Agents for inhibiting the destruction of gingival tissue

Abstract

To provide inhibitors of gingival tissue destruction, inhibiting gingival tissue destruction so as to restore the tissue to normal conditions.SOLUTION: A phosphocholine group-containing polymer inhibits the activity of collagenolytic enzyme MMP-1 produced in gingival cells with inflammation or bacterial infection so that it inhibits degradation of collagen functioning as an extracellular substrate in the gingival tissue. Thus the polymer is effective in inhibition of gingival tissue destruction.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to an agent for inhibiting destruction of gingival tissue, which is capable of inhibiting destruction of gingival tissue. [Background technology]

[0002] Gingival (dental) tissue is a periodontal tissue that supports the teeth, and is formed by gingival cells (gingival epithelial cells, gingival fibroblasts, etc.) and the extracellular matrix (collagen, etc.) produced by the gingival cells. When gingival cells are damaged by bacterial infection, inflammation, etc., excessive production of collagen-degrading enzyme MMP-1 occurs, resulting in a decrease in cell proliferation ability and destruction of collagen, which leads to gingival recession. Such gingival recession leads to the progression of periodontal disease and is also a factor in tooth loss. Therefore, it is important for oral hygiene to suppress the destruction of gingival tissue and maintain healthy gingival tissue.

[0003] Various ingredients effective for normalizing gingival tissue have been reported. For example, Patent Document 1 discloses that plant extracts such as lychee, red ginger, and Houttuynia cordata can be used as gingival health maintenance agents. However, the requirements for oral hygiene products to maintain or improve the health of the gums are increasing year by year, and it is necessary to respond to the diversification of the formulations of oral hygiene products, and there is a demand for the development of new formulations that can more effectively normalize gingival tissue.

[0004] On the other hand, phosphocholine group-containing polymers such as 2-methacryloyloxyethyl phosphorylcholine-butyl methacrylate copolymer have been reported to have high affinity for the body and also to have moisturizing properties, and are mainly used in topical preparations. However, the effects of phosphocholine group-containing polymers on gingival tissues have not been elucidated. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] JP 2009-263332 A Summary of the Invention [Problem to be solved by the invention]

[0006] An object of the present invention is to provide an agent for inhibiting the destruction of gingival tissue, which can restore the gingiva to a normal state. Another object of the present invention is to provide an agent for preventing or improving gingival recession, which can normalize the gingival tissue and prevent or improve gingival recession. [Means for solving the problem]

[0007] The present inventors have conducted extensive research to solve the above problems, and have found that a phosphocholine group-containing polymer can suppress the activity of collagen decomposition enzyme MMP-1, which is excessively produced in gingival cells when inflammation or bacterial infection occurs, and can suppress the degradation of collagen that functions as an extracellular matrix in gingival tissue, and is effective in suppressing the destruction of gingival tissue and preventing or improving gingival recession. The present invention was completed based on this finding and through further research.

[0008] That is, the present invention provides the following aspects. Item 1. An agent for inhibiting destruction of gingival tissue, comprising a polymer containing a phosphocholine group. Item 2. The agent for inhibiting destruction of gingival tissue according to Item 1, wherein the phosphocholine group-containing polymer is a 2-methacryloyloxyethyl phosphorylcholine-butyl methacrylate copolymer. Item 3. The agent for inhibiting destruction of gingival tissue according to Item 1 or 2, which is a liquid dentifrice, a liquid dentifrice, a toothpaste, or a mouthwash. Item 4. An inhibitor of MMP-1 activity produced in gingival tissue, comprising a phosphocholine group-containing polymer. Item 5. The MMP-1 activity inhibitor according to Item 4, wherein the phosphocholine group-containing polymer is a 2-methacryloyloxyethyl phosphorylcholine / butyl methacrylate copolymer. Item 6. The MMP-1 activity inhibitor according to Item 4 or 5, which is in the form of a liquid dentifrice, a liquid dentifrice, a toothpaste, or a mouthwash. Effect of the Invention

[0009] According to the present invention, the activity of collagen decomposition enzyme MMP-1, which is excessively produced in gingival tissue when inflammation, bacterial infection, etc. occurs, can be reduced, and collagen in the gingival tissue can be stably maintained, thereby suppressing the destruction of the gingival tissue. Furthermore, since gingivitis and periodontal disease are often accompanied by the destruction of gingival tissue due to the promotion of the production of collagen decomposition enzyme MMP-1, the present invention is also effective in preventing or improving gingivitis and periodontal disease.

[0010] Furthermore, according to the present invention, the activity of MMP-1 (a collagen-degrading enzyme) that is excessively produced in gingival tissue when inflammation, bacterial infection, etc. occurs is suppressed, and collagen is stably maintained in the gingival tissue, thereby effectively preventing or ameliorating gingival recession. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] 1. Agents that inhibit the destruction of gingival tissue The gingival tissue destruction inhibitor of the present invention is characterized by containing a phosphocholine group-containing polymer. Hereinafter, the "gingival tissue destruction inhibitor" may be simply referred to as the "destruction inhibitor". Hereinafter, the destruction inhibitor of the present invention will be described in detail.

[0012] [Polymer containing phosphocholine groups] The destruction inhibitor of the present invention uses a phosphocholine group-containing polymer as an active ingredient. The phosphocholine group-containing polymer can suppress the activity of MMP-1 (collagen decomposition enzyme) that is excessively produced when inflammation or bacterial infection occurs in the gingival tissue, and can stably maintain collagen in the gingival tissue, thereby suppressing the destruction of the gingival tissue.

[0013] The phosphocholine group-containing polymer is a polymer formed by polymerizing a monomer containing a phosphocholine group (hereinafter, sometimes referred to as a "phosphocholine group-containing monomer"), and is a known component having moisturizing properties, etc.

[0014] In the phosphocholine group-containing polymer, the type of phosphocholine group-containing monomer is not particularly limited, and examples thereof include monomers having a phosphocholine group and a vinyl group. More specifically, examples of the phosphocholine group-containing monomer include 2-methacryloyloxyethyl phosphorylcholine, 2-methacryloyloxyethyl phosphorylethanolamine, etc. In the phosphocholine group-containing polymer, the phosphocholine group-containing monomer may be contained alone or in combination of two or more kinds. Among these phosphocholine group-containing monomers, 2-methacryloyloxyethyl phosphorylcholine is preferred from the viewpoint of more effectively suppressing the destruction of gingival tissue.

[0015] The phosphocholine group-containing polymer used in the present invention may be a homopolymer consisting of one type of phosphocholine group-containing monomer, or a copolymer consisting of two or more types of monomers.

[0016] When the phosphocholine group-containing polymer is a copolymer, it may be a copolymer consisting of two or more types of phosphocholine group-containing monomers, or it may be a copolymer consisting of at least one type of phosphocholine group-containing monomer and at least one type of monomer other than the phosphocholine group-containing monomer.

[0017] The type of monomer other than the phosphocholine group-containing monomer contained in the phosphocholine group-containing polymer is not particularly limited, so long as it is pharma- ceutical acceptable and capable of radical polymerization with the phosphocholine group-containing monomer, and examples thereof include monomers having a vinyl group. Specific examples of monomers other than the phosphocholine group-containing monomer include alkyl (meth)acrylates such as methyl (meth)acrylate, ethyl (meth)acrylate, butyl (meth)acrylate, lauryl (meth)acrylate, stearyl (meth)acrylate, and 2-ethylhexyl (meth)acrylate; benzyl (meth)acrylate, phenoxyethyl (meth)acrylate, cyclohexyl (meth)acrylate, polypropylene glycol mono(meth)acrylate, polytetramethylene glycol mono(meth)acrylate, polypropylene glycol di(meth)acrylate, polytetramethylene glycol mono(meth)acrylate, polypropylene glycol polyethylene glycol mono(meth)acrylate, sodium methacrylate, and 2-hydroxy-3-methacryloyloxypropyltrimethylammonium. In the phosphocholine group-containing polymer, the monomers other than the phosphocholine group-containing monomer may be contained alone or in combination of two or more. Among these monomers other than the phosphocholine group-containing monomer, from the viewpoint of more effectively suppressing the destruction of gingival tissue, preferred are alkyl(meth)acrylates and 2-hydroxy-3-methacryloyloxypropyltrimethylammonium, more preferably alkyl(meth)acrylates having an alkyl group with 1 to 18 carbon atoms, even more preferably alkyl(meth)acrylates having an alkyl group with 3 to 5 carbon atoms, and particularly preferably butyl(meth)acrylate. In this specification, "(meth)acrylate" refers to methacrylate and / or acrylate.

[0018] Specific examples of the phosphocholine group-containing polymer used in the present invention include polymethacryloyloxyethyl phosphorylcholine homopolymer, 2-methacryloyloxyethyl phosphorylcholine-butyl methacrylate copolymer (polyquaternium-51), 2-methacryloyloxyethylene phosphorylcholine-butyl methacrylate-sodium methacrylate copolymer (polyquaternium-65), 2-methacryloyloxyethyl phosphorylcholine-2-hydroxy-3-methacryloyloxypropyltrimethylammonium copolymer (polyquaternium-64), 2-methacryloyloxyethyl phosphorylcholine-stearyl methacrylate copolymer (polyquaternium-61), etc. In the above description of the phosphocholine group-containing polymer, the name in parentheses indicates the cosmetic ingredient name.

[0019] In the breakdown inhibitor of the present invention, one type of phosphocholine group-containing polymer may be used as the active ingredient, or two or more types of phosphocholine group-containing polymers may be used in combination.

[0020] Among these phosphocholine group-containing polymers, from the viewpoint of more effectively suppressing destruction of gingival tissue, preferred are 2-methacryloyloxyethyl phosphorylcholine / butyl methacrylate copolymer, polymethacryloyloxyethyl phosphorylcholine homopolymer, and 2-methacryloyloxyethyl phosphorylcholine / 2-hydroxy-3-methacryloyloxypropyltrimethylammonium copolymer; more preferred are 2-methacryloyloxyethyl phosphorylcholine / butyl methacrylate copolymer, and 2-methacryloyloxyethyl phosphorylcholine / 2-hydroxy-3-methacryloyloxypropyltrimethylammonium copolymer; and even more preferred are 2-methacryloyloxyethyl phosphorylcholine / butyl methacrylate copolymer.

[0021] In the breakdown inhibitor of the present invention, the content of the phosphocholine group-containing polymer may be appropriately set depending on the type of phosphocholine group-containing polymer used, the formulation form of the breakdown inhibitor, etc., and may be, for example, 0.005 to 0.5 wt %, preferably 0.025 to 0.25 wt %, and more preferably 0.05 to 0.1 wt %.

[0022] [Other ingredients] The destruction inhibitor of the present invention may contain, in addition to the phosphocholine group-containing polymer, components that are generally used in the art according to the formulation, within the scope that does not impair the effect of the present invention. Such components include, for example, preservatives, bactericides, antibacterial agents, anti-inflammatory agents, abrasives, glucosyltransferase (GTase) inhibitors, plaque inhibitors, dentin hypersensitivity inhibitors, tartar prevention agents, tooth strengthening / remineralization agents, thickeners, humectants, excipients, flavors, sweeteners, colorants, deodorants, surfactants, solvents, pH adjusters, etc.

[0023] Examples of preservatives, disinfectants, and antibacterial agents include hinokitiol, benzoic acids, salicylic acids, sorbic acids, parabens, dequalinium chloride, benzethonium chloride, benzalkonium chloride, chlorhexidine chloride, chlorhexidine gluconate, isopropylmethylphenol, triclosan, cetylpyridinium chloride, lysozyme chloride, chlorhexidine hydrochloride, and potassium iodide.

[0024] Examples of anti-inflammatory agents include dipotassium glycyrrhizinate, glycyrrhetinic acid, allantoin, tranexamic acid, epsilon aminocaproic acid, azulene, sodium chloride, vitamins, and the like.

[0025] Examples of the abrasive include anhydrous silicic acid, hydrous silicic acid, aluminum oxide, aluminum hydroxide, calcium hydrogen phosphate, calcium phosphate, calcium pyrophosphate, calcium carbonate, crystalline cellulose, polyethylene powder, and charcoal particles.

[0026] Examples of GTase inhibitors include extracts of plants of the genus Oenothera in the Onagraceae family, extracts of plants of the genus Vitis in the Vitaceae family, dextranase, mutanase, tastein, tannins, ellagic acid, polyphenols, oolong tea extract, green tea extract, Swertia japonica, Chinese laurel, fennel, peony, gentiana, Senso, gentian, Coptis chinensis, and Coptis Rhizome.

[0027] Examples of plaque inhibitors include zinc citrate and gluconic acid.

[0028] Examples of the dentin hypersensitivity inhibitor include potassium nitrate, aluminum lactate, and strontium chloride.

[0029] Anti-calculus agents include, for example, polyphosphates, zeolites, ethanehydroxydiphosphonate, and the like.

[0030] Examples of tooth strengthening / remineralizing agents include fluoride, sodium fluoride, sodium fluorophosphate, and stannous fluoride.

[0031] Examples of thickening agents include polysaccharides such as pullulan, pullulan derivatives, and starch; hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl methyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose salts (sodium carboxymethyl cellulose, potassium carboxymethyl cellulose, etc.), methyl cellulose, ethyl cellulose, polyacrylic acid, polyacrylates (sodium polyacrylate, acrylic acid / octyl acrylate copolymer, etc.), copolymers of methacrylic acids (methacrylic acid and acrylic acid Examples of such polymeric substances include cellulose-based polymeric substances such as n-butyl polymers, polymers of methacrylic acid and methyl methacrylate, and polymers of methacrylic acid and ethyl acrylate; synthetic polymeric substances such as carboxyvinyl polymers, polyethylene glycol, polyvinyl alcohol, and polyvinylpyrrolidone; natural polymeric substances such as lectin, alginic acid, alginates (sodium alginate, potassium alginate, magnesium alginate, propylene glycol alginate, triethanolamine alginate, triisopropanolamine alginate, ammonium alginate, butylamine alginate, and diamylamine alginate), sodium chondroitin sulfate, agar, chitosan, and carrageenan; amino acid-based polymeric substances such as collagen and gelatin; and rubber-based polymeric substances such as gum arabic, karaya gum, tragacanth gum, xanthan gum, locust bean gum, guar gum, tamarind gum, and gellan gum.

[0032] Examples of humectants include glycerin, sorbitol, ethylene glycol, propylene glycol, polyethylene glycol, polypropylene glycol, xylitol, maltitol, lactol, and erythritol.

[0033] Examples of excipients include lactose, sucrose, mannitol, starch, dextrin, crystalline cellulose, and silica (light anhydrous silicic acid, etc.).

[0034] Examples of the flavoring include natural flavorings (such as fennel oil), synthetic flavorings, and blends of these.

[0035] Examples of sweeteners include sodium saccharin, stevioside, stevia extract, aspartame, xylitol, starch syrup, honey, sorbitol, maltitol, mannitol, erythritol, and sugars (lactose, sucrose, fructose, glucose, etc.).

[0036] The dyes include, for example, natural dyes, synthetic dyes, and mixtures thereof.

[0037] Examples of deodorants include zinc chloride, sodium copper chlorophyllin, coffee bean extract, burdock powder, green tea, roasted rice bran extract, and the like.

[0038] Examples of the surfactant include anionic surfactants such as polyoxyethylene lauryl ether sodium sulfate, sodium lauryl sulfate, sodium myristyl sulfate, sodium N-lauroyl sarcosinate, sodium N-myristyl sarcosinate, sodium dodecylbenzenesulfonate, hydrogenated coconut fatty acid monoglyceride sodium monosulfate, sodium lauryl sulfoacetate, sodium α-olefin sulfonate, sodium N-palmitoyl glutamate, and sodium N-methyl-N-acyltaurate; polyoxyethylene hydrogenated castor oil, sucrose fatty acid ester, maltose fatty acid ester, maltitol fatty acid ester, lactol fatty acid ester, sorbitan fatty acid ester, polyoxyethylene sorbitan monostearate, polyoxyethylene higher aryl fatty acid ester, polyoxyethylene ... Examples of the surfactants include nonionic surfactants such as cholester, polyoxyethylene polyoxypropylene copolymer, polyoxyethylene polyoxypropylene fatty acid ester, and polyglycerin fatty acid ester; amphoteric surfactants such as coconut oil fatty acid amidopropyl betaine, lauryl dimethylaminoacetate betaine, lauryl dimethylamine oxide, 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazolium betaine, N-lauryl diaminoethyl glycine, N-myristyl diaminoethyl glycine, and N-alkyl-1-hydroxyethyl imidazoline betaine sodium; and cationic surfactants such as lauryl trimethyl ammonium chloride, stearyl trimethyl ammonium chloride, benzethonium chloride, benzalkonium chloride, and stearyl dimethyl benzyl ammonium chloride.

[0039] Examples of the solvent include water; monohydric alcohols such as ethanol, propanol, butanol, pentanol, hexanol, and isopropanol; and the like.

[0040] Examples of pH adjusters include acetic acid, hydrochloric acid, sulfuric acid, nitric acid, citric acid, malic acid, lactic acid, phosphoric acid, benzoic acid, sodium hydroxide, potassium hydroxide, sodium acetate, sodium carbonate, sodium citrate, sodium hydrogen citrate, sodium lactate, calcium lactate, sodium phosphate, sodium hydrogen phosphate, and sodium benzoate.

[0041] When these components are contained in the fracture inhibitor of the present invention, the content thereof may be appropriately set within the range usually used in the technical field.

[0042] [Dosage form / formulation] The dosage form of the disruption inhibitor of the present invention is not particularly limited as long as it can be applied to the oral cavity, and examples thereof include liquid and semi-solid forms (gel and paste).

[0043] The formulation of the destruction inhibitor of the present invention is not particularly limited as long as it can be applied to the oral cavity and remain there for a certain period of time, and examples thereof include oral hygiene agents such as liquid dentifrice, liquid dentifrice, toothpaste, mouthwash (liquid dentifrice and mouthwash are generally sometimes called mouth rinse, mouthwash, dental rinse, etc.), mouth fresheners (mouth spray, etc.), and oral ointments. Among these, preferred are liquid dentifrice, liquid dentifrice, toothpaste, and mouthwash, more preferred are liquid dentifrice, toothpaste, and mouthwash, and particularly preferred are toothpaste.

[0044] [Applications / How to use] The destruction inhibitor of the present invention is applied to the oral cavity for the purpose of destruction inhibition of gingival tissue. In the present invention, "destruction inhibition of gingival tissue" means the inhibition of weakening and destruction of gingival tissue caused by decomposition of collagen in gingival tissue, and includes not only preventing destruction of gingival tissue but also inhibiting the progress of destruction of gingival tissue.

[0045] Furthermore, since gingivitis and periodontal disease promote the production of the collagen-degrading enzyme MMP-1 and are often accompanied by the destruction of gingival tissue, the destruction inhibitor of the present invention can also be used as an agent for preventing or improving gingivitis, or an agent for preventing or improving periodontal disease, etc.

[0046] The destruction inhibitor of the present invention may be applied to the oral cavity in a form appropriate for its formulation and allowed to remain in the oral cavity for a certain period of time. The amount and frequency of use of the destruction inhibitor of the present invention are not particularly limited, but for example, the amount of phosphocholine group-containing polymer that is about 0.05 to 5 mg per use may be used once to several times, preferably about 1 to 3 times per day.

[0047] 2. Agents for preventing or improving gingival recession In gingival tissue, collagen contributes to the formation of normal gingival tissue as an extracellular matrix. The phosphocholine group-containing polymer can prevent or improve gingival recession by suppressing the activity of MMP-1 (collagen decomposition enzyme) that is excessively produced in gingival tissue when inflammation or bacterial infection occurs, and stably maintaining collagen in gingival tissue. Therefore, the present invention further provides an agent for preventing or improving gingival recession, which comprises a phosphocholine group-containing polymer.

[0048] In the agent for preventing or improving gingival recession of the present invention, the type and content of the phosphocholine group-containing polymer used, other ingredients to be blended, dosage form / formulation, method of use, etc. are as described in the section "1. Agent for inhibiting destruction of gingival tissue" above.

[0049] Prevention or improvement of gingival recession is effective in preventing or improving diseases or disorders associated with gingival recession by restoring or maintaining receding gums to a healthy state, and therefore the agent for preventing or improving gingival recession of the present invention can also be used as an agent for preventing or improving diseases or disorders associated with gingival recession.

[0050] 3. Agents for preventing or improving gingival recession The phosphocholine group-containing polymer can inhibit the activity of MMP-1 (collagen decomposition enzyme) produced in gingival tissue. Therefore, the present invention further provides an MMP-1 inhibitor comprising the phosphocholine group-containing polymer.

[0051] In the MMP-1 inhibitor of the present invention, the type and content of the phosphocholine group-containing polymer used, other ingredients to be blended, dosage form / formulation, method of use, etc. are as described in the section "1. Inhibitor of destruction of gingival tissue" above.

[0052] The MMP-1 inhibitor of the present invention is applied to the oral cavity for the purpose of inhibiting the activity of MMP-1 produced in gingival tissue. EXAMPLES

[0053] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these.

[0054] Test Example 1: Verification of the inhibitory effect of MMP-1 activity produced by gingival cells stimulated by LPS Human oral gingival fibroblasts HGF-1 (CRL-2014, ATCC) were suspended in D-MEM high glucose medium containing 10% FBS (fetal bovine serum) and plated on a 96-well plate at 1 × 10 4 One day after cell seeding, the culture medium was removed, and a test solution shown in Table 1 was added to each well at 100 μL / well.

[0055] [Table 1]

[0056] After adding the test solution shown in Table 1, the cells were cultured in a 37°C 5% CO2 incubator. 24 hours after the addition of the test solution, the culture solution was removed, and MMP-1 in the culture solution was quantified using an ELISA kit for MMP-1 quantification (Duo Set Human Total MMP-1, manufactured by R&D). At the same time, absorbance at 450 nm, which is an index of living cells, was measured using Cell Couting kit-8 (manufactured by Dojindo Chemical Industries, Ltd., product code CK04). Separately, absorbance at 450 nm was measured using the Cell Couting kit-8 for a known cell number to create a standard curve of cell number vs. absorbance, and the number of cells after the addition of the test solution was calculated using the standard curve. Next, the amount of MMP-1 per living cell was calculated, and the collagenolytic activity (%) was calculated according to the following formula. This test was performed under the condition of n=3, and the collagenolytic activity was calculated as the average value thereof.

number

[0057] The results are shown in Table 2. As a result, it was confirmed that when 2-methacryloyloxyethyl phosphorylcholine-butyl methacrylate copolymer was added (Example 1), the activity of collagen decomposition enzyme (MMP-1) could be reduced compared to when no additive was added (Comparative Example 1). In other words, from these results, it became clear that 2-methacryloyloxyethyl phosphorylcholine-butyl methacrylate copolymer can stably maintain collagen in gingival tissue during inflammation or bacterial infection, and can suppress the destruction of gingival tissue and gingival recession.

[0058] [Table 2]

[0059] Prescription Examples The toothpastes shown in Table 3 and the mouthrinses shown in Table 4 were prepared. The toothpastes and mouthrinses contain a phosphocholine group-containing polymer (2-methacryloyloxyethyl phosphorylcholine-butyl methacrylate copolymer, polymethacryloyloxyethyl phosphorylcholine, or polyquaternium-64), and have the effect of suppressing the destruction of gingival tissue and gingival recession by stably maintaining collagen in the gingival tissue during inflammation or bacterial infection, and the effect of preventing gingival recession caused by collagen decomposition.

[0060] [Table 3]

[0061] [Table 4]

Claims

1. An MMP-1 production inhibitor (excluding those used for preventing gingivitis) which contains a phosphocholine group-containing polymer and is used to inhibit the production of MMP-1 in gingival fibroblasts caused by stimulation with lipopolysaccharide.

2. 2. The MMP-1 production inhibitor according to claim 1, wherein the phosphocholine group-containing polymer is a 2-methacryloyloxyethyl phosphorylcholine / butyl methacrylate copolymer.

3. The MMP-1 production inhibitor according to claim 1 or 2, which is in the form of a liquid dentifrice, a liquid dentifrice, a toothpaste, or a mouthwash.

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