JP7535839B2 - Agent for revitalizing gums with inflammation and/or bacterial infection - Google Patents

Description

The present invention relates to a gingival activator that can activate gingival cells in gingivae with inflammation and/or bacterial infection, thereby restoring the gingivae to a normal state.

The gingiva (dental gums) are periodontal tissues that support the teeth and are formed by gingival cells (gingival epithelial cells, gingival fibroblasts, etc.) and the extracellular matrix (collagen, etc.) produced by these gingival cells. When gingival cells are damaged by bacterial infection or contact with toxins, the cell proliferation ability decreases and collagen is destroyed, resulting in gingival recession. Such gingival recession leads to the progression of periodontal disease and is also a factor in tooth loss. For this reason, it is important for oral hygiene to revitalize inflamed or bacterially infected gingiva, restore it to a healthy state, and turn it into healthy periodontal tissue.

Various ingredients have been reported so far that are effective in normalizing gingiva accompanied by inflammation or bacterial infection. For example, Patent Document 1 discloses that plant extracts such as lychee, red ginger, and dokudami can be used as anti-gingivitis agents. Patent Document 2 discloses that astaxanthin and/or its fatty acid esters can improve the survival rate of gingival fibroblasts in the presence of liposaccharide derived from Porphyromonas gingivalis. However, the requirements for maintaining or improving the healthy state of gingiva in oral hygiene products are increasing year by year, and it is necessary to respond to the diversification of formulations of oral hygiene products, and there is a demand for the development of new formulations that can effectively activate gingiva accompanied by inflammation or bacterial infection.

On the other hand, phosphocholine group-containing polymers such as 2-methacryloyloxyethyl phosphorylcholine/butyl methacrylate copolymers have been reported to have high affinity for the body and also have a moisturizing effect, and are mainly used in topical preparations. However, the effect of phosphocholine group-containing polymers on gingiva accompanied by inflammation or bacterial infection has not been clarified.

JP 2009-263332 A JP 2015-110526 A

The object of the present invention is to provide a gingival activator, gingival normalizer, or gingival repair promoter that can activate gingival cells in gingivae with inflammation and/or bacterial infection, thereby restoring the gingivae to a normal state.

The present inventors conducted extensive research to solve the above problems and discovered that a phosphocholine group-containing polymer can activate gingival cells in gingiva accompanied by inflammation and/or bacterial infection, effectively activating the gingiva, normalizing the gingiva, or promoting gingival repair. The present invention was completed based on this knowledge and further research.

That is, the present invention provides the following aspects.
Item 1. An agent for activating gums accompanied by inflammation and/or bacterial infection, comprising a phosphocholine group-containing polymer.
Item 2. The gum activator according to Item 1, wherein the phosphocholine group-containing polymer is a 2-methacryloyloxyethyl phosphorylcholine/butyl methacrylate copolymer.
Item 3. The activator according to Item 1 or 2, which is a liquid dentifrice, a liquid dentifrice, a toothpaste, or a mouthwash.
Item 4. An agent for normalizing gingiva accompanied by inflammation and/or infection, comprising a phosphocholine group-containing polymer.
Item 5. A repair promoter for gingiva accompanied by inflammation and/or infection, comprising a phosphocholine group-containing polymer.

The present invention can activate gingiva accompanied by inflammation and/or infection, and is therefore effective in revitalizing the gingiva, promoting metabolism, improving homeostasis, and the like. Furthermore, the present invention can improve the proliferation ability of gingival cells in gingiva with inflammation or gingiva with infection such as periodontal disease, thereby promoting recovery from these symptoms and diseases.

In addition, by activating gingiva accompanied by inflammation and/or infection, the gingiva can be restored to a normal state, and thus the phosphocholine group-containing polymer is also effective in normalizing and promoting the repair of gingiva accompanied by inflammation and/or infection.

1. Gingival activator with inflammation and/or bacterial infection The present invention is an activator for gingival inflammation and/or bacterial infection, characterized in that it contains a phosphocholine group-containing polymer. In the following, the term "gingival activator with inflammation and/or bacterial infection" may be simply referred to as "activator". The activator of the present invention will be described in detail below.

[Phosphocholine group-containing polymer]
The activator of the present invention uses a phosphocholine group-containing polymer as an active ingredient. The phosphocholine group-containing polymer has an effect of promoting and activating the proliferation of gingival epithelial cells and gingival fibroblasts in gingiva accompanied by inflammation and/or bacterial infection, and can activate and normalize the gingiva.

A 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 that has moisturizing properties, etc.

In the phosphocholine group-containing polymer, the type of phosphocholine group-containing monomer is not particularly limited, but examples thereof include monomers having a phosphocholine group and a vinyl group. More specific examples of the phosphocholine group-containing monomer include 2-methacryloyloxyethyl phosphorylcholine, 2-methacryloyloxyethyl phosphorylethanolamine, and the like. In the phosphocholine group-containing polymer, the phosphocholine group-containing monomer may be one type alone or two or more types may be combined. Among these phosphocholine group-containing monomers, 2-methacryloyloxyethyl phosphorylcholine is preferred from the viewpoint of more effectively activating the gums accompanied by inflammation and/or bacterial infection.

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.

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

The type of monomer other than the phosphocholine group-containing monomer contained in the phosphocholine group-containing polymer is not particularly limited, provided that it is pharma- ceutical acceptable and capable of radical polymerization with the phosphocholine group-containing monomer, but examples of such monomers 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 monomers, from the viewpoint of more effectively activating the gums accompanied by inflammation and/or bacterial infection, 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.

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 notation regarding the phosphocholine group-containing polymer, the name in parentheses indicates the cosmetic ingredient name.

In the activator 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.

Among these phosphocholine group-containing polymers, from the viewpoint of more effectively activating the gums accompanied by inflammation and/or bacterial infection, 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.

In the activator 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 activator, etc., and may be, for example, 0.005 to 0.5% by weight, preferably 0.025 to 0.25% by weight, and more preferably 0.05 to 0.1% by weight.

[Other ingredients]
The activator 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.

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.

Examples of anti-inflammatory agents include dipotassium glycyrrhizinate, glycyrrhetinic acid, allantoin, tranexamic acid, epsilon aminocaproic acid, azulene, sodium chloride, vitamins, etc.

Examples of abrasives 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.

GTase inhibitors include, for example, 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 root, gentiana, Chinese laurel, gentian, Coptis chinensis, and the like.

Examples of plaque inhibitors include zinc citrate and gluconic acid.

Examples of anti-dentin hypersensitivity agents include potassium nitrate, aluminum lactate, and strontium chloride.

Examples of anti-tartar agents include polyphosphates, zeolites, and ethanehydroxydiphosphonate.

Examples of tooth strengthening/remineralizing agents include fluoride, sodium fluoride, sodium fluorophosphate, stannous fluoride, etc.

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 copolymers, etc.), copolymers of methacrylic acids (methacrylic acid and acrylic acid Examples of such polymers include cellulose-based polymers such as n-butyl polymers, polymers of methacrylic acid and methyl methacrylate, and polymers of methacrylic acid and ethyl acrylate; synthetic polymers such as carboxyvinyl polymers, polyethylene glycol, polyvinyl alcohol, and polyvinylpyrrolidone; natural polymers 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 polymers such as collagen and gelatin; and rubber-based polymers such as gum arabic, karaya gum, tragacanth gum, xanthan gum, locust bean gum, guar gum, tamarind gum, and gellan gum.

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

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

Fragrances include, for example, natural fragrances (such as fennel oil), synthetic fragrances, and blends of these fragrances.

Sweetening agents include sodium saccharin, stevioside, stevia extract, aspartame, xylitol, starch syrup, honey, sorbitol, maltitol, mannitol, erythritol, and sugars (lactose, sucrose, fructose, glucose, etc.).

Examples of dyes include natural dyes, synthetic dyes, and mixtures thereof.

Examples of deodorants include zinc chloride, sodium copper chlorophyllin, green coffee bean extract, burdock powder, green tea, roasted rice bran extract, etc.

Examples of surfactants 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 esters, maltose fatty acid esters, maltitol fatty acid esters, lactol fatty acid esters, sorbitan fatty acid esters, polyoxyethylene sorbitan monostearate, polyoxyethylene higher alcohols, and the like. nonionic surfactants such as diol ether, polyoxyethylene polyoxypropylene copolymer, polyoxyethylene polyoxypropylene fatty acid ester, 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-hydroxyethylimidazolium 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.

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

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.

When these components are contained in the activator of the present invention, their content may be appropriately set within the range normally used in the relevant technical field.

[Dosage form/formulation]
The dosage form of the activator 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).

The formulation of the activator 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 sprays, 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.

[Use and Usage]
The activator of the present invention is applied to the oral cavity for the purpose of activating gingiva accompanied by inflammation and/or infection. In the present invention, "activating gingiva accompanied by inflammation and/or infection" refers to improving the proliferation ability of gingival cells (gingival epithelial cells, gingival fibroblasts) in gingiva accompanied by inflammation and/or infection. In gingiva accompanied by inflammation or infection such as periodontal disease, the proliferation ability of gingival cells is reduced, making it difficult to recover from these symptoms or diseases. However, the activator of the present invention can improve the proliferation ability of gingival cells in gingiva accompanied by inflammation and/or infection, and promote recovery from these symptoms or diseases.

Since activating gums accompanied by inflammation and/or infection brings about revitalization, promotion of metabolism, improvement of homeostasis, etc. in the gums, the activator of the present invention can also be used as an agent for activating gums accompanied by inflammation and/or infection, an agent for promoting metabolism, an agent for improving homeostasis, etc.

In addition, since activating gums accompanied by a bacterial infection such as periodontal disease can improve the bacterial infection, the activator of the present invention can also be used as an agent for improving bacterial infections such as periodontal disease. Furthermore, since activating gums accompanied by gingivitis is effective in improving the symptoms of gingivitis, the activator of the present invention can also be used as an agent for improving periodontal disease.

The activator of the present invention may be applied to the oral cavity in a form appropriate for the formulation and allowed to remain in the oral cavity for a certain period of time. There are no particular limitations on the amount and frequency of use of the activator of the present invention, but it may be used, for example, in an amount that provides about 0.05 to 5 mg of phosphocholine group-containing polymer per application, once to several times per day, preferably about 1 to 3 times.

2. Agent for normalizing gingiva accompanied by inflammation and/or infection; agent for promoting repair of gingiva accompanied by inflammation and/or infection The phosphocholine group-containing polymer can restore gingiva accompanied by inflammation and/or infection to a normal state by activating the gingiva accompanied by inflammation and/or infection, so the phosphocholine group-containing polymer can also be used as an agent for normalizing gingiva accompanied by inflammation and/or infection. Furthermore, the phosphocholine group-containing polymer can promote the restoration of gingiva accompanied by inflammation and/or infection to a normal state by activating the gingiva accompanied by inflammation and/or infection, so the phosphocholine group-containing polymer can also be used as an agent for promoting repair of gingiva accompanied by inflammation and/or infection.

In the normalizing agent and repair promoter 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 above section "1. Gingival activator accompanied by inflammation and/or infection."

The normalizing agent of the present invention can normalize gingiva accompanied by inflammation and/or infection, and is particularly effective as an agent for improving gingivitis, periodontal disease, etc. Furthermore, the repair promoter of the present invention can promote the recovery of gingiva accompanied by inflammation and/or infection to a healthy and hygienic state, and is particularly effective as an agent for improving gingivitis, periodontal disease, etc.

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

Test Example 1: Verification of the activation effect of gingival cells in the presence of LPS Human oral gingival squamous epithelial cells Ca9-22 (JCRB0625, JCRB Bioresource Bank) were suspended in E-MEM medium containing 10% FBS (fetal bovine serum) and seeded onto a 96-well plate at 5 x ¹⁰³ cells/well. One day after cell seeding, the culture medium was removed and the test solution shown in Table 1 was added to each well at 100 μL/well.

After adding the test solution shown in Table 1, the cells were cultured in a 37°C 5% _CO2 incubator. The culture solution was removed 48 hours and 72 hours after the addition of the test solution, and the absorbance at 450 nm, which is an index of viable cells, was measured using Cell Couting kit-8 (Dojindo Chemical Co., Ltd., product code CK04). Separately, the 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 increase in the number of viable cells (cells) was calculated according to the following formula. This test was performed under the condition of n = 3, and the increase in the number of viable cells was calculated as the average value of the results.

The results are shown in Table 2. As a result, when 2-methacryloyloxyethyl phosphorylcholine/butyl methacrylate copolymer was added (Example 1), an increase in the number of viable gingival epithelial cells was observed compared to when no additive was added (Comparative Example 1), confirming that gingival epithelial cells were activated in the presence of LPS. In other words, these results demonstrate that 2-methacryloyloxyethyl phosphorylcholine/butyl methacrylate copolymer can activate gingiva in the presence of LPS.

The toothpaste shown in Formulation Example Table 3 and the mouthrinse shown in Table 4 were prepared. The toothpaste and mouthrinse contain a phosphocholine group-containing polymer (2-methacryloyloxyethyl phosphorylcholine-butyl methacrylate copolymer, polymethacryloyloxyethyl phosphorylcholine, or polyquaternium-64), and have the effect of revitalizing and repairing gums that have been weakened due to inflammation and/or bacterial infection.

Claims (3)

A gingival activator for improving proliferation ability of gingival cells in gingiva accompanied by periodontal disease in which lipopolysaccharide is present (excluding gingiva in which gingivitis has occurred), comprising:
The activating agent comprises a polymer containing a phosphocholine group. The activator according to claim 1, wherein the phosphocholine group-containing polymer is a 2-methacryloyloxyethyl phosphorylcholine-butyl methacrylate copolymer. 3. The activator according to claim 1 or 2, provided as a liquid dentifrice, liquid dentifrice, toothpaste, or mouthwash.