Oral care compositions and uses

Abstract

The application discloses an oral care composition and use, which comprises a compound shown in formula (I) and an oral auxiliary material, and by controlling the concentration or amount of component (a) in the oral care composition, the oral care composition can generate a drug effective concentration in the range of 1.35-13 mM in the oral cavity after being applied to the oral cavity, can more effectively inhibit Porphyromonas gingivalis, has no substantial influence on Lactobacillus reuteri and the total amount of the bacterial flora in the oral cavity of healthy people, and thus can effectively improve the microenvironment of the oral bacterial flora and the imbalance of the bacterial flora, and further avoid or prevent oral diseases.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of oral care, in particular to an oral care composition and use capable of improving the microenvironment of oral flora, and further improving periodontal related diseases or conditions. BACKGROUND

[0002] Different bacteria in the oral cavity work together to maintain and build a healthy oral environment. When the oral flora is imbalanced due to poor eating habits, overuse of drugs, etc., halitosis, oral ulcers, and other problems may occur, and may even further lead to gum or periodontal related diseases. Therefore, oral flora balance is crucial for good oral health.

[0003] An important feature of oral flora imbalance is the rapid proliferation of harmful bacteria such as Porphyromonas gingivalis. Current inhibitory drugs have no bias in inhibiting oral flora. Some drugs can control the number of bacteria in the oral cavity to some extent, but the effect is generally poor, and the beneficial bacteria are inhibited or killed, which is not conducive to the control of oral flora. SUMMARY

[0004] To solve at least some of the technical problems in the prior art, the present application provides an oral care composition and use. Specifically, the present application includes the following.

[0005] In a first aspect of the present application, an oral care composition is provided, comprising:

[0006] (a) a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof:

[0007]

[0008] wherein:

[0009] R1 is H or CH3;

[0010] R2 is H, CH3 or OCH3;

[0011] R3 is OH or OCH3,

[0012] and (b) an oral adjuvant.

[0013] In the present application, preferably, the compound represented by (I) is:

[0014]

[0015] In the present application, preferably, the concentration or amount of component (a) in the oral care composition is controlled so that the oral care composition can produce a drug effective concentration in the range of 1.35-13 mM in the oral cavity after being applied to the oral cavity.

[0016] In preferred embodiments of the present application, wherein component (b) comprises at least one of an abrasive, a thickening agent, a surfactant, a preservative, a humectant, a sweetener, and a flavoring agent.

[0017] In preferred embodiments of the present application, wherein the oral care composition comprises at least one of a toothpaste, a tooth gel, a subgingival gel, a mouthwash, a mouth spray, a lozenge, a chewable tablet, a chewing gum, a tooth whitening strip, a dental floss, and a dental floss coating.

[0018] In preferred embodiments of the present application, the oral care composition is effective in inhibiting P. gingivalis without showing significant killing effect on L. reuteri.

[0019] In another aspect of the present application, there is provided a use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or any of the oral care compositions in the care of an oral cavity:

[0020]

[0021] wherein:

[0022] R1is H or CH3;

[0023] R2is H, CH3, or OCH3;

[0024] R3is OH or OCH3.

[0025] In preferred embodiments of the present application, for the use, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is effective in inhibiting P. gingivalis without showing significant killing effect on L. reuteri.

[0026] In preferred embodiments of the present application, for the use according to the present application, wherein the concentration or amount of component (a), i.e., the compound of formula (I) or a pharmaceutically acceptable salt thereof, in the oral care composition is controlled so that the oral care composition, after being applied to the oral cavity, is capable of producing a pharmaceutically effective concentration in the range of 1.35-13 mM in the oral cavity.

[0027] In preferred embodiments of the present application, for the use according to the present application, wherein the oral care comprises modulating the microenvironment of the oral flora, thereby improving an oral disease or condition.

[0028] In preferred embodiments of the present application, for the use according to the present application, wherein the oral disease or condition comprises oral ulceration, periodontal soft tissue atrophy and / or loss, alveolar bone resorption and / or reduction in bone density.

[0029] In preferred embodiments of the application, the use according to the application, wherein the oral microbiota microenvironment comprises increasing the proportion of beneficial bacteria and / or decreasing the proportion of harmful bacteria in the oral cavity.

[0030] In preferred embodiments of the application, the use according to the application, wherein the care further comprises substantially maintaining the total amount of bacteria in the oral cavity.

[0031] In preferred embodiments of the application, the use according to the application, wherein the oral disease or condition comprises oral ulceration, periodontal soft tissue atrophy and / or loss, alveolar bone resorption and / or reduced bone density.

[0032] The oral care composition of the present application contains a specific compound of formula (I) or a pharmaceutically acceptable salt thereof, which is able to more effectively control harmful bacteria in the oral cavity, while having no substantial impact on beneficial bacteria and the total amount of bacteria in the oral cavity, thereby being able to effectively improve the oral microbiota microenvironment and the imbalance of the microbiota, and further avoid causing oral diseases such as gingival or periodontal related diseases. BRIEF DESCRIPTION OF DRAWINGS

[0033] Figure 1 Live / Dead staining of compound 1 of formula I killing P. gingivalis.

[0034] Figure 2 Toothpaste containing compound 1 of formula I.

[0035] Figure 3 Preventive and therapeutic effect of toothpaste containing compound 1 of formula I on alveolar bone destruction caused by periodontitis in mice in vivo (left) and micro-CT bone resorption height quantitative analysis (right). DETAILED DESCRIPTION

[0036] Various exemplary embodiments of the present application will now be described in detail with reference to the drawings, which are not to be construed as limiting the application. It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the application. Additionally, the use of the term "about" in the description above and below means that the value is within 10% of the value being described.

[0037] It is to be understood that the terms used in the present specification are merely for the purpose of describing particular embodiments and are not intended to limit the application. In addition, for numerical ranges in the present application, it is to be understood that the upper limit and the lower limit of the range and every intermediate value between them are specifically disclosed. Each smaller range within the range of any stated value or stated range of values, as well as any other stated value or stated range of values within the stated range, is also included within the present application. The upper and lower limits of these smaller ranges can be independently included or excluded from the range.

[0038] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Although preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application. All documents mentioned herein are incorporated by reference to disclose and describe in full the methods and / or materials which are described therein. In the case of conflict between the present specification and any document incorporated herein by reference, the present specification will control.

[0039] As used herein, the term "oral care composition" refers to a product that is applied to the oral cavity and remains in the oral cavity long enough to contact the dental surfaces or oral tissues, and in particular, a product that has a beneficial effect on the oral cavity. The product form of the oral care composition is not specific, including but not limited to toothpaste, tooth gel, subgingival gel, mouth rinse, mouth spray, lozenge, chewable tablet, chewing gum, tooth whitening strip, dental floss, and flossing paste. The form of the oral care composition is not limited, including but not limited to solid, liquid, powder, paste, or a combination thereof.

[0040] In preferred embodiments of the present application, as used herein, the term "compound represented by Formula (I)" refers to a compound that has antibacterial activity, in particular, a compound that has specific killing activity against harmful bacteria in the oral cavity, and has the following structure:

[0041]

[0042] wherein:

[0043] R1 is H or CH3;

[0044] R2 is H, CH3, or OCH3;

[0045] R3 is OH or OCH3.

[0046] In preferred embodiments of the present application, the compound represented by Formula (I) of the present application can be, for example, one of the following compounds:

[0047]

[0048]

[0049]

[0050] The compound represented by Formula (I) of the present application can be a natural compound or an artificially synthesized compound. The natural compound can be obtained by, for example, extraction from a plant, such as Litsea cubeba. Specifically, it can be obtained by alcohol extraction, water extraction, or a combination of both.

[0051] The crystallinity of the compound of formula (I) is not limited, and can be amorphous and / or any crystal form.

[0052] In the preferred embodiment of the present application, the concentration or amount of the compound of formula (I) in the oral care composition is controlled herein so that the oral care composition can produce an effective antibacterial concentration in the oral cavity after being applied to the oral cavity, and the specific concentration or amount is not particularly limited, and the effective antibacterial concentration is generally in the range of 1.35-13 mM, preferably in the range of 1.5-12 mM, such as 1.4 mM, 1.5 mM, 1.6 mM, 1.7 mM, 1.8 mM, 1.9 mM, 2 mM, 2.2 mM, 2.5 mM, 3 mM, 3.5 mM, 4 mM, 4.5 mM, 5 mM, 5.5 mM, 6 mM, 6.5 mM, 7 mM, 7.5 mM, 8 mM, 8.5 mM, 9 mM, 9.5 mM, 10 mM, 10.5 mM, 11 mM, 11.5 mM, 12 mM, 12.5 mM, and the like. Within the above range, the concentration of the compound of formula (I) can effectively control, inhibit or reduce the concentration of harmful bacteria, especially P. gingivalis, without substantially affecting the beneficial bacteria such as Lactobacillus reuteri and the total amount of oral flora, thereby achieving selective antibacterial and achieving the purpose of regulating oral flora.

[0053] In the preferred embodiment of the present application, if the concentration of the compound of formula (I) in the oral cavity is too high, it tends to have an adverse effect on beneficial bacteria and / or the overall oral flora, and even affect health. On the other hand, if the concentration of the compound of formula (I) in the oral cavity is too low, it tends to be unable to effectively inhibit or reduce harmful bacteria due to the small amount, and the purpose of regulating oral flora of the present application cannot be achieved.

[0054] The term "oral care adjuvant" herein includes any material that can be used in the field of oral care. Exemplary examples include, but are not limited to, abrasives, thickeners, surfactants, preservatives, humectants, sweeteners, fragrances, and the like. The oral care adjuvant of the present application can be a combination of one or more of the above.

[0055] As used herein, the term "abrasive" refers to fine particles that have a polishing and cleaning effect, examples of which include, but are not limited to, calcium-based abrasives and / or non- calcium abrasives. Examples of non-calcium abrasives include bentonite, colloidal silica, precipitated silica, amorphous precipitated silica, silica hydrate, perlite, titanium dioxide, calcium pyrophosphate, dicalcium phosphate dihydrate, aluminum oxide, aluminum oxide hydrate, calcined aluminum oxide, aluminum silicate, insoluble sodium metaphosphate, insoluble potassium metaphosphate, insoluble magnesium carbonate, zirconium silicate, microparticulate thermoset resin, and other suitable abrasive materials. The amount of abrasive can range from about 5% to about 70%, from about 10% to about 50%, from about 10% to about 60%, from about 20% to about 50%, from about 25% to about 40%, or from about 1% to about 50%, by total weight of the oral care composition.

[0056] As used herein, the term "thickening agent" refers to a substance used to provide a gel-like structure to a composition to stabilize the composition, such as a toothpaste, against phase separation. Examples of thickening agents include, but are not limited to, polysaccharides, polymers, and / or inorganic thickening agents.

[0057] As used herein, "polysaccharides" suitable for use as thickening agents in the present application are not particularly limited, non-limiting examples of which include, but are not limited to, starches, starch glycerols, gums, carrageenan, sodium alginate, agar, pectin, gelatin, cellulose compounds. Examples of gums include, but are not limited to, gum karaya (sterculia gum), gum tragacanth, gum arabic, ghatti gum, acacia gum, xanthan gum, guar gum, and cellulose gum, for example. Examples of cellulose compounds include cellulose, microcrystalline cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxymethyl carboxypropyl cellulose, methyl cellulose, ethyl cellulose, and sulfated cellulose, for example. One or a combination of the above polysaccharides can be used in the present application.

[0058] As used herein, examples of "polymers" suitable for use as thickening agents in the present application include polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), polyacrylic acid, copolymer of maleic anhydride and methyl vinyl ether, cross-linked polyacrylic acid polymers.

[0059] As used herein, examples of "inorganic thickening agents" suitable for use as thickening agents in the present application include, but are not limited to, silica, magnesium aluminum silicate (veegum), natural and synthetic clays, such as hectorite clay, and the like.

[0060] As used herein, the amount of thickening agent can range from 0.01% to about 15%, from 0.1% to about 10%, from about 0.2% to about 5%, or from about 0.5% to about 2%, by weight of the oral care composition. The thickening agent can be one or more of the above thickening agents.

[0061] As used herein, the term "surfactant" refers to a detersive material used to impart detersive and foaming properties to an oral care composition. Suitable surfactants include anionic, cationic, nonionic, zwitterionic surfactants, and the like.

[0062] Examples of suitable anionic surfactants for use in the present application include, for example, water-soluble salts of alkyl sulfates having an alkyl group containing 8 to 20 carbon atoms and water-soluble salts of sulfonated monoglycerides of fatty acids having 8 to 20 carbon atoms. Examples of such anionic surfactants include, but are not limited to, sodium lauryl sulfate (SLS) and sodium coconut monoglyceride sulfonate. Other suitable anionic surfactants include sarcosinates such as sodium lauroyl sarcosinate, taurinates, sodium lauryl sulfoacetate, sodium lauroyl hydroxyethylsulfonate, sodium lauryl polyoxyethylene ether carboxylate, and sodium dodecylbenzenesulfonate. One of the above surfactants can be used in the present application, or two or more anionic surfactants can be used in combination.

[0063] In certain embodiments, the anionic surfactant of the present application uses alkyl phosphate salts, thereby having a strong affinity to enamel surface and having a sufficient surface binding tendency to desorb pellicle proteins and remain attached to the enamel surface.

[0064] In certain embodiments, the anionic surfactant of the present application is a sarcosinate, a hydroxyethylsulfonate, and a taurinate, such as an alkali metal salt or an ammonium salt. Examples of such surfactants include lauroyl sarcosinates, myristoyl sarcosinates, palmitoyl sarcosinates, stearoyl sarcosinates, oleoyl sarcosinates, or combinations thereof.

[0065] Examples of suitable cationic surfactants for use in the present application include, for example, derivatives of quaternary ammonium compounds comprising long alkyl chains of 8 to 18 carbon atoms, such as lauryltrimethylammonium chloride; cetylpyridinium chloride; cetyltrimethylammonium bromide; cetylfluoropyridinium; or combinations thereof.

[0066] Examples of suitable nonionic surfactants for use in the present application include, for example, compounds resulting from the condensation of alkylene oxide groups with an organic hydrophobic compound, which can itself be aliphatic or alkyl aromatic. Examples of suitable nonionic surfactants can include poloxamers, polyethylene oxide condensates of alkyl phenols, products derived from the condensation of ethylene oxide with reaction products of propylene oxide and ethylene diamine, ethylene oxide condensates of fatty alcohols, long chain tertiary amine oxides, long chain tertiary phosphine oxides, long chain dialkyl sulfoxides, and combinations of these. Other suitable nonionic surfactants include alkylglucamides, alkylglucosides, and / or combinations thereof.

[0067] Herein, suitable amphoteric surfactants for use in the present application include derivatives of aliphatic quaternary ammonium, phosphonium and sulfonium compounds in which the aliphatic groups can be straight or branched chain and one of the aliphatic substituents contains 8 to 18 carbon atoms and one of the aliphatic substituents contains an anionic water-solubilizing group, e.g., carboxylate, sulfonate, sulfate, phosphate, or phosphonate. Typical alkyl dimethyl betaines include decyl betaine or 2-(N-decyl-N,N-dimethylammonio) acetate, coco-betaine or 2-(N-coco-N,N-dimethylammonio) acetate, myristalkonium chloride, palmethyl betaine, lauryl betaine, cetyl betaine, cetyl betaine, stearyl betaine, and the like. Amido betaines can be exemplified by cocamidopropyl betaine, cocoamidopropyl betaine (CADB), and lauramidopropyl betaine. Other suitable amphoteric surfactants include betaines, sulfobetaines, sodium lauryl lactylate, alkyl amphodiacetates, and / or combinations thereof.

[0068] In certain embodiments, the surfactants of the present application can also include one or more natural and / or naturally derived surfactants. Natural surfactants can include surfactants derived from natural products and / or minimally processed or unprocessed surfactants. Natural surfactants can include: hydrogenated, non-hydrogenated, or partially hydrogenated vegetable oil, passion fruit oil, candelilla wax, coco-oclyl acid ester, decanoic acid ester, dioctyl ether, lauryl alcohol, myristyl myristate, dioctyl ether, octanoic acid, octyl ester, octyl decanoate, octyl octanoate, undecane, tridecane, decyl oleate, glyceryl oleate, cetyl palmitate, stearic acid, palmitic acid, glyceryl stearate, hydrogenated, non-hydrogenated, or partially hydrogenated vegetable glycerides, polyglyceryl-2 dipolyhydroxystearate, cetearyl alcohol, sucrose polystearate, glycerin, octadecanol, hydrolyzed, partially hydrolyzed, or unhydrolyzed vegetable protein, hydrolyzed, partially hydrolyzed, or unhydrolyzed wheat protein hydrolysate, polyglyceryl-3 diisostearate, glyceryl oleate, myristyl alcohol, cetyl alcohol, sodium cetylstearyl sulfate, cetylstearyl alcohol, glyceryl laurate, capric triglyceride, coco-glycerides, lecithin, dioctyl ether, xanthan gum, sodium coco-sulfate, ammonium lauryl sulfate, sodium coco-sulfate, sodium coco-glutamate, polyalkyl glucosides such as decyl glucoside, cetearyl glucoside, cetearyl polyglucoside, coco-glucoside, and lauryl glucoside, and / or combinations thereof.

[0069] Herein, the surfactant is generally used in an amount of from about 0.01% to about 15%, from about 0.3% to about 10%, or from about 0.3% to about 2.5%, based on the total weight of the oral care composition.

[0070] As used herein, the term "preservative" refers to a substance added to an oral care composition to prevent mold or bacterial growth, examples of which include, but are not limited to, methyl paraben, propyl paraben, benzoic acid, and sodium benzoate.

[0071] As used herein, the term "humectant" refers to a substance used to increase the consistency or mouth feel of an oral care composition and to prevent it from drying out. Examples of suitable humectants include, but are not limited to, polyethylene glycol, propylene glycol, glycerin, erythritol, xylitol, sorbitol, mannitol, butylene glycol, lactitol, hydrogenated starch hydrolysate, and / or mixtures thereof. The humectant is generally used in an amount of 0% to about 70%, about 5% to about 50%, about 10% to about 60%, or about 20% to about 50%, based on the total weight of the oral care composition.

[0072] As used herein, the term "sweetener" refers to a substance added to an oral care composition to impart a pleasant taste thereto. Suitable sweeteners include saccharin (e.g., sodium, potassium, or calcium saccharin), cyclamate (e.g., sodium, potassium, or calcium salt), Acesulfame-K, thaumatin, neohesperidin dihydrochalcone, ammoniated glycyrrhizin, dextrose, levulose, sucrose, mannose, chloro sucrose, stevia, and dextrose.

[0073] As used herein, the term "flavorant" refers to a substance added to an oral care composition to improve or alter its taste or to produce a pleasant sensation, examples of which include, e.g., peppermint, spearmint, wintergreen. Illustratively, the oral care composition includes a peppermint oil consisting essentially of menthol, menthone, and menthyl acetate. As used herein, the flavorant is generally used in an amount of about 0.001% to about 2%, alternatively 0.01% to about 1.75%, alternatively 0.1% to about 1.5%, and alternatively 0.5% to about 1.25%, based on the total weight of the oral composition.

[0074] In preferred embodiments, the oral care composition of the present application does not include any antibacterial or inhibitory ingredients other than the compound of Formula (I) or a pharmaceutically acceptable salt, crystalline form, prodrug, derivative thereof.

[0075] As used herein, the oral care composition optionally comprises a buffering agent. The buffering agent can be a weak acid or a weak base that can maintain a particular pH at a selected site in the oral cavity. For example, the buffering agent can maintain the pH of the surface of the teeth to mitigate the effects of plaque acids produced by bacteria. Suitable buffering systems can include phosphate, citrate, carbonate / bicarbonate, tris, imidazole, urea, borate, and / or combinations thereof. Suitable buffering agents include bicarbonate salts such as sodium bicarbonate, glycine, orthophosphate, arginine, urea, and / or combinations thereof. The buffering agent is generally used in an amount of about 1% to about 30%, about 5% to about 25%, or about 10% to about 20%, based on the total weight of the oral care composition.

[0076] Herein, the oral care composition optionally further comprises a beneficial ion, examples of which include fluoride ions and calcium ions. Such beneficial ions can be provided by a compound comprising the corresponding ion. Exemplary soluble compounds comprising fluoride ions include, but are not limited to, stannous fluoride, sodium fluoride, titanium fluoride, calcium fluoride, calcium phosphate silicate fluoride, potassium fluoride, amine fluoride, sodium monofluorophosphate, zinc fluoride, and / or mixtures thereof. The concentration of fluoride ions in the oral care composition is generally from about 50 ppm to about 5000 ppm, preferably from about 500 ppm to about 3000 ppm. To this end, the amount of the compound comprising fluoride ions in the oral care composition is from about 0.0025% to about 5%, from about 0.01% to about 10%, from about 0.2% to about 1%, from about 0.5% to about 1.5%, or from about 0.3% to about 0.6%, based on the total weight of the oral care composition.

[0077] In certain embodiments, the oral care composition of the present application optionally comprises calcium ions. The desired calcium ions can be provided by a compound comprising calcium ions. Examples of compounds comprising calcium ions include, but are not limited to, calcium chloride, calcium nitrate, calcium phosphate, calcium lactate, calcium oxalate, calcium oxide, calcium gluconate, calcium citrate, calcium bromide, calcium iodate, calcium iodide, hydroxyapatite, fluorapatite, calcium sulfate, calcium glycerophosphate, and / or combinations thereof. The amount of the compound comprising calcium ions in the oral care composition is from about 5% to about 70%, from about 10% to about 50%, from about 10% to about 60%, from about 20% to about 50%, from about 25% to about 40%, or from about 1% to about 50%, based on the total weight of the oral care composition.

[0078] Herein, the term "care" refers to taking measures to improve the microenvironment of the oral flora so as to be more conducive to human health. The care herein particularly refers to improving the microenvironment of the oral flora by the oral care composition. The improvement includes increasing the proportion of beneficial bacteria in the oral cavity, and / or decreasing the proportion of harmful bacteria. Preferably, the total amount of the flora in the oral cavity is substantially maintained. The term "substantially" refers to no substantial adverse effect on the total amount of the oral flora or the beneficial bacteria. For example, there is no any adverse effect such as inhibition, killing, etc. on the total amount of the oral flora or the beneficial bacteria, or the inhibition, killing, etc. is less than 20%, preferably less than 15%, more preferably less than 10%, such as 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less. The care of the present application also includes improving diseases or conditions caused by the imbalance of the flora, including periodontal-related diseases or conditions, such as periodontal soft tissue atrophy and / or loss, alveolar bone resorption and / or reduced bone density.

[0079] The term "microflora microenvironment" also referred to as "microecological flora" herein refers to the ecological system of microorganisms, particularly bacteria, in the oral cavity, which is required for a normal oral cavity, and these bacteria form a unity of interdependence, mutual restriction and influence with the oral environment of the human body. The microflora microenvironment usually includes harmful bacteria, beneficial bacteria or probiotics, and neutral bacteria.

[0080] The term "harmful bacteria" herein refers to a type of bacteria that is harmful to oral health per se or can produce harmful substances to the oral cavity, and once the number of such bacteria grows out of control, it will cause various diseases in the oral cavity, including halitosis, oral ulcers, gum or periodontal diseases, etc.

[0081] The term "beneficial bacteria" also referred to as "beneficial bacteria" herein refers to a type of bacteria that is indispensable to oral health, which can synthesize various beneficial ingredients such as vitamins. Examples of beneficial bacteria include but are not limited to Bifidobacterium, Lactobacillus such as Lactobacillus reuteri, lactic acid bacteria, etc.

[0082] The term "neutral bacteria" herein refers to a type of bacteria that has a dual role in the oral cavity, which is beneficial to health under normal circumstances, and once the proliferation is out of control or is transferred from the intestine to other parts of the body, it can cause many diseases.

[0083] Examples

[0084] Example 1: In vitro antibacterial experiment of compound 1 of formula I.

[0085] Compound 1 of formula I was co-cultured with harmful bacteria Porphyromonas gingivalis which can cause periodontitis, Lactobacillus reuteri which belongs to probiotics for the oral cavity, and the oral flora of clinically healthy subjects for 24 h, and as a comparison, the inhibitory effect of compound of formula II on harmful bacteria Porphyromonas gingivalis which can cause periodontitis was investigated. The inhibitory effect of the compounds on various bacteria was evaluated by quantitative enzyme reader reading and plaque biofilm crystal violet staining.

[0086]

[0087] The results show that compound 1 of formula I significantly inhibits the growth of Porphyromonas gingivalis, and the minimum inhibitory concentration is 1.35 mM, while the minimum inhibitory concentration of compound of formula II for inhibiting the growth of Porphyromonas gingivalis is 6.75 mM.

[0088] In addition, compound 1 of formula I has no obvious killing effect on Lactobacillus reuteri and the oral bacterial population of clinically healthy subjects, even when the concentration of compound 1 of formula I reaches 10 mM. The minimum inhibitory concentration of compound 1 of formula I for Lactobacillus reuteri is 13.5 mM.

[0089] The ratio of live (green fluorescence) and dead (red fluorescence) P. gingivalis after intervention of compound 1 of formula I was labeled by Live / Dead staining, as shown in Figure 1 Figure 1. Compound 1 of formula I showed good killing effect on P. gingivalis in vitro.

[0090] Example 2: Toothpaste containing compound 1 of formula I and in vivo test in mice.

[0091] A toothpaste composition containing compound 1 of formula I was prepared, which contained 0.2% of compound 1 of formula I by mass percentage. Compound 1 of formula I could produce an effective concentration of about 10 mM in the oral cavity after the toothpaste composition was applied to the oral cavity. Other components of the toothpaste composition were: 25% glycerol; 24% silicon dioxide; 5% sodium N-lauroyl glutamate; 2% carboxymethyl cellulose; 2% xanthan gum, and the rest was ultrapure water. The various raw materials were mixed in the formula proportion, and a homogenizer was used for mixing to ensure uniform distribution of the ingredients and fine texture. The mixed toothpaste composition was as shown in Figure 2 .

[0092] The maxillary second molars of 6-week-old C57BL / 6J male mice were ligated with 5-0 nylon silk, and then the mice were coated with P. gingivalis in the oral cavity every other day for 4 weeks. The mice were detected by micro-CT, and the maxillary second molars showed obvious alveolar bone resorption and root bifurcation exposure, confirming that the mouse periodontal disease model was successfully modeled.

[0093] Four mice in the healthy control group (Control), four mice in the periodontitis group (Periodontitis) whose periodontal disease model was successfully modeled, and four mice in the periodontitis + compound 1 toothpaste treatment group (LA) whose periodontal disease model was successfully modeled were selected. The mice in the periodontitis + compound 1 toothpaste treatment group were intervened with tooth brushing once a day using the toothbrush shown in Figure 2 and the toothpaste prepared. After 4 weeks, the mice were examined by micro-CT, and the results are shown in Figure 3 . The alveolar bone resorption height of the healthy mouse group was 84.26 ± 10.91 mm, and the alveolar bone resorption height of the periodontitis mouse group was 609.83 ± 110.46 mm. The alveolar bone resorption height of the periodontitis + compound 1 toothpaste treatment mouse group was 214.26 ± 61.00 mm, which indicated that the toothpaste containing compound 1 of formula I could significantly inhibit the alveolar bone destruction and resorption caused by periodontal disease.

[0094] While the application has been described with reference to the example embodiments thereof, it is to be understood that the application is not limited to the example embodiments disclosed. Numerous modifications or changes can be made to the example embodiments of the present application without departing from the scope or spirit of the application. The scope of the claims should be based on the claims as they are worded rather than the example embodiments described.

Claims

1. An oral care composition characterized in that, Compositions comprising: (a) a compound represented by the following formula or a pharmaceutically acceptable salt thereof: ， and (b) an oral adjuvant, wherein the oral care composition is effective in inhibiting P. gingivalis without showing significant killing effect on L. reuteri, wherein the concentration or amount of component (a) in the oral care composition is controlled so that the oral care composition is capable of producing a pharmaceutically effective concentration in the range of 1.35-13 mM in the oral cavity after the oral care composition is applied to the oral cavity, wherein the component (b) comprises at least one of an abrasive, a thickening agent, a surfactant, a preservative, a humectant, a sweetener, and a flavoring agent, wherein the oral care composition is a toothpaste.

2. Use of a compound of the formula ###0002### or a pharmaceutically acceptable salt thereof, or an oral care composition as described in claim 1, in the preparation of an oral care product, characterised in that, The compound has the following structure: ， wherein the compound represented by the following formula or a pharmaceutically acceptable salt thereof is effective in inhibiting P. gingivalis without showing significant killing effect on L. reuteri, wherein the concentration or amount of the compound represented by the following formula or a pharmaceutically acceptable salt thereof in the oral care composition is controlled so that the oral care composition is capable of producing a pharmaceutically effective concentration in the range of 1.35-13 mM in the oral cavity after the oral care composition is applied to the oral cavity, wherein the oral care product is used to modulate the microenvironment of the oral cavity bacterial flora, thereby improving the oral disease or condition, wherein the oral disease or condition is selected from the group consisting of oral ulcer, periodontal soft tissue atrophy and / or loss, alveolar bone resorption and / or reduced bone density.

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