. of the present antiglycation agent. Well, it is preferably 0.0001% by mass to 100% by mass, more preferably 0.001% by mass to 100% by mass, more preferably 0.01% by mass to 100% by mass, and 0 It is more preferably 0.1% by mass to 100% by mass, more preferably 0.1% by mass to 95% by mass, more preferably 0.1% by mass to 90% by mass, and 0.1% by mass. It is more preferably 0.1% by mass to 80% by mass, more preferably 0.1% by mass to 70% by mass, more preferably 0.1% by mass to 60% by mass, and 0.1% by mass. It is more preferably 50% by mass, more preferably 0.1% by mass to 40% by mass, more preferably 0.1% by mass to 30% by mass, and 0.1% by mass to 20% by mass. It is more preferably 0.1% by mass to 10% by mass, and particularly preferably 0.1% by mass to 5% by mass.

The amount of ingredients other than the active ingredient contained in the present anti-glycation agent is not particularly limited. The amount of ingredients other than the active ingredient may be, for example, 0% by mass to 99.99995% by mass, and be 0% by mass to 99.9999% by mass, relative to the total mass of the present antiglycation agent. Is preferably 0% by mass to 99.999% by mass, more preferably 0% by mass to 99.99% by mass, more preferably 0% by mass to 99.9% by mass , More preferably 5% by mass to 99.9% by mass, more preferably 10% by mass to 99.9% by mass, more preferably 20% by mass to 99.9% by mass, 30 It is more preferably 99.9% by mass, more preferably 40% by mass to 99.9% by mass, more preferably 50% by mass to 99.9% by mass, and 60% by mass. It is more preferably 99.9% by mass, more preferably 70% by mass to 99.9% by mass, more preferably 80% by mass to 99.9% by mass, and 90% by mass to 99% by mass. 0.9% by weight is more preferred, and 95% to 99.9% by weight is particularly preferred.

(2-4. Administration subject, dosage form and dosage form)
Subjects to which the present anti-glycation agent is administered are not particularly limited, and may be humans or non-human animals (eg, domestic animals, pets, and experimental animals). Non-human animals include, for example, monkeys, chimpanzees, cows, pigs, sheep, goats, horses, dogs, cats, rabbits, mice, rats, chickens, and seafood.

The dosage of the present anti-glycation agent is not particularly limited as long as the desired effect is obtained. A suitable dosage varies depending on the subject of administration, dosage form, and the like.

When the subject of administration is an adult human and the present anti-glycation agent is orally administered, a suitable dose is, for example, 50 to 3,000 mg/kg of the active ingredient (dihydroxybenzalacetone or its salt) ( body weight), more preferably 100 to 2,000 mg/kg (body weight). In addition, when the present anti-glycation agent is orally administered on a daily basis over a long period of time, a suitable dose is, for example, 1 to 500 mg/kg (body weight) as the mass of the active ingredient (dihydroxybenzalacetone or its salt). .

When the subject of administration is a non-human animal and the present anti-glycation agent is orally administered, a suitable dose is, for example, 50 to 3,000 mg/kg of active ingredient (dihydroxybenzalacetone or its salt) ( body weight), more preferably 100 to 2,000 mg/kg (body weight). In addition, when the present anti-glycation agent is orally administered on a daily basis over a long period of time, a suitable dose is, for example, 1 to 500 mg/kg (body weight) as the mass of the active ingredient (dihydroxybenzalacetone or its salt). .

The anti-glycation agent can be administered to a subject by any route of administration. Examples of routes of administration include oral administration and parenteral administration (eg, transdermal administration, transmucosal administration, nasal administration, intravenous administration).

The present anti-glycation agent may be in any form such as solid (powder, granules, etc.), liquid (solution, suspension, etc.), paste, and the like. Moreover, the dosage form of the present anti-glycation agent may be any dosage form. Examples of dosage forms include powders, pills, granules, tablets, coated tablets, capsules, lozenges, solutions, suspensions, emulsions, syrups, infusions, decoctions, tinctures, injections, ointments, Examples include creams, gels, patches, liquids for external use, powders for external use, suppositories, inhalants, eye drops and the like.

The present anti-glycation agent can be used, for example, as a component of products such as food and drink (food and drink compositions, food and drink additives, etc.), feeds (feed compositions, feed additives, etc.), cosmetics, and pharmaceuticals. can.

[3. Food and drink]
The food and drink according to one embodiment of the present invention is the above [2. antiglycation agent]. The food and drink according to one embodiment of the present invention may be hereinafter referred to as "the present food and drink". Since the present food and drink contains the present antiglycation agent, it has the advantage of exhibiting high antiglycation activity. Therefore, the present food and drink may be an anti-glycation food and drink whose package or the like indicates that it is based on the concept of anti-glycation.

Food and drink (that is, beverages and foods) include food and drink compositions, food and drink additives, and the like. Food and drink compositions include health foods, foods with function claims, foods for special dietary uses, dietary supplements, supplements, and foods for specified health uses.

The form of the food and drink is not particularly limited, and may be in various processed forms such as general food, food for the sick, liquid food, drink and the like. Examples of food and drink forms include seasonings (e.g., soy sauce, miso, sauces, etc.), beverages (e.g., soft drinks, fruit juice drinks, alcoholic drinks, carbonated drinks, sports drinks, tea, coffee, cocoa, milk, soup etc.), confectionery (e.g., candy, gum, gummies, yogurt, jelly, pudding, chocolate, cookies, snacks, bread, cake, cream puff, ice cream, popsicle, etc.), processed food (e.g., ham, kamaboko, sausage, meat sauce, curry, stew, dressing, cheese, butter, etc.).

This food and drink contains edible ingredients (e.g. proteins, carbohydrates, lipids, vitamins, minerals, organic acids, organic bases, etc.) as "other ingredients" other than the active ingredient (dihydroxybenzalacetone or its salt). may contain. In addition, this food and drink contains [6. Pharmaceuticals] may contain excipients for formulations described later.

Examples of the above proteins include animal proteins, vegetable proteins, and hydrolysates thereof such as whole milk powder, skimmed milk powder, casein, soybean protein, chicken egg protein, gelatin, collagen, whey protein, and the like.

Examples of carbohydrates include saccharides, dietary fibers, starch (eg, oxidized starch, soluble starch, starch ester, starch ether, corn starch, tapioca starch, potato starch, wheat starch, etc.).

The above lipids include vegetable and animal oils, and processed fats such as lard, beef tallow, milk fat, corn oil, cottonseed oil, castor oil, rapeseed oil, olive oil, coconut oil, soybean oil, safflower oil, hydrogenated oil, fractionated oil, Examples include transesterified oil.

The above vitamins include vitamin A, vitamin B group, vitamin C, vitamin D group, vitamin E, vitamin K group, folic acid, ubiquinone, flavonoids, niacin, carotene, nicotinic acid, pantothenic acid, biotin, inositol, and choline, and Derivatives of these and the like are included.

Examples of the minerals include sodium, potassium, calcium, magnesium, iron, copper, zinc, manganese, and selenium.

Examples of the organic acid include lactic acid, malic acid, tartaric acid and citric acid.

For the preferred range of the amount of the active ingredient (dihydroxybenzalacetone or its salt) contained in this food or drink, the description in the above section (2-3. Contents of active ingredients and other ingredients) is incorporated as appropriate. be done. In addition, the preferred intake of the present food and drink is the amount of the active ingredient (dihydroxybenzalacetone or its salt), and the description in the above section (2-4. Administration subject, dosage form and dosage form) is appropriately incorporated. be.

[4. feed〕
The feed according to one embodiment of the present invention is the above [2. antiglycation agent]. The feed according to one embodiment of the present invention may be hereinafter referred to as "main feed". Since the present feed contains the present antiglycation agent, it has the advantage of exhibiting high antiglycation activity. Therefore, the present feed may be an anti-glycation feed indicated on the package or the like to the effect that anti-glycation is the concept.

Feed includes feed compositions and feed additives, and includes all formulations orally administered to non-human animals. Feed compositions include compound feeds such as livestock feeds, poultry feeds, farmed fish feeds, pet feeds (eg, dog food, cat food, etc.).

This feed contains edible ingredients (e.g. proteins, carbohydrates, lipids, vitamins, minerals, organic acids, organic bases, etc.) as "other ingredients" other than the active ingredient (dihydroxybenzalacetone or its salt). can be anything. Specific examples of edible ingredients include [3. Food and Beverage] section is incorporated as appropriate. In addition, the present feed may contain feed excipients used in the production of feed compositions or feed additives as "other ingredients". Feed excipients include starch, dextrin, gluten, wheat flour, wheat bran, defatted bran, soybeans, sugars, fats and oils, fishmeal, yeast, minerals (e.g., diatomaceous earth, bentonite, etc.), silicon compounds, phosphates, etc. is mentioned.

The preferred range of the amount of the active ingredient (dihydroxybenzalacetone or its salt) contained in this feed is described in the above section (2-3. Contents of active ingredients and other ingredients) as appropriate. be. In addition, the preferred intake of this feed is the amount of the active ingredient (dihydroxybenzalacetone or its salt), and the description in the above section (2-4. Administration subject, dosage form and dosage form) is appropriately incorporated. .

The present feed can be produced by a known method, except that the present antiglycation agent is added to the feed. For example, by mixing feed excipients (e.g., corn starch, dextrin and defatted bran) with the active ingredient (dihydroxybenzalacetone or its salt), a solid (e.g., powder, granule, or tablet) can be obtained. shape, etc.) can be manufactured.

[5. cosmetic〕
The cosmetic according to one embodiment of the present invention is the above [2. antiglycation agent]. The cosmetics according to one embodiment of the present invention may be hereinafter referred to as "present cosmetics". Since the present cosmetic contains the present anti-glycation agent, it has the advantage of exhibiting high anti-glycation activity. Therefore, the present cosmetic may be an anti-glycation cosmetic that is indicated on the package or the like to the effect that it is based on the concept of anti-glycation. In one embodiment, the cosmetic product may be a cosmetic product that improves skin conditions associated with AGEs (eg, wrinkle-reducing cosmetics, whitening cosmetics, acne-reducing cosmetics, etc.).

The form of the cosmetic is not particularly limited, and may be liquid (e.g., solution, suspension, milky lotion, etc.), solid (e.g., powder, granules, etc.), semi-solid (e.g., cream, ointment, gel, etc.), or the like. It's okay. The forms of the cosmetics include basic cosmetics (e.g. face wash, lotion, milky lotion, cream, gel, essence (beauty essence), pack, mask, etc.), makeup cosmetics (e.g. foundation, lipstick, etc.), hair cosmetics, Body cosmetics (eg, body soap, soap, etc.) and the like.

In this cosmetic product, as "other ingredients" other than the active ingredient (dihydroxybenzalacetone or its salt), ingredients normally used in cosmetics, such as surfactants, water-soluble polymers, oils and fats, organic acids, inorganic salts, Inorganic acids, polymers, powder ingredients, other additives (antioxidants, ultraviolet absorbers, chelating agents, pH adjusters, preservatives, disinfectants, pigments, coloring agents, fragrances, aqueous ingredients, water, etc.), various Skin nutrients (whitening agents, oligopeptides, tranexamic acid and its derivatives, amino acids, animal or plant extracts, microbial culture metabolites, phospholipids, ceramides, vitamins, sulfur, Yunohana, rice bran, etc.), etc., as needed may be included as appropriate.

Surfactants (natural surfactants or synthetic surfactants) include anionic surfactants, cationic surfactants, amphoteric surfactants, nonionic surfactants, fluorosurfactants, and silicone surfactants. Surfactants and the like are included. Examples of anionic surfactants include carboxylic acid type, sulfonic acid type, sulfate type, and phosphate type. Cationic surfactants include amine salt type and quaternary ammonium salt type. Amphoteric surfactants include betaine type, imidazoline type, amino acid type and the like. Examples of nonionic surfactants include ester types such as glycerin fatty acid esters, ether types such as polyoxyethylene alkyl ethers and polyoxyethylene polyoxypropylene glycol, ester ether types such as polyoxyethylene sorbitan fatty acid esters, and castor oil derivatives. , hydrogenated castor oil derivatives and the like.

Water-soluble polymers (humectants or thickeners) include polyethylene glycol, methyl cellulose, hydroxypropyl cellulose (HPC), carboxymethyl cellulose and its salts, cationized cellulose, polyvinyl alcohol, polyvinyl methyl ether, polyvinyl pyrrolidone, alginic acid and its salts or esters, gum tragacanth, gum arabic, xanthan gum, poly(N,N'-dimethyl-3,5-methylenepiperidinium) chloride, carboxyvinyl polymer, polyvinylpyrrolidone, dextran, cyclodextrin, mucopolysaccharides, chitosan, starch, gelatin, pectin, sodium caseinate, whey protein, soybean protein, chicken egg protein, whey protein and the like.

Examples of oils include vegetable oils and animal oils (olive oil, avocado oil, palm oil, coconut oil, castor oil, soybean oil, jojoba oil, almond oil, cocoa oil, sesame oil, persic oil, bran oil, etc.) and animal oils: beef tallow. , lard, and mink oil, and their hydrogenated oils, synthetic triglycerides and diglycerides, etc.), waxes (e.g., beeswax, carnauba wax, whale wax, lanolin, etc.), mineral oils (e.g., liquid paraffin, petrolatum, paraffin, squalene , squalane, microcrystalline wax, ceresin, pristane, etc.), fatty acids (e.g., lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, oleic acid, linoleic acid, linolenic acid, lanolinic acid, isostearic acid, isononanoic acid, caproic acid, etc.), alcohols (e.g., 2-hexyldecanol, isostearyl alcohol, 2-octyldodecanol, lauryl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol, cholesterol, etc.), esters (e.g., cetyl octanoate, myristyl lactate, cetyl lactate, isopropyl myristate, myristyl myristate, isopropyl palmitate, isopropyl adipate, butyl stearate, decyl oleate, cholesterol isostearate, etc.), essential oils, silicone oils and the like.

Organic acids include succinic acid, fumaric acid, citric acid, lactic acid, malic acid, tartaric acid, pyruvic acid, glucuronic acid, tartronic acid, and 2-hydroxybutyric acid, and salts and esters thereof.

Inorganic salts include sodium carbonate, sodium hydrogen carbonate, sodium sesquicarbonate, borax, sodium sulfate, sodium sulfide, sodium nitrate, sodium thiosulfate, sodium polyphosphate, sodium phosphate, potassium chloride, potassium sulfide, calcium oxide, oxide Examples include magnesium, calcium carbonate, and magnesium carbonate.

Inorganic acids include boric acid, metasilicic acid, silicic anhydride, and the like.

Polymers include nylon, polyethylene, polypropylene, polyvinyl chloride, polyethylene terephthalate resin, acrylic resin, epoxy resin, styrene resin, polytetrafluoroethane, and the like.

Powder components include silicic acid, calcium silicate, aluminum silicate, zeolite, titanium oxide, talc, kaolin, mica, bentonite, mineral sand, mica, clay and the like.

A suitable range of the amount of the active ingredient (dihydroxybenzalacetone or salt thereof) contained in the cosmetic is not particularly limited as long as the desired effect is obtained. A suitable amount of the active ingredient is, for example, 0.00005% by mass or more, preferably 0.0001% by mass or more, and 10% by mass or less, preferably 5% by mass, based on the total mass of the cosmetic. % by mass or less.

The present cosmetic can be produced by a known method, except that the present anti-glycation agent is added. The addition method and addition timing of the present anti-glycation agent are not particularly limited. The form of packaging of the cosmetic is not particularly limited, and it can be provided in a packaging container such as a bottle, can, bag, spray container, box, spray can, pack, or the like.

[6. Pharmaceutical]
The drug according to one embodiment of the present invention is the drug described in [2. antiglycation agent]. The drug according to one embodiment of the present invention may be hereinafter referred to as "this drug". Since the pharmaceutical contains the anti-glycation agent, it has the advantage of exhibiting high anti-glycation activity. Therefore, this drug is used for the prevention or treatment of various diseases related to AGEs (e.g., age-related diseases, diabetic complications, inflammation, breast cancer, prostate cancer, osteoporosis, heart disease, menopause, etc.). can be used. The age-related diseases include skin aging and the like. The diabetic complications include complications such as cataract, arteriosclerosis, and renal dysfunction.

As used herein, "prevention" means preventing or reducing the risk of developing or recurring one or more symptoms of a disease compared to not administering the medicinal product. . In addition, “treatment” means reducing the severity of one or more symptoms associated with a disease, preventing their increase or progression, or It means reducing the rate of increase or progression of severity.

The dosage form of the pharmaceutical product may be any dosage form. For examples of dosage forms, the descriptions in the section (2-4. Administration subject, dosage form and dosage form) are incorporated as appropriate.

The drug may optionally contain ingredients commonly used in drugs as "other ingredients" other than the active ingredient (dihydroxybenzalacetone or its salt). Ingredients commonly used in pharmaceuticals may be any pharmaceutically acceptable ingredient, and examples include excipients, buffers, pH adjusters, tonicity agents, solvents, preservatives, antioxidants, high molecular weight weights. Aggregators, fillers, bulking agents, solubilizers, binders, stabilizers, lubricants, thickeners, surfactants, disintegrants, disintegration inhibitors, absorption promoters, adsorbents, humectants, preservatives , flavors, sweeteners, fragrances, colorants, emulsifiers, enzymes, solubilizers and the like.

Examples of the excipient include various excipients for formulation. Pharmaceutical excipients include lactose, sucrose, D-mannitol, xylitol, sorbitol, erythritol, starch, microcrystalline cellulose and the like. Among these excipients, reducing sugars (e.g., lactose) and sucrose, which produces reducing sugars by hydrolysis, can cause saccharification, so it is preferable to use them in small amounts or preferably not to use them. .

Examples of said buffers include phosphoric acid or phosphate, boric acid or borate, citric acid or citrate, acetic acid or acetate, carbonic acid or carbonate, tartaric acid or tartrate, ε-aminocaproic acid, trometamol etc. Examples of the phosphate include sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, and dipotassium hydrogen phosphate. Examples of the borate include borax, sodium borate, potassium borate, and the like. Examples of the citrate include sodium citrate, disodium citrate, and trisodium citrate. Examples of the acetate include sodium acetate and potassium acetate. Examples of the carbonate include sodium carbonate and sodium hydrogen carbonate. Examples of the tartrate include sodium tartrate and potassium tartrate.

Examples of the pH adjuster include hydrochloric acid, phosphoric acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide and the like.

Examples of the tonicity agents include ionic tonicity agents (sodium chloride, potassium chloride, calcium chloride, magnesium chloride, etc.) and nonionic tonicity agents (glycerin, propylene glycol, sorbitol, mannitol, etc.). mentioned.

Examples of the solvent include water, physiological saline, alcohol and the like.

Examples of the antiseptic include benzalkonium chloride, benzalkonium bromide, benzethonium chloride, sorbic acid, potassium sorbate, methyl parahydroxybenzoate, propyl parahydroxybenzoate, chlorobutanol and the like.

Examples of the antioxidant include ascorbic acid, tocopherol, dibutylhydroxytoluene, butylhydroxyanisole, sodium erythorbate, propyl gallate, sodium sulfite and the like.

Examples of the high molecular weight polymers include methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate. , carboxymethylethylcellulose, cellulose acetate phthalate, polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, polyethylene glycol, atelocollagen, and the like.

In addition, the drug may contain, as other ingredients, a medicinal ingredient having a desired effect, and may be used in combination with a medicinal ingredient having a desired effect.

The preferred range of the amount of the active ingredient (dihydroxybenzalacetone or a salt thereof) contained in the drug is as described in the above section (2-3. Contents of active ingredients and other ingredients). be. In addition, the preferred dosage of the drug is the amount of the active ingredient (dihydroxybenzalacetone or its salt), and the description in the above section (2-4. Administration subject, dosage form and dosage form) is appropriately incorporated. .

The drug can be produced by a known method, except that the antiglycation agent is added.

The present invention is not limited to the above-described embodiments, but can be modified in various ways within the scope of the claims, and can be obtained by appropriately combining technical means disclosed in different embodiments. is also included in the technical scope of the present invention.

EXAMPLES The present invention will be described in more detail below with reference to Examples, but the present invention is not limited to these Examples.

[Example 1] Antiglycation activity against glycation of bovine serum albumin The antiglycation activity (AGE production inhibitory activity) of the present antiglycation agent against glycation of bovine serum albumin (BSA) by sugar (glucose or fructose) was evaluated according to the following method. evaluated. (E)-3,4-dihydroxybenzalacetone (manufactured by Fujifilm Wako Chemical Co., Ltd., hereinafter also referred to as "DBL") was used as the anti-glycation agent.

First, 300 μL of 40 g/L bovine serum albumin aqueous solution, 150 μL of 2 M glucose aqueous solution or 2 M fructose aqueous solution, 50 μL of DBL aqueous solution, and 900 μL of phosphate buffered saline (pH 7.4) were added to a 2 mL screw cap tube and stirred. to obtain a mixture. The DBL aqueous solution was prepared by diluting the stock solution (high concentration DBL aqueous solution) with water so that the final concentration of DBL in the mixture was 0.0004 to 0.0500 g/L. As a positive control, an aqueous aminoguanidine solution (final concentration of aminoguanidine in the mixture 0.060-0.500 g/L) was used instead of the aqueous DBL solution.

Then, the fluorescence intensity of the resulting mixture was measured at 0 hours of reaction. Next, the above mixture was incubated at 60° C. for 48 hours under light-shielding conditions, and the fluorescence intensity of the obtained reaction solution was measured. Fluorescence intensity was measured using a microplate reader at an excitation wavelength of 370 nm and a fluorescence wavelength of 440 nm.

式中、Ｅ_{ｓａｍｐｌｅ}（０ｈ）は、反応０時間における混合物（ＤＢＬ）の蛍光強度であり、Ｅ_{ｓａｍｐｌｅ}（４８ｈ）は、４８時間インキュベート後に得られた反応溶液（ＤＢＬ）の蛍光強度であり、Ｅ_{ｃｏｎｔｒｏｌ}（０ｈ）は、反応０時間における混合物（アミノグアニジン）の蛍光強度であり、Ｅ_{ｃｏｎｔｒｏｌ}（４８ｈ）は、４８時間インキュベート後に得られた反応溶液（アミノグアニジン）の蛍光強度である。 From the measured fluorescence intensity, the AGE production inhibition rate of DBL and aminoguanidine was calculated according to the following formula. The results are shown in Figure 1 (glucose) and Figure 2 (fructose).

In the formula, E _sample (0h) is the fluorescence intensity of the mixture (DBL) at reaction 0 hours, E _sample (48h) is the fluorescence intensity of the reaction solution (DBL) obtained after 48 hours of incubation, and E _Control (0h) is the fluorescence intensity of the mixture (aminoguanidine) at reaction time 0, and E _control (48h) is the fluorescence intensity of the reaction solution (aminoguanidine) obtained after 48 hours of incubation.

The _EC50 values of DBL and aminoguanidine were calculated from the calculated AGEs production inhibition rate. The results are shown in Table 1 below.

As shown in Table 1, the _EC50 values of DBL were as low as 1/13 of those of aminoguanidine on both glucose and fructose. These results revealed that DBL exhibits a high anti-glycation activity that remarkably exceeds that of the positive control, aminoguanidine.

[Example 2] Antiglycation activity against glycation of collagen The antiglycation activity (AGE production inhibitory activity) of the present antiglycation agent against glycation of collagen by glyceraldehyde was measured using "Collagen Antiglycation Assay Kit Glycer" manufactured by Cosmo Bio Co., Ltd. Aldehyde” was used for evaluation. DBL was used as the present anti-glycation agent. A specific test method followed the protocol attached to the above kit. The test method will be briefly described below.

First, the DBL aqueous solution was added to the collagen solution, glyceraldehyde solution, and buffer solution of the kit, and the mixture was stirred to obtain a mixture. The DBL aqueous solution was prepared by diluting the stock solution (high concentration DBL aqueous solution) with water so that the final concentration of DBL in the mixture was 0.001 to 0.250 g/L. As a positive control, an aqueous aminoguanidine solution (final concentration of aminoguanidine in the mixture 0.001-0.250 g/L) was used instead of the aqueous DBL solution.

Then, the fluorescence intensity of the resulting mixture was measured at 0 hours of reaction. Next, the mixture was incubated at 37° C. for 24 hours, and the fluorescence intensity of the resulting reaction solution was measured. The fluorescence intensity was measured in the same manner as in Example 1.

From the measured fluorescence intensity, in the same manner as in Example 1, the AGE production inhibition rate of DBL and aminoguanidine was calculated. The results are shown in FIG.

As shown in FIG. 3, DBL exhibited a high anti-glycation activity against glycation of collagen by glyceraldehyde, significantly exceeding that of the positive control, aminoguanidine, especially in the high concentration range. Moreover, even in the low concentration range, it exhibited a good anti-glycation activity equivalent to that of aminoguanidine.

[Example 3] Antiglycation activity against elastin glycation The antiglycation activity (AGE production inhibitory activity) of the present antiglycation agent against elastin glycation by glyceraldehyde was measured using Cosmo Bio Co., Ltd.'s "Elastin Antiglycation Assay Kit ( Glyceraldehyde)” was used for evaluation. DBL was used as the present anti-glycation agent. A specific test method followed the protocol attached to the above kit. The test method will be briefly described below.

50 μL of saccharification protein (2 g/L BSA solution, elastin solution) was placed in each well of a 96-well plate (Greiner bio-one, 96-well microplate, black, 655076, with lid). The aqueous aminoguanidine solution and the sample were prepared with a buffer solution to a final concentration of 0.005 to 0.5 g/L, sterilized, and then 40 μL were added to each well. Next, 10 μL of a 500 mM glyceraldehyde solution was added to each well, and fluorescence (excitation wavelength: 355 nm, fluorescence wavelength: 460 nm) was measured with a microplate reader at time 0 of the reaction. After the measurement, the plate was placed in a bag together with a wet Prowipe (manufactured by Daio Paper Co., Ltd.) and incubated at 37° C. under light shielding. . The results are shown in FIG.

As shown in FIG. 4, DBL exhibited high anti-glycation activity against glycation of elastin by glyceraldehyde, significantly exceeding that of the positive control, aminoguanidine.

Further, the _EC50 values of DBL and aminoguanidine were calculated from the calculated AGEs production inhibition rate, and the _EC50 value of DBL was about 1/7 of the _EC50 value of aminoguanidine. This result also revealed that DBL exhibits a high anti-glycation activity that remarkably exceeds that of the positive control, aminoguanidine.

INDUSTRIAL APPLICABILITY The present invention can be used for anti-glycation foods, feeds, cosmetics, pharmaceuticals, and the like.

Claims (5)

An anti-glycation agent containing dihydroxybenzalacetone or a salt thereof as an active ingredient. 2. The anti-glycation agent according to claim 1, which is for suppressing glycation of collagen or elastin. 3. The anti-glycation agent according to claim 1, which is for suppressing saccharification by glucose, fructose, xylose, arabinose, galactose, lactose, or glyceraldehyde. Food, drink, feed, cosmetics or pharmaceuticals containing the anti-glycation agent according to claim 1 or 2. Food, drink, feed, cosmetics or pharmaceuticals containing the anti-glycation agent according to claim 3.

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