KR20230123915A - anti-inflammatory - Google Patents

Abstract

An object of the present invention is to provide a method capable of suppressing inflammation from the root by directly acting on macrophages and activating their functions. That is, the present invention is the following general formula (1):

(In the formula, R ¹ represents an organic group, and n1 represents a number greater than or equal to 1.)
Provided is an anti-inflammatory agent comprising at least one 2-ethylhexyl compound represented by

Description

anti-inflammatory

The present invention relates to anti-inflammatory agents.

Macrophage is one of the immune cells involved in the inflammatory process through epicytosis. That is, after neutrophils phagocytosing foreign substances such as pathogens that have invaded the living body die, macrophages remove the dead cells and exert anti-inflammatory and tissue repair actions to relieve inflammation. On the other hand, when immune function is lowered, macrophages cannot remove dead neutrophils, and dead cells that are not removed cause additional inflammation. In addition, since macrophages are not transformed into an anti-inflammatory type by removing dead cells, inflammation is not remitted and chronic inflammation is caused (see, for example, Non-Patent Document 1). Such chronic inflammation is one of the causes of periodontal disease, and development of agents for treatment or prevention thereof has been progressed.

Patent Literature 1 describes that ε-aminocaproic acid and tranexamic acid have an antagonistic action against plasmin, which inhibits blood coagulation, and are blended into oral compositions.

Japanese Unexamined Patent Publication No. 2018-20995

Serhan CN, et al. Resolution of information: state of the art, definitions and terms. FASEB J. 2007;21:325-332

However, the anti-inflammatory action by plasmin antagonism is a so-called symptomatic therapy for relieving symptoms, and is not an action against the cause of chronic inflammatory action.

An object of the present invention is to provide a method capable of suppressing inflammation from the root by directly acting on macrophages and activating their functions.

The present invention provides the following.

[1] the following general formula (1):

(In the formula, R ¹ represents an organic group, and n1 represents a number greater than or equal to 1.)

An anti-inflammatory agent comprising at least one 2-ethylhexyl compound represented by

[2] In [1],

R ¹ in Formula (1) is

Formula (2):

(In the formula, R ² represents a dialkylamino group, an alkyloxy group or a hydroxyl group. n2 is an integer of 1 to 6.)

An aryl group which may have a substituent represented by , or

An anti-inflammatory agent that is an alkyl group which may have a substituent.

[3] In [2],

An anti-inflammatory agent wherein the alkyl group is an alkyl group having a hydroxyl group or a sulfo group, or an alkyl group having no substituent.

[4] A macrophage function activator containing at least one 2-ethylhexyl compound represented by the above general formula (1).

[5] A preventive or therapeutic agent for periodontal disease containing at least one ethylhexyl compound represented by the general formula above.

According to the present invention, an anti-inflammatory agent capable of directly acting on macrophages and suppressing inflammation from the root by activating the function is provided.

[1.2-ethylhexyl compound]

The agent of the present invention contains 2-ethylhexyl compound as an active ingredient. The 2-ethylhexyl compound is an ester of 2-ethylhexyl alcohol and is represented by formula (1):

In the formula, R ¹ represents an organic group. In this specification, an organic group should just be a group containing a carbon atom, and may further contain atoms (for example, an oxygen atom, a nitrogen atom, and a sulfur atom) other than a carbon atom. As R ¹ , an alkyl group and an aryl group are exemplified, and each may have a substituent. The aryl group which may have a substituent represented by General formula (2), or the alkyl group which may have a substituent is preferable. n1 is an integer greater than or equal to 1, and is usually 1 to 5, preferably 1 to 4, and more preferably 1 to 3.

[1.1 Aryl group represented by general formula (2) (example of R ¹ )]

Formula (2):

In, R ² represents a dialkylamino group, an alkyloxy group or a hydroxyl group. The number of carbon atoms in the alkyl group of the dialkylamino group and the alkyloxy group is usually 1 to 5, preferably 1 to 3, more preferably 1 to 2. The alkyl group may be branched or straight chained. The two alkyl groups of the dialkylamino group may be identical to or different from each other. As for ^R2 , it is more preferable that it is a dimethylamino group, a methyloxy group, or a hydroxyl group.

The binding site for R ² is not particularly limited, but an ortho position or para position is preferred. n2 is an integer of 1 to 6, preferably 1 to 3, and more preferably 1.

[1.2 Alkyl group which may have a substituent (example of R ¹ )]

The alkyl group may be branched or straight chain, but is preferably straight chain. The number of carbon atoms in the alkyl group is usually 1 or more, preferably 2 or more, 3 or more, 4 or more, or 5 or more, more preferably 6 or more, 7 or more, 8 or more, 9 or more, or 10 or more, still more preferably It is 11 or more, 12 or more, or 13 or more. Therefore, it is usually 1 to 30, preferably 1 to 25, more preferably 1 to 20, still more preferably 1 to 18, even more preferably 5 to 18, 7 to 18, 9 to 18, 11 to 18 or 13 to 18. The alkyl group is preferably an alkyl group having at least one (preferably one) hydroxyl group or sulfo group, or an alkyl group having no substituent. When the number of carbon atoms in the alkyl group is 6 or less (preferably 6 or less, more preferably 5 or less, still more preferably 4 or less, still more preferably 2 to 3), n1 in the general formula (1) is An integer of 2 or more is preferable, and 2 to 3 are more preferable. In this specification, when a substituent is not specifically defined, it may just be an organic group.

[1.3 Molecular weight of 2-ethylhexyl compound]

The molecular weight of the 2-ethylhexyl compound is usually 100 to 800, preferably 150 to 700, and more preferably 200 to 600.

[1.4 Examples of 2-ethylhexyl compounds]

As a 2-ethylhexyl compound, the following compounds are illustrated, for example.

(Example 1) 2ethylhexyl salicylate (octyl salicylate): ester of salicylic acid and 2-ethylhexyl alcohol, molecular weight 250.33

(Example 2) 2-ethylhexyl para-dimethylaminobenzoic acid: ester of dimethyl para-aminobenzoic acid and 2-ethylhexyl alcohol, molecular weight 277.40

(Example 3) 2ethylhexyl palmitate: ester of palmitic acid and 2-ethylhexyl alcohol, molecular weight 368.64

(Example 4) 2ethylhexyl stearate: ester of stearic acid and 2-ethylhexyl alcohol, molecular weight 396.69

(Example 5) 2ethylhexyl methoxycinnamic acid: ester of methoxycinnamic acid and 2-ethylhexyl alcohol, molecular weight 290.4

(Example 6) Tri2ethylhexyl citrate: triester of citric acid and 2-ethylhexyl alcohol, molecular weight 525.7

(Example 7) Di2ethylhexyl succinate: diester of succinic acid and 2-ethylhexyl alcohol, molecular weight 342.5

(Example 8) 2-ethylhexyl hydroxystearic acid: ester of hydroxystearic acid and 2-ethylhexyl alcohol, molecular weight 412.7

(Example 9) Di(2-ethylhexyl)sodium sulfosuccinate: Sodium salt of diester of sulfosuccinic acid and 2-ethylhexyl alcohol, molecular weight 421.6

(Example 10) Adipic acid bis(2-ethylhexyl): diester of adipic acid and 2-ethylhexyl alcohol, molecular weight 370.57

As other examples, the following are exemplified: 2,4,6-tris[4-(2-ethylhexyloxycarbonyl)anilino]-1,3,5-triazine, 2-ethylhexyl isononanoate, no Ethylhexyl nitrate, 2-ethylhexyl isopalmitate, dimethoxybenzylidenedioxoimidazolidinepropionic acid 2-ethylhexyl, di2-ethylhexyl sebacate, 2-ethylhexyl pelargonic acid, di2-ethyl maleate Hexyl, Diethylhexyl Phthalate, Ethylhexyl Laurate, Diethylhexyl Carbonate, Ethylhexyl Benzoate, Ethylhexyl Benzoate Hydroxystearate, Ethylhexyl Hydrogenated Olive Oil, Diethylhexyl Malate, Ethylhexyl Ricinoleate, Ethyl Coconut Fatty Acid hexyl, palm oil fatty acid ethylhexyl, methacrylate ethylhexyl, bisethylhexylhydroxydimethoxybenzyl malonate, diethylhexylsyringylidene malonate, ethylhexyl polyricinoleate, ethylhexyl polyhydroxystearate, Ethylhexyl neopentanoate, diethylhexyl naphthalenedicarboxylic acid, triethylhexyl trimellitate, ethylhexyl stearoylhydroxystearate, ethylhexylmethoxycrylene, ethylhexyltriazone, ethylhexylglycerin, ethylhexanoic acid Ethylhexyl, diethylhexyl isoeicosan diacid, (caprylic acid/capric acid) ethylhexyl, (adipic acid/palmitic acid/stearic acid) ethylhexyl; Branched fatty acid ethylhexyl (eg, branched fatty acid ethylhexyl having a C12-31 branched alkyl group) and branched fatty acid ethylhexyl (eg, branched fatty acid ethylhexyl having a C10-40 branched alkyl group) other than the above. Among these, the compounds of Examples 1 to 10 are preferred, the compounds of Examples 1, 3, 4, 6, 7 and 8 are more preferred, the compounds of Examples 1, 3 and 4 are still more preferred, and Example 3 , each compound of 4 is more preferable.

[Effective amount of 2.2-ethylhexyl compound]

The effective amount (amount of ethylhexyl compound) per day of the agent is, for example, 0.01 mg to 1000 mg, preferably 0.03 mg to 800 mg, and more preferably 0.05 mg to 500 mg in the case of an adult. The dosage may be appropriately determined according to administration conditions such as administration method, whichever is used among pharmaceuticals, quasi-drugs, cosmetics, and foods.

[3. Action〕

The 2-ethylhexyl compound activates the functions of macrophages in the immune response (foreign substance removal ability, inflammation healing function, immune response dissipation function, immune response-induced symptom remission function, anti-inflammatory function), and can promote the inflammatory process. and can normalize and/or enhance immune function. For that reason, agents containing 2-ethylhexyl compounds are useful as anti-inflammatory agents. It is also useful as an immune function normalizer, immune function enhancer, and macrophage activator or enhancer.

〔4. Formulation]

As the dosage form, for example, tablets (tablets, tablets), liquids (liquids), syrups (syrups), capsules (capsules), powders (granules, fine granules), soft capsules (soft capsules such as gelatin base) , Hard capsule form (hard capsule formulation), liquid form (liquid formulation), syrup form (syrup formulation), solid form, semi-liquid form, cream form, and paste form are exemplified, and may be appropriately selected depending on the dosage form.

[5. Administration method / subject]

As the method of administration of the agent, for example, oral administration (eg intraoral administration, sublingual administration), parenteral administration (eg intravenous administration, intramuscular administration, subcutaneous administration, transdermal administration, intranasal administration, transpulmonary administration) Administration) is exemplified, and among these, a dosage form with less invasiveness is preferable, and oral administration (internal administration) and transdermal administration (external administration) are more preferable.

The subject of administration may be an animal including a human, and is usually a human. The target of administration may be a healthy person, but patients with diseases accompanying inflammation (eg, periodontal disease, pneumonia, hepatitis, cancer, autoimmune diseases, diabetes, infectious diseases) are preferable, and patients with chronic inflammation are more likely to be treated. desirable. Examples of animals other than humans include mammals such as mice, rats, hamsters, dogs, cats, sheep, goats, cows, pigs, and monkeys.

[6. Optional ingredient]

The anti-inflammatory agent may consist only of a compound having a 2-ethylhexyl structure, or may be in the form of a so-called composition containing other components as necessary. Examples of other ingredients include oily ingredients, excipients, disintegrants, binders, lubricants, medicinal ingredients, coating agents, coloring agents, coloring agents, flavoring agents, flavoring agents, antioxidants, preservatives, flavoring agents, acidulants, sweeteners, strengthening agents, Expanding agents, thickeners, surfactants, ingredients having an action of inhibiting an increase in blood sugar level and/or an action of accelerating sugar absorption other than compounds having a 2-ethylhexyl structure, anti-inflammatory agents, amino acids, vitamins, refreshing agents, flavoring agents, sweeteners, abrasives, binders, pH adjusters, chelating agents, astringents, plant extracts, ultraviolet absorbers, humectants, solvents, seasonings, and food raw materials (including food additives) are exemplified. Arbitrary components may be selected according to each application and/or dosage form of pharmaceuticals, quasi-drugs, food compositions, and cosmetics, and may be one type or a combination of two or more types.

As the oily component, for example, fatty acid esters (eg, glycerin fatty acid ester, isopropyl myristate), hydrocarbons (eg, paraffin, ceresin, squalane, vaseline, microcrystalline wax), higher fatty acids (eg, laur fatty acids having 8 to 22 carbon atoms such as acid, myristic acid, oleic acid, and isostearic acid), higher alcohols (eg, oleyl alcohol, cetanol, lauryl alcohol, cetostearyl alcohol), vegetable oils (eg, vegetable oils such as olive oil, castor oil, and palm oil), and beeswax.

Examples of the excipient include cellulose and pharmacologically acceptable derivatives thereof such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, crystalline cellulose, ethyl cellulose, and low-substituted hydroxypropyl cellulose; synthetic polymers such as polyvinylpyrrolidone and partially saponified polyvinyl alcohol; polysaccharides such as gelatin, gum arabic powder, pullulan, agar, arginic acid, sodium alginate and xanthan gum; starches and pharmacologically acceptable derivatives thereof, such as corn starch, potato starch, α-starch, and hydroxypropyl starch; Sugars such as lactose, fructose, glucose, white sugar, granulated sugar, hydrous glucose, trehalose, palatinose, mannitol, sorbitol, erythritol, xylitol, maltotetraose, reduced palatinose, powdered reduced maltose starch syrup, and maltitol; sugar alcohols; inorganic excipients such as magnesium carbonate, calcium carbonate, light anhydrous silicic acid, silicon dioxide (other names: silicic anhydride, fine-grained silicon oxide), titanium oxide, and aluminum hydroxide gel; and the like are exemplified.

As the disintegrant, for example, crospovidone, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl starch sodium, croscarmellose sodium, cross-linked insoluble poly Vinylpyrrolidone, hydroxypropyl starch, partially pregelatinized starch, and corn starch are exemplified.

Examples of the binder include hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, ethyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, gelatin, dextrin, starch, and pregelatinized starch.

Examples of the lubricant include calcium stearate, magnesium stearate, sucrose fatty acid ester, light anhydrous silicic acid, sodium stearyl fumarate, polyethylene glycol, talc, and stearic acid.

Examples of medicinal components include bactericidal or antibacterial agents such as cetylpyridinium chloride, benzalkonium chloride, benzethonium chloride, isopropylmethylphenol, zinc gluconate, zinc citrate, triclosan, thymol, hinokitiol, and lysozyme chloride; Enzymes such as dextronase, mutanase, amylase, protease, and retec enzyme; fluorides such as sodium fluoride, sodium monofluorophosphate, and tin fluoride; ε-Aminocaproic acid, allantoin, tranexamic acid, glycyrrhizinate (e.g., glycyrrhizin dipotassium salt), glycyrrhitic acid, stearyl glycyrrhetinate, allantoin chlorohydroxyaluminum, azulene, dihydrocholesterol, etc. of anti-inflammatory; metal salts such as zinc, copper salts and tin salts; dental calculus preventives such as condensed phosphate and ethanehydroxydiphosphonate; blood flow promoters such as vitamin E (eg, tocopherol acetate); Hypersensitivity inhibitors, such as potassium nitrate, aluminum lactate, and strontium chloride; coating agents such as hydroxyethyl cellulose and dimethyldiallylammonium chloride; astringents such as vitamins (eg, vitamin C), lysozyme chloride, and sodium chloride; water-soluble copper compounds such as copper chlorophyll and copper gluconate; plaque preventives such as zeolite, amino acids such as alanine, glycine, and proline; plant extracts such as thyme, gold, cloves, and hamamelis; A calopeptide, polyvinylpyrrolidone, an anti-calculus agent, and an anti-dental anti-dental agent can be exemplified. A medicinal component may be used individually by 1 type, and may be used in combination of 2 or more types. As for the content of active ingredients other than the above, an effective amount can be appropriately set.

Examples of preservatives include phenoxyethanol, para-oxybenzoic acid esters (for example, methyl para-oxybenzoate, ethyl para-oxybenzoate, and butyl para-oxybenzoate), sodium benzoate and the like. Preservatives may be used individually by 1 type, and may be used in combination of 2 or more types.

As surfactant, an anionic surfactant, a nonionic surfactant, an amphoteric surfactant, and a cationic surfactant are illustrated, for example.

As fragrance, for example, peppermint oil, spearmint oil, eucalyptus oil, wintergreen oil, clove oil, thyme oil, sage oil, cardamom oil, rosemary oil, marjoram oil, lemon oil, orange oil, nutmeg oil, lavender natural essential oils such as oil, paracress oil, cinnamon oil, pimento oil, cinnamon oil, perilla oil, and wintergreen oil; Menthol, 1-carvone, cinnamic aldehyde, anethol, 1,8-cineol, methyl salicylate, eugenol, thymol, linalool, limonene, menthone, menthyl acetate, citral, camphor, borneol, pinene , Spirantol, n-decyl alcohol, citronerol, α-terpineol, citroneryl acetate, cineol, ethylinalol, flavor components contained in the natural essential oil, such as vanillin; Ethyl acetate, ethyl butylate, isoamyl acetate, hexanal, hexenal, methyl anthranilate, ethyl methylphenyl glycidate, benzaldehyde, vinyline, ethylvinyline, franeol, N-ethyl-p-methane-3- fragrance components such as carboxamide, menthyl lactate, and ethylene glycol-l-menthyl carbonate; and various combination flavors such as mint, fruit, and herb based flavors obtained by combining several flavor components and natural essential oils. A fragrance|flavor may be used individually by 1 type, and may be used in combination of 2 or more types. The content of the fragrance is usually 0.00001 to 3% by mass with respect to the total amount of the composition.

As the occupant, for example, a cellulose occupant (e.g., sodium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, cationized cellulose), carrageenan, xanthan gum , Guar gum, tragant gum, karaya gum, gum arabic, locust bean gum, sodium alginate, sodium polyacrylate, polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymer (trade name: Carbopol), propylene glycol alginate, etc. organic occupants of; Inorganic occupants such as aluminum silicate and thickening silica are exemplified. The content of the occupant is preferably 0.1 to 10% by mass, more preferably 1.4 to 8% by mass of the total composition.

Examples of the pH adjuster include organic acids such as phthalic acid, citric acid, succinic acid, acetic acid, fumaric acid, malic acid and lactic acid, or salts thereof (eg, sodium citrate), inorganic acids such as phosphoric acid (orthophosphoric acid), or salts thereof (eg, phosphoric acid Hydroxides, such as disodium monohydrogen) and sodium hydroxide, are illustrated. The content of the pH adjuster is usually such that the pH of the composition after addition is 5 to 9, preferably 6 to 8.5. In this specification, a pH value is a value 25 degreeC and 3 minutes after the start of measurement normally, and can be measured using TOA Electronics Ltd. pH meter (model number Hm-30S).

As a humectant, a polyhydric alcohol is preferable, for example, sugar alcohols, such as sorbitol, erythritol, maltitol, lactitol, and xylitol; trimethylglycine; glycerin; Glycols, such as propylene glycol, ethylene glycol, and polyethylene glycol (for example, molecular weight 200-6000); Starch saccharide as a reduction is illustrated. The content of the humectant is usually 5 to 50% by mass, preferably 20 to 45% by mass.

As the sweetener, for example, xylitol, maltitol, saccharin, saccharin sodium, stevioside, aspartame, sucralose, erythritol, stevia extract, paramethoxycinnamic aldehyde, neohesperidindihydrochalcone, perilartin, glycyrrhizin, thomastin , Asparamethylphenylalanine methyl ester is exemplified.

[7. Purpose of offering]

The agent of the present invention can be used as a food composition, medicine, quasi-drug, or cosmetic. As a food composition, for example, beverages (soft drinks, carbonated drinks, nutritional drinks, powder drinks, fruit drinks, milk drinks, jelly drinks, etc.), confectionery (cookies, cakes, gum (chewing gum), candy, soft candy, tablets) , Gummi, Jeonggwa, manju, yokan, purin, jelly, ice cream, sherbet, etc.), processed fishery products (fish cake, oden, hardened fish, etc.), processed livestock products (hamburger, ham, sausage, biener, cheese, butter, yogurt, fresh cream) , cheese, margarine, fermented milk, etc.), soup (powdered soup, liquid soup, etc.), staple food (rice, noodles (dried, raw), bread, cereal, etc.), condiments (mayonnaise, shortening, dressing, sauce, seasoning, soy sauce) Etc.) and the like are exemplified. Among these, sweets are preferred, and gums, candies, soft candies, gummies, and frozen confections are more preferred.

As a food composition, for example, health food, functional food, health food, health supplement (supplement), nutritional supplement, food for specified health use, medical food, food for the sick, infant food, nursing food, food for the elderly, etc. Food compositions having uses of are also exemplified.

As a medicine or quasi-drug, it can be used as a preventive or therapeutic agent for various diseases involving inflammation as an internal or external agent. Examples of the disease include diseases associated with inflammation such as periodontal disease, pneumonia, hepatitis, cancer, autoimmune disease, diabetes, and infectious disease, and periodontal disease is preferred. As a periodontal disease treatment or prevention agent, for example, dentifrices such as cream toothpaste, gel toothpaste, polished toothpaste, liquid toothpaste, mouthwash, mouthwash, gel, ointment, mouth freshener, mouthwash tablets, oral preparations, oral pasta, It can be used as a gum, intraoral spray, intraoral tablet, and sheet for teeth.

As cosmetics, it can be used in formulations such as creams, emulsions, packs, gels, aerosols, and sheets, for example. Specifically, for example, skin cosmetics such as lotion, serum, whitening agent, moisturizer, face mask, lotion, foundation, eye shadow, mascara, eyebrow pencil, eyeliner, cheek powder, lipstick, lip balm; Hair cosmetics such as hair rinse, hair conditioner, hair treatment, hair lotion, hair tonic, hair pack, hair cream, conditioning mousse, hair mousse, hair spray, shampoo, leave on the treatment, hair dye, and hairdressing are exemplified. .

〔8. Manufacturing method of cloth]

The preparation method of the agent is not particularly limited, and may be prepared by any method depending on the dosage form, use, and the like. For example, when using as a dentifrice, after preparing a component soluble in a solvent, a method of mixing an insoluble component other than that and performing degassing (eg, reduced pressure) as needed is exemplified. As another example, for example, a composition is prepared by dispersing and dissolving the active ingredient and ingredients other than those used as necessary in an aqueous solvent (eg, purified water, water such as sterilized water), and dissolving in an appropriate container (eg For example, a method of filling glass or resin) is exemplified. As for the container, for example, a laminate tube is exemplified as a container for mouthwash, and resin such as polyethylene, polypropylene, polyethylene terephthalate, and nylon can be used as the material. In the case of a spray agent, it is good to select a container provided with a spraying means (for example, a trigger type, pump type, or aerosol type container). The obtained cream dentifrice can be accommodated in a container and used as a product. The shape and material of the container are not particularly limited, and a container used for a conventional oral composition may be used.

[9. How to use〕

As for the method of using the agent, for example, a method of administering the agent to the application site is exemplified. In the case of oral preparations, brushing the surface of the teeth by putting an appropriate amount of the agent on a toothbrush and rinsing with water after use (dentifrice), holding an appropriate amount of the agent in the mouth, brushing the teeth, and then spitting it out (mouthwash) good according to In the case of an external preparation (eg oral ointment), the number of administrations per day is not particularly limited, but may be, for example, 1 to 6 times or more.

Example

Hereinafter, the present invention will be described in detail by examples. The following examples are intended to suitably illustrate the present invention, and the present invention is not limited to the following examples.

Experimental Example 1 [Evaluation of phagocytosis of macrophages against bacteria]

Macrophage cultured cells (RAW264.7) were cultured in RPMI1640 medium (10% fetal bovine serum (FBS)), and incubated at 37°C, 5% CO ₂ . RAW264.7 cells were prepared at 50,000 cells/well in a 96-well plate, and ethylhexyl compounds (Table 1) at various concentrations were added thereto to a concentration of 100 µl/well, and incubated for 16 hours. In addition, adjustment to various concentrations of the ethylhexyl compound was performed by diluting with a culture medium (RPMI1640) after preparing a 1000-fold solution with DMSO. Then, E. coli BioParticles (pHrodo ^TM Green E. coli BioParticles ^TM Conjugate for Phagocytosis) labeled with a fluorochrome was adjusted to 1 mg/ml, and after sonication for 5 minutes, 100 μl/well was added to all wells containing cells. were added and incubated at 37°C for 1 hour. After incubation, phagocytic activity was measured with a plate reader (Ex/Em: 509/533 nm). The fluorescence value of the wells to which no cells were added was subtracted as the signal value of each well, and the average fluorescence value of the non-seed ctrl group was set as 1 for comparison (Table 2).

Experimental Example 2 [Evaluation of macrophage phagocytic ability (dead cell removal ability)]

Macrophage cultured cells (RAW264.7) were prepared at 100,000 cells/ml, and labeled using the CellTrace Violet Cell Proliferation Kit (invitrogen) for 20 minutes in the dark. In addition, this pigment can enter cells and label RAW264.7 cells by binding to proteins. After the reaction, centrifugal washing was performed twice in RPMI1640 medium. Prepare labeled RAW264.7 cells at 10,000 cells/well, add ethylhexyl compounds (Table 1) at various concentrations in the same manner as in Experimental Example 1 to 100 μl/well, and incubate for 16 hours did.

Jurkat cells (human lymphocytes) cultured in RPMI1640 medium in the same way as RAW264.7 cells were adjusted to 100,000 cells/ml and treated with 10 µM camptothecin for 16 hours to induce apoptosis. Apoptosis-induced Jurkat cells were washed with PBS, adjusted to 1000,000 cells/ml, and labeled with IncuCyte pHrodo Red cell Labeling Dye (sartorius) for 1 hour in the dark. In addition, this pigment can label Jurkat cells by binding to the cell membrane.

After the reaction, it was centrifuged twice in RPMI medium, and adjusted to 500,000 cells/ml in fresh RPMI 1640 medium. 100 μl of each was added to wells containing seeded RAW264.7 cells prepared above, and incubated for 3 hours with the apoptotic Jurkat cells. After the action, each well was washed three times with sterile PBS in order to remove non-phagocytic Jurkat cells. Thereafter, in order to peel off the adhered macrophage cells, 0.1 ml of Trypsin treatment solution (PBS-0.5mM EDTA+0.05% Trypsin) was added and peeled off. To stop the action of Trypsin, 0.1 ml of fresh RPMI1640 medium was added. Thereafter, after washing once with PBS, 0.25 ml of PBS was added to suspend and analyzed using flow cytometry (Table 3).

In the group to which the ethylhexyl compound was added, both the phagocytic ability of macrophages and the phagocytic ability of dead cells were highly evaluated compared to the ctrl group (Tables 2 and 3).

Experimental Example 3 [Evaluation of periodontitis improvement effect]

3-1. Evaluation by Composition for Oral Use (Dental) (Samples 1 to 6 and Comparative Sample 1)

The following <periodontitis evaluation> was performed for adult males, and subjects (27 to 51 years old, total of 35 patients, including periodontal patients and healthy patients) with a periodontitis score of 0.5 or more and less than 1.5 were selected as subjects. The subjects were divided into 7 groups so that the average values of gingivitis scores were almost the same (5 people in each group). Subjects were brushed with about 1.0 g of the test composition described in Table 4 twice a day for about 3 minutes, and then gargled with water once. After 4 weeks of use, gingivitis was evaluated again, and the anti-inflammatory effect of the test composition was determined according to the following evaluation criteria (Table 4).

[Preparation method of dentifrice composition]

The raw materials shown in Table 4 were blended by the usual method, mixed at room temperature using a 1.5 L kneader (manufactured by ISHIYAMA CO., LTD.), degassed under reduced pressure (4 kPa pressure), and a test composition was obtained.

<Evaluation of gingivitis>

For representative teeth 6 teeth (maxilla 2 and 6 on the left and right, and mandible 4), 4 parts of mesial and distal, and mesial and distal on the lingual side of each tooth, and mesial and distal on the buccal side, that is, the total number of parts is 24 ( 6 teeth × 4 sites), gingivitis was evaluated according to the following evaluation criteria, and the average value of the ratings of 24 sites was obtained. Moreover, the degree of gingivitis improvement was calculated|required from the said average value by the following formula.

<Evaluation criteria for gingivitis>

0 point: No inflammation was confirmed.

1 point: Mild inflammation. There is a slight color change, but no bleeding is confirmed by probing.

Score 2: Moderate inflammation. There is redness, swelling, swelling, and bleeding is confirmed by probing.

Score 3: severe inflammation. Significant redness and spontaneous bleeding were observed.

<Calculation formula of gingivitis improvement>

(Gingivitis improvement degree) = (A-B) / (number of subjects in each group)

A and B in the table represent the following.

A = (the sum of the average values of the periodontitis scores of 24 sites before the test for each subject)

B = (the sum of the average values of the periodontitis scores of 24 sites after the test for each subject)

The degree of gingival improvement can be judged to have a gingivitis inhibitory effect as the numerical value increases, preferably 0.2 points or more, 0.25 points or more, or 0.3 points or more, more preferably 0.4 points or more, still more preferably 0.5 points or more. am.

From Table 4, it can be seen that samples 1 to 6 showed a gingivitis inhibitory effect compared to comparative sample 1. Specifically, 2-ethylhexyl palmitate (Sample 2) and 2-ethylhexyl stearate (Sample 3) showed a high gingivitis inhibitory effect.

3-2. Evaluation by oral ointment (samples 7 to 9 and comparative sample 2)

Adult males (27 to 51 years old, a total of 20 people, including patients with periodontal disease and healthy patients) were subjected to the above <evaluation of gingivitis>, and subjects with a gingivitis score of 0.5 or more and less than 1.5 were selected as subjects. . The subjects were divided into 4 groups so that the average values of the gingivitis scores were almost the same (5 people in each group). Subjects took about 0.3 g of the test composition listed in Table 5 with their fingers and applied it to their gums twice a day. After 3 weeks, gingivitis was evaluated again, and the anti-inflammatory effect of the test composition was determined according to the following evaluation criteria. About the evaluation method and criterion, it carried out similarly to item 3-1.

[Preparation method of ointment]

An oral ointment having the composition shown in Table 5 was prepared by a conventional method.

From Table 5, it can be seen that Samples 7 to 9 showed a gingivitis inhibitory effect compared to Comparative Sample 2. Among them, 2-ethylhexyl palmitate (Sample 8) and 2-ethylhexyl stearate (Sample 9) were highly effective in inhibiting gingivitis.

These results indicate that the ethylhexyl compound can exert a favorable anti-inflammatory effect in the present invention.

Below, typical formulation examples of the present invention are shown. % in composition is mass %.

Prescription Example 1: Chemotherapy

Salicylate 2ethylhexyl 0.01%

Sodium Fluoride 0.32%

Xanthan Gum 0.8%

Sorbit liquid (70%) 40%

12% Silicic Anhydride

Saccharin Sodium 0.2%

thickened silica 6%

Titanium oxide 0.5%

Propylene glycol 3%

Citric acid 0.1%

Sodium Hydroxide 0.1%

Sodium Lauryl Sulfate 1.5%

Flavor 0.8%

Remaining amount of purified water

Total 100%

Formulation Example 2: mouthwash

2-Ethylhexyl Salicylate 0.01%

Xanthan Gum 0.1%

Propylene glycol 3%

Glycerin (85%) 6%

Ethanol 2%

Citric acid 0.015%

Sodium Citrate 0.12%

Disodium monohydrogen phosphate 0.1%

Flavor 0.2%

Remaining amount of purified water

Total 100%

Prescription Example 3: Mouthwash

Salicylate 2ethylhexyl 0.01%

Agroglycerin 10%

Propylene glycol 2%

Ethanol 15%

Cetylpyridinium Chloride 0.05%

Citric acid 0.05%

Sodium Citrate 3.95%

Spices 0.10%

Remaining amount of purified water

Total 100%

Prescription Example 4: Chewing Gum

Sugar 50.0%

Gum Base 20.0%

Glucose 14.0%

Starch Syrup 15.0%

Spices 0.5%

Salicylate 2ethylhexyl 0.01%

remaining water

Total 100%

Formulation Example 5: Tablets

Salicylate 2ethylhexyl 125mg

Propylene Glycol 5mg

Light Anhydrous Silicic Acid 30mg

Crospovidone 5mg

D-Mannitol 150mg

l-Menthol 5mg

Corn Starch 5mg

Crystalline Cellulose 60mg

Prescription Example 6: Oral solution

Salicylate 2ethylhexyl 125mg

Propylene Glycol 5mg

Polysorbate 80 30mg

l-Menthol 5mg

Citric acid 3mg

Purified water 100mg

50 mg per bag

Formulation Example 7: Cream

Salicylate 2ethylhexyl 0.01%

Polyoxyethylene Hydrogenated Castor Oil (10E.O.) 10.0 %

Oleyl Alcohol 2.0%

Macrogol (Polyethylene glycol) 20000 2.0 %

Ceresin 1.0%

Squalane 10.0%

Remaining amount of purified water

Total 100%

Prescription Example 8: Ointment

Salicylate 2ethylhexyl 0.01%

Maltotetraose 1.0%

Glycerin Monostearate 7.2%

Sorbitan Monostearate 3.2%

Setanol 7.3%

3.5% White Vaseline

Polyoxyethylene (60) hydrogenated castor oil 4.0 %

Propylene glycol 6.5%

Liquid Paraffin 9.0%

Remaining amount of purified water

Total 100%

Formulation Example 9: Lotion

Salicylate 2ethylhexyl 0.01%

Trimethylglycine 3.0%

Glycerin 3.0%

Hydroxypropylmethyl Cellulose 0.1 %

Phenoxyethanol 0.3%

Remaining amount of purified water

Total 100%

Claims (5)

The following general formula (1):

(In the formula, R ¹ represents an organic group, and n1 represents a number greater than or equal to 1.)
An anti-inflammatory agent comprising at least one 2-ethylhexyl compound represented by According to claim 1,
R ¹ in Formula (1) is
Formula (2):

(In the formula, R ² represents a dialkylamino group, an alkyloxy group or a hydroxyl group. n2 is an integer of 1 to 6.)
An aryl group which may have a substituent represented by , or
An anti-inflammatory agent that is an alkyl group which may have a substituent. According to claim 2,
An anti-inflammatory agent wherein the alkyl group is an alkyl group having a hydroxyl group or a sulfo group, or an alkyl group having no substituent. The following general formula (1):

(In the formula, R ¹ represents an organic group, and n1 represents a number greater than or equal to 1.)
A macrophage function activator containing at least one 2-ethylhexyl compound represented by The following general formula (1):

(In the formula, R ¹ represents an organic group, and n1 represents a number greater than or equal to 1.)
A preventive or therapeutic agent for periodontal disease comprising at least one ethylhexyl compound represented by