Oral care composition comprising a dicarboxylic acid

Abstract

Disclosed are oral care compositions comprising: a tooth ligand mixture comprising a monocarboxylic acid, a dicarboxylic acid, and / or a tetracarboxylic acid; and a stannous ion source and a fluoride ion source, such as stannous fluoride. The oral care compositions show the ability to prevent and / or treat dental erosion and / or dental caries.

Description

Technical Field

[0001] This invention relates to oral care compositions comprising stannous fluoride and monocarboxylic acids, dicarboxylic acids, tricarboxylic acids, tetracarboxylic acids, or combinations thereof, and their salts, which have an improved hydroxyapatite protective effect against citric acid irritation or improved fluoride uptake. The invention also relates to methods for treating and / or preventing acid erosion and / or dental caries, comprising instructing a user to apply an oral care composition comprising stannous fluoride and carboxylic acids to the oral cavity. Background Technology

[0002] Oral care compositions, such as toothpaste and / or dental cleaning compositions, are applied to the oral cavity to clean and / or maintain the aesthetics and / or health of teeth, gums, and / or tongue. Additionally, many oral care compositions are designed to deliver active ingredients directly to oral care surfaces. For example, toothpaste compositions may contain a stannous ion source. The stannous ion source can be deposited on the tooth surface to create an acid-resistant coating that helps teeth resist dissolution from dietary acids. It may also contain a fluoride source, which helps teeth resist pectin to prevent cavities. Stannous fluoride provides both stannous and fluoride ions for protecting teeth from the effects of dietary and pectin acids.

[0003] However, properly formulating stannous fluoride in oral care compositions can be challenging due to the reactivity of stannous fluoride with other components. Insufficient or overly stable stannous fluoride can reduce the availability of stannous ions to provide the desired benefits. For example, if the stannous fluoride is insufficient, it can react with other components of the oral care composition, such as silica, water, etc., which can reduce the amount of usable stannous ions. Additionally, when delivered to the oral cavity, the remaining insufficiently stable stannous fluoride can overreact with various oral surfaces, thereby hindering the action of other components or creating excess stains. In contrast, if the stannous fluoride is overly stable or the chelating agent-stannous fluoride interaction is too strong, the stannous ions will be unusable upon delivery to the oral cavity, which can also reduce the amount of bioavailable stannous ions that produce the desired beneficial effects of oral care.

[0004] Therefore, the stannous-chelating agent ratio and binding affinity must be carefully balanced to maximize the amount of available stannous ions. Consequently, there is a need for oral care compositions containing a high concentration of available stannous ions with optimal bioavailability for the desired product benefits. Summary of the Invention

[0005] This invention relates to an oral care composition comprising:

[0006] a) an oral care active substance, wherein the oral care active substance comprises a fluoride ion source and a stannous ion source; and

[0007] b) A tooth ligand mixture comprising:

[0008] i. a first polydentate ligand, wherein the first polydentate ligand is oxalic acid, its salt, or a combination thereof; and ii. a monodentate ligand, wherein the monodentate ligand is gluconic acid or its salt, or a combination thereof, and the molar ratio of the stannous ion disclosed in a) to the mixture of the dental ligands disclosed in bi) and bii) is in the range of 1:3 to 1:4, preferably 1:3 or 1:4; and / or

[0009] iii. A second polydentate ligand, wherein the second polydentate ligand comprises a tridentate ligand or a combination thereof, preferably wherein the second polydentate ligand comprises a tricarboxylic acid, a salt thereof, or a combination thereof.

[0010] The present invention also relates to an oral care composition comprising:

[0011] a) An oral care active substance, wherein the oral care active substance comprises a fluoride ion source and a stannous ion source, and

[0012] b) A multidentate ligand, wherein the multidentate ligand is a tetracarboxylic acid, preferably comprising ethylenediaminetetraacetic acid, ethylenetetracarboxylic acid, ethane-1,1,2,2-tetracarboxylic acid, or salts thereof, or combinations thereof; and

[0013] The ratio of stannous ions to the polydentate ligand is in the range of about 1:1 to about 1:2, preferably about 1:1.

[0014] The present invention also relates to an oral care composition wherein the pH of the composition is 4 to 5.

[0015] The present invention also relates to oral care compositions as disclosed herein for treating acid erosion, preventing acid erosion, treating dental caries, preventing dental caries, or combinations thereof.

[0016] In addition, a method for treating acid erosion, preventing acid erosion, treating dental caries, preventing dental caries, or combinations thereof, is disclosed, the method comprising:

[0017] a. Depositing an oral care composition as disclosed herein onto a suitable application device, wherein in one embodiment, the application device may be a toothbrush;

[0018] b. For example, by brushing teeth to apply the oral care composition of a) to the surface of the oral cavity;

[0019] c. Apply the oral care composition to the surface of the oral cavity for at least 2 minutes; and

[0020] d. Remove the oral care cavity composition from the oral care cavity by swallowing and optionally rinsing. Detailed Implementation

[0021] This invention relates to oral care compositions having a stannous-chelating agent and / or stannous-ligand ratio that produces an optimal composition with good bioavailability and storage stability. Therefore, this invention provides the beneficial effects of effectively reducing solubility in oral hard tissues and fluoride uptake, while increasing the soluble stannous content of the oral care composition throughout its shelf life. This achievement is made by discovering the optimal ratio of metal ligands that produces the desired stability and reactivity results.

[0022] The chelation effect assumes that complexes of polydentate ligands with metals are more stable than metal complexes of normalized monodentate ligands (e.g., 1 mole of bidentate ligands compared to 2 moles of similarly structured monodentate ligands) because the molar entropy of the bidentate chelate is lower than that of the monodentate complex.

[0023] While not wishing to be bound by theory, the use of conventional stabilizers (e.g., citrate anions) that thus favor the formation of metal-monodentate-polydentate complexes often leads to configurational limitations in the bonding geometry when metals form complexes in excess ligands and / or in mixed polydentate / monodentate solutions. The case of tin ions chelated by citrate anions is considered. Sn 2+ A tetrahedral bonding geometry is preferred. Due to spatial constraints, the tridentate citrate anion occupies only two of the four coordination sites with stannous in this geometry. Therefore, a monodentate ligand (e.g., gluconate) can join the complex at the third coordination site. The excess electron density (one electron from each of the three coordinated carboxylate anions minus the 2+ valence of stannous) is then distributed within the Sn-bonded orbitals to the fourth coordination site, which can acquire hydrogen-bonded water or hydrated hydrogen ions when in solution.

[0024] While not wishing to be bound by theory, if, conversely, in the previous example, the citrate ion is replaced by a tetradentate ligand and no monodentate ligand capable of occupying three coordination sites simultaneously with very high binding affinity is present, the metal chelate may be overly stable, leading to reduced Sn availability and loss of beneficial oral care effects. This is a direct consequence of the chelation effect. Additionally, if too few polydentate ligands are used in mixed or only polydentate cases, the metal complex is understability, also resulting in a loss of beneficial oral care effects. Due to the unique properties of stannous ions in solution (having a tetrahedral bonding geometry with a 2+ valence), and in the presence of mixed monodentate / polydentate ligands, Sn... 2+Mixed toothed complexes are preferred. This is because, although two polydentate ligands can form a chelate complex, the resulting electron density distribution is not favorable, thus providing an enthalpy penalty for complex formation.

[0025] In the case of metal complexes that are stable only at monodentate sites, there is no chelating effect, and the stabilizing ligand can be readily replaced by a chemical component with a higher binding affinity. This results in understressed tin in the composition, which loses formulation components (e.g., silica) over time. Therefore, unexpectedly, an optimal mixture of monodentate and polydentate coordinating ligands is required to properly stabilize the metal ion without impairing its reactivity. Therefore, the present invention relates to an oral care composition that provides an unexpectedly high amount of soluble tin throughout the entire shelf life of the oral care composition, while providing optimally reactive tin capable of providing the beneficial oral care effects associated with tin without interfering with the activity of other resulting substances.

[0026] Finally, bidentate ligands are a special case because they sometimes behave as monodentate ligands and sometimes as polydentate ligands, depending on their size and the orientation / spacing between carboxylate anions on the central molecule (especially relative to the coordinating cation). The resulting properties of metal complexes containing monodentate, bidentate, and / or tripentate ligands vary depending on the nature of the bidentate ligands. Therefore, combining bidentate ligands that behave like monodentate ligands with bidentate ligands that behave like polydentate ligands can effectively stabilize tin.

[0027] definition

[0028] To more clearly define the terms used herein, the following definitions are provided. Unless otherwise indicated, the following definitions apply to this disclosure. If a term is used in this disclosure but is not specifically defined herein, the definition from IUPAC Compendium of Chemical Terminology, 2nd Edition (1997) may be applied, provided that the definition does not conflict with any other disclosure or definition applied herein, or render any claim to which the definition is applied uncertain or unenforceable.

[0029] As used herein, the term "oral care composition" includes products that are not intended for systemic administration of a particular therapeutic agent during ordinary use, but rather to remain in the oral cavity for a sufficient duration to contact the tooth surface or oral tissues. Examples of oral care compositions include dental floss, toothpaste, teething gel, subgingival gel, lotion, mouthwash, mousse, foam, oral spray, lozenges, chewing tablets, chewing gum, teeth whitening strips, dental floss and floss coatings, breath freshening soluble strips, unit-dose compositions, fiber compositions, or denture care or adhesive products. Oral care compositions may also be incorporated into strips or films for direct application or attachment to oral surfaces (such as teeth whitening strips). Examples of lotion compositions include the lotion composition of U.S. Patent No. 11,147,753, and clogging lotions, such as the clogging oil-in-water emulsion of U.S. Patent No. 11,096,874. Examples of unit-dose compositions include the unit-dose composition of U.S. Patent Application Publication No. 2019 / 0343732.

[0030] Unless otherwise specified, as used herein, the term "dental cleaning composition" includes dental or subgingival pastes, gels, or liquid formulations. A dental cleaning composition may be a monophasic composition or a combination of two or more individual dental cleaning compositions. A dental cleaning composition may be in any desired form, such as deep streaks, light streaks, multilayers, pastes surrounded by gels, or any combination thereof. In dental cleaning compositions comprising two or more individual dental cleaning compositions, each composition may be contained in a physically separate dispenser compartment and dispensed side-by-side.

[0031] The “active ingredients and other ingredients” used herein may be classified or described according to their cosmetic and / or therapeutic benefits or their assumed mode of action or function. However, it should be understood that in some cases, the active substances and other ingredients used herein may provide more than one cosmetic and / or therapeutic benefit or function, or act or function via more than one mode of action. Therefore, the classification herein is for convenience only and is not intended to limit the ingredients to the specific functions or activities listed. Oral care active substances, for example, exhibit cosmetic and / or therapeutic benefits for the oral cavity.

[0032] The term "orally acceptable carrier" includes one or more compatible solid or liquid excipients or diluents suitable for topical oral administration. As used herein, "compatible" means that the components of a composition can be mixed but do not interact with each other in a way that would significantly reduce the stability and / or efficacy of the composition. Carriers or excipients that can be used in embodiments of the present invention may include common and conventional components of mouthwashes or mouthwashes. Mouthwash or mouthwash carrier materials generally include, but are not limited to, one or more of water, alcohols, humectants, surfactants, and acceptability improvers such as flavoring agents, sweeteners, coloring agents, and / or cooling agents.

[0033] As used herein, the term “substantially free” means that the composition contains no more than 0.05%, preferably no more than 0.01%, and more preferably no more than 0.001% of the specified material on a total weight basis.

[0034] As used herein, the term "substantially free of" means that the indicated material is not intentionally added to the composition, or preferably is not present at an analytically detectable level. This means a composition in which the indicated material is present only as an impurity among other intentionally added materials.

[0035] The term “oral hygiene program” or “program” can be used to describe the use of two or more separate and distinct steps of oral health care, such as toothpaste, mouthwash, dental floss, toothpicks, sprays, rinsing devices, and massagers.

[0036] As used herein, the term "total water content" refers to both free water and water bound to other components in the oral care composition.

[0037] For the purposes of this description, the relevant molecular weight (MW) to be used is the relevant molecular weight of the material added during the preparation of the composition. For example, if the chelating agent is a citrate substance, it may be provided in the form of citric acid, sodium citrate, or virtually any other salt. The MW used is the MW of the specific salt or acid added to the composition, but any water of crystallization that may be present is ignored.

[0038] Unless otherwise stated, although compositions and methods are described herein by way of “comprising” various components or steps, compositions and methods may also “consist of essentially various components or steps” or “comprise various components or steps”.

[0039] As used in this article, the word "or" when used as a conjunction for two or more elements means including either the element alone or a combination of the elements; for example, X or Y means X or Y or both.

[0040] As used herein, the articles “an” and “a” are understood to mean one or more of the materials protected or described in the claims, such as “oral care composition” or “bleaching agent”.

[0041] Unless otherwise specified, all measurements mentioned herein were performed at approximately 23°C (i.e., room temperature).

[0042] Generally, the numbering scheme shown in the version of the periodic table published in Chemical and Engineering News, 63(5), 27, 1985, is used to indicate element groups. In some cases, the common name assigned to the group may be used to indicate the element group; for example, for alkali metals in group 1, for alkaline earth metals in group 2, and so on.

[0043] Several types of scopes are disclosed in respect of embodiments of the present invention. When any type of scope is disclosed or protected by claims, the purpose is to disclose or protect by claims every possible value that such scope can reasonably cover, including the endpoints of the scope and any sub-scopes and combinations thereof covered therein.

[0044] Oral care compositions may be in any suitable form, such as solid, liquid, powder, paste, or combinations thereof. Oral care compositions may be dental cleaning agents, teeth whitening gels, subgingival gels, mouthwashes, mousses, foams, oral sprays, lozenges, chewing tablets, chewing gum, teeth whitening strips, dental floss and floss coatings, breath freshening soluble strips, or denture care or adhesive products. Components of dental cleaning agent compositions may be incorporated into film, strip, foam, or fiber-based dental cleaning agent compositions.

[0045] Oral care compositions may contain a variety of active and inactive ingredients, such as, but not limited to, hops extract, dicarboxylic acid, tin ion source, calcium ion source, water, fluoride ion source, zinc ion source, one or more polyphosphates, humectants, surfactants, other ingredients, and any combination thereof, as described below. The following section headings are provided for organization and convenience only. In some cases, a compound may fall within one or more sections. For example, stannous fluoride may be a tin compound and / or a fluoride compound. Additionally, oxalic acid or a salt thereof may be a dicarboxylic acid, a polydentate ligand, and / or a whitening agent.

[0046] Dental ligands

[0047] The oral care compositions of the present invention comprise a mixture of dental ligands. This mixture may comprise a monodentate ligand, one or more multidentate ligands, or a combination thereof. For example, the mixture may comprise a monodentate ligand and a bidentate ligand, or the mixture may comprise a monodentate ligand and a tridentate ligand. Furthermore or alternatively, the mixture may comprise, for example, a first multidentate ligand and a second multidentate ligand, or the mixture may comprise a first multidentate ligand and a monodentate ligand, or the mixture may comprise a first multidentate ligand, a second multidentate ligand, and a monodentate ligand. Furthermore, the first multidentate ligand may be a bidentate ligand, and the second multidentate ligand may be a bidentate ligand, or the first multidentate ligand may be a bidentate ligand, and the second multidentate ligand may be a tridentate ligand. Furthermore or alternatively, the oral care compositions disclosed herein may comprise only one multidentate ligand, wherein the multidentate ligand is a tetradentate ligand, such as a tetracarboxylic acid.

[0048] Monodentate ligands

[0049] Oral care compositions may contain a monodentate ligand having a molecular weight (MW) of less than 1000 g / mol. The monodentate ligand has a single functional group capable of interacting with a central atom such as a tin ion. The monodentate ligand must be suitable for use in oral care compositions and may be included in oral care compositions listed on the FDA's Generally Recognized As Safe (GRAS) list or other suitable lists within the jurisdiction of concern.

[0050] As described herein, monodentate ligands may contain a single functional group capable of chelating, associating, and / or bonding with tin. Suitable functional groups capable of chelating, associating, and / or bonding with tin include carbonyl, amine, and other functional groups known to those skilled in the art. Suitable carbonyl functional groups may include carboxylic acids, esters, amides, or ketones.

[0051] Monodentate ligands may preferably contain a single carboxylic acid functional group. Suitable monodentate ligands containing carboxylic acids may include compounds having the formula R-COOH, where R is any organic structure. Suitable monodentate ligands containing carboxylic acids may also include aliphatic carboxylic acids, aromatic carboxylic acids, sugar acids, their salts, and / or combinations thereof.

[0052] Aliphatic carboxylic acids may contain a carboxylic acid functional group attached to a straight-chain hydrocarbon chain, a branched hydrocarbon chain, and / or a cyclic hydrocarbon molecule. Aliphatic carboxylic acids may be fully saturated or unsaturated and have one or more alkene and / or alkyne functional groups. Other functional groups may be present and bonded to the hydrocarbon chain, including halogenated variants of the hydrocarbon chain. Aliphatic carboxylic acids may also include hydroxy acids, which are organic compounds having an alcohol functional group at the α, β, or γ position relative to the carboxylic acid functional group. Suitable α-hydroxy acids include lactic acid and / or its salts.

[0053] Aromatic carboxylic acids may contain a carboxylic acid functional group attached to at least one aromatic functional group. Suitable aromatic carboxylic acid groups may include benzoic acid, salicylic acid, and / or combinations thereof.

[0054] Carboxylic acids may include formic acid, acetic acid, propionic acid, butyric acid, valeric acid, hexanoic acid, heptanoic acid, octanoic acid, ascorbic acid, benzoic acid, octanoic acid, cholic acid, glycine, alanine, valine, isoleucine, leucine, phenylalanine, linoleic acid, nicotinic acid, oleic acid, propionic acid, sorbic acid, stearic acid, gluconate, lactate, carbonate, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, their salts and / or combinations thereof.

[0055] The oral care composition may contain about 1% to about 7.5%, about 1.5% to about 5%, about 1.7% to about 4.0% of monodentate ligand anions by weight of the composition.

[0056] Multidentate ligands

[0057] Oral care compositions may contain polydentate ligands with a molecular weight (MW) of less than 1000 g / mol or less than 2500 g / mol. The polydentate ligands have at least two functional groups that can interact with a central atom such as a tin ion. Additionally, the polydentate ligands must be suitable for use in oral care compositions and may be included in oral care compositions listed on the FDA's Generally Recognized As Safe (GRAS) list or another suitable list within the jurisdiction of concern.

[0058] As described herein, polydentate ligands may contain at least two functional groups that can chelate, associate, and / or bond with tin. Polydentate ligands may include dipentate ligands (i.e., having two functional groups), tripentate ligands (i.e., having three functional groups), tetradentate ligands (i.e., having four functional groups), etc.

[0059] Suitable functional groups that can chelate, associate, and / or bond with tin include carbonyl, phosphate, nitrate, amine, and other functional groups known to those skilled in the art. Suitable carbonyl functional groups may include carboxylic acids, esters, amides, or ketones.

[0060] Polydentate ligands can contain two or more carboxylic acid functional groups. Suitable polydentate ligands containing carboxylic acids can include compounds having the formula HOOC-R-COOH, where R is any organic structure. Suitable polydentate ligands containing two or more carboxylic acids can also include dicarboxylic acids, tricarboxylic acids, tetracarboxylic acids, etc.

[0061] Polydentate ligands may include oxalic acid, malonic acid, methylmalonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, octanoic acid, azelaic acid, sebacic acid, undecanoic acid, dodecanoic acid, tridecanoic acid, hexadecanoic acid, nisine, phellogenic acid, equisetolic acid, maleic acid, malic acid, tartaric acid, phthalic acid, citric acid, isocitric acid, aconitic acid, propane-1,2,3-tricarboxylic acid, pyromellitic acid, ethylenediaminetetraacetic acid, their salts, and / or combinations thereof. For example, malonic acid and oxalic acid, malonic acid and citric acid, oxalic acid and citric acid, or tartaric acid and citric acid, or combinations thereof.

[0062] The oral care composition may contain about 1% to about 7.5%, about 1.5% to about 5%, about 1.7% to about 4.0% of the multidentate ligand anion by weight of the composition.

[0063] Dicarboxylic acid

[0064] Oral care compositions contain dicarboxylic acids. Dicarboxylic acids include compounds having two carboxylic acid functional groups. Dicarboxylic acids may include compounds defined by formula VIII-A, formula VIII-B, and / or formula VIII-C, or salts thereof.

[0065]

[0066] Formula VIII-A. dicarboxylic acid

[0067] R can be empty, alkyl, alkenyl, allyl, phenyl, benzyl, acetyl, aliphatic, aromatic, polyethylene glycol, polymer, O, N, P, or combinations thereof. R can also be further functionalized with one or more functional groups such as -OH, -NH2 and / or alkyl, alkenyl, aromatic, or combinations thereof.

[0068]

[0069] Formula VIII-B. dicarboxylic acid

[0070] R can be empty, alkyl, alkenyl, allyl, phenyl, benzyl, acetyl, aliphatic, aromatic, polyethylene glycol, polymer, O, N, P, or combinations thereof. R can also be further functionalized with one or more functional groups such as -OH, -NH2 and / or alkyl, alkenyl, aromatic, or combinations thereof.

[0071] X1 and X2 can be independently H, an alkali metal, an alkaline earth metal, a transition metal, or a combination thereof. Suitable alkali metals include lithium, sodium, potassium, or a combination thereof. Suitable alkaline earth metals include magnesium, calcium, barium, or a combination thereof. Suitable transition metals include titanium, chromium, iron, nickel, copper, zinc, tin, gold, silver, or a combination thereof.

[0072]

[0073] Formula VIII-C. dicarboxylic acid.

[0074] R1 can be empty, alkyl, alkenyl, allyl, phenyl, benzyl, acetyl, aliphatic, aromatic, polyethylene glycol, polymer, O, N, P, or combinations thereof. R can also be further functionalized with one or more functional groups such as -OH, -NH2 and / or alkyl, alkenyl, aromatic, or combinations thereof.

[0075] X1 and X2 can be independently H, an alkali metal, an alkaline earth metal, a transition metal, or a combination thereof. Suitable alkali metals include lithium, sodium, potassium, or a combination thereof. Suitable alkaline earth metals include magnesium, calcium, barium, or a combination thereof. Suitable transition metals include titanium, chromium, iron, nickel, copper, zinc, tin, gold, silver, or a combination thereof.

[0076] Dicarboxylic acids can be added to formulations as neutral acids (as shown in Formula VIII-A) or as monosalts of dicarboxylic acids (where one of the carboxylic acid functional groups is a salt and the other is neutral), disalts of dicarboxylic acids (where both carboxylic acid functional groups are salts), or combinations thereof. Furthermore, as is well known to those skilled in the art, whether one or both carboxylic acid functional groups of a dicarboxylic acid are neutral or charged in solution can be affected by the pH of the solution. For example, a neutral dicarboxylic acid can be added to an aqueous solution, and if the pH is below the pKa of the carboxylic acid functional groups, one or both protons from the two carboxylic acid functional groups can be removed, as shown in Formula VIII-D below.

[0077]

[0078] Acid-base properties of formula VIII-D. dicarboxylic acids, where M is any metal.

[0079] Dicarboxylic acids may include oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, octanoic acid, azelaic acid, sebacic acid, undecanoic acid, dodecanoic acid, tridecanoic acid, hexadecanoic acid, jasminoides, eurythic acid, malic acid, maleic acid, tartaric acid, phthalic acid, methylmalonic acid, dimethylmalonic acid, tartaric acid, hydroxymalonic acid, mesooxalic acid, dihydroxymalonic acid, dihydroxymalonic acid, fumaric acid, terephthalic acid, glutaric acid, their salts, or combinations thereof. Dicarboxylic acids may include suitable salts of dicarboxylic acids, such as, when a dicarboxylic acid includes a salt of oxalic acid: monoalkali metal oxalates, dialkali metal oxalates, monopotassium monohydrooxalate, dipotassium oxalate, monosodium monohydrooxalate, disodium oxalate, titanium oxalate, and / or other metal salts of oxalate. Dicarboxylic acids may also include hydrates of dicarboxylic acids and / or hydrates of salts of dicarboxylic acids.

[0080] Suitable dicarboxylic acid compounds include malonic acid, methylmalonic acid, hydroxymalonic acid, malic acid, maleic acid, dimethylmalonic acid, oxalic acid, dihydroxymalonic acid, oxalic acid, tartaric acid, their salts, or combinations thereof. These dicarboxylic acid compounds are particularly suitable because they have shown surprisingly high whitening benefits. While not wishing to be bound by theory, it is believed that certain dicarboxylic acid compounds have a surprisingly high affinity for certain cationic crosslinking agents in the colored matrix commonly present on the hard surfaces of the oral cavity, thereby leading to the removal of stains from the surface. Without being bound by theory, it is assumed that the whitening efficacy of dicarboxylic acids and their corresponding anions is driven by the ability of dicarboxylic acids to reach and remove chromophores and tooth surfaces, as well as cationic bridges between chromophores and epidermal proteins.

[0081] Suitable dicarboxylic acid compounds include dicarboxylic acids described by formula VIII-A, wherein R is a methylene or ethylene group that is absent or includes one or two substituents, and / or an acetyl group.

[0082] Fluorides

[0083] The oral care composition contains fluoride, which may be provided by a fluoride ion source. The fluoride ion source may contain one or more fluorine-containing compounds, such as stannous fluoride, sodium fluoride, titanium fluoride, calcium fluoride, calcium phosphate silicate fluoride, potassium fluoride, amine fluoride, sodium monofluorophosphate, zinc fluoride, and / or mixtures thereof.

[0084] The fluoride ion source and the tin ion source can be the same compound, such as stannous fluoride, which can generate tin ions and fluoride ions. Alternatively, the fluoride ion source and the tin ion source can be separate compounds, such as when the tin ion source is stannous chloride and the fluoride ion source is sodium monofluorophosphate or sodium fluoride.

[0085] The fluoride ion source and the zinc ion source can be the same compound, such as zinc fluoride, which can generate both zinc and fluoride ions. Alternatively, the fluoride ion source and the zinc ion source can be separate compounds, such as when the zinc ion source is zinc phosphate and the fluoride ion source is stannous fluoride.

[0086] The fluoride ion source may be substantially free of stannous fluoride or contain no stannous fluoride. Therefore, oral care compositions may contain sodium fluoride, potassium fluoride, amine fluoride, sodium monofluorophosphate, zinc fluoride, and / or mixtures thereof.

[0087] The oral care composition may contain a fluoride ion source capable of providing about 50 ppm to about 5000 ppm, and preferably about 500 ppm to about 3000 ppm, of free fluoride ions. To deliver the desired amount of fluoride ions, the fluoride ion source may be present in the oral care composition in an amount of about 0.0025% to about 5%, about 0.01% to about 5%, about 0.2% to about 1%, about 0.5% to about 1.5%, or about 0.3% to about 0.6% by weight of the oral care composition. Alternatively, the oral care composition may contain less than 0.1%, less than 0.01%, substantially no, substantially no, or no fluoride ion source.

[0088] Metal

[0089] Oral care compositions as described herein may contain a metal, which may be provided by a metal ion source comprising one or more metal ions. As described herein, the metal ion source may comprise a tin ion source and / or a zinc ion source, or other than a tin ion source and / or a zinc ion source. Suitable metal ion sources include compounds having metal ions, such as, but not limited to, Sn, Zn, K, Cu, Mn, Mg, Sr, Ti, Fe, Mo, B, Ba, Ce, Al, In, and / or mixtures thereof. The metal ion source may be any compound having a suitable metal and any associated ligands and / or anions.

[0090] Suitable ligands and / or anions that can pair with a metal ion source include, but are not limited to, acetate, ammonium sulfate, benzoate, bromide, borate, carbonate, chloride, citrate, gluconate, glycerophosphate, hydroxide, iodide, oxalate, oxides, propionate, D-lactate, DL-lactate, orthophosphate, pyrophosphate, sulfate, nitrate, tartrate, and / or mixtures thereof.

[0091] Oral care compositions may contain about 0.01% to about 10%, about 1% to about 5%, or about 0.5% to about 15% of a metal and / or metal ion source.

[0092] tin

[0093] The oral care composition according to an embodiment of the invention comprises tin, which may be provided by a tin ion source. The tin ion source may be any suitable compound that, when the oral care composition is applied to the oral cavity, provides tin ions in the oral care composition and / or delivers tin ions to the oral cavity. The tin ion source may comprise one or more tin-containing compounds, such as stannous fluoride, stannous chloride, stannous bromide, stannous iodide, stannous oxide, stannous oxalate, stannous sulfate, stannous sulfide, tin fluoride, stannous chloride, stannous bromide, stannous iodide, stannous sulfide, and / or mixtures thereof. The tin ion source may comprise stannous fluoride, stannous chloride, and / or mixtures thereof. The tin ion source may also be a fluorine-free tin ion source, such as stannous chloride.

[0094] The oral care composition may contain about 0.0025% to about 5%, about 0.01% to about 5%, about 0.2% to about 1%, about 0.4% to about 1%, or about 0.3% to about 0.6% of tin and / or a tin ion source by weight of the oral care composition.

[0095] Zinc

[0096] Oral care compositions may contain zinc, which may be provided by a zinc ion source. The zinc ion source may include one or more zinc-containing compounds, such as zinc fluoride, zinc lactate, zinc oxide, zinc phosphate, zinc chloride, zinc acetate, zinc hexafluorozirconate, zinc sulfate, zinc tartrate, zinc gluconate, zinc citrate, zinc malate, zinc glycinate, zinc pyrophosphate, zinc metaphosphate, zinc oxalate, and / or zinc carbonate. The zinc ion source may also be a fluoride-free zinc ion source, such as zinc phosphate, zinc oxide, and / or zinc citrate.

[0097] Zinc and / or a zinc ion source may be present in the total oral care composition in amounts of about 0.01% to about 10%, about 0.2% to about 1%, about 0.4% to about 1%, about 0.5% to about 1.5%, or about 0.3% to about 0.6% by weight of the oral care composition. Alternatively, the oral care composition may be substantially free of, substantially free of, or free of zinc.

[0098] Potassium

[0099] Oral care compositions may contain potassium, which may be provided by a potassium ion source. The potassium ion source may include one or more potassium-containing compounds, such as potassium nitrate, potassium fluoride, potassium chloride, or combinations thereof.

[0100] The oral care composition may contain about 0.01% to about 10%, about 0.2% to about 1%, about 0.4% to about 1%, or about 0.3% to about 0.6% of potassium and / or a potassium ion source by weight of the oral care composition. Alternatively, the oral care composition may be substantially free of, substantially free of, or free of potassium.

[0101] pH

[0102] The pH of the oral care compositions described herein may be from about 4 to about 6, from about 4.5 to about 5.5, from about 4 to less than 5.5, from about 4.5 to less than 5.5, from more than 4 to less than 5, from more than 4 to about 4.9, from about 4.9, from about 4 to about 5.4, from about 4 to about 5.3, from about 4 to about 5.2, from about 4 to about 5.1, from about 4 to about 5, from about 4 to about 4.9, from about 4 to about 4.8, or from about 4 to about 4.7. The pH of the mouthwash aqueous solution may be determined as the pH of the pure solution. The pH of the dental cleaning composition may be determined as the slurry pH, which is the pH of a mixture of the dental cleaning composition and water (such as a 1:4, 1:3, or 1:2 mixture of the dental cleaning composition and water).

[0103] If the oral care composition contains one or more dicarboxylic acids, the preferred pH is below about 7 or below about 6 due to the pKa of the dicarboxylic acids. While not wishing to be bound by theory, it is believed that dicarboxylic acids exhibit unique properties at pH below about 7, and particularly below about 6, but surfaces in the oral cavity may also be sensitive to low pH. Additionally, at pH values ​​above about 7, metal ion sources can react with water and / or hydroxide ions to form insoluble metal oxides and / or metal hydroxides. The formation of these insoluble compounds can limit the ability of dicarboxylic acids to stabilize metal ions in the oral care composition and / or can limit the interaction between dicarboxylic acids and target metal ions in the oral cavity. Furthermore, at pH values ​​below 4, the likelihood of demineralization increases significantly. Therefore, as described herein, oral care compositions containing dicarboxylic acids may preferably have a pH of about 4 to about 6, about 4 to about 5, about 4 to less than 5, about 4 to about 4.9, or about 4.5 to less than 5.5 to minimize the formation of metal hydroxides / metal oxides in the oral cavity and any increased demineralization.

[0104] As described herein, the pH of an oral care composition can be measured immediately after mixing, or after aging the composition by placing it under ambient temperature or accelerated temperature and humidity conditions, such as measuring pH for approximately 28 days or longer prior to measurement at temperatures of 25°C, 30°C and / or 40°C and relative humidity of 30%, 60% and / or 75%.

[0105] buffer

[0106] Oral care compositions may contain one or more buffers. As used herein, a buffer is a reagent that can be used to adjust the pH of the slurry in an oral care composition. These buffers include alkali metal hydroxides, carbonates, sesquicarbonates, borates, silicates, phosphates, imidazoles, and mixtures thereof. Specific buffers include monosodium phosphate, trisodium phosphate, sodium hydroxide, potassium hydroxide, alkali metal carbonates, sodium carbonate, imidazoles, pyrophosphates, citric acid, and sodium citrate. Oral care compositions may contain one or more buffers, each in an amount of about 0.1% to about 30%, about 1% to about 10%, or about 1.5% to about 3% by weight of the composition of the invention.

[0107] Oral acceptable carrier

[0108] In addition to the oral care active ingredients and components specified in detail herein, the oral care compositions disclosed herein may also contain an orally acceptable carrier. An orally acceptable carrier may include surfactants, thickeners, abrasives, humectants, water, and other ingredients.

[0109] surfactants

[0110] Oral care compositions may contain one or more surfactants. Surfactants can be used to make the composition more cosmetically acceptable. Surfactants are preferably detergency agents that impart detergency and foaming properties to the composition. Suitable surfactants are anionic, cationic, nonionic, amphoteric, amphoteric, and betaine surfactants in safe and effective amounts.

[0111] Suitable anionic surfactants include, for example, water-soluble salts of alkyl sulfates having 8 to 20 carbon atoms in the alkyl group and water-soluble salts of sulfonated monoglycerides of fatty acids having 8 to 20 carbon atoms. Examples of such anionic surfactants are sodium lauryl sulfate (SLS) and sodium coconut monoglyceride sulfonate. Other suitable anionic surfactants include sarcosine salts (such as sodium lauroyl sarcosine), taurine salts, sodium lauryl sulfoacetate, sodium lauroyl hydroxyethyl sulfonate, sodium lauryl polyoxyethylene ether carboxylate, and sodium dodecylbenzene sulfonate. Combinations of anionic surfactants may also be used.

[0112] The zwitterionic surfactants or amphoteric surfactants that can be used herein include derivatives of aliphatic quaternary ammonium, phosphonium, and sulfonium compounds, wherein the aliphatic group can be straight-chain or branched, and one of the aliphatic substituents contains 8 to 18 carbon atoms, and one of the aliphatic substituents contains an anionic water-solubilizing group, such as a carboxyl, sulfonate, sulfate, phosphate, or phosphonate group. Suitable betaine surfactants are disclosed in U.S. Patent No. 5,180,577. Typical alkyl dimethyl betaines include decyl betaine or 2-(N-decyl-N,N-dimethylamine) acetate, cocoyl betaine or 2-(N-cocoyl-N,N-dimethylamine) acetate, tetradecyl betaine, palmityl betaine, lauryl betaine, hexadecyl betaine, hexadecyl betaine, stearyl betaine, etc. Amide betaines can be exemplified by cocamidoethyl betaine, cocamidopropyl betaine (CADB), and lauramidopropyl betaine. Other suitable amphoteric surfactants include betaine, sulfobetaine, sodium lauryl amphoteric acetate, alkyl amphoteric diacetates, and / or combinations thereof.

[0113] Suitable cationic surfactants include, for example, quaternary ammonium compound derivatives having a long alkyl chain containing 8 to 18 carbon atoms, such as lauryltrimethylammonium chloride; cetylpyridinium chloride; hexadecyltrimethylammonium bromide; hexadecylpyridinium fluoride or combinations thereof.

[0114] Suitable nonionic surfactants include, for example, compounds prepared by the condensation of an alkylene group (which is inherently hydrophilic) with an organic hydrophobic compound, which may be aliphatic or alkyl aromatic in nature. Examples of suitable nonionic surfactants may include Pluronics. ® (i.e., poloxamer), alkylphenol polyoxyethylene condensates, products derived from the condensation of ethylene oxide with propylene oxide and ethylenediamine, fatty alcohol ethylene oxide condensates, long-chain tertiary amine oxides, long-chain tertiary phosphine oxides, long-chain dialkyl sulfoxides, and combinations thereof. Other suitable nonionic surfactants include alkyl glucosamides, alkyl glucosides, and / or combinations thereof.

[0115] The oral care composition may contain one or more surfactants, each surfactant being present in a concentration of about 0.01% to about 15%, about 0.3% to about 10%, or about 0.3% to about 2.5% by weight of the oral care composition.

[0116] Thickener

[0117] Oral care compositions may contain one or more thickeners. Thickeners may be used in oral care compositions to provide a gel-like structure that stabilizes the composition and prevents phase separation. Suitable thickeners include polysaccharides, polymers, and / or silica thickeners.

[0118] Thickeners may contain one or more polysaccharides. Some non-limiting examples of polysaccharides include starch; starch glycerol; gums such as carrageenan gum, tragacanth gum, gum arabic, solanum, xanthan gum, guar gum, and cellulose gum; magnesium aluminum silicate (colloidal magnesium aluminum silicate); carrageenan; sodium alginate; agar; pectin; gelatin; cellulose compounds such as cellulose, microcrystalline cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxymethyl carboxypropyl cellulose, methyl cellulose, ethyl cellulose, and sulfated cellulose; natural and synthetic clays, such as lithium montmorillonite clay; and mixtures thereof.

[0119] Other polysaccharides applicable to this document include carrageenan, gellan gum, locust bean gum, xanthan gum, carbomer, poloxamer, modified cellulose, and mixtures thereof. Carrageenan is a polysaccharide derived from seaweed. Several types of carrageenan exist, which can be distinguished by their seaweed origin and / or by their degree and position of sulfation. Thickeners may include κ-carrageenan, modified κ-carrageenan, ι-carrageenan, modified ι-carrageenan, λ-carrageenan, and mixtures thereof. Carrageenan applicable to this document includes those commercially available under the series name "Viscarin" from FMC Company, including but not limited to Viscarin TP 329, Viscarin TP 388, and Viscarin TP 389.

[0120] The thickener may comprise one or more polymers. The polymer may be polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), polyacrylic acid, a polymer derived from at least one acrylic acid monomer, a copolymer of maleic anhydride and methyl vinyl ether, or a crosslinked polyacrylic acid polymer having various weight percentages and a wide range of average molecular ranges in the oral care composition. Alternatively, the oral care composition may be free of, substantially free of, or substantially free of copolymers of maleic anhydride and methyl vinyl ether. The polymer may include a polyacrylate crosslinker, such as polyacrylate crosslinker-6. Suitable sources of polyacrylate crosslinker-6 may include Sepimach Zen, commercially available from Seppic. ™ .

[0121] Thickeners may include inorganic thickeners. Some non-limiting examples of suitable inorganic thickeners include colloidal magnesium aluminum silicate and silica thickeners. Non-limiting examples of silica thickeners that may be used include, for example, amorphous precipitated silica, such as ZEODENT. ® 165% silica. Other non-limiting silica thickeners include ZEODENT. ®153, 163, and 167, and ZEOFREE ® 177 and 265 silica products (both purchased from Evonik Corporation) and AEROSIL ® Pyrolytic silicon dioxide.

[0122] Oral care compositions may contain one or more thickeners in amounts of 0.01% to about 15%, 0.1% to about 10%, about 0.2% to about 5%, or about 0.5% to about 2%.

[0123] friction agent

[0124] The oral care composition of embodiments of the present invention may include an abrasive. The abrasive may be added to the oral care formulation to help remove surface stains on the teeth. The oral care formulation may include calcium abrasives and / or non-calcium abrasives, such as silica abrasives.

[0125] Oral care compositions may contain calcium abrasives. The calcium abrasive may be any suitable abrasive compound that, when applied to the oral cavity, provides and / or delivers calcium ions into the oral cavity. Oral care compositions may contain about 5% to about 70%, about 10% to about 60%, about 20% to about 50%, about 25% to about 40%, or about 1% to about 50% of calcium abrasives. The calcium abrasive may contain one or more calcium abrasive compounds, such as calcium carbonate, precipitated calcium carbonate (PCC), ground calcium carbonate (GCC), chalk, dicalcium phosphate, calcium pyrophosphate, and / or mixtures thereof.

[0126] Oral care compositions may contain non-calcium abrasives, such as bentonite, silica gel (alone and of any structure), precipitated silica, amorphous precipitated silica (alone and also of any structure), silica hydrate, perlite, titanium dioxide, calcium pyrophosphate, calcium hydrogen phosphate dihydrate, alumina, alumina hydrate, calcined alumina, aluminum silicate, insoluble sodium metaphosphate, insoluble potassium metaphosphate, insoluble magnesium carbonate, zirconium silicate, particulate thermosetting resins, and other suitable abrasive materials. Such materials may be incorporated into oral care compositions to tailor the polishing properties of the targeted dental cleaning formulation. Oral care compositions may contain approximately 5% to approximately 70%, approximately 10% to approximately 50%, approximately 10% to approximately 60%, approximately 20% to approximately 50%, approximately 25% to approximately 40%, or approximately 1% to approximately 50% of the non-calcium abrasives by weight of the oral care composition.

[0127] Alternatively, the oral care composition may be substantially free of, substantially free of, substantially free of, or free of silica, alumina, or any other non-calcium abrasive. The oral care composition may contain less than about 5%, less than about 1%, less than about 0.5%, less than about 0.1%, or 0% of non-calcium abrasives, such as silica and / or alumina.

[0128] Oral care compositions may also contain silica abrasives, such as silica gel (in its own form or of any structure), precipitated silica, amorphous precipitated silica (in its own form or of any structure), silica hydrates, and / or combinations thereof. Oral care compositions may contain about 5% to about 70%, about 10% to about 60%, about 10% to about 50%, about 20% to about 50%, about 25% to about 40%, or about 1% to about 50% of silica abrasives.

[0129] When an oral care composition contains dicarboxylic acid, the composition may include a low amount of abrasive or contain no abrasive, because dicarboxylic acid can provide sufficiently high whitening benefits without the need for abrasive.

[0130] While mouthwash compositions typically do not contain abrasives, dental cleaning compositions typically do. However, the dental cleaning compositions and / or toothpaste compositions of embodiments of the present invention may contain low amounts of abrasives or none at all. Therefore, oral care compositions or dental cleaning compositions may contain less than about 5%, about 0.5% to about 2%, or less than about 2% of abrasives by weight of the composition. Oral care compositions or dental cleaning compositions may also be substantially free of, substantially free of, or contain no abrasives.

[0131] wetting agent

[0132] Oral care compositions may contain one or more humectants, or have a low content of humectants, or be substantially free of, substantially free of, or contain no humectants. Humectants are used to increase the consistency or "texture" of oral care compositions or dental cleanings and to prevent dental cleanings from drying out. Suitable humectants include polyethylene glycol (of a variety of different molecular weights), propylene glycol, glycerin, erythritol, xylitol, sorbitol, mannitol, butylene glycol, lactitol, hydrogenated starch hydrolysate, and / or mixtures thereof. Oral care compositions may contain one or more humectants, each humectant in an amount of 0% to about 70%, about 5% to about 50%, about 10% to about 60%, or about 20% to about 80% by weight of the oral care composition.

[0133] water

[0134] The oral care composition according to embodiments of the present invention may be an anhydrous, low-water, or high-water formulation. Generally, the oral care composition may contain 0% to about 99%, about 5% to about 75%, about 20% or more, about 30% or more, about 50% or more, up to about 45%, or up to about 75% of water by weight of the composition.

[0135] In high-water oral care compositions and / or toothpaste formulations, the oral care composition comprises about 45% to about 75% water by weight of the composition. The high-water oral care composition and / or toothpaste formulation may comprise about 45% to about 65%, about 45% to about 55%, or about 46% to about 54% water by weight of the composition. Water may be added to the high-water formulation, and / or water may enter the composition due to the inclusion of other ingredients.

[0136] In low-water oral care compositions and / or toothpaste formulations, the oral care composition contains about 5% to about 45% water by weight of the composition. The low-water oral care composition may contain about 5% to about 35%, about 10% to about 25%, or about 20% to about 25% water by weight of the composition. Water may be added to the low-water formulation, and / or water may be incorporated into the composition due to the inclusion of other ingredients.

[0137] In anhydrous oral care compositions and / or toothpaste formulations, the oral care composition contains less than about 10% water by weight of the composition. The anhydrous composition contains less than about 5%, less than about 1%, or 0% water by weight of the composition. Water may be added to the anhydrous formulation, and / or water may be incorporated into the composition due to the inclusion of other ingredients.

[0138] Oral care compositions may also be mouthwash formulations. Mouthwash formulations may contain about 75% to about 99%, about 75% to about 95%, or about 80% to about 95% water.

[0139] The dental cleaning composition may also contain other oral-acceptable carrier materials, such as alcohols, humectants, polymers, surfactants, and acceptability improvers (such as flavoring agents, sweeteners, coloring agents, and / or cooling agents).

[0140] Antibacterial agents

[0141] Oral care compositions may contain one or more antimicrobial agents. Suitable antimicrobial agents include any molecule that provides antimicrobial activity in the oral cavity. Suitable antimicrobial agents include hop acid, tin ion source, benzyl alcohol, sodium benzoate, menthyl acetate, menthyl lactate, L-menthol, o-menthol, copper chlorophyllin complexes, phenol, hydroxyquinoline, and / or combinations thereof.

[0142] Oral care compositions may contain about 0.01% to about 10%, about 1% to about 5%, or about 0.5% to about 15% of an antimicrobial agent.

[0143] Bioactive substances

[0144] Oral care compositions may also contain bioactive substances suitable for tooth remineralization. Suitable bioactive substances include bioactive glass and Novamin. ™ Recaldent ™ Hydroxyapatite, one or more amino acids (e.g., arginine, citrulline, glycine, lysine, or histidine), or combinations thereof. Suitable examples of compositions containing arginine can be found in U.S. Patent Nos. 4,154,813 and 5,762,911, the entire contents of which are incorporated herein by reference. Other suitable bioactive substances include any calcium phosphate compound. Other suitable bioactive substances include compounds comprising both a calcium source and a phosphate source.

[0145] Amino acids are organic compounds containing an amine functional group, a carboxyl functional group, and a side chain unique to each amino acid. Suitable amino acids include, for example, amino acids with positive or negative side chains, amino acids with acidic or basic side chains, amino acids with polar, uncharged side chains, amino acids with hydrophobic side chains, and / or combinations thereof. Suitable amino acids also include, for example, arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, selenocysteine, glycine, proline, alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, tryptophan, citrulline, ornithine, creatine, diaminobutyric acid, diaminopropionic acid, their salts, and / or combinations thereof.

[0146] Bioactive glasses contain calcium and / or phosphate, which may be present in proportions similar to hydroxyapatite. These glasses are tissue-adhesive and biocompatible. Bioactive glasses may contain phosphopeptides, calcium sources, phosphate sources, silica sources, sodium sources, and / or combinations thereof.

[0147] The oral care composition may contain about 0.01% to about 20%, about 0.1% to about 10%, or about 1% to about 10% of a bioactive substance based on the weight of the oral care composition.

[0148] Quaternary ammonium compounds

[0149] Oral care compositions may contain quaternary ammonium compounds. Quaternary ammonium compounds in compositions of embodiments of the present invention may include those in which one or two substituents on the quaternary nitrogen have a carbon chain length (typically an alkyl group) of about 8 to about 20, typically about 10 to 18 carbon atoms, while the remaining substituents (typically alkyl or benzyl groups) have a lower number of carbon atoms, such as about 1 to about 7, typically those of methyl or ethyl groups. Cetylpyridinium chloride, hexadecyl fluorinated pyridinium, tetradecyl pyridinium chloride, N-tetradecyl-4-ethyl pyridinium chloride, domethacin, benzalkonium chloride, benzyl chloride, methylbenzyl chloride, dodecyltrimethylammonium bromide, dodecyl dimethyl (2-phenoxyethyl)ammonium bromide, benzyl dimethoxystearyl ammonium chloride, quaternized 5-amino-1,3-bis(2-ethylhexyl)-5-methylhexahydropyrimidine, lauryltrimethylammonium chloride, cocoyltrimethylammonium chloride, hexadecyltrimethylammonium bromide, diisobutylphenoxyethyl dimethylbenzylammonium chloride, and dodecyltrimethylammonium bromide are typical examples of quaternary ammonium antimicrobial agents. Other compounds are bis[4-(R-amino)-1-pyridinium]alkanes, as disclosed in U.S. Patent No. 4,206,215 to Bailey. Pyridinium compounds are preferred quaternary ammonium compounds, particularly hexadecylpyridinium or tetradecylpyridinium halide salts (i.e., chlorides, bromides, fluorides, and iodides). Hexadecylpyridinium chloride and fluoride salts are particularly preferred.

[0150] The oral care composition may contain at least about 0.025%, at least about 0.035%, at least about 0.045% to about 1.0%, about 0.025% to about 1%, or about 0.01% to about 10% of a quaternary ammonium compound by weight of the composition. Alternatively, the oral care composition may be substantially free of, substantially free of, or contain no quaternary ammonium compound.

[0151] Isoprene-modified flavonoids

[0152] Oral care compositions may contain isoprene-modified flavonoids. Flavonoids are a group of natural substances widely found in fruits, vegetables, grains, bark, roots, stems, flowers, tea, and wine. Flavonoids can have a variety of beneficial effects on health, such as antioxidant, anti-inflammatory, antimutagenic, anticancer, and antibacterial effects. Isoprene-modified flavonoids are flavonoids that include at least one isoprene functional group (3-methylbut-2-en-1-yl, as shown in Formula IX), which has previously been identified as promoting binding to cell membranes. Therefore, while not wishing to be bound by theory, it is believed that the addition of an isoprene group (i.e., isoprene modification) to flavonoids can enhance the activity of the original flavonoid by increasing the lipophilicity of the parent molecule and improving the permeability of the isoprene molecule to bacterial cell membranes. Increasing lipophilicity to increase permeability to cell membranes may be a double-edged sword, as isoprene-modified flavonoids tend to be insoluble at high Log P values ​​(high lipophilicity). Log P can be an important indicator of antibacterial efficacy.

[0153] Therefore, the term isoprene flavonoids may include naturally occurring flavonoids having one or more isoprene functional groups, flavonoids having synthetically added isoprene functional groups, and / or isoprene flavonoids having synthetically added additional isoprene functional groups.

[0154]

[0155] Formula IX. Isoprene functional group, where R represents other parts of the molecule.

[0156] Other suitable functional groups of the parent molecule that improve the structure-activity relationship (e.g., structure-MIC relationship) of the isoprene molecule include additional heterocycles containing nitrogen or oxygen, alkyl amino chains, or alkyl chains substituted to one or more aromatic rings of the parent flavonoid.

[0157] Flavonoids may have a 15-carbon backbone having at least two benzene rings and at least one heterocycle. Some suitable flavonoid backbones may be shown in formula X (flavonoid backbone), formula XI (isoflavone backbone), and / or formula XII (neoflavonoid backbone).

[0158]

[0159] Formula X. Flavonoid backbone

[0160]

[0161] Formula XI. Isoflavone backbone

[0162]

[0163] Formula XII. New flavonoid backbone

[0164] Other suitable flavonoid subgroups include anthocyanins, flavonoids, flavanones, flavanols, flavans, isoflavones, chalcones, and / or combinations thereof.

[0165] Isoprene flavonoids may include naturally isolated isoprene flavonoids or naturally isolated flavonoids, which are synthetically modified by a variety of synthetic methods known to those skilled in the art of synthetic organic chemistry to incorporate one or more isoprene functional groups.

[0166] Other suitable isoprene-based flavonoids may include psoralen chalcone, psoralen dihydroflavonoid, methyl psoralen chalcone, Corylifol A, icariin A, icariin A1, icariin B, icariin C, icariin, icariin I, icariin II, icariin, isopsoralen chalcone, isoflavone, neopsoralen isoflavone, 6-isoprene naringenin, 8-isoprene naringenin, sophoranone G, (-)-stigmocarpin, flavol, quercetin, myristoyl phenol, sophora flavescens chalcone, sophoraecin, morinone G, morinone C, panduratin A, 6-geranyl naringenin, Australone A, 6,8-diisoprene sennaol, dorsmanin C, dorsmanin F, 8-isoprene kaempferol, 7-O-methyl lupin isoflavone, lupin isoflavone, 6-isoprene genistein, isowighteone, yellow lupin veneterone, and / or combinations thereof. Other suitable isoprene-based flavonoids include cannabinoids, such as cannabinoid A, cannabinoid B, and / or cannabinoid C.

[0167] Preferably, isoprene flavonoids are highly likely to have a MIC of less than about 25 ppm against Staphylococcus aureus (a Gram-positive bacterium). Suitable isoprene flavonoids include psoralen dihydroflavonoids, methyl psoralen, Corylifol A, icariin, isoflavone, neopsoralen isoflavone, 6-isoprene naringenin, 8-isoprene naringenin, sophoranone G, (-)-stigmosiderin, matrine, morinone C, pandanatin A and / or combinations thereof.

[0168] Preferably, isoprene flavonoids are highly likely to have a MIC of less than about 25 ppm against *Escherichia coli* (a Gram-negative bacterium). Suitable isoprene flavonoids include methyl psoralen, isoxoflavone, 8-isoprene naringenin, sophoranone G, matrine, pandanatin A, and / or combinations thereof.

[0169] Approximately 1000 isoprene flavonoids have been identified from plants. Based on previously reported numbers of isoprene flavonoids, isoprene flavonoids are the most common subclass, while isoprene flavanols are the rarest. Although naturally occurring isoprene flavonoids have been detected with diverse structural characteristics, their distribution in plants is narrow, unlike their parent flavonoid counterparts which are present in almost all plants. Most isoprene flavonoids are found in the following families: Cannabaceae, Guttiferae, Leguminosae, Moraceae, Rutaceae, and Umbelliferae. Leguminosae and Moraceae, due to their use as fruits and vegetables, are the most frequently studied families, and many novel isoprene flavonoids have been explored. Hops from the Cannabaceae family contain 8-isoprene naringenin and isoflavones, which may contribute to the health benefits of beer.

[0170] Isoprene flavonoids can be incorporated through hop extract, incorporated into a separately added extract, or added as a separate component of the oral care compositions disclosed herein.

[0171] Suitable isoprene-modified flavonoids can possess specific octanol-water partition coefficients. Octanol-water partition coefficients can be used to predict the lipophilicity of compounds. Without wishing to be bound by theory, compounds falling within the scope described herein are believed to be able to enter and / or disrupt the major hydrophobic phospholipid bilayer that constitutes the microbial cell membrane. Therefore, octanol-water partition coefficients can be correlated with the antibacterial activity of isoprene-modified flavonoids. Suitable isoprene-modified flavonoids may have log P values ​​of at least about 2, at least about 4, about 2 to about 10, about 4 to about 10, about 4 to about 7, or about 4 to about 7.

[0172] The oral care composition may contain at least about 0.001%, about 0.001% to about 5%, about 0.01% to about 2%, about 0.0001% to about 2%, or at least about 0.05% of isoprene flavonoids.

[0173] amino acids

[0174] Oral care compositions may contain amino acids. As described herein, amino acids may include one or more amino acids, peptides, and / or polypeptides.

[0175] As shown in Formula XIII, an amino acid is an organic compound containing an amine functional group, a carboxyl functional group, and a side chain (R in Formula XIII) specific to each amino acid. Suitable amino acids include, for example, amino acids with positive or negative side chains, amino acids with acidic or basic side chains, amino acids with polar, uncharged side chains, amino acids with hydrophobic side chains, and / or combinations thereof. Suitable amino acids also include, for example, arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, selenocysteine, glycine, proline, alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, tryptophan, citrulline, ornithine, creatine, diaminobutyric acid, diaminopropionic acid, their salts, and / or combinations thereof.

[0176] Suitable amino acids include compounds of formula XIII, naturally occurring or synthetically derived compounds. Based on the R group and the environment, amino acids can be zwitterionic, neutral, positively charged, or negatively charged. The charge of amino acids and whether specific functional groups can interact with tin under specific pH conditions are well known to those skilled in the art.

[0177]

[0178] Formula XIII. Amino acids. R is any suitable functional group.

[0179] Suitable amino acids include one or more basic amino acids, one or more acidic amino acids, one or more neutral amino acids, or combinations thereof.

[0180] The oral care composition may contain about 0.01% to about 20%, about 0.1% to about 10%, about 0.5% to about 6%, or about 1% to about 10% of amino acids by weight of the oral care composition.

[0181] As used herein, the term "neutral amino acid" includes not only naturally occurring neutral amino acids such as alanine, asparagine, cysteine, glutamine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine, but also biologically acceptable amino acids with an isoelectric point in the pH range of 5.0 to 7.0. Biologically preferred acceptable neutral amino acids have a single amino group and a carboxyl group in the molecule or its functional derivatives, such as functional derivatives with modified side chains, although having similar or substantially similar physicochemical properties. In another embodiment, the amino acid will be at least partially water-soluble and provide a pH of less than 7 in an aqueous solution of 1 g / 1000 ml at 25°C.

[0182] Therefore, the neutral amino acids suitable for embodiments of the present invention include, but are not limited to, alanine, GABA, asparagine, cysteine, cystine, glutamine, glycine, hydroxyproline, isoleucine, leucine, methionine, phenylalanine, proline, serine, taurine, threonine, tryptophan, tyrosine, valine, their salts, or mixtures thereof. Preferably, the neutral amino acids used in embodiments of the present invention may include asparagine, glutamine, glycine, their salts, or mixtures thereof. Neutral amino acids may have an isoelectric point of 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, or 7.0 in an aqueous solution at 25°C. Preferably, the neutral amino acid is selected from proline, glutamine, or glycine, more preferably in its free form (i.e., uncoordinated). If the neutral amino acid is in its salt form, suitable salts include those known in the art as pharmaceutically acceptable and considered physiologically acceptable at the provided amounts and concentrations. Preferably, the neutral amino acid is present in amounts of about 0.0001% to about 10%, preferably about 0.05% to about 5%, preferably about 0.1% to about 3%, preferably about 0.5% to about 3%, and preferably about 1% to about 3% by weight of the composition. In one aspect, the neutral amino acid is glutamine (or a salt thereof). In another aspect, the neutral amino acid is proline (or a salt thereof). In yet another aspect, the neutral amino acid is glycine (or a salt thereof).

[0183] The oral care composition may contain about 0.0001% to about 20%, about 0.1% to about 10%, about 0.5% to about 6%, or about 1% to about 10% of neutral amino acids by weight of the oral care composition.

[0184] Hops

[0185] The oral care composition of the present invention may comprise hops. The hops may comprise at least one hop compound of Formula I and / or Formula IV. The compounds of Formula I and / or Formula IV may be provided from any suitable source, such as extracts from hops or hops (Humulus lupulus), hops themselves, their synthetic derivatives and / or salts, prodrugs, or other similar substances. The hop extract may comprise one or more hop α-acids, one or more hop iso-α-acids, one or more hop β-acids, one or more hop oils, one or more flavonoids, one or more solvents, and / or water. Suitable hop α-acids (generally represented by Formula I) may include humulone (Formula II), polyhumulone, humulone-like humulone, post-humulone, pro-humulone, and / or mixtures thereof. Suitable hop iso-α-acids may include cis-isohumulone and / or trans-isohumulone. The isomerization of humulone to trans-isohumulone may be represented by Formula III.

[0186]

[0187] Formula I. Hops α-acid. A is an acidic hydroxyl functional group at the α-position, B is an acidic hydroxyl functional group at the β-position, and R is an alkyl functional group.

[0188]

[0189] Formula II. Humulin

[0190]

[0191] Formula III. Humulone is isomerized to isohylocourne.

[0192] Suitable hop β-acids may include humulone, humulone-like compounds, polyhumulone, and / or mixtures thereof. Suitable hop β-acids may include compounds described in formulas IV, V, VI, and / or VII.

[0193]

[0194] Formula IV. Hops β-acid. B is an acidic hydroxyl functional group at the β-position, and R is an alkyl functional group.

[0195]

[0196] Formula V. Humulone

[0197]

[0198] Formula VI. Polyhumulone

[0199]

[0200] Formula VII. Humulone

[0201] While hop alpha acids exhibit some antibacterial activity, they also possess a bitter taste. The bitterness provided by hop alpha acids is suitable for beer, but not for oral care compositions. In contrast, hop β acids can be associated with higher antibacterial and / or anti-caries activity, but are less bitter. Therefore, hop extracts with a higher ratio of β to alpha acids than typically found in nature could be suitable for use in oral care compositions as antibacterial and / or anti-caries agents.

[0202] Depending on the type of hops, natural hop sources may contain about 2% to about 12% hop β-acid by weight of the hop source. Hop extracts used in other applications, such as in beer brewing, may contain about 15% to about 35% hop β-acid by weight of the extract. The hop extracts desired herein may contain at least about 35%, at least about 40%, at least about 45%, about 35% to about 95%, about 40% to about 90%, or about 45% to about 99% hop β-acid. Hop β-acid may be in acidic form (i.e., having hydrogen atoms attached to hydroxyl functional groups) or in salt form.

[0203] Suitable hop extracts are described in detail in U.S. Patent No. 7,910,140, ​​the entire contents of which are incorporated herein by reference. The desired hop β-acids may be non-hydrogenated, partially hydrogenated by a non-naturally occurring chemical reaction, or hydrogenated by a non-naturally occurring chemical reaction. Hop β-acids may be substantially free of or substantially free of hydrogenated hop β-acids and / or hop acids. Non-naturally occurring chemical reactions are those involving compounds not present in hops, such as chemical hydrogenation reactions carried out at high temperatures and / or with metal catalysts that are not typically experienced in wild hops.

[0204] Natural hop sources may contain about 2% to about 12% hop alpha acid by weight of the hop source. Hop extracts used in other applications, such as in beer brewing, may contain about 15% to about 35% hop alpha acid by weight of the extract. The hop extracts used herein may contain less than about 10%, less than about 5%, less than about 1%, or less than about 0.5% hop alpha acid by weight of the extract.

[0205] Hop oil may contain terpenes such as myrcene, humulene, caryophyllene, and / or mixtures thereof. The hop extract desired herein may contain less than 5%, less than 2.5%, or less than 2% by weight of the extract of one or more hop oils.

[0206] Flavonoids present in hop extracts may include xanthohumol, 8-isoprene naringenin, isoxanthohumol, and / or mixtures thereof. Hop extracts may be substantially free of, substantially free of, contain no, or have less than 250 ppm, less than 150 ppm, and / or less than 100 ppm of one or more flavonoids.

[0207] As described in U.S. Patent No. 5,370,863, hop acid has previously been incorporated into oral care compositions. However, the oral care composition taught in U.S. Patent No. 5,370,863 contains only up to 0.01% by weight of the oral care composition. While not wishing to be bound by theory, it is believed that only small amounts of hop acid can be incorporated in U.S. Patent No. 5,370,863 because hop alpha acid has a bitter taste. Hop extracts with low levels of hop alpha acid do not have this problem.

[0208] Hops compounds can be combined with extracts from another plant, such as Magnolia species, or without extracts from another plant.

[0209] Oral care compositions may contain about 0.01% to about 10%, greater than 0.01% to about 10%, about 0.05%, about 10%, about 0.1% to about 10%, about 0.2% to about 10%, about 0.2% to about 10%, about 0.2% to about 5%, about 0.25% to about 2%, about 0.05% to about 2%, or greater than 0.25% to about 2% of hops, such as hop β-acid, as described herein. Hop, such as hop β-acid, may be provided from suitable hop extracts, the hop plant itself, or synthetic derivatives. Hop, such as hop β-acid, may be provided as a neutral, acidic compound and / or as a salt having a suitable counterion such as sodium, potassium, ammonia, or any other suitable counterion.

[0210] Hops may be provided by hop extracts, such as extracts derived from hops, having at least 35% hop β-acid and less than 1% hop α-acid by weight of the extract. Oral care compositions may contain 0.01% to about 10%, greater than 0.01% to about 10%, about 0.05%, about 10%, about 0.1% to about 10%, about 0.2% to about 10%, about 0.2% to about 10%, about 0.2% to about 5%, about 0.25% to about 2%, about 0.05% to about 2%, or greater than 0.25% to about 2%, as described herein.

[0211] Polyphosphate

[0212] Oral care compositions may contain polyphosphates, which may be provided by a polyphosphate source. A polyphosphate source may contain one or more polyphosphate molecules. Polyphosphates are a class of substances obtained by the dehydration and condensation of orthophosphates to form linear and cyclic polyphosphates of varying chain lengths. Therefore, polyphosphate molecules are typically identified by the average number (n) of polyphosphate molecules, as described below. Although some cyclic derivatives may exist, polyphosphates are generally considered to consist of two or more phosphate molecules arranged primarily in a linear configuration.

[0213] Preferred polyphosphates are those having an average of two or more phosphate groups, so that sufficient unbound phosphate functional groups are generated for effective surface adsorption, which enhances the anionic surface charge and the surface's hydrophilic properties. Preferred polyphosphates include straight-chain polyphosphates having the following formula: XO(XPO3). n X, where X is sodium, potassium, ammonium, or any other alkali metal cation, and n on average is from about 2 to about 21. Alkaline earth metal cations (such as calcium) are not preferred because they tend to form insoluble fluoride salts from aqueous solutions containing fluoride ions and alkaline earth metal cations. Therefore, the oral care compositions disclosed herein may be free of, substantially free of, or substantially free of calcium pyrophosphate.

[0214] Some examples of suitable polyphosphate molecules include, for example, pyrophosphate (n=2), tripolyphosphate (n=3), tetrapolyphosphate (n=4), sodium polyphosphate (n=6), hexapolyphosphate (n=13), benzene polyphosphate (n=14), and hexametaphosphate (n=21), which is also known as Glass H. Polyphosphates may include those polyphosphate compounds produced by FMC Corporation, ICL Performance Products, and / or Astaris.

[0215] The oral care composition may contain about 0.01% to about 15%, about 0.1% to about 10%, about 0.5% to about 5%, about 1% to about 20%, or about 10% or less of a polyphosphate source based on the weight of the oral care composition. Alternatively, the oral care composition may be substantially free of, substantially free of, or contain no polyphosphate.

[0216] Whitening agent

[0217] The oral care composition may contain a whitening agent in amounts of about 0.1% to about 10%, about 0.2% to about 5%, about 1% to about 5%, or about 1% to about 15% by weight of the oral care composition. The whitening agent may be a compound suitable for whitening at least one tooth in the oral cavity. The whitening agent may include peroxides, metal chlorites, perborates, percarbonates, peroxy acids, persulfates, dicarboxylic acids, and combinations thereof. Suitable peroxides include solid peroxides, hydrogen peroxide, urea peroxide, calcium peroxide, benzoyl peroxide, sodium peroxide, barium peroxide, inorganic peroxides, hydroperoxides, organic peroxides, and mixtures thereof. Suitable metal chlorites include calcium chlorite, barium chlorite, magnesium chlorite, lithium chlorite, sodium chlorite, and potassium chlorite. Other suitable whitening agents include sodium persulfate, potassium persulfate, peroxydone complex (polyvinylpyrrolidone and hydrogen peroxide), 6-phthaliminoperoxyhexanoic acid, phthaliminoperoxyhexanoic acid, or mixtures thereof.

[0218] Other ingredients

[0219] Oral care compositions may contain a variety of other ingredients, such as flavoring agents, sweeteners, coloring agents, preservatives, buffers, or other ingredients suitable for use in oral care compositions, as described below.

[0220] Flavoring agents can also be incorporated into oral care compositions. Suitable flavoring agents include wintergreen oil, peppermint oil, spearmint oil, clove bud oil, menthol, p-propenyl anisole, methyl salicylate, eucalyptol, cinnamon, 1-menthol acetate, sage, eugenol, parsley oil, hydroxyphenyl ethyl ketone, α-ionone, oregano, lemon, orange, propenyl ethyl guaiacol, cinnamon, vanillin, ethyl vanillin, heliotrope, 4-cis-heptenal, dimethyl butyl ketone, methyl p-tert-butylphenylacetate, and mixtures thereof. Cooling agents can also be part of the flavoring system. Preferred cooling agents in the compositions of the present invention are p-menthanecarbamoyl reagents, such as N-ethyl-p-menthane-3-carboxamide (commercially known as "WS-3") or N-(ethoxycarbonylmethyl)-3-p-menthanecarboxamide (commercially known as "WS-5"), and mixtures thereof. Flavoring systems are typically used in compositions at a concentration of about 0.001% to about 5% by weight of the oral care composition. These flavorings typically contain aldehydes, ketones, esters, phenols, acids, and mixtures of aliphatic, aromatic, and other alcohols.

[0221] Sweeteners can be added to oral care compositions to give the product a pleasant taste. Suitable sweeteners include saccharin (such as sodium saccharin, potassium saccharin, or calcium saccharin), cyclosulfonates (such as sodium, potassium, or calcium salts), acesulfame K, arbutin, neohesperidin dihydrochalcone, aminoglycoside, dextrose, levulose, sucrose, mannose, sucralose, stevia, and glucose.

[0222] Colorants may be added to improve the aesthetic appearance of the product. Suitable colorants include, but are not limited to, those approved by the relevant regulatory agencies such as the FDA and those listed in the European Food and Drug Directive, and include pigments such as TiO2, as well as colors such as FD&C and D&C dyes.

[0223] Preservatives can also be added to oral care compositions to prevent bacterial growth. Suitable preservatives approved for use in oral compositions, such as methylparaben, propylparaben, benzoic acid, and sodium benzoate, can be added in safe and effective amounts.

[0224] Titanium dioxide may also be added to the compositions of the present invention. Titanium dioxide is a white powder that increases the opacity of the composition. Titanium dioxide typically comprises about 0.25% to about 5% by weight of the oral care composition.

[0225] Other ingredients may be used in oral care compositions, such as desensitizers, rehabilitative agents, other caries prevention agents, chelating agents / polyvalent chelating agents, vitamins, amino acids, proteins, other anti-plaque / anti-tartar agents, light-blocking agents, antibiotics, anti-enzymes, enzymes, pH control agents, oxidants, antioxidants, etc.

[0226] Oral care composition form

[0227] Suitable compositional forms include emulsion compositions such as the emulsion composition of U.S. Patent No. 11,147,753 (the entire contents of which are incorporated herein by reference), unit-dose compositions such as the unit-dose composition of U.S. Patent Application Publication No. 2019 / 0343732 (the entire contents of which are incorporated herein by reference), no-rinse oral care compositions, clogging emulsions such as the clogging oil-in-water emulsion of U.S. Patent No. 11,096,874 (the entire contents of which are incorporated herein by reference), dental cleaning compositions, mouthwash compositions, mouthwash compositions, teeth whitening gels, subgingival gels, mouthwashes, mousses, foams, oral sprays, tablets, chewing tablets, chewing gum, teeth whitening strips, dental floss and floss coatings, breath freshening soluble strips, denture care products, denture adhesive products, or combinations thereof.

[0228] method

[0229] The oral care compositions described herein can produce beneficial effects on oral health, such as treating, reducing, and / or preventing tooth decay, cavities, gingivitis, and / or combinations thereof, and / or whitening teeth, removing stains from teeth, and / or preventing stain buildup when applied to the oral cavity. For example, a user may dispense at least one inch of a suitable oral care composition strip as described herein into an oral care appliance such as a toothbrush, applicator, and / or dental tray, and apply it to the oral cavity and / or teeth.

[0230] It can instruct users to brush their teeth thoroughly for at least 30 seconds, at least one minute, at least 90 seconds, or at least two minutes, at least once, at least twice, or at least three times a day. It can also instruct users to spit out the oral care composition after brushing.

[0231] Users may also be instructed to rinse with the mouthwash and / or mouthwash composition after or in place of brushing. Users may be instructed to rinse thoroughly with the oral care composition for at least 30 seconds, at least one minute, at least 90 seconds, or at least two minutes, at least once, at least twice, or at least three times a day. Users may also be instructed to spit out the oral care composition after the process is complete.

[0232] Oral care compositions according to embodiments of the present invention can be used to treat, reduce, and / or prevent dental caries, cavities, gingivitis, and / or combinations thereof. Oral care compositions according to embodiments of the present invention can be used to provide beneficial whitening effects, such as whitening teeth, removing stains from teeth, and / or preventing stain buildup on teeth. For example, as described herein, hop β-acid can be used as an anti-gingivitis agent. Therefore, adding hops to any oral care composition can provide anti-gingivitis protection.

[0233] Oral care compositions may include primary packaging, such as tubes, bottles, and / or drums. The primary packaging may be placed within secondary packaging, such as cartons, shrink wrap, etc. Instructions for use of the oral care composition may be printed on the primary and / or secondary packaging. The scope of this method is intended to include instructions provided by the manufacturer, distributor, and / or producer of the oral care composition.

[0234] If the oral care composition is toothpaste, the user can be instructed to dispense the toothpaste from the tube.

[0235] The user may be instructed to apply a portion of toothpaste to the toothbrush. This portion of toothpaste may be in any suitable shape, such as a strip, a pea-sized amount, or various other shapes that will fit onto any mechanical and / or manual brush head. The user may be instructed to apply a strip of toothpaste at least about 1 inch, at least about 0.5 inches, at least 1 inch, and / or at least 0.5 inches to the bristles of the toothbrush (such as a soft-bristled toothbrush).

[0236] Users may be instructed to apply a pea-sized or rice-grain-sized amount of toothpaste to the bristles of the toothbrush, such as when used by children under 6 years of age and / or under 2 years of age. Users may be instructed to brush their teeth for at least approximately 30 seconds, at least approximately 1 minute, at least approximately 90 seconds, at least approximately 2 minutes, at least 30 seconds, at least 1 minute, at least 90 seconds, and / or at least 2 minutes. Users may be instructed to brush their teeth thoroughly and / or as directed by a doctor and / or dentist.

[0237] Users can be instructed to brush their teeth after each meal. Users can be instructed to brush their teeth at least once, at least twice, and / or at least three times a day. Users can be instructed to brush their teeth no more than three times a day, for example, to prevent Sn staining. Users can be instructed to brush their teeth in the morning and / or before going to bed at night.

[0238] Because it contains ingredients that are not suitable for ingestion, such as fluoride, users can be instructed not to swallow the toothpaste composition. Users can be instructed to spit out (or cough up) the toothpaste composition after stopping the brushing cycle.

[0239] If the oral care composition is a mouthwash, the user may be instructed to dispense the mouthwash from the bottle containing the mouthwash. The user may be instructed to use the mouthwash at least once daily, at least twice daily, and / or at least three times daily. The user may be instructed to use the mouthwash composition after using toothpaste and / or dental floss. The user may be instructed to rinse in the mouth for a period of time, such as between the teeth. The user may be instructed to rinse vigorously with a portion of the mouthwash. The user may be instructed to use approximately 5 mL to approximately 50 mL, approximately 10 mL to approximately 40 mL, 10 mL, 20 mL, 25 mL, 30 mL, 40 mL, 2 teaspoons, and / or 4 teaspoons of mouthwash. The user may be instructed to rinse with the mouthwash for at least approximately 30 seconds, at least approximately 1 minute, at least approximately 90 seconds, at least approximately 2 minutes, at least 30 seconds, at least 1 minute, at least 90 seconds, and / or at least 2 minutes. Because it contains ingredients that are not suitable for ingestion, such as fluoride, the user may be instructed not to swallow the mouthwash composition. However, in the case of oral care compositions containing hops but not fluoride, it may not be necessary to instruct the user not to swallow the mouthwash. The user may be instructed to spit out (or cough up) the mouthwash composition after stopping the rinsing cycle.

[0240] Instructions for use of oral care compositions such as toothpaste compositions and / or mouthwash compositions may vary based on age. For example, one set of instructions may be provided for adults and children aged at least 6 years or at least 2 years, while a second set of instructions may be provided for children under 6 years or under 2 years.

[0241] As described herein, oral care compositions can be used as medicines, such as the anti-cavity treatment and / or anti-gingivitis treatment described herein. Suitable medicines include oral care compositions, toothpaste compositions, mouthwash compositions, dental floss coatings, chewing gum, and / or other suitable compositions to be applied to the oral cavity.

[0242] Additionally, as described herein, oral care compositions can be used to reduce the number and / or intensity of white patches on teeth that may be attributable to the presence of dental caries in the oral cavity. Alternatively, as described herein, oral care compositions can be used to reduce redness, swelling, tenderness, and / or edema of the gums immediately adjacent to the tooth surface at the gingival line (which may be attributable to the presence of gingivitis in the oral cavity).

[0243] Example

[0244] The following embodiments further illustrate the invention, and these embodiments should not be construed in any way as limiting the scope of the invention. After reading this specification, various other aspects, modifications, and equivalents thereof may be proposed to those skilled in the art without departing from the spirit of the invention or the scope of the appended claims.

[0245] Fluoride intake

[0246] FDA Method 40, enamel fluoride uptake, is a method for determining the amount of fluoride delivered to a demineralized enamel sample derived from a single 30-minute treatment of a 1:3 dental cleaning slurry supernatant.

[0247] Extract high-quality human enamel cores, 3mm-4mm in diameter, from whole human teeth. Mount the cores on an acrylic rod and abrade the surface using 600-grit wet / dry sandpaper. Then polish the cores to a mirror finish using 0.05µ polishing compound (alumina suspension γB, MetLabCorp, catalog number M303-128). Store the samples in an airtight container in a standard laboratory refrigerator (approximately 2°C-4°C) with a small amount of deionized water (approximately 1-5 mL).

[0248] Inspect each enamel sample and discard those with large cracks or uneven calcification. Polish the sample again for 10 minutes using 0.05µ polishing compound. Sonicate the sample in deionized water for 15-30 minutes using an ultrasonic homogenizer. Then rinse the enamel sample with standard deionized water and wipe to remove any residual polishing compound.

[0249] The enamel samples were then demineralized. For each sample, 25 mL of MHDP (N-2-hydroxyethyl, methanehydroxybisphosphonate) demineralization solution (0.025 M lactic acid, 2 x 10⁻⁶) was applied. -4Place the MHDP (methyl methacrylate) solution in 30 mL plastic vials. Place the enamel sample through the cap of each vial. Place each cap on top of the vial to immerse the enamel sample in the MHDP demineralization solution. Do not allow the enamel sample to touch the bottom of the vial. Allow the sample to remain in the demineralization solution under ambient conditions for 48 hours to allow artificial caries lesions to form. Tap the stick twice daily to remove any air bubbles. After 48 hours, remove the sample from the demineralization solution and rinse thoroughly with deionized water.

[0250] If the sample is a paste-like dental cleaning agent, place 10g of the agent in a 50mL triangular pourable plastic beaker. Add 30mL of deionized water to the beaker. Place an X-shaped stir bar on top of the dental cleaning agent in each beaker and place the beaker on a magnetic stirring plate. Break up the dental cleaning agent with a wooden stick until the stir bar can rotate freely at 300-400rpm. Stir the dental cleaning agent slurry for 20 minutes. Transfer the slurry to a centrifuge tube and centrifuge at 11,000rpm for 30 minutes.

[0251] Decant the supernatant of the slurry into a 50 mL triangular pourable plastic beaker. Place an X-shaped stir bar in the beaker and then place the beaker on a magnetic stir plate. Set the stir plate to 300-400 rpm. Suspend the diseased enamel sample in each treatment. Treat each sample for 30 minutes. After 30 minutes, rinse each sample with deionized water. Store the samples in an airtight container with a small amount of deionized water (approximately 1-5 mL) in a standard laboratory refrigerator (approximately 2°C-4°C).

[0252] Fluoride content analysis was performed on a sample by collecting a portion of the milled glaze powder after drilling to a depth of 50 micrometers, dissolving the glaze in acid, and then neutralizing and buffering it. The area of ​​glaze extracted during drilling was recorded.

[0253] Fluoride uptake was measured directly using a fluoride ion-specific electrode (Thermo Scientific, Orion, 96-09-00, Waltham, MA, USA). Each sample was placed on the end of the electrode. The mV value was recorded. This value was converted to ppm fluoride using a standard curve of prepared fluoride standards. Fluoride uptake was calculated by dividing the mass of fluoride in µg by the total area sampled using a microdrill biopsy.

[0254] HAP Dissolution

[0255] The HAP dissolution method was designed to test the acid-protective effect of selected oral care compositions. After treating hydroxyapatite powder (HAP) with a test dilution solution, the HAP was added to an acidic medium, and the change in pH was used as an indicator of the degree of surface acid protection.

[0256] Diluted solutions (1:3 concentrated solution: water) were prepared for all treatment compositions. Specifically, 10 g of the oral care composition was mixed with 30 g of deionized ultrapure water in a 50 mL container equipped with a stir bar. If a dental flake is used, 10 g of dental flake is broken up with a small spatula until the stir bar moves freely at 300-400 rpm. The slurry is mixed on a stirring plate for 10-20 minutes and / or until a homogeneous slurry is formed. The paste slurry is centrifuged at 15,000 rpm for 15 min to separate the solid components from the supernatant. If a solution is used, this centrifugation step is omitted.

[0257] For each treatment, including the water control, 0.300 g of hydroxyapatite powder (HAP) was placed in a 50 mL round-bottom centrifuge tube containing four 4 mm glass beads. For the treatment with the oral care composition, 24 mL of the prepared dental cleaning supernatant or diluted solution was added to the HAP. Each treated HAP sample was immediately vortexed at 2500 rpm for 2 minutes. All samples were then centrifuged at 15,000 rpm for 15 minutes. The liquid phase was decanted from the centrifuge tube, leaving the HAP particles and glass beads. The remaining HAP particles were rinsed by adding deionized water, vortexing at 2500 rpm for 1 minute to fully disperse the particles, centrifuging at 15,000 rpm for 15 minutes, and decanting and discarding the liquid phase. This rinsing step was repeated twice. The treated HAP particles were dried overnight in a 55°C oven.

[0258] The ΔpH of the HAP sample was analyzed. 25 mL of 10 mM citric acid (1.9212 g citric acid in 1 L of deionized water) was added to a 50 mL beaker equipped with a stir bar. The beaker was placed on a stirring plate (Metrohm, Herisau, Switzerland, Model 728) and turned on. A Titrano pH electrode (Metrohm, Herisau, Switzerland, Model 719S) was placed in the stirred beaker containing citric acid. After the citric acid solution equilibrated (until the pH reading was 2.5 ± 0.001 pH over 30 seconds), 50 mg of dried HAP powder was added to the citric acid solution. The pH was monitored and recorded at 5 min. The ΔpH was determined by subtracting the pH reading at 5 min from the stable pH reading obtained immediately before the addition of the treated HAP powder. Results regarding the decrease in HAP solubility are presented in this paper.

[0259] An exemplary oral care composition was prepared by dissolving the necessary carboxylic acid in 90 mL of ultrapure water in a glass beaker using a stirring rod and magnetic stirring plate. After the acid was completely dissolved, stannous fluoride (0.454 g / 100 g solution) was added and stirred until completely dissolved. Then, 1 N NaOH was added dropwise to neutralize the solution until pH 4.5 was reached. The solution was transferred to a 100 mL Erlenmeyer flask, and ultrapure water was added to bring the total volume to 100 mL. The solution was then tightly sealed and stored in a refrigerator until use. To process HAP powder, a certain amount of the solution was diluted to 1 part solution (10 g) and 3 parts ultrapure water (30 g), as if it were toothpaste. The HAP powder was then processed normally according to the method described above.

[0260] The amount of chelating stabilizer used is defined by the molar ratios indicated in Tables 1 to 8. As an illustrative example, when the stannous component in the composition is obtained by adding 0.454 g stannous fluoride / 100 g solution, Example 1 contains one mol of gluconate ions for every 1 mol of stannous ions. Thus, Example 1 contains 0.454 g stannous fluoride / 100 g solution and 0.568 g gluconate / 100 g solution.

[0261] As a second illustrative example, for every mol of stannous fluoride, Example 56 contains one mol of malonate and 1.67 mol of oxalate. Thus, Example 56 contains 0.454 g stannous fluoride / 100 g solution, 0.302 g malonate / 100 g solution, and 0.436 g oxalate / 100 g solution.

[0262] Table 1: Molar ratio of Sn to stabilizer in solution (0.454% SnF2) (Sn: stabilizer)

[0263] gluconate lactate malonate oxalate malate Tartrate citrate total Example 1 1:1 0 0 0 0 0 0 1:1 Example 2 1:2 0 0 0 0 0 0 1:2 Example 3 1:3 0 0 0 0 0 0 1:3 Example 4 0 1:1 0 0 0 0 0 1:1 Example 5 0 1:2 0 0 0 0 0 1:2 Example 6 0 1:3 0 0 0 0 0 1:3 Example 7 0 0 1:1 0 0 0 0 1:1 Example 8 0 0 1:2 0 0 0 0 1:2 Example 9 0 0 1:3 0 0 0 0 1:3 Example 10 0 0 0 1:1 0 0 0 1:1 Example 11 0 0 0 1:2 0 0 0 1:2 Example 12 0 0 0 1:3 0 0 0 1:3 Example 13 0 0 0 0 1:1 0 0 1:1 Example 14 0 0 0 0 1:2 0 0 1:2 Example 15 0 0 0 0 1:3 0 0 1:3 Example 16 0 0 0 0 0 1:1 0 1:1 Example 17 0 0 0 0 0 1:2 0 1:2 Example 18 0 0 0 0 0 1:3 0 1:3

[0264] Table 2: Molar ratio of Sn to stabilizer in solution (0.454% SnF2) (Sn: stabilizer)

[0265] gluconate lactate malonate oxalate malate Tartrate citrate total Example 19 1:1 1:1 0 0 0 0 0 1:2 Example 20 1:1 0 1:1 0 0 0 0 1:2 Example 21 1:1 0 0 1:1 0 0 0 1:2 Example 22 1:1 0 0 0 1:1 0 0 1:2 Example 23 1:1 0 0 0 0 1:1 0 1:2 Example 24 0 1:1 1:1 0 0 0 0 1:2 Example 25 0 1:1 0 1:1 0 0 0 1:2 Example 26 0 1:1 0 0 1:1 0 0 1:2 Example 27 0 1:1 0 0 0 1:1 0 1:2 Example 28 1:1 1:2 0 0 0 0 0 1:3 Example 29 1:1 0 1:2 0 0 0 0 1:3 Example 30 1:1 0 0 1:2 0 0 0 1:3 Example 31 1:1 0 0 0 1:2 0 0 1:3 Example 32 1:1 0 0 0 0 1:2 0 1:3 Example 33 0 1:1 1:2 0 0 0 0 1:3 Example 34 0 1:1 0 1:2 0 0 0 1:3 Example 35 0 1:1 0 0 1:2 0 0 1:3 Example 36 0 1:1 0 0 0 1:2 0 1:3

[0266] Table 3: Molar ratio of Sn to stabilizer in solution (0.454% SnF2) (Sn: stabilizer)

[0267] gluconate lactate malonate oxalate malate Tartrate citrate total Example 37 1:2 1:1 0 0 0 0 0 1:3 Example 38 1:2 0 1:1 0 0 0 0 1:3 Example 39 1:2 0 0 1:1 0 0 0 1:3 Example 40 1:2 0 0 0 1:1 0 0 1:3 Example 41 1:2 0 0 0 0 1:1 0 1:3 Example 42 0 1:2 1:1 0 0 0 0 1:3 Example 43 0 1:2 0 1:1 0 0 0 1:3 Example 44 0 1:2 0 0 1:1 0 0 1:3 Example 45 0 1:2 0 0 0 1:1 0 1:3 Example 46 0 0 1:1 1:1 0 0 0 1:2 Example 47 0 0 1:1 1:2 0 0 0 1:3 Example 48 0 0 1:2 1:1 0 0 0 1:3

[0268] Table 4: Molar ratio of Sn to stabilizer in solution (0.454% SnF2) (Sn: stabilizer)

[0269] gluconate lactate malonate oxalate malate Tartrate citrate total Example 49 1:1 0 0 0 0 0 1:1 1:2 Example 50 0 0 1:1 0 0 0 1:1 1:2 Example 51 0 0 0 1:1 0 0 1:1 1:2 Example 52 0 0 0 0 1:1 0 1:1 1:2 Example 53 0 0 0 0 0 1:1 1:1 1:2

[0270] Table 5: Molar ratio of Sn to stabilizer in solution (0.454% SnF2) (Sn: stabilizer)

[0271] gluconate lactate malonate oxalate malate Tartrate citrate total Example 54 0 0 1:1 1:1 0 0 0 1:2 Example 55 0 0 1:1 1:1.33 0 0 0 1:2.33 Example 56 0 0 1:1 1:1.67 0 0 0 1:2.67 Example 57 0 0 1:1 1:2 0 0 0 1:3 Example 58 0 0 1:1.33 1:2 0 0 0 1:3.33 Example 59 0 0 1:1.67 1:2 0 0 0 1:3.67 Example 60 0 0 1:2 1:2 0 0 0 1:4

[0272] Table 6: Molar ratio of Sn to stabilizer in solution (0.454% SnF2) (Sn: stabilizer)

[0273] gluconate lactate malonate oxalate malate Tartrate citrate total Example 61 1:1 0 0 0 0 0 1:1 1:2 Example 62 1:0.75 0 0 1:0.5 0 0 1:0.75 1:2 Example 63 1:0.5 0 0 1:1 0 0 1:0.5 1:2 Example 64 1:0.25 0 0 1:1.5 0 0 1:0.25 1:2 Example 65 0 0 0 1:2 0 0 0 1:2 Example 66 1:1 0 0 1:1 0 0 1:1 1:3 Example 67 1:0.75 0 0 1:2 0 0 1:1 1:4

[0274] Table 7: Molar ratio of Sn to stabilizer in solution (0.454% SnF2) (Sn: stabilizer)

[0275] gluconate lactate malonate oxalate malate Tartrate citrate total Example 68 0 1:1 0 0 0 0 1:1 1:2 Example 69 0 1:0.75 0 1:0.5 0 0 1:0.75 1:2 Example 70 0 1:0.5 0 1:1 0 0 1:0.5 1:2 Example 71 0 1:0.25 0 1:1.5 0 0 1:0.25 1:2 Example 72 0 0 0 1:2 0 0 0 1:2 Example 73 0 1:1 0 1:1 0 0 1:1 1:3 Example 74 0 1:0.75 0 1:2 0 0 1:1 1:4

[0276] Table 8: Molar ratio of Sn to stabilizer in solution (0.454% SnF2) (Sn: stabilizer)

[0277] Disodium ethylenediaminetetraacetate total Example 75 1:1 1:1

[0278] Table 9: Molar ratio of Sn to stabilizer in solution (0.454% SnF2) (Sn: stabilizer)

[0279] gluconate lactate malonate oxalate malate Tartrate citrate total Example 76 1:1 0 0 0 0 0 1:1 1:2

[0280] The molar ratio in Example 76 is the same as that in Example 49; however, the target pH of the compositions in Table 9 is 7.

[0281] The results of the reduction in HAP solubility by the HAP dissolution method; the fluoride uptake of enamel by the fluoride uptake method; and the treatment pH of the embodiments of the present invention are described below. The values ​​of the embodiments of the present invention are compared with those obtained for sodium fluoride in water at pH 4.5, Crest Cavity Protection, USP sodium fluoride reference dental cleaning agent, ultrapure water, and a 1:1:1 mixture of stannous fluoride with gluconic acid and citric acid (Example 49).

[0282] Table A. Results of decreased HAP solubility, enamel fluoride uptake, and fluoride activity

[0283] Processing materials HAP solubility decreased (compared to water, %) <![CDATA[Fluoride uptake (µg F / cm 2 )]]> pH treatment water 0 -- -- 0.243% NaF in water -- 20.93 4.5 Crest Cavity Protection 32.7 -- 7.0 USP Sodium Fluoride -- 8.17 7.0 Example 49 56.9* 15.4^ 4.5 Example 1 76.5 4.5 Example 2 75.1 4.5 Example 3 75.2 8.24 4.5 Example 4 76.3 4.5 Example 5 77.7 4.5 Example 6 76.4 4.5 Example 7 79.8 4.5 Example 8 74.1 4.5 Example 9 70.7 5.55 4.5 Example 10 67.3* 4.5 Example 11 62.0* 19.9^ 4.5 Example 12 59.2* 20.6^ 4.5 Example 13 72.7 4.5 Example 14 68.6* 4.5 Example 15 65.9* 4.5 Example 16 73.1 4.5 Example 17 66.8* 4.5 Example 18 66.1* 4.5

[0284] Table A illustrates the reduction in HAP solubility and fluoride uptake performance of stannous fluoride mixed with gluconic acid (Examples 1, 2, 3); lactic acid (Examples 4, 5, 6); malonic acid (Examples 7, 8, 9); oxalic acid (Examples 10, 11, 12); malic acid (Examples 13, 14, 15); and DL-tartaric acid (Examples 16, 17, 18) at ratios of 1:1, 1:2, and 1:3. The optimal reduction in HAP solubility was between 35% and 70% compared to water. Examples achieving this optimal value are indicated by "*". Optimal fluoride uptake is greater than 10 µg F / cm³. 2Examples achieving this optimal value are indicated by "^". Stannous fluoride stabilized only by gluconic acid, lactic acid, or malonic acid cannot achieve optimal values ​​for HAP solubility reduction, fluoride uptake, or any ratio of ligand to stannous fluoride. Oxalic acid at a molar ratio of 1:1, 1:2, or 1:3 with stannous fluoride achieves optimal HAP solubility reduction. Malic acid at a molar ratio of 1:2 or 1:3 with stannous fluoride achieves optimal HAP solubility reduction. DL-tartaric acid at a molar ratio of 1:2 or 1:3 with stannous fluoride achieves optimal HAP solubility reduction. Oxalic acid at a molar ratio of 1:2 or 1:3 with stannous fluoride also achieves optimal fluoride uptake.

[0285] Table B. Results of decreased HAP solubility, enamel fluoride uptake, and fluoride activity

[0286] Processing materials HAP solubility decreased (compared to water, %) <![CDATA[Fluoride uptake (µg F / cm 2 )]]> Target pH water 0 -- -- 0.243% NaF in water -- 20.93 4.5 Crest Cavity Protection -- 7.0 USP Sodium Fluoride -- 8.17 7.0 Example 49 56.9* 15.4^ 4.5 Example 19 78.9 4.5 Example 20 80.4 7.8 4.5 Example 21 64.7* 10.6^ 4.5 Example 22 76.3 4.5 Example 23 72.9 4.5 Example 24 70.9 4.5 Example 25 63.8* 4.5 Example 26 70.0* 4.5 Example 27 65.1* 4.5 Example 28 77.3 4.5 Example 29 76.4 7.5 4.5 Example 30 60.0* 20.5^ 4.5 Example 31 68.6* 4.5 Example 32 66.9* 4.5 Example 33 73.4 4.5 Example 34 58.0* 4.5 Example 35 66.8* 4.5 Example 36 63.8* 4.5

[0287] The results in Table B illustrate the reduction in HAP solubility and fluoride uptake performance of stannous fluoride mixed with ligands A and B in a 1:1:1 or 1:1:2 ratio. The optimal reduction in HAP solubility is between 35% and 70% relative to water. Examples achieving this optimal value are indicated by "*". Optimal fluoride uptake is greater than 10 µg F / cm³. 2 Examples achieving this optimal value are indicated by "^". Regarding the reduction in HAP solubility, only 1:1:1 mixtures of stannous:gluconate:oxalate (Example 21); stannous:lactate:oxalate (Example 25); stannous:lactate:malate (Example 26); and stannous:lactate:DL-tartrate (Example 27) achieve this optimal value. Interestingly, more of the 1:1:1 mixtures work when lactate is used than when gluconate is used. For 1:1:2 mixtures, only mixtures of stannous:gluconate:oxalate (Example 30); stannous:gluconate:malate (Example 31); stannous:gluconate:DL-tartrate (Example 32); stannous:lactate:oxalate (Example 34); stannous:lactate:malate (Example 35); and stannous:lactate:DL-tartrate (Example 36) achieve this optimal value. Interestingly, gluconate:malate and gluconate:DL-tartrate worked at a 1:1:2 ratio but not at a 1:1:1 ratio. Regarding fluoride uptake, the 1:1:1 stannous:gluconate:oxalate system (Example 21) delivered greater than 10 µg F / cm². 2 The optimal fluoride uptake was achieved. However, when the ligand ratio was increased to 1:1:2 (Example 30), fluoride uptake almost doubled.

[0288] Table C. Results of decreased HAP solubility, enamel fluoride uptake, and fluoride activity

[0289] Processing materials HAP solubility decreased (compared to water, %) <![CDATA[Fluoride uptake (µg F / cm 2 ).]]> Target pH water 0 -- -- 0.243% NaF in water -- 20.93 4.5 Crest Cavity Protection 32.9 -- 7.0 USP Sodium Fluoride -- 8.17 7.0 Example 49 56.9* 15.4^ 4.5 Example 37 74.5 4.5 Example 38 75.9 9.0 4.5 Example 39 64.4* 13.1^ 4.5 Example 40 72.0 4.5 Example 41 69.3* 4.5 Example 42 75.1 4.5 Example 43 63.3* 4.5 Example 44 71.7 4.5 Example 45 69.2* 4.5 Example 46 66.4* 8.6 4.5 Example 47 60.1* 17.8^ 4.5 Example 48 64.4* 7.0 4.5

[0290] The results in Table C illustrate the reduction in HAP solubility and fluoride uptake performance of stannous fluoride in a 1:2:1 mixture of ligand A and ligand B (Examples 37-45) or a mixture of stannous fluoride with malonic acid and oxalic acid (Examples 46-48). The optimal reduction in HAP solubility was between 35% and 70% compared to water. Examples achieving this optimal value are indicated by "*". Optimal fluoride uptake is greater than 10 µg F / cm³. 2 Examples achieving this optimal value are indicated by "^". Regarding the reduction in HAP solubility, only 1:2:1 mixtures of stannous:gluconate:oxalate (Example 39); stannous:gluconate:DL-tartrate (Example 41); stannous:lactate:oxalate (Example 43); and stannous:lactate:DL-tartrate (Example 45) achieve this optimal value. Regarding fluoride uptake, the 1:2:1 stannous:gluconate:oxalate system (Example 39) delivers greater than 10 µg F / cm³. 2 The optimal fluoride uptake was achieved in the case of stannous mixtures with malonic acid and oxalic acid. In the case of stannous:malonate:oxalate mixtures of 1:1:1 (Example 46) and 1:2:1 (Example 48) achieved optimal HAP solubility reduction but not optimal fluoride uptake. Only the stannous:malonate:oxalate mixture of 1:1:2 (Example 47) achieved both optimal solubility reduction and optimal fluoride uptake.

[0291] Table D. Results of decreased HAP solubility, enamel fluoride uptake, and fluoride activity

[0292] Processing materials HAP solubility decreased (compared to water, %) <![CDATA[Fluoride uptake (µg F / cm 2 )]]> Target pH water 0 -- -- 0.243% NaF in water -- 20.93 4.5 Crest Cavity Protection 29.7 -- 7.0 USP Sodium Fluoride -- 8.17 7.0 Example 49 56.9* 15.4^ 4.5 Example 50 56.8* 16.7^ 4.5 Example 51 56.0* 14.0^ 4.5 Example 52 55.5* 4.5 Example 53 54.3* 4.5

[0293] The results in Table D illustrate the reduction in HAP solubility and fluoride uptake performance of stannous fluoride mixed with bidentate ligands and citric acid in a 1:1:1 ratio (Examples 49-53). The results for Example 49 are for a 1:1:1 mixture of stannous fluoride:glucuronide:citrate. The optimal reduction in HAP solubility was between 35% and 70% compared to water. Examples achieving this optimal value are indicated by "*". The optimal fluoride uptake is greater than 10 µg F / cm³. 2 Examples achieving this optimal value are indicated by “^”. Examples 50-53 all achieved optimal reduction in HAP solubility and fluoride uptake. Interestingly, a 1:1:1 mixture of stannous:bident:tridentate ligands appears to be particularly effective in stannous ...

[0294] Table E. Results of decreased HAP solubility, enamel fluoride uptake, and fluoride activity

[0295] Processing materials HAP solubility decreased (compared to water, %) <![CDATA[Fluoride uptake (µg F / cm 2 )]]> Target pH water 0 -- -- 0.243% NaF in water -- 20.93 4.5 Crest Cavity Protection 32.1 -- 7.0 USP Sodium Fluoride -- 8.17 7.0 Example 49 56.9* 15.4^ 4.5 Example 54 63.2* 8.2 4.5 Example 55 62.2* 10.9^ 4.5 Example 56 62.4* 14.2^ 4.5 Example 57 59.0* 17.9^ 4.5 Example 58 58.2* 17.6^ 4.5 Example 59 55.6* 17.4^ 4.5 Example 60 58.2* 14.2^ 4.5

[0296] The results in Table E illustrate the reduction in HAP solubility and fluoride uptake performance of fractional mixtures of stannous fluoride with malonic acid and oxalic acid. Examples 54-57 considered increasing the amount of oxalic acid while keeping malonic acid constant, increasing the ligand-to-stannous ratio in the following order: 1:1:1 (Example 54); 1:1:1.33 (Example 55); 1:1:1.67 (Example 56); and 1:1:2 (Example 57). Examples 58-60 then increased the amount of malonic acid while keeping oxalic acid constant, increasing the ligand-to-stannous ratio in the following order: 1:1.33:2 (Example 58); 1:1.67:2 (Example 59); and 1:2:2 (Example 60). The optimal reduction in HAP solubility was between 35% and 70% compared to water. Examples achieving this optimal value are indicated by “*”. The optimal fluoride uptake is greater than 10 µg F / cm³. 2 Examples achieving this optimal value are indicated by "^". Examples 54-60 all achieved optimal HAP solubility reduction. Only Example 54 failed to deliver optimal fluoride uptake, with results nearly identical to Example 46. Interestingly, for fluoride uptake, the optimal fraction ratio of ligand to stabilizer appears to be between 1:1:2 and 1:1.33:2.

[0297] Table F. Results of decreased HAP solubility, enamel fluoride uptake, and fluoride activity

[0298] Processing materials HAP solubility decreased (compared to water, %) <![CDATA[Fluoride uptake (μg F / cm 2 ).]]> Target pH water 0 -- -- 0.243% NaF in water -- 20.93 4.5 Crest Cavity Protection 32.1 -- 7.0 USP Sodium Fluoride -- 8.17 7.0 Example 49 56.9* 15.4^ 4.5 Example 61 55.5* 9.6^ 4.5 Example 62 57.1* 10.8^ 4.5 Example 63 59.9* 11.3^ 4.5 Example 64 59.5* 15.0^ 4.5 Example 65 61.2* 12.2^ 4.5 Example 66 53.3* 13.1^ 4.5 Example 67 53.1* 17.1^ 4.5

[0299] The results in Table F illustrate the reduction in HAP solubility and fluoride uptake performance of fractional mixtures of stannous fluoride with gluconic acid ligands, oxalic acid ligands, and citrate ligands. The results for Examples 49 and 61 are for stannous:gluconic acid:citrate 1:1:1 mixtures. Differences in fluoride uptake represent biological differences relative to the fluoride uptake method. Examples 62-65 considered increasing the amount of oxalic acid while decreasing the amounts of gluconic acid and citrate, such that the total molar amount of all ligands in the ligands was twice the molar amount of stannous fluoride. The gluconic acid:oxalic acid:citrate ratio varied in the following order: 0.75:0.5:0.75 (Example 62); 0.5:1:0.5 (Example 63); 0.25:1.5:0.25 (Example 64); and 0:2:0 (Example 65). All four examples achieved optimal reduction in both HAP solubility and fluoride uptake. For Example 64, apparent optimal fluoride uptake was achieved. Examples 66 and 67 increased the total stabilizer used. The ratio of gluconate:oxalate:citate was increased in the following order: 1:1:1 (Example 66); and 1:2:1 (Example 67). Similarly, both examples achieved optimal reduction in HAP solubility and fluoride uptake. For Example 67, apparent optimal fluoride uptake was achieved.

[0300] Table G. Results of decreased HAP solubility, enamel fluoride uptake, and fluoride activity

[0301] Processing materials HAP solubility decreased (compared to water, %) <![CDATA[Fluoride uptake (µg F / cm 2 ).]]> Target pH water 0 -- -- 0.243% NaF in water -- 20.93 4.5 Crest Cavity Protection 32.1 -- 7.0 USP Sodium Fluoride -- 8.17 7.0 Example 49 56.9* 15.4^ 4.5 Example 68 54.1* 7.7 4.5 Example 69 54.7* 8.0 4.5 Example 70 57.1* 13.9^ 4.5 Example 71 57.4* 10.4^ 4.5 Example 72 60.9* 10.6^ 4.5 Example 73 54.4* 14.3^ 4.5 Example 74 52.5* 19.1^ 4.5 Example 75 40.8* 23.0^ 4.5

[0302] The results in Table G illustrate the reduction in HAP solubility and fluoride uptake performance of fractional mixtures of stannous fluoride with lactic acid ligands, oxalic acid ligands, and citrate ligands. The results for Example 49 are for a 1:1:1 mixture of stannous fluoride: gluconate: citrate. The results in Table G are for a similar stabilizer ratio as in Table F, but gluconate has been replaced with lactic acid. Examples 68-72 consider increasing the amount of oxalic acid while decreasing the amounts of lactic acid and citrate, such that the total molar amount of all ligands in the ligands is twice the molar amount of stannous fluoride. The lactate:oxalate:citrate ratios vary in the following order: 1:0:1 (Example 68); 0.75:0.5:0.75 (Example 69); 0.5:1:0.5 (Example 70); 0.25:1.5:0.25 (Example 71); and 0:2:0 (Example 72). Only Examples 70-72 achieved optimal reduction in both HAP solubility and fluoride uptake. For Example 70, apparent optimal fluoride uptake was achieved. Examples 73 and 74 increased the total stabilizer used. The ratio of lactate:oxalate:citate was increased in the following order: 1:1:1 (Example 73); and 1:2:1 (Example 74). Again, both examples achieved optimal reduction in HAP solubility and fluoride uptake. For Example 74, apparent optimal fluoride uptake was achieved. Finally, Example 75 is for a stannous composition stabilized entirely by ethylenediaminetetraacetic acid (EDTA) as a tetracarboxylic acid. Example 75 achieved both optimal reduction in HAP solubility and fluoride uptake.

[0303] Table H. Results of decreased HAP solubility, enamel fluoride uptake, and fluoride activity

[0304] Processing materials HAP solubility decreased (compared to water, %) <![CDATA[Fluoride uptake (µg F / cm 2 )]]> Target pH water 0 -- -- Crest Cavity Protection 32.1 -- 7.0 Example 76 54.9* 8.0 7.0

[0305] The results in Table H illustrate the reduction in HAP solubility and fluoride uptake performance of fractional mixtures of stannous fluoride with glucuronide and citrate ligands. The results for Example 76 were for a 1:1:1 mixture of stannous:glucuronide:citrate. For this composition, optimal reduction in HAP solubility was achieved; however, optimal fluoride uptake was not achieved. Not wanting to be bound by theory, we believe this is because the pH of the composition was not optimal for the combined amplification of HAP solubility reduction and enamel fluoride uptake.

[0306] As may be used herein, the terms “substantially,” “about,” and “approximately” indicate the inherent degree of uncertainty that may belong to any quantitative comparison, value, measure, or other representation. These terms also indicate the extent to which a quantitative representation may differ from the stated reference value without causing a change in the essential function of the subject matter under discussion. Furthermore, the dimensions and values ​​disclosed herein are not intended to be construed as strictly limited to the stated precise numerical values. Rather, unless otherwise specified, each such dimension is intended to represent the stated value and the range surrounding its functional equivalent. For example, a dimension disclosed as “40 mm” is intended to represent “about 40 mm.”

[0307] Unless expressly excluded or otherwise limited, every reference cited herein, including any cross-references or related patents or patent applications, and any patent application or patent claiming priority to or benefiting from it, is incorporated herein by reference in its entirety. Reference to any reference is not an endorsement of it as prior art to any disclosed or protected art herein, nor is it an endorsement of any such invention, either on its own or in combination with any one or more references. Furthermore, where any meaning or definition of a term in this invention conflicts with any meaning or definition of the same term in referenced documents, the meaning or definition given to that term in this invention shall prevail.

[0308] While specific embodiments of the invention have been illustrated and described, it will be apparent to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. Therefore, it is intended that all such changes and modifications falling within the scope of the invention be covered by the appended claims.

Claims

1. An oral care composition comprising: a. An oral care active substance, wherein the oral care active substance comprises a fluoride ion source and a stannous ion source; and b. A dental ligand mixture, wherein the dental ligand mixture comprises: i. a first polydentate ligand, wherein the first polydentate ligand is oxalic acid or a salt thereof or a combination thereof; and ii. A monodentate ligand, wherein the monodentate ligand is gluconic acid or a salt thereof or a combination thereof, and the molar ratio of the stannous ion as described in a. to the mixture of the monodentate ligands as described in bi and bii. is in the range of 1:1 to 1:4, preferably 1:1 to 1:3; or iii. A second polydentate ligand, wherein the second polydentate ligand comprises a tridentate ligand or a combination thereof, preferably wherein the second polydentate ligand comprises a tricarboxylic acid, a salt thereof, or a combination thereof.

2. An oral care composition, said oral care composition comprising: a. An oral care active substance, wherein the oral care active substance comprises a fluoride ion source and a stannous ion source; and b. A dental ligand mixture, wherein the dental ligand mixture comprises: i. a first polydentate ligand, wherein the first polydentate ligand is oxalic acid or a salt thereof or a combination thereof; and ii. A monodentate ligand, wherein the monodentate ligand is gluconic acid or a salt thereof or a combination thereof, and the molar ratio of the stannous ion as described in a. to the mixture of the monodentate ligands as described in bi. and bii. is in the range of 1:1 to 1:4, preferably 1:1 to 1:3; and iii. A second polydentate ligand, wherein the second polydentate ligand comprises a tridentate ligand or a combination thereof, preferably wherein the second polydentate ligand comprises a tricarboxylic acid, a salt thereof, or a combination thereof.

3. The oral care composition according to claim 1 or 2, wherein the tricarboxylic acid comprises citric acid, isocitric acid, aconitic acid, propane-1,2,3-tricarboxylic acid, pyromellitic acid, their salts or combinations thereof, preferably wherein the tricarboxylic acid comprises citric acid or its salts or combinations thereof.

4. The oral care composition according to any one of the preceding claims, wherein the oral care composition comprises about 1.0% to about 7.5%, preferably about 1.5% to about 5.0%, more preferably about 1.7% to about 4.0% by weight of the oral care composition.

5. The oral care composition according to any one of the preceding claims, wherein the oral care composition comprises about 1.0% to about 7.5%, preferably about 1.5% to about 5.0%, more preferably about 1.7% to about 4.0% by weight of the oral care composition.

6. The oral care composition according to any one of the preceding claims, wherein the oral care composition comprises about 1.0% to about 7.5%, preferably about 1.5% to about 5.0%, more preferably about 1.7% to about 4.0% of the monodentate ligand by weight of the oral care composition.

7. An oral care composition, said oral care composition comprising: a. An oral care active substance, wherein the oral care active substance comprises a fluoride ion source and a stannous ion source; and b. A polydentate ligand, wherein the polydentate ligand is a tetracarboxylic acid, preferably wherein the tetracarboxylic acid comprises ethylenediaminetetraacetic acid, ethylenetetracarboxylic acid, ethane-1,1,2,2-tetracarboxylic acid, or salts thereof, or combinations thereof; and The ratio of the stannous ion to the polydentate ligand is in the range of about 1:1 to about 1:2, preferably about 1:

1.

8. The oral care composition of claim 7, wherein the tetracarboxylic acid comprises ethylenediaminetetraacetic acid, its salts, or combinations thereof, preferably wherein the tetracarboxylic acid is ethylenediaminetetraacetic acid, its salts, or combinations thereof.

9. The oral care composition according to claim 7 or 8, wherein the oral care composition comprises about 1.0% to about 7.5%, preferably about 1.5% to about 5.0%, more preferably about 1.7% to about 4.0% by weight of the oral care composition.

10. The oral care composition according to any one of the preceding claims, wherein the fluoride ion source comprises stannous fluoride, sodium fluoride, sodium monofluorophosphate, amine fluoride, or a combination thereof, preferably stannous fluoride.

11. The oral care composition according to any one of the preceding claims, wherein the composition comprises at least about 1000 ppm of soluble fluoride ions, preferably wherein the composition comprises about 0.2% to about 1% of the fluoride ion source by weight of the oral care composition, more preferably about 0.3% to about 0.6% of the fluoride ion source by weight of the oral care composition.

12. The oral care composition according to any one of the preceding claims, wherein the stannous ion source comprises stannous fluoride, stannous chloride, or a combination thereof, preferably stannous fluoride, more preferably wherein the stannous ion source, the fluoride ion source, and the fluoride ion source comprise stannous fluoride.

13. The oral care composition according to any one of the preceding claims, wherein the composition comprises about 0.2% to about 1.0% of the stannous ion source by weight of the oral care composition, more preferably about 0.4% to about 1.0% of the stannous ion source by weight of the oral care composition.

14. The oral care composition according to any one of the preceding claims, wherein the pH value of the oral care composition is from about 4 to about 6, preferably wherein the pH value of the oral care composition is from about 4 to about 5.5, more preferably wherein the pH value of the oral care composition is from about 4.5 to about 5.5, and even more preferably wherein the pH value of the oral care composition is about 4.

5.

15. The oral care composition according to any one of the preceding claims, wherein the oral care composition is used to treat and / or prevent acid erosion and / or dental caries.

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