阅读说明：本技术 口腔组合物及使用方法 (Oral compositions and methods of use ) 是由 理查德·P·鲁辛 杨杰 彼得拉·L·科赫莱尔里迪 约迪·L·康奈尔 英戈·R·黑贝尔莱因 于 2020-05-18 设计创作，主要内容包括：本发明提供一种组合物,所述组合物包含：基于所述组合物的总重量计,总共1重量％至3重量％的葡糖胺、葡糖胺的衍生物或它们的组合物；以及基于所述组合物的总重量计,总共0.3重量％至3重量％的一种或多种式(I)的表面活性剂：HOCH-(2)-(CHOH)-(n)-CH-(2)NR～(1)R～(2) (I)其中R～(1)和R～(2)独立地选自氢原子、烷基基团、C(O)R～(3)和SO-(2)R～(4),其中R～(3)和R～(4)独立地选自烷基基团、芳基基团和芳烷基基团,其中n为2至5的整数。(The present invention provides a composition comprising: from 1 to 3 wt.% in total, based on the total weight of the composition, of glucosamine, derivatives of glucosamine, or combinations thereof; and from 0.3 to 3 wt.% in total, based on the total weight of the composition, of one or more surfactants of formula (I): HOCH 2 ‑(CHOH) n ‑CH 2 NR 1 R 2 (I) Wherein R is 1 And R 2 Independently selected from hydrogen atom, alkyl group, C (O) R 3 And SO 2 R 4 Wherein R is 3 And R 4 Independently selected from alkyl groups, aryl groups and aralkyl groups, wherein n is an integer from 2 to 5.)

1. A composition, comprising:

from 1 to 3 wt.% in total, based on the total weight of the composition, of glucosamine, derivatives of glucosamine, or combinations thereof; and

from 0.3 to 3 wt% in total, based on the total weight of the composition, of one or more surfactants of formula I:

HOCH₂-(CHOH)_n-CH₂NR¹R² (I)

wherein R is¹And R²Independently selected from hydrogen atom, alkyl group, C (O) R³And SO₂R⁴(ii) a Wherein R is³And R⁴Independently selected from alkyl groups, aryl groups and aralkyl groups; wherein n is an integer from about 2 to about 5.

2. The composition of claim 1, wherein R¹Is a hydrogen atom or C₁-C₂An alkyl group.

3. The composition of claim 2, wherein R³Is C₇-C₉An alkyl group.

4. The composition of claim 2, wherein R³Is C_8-An alkyl group.

5. The composition of claim 1, wherein glucosamine, derivatives of glucosamine, or combinations thereof, collectively comprise from 1.5 to 2.5 weight percent, based on the total weight of the composition.

6. The composition of claim 1, wherein the one or more surfactants of formula I total 0.5 to 3 wt% based on the total weight of the composition.

7. The composition of any one of claims 1 to 6, further comprising water in an amount ranging from 5% to 98% by weight, based on the total weight of the composition.

8. The composition of claim 7, wherein the composition is a gel and has from 10 to 95 weight percent water, based on the total weight of the composition.

9. The composition of claim 7, wherein the composition is a rinse concentrate and the composition has from 5 wt% to 65 wt% water.

10. The composition of claim 7, wherein the composition is a mouthwash and the composition is an emulsion having an aqueous phase and an oil phase.

11. The composition of claim 1, wherein the composition is a toothpaste and further comprises one or more dental abrasives.

12. The composition of claim 1, further comprising arginine, glycine, or a combination thereof, in an amount of 0.2 to 3 weight percent, based on the total weight of the composition.

13. A method of preventing, inhibiting, disrupting, or any combination thereof, formation or maintenance of a biofilm in oral tissue, the method comprising:

contacting an oral tissue with a composition according to any one of claims 1 to 12.

14. A method of treating a surface in an oral cavity of a subject, the method comprising:

(a) providing a composition according to any one of claims 1 to 12; and

(b) applying the composition to a surface in the oral cavity of the subject.

Technical Field

The present disclosure relates to oral compositions, and more particularly to oral compositions and methods for inhibiting biofilm formation in the oral cavity of a subject.

Background

For example, plaque, which may contain bacteria such as Streptococcus mutans (Streptococcus mutans), includes biofilm formed on oral surfaces. Plaque is at least partially responsible for caries, gingivitis and periodontal disease. Bacteria in dental plaque metabolize carbohydrates (e.g., monosaccharides) in the mouth and produce acids that can attack the enamel. The exposed dentin can then be colonised by bacteria. Plaque may serve as a substrate for the deposition of calculus or tartar. The accumulation of calculus can lead to gingivitis and ultimately periodontal disease. Currently available methods of removing plaque from teeth are mechanical removal using, for example, a dental floss or a toothbrush. Toothbrushes can help remove plaque from exposed surfaces of teeth, and flossing can help remove plaque from, for example, interdental and subgingival surfaces. Proper and regular use of dental floss and toothbrushes can mechanically remove or reduce dental plaque and can reduce the incidence of caries, gingivitis and periodontal disease. Regular visits to dentists or health workers to receive professional prophylaxis may also help to reduce such oral diseases. Certain antimicrobial formulations are available (e.g., in the form of mouthwashes, rinses, and toothpastes) to help control and treat dental plaque, caries, gingivitis, and periodontal disease. Therapeutic dental compositions and related methods for inhibiting biofilm formation have been described in U.S. patent No. 8,968,709(Yang et al).

Biofilm formation can also be problematic in subjects with dry mouth or dry mouth caused by insufficient saliva.

Disclosure of Invention

Disclosed herein are compositions comprising: from 1 to 3 wt.% in total, based on the total weight of the composition, of glucosamine, derivatives of glucosamine, or combinations thereof; and from 0.3% to 3% by weight, based on the total weight of the composition, of one or more surfactants of formula I in total:

HOCH₂-(CHOH)_n-CH₂NR¹R² (I)

wherein R is¹And R²Independently selected from hydrogen atom, alkyl group, C (O) R³And SO₂R⁴(ii) a Wherein R is³And R⁴Independently selected from alkyl groups, aryl groups and aralkyl groups; wherein n is an integer from about 2 to about 5.

In another aspect, a method of treating a surface in an oral cavity of a subject is provided. The method can comprise the following steps: (a) providing a dental paste; and (b) applying the dental paste to a surface in the oral cavity of the subject.

In another aspect, a method of inhibiting biofilm formation on a surface in an oral cavity of a subject is provided. The method can comprise the following steps: (a) providing a dental paste; and (b) applying the dental paste to a surface in the oral cavity of the subject.

The above summary is not intended to describe each embodiment of the present disclosure. The details of one or more embodiments of the disclosure are also set forth in the description below. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims.

Detailed Description

Disclosed herein are compositions useful, for example, as oral compositions. The disclosed compositions comprise a specific type of surfactant and glucosamine, derivatives thereof, or combinations thereof. The disclosed compositions can have an effect on biofilm formation. In some embodiments, the disclosed compositions may have a better impact on biofilm formation, and in some embodiments exhibit a synergistic effect, when compared to compositions having a particular type of surfactant and compositions having glucosamine or compositions thereof.

One or more components of the disclosed compositions, or both may be characterized as edible. Reference to a component or composition as edible may mean that the particular ingredient or composition is safe for daily long-term ingestion at the recommended level of use. In some embodiments, the GRAS (generally recognized as safe) list of the U.S. Food and Drug Administration (FDA) may be used to determine whether a component is edible at the levels used in the composition.

The disclosed compositions comprise at least glucosamine or a derivative thereof, and a surfactant of formula I:

HOCH₂-(CHOH)_n-CH₂NR¹R² (I)

wherein R is¹And R²Independently selected from hydrogenAtom, alkyl group, C (O) R³And SO₂R⁴(ii) a Wherein R is³And R⁴Independently selected from alkyl groups, aryl groups and aralkyl groups; and n is an integer from about 2 to about 5.

The disclosed compositions comprise glucosamine or a derivative thereof. Glucosamine can also be referred to as (3R,4R,5S) -3-amino-6- (hydroxymethyl) oxacyclohexane-2, 4, 5-triol or 2-amino-2-deoxy-glucose. Derivatives of glucosamine include, for example, salts of glucosamine. Commonly used forms of glucosamine salts include, for example, glucosamine sulfate and glucosamine hydrochloride. Another common derivative of glucosamine is N-acetylglucosamine, which is an amide formed from glucosamine and acetic acid. Any combination of glucosamine and their derivatives can be used in the disclosed compositions.

The disclosed compositions can comprise no greater than 3 wt.% glucosamine or a derivative thereof based on the total weight of the composition, no greater than 2.5 wt.% glucosamine or a derivative thereof based on the total weight of the composition, or no greater than 2.2 wt.% glucosamine or a derivative thereof based on the total weight of the composition. In some embodiments, the disclosed compositions can comprise not less than 1 wt.% glucosamine or a derivative thereof based on the total weight of the composition, not less than 1.2 wt.% glucosamine or a derivative thereof based on the total weight of the composition, or not less than 1.5 wt.% glucosamine or a derivative thereof based on the total weight of the composition.

The disclosed compositions comprise a surfactant of formula I:

HOCH₂-(CHOH)_n-CH₂NR¹R² (I)

wherein R is¹And R²Independently selected from hydrogen atom, alkyl group, C (O) R³And SO₂R⁴(ii) a Wherein R is³And R⁴Independently selected from alkyl groups, aryl groups and aralkyl groups; and n is an integer from about 2 to about 5. Radical R¹And R²Independently selected from hydrogen atom, alkyl group, C (O) R³And SO₂R⁴。

In the formula I, the compound is shown in the specification,R¹and R²May be a hydrogen atom, R¹And R²Each of which may be an alkyl group, R¹And R²May be C (O) R³Or R is¹And R²May be SO₂R⁴. In some embodiments, R¹May be a hydrogen atom, and R²May be an alkyl group, C (O) R³Or SO2R⁴. In other embodiments, R¹May be an alkyl group, and R²May be C (O) R³Or SO₂R⁴. In other embodiments, R¹May be C (O) R³And R is²May be SO₂R⁴. When R is¹And R²When either or both are alkyl groups, the alkyl groups may comprise about one carbon atom, more than about two carbon atoms, more than about four carbon atoms, more than about six carbon atoms, more than about eight carbon atoms, more than about ten carbon atoms, more than about twelve carbon atoms, more than about fourteen carbon atoms, more than about sixteen carbon atoms, or more than about eighteen carbon atoms. In some embodiments, the alkyl group contains less than about thirty carbon atoms, less than about twenty-six carbon atoms, or less than about twenty carbon atoms. For example, when R is¹When it is an alkyl group, R¹May be C₁–C₁₂Alkyl radical, C₁–C₁₀Alkyl radical, C₁–C₆Alkyl radicals or C₂–C₇An alkyl group. In certain embodiments, R¹Is a hydrogen atom or C₁–C₂An alkyl group. In some embodiments, the alkyl group comprises a straight chain alkyl group. In other embodiments, the alkyl group comprises a branched alkyl group. In other embodiments, the alkyl group comprises a cycloalkyl group. When R is¹And R²When each of (a) contains an alkyl group, R¹And R²May contain the same alkyl groups, or R¹And R²Different alkyl groups may be included. Non-limiting examples of alkyl groups include methyl, ethyl, 1-propylIsopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, neopentyl, hexyl, 2-ethylhexyl, octyl, decyl, undecyl, dodecyl, tetradecyl, pentadecyl, octadecyl, cyclohexyl, 4-methylcyclohexyl, cyclohexylmethyl, cyclopentyl and cyclooctyl.

Radical R³And R⁴Independently selected from alkyl groups, aryl groups and aralkyl groups. When R is³Or R⁴When either or both are alkyl groups, the alkyl groups may comprise about one carbon atom, more than about two carbon atoms, more than about four carbon atoms, more than about six carbon atoms, more than about eight carbon atoms, more than about ten carbon atoms, more than about twelve carbon atoms, more than about fourteen carbon atoms, more than about sixteen carbon atoms, or more than about eighteen carbon atoms. In some embodiments, the alkyl group contains less than about thirty carbon atoms, less than about twenty-six carbon atoms, or less than about twenty carbon atoms. In some embodiments, the group R³Is C₇-C₉Alkyl radicals, e.g. containing about seven carbon atoms (i.e. C)₇) About eight carbon atoms (i.e., C)₈) Or about nine carbon atoms (i.e., C)₉) An alkyl group of (2). In some embodiments, the alkyl group comprises a straight chain alkyl group. In other embodiments, the alkyl group comprises a branched alkyl group. In other embodiments, the alkyl group comprises a cycloalkyl group. In a compound of formula I or a pharmaceutically acceptable salt thereof, when R³And R⁴When both radicals are present, and when R is present³And R⁴When each of (a) contains an alkyl group, R³And R⁴May contain the same alkyl groups, or R³And R⁴Different alkyl groups may be included. Non-limiting examples of alkyl groups include methyl, ethyl, 1-propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, neopentyl, hexyl, 2-ethylhexyl, octyl, decyl, undecyl, dodecyl, tetradecyl, pentadecyl, octadecyl, cyclohexyl, 4-methylcyclohexyl, cyclohexylmethyl, cyclopentyl, and cyclooctyl.

When R is³Or R⁴When either or both are aryl groups, the aryl group may contain one aromatic ring or more than one aromatic ring. The aromatic ring may contain up to six carbon atoms, up to eight carbon atoms, up to ten carbon atoms, up to twelve carbon atoms, up to fourteen carbon atoms, up to sixteen carbon atoms, or up to eighteen carbon atoms. The aromatic ring may contain heteroatoms such as nitrogen, oxygen or sulfur. If more than one aromatic ring is present, the aromatic rings may be fused together, or they may be linked by chemical bonds. In a compound of formula I or a pharmaceutically acceptable salt thereof, when R³And R⁴Both are present, and when R is³And R⁴When each of (1) contains an aryl group, R³And R⁴May contain the same aryl group, or R³And R⁴Different aryl groups may be included. Non-limiting examples of aryl groups include substituted and unsubstituted phenyl, 1-naphthyl, 2-naphthyl, 9-anthracenyl.

When R is³Or R⁴When either or both are aralkyl groups, the aralkyl group may contain one aromatic ring or more than one aromatic ring. An aralkyl group may contain up to six carbon atoms, up to eight carbon atoms, up to ten carbon atoms, up to twelve carbon atoms, up to fourteen carbon atoms, up to sixteen carbon atoms, up to eighteen carbon atoms, or up to twenty carbon atoms. If more than one aromatic ring is present on the aralkyl group, the aromatic rings may be fused together, or they may be joined by chemical bonds. The aromatic ring may contain heteroatoms such as nitrogen, oxygen or sulfur. In a compound of formula I or a pharmaceutically acceptable salt thereof, when R³And R⁴When both radicals are present, and when R is present³And R⁴When each of (a) contains an aralkyl group, R³And R⁴May contain the same aralkyl groups, or R³And R⁴Different aralkyl groups may be included. Non-limiting examples of aralkyl groups include benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-naphthylethyl and 9-anthracenemethyl.

In formula I, n is an integer from about 2 to about 5. In some embodiments, the dental composition comprises a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein n is an integer having a value of about 5, about 4, about 3, or about 2. In some embodiments, n is an integer having a value of 5, or 4, or 3, or 2. It is to be understood that the dental composition may comprise more than one compound of formula I or a pharmaceutically acceptable salt thereof, and that the compounds may be represented by formula I having different integer values of n. In these embodiments, the average value of n for the composition may be a non-integer.

It is well known that compounds of formula I contain chiral carbon atoms. For simplicity, in formula I, the stereochemical configuration with respect to each of the chiral carbon atoms is not specified. It is intended that formula I as used in the specification and claims represents each compound having any possible stereochemical configuration. In some embodiments, the compounds of formula I are amino sugar alcohols and their derivatives, commonly known by the generic names D-glucosamine, N-methyl-D-glucosamine, N-ethyl-D-glucosamine, N-octyl-D-glucosamine, and N-methyl-N-octanoyl-D-glucosamine, N-methyl-N-nonanoyl-D-glucosamine, N-methyl-N-decanoyl-D-glucosamine. Many of the compounds of formula I are commercially available. For example, N-methyl-N-nonanoyl-D-glucamine ("MEGA-9") is commercially available from EMD Chemicals, inc.

Pharmaceutically acceptable salts of the compounds of formula I may also be used and may include ammonium salts. In some embodiments, the dental compositions of the present invention comprise an ammonium salt. The ammonium salt may be represented as the reaction product of an acid with an amine, or as the reaction product of an amine with an alkylating agent such as, for example, methyl iodide, ethyl bromide, or benzyl bromide. Ammonium salts include protonated amine compounds, e.g. wherein NR¹R²A compound of formula I wherein R is a group which has been protonated by an inorganic or organic acid¹And R²The groups are independently selected from hydrogen atoms and alkyl groups. Ammonium salts include alkylated amine compounds, e.g. wherein NR¹R²A compound of formula I wherein R is a group which has been alkylated with an alkylating agent¹And R²Independently selected from hydrogen atoms and alkyl groups.

The ammonium salt is contained inAt least one counterion, which can be an inorganic anion, an organic anion, or a combination of anions. Anionic compositions include compositions of more than one inorganic anion, more than one organic anion, or a combination of inorganic and organic anions. Inorganic ions include, for example, halides (fluoride, chloride, bromide, and iodide), nitrates, sulfates, tetrafluoroborates, and tetrakis (aryl) borates. The tetra (aryl) borate salt comprises a compound having the formula Z₄B^-Wherein Z is an aromatic group, such as a substituted or unsubstituted phenyl group. Examples of tetrakis (aryl) borates include, but are not limited to, tetraphenyl borate, tetrakis (4-methylphenyl) borate, tetrakis (2-methylphenyl) borate, tetrakis (1,3, 5-trimethylphenyl) borate, tetrakis (4-fluorophenyl) borate, tetrakis (pentafluorophenyl) borate, and tetrakis (4-trifluoromethylphenyl) borate. Organic anions include, for example, alkanoates (such as, for example, acetate, propionate, and butyrate), benzoate, fumarate, maleate, tartrate, ascorbate, benzene sulfonate, toluene sulfonate, and citrate. In some embodiments, the pharmaceutically acceptable salt is free of unsubstituted or substituted tropolone.

In certain embodiments, the ammonium salt may be formed by protonating a compound of formula I with a mineral acid, an organic acid, or a combination of a mineral acid and an organic acid, wherein R is¹And R²Independently selected from hydrogen atoms and alkyl groups. In another embodiment, the ammonium salt may be formed by alkylating a compound of formula I, wherein R is¹And R²Independently selected from hydrogen atoms and alkyl groups. In another embodiment, the ammonium salt may be formed by an ion exchange or metathesis reaction with a previously formed ammonium salt. In some embodiments, R¹Comprises an alkyl group, and R²Is C (O) R³Wherein R is³Including alkyl groups. In certain embodiments, R¹Including alkyl groups having from about one to about four carbon atoms, R³Including alkyl groups having from about four to about sixteen carbon atoms. In some embodiments, R¹Comprising methyl groupsAnd R is³Including alkyl groups having seven, eight, or nine carbon atoms. In some embodiments, the dental composition comprises a compound of formula III, formula IV, or formula V.

The disclosed compositions can comprise no greater than 3 wt.% of one or more surfactants of formula I based on the total weight of the composition, no greater than 2.5 wt.% of one or more surfactants of formula I based on the total weight of the composition, no greater than 2 wt.% of one or more surfactants of formula I based on the total weight of the composition, or no greater than 1 wt.% of one or more surfactants of formula I based on the total weight of the composition. In some embodiments, the disclosed compositions may comprise not less than 0.3 wt% of one or more surfactants of formula I based on the total weight of the composition, not less than 0.4 wt% of one or more surfactants of formula I based on the total weight of the composition, or not less than 0.5 wt% of one or more surfactants of formula I based on the total weight of the composition.

In some embodiments, the disclosed compositions may further comprise water. The amount of water in the composition can vary greatly depending on the type of composition formed and the manner in which it is applied to the oral cavity of the subject. Exemplary types of compositions can include, for example, mouthwashes or rinses, toothpastes, gels, mouth rinse concentrates, and emulsions designed for the treatment of xerostomia.

In some embodiments, where the formed composition is a mouthwash or mouthrinse, the amount of water can be no less than 60 weight%, no less than 65 weight%, no less than 70 weight%, no less than 75 weight%, no less than 80 weight%, or no less than 85 weight%, based on the total weight of the composition. In some embodiments, wherein the formed composition is a mouthwash or mouthrinse, the amount of water can be no greater than 98 weight%, no greater than 97 weight%, no greater than 95 weight%, no greater than 93 weight%, or no greater than 90 weight%, based on the total weight of the composition.

In some embodiments, where the formed composition is a toothpaste, the amount of water may be no less than 5 wt%, no less than 7 wt%, no less than 10 wt%, no less than 15 wt%, no less than 20 wt%, or no less than 25 wt%, based on the total weight of the composition. In some embodiments, where the formed composition is a toothpaste, the amount of water may be no greater than 65 wt-%, no greater than 60 wt-%, no greater than 55 wt-%, or no greater than 50 wt-%, based on the total weight of the composition.

In some embodiments, where the formed composition is a gel, the amount of water may be no less than 10 wt.%, no less than 15 wt.%, no less than 20 wt.%, no less than 30 wt.%, no less than 40 wt.%, or no less than 50 wt.%, based on the total weight of the composition. In some embodiments, where the formed composition is a gel, the amount of water may be no greater than 95 wt.%, no greater than 90 wt.%, no greater than 85 wt.%, no greater than 80 wt.%, no greater than 75 wt.%, or no greater than 70 wt.%, based on the total weight of the composition.

In some embodiments, where the formed composition is a concentrate for preparing a mouth rinse, the amount of water can be no less than 5 weight%, no less than 7 weight%, no less than 10 weight%, no less than 15 weight%, no less than 20 weight%, or no less than 25 weight%, based on the total weight of the composition. In some embodiments, wherein the formed composition is a concentrate for preparing a mouth rinse, the amount of water can be no greater than 65 weight%, no greater than 60 weight%, no greater than 55 weight%, or no greater than 50 weight%, based on the total weight of the composition.

In some embodiments, wherein the composition formed is an emulsion for treating xerostomia, the amount of water can be characterized by the amount of aqueous phase in the composition. In some embodiments, the amount of the aqueous phase of such compositions may be not less than 70 weight percent, not less than 75 weight percent, or not less than 78 weight percent, based on the total weight of the composition. In some embodiments, wherein the formed composition is an emulsion for treating xerostomia, the amount of aqueous phase may be no greater than 95 weight%, no greater than 92 weight%, no greater than 90 weight%, or no greater than 89.5 weight%, based on the total weight of the composition.

The disclosed compositions may also optionally comprise additional components other than glucosamine or derivatives thereof and the surfactant of formula I. Exemplary optional components may include, for example, amino acids, sweeteners, humectants, mineral salts, buffering components, flavoring agents, preservatives, tooth remineralizing agents, anticaries agents, or combinations thereof. Other optional beneficial ingredients may also be included at appropriate levels, such as folic acid (associated with B12), hyaluronic acid (lubricating, healthy skin), ceramides (healthy skin), arginine, betaine or oxidized triglycerides, vitamin E (antioxidants and preservatives), vitamin B12 (healthy skin, etc.), EDTA, cetylpyridinium chloride, chlorhexidine, other preservatives, and the like, or combinations thereof.

In some embodiments, the disclosed compositions can comprise an amino acid, such as glycine, arginine, or a combination thereof. In some embodiments, the amount of glycine, arginine, or a combination thereof in the disclosed compositions can be not less than 0.2 weight percent, not less than 0.25 weight percent, not less than 0.5 weight percent, or not less than 0.75 weight percent, based on the total weight of the composition. In some embodiments, the amount of glycine, arginine, or a combination thereof in the disclosed compositions can be no greater than 3 weight percent, no greater than 2.5 weight percent, or no greater than 2 weight percent, based on the total weight of the composition.

In some embodiments, the disclosed compositions can include flavoring agents including, for example, peppermint, strawberry, butter, vanilla, coconut, almond, bubble gum, berry, fruit juice beverages, creamy candy, caramel, or combinations thereof. In some embodiments, some flavors such as mint, citrus, and the like may also be advantageous because they stimulate saliva production when used in the compositions. Artificial sweeteners (e.g., stevia, aspartame, sucralose, neotame, acesulfame potassium (Ace-K), saccharin, and high sweeteners (advatame)) may also be used. In some embodiments, the disclosed compositions may comprise one or more sweeteners, including, for example, non-cariogenic polyols or sugar substitutes (e.g., sucralose). In some embodiments, the disclosed compositions may comprise non-cariogenic polyol sweeteners, such as xylitol, sorbitol, maltitol, erythritol, isomalt, or combinations thereof. In compositions comprising the optional sweetener, the sweetener may be present in an amount of not less than 2.5 wt% based on the total weight of the composition or not less than 1 wt% based on the total weight of the composition. In some embodiments, the optional sweetener may be present in an amount of no greater than 35 wt% based on the total weight of the composition, or no greater than 20 wt% based on the total weight of the composition, or no greater than 15 wt% based on the total weight of the composition.

In some embodiments, the disclosed compositions may comprise one or more humectants, including, for example, glycerin, propylene glycol, or sucrose, or combinations thereof. In some embodiments, the disclosed compositions can comprise one or more humectants including, for example, glycerin, propylene glycol, sucrose, or combinations thereof. In compositions comprising the optional humectant, the one or more humectants can be present in an amount of not less than 2.5 wt% based on the total weight of the composition, not less than 5 wt% based on the total weight of the composition, or not less than 10 wt% based on the total weight of the composition. In compositions comprising the optional humectant, the one or more humectants can be present in an amount of no greater than 40 weight percent based on the total weight of the composition, no greater than 35 weight percent based on the total weight of the composition, or no greater than 30 weight percent based on the total weight of the composition.

In various embodiments, the disclosed compositions can further comprise one or more tooth remineralizing agents alone or in combination with one or more minerals that can be useful or beneficial for intake or oral health.

In some embodiments, the disclosed compositions may optionally comprise one or more minerals that may be useful or beneficial for ingestion or oral health. Exemplary optional minerals that may be included in the disclosed compositions may include calcium (Ca), phosphorus (P), magnesium (gMg), fluorine (F), iron (Fe), strontium (Sr), zinc (Zn), potassium (K), or combinations thereof. In some embodiments, some minerals may be formed by including magnesium chloride (MgCl)₂) Calcium chloride (CaCl)₂) Strontium chloride, zinc gluconate, potassium nitrate, and dipotassium hydrogen phosphate (KH)₂PO₄) Or a combination thereof. In some embodiments, where fluorine is included, it may be in the form of a salt (MgF)₂、CaF₂Etc.) is contained at a concentration of not more than 4 milligrams per liter (mg/L).

In particular, some calcium-containing compounds are particularly advantageously included in the disclosed compositions. Such calcium compounds include: calcium chloride, calcium carbonate, calcium caseinate, calcium citrate, calcium glubionate, calcium glucoheptonate, calcium glycerophosphate, calcium gluconate, calcium hydroxide, calcium hydroxyapatite, calcium lactate, calcium oxalate, calcium lime oxide, calcium pantothenate, dibasic and tribasic calcium phosphates, calcium polycarbophil, calcium propionate, calcium pyrophosphate, calcium silicate, and calcium sulfate. These compounds have been found to minimize demineralization of calcium hydroxyapatite at the surface of a patient's teeth.

In some embodiments, the tooth remineralizing agent (compound) comprises a phosphate compound. Suitable phosphate compounds include, but are not limited to, aluminum phosphate, bone phosphate, calcium orthophosphate, anhydrous calcium hydrogen phosphate, calcium phosphate-bone ash, calcium hydrogen phosphate dihydrate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, tribasic calcium phosphate, dibasic calcium phosphate dihydrate, dicalcium phosphate, neutral calcium phosphate, tribasic calcium phosphate, tricalcium phosphate, precipitated calcium phosphate, tricalcium phosphate, whitlockite, magnesium phosphate, potassium phosphate, dipotassium hydrogen phosphate, dipotassium monophosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, potassium acid phosphate, potassium dihydrogen orthophosphate, potassium hydrogen phosphate, sodium phosphate, anhydrous sodium phosphate, disodium hydrogen orthophosphate, disodium hydrogen phosphate dodecahydrate, disodium hydrogen phosphate, disodium phosphate, and mixtures and combinations thereof.

In some embodiments, the calcium compound, the phosphate compound, or both are present in an amount sufficient to combineQuilt Ca²⁺Ions and PO₄ ^3-At least one of the ions is present in the composition of the present invention in a saturated amount. In some embodiments, saturation with at least one of calcium ions or phosphate ions can substantially reduce or prevent demineralization on the surface of a patient's teeth, or enhance remineralization on the surface of a patient's teeth, or both.

In various embodiments, the tooth remineralizing agent is present in an amount of up to about 1 part by weight, or up to about 2 parts by weight, or up to about 5 parts by weight.

In some embodiments, the disclosed compositions may include one or more preservatives to render the composition microbiologically stable, to increase its microbiologically stability, or some combination thereof. In some embodiments, preservatives that can be used include those that function at neutral pH, do not adversely affect taste, are edible, are effective against multiple pathogens, or combinations thereof. Specific exemplary useful preservatives may includePreservatives, which are commercially available from Lonza corporation, Basel, Switzerland, of Basel, Switzerland, include, for example, benzyl alcohol, sodium benzoate, potassium sorbate, parabens, natural preservatives, polyglycerol esters, monolaurate, 1, 2-octanediol, caprylic/capric triglyceride, DHA, aloe, potassium sorbate, CPC, PHMB, CHG, vitamin E, triethyl citrate, and EDTA.

In some embodiments, the disclosed compositions can be a paste or more specifically a toothpaste. Additional optional paste components may include those listed above as well as dental abrasives, carriers, additives, adjuvants, agents, and/or modifiers. Examples of such components include, but are not limited to, anticaries agents (e.g., fluoride sources), desensitizing agents, antigingivitis agents, antiplaque agents, rheology modifiers, buffering agents, diluents, solvents, surfactants, fillers, emulsifiers, foaming agents, pH adjusting agents, humectants, antimicrobial agents (e.g., antibacterial agents), mouth feel agents, texture modifying agents, oils, dry mouth reducers (e.g., saliva stimulants), anti-halitosis agents, breath fresheners, pharmaceuticals, therapeutic agents, anti-inflammatory agents, colorants (e.g., pigments or dyes), stabilizers, tartar control agents, carbon black, anti-corrosion agents, decorative agents, nutrients, enzymes (e.g., lysozyme, oxidase, etc.), proteins (e.g., enamel matrix protein, prolin-rich protein), waxes, other suitable materials, and combinations and mixtures thereof, including, for example, those indicated in the categories set forth below. Various dental paste components that may be used in the dental pastes of the present disclosure may also include those disclosed in U.S. patent No. 5,624,906(Vermeer), which is incorporated herein by reference in its entirety.

The disclosed compositions, particularly those formed for use as toothpastes, may also contain a dental abrasive. In general, the dental abrasive should be suitable for use in an oral environment. The type and characteristics of the dental abrasive (e.g., particle size, hardness, etc.) and the amount of dental abrasive in the dental paste can be selected such that the enamel and dentin are not excessively abraded during normal use of the dental paste, such as during brushing or during a prophylaxis procedure. Dental abrasives can serve one or more functions including, but not limited to, abrading and/or otherwise cleaning debris and/or plaque from the surface of the teeth, removing stains from the surface of the teeth, polishing the surface of the teeth, and/or providing a whitening effect on the teeth.

Examples of suitable dental abrasives may include, but are not limited to, silica gel, silica hydrates, precipitated silica, fused silica, alumina, calcined alumina, insoluble phosphates, calcium carbonate, ground glass, silicon carbide, ilmenite, sodium bicarbonate, bentonite, mica, zirconia silicates, topaz, titanium dioxide, precipitated lime, chalk, pumice (e.g., pumice), zeolites, talc, kaolin, diatomaceous earth, silicates, glycine, resinous abrasives such as urea-formaldehyde condensation products, and the like. Phosphates useful as dental abrasives include orthophosphates, polymetaphosphates and pyrophosphates, and salts thereof; illustrative examples are dibasic calcium phosphate dihydrate, dicalcium phosphate, calcium pyrophosphate, tricalcium phosphate, calcium polymetaphosphate, hydroxyapatite, magnesium orthophosphate, and insoluble sodium polymetaphosphate.

Perlite can also be used as the dental abrasive of the present disclosure, for example, as described in U.S. patent nos. 5,266,304(Baffelli et al) and 6,576,225(Kilcher et al), each of which is incorporated herein by reference in its entirety.

In some embodiments, water-soluble dental abrasives (used alone or in combination with other dental abrasives, each of which may be water-soluble or water-insoluble) can be used, such as described in U.S. patent No. 8,858,921(Schmid et al), which is incorporated herein by reference in its entirety. In such embodiments, the dental paste may be substantially free of water (e.g., less than about 5 weight percent water or less than about 1 weight percent water, based on the total weight of the dental paste), and optionally include a water-miscible or water-soluble liquid.

The average particle size of the dental abrasive is typically about 0.1 microns, about 1 micron, about 5 microns, about 10 microns, about 15 microns, about 20 microns, about 25 microns, about 30 microns, about 35 microns, about 40 microns, about 50 microns, about 75 microns, about 90 microns, about 100 microns, about 150 microns, about 200 microns, about 250 microns, about 300 microns, or a range between and including any two of these values. For example, in some embodiments, the dental abrasive has an average particle size of about 0.1 to about 300 microns, about 20 to about 300 microns, about 90 to about 300 microns, about 0.1 to about 50 microns, about 1 to about 40 microns, or about 5 to about 30 microns. As should be appreciated, the dental pastes of the present disclosure may include more than one dental abrasive. In such cases, the average particle size is intended to refer to the average particle size of each dental abrasive contained in the dental paste. For example, the dental paste may comprise silica having an average particle size of about 1 to about 40 microns as a first dental abrasive and calcium carbonate having an average particle size of about 30 to about 75 microns as a second dental abrasive.

In certain embodiments of the dental pastes of the present disclosure, various types of silica-containing dental abrasives are incorporated because they provide excellent tooth cleaning and polishing performance without unduly abrading tooth enamel or dentine. The silica-containing dental abrasives and other dental abrasives described herein typically have an average particle size in the range of about 0.1 to about 30 microns or about 5 to about 15 microns. The silica-containing dental abrasive can be precipitated silica or silica gel, such as silica xerogels described in U.S. Pat. Nos. 3,538,230(Pader et al) and 3,862,307(DiGuilio), each of which is incorporated herein by reference in its entirety. Additional types of silica-containing dental abrasives that can be used in the dental pastes of the present disclosure are described in U.S. Pat. nos. 4,340,583(Wason), 5,589,160(Rice), 5,603,920(Rice), 5,651,958(Rice), 5,658,553(Rice), and 5,716,601(Rice), each of which is incorporated by reference herein in its entirety. Suitable silica-containing dental abrasives for inclusion in the dental pastes described herein are available from qiubo engineering Materials (Huber Engineered Materials) under the trade name ZEODENT; available from Grace (Grace) under the trade names SYLOID and SYLODENT; and from scratch (Evonik) under the trade name SIDENT.

The one or more dental abrasives are present in a total amount of about 4 weight%, about 5 weight%, about 6 weight%, about 8 weight%, about 10 weight%, about 15 weight%, about 20 weight%, about 30 weight%, about 40 weight%, about 50 weight%, about 60 weight%, about 70 weight%, about 80 weight%, or a range between and including any two of these values, based on the total weight of the dental paste. In some embodiments, the dental paste comprises about 4% to about 80% by weight of the dental abrasive, based on the total weight of the dental paste. In other embodiments, the dental paste comprises about 8% to about 50%, about 10% to about 30%, or about 5% to about 25% by weight dental abrasive, based on the total weight of the dental paste.

Any of the individual components of the dental pastes of the present disclosure may be dissolved, dispersed, suspended, or emulsified in the dental paste. It should be understood that while the general attributes of each type of component may differ; there may be some common attributes, and any given component may serve multiple purposes within two or more of such categories of components. For example, if sorbitol is included in a toothpaste, sorbitol may act as a sweetener and humectant. It is also to be understood that the components of the dental paste should be suitable for use in an oral environment (e.g., pharmaceutically acceptable and/or food grade).

In various embodiments, the dental pastes of the present disclosure may comprise a carrier. The carrier, if present, may comprise a liquid, a solid, or both. In some embodiments, the carrier may be a liquid at about room temperature. In other embodiments, the support may be a solid at about room temperature. In some embodiments, the carrier can be a liquid at a temperature of about the human oral cavity (i.e., at about 37 ℃). In other embodiments, the carrier can be a solid at about the temperature of the human oral cavity. It will be appreciated that a variety of carriers may be used. Examples of liquid carriers include, but are not limited to, water, glycerol, propylene glycol, polyalkylene glycols (e.g., polyethylene glycol, polypropylene glycol, and the like), and combinations thereof.

Further examples of suitable carriers include those described in U.S. Pat. Nos. 6,669,929(Boyd et al), 6,379,654 (Gebreselasie et al), and 4,894,220(Nabi et al), each of which is incorporated herein by reference in its entirety. In some embodiments, the carrier (or composition of carriers) is substantially free of water (e.g., less than about 5 wt% or less than about 1 wt% water, based on the total weight of the carrier). In some embodiments, wherein the carrier or composition of carriers is substantially free of water, such carrier or composition of carriers is water-miscible (e.g., water-soluble). In further embodiments comprising a substantially water-free carrier (or combination of carriers), the dental paste is also substantially water-free (e.g., less than about 5 weight percent water or less than about 1 weight percent water, based on the total weight of the dental paste). In other embodiments, the dental paste comprises water, and the water is present in an amount of at least about 10 weight percent, at least about 20 weight percent, at least about 30 weight percent, at least about 40 weight percent, or at least about 50 weight percent, based on the total weight of the dental paste.

Each of the non-carrier components of the dental paste (including but not limited to the compound of formula I or a pharmaceutically acceptable salt thereof) and the dental abrasive can be independently dissolved, dispersed, suspended, or emulsified in the carrier. In some embodiments, at least one component of the dental paste is dissolved in the carrier. In some embodiments, at least one component of the dental paste is dispersed in a carrier. In some embodiments, at least one component of the dental paste is suspended in the carrier. In some embodiments, at least one component of the dental paste is emulsified in the carrier. In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is each dissolved in a carrier.

In some embodiments, the dental pastes of the present disclosure may include one or more anticaries agents, such as one or more fluoride sources. Such fluoride sources release or otherwise provide fluoride ions in the oral cavity. The fluoride source may be an inorganic fluoride source, an organic fluoride source, or a combination thereof.

Examples of inorganic fluoride sources may include, but are not limited to, alkali metal, alkaline earth metal, and ammonium salts of fluoride, such as potassium fluoride, sodium fluoride, ammonium bifluoride, calcium fluoride, copper fluoride (e.g., cuprous fluoride, copper fluoride), barium fluoride, sodium fluorosilicate, ammonium fluorosilicate, sodium fluorozirconate, sodium monofluorophosphate, aluminum monofluorophosphate, and aluminum difluorophosphate, sodium calcium fluoropyrophosphate, stannous fluoride, zinc fluoride, lithium fluoride, cesium fluoride, aluminum fluoride, indium fluoride, stannous fluorozirconate, iron fluoride, nickel fluoride, palladium fluoride, silver fluoride, zirconium fluoride, silver diamine fluoride, and combinations thereof. Another type of fluoride source is fluoride-containing glasses, such as fluoroaluminosilicate glasses. Suitable fluoroaluminosilicate glasses are described in U.S. Pat. Nos. 5,063,257(Boyd et al), 4,209,434(Wilson et al), and 4,043,327(Potter et al), each of which is incorporated herein by reference in its entirety. In some embodiments, the dental paste comprises an inorganic fluoride source such as sodium fluoride, stannous fluoride, sodium monofluorophosphate, silver diammine fluoride, strontium fluoride, calcium fluoride, fluoroaluminosilicate glass, or combinations thereof.

Sources of organofluorides can include, but are not limited to, N, N, N ' -tris (2-hydroxyethyl) -N ' -octadecyl-1, 3-diaminopropane dihydrofluoride, hexylamine hydrofluoride, laurylamine hydrofluoride, tetradecylamine hydrofluoride, decylamine hydrofluoride, octadecenylamine hydrofluoride, tetradecyloxy-amine hydrofluoride, diethylaminoethyl octylamide hydrofluoride, diethanolamine ethyl oleamide hydrofluoride, diethanolaminopropyl-N ' -octadecenylamine dihydrofluoride, 1-ethanol-2-hexadecylimidazoline dihydrofluoride, octylethanolamine hydrofluoride, octyltrimethylammonium fluoride, dodecylethyldimethylammonium fluoride, tetraethylammonium fluoride, dilauryldimethylammonium fluoride,. DELTA.8-9 octadecenylbenzyldimethylammonium fluoride, dioctyldiethylammonium fluoride, cyclohexylcetyldimethylammonium fluoride, furfuryllauryl dimethylammonium fluoride, phenoxyethylcetyldimethylammonium fluoride, N '-tetramethyl-N, N' -dilaurylethylenediammonium fluoride, N-cetylpyridinium fluoride, N-dilaurylmorpholinium fluoride, N-tetradecyl-N-ethylmorpholinium fluoride, N- (octylaminocarbonylethyl) -N-benzyldimethylammonium fluoride, N- (B-hydroxydodecyl) trimethylammonium fluoride, N-phenyl-N-hexadecyldiethylammonium fluoride, N-cyclohexyl-N-octadecyldimethylammonium fluoride, N- (2-carbomethoxyethyl) -N-benzyldimethylammonium fluoride, N-tert-butylammonium fluoride, N-dodecyltrimethylammonium fluoride, N-phenyl-N-hexadecyldiethylammonium fluoride, N-cyclohexyl-N-octadecyldimethylammonium fluoride, N- (2-carboximinoethyl) -N-benzyldimethylammonium fluoride, N-dodecyldimethylammonium fluoride, N-tert-butylammonium fluoride, N-dodecyldimethylammonium fluoride, N-dodecyltrimethylammonium fluoride, N-dodecyldimethylammonium fluoride, N-benzyldimethylammonium fluoride, N-dodecyltrimethylammonium, N-dodecyldimethylammonium fluoride, N-dodecyltrimethylammonium, N-benzyldimethylammonium fluoride, N-dodecylammonium fluoride, N-dodecyltrimethylammonium, N-dodecylammonium fluoride, N-dodecyltrimethylammonium, and a, N- (2-carbocyclic hexyloxyethyl) -N-tetradecyldimethylammonium fluoride, N- (2-carbobenzyloxyethyl) -N-dodecyldimethylammonium fluoride, N- [2- - (N, N '-dimethylaminocarbonyl) -ethyl ] -N-dodecyldiethylammonium fluoride, N-carboxymethyl-N-eicosyldimethylammonium fluoride, olafluoro (N' -octadecyltrimethylenediamine-N, N, N '-tris (2-ethanol) dihydrofluoride), betaine hydrofluoride, sarcosine stannous fluoride, alanine stannous fluoride, glycine potassium fluoride, sarcosine potassium fluoride, glycine hydrofluoride, tetrapropylammonium tetrafluoroborate, tetrabutylammonium tetrafluoroborate, benzyltriethylammonium tetrafluoroborate, N-dodecyldimethylammonium fluoride, N- [2- (N, N' -dimethylaminocarbonyl) -ethyl ] -N-dodecyldimethylammonium fluoride, Ordofluoro-fluoro-N-methyl-N-eicosyldimethylammonium fluoride, Ordofluoro-fluoro-fluoride, Ordofluoro-N '-octadecyltrimethyldiaminodiaminodiaminodiaminodiaminomethylenediamine-N, N, N' -tris (2-ethanol) dihydrofluoride, betaine hydrofluoride, betaine, and betaine, N-tetradecylbetaine, N-tetramethylammonium, N-trimethyltetrafluoroborate, N, N, N-trimethylbetaine, N-N, Lysine hydrofluoride, alanine hydrofluoride, betaine zirconium fluoride, and mixtures thereof. In some embodiments, the organofluoride source can include tetrapropylammonium tetrafluoroborate, tetrabutylammonium tetrafluoroborate, benzyltriethylammonium tetrafluoroborate, or combinations thereof.

The fluoride source (if present) may be present in the dental paste in an amount sufficient to release between about 200ppm and 6,000ppm of fluoride ions, in some embodiments between about 800ppm and about 1,500ppm of fluoride ions or between about 2,500ppm and about 5,000ppm of fluoride ions. In some dental pastes intended for in-office procedures, the fluoride source is present in an amount sufficient to release between about 10,000 and 23,000ppm of fluoride ions. The fluoride source may be present in the dental paste in about 0.001 wt% to about 5 wt%, based on the total weight of the dental paste. It is to be understood that combinations of fluoride sources may be used. The fluoride source may be dissolved, dispersed, suspended or emulsified in the dental paste. In some embodiments, wherein the dental paste comprises a carrier, the fluoride source may be dissolved, dispersed, suspended, or emulsified in the carrier.

In some embodiments, the dental pastes of the present disclosure may include one or more antibacterial agents. Examples of suitable antimicrobial agents may include, but are not limited to, aldehydes (glutaraldehyde, phthalaldehyde), salts of phenols or acids, chlorhexidine or derivatives thereof (including acid adducts such as acetates, gluconates, chlorides, nitrates, sulfates, or carbonates), and combinations thereof.

Non-limiting examples of antimicrobial agents include: zinc salts, zinc oxide, tin salts, tin oxide, benzalkonium chloride, hexetidine, long chain alkylammonium or pyridinium salts (e.g., cetylpyridinium chloride, tetradecylpyridinium chloride), essential oils (e.g., thymol), furanones, chlorhexidine and salt forms thereof (e.g., chlorhexidine gluconate), sanguinarine, triclosan, stannous chloride, stannous fluoride, octenidine, nonionic or ionic surfactants (e.g., quaternary ammonium compounds), alcohols (monomers, polymers, monohydric alcohols, polyhydric alcohols), aromatic alcohols (e.g., phenol)), antimicrobial peptides (e.g., histamines), bacteriocins (e.g., nisin), antibiotics (e.g., tetracycline), aldehydes (e.g., glutaraldehyde), inorganic and organic acids (e.g., benzoic acid, salicylic acid, fatty acids, etc.) or salts thereof, derivatives of such acids as esters (e.g., parabens or other parabens, glycerol esters of fatty acids such as dihydroxypropyl dodecanoate), silver compounds, silver salts, silver nanoparticles, peroxides (e.g., hydrogen peroxide), and combinations thereof. The antibacterial agent may be dissolved, dispersed, suspended or emulsified in the dental paste. In some embodiments, wherein the dental paste comprises a carrier, the antibacterial agent may be dissolved, dispersed, suspended, or emulsified in the carrier. In other embodiments, the dental paste is free of an antibacterial agent.

The dental pastes of the present disclosure may comprise one or more inorganic or natural or synthetic thickening or gelling agents. Optionally, the one or more thickening agents are present in a total amount of about 0.01 to about 15, in some embodiments about 0.1 to about 10, in some embodiments about 0.10 to about 5, in some embodiments about 0.2 to about 5, and in some embodiments, about 0.2 to about 1 weight percent, based on the total weight of the dental paste. In some embodiments, the proportion of thickener in the dental paste is sufficient to form an extrudable shape-retaining product that can be squeezed from the tube onto the toothbrush and does not fall between the bristles of the brush, but substantially retains its shape thereon. In some embodiments, the thickening agent is sufficient to minimize the sputtering of the dental paste if, for example, a rotary polishing device (such as a prophy cup) is used during the polishing or cleaning procedure. In some embodiments, the dental pastes of the present disclosure may include at least one thickening agent, which may be used, for example, to impart a desired consistency and/or mouthfeel to the dental paste.

Any orally acceptable thickening agent can be used. Suitable thickening or gelling agents that may be used in the dental pastes of the present disclosure include amorphous silica (e.g., available from qiubo Corporation under the tradename ZEODENT 165), fumed silica, precipitated silica, colloidal silica, natural and synthetic gums and colloids, poloxamers, carbomers (also known as carboxyvinyl polymers), carrageenans, irish moss, iota-carrageenan, cellulosic polymers such as hydroxyethylcellulose, carboxymethylcellulose (carboxymethylcellulose, cellulose gum) and their salts, e.g., sodium carboxymethylcellulose, natural gums such as karaya, xanthan gum, gum arabic, tragacanth gum, polyvinylpyrrolidone, agar, colloidal magnesium aluminum silicate, and combinations thereof. One or more thickening agents are optionally present in a total amount of about 0.01 wt% to about 15 wt%, for example about 0.1 wt% to about 10 wt% or about 0.2 wt% to about 5 wt%, based on the total weight of the dental paste. The thickening or gelling agent may be dissolved, dispersed, suspended or emulsified in the dental paste. In some embodiments, where the dental paste comprises a carrier, the thickening or gelling agent may be dissolved, dispersed, suspended, or emulsified in the carrier.

In some embodiments, the dental pastes of the present disclosure may include a buffer or a buffer system or a plurality of buffers or systems. Examples of suitable buffers include phosphate buffers as further described in U.S. patent No. 9,149,661(Pilch et al), which is incorporated herein by reference in its entirety. The buffer or buffer system may be dissolved, dispersed, suspended or emulsified in the dental paste. In some embodiments, where the dental paste comprises a carrier, the buffer or buffer system may be dissolved, dispersed, suspended, or emulsified in the carrier.

In some embodiments, the dental pastes of the present disclosure may comprise a colorant or colorants. The colorant can be any dye or pigment. The colorant may be dissolved, dispersed, suspended or emulsified in the dental paste. In some embodiments, wherein the dental paste comprises a carrier, the colorant may be dissolved, dispersed, suspended, or emulsified in the carrier.

In some embodiments, the dental pastes of the present disclosure may comprise a desensitizing agent or agents. Desensitizing agent can be used for preventing and treating dentin hypersensitivity. Examples of desensitizing agents include, but are not limited to, tubule blocking agents, nerve desensitizing agents, and combinations thereof. Examples of desensitizing agents also include, but are not limited to, strontium salts (e.g., strontium chloride, strontium acetate, and/or strontium nitrate), potassium salts (e.g., potassium citrate, potassium chloride, potassium bicarbonate, potassium gluconate, and/or potassium nitrate), stannous fluoride; basic amino acids in free or salt form (e.g., arginine, lysine, citrulline, ornithine, creatine, histidine, diaminobutyric acid, and/or diaminopropionic acid, and salts thereof), and combinations thereof. The desensitizing agent may be dissolved, dispersed, suspended or emulsified in the dental paste. In some embodiments, where the dental paste comprises a carrier, the desensitizing agent may be dissolved, dispersed, suspended, or emulsified in the carrier.

In some embodiments, a dental paste of the present disclosure can include a therapeutic agent or agents. Such therapeutic agents may be additives with therapeutic properties. The therapeutic properties can include, for example, antiplaque activity, anticaries activity, or antimicrobial (e.g., antibacterial) activity. In some embodiments, the therapeutic agent may have biofilm inhibiting or biofilm disrupting activity. The therapeutic agent may be dissolved, dispersed, suspended or emulsified in the dental paste. In some embodiments, where the dental paste comprises a carrier, the therapeutic agent may be dissolved, dispersed, suspended, or emulsified in the carrier.

In some embodiments, the dental pastes of the present disclosure may include a binder or binders. The binder may provide a reservoir of the compound of formula I in the oral cavity of the subject. The compound of formula I may be released from the binder. The binder can hold the compound of formula I on or near a surface in the oral cavity of a subject such that, for example, the surface can be exposed to the compound. The surface may be a hard surface, for example, comprising teeth. The surface may be a dental restoration. Examples of suitable binders are described in U.S. patent No. 8,968,709(Yang et al), which is incorporated herein by reference in its entirety.

Dental pastes may have forms including solutions, dispersions, suspensions, emulsions, solids, pastes, foams or gels. In some embodiments, the dental paste is a toothpaste. In some embodiments, the dental paste is a dentifrice paste. Any component of the dental paste may be dissolved, dispersed, suspended, or emulsified in any other component of the dental paste. In some embodiments, one or more of the components are miscible (i.e., miscible with each other).

In some embodiments, the dental paste is provided in a single part or phase. In other embodiments, the dental paste includes both a first part and a second part that are separately retained prior to mixing at the time of use. Holding the first and second parts separately only requires that the parts be held in a manner that substantially prevents one part of the dental paste from interacting with another part of the dental paste. Where one or more incompatible ingredients (components) are included in the dental paste, a two-part dental paste may be employed. For example, if the dental paste comprises two incompatible active ingredients, it may be advantageous to keep them separately. The disclosed compositions may have varying properties. In some embodiments, the disclosed compositions can be described by their pH, their viscosity, their stability, various other characteristics, or combinations thereof.

In some embodiments, the disclosed compositions can have a pH that is acceptable for use, for example, in the oral cavity of a human. In some embodiments, the disclosed compositions can have a pH of, for example, 4.5 to 9.5. In some embodiments, the pH of the composition may be in a more neutral range, e.g., 5.0-8.5 or 5.5-8.5, as a patient with dry mouth may have a higher sensitivity to pH. The composition may naturally have such a pH, or may be buffered to have a pH in a useful, e.g., "neutral," range.

In some embodiments, the disclosed compositions can have a viscosity that makes them useful as, or deliverable as, sprayable compositions. The composition can be sprayable, for example, via a non-pressurized dispenser or a pressurized pump dispenser. In some embodiments, the disclosed compositions can have a viscosity of no greater than 80,000 centipoise (cps), no greater than 50,000cps, no greater than 20,000cps, or no greater than 10,000 cps. In some embodiments, the disclosed compositions may have more desirable rheological properties that make them less shear thinning. In some embodiments, the less shear-thinning composition has a more widely dispersed spray pattern when delivered in a non-pressurized dispenser.

In some embodiments, the disclosed compositions can have desirable stability characteristics. The stability of the composition can include microbial stability, physical stability, or a combination thereof. In some embodiments, the disclosed compositions are microbiologically stable for at least 6 months, in some embodiments for 1 year, in some embodiments for greater than 2 years.

In some embodiments, the disclosed compositions are capable of preventing, inhibiting, disrupting the formation or maintenance of a biofilm in an area in contact with the composition. The area of contact may be in vivo or in vitro. In some embodiments, the composition can prevent, inhibit, disrupt the formation or maintenance of biofilm in the mouth when the composition is applied to the mouth of a user (e.g., by spraying the composition into the mouth) when compared to the mouth without the composition applied. In some embodiments, the composition can prevent, inhibit, disrupt the formation or maintenance of a biofilm in a container in which the biofilm is present when compared to a container to which the composition is not applied, and the composition is applied to the container by pouring, spraying, or the like. Prevention, inhibition, disruption, or some combination thereof of biofilm formation or maintenance can be measured using a modified version of the MBEC assay (described in ASTM E2799-12), which measures disruption of streptococcus mutans biofilms grown on special spikes in microtiter plates. Biofilms grown on the pins were treated by periodic immersion in the test material, followed by washing in saliva and water. By measuring the amount of fluorescently labeled bacteria that elute from the staples at the end of the treatment cycle, the biofilm remaining on each staple after treatment can be quantified (see examples). In some embodiments, the disclosed compositions can affect the accumulation of plaque in the area contacted with the composition. The area of contact may be in vivo or in vitro. In some embodiments, the composition can reduce plaque accumulation on at least one tooth in the mouth when the composition is applied to the mouth of a user (e.g., by spraying the composition into the mouth) when compared to the mouth without the composition applied. In some embodiments, the composition can reduce the accumulation of plaque in containers in which plaque can form when compared to containers in which the composition is not applied, and the composition is applied to the container by pouring, spraying, or the like. Reduced plaque accumulation can be measured by a variety of in vivo methods, including, for example, plaque nicking, plaque staining, and the like.

In another aspect, the present disclosure provides a method of treating a surface in an oral cavity of a subject, the method comprising the steps of: (a) providing any of the dental pastes disclosed herein, and (b) applying the dental paste to a surface in the oral cavity of a subject. Surfaces in the oral cavity of a subject include, for example, buccal surfaces, gingival surfaces, teeth, dental restorations, and bones. In some embodiments, the surface is a hard surface, for example a tooth surface (including active surfaces, such as enamel and/or dentin, and inactive surfaces, such as the surface of a dental restoration). The dental paste can be applied to the oral cavity of a subject by, for example, brushing (e.g., brushing), polishing, wiping, or a combination thereof. The surfaces to which the dental paste is applied in the oral cavity may also include polishing surfaces, such as polishing the surfaces of teeth. While polishing surfaces can occur during brushing (e.g., regular brushing at home), polishing can be performed during a tooth prophylaxis procedure, such as by a dental professional (e.g., dental hygienist) in a clinical setting. The subject may be a human, or the subject may be a non-human animal. Non-human animals include mammals such as canines and felines. The toothpastes of the present disclosure can be used to inhibit biofilm formation, for example on surfaces in the oral cavity of a subject. Thus, in another aspect, the present disclosure also provides a method of treating a surface in the oral cavity of a subject, the method comprising the steps of: (a) providing any of the dental pastes disclosed herein, and (b) applying the dental paste to a surface in the oral cavity of a subject. The surface in the subject's mouth and the manner of application of the dental paste may be any of those previously described.

In some embodiments, the disclosed compositions can affect loss of hydration in the area in contact with the composition. The area of contact may be in vivo or in vitro. In some embodiments, the composition can reduce hydration loss in the mouth where the composition is applied to the mouth of a user (e.g., by spraying the composition into the mouth) when compared to the mouth without the composition applied. In some embodiments, the composition can reduce loss of hydration from tissues where hydration may be lost when compared to tissues without the composition applied, and the composition is applied to the tissues by pouring, spraying, or the like. Hydration loss can be measured by exposing a uniform sized treated tissue to a controlled 37 ℃ environment for a set period of time (4 hours) and recording the weight% loss of the treated tissue sample. The treated tissue was then exposed to elevated temperatures to remove all water in the sample (95 ℃/4 hours and 115 ℃/4 hours). The water loss at 4 hours was divided by the total water loss (after the 115 ℃ step) and represents the water lost from the tissue at 4 hours. In some embodiments, the disclosed compositions can affect less than 65% water loss or less than 60% water loss.

In some embodiments, the disclosed compositions can affect the lubricity or lubricity of a region in contact with the composition. The area of contact may be in vivo or in vitro. In some embodiments, the composition can maintain or increase the lubricating ability in the mouth when the composition is applied to the user's mouth (e.g., by spraying the composition into the mouth) when compared to the mouth without the composition applied. In some embodiments, the composition may, for example, provide the same degree of lubricating properties to the mouth as saliva can provide. In some embodiments, the composition may maintain or increase the lubricating ability on a substrate where lubricating ability may be lost when compared to a substrate without the composition applied, and the composition is applied to the substrate by pouring, spraying, or the like. The ability to lubricate or provide lubricating properties can be measured by the coefficient of friction against a suitable substrate. A low coefficient of friction (compared to saliva) is desired.

Also disclosed herein are methods of using the disclosed compositions. The disclosed methods can comprise contacting the oral cavity or oral tissue with the disclosed compositions. The step of contacting the oral cavity or oral tissue can be accomplished by applying the composition in any manner, such as spraying. The disclosed methods can be used to prevent, inhibit, disrupt, or any combination thereof, the formation or maintenance of a biofilm in a region in contact with a composition; for affecting hydration loss in areas contacted with the composition; for influencing the lubricity or lubricity of the area in contact with the composition.

Unless defined otherwise, all scientific and technical terms used herein have the same meaning as commonly understood in the art. The definitions provided herein will facilitate understanding of certain terms used frequently herein and are not meant to limit the scope of the present disclosure.

"paste" refers to a substance that behaves as a solid until a sufficient load or stress is applied thereto, but flows like a liquid when a sufficient load or stress is applied thereto. Pastes may include suspensions of solids in a background fluid or carrier. Pastes can be classified according to their viscosity or their consistency.

The term "dental paste" refers to a paste for use in the oral cavity of a subject.

The term "toothpaste" refers to a type of dental paste used as a cleanser for regular individual care, such as by daily brushing. The toothpaste can be used as a preventive measure against dental caries, gingivitis or periodontitis.

The term "prophylaxis paste" (or more simply, "dentifrice paste") refers to a type of dental paste used by a dental professional, such as a dentist or dental hygienist, to remove adherent deposits, such as stains, plaque or tartar, which can adhere to hard surfaces in the oral cavity of a subject. Such adherent deposits may not be completely removed during regular brushing. The dentifrice paste may be used on a rotating dentifrice paste holder known as a "prophy cup" (or more simply, a "prophy cup"). The dentifrice paste may also be applied with a brush, such as a rotating brush. Commercially available dentifrice pastes may have different viscosities than commercially available toothpastes.

The term "treating" refers to preventing, ameliorating, treating, ameliorating, or curing a disease or disorder.

The term "biofilm" refers to a substrate comprising bacteria. Along with bacteria, the biofilm in the oral cavity of a subject may also include epithelial cells, leukocytes, macrophages, and other oral exudates.

The term "biofilm inhibition" refers to limiting the formation or growth of a biofilm.

The term "hard surface" refers to a surface in the oral cavity of a subject, including hard materials such as bone, enamel, dentin, and dental restorations.

The term "dental restoration" refers to fillings, inlays, onlays, veneers, temporary and permanent crowns or bridges, implants or orthodontic devices and appliances such as brackets or archwires.

The term "alkyl" refers to a monovalent group that is a radical of an alkane, which is a saturated hydrocarbon. The alkylene group can be linear, cyclic, or a combination thereof, and can have 1 to 20 carbon atoms. In some embodiments, the alkyl group contains 1 to 18, 1 to 12, 1 to 10, 1 to 8, 1 to 6, or 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, cyclohexyl, n-heptyl, n-octyl, and ethylhexyl.

The terms "room temperature" and "ambient temperature" are used interchangeably and mean a temperature in the range of 20 ℃ to 25 ℃.

As used in this specification and the appended claims, the singular forms "a", "an", and "the" encompass embodiments having plural referents, unless the content clearly dictates otherwise.

As used in this specification and the appended claims, the term "or" is generally employed in its sense including "and/or" unless the content clearly dictates otherwise. The term "and/or" means one or all of the listed elements or a combination of any two or more of the listed elements.

As used herein, "having," including, "" comprising, "and the like are used in their open sense and generally mean" including, but not limited to. It is to be understood that "consisting essentially of … …", "consisting of … …", and the like are encompassed by "comprising" and the like. For example, a composition "comprising" silver can be a composition "consisting of" or "consisting essentially of" silver.

As used herein, when "consisting essentially of … …" refers to a composition, device, system, method, etc., it is meant that the elements of such composition, device, system, method, etc., are limited to the enumerated elements and any other elements that do not materially affect the basic and novel characteristics of such composition, device, system, method, etc.

The words "preferred" and "preferably" refer to embodiments that may provide certain benefits under certain circumstances. However, other embodiments may also be preferred, under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, and is not intended to exclude other embodiments from the scope of the disclosure, including the claims.

Also herein, the recitation of numerical ranges by endpoints includes all numbers subsumed within that range (e.g. 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4,5, etc. or 10 or less, includes 10, 9.4, 7.6, 5, 4.3, 2.9, 1.62, 0.3, etc.). When a range of values is "up to" a particular value, that value is included in the range.

The use of "first," "second," etc. in the foregoing description and in the following claims is not necessarily intended to indicate that an enumerated number of objects exist. For example, a "second" substrate is only intended to be distinguished from another substrate (such as a "first" substrate). The use of "first", "second" in the description above and in the claims that follow is also not necessarily intended to mean that one is earlier in time than the other.

Exemplary articles and techniques according to the present disclosure are illustrated by the following non-limiting examples.

Examples

TABLE 1 materials

As used herein, all parts and percentages are by weight, all water is deionized water ("DI water"), and all molecular weights are average molecular weights, unless otherwise specified.

MBEC biofilm disruption assay procedure：

The assay utilizes a high throughput MBEC assay system (Innovotech, AB Canada), to assess the efficacy of treatment in disrupting biofilms by quantifying the amount of fluorescently labeled biofilm that remains on MBEC inoculator pins after exposure to relevant treatment conditions. The assay is similar to ASTM E2799-12 (using MBEC)^TMAssays test standard methods of disinfection efficacy against pseudomonas aeruginosa biofilms), but modified for use with streptococcus mutans as the relevant organism, and modified protocols were used to expose the biofilm to the test material.

An overnight culture of Streptococcus mutans (ATCC 25175) was prepared by introducing a small volume of the frozen stock solution into 5mL Brain Heart Infusion (BHI) broth in a 15mL conical tube using a sterile inoculating loop. The cultures were grown at 37 deg.C (standing without shaking) for 12-16 hours. The density of overnight cultures (OD600) was estimated by turbidity measurements and was adjusted to 10,000MW (Molecular) in supplemented with 1% sucrose and 1 micromole per liter of ALEXA FLUOR 488 glucanPN/D22910) to an OD600 of 0.01 to obtain an appropriate volume of inoculum to fill the desired 96-well plate. Add 150 microliters of inoculum to the appropriate wells of a 96-well MBEC biofilm inoculator plate (Innovotech). Control wells for fluorescence readings were also filled with 150 microliters of Phosphate Buffered Saline (PBS) or bacteria-free medium consisting of BHI with 1% sucrose and 1 micromole per liter ALEXA FLUOR 488 dextran. MBEC inoculator lids (pins dipped into each well) were placed on the inoculation plate. Wrap the plate in parafilmAnd incubated in a sealed plastic container humidified by lining the bottom of the plastic container with a wet paper towel (37 ℃, shaken at 250 RPM). Biofilms were allowed to form on the spikes for 4 hours before exposure to the example formulations. In this modified assay, biofilms grown on the pins were exposed 3 times to the example formulation at 4, 7 and 24 hours post-inoculation during the assay. Exposure to the example formulations was performed as a treatment cycle with additional washing steps in artificial saliva and water. The treatment was performed by transferring the spikes into multiple 96-well plates filled with 150 microliters/well of the example formulation or 150 microliters/well of artificial saliva or water.

The process cycle steps (performed at 4, 7 and 24 hours) were:

1) exposure to test material for 1 minute (150. mu.L/well) -37 deg.C-shaking)

2) Exposure to sterile Water for 1 minute (200. mu.l/well) 37 ℃ C., shaking)

After rinsing with water, the spikes were placed back into a 96-well plate filled with growth medium (BHI broth with 1% sucrose and 1 micromole per liter ALEXA FLUOR 488 dextran-10,000 MW) and placed back into the incubator to allow additional biofilm growth until the next treatment or until the end of the final growth phase. After the last treatment exposure cycle (24 hours post inoculation), the spikes were incubated in growth medium for an additional 4 hours, then the MBEC spikes were transferred to a final wash plate for 1 minute (200 microliters of sterile water per well, shaking at 37 ℃ for final rinsing), then transferred to a 96-well black plate (suitable for fluorescence quantification in a plate reader) filled with 210 uL/well of 50U/mL dextranase in 0.2M acetate (ph5.5) (from Penicillum sp., SIGMA D4668-1 KU). The pins were incubated in the extraction solution wells by shaking at 37 ℃ for 30 minutes at 250 RPM. The plate was then placed in an ultrasonic water bath at room temperature for at least 1 hour to elute accumulated biofilm from the spikes into the dextranase/acetate solution. After sonication, the fluorescence in each well was read in a fluorescence plate reader (excitation 488nm, emission 525 nm). Each treatment was performed in 4-8 well replicates.

MBEC biofilmResults of destructive assay

Table 2 shows the average relative fluorescence readings for each example formulation treatment. A low value means a higher biofilm-disrupting activity than a high value. PERIDEX was used as a positive treatment control and was not expected to show biofilm accumulation. Glucosamine HCl enhances the biofilm disruption effect of MEGA-9, and in some cases, the effect is synergistic.

TABLE 2 comparative examples C1-C13 and examples Ex.1-Ex.4, formulations (weight percent) and MBEC biofilm test numbers According to

Microenvironment biofilm disruption test-procedure

A 1L stock solution of mucin-containing medium (MCM) supplemented with about 5 wt% sucrose was prepared as follows. 1g of Lab-Lemco beef extract powder (Thermo Fisher Scientific, Waltham, MA)), 2g of yeast extract powder (BD, Becton, Dickinson and Company, Franklin Lakes, N) from Franklin lake, Franklin, N) 5g of peptone (BD, U.S. from Franklin lake, N), 2.5g of porcine gastric mucin type III (Sigma-Aldrich, St.Louis, MO, St.) 0.35g of sodium chloride, 0.2g of calcium chloride dihydrate and 0.2g of potassium chloride were dissolved in 800 ml of deionized water. The pH was measured with a calibrated pH electrode (pH 6.9). An additional 100 ml of deionized water was added and the resulting solution was autoclaved at 121 ℃ for 15 minutes. After cooling to room temperature, 1.25 ml of filter-sterilized 40 w/v% aqueous urea solution was added, followed by 98.75 ml of autoclaved 50 w/v% aqueous sucrose solution.

Composite discs (10mm diameter x2.1mm thickness) segmented and polished to a final thickness of 2.0mm and having 1000 grit finish were used as biofilm-grown substrates from a commercially available dental mill stock (paradigm MZ100, available from 3M corp., st. paul, MN) from st paul, MN. Before use, the discs were sterilized in 75 v/v% ethanol for 45 to 60 minutes. The disks were cleaned for reuse by shaking them in 1% aqueous sodium hydroxide to remove biofilm growth, rinsed with water, and stored in 50% aqueous ethanol.

One sterilized composite plate was placed in each well of a sterile 24-well plate. Human saliva from a single healthy donor was mixed with MCM as saliva MCM 1: 4; 1.8 ml of this mixture was added to each well containing a disc. The 24-well plate was placed in an incubator at 37 ℃ and shaken (60rpm) for 4 hours. The plate was removed from the incubator, growth medium was removed, 1.8 ml of fresh MCM (without saliva) was added to each well, and the plate was then incubated at 37 ℃ for 4 hours with shaking. In the following, further medium exchange was performed using saliva-free MCM only.

The discs were then subjected to five treatment/growth cycles, as follows. The liquid is removed from the well via a pipette. 1.8 ml of the treatment solution was added to each well and then removed after 1 minute of disc exposure. Each dish was then rinsed with deionized water for 2 minutes, 1.8 ml MCM was added to each well, and the plates were incubated at 37 ℃ for 4 hours. For storage overnight under refrigeration, MCM is removed and replaced with phosphate buffered saline (PBS; also known as "Dulbecco A", described by Dulbecco & Vogt 1954, J.exp.Med.99, 167-182). The final medium change was performed two hours before the end of the test method.

On the fourth day, after the final treatment/growth cycle, the biofilm was collected with dry filter paper to determine the anhydrous biofilm mass for each disc. The disc with the grown biofilm was carefully transferred to a new 24-well plate filled with 1.0 ml of deionized water per well. Each tray was washed three times with 1.0 ml of deionized water for 1 minute with moderate shaking (approximately 400 rpm). After washing, the dish was carefully blotted dry on filter paper to remove excess liquid. The biofilm was then removed from the disks by wiping the surface of each disk with filter paper that had been dried overnight in a microcentrifuge tube at 70 ℃, and weighed to determine the total weight of the dry paper and the microcentrifuge tube. Each filter paper with wet biofilm was then placed back into the same microcentrifuge tube, dried at 70 ℃ overnight, and the biofilm mass was determined by weighing the dried biofilm, paper and microcentrifuge tube and subtracting the initial mass of tube and paper. The procedures of the microenvironment biofilm disruption test are summarized in table 3.

Table 3.

TABLE 4 toothpaste formulations (weight percent)

To prepare the test (treatment) solutions for use in the biofilm microenvironment test method, each of the toothpaste formulations in table 4 was mixed with DI water (toothpaste: DI water 1:3 by weight), the resulting mixture was centrifuged, and the supernatant aqueous layer was removed from the centrifuged mixture and used as the test solution. In the same manner, test solutions were prepared from commercially available toothpastes (high distillate all effect cleaning mint anti-caries fluoride and anti-gingivitis toothpaste containing 0.30% triclosan, "CTOT") by mixing with DI water (toothpaste: DI water 1:3 by weight), centrifuging the mixture, and recovering the supernatant for testing.

Table 5. microenvironment biofilm test data. Groups with the same letter are analyzed by one-way anova with Tukey t The test was Statistically Not Different (SND). StDev ═ standard deviation; number of replicates。

The data in table 5 show that toothpastes containing MEGA-9 alone (C15) or glucosamine alone (C16) showed little inhibition of biofilm growth, resulting in a biological quality similar to the negative control (DI water) and base toothpastes (C14). In contrast, the toothpaste comprising both MEGA-9 and glucosamine (example 5) provided significant inhibition of biofilm growth, similar to the commercially available antibacterial containing toothpaste total dew (CTOT).

Example ex.6: oral care aqueous solution

The aqueous formulations are shown in table 6. It can be used as collutory, spray, lozenge filler, etc. for treating xerostomia, halitosis, etc. Other additives may be incorporated for purposes such as anticaries, antiplaque, antigingivitis, antiallergic, etc.

TABLE 6 examples of aqueous oral formulations

Composition (I)	By weight%
		MEGA-9	0.4％
Glucosamine	1.0％
		Glycerol (Sibaiquan)	15.6％
Sucralose	0.0857％
		Hydroxyethyl cellulose	0.05％
Cetyl pyridinium chloride	0.05％
		K2HPO4	1.0712％
KH2PO4	0.5239％
		Xylitol, its preparation method and use	1.0％
Sorbitol (Sigma)	1.0％
		Erythritol and its preparation method	1.0％
Glycine	1.0％
		Arginine	1.0％
Spearmint flavoring agent	0.2％
		DI water	76％

Coefficient of friction program

The coefficient of friction was measured using a FORCEBOARD Universal Friction tester (Industrial Dynamics, Sweden AB) with a 10 Newton (N) load cell. Use of natural lamb skin condom (Trojan NATURALAMB) made of sheep caecum^TMLuxurious condom, Chelate Duway of you Ying, N.J. (Church)&Dwight co., inc. ewing, NJ)) to mimic the oral mucosal tissue. The condom was rinsed thoroughly and excess liquid removed before use and between measurements to ensure that no lubricant or test formulation remained to interfere with subsequent measurements. The condom was placed on a glass slide, smoothed to remove wrinkles, and then secured to a forcebook rub tester using a binder clip. 0.5 ml of the test solution was metered using a syringe onto the surface of the condom near the front (furthest from the motor) of the forcebird. The second layer of condom was then secured around the gloved finger and the covered finger was moved down the surface of the forcebird (towards the motor) while applying a target vertical force of 3N. This movement was repeated 6 times. The coefficient of friction (at a vertical force of 2.9 to 3.1N) was calculated by the FORCEBOARD Analyzer software (Industrial Dynamics, Sweden).

The results of the friction coefficient are shown in table 7. Low coefficient of friction values are smoother and therefore desirable properties for formulations used to treat xerostomia. The coefficient of friction of example 19 is less than that of water.

TABLE 7 coefficient of friction results。

	Average coefficient of friction	Standard deviation of	N
				Deionized water	0.39	0.05	3
Example Ex.6	0.27	0.03	3

Illustrative embodiments：

1. A composition, comprising:

from 1 to 3 wt.% in total, based on the total weight of the composition, of glucosamine, derivatives of glucosamine, or combinations thereof; and

from 0.3% to 3% by weight in total, based on the total weight of the composition, of one or more surfactants of formula I:

HOCH₂-(CHOH)_n-CH₂NR¹R² (I)

wherein R is¹And R²Independently selected from hydrogen atom, alkyl group, C (O) R³And SO₂R⁴(ii) a Wherein R is³And R⁴Independently selected from alkyl groups, aryl groups and aralkyl groups; wherein n is an integer from about 2 to about 5.

2. The composition of embodiment 1, wherein R¹Is a hydrogen atom or C₁–C₂An alkyl group.

3. The composition of embodiment 2, wherein R³Is C_7-C₉An alkyl group.

4. The composition of embodiment 2, wherein R³Is C_8-An alkyl group.

5. The composition according to any one of embodiments 1 to 3, wherein n is 4.

6. The composition according to any one of embodiments 1 to 5, wherein R¹Is C₁An alkyl group; r³Is C₈An alkyl group; and n is 4.

7. The composition according to embodiment 1, wherein glucosamine, derivatives of glucosamine, or a composition thereof, collectively range from 1.5 to 2.5 weight percent based on the total weight of the composition.

8. The composition according to any of embodiments 1 or 2, wherein the derivative of glucosamine is selected from glucosamine sulfate, glucosamine hydrochloride, N-acetylglucosamine, or a combination thereof.

9. The composition according to any of embodiments 1 to 3, wherein the one or more surfactants of formula I total from 0.5% to 3% by weight, based on the total weight of the composition.

10. The composition according to any one of embodiments 1 to 3, wherein the one or more surfactants of formula I total from 0.5 wt% to 2.5 wt%, based on the total weight of the composition.

11. The composition according to any one of embodiments 1 to 10, further comprising water.

12. The composition of embodiment 11 wherein the composition is a mouthwash and the composition has from 60 to 98 weight percent water based on the total weight of the composition.

13. The composition of embodiment 12, wherein the composition has not less than 65 wt.% water, not less than 70 wt.% water, not less than 75 wt.% water, not less than 80 wt.% water, or not less than 85 wt.% water, based on the total weight of the composition.

14. The composition of embodiment 12, wherein the composition has no greater than 97 wt.% water, no greater than 95 wt.% water, no greater than 93 wt.% water, or no greater than 90 wt.% water, based on the total weight of the composition.

15. The composition of embodiment 11, wherein the composition is a toothpaste and the composition has from 5 to 65 wt% water, based on the total weight of the composition.

16. The composition of embodiment 15, wherein the composition has not less than 7 wt.% water, not less than 10 wt.% water, not less than 15 wt.% water, not less than 20 wt.% water, or not less than 25 wt.% water, based on the total weight of the composition.

17. The composition of embodiment 15, wherein the composition has no greater than 60 wt.% water, no greater than 55 wt.% water, or no greater than 50 wt.% water, based on the total weight of the composition.

18. The composition of embodiment 11, wherein the composition is a gel and the composition has from 10 to 95 weight percent water, based on the total weight of the composition.

19. The composition of embodiment 18, wherein the composition has not less than 15 wt.% water, not less than 20 wt.% water, not less than 30 wt.% water, not less than 40 wt.% water, or not less than 50 wt.% water, based on the total weight of the composition.

20. The composition of embodiment 18, wherein the composition has no greater than 90 wt.% water, no greater than 85 wt.% water, no greater than 80 wt.% water, no greater than 75 wt.% water, or no greater than 70 wt.% water, based on the total weight of the composition.

21. The composition of embodiment 11, wherein the composition is a rinse concentrate and the composition has from 5 to 65 weight percent water.

22. The composition of embodiment 21, wherein the composition has not less than 7 wt.% water, not less than 10 wt.% water, not less than 15 wt.% water, not less than 20 wt.% water, or not less than 25 wt.% water, based on the total weight of the composition.

23. The composition of embodiment 21, wherein the composition has no greater than 60 wt.% water, no greater than 55 wt.% water, or no greater than 50 wt.% water, based on the total weight of the composition.

24. The composition of embodiment 11, wherein the composition is a mouthwash and the composition is an emulsion having an aqueous phase and an oil phase.

25. The composition of embodiment 24, wherein the composition has from 70 to 95 weight percent aqueous phase, based on the total weight of the composition.

26. The composition of embodiment 24, wherein the composition has no less than 75% by weight aqueous phase or no less than 78% by weight aqueous phase, based on the total weight of the composition.

27. The composition of embodiment 24, wherein the composition has no greater than 92% by weight aqueous phase, no greater than 90% by weight aqueous phase, or no greater than 89.5% by weight aqueous phase.

28. The composition of embodiment 1, wherein the composition is a toothpaste and further comprises one or more dental abrasives.

29. The dental paste of embodiment 28 wherein the dental abrasive comprises at least one of silica, alumina, perlite, pumice, calcium carbonate, calcium pyrophosphate, dicalcium phosphate, tricalcium phosphate, sodium bicarbonate, glycine, and combinations thereof.

30. The composition according to any one of embodiments 1 to 29, further comprising at least one of: sweetening agents, humectants, mineral salts, remineralizing agents, anticaries agents, buffering components, flavoring agents, preservatives, or combinations thereof.

31. The composition according to any one of embodiments 1 to 30, further comprising arginine, glycine, or a combination thereof.

32. The composition of embodiment 31, wherein arginine, glycine, or a combination thereof is present in an amount of 0.2 to 3 weight percent, based on the total weight of the composition.

33. The composition of embodiment 31, wherein arginine, glycine, or a combination thereof is present in an amount of 0.25 to 2.5 weight percent based on the total weight of the composition.

34. The composition of embodiment 31, wherein arginine, glycine, or a combination thereof is present in an amount of 0.5 to 2 weight percent, based on the total weight of the composition.

35. The composition according to any one of embodiments 1 to 34, wherein the composition is capable of preventing, inhibiting, disrupting, or any combination thereof the formation or maintenance of a biofilm in a region in contact with the composition.

36. A method of preventing, inhibiting, disrupting, or any combination thereof, formation or maintenance of a biofilm in oral tissue, the method comprising:

contacting an oral tissue with the composition according to any one of embodiments 1 to 34.

37. A method of treating a surface in an oral cavity of a subject, the method comprising:

(a) providing a composition according to any one of embodiments 1 to 34; and

(b) the composition is applied to a surface in the oral cavity of a subject.

38. The method of embodiment 37, wherein the surface is a hard surface.

39. The method of embodiment 37 or 38, wherein the surface is a surface of a tooth.

40. The method of any of embodiments 37-39, wherein the composition is a dental paste and applying the dental paste comprises brushing, wiping, or a combination thereof.

Thus, embodiments of oral compositions and methods of use are disclosed. The above-described embodiments and other embodiments are within the scope of the following claims. One skilled in the art will appreciate that the present disclosure can be practiced with embodiments other than those disclosed. The disclosed embodiments are presented for purposes of illustration only and not of limitation.