Composition containing glycyrrhetinic acid, cetylpyridinium chloride and / or isopropylmethylphenol

Abstract

To provide a means for inhibiting osteoclast differentiation. [Solution] A composition for inhibiting alveolar bone resorption and / or osteoclast differentiation, which comprises glycyrrhetinic acid, and cetylpyridinium chloride and / or isopropylmethylphenol.

Description

[Technical Field]

[0001] The present disclosure relates to a composition containing glycyrrhetinic acid, and cetylpyridinium chloride and / or isopropylmethylphenol, and uses thereof. [Background technology]

[0002] As periodontal disease progresses, the alveolar bone, which supports the teeth, is destroyed (bone resorption), leading to tooth loss. Alveolar bone resorption occurs through the breakdown of bone tissue by osteoclasts, and this occurs due to excessive differentiation of osteoclast precursor cells into osteoclasts as periodontal disease progresses.

[0003] Glycyrrhetinic acid has been reported to have inhibitory effects on osteoclast differentiation and alveolar bone resorption (Non-Patent Documents 1 and 2, Patent Document 1), and is widely used in oral compositions such as toothpaste. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Japanese Patent Application Laid-Open No. 2009-209115 [Non-patent literature]

[0005] [Non-Patent Document 1] J Periodontal Res. 2018 Jun;53(3):422-429. [Non-patent document 2] Front Pharmacol. 2018 Jun 20;9:647. Summary of the Invention [Problem to be solved by the invention]

[0006] The present disclosure has been carried out with the aim of providing a means for inhibiting osteoclast differentiation. [Means for solving the problem]

[0007] The present inventors have found that the inhibitory effect of glycyrrhetinic acid on osteoclast differentiation is enhanced by combining glycyrrhetinic acid with cetylpyridinium chloride or isopropylmethylphenol, and have made further improvements.

[0008] The present disclosure encompasses, for example, the subject matter described in the following sections: Section 1. A composition for inhibiting alveolar bone resorption and / or osteoclast differentiation, comprising glycyrrhetinic acid, and cetylpyridinium chloride and / or isopropylmethylphenol. Section 2. Item 2. The composition according to item 1, containing 0.005 to 0.5% by mass of glycyrrhetinic acid. Section 3. When the composition contains cetylpyridinium chloride, the composition contains 0.005 to 0.3 mass% of cetylpyridinium chloride, Item 3. The composition according to item 1 or 2, wherein when the composition contains isopropylmethylphenol, the composition contains 0.005 to 0.3 mass % of isopropylmethylphenol. Section 4. Item 4. The composition according to any one of Items 1 to 3, which is an oral composition. Section 5. Combining glycyrrhetinic acid with cetylpyridinium chloride and / or isopropylmethylphenol, A method for improving the ability of glycyrrhetinic acid to inhibit alveolar bone resorption and / or osteoclast differentiation. [Effects of the Invention]

[0009] It inhibits osteoclast differentiation and alveolar bone resorption. [Brief explanation of the drawings]

[0010] [Figure 1] The results of measuring the differentiation rate of osteoclasts are shown. [Figure 2] 1 shows the measurement results of the amount of β-glycyrrhetinic acid contained in the permeation sample. DETAILED DESCRIPTION OF THE INVENTION

[0011] Each embodiment included in the present disclosure will be described in further detail below. The composition encompassed by the present disclosure includes glycyrrhetinic acid, and cetylpyridinium chloride and / or isopropylmethylphenol. In this specification, the composition may be referred to as the "composition of the present disclosure."

[0012] Examples of glycyrrhetinic acid include α-glycyrrhetinic acid and β-glycyrrhetinic acid. These can be used alone or in combination. Of these, β-glycyrrhetinic acid is preferred.

[0013] β-Glycyrrhetinic acid has the following formula:

[0014] [ka]

[0015] It is a compound represented by the formula:

[0016] The glycyrrhetinic acid used in the composition of the present disclosure may be a synthetic product, or may be obtained by hydrolyzing glycyrrhetinic acid extracted from a natural product (such as licorice).

[0017] The content of glycyrrhetinic acid in the composition of the present disclosure is preferably, for example, about 0.005 to 0.5% by mass. The upper or lower limit of this range may be, for example, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, or 0.45. For example, it can be about 0.01 to 0.2% by mass.

[0018] The compositions of the present disclosure may comprise cetylpyridinium chloride or isopropylmethylphenol, or may comprise cetylpyridinium chloride and isopropylmethylphenol.

[0019] When the composition of the present disclosure contains cetylpyridinium chloride, the content of cetylpyridinium chloride in the composition of the present disclosure is preferably, for example, about 0.005 to 0.3% by mass. The upper or lower limit of this range may be, for example, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, or 0.25. For example, it can be about 0.007 to 0.1% by mass, or about 0.01 to 0.05% by mass.

[0020] When the composition of the present disclosure contains isopropylmethylphenol, the content of isopropylmethylphenol in the composition of the present disclosure is preferably, for example, about 0.005 to 0.3% by mass. The upper or lower limit of this range may be, for example, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, or 0.25. For example, it can be about 0.01 to 0.1% by mass.

[0021] When the composition of the present disclosure contains cetylpyridinium chloride, the composition of the present disclosure may contain, for example, about 0.01 to 10 parts by mass of cetylpyridinium chloride per part by mass of glycyrrhetinic acid. The upper or lower limit of this range may be, for example, 0.02, 0.03, 0.04, 0.05, 0.06, 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, 7, 8, or 9. More specifically, the composition may contain about 0.05 to 1 part by mass of cetylpyridinium chloride.

[0022] When the composition of the present disclosure contains isopropylmethylphenol, the composition of the present disclosure may contain, for example, about 0.01 to 10 parts by mass of isopropylmethylphenol per 1 part by mass of glycyrrhetinic acid. The upper or lower limit of this range may be, for example, 0.02, 0.03, 0.04, 0.05, 0.06, 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, 7, 8, or 9. More specifically, the composition may contain about 0.05 to 1 part by mass.

[0023] The composition of the present disclosure contains the active ingredient described above and may further contain other ingredients. Examples of such other ingredients include pharmacologically or food hygienically acceptable bases, carriers, solvents, dispersants, emulsifiers, buffers, stabilizers, excipients, binders, disintegrants, lubricants, thickeners, surfactants, antioxidants, preservatives, coating agents, colorants, flavoring agents, sweeteners, humectants, antiseptics, pH adjusters, gastric mucosa protective agents, and other pharmaceutical agents, and / or other ingredients or materials that can be used as foods or feeds. These ingredients may be used alone or in combination of two or more.

[0024] For example, the surfactant may be a nonionic surfactant, an anionic surfactant, or an amphoteric surfactant. Specific 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; sorbitan fatty acid esters; fatty acid monoglycerides; polyoxyethylene alkyl ethers having a polyoxyethylene addition coefficient of 8 to 10 and an alkyl group having 13 to 15 carbon atoms; polyoxyethylene alkylphenyl ethers having a polyoxyethylene addition coefficient of 10 to 18 and an alkyl group having 9 carbon atoms; 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 polyoxyethylene lauryl ether sodium sulfate; sulfosuccinates such as sodium lauryl sulfosuccinate and polyoxyethylene lauryl ether sodium sulfosuccinate; acylamino acid salts such as sodium cocoyl sarcosinate and sodium lauroyl methyl alanine; and sodium cocoyl methyl taurate. Examples of zwitterionic surfactants include acetate betaine surfactants such as lauryl dimethylaminoacetate betaine and coconut oil fatty acid amidopropyl dimethylaminoacetate betaine; imidazoline surfactants such as N-cocoyl-N-carboxymethyl-N-hydroxyethylethylenediamine sodium; and amino acid surfactants such as N-lauryl diaminoethylglycine and N-cocoyl acyl-L-arginine ethyl DL-pyrrolidone carboxylate. These surfactants can be used alone or in combination of two or more. The amount of surfactant used can typically be about 0.1 to 5% by mass of the total composition.

[0025] Flavoring agents that can be used include, for example, menthol, carboxylic acids, 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, cinnamon aldehyde, peppermint oil, and vanillin. These can be used alone or in combination of two or more. The amount of the flavoring agent can be, for example, about 0.001 to 1.5% by mass of the total amount of the composition.

[0026] Examples of sweeteners that can be used include saccharin sodium, acesulfame potassium, stevioside, neohesperidyl dihydrochalcone, perillartine, thaumatin, aspartyl phenylalanyl methyl ester, and p-methoxycinnamic aldehyde. These can be used alone or in combination of two or more. The amount of the sweetener can be, for example, about 0.01 to 1% by mass of the total amount of the composition.

[0027] As the humectant, sorbitol, ethylene glycol, propylene glycol, glycerin, 1,3-butylene glycol, polypropylene glycol, xylitol, maltitol, lactite, erythritol, polyoxyethylene glycol, etc. can be blended alone or in combination of two or more.

[0028] Examples of binders that can be used include cellulose derivatives such as sodium carboxymethylcellulose, carboxymethylethylcellulose salts, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, crystalline cellulose, and crystalline cellulose-carmellose sodium; microbial polymers such as xanthan gum; natural polymers or natural rubbers such as tragacanth gum, karaya gum, gum arabic, 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; thickening silica; inorganic binders such as Veegum; and cationic binders such as O-[2-hydroxy-3-(trimethylammonio)propyl]hydroxyethylcellulose chloride. These can be used alone or in combination of two or more.

[0029] Preservatives that can be added include parabens such as methylparaben, ethylparaben, propylparaben, and butylparaben, sodium benzoate, phenoxyethanol, alkyldiaminoethylglycine hydrochloride, etc. These can be added alone or in combination of two or more.

[0030] As coloring agents, legal pigments such as Blue No. 1, Yellow No. 4, Red No. 202, and Green No. 3, mineral pigments such as ultramarine, enhanced ultramarine, and Prussian blue, titanium oxide, etc. may be blended. These may be blended alone or in combination of two or more.

[0031] The pH adjuster may be citric acid, phosphoric acid, EDTA, malic acid, pyrophosphoric acid, lactic acid, tartaric acid, glycerophosphoric acid, acetic acid, nitric acid, or chemically acceptable salts thereof, or sodium hydroxide. These may be added alone 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 added may be, for example, about 0.01 to 2% by weight.

[0032] As the abrasive, for example, calcium carbonate, magnesium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, magnesium phosphate, silica, zeolite, sodium metaphosphate, aluminum hydroxide, magnesium hydroxide, calcium pyrophosphate, red iron oxide, calcium sulfate, silicic anhydride, etc. can be blended alone or in combination of two or more.

[0033] Drugs include vitamin E compounds such as dl-α-tocopherol acetate, tocopherol succinate, and tocopherol nicotinate; vitamin C compounds such as ascorbic acid or its metal salts; amphoteric disinfectants such as dodecyldiaminoethylglycine; nonionic disinfectants such as thymol, triclosan, and hinokitiol; anionic disinfectants such as sodium lauroyl sarcosinate; cationic disinfectants such as chlorhexidine hydrochloride and benzethonium chloride; enzymes such as dextranase, amylase, protease, mutanase, lysozyme, and lytic enzymes (retic enzymes); and monofluororin. Alkali metal monofluorophosphates such as sodium fluoride and potassium monofluorophosphate; fluorides such as sodium fluoride and stannous fluoride; tranexamic acid, epsilon aminocaproic acid, aluminum chlorohydroxyl allantoin, dihydrocholesterol, glycyrrhizic acid, pyridoxine, copper chlorophyllin sodium, glycerophosphate, chlorophyll, sodium chloride, callopeptide, allantoin, carbazochrome, hinokitiol, potassium nitrate, palatinit, etc. can be blended alone or in combination of two or more.

[0034] It is also possible to add alcohols, silicone, apatite, white petrolatum, paraffin, liquid paraffin, microcrystalline wax, squalane, plastibase, etc. as bases. These can be blended alone or in combination of two or more.

[0035] The compositions of the present disclosure can be solid compositions or liquid compositions. Furthermore, the form of the composition of the present disclosure is not particularly limited, and can be, for example, an ointment, paste, paste, gel, liquid, spray, rinse, mouthwash, liquid dentifrice, toothpaste, gum, etc. Among these, mouthwash, liquid dentifrice, toothpaste, ointment, paste, liquid, gel, and rinse are preferred.

[0036] The composition of the present disclosure can be prepared by a conventional method by combining the above-mentioned active ingredient and, if necessary, other ingredients.

[0037] The composition of the present disclosure can be suitably used as an oral composition. The composition of the present disclosure can also be used, for example, as a pharmaceutical composition or a quasi-drug composition.

[0038] The composition of the present disclosure can be used to inhibit osteoclast differentiation (more specifically, to inhibit the differentiation of osteoclast precursor cells into osteoclasts). Furthermore, since the composition of the present disclosure has an inhibitory effect on osteoclast differentiation, it can be used to inhibit alveolar bone resorption.

[0039] Furthermore, since the composition of the present disclosure can be used to inhibit alveolar bone resorption and / or osteoclast differentiation, it can be used, for example, to protect the foundation of the teeth and gums (gingiva) (e.g., periodontal tissues such as gums or alveolar bone), to maintain the strength that supports the teeth and gums (gingiva), to prevent gingival recession (recession of the gums), to prevent exposure of the tooth root surface, to balance bone metabolism in the gums, to prevent the formation and deepening of periodontal pockets, to prevent gingival inflammation, and to prevent the onset and / or progression of periodontal disease.

[0040] The compositions of the present disclosure can be applied to, for example, humans and non-human mammals (e.g., rats, mice, dogs, cats, monkeys, cows, horses, sheep, goats, pigs, rabbits, camels, llamas, etc.), among which humans are preferred. Examples of target humans include periodontal disease patients, people suspected of having periodontal disease, people who wish to prevent periodontal disease, people in the maintenance phase after periodontal disease treatment, people in the stable period of periodontal disease treatment, people with implants, people undergoing orthodontic treatment, elderly people, and diabetic patients.

[0041] The present disclosure also encompasses a method for improving the ability of glycyrrhetinic acid to inhibit alveolar bone resorption and / or osteoclast differentiation, which comprises combining glycyrrhetinic acid with cetylpyridinium chloride and / or isopropylmethylphenol. In this specification, this method may be referred to as the "method of the present disclosure."

[0042] The method of the present disclosure may combine glycyrrhetinic acid with cetylpyridinium chloride or isopropylmethylphenol, or may combine glycyrrhetinic acid with cetylpyridinium chloride and isopropylmethylphenol.

[0043] In the method of the present disclosure, the method for combining glycyrrhetinic acid with cetylpyridinium chloride and / or isopropylmethylphenol is not particularly limited, and examples thereof include a method of mixing glycyrrhetinic acid with cetylpyridinium chloride and / or isopropylmethylphenol in any solvent, and a method of mixing a solution containing glycyrrhetinic acid with a solution containing cetylpyridinium chloride and / or isopropylmethylphenol.

[0044] The above description of the composition of the present disclosure can be used to refer to the concentrations and ratios of each component when combining glycyrrhetinic acid with cetylpyridinium chloride and / or isopropylmethylphenol.

[0045] According to the method of the present disclosure, by combining glycyrrhetinic acid with cetylpyridinium chloride and / or isopropylmethylphenol, the ability of glycyrrhetinic acid to inhibit alveolar bone resorption and / or osteoclast differentiation can be improved.

[0046] In this specification, the term "comprising" includes "consisting essentially of" and "consisting of." In addition, the present disclosure includes any and all combinations of the constituent elements described in this specification.

[0047] Furthermore, the various characteristics (properties, structures, functions, etc.) described in each embodiment of the present disclosure above may be combined in any way to specify the subject matter encompassed by the present disclosure, i.e., the present disclosure encompasses all subject matter consisting of any combination of the combinable characteristics described herein. [Example]

[0048] The contents of the present disclosure will be specifically explained using the following experimental examples. However, the present disclosure is not limited to these examples. In the following, unless otherwise specified, experiments were performed under atmospheric pressure and room temperature conditions. Furthermore, unless otherwise specified, "%" indicating concentration means "mass-to-volume concentration (w / v)%."

[0049] (1) Permeabilization The materials were prepared by dissolving β-glycyrrhetinic acid (GR), cetylpyridinium chloride (CPC), and isopropylmethylphenol (IPMP) in PBS at the specified concentrations (ppm). A 3D gingival epithelial model (SkinEthic™ HGE) was placed in a 12-well plate with 1500 μL of PBS applied. 300 μL of the prepared materials were applied to the 3D model and incubated at 37°C and 5% CO2 for 24 hours. Afterwards, the permeation samples (PBS in 12 wells) were collected.

[0050] (2) Osteoclast differentiation (2-1) RAW264 osteoclast precursor cells were seeded onto a 96-well plate at 5,000 cells per well. The cells were cultured at 37°C in a 5% CO environment for 4 hours to allow the cells to adhere to the plate. (2-2) The permeabilized samples collected in (1) were supplemented with 1 / 5 the volume of 5x concentrated culture medium and RANKL at 250 ng / mL. The positive control was treated with PBS instead of the permeabilized samples from (1), and the negative control was treated with PBS without RANKL. (2-3) The medium was removed from the cells adhered in (2-1), and 100 μL of the sample prepared in (2-2) was added and cultured for 5 days. (2-4) The culture supernatant was collected and TRAP (a specific enzyme for osteoclasts) activity was measured. The osteoclast differentiation rate was calculated by setting the negative control group as 0% and the positive control group as 100%. The results are shown in Figure 1.

[0051] (3) Measurement of βGR levels The amount of βGR in the samples collected in (1) was determined by a known quantitative method using liquid chromatography. The results are shown in Figure 2.

[0052] As shown in Figure 1, it was confirmed that the addition of CPC or IPMP in combination with GR at 125 ppm (0.0125%) or 500 ppm (0.05%) more effectively inhibited osteoclast differentiation than the addition of GR alone at 250 ppm (0.025%) or 500 ppm (0.05%). As shown in Figure 2, the combination of GR with CPC or IPMP did not result in any difference in the amount of GR in the transmission sample.

[0053] An example of a prescription is shown below. [Table 1] [Table 2] [Table 3] [Table 4] Table 5 Table 6 Table 7 Table 8 Table 9 Table 10 Table 11 Table 12

Claims

[Claim 1] A method for improving the ability of glycyrrhetinic acid to inhibit alveolar bone resorption and / or osteoclast differentiation, comprising combining glycyrrhetinic acid with cetylpyridinium chloride and / or isopropylmethylphenol.

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