JP6972120B2 - Oral care composition to promote gingival health - Google Patents

Description

The present invention relates to an oral care composition comprising a stannous ion source and an anti-fibrinolytic agent for promoting consumer gingival health. In particular, such oral care compositions are useful for improving gingival wound healing and improving the reduction of bacterial activity in the consumer's oral cavity.

Gingival diseases such as gingival inflammation and / or periodontitis cause acute and chronic gingival inflammation in the oral cavity. "Periodontitis" is a milder form of the disease. Symptoms of gingival inflammation include gingival bleeding and redness, swelling, or tender gingiva. If left untreated, gingival inflammation can progress to "periodontitis". Periodontitis pulls the gums away from the teeth, forming a space called a "periodontal pocket" that can be infected with pathogenic bacteria. Bacteria are present on the root surface as a biofilm. Bacteria in the biofilm can attack the gingiva and the underlying alveolar bone supporting teeth. These attacks can cause major damage to the soft tissues and bones that support the teeth. In the later stages of gingival disease (ie, "advanced periodontitis"), the more serious problems of tooth loosening and final tooth loss can arise.

Some over-the-counter oral care compositions are primarily aimed at alleviating one or more symptoms of early stage gingival disease (ie, gingival inflammation), such as redness, swelling, or tenderness. Includes gingival relaxation and / or stalk gingival bleeding. Typically, these compositions claim benefits such as "gingival care", "oral care", "oral hygiene", "dental care", or "dental hygiene" to consumers. An example of such a composition is the "Colgate® Total" toothpaste, which claims to "help reduce the first stage of gingivitis" as defined as "gingivitis or hemorrhagic gingiva". (See http: //www.colgatetotal.com/total-benefits/wole-mouth-health/gingivitis-control). To help distinguish the benefits of over-the-counter oral care compositions as compared to the present invention, the inventors herein collectively refer to the aforementioned benefits of these over-the-counter oral care compositions as "gingiva." Called "care". This is because these over-the-counter oral care compositions primarily care for the gums and cause symptoms associated with early stage periodontal disease (ie, periodontitis) (eg, gingival bleeding and / or redness, swelling, or This is because it is formulated to relieve tender gingiva).

However, there is a need to provide an overall "gingival health" effect, which, as used herein, is a broader term that includes at least some of the aforementioned gingival care effects. , As well as an additional antibacterial effect to mitigate the harmful effects of bacteria associated with gingival disease, including gingival inflammation, periodontitis, or both.

The conventional method described above has at least one of several drawbacks. First, these over-the-counter oral care compositions can promote gingival care, but not to the extent that they also promote gingival health. In fact, these commercially available oral care compositions are generally unable to provide any significant antibacterial effect in addition to gingival care effects (eg, antihemorrhea and / or antiswelling). This is a problem because if the bacteria in the biofilm are not controlled, it can increase the size of the periodontal pockets that lead to periodontitis. Second, gingival health can correlate with general health. In other words, an individual's gingival health can be an indicator of the person's general health. Studies have shown that as overall gingival health declines, one of these potential life-threatening conditions such as heart disease and stroke, diabetes, kidney disease, preterm birth, and / or osteoporosis ( It suggests that the risk of developing (or more than one) may be increased (US Pat. No. 6,846,478, Doile, MJ, and US Pat. No. 8,283,135, See Doile, MJ). Therefore, it is desirable to improve overall gingival health as well as gingival care to ensure better overall general health.

Other commercially available oral care compositions may contain antibacterial agents aimed at controlling the growth of bacteria in biofilms. Some oral compositions may also contain tranexamic acid and fluoride sources. Tranexamic acid has been described as a useful antihemorrhagic agent for gingival wound healing. It has also been described to inhibit gingival inflammation and / or act as an anti-swelling agent (US Pat. Nos. 4,272,513, Gaffar, A., and 4,272,512). See Gaffar, A.). Fluoride has been well demonstrated to prevent and control tooth decay. One drawback of oral care compositions containing tranexamic acid is that tranexamic acid can become unstable and lose its activity during aging. In addition, unstable tranexamic acid can discolor oral care compositions, which turn them yellow and dark brown, which is not desirable for consumers. Previous oral care compositions that accounted for the problem of instability and discoloration were formulated with tranexamic acid at higher levels of 1.5% to 2% (US Pat. No. 4,272,513, Gaffar, A). And the examples in Nos. 4,272,512, Gaffar, A.). According to these references, higher levels are needed to provide sufficient tranexamic acid efficacy for wound healing and other benefits. To overcome the problem, these previous attempts were made of _{tranexamic acid by adding additional ingredients such as, for example, TiO 2} , folic acid, or flavor mixtures (eg, methyl salicylate, menthol, eugenol, and cineole). Prevents the above discoloration during storage without significantly reducing stability and activity. However, there remains a need to simplify formulation and processing steps in order to provide cost-effective and effective toothpastes and other oral care formulations.

Useful antibacterial agents for these other commercially available oral care compositions include, for example, zinc citrate (eg, Darlie ™ Expert toothpaste), IPMP (eg, Lion ™ Systemma toothpaste), and chloride. Cetylpyridinium (CPC) and the like can be mentioned. Unfortunately, these antibacterial agents may have poor biofilm permeability. As a result, these antibacterial agents can simply be chemically degraded before they can interact with the bacteria deep in the biofilm. Alternatively, antibacterial agents may exhibit a significantly slower penetration rate into the biofilm. As a result, these antibacterial agents can have inefficient penetration rates into the biofilm, taking longer to engage and kill bacteria. These oral care compositions are not considered effective in promoting gingival health, as one or more of these drawbacks is particularly associated with reduced bacterial activity.

One solution is to add larger amounts of antibacterial agents to accommodate degradation and / or suboptimal or inefficient penetration rates in the biofilm. However, the amount of these antibacterial agents required in oral care products to provide efficacy is unreasonably high given the relatively high Minimum Inhibitory Concentrations (MIC) (data not shown). In some cases. MIC is the minimum concentration of micrograms per milliliter of antibacterial agent with no observed bacterial growth. At lower concentrations than the MIC, antibacterial agents are not effective in killing bacteria or inhibiting their growth and reproduction. At higher concentrations than MICs, antibacterial agents are effective in killing bacteria or inhibiting their growth and reproduction.

This is then oral care due to the maximum safety limit or cost limit by using ever-increasing amounts of these antibacterial agents and / or the harmful side effects that may be associated with higher concentrations of these antibacterial agents. It can be disadvantageous for some aspects, including restrictions on the effectiveness of the product. In short, there is still a need for improved oral care compositions that promote gingival health benefits due to the chemical decomposition and / or suboptimal or inefficient penetration rates of these antibacterial agents into biofilms. .. It is desirable that this novel oral care composition have an improved antibacterial activity in the biofilm.

U.S. Pat. No. 6,846,478 U.S. Pat. No. 8,283,135 U.S. Pat. No. 4,272,513 U.S. Pat. No. 4,272,512

Thus, an oral care composition that provides the consumer with gingival health benefits, or at least the associated gingival health benefits that are better than the commercially available composition (eg, gingival wound healing and antibacterial effects). There is a need to provide things.

The present invention, at least in part, the combination of an anti-fibrinolytic agent such as tranexamic acid with a stannous ion source in an oral care composition provides gingival health benefits, including at least gingival wound healing and antibacterial effects. We try to address this need based on the surprising discovery of facilitating. In particular, the oral care composition comprises tranexamic acid for gingival wound healing and a stannous ion source as an antibacterial agent to counter the undesired effects of bacterial activity in the oral cavity.

One advantage of the present invention is "deeper biofilm penetration and / or bacterial killing". For this purpose, even more surprisingly, it is found that when used in combination with tranexamic acid, it is possible to increase the permeation depth and / or permeation rate of stannous ions into the biofilm. In short, the synergistic combination of tranexamic acid and stannous ion source in the oral care composition may be such that an improvement in gingival health benefits is achieved. Moreover, the use of the oral care compositions of the present invention can provide consumers with improved gingival health benefits.

Another advantage of the present invention is to provide an oral care composition for promoting gingival health as it relates to the wholeness of symptoms associated with gingival inflammation, periodontitis or both. It is still a further advantage that the oral care compositions of the present invention have improved gingival health benefits. A still further advantage of the present invention is to provide an oral care composition having an improved penetration depth of the antibacterial agent (s) into the biofilm. A still further advantage of the present invention is to provide an oral care composition having an improved permeation rate of the antibacterial agent (s) into the biofilm. A still further advantage of the present invention is to provide a cost effective and effective oral care composition for promoting gingival health. Yet a further advantage is that the oral care composition is a dentifrice, preferably providing a pleasing taste and mouthfeel experience. Yet a further advantage is that the oral care composition has physical and chemical stability over the range of manufacturing, handling and storage conditions. Yet a further advantage is that the oral care composition has a stable quality final product (eg, consistent visual appearance and no discoloration, gingival wound healing performance, etc.) even after storage at 40 ° C. for 3 months. That is. Yet a further advantage is that the oral care compositions of the present invention minimize the use of antibacterial agents. Yet a further advantage is that the oral compositions of the present invention minimize the amount of anti-fibrinolytic agent to reduce and / or eliminate the instability and / or discoloration problems described above. ..

In one aspect, the invention a) a stannous ion source of 0.01% to 5% by weight, preferably 0.05% to 4% by weight of the composition and b) 0.01% by weight of the composition. % 10% by weight, preferably less than 5% by weight, more preferably less than 3% by weight, even more preferably less than 1% by weight, the oral care composition comprising an antifibrinolytic agent.

In another aspect, the invention a) a stannous ion source of 0.01% to 5% by weight, preferably 0.05% to 4% by weight of the composition, and b) 0.01 of the composition. From% to 10% by weight, preferably less than 5% by weight, more preferably less than 3% by weight, even more preferably less than 1% by weight, from tranexamic acid, εaminocaproic acid, p-aminomethylbenzoic acid and combinations thereof. The subject is an oral care composition comprising one or more compounds selected from the group.

In another aspect of the invention, the oral care composition described above is c) preferably further comprising 0.01% to 5% by weight, preferably 1% to 2.5% by weight of thickener of the composition. The thickeners thereof include (i) linear sulfated polysaccharides, (ii) natural gums, (iii) nonionic cellulose derivatives, (iv) polyvinylpyrrolidone (PVP), (v) at least. Polymers containing a polycarboxylated ethylene skeleton, (vi) polyacrylamide, copolymers containing (vii) acrylamide, (viii) pectin, (ix) proteins, (x) polyethylene glycols (PEG), preferably high molecular weight PEG. , And (xi) include at least one agent, preferably at least two agents, selected from the group consisting of combinations thereof.

In yet another aspect of the invention, the oral care composition described above d) further comprises 0% by weight to less than 0.001 wt% folic acid, or preferably contains or is substantially free of folic acid. Not included in.

Yet another aspect of the invention is gingival health in a human subject comprising administering the oral care composition of the invention preferably once daily, more preferably twice daily to the subject's oral cavity. A method is provided to promote.

These and other features of the invention will be apparent to those skilled in the art by examining the following detailed description in conjunction with the appended claims.

Although the present specification concludes with the scope of claims that specify, point out, and explicitly claim the invention, the invention is believed to be better understood from the following description of the accompanying drawings.
A timeline for assessing Mazza indexed bleeding sites for an assay to measure improvement in gingival wound healing. The number of Mazza indexed bleeding sites at various time intervals (baseline, 3rd day and 4th week) was determined in Example 2 of the composition of the invention (including stannous and antifibrinolytic agents), as well. FIG. 6 is a bar graph provided for positive and negative controls. FIG. 3 is a perspective view of an oral sprint to which a hydroxyapatite (HA) disc is attached. It is a perspective view of the HA disk which has a groove inside. It is the schematic of the cross-sectional view of the groove which has a biofilm inside. 8 is an image of wound healing of human gingival fibroblasts 24 hours after treatment with Example 2 (containing stannous and TA) of the composition of the invention or Example 9 (Sn only) of the control composition.

Definitions of Terms As used herein, articles such as "a" and "an" mean one or more of the claims or statements when used in the "claims". Is understood.

The terms "alleviate" and "alleviating" are used interchangeably to minimize, prevent, delay and / or treat at least one symptom of gingival disease and to correct the consumer. Means to bring about a change (ie, profit) in.

As used herein, the term "biofilm" means that the matrix-encapsulated bacterial populations are adhesive to each other and / or the surface or interface in the oral cavity.

As used herein, the term "comprising" means that steps and ingredients other than those specifically mentioned can be added. This term includes the terms "consisting of" and "consisting essentially of". The compositions of the invention include the essential elements and limitations of the invention described herein, as well as any additional or optional components, components, steps, or restrictions described herein. It can consist of, or can be essentially from these.

As used herein, the term "dentifrice" means a paste, gel, powder, tablet, or liquid formulation used to clean the oral surface, unless otherwise specified.

As used herein, the term "free" refers to the absence of any amount of the material in the composition.

As used herein, the term "gingival care" is used primarily to relieve one or more symptoms associated with early stage gingival disease (ie, gingival inflammation). Refers to the inherent or promoted benefit of an object. Such symptoms may include, for example, hemorrhagic gingiva and redness, swelling or tender gingiva.

As used herein, the term "gingival health" provides "gingival care" benefits, including at least improving gingival wound healing, as well as gingiva including gingival inflammation, periodontitis, or both. As for the disease, it refers to the inherent or enhanced benefit of an oral care composition that provides a further improvement in the reduction of bacterial activity so as to mitigate the harmful effects of the bacterium.

As used herein, the term "improving gingival wound healing" is determined by any generally accepted in vitro or in vivo gingival bleeding assay or test or assay described in Example 11. Means to reduce gingival bleeding.

As used herein, the term "improving reduction of bacterial activity" refers to any generally accepted in vitro or in vivo antibacterial assay or test, or preferably the assay and example described in Example 12. 13 means reducing bacterial activity in the oral cavity as determined by the in vivo wound healing assay.

As used herein, the term "oral care composition" or "oral care compositions" is used in part or in whole for the purposes of oral action during normal use. Means a product that is retained in the oral cavity for a sufficient period of time to contact the dental surface and / or oral tissue. In one embodiment, the composition provides benefits when used orally. The oral composition of the present invention is a toothpaste, a toothpaste, a dental gel, a toothpaste, a tablet, a rinse agent, a mouthwash, a subgingival gel, a foam, a mousse, a chewing gum, a lipstick, a sponge, a floss, and a preventive paste. , Vaseline gel, dentifrice adhesive, or dentifrice products. In one embodiment, the oral composition is in the form of a paste or gel. In another embodiment, the oral composition is in the form of a dentifrice. The oral composition may also be incorporated onto strip pieces or films for direct application or attachment to the oral surface, or for incorporation into floss.

As used herein, the words "preferably", "preferably", and variants thereof relate to embodiments of the invention that provide constant benefit under certain conditions. However, under the same or other circumstances, other embodiments may be preferred. Furthermore, the detailed description of one or more preferred embodiments does not indicate that the other embodiments are not useful and is not intended to exclude the other embodiments from the scope of the invention.

As used herein, the term "promoting" means promoting and / or enhancing the gingival health benefits associated with the use of the oral care compositions of the present invention in the oral cavity.

As used herein, the term "substantially free" means that no intentional amount of the material is added to the composition, or 0.05%, 0.01%, or 0 of the composition. . Refers to the amount of material less than 001%.

As used herein, the term "synergistic gingival health benefits" is more than an additive, including at least improving gingival wound healing and improving reduction of bacterial activity in the oral cavity. Means an analytically measurable increase in any two gingival health benefits.

As used herein, the term "teeth" means natural teeth as well as artificial teeth or dental prostheses.

As used herein, the term "total water content" means both free water and water bound by other components in the oral care composition.

All percentages, parts and ratios are based on the total weight of the compositions of the invention, unless otherwise specified. When it comes to the listed ingredients, all of these weights are based on activity levels and are therefore free of solvents or by-products that may be found in commercially available materials, unless otherwise specified.

Unless otherwise specified, all measurements referred to herein are made at 25 ° C. (ie, room temperature).

Oral Care Compositions Surprisingly, the combination of anti-fibrinolytic agents, preferably tranexamic acid, in oral care compositions with stannous ions (ie, antibacterial agents) provides gingival health benefits to consumers. It has been found to be particularly useful in facilitating. In particular, a surprising finding was that when combined with tranexamic acid, the penetration of stannous ions into biofilms was significantly improved. Although not bound by theory, tranexamic acid contains both carboxylic acid groups and amine groups. It is believed that stannous ions can bind strongly to these chemical moieties on tranexamic acid and have a positive effect on the penetration of stannous ions into the biofilm.

Surprisingly, it has also been found that when formulated with tranexamic acid, it is possible to increase or significantly increase the permeation depth and / or permeation rate of stannous ions into the biofilm. In short, the presence of tranexamic acid in combination with a stannous ion source in oral care compositions aids in the effectiveness of compositions that mediate the harmful effects of bacteria in biofilms on the gingiva.

In one aspect, the invention a) a stannous ion source of 0.01% to 5% by weight, preferably 0.05% to 4% by weight of the composition and b) 0.01% by weight of the composition. % 10% by weight, preferably less than 1% by weight, of an antifibrinolytic agent. Preferably, the oral care composition further comprises 0.01% to 5% by weight, preferably 1% to 2.5% by weight of a thickener of the composition, wherein the thickener is (i). Linear sulfated polysaccharides, (ii) natural gums, (iii) nonionic celluloses or derivatives thereof, (iv) polyvinylpyrrolidone (PVP), (v) polymers containing at least a polycarboxylated ethylene skeleton, (vi). Selected from the group consisting of polyacrylamide, copolymers containing (vii) acrylamide, (viii) pectin, (ix) protein, (x) polyethylene glycol (PEG), preferably high molecular weight PEG, and (xi) combinations thereof. , At least one agent, preferably at least two agents.

Antibacterial Agent In a preferred embodiment, the present invention provides 0.01% by weight to 5% by weight, preferably 0.05% by weight to 4% by weight, or more preferably 0.1 of the composition in order to provide an antibacterial effect. The above-mentioned oral care composition comprising a stannous ion source present in an amount of% to 2% by weight. The tin ion source used herein may include any safe and effective stannous salt. Suitable examples of stannous ion sources are stannous chloride, stannous fluoride, stannous acetate, tin gluconate, stannous oxalate, stannous sulfate, stannous lactate, stannous tartrate. , Stannous iodide, stannous fluoride, stannous hexafluorozirconate, stannous citrate, stannous malate, stannous glycicate, stannous carbonate, stannous phosphate, It is selected from the group consisting of stannous pyrophosphate, stannous metaphosphate and combinations thereof. Preferably, the stannous ion source is selected from stannous fluoride, stannous chloride and combinations thereof. More preferably, the stannous ion source comprises stannous chloride. Other examples of stannous salts include US Pat. No. 5,578,293, Plencipe, M. et al. And No. 5,281,410, Lukacovic, M. et al. Found in F. In addition to stannous ion sources, other components used to stabilize stannous ions, such as US Pat. No. 5,004,597, Majeti, S. et al. And the components described in No. 5,578,293, Plencipe, M and the like may be contained.

The oral care composition of the present invention is optionally other antibacterial present in an amount of 0.035% by weight or more, 0.05% by weight to 2% by weight or more, and 0.1% by weight to 1% by weight of the composition. It may contain an agent. Examples of these other antibacterial agents include, for example, halogenated diphenyl ethers, phenolic compounds including phenols and their homologues, monoalkyl and polyalkyl and aromatic halophenols, resorcinol and its derivatives, xylitol, bisphenol compounds and halogenated. Non-cationic antibacterial agents such as sultylanilides, benzoic acid esters and halogenated carbanylides can be mentioned. Enzymes such as endoglycosidases, papain, dextranase, mutanase and combinations thereof are also useful antibacterial agents. These agents are described in US Pat. No. 2,946,725, Norris, P. et al. E. And No. 4,051,234, Gieske, H. et al. A. It is disclosed in. Examples of other antibacterial agents include flavor oils such as chlorhexidine and thymol. In another example, other antibacterial agents can include triclosan (5-chloro-2- (2,4-dichlorophenoxy) phenol).

Anti-fibrinolytic agent The present invention further relates to the above-mentioned oral care composition comprising an anti-fibrinolytic agent in a preferred embodiment. Preferably, the anti-fibrinolytic agent is a compound of formula (I) and

式中、Ｘは、分岐状若しくは非分岐状、飽和若しくは不飽和の脂肪族基、又は芳香族基である。

In the formula, X is a branched or unbranched, saturated or unsaturated aliphatic group or aromatic group.

As used herein, the term "aliphatic group" is saturated and unsaturated, unsaturated (ie, linear) and branched, acyclic, containing 1 to 20 carbon atoms. It contains both cyclic or polycyclic aliphatic hydrocarbons, which are optionally substituted. Aliphatic groups are intended herein to include, but are not limited to, groups such as alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene and cycloalkyl moieties.

As used herein, the term "aromatic group" refers to an aryl ring, which is monocyclic or polycyclic, consisting of, but not limited to, only hydrogen and carbon and containing 6-18 carbon atoms. It comprises a hydrocarbon ring system, which may be partially saturated. Unless otherwise specified herein, aryl rings are optionally substituted. Aromatic groups are herein intended to include groups such as, but not limited to, phenyl, naphthyl and fluorenyl.

The term "cyano" refers to the -CN functional group.

The term "halo" or halogen refers to a fluorine, chlorine, bromine, or iodine atom as itself or as part of another substituent.

The term "oxo" refers to the = O substituent.

"Alkyl" contains a linear or branched hydrocarbon chain consisting only of carbon and hydrogen atoms, is unsaturated and contains 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, preferably 1 to 12 carbon atoms. The rest of the molecule having 1-8 or preferably 1-6 carbon atoms and with a single bond, eg, methyl, ethyl, propyl, 1-methylethyl (iso-propyl), butyl, pentyl, etc. Refers to a group attached to. The alkyl may be optionally substituted.

An "alkenyl" contains a linear or branched hydrocarbon chain consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms. Refers to a group having a carbon atom of 1 or preferably 1 to 8 carbon atoms, for example, ethenyl, propa-2-enyl, buta-1-enyl, penta-1-enyl, penta-1,4-dienyl and the like. The alkenyl may be optionally substituted.

"Alkinyl" contains a linear or branched hydrocarbon chain consisting only of carbon and hydrogen atoms, contains at least one carbon-carbon triple bond, and has 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms. Refers to a group having 1 to 8 carbon atoms or preferably 1 to 8 carbon atoms, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like. The alkynyl may be optionally substituted.

An "alkylene" or "alkylene chain" contains a linear or branched hydrocarbon chain that is attached based on the rest of the molecule, consists of carbon and hydrogen only, is unsaturated and contains 1-12 pieces. Refers to a group having a carbon atom of, for example, methylene, ethylene, propylene, butylene and the like. The alkylene may be optionally substituted.

An "alkenylene" or alkenylene chain is bonded on the basis of the rest of the molecule and consists only of carbon and hydrogen, contains at least one carbon-carbon double bond, and has 2 to 20 carbon atoms, preferably 2 to 20 carbon atoms. Refers to a straight or branched hydrocarbon chain having 2 to 12 carbon atoms, such as ethenelen, propenylene, butenylene and the like. Alkenylene may be optionally substituted.

An "alkynylene" or "alkynylene chain" is bonded on the basis of the rest of the molecule and consists only of carbon and hydrogen, contains at least one carbon-carbon triple bond, and has 2 to 20 carbon atoms, eg, 2 to 20 carbon atoms. Refers to a linear or branched hydrocarbon chain having propynylene, butynylene, or the like. Alkinylene may be optionally substituted.

"Cycloalkyl" refers to a stable saturated monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, which are 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms. Alternatively, it may comprise a fused or crosslinked ring system having 3-7 carbon atoms, eg, cyclohexane. Cycloalkyl may be optionally substituted.

"Haloalkyl" is one or more halogen groups such as trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, Refers to the above-defined alkyl substituted with 1,2-dibromoethyl or the like. The haloalkyl may be optionally substituted.

"Heterocyclyl" refers to a stable 3- to 24-membered saturated ring consisting of 2 to 20 carbon atoms and 1 to 6 heteroatoms selected from atoms consisting of nitrogen, oxygen or sulfur. Unless otherwise specified herein, the heterocyclyl may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system and may include a fused or cross-linked ring system, nitrogen in the heterocyclyl. , Carbon or sulfur atoms may be optionally oxidized and nitrogen atoms may be optionally quaternized. Heterocyclyl may be optionally substituted.

"Heterocycloalkyl" refers to a functional group of the formula -R _a -R _e, wherein, R _a is alkylene as defined above, R _e is a heterocyclyl as defined above, heterocyclyl nitrogen If it is a contained heterocyclyl, the heterocyclyl may be attached to the alkylene at a nitrogen atom. The heterocyclylalkyl may be optionally substituted.

"Heteroaryl" refers to a 5-20 membered aromatic ring consisting of 1 to 17 carbon atoms and 1 to 3 heteroatoms selected from atoms consisting of nitrogen, oxygen and sulfur. The heteroaryl may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system which may include a fused or crosslinked ring system. Heteroaryl may be optionally substituted.

“Heteroarylalkyl” refers to a functional group of the formula −R _a −R _{f , where Ra} is the alkylene defined above and R _f is the heteroaryl defined above. The heteroarylalkyl may be optionally substituted.

"Arbitrarily replaced" means that the event of the situation described below may or may not occur, and the description includes the case where the event or situation occurs and the case where it does not occur. Means that. For example, unless otherwise stated, "arbitrarily substituted" means that the chemical moiety is the following group, alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo,-. OR ¹ , -OC (O) -R ¹ , -N (R ¹ ) ₂ , -C (O) R ¹ , -C (O) OR ¹ , -C (O) N (R ¹ ) ₂ , -N (R ¹ ) C (O) OR ² , -N (R ¹ ) C (O) R ² , -N (R ¹ ) S (O) _t R ² (t is 1 to 2 in the equation), -S (O) _t OR ² (in the formula, t is 1 to 2), -S (O) _x R ² (in the formula, x is 0 to 2) and -S (O) _t N ( R ¹ ) ₂ may or may not be substituted by one or more of 2 (in the equation, t is 1-2), in which each R ¹ is independently hydrogen, alkyl. , Haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (arbitrarily substituted with one or more halogen groups), aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, each R ² being alkyl, haloalkyl. , Cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, each of the above substituents being unsubstituted unless otherwise indicated.

Preferably, the antifibrinolytic agent is selected from tranexamic acid, εaminocaproic acid, p-aminomethylbenzoic acid or a combination thereof. Preferably, the anti-fibrinolytic agent is from about 0.1% by weight to less than 1% by weight, preferably 0.2% by weight to 0.7% by weight, or more preferably 0.25% by weight to 0% by weight. It is present in an amount of 55% by weight. Preferably, the antifibrinolytic agent is a trans-4-aminomethyl-cyclohexanecarboxylic acid (CAS No. 1197-18-8) having the chemical name trans-4-aminomethyl-cyclohexanecarboxylic acid (CAS No. 1197-18-8) and tranexamic acid (TA) having the following structural formula (II). be.

Tranexamic acid is an anti-fibrinolytic agent used to prevent the dissolution of fibrin clots (“lysis” or “dissolution”). It helps stabilize the fibrin clot, which maintains coagulation and helps control bleeding. Tranexamic acid has been described as non-antibacterial and has been described as being very effective in inhibiting gingival inflammation, bleeding and / or swelling (US Pat. No. 4,272,513, Gaffar, A). Please refer to.). The term "tranexamic acid" includes the acid itself having the desired antihemorrhagic activity, or a bioprecursor or salt thereof. Preferably, tranexamic acid, free acid form, or in the form of its orally acceptable salt, preferably, for example, alkali metal (e.g., Na or K), ammonium or C ₁ -C ₈ mono-, di- It may be used in water-soluble form with substituted or tri-substituted ammonium (eg, alkanol-substituted, eg, mono-, di-, or tri-ethanolammonium) cations. Tranexamic acid is commercially available as Cyclokapron®. Alternatively, tranexamic acid may be synthesized or isolated from its cis-trans mixture (see US Pat. No. 3,499,925, Naito, T. et al.).

It has been discovered that the tranexamic acid stability and discoloration problems described above can be solved by reducing the concentration of tranexamic acid in the composition. Surprisingly, it has been found that only minimal reductions, such as less than 1% by weight tranexamic acid, in the composition can result in material differences in their stability and formulation compatibility. Reducing the concentration of tranexamic acid adversely affects the activity and / or effectiveness of gingival wound healing due to the effect, potentially synergistic effect, of combining it with stannous ion in the preferred oral care composition of the present invention. It does not reach. Although not bound by theory, stannous ions bind strongly to these chemical moieties on tranexamic acid and have a positive effect on osmosis to maintain sufficient efficacy at lower concentrations. It is thought that it can affect.

In another embodiment, the anti-fibrinolytic agent is εylon aminocaproic acid (EACA). Preferably, EACA is present in an amount of 0.01% to 5% by weight, preferably 0.1% to 1% by weight or more preferably less than 1% by weight of the composition. EACA has the chemical name caproic acid, 6-amino- (CAS No. 60-32-2) and the following structural formula (III).

εAminocaproic acid and its analogs are commercially available under the trade name Amicar®. The term "εaminocaproic acid" includes the acid itself or a bioprecursor or a salt thereof having the desired antihemorrhagic activity. It is a derivative of the amino acid lysine and is an antiplasmin agent. As with tranexamic acid, the use of εaminocaproic acid can also pose a discoloration problem in oral care compositions (see US Pat. No. 4,649,044, Gomi, T. et al.). Previous oral care compositions that have described the problem of instability and discoloration have been formulated with εaminocaproic acid at a level of 0.05% to 1% (US Pat. No. 4,272,513, Gaffar, A. et al. And No. 4,272,512, Gaffar, A.). Although not bound by theory, the discoloration is thought to be due to the reaction of εaminocaproic acid with the aldehyde groups in the flavor components. To avoid discoloration, the above references suggest the introduction of cyclodextrin and the use of flavor components that are substantially free of aldehyde groups. However, this solution is not desirable because it complicates the formulation and limits the types of flavoring materials that can be used. Instead, the present invention advises combining ε-aminocaproic acid with stannous ions to overcome the above problems.

In yet another embodiment, the anti-fibrinolytic agent is p-aminomethylbenzoic acid (PAMBA). Preferably, PAMBA is present in an amount of 0.01% to 5% by weight, preferably 0.1% to 1% by weight or more preferably less than 1% by weight of the composition. p-Aminomethylbenzoic acid (CAS No. 56-91-7) has the following structural formula (IV).

The term "p-aminomethylbenzoic acid" includes the acid itself with the desired antibleeding activity, or a bioprecursor or salt thereof.

Thickeners Preferably, the oral care composition of the invention herein may contain one or more thickeners, more preferably at least two thickeners. Preferably, the thickener is present in an amount of 0.01% to 10% by weight, preferably 1% to 2.5% by weight of the composition. In particular, the present invention relates further to the oral care composition described above, which comprises, in a preferred embodiment, a thickener selected from the group consisting of:
(I) The linear sulfated polysaccharide is carrageenan.
(Ii) Natural gum is selected from the group consisting of xanthan gum, karaya gum, gum arabic, tragacanth gum and combinations thereof.
(Iii) The nonionic cellulose or its derivative has an average molecular weight range of 50,000 to 1,300,000 daltons, preferably an average degree of polymerization of 300 to 4,800.
(Iv) The polymer contains at least a polycarboxylated ethylene skeleton, a copolymer of methylvinyl ether and maleic anhydride having a molecular weight of 30,000 to 1,000,000 daltons, a homopolymer of acrylic acid, and maleic acid and acrylic. It is selected from the group consisting of copolymers with acid or methacrylic acid. And (v) a combination of these.

Preferably, in the oral care composition according to the invention, the thickener is selected from the group consisting of: (I) Carrageenan is selected from the group consisting of κ-carrageenan, ι-carrageenan, λ-carrageenan and combinations thereof. (Ii) The natural gum is xanthan gum. (Iii) Nonionic cellulose or a derivative thereof is hydroxyethyl cellulose (HEC). (Iv) The copolymer of maleic anhydride and methyl vinyl ether is Gantrez AN139 (MW 500,000 Dalton), Gantrez AN119 (MW 250,000 Dalton) or S-97 pharmaceutical grade (MW). At least one of 70,000 daltons), homopolymers of acrylic acid, and copolymers of maleic acid with acrylic acid or methacrylic acid are Acusol 445, Acusol 445N, Acusol 531, Acusol 463, Acusol 448, Acusol. It is at least one of 460, Acrylan 465, Acryl 490, Sokalan CP5, Sokalan CP7, Sokalan CP45, or Sokalan CP12S. And (v) a combination of these.

In an example, the GANTREZ ™ series polymer is a copolymer of maleic anhydride and methyl vinyl ether having a molecular weight (MW) of 30,000 to 1,000,000 daltons. These copolymers are, for example, GANTREZ ™ AN139 (MW 500,000 Dalton), AN119 (MW 250,000 Dalton) and S-97 Pharmaceutical Grade (MW 70,000 Dalton). As a result, it is available from Ashland Chemicals (Kentucky, USA).

In another embodiment, ACUSOL ™ and SOKALAN series polymers include homopolymers of acrylic acid and copolymers of maleic acid with acrylic acid or methacrylic acid. An example is a 0: 1000 to 1000: 0 copolymer of maleic acid and acrylic acid having a molecular weight (MW) of about 2,000 to about 1,000,000. These copolymers are available from Dow Chemicals (Michigan, USA) ACUSOL ™ 445 and 445N, ACUSOL ™ 531, ACUSOL ™ 463, ACUSOL ™ 448, ACUSOL ™ 460, ACUSOL ™ 465. , ACUSOL ™ 497, ACUSOL ™ 490, and from BASF (New Jersey, USA) Sokalan® CP5, Sokalan® CP7, Sokalan® CP45, and Sokalan®. It is commercially available as CP12 S.

Anti-dental caries The oral care composition may contain an effective amount of anti-caries agent. In one aspect, the anti-cariogenic agent is a fluoride ion source. The fluoride ion source may be present in the composition in an amount sufficient to provide the fluoride ion concentration at 25 ° C. and / or 0.0025% by weight to 2% by weight or preferably 0.0025% by weight of the composition. Used in concentrations of 0.5% by weight to 1.5% by weight, it can provide an anti-cariogenic effect. A wide variety of fluoride ion-producing materials can be used as a source of the soluble fluoride of the present invention. Examples of fluoride ions include US Pat. No. 3,535,421, Briner, W. et al. W. And Nos. 3,678,154, Wider, J. et al. S. It is disclosed in. Suitable examples of fluoride ions are selected from sources containing sodium fluoride, indium fluoride, amine fluoride, sodium monofluorophosphate (“MFP”), potassium fluoride, zinc fluoride and mixtures thereof. obtain.

Anti-dental plaque agent Oral care composition is one of anti-dental plaque or anti-tartar agents present in an amount of 0.001% by weight to 20% by weight, or 0.1% by weight to 5% by weight of the composition. It may contain more than a seed. As a non-limiting example, pyrophosphate can be mentioned as a source of pyrophosphate ion. Other examples are US Pat. No. 8,691,190, Haught, J. Mol. C. , Disclosed in paragraph 55.

pH
The pH of the oral care composition can be 4.5-11 or preferably 5-10. Different pH may be desired depending on the active substance used in the oral care composition. It may be desired that the preparation containing stannous fluoride has a slightly lower pH than a general dentifrice. The pH is typically measured using a 1: 3 paste: water ratio, which mixes 1 gram of oral care composition (eg toothpaste) with 3 grams of deionized water. The pH is then assessed with an industry-accepted pH probe calibrated under ambient conditions. pH is measured by a pH meter using an Automatic Temperature Compensating (ATC) probe. The pH meter can read in units of 0.001 pH.

After each use, the electrodes must be washed with water from the sample solution. Remove excess water by wiping with a tissue such as a Kimwipe or equivalent. When the electrode is not in use, the tip of the electrode is kept immersed in a pH 7 buffer solution or an electrode storage solution. The details of the equipment are as follows.
pH meter: A meter that can read in units of 0.01 or 0.001 pH.
Electrode: Orion Ross Sure-Flow Combination: Glass-VWR # 34104-834 / Orion # 8172BN or VWR # 10010-772 / Orion # 8172BNWP.
Epoxy-VWR # 34104-830 / Orion # 8165BN or VWR # 10010-770 / Orion # 8165BNWP.
Semi-micro epoxy body-VWR # 34104-837 / Orion # 8175BN or VWR # 10010-774 / Orion # 3175BNWP.
Orion Perpfect combination: VWR # 34104-843 / Orion # 8203BN semi-micro glass body.
ATC probe: Fisher Scientific, Cat. # 13-620-16.

pH Buffering Agents The oral care compositions herein may contain an effective amount of a buffering agent or a pH regulator, and when used herein, bring the pH of the oral care composition to the pH range specified above. Refers to a drug that can be used to regulate. Buffers include alkali metal hydroxides, ammonium hydroxide, organic ammonium compounds, carbonates, sesquicarbonates, borates, silicates, phosphates, imidazoles, and mixtures thereof.

Specific buffers include monosodium phosphate (monobasic sodium phosphate), trisodium phosphate (tribasic sodium phosphate duhydrate or TSP), sodium benzoate, benzoic acid, sodium hydroxide. , Potassium hydroxide, alkali metal carbonate, sodium carbonate, imidazole, pyrophosphate, sodium gluconate, lactic acid, sodium lactate, citric acid, sodium citrate, or phosphoric acid.

In one embodiment, 0.01% by weight to 3% by weight of the composition, preferably 0.1% by weight to 1% by weight of TSP, and 0.001% to 2% by weight of the composition, preferably 0. 01% to 0.3% by weight monosodium phosphate is used. Although not bound by theory, TSP and monosodium phosphate may have calcium ion chelating activity, and thus some (in these formulations containing monoflulophosphate). Provides stabilization of monofluorophosphate.

Water Water is commonly used as a carrier material in oral care compositions due to its many advantages. For example, water is useful as a processing aid, is harmless to the oral cavity, and aids in rapid foaming of toothpaste. Water may be added as a component by itself, or may be present as a carrier in other common raw materials such as, for example, sorbitol and sodium lauryl sulfate.

The oral care composition herein may contain a total water content of 10% to 70% by weight, or preferably 15% to 30% by weight of the composition. As used herein, the term "total water content" means the total amount of water present in an oral care composition, either added separately or as a solvent or carrier for other raw materials. Excludes those that may exist as water for the crystallization of certain inorganic salts. Preferably, the water is USP water.

Flavor Compositions The oral care compositions herein may comprise 0.01% by weight to 5% by weight, preferably 0.1% by weight to 2% by weight of the oral care composition. Examples of suitable flavoring agents that can be used in flavor compositions include US Pat. No. 8,691,190, Haught, J. Mol. C. , Paragraphs 39 and 40-45. Preferably, the flavor composition is
(I) Methylsalicylate of more than 0% by weight to less than 55% by weight or more than 65% by weight to 95% by weight of the flavor composition; more than 0% by weight to less than 30% by weight of the flavor composition, or 35% by weight. Ultra-65% by weight menthol; more than 0% by weight to less than 1% by weight of flavor composition, or more than 5% by weight to 50% by weight of Eugenol; and more than 0% by weight to less than 3% by weight of the flavor composition, Alternatively, a flavor mixture containing> 8% by weight to 30% by weight of cineole; or (ii) a flavor mixture containing or substantially not containing methylsalicylate, menthol, eugenol and cineole.

Sweeteners The oral care compositions herein may include sweeteners. The sweetener is generally present in the oral care composition at a concentration of 0.005% by weight to 5% by weight of the composition. Suitable examples of sweeteners include saccharin, dextrose, sucralose, lactose, xylitol, maltose, fructose, aspartame, sodium cyclamate, D-tryptophan, dihydrocalcone, acesulfame, sucralose, neotame, and mixtures thereof. Other suitable examples of sweeteners are U.S. Pat. No. 8,691,190, Haught, J. Mol. C. It is described in.

Colorants The oral care compositions herein may contain colorants present in an amount of 0.001% to 0.01% by weight of the composition. The colorant may be in the form of an aqueous solution, preferably a 1% aqueous colorant solution. Suitable examples of colorants are pigments, pealing agents, filler powders, talc, mica, magnesium carbonate, calcium carbonate, bismuth oxychloride, zinc oxide, and making visual changes in oral care compositions. Other substances that can be mentioned can be mentioned. Another suitable example may be titanium dioxide (TIM _2). Titanium dioxide is a white powder that adds opacity to the composition and is generally present in the oral care composition at a concentration of 0.25% to 5% by weight of the composition.

Interface Activators The oral care compositions herein are 0.1% to 50% by weight, 0.025% to 9% by weight, 0.05% to 5% by weight, 0.1% by weight of the composition. It may contain a surfactant present in an amount of% to 2.5% by weight, 0.5% by weight to 2% by weight, or 0.1% by weight to 1% by weight. The surfactant may be selected from anionic, nonionic, amphoteric, bipolar, cationic surfactants, or mixtures thereof. Suitable examples of anionic surfactants include US Pat. No. 8,691,190, Haught, J. Mol. C. , Paragraphs 32, 33, 34 and 35. Suitable examples of zwitterionic or amphoteric surfactants are described in US Pat. No. 8,691,190, Haught, J. Mol. C. Paragraph 36, cationic surfactants are described in paragraph 37, and nonionic surfactants are described in paragraph 38.

Wetting Agents The oral care compositions herein may contain wetting agents present in an amount of 0% to 70% by weight, or 15% to 55% by weight of the composition. Wetting agents prevent the oral care composition from hardening due to exposure to air, and certain wetting agents can also impart the desired sweet flavor to the dentifrice composition. Suitable examples of wetting agents include glycerin, sorbitol, polyethylene glycol, propylene glycol, xylitol, trimethylglycine, and mixtures thereof. Other examples include other edible polyhydric alcohols.

Abrasives The oral care compositions herein are 0.1% to 60% by weight, or 1% to 50% by weight, or 2% to 40% by weight, or 4% to 30% by weight. It may further contain one or more abrasives present in an amount of%. Suitable examples include precipitated silica, fused silica, calcium carbonate, dicalcium phosphate dihydrate, phosphate (including orthophosphate), pyrophosphate, pearlite, pebbles, nanodiamonds, surface-treated dehydrated precipitated silica, paddy husk silica, etc. Silica gel, alumina, polymethaphosphate, other inorganic fine particles, and mixtures thereof can be mentioned. Other examples of abrasive materials useful herein include dicalcium orthrinate dihydrate, calcium pyrophosphate, tricalcium phosphate, calcium polymethaphosphate, insoluble sodium polymethaphosphate, hydrated alumina, calcium β-pyrophosphate. Calcium carbonate, and resinous abrasive materials such as the particulate condensation products of urea and formaldehyde, as well as US Pat. No. 3,070,510, Cooley, W. et al. E. Others such as those disclosed in.

Antisensitive Agents The oral care compositions herein may contain an antisensitive agent present in an amount of 0.001% to 20% by weight, or 0.1% to 5% by weight, of the composition. Suitable examples of anti-sensitizers include US Pat. No. 8,926,949, Dayanim, R. et al. Paragraph 41 and US Patent Publication No. 2009/0311200, Lambert, P. et al. The ones described in paragraph 59 can be mentioned.

Whitening and Oxidizing Agents The oral care compositions herein are 0.01% to 30% by weight, or 0.1% to 10% by weight, or 0.5% to 5% by weight of the composition. It may contain a whitening agent or an oxidizing agent present in an amount. Suitable examples include hydrogen peroxide, urea peroxide, calcium peroxide, sodium peroxide, zinc peroxide, or a combination thereof. Other examples are US Pat. No. 8,691,190, Haught, J. Mol. C. It is described in paragraph 56.

Anti-inflammatory Agents The oral care active substances herein may contain effective amounts of anti-inflammatory agents. Suitable examples include US Patent Publication No. 2011/0104081, Scott, D. et al. C. The ones described in paragraph 55 can be mentioned.

Anti-tartar agents The oral care compositions herein are in an amount of 0.05% to 50% by weight, or 0.05% to 25% by weight, or 0.1% to 15% by weight of the composition. It may contain an existing anti-tartar agent. Suitable examples are US Patent Publication No. 2011/0104081, Scott, D. et al. C. Paragraph 64 and US Patent Publication No. 2012/0014883, Scott, D. et al. G. The ones described in paragraphs 63-68 can be mentioned.

Chelating Agents The oral care compositions herein may contain effective amounts of chelating agents, also referred to as sequestering agents, many of which also have anti-tartar activity or tooth substantive activity. .. The use of chelating agents in oral care products is advantageous due to their ability to complex calcium, grind plaque and complex with metal ions, such as those found in bacterial cell walls. Chelation of ions such as iron or copper helps delay the oxidative alteration of the final product. Suitable examples of chelating agents include US Patent Publication No. 2011/0020246, Strand, R. et al. The ones described in paragraphs 21-28 can be mentioned.

Tooth parenchyma The oral care composition herein may contain an effective amount of the tooth parenchyma. For the purposes of this application, tooth parenchyma is also included as a chelating agent. Preferable examples include polymeric surface active agents (PMSAs), including polyelectrolytes, more specifically anionic polymers. Other examples include US Patent Publication No. 2012/0014883, Scott, D. et al. G. The ones described in paragraphs 74-84 can be mentioned.

Analgesics and Anesthetics The oral care compositions herein may contain effective amounts of analgesics or desensitizers. Suitable examples are US Pat. No. 9,005,585, Deckner, G. et al. E. The ones described in paragraph 117 can be mentioned.

Other Ingredients The oral care compositions of the present invention may contain conventional and conventional auxiliary ingredients known to those of skill in the art. It will be appreciated that the ingredients selected for the oral care composition must be chemically and physically compatible with each other.

Methods of Use In one aspect, the invention relates to a method for cleaning or polishing teeth of a human subject. The cleaning or polishing method herein comprises contacting the tooth of interest with the oral care composition according to the invention.

In another aspect, the invention also relates to a method of promoting gingival health in a human subject, comprising administering to the oral cavity of the subject the oral care composition according to the invention. Preferably, the method of promoting gingival health is performed at least within a period selected from the group consisting of:
a) Time from 0 hours to 72 hours,
b) Time from 0 hours to 48 hours,
c) Time from 0 hours to 24 hours,
Here, the time of 0 hours is the time of administration of the oral care composition according to the present invention.

In yet another aspect, the invention also relates to a method of promoting gingival health.
(I) Improving gingival wound healing in the oral cavity,
(Ii) to improve the reduction of bacterial activity in the oral cavity, or (iii) to be selected from a combination of these.

The above method may be by brushing with an oral care composition (eg, dentifrice) (eg, dentifrice), or by rinsing with an oral care composition (eg, dentifrice slurry or mouthwash). The oral care composition may be applied undiluted or via a delivery device such as a toothbrush. Other methods include topical oral gel, mouth spray, toothpaste, dentifrice, toothpaste, toothpaste, tablets, subgingival gel, foam, mousse, chewing gum, lipstick, sponge, floss, petrolatum gel, or It involves contacting a prosthesis product, or other form, with the subject's teeth and oral mucosa. Depending on the embodiment, the oral care composition may be used as often as toothpaste, or less frequently, eg weekly, or for toothpaste or other intensive care. In form, it may be used by a specialist.

The following examples and description further clarify embodiments within the scope of the present invention. These examples are for purposes of illustration only and should not be construed as a limitation of the invention as many of these modifications are possible without departing from the spirit and scope of the invention.

A: Examples 1-10
Examples 1 to 10 are the dentifrice compositions shown below, and the amount of the component is% by weight. These may be suitably prepared by conventional methods selected by the prescriber. Examples 1-6 are according to the present invention made with a first zion source (eg, stannous chloride) and a single antifibrinolytic agent (eg, TA, EACA, or PAMBA) at two concentrations each. It is a pharmaceutical product of the invention. Example 7 is a pharmaceutical product of the present invention prepared with stannous chloride and two antifibrinolytic agents (eg, TA and EACA). In parallel, Examples 8 to 10 of the control preparation are prepared. Example 8 is made without stannous ion source, Example 9 is made without anti-fibrinolytic agent, and Example 10 is made without any component. All compositions are prepared by mixing the components of Tables 1 and 2 in the indicated proportions.

Example 11- Assays for Measuring Improvements in Oral Gingival Wound Healing The following assays are used to determine improved oral gingival wound healing in the oral care compositions and controls of the present invention. The assay involves gentle probing of the gingival gap to assess the presence or absence of bleeding. Dermatitis is the Mazza index (according to Papillary Bleeding Index, PBI, and Muchlemann, HR: J. Prev. Dent. 1977; 4: 6), otherwise referred to as the "Mazza index". Evaluated by modification to determine the number of bleeding sites (defined by Mazza, 1981). For this measurement, probing is performed at a maximum of 56 points on the mesial and distal surfaces of each tooth. The probe is placed within the gingival sulcus to a depth of approximately 0.5 mm to 1.0 mm and is cleaned from its insertion point to the tip of the interdental papilla along the soft tissue aspect of the sulcus. All facial or lingual surfaces of each quadrant are cleaned before the measurement is made. The measurement begins with the cleaning of the first tooth.

Oral soft tissue and gingival inflammation tests using the Mazza index are performed at baseline (ie, 0 hours) at days 3, 4 and 4. The Mazza index is defined as shown in Table 3.

The experiment was carried out by Procter & Gable (Beijing) Technology Co., Ltd. , Ltd. Oral Care Facility, with the approval of the P & G Beijing Technical Center (China) Institutional Review Board, in accordance with the World Medical Association Declaration of Helsinki (1996 amendment). Follow Good Clinical Practice (GCP) for clinical trials of ICH drugs.

Initially, subjects who meet the study participation requirements are randomly assigned to a treatment or control group balanced with a baseline Mazza index score using a SAS randomization program. Individuals who meet the following criteria are included: at least 18 years old; have a minimum of 12 natural anterior teeth; have at least 5 bleeding sites as measured by the Mazza index at initial visit (ie, baseline) Has gingival inflammation but not periodontitis; good overall health as judged by the investigator / instructor based on medical history / update reviews to participate in the study. Individual exclusion criteria include: Self-reported pregnancy, any condition requiring antibiotic pre-drugs for administration of purulent exudates, severe periodontal disease characterized by diffuse mobility and / or severe regression, administration of dental prophylaxis Or women who intend to become pregnant during the study process, and women who are breastfeeding, atypical discoloration or pigmentation in the gingival tissue, fixed facial correction device, atypical discoloration or pigmentation in the gingival tissue, any time during the study Use of antibiotics in, any disease or condition that may be expected to interfere with the subject to safely complete the study. The clinical parameters of each subject will be monitored throughout the study. Individuals who meet the exclusion criteria are excluded from study participation.

The study is a 4-week, double-blind and parallel group. Subjects are treated with products from the negative control group, the positive control group and the treatment group (ie, the composition of the invention). Negative control groups include regular fluoride toothpaste products (eg, 0.321% Sodium Fluoride-Crest® Oral Protection Products, Lot No. 60771864AA, 2018.03.17) (“CCP Products”). Accept. Positive controls receive over-the-counter traditional herbal medicine and TA formulation Yun Nan Bai Yao Liu Lan product, lot number 20190408 F05 (YNBY product). The treatment group received any one of the compositions of the invention disclosed in Examples 1-7, containing stannous chloride and one or more anti-fibrinolytic agents (s). Each of the control or treated legs is applied topically to the tooth / gingival surface twice daily over a period of 4 weeks. A Mazza index assessment is performed on the subject and assessed for reduction of bleeding sites at baseline, days 3, and 4 (ie, at the end of the study), as shown in FIG. Using the Statistical Analysis System (SAS), each baseline is used as a model covariance to analyze the data in an analysis of covariance (ANCOVA).

Results: 150 certified subjects completed the study. The treatment group received Example 2 of the composition of the invention. The control and treatment groups are well balanced for age and gender. Baseline means are equilibrated between the control and treatment groups (p> 0.43). Results (and their confidence intervals) for the number of bleeding sites based on the Mazza index of the control and treatment groups were averaged and then plotted as a bar graph as shown in FIG. 2 between the control and treatment groups. Allows comparison. The p value of the product difference is obtained at p <0.01.

FIG. 2 shows the effects of Sn and TA on reducing gingival bleeding in Example 2 of the composition of the invention. Referring to FIG. 2, Example 2 of the composition of the invention (including both TA and Sn) has an average of 10.7 bleeding sites on day 3 and 6.73 bleeding sites on week 4. In contrast, the positive control YNBY product has an average 11.67 bleeding site on day 3 and a bleeding site on day 8.49 at week 4. Negative control CCP products containing neither Sn nor TA have an average of 15.01 bleeding sites on day 3 and 13.41 bleeding sites on week 4. The results show that the addition of Sn to TA in Example 2 of the composition of the invention greatly improves the reduction in the number of bleeding sites between baseline and week 4 (ie, approximately -10 bleeding sites). However, positive control YNBY products with only TA have a smaller reduction in the number of bleeding sites over the same time frame (ie, approximately -5 bleeding sites). Negative control CCP products containing neither Sn nor TA show only a slight reduction in the number of bleeding sites over a 4-week study (ie approximately -2 bleeding sites).

The results demonstrate that the combination of an anti-fibrinolytic agent and an antibacterial agent (eg, a stannous ion source) provides an enhanced gingival antihemorrhagic effect. In fact, Example 2 of the composition of the invention demonstrates its effectiveness in low concentrations of anti-fibrinolytic agents (ie, 0.50% TA). This is because certain anti-fibrinolytic agents (eg, TA, EACA, etc.) are effective, but at higher concentrations that have been used specifically to provide efficacy, discoloration of the oral care composition and It is advantageous because it is known to cause instability problems. Therefore, by using lower levels, both discoloration and instability are avoided.

B: Assay for Measuring Permeation Improvement of Antibacterial Agent in Biofilm The following assay is used to determine the permeation improvement of antibacterial agent in biofilm, and the oral care composition of the present invention and Bacterial and stannous ion co-localization percentages are assessed via a control, in-situ plaque biofilm. Details of the assay are described below.

(A) Substrate for biofilm growth Hydroxyapatite (HA) discs are used for in-situ growth of biofilms. HA discs are designed so that each disc has three parallel grooves (ie, two lateral grooves width 200 μm, depth 200 μm, central groove width 500 μm and depth 500 μm). When attaching the disc to the mouth of the subject, keep these grooves vertical so as to mimic the adjacent interdental gaps between the teeth, which is generally a difficult area to clean where plaque tends to accumulate. This model allows for smooth plaque collection from the groove. HA discs are manufactured by the Shanghai Bei'erkang biomedicine limited company.

(B) Wearing a sprint Human subjects wear a sprint. Each subject wears up to 12 HA discs on the sprint to ensure that at least 9 HA discs are available after 48 hours. Non-limiting examples of such sprints and HA discs are shown in FIG. Referring to FIG. 3, the device (1) holds a plurality of HA disks (2a-2d). In a particular example, referring to FIG. 4, the HA disk (201) has three parallel grooves (203), although the two lateral grooves (203a and 203c) are 300 μm wide and 300 μm deep. , The intermediate groove (203b) (between the two side grooves) is 500 μm wide and 500 μm deep). The intermediate groove is designed to be wider and deeper than the two side grooves so that the HA disc can be more easily separated into two identical half discs for head-to-head comparison purposes. FIG. 5 is a schematic cross-sectional view of a groove (2003) having a biofilm (2005) inside. Further details of the HA disc are described in PCT Patent Application No. PCT / CN2015 / 089238, whose international filing date is September 9, 2015.

Although not shown in FIG. 5, the disc can be positioned so that the interdental space between the teeth is retracted (because this position is prone to plaque (considering difficulty in cleaning, etc.)). .. Subjects remove the sprint only during meals (store the sprint in a damp condition in an opaque container) and perform oral hygiene procedures. Shortly thereafter, wear the sprint again. Subjects are asked to use a straw when drinking.

(C) In-situ biofilm release from HA discs All HA discs are removed from the sprint by tweezers in 48 hours. Using tweezers, hold the edge of the HA chip and transfer the HA disk to a 2 mL centrifuge tube containing a PBS (phosphate buffered saline) solution. Thoroughly wash the tweezers (water, 75% alcohol, then deionized water) before transferring the disc each time.

(D) Preparation of toothpaste supernatant 15 grams of deionized water is 5 grams of toothpaste (Examples 1 to 7 of the composition of the invention, Examples 8 to 10 of the control composition or a commercially available formulation (eg, for example). Add to traditional Chinese herbal medicine and TA preparation, Yun Nan Bai Yao Liu Lan product, lot number 20190408 F05 (“YNBY product”). After complete stirring, the mixture is centrifuged at 12,000 RPM for 20 minutes. Prepare 1 day before use and store at 4 ° C.

(E) Confocal laser scanning microscopy After removing the HA disk from the sprint. HA discs are used for Exvivo treatment with compositions of different inventions and control compositions. After treatment with the supernatant of the subject and labeled with a microbial fluorescent probe and a stannous fluorescent probe (eg, described in PCT Publication No. 2015/139263, Shi et al.), The biofilm in the groove was Measured by confocal laser scanning microscopy (CLSM) (described below). Preferably, the stannous fluorescent probe is tert-butoxy-carboxamide, N- [3', 6'-bis (diethylamino) -3-oxospiro [1H-isoindole-1,9'-[9H] xanthene]-. H) -Il] (available from Dr. Tao Yu, Fudan University, Shanghai, China). Preferably, the microbial fluorescent probe is a Molecular Probes ™ LIVE / DEAD® BacLight ™ system (available from Thermo Fisher).

(F) Preparation of discs Rinse HA discs with PBS solution and divide each HA disc into two halves with tweezers. Then, each half disk is allowed to stand in 500 to 1000 μL of PBS solution for 1 minute. Each disc is treated with either PBS solution or toothpaste supernatant for 2 minutes. Wash each disc by holding each disc with tweezers, shake 10 times back and forth in 1 mL of PBS solution, then repeat this wash cycle. Each disc is then allowed to stand in 500-1000 μL PBS solution for 5 minutes.

(G) Fluorescent Staining and Microscopy The LIVE / DEAD® BacLight ™ system is a reliable alternative for assessing bacterial activity in natural plaque biofilms in which several types of bacteria are present. It has been reported. The LIVE / DEAD® BacLight® fluorescence assay stains bacteria red or green, depending on the permeability of their membranes. The green / red ratio correlates well with the life / death ratio. The live / death staining method is considered to be highly reliable in analyzing antibacterial activity. After treatment and immersion, each half-disc is stained with a Sn probe together with a Syto-9 probe (including 5 μM Syto-9 and 5 μM Sn probe) for 30 minutes in the dark and the other half-disc is stained. Stain with L7012 LIVE / DEAD® dye solution (containing 5 μM Syto-9 + 30 μM propidium iodide) for 15 minutes in the dark. After staining, each disc is immersed in 500-1000 μL PBS solution and allowed to stand for 2 minutes. Wash each disc again by holding it with tweezers, shake back and forth 5 times in 1 mL of PBS solution, and repeat. For L7012 LIVE / DEAD® dye-stained samples, the following parameters are used: λex = 488 nm, λem = 500/635 nm, 20x objective, and scanning over 60 μm from the bottom of surface bacteria at step size = 3 μm. do. For SYTO-9 / Sn dye-stained samples, use the following parameters: λex = 488 nm / 543 nm, λem = 500/580 nm, 20x objective, and scan over 60 μm from the bottom of surface bacteria at step size = 3 μm. ..

(H) Confocal laser scanning microscopy A Leica ™ TCS SP8 AOBS spectroconfocal microscope is used. The confocal system consists of a Leica ™ DM6000B upright microscope and a Leica ™ DMIRE2 inversion microscope. Upright stands are used for applications involving slide-mounted specimens, while _{inverted stands with a 37 ° C. incubation chamber and CO 2} enrichment accessories provide live cell applications. The microscope shares a galvanometer-driven precision Z stage that facilitates rapid imaging in the focal (Z) plane, in addition to an interchangeable laser scanning head and its own electric motor drive stage. In addition to epi-fluorescence, the microscope supports a variety of transmitted light contrast methods, including brightfield, polarized light and differential interference contrast, 5x, 20x, 40x, 63x (oil and dry) and 100x. (Oil) Equipped with a Leica ™ objective lens.

A laser scanning and detection system will be described. The TCS SP2 AOBS confocal system is supplied with four lasers (one diode, one argon and two helium neon lasers), thereby providing a wide range of fluorescent dyes within the UV, visible and remote red range of the electromagnetic spectrum. Allows excitation. Laser scanning head design incorporating acoustic-optical tunable filter (AOTF), acoustic-optical beam splitter (AOBS) and four prism spectrophotometer detectors has three fluorescence. Allows simultaneous excitation and detection of dyes. The upright microscope also has a transmitted photodetector, which allows the transmitted light image to be superimposed on the fluorescence recording.

Leica ™ confocal software is used. Confocal is controlled via a standard Pentium PC equipped with dual monitors and Leica ™ confocal software. Leica confocal software includes multidimensional image sequence including 3D reconstruction and measurement, physiological recording and analysis, time course, fluorescent chromium colocalization, light bleaching techniques such as FRAP and FRET, spectral mismatch and multicolor recovery. Provides an interface for acquisition, processing and analysis. For image analysis, L7012 LIVE / DEAD® dye-stained samples were selected to quantify the ratio of red and green pixels, and SYSTO-9 / to quantify the overlapping efficiency of red and green pixels. Select a Sn dye-stained sample. The software was used to identify pixel overlap between the "green" bacterial probe and the "red" stannous probe, then this value was divided by all non-black pixels (including the non-overlapping stannous probe). It provides a co-localized percentage of stannous tin in bacteria. In general, the higher this co-localization rate, the more effective the oral care product is in delivering stannous into the bacterium.

Results: Subjects are treated with Example 2 of the composition of the invention (ie, Sn + 0.50% TA), Example 9 of the control composition (ie, Sn only) and a commercially available YNBY product. The results are provided in Table 4.

The results show that Example 2 of the composition of the invention containing an anti-fibrinolytic agent (eg, tranexamic acid) and an antibacterial agent (eg, a stannous ion source) contains an antibacterial agent and stannous, but tranexamic acid. It is shown that the reduction in bacterial activity (55.00% bacterial killing) is effectively ameliorated for the lower bacterial killing (46.39%) of Example 10 of the acid-free control composition. Commercially available YNBY products show comparable bacterial killing (47.86%) compared to Example 9 of the control composition.

The results show that Example 2 (82.29%) of the composition of the invention has significantly higher stannous tin than Example 9 (61.48%) of the control composition and YNBY product (2.25%). Demonstrate having a localization rate. The results also show that TA does not inhibit the stannous release efficiency as measured via the Sn overlap factor, Example 2 (0.9301) of the composition of the invention and Example 9 of the control composition. The Sn overlap coefficient of (0.9206) is substantially the same. In fact, this data supports that when combined with an anti-fibrinolytic agent (eg, tranexamic acid), the penetration of stannous ions into the biofilm is improved over control and commercial formulations.

C: Assay for Measuring Improved Wound Healing of Human Gingival Fibroblasts Using in vitro human gingival fibroblasts, the effect of wound healing transition as a result of treatment with the compositions and control compositions of the invention. evaluate. This method involves three steps.

Stage 1-Human Gingival Fibroblasts (HGF) are cultured Human gingival fibroblasts are collected from tooth extraction patients and washed with 5 mL of PBS (phosphate buffered saline). Cut the tissue into small pieces and place in a 15 mL centrifuge tube. The sample should be digested with equal volumes of 1 mL 8% dispase and 1 mL 6% collagenase for 1 hour at 37 ° C., during which time the sample should be shaken every 15 minutes. When the digestion process is complete, the tube is centrifuged at 1100 RPM for 6 minutes at room temperature. After centrifugation, cell pellets are formed at the bottom of the tube. Separate these from the supernatant solution. The supernatant is then discarded and the cell pellet is suspended in 3 mL of fresh Minimum Essential Medium (available from MEM, Thermo Fisher) culture medium and then transferred to Petri dishes. Petri dishes with cells are placed in an incubator at 37 ° C. and 5% CO _{2 for about 10 days.} Check the Petri dish every two days for changes in medium color. If the color of the medium changes, replace the fresh culture medium.

Step 2-If 80-90% cell monolayer coverage of Petri dishes for subcultured human gingival fibroblasts is present, the main culture medium is removed and washed with 5 mL PBS. Add 1 mL of 0.25% trypsin-EDTA solution and allow the cells to stand at 37 ° C. for about 1-2 minutes until the cells are visually rounded. It may be necessary to tap the Petri dish to remove any sticky cells from the Petri dish surface. Add at least 1 mL of fresh MEM culture medium to inactivate trypsin and collect cells in a 15 mL centrifuge tube. The tube is then centrifuged at 1100 RPM for 6 minutes at room temperature. Discard the supernatant and resuspend the cell pellet in 4 mL of fresh MEM culture medium in the same centrifuge tube. Incubator at _{37 ° C., 5% CO 2} with 1 mL cell suspension and 9 mL fresh MEM culture medium, respectively, in each of the four Petri dishes until 80-90% cell monolayer coverage was observed on the Petri dishes. Place in for about 3-5 days. This step should be repeated 2-4 times prior to the wound healing assay to achieve the highest cell viability.

Stage 3-Wound Healing Assay If 80-90% cell monolayer coverage is present on Petri dishes, remove the culture medium and wash with 5 mL PBS. Add 1 mL of 0.25% trypsin-EDTA solution and allow the cells to stand at 37 ° C. for about 1-2 minutes until the cells are visually rounded. It may be necessary to tap the cultured Petri dish to remove any sticky cells from the Petri dish surface. Add at least 1 mL of fresh MEM culture medium to inactivate trypsin and collect cells in a 15 mL centrifuge tube. The tube is then centrifuged at 1100 RPM for 6 minutes at room temperature. Discard the supernatant and resuspend the cell pellet in 6 mL of fresh MEM culture medium. 1 mL of cell suspension and 1 mL of fresh MEM medium are added to each well of the 6-well plate, respectively. Plates are incubated at _{37 ° C. and 5% CO 2} until a 50-70% cell monolayer coating is formed. Then, during image acquisition, the outer bottom of the well is marked with an intermediate line as a reference line. Wounds are created manually by scraping the right half of the cell monolayer with a sterile 1 mL pipette tip. Wash the cells with 2 mL PBS and remove any suspended cells until the suspended cells are no longer visible. Add 2 mL of culture medium and 2 mL of culture medium containing 1% control composition or 2 mL of culture medium containing 1% of the composition of the invention to the wells.

High-density digital images of HGF are taken using an Olympus® IX71 digital SLR camera with an Olympus® UIS2 WHN 10x objective lens. The first image is acquired at time 0 hours (ie, baseline) by using the midline marking on the plate as a reference line. The plates are then incubated at 37 ° C. and 5% CO ₂ over various time intervals as described below. Matched imaging areas were previously acquired and images were acquired at later time intervals after baseline (eg, 16 hours, 24 hours, 48 hours, 65 hours, 72 hours, etc.) and under different treatment legs. The cell coverage (%) is evaluated as an index of the wound healing performance in. The images were evaluated by the Wimasis® WimScratch software (available from Wimasis GmbH, Germany) and compared to the matching baseline images of each sample, as shown by the dotted lines, that is, the coverage of the HGF cells (ie, Determine the degree (ie, percentage) of wound healing). WimScratch software utilizes advanced edge detection and overlay techniques to recognize cells and blank areas, i.e., a green overlay in an image (shown as a gray area in FIG. 6) is a cell covering area of a particular image. And gray areas (shown as black areas in FIG. 6) represent wound areas. Reads are presented for both regions and normalized as a percentage of the total area.

Results: FIG. 6 shows images of HGF 24 hours after treatment with Example 2 (ie, Sn + 0.50% TA) of the composition of the invention or Example 9 (ie, Sn only) of the control composition. Referring to FIG. 6, the result is that Example 2 of the composition of the invention containing an antifibrinolytic agent and an antibacterial agent (eg, stannous ion source) was treated with Example 9 of the control composition for HGF. Increased cell coverage (22.4) after significant wounds (marked with dotted lines) for lower cell coverage (3.3% = 53.3% total coverage-50% baseline) % = 72.4% total coverage-50% baseline) effectively improves wound healing.

D: Mouthwash composition The mouthwash composition according to the present invention is shown below as Examples 11 to 14 in Table 5. These compositions contain a stannous ion source and an anti-fibrinolytic agent. Preferably, these compositions exhibit improved gingival health benefits compared to commercially available formulations that do not contain these ingredients.

The dimensions and values disclosed herein should not be understood as being strictly limited to the exact numbers listed. Rather, unless otherwise indicated, each such dimension shall mean both the stated value and the functionally equivalent range around that value. For example, the dimension disclosed as "40 mm" is intended to mean "about 40 mm".

Exclusion or limitation of all documents cited in this application, including all cross-referenced or related patents or patent applications, and any patent application or patent in which this application claims priority or its interests. Unless otherwise stated, the entire contents are incorporated herein by reference. Citation of any document is not considered prior art to any invention disclosed or claimed herein, or it may be used alone or in combination with any other reference (s). Sometimes it is not considered to teach, suggest or disclose all such inventions. In addition, if any meaning or definition of a term in this document conflicts with the meaning or definition of the same term in the document incorporated by reference, the meaning or definition given to that term in this document applies. It shall be.

Exclusion or limitation of all documents cited in this application, including all cross-referenced or related patents or patent applications, and any patent application or patent in which this application claims priority or its interests. Unless otherwise stated, the entire contents are incorporated herein by reference. Citation of any document is not considered prior art to any invention disclosed or claimed herein, or it may be used alone or in combination with any other reference (s). Sometimes it is not considered to teach, suggest or disclose all such inventions. In addition, if any meaning or definition of a term in this document conflicts with the meaning or definition of the same term in the document incorporated by reference, the meaning or definition given to that term in this document applies. It shall be.

Having exemplified and described specific embodiments of the invention, it will be apparent to those skilled in the art that various other modifications and modifications can be made without departing from the spirit and scope of the invention. Accordingly, all such modifications and amendments contained within the scope of the present invention are intended to be covered by the appended claims.

Claims (11)

Oral care composition,
a) 0.01% by weight to 5% by weight of the stannous ion source of the composition and
b) 0.1% by weight to 10% by weight of the composition, one or more compounds selected from the group consisting of tranexamic acid, εaminocaproic acid, p-aminomethylbenzoic acid, and combinations thereof .
Only containing the stannous ion source comprises stannous chloride, oral care composition. The oral care composition according to claim 1, wherein the stannous ion source is present in an amount of 0.05% by weight to 4% by weight of the composition. A thickener of 0.01% by weight to 5% by weight of the composition.
(I) Linear sulfated polysaccharide,
(Ii) Natural gum,
(Iii) Nonionic cellulose,
(Iv) polyvinylpyrrolidone (PVP),
(V) A polymer containing at least a polycarboxylated ethylene skeleton,
(Vi) Polyacrylamide,
(Vii) Copolymer containing acrylamide,
(Viii) Pectin,
(Ix) protein,
(X) The oral care composition according to claim 1 or 2, further comprising at least one thickener selected from the group consisting of polyethylene glycol (PEG) and (xi) a combination thereof. The thickener is present in an amount of 1% to 2.5% by weight of the composition.
(I) The linear sulfated polysaccharide is carrageenan.
(Ii) The natural gum is selected from the group consisting of xanthan gum, karaya gum, gum arabic, tragacanth gum, and combinations thereof.
(Iii) The nonionic cellulose has an average molecular weight range of 50,000 to 1,300,000 daltons and an average degree of polymerization of 300 to 4,800.
(Iv) The polymer comprises a polycarboxylated ethylene skeleton and has a molecular weight of 30,000 to 1,000,000 daltons, a copolymer of methyl vinyl ether and maleic anhydride, a homopolymer of acrylic acid, and maleic acid. And selected from the group consisting of copolymers of acrylic acid or methacryl,
(V) The oral care composition according to claim 3, which is a combination thereof. (I) The carrageenan is selected from the group consisting of κ-carrageenan, ι-carrageenan, λ-carrageenan, and combinations thereof.
(Ii) The natural gum is xanthan gum,
(Iii) The nonionic cellulose is hydroxyethyl cellulose (HEC).
(Iv) The polymer containing at least a polycarboxylated ethylene skeleton is a copolymer of maleic acid or anhydrate with methyl vinyl ether.
(V) The oral care composition according to claim 4, which is a combination thereof. The oral care composition according to any one of claims 1 to 5, wherein the content of folic acid in the composition is 0% by weight to less than 0.001% by weight. Further comprising 0.01% by weight to 5% by weight of the flavor composition, the flavor composition comprises.
(I) More than 0% by weight to less than 55% by weight of the flavor composition, or more than 65% by weight to 95% by weight of methylsalicylate, more than 0% by weight to less than 30% by weight of the flavor composition, or 35. More than 0% by weight to 65% by weight of menthol, more than 0% by weight to less than 1% by weight of the flavor composition, or more than 5% by weight to 50% by weight of Eugenol, and more than 0% by weight to 3% by weight of the flavor composition. %, Or more than 8% by weight to 30% by weight, a flavor mixture, or (ii) a flavor mixture free of methylsalicylate, menthol, eugenol, and cineole, according to claims 1-6. The oral care composition according to any one of the above. The oral care composition according to any one of claims 1 to 7, further comprising a fluoride ion source of 0.0025% by weight to 2% by weight of the composition. The fluoride ion source is selected from the group consisting of sodium fluoride, indium fluoride, amine fluoride, sodium monofluorophosphate (MFP), potassium fluoride, zinc fluoride, and combinations thereof. The oral care composition according to claim 8. The oral care composition according to any one of claims 1 to 9, further comprising a total water content of 10% by weight to 70% by weight of the composition. The oral care composition according to any one of claims 1 to 10, wherein the composition has a pH of 4.5 to 11.

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