JP2022158120A - glycative stress inhibitor - Google Patents

Abstract

To provide novel glycative stress suppressors with activity to suppress glycative stress occurring in vivo.SOLUTION: Provided are a glycative stress inhibitor, glycation reaction inhibitor, or inflammatory response inhibitor that suppresses inflammatory response caused by AGEs containing one or more selected from the group consisting of glycyrrhizic acids, allantoins, azulenes, pyridoxine hydrochloride, hinokitiols, copper chlorophyll, lysozyme chloride, and epsilon aminocaproic acid. Each agent is useful as an external agent, an oral agent, a gum care agent, and an agent for preventing periodontal disease.SELECTED DRAWING: None

Description

TECHNICAL FIELD The present invention relates to a glycative stress inhibitor.

BACKGROUND ART It has been well known for a long time as a browning phenomenon of food products that a Maillard reaction (saccharification reaction) occurs between a reducing sugar such as glucose and a protein to produce a saccharification product. This saccharification reaction also occurs in vivo, and substances produced by the saccharification reaction are called advanced glycation end products (hereinafter referred to as AGEs). The production of AGEs is an irreversible reaction, and the produced AGEs are excreted from the body through metabolism. However, when the metabolic rate slows down due to aging or the like, it tends to accumulate in each tissue in the body (Patent Document 1).

When AGEs bind to RAGE (Receptor for AGE; AGEs receptor) expressed in cell membranes such as monocytes/macrophages, vascular endothelial cells, and fibroblasts, AGEs-derived oxidative stress, activation of NF-κB activity, mitogen Inflammation is induced by factors such as activation of intracellular signals such as activated protein kinase (MAPK) and protein kinase C (PKC). This inflammatory response by AGEs is called glycative stress or AGE-RAGE interaction, and is known to cause various symptoms. Glycation stress is used as a comprehensive expression of not only the inflammatory reaction caused by AGEs, but also the biological stress generated in the process of producing AGEs and various effects on the living body. For example, glycative stress contributes to skin browning and dullness in the skin, and hyperglycemia causes cataracts, vascular disorders, and renal dysfunction (Non-Patent Document 1). Therefore, it can be said that it is extremely important to prevent or suppress glycative stress.

Patent Document 1 describes that citrus volatile oils have Maillard reaction inhibitory activity and AGE-protein cross-linker cleaving activity. In Patent Document 2, Coptis extract, Phellodendron bark extract and Sanshishi extract have the effect of suppressing AGEs production and are safe materials that do not irritate the skin, so they can be used in various skin cosmetics, bath agents, etc. It is described that it is possible to prevent skin aging. Patent Literature 3 describes that an extract of a plant belonging to the genus Hangeshou suppresses inflammation caused by AGEs by inhibiting the binding of AGEs and RAGE. Patent Document 4 describes that a combination of quercetin and sulforaphane is effective against AGE-derived inflammation by suppressing the expression of RAGE.

On the other hand, various anti-inflammatory ingredients have been conventionally known. For example, allantoin is known to have skin growth and wound healing promotion, anti-inflammatory effects, etc., but its mechanism of action is unknown. Dipotassium glycyrrhizinate is widely used as an anti-inflammatory ingredient, and its mechanism of action is inhibition of the arachidonic acid cascade. The arachidonic acid cascade is a metabolic pathway in which inflammatory substances such as prostaglandins and thromboxanes are produced from arachidonic acid derived from phospholipids that constitute cell membranes. Dipotassium glycyrrhizinate suppresses the production of phospholipid-derived inflammatory substances by inhibiting the activation of enzymes such as phospholipase A and lipoxygenase, thereby exerting an anti-inflammatory action. Pyridoxine hydrochloride is a vitamer of vitamin B6 that is most commonly contained in vitamin B6 supplements. Pyridoxine hydrochloride is known to improve metabolism and suppress inflammation in the skin and mucous membranes when pyridoxine hydrochloride is deficient, but it does not suppress inflammation caused by other factors ( Non-Patent Documents 2 and 3). Hinokitiol is known to have antibacterial activity against bacteria and fungi, and anti-inflammatory action. It is known that this anti-inflammatory action results from the inhibitory action of 11β-hydroxysteroid dehydrogenase (11β-HSD), which is one of local cortisol-modifying enzymes (Non-Patent Document 4). Epsilon aminocaproic acid is known to have hemostatic and anti-inflammatory effects, which are known to be caused by antiplasmin effects.

JP-A-2004-35424 JP 2016-210729 A JP 2021-31424 A JP 2017-145236 A

Yagi et al., "Evaluation of glycative stress and anti-glycation effect", Oleoscience, Vol. 18, No. 2 (2018), pp. 67-73 Chiang EP et al. , Arthritis Research & Therapy 2005, 7: R1254-R1262. Chiang EP et al. , Arthritis Research & Therapy 2005, 7: R1404-R1411 Itoi-Ochi et al. , Japanese Society for Investigative Dermatology Annual Conference/General Assembly Program 42nd Page225 (2017)

However, since the mechanism of anti-inflammatory action of any component is different from the onset mechanism of inflammation derived from AGEs, it cannot be said that the anti-inflammatory component is effective against the inflammatory reaction caused by AGEs. The present invention provides a novel glycative stress inhibitor, especially an AGE production inhibitor and a glycative reaction, having an activity to inhibit glycative stress occurring in vivo, particularly an AGE production inhibitory action, a glycative reaction inhibitory action, and an AGE-induced inflammation inhibitory action. An object of the present invention is to provide an anti-inflammatory agent derived from AGEs.

The present invention provides the following [1] to [12].
[1] A glycyrrhizic stress inhibitor containing one or more selected from the group consisting of glycyrrhizic acids, allantoins, azulenes, pyridoxine hydrochloride, hinokitiols, copper chlorophylls, lysozyme chloride, and epsilon aminocaproic acid.
[2] AGEs (Advanced Glycation End Products) containing one or more selected from the group consisting of glycyrrhizic acids, allantoins, azulenes, pyridoxine hydrochloride, hinokitiols, copper chlorophylls, lysozyme chloride, and epsilon aminocaproic acid; final saccharification product) production inhibitor.
[3] The AGE production inhibitor according to [2], wherein the AGEs are collagen-derived AGEs.
[4] The AGE production inhibitor according to [2] or [3], wherein the AGEs are derived from collagen and glyceraldehyde.
[5] A saccharification reaction inhibitor containing one or more selected from the group consisting of glycyrrhizic acids, allantoins, azulenes, pyridoxine hydrochloride, hinokitiols, copper chlorophylls, lysozyme chloride, and epsilon-aminocaproic acid.
[6] The glycation reaction inhibitor of [5], which inhibits the glycation reaction of collagen.
[7] The saccharification reaction inhibitor according to [5] or [6], which inhibits the saccharification reaction of collagen by glyceraldehyde.
[8] containing one or more selected from the group consisting of glycyrrhizic acids, allantoins, azulenes, pyridoxine hydrochloride, hinokitiols, copper chlorophylls, lysozyme chloride, and epsilon aminocaproic acid, suppressing inflammatory reactions caused by AGEs; Inflammatory response inhibitor.
[9] An external preparation containing the agent according to any one of [1] to [8].
[10] An oral preparation containing the agent according to any one of [1] to [8].
[11] The oral preparation of [10], which is a gum care agent.
[12] The agent for oral cavity according to [10], which is an agent for preventing periodontal disease.

According to the present invention, a glycation stress inhibitor that suppresses glycation stress that occurs in vivo, an AGE production inhibitor that has activity to inhibit AGE production reaction, a glycation reaction inhibitor that inhibits glycation reaction (Maillard reaction), Provided is an inflammatory response inhibitor that suppresses an inflammatory response. These agents can be used as external preparations, oral preparations, gum care agents, periodontal disease preventive agents, and the like.

FIG. 1 is a diagram showing the results of IL-6 concentration in Test Example 1. FIG. FIG. 2 is a diagram showing the action of suppressing inflammation by AGEs in Test Example 3. FIG.

[1. Glycation stress inhibitor, AGE production inhibitor, glycation reaction inhibitor, inflammatory reaction inhibitor]
[1.1 Active ingredient]
In the present invention, one or more selected from the group consisting of glycyrrhizic acids, allantoins, pyridoxine hydrochloride, hinokitiols, copper chlorophylls, lysozyme chloride, and epsilon aminocaproic acid are used as active ingredients.

<Glycyrrhizic acids>
As used herein, glycyrrhizic acids mean glycyrrhizin, glycyrrhizic acid, hydrolysates thereof, derivatives thereof, and plants and plant extracts containing these. Examples of glycyrrhizic acids include dipotassium glycyrrhizinate, glycyrrhizinate such as monoammonium glycyrrhizinate, glycyrrhetinic acid which is an acid decomposition product of glycyrrhizic acid, glycyrrhetic acid derivatives such as stearyl glycyrrhetinate, licorice (for example, root), and licorice extract. dipotassium glycyrrhizinate, glycyrrhetinic acid, and stearyl glycyrrhetinate are preferred.

<Allantoins>
As used herein, allantoins mean allantoin, derivatives thereof and salts thereof. Examples of allantoins include allantoin, allantoin chlorohydroxyaluminum, allantoin dihydroxyaluminum, and combinations of two or more thereof, preferably allantoin.

<Azulenes>
As used herein, azulenes mean azulene, its derivatives and salts thereof. Examples of azulenes include sodium azulene sulfonate, azulene, 1,4-dimethyl-7-isopropylazulene, 4,8-dimethyl-2-isopropylazulene, combinations of two or more thereof, and sodium azulene sulfonate. is preferred.

<Pyridoxine hydrochloride>
Pyridoxine hydrochloride is the hydrochloride salt of pyridoxine.

<Hinokitiols>
As used herein, hinokitiols refer to hinokitiol, derivatives thereof, and salts thereof (sodium salt, etc.). Examples of the method for producing hinokitiol include, but are not limited to, a method of obtaining hinokitiol from oil obtained by distilling the wood or root of Taiwan cypress or Aomori hiba. Examples of hinokitiols include hinokitiol, salts thereof, metal complexes, and combinations of two or more selected from these, and hinokitiol is preferred from the viewpoint of exhibiting the desired effects of the present invention. Hinokitiol is known to have 1) antibacterial action and 2) anti-inflammatory action.

<Copper chlorophyll>
As used herein, copper chlorophylls refer to copper chlorophyllin and copper chlorophyllin salts. Examples of methods for producing copper chlorophyllin and salts thereof include, but are not limited to, a method of stabilizing by substituting copper for magnesium in the chlorophyll molecule of a plant. Examples of copper chlorophylls include copper chlorophyllin, copper chlorophyllin salts (e.g., alkali metal salts such as sodium salts, potassium salts, calcium salts, alkaline earth metal salts), and combinations of two or more thereof. Sodium copper chlorophyllin is preferable as the copper chlorophylls from the viewpoint of more efficiently expressing the desired effect of .

<Lysozyme chloride>
Lysozyme chloride is a component contained in chicken eggs, and its production method is not particularly limited and may be a known method. Lysozyme chloride described in the Japanese Pharmacopoeia or Standards for Cosmetic Ingredients can be used as the lysozyme chloride.

<Epsilon aminocaproic acid>
Epsilon-aminocaproic acid described in the Japanese Pharmacopoeia or the Standards for Cosmetic Ingredients can be used as epsilon-aminocaproic acid.

The active ingredient preferably contains at least one selected from glycyrrhizic acids, pyridoxine hydrochloride, allantoin, hinokitiol, and epsilon aminocaproic acid, more preferably glycyrrhizic acid, glycyrrhizinate, allantoin, hinokitiol, or pyridoxine hydrochloride. .

[1.2 Effective amount]
The effective amount of each active ingredient can be appropriately determined according to the subject of application, but the amount used per human is usually 0.00001 mg or more, preferably 0.001 mg or more, more preferably 0.01 mg or more. is. The upper limit is usually 1 g or less, preferably 0.1 g or less. In particular, when the administration means is local administration (external use), the lower limit of the effective concentration in the administration preparation is preferably 0.0001% by mass or more, more preferably 0.001% by mass. The upper limit is preferably 10% by mass or less, more preferably 1% by mass or less.

[1.3 Action]
The above active ingredient can control glycative stress. As used herein, glycative stress refers to each of the above reactions from the binding of sugars and proteins (glycation reaction; Maillard reaction) to the production of AGEs (AGE production reaction) to the action of AGEs on cells (inflammatory reaction). encompasses Inflammatory reactions by AGEs transmit intracellular signals by binding to RAGE (Receptor for AGE) expressed in the cell membranes of monocytes/macrophages, vascular endothelial cells, fibroblasts, etc., resulting in oxidative stress derived from AGEs, It is a reaction in which NF-κB activity, mitogen-activated protein kinase (MAPK), and protein kinase C (PKC) are activated to cause inflammation. The active ingredient can suppress at least a part of glycation stress, and is, for example, a glycation stress inhibitor, an AGEs production inhibitor (can be rephrased as a glycation product production inhibitor, an AGEs formation inhibitor, a glycation product formation inhibitor, etc.). , as a saccharification reaction (Maillard reaction) inhibitor (can be rephrased as an anti-glycation agent, a saccharification inhibitor, etc.). The agent of the present invention is preferably used for the purpose of preventing skin aging, gum care, periodontal disease, dry eye, cataract prevention, retinopathy, and presbyopia.

[1.4 Optional Components]
The agents of the present invention (glycation stress inhibitors, AGE production inhibitors, glycation reaction inhibitors, AGEs-induced inflammatory reaction inhibitors) are used in various dosage forms as described later. The above agent may consist of the components concerned, or may contain other optional components in addition to these components. Optional ingredients include, for example, surfactants, buffers, diluents, binders, thickeners, preservatives, excipients, dispersants, disintegrants, solvents, antioxidants, stabilizers, sweeteners, coloring agents. agents, flavoring agents, preservatives, emulsifiers, and combinations of two or more selected from these agents, but are not particularly limited as long as they are additives used in the field of each dosage form.

[1.5 dosage form]
Examples of the dosage form of the glycative stress inhibitor, AGE production inhibitor, glycative reaction inhibitor, and AGE-induced inflammatory reaction inhibitor include liquid, gel, cream (paste), powder (powder), and granules. , tablet-like, film-like, and sheet-like, and are not particularly limited.

[2. Application]
The glycative stress inhibitors, AGE production inhibitors, glycation reaction inhibitors, and AGEs-mediated inflammatory reaction inhibitors can be used as quasi-drugs, medicines, cosmetics, and foods.

[2.1 Application target, application part]
The agent of the present invention can be applied to any animal including humans, and usually mammals, birds and fish, preferably mammals, and more preferably humans. The subject of application may be a healthy person, an elderly person, an infected person, or a person suspected of being infected. Non-human animals include, for example, mice, rats, hamsters, dogs, cats, sheep, goats, cows, pigs, and monkeys.

The agent of the present invention may be applied locally (for oral cavity, ophthalmic mucosa, skin, hair) or systemically (for internal use).

[2.2 Dosage form]
Examples of dosage forms of the agent include oral administration (oral administration) and parenteral administration (e.g., transdermal and transmucosal administration, intravenous administration, intramuscular administration, subcutaneous administration, nasal administration, and pulmonary administration). Among these, less invasive administration forms are preferred, and transdermal transmucosal administration (external use) and oral administration are more preferred.

[2.3 Dosage form]
The agent of the present invention can be used as pharmaceuticals, quasi-drugs, cosmetics, functional foods, and the like. The dosage form is not particularly limited and includes, for example, liquids, sprays, solids, semi-solids, powders, granules, and sheets.

[2.4 Use in formulations]
The agent of the present invention is one or more glycyrrhizic stress inhibitors selected from the group consisting of glycyrrhizinates, allantoins, azulenes, pyridoxine hydrochloride, hinokitiols, copper chlorophylls, lysozyme chloride, and epsilon aminocaproic acid, and suppresses AGEs production. It is possible to prepare various preparations such as external preparations and oral preparations containing, as active ingredients, agents, glycation reaction inhibitors, or inflammatory reaction inhibitors caused by AGEs.

Examples of external preparations include mucosal preparations, skin preparations, and hair preparations, but mucosal preparations are preferred, oral preparations are more preferred, and gum care and periodontal disease prevention are particularly preferred.

Oral formulations include dentifrices (e.g., toothpaste, gel toothpaste, wet toothpaste, liquid toothpaste), gum care agents, mouthwashes, tongue polishes, oral sprays, oral tablets, gums, and mouth fresheners. , gargle tablets, oral pastes, oral gels, and oral ointments.

Skin formulations (external preparations for skin) include, for example, gels, ointments, creams, liquids for external use, lotions, sprays, and packs.

Internal dosage forms (drugs, functional foods) include, for example, internal liquids, syrups, creams, jellies, pastes, tablets, granules, fine granules, capsules (soft capsules, hard capsules) and the like.

As cosmetics, for example, it can be used in dosage forms such as creams, milky lotions, packs, gels, aerosols, and sheets. Specifically, for example, lotions, serums, whitening agents, moisturizers, face masks, milky lotions, foundations, eye shadows, mascara, eyebrows, eyeliners, cheek powders, lipsticks, lip balms, packs, soaps, and other skin products Cosmetics; hair cosmetics such as hair rinses, hair conditioners, hair treatments, hair lotions, hair tonics, hair packs, hair creams, conditioning mousses, hair mousses, hair sprays, shampoos, leave-on treatments, hair dyes, hair styling agents, etc. be done.

Foods (food compositions) include, for example, health foods, functional foods, health foods, health supplements (supplements), dietary supplements, foods for specified health uses, functional nutritive foods, medical foods, foods for the sick, and infants. Food compositions with uses such as food for nursing care, food for nursing care, and food for the elderly.

[2.5 Agent content]
The content of the active ingredients of the present invention (azulenes, allantoins, glycyrrhizic acids, pyridoxine hydrochloride, copper chlorophylls, hinokitiols, lysozyme chloride, and epsilon aminocaproic acid) in each of the above applications is particularly limited. not. For example, it is preferably 0.0001% by mass or more, more preferably 0.001% by mass or more, relative to the total mass of the agent. The upper limit is preferably 10% by mass or less, more preferably 2% by mass or less, and particularly preferably 1% by mass or less. Azulenes and allantoins are preferably 2% by mass or less, more preferably 1% by mass. Therefore, from the viewpoint of expressing the desired effect of the present invention, it is preferably 0.0001 to 10% by mass, more preferably 0.0001 to 2% by mass, and particularly 0.001 to 1% by mass with respect to the total mass of the agent preferable. When licorice extract is used as glycyrrhizic acids, the content is the amount converted to the total amount of glycyrrhizic acid, glycyrrhetinic acid and salts thereof.

[2.6 Optional Components]
When the agent of the present invention is in the form of a so-called composition containing other optional ingredients, the other ingredients include, for example, a medicinal ingredient, a buffering agent, a solubilizing agent, a tonicity agent, a stabilizer, a chelating agent, pH adjusters, preservatives, oily ingredients, excipients, disintegrants, binders, lubricants, coating agents, coloring agents, coloring agents, corrigents (acidifiers, flavors, sweeteners), antioxidants, enhancers agents, swelling agents, thickeners, surfactants, abrasives, humectants, moisturizing agents, cooling agents, abrasives, binders, astringents, plant extracts, UV absorbers, aqueous solvents, preservatives, seasonings Ingredients other than the above active ingredients, such as food ingredients and food ingredients (including food additives). The type and content of optional ingredients may be selected according to the application of pharmaceuticals, quasi-drugs, food compositions, cosmetics, dosage forms, administration methods, etc., and may be one or two. A combination of the above may also be used.

<Medicinal Ingredients>
Examples of medicinal ingredients include enzymes such as dextranase, mutanase, amylase, protease, and lytechenzyme; fluorides such as sodium fluoride, sodium monofluorophosphate, and stannous fluoride; anti-inflammatory agents such as tranexamic acid and dihydrocholesterol. metal salts such as zinc salts, copper salts, tin salts; anticalculus agents such as condensed phosphates and ethanehydroxydiphosphonate; blood flow promoters such as vitamin E (e.g., tocopherol acetate); potassium nitrate, lactic acid Hypersensitivity inhibitors such as aluminum and strontium chloride; coating agents such as hydroxyethylcellulose dimethyldiallylammonium chloride; astringents such as vitamin C (eg, ascorbic acid or its salts) and sodium chloride; water-soluble copper compounds such as copper gluconate. anticalculus agents; amino acids such as alanine, glycine and proline; plant extracts such as thyme, scutellaria root, clove and hamamelis; Other examples include decongestants, antiphlogistic agents, astringents, antihistamines, vitamins, amino acids, bactericides, local anesthetics, and ingredients other than the active ingredients of the present invention that inhibit the production of AGEs or have anti-inflammatory effects. , and a combination of two or more selected from these. Examples of decongestants include naphazoline hydrochloride, tetrahydrozoline hydrochloride, phenylephrine hydrochloride, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, dl-methylephedrine hydrochloride, tetrahydrozoline nitrate, and naphazoline nitrate. Examples of anti-inflammatory and astringent agents include neostigmine methyl sulfate, berberine chloride, berberine sulfate, zinc sulfate, zinc lactate, bromelain, chamomile, and sodium cromoglycate. Antihistamines include, for example, iproheptine hydrochloride, diphenhydramine hydrochloride, diphenhydramine, isothipendyl hydrochloride, and chlorpheniramine maleate. Examples of vitamins include flavin adenine dinucleotide sodium, cyanocobalamin, vitamins A (eg, retinol acetate, retinol palmitate), and vitamins E (tocopherol acetate (eg, d-α-tocopherol acetate)). Amino acids include, for example, potassium L-aspartate, magnesium L-aspartate, aminoethylsulfonic acid, and sodium chondroitin sulfate. Bactericides include, for example, cetylpyridinium chloride, chlorhexidine gluconate, decalinium chloride, benzalkonium chloride, benzetrium chloride, iodine, potassium iodide, sulfamethoxazole, sulfamethoxazole sodium, sulfisoxa sol, sulfisomidine sodium, isopropylmethylphenol. Local anesthetics include, for example, lidocaine, lidocaine hydrochloride, dibucaine hydrochloride, chlorobutanol. Each medicinal ingredient may be used singly or in combination of two or more. The content of the medicinal ingredient can be appropriately set to an effective amount according to a conventional method.

<Surfactant>
Surfactants can be blended with anionic surfactants, nonionic surfactants, and amphoteric surfactants.

Anionic surfactants include, for example, alkyl sulfates, acyl amino acid salts, acyl taurine salts, α-olefin sulfonates, hydrogenated coconut fatty acid monoglyceride monosulfate, and lauryl sulfoacetate. Alkyl groups and acyl groups may be linear or branched, saturated or unsaturated, and usually have 10 to 20 carbon atoms, preferably 12 to 18 carbon atoms, more preferably 12 to 14. Salts may be selected from pharmacologically acceptable salts. Pharmaceutically acceptable salts include, for example, base addition salts and amino acid salts. Specific examples thereof include inorganic base salts such as sodium salts, potassium salts, calcium salts, magnesium salts and ammonium salts; organic base salts such as triethylammonium salts, triethanolammonium salts, pyridinium salts and diisopropylammonium salts; arginine salts and the like. and basic amino acid salts of Among them, inorganic base salts are preferred, alkali metal salts (eg, sodium salts, potassium salts) or ammonium salts are more preferred, and sodium salts are even more preferred.

Examples of alkyl sulfates include lauryl sulfate (sodium lauryl sulfate) and myristyl sulfate. Acyl amino acid salts include acyl glutamates such as lauroyl glutamate, myristoyl glutamate and palmitoyl glutamate; acylglycinates such as N-lauroyl-N-methylglycinate and cocoylglycinate; N-lauroyl-β- Alanine salt, N-myristyl-β-alanine salt, N-cocoyl-β-alanine salt, N-lauroyl-N-methyl-β-alanine salt, N-myristoyl-N-methyl-β-alanine salt, N-methyl - acyl alanine salts such as N-acyl alanine salts; and acyl aspartates such as lauroyl aspartate. Acyl taurine salts include, for example, lauroyl methyl taurine salts, N-methyl-N-acyl taurine salts, and N-cocoyl methyl taurine salts. Examples of α-olefin sulfonates include α-olefin sulfonates having 12 to 18 carbon atoms such as tetradecene sulfonate. Other examples of anionic surfactants include, for example, hydrogenated coconut fatty acid monoglyceride monosulfate, sodium lauryl sulfoacetate.

Nonionic surfactants include, for example, polyoxyethylene alkyl ether, polyoxyethylene hydrogenated castor oil, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester (eg, polyoxyethylene sorbitan monostearate), alkylolamide , polyoxyethylene fatty acid ester, polyoxyethylene alkenyl ether, polyglycerin fatty acid ester, sucrose fatty acid ester (eg, maltose fatty acid ester), sugar alcohol fatty acid ester (eg, maltitol fatty acid ester, lactitol fatty acid ester), fatty acid diethanolamide (eg, lauric acid mono- or diethanolamide), polyoxyethylene-polyoxypropylene copolymers, and polyoxyethylene-polyoxypropylene fatty acid esters. The number of carbon atoms in the alkyl chain of the polyoxyethylene alkyl ether is generally 14-18, and the average number of moles of ethylene oxide added is generally 5-30 mol. The average mole number of ethylene oxide added to the polyoxyethylene hydrogenated castor oil is generally 20 to 100 mol, preferably 20 to 60 mol. The number of carbon atoms in the fatty acid of the sorbitan fatty acid ester is usually 12-18. The number of carbon atoms in the fatty acid of the polyoxyethylene sorbitan fatty acid ester is generally 16-18, and the average number of moles of ethylene oxide added is generally 10-40 mol. The alkyl chain of the alkylolamide usually has 12-14 carbon atoms.

Examples of amphoteric surfactants include betaine-type amphoteric surfactants such as alkyldimethylaminoacetic acid betaine (eg, lauryldimethylaminoacetic acid betaine), fatty acid amidopropyldimethylaminoacetic acid betaine (eg, cocamidopropyl betaine); Fatty acid acyl-N-carboxymethyl-N-hydroxyethylethylenediamine salts (e.g., N-cocoate acyl-N-carboxymethyl-N-hydroxyethylimidazolinium betaine), cocoate imidazolinium betaine, 2-alkyl imidazoline type amphoteric surfactants such as -N-carboxymethyl-N-hydroxyethylimidazolinium betaine; and alkylbetaines such as lauryldimethylaminoacetate betaine.

When a surfactant is included, the content of each of the anionic, nonionic, and amphoteric surfactants is usually 0.01 to 10% by mass, preferably 0.1 to 5% by mass, more preferably 0% of the total agent. .2 to 3% by mass.

<Abrasive>
The abrasive may be, for example, either an inorganic abrasive or an organic abrasive. Examples of inorganic abrasives include abrasive silica such as precipitated silica, aluminosilicate, zirconosilicate, crystalline zirconium silicate, and titanium-bonded silica; Calcium phosphate compounds such as tribasic calcium phosphate and calcium pyrophosphate; calcium carbonate abrasives such as calcium carbonate; calcium hydroxide, calcium sulfate and other calcium-based abrasives other than carbonate/phosphate; aluminum oxide, aluminum hydroxide, Aluminum-based materials such as alumina; Silicic acid-based materials such as silicic anhydride, zeolite, and zirconium silicate; Magnesium-based materials, such as magnesium carbonate and magnesium triphosphate; Apatite-based materials, such as hydroxyapatite, fluoroapatite, and calcium-deficient apatite Materials; Titanium-based materials such as titanium dioxide, titanium mica, and titanium oxide; and minerals such as bentonite. Examples of organic abrasives include polymethyl methacrylate and synthetic resin abrasives. Among these, abrasive silica and calcium phosphate compounds are preferred, and silicic anhydride is more preferred. The amount of abrasive is preferably 50% by mass or less, more preferably 8 to 50% by mass, based on the total amount of the agent.

<Wetting agent>
Wetting agents include, for example, sugar alcohols and polyhydric alcohols other than sugar alcohols. Examples of sugar alcohols include sorbitol (sorbitol), erythritol, maltitol, lactitol, and xylitol. Examples of polyhydric alcohols other than sugar alcohols include glycerin; glycols such as ethylene glycol, propylene glycol, dipropylene glycol, butylene glycol and polyethylene glycol (PEG); and reduced starch saccharification products. As polyethylene glycol, for example, polyethylene glycol having an average molecular weight of 150 to 6000 is preferable, and polyethylene glycol having an average molecular weight of 190 to 630 (PEG200, PEG300, PEG400, PEG600) is preferable. The average molecular weight is the average molecular weight described in the Standards for Quasi-drug Ingredients 2006. The content of the wetting agent is usually 40% by mass or less, preferably 1 to 30% by mass, based on the entire agent.

<Binder>
As the binding agent, any suitable conventionally known organic binding agent such as polysaccharides, cellulose-based binding agents (e.g., carboxymethylcellulose (CMC), hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, cationic cellulose, etc.), other polysaccharide thickeners (e.g., xanthan gum, guar gum, gellan gum, tragacanth gum, karaya gum, gum arabic, locust bean gum, carrageenan, sodium alginate), synthetic water-soluble polymers (e.g., sodium polyacrylate, carboxyvinyl polymer, polyvinylpyrrolidone, polyvinyl alcohol, propylene glycol alginate). Furthermore, inorganic binders such as thickening silica and aluminum silicate can also be contained. The content of the organic binder is preferably 0 to 3% by mass, more preferably 0.1 to 2% by mass, relative to the total agent. The content of the inorganic binder is preferably 0 to 10% by mass, more preferably 1 to 8% by mass.

<Buffer>
Examples of buffering agents include citric acid or salts thereof (e.g., sodium citrate), phosphoric acid or salts thereof (e.g., sodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium phosphate, potassium dihydrogen phosphate). , tartaric acid or its salts (e.g. sodium tartrate), gluconic acid or its salts (e.g. sodium gluconate), acetic acid or its salts (e.g. sodium acetate), carbonic acid or its salts (e.g. sodium bicarbonate), trometamol, Amino acids (eg, potassium aspartate, aminoethylsulfonic acid, glutamic acid, sodium glutamate), combinations of two or more thereof. Examples of solubilizers include polyoxyethylene (e.g., p=60) polyoxyethylene higher fatty acid esters such as hydrogenated castor oil, polyoxyethylene (e.g., p=20) polyoxyethylene sorbitan such as sorbitan monooleate. higher fatty acid esters, propylene glycol, polyethylene glycol, and combinations of two or more of these. Tonicity agents include, for example, sodium chloride, potassium chloride, glycerin, combinations of two or more thereof. Stabilizers include, for example, sodium edetate, cyclodextrins, sulfites, citric acid or salts thereof, dibutylhydroxytoluene, ascorbic acid, combinations of two or more thereof. Chelating agents include, for example, sodium edetate, sodium citrate, and combinations thereof. Examples of pH adjusters include sodium hydroxide, potassium hydroxide, hydrochloric acid, and combinations of two or more of these. Examples of antiseptics include paraoxybenzoic acid esters such as methylparaben, ethylparaben, propylparaben, and butylparaben; alcohol derivatives such as phenylethyl alcohol, benzyl alcohol, phenol, and acrinol; sorbic acid and salts thereof (potassium sorbate, etc.); ), benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, cetylpyridinium chloride, alkylpolyaminoethylglycine, combinations of two or more thereof.

<Moisturizer>
Humectants include, for example, glycerin, concentrated glycerin, sugar alcohols (eg, sorbitol, xylitol, maltitol, mannitol, reduced starch syrup, reduced palatinose, erythritol, lactitol, isomalt), and combinations of two or more thereof.

<Flavoring agent>
Examples of flavoring agents include sweeteners (e.g., sodium saccharin, aspartame, stevia, stevioside, paramethoxycinnamic aldehyde, neohesperidin dihydrochalcone, perillartine, aspartylphenylalanine methyl ester, thaumatin, acesulfame potassium, sucralose, maltitol, sorbitol, , mannitol, reduced starch syrup, reduced palatinose, xylitol, erythritol, artificial sweeteners such as lactitol, etc.), fragrances (e.g. anise oil, cassia oil, wintergreen oil, mastic oil, neroli oil (orange flower oil), lemongrass oil) , jasmine oil, rose oil, iris oil, clove oil, sage oil, cardamom oil, rosemary oil, laurel oil, chamomile oil, basil oil, marjoram oil, lemon oil, orange oil, lime oil, yuzu oil, nutmeg oil, Natural essential oils such as lavender oil, paracress oil, vanilla oil, cinnamon oil, pimento oil, cinnamon oil, perilla oil, wintergreen oil, peppermint oil, lychee oil); menthol, carvone, cinnamic aldehyde, anethole, methyl salicylate, eugenol , linalool, limonene, menthone, menthyl acetate, citral, decanal, camphor, borneol, pinene, spiranthol, n-decyl alcohol, citronellol, α-terpineol, citronellyl acetate, ethyl linalool, vanillin, etc. Perfume ingredients: ethyl acetate, ethyl butyrate, isoamyl acetate, hexanal, hexenal, methyl anthranilate, ethyl methyl phenyl glycidate, benzaldehyde, vanillin, ethyl vanillin, furaneol, N-ethyl-p-menthane-3-carboxamide, menthyl Fragrant ingredients such as lactate and ethylene glycol-l-menthyl carbonate; and various compounded flavors such as mint, fruit, and herb that combine several fragrance ingredients and natural essential oils (e.g., peppermint micron X-8277-T , dry coat matcha #421), acidulants (eg, citric acid, tartaric acid, malic acid), green tea powder.

<Oil component>
Oily components include, for example, fatty acid esters (e.g. glycerin fatty acid esters), hydrocarbons (e.g. paraffin, liquid paraffin, ceresin, squalane, vaseline, microcrystalline wax), higher fatty acids (e.g. lauric acid, myristic acid, olein acids, fatty acids with 8 to 22 carbon atoms such as isostearic acid), higher alcohols (for example, alcohols with 8 to 22 carbon atoms such as lauryl alcohol, cetyl alcohol, cetostearyl alcohol, oleyl alcohol, and isostearyl alcohol), plants Oils and fats (eg, vegetable oils such as olive oil, castor oil, and coconut oil; fatty acid esters such as isopropyl myristate), beeswax, and combinations of two or more thereof.

<Preservative>
Preservatives include, for example, parahydroxybenzoic acid esters (eg, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, butyl parahydroxybenzoate), sodium benzoate, and combinations of two or more thereof.

<Wetting agent>
Wetting agents include, for example, sugar alcohols and polyhydric alcohols other than sugar alcohols. Examples of sugar alcohols include sorbitol (sorbitol), erythritol, maltitol, lactitol, and xylitol. Examples of polyhydric alcohols other than sugar alcohols include glycerin; glycols such as ethylene glycol, propylene glycol, dipropylene glycol, butylene glycol and polyethylene glycol (PEG); and reduced starch saccharification products. As polyethylene glycol, for example, polyethylene glycol having an average molecular weight of 150 to 6000 is preferable, and polyethylene glycol having an average molecular weight of 190 to 630 (PEG200, PEG300, PEG400, PEG600) is preferable. The average molecular weight is the average molecular weight described in the Standards for Quasi-drug Ingredients 2006. The amount of the wetting agent is generally 40% by mass or less, preferably 1 to 30% by mass, based on the total agent.

<Colorant>
Examples of coloring agents include natural pigments such as safflower red pigment, gardenia yellow pigment, gardenia blue pigment, perilla pigment, monascus pigment, red cabbage pigment, carrot pigment, hibiscus pigment, cacao pigment, spirulina blue pigment, tamarind pigment, Legal pigments such as Red No. 2, Red No. 3, Red No. 104, Red No. 105, Red No. 106, Red No. 227, Yellow No. 4, Yellow No. 5, Green No. 3, Blue No. 1, riboflavin, titanium dioxide, etc. mentioned. When a coloring agent is included, its content is preferably 0.00001 to 3% by mass with respect to the entire agent.

<pH adjuster>
Examples of pH adjusters include organic acids such as phthalic acid, citric acid, succinic acid, acetic acid, fumaric acid, malic acid, and lactic acid, salts thereof (sodium citrate), and inorganic acids such as phosphoric acid (orthophosphoric acid). Acids or salts thereof (eg, potassium salts, sodium salts and ammonium salts), hydroxides such as sodium hydroxide and potassium hydroxide. Examples of inorganic acid salts include disodium hydrogen phosphate and sodium dihydrogen phosphate. The content of the pH adjuster can be adjusted so that the pH of the agent after addition is usually 5 to 9, preferably 6 to 8.5. In this specification, the pH value usually refers to the value after 3 minutes at 25°C from the start of measurement. The pH value can be measured, for example, using a pH meter (model number Hm-30S) manufactured by Toa Denpa Kogyo Co., Ltd.

<Solvent>
Examples of the solvent include water (purified water) and ethanol, with water being preferred. A solvent may be used individually by 1 type, or may be used in combination of 2 or more type.

<Excipient>
Excipients include, for example, cellulose such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, crystalline cellulose, ethyl cellulose, methyl ethyl cellulose, low-substituted hydroxypropyl cellulose, and pharmacologically acceptable derivatives thereof; Synthetic polymers such as saponified polyvinyl alcohol; Polysaccharides such as gelatin, gum arabic powder, pullulan, agar, alginic acid, sodium alginate, and xanthan gum; Starches such as corn starch, potato starch, pregelatinized starch, and hydroxypropyl starch, and their pharmacology lactose, lactose granules, fructose, glucose, white sugar, granulated sugar, hydrated glucose, trehalose, palatinose, mannitol, sorbitol, erythritol, xylitol, maltotetraose, lactitol, isomalt, reduced palatinose, reduced starch syrup, powdered reduced maltose syrup, maltitol; magnesium carbonate, calcium carbonate, light anhydrous silicic acid, silicon dioxide (a.k.a. anhydrous silicic acid, fine silicon dioxide), titanium oxide, inorganic excipients such as aluminum hydroxide gel; A combination of two or more of

<Disintegrant>
Examples of disintegrants include crospovidone, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl starch sodium, croscarmellose sodium, cross-linked insoluble polyvinylpyrrolidone, and hydroxypropyl starch. , partially pregelatinized starch, corn starch, combinations of two or more thereof.

<Binder>
Binders include, for example, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, gelatin, dextrin, starch, pregelatinized starch, combinations of two or more thereof.

<Lubricant>
Lubricants include, for example, calcium stearate, magnesium stearate, sucrose fatty acid esters, light anhydrous silicic acid, sodium stearyl fumarate, polyethylene glycol, talc, stearic acid, and combinations of two or more of these.

<Other optional ingredients>
Examples of optional components other than the above include polyisobutylene, polybutadiene, urethane, silicon, and natural rubber. The content of these other optional components can be appropriately set within a range that does not impair the effects of the present invention.

[3. Production method〕
The manufacturing method of oral preparations, topical preparations, and other agents that use glycation stress inhibitors, AGE production inhibitors, glycation reaction inhibitors, or AGE-induced inflammatory reaction inhibitors is determined according to the dosage form, application, and application site. Just do it. For example, when it is used as a toothpaste, after preparing a component that dissolves in a solvent, other insoluble components are mixed, and defoaming (e.g., reduced pressure, etc.) as necessary. Examples include dispersing and dissolving the active ingredient and optionally other ingredients in an aqueous solvent (e.g. water such as purified water and sterilized water) to prepare a composition and dissolving it in an appropriate container (e.g. , glass, or resin). As for the container, for example, a container for an oral agent includes a laminated tube, and resin such as polyethylene, polypropylene, polyethylene terephthalate, and nylon can be used as the material. In the case of a spray, a container equipped with an atomizing means (for example, a trigger-type, pump-type, or aerosol-type container) may be selected. The obtained toothpaste can be put into a container to be used as a product. The shape and material of the container are not particularly limited, and containers commonly used for oral compositions can be used.

[4. how to use〕
Oral preparations, topical preparations, and other agents that use glycative stress inhibitors, AGE production inhibitors, glycation reaction inhibitors, or AGE-induced inflammatory reaction inhibitors may be used by, for example, administering the agent to the application site. The number of administrations per day is not particularly limited, but may be, for example, 1 to 6 times or more. In the case of oral preparations, put an appropriate amount of the agent on the toothbrush and brush the surface of the teeth, then rinse with water after use (dentifrice), or spit out after gargling with an appropriate amount of the agent in the mouth (mouthwash). According to

[Test Example 1] Evaluation of gingival inflammation reaction due to saccharification (reference example)
Human gingival fibroblasts were seeded in a multiwell plate and cultured to subconfluence in α-MEM (manufactured by ThermoFischer) containing 10% bovine serum. After that, the medium was removed, Control-BSA (hereinafter BSA, manufactured by BioVision) at 0, 250, 500, 1000 μg / mL, AGEs-BSA (saccharified product of Control-BSA, hereinafter AGEs, manufactured by BioVision) at 0, 250, 500 and 1000 μg/mL were added to the medium, respectively. After 24 hours, the culture supernatant was collected, and the amount of IL-6 protein in the supernatant was evaluated by ELISA (manufactured by R&D Systems). (Fig. 1). The concentration of IL-6 was higher in the AGEs-supplemented cell supernatant compared to the BSA-supplemented cell supernatant. It was also revealed that the IL-6 concentration increased depending on the AGEs concentration. The results of this test example indicate that AGEs promote inflammation in a concentration-dependent manner.

[Test Example 2] AGEs production inhibitory activity test (Examples 1 to 8 and Comparative Example 1)
<Preparation of collagen gel>
The ice-cooled neutralized collagen solution was dispensed into 96-well black plates at 50 μL/well, and allowed to stand overnight in a 37° C. incubator under wet conditions.

<Preparation of sample solution>
Sodium azulene sulfonate (manufactured by Tokyo Chemical Industry Co., Ltd.), allantoin (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.), dipotassium glycyrrhizinate (manufactured by Alps Pharmaceutical Co., Ltd.), pyridoxine hydrochloride (manufactured by DSM Co., Ltd.), sodium copper chlorophyllin (manufactured by DSM Co., Ltd.) Tama Biochemical Co., Ltd.), hinokitiol (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.), lysozyme chloride (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.), and epsilon aminocaproic acid (manufactured by Nippon Rika Chemical Co., Ltd., Example 8) are each It was prepared by diluting with phosphate buffer solution (PBS) so that the components had predetermined concentrations. Tocopherol acetate (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was dissolved in ethanol and then diluted with PBS to a final ethanol concentration of 1% or less. The samples used in the following test examples were the same commercially available products as in this test example.

<Preparation of test substance>
40 μL of the sample solution group and 10 μL of the 500 mM glyceraldehyde solution were mixed on a previously prepared collagen gel. After that, it was allowed to stand at 37° C. under moist conditions for 24 hours. Then, the collagen gel was irradiated with excitation light of 370 nm, and the resulting fluorescence of 440 nm was measured. The result obtained by this measurement was defined as measured value A.

<Preparation of blank>
Preparation of blank was performed as follows. 40 μL of PBS and 10 μL of 500 mM glyceraldehyde solution were mixed on the collagen gel prepared in advance. After that, it was allowed to stand at 37° C. under moist conditions for 24 hours. Then, the collagen gel was irradiated with excitation light of 370 nm, and the resulting fluorescence of 440 nm was measured. The result obtained by this measurement was defined as measured value B.

<Test results>
The test results were calculated by AGEs production suppression rate (%) = 100-{(measured value A/measured value B) × 100}. Each value is an average value of N=3.

In Comparative Example 1, the AGEs production inhibition rate was 0% or less, while in Examples 1 to 8, the AGEs production inhibition rate exceeded 0%. In the case of 1%, the production inhibition rate was as high as 20% or more. The results show that each compound of Examples inhibits saccharification reaction and acts as a saccharification reaction inhibitor. In addition, as a result, AGEs production is suppressed, indicating that it acts as an AGEs production inhibitor.

Oxidative stress is known to be involved in glycation reactions, and tocopherol acetate (Comparative Example 1) is an antioxidant substance, and both were expected to suppress glycation reactions. However, in this example, tocopherol acetate did not inhibit AGEs production (Table 1), so the results of this test example show that substances having antioxidant activity do not necessarily have AGEs production inhibitory activity. showing.

[Test Example 3] Inflammatory reaction inhibition evaluation by AGEs <Preparation of sample solution>
Components 1 to 7 shown in Table 2 were added to α-MEM (manufactured by ThermoFischer) to prepare sample solutions.

<Evaluation of inflammatory response of sample solution>
Human gingival fibroblasts were seeded in a multiwell plate and cultured in a medium containing 10% bovine serum until subconfluent. After that, the medium was removed and replaced with the sample solution. After 6 hours, human gingival fibroblasts were collected, RNA was extracted, cDNA was prepared, and gene expression analysis of IL-6 concentration was performed by RT-PCR. The IL-6 gene expression level was standardized using the gene expression level of GAPDH, which is an endogenous control, and the IL-6 gene expression ratio was calculated using the negative control as 1 (Fig. 2).

The IL-6 gene expression ratio of 250 μg/mL AGEs (positive control: Comparative Example 3) was about 2.5 times higher than that of BSA 250 μg/mL (negative control: Comparative Example 2). In the sample solution containing 250 μg/mL of AGEs and 0.1% each of allantoin, dipotassium glycyrrhizinate, pyridoxine hydrochloride, hinokitiol, and epsilonaminocaproic acid, the IL-6 gene expression ratio was decreased compared to the positive control. (Examples 9-13).

The results of this test indicate that AGEs induce inflammatory reactions and that the agent of the present invention can suppress inflammatory reactions caused by AGEs.

From the above examples, it can be seen that each active ingredient has activity to suppress glycation stress occurring in vivo and AGE production reaction that causes inflammatory reaction, and activity to suppress inflammatory reaction itself caused by AGEs, and inflammation caused by AGEs. can be suppressed.

Claims (12)

A glycyrrhizic stress inhibitor containing at least one selected from the group consisting of glycyrrhizic acids, allantoins, azulenes, pyridoxine hydrochloride, hinokitiols, copper chlorophylls, lysozyme chloride, and epsilon aminocaproic acid. Production of AGEs (Advanced Glycation End Products) containing one or more selected from the group consisting of glycyrrhizic acids, allantoins, azulenes, pyridoxine hydrochloride, hinokitiols, copper chlorophylls, lysozyme chloride, and epsilon aminocaproic acid inhibitor. 3. The AGE production inhibitor according to claim 2, wherein the AGEs are collagen-derived AGEs. 4. The AGE production inhibitor according to claim 2 or 3, wherein the AGEs are AGEs derived from collagen and glyceraldehyde. A saccharification reaction inhibitor containing at least one selected from the group consisting of glycyrrhizic acids, allantoins, azulenes, pyridoxine hydrochloride, hinokitiols, copper chlorophylls, lysozyme chloride, and epsilon aminocaproic acid. The glycation reaction inhibitor according to claim 5, which inhibits the glycation reaction of collagen. 7. The saccharification reaction inhibitor according to claim 5, which inhibits saccharification reaction of collagen by glyceraldehyde. Contains one or more selected from the group consisting of glycyrrhizic acids, allantoins, azulenes, pyridoxine hydrochloride, hinokitiols, copper chlorophylls, lysozyme chloride, and epsilon aminocaproic acid, and suppresses inflammatory reactions caused by AGEs. agent. An external preparation containing the agent according to any one of claims 1 to 8. An oral preparation containing the agent according to any one of claims 1 to 8. 11. The oral agent according to claim 10, which is a gum care agent. The oral preparation according to claim 10, which is a periodontal disease preventive agent.

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