JP7159265B2 - Anti-periodontal disease composition - Google Patents

Description

The present invention relates to anti-periodontal disease compositions.

Interleukin 12 (IL-12) induces differentiation of Th1 cells, which is one of immune cells (for example, Non-Patent Document 1), and acts as a major factor in IFN-γ production of NK cells and NKT cells ( For example, Non-Patent Document 2) is known. It is also known that stimulation of dendritic cells with lipopolysaccharide (LPS) promotes IFN-γ production in NK cells and activates the immune system (eg, Non-Patent Document 3). On the other hand, IFN-γ is also known to activate NK cells and exhibit cytotoxicity. Based on these facts, it is considered that excessive activation of NK cells in patients with periodontal disease (especially chronic periodontal disease) leads to cell destruction when immune function is not functioning normally. Therefore, in patients with periodontal disease (especially chronic periodontal disease), suppression of IL-12 production (especially IL-12 production in the oral cavity) and suppression of overactivation of NK cells are effective in periodontal disease ( In particular, it is important for improving the symptoms of chronic periodontal disease. The above contents are illustrated in FIG.

Int J Mol Sci. 2010 Feb 26;11(3):789-806. Clin Diagn Lab Immunol. 2002 May;9(3):530-43. Infect Immun. 2004 Sep;72(9):5089-96.

An object of the present invention is to provide means for suppressing IL-12 production.

The present inventors have found that a combination of specific anti-inflammatory agents can provide an excellent IL-12 production inhibitory effect, and have made further improvements to complete the present invention.

The invention includes, for example, the subject matter described in the following sections.
Section 1.
An anti-periodontal disease composition comprising at least one selected from the group consisting of tranexamic acid and β-glycyrrhetinic acid (preferably tranexamic acid or β-glycyrrhetinic acid) and monoammonium glycyrrhizinate.
Section 2.
An IL-12 production inhibitory composition comprising at least one selected from the group consisting of tranexamic acid and β-glycyrrhetinic acid (preferably tranexamic acid or β-glycyrrhetinic acid) and monoammonium glycyrrhizinate.
Item 3.
Item 3. The composition according to Item 1 or 2, which is an oral composition.
Section 4.
An IL-12 production inhibitory effect enhancer of monoammonium glycyrrhizinate or dipotassium glycyrrhizinate, comprising β-glycyrrhetinic acid.
Item 5.
An anti-periodontal effect enhancer of monoammonium glycyrrhizinate or dipotassium glycyrrhizinate, comprising β-glycyrrhetinic acid.

INDUSTRIAL APPLICABILITY The composition according to the present invention is useful for improving symptoms of periodontal disease (especially chronic periodontal disease) because it exhibits an excellent IL-12 production inhibitory effect.

Fig. 2 shows the results of an investigation to determine whether an IL-12 production inhibitory effect can be obtained by combining tranexamic acid with other anti-inflammatory ingredients. In a, the results of GMA and TXA alone or in combination, in b, the results of ALA and TXA alone or in combination, in c, the results of GK2 and TXA alone or in combination, and in d. indicates the results of single or combined addition of β-GR and TXA, respectively. Fig. 2 shows the results of an investigation to determine whether a combination of β-glycyrrhetinic acid and other anti-inflammatory components has an IL-12 production inhibitory effect. In a, the results of the single or combined addition of GMA and β-GR, in b, the results of the single or combined addition of GK2 and β-GR, and in c, the single or combined addition of TXA and β-GR are shown, respectively. Schematic representation of the function of IL-12.

Each embodiment of the present invention will be described in further detail below.

The anti-periodontal disease composition included in the present invention contains at least one selected from the group consisting of tranexamic acid and β-glycyrrhetinic acid, and monoammonium glycyrrhizinate. That is, the anti-periodontal disease composition comprises at least (i) tranexamic acid and monoammonium glycyrrhizinate, or at least (ii) β-glycyrrhetinic acid and monoammonium glycyrrhizinate.

Each component contained in these anti-periodontal disease compositions (tranexamic acid, β-glycyrrhetinic acid, and monoammonium glycyrrhizinate) is a component known as an anti-inflammatory agent, and is also used for anti-inflammatory purposes in the oral cavity composition field. It has been conventionally used in

In the above combination (i), the content ratio of tranexamic acid and monoammonium glycyrrhizinate contained in the anti-periodontal disease composition is not particularly limited. About 0.06 to 50 is preferable, about 10:0.1 to 30 is more preferable, about 10:0.15 to 20 is even more preferable, and about 10:0.3 to 10 is even more preferable. It can also be 10:0.3-5, 10:0.3-2, or 10:0.3-1.

In the above combination (ii), the content ratio of β-glycyrrhetinic acid and monoammonium glycyrrhizinate contained in the anti-periodontal disease composition is not particularly limited. is preferably about 1:0.001 to 150, more preferably about 1:0.003 to 90, even more preferably about 1:0.005 to 60, and even more preferably about 1:0.01 to 50. It can also be 1:0.05-50, 1:10-50, or 1:20-50.

The content of each component contained in the anti-periodontal disease composition is not particularly limited and can be set as appropriate. For example, the total amount of the components contained in the above three components is preferably about 0.0001 to 50% by weight, more preferably about 0.001 to 5% by weight.

The anti-periodontal disease composition of the present invention can be used as an oral composition. Moreover, for example, it can be used as a pharmaceutical product and a quasi-drug. These can be manufactured according to a conventional method. In addition, the form of the anti-periodontal disease composition of the present invention is not particularly limited. It can be in the form (dosage form) of an agent, toothpaste, gum, tablet, troche, drop, film, and the like. Among them, mouthwashes, liquid dentifrices, toothpastes, ointments, pastes, liquids, sprays and gels are preferred, and oral compositions are more preferred.

The anti-periodontal disease composition according to the present invention can suppress IL-12 production. Therefore, the anti-periodontal disease composition according to the present invention can also be called an IL-12 production-suppressing composition, and the present invention also includes the IL-12 production-suppressing composition.

In addition, the anti-periodontal disease composition according to the present invention suppresses IL-12 production (especially IL-12 production in the oral cavity) and suppresses overactivation of NK cells, thereby suppressing periodontal disease (especially chronic Periodontal disease) can be effective in improving symptoms. Therefore, it can also be called a periodontal disease improving composition. In particular, it can be used to relieve or improve various symptoms in the oral cavity caused by periodontal disease. The various symptoms include, for example, gingival redness, swelling, swelling, pain, itching, recession, bleeding from the gingiva, deepening of periodontal pockets or stickiness in the mouth, and halitosis.

The anti-periodontal disease composition according to the present invention may further contain a known pharmaceutically acceptable component or a known food hygienically acceptable component within a range that does not impair the effects of the present invention. In particular, it may further preferably contain known known components that can be blended in oral compositions. Examples of such components include surfactants, abrasives, binders, flavoring agents, sweeteners, wetting agents, conditioning agents, preservatives, preservatives, coloring agents, pH adjusters, and the like. It is not particularly limited. The known components will be described below, but the description is only an example and the invention is not limited thereto.

For example, as surfactants, nonionic surfactants, anionic surfactants or amphoteric surfactants can be blended. Specific examples of anionic surfactants include alkyl sulfates, polyoxyethylene alkyl ether sulfates, alkyl phosphates, polyoxyalkyl ether phosphates, fatty acid soaps, and polyoxyethylene alkyl ether carboxylic acids. salt, polyoxyethylene alkyl ether sulfate, α-olefin sulfonate, alkyl sulfosuccinate, polyoxyalkyl ether sulfosuccinate, acyl amino acid salt, glycerin fatty acid ester sulfate, alkyl ether phosphate, alkyl glutamate, etc. is mentioned. Cationic surfactants include monoalkyltrimethylammonium salts, dialkyldimethylammonium salts, alkylamine salts and the like. Examples of nonionic surfactants include sugar fatty acid esters, fatty acid alkanolamides, sorbitan fatty acid esters, glycerin fatty acid esters, polyglycerin fatty acid esters, polyoxyethylene glycerin fatty acid esters, polyoxyethylene alkyl ethers, polyoxyethylene polypropylene alkyl ethers, polyoxyethylene Ethylene alkylphenyl ethers, polyoxyethylene hydrogenated castor oil, alkyl glucosides, polyoxyethylene polyoxypropylene block copolymers, lecithin, and the like. Amphoteric surfactants include betaine alkyldimethylaminoacetate, betaine fatty acid amidopropyldimethylaminoacetate, 2-alkyl-N-carboxymethyl-N-hydroxyethylimidazolinium betaine, alkylsulfobetaine, alkylbetaine and the like. These surfactants can be used alone or in combination of two or more.

Abrasives include abrasive silica, calcium hydrogen phosphate, calcium phosphate, tricalcium phosphate, trimagnesium phosphate, calcium pyrophosphate, hydroxyapatite, insoluble sodium metaphosphate, aluminum silicate, zirconium silicate, calcium silicate, and carbonate. Calcium, magnesium carbonate, magnesium oxide, alumina, aluminum hydroxide, calcium sulfate, polymethyl methacrylate, pumice, bentonite, synthetic resins, and the like. These abrasives can be used alone or in combination of two or more.

Binders include sodium carboxymethyl cellulose, carboxymethyl ethyl cellulose salt, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, crystalline cellulose, cellulose derivatives such as crystalline cellulose and carmellose sodium, and microbial productivity such as xanthan gum. Natural polymers or natural gums such as molecules, tragacanth gum, karaya gum, gum arabic, carrageenan, dextrin, agar, pectin, pullulan, gellan gum, locust bean gum, sodium alginate, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, polyvinyl methyl ether, Synthetic polymers such as sodium polyacrylate, thickening silica, inorganic binders such as Veegum, and cationic binders such as O-[2-hydroxy-3-(trimethylammonio)propyl]hydroxyethylcellulose chloride. be done. These caking agents can be used individually or in combination of 2 or more types.

Flavoring agents include menthol, carvone, methyl salicylate, vanillin, benzylsuccinate, methyl eugenol, anethole, limonene, ocimene, n-decyl alcohol, methyl acetate, citronenyl acetate, cineole, ethyl linalool, vanillin, thyme, Nutmeg, cinnamic aldehyde, benzaldehyde, thymol, spearmint oil, peppermint oil, lemon oil, orange oil, sage oil, rosemary oil, cinnamon oil, perilla oil, wintergreen oil, clove oil, eucalyptus oil, pimento oil, tea Tree oil, tabana oil, star anise oil, fennel oil, diatom oil, basil oil, and the like. These fragrances can be used alone or in combination of two or more.

Sweeteners include saccharin, saccharin sodium, acesulfame potassium, stevia extract, stevioside, neohesperidyl dihydrochalcone, glycyrrhizin, perillartine, soumatin, aspartylphenylalanine methyl ester, methoxycinnamic aldehyde, palatinose, palatinit, erythritol, maltitol. , xylitol, lactitol and the like. These sweeteners can be used alone or in combination of two or more.

Wetting agents/hydrotropic agents include ethanol, propylene glycol, dipropylene glycol, 1,3-butylene glycol, isoprene glycol, glycerin, diglycerin, sorbitol, polyethylene glycol, tornare, trehalose, hyaluronic acid and the like. These can be used alone or in combination of two or more.

Conditioning agents include silicone derivatives, cation-modified water-soluble polymers, fatty acid esters, trimethylglycine, protein hydrolysates, amino acids and their derivatives, urea, phospholipids, glycolipids, ceramides and the like. These can be used alone or in combination of two or more.

As an antiseptic/preservative, parabens such as methylparaben, ethylparaben, propylparaben and butylparaben, sodium benzoate, phenoxyethanol, alkyldiaminoethylglycine hydrochloride, and the like can be blended.

As a coloring agent, legal dyes such as Blue No. 1, Yellow No. 4, Red No. 202 and Green No. 3, mineral dyes such as ultramarine blue, enhanced ultramarine blue and Prussian blue, titanium oxide, and the like may be blended.

As a pH adjuster, citric acid, phosphoric acid, malic acid, pyrophosphoric acid, lactic acid, tartaric acid, glycerophosphoric acid, acetic acid, nitric acid, or chemically possible salts thereof, sodium hydroxide, or the like may be added. These may be blended singly or in combination of two or more so that the pH of the composition is in the range of 4-8, preferably 5-7. The usual blending amount of the pH adjuster is 0.01 to 2% by weight.

Other ingredients include animal and vegetable oils, powders, ultraviolet absorbers, and animal and plant extracts.

The anti-periodontal disease composition according to the present invention may further contain active ingredients such as benzethonium chloride, benzalkonium chloride, chlorhexidine gluconate, and hydrochloric acid as bactericidal agents, as long as the effects of the present invention are not impaired. cationic fungicides such as chlorhexidine and cetylpyridinium chloride; amphoteric fungicides such as dodecyldiaminoethylglycine; halogenated diphenyl ethers such as triclosan (2',4,4'-trichloro-2-hydroxy-diphenyl ether) and isopropylmethylphenol; Hinokitiol; Vitamin E such as dl-α-tocopherol acetate, tocopherol succinate, and tocopherol nicotinate as a blood circulation promoter; dextranase, amylase, protease, mutanase, lysozyme, lytic enzyme (retech enzyme) Enzymes such as; anti-inflammatory agents such as epsilon aminocaproic acid; bleeding improving agents such as ascorbic acid; tissue repair agents such as allantoin;
Examples of remineralizing agents include fluorine compounds such as sodium fluoride; and plant extracts extracted with a water-soluble solvent, chlorophyll, sodium chloride, zinc chloride, potassium nitrate, and the like. These medicinal ingredients can be used alone or in combination of two or more.

When the anti-periodontal disease composition according to the present invention contains tranexamic acid, it is more preferable that the anti-periodontal disease composition does not contain β-glycyrrhetinic acid. This is because β-glycyrrhetinic acid may inhibit the IL-12 production inhibitory effect of tranexamic acid.

As a base, water, alcohols, silicon, apatite, white petrolatum, paraffin, liquid paraffin, microcrystalline wax, squalane, and the like can be used.

The present invention also includes an IL-12 production inhibitory effect enhancer or an anti-periodontal disease enhancer of monoammonium glycyrrhizinate or dipotassium glycyrrhizate containing β-glycyrrhetinic acid. Although β-glycyrrhetinic acid alone does not exhibit an IL-12 production inhibitory effect, when combined with monoammonium glycyrrhizinate or dipotassium glycyrrhizinate, it exerts an effect of significantly enhancing these IL-12 production inhibitory effects. The agent can also contain the known components described in the anti-periodontal disease composition, and can be produced according to a conventional method. Also, the content of β-glycyrrhetinic acid in the agent is not particularly limited, and may be, for example, about 0.1 to 100% by weight, or about 50 to 95%.

In this specification, the term "comprising" includes "consisting essentially of" and "consisting of."

The present invention will be specifically described below, but the present invention is not limited to the following examples.

Investigation of suppression of IL-12 production in human gingival fibroblasts The effect of suppressing IL-12 production when using known anti-inflammatory agents in combination was studied.

Human gingival fibroblast HGF-1 ((Gingival Fibroblast; Human (Homo sapiens)) ATCC Item No. CRL-2014) was subcultured. Specifically, 200 μL of each was seeded in a 96-well adherent cell plate at 0.5×10 ⁴ cells/well and cultured (37° C., 5% CO ₂ , 24 hours). Then, the culture medium of the cultured cells was removed by decanting, and 200 μL of each anti-inflammatory component solution or each anti-inflammatory component combination solution was added at an appropriate concentration, followed by culturing (37° C., 5% CO ₂ , 2 hours). Table 1 shows the final concentrations of the anti-inflammatory components added alone. Also, when anti-inflammatory components were added in combination, each anti-inflammatory component combination solution was prepared so that the final concentration of each anti-inflammatory component was the same as the concentration shown in Table 1. For example, when monoammonium glycyrrhizinate (GMA) or β-glycyrrhetinic acid (β-GR) is added alone, the final concentrations are 0.5 mM and 0.01 mM, respectively. -glycyrrhetinic acid (β-GR) is also added in combination with final concentrations of 0.5 mM and 0.01 mM, respectively.

Table 1 also shows the abbreviations of the anti-inflammatory agents. Each anti-inflammatory component may be described using the abbreviation.

Thereafter, LPS of Aggregatebacter actinomycetemcomitans (A.a.) was further added to a final concentration of 1 mg/mL and cultured (37°C, 5% CO ₂ , 24 hours), and the supernatant was Recovered. Aggregatebacter actinomycetemcomitans (A.a.) is known as one of the causative bacteria of periodontal disease, and particularly causes invasive periodontitis. Using Bio-Plex (Bio-rad), the amount of IL-12 contained in the supernatant was measured. Using LPS alone (no anti-inflammatory component added) as a control, the inhibition rate of IL-12 production was calculated by the following formula.
Suppression rate =
{1-(IL-12 production amount when anti-inflammatory component is added/IL-12 production amount when only LPS is added)}×100

<Study on combination of tranexamic acid (TXA) and other anti-inflammatory ingredients>
Tranexamic acid has anti-inflammatory and anti-allergic effects and is known as a very safe ingredient, and is often used in oral compositions and cosmetics. It was examined whether an IL-12 production inhibitory effect could be obtained by combining with an inflammatory component.

The results are shown in FIG. The vertical axis of the figure indicates the IL-12 production suppression rate (%). Figure 1a shows the results of GMA and TXA alone or in combination, Figure 1b shows the results of ALA and TXA alone or in combination, and Figure 1c shows the results of GK2 and TXA alone or in combination. , and FIG. 1d shows the results of the addition of β-GR and TXA alone or in combination, respectively. These figures show four bar graphs, the left end is the addition of anti-inflammatory ingredients other than tranexamic acid alone, the second from the left is the addition of tranexamic acid alone, and the third from the left is other anti-inflammatory ingredients other than tranexamic acid. It shows the IL-12 production suppression rate of the combined addition of the anti-inflammatory ingredient and tranexamic acid. The bar graph on the far right shows the value obtained by simply adding the IL-12 production suppression rate when other anti-inflammatory ingredients other than tranexamic acid are added alone and the IL-12 production suppression rate when tranexamic acid is added alone. . Therefore, when the third bar graph from the left is higher than the rightmost bar graph, it indicates that more than just an additive effect was obtained.

As shown in FIG. 1b, even if ALA and TXA were combined, no IL-12 production inhibitory effect was obtained. As shown in FIG. 1c, even when GK2 and TXA were combined, only the same level of IL-12 production inhibitory effect as that exhibited by each alone was obtained. As shown in FIG. 1d, the combination of β-GR and TXA abolished the IL-12 production inhibitory effect exhibited by TXA alone. On the other hand, as shown in FIG. 1a, when GMA and TXA are combined, the IL-12 production inhibitory effect far surpasses the combined effect of the IL-12 production inhibitory effects exhibited by each alone. It was found that an effect (almost double the addition effect) can be obtained.

<Study on combination of β-glycyrrhetinic acid (β-GR) with other anti-inflammatory ingredients>
β-Glycyrrhetinic acid (β-GR) is a naturally derived ingredient obtained by hydrolysis of glycyrrhizic acid obtained from licorice, and is known to have excellent anti-inflammatory action, and is widely used in oral compositions and cosmetics. Therefore, we investigated whether β-glycyrrhetinic acid and other anti-inflammatory components could be combined to inhibit the production of IL-12.

The results are shown in FIG. The vertical axis of the figure indicates the IL-12 production suppression rate (%). Figure 2a shows the results of the addition of GMA and β-GR alone or in combination, Figure 2b shows the results of the addition of GK2 and β-GR alone or in combination, and Figure 2c shows the results of TXA and β-GR alone. Or the results of combined addition are shown, respectively. Figures 2a and 2b show four bar graphs, the left end is the addition of anti-inflammatory ingredients other than β-glycyrrhetinic acid alone, the second from the left is the addition of β-glycyrrhetinic acid alone, and the third from the left is β. - IL-12 production suppression rate of the combined addition of other anti-inflammatory components other than glycyrrhetinic acid and β-glycyrrhetinic acid. The bar graph on the right is the value obtained by simply adding the IL-12 production suppression rate when other anti-inflammatory ingredients other than β-glycyrrhetinic acid are added alone and the IL-12 production suppression rate when β-glycyrrhetinic acid is added alone. is shown. Therefore, when the third bar graph from the left is higher than the rightmost bar graph, it indicates that more than just an additive effect was obtained. Note that FIG. 2c is the same as FIG. 1d.

As shown in Figures 2a to 2c, β-glycyrrhetinic acid alone does not have any inhibitory effect on IL-12 production. The production inhibitory effect disappeared (Fig. 2c), whereas the combination of GMA and β-GR or GK2 and β-GR surpassed the effect of GMA alone or GK2 alone. An IL-12 production inhibitory effect was obtained. From this, β-
It was found that GR alone does not exhibit an IL-12 production inhibitory effect, but when combined with GMA or GK2, it has the effect of significantly enhancing these IL-12 production inhibitory effects. In other words, β-GR was found to work as an IL-12 production inhibitory effect enhancer of GMA or GK2. The potentiating effect was found to be higher when combined with GMA, enhancing the effect of GMA alone by more than 2.5 times.

Claims (3)

An anti-periodontal disease composition containing β-glycyrrhetinic acid and monoammonium glycyrrhizinate at a molar ratio of 1:0.001 to 150 and exhibiting an anti -periodontal disease effect . An IL-12 production inhibitory composition having an IL-12 production inhibitory effect , comprising β-glycyrrhetinic acid and monoammonium glycyrrhizinate at a molar ratio of 1:0.001 to 150 . 3. The composition according to claim 1 or 2, which is an oral composition.

Images