Composition containing β-glycyrrhetinic acid and zinc gluconate

Abstract

To provide a composition that inhibits neutrophil collagenase activity.SOLUTION: An oral composition contains β-glycyrrhetinic acid and zinc gluconate. A content of the zinc gluconate is 0.06-7.5 pts.mass relative to 1 pt.mass of the β-glycyrrhetinic acid in the oral composition.SELECTED DRAWING: None

Description

Technical Field

[0006] , , , , , , , ,

[0001] The present disclosure relates to a composition containing beta-glycyrrhetinic acid and zinc gluconate, and its uses and the like.

Background Art

[0002] Matrix metalloproteinase (MMP) is a general term for extracellular matrix degrading enzymes that possess zinc (II) ions at the active site. Its main substrates are biopolymers such as collagen, laminin, gelatin, and fibronectin.

[0003] MMP is considered to play a role in maintaining homeostasis by decomposing unnecessary extracellular matrix and controlling angiogenesis and the construction of new tissues during tissue remodeling and wound healing processes in the living body. However, if the activity of MMP is overly enhanced, tissue destruction progresses, and it is said to be involved in periodontal disease, rheumatoid arthritis, tumor invasion and metastasis phenomena, etc. Therefore, searches for components that can control its activity are being conducted.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Non-Patent Documents

[0007] The object of this disclosure is to provide a composition that inhibits neutrophil collagenase activity. Another objective is to provide a composition that prevents the progression of periodontal disease. [Means for solving the problem]

[0008] The inventors discovered that using β-glycyrrhetinic acid and zinc gluconate in a specific ratio exhibits excellent inhibitory activity against neutrophil collagenase, and have further refined this method.

[0009] This disclosure includes, for example, the following subjects: Section 1. It contains β-glycyrrhetinic acid and zinc gluconate, An oral composition comprising 0.06 to 7.5 parts by mass of zinc gluconate per 1 part by mass of β-glycyrrhetinic acid. Section 2. The composition described in item 1 for preventing the progression of periodontal disease. Section 3. The composition according to claim 1 or 2, for use in at least one application selected from the group consisting of inhibiting periodontal tissue destruction, inhibiting gum recession, inhibiting gingival recession, inhibiting periodontal pocket formation, inhibiting periodontal pocket deepening, inhibiting attachment loss, inhibiting gingival collagen degradation, and inhibiting neutrophil collagenase activity. Section 4. The composition according to any one of items 1 to 3, wherein the content of β-glycyrrhetinic acid in the composition is 0.01% by mass or more. Item 5. The composition according to any one of items 1 to 4, wherein the content of zinc gluconate in the composition is 0.005% by mass or more.

Advantages of the Invention

[0010] It can inhibit neutrophil collagenase activity. Further, an effective composition for preventing the progression of periodontal disease can be provided.

Brief Description of the Drawings

[0011] [Figure 1] It shows the measurement results of neutrophil collagenase activity when β-glycyrrhetinic acid and zinc gluconate are added.

Modes for Carrying Out the Invention

[0012] Hereinafter, each embodiment included in the present disclosure will be described in more detail. The composition included in the present disclosure contains β-glycyrrhetinic acid and zinc gluconate. In this specification, the composition may be referred to as "the composition of the present disclosure".

[0013] β-Glycyrrhetinic acid is a compound represented by the following formula:

[0014]

Chemical formula

[0015] The β-glycyrrhetinic acid used in the composition of the present disclosure may be a synthetic product, or may be a product obtained by hydrolyzing glycyrrhizic acid extracted from natural products (such as licorice).

[0016] The content of β-glycyrrhetinic acid in the composition of the present disclosure is not particularly limited as long as the effect is achieved. For example, in the composition of the present disclosure, the content of β-glycyrrhetinic acid can be 0.01% by mass or more. The upper limit or lower limit of this range may be, for example, 0.015, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, or 0.5% by mass. For example, it may be 0.01 to 0.5% by mass, or 0.02 to 0.2% by mass.

[0017] The content of zinc gluconate in the composition of the present disclosure is not particularly limited as long as the effect is achieved. For example, in the composition of the present disclosure, the content of zinc gluconate can be 0.005% by mass or more. The upper limit or lower limit of this range may be, for example, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, or 0.5% by mass. For example, it may be 0.005 to 0.5% by mass, or 0.01 to 0.3% by mass.

[0018] The content of zinc gluconate relative to 1 part by mass of β-glycyrrhetinic acid in the composition of the present disclosure is preferably 0.06 to 7.5 parts by mass. The upper limit or lower limit of this range may be, for example, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, or 7 parts by mass. For example, it may be 0.1 to 7 parts by mass, or 0.5 to 5 parts by mass.

[0019] Neutrophil collagenase (EC 3.4.24.34) is a collagenase produced by neutrophils and is also referred to as MMP-8.

[0020] Inhibition of neutrophil collagenase activity means inhibiting the degradation of substrates (such as collagen such as type I collagen, type II collagen, type III collagen, etc.) by neutrophil collagenase.

[0021] The compositions of this disclosure inhibit the degradation of substrates by neutrophil collagenase, thereby suppressing the destruction of tissues (e.g., attached epithelium, gingival sulcus epithelium, periodontal ligament, etc.) and the degradation of gingival collagen (collagen fibers that make up the gums) by neutrophil collagenase. Furthermore, since the compositions of this disclosure have neutrophil collagenase activity inhibitory effects, they can inhibit the activity of neutrophil collagenase that has already been produced.

[0022] For this reason, the compositions of the present disclosure are suitable as oral compositions. More specifically, the compositions of the present disclosure can be used, for example, to prevent the progression of periodontal disease, such as inhibiting the progression of periodontal disease, inhibiting neutrophil collagenase activity, inhibiting gingival recession, inhibiting periodontal pocket formation, inhibiting periodontal pocket deepening, inhibiting periodontal tissue destruction, inhibiting gum recession, inhibiting gingival collagen degradation, inhibiting attachment loss, protecting periodontal tissue collagen, and / or inhibiting the destruction of periodontal tissue associated with chronic inflammation, and / or to protect dentin collagen, etc. In this specification, "inhibition of periodontal pocket formation" means inhibiting the formation of periodontal pockets (grooves between the tooth and the gums (gingiva)). In this specification, "inhibition of periodontal pocket deepening" means inhibiting the deepening of periodontal pockets (grooves between the tooth and the gums (gingiva)). In this specification, "inhibition of attachment loss" means inhibiting the separation of the gingival epithelium from the tooth surface and the shift of the attachment position between the gingiva and the tooth toward the tooth root. In this specification, "inhibition of gingival recession" means inhibiting the movement of the entire gingiva toward the tooth root. In this specification, "inhibition of gum recession" means inhibiting the exposure of the tooth root due to the movement of the entire gingiva toward the tooth root.

[0023] The composition disclosed herein is preferably applied to subjects with elevated neutrophil collagenase activity. More specifically, examples include individuals who meet the diagnostic criteria for periodontal disease at stages 1, 2, 3, or 4, or those who meet grade C (Non-Patent Literature 2). The diagnostic criteria for periodontal disease were developed at a workshop co-sponsored by the American Academy of Periodontology and the European Federation of Periodontology, and can be found on the website of the Japanese Society of Periodontology (https: / / www.perio.jp / file / news / info_191220.pdf). Examples of individuals who meet the diagnostic criteria for stage 1 of periodontal disease include those whose largest interdental clinical attachment level (distance from the cementoenamel junction to the gingival sulcus epithelium (measured in 1mm units)) is approximately 1-2 mm. Examples of individuals who meet the diagnostic criteria for stage 2 of periodontal disease include those whose largest interdental clinical attachment level is approximately 3-4 mm. Individuals who meet the diagnostic criteria for periodontal disease at stage 3 or 4 include, for example, those whose largest interdental clinical attachment level is 5 mm or more. Specifically, those meeting the diagnostic criteria for stage 3 include, for example, those who have experienced tooth loss due to periodontal disease (1 to 4 teeth). Those meeting the diagnostic criteria for stage 4 include, for example, those who have experienced tooth loss due to periodontal disease (5 or more teeth). Individuals meeting the diagnostic criteria for grade C include, for example, those whose clinical attachment level changes over time by 2 mm or more in 5 years. Furthermore, examples of animals to which the disclosed compositions can be applied include mammals, including humans (e.g., dogs, cats, mice, rats, sheep, horses, cattle, monkeys, etc.). Humans are particularly preferred.

[0024] The compositions disclosed herein may be, for example, solid compositions, liquid compositions, etc. Furthermore, the compositions disclosed herein (especially oral compositions) can be made into forms (dosage forms) such as ointments, pastes, pastes, gels, liquids, sprays, mouthwashes, liquid toothpastes, toothpastes, gums, tablets, drops, etc., according to conventional methods. Among these, mouthwashes, liquid toothpastes, toothpastes, ointments, pastes, liquids, and gels are preferred.

[0025] The compositions of this disclosure may contain, alone or in combination of two or more optional components that can be incorporated into, for example, oral compositions, as long as they do not impair the effects.

[0026] For example, nonionic surfactants, anionic surfactants, or amphoteric surfactants can be incorporated as surfactants. Specifically, examples of nonionic surfactants include sugar fatty acid esters such as sucrose fatty acid esters, maltose fatty acid esters, and lactose fatty acid esters; fatty acid alkanolamides; glycerin fatty acid esters; sorbitan fatty acid esters; fatty acid monoglycerides; polyoxyethylene alkyl ethers with a polyoxyethylene addition coefficient of 8 to 10 and 13 to 15 carbon atoms in the alkyl group; polyoxyethylene alkylphenyl ethers with a polyoxyethylene addition coefficient of 10 to 18 and 9 carbon atoms in the alkyl group; diethyl sebacate; polyoxyethylene hydrogenated castor oil; and fatty acid polyoxyethylene sorbitan. Examples of anionic surfactants include sulfate ester salts such as sodium lauryl sulfate and sodium polyoxyethylene lauryl ether sulfate; sulfosuccinates such as sodium lauryl sulfosuccinate and sodium polyoxyethylene lauryl ether sulfosuccinate; acyl amino acid salts such as sodium cocoyl sarcosinate and sodium lauroyl methylalanine; and sodium cocoyl methyl taurate. Examples of amphoteric surfactants include betaine-type surfactants such as lauryldimethylaminoacetic acid betaine and coconut oil fatty acid amidopropyldimethylaminoacetic acid betaine; and imidazoline-type surfactants such as N-cocoyl-N-carboxymethyl-N-hydroxyethylethylenediamine sodium. These surfactants can be used individually or in combination of two or more. The amount used is usually 0.1 to 5% by mass of the total composition.

[0027] Furthermore, as flavoring agents, for example, menthol, carvone, anethole, eugenol, methyl salicylate, limonene, ocimene, n-decyl alcohol, citronellol, α-terpineol, methyl acetate, citronenyl acetate, methyl eugenol, cineole, linalool, ethyl linalool, 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, d-camphor, d-borneol, fennel oil, cinnamon oil, cinnamaldehyde, peppermint oil, vanillin, and other fragrances can be used. These can be added individually or in combination of two or more in amounts of, for example, 0.001 to 1.5% by mass of the total composition.

[0028] Furthermore, sweeteners such as sodium saccharin, potassium acesulfamethamate, stevioside, neohesperidyl dihydrochalcone, perillartin, thaumatin, aspartylphenylalanyl methyl ester, and p-methoxycinnamic aldehyde can be used. These can be added in amounts of, for example, 0.01 to 1% by mass relative to the total amount of the composition.

[0029] Furthermore, sorbitol, ethylene glycol, propylene glycol, glycerin, 1,3-butylene glycol, polypropylene glycol, xylitol, maltitol, lactitol, polyoxyethylene glycol, etc., can be used as humectants, either individually or in combination of two or more.

[0030] Examples of binders include cellulose derivatives such as sodium carboxymethylcellulose, carboxymethyl ethylcellulose salt, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, crystalline cellulose, and crystalline cellulose-carmellose sodium; microbially produced polymers such as xanthan gum; natural polymers or natural rubbers such as tragacanth gum, karaya gum, arabic gum, carrageenan, dextrin, agar, pectin, pullulan, gellan gum, locust bean gum, and sodium alginate; synthetic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, polyvinyl methyl ether, and sodium polyacrylate; inorganic binders such as thickening silica and bee gum; and cationic binders such as O-[2-hydroxy-3-(trimethylammonio)propyl]hydroxyethylcellulose chloride. These binders can be used individually or in combination of two or more.

[0031] As preservatives, parabens such as methylparaben, ethylparaben, propylparaben, and butylparaben, sodium benzoate, phenoxyethanol, and alkyldiaminoethylglycine hydrochloride may be included.

[0032] As coloring agents, legally approved pigments such as Blue No. 1, Yellow No. 4, Red No. 202, and Green No. 3, mineral pigments such as ultramarine, enhanced ultramarine, and navy blue, and titanium dioxide may be added.

[0033] As pH adjusters, citric acid, phosphoric acid, malic acid, pyrophosphate, lactic acid, tartaric acid, glycerophosphate, acetic acid, nitric acid, or chemically possible salts thereof, or sodium hydroxide may be included. These can be included individually or in combination of two or more so that the pH of the composition is in the range of 4 to 8, preferably 5 to 7. The amount of pH adjuster may be, for example, 0.01 to 2% by weight.

[0034] Furthermore, the oral composition disclosed herein may also contain, as pharmaceutically active ingredients, vitamin E derivatives such as dl-α-tocopherol acetate, tocopherol succinate, or tocopherol nicotinate; amphoteric bactericides such as dodecyldiaminoethylglycine; nonionic bactericides such as triclosan and isopropylmethylphenol; anionic bactericides such as sodium lauroyl sarcosinate; cationic bactericides such as cetylpyridinium chloride, chlorhexidine hydrochloride, benzalkonium chloride, and benzethonium chloride; dextranase, amylase, protease, mutanase, lysozyme, and lytic enzymes (Litecenza) Enzymes such as IMU, alkali metal monofluorophosphates such as sodium monofluorophosphate and potassium monofluorophosphate, fluorides such as sodium fluoride and stannous fluoride, tranexamic acid, epsilon-aminocaproic acid, aluminum chlorohydroxyl allantoin, dihydrocholesterol, hinokitiol, glycyrrhizic acid, copper chlorophyllin sodium, glycerophosphate, chlorophyll, sodium chloride, caropeptide, allantoin, carbazochrome, potassium nitrate, and palatinite can be formulated individually or in combination of two or more.

[0035] Furthermore, it is possible to add alcohols, silicones, apatite, white petrolatum, paraffin, liquid paraffin, microcrystalline wax, squalane, Plastibase, etc., as base materials.

[0036] In this specification, the term "comprising" includes both "consisting essentially of" and "consisting of." Furthermore, this disclosure encompasses all combinations of the constituent elements described herein.

[0037] Furthermore, the various characteristics (properties, structure, function, etc.) described in each embodiment of this disclosure above may be combined in any way to identify the subject matter covered by this disclosure. In other words, this disclosure covers all subject matter consisting of any combination of the combinable characteristics described herein. [Examples]

[0038] The contents of this disclosure will be specifically explained using the following experimental examples. However, this disclosure is not limited to these examples. Unless otherwise specified below, the experiments were conducted under atmospheric pressure and room temperature conditions. Unless otherwise specified, "%" means "(weight / volume)%".

[0039] Neutrophil collagenase activity inhibition 1. β-glycyrrhetinic acid (β-GR) and zinc gluconate were dissolved in a solvent (buffer included in the kit + 5% DMSO) to a concentration twice the desired concentration. Equal volumes of β-GR and zinc gluconate at each concentration were mixed to prepare a mixed solution of the desired concentration. 2. Neutrophil collagenase activity was evaluated using the MMP-8 fluorimetric drug discovery kit (Enzo Life Sciences, Inc., BML-AK415-0001). Specifically, 20 μl of each material solution prepared in 1 above, 20 μl of MMP-8 diluted 200-fold, and 50 μl of the buffer provided with the kit were mixed and reacted at 37°C for 60 minutes. At this time, a sample with an equal volume of buffer added without the material was prepared as a positive control, and a sample with an equal volume of buffer added without MMP-8 was prepared to measure the background of the substrate only. 3. The fluorescent substrate (BML-P126-9090) was dissolved and diluted 10-fold with buffer (concentration 40 μM). 10 μl of the diluted fluorescent substrate was added and reacted at 37°C for 20 minutes. The fluorescence intensity was then measured at excitation light: 328 nm and emission light: 420 nm. The enzyme activity was calculated as the ratio of the fluorescence intensity of each sample with added material solution to the fluorescence intensity of the substrate alone (NC), which was set as 100% (the difference between the fluorescence intensity of the substrate alone and the background fluorescence intensity of the positive control sample).

[0040] To evaluate the effect of combining β-glycyrrhetinic acid (β-GR) and zinc gluconate, the Combination Index (CI) value was calculated according to the following formula (TING-CHAO CHOU, et al. Trends Pharmacol Sci. 1983;4:450-454, C Patrick Reynolds, et al. Methods Mol Med. 2005;110:173-83). CI = (D)1 / (Dx)1 + (D)2 / (Dx)2 (D)1:β-GR addition concentration (D)2: Concentration of zinc gluconate added (Dx)1: The concentration (IC50 value) that inhibits neutrophil collagenase activity by 50% using β-GR alone. (Dx)2: Concentration (IC50 value) that inhibits neutrophil collagenase activity by 50% using zinc gluconate alone. If CI < 1, a synergistic effect was determined; if CI = 1, an additive effect was determined; and if CI > 1, an antagonistic effect was determined. The results are shown in Table 1. Note that the concentrations in Table 1 represent the concentrations of each material during the preparation described in 1 above, and are five times higher than the concentrations in the reaction system described in 3 above. This is because oral compositions such as toothpaste are diluted by saliva, etc., so the evaluation is conducted assuming the conditions under which they are actually used in the oral cavity.

[0041] [Table 1]

[0042] As shown in Table 1, a synergistic effect on inhibitory activity against neutrophil collagenase was confirmed when the zinc gluconate:β-GR ratio was 5:1 to 0.078125:1. In the combinations where a synergistic effect was confirmed (5:1, 2.5:1, 1.25:1, 0.625:1, 0.3125:1, 0.15625:1, 0.078125:1), neutrophil collagenase activity was reduced to approximately 31%, 36%, 34%, 26%, 28%, 31%, and 44%, respectively. Some of the results are shown in Figure 1. The concentrations in Figure 1 represent the concentrations of each material during the preparation described in item 1 above.

Claims

1. It contains β-glycyrrhetinic acid and zinc gluconate, An oral composition having a zinc gluconate content of 0.07 to 5 parts by mass per 1 part by mass of β-glycyrrhetinic acid. An oral composition for preventing the progression of periodontal disease.

2. The composition according to claim 1, for use in at least one application selected from the group consisting of inhibiting periodontal tissue destruction, inhibiting gum recession, inhibiting gingival recession, inhibiting periodontal pocket formation, inhibiting periodontal pocket deepening, inhibiting attachment loss, inhibiting gingival collagen degradation, and inhibiting neutrophil collagenase activity.

3. The composition according to claim 1 or 2, wherein the content of β-glycyrrhetinic acid in the composition is 0.01% by mass or more.

4. The composition according to any one of claims 1 to 3, wherein the content of zinc gluconate in the composition is 0.005% by mass or more.

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