Composition for preventing or treating oral diseases

Abstract

The present invention relates to a composition for preventing or treating oral diseases containing a natural compound, and more particularly, to a medical external preparation composition having an effect of preventing or improving caries, periodontal disease, toothache, tooth hypersensitivity, and halitosis. The composition of the present invention has excellent antibacterial activity against bacteria that cause caries and periodontal disease, and inhibits PGE2, which is a marker of pain and inflammation, in a concentration-dependent manner, and has excellent effects of inhibiting gingivitis formation, inhibiting tooth hypersensitivity symptoms, and removing halitosis, thereby being highly useful as a medical external preparation composition for preventing or improving one or more oral diseases selected from the group consisting of caries, periodontal disease, tooth hypersensitivity, and halitosis. In addition, the composition of the present invention can be used as a pharmaceutical composition.

Description

TECHNICAL FIELD

[0001] The present application relates to a composition for preventing or treating oral diseases, which comprises a natural compound as an active ingredient, and more particularly, to a medical external preparation composition having a preventive or ameliorating effect on dental caries, periodontal disease, toothache, tooth hypersensitivity, and halitosis. In addition, the present application relates to a pharmaceutical composition and an oral composition, which comprise a natural compound as an active ingredient. BACKGROUND

[0002] Healthy teeth are one of the five blessings, and are an important factor in determining the quality of life. Dental caries and periodontal disease, which are among the highest incidence of diseases in the world, are known to cause various clinical symptoms such as pain, masticatory dysfunction, destruction of periodontal tissue, halitosis, and tooth hypersensitivity, and are the main cause of tooth loss, and due to changes in dietary life, the causative elements of oral diseases are further increasing.

[0003] It is well known that there are about 600 to 800 or more kinds of microorganisms in the oral cavity of a human being, and these microorganisms are controlled by enzymes such as lysozyme secreted from saliva. However, the oral environment rich in nutrients and moisture provides a good growth condition for microorganisms, and the tongue or dental plaque provides an ideal habitat for microorganisms. Some of these microorganisms act as opportunistic pathogens, and are the cause of diseases such as dental caries, periodontal disease, and tooth hypersensitivity (dentin hypersensitivity) as well as halitosis.

[0004] As a method of inhibiting the proliferation of oral pathogenic bacteria that inhabit dental plaque and cause dental caries, periodontal disease, halitosis, and tooth hypersensitivity, there are antibacterial agents, and various antibacterial agents have been developed as inhibitors and therapeutic agents for dental caries, periodontal disease, pulp, and periapical infection, which comprise antibiotics having a bactericidal and bacteriostatic effect on oral pathogenic bacteria.

[0005] However, since antibiotics have systemic side effects on our body, and can cause the emergence of resistant bacteria in the oral cavity and superinfection, they have the disadvantage of being difficult to use for a long time and can only be used as a therapeutic agent. In addition, as antibacterial agents used as oral cleaning agents, there are Sangquinarine, Listerine, Peroxide, Chlorhexidine, etc., and Sangquinarine has the disadvantages of not only having unclear effects on bacteria in the oral cavity, but also having unclear effects on the treatment of periodontal disease, and being expensive, and the main component of Listerine is ethanol, which has a certain bacteriostatic effect, but only shows a short-term effect in the oral cavity, and can cause harmful effects on tissues when used for a long time. Also, peroxide, which has been added in recent years for whitening effects, is toxic to bacteria, but also shows toxicity to human tissues, so not only is there a problem with safety, but occasionally resistant bacteria to peroxide can also appear in bacteria. In addition, chlorhexidine is the most superior agent known for inhibiting plaque formation and preventing and treating periodontal disease, however, chlorhexidine not only causes irritation to tissues, staining and denaturation of tissues, and in particular has the problems of strong irritation and heavy odor, and also causes superinfection, has carcinogenicity, and thus has the disadvantage of being unable to be used for long-term use for the purpose of treatment or, in particular, prevention, due to restrictions on use by pregnant women.

[0006] In addition, compounds artificially synthesized by chemical reactions can have side effects such as showing cytotoxicity or accumulating in the human body, and thus the current situation is that the pharmacological activity of natural compounds that have a low risk of side effects in terms of safety needs to be studied. SUMMARY

[0007] PROBLEMS TO BE SOLVED BY THE INVENTION

[0008] The present inventors have conducted research to find a natural material that not only does not have the side effects described above, but also has excellent effects on preventing and improving dental caries, periodontal disease, toothache, tooth hypersensitivity, and halitosis. As a result, a natural compound that can be used safely and with confidence in the body was identified, showing antibacterial effects on bacteria that cause dental caries and periodontal disease, toothache relief effects through PGE2 inhibition effects, gingivitis formation inhibition effects, tooth hypersensitivity inhibition effects, and halitosis removal effects, thereby completing a medical external preparation composition, a pharmaceutical composition, and an oral composition using a natural compound.

[0009] TECHNICAL SOLUTION

[0010] An object of the present application is to provide a medical external preparation composition for preventing or ameliorating oral diseases, comprising a natural compound or a pharmaceutically acceptable salt thereof as an effective ingredient.

[0011] Another object of the present application is to provide a pharmaceutical composition for preventing or treating oral diseases, comprising a natural compound or a pharmaceutically acceptable salt thereof as an effective ingredient.

[0012] Still another object of the present application is to provide a composition for oral use, comprising a natural compound or a pharmaceutically acceptable salt thereof as an effective ingredient.

[0013] Effects of the Invention

[0014] The medical external preparation composition of the present application comprising a natural compound or a pharmaceutically acceptable salt thereof as an effective ingredient has excellent effects of preventing or ameliorating oral diseases. Specifically, the composition of the present application has excellent antibacterial activity against bacteria that cause dental caries and periodontal diseases, and inhibits PGE2, which is a marker of pain and inflammation, in a concentration-dependent manner, and has excellent effects of inhibiting gingivitis formation, inhibiting tooth hypersensitivity symptoms, and removing halitosis, thereby being highly useful as a medical external preparation composition for preventing or ameliorating one or more of oral diseases selected from the group consisting of dental caries, periodontal diseases, tooth hypersensitivity, and halitosis. In addition, the composition of the present application comprising a natural compound can be used as a pharmaceutical composition. DETAILED DESCRIPTION

[0015] An object of the present application is to provide a medical external preparation composition for preventing or ameliorating oral diseases, comprising a natural compound or a pharmaceutically acceptable salt thereof as an effective ingredient.

[0016] Another object of the present application is to provide a pharmaceutical composition for preventing or treating oral diseases, comprising a natural compound or a pharmaceutically acceptable salt thereof as an effective ingredient.

[0017] Still another object of the present application is to provide a composition for oral use, comprising a natural compound or a pharmaceutically acceptable salt thereof as an effective ingredient.

[0018] In the present application, a medical external preparation composition comprising a natural compound or a pharmaceutically acceptable salt thereof as an effective ingredient is provided.

[0019] The "natural compound" refers to a substance directly made by a microorganism, a plant, an animal, or the like, and can be extracted, isolated, or purified therefrom, as specific examples of the natural compound, there are Albiflorin, Astragaloside I, Brassinolide, Eleutheroside E, Gentiopicrin, Gramine, Liensinine, Macranthoidin B, Neohesperidin dihydrochalcone, Obacunone, Oxysophocarpine, Sclareolide, Sophoricoside, Sweroside, Synephrine, and the like, but are not limited thereto.

[0020] [Chemical Formula 1]

[0021]

[0022] In the present application, the Albiflorin is represented by the Chemical Formula 1, has a molecular formula of C 23 H 28 O 11 , and is an organic compound having a molecular weight of 408.4.

[0023] [Chemical Formula 2]

[0024]

[0025] In the present application, the Astragaloside I is represented by the Chemical Formula 2, has a molecular formula of C 45 H 72 O 16 , and is an organic compound having a molecular weight of 869.0.

[0026] [Chemical Formula 3]

[0027]

[0028] In the present application, the Brassinolide is represented by the Chemical Formula 3, has a molecular formula of C 28 H 48 O6, and is an organic compound having a molecular weight of 480.6.

[0029] [Chemical Formula 4]

[0030]

[0031] In the present invention, the Eleutheroside E is represented by the Chemical Formula 4, and has a molecular formula of C 34 H 46 O 18 , and is an organic compound having a molecular weight of 742.7.

[0032] [Chemical Formula 5]

[0033]

[0034] In the present invention, the Gentiopicrin is represented by the Chemical Formula 5, and has a molecular formula of C 16 H 20 O9, and is an organic compound having a molecular weight of 356.3.

[0035] [Chemical Formula 6]

[0036]

[0037] In the present invention, the Gramine is represented by the Chemical Formula 6, and has a molecular formula of C 11 H 14 N2, and is an organic compound having a molecular weight of 174.

[0038] [Chemical Formula 7]

[0039]

[0040] In the present invention, the Liensinine is represented by the Chemical Formula 7, and has a molecular formula of C 37 H 42 N2O6, and is an organic compound having a molecular weight of 610.7.

[0041] [Chemical Formula 8]

[0042]

[0043] In the present invention, the Macranthoidin B is represented by the Chemical Formula 8, and has a molecular formula of C 65 H 106 O 32 , and is an organic compound having a molecular weight of 1399.5.

[0044] [Chemical Formula 9]

[0045]

[0046] In the present invention, the Neohesperidin dihydrochalcone is represented by the Chemical Formula 9, and is an organic compound having a molecular formula of C 28 H 36 O 15 , a molecular weight of 612.5.

[0047] [Chemical Formula 10]

[0048]

[0049] In the present invention, the Obacunone is represented by the Chemical Formula 10, and is an organic compound having a molecular formula of C 25 H 30 O7, a molecular weight of 455.

[0050] [Chemical Formula 11]

[0051]

[0052] In the present invention, the Oxysophocarpine is represented by the Chemical Formula 11, and is an organic compound having a molecular formula of C 15 H 22 N2O2, a molecular weight of 262.4.

[0053] [Chemical Formula 12]

[0054]

[0055] In the present invention, the Sclareolide is represented by the Chemical Formula 12, and is an organic compound having a molecular formula of C 16 H 26 O2, a molecular weight of 250.3.

[0056] [Chemical Formula 13]

[0057]

[0058] In the present invention, the Sophoricoside is represented by the Chemical Formula 13, and is an organic compound having a molecular formula of C 21 H 20 O 10 , a molecular weight of 432.

[0059] [Chemical Formula 14]

[0060]

[0061] In the present application, the Sweroside is represented by Chemical Formula 14, and has a molecular formula of C 16 H 22 O9, and is an organic compound having a molecular weight of 358.3.

[0062] [Chemical Formula 15]

[0063]

[0064] In the present application, the Synephrine is represented by Chemical Formula 15, and has a molecular formula of C9H 13 NO2, and is an organic compound having a molecular weight of 167.2.

[0065] The present application is not particularly limited in the method of obtaining the compound, and the compound can be chemically synthesized by a method known in the art, or a commercially available material can be used.

[0066] The compound of the present application can exist in a solvated form, and can also exist in an unsolvated form. The compound of the present application can exist in a crystalline form or an amorphous form, and all of these physical forms are included in the scope of the present application.

[0067] The present application provides a medical external preparation composition for preventing or improving oral diseases, comprising the natural compound or a pharmaceutically acceptable salt thereof as an effective ingredient.

[0068] In addition, specifically, the present application can provide a medical external preparation composition for preventing or improving one or more oral diseases selected from the group consisting of dental caries, periodontal disease (periodontitis or gingivitis), toothache, tooth hypersensitivity, and halitosis, comprising the natural compound or a pharmaceutically acceptable salt thereof as an effective ingredient.

[0069] The "natural compound" is described above.

[0070] In the present application, "oral diseases" refer to various diseases occurring in the oral cavity region, and the oral cavity region refers to a space within the oral cavity from the front lip to the posterior faucial isthmus to the pharyngeal head. In the present application, the oral diseases refer to all diseases occurring in the oral cavity regardless of the condition, and as non-limiting examples of the oral diseases, include dental caries, periodontal disease (periodontitis or gingivitis), toothache, tooth hypersensitivity, halitosis, etc.

[0071] In the present application, "dental cavities" as an infectious disease caused by bacteria inhabiting the surface of teeth, also known as tooth decay, is a symptom in which the hard tissue of teeth is eroded and defects appear. Specifically, it refers to the ivory-colored, translucent, and hard substance that covers the surface of the crown portion of teeth and protects the tooth dentin, which is called tooth enamel or dental enamel, and the enamel of the teeth is damaged by the acid produced by the decomposition of sugars and starches and the like by oral pathogenic bacteria inhabiting the oral cavity, thereby producing tooth decay. As a major cause of dental cavities, dental plaque (dental plaque), which is a bacterial film formed on the surface of the teeth, can be cited, and saliva forms a thin and sticky film on the teeth, and oral microorganisms such as Streptococcus sobrinus and Streptococcus mutans, which are one of Streptococcus, adhere to the film to form a biofilm, thereby forming dental plaque (dental plaque), and become thicker due to Fusobacterium. Dental cavities of the present application include various pathogenic bacteria that cause dental cavities, regardless of their species, and specifically, can be one or more bacteria selected from the group consisting of Streptococcus mutans, Streptococcus sanguinis, Streptococcus sobrinus, Streptococcus ratti, Streptococcus criceti, Streptococcus anginosus, and lactic acid bacteria, and more specifically, can be Streptococcus mutans.

[0072] The Streptococcus mutans, which is one of Streptococcus, is a gram-positive bacterium, also known as a tooth decay bacterium. The Streptococcus mutans only proliferates on the surface of teeth, and the deciduous teeth are not complete until around 30 months after birth. Therefore, until this period, the Streptococcus mutans is difficult to proliferate as much as after infancy. Infancy does not infect the Streptococcus mutans from the oral cavity of adults, and when the oral cavity is implanted by other oral bacteria, the Streptococcus mutans is difficult to enter the ecological system in the balanced oral cavity, making the probability of tooth decay significantly reduced throughout life after infancy. If the pathogenic bacteria have been transmitted through the oral cavity of adults, brushing teeth frequently and maintaining oral cleanliness help prevent tooth decay. However, once the Streptococcus mutans is implanted in the oral cavity, it is not possible to eradicate the Streptococcus mutans.

[0073] In an embodiment of the present application, the results of measuring the size of the growth inhibition ring after inoculating a disk containing the natural compound of the present application in a culture medium coated with Streptococcus mutans, in the case of the experimental group containing the compound, the growth inhibition ring diameter was 10.0 mm or more, showing very excellent antibacterial activity against Streptococcus mutans, and confirming the use of a composition containing the natural compound for preventing or improving dental caries (Table 2).

[0074] In the present application, "periodontal disease" is a disease in which inflammation occurs in the gingiva and periodontal ligament and bone tissue supporting the teeth, and is generally referred to as pyorrhea, and is classified into gingivitis and periodontitis according to the degree of the disease. As a periodontal disease that is relatively light and recovers quickly, a form that is limited to the gingiva, i.e., soft tissue, is referred to as gingivitis, and if such inflammation spreads to the gingiva and the surrounding gingival bone, it is referred to as periodontitis. There is a V-shaped gap between the gingiva (gingival) and the teeth, and the part of the gingival sulcus below the gum line is attacked by oral pathogenic bacteria, and releases Lipopolysaccharide (LPS) as an inflammation stimulus, thereby causing inflammation such as gingival swelling, bleeding, and the like, thereby damaging the periodontal ligament and adjacent tissues. If periodontitis continues, it damages the periodontal ligament, and even damages the alveolar bone, and eventually the teeth are damaged. Malnutrition, such as protein, vitamin, etc., pregnancy, or hormone disorders such as diabetes, smoking, acquired immune deficiency syndrome (AIDS), etc., can exacerbate the disease. In addition, as other causes of periodontal disease, dental plaque and dental calculus can be listed. The periodontal disease of the present application includes all pathogenic bacteria that cause periodontal disease, regardless of their species, and specifically, can be one or more selected from the group consisting of Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola, and Fusobacterium nucleatum, and more specifically, can be Porphyromonas gingivalis.

[0075] The Porphyromonas gingivalis is one of the Bacteroides group of bacteria, is a gram-negative bacterium, and is an anaerobic bacterium. The Porphyromonas gingivalis is found in the oral cavity in which periodontal disease occurs, and is also found in the upper gastrointestinal tract, respiratory tract, and colon. The collagenase of the Porphyromonas gingivalis breaks down collagen in chronic periodontal disease patients, the Porphyromonas gingivalis can invade gingival fibroblasts, and can survive even in a high concentration of antibiotics. In addition, the Porphyromonas gingivalis can invade gingival epithelial cells and survive for a long time.

[0076] In an embodiment of the present application, the results of measuring the size of the growth inhibition ring after inoculating a disk containing the natural compound of the present application in a culture medium coated with Porphyromonas gingivalis, in the case of the experimental group containing the compound, the growth inhibition ring diameter was 10.0 mm or more, showing very excellent antibacterial activity against Porphyromonas gingivalis, and confirming that the composition containing the compound can be used for the purpose of preventing or improving periodontal disease (Table 2).

[0077] In addition, in an embodiment of the present application, the results of a clinical test by selecting experimental subjects having gingival inflammation, in the case of the experimental group using a toothpaste of the experimental group containing the compound, the inhibitory effect of gingival inflammation was excellent, even after 6 months, it remained in a normal bleeding state, continuously inhibited gingival inflammation, and confirmed that the composition containing the natural compound can be used for the purpose of preventing or improving periodontal disease including gingivitis (Table 4).

[0078] In the present application, "toothache" means pain of the teeth when eating sweets, very cold or hot food, and generally includes not only pain of the teeth themselves, but also pain of the periodontal tissue supporting the teeth in the jaw. In general, pain occurs when chewing, the gums swell and secrete a foul-smelling secretion. Toothache shows slightly different pain depending on the disease, and in particular, pain caused by caries is initially painless, but gradually develops to pain when the nerve inside the tooth is deeply eroded, when there is an impacted tooth, pain is induced by inflammation of the surrounding tissue of the tooth, and in the case of tooth fragmentation or cracking, when contacting cold food or strong occlusion, the tooth splits and stimulates the nerve, thereby causing pain. In the case of toothache caused by pulpitis, pain is felt when contacting cold food at the initial stage, and when further deteriorating, pain is felt against hot food, and if the inflammation progresses to cause death of the pulp tissue, there is no response to cold and heat, and pain caused by apical (root end) inflammation occurs.

[0079] In an embodiment of the present application, the results of confirming the inhibitory effect of PGE2, which is a marker of pain and inflammation, in the case of the experimental group containing the natural compound of the present application, it was confirmed that the effect of inhibiting PGE2 in a concentration-dependent manner was shown (Table 5).

[0080] In the present application, "tooth hypersensitivity" refers to hypersensitive dentine, and tooth hypersensitivity symptoms refer to dentine hyperesthesia. Tooth hypersensitivity symptoms are a feeling of sensitivity when the exposed dentine portion of a tooth contacts cold air or a stimulating food, etc., and 60 to 98% of adults having periodontal disease exhibit this symptom. Tooth hypersensitivity symptoms can occur in cases of tooth loss on the gingival side due to incorrect brushing habits or excessive biting force, cases of poor oral hygiene, cases of tooth dissolution due to acid dissolution after periodontal treatment, cases of tooth dissolution due to acidification after restorative treatment, etc. The root cause of tooth hypersensitivity symptoms is that many tubules present in the dentine of a tooth are exposed to the outside, and due to the exposure, all stimuli are directly transmitted to the nerves inside the pulp, so that the same stimuli are more sensitive than usual, and thus pain can be induced. Tooth hypersensitivity symptoms exhibit a variety of symptoms from mild symptoms to severe and persistent pain, and since teeth have the characteristic of not being able to regenerate, the administration of analgesics or anti-inflammatory agents, etc. cannot fundamentally solve the tooth hypersensitivity phenomenon. Tooth hypersensitivity symptoms not only occur on the entire tooth, but also can occur locally in the upper jaw, lower jaw, or right side, left side, etc. The frequently occurring sites differ depending on the cause, but the main sites are the cuspid teeth and the small molar teeth, and the most severe pain site is the cervical portion of the boundary portion of the gum and the tooth in 90% or more of cases.

[0081] In an embodiment of the present application, the results of a clinical test performed by selecting experimental subjects having hypersensitive dentine teeth were as follows: in the case of an experimental group using a toothpaste containing the compound of the present application, the inhibitory effect on tooth hypersensitivity symptoms was excellent, and the use of a composition containing the natural compound for the prevention or improvement of tooth hypersensitivity was confirmed (Table 7).

[0082] In the present application, "halitosis" is an odor from the oral cavity and adjacent organs, 85 to 90% of halitosis is from the oral cavity, particularly from the back of the tongue. The main components of halitosis are volatile sulfur compounds, 90% of the total amount of volatile sulfur compounds is hydrogen sulfide produced from cysteine and methyl mercaptan and dimethyl sulfide produced from methionine. These components are mainly produced by proteases secreted by anaerobic bacteria, and the back of the tongue is the most important habitat. This site is not cleaned by saliva and has many small depressions, making it a place for bacteria to survive. The production of volatile sulfur compounds by anaerobic bacteria is the most important cause of halitosis, but in addition, halitosis can also be caused by oral diseases such as dental caries, periodontitis, and xerostomia. Many types of anaerobic bacteria are involved in the production of halitosis, and as non-limiting examples of pathogenic bacteria that cause halitosis, Porphyromonas gingivalis, which secretes a variety of enzymes, can be cited.

[0083] In an embodiment of the present application, the results of a clinical test on subjects without dental caries showed that the removal effect of halitosis was excellent in the case of an experimental group using a toothpaste containing the natural compound of the present application, and the use of a composition containing the compound for preventing or improving halitosis was confirmed (Table 8).

[0084] The medical external preparation composition of the present application can include an oral medical external preparation. The components included in the medical external preparation composition of the present application, as effective ingredients, can include, in addition to the effective ingredients, components commonly used in oral medical external preparation compositions, for example, abrasives, humectants, binders, foaming agents, sweeteners, preservatives, medicinal ingredients, flavoring agents, pigments, solvents, whitening agents, solubilizing agents, or pH adjusting agents.

[0085] The oral medical external preparation composition of the present application can also be manufactured in any dosage form commonly manufactured in the art, for example, can be a toothpaste, an oral rinse, an oral cleanser, chewing gum, a confectionery, an oral spray, an oral ointment, an oral desensitizer, an oral mouthwash, and a gingival massage cream, etc., but is not limited thereto.

[0086] As an example, in the case of the oral medical external preparation composition of the present application being in the dosage form of a toothpaste, a humectant, an abrasive, a binder, a foaming agent, a flavoring agent, a sweetener, a coloring agent, a preservative, a medicinal ingredient, a solvent, a pH adjusting agent, etc. can be included.

[0087] The wetting agent is used to make the powder in the toothpaste ingredients into a paste, to prevent the toothpaste from solidifying in the air, and can use glycerin, sorbitol solution, propylene glycol, polyethylene glycol, etc. alone or in combination of two or more after 1 to 60 wt%, specifically 10 to 50 wt% of the total weight of the composition.

[0088] The foaming agent is used to diffuse the toothpaste into the oral cavity to improve the cleaning effect, and to clean the oral cavity dirt as a surfactant, and can use sodium dodecyl sulfate, sodium dodecyl sarcosinate, sodium alkyl sulfosuccinate, and sucrose fatty acid ester, etc. surfactants alone or in combination of two or more after 0.5 to 10 wt%, specifically 0.5 to 5 wt% of the total weight of the composition.

[0089] The binder is used to prevent separation between the powder and liquid ingredients in the toothpaste, and can use cellulose derivatives of carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, and sodium alginate, carrageenan, xanthan gum, etc. alone or in combination of two or more after 0.1 to 5 wt%, specifically 0.3 to 2 wt% of the total weight of the composition.

[0090] The abrasive is used to remove the adherent on the tooth surface without damaging the tooth surface to show the luster of the tooth itself, and can use calcium carbonate (CaCO3), calcium hydrogen phosphate (CaHPO4, CaHPO4 2H2O), anhydrous silicic acid (SiO2 2H2O), aluminum hydroxide (Al(OH)3), potassium pyrophosphate, magnesium carbonate, etc. alone or in combination of two or more after 1 to 60 wt%, specifically 10 to 50 wt% of the total weight of the composition.

[0091] The flavoring agent is used to give a cool feeling and odor to the toothpaste to enhance the use feeling, and can use peppermint oil, spearmint oil, menthol, etc. alone or in combination of two or more after 1 to 60 wt%, specifically 0.01 to 5 wt% of the total weight of the composition.

[0092] The sweetening agent is used to remove the unpleasant taste of the toothpaste raw materials and improve the cooling sensation, and can use saccharin acid, aspartame, xylitol, glycyrrhizic acid, etc. alone or in combination of two or more after 1 to 60 wt%, specifically 0.01 to 5 wt% of the total weight of the composition.

[0093] The pharmaceutical ingredient is used for the effect of preventing dental caries, preventing periodontal disease, preventing toothache, preventing tooth hypersensitivity, removing bad breath, etc., and can use fluoride, zinc chloride, chlorhexidine, aminohexanoic acid, tranexamic acid, cetylpyridinium chloride, pyridoxine chloride, triclosan, tocopheryl acetate, sodium monofluorophosphate, etc. alone or in combination of two or more. In the present invention, the compound can be used as an additional pharmaceutical ingredient.

[0094] The oral medical external preparation composition of the present application can be used alone or in combination, or can also be used in combination with other oral medical external preparation compositions other than the present application.

[0095] In another aspect of the present application, a pharmaceutical composition comprising the natural compound or a pharmaceutically acceptable salt thereof as an active ingredient is provided. In particular, the present application can provide a pharmaceutical composition for preventing or treating one or more oral diseases selected from the group consisting of dental caries, periodontal disease (periodontitis or gingivitis), toothache, tooth hypersensitivity, and halitosis, the pharmaceutical composition comprising the natural compound as an active ingredient. The natural compound, oral disease, dental caries, periodontal disease, toothache, tooth hypersensitivity, and halitosis are as described above.

[0096] The pharmaceutical composition of the present application can be formulated in the form of tablets, pills, powders, granules, capsules, suspensions, internal solution, emulsions, syrups, aerosols, sterilized injection solutions, etc. according to the conventional method for preventing and treating oral diseases.

[0097] Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., which can be prepared by mixing at least one or more excipients such as starch, calcium carbonate, sucrose, gelatin, etc. In addition, lubricants such as magnesium stearate and talc can be used in addition to simple excipients. Liquid preparations for oral administration include suspensions, internal solutions, emulsions, syrups, etc., and various excipients such as wetting agents, sweeteners, fragrances, preservatives, etc. can be used in addition to water and liquid paraffin, which are commonly used as simple diluents.

[0098] Preparations for non-oral administration can include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, etc. Non-aqueous solvents and suspensions can use vegetable oils such as propylene glycol, polyethylene glycol, olive oil, etc. and injectable esters such as ethyl oleate, etc.

[0099] In addition, the pharmaceutical composition of the present application can further include a carrier, an excipient, or a diluent. As the carrier, excipient, or diluent, mineral oils such as lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, hydroxypropyl methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, silicon dioxide, etc. can be used.

[0100] The specific administration amount of the pharmaceutical composition of the present application can be variously selected by those skilled in the art according to the formulation method, the state and weight of the patient, the sex, age, degree of disease of the patient, the shape of the drug, the administration route and period, the excretion rate, the reaction sensitivity, and the like, and the administration amount and frequency do not limit the scope of the present application in any way.

[0101] The pharmaceutical composition of the present application can be administered to mammals such as rats, mice, livestock, humans, and the like through various routes. All administration methods are predictable, and administration can be performed by, for example, oral administration, intravenous injection, intramuscular injection, or subcutaneous injection.

[0102] [Embodiment] Hereinafter, the constitution and effects of the present application are explained in more detail through examples and experimental examples. These examples and experimental examples are only for exemplification of the present application, but the scope of the present application is not limited by these examples and experimental examples.

[0103] Experimental Example 1: Antibacterial effect against caries and periodontitis pathogens

[0104] In order to confirm the preventive or therapeutic effect of the compounds of Chemical Formula 1 to Chemical Formula 15 on dental caries and periodontitis, an antibacterial activity experiment was performed. In order to confirm the growth inhibition effect of oral pathogenic bacteria, Streptococcus mutans, which is a representative bacterium that causes dental caries, and Porphyromonas gingivalis, which is a representative bacterium that causes periodontal disease, were used to perform an antibacterial test by using a disc method.

[0105] After increasing the activity of each of the above oral pathogenic bacteria under the optimal culture conditions of Table 1 below, each bacterium was cultured in an optimal culture medium for about 4 to 6 hours, the turbidity of the culture solution was adjusted to Macfarland turbidity No. 0.5 (1.5 x 10 8 Each of the above oral pathogenic bacteria was uniformly applied to a flat culture medium at 0.1 mL. Then, the compounds of Chemical Formula 1 to Chemical Formula 15 were inoculated on sterilized paper discs (Whatman no. 5 paper, 8 mm in diameter) at a concentration of 10 mg / disc and absorbed and dried for 1 hour. Then, after culturing for 24 to 48 hours at the optimal temperature of each of the above oral pathogenic bacteria, the size (diameter mm) of the growth inhibition ring was measured, and the results are shown in Table 2 below.

[0106] [Table 1]

[0107]

[0108] [Table 2]

[0109] Results of the determination of the antibacterial activity of the compounds of Chemical Formula 1 to Chemical Formula 15 against oral pathogenic bacteria

[0110] As shown in Table 2 above, in the groups treated with the compounds of Chemical Formula 1 to Chemical Formula 15, the growth inhibition ring diameter of the two oral pathogenic bacteria was 9.5 mm or more, showing very excellent antibacterial activity against Streptococcus mutans and Porphyromonas gingivalis, compared to the untreated group. Thus, it can be seen that the compounds of Chemical Formula 1 to Chemical Formula 15 can be used for the prevention or treatment of dental caries or periodontal disease.

[0111] Experimental Example 2: Gingivitis formation inhibition effect

[0112] In order to confirm the prevention or treatment effect of the compounds of Chemical Formula 1 to Chemical Formula 15 on gingivitis, a clinical experiment was conducted by selecting an experimental subject group.

[0113] First, a control group toothpaste was manufactured using sodium carboxymethyl cellulose, sodium dodecyl sulfate, glycerin, colloidal silicon dioxide, silicon dioxide, sodium cocoyl isethionate, dodicin, and a sweetener, a fragrance, a coloring agent, etc. commonly used in the manufacture of toothpaste, and an experimental group toothpaste was manufactured by adding 0.01 wt% of one of the compounds of Chemical Formula 1 to Chemical Formula 15 to the control group toothpaste.

[0114] In order to select an experimental subject, gingivitis patients with well-aligned teeth and no defects were selected as subjects, and a precise oral examination was performed on each of 30 people in each of 10-year intervals from the age of 30 to 50 years old according to gender, and then, after selecting 120 experimental subject groups, each of 60 people, a clinical experiment on the treatment effect on gingivitis was performed as follows.

[0115] Specifically, the experimental subject group was divided into a control group and an experimental group, and the control group was instructed to use the above-manufactured control group toothpaste three times a day after 2 hours after meals and before sleep, and the experimental group was instructed to use the above-manufactured experimental group toothpaste three times a day at the same time. Then, a tooth surface wash was performed, and an initial gingivitis index was scored, and the control group was asked to use the above-manufactured control group toothpaste, and the experimental group was asked to use the above-manufactured experimental group toothpaste, and an oral examination was performed after 1 week, 1 month, 3 months, and 6 months, respectively, and a gingivitis index was checked. The method of measuring the gingivitis index was to insert a periodontal probe into a gingival cleft, and to perform a continuous detection around each tooth without applying force, and after 30 seconds, the bleeding state was measured, and the score was recorded according to the standard shown in Table 3 below, and the results are shown in Table 4.

[0116] [Table 3]

[0117] Gingivitis index standard

[0118] Score Content 0 points No bleeding state 1 point Normal bleeding state 2 points Linear bleeding state 3 points Interdental site triangular bleeding state 4 points Whole gingival bleeding state

[0119] [Table 4]

[0120] Gingivitis inflammation suppression effect

[0121] 0 weeks 1 week 1 month 3 months 6 months Control group 1.04 1.60 2.69 2.77 2.85 Paeonol glycoside 1.05 1.08 1.09 1.11 1.12 Astragaloside I 1.05 1.06 1.09 1.12 1.16 Brassinin 1.06 1.08 1.10 1.13 1.15 Eleutheroside E 1.05 1.08 1.09 1.12 1.14 Gentiopterin 1.05 1.05 1.06 1.08 1.08 Artemisinine 1.04 1.07 1.08 1.10 1.12 Nepetaline 1.05 1.04 1.08 1.11 1.14 Megoside B 1.04 1.06 1.10 1.12 1.14 Neohesperidin dihydrochalcone 1.04 1.05 1.08 1.10 1.12 Phellopterin 1.04 1.04 1.06 1.06 1.07 Oxymatrine 1.05 1.07 1.09 1.13 1.15 Sclareolide 1.06 1.06 1.07 1.08 1.09 Sophoricoside 1.06 1.08 1.09 1.11 1.14 Swertiamarin 1.05 1.08 1.09 1.12 1.14 Synephrine 1.04 1.05 1.08 1.10 1.11

[0122] As shown in Table 4 above, the experimental group using the toothpaste containing one of the compounds of Chemical Formula 1 to Chemical Formula 15 maintained a normal bleeding state even after 6 months, and the gingivitis inflammation suppression effect was continued compared to the control group. Thus, it can be seen that the compounds of Chemical Formula 1 to Chemical Formula 15 can be used for the purpose of preventing or treating gingivitis.

[0123] Experimental Example 3: PGE2 inhibition effect as a marker of pain and inflammation

[0124] In order to confirm the prevention or treatment effect of the compounds of Chemical Formula 1 to Chemical Formula 15 on toothache, the PGE2 suppression effect as a pain and inflammation marker was confirmed.

[0125] First, macrophages were inoculated at a concentration of 1.5 x 10 5 cells / mL in a DMEM medium containing 10% FBS and cultured in a 24-well plate at 37°C and 5% CO2 for 24 hours. Then, 1 μg / mL of LPS as an inflammation induction stimulus and each of the compounds of Chemical Formula 1 to Chemical Formula 15 were treated at different concentrations, and after further culturing for 24 hours, a PGE2 ELISA assay kit (Thermo SCIENTIFIC) was purchased, and the PGE2 suppression ability according to the different concentrations of the compounds of Chemical Formula 1 to Chemical Formula 15 was analyzed using the supernatant (Table 5).

[0126] [Table 5]

[0127] Confirmation of PGE2 suppression effect (PGE2 relative ratio (%))

[0128] (-) / (-) LPS / (-) Control group 3 100 LPS / 2ppm LPS / 20ppm Paeonol glycoside 50 28 Astragaloside I 79 58 Brassinin 51 23 Eleutheroside E 56 37 Gentiopterin 26 9 Artemisinine 72 42 Nepetaline 61 34 Megoside B 60 37 Neohesperidin dihydrochalcone 26 9 Phellopterin 37 16 Oxymatrine 79 50 Sclareolide 42 17 Sophoricoside 70 46 Swertiamarin 59 38 Synephrine 80 59

[0129] As shown in Table 5, it was confirmed that the compounds of Chemical Formula 1 to Chemical Formula 15 all showed a PGE2 suppression effect in a concentration-dependent manner compared to the group treated only with LPS, and thus the prevention and treatment effect on toothache was excellent.

[0130] Experimental Example 4: Inhibition effect of tooth hypersensitivity

[0131] To confirm the preventive or therapeutic effect of the compounds of Chemical Formula 1 to Chemical Formula 15 on tooth hypersensitivity, a clinical experiment was performed by selecting experimental subjects, and the control group toothpaste and the experimental group toothpaste for the clinical experiment were each manufactured in the same manner as the toothpaste of Experimental Example 2 above.

[0132] The experimental subjects were 40 volunteers who agreed to participate in the experiment, and the total number of teeth of the experimental subjects was 80. In addition, 20 of the experimental subjects were male, and 20 were female, and the age of the experimental subjects was between 20 and 50 years old. The experimental subjects were not allowed to know the contents of the toothpaste, and the total experimental period was set to 2 weeks.

[0133] The experiment was performed by measuring the reaction of the experimental subjects after applying a temperature stimulus. Before performing the experiment, the hypersensitive sites of the dentin hypersensitivity teeth of each experimental subject were checked in advance, and after dropping about 5℃ of cold water on the hypersensitive sites of the teeth using a dropper and scoring according to the criteria shown in Table 6 below, the control group was asked to use the above-mentioned control group toothpaste three times a day for 2 weeks, and the experimental group was asked to use the above-mentioned experimental group toothpaste three times a day for 2 weeks, and after 2 weeks, the reaction score after the temperature stimulus was measured by dropping about 5℃ of cold water using a dropper. Statistical processing was performed by performing a paired Student-t test on the scores before and after the experiment for 2 weeks, and the reaction score after 2 weeks for the temperature stimulus is shown in Table 7 below.

[0134] [Table 6]

[0135] Scoring criteria for the experimental subjects after the stimulus

[0136] Score Content 0 points No discomfort at all 1 point Slightly uncomfortable or a little cool 2 points Very cool 3 points Pain

[0137] [Table 7]

[0138] Degree of inhibition of tooth hypersensitivity

[0139] 0 weeks 2 weeks Control group 2.15±0.22 2.13±0.20 p>0.05 Paeonol glycoside 2.14±0.18 1.87±0.23 *p<0.05 Astragaloside I 2.15±0.15 1.90±0.11 *p<0.05 Brassinin 2.14±0.07 1.83±0.21 *p<0.05 Eleutheroside E 2.13±0.15 1.87±0.23 *p<0.05 Gentiopterin 2.14±0.17 1.73±0.11 *p<0.05 Artemisinine 2.13±0.21 1.90±0.10 *p<0.05 Nepetaline 2.14±0.13 1.89±0.17 *p<0.05 Megoside B 2.14±0.16 1.88±0.20 *p<0.05 Neohesperidin dihydrochalcone 2.13±0.08 1.85±0.12 *p<0.05 Phellopterin 2.14±0.18 1.73±0.10 *p<0.05 Oxymatrine 2.13±0.14 1.89±0.02 *p<0.05 Sclareolide 2.15±0.10 1.78±0.09 *p<0.05 Sophoricoside 2.13±0.14 1.84±0.20 *p<0.05 Swertiamarin 2.14±0.10 1.88±0.01 *p<0.05 Synephrine 2.14±0.07 1.86±0.18 *p<0.05

[0140] ※p>0.05: 95% confidence, no statistically significant difference. *p<0.05: 95% confidence, statistically significant difference.

[0141] As shown in Table 7 above, the experimental group using the toothpaste containing each of the compounds of Chemical Formula 1 to Chemical Formula 15 inhibited the tooth hypersensitivity phenomenon after 2 weeks compared to the control group. Therefore, it can be seen that the compounds of Chemical Formula 1 to Chemical Formula 15 can be used for the prevention or treatment of tooth hypersensitivity.

[0142] Experimental Example 5: Bad breath removal effect

[0143] To confirm the preventive or therapeutic effect of the compounds of Chemical Formula 1 to Chemical Formula 15 on halitosis, a clinical test was performed by selecting test subjects, and the control group toothpaste and the experimental group toothpaste used for the clinical test were each manufactured in the same manner as the toothpaste of Experimental Example 2 above.

[0144] Fifty men and women having no dental caries were selected as test subjects, and a cross-over test was performed on the control group toothpaste and the experimental group toothpaste above. Garlic powder commercially available was dispersed in water, and after standing for 24 hours, a dilution was made so that the measurement value of a halimeter was 700 ppb or more, and the dilution was used as a halitosis inducing source. The test subjects gargled with 15 mL of the garlic powder dilution for 30 seconds, and after 1 minute, the degree of halitosis was measured using a halimeter, and then, the control group and the experimental group each used the control group toothpaste and the experimental group toothpaste above for brushing for 30 seconds to 1 minute. After brushing, the degree of halitosis was measured using a halimeter at 1 minute, 5 minutes, and 30 minutes after brushing, and whether or not the halitosis inhibition was sustained was determined, and the results are shown in Table 8 below.

[0145] [Table 8]

[0146] Halitosis removal effect (%)

[0147] 1 minute 5 minutes 30 minutes Control group 54.9 47.5 38.7 Paeonol glycoside 95.1 89.6 82.2 Astragaloside I 94.2 89.7 84 Brassinin 94.2 90 87.8 Eleutheroside E 96.1 87.8 85.4 Gentiopterin 97.2 93.9 89.9 Artemisinine 94.9 88.9 83.4 Nepetaline 95 88.3 83.8 Megoside B 95.2 88.1 83.8 Neohesperidin dihydrochalcone 95.2 89.9 82 Phellopterin 97.5 94.8 90 Oxymatrine 96 91.2 95.9 Sclareolide 97.6 94 91.4 Sophoricoside 95 85.6 80.1 Swertiamarin 95.1 88 84.4 Synephrine 96.1 89.5 85.2

[0148] As shown in Table 8 above, the experimental group using the toothpaste containing each of the compounds of Chemical Formula 1 to Chemical Formula 15 removed about 95% or more of halitosis at the time point of 1 minute after brushing compared to the control group, and even after 30 minutes after brushing, the halitosis removal rate reached 80% or more, and the halitosis removal effect was significantly superior to that of the control group. Therefore, it can be seen that the compounds of Chemical Formula 1 to Chemical Formula 15 can be used for the prevention or treatment of halitosis.

Claims

1. Use of a tertiary pharmaceutical composition comprising paeoniflorin or a pharmaceutically permissible salt thereof as the active ingredient in the preparation of a tertiary pharmaceutical for the prevention or improvement of periodontal disease caused by Porphyromonas gingivalis.

2. The use according to claim 1, wherein, The periodontal disease mentioned is periodontitis or gingivitis.

3. The use according to claim 1, wherein, The dosage form of the pharmaceutical composition is selected from one or more of the following groups: oral cleansers, confectionery, oral sprays, oral ointments, oral desensitizers, and gum massage creams.

4. The use according to claim 1, wherein, The dosage form of the pharmaceutical composition is toothpaste.

5. The use according to claim 1, wherein, The dosage form of the pharmaceutical composition is selected from one or more dosage forms in the group consisting of oral cleansers and chewing gum.

6. The use according to claim 1, wherein, The dosage form of the pharmaceutical composition is a mouthwash.

7. Use of a pharmaceutical composition comprising paeoniflorin or a pharmaceutically permissible salt thereof as the active ingredient in the preparation of a medicament for the prevention or treatment of periodontal disease caused by Porphyromonas gingivalis.

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