Antifungal composition

Abstract

The present invention addresses the problem of providing an antifungal composition which contains highly safe ingredients derived from natural products, and exhibits antibacterial effects not only on Candida albicans but also on other Candida fungi or various fungi that live in the oral cavity.　The present invention relates to an antifungal composition which contains the following components (a), (b) and (c). (a) a saturated fatty acid having 6-12 carbon atoms, (b) a plant essential oil having antifungal activity, and (c) at least one selected from among polyphenols and saponins.

Description

Antifungal composition

[0001] The present invention relates to an antifungal composition, particularly to an oral antifungal composition.

[0002] In humans, periodontal disease, which is a disease characterized by symptoms such as dental caries (cavities), gingivitis, or inflammation of periodontal tissues, is generally caused by the accumulation of plaque. It has long been recognized that its removal and prevention, i.e., plaque control, are important in oral hygiene.

[0003] The main methods for plaque control are mechanical plaque removal using a toothbrush or oral disinfection using oral disinfectants. However, mechanical plaque removal using a toothbrush requires a long period of time and skilled brushing techniques to remove plaque. Furthermore, methods using oral disinfectants have the problem that the disinfectant components do not penetrate deep into bacterial aggregates such as plaque, resulting in insufficient effectiveness.

[0004] Furthermore, in addition to bacteria that cause dental caries and periodontal disease, the oral cavity also contains resident bacteria such as Candida, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus. These resident bacteria are generally non-toxic or attenuated, and healthy individuals rarely develop infectious diseases caused by these resident bacteria. However, individuals with underlying diseases such as blood diseases, immunodeficiency, diabetes, and visceral diseases, elderly people with weakened immune systems, individuals unable to adequately clean their mouths, and young children may suffer from opportunistic infections, i.e., infectious diseases, caused by these resident bacteria. Depending on their physical condition, these infections may lead to serious diseases such as aspiration pneumonia, meningitis, and sepsis. Thus, the treatment and prevention of infectious diseases caused by these resident oral bacteria typically involves mechanical cleaning and pharmaceutical treatment, similar to the treatment and prevention of dental caries and periodontal disease. However, even if such treatments result in improvement in the affected area, there is a concern that other healthy cells may be damaged or that side effects of the drugs may cause disease in healthy organs. For these reasons, it has become known in recent years that oral care can significantly prevent not only dental caries and periodontal disease, but also opportunistic infectious diseases caused by resident bacteria.

[0005] Among the above-mentioned normal bacteria, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus are roughly classified as bacteria, while Candida is a type of fungus, or mold. Generally speaking, Candida fungi include those involved in the brewing of miso, soy sauce, and wine, such as Candida etchelsii, Candida versatilis, and Candida stellata, as well as pathogenic ones such as Candida albicans, Candida glabrata, Candida parapsilosis, Candida tropicalis, and Candida krusei. Among the pathogenic Candida fungi, Candida albicans is the main causative agent of oral candidiasis and cutaneous candidiasis.

[0006] It is known that oral Candida infections can be prevented more effectively through oral care such as gargling and tooth brushing. For example, Patent Document 1 discloses a mouthwash containing an antifungal antibiotic as an active ingredient, which is expected to improve systemic diseases caused by Candida and normalize biological functions. The mouthwash described in Patent Document 1 reduces the amount of Candida by using a substance such as amphotericin B (AMPH-B) or nystatin, which has a broad antibacterial spectrum, as its main ingredient. Incidentally, the present inventors' group has also specifically reported the anti-Candida effect of amphotericin B (see Non-Patent Document 1).

[0007] Meanwhile, various oral antibacterial agents have been developed that are effective with a small amount of active ingredient, are made of materials (e.g., natural materials) that are easy to handle, and have anti-Candida albicans activity. As one example, a group at the Teikyo University Medical Mycology Research Center has disclosed in Patent Document 2 an anti-Candida composition that uses a combination of capric acid and essential oils such as geraniol to inhibit the growth of Candida albicans as a therapeutic agent for oral candidiasis. In addition, in parallel with Patent Document 2, the same group has also developed an anti-Candida composition that uses four saturated fatty acids including capric acid (caproic acid C6, caprylic acid C8, capric acid C9, capric acid C10, capric acid C11, capric acid C12, capric acid C13, capric acid C14, capric acid C15, capric acid C16, capric acid C17, capric acid C18, capric acid C19, capric acid C20, capric acid C21, capric acid C22, capric acid C23, capric acid C24, capric acid C25, capric acid C26, capric acid C27, capric acid C28, capric acid C29 ... 10 , lauric acid C 12 have reported the anti-Candida albicans effect of ) (see Non-Patent Document 2).

[0008] Furthermore, Patent Document 3 discloses an example of an oral antibacterial agent whose main ingredients are naturally derived substances and essential oils, which uses mastic (mainly its resin and essential oil) and egg yolk oil.

[0009] Patent No. 4323141 Patent No. 5820194 Patent No. 6986742

[0010] Yosuke Kimura, Tomoo Yamamoto, Eiji Kusashio, and Nobuko Maeda (co-authors), "Long-term Use of Antifungal Agents Reduces Plaque Volume," Dental Therapy, Vol. 36, No. 1, 2017, pp. 9-14. Miki Takahashi, Shigeharu Inoue, Kazumi Hayama, Kentaro Ninomiya, and Shigeru Abe (co-authors), "Inhibitory Effect of the Medium-Chain Fatty Acid Capric Acid on the Growth of Candida Mycelium and Its Therapeutic Effect on Oral Candidiasis," Med. Mycol. J., Vol. 53 (No. 4), 2012, pp. 255-261.

[0011] However, the inventions described in Patent Document 1 and Non-Patent Document 1 use AMPH-B, a designated highly toxic drug, as the antifungal antibiotic in the mouthwash (oral composition). While low concentrations provide sufficient anti-Candida efficacy, incorrect dosages may result in various side effects. While numerous antifungal drugs other than AMPH-B exist, they have been associated with numerous serious side effects, making them difficult to use unless one is suffering from oral candidiasis. Furthermore, all oral antifungal medications, including AMPH-B, are prescription-only. Therefore, those who are not already suffering from or highly suspected of having candidiasis cannot obtain a prescription and therefore cannot obtain them. Furthermore, the anti-Candida efficacy of capric acid and / or essential oils (especially those derived from ginger) described in Patent Document 2 and Non-Patent Document 2 remains insufficient. Furthermore, the mastic resin and resin liquid described in Patent Document 3 are exclusively cultivated on the Greek island of Chios, raising concerns about the high production volume and transportation costs required to meet demand.

[0012] Therefore, an object of the present invention is to provide an antifungal composition that contains highly safe ingredients derived from natural products and that exhibits antibacterial effects not only against Candida albicans, the fungus that is the primary cause of candidiasis, but also against other Candida species and various types of fungi that inhabit the oral cavity.

[0013] Therefore, the present inventors have extensively investigated the antifungal effects of saturated fatty acids such as capric acid, the antifungal effects of plant essential oils, and the antifungal effects of these ingredients when combined with other plant-derived ingredients. As a result, they have found that by combining saturated fatty acids and plant essential oils with polyphenols and / or saponins, the antifungal effects are synergistically enhanced and a highly safe antifungal composition can be obtained, thereby completing the present invention.

[0014] That is, the present invention provides the following inventions [1] to [8]. [1] An antifungal composition containing the following components (a), (b), and (c): (a) a saturated fatty acid having 6 to 12 carbon atoms, (b) a plant essential oil having antifungal activity, and (c) one or more selected from polyphenols and saponins. [2] The antifungal composition according to [1], which is an oral antifungal composition. [3] The antifungal composition according to [1] or [2], wherein component (a) is a saturated fatty acid selected from caprylic acid, capric acid, and lauric acid. [4] The antifungal composition according to any one of [1] to [3], wherein component (b) is an essential oil of one or more plants selected from peppermint, spearmint, eucalyptus (such as Eucalyptus globulus and Eucalyptus radiata), thyme, clove, geranium, rose, palmarosa, lavender, ravensara, tea tree, lemon, lemongrass, orange, yuzu, lime, grapefruit, marjoram, fennel, cinnamon / cinnamon leaf, rosemary, cypress, oregano, wintergreen, ginger, and mastic. [5] The antifungal composition according to any one of [1] to [4], wherein the polyphenols are derived from one or more plants selected from indigo, tea (green tea, oolong tea, black tea), sweet tea, cherry leaves (sakuraba), lemon, white birch, persimmon, grapes, apple, blueberry, raspberry, cacao (chocolate, cocoa), soybean, loquat leaf, burnet, St. John's wort, hamamelis, olive, olive leaf, Scutellaria root, white birch, wild rose, perilla seed, guava leaf, sword bean, lychee, burdock, mulberry leaf, grape seed, grape leaf, apple, and ginger. [6] The antifungal composition according to any one of [1] to [5], wherein the saponins are derived from one or more plants selected from licorice, honeysuckle, soybean, adzuki bean, sword bean, Astragalus membranaceus, Soapberry, horse chestnut, Styrax japonica, olive, ginseng, platycodon, grape, soapwort, tea leaves, tea seeds, tea flowers, yucca (schidigera), Sophora japonica, Senega, camellia, and Lotus japonicus, or saponins derived from echinoderms. [7] The antifungal composition according to any one of [1] to [6], wherein the component (c) contains polyphenols and saponins.[8] The antifungal composition according to any one of [1] to [7], wherein the target fungus is at least one or more species selected from Candida albicans, Candida krusei, Candida tropicalis, Candida glabrata, and Candida parapsilosis.

[0015] The antifungal composition of the present invention has a strong antibacterial effect against pathogenic Candida fungi, such as Candida albicans, Candida krusei, Candida tropicalis, Candida glabrata, and Candida parapsilosis, present in the oral cavity, and can reduce the number of these fungi in the oral cavity. Furthermore, the antifungal composition of the present invention can reduce not only the number of Candida fungi but also the number of fungi other than Candida, such as Aspergillus fungi, and, for unknown reasons, as a result, it can reduce the total number of motile bacilli and cocci in the oral cavity. Furthermore, because the antifungal composition of the present invention reduces fungi in the oral cavity, it can reduce the amount of dental plaque adhesion and make the resulting dental plaque nontoxic or attenuated, thereby enabling the prevention of periodontal disease and the suppression of gingivitis, etc. Furthermore, the reduction in the number of fungi in the oral cavity improves the oral bacterial flora (a reduction in the number of oral bacteria due to changes in the properties of dental plaque), which can contribute to improving oral health and bad breath. In addition, a reduction in the number of fungi also leads to a reduction in dental plaque, improvement of gingivitis, reduction in bad breath, improvement of tongue coating, reduction in motile bacteria, and improvement of oral discomfort.

[0016] 1 is an image showing the state of an antibacterial test against Candida albicans in Example 4. FIG. 2 is an image showing the state of an antibacterial test against Candida krusei in Example 4. FIG. 3 is an image showing the state of an antibacterial test against Candida tropicalis in Example 4. FIG. 4 is an image showing the state of an antibacterial test against Candida glabrata in Example 4. FIG. 5 is an image showing the state of an antibacterial test against Candida parapsilosis in Example 4. FIG. 6 is an image showing the state of an antibacterial test against Aspergillus in Example 4.

[0017] Unless otherwise specified, the terms used in this specification are used in the sense commonly used in the dental field.

[0018] One aspect of the present invention is an antifungal composition containing the following components (a), (b), and (c): (a) a saturated fatty acid having 6 to 12 carbon atoms, (b) a plant essential oil having antifungal activity, and (c) one or more selected from polyphenols and saponins. Components (a), (b), and (c) are described below.

[0019] Component (a) is a saturated fatty acid having 6 to 12 carbon atoms. Specific examples include caproic acid, caprylic acid, capric acid, and lauric acid. Of these, caprylic acid, capric acid, and lauric acid are preferred from the standpoint of antifungal activity, with caprylic acid and capric acid being more preferred, and capric acid being even more preferred. These saturated fatty acids are used in various chemical industries, including as raw materials (mainly intermediates) in the field of organic synthetic chemistry, surfactant materials, fragrances, lubricants, grease, rubber, dyes, synthetic fibers, food additives, and pharmaceuticals. These fatty acids can be produced industrially by oxidizing alcohols or aldehydes, but can also be produced by hydrolyzing various fats and oils.

[0020] The content of component (a) in the antifungal composition of the present invention varies depending on the form of the composition, but from the viewpoints of antifungal activity, taste, ease of administration such as irritation, viscosity of the composition, etc., it is preferably 0.005 to 15% by mass, more preferably 0.01 to 10% by mass, even more preferably 0.05 to 5% by mass, and even more preferably 0.5 to 4% by mass.

[0021] Component (b) is a plant essential oil with antifungal activity. Plant essential oils are volatile oils produced by plants. Each has its own unique fragrance and can be distilled from plants by steam distillation, hot water distillation (direct distillation), or other methods. Also known as essential oils, they are generally complex mixtures of numerous compounds and are primarily used as flavorings in the food industry due to their fragrance. In the present invention, plant essential oils with antifungal activity are used. Examples of plant essential oils with antifungal activity include essential oils of one or more plants selected from peppermint, spearmint, eucalyptus (Eucalyptus globulus, Eucalyptus radiata, etc.), thyme, clove, geranium, rose, palmarosa, lavender, ravensara, tea tree, lemon, lemongrass, orange, yuzu, lime, grapefruit, marjoram, fennel, cinnamon, cinnamon leaf, rosemary, cypress, oregano, wintergreen, ginger, and mastic. Of these, essential oils of one or more plants selected from eucalyptus, citronella, tea tree, grapefruit, lemon, lemongrass, oregano, geranium, thyme, cinnamon, cypress, oregano, wintergreen, and ginger are preferred, and essential oils of one or more plants selected from eucalyptus, thyme, tea tree, lemongrass, geranium, cinnamon, cypress, oregano, and ginger are more preferred.

[0022] Examples of the bactericidal or antibacterial components (hereinafter referred to as "bacteriostatic components") in these essential oils include thymol, carvacrol, geranial, geraniol, cinnamaldehyde, eugenol, citral, cineole, α-pinene, limonene, camphene, terpinene, linalool, α-terpineol, terpinen-4-ol, citronellol, 1-menthol, p-cresol methyl ether, linalyl acetate, 1,8-cineole, hinokitiol, methyl salicylate, shogaol, 6-gingerol, and the like. Among these, a component selected from thymol, carvacrol, geraniol, cinnamaldehyde, eugenol, citral, cineole, α-pinene, limonene, linalool, α-terpineol, terpinen-4-ol, hinokitiol, shogaol, and 6-gingerol is more preferred, and a component selected from thymol, carvacrol, geraniol, cinnamaldehyde, terpinen-4-ol, hinokitiol, and 6-gingerol is even more preferred. As the essential oil of the plant, a plant essential oil containing these bacteriostatic components is preferred.

[0023] In the antifungal composition of the present invention, the plant essential oil may be used as it is, i.e., commercially available, or the bacteriostatic component may be isolated from the essential oil or industrially produced. Also, a plant extract containing the essential oil may be used.

[0024] The content of component (b) in the antifungal composition of the present invention varies depending on the form of the composition, the type of component (b) to be blended, the degree of purification, etc., but from the viewpoints of antifungal activity, ease of administration such as taste and smell, irritation, etc., it is preferably 0.001 to 5 mass%, more preferably 0.005 to 3 mass%, even more preferably 0.01 to 3 mass%, and even more preferably 0.02 to 1 mass%.

[0025] Component (c) is one or more selected from (c1) polyphenols and (c2) saponins. When used in combination with components (a) and (b), component (c) synergistically enhances the antifungal effect. (c1) Polyphenols is a general term for plant components having multiple phenolic hydroxy groups in the molecule. Examples of aromatic rings include benzene rings and naphthalene rings. Preferred polyphenols include polyphenols derived from one or more plants selected from indigo, tea (green tea, oolong tea, black tea), sweet tea, cherry leaves, lemon, white birch, persimmon, grapes, apples, blueberries, raspberries, cacao (chocolate, cocoa), soybeans, loquat leaves, burnet, St. John's wort, hamamelis, olives, olive leaves, Scutellaria root, white birch, wild rose, perilla seeds, guava leaves, mulberry leaves, grape seeds, grape leaves, apples, and ginger. Extracts of these plants, namely, indigo extract, tea (green tea, oolong tea, black tea) extract, sweet tea extract, matcha powder, cherry leaf extract, lemon extract, white birch extract, persimmon rind extract, grape extract, lychee, apple extract, blueberry extract, raspberry extract, cacao extract (chocolate, cocoa), soybean extract, loquat leaf extract, burnet extract, St. John's wort extract, witch hazel extract, olive extract, olive leaf extract, Scutellaria root extract, white birch extract, wild rose extract, ginger extract, perilla seed extract, guava leaf extract, mulberry leaf extract, grape seed extract, wine extract, grape leaf extract, and extracts containing flavonoids such as apple tannin, catechins, and tannin-based polyphenols can be used. Of these plant-derived polyphenols, polyphenols derived from one or more plants selected from tea (green tea, oolong tea, black tea), sweet tea, persimmon, grapes, cacao (chocolate, cocoa), persimmon tannin extract, grape extract, olive leaf extract, ginger extract, perilla seed extract, wine extract, grape leaf extract, and apple tannin are more preferred, and polyphenols derived from one or more plants selected from tea (green tea, oolong tea, black tea), persimmon, persimmon tannin extract, grape extract, ginger extract, perilla seed extract, and wine extract are even more preferred.The polyphenols may be isolated, commercially available, extracted with water or alcohol (ethanol), or the like.

[0026] The content of the (c1) polyphenols in the antifungal composition of the present invention varies depending on the form of the composition, the degree of purification of the polyphenols to be blended, etc., but from the viewpoints of antifungal activity, ease of administration such as bitterness, etc., it is preferably 0.005 to 5% by mass, more preferably 0.01 to 3% by mass, even more preferably 0.05 to 3% by mass, and even more preferably 0.05 to 2% by mass.

[0027] (c2) Saponins are a general term for glycosides composed of sapogenin and sugar, and sapogenin is an aglycone containing a steroid skeleton or a triterpene skeleton. Examples of sapogenins with a steroid skeleton include yamogenin, tigenin, neogitogenin, tocologenin, diosgenin, and hecogenin. Examples of saponins include saponins derived from one or more plants selected from licorice, honeysuckle, soybean, adzuki bean, sword bean, Astragalus membranaceus, soapberry, horse chestnut, snowbell, olive, ginseng, bellflower, grape, soap grass, tea leaves, tea seeds, tea flowers, yucca (schidigera), Sophora japonica, Senega, camellia, and Lotus japonicus, as well as saponins derived from echinoderms such as sea cucumbers. Saponins derived from licorice and soybean are particularly preferred. Furthermore, saponins derived from licorice such as glycyrrhizinic acid or a salt thereof, glycyrrhetinic acid or a salt thereof, soybean saponin (soyasaponin), soapberry saponin, tea flower saponin, yucca (schidigera) saponin, etc. are commercially available, and one or more selected from these can be used, and soybean saponin, soapberry saponin, and glycyrrhizinic acid or a salt thereof are more preferred.

[0028] The content of (c2) saponins in the antifungal composition of the present invention varies depending on the form of the composition, the types of saponins to be blended, the degree of purification, etc., but from the viewpoints of antifungal activity, ease of administration, etc., it is preferably 0.005 to 5 mass%, more preferably 0.01 to 3 mass%, even more preferably 0.1 to 3 mass%, and even more preferably 0.2 to 3 mass%.

[0029] The total content of (c) one or more selected from polyphenols and saponins in the antifungal composition of the present invention varies depending on the form of the composition, the types of polyphenols and saponins to be blended, the degree of purification, etc., from the viewpoint of enhancing the antifungal activity, but is preferably 0.2 to 8 mass%, more preferably 0.4 to 6 mass%, and even more preferably 0.5 to 5 mass%. Furthermore, the mass ratio (a / c) of component (a) to component (c) varies depending on the type of component (c), but from the viewpoint of obtaining an excellent antifungal activity, is preferably 0.5 to 30, more preferably 1 to 30, and even more preferably 1 to 20.

[0030] The combined use of (c1) polyphenols and (c2) saponins is more preferred because it synergistically enhances the antifungal effects of the components (a) and (b). The mass ratio (c1 / c2) of the two components (c1) and (c2) when used in combination varies depending on the type of polyphenols and saponins, but is preferably 0.1 to 20, more preferably 0.5 to 20, from the viewpoints of the antifungal effect enhancement effect and ease of administration, such as taste.

[0031] As will be shown in the Examples below, the antifungal composition of the present invention exhibits antibacterial activity not only against Candida fungi such as Candida albicans, Candida krusei, Candida tropicalis, Candida glabrata, and Candida parapsilosis, but also against Aspergillus fungi (e.g., Aspergillus niger (A. niger)), which are normal inhabitants of the oral cavity. In other words, it becomes possible to reduce the many types of fungi that inhabit the oral cavity and the total number of fungi in the oral cavity. Therefore, the antifungal composition of the present invention is useful as an antifungal composition for skin and oral cavity, and is particularly useful as an antifungal composition for oral cavity, which requires high safety.

[0032] The dosage form of the antifungal composition of the present invention is not particularly limited as long as it is a dosage form that can be used as a skin or oral composition. In the case of an oral composition, for example, it may be selected from toothpaste, gel, liquid toothpaste, powder toothpaste, mouthwash, film, chewing gum, capsule, tablet, mouthwash, oral lozenge, etc.

[0033] The antifungal composition of the present invention may contain the above-mentioned components, but may also contain various additives, such as pharmaceutically acceptable carriers, to form the above-mentioned dosage forms. Examples of such additives include solvents, abrasives, wetting agents, binders (thickeners), foaming agents, preservatives, pH adjusters, retention agents, sweeteners, antiseptics, fragrance components, and other active ingredients.

[0034] Examples of solvents that can be used include water, ethanol, glycerin, concentrated glycerin, diglycerin, sorbitol, maltitol, dipropylene glycol, propylene glycol, 1,3-butylene glycol, xylitol, polyethylene glycol, polyhydric alcohols such as PEG-8 and PEG-60, vegetable oils such as coconut oil, palm oil, soybean oil, rapeseed oil, sunflower oil, palm kernel oil, cottonseed oil, peanut oil, olive oil, coconut oil, corn oil, castor oil, and linseed oil, and hydrogenated vegetable oils. These solvents may be used alone or as a mixed solvent of two or more. These solvents are preferably the remainder after the above-mentioned components and other components have been combined.

[0035] Examples of abrasives include silica-based abrasives such as silica gel, precipitated silica, additive silica, hydrous silicic acid, anhydrous silicic acid, zeolite, aluminosilicate, and zirconosilicate; crystalline cellulose, dicalcium phosphate dihydrate, anhydrous dicalcium phosphate, calcium pyrophosphate, tribasic magnesium phosphate, tribasic calcium phosphate, aluminum hydroxide, alumina, light calcium carbonate, heavy calcium carbonate, magnesium carbonate, zirconium silicate; and synthetic resin abrasives. One or more of these can be used in combination. It is also possible to use no abrasive at all. The content of these abrasives is preferably 0 to 10% by mass based on the total amount of the antifungal composition of the present invention.

[0036] Examples of humectants include polyhydric alcohols such as glycerin, concentrated glycerin, diglycerin, sorbitol, maltitol, dipropylene glycol, propylene glycol, 1,3-butylene glycol, xylitol, polyethylene glycol, PEG-8, and PEG-60; plant extracts such as rosemary extract, kumazasa extract, chrysanthemum flower extract, and papaya extract; carbohydrates such as sorbitol solution; and milk-derived whey; and one or more of these may be used.

[0037] Examples of binders (thickeners) include chitosan, carrageenans, alginic acid, sodium alginate, propylene glycol alginate, calcium-containing sodium alginate, potassium alginate, calcium alginate, ammonium alginate, and other alginic acid and derivatives thereof, xanthan gum, guar gum, gelatin, agar, sodium carboxymethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium polyacrylate, and pullulan, and these can be used alone or in combination. The thickener also serves as a gelling agent. Furthermore, when chitosan is used as the binder, it can also be used as an antibacterial (bacteriostatic) agent or a coating agent for tooth surfaces.

[0038] Examples of foaming agents include sodium lauryl sulfate, sodium lauroyl sarcosinate, sodium alkyl sulfosuccinate, sodium coconut oil fatty acid monoglycerin sulfonate, sodium α-olefin sulfonate, N-acylamino acid salts such as N-acyl glutamate, 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazolinium betaine, maltitol fatty acid esters, sucrose fatty acid esters, polyglycerin fatty acid esters, fatty acid diethanolamides, polyoxyethylene sorbitan monostearate, polyoxyethylene hydrogenated castor oil, polyoxyethylene fatty acid esters, and poly-ε-lysine, and these can be used alone or in combination of two or more. Note that no foaming agent may be used.

[0039] Examples of preservatives include hinokitiol, natural perfume oils such as clove oil and peppermint oil, and essential oils, and these can be used alone or in combination of two or more. These essential oils may also function as the component (b).

[0040] Examples of pH (hydrogen ion concentration) adjusters include citric acid, (mono- or di-)sodium citrate, malic acid, (mono- or di-)sodium malate, gluconic acid, (mono- or di-)sodium gluconate, succinic acid, sodium succinate, lactic acid, (mono- or di-)sodium lactate, potassium carbonate, and sodium hydrogen carbonate, and these can be used alone or in combination.

[0041] As a retention agent for retaining (sustaining) the active ingredient of the oral antifungal composition of the present invention, liquid paraffin, gelling hydrocarbons which are mixtures of liquid paraffin and polyethylene, vegetable oil, beeswax, etc. can be used, and these can be used alone or in combination of two or more. The gelling hydrocarbons also function as a gelling agent.

[0042] Examples of sweeteners include aspartame, trehalose, stevioside, stevia extract, neohesperidyl dihydrochalcone, perillartine, xylitol, sorbitol, maltose, maltitol, licorice extract, and monk fruit extract.

[0043] Preservatives include parabens such as methylparaben, ethylparaben, propylparaben, and butylparaben, sodium benzoate, phenoxyethanol, and alkyldiaminoethylglycine hydrochloride.

[0044] The fragrance component may be one or a combination of two or more selected from 1-menthol, anethole, menthone, cineole, limonene, carvone, methyl salicylate, ethyl butyrate, eugenol, thymol, cinnamaldehyde, trans-2-hexenal, etc. The essential oil components in these essential oils may also function as the component (b).

[0045] The content of each component, such as the humectant, binder, foaming agent, preservative, retention agent, sweetener, antiseptic, and flavoring component, is not particularly limited, but is preferably in the range of 0.001 to 20% by mass relative to the total amount of the oral antifungal composition of the present invention.

[0046] The oral antifungal composition of the present invention may contain, in addition to the above, further active ingredients. Examples of such active ingredients include lysozyme chloride, sodium fluoride, potassium fluoride, sodium monofluorophosphate, potassium nitrate, sodium polyphosphate, polyethylene glycol, polyvinylpyrrolidone, hinokitiol, ascorbic acid (vitamin C), ascorbate salts, chlorhexidine salts, cetylpyridinium chloride, benzalkonium chloride, benzethonium chloride, bisabolol, triclosan, isopropylmethylphenol, tocopherol, tocopherol acetate, ε-aminocaproic acid, tranexamic acid, aluminum hydroxyl allantoin, aluminum lactate, dihydrocholesterol, glycyrrhetinic acid, glycyrrhizinate salts, copper chlorophyllin salt, sodium chloride, guaiazulene sulfonate, dextranase, pyridoxine hydrochloride, and medicinal hydroxyapatite, and one or more of these may be incorporated. The content of the active ingredient is preferably in the range of 0.001 to 20% by mass based on the total amount of the oral antifungal composition of the present invention.

[0047] The antifungal composition of the present invention can be produced in accordance with a conventional method, and the production method is not particularly limited. However, the above-mentioned components may be mixed, heated as necessary, and stirred to form a liquid, emulsion, gel, or the like.

[0048] The antifungal composition of the present invention can be used by applying it to the skin, for example, by spreading it on the required area, and in the case of an oral antifungal composition, it can be applied once to several times a day as a toothpaste, gargle, mouthwash, lozenge, oral application agent, film-like adhesive agent, etc.

[0049] The above describes embodiments of the oral composition of the present invention, but it goes without saying that various embodiments can be adopted without departing from the scope of the claims and the matters described in this specification, without being limited to the above embodiments.

[0050] The present invention will now be described in more detail with reference to examples, but the present invention is not limited to these examples. The scores in the examples below are based on the general dental clinical terminology standard. Percentages in the examples are by weight.

[0051] Example 1 (Antifungal Effect of Combined Use of Each Ingredient) (Materials and Methods) The following six types of fungi were used in combination: Candida parapsilosis collected from the oral cavity, as well as Candida albicans, Candida krusei, Candida tropicalis, Candida glabrata, and Aspergillus fungi.

[0052] The Candida Yellow reagent utilizes the fungus' ability to produce acid through the decomposition of sugars in the culture solution by fungi, and measures the number of fungi by the color change caused by the added chromium phenol red, which changes the pH of the test solution due to the acid caused by the growth of the fungus. The color changes from red to orange-red and then to yellow. After 24 hours of culture, the number of fungi in 1 ml is 1 x 10, with no color change. 2 Below, the light red color is approximately 3 x 10 3 , yellow is about 3 x 10 5 becomes.

[0053] While this method appears suitable for measuring fungal load using samples collected directly from the oral cavity, it is not suitable for measuring the antifungal activity of various samples. This is because samples are not necessarily neutral or may have buffering capacity, making it difficult to measure pH changes. In agar medium, the agent is applied directly to the fungus spread on the solid agar surface, maintaining direct contact between the fungus and the agent, allowing for confirmation of antibacterial activity. However, this method only reveals the presence or absence of antibacterial activity and the minimum effective drug concentration, regardless of the oil-solubility or water-solubility of the agent and the fungal cells, or their accessibility and invasion. In the oral cavity, where liquid and solid coexist, the agent is not always uniformly exposed to fungal cells as it is on the agar surface. Therefore, antifungal testing is required in liquid medium, such as test tubes, which contain a solid phase more similar to the oral environment and an aqueous liquid phase similar to saliva. To use capric acid or essential oils in the oral cavity, a solvent is required to dissolve and homogenize them. Therefore, an antifungal test was carried out using test tubes and a Candida Yellow medium, which is an aqueous liquid medium, with a solvent when the sample was oily. Candida Yellow test medium was used as the liquid medium, and the number of yeasts, which are fungi, was measured using a Thoma-type hemocytometer according to the usual method to determine the number of live fungi. The Thoma-type hemocytometer is a common method that is often used to measure the number of yeasts, as the size of fungal yeast is similar to that of red blood cells. The Thoma-type hemocytometer has a lower measurement accuracy when the number of measurement objects per square is less than one, so a 2 x 10 5 If the number of live yeast cells in the 5 squares measured with a Thoma-type hemocytometer is 1 to 0, the accuracy may vary. 4 > 1 mm measured with a Thoma-type hemocytometer 3 If no live yeast was found in the solution, the number of fungi in 1 ml was 1 x 10 3 The five Candida species (including Candida parapsilosis) and one Aspergillus species were collected from the agar medium colonies and cultured in Candida Yellow liquid medium. The cultures were then diluted to 5 × 10 2 Number of specimens / ml collected, total 3 x 10 3A culture solution was prepared with a concentration of 1000 cells / ml. 2 ml inner-cap type serum tubes manufactured by Sumitomo Bakelite Co., Ltd. were used as test tubes. In order to grow the fungi in a yeast form rather than a mycelium form, the culture solution volume was set to 2 ml, with 0.5 ml of air remaining in the upper part of the test tube, and the tube was sealed and cultured aerobically at 31°C for 24 hours. 1,3-butylene glycol (manufactured by Senken Co., Ltd.) was used as the solvent for capric acid and essential oil. To distinguish between live and dead yeast, cells with a transparent cell wall were considered live, while cells with a broken cell wall or those with an opaque cell wall were considered dead. As a control, a total of 3 x 10 cells of six types of fungi were used. 3 The number of viable yeast cells / ml of culture solution after 24 hours at 31°C was 3 x 10 7 Since this is a bacterial count culture calculation (which doubles in about 2 hours), the numbers after the first digit were rounded up to the nearest 4.

[0054] (Results) 1. Capric acid concentration and viable fungal counts The capric acid used was decanoic acid (also known as capric acid) manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.

[0055]

[0056] According to literature, the minimum effective concentration of capric acid against Candida albicans is around 0.05%, but in a medium containing six fungal species, it did not have the same antifungal activity as Candida albicans alone. It was found that even when an oral preparation was prepared with a capric acid concentration effective against Candida albicans, it was unable to sufficiently reduce the amount of fungi in the oral cavity. Even at a high concentration of 10%, the yeast count exceeded the number before the start of cultivation.

[0057] 2. Essential Oil Concentration and Viable Fungal Counts The essential oils used were a mixture of equal amounts of 100% pure oil solutions of oregano oil and tea tree oil manufactured by AndSH.

[0058]

[0059] The antifungal effect of essential oils was different from that observed when the medium was mixed with six fungal species and only Candida albicans was used.

[0060] 3. Tea polyphenol concentration and viable fungal counts Tea polyphenol (product name: Tea catechin powder, polyphenol 98%, manufactured by Globalfort LLC) was used as the polyphenol.

[0061]

[0062] 4. Persimmon polyphenol concentration and viable fungal count Persimmon polyphenol (product name: Kamikakishibuirojin, manufactured by Shimamoto Co., Ltd.) was used.

[0063]

[0064] 5. Saponin concentration and viable fungal counts The saponins used were dipotassium glycyrrhizinate (manufactured by Natural Cosmetics Research Institute Co., Ltd.), Quillaja saponin (Quillaja extract BG, manufactured by Maruzen Pharmaceuticals Co., Ltd.), and Sapindus mukorossi saponin (Sapindus mukorossi extract BG80C, manufactured by Maruzen Pharmaceuticals Co., Ltd.).

[0065]

[0066] Dipotassium glycyrrhizinate alone did not show any significant antifungal effect, but because dipotassium glycyrrhizinate acts as a surfactant for capric acid, it is possible to reduce the amount of capric acid solvent used.

[0067]

[0068]

[0069] 6. Testing the combined effects of capric acid and essential oils Capric acid was tested at a 1% solution concentration. 1% capric acid was used as the control.

[0070]

[0071] 7. Test of the combined effect of 1% capric acid and polyphenols. The polyphenols used were equal weights of tea polyphenols and persimmon tannin extract. 1% capric acid was used as a control.

[0072]

[0073] 1% capric acid and saponin The saponin used was a mixture of equal weights of glycyrrhizin and soapberry saponin. 1% capric acid was used as a control.

[0074]

[0075] 8. Testing the combined effect of capric acid, essential oils, and polyphenols Capric acid, essential oils, and polyphenols (tea polyphenols and persimmon tannin extract) Polyphenols were added to a 1% capric acid and 0.1% essential oil solution and measurements were taken. A 1% capric acid and 0.1% essential oil solution was used as the control.

[0076]

[0077] Table 11 shows that the combined use of capric acid, plant essential oils, and polyphenols synergistically enhances the antifungal activity.

[0078] 9. Test of the combined effect of capric acid, essential oils and saponin Capric acid, essential oils and saponin (glycyrrhizic acid and soapberry saponin) A 1% capric acid and 0.05% essential oil solution was used as the control.

[0079]

[0080] From Table 12, it was found that the combined use of capric acid, plant essential oils and saponin synergistically enhanced the antifungal activity.

[0081] 10. Test of combined effects of capric acid, essential oil, polyphenol and saponin Capric acid, essential oil, polyphenol and saponin 1% capric acid, 0.05% essential oil solution and 0.1% polyphenol were used as controls.

[0082]

[0083] These tests demonstrated that the combined use of capric acid, essential oils, polyphenols, and saponins in a liquid medium, which more closely resembles the oral cavity than solid agar medium, synergistically enhanced the antifungal activity.

[0084] Example 2 (Effect of reducing the number of viable fungi by short-term contact) The culture time in the liquid medium in the test of Example 1 was 24 hours. However, in the case of oral compositions intended for oral use, the use time as a mouthwash is at most about 10 seconds, and the general use time for toothpaste is about 2 minutes. Therefore, the important factor in determining the actual clinical effect is not bacteriostatic effect but the degree of reduction in viable fungi within the short period of oral use. Therefore, a total of 3 × 10 6 Each sample was added to purified water at a concentration of 1000 / ml, and the live yeast cell percentage was measured under a microscope 2 minutes after stirring using a test tube vibrator, including the time when stirring began. The concentration of the sample for synergistic effect was based on the test results of Example 1.

[0085]

[0086]

[0087]

[0088]

[0089]

[0090]

[0091] CPG 50% solution with a viable fungus count of 3 x 10 6 The viable fungus rate after 2 minutes of exposure to the solution was also 30%.

[0092] Tables 14 to 19 show that even when the contact time with fungi is as short as 2 minutes, the combined use of capric acid, plant essential oil, polyphenols and / or saponin synergistically enhances the antifungal effect.

[0093] [Production Example] Production of oral composition gel (typical example) According to the blending ratios shown in Table 20, oral compositions of the present invention (gel-type dentifrice, hereinafter referred to as "CPG") were produced.

[0094]

[0095] The "appropriate amount" in Table 20 above refers to a component that is not directly involved in the composition responsible for the antifungal effect of the oral composition of the present invention, i.e., the CPG (gel). These components can be modified as appropriate during the production of a typical CPG gel. Incidentally, in this case, spearmint oil is used not as an essential oil but as a flavoring and deodorizer for capric acid and other components. Sorbitol, xylitol, and cellulose gum are used as sweeteners, while pentylene glycol, PEG-8, and PEG-60 hydrogenated castor oil are used as solvents for capric acid and essential oils. Concentrations can be modified as appropriate, provided they fall within the ranges described in the above embodiments. In this production example, the "essential oil component mixture" refers to a mixture of cinnamaldehyde and other essential oil components. However, the combination of essential oils or antibacterial components contained in essential oils described in the above embodiments can be modified as appropriate.

[0096] The oral composition gel having the above composition was produced according to a conventional method.

[0097] Example 3 (Antibacterial Test Against Candida Fungi and Aspergillus Fungi) Next, the cultivation of Candida fungi and Aspergillus fungi (hereinafter simply referred to as "Aspergillus") used in the antibacterial effect test described below and the antibacterial test will be described.

[0098] First, four species of Candida fungi were cultured: Candida albicans, Candida krusei, Candida tropicalis, and Candida parapsilosis. These three species of Candida fungi were commonly cultured on Chromagar Candida Raw Medium (CHROMager TM Each fungus was placed in a petri dish and cultured in an incubator at 35°C for 48 hours using Candida Plus (manufactured by Kanto Chemical Co., Inc.). TM CHROMagar TMEach bacterium was placed in a petri dish and cultured in an incubator (manufactured by Nippon Becton Dickinson) at 35°C for 43 hours.

[0099] On the other hand, the fungus of the genus Aspergillus was placed in a petri dish on Sabouraud glucose agar medium (manufactured by Kanto Chemical Co., Inc.) and cultured in an incubator at 35° C. for 48 hours.

[0100] At the same time as the start of the culture, the oral composition gel prepared in the above-mentioned Preparation Example was diluted 5-fold with water and applied with a brush to half of each of the petri dishes for the four Candida fungi (Candida albicans, Candida krusei, Candida tropicalis, and Candida parapsilosis) and Aspergillus. For Candida glabrata, the oral composition gel prepared in the above-mentioned Preparation Example was diluted 3-fold with water and applied with a brush. Although the dilution ratio differed for each fungus, the dilution ratio will be referred to as the "CPG dilution" hereafter.

[0101] Figures 1 to 6 are diagrams showing antibacterial tests against Candida albicans, Candida krusei, Candida tropicalis, Candida glabrata, Candida parapsilosis, and Aspergillus fungi, respectively. Incidentally, the line segment AB common to Figures 1 to 6 indicates the boundary dividing the area of ​​each petri dish into approximately half. That is, in Figures 1 to 3, 5, and 6, the diluted CPG solution is applied to approximately the right half of the dish, with the line segment AB as the boundary. On the other hand, in Figure 4, the diluted CPG solution is applied to approximately the left half of the dish, with the line segment AB as the boundary.

[0102] In Figures 1 to 3 and Figures 5 and 6, a bacteriostatic (antibacterial) effect was observed for all three species of Candida and Aspergillus in the area where the diluted CPG solution was applied, i.e., the right half of the petri dish. This demonstrates, although qualitatively, that the oral composition of the present invention exhibits an antifungal effect not only against Candida albicans, but also against other Candida species such as Candida krusei, Candida tropicalis, and Candida parapsilosis, as well as other oral fungi such as Aspergillus. Furthermore, in Figure 4, a bacteriostatic (antibacterial) effect was observed for Candida glabrata in the area where the diluted CPG solution was applied, i.e., the left half of the petri dish. This demonstrates, although qualitatively, that the oral composition of the present invention exhibits an antifungal effect against Candida glabrata.

[0103] Example 4 (Measurement of Minimum Effective Concentration) As in Example 3 above, the minimum effective concentration of the components (constituents) in the oral composition of the present invention, i.e., essential oils or polyphenols, that exhibit antibacterial effects against fungi such as Candida and Aspergillus was measured.

[0104] First, fungi were collected from the cervical and lingual surfaces of all remaining buccal teeth of each subject (33 subjects) by tracing each site (cervical and lingual surfaces) with a sterile cotton swab. The swabs used to collect these fungi were also used in the examples described below.

[0105] The collected swabs with the fungi attached were then placed in a culture medium for cultivation. The medium used was Candida Yellow Medium "F" (Fuji Pharma Co., Ltd.), a medical in vitro diagnostic agent, and the fungal culture components were 40 mg glucose and 10 mg polypeptone per ml, and 0.3 mg chloramphenicol was added as an antibacterial agent to prevent the proliferation of bacteria other than fungi.

[0106] The medium solution was then mixed with diluted solutions of each antifungal component of the CPG used in Example 1, and 0.06 mg of chromium phenol red was added to measure the degree of fungal growth based on the color change. This revealed the following minimum effective concentrations for each component as effective concentrations against oral fungi. The minimum effective concentrations for each component are shown in Table 21 below.

[0107]

[0108] Here, the essential oil component mixture in Table 20 is a mixture of cinnamaldehyde and other essential oil components, as in Table 20 (the above manufacturing example), but the combination thereof can be changed as appropriate by using the essential oils or antibacterial components contained in the essential oils described in the above embodiments.

[0109] In Example 4, the minimum effective concentration or regulated concentration of capric acid against fungi such as Candida and Aspergillus was not confirmed, but the minimum effective concentration of essential oils or essential oil components was identified, which provided an indicator of the minimum amount to be incorporated to exhibit antifungal activity.

[0110] Example 5 (Change in fungal load in the oral cavity) Using the oral dentifrice (CPG gel) of the present invention, the change in fungal load in the oral cavity was measured using Candida yellow on a 7-point scale depending on the use of CPG.

[0111] Here, the subjects (33 people) were used under the conditions shown in Table 22 as the method of using the CPG of the present invention.

[0112]

[0113] As a comparative example, amphotericin B (hereinafter referred to as AMPH-B) syrup and / or a dentifrice containing sodium fluoride was used in place of the CPG of the present invention under the same conditions as in Table 22 above.

[0114] The number of oral fungi was measured using the medical in vitro diagnostic Candida Yellow Medium "F" (Fuji Pharma Co., Ltd.). While this medium is primarily designed for measuring Candida, other fungi also produce acid as a metabolic product, making it effective for measuring oral fungal groups such as Aspergillus. Furthermore, because it contains an antibacterial agent, it is unlikely to be affected by other oral bacteria.

[0115] As in Example 4, fungi were collected from the cervical and lingual surfaces of all buccal teeth of each of the 33 subjects and the comparative subject by tracing each area (cervical and lingual) with a sterile cotton swab. The collected fungi were cultured at 36°C for 24 hours, and were scored on a 7-point scale: those that turned yellow (+3), those that showed a slight change (+2), those that showed no change but showed a change after 48 hours of culture (+1), and those that showed no change but remained the same red (0). The intermediate scores were 0.5, 1.5, and 2.5, respectively, from no change to no change. The results are shown below in Table 23 and Table 24 (Comparative Example).

[0116]

[0117]

[0118] The first factor that can be considered to affect the amount of fungi in the oral cavity is the amount of saliva secreted. Factors that affect saliva secretion include the many medications taken, such as beta-blocker-containing hypertensive drugs, diabetes medications, and painkillers, which can fluctuate over the course of several months in the same subject. Diseases include Sjögren's syndrome, diabetes, salivary gland disease, and radiation therapy around the salivary glands. Short-term factors include physical condition, and psychological factors such as lack of sleep, overwork, and stress also have an impact.

[0119] A factor other than saliva that may affect the amount of oral fungi is the bacterial replacement phenomenon caused by taking antibiotics.

[0120] Therefore, when conducting oral fungal count tests, the above points were taken into consideration when interviewing subjects, and subjects were selected based on whether they had any medication or signs of dry mouth, and whether there were any other factors other than the toothpaste gel. Subjects who showed fluctuations during the test were also excluded, as were those whose initial test value was 0.

[0121] There was almost no correlation between the oral condition (number of implants, number of prostheses, number of temporary teeth, number of conservative treatments, state of periodontitis, use of dentures, daily cleaning status, presence or absence of crowding) and fungal count, including periodontitis and dentures, but a strong correlation was found before treatment in the AMPH-B test. Also, subjects with good oral hygiene showed a more significant reduction in the values, as inferred from the AMPH-B (comparison) test, and the results showed the same trend. With this CPG, a reduction in oral fungal count was confirmed in the short term of 1 to 2 weeks after starting use.

[0122] When the oral fungal load of the same individual was examined over a period of years without the use of CPG or AMPH-B, some subjects showed changes in their physical condition, diet, and cleaning ability, while others showed almost no change, indicating individual differences in the fluctuation of fungal load. The amount of change in this case was ±1% of the initial value. Although some subjects experienced increases in their values ​​during CPG treatment, these were only temporary.

[0123] The return of fungal counts when CPG was discontinued was similar to that when AMPH-B was used, and returned to the original state in approximately two weeks. In subjects using AMPH-B, a decrease in the values ​​was confirmed when AMPH-B was discontinued and CPG was used.

[0124] Example 6 (Changes in motile bacteria: rods (including spiral bacteria) and cocci) It is known that many motile bacteria and cocci tend to be observed in microscopic images of patients with periodontitis and other conditions. Furthermore, many dentists have empirically known that the use of antifungal agents in the oral cavity results in a decrease in motile bacteria. However, the decrease in motile bacteria in this case is thought to be due to the simultaneous use of antibiotics such as macrolides.

[0125] In Example 6, the oral composition (CPG gel) of the present invention was used alone, without any antibiotics, to observe dental plaque at specific sites of each subject during a chronic poorly cleaned gingivitis test under a phase-contrast microscope, and changes in the motile rod-shaped bacteria (including spiral bacteria) and cocci at those sites were examined. Incidentally, when dental plaque for microscopic observation could not be collected from a site due to changes in the properties of the plaque, it was collected from a nearby site. Here, when each subject's dental plaque was observed under a phase-contrast microscope, a score of 3 was assigned if a large number of motile rod-shaped bacteria and spiral bacteria were observed, a score of 2 was assigned if a moderate number of rod-shaped bacteria and spiral bacteria were observed, a score of 1 was assigned if only a small number were observed, and a score of 0 was assigned if no motile bacteria were observed. The test results are shown in Tables 25 and 26. The tendency is that changes become smaller from the second time onwards.

[0126]

[0127]

[0128] These results suggest that the oral composition of the present invention also has an antibacterial effect on motile bacteria and spiral bacteria, although this effect depends on the shape of the bacteria. It is possible that the reduction in fungi may have created an oral environment that is difficult for motile bacteria to inhabit.

[0129] Example 7 (Oral discomfort upon waking up) Since saliva secretion decreases during sleep, the oral cavity becomes an environment in which bacteria and fungi can easily grow in the oral cavity during sleep. Therefore, oral discomfort tends to be felt upon waking up.

[0130] Therefore, a test was conducted using the oral composition (CPG gel) of the present invention to examine changes in oral discomfort upon waking. The test was conducted on subjects without confirmed dental caries or periodontal disease, and xerostomia symptoms due to mouth breathing during sleep were excluded. The test was conducted by scoring subjects as follows: 3 for consistently severe discomfort upon waking, 2 for daily discomfort upon waking, 1 for occasional slight discomfort upon waking, and 0 for no discomfort upon waking. The test results are shown in Table 27.

[0131]

[0132] It was confirmed that the score decreased in correlation with the amount of fungus. As a result, the score decreased over time even after the second test.

[0133] It was suggested that the oral composition of the present invention has a broad spectrum of antibacterial activity that is weaker than that of commonly available commercially available compositions that have strong antibacterial activity. This test suggests that the use of the oral composition of the present invention is effective in reducing oral discomfort upon waking, that fungi themselves are involved in the discomfort, and that changes in the microbiome may have reduced the bacterial groups involved in oral discomfort upon waking.

[0134] Example 8 (Dental Plaque Properties) Dental plaque adhering to teeth and prostheses is usually white to the naked eye, but there are differences in physical properties such as plaque transparency, stickiness, and hardness. That is, when plaque lacks stickiness or hardness, it appears to be transparent, while when it does, it tends to lack transparency. When plaque is observed under a phase-contrast microscope, it is difficult to find subjects in which hyphae are not found in the plaque, and in most cases, hyphae appear to form part of the plaque structure. From these findings, it is clear that fungi, primarily Candida species, are present in the oral cavity; however, there have been few detailed studies, other than those by Lindsay E. O'Donnell et al., that have investigated the interactions between bacteria and fungi in plaque in detail.

[0135] In Example 8, the oral composition (CPG gel) of the present invention was used to test changes in the physical properties of dental plaque on 33 subjects with good oral hygiene. Dental plaque samples were collected and tested at specific sites during the chronic poorly cleansing gingivitis test, and the dental plaque at each specific site of each subject was examined.

[0136] The scores for the amount of plaque and the physical properties of the plaque were as follows: a state in which there was very little plaque and it was impossible to collect it with a dental probe was given a score of 0; a state in which plaque was attached but soft, not sticky, and transparent was given a score of 1; a state in which the plaque was slightly hard, sticky, and not very transparent was given a score of 2; and a state in which the plaque was hard, sticky, and not transparent was given a score of 3. The results are shown in Table 28.

[0137]

[0138] A change in the properties of plaque was confirmed. A decrease in score was confirmed in correlation with the amount of fungi. As a general rule, the change became smaller from the second test onwards. A decrease in the amount of plaque adhesion was also observed in relation to the change in plaque properties. Normally, the amount of plaque adhesion is measured by the adhesion area, but this was observed as a decrease in the thickness of the plaque adhesion site rather than a decrease in area. This result suggests that the use of the oral composition of the present invention has the effect of physically changing the properties of plaque and tending to reduce the amount of plaque adhesion.

[0139] Example 9 (Chronic Poorly Cleaned Gingivitis (Chronic Plaque-Induced Gingivitis / Chronic Simple Gingivitis)) In Example 9, the inhibitory effect of chronically poorly cleaned gingivitis (hereinafter sometimes simply referred to as "gingivitis") on 33 subjects who had chronically poorly cleaned gingivitis was observed. The subjects were selected to have 15 or more natural teeth and be 16 years of age or older. Furthermore, for each subject whose condition had not changed in previous observations, changes were examined using the oral composition of the present invention (CPG) at one or two specific sites. A specific site on the gingiva of each subject was determined, and the same site was examined each time. The degree of gingival swelling was scored as follows: severe gingivitis, where clear swelling was observed, was scored as 3; moderate gingivitis, where swelling was observed, was scored as 2; and mild gingivitis, where slight swelling was observed, was scored as 1, with the median being 0.5. The test results are shown in Table 29.

[0140]

[0141] A decrease in score was confirmed in correlation with the amount of fungus. As a general rule, the change became smaller after the second treatment. This confirmed the effectiveness of the treatment on chronic gingivitis, which shows little change over a period of several months to several years.

[0142] Example 10 (Amount and length of hyphae in dental plaque) In Example 10, dental plaque was collected from each specific site of each subject during the chronic poor cleaning gingivitis test in Example 9 and observed under a phase contrast microscope to examine the amount and length of hyphae at each site. Here, when plaque for microscopic observation could not be collected from a specific site due to changes in the properties of the plaque, it was collected from a neighboring site.

[0143] Incidentally, the amount of fungi in the entire oral cavity was measured using Candida yellow, but the amount of fungal hyphae (i.e., the amount of fungi) at specific sites of each subject during the chronic poor cleaning gingivitis test, and changes in the length of the fungal hyphae, were further examined using a phase-contrast microscope.

[0144] Many fungi take two forms: yeast and hyphae, and are often found in the oral cavity in the hyphae form. Candida glabrata is an exception, as it only takes the yeast form. Therefore, even if no hyphae are visible in the microscopic photograph, the test may be positive with Candida Yellow.

[0145] Based on these findings, the amount of mycelia in dental plaque was first observed using a phase-contrast microscope. The amount of mycelia in dental plaque, i.e., the number of mycelia observed, was scored as 3, a moderately high number as 2, a slight number as 1, and no mycelia observed as 0, with the intermediate scores in 0.5 increments. The test results are shown in Table 30.

[0146]

[0147] As a general rule, there is less change from the second time onwards.

[0148] Next, the length of the hyphae in the dental plaque was observed under a phase-contrast microscope. In this case, a score of 3 was given when many hyphae were generally long, a score of 2 when some hyphae were generally long, a score of 1 when hyphae were generally short, and a score of 0 when no hyphae were observed, with the intermediate values ​​being in increments of 0.5. The test results are shown in Table 31. A decrease in the amount of hyphae observed under a phase-contrast microscope was confirmed to correlate with a decrease in the score using the Candida Yellow test agent.

[0149]

[0150] As a result, the changes tended to be smaller from the second time onwards. There was also a correlation between the amount of hyphae in the plaque at the observation site and their length. The fact that the hyphae became shorter is thought to indicate that the oral composition (CPG gel) made it difficult for mycelial fungi to grow.

[0151] From the above, it was suggested that the use of the oral composition (CPG gel) of the present invention can suppress the amount of mycelia and reduce the length of the mycelia.

[0152] Example 11 (Bad breath suppression effect (bad breath evaluation)) Bad breath is breath that causes discomfort to others. There are various causes of bad breath, such as food and drink, smoking, oral diseases, poor oral hygiene, dry mouth, as well as diabetes, liver disease, respiratory and digestive tract diseases including the pharynx. In this study, the cause of bad breath was in the oral cavity, and changes in the objective bad breath of subjects who had no dental caries or acute periodontitis in the oral cavity were tested using the oral composition (CPG gel) of the present invention.

[0153] The problem with bad breath here is related to sociality. If a person has cavities or periodontal disease and also has bad breath, treatment for those issues will be prioritized, but if bad breath persists even after such treatment, it can become a serious concern for the person. If the cause is within the oral cavity, there is no caries or periodontal disease to treat, and the person's oral hygiene is good but still has bad breath, there may be a problem with the oral bacterial flora. In such cases, methods of dealing with bad breath include using mint-based air fresheners to mask the bad breath or using antibacterial agents to temporarily reduce oral bacteria, but both methods only have a temporary effect.

[0154] A common method for measuring bad breath is a halitosis meter. This measures volatile sulfur compounds (VSCs), but it can only measure a portion of the various types of bad breath. The meter cannot accurately measure the bad breath of people who have no particular oral diseases and who have good oral hygiene. Medical institutions specializing in bad breath, such as halitosis clinics, ultimately use a method to measure the degree of discomfort using a person's nose (although some measurements may not be possible at present due to the impact of COVID-19).

[0155] Therefore, in Example 11, measurements were taken based on the opinions of the subject's family and those around them who had frequent contact with them, as well as the judgement of a dentist.

[0156] Here, there are some precautions to be taken regarding the measurement of bad breath in Example 11. First, all subjects were required to follow the same conditions, namely, as a first precaution, to visit the clinic and have the measurement taken at least one hour after eating or drinking, and as a second precaution, to refrain from using mouthwash, toothpaste, mouth spray, etc. for two hours before the measurement.

[0157] In this Example 11, bad breath was measured on a three-point scale. A strong unpleasant bad breath perceived by the subjects and dentists was scored as 3, an unpleasant bad breath as 2, a slight unpleasant bad breath as 1, and no unpleasant breath as 0, with the intermediate scores in 0.5 increments. The test results are shown in Table 32.

[0158]

[0159] As a general rule, there is less change from the second time onwards.

[0160] It was confirmed that the oral composition of the present invention, when used once a day, has a long-term, objectively effective reduction in bad breath. This confirms that the oral composition of the present invention is not a conventional bad breath preventative that can only be expected to have a temporary effect, but rather a completely new, long-lasting bad breath preventative.

[0161] Example 12 (Evaluation of Tongue Coating) Tongue coating is a grayish-white or yellowish-white deposit that adheres to the dorsum of the tongue. Proteins in saliva, food particles, exfoliated mucous membranes, and decomposition products of various bacteria and fungi can be observed.

[0162] The tongue is usually the biggest cause of bad breath, unless there is advanced dental or periodontal caries or periodontal disease. Some studies have suggested that Candida is involved in the formation of biofilms that adhere to hard tissues in the oral cavity, which may be related to the amount of tongue coating. Furthermore, fungi secrete proteolytic enzymes, which may promote bacterial adhesion to the tongue surface. Bad breath caused by anaerobic bacteria on the dorsum of the tongue is becoming a daily problem. While it is medically recognized that increased tongue coating due to long-term antibiotic use or dry mouth is also associated with an increase in the amount of fungi, both are known to be associated with an increase in the amount of fungi.

[0163] Therefore, in Example 12, changes in tongue coating due to the use of an antifungal CPG (the oral composition of the present invention) were tested. Here, a score of 0 was assigned to no tongue coating, and scores were assigned to six levels based on the amount of coating: 0.5, 1.0, 1.5, 2.0, 2.5, and 3.0. The results are shown in Table 33. Of the 33 subjects, none had been taking antibiotics for a long time during the study, nor did any suffer from dry mouth.

[0164]

[0165] As a result, it was confirmed that the oral composition (CPG gel) of the present invention was effective in reducing the amount of tongue coating.

[0166] In the above-mentioned embodiments and examples, the antifungal composition of the present invention has been mentioned. Since the antifungal composition of the present invention uses capric acid, essential oils, and polyphenols and / or saponins, it can be used as a preventive agent for various fungal infections (for example, stomatitis, angular cheilitis, etc.), and depending on the dosage form (for example, capsule or gel), it can be used as an inhibitor or preventive agent for all oral fungal infections.

Claims

1. The following components (a), (b) and (c): (a) saturated fatty acids having 6 to 12 carbon atoms; (b) plant essential oils having antifungal activity; (c) one or more selected from polyphenols and saponins An antifungal composition comprising: The antifungal composition, wherein the polyphenols are polyphenols derived from one or more plants selected from indigo, tea (green tea, oolong tea, black tea), sweet tea, cherry leaves (sakuraba), lemon, white birch, persimmon, grape, apple, blueberry, raspberry, cacao (chocolate, cocoa), soybean, loquat leaf, burnet, St. John's wort, hamamelis, olive, olive leaf, Scutellaria root, white birch, wild rose, perilla seed, guava leaf, mulberry leaf, sword bean, burdock, grape seed, grape leaf, apple, and ginger.

2. The antifungal composition according to claim 1, which is an oral antifungal composition.

3. 3. The antifungal composition according to claim 1, wherein the component (a) is a saturated fatty acid selected from caprylic acid, capric acid and lauric acid.

4. 3. The antifungal composition according to claim 1 or 2, wherein component (b) is an essential oil of one or more plants selected from peppermint, spearmint, eucalyptus, thyme, clove, geranium, rose, palmarosa, lavender, ravensara, tea tree, lemon, lemongrass, orange, yuzu, lime, grapefruit, marjoram, fennel, rosemary, cypress, oregano, wintergreen, ginger, and mastic.

5. The antifungal composition according to claim 1 or 2, wherein the saponins are derived from one or more plants selected from licorice, honeysuckle, soybean, adzuki bean, sword bean, Astragalus membranaceus, soapberry, horse chestnut, snowbell, olive, ginseng, bellflower, grape, soap grass, tea leaves, tea seeds, tea flowers, yucca (schidigera), sophora japonica, Senega, camellia, and Lotus japonicus, or saponins derived from echinoderms.

6. 3. The antifungal composition according to claim 1, wherein the component (c) contains the polyphenols and saponins.

7. 3. The antifungal composition according to claim 1, wherein the target fungus is at least one or more species selected from the group consisting of Candida albicans, Candida krusei, Candida tropicalis, Candida parapsilosis, Candida glabrata, and Aspergillus niger.