RU2776381C2 - Composition for oral care - Google Patents

Abstract

FIELD: personal hygiene.

SUBSTANCE: invention relates to a composition for oral care for inhibition of teeth demineralization. The proposed composition contains a carrier acceptable for oral administration and cationic copolymer with repeated links obtained from n-vinylpyrrolidone (VP) and repeated links obtained from monomers containing amines or guanidine, selected from a group consisting of n-vinyl phthalimide, 2-N-morpholinoethylacrylate, 2-N-morpholinoethylmethacrylate, 2-diisopropylaminoethylmethacrylate, 2-aminoethylmethacrylate, methacryloyl-L-lysine, N-(2-aminoethyl)methacrylamide, 2-(tert-butylamino)ethyl methacrylate, 2-acryloxyethyltrimethylammonium, 3-guanidinopropylmethacrylate, N-(3-guanidinopropyl)methacrylamide, arginine methacrylamide, N-(diaminomethylene)-2-methylprop-2-enamide, 1-(2-aminoethyl)-1H-pyrrole-2,5-dione and 1-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl)ethyl)guanidine, spermidine and 1-(4-aminobutyl) guanidine.

EFFECT: use of the above-mentioned cationic copolymers of vinylpyrrolidone in compositions for oral care allows for achievement of useful effects of demineralization prevention.

11 cl, 8 tbl, 6 ex

Description

FIELD OF THE INVENTION

The present invention relates to compositions containing cationic polyvinylpyrrolidone (PVP) copolymers for use in an oral care composition to prevent demineralization. In certain embodiments, the present invention relates to amine-containing vinylpyrrolidone copolymers used to achieve beneficial demineralization prevention effects.

BACKGROUND OF THE INVENTION

Caries is one of the most common diseases affecting people worldwide. It results from a complex relationship between dental biofilms (plaque), the host organism, and the enzymatic conversion of dietary sugars to organic acids. As such, the resulting acids effectively reduce the pH of the microenvironment below 5.5, resulting in enamel dissolution or demineralization. The rapid adjustment to near neutral pH is due to the high buffering capacity of saliva, which leads to remineralization on the enamel surface. An imbalance in the cycles of de- and remineralization, in which demineralization takes longer, leads to caries.

Fluoride, known as a caries prevention and treatment agent, has been considered as a possible solution for the regulation of dental erosion. Recently, various types of micro-/nanoparticles (hydroxyapatite, bioglass, silica particles, etc.) have also been studied to determine their anti-erosion properties. Some divalent cations such as calcium, zinc and tin have also been used to prevent demineralization.

Despite the widespread use of fluoride in consumer products, almost half of the population still suffers from tooth decay. Micro-/nanoparticles show some efficiency in terms of remineralization, but they are very difficult to formulate in a mouthrinse, and this efficiency is highly dependent on the retention time on the enamel surface. For example, bioglass, such as those sold under the trademark NOVAMIN, can only be prepared as anhydrous formulations. Divalent cations also have limitations related to preparation or consumer experience, for example zinc has a bitter aftertaste and tin is known to cause tooth staining.

Prevention of tooth demineralization is receiving increasing attention as a viable strategy to reduce the incidence and/or slow the progression of tooth decay. Thus, there is always a need to develop oral care compositions that prevent demineralization.

SUMMARY OF THE INVENTION

According to one aspect, compositions are described comprising an orally acceptable carrier and a cationic copolymer obtained by polymerizing n-vinylpyrrolidone (VP) with cationic amine-containing monomers or by copolymerizing n-vinylpyrrolidone (VP) monomers with cationic amide-containing monomers. , followed by deprotection to form amines. Another aspect relates to the use of such compounds in the oral cavity to inhibit tooth demineralization.

DETAILED DESCRIPTION OF THE INVENTION

The compositions of the present invention may contain, consist of or essentially consist of the essential elements and features of the invention described herein, as well as any additional or optional ingredients, components or features described herein. In this document, the term "comprising" (and its grammatical variants) is used in a broad sense in the sense of "having" or "including", and not in a narrow sense in the sense of "consisting only of".

In this document, the singular forms are considered to cover both the plural and the singular.

Unless otherwise noted, all documents cited in the relevant part are considered to be incorporated herein by reference; mention of any document should not be taken as an admission that it is prior art with respect to the present invention. Moreover, all documents, the contents of which are incorporated herein by reference in their entirety, are incorporated herein only to the extent that they do not contradict this description.

All percentages given herein are percentages by weight (wt%) of solids/actives, unless specifically stated otherwise.

The present invention relates to cationic vinylpyrrolidone copolymers useful for achieving beneficial effects, including mineralization and anti-erosion benefits, in oral care formulations. In certain embodiments, the implementation of the cationic copolymers used in the present invention, described by formula I:

(I),

(I)

where R ₁ is a repeating unit containing an amine group, and "x" represents the number of VP units and is an integer; "y" represents the number of units R ₁ and is an integer; and the x to y ratio is about 1:99 to about 99:1. The x and y repeat units in the copolymer of the present invention may be randomly distributed.

Cationic vinylpyrrolidone copolymers (cationic PVP copolymers) are prepared by copolymerizing n-vinylpyrrolidone (VP) monomers with cationic amine-containing monomers, or by copolymerizing n-vinylpyrrolidone (VP) monomers with cationic amide-containing monomers, followed by deprotection to form amines . Examples of suitable amine-containing monomers include, for example, n-vinylphthalimide (VPA), 2-N-morpholinoethyl acrylate, methacryloylchloin methyl sulfate, 2-N-morpholinoethyl methacrylate, 2-diisopropylaminoethyl methacrylate, 2-aminoethyl methacrylate, methacryloyl-L-lysine, N -[3-(N, N-dimethylamino)propyl]methacrylamide, N-(2-aminoethyl)methacrylamide, 2-(N,N-dimethylamino)ethyl acrylate, 2-(N,N-diethylamino)ethyl methacrylate, 2-(tert -butylamino)ethyl methacrylate, 2-(N,N-dimethylamino)ethyl methacrylate, 2-acryloxyethyltrimethylammonium, and the like. Examples of suitable amide-containing monomers include n-vinylformamide (VF), N-(3-aminopropyl)methacrylamide, N-(3-BOC-aminopropyl)methacrylamide, N-[2-(N,N-dimethylamino)ethyl]methacrylamide, N-[3-(N,N-dimethylamino)propyl]acrylamide, and the like.

Other examples of amine-containing monomers include, for example, guanidinium-containing monomers, 3-guanidinopropyl methacrylate, N-(3-guanidinopropyl)methacrylamide, arginine methacrylamide, N-(diaminomethylene)-2-methylprop-2-enamide, 1-( 2-aminoethyl)-1H-pyrrol-2,5-dione and 1-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethyl)guanidine, combinations of two or more of them, etc.

Also other examples of monomers include, for example, monomers that can be modified after polymerization to open an amine or guanidine functional group, such as maleic anhydride, followed by a condensation reaction with a primary amine and/or a primary amine to open a guanidine functional group, for example spermidine and 1-(4-aminobutyl)guanidine), respectively. In particular, for monomers containing multiple amines, one amine will be available to carry out the reaction, while the other will be protected to prevent cross-linking. In this case, after completion of the polymerization, the protected amine is deprotected to reveal the primary amine. This approach can also be applied to other amine-containing functional groups.

Some of the monomers and post-polymerization modifications may eventually show both positive and negative charges, or be zwitterionic.

According to some preferred embodiments, cationic vinylpyrrolidone copolymers are prepared by copolymerizing n-vinylpyrrolidone (VP) monomers with amine group-containing monomers such as n-vinylphthalimide. In other preferred embodiments, cationic vinylpyrrolidone copolymers are prepared by copolymerizing n-vinylpyrrolidone (VP) monomers with cationic monomers containing amides, such as n-vinylformamide, followed by deprotection to form amines. As will be understood by those skilled in the art with respect to Formula I, the R ₁ repeating unit can be described as derived from an amine-containing cationic monomer or an amide-containing cationic monomer that has been deprotected to form an amine as described herein. For example, R ₁ is a repeat unit derived from n-vinylphthalimide or deprotected n-vinylformamide.

Cationic copolymers for use in the present invention may be heterogeneous in distribution of R ₁ monomers and may be different in weight percentage of each repeating unit and respective monomer/repeating unit ratio. For example, in certain embodiments, repeat units derived from vinylpyrrolidone and cationic monomers (R ₁ ) independently comprise from about 5% to about 95% by weight of the polymer, including from about 10% to about 90%, from 20% to about 80%, from 20 to about 50%, 30 to about 50%, 30 to about 40%, 50 to about 90%, 50 to about 70%, 50 to about 60%, 60 to about 70% by weight of polymer . In certain preferred embodiments, vinylpyrrolidone derived repeating units comprise from about 60% to about 80%, including about 65%, by weight of the polymer, or from about 70% to about 90%, including about 85%, by weight of the polymer.

The ratio of repeating units derived from vinylpyrrolidone to repeating units derived from cationic monomers (R ₁ ) is from about 10:90 to about 90:10, including from about 20:80 to about 80:20, from about 30 : 70 to about 70:30, about 40:60 to about 60:40, and about 50:50. In certain preferred embodiments, the ratio of repeat units derived from vinylpyrrolidone to repeat units derived from cationic monomers (R ₁ ), is from about 50:50 to about 70:30, including from about 60:30 to about 70:30. In certain preferred embodiments, the ratio of repeat units derived from vinylpyrrolidone to repeat units derived from cationic monomers (R ₁ ), ranges from about 70:30 to about 90:10, including about 85:15.

The copolymers of the present invention may be of any suitable molecular weight. In certain embodiments, the polymers have a weight average molecular weight of about 10,000 to about 1,000,000, including about 10,000 to about 750,000, about 10,000 to about 500,000, about 10,000 to about 250,000, and about 150,000 In certain preferred embodiments, the average molecular weight is from about 10,000 to about 500,000, including from about 10,000 to about 250,000. In certain preferred embodiments, the average molecular weight is from about 10,000 to about 250,000, including about 150 000.

The copolymers may contain cross-linking agents. Cross-linking agents suitable for use in the present invention contain at least two reactive sites, which are electrophiles, made with the possibility of easy reaction with amines. If the cross-linking agent has two reactive sites, it is bifunctional and thus can interact with two amino groups, for example two cationic units in different polymer chains. The distance between reactive groups can be increased using a spacer fragment. Such a spacer is often an aliphatic chain or a polyester construct, such as poly- or oligoethylene glycols. Preferably the crosslinker is bi-, tri-, or tetra-functional, although bi-functional or tri-functional is preferred, and bi-functional is most preferred. Typical examples of such cross-linking functional groups are reactive esters, Michael acceptors and epoxides. Suitable cross-linking agents are known and include glycosaminoglycans such as hyaluronic acid and chondroitin sulfate, glutaraldehyde, glyoxal, diethyl squarate, diepoxides such as diglycidyl ether, genipin, formaldehyde. Preferred cross-linking molecules are ester derivatives of squaric acid, diepoxides and acrylamide derivatives, diethyl squarate (3,4-diethoxy-3-cyclobutene-1,2-dione) and its structurally similar analogs, 1,4-butanediol diglycidyl ether, acrylamide derivatives and their structurally similar counterparts. The most preferred cross-linking molecules are phosphate-containing molecules such as tripolyphosphate, pyrophosphate, hexametaphosphate, phytic acid, inositol phosphate, and the like. Other suitable cross-linking agents may include, but are not limited to, sulfate-containing molecules, citric acid, and the like. These cross-linking agents can be used singly or in combination with each other. In general, to obtain the desired type of composition, it is preferable to have higher polymer concentrations and lower cross-linking agent concentrations. It is preferable to minimize the amount of cross-linking agent used. The molar ratio of crosslinker to polymer in terms of the number of functional groups in the crosslinker and the amount of amino groups available in the polymer is preferably 0.2:1 or less, more preferably 0.1:1 or less, and most preferably 0.05:1 or less. This molar ratio is based on the number of groups available for crosslinking on the crosslinker and on the polymer. For a crosslinking agent, it will depend on the number of functional groups (bi-, tri-, tetrafunctional, etc.), and on a polymer, on the availability of cationic groups.

The compositions of the present invention may contain from about 0.01~10% of the cationic polymers of the present invention. In certain preferred embodiments, the compositions comprise about 0.01% to about 5%, about 0.01% to about 3%, about 0.01% to about 2%, about 0.01% to about 1%, or about 0.01 to about 0.5%, or about 0.01 to about 0.05%, by weight of the cationic polymer of formula I. In certain preferred embodiments, the composition contains from about 0.01 to about 5%, preferably from about 0 01 to about 3% or about 0.01 to about 1% by weight of the cationic polymer of Formula I.

Any of a wide variety of carriers suitable for oral administration may be used in the present compositions. The carrier medium may be aqueous or non-aqueous. The aqueous carrier medium is usually water, although water-alcohol mixtures can also be used. In certain embodiments, water is added q.s. (Quantum Sufficit - translated from Latin "in sufficient quantity as needed") to the composition. In certain embodiments, the implementation of the aqueous phase is from about 60% to about 95% or from about 75% to about 90% by weight of the composition. In certain compositions, water is present in an amount of from about 60% to about 95%, or from about 75% to about 90%. Alternatively, the compositions of the present invention may be formulated as a dry powder, chewing gum, film, semi-solid, solid or liquid concentrate. In such embodiments, for example, water is added q.s as needed in the case of liquid concentrates or powder formulations, or water can be removed using standard evaporation procedures known in the art to obtain a dry powder composition. Evaporated or freeze-dried forms are preferred for storage and shipping.

In some embodiments, alcohol can be added to the composition. Any of a number of alcohols represented by the formula R ₃ -OH, where R ₃ is an alkyl group having 2 to 6 carbon atoms, can be used in the present invention. Examples of suitable alcohols of the formula R ₃ -OH include ethanol; n-propanol, isopropanol; butanols; pentanols; hexanols; and combinations of two or more of them; and the like. In certain embodiments, the alcohol is or contains ethanol.

In some embodiments, alcohol may be present in the composition in an amount of about 10.0% v/v. or more of the total composition, or from about 10.0% to about 35.0% vol./about. total composition, or from about 15.0% to about 30.0% vol./about. total composition and can be from about 20.0% to about 25.0% vol./about. overall composition.

In some embodiments, the compositions may contain a reduced level of alcohol. The phrase "reduced level" of alcohol means the amount of alcohol R ₃ -OH about 10% vol./about. or less, or about 5% vol./about. or less, or about 1.0% vol./about. or less, or about 0.1% vol./about. or less by volume of the total composition. In certain embodiments, the compositions of the present invention are free of R ₃ -OH alcohols.

The compositions of the present invention preferably have a pH of about 11 or less. In certain embodiments, the composition has a pH of about 3 to less than 7, or about 3.5 to less than 7, or about 3.5 to about 6.5, or about 3.5 to about 5.5, or from about 3.5 to about 5.0.

As will be appreciated by those skilled in the art, the pH of the composition may be adjusted or achieved using an amount of buffer effective to provide the composition with a pH below 11. The composition may optionally contain at least one pH modifying agent as used herein, including acidifying agents for pH lowering agents, alkalizing agents to raise the pH, and buffering agents to adjust the pH within the desired range. For example, one or more compounds selected from acidifying, alkalizing, and buffering agents may be included to provide a pH of about 2 to about 7, or in various embodiments, about 3 to about 6 or about 4 to about 5. Any an orally acceptable pH modifying agent, including, but not limited to, carboxylic and sulfonic acids, acid salts (e.g., disodium citrate, disodium citrate, disodium malate, etc.), alkali metal hydroxides such as sodium hydroxide, borates, silicates, imidazole and mixtures thereof. One or more pH modifying agents are optionally present in a total amount effective to maintain the composition in a pH range acceptable for oral administration. In certain embodiments, inorganic acids can be used as a buffer added to the composition.

In certain embodiments, organic acids can be used as a buffer added to the composition. Suitable organic acids for use in the compositions of the present invention include, without limitation, ascorbic acid, sorbic acid, citric acid, glycolic acid, lactic acid and acetic acid, benzoic acid, salicylic acid, phthalic acid, phenolsulfonic acid, and mixtures thereof. wherein the organic acid is optionally selected from the group consisting of benzoic acid, sorbic acid, citric acid and mixtures thereof, or the organic acid is optionally benzoic acid.

In some embodiments, buffer systems used have been found to be sodium benzoate/benzoic acid, sodium citrate/citric acid, phosphoric acid/sodium/potassium phosphate.

As such, the amount of buffer is from about 0.001% (or about 0.001% w/v) to about 5.0% (or about 5.0% w/v) of the composition. In certain embodiments, the buffer is present in amounts of 0.001% (or about 0.001% w/v) to 1.0% w/v. (or about 1.0% w/v) of the composition, or from 0.100% (or about 0.100% w/v) to about 1.0% (or about 1.0% w/v) of the composition.

The compositions of the present invention may further contain any of a variety of optional ingredients, including, without limitation, oily components, active ingredients, additional surfactants, humectants, solvents, flavoring agents, sweeteners, coloring agents, preservatives, and the like.

Any of a variety of oily components can be used in the present compositions. The oily component may contain any of one or more oils or other materials that are water insoluble or substantially water insoluble, meaning that their solubility is less than about 1% by weight in water at 25°C, or optionally less than about 0.1%. In certain embodiments, the oily component of the present invention comprises, consists essentially of, or consists of at least one essential oil, i.e., natural or synthetic (or a combination thereof) concentrated plant-derived hydrophobic material, typically containing volatile compounds of at least one flavor oil. , or combinations of two or more of them. Examples of suitable essential oils, flavor oils and their amounts are described below. In certain embodiments, the implementation of the composition contains a total amount of oily component of about 0.05% wt./mass. or more, about 0.1% wt./mass. or more or about 0.2% wt./mass. or more oily component.

In certain embodiments, the compositions of the present invention contain essential oils. Essential oils are volatile aromatic oils, which may be synthetic or may be obtained from plants by distillation, expression or extraction, and which usually have the scent or fragrance of the plant from which they are derived. The essential oils used can provide antiseptic activity. Some of these essential oils also act as fragrance agents. Essential oils used include, without limitation, citrus, thymol, menthol, methyl salicylate (oil of wintergreen), eucalyptol, carvacrol, camphor, anethole, carvone, eugenol, isoeugenol, limonene, ozimene, n-decyl alcohol, citronel, a-salpineol , Methyl Acetate, Citronellyl Acetate, Methyl Eugenol, Cineole, Linalool, Ethyllinalaol, Safrole, Vanillin, Spearmint Oil, Peppermint Oil, Lemon Oil, Orange Oil, Sage Oil, Rosemary Oil, Cinnamon Oil, Allspice Oil, Laurel Leaf Oil, Oil cedar leaves, geraniol, verbenone, anise oil, laurel fruit oil, benzaldehyde, bergamot oil, bitter almond, chlorthymol, cinnamaldehyde, citronella oil, clove oil, coal tar, eucalyptus oil, guaiacol, tropolone derivatives such as hinokitiol, lavender oil , mustard oil, phenol, phenyl salicylate, pine oil, pine needle oil, sassafras oil, lavender broadleaf oil, styrax, thyme oil, tolua nsky balsam, turpentine oil, clove oil and combinations thereof.

In certain embodiments, essential oils are selected from the group consisting of thymol ((CH ₃ ) ₂ CHC ₆ H ₃ (CH ₃ )OH, also known as isopropyl-m-cresol), eucalyptol (C ₁₀ H ₁₈ O, also known as cineole), menthol (CH ₃ C ₆ H ₉ (C ₃ H ₇ )OH), also known as hexahydrothymol), methyl salicylate (C ₆ H ₄ OHCOOCH ₃ , also known as wintergreen oil), isomers of each of these compounds, and a combination of two or more of them. In some embodiments, the compositions of the present invention contain thymol. In some embodiments, the compositions of the present invention contain menthol. In some embodiments, the compositions contain all four of these essential oils.

In certain embodiments, thymol is used in amounts from about 0.0001% to about 0.6% w/v. or from about 0.005% to about 0.07% wt./about. compositions. In certain embodiments, eucalyptol can be used in amounts from about 0.0001% to about 0.51% w/v. or from about 0.0085% to about 0.10% wt./about. compositions. In certain embodiments, menthol is used in amounts from about 0.0001% to about 0.25% w/v. or from about 0.0035% to about 0.05% wt./about. compositions. In certain embodiments, methyl salicylate is used in amounts from about 0.0001% to about 0.28% w/v. or from about 0.004% to about 0.07% wt./about. compositions. In certain embodiments, the total amount of all such essential oils present in the described compositions may be from about 0.0004% to about 1.64% w/v. or from about 0.0165% to about 0.49% wt./about. compositions.

In certain embodiments, fluoride source compounds may be present in the mouthrinse compositions of the present invention. These compounds may have little or no water solubility and are characterized by their ability to release fluoride ions or fluoride-containing ions in water. Typical fluoride source compounds are inorganic fluorides such as soluble alkali metal, alkaline earth metal and heavy metal fluorides, e.g. sodium fluoride, potassium fluoride, ammonium fluoride, copper fluoride, zinc fluoride, stannous fluoride, stannous fluoride, barium fluoride, hexafluorosilicate sodium, ammonium hexafluorosilicate, sodium fluorozirconate, sodium monofluorophosphate, aluminum mono- and difluorophosphate, and fluorinated sodium calcium pyrophosphate. Amine fluorides can also be used, for example N'-octadecyltrimethylenediamine-N, N,N'-tris(2-ethanol)-dihydrofluoride and 9-octadecenylamine hydrofluoride. In certain embodiments, the fluoride source compound is typically present in an amount sufficient to release up to about 5%, or about 0.001% to about 2%, or about 0.005% to about 1.5% fluoride by weight of the composition.

In certain embodiments, desensitizing agents such as potassium salts, nitrate, and oxalate may be included in the present invention in an amount of from about 0.1% to about 5.0% w/v. compositions. Other compounds that release potassium ions (eg KCl) are also acceptable. Calcium phosphates at high concentrations may also provide some additional desensitization. It is believed that the action of these agents is due either to the formation of a barrier mineral layer on the surface of the teeth, or to the delivery of potassium to the dental nerves to depolarize the nerves. A more detailed description of suitable desensitizing agents can be found in US Pat. No. 2006/0013778 to Hodosh and US Pat. No. 6,416,745 to Markowitz et al., both of which are incorporated herein by reference in their entirety.

In certain embodiments, antitartar compounds (eg, various carboxylates, polyaspartic acid, etc.) may be incorporated into the present invention. Anionic polymeric polycarboxylates are also used as antitartar agents. Such materials are well known in the art and are used in the form of free acids or partially or preferably completely neutralized water soluble alkali metal salts (eg potassium and preferably sodium) or ammonium salts. Preferred are copolymers of maleic anhydride or acid with another polymerizable ethylenically unsaturated monomer, preferably methyl vinyl ether (methoxyethylene), in a ratio of 1:4 to 4:1 by weight, having a molecular weight (MW) of from about 30,000 to about 1,000,000. These copolymers are available, for example, as Gantrez 25 AN 139 (MM 500,000), AN 119 (MM 250,000) and preferably pharmaceutical grade S-97 (MM 70,000) from GAF Chemicals Corporation.

Additional antitartar agents may be selected from the group consisting of polyphosphates (including pyrophosphates) and salts thereof; polyaminopropanesulfonic acid (AMPS) and its salts; polyolefinsulfonates and their salts; polyvinyl phosphates and their salts; polyolefin phosphates and their salts; diphosphonates and their salts; phosphonoalkanocarboxylic acid and its salts; polyphosphonates and their salts; polyvinylphosphonates and their salts; polyolefin phosphonates and their salts; polypeptides and mixtures thereof; carboxyl-substituted polymers and mixtures thereof. In one embodiment, the salts are alkali metal or ammonium salts. Polyphosphates are usually used in the form of fully or partially neutralized water-soluble alkali metal salts such as potassium, sodium, ammonium salts and mixtures thereof. Inorganic polyphosphate salts include alkali metal (e.g., sodium) tripolyphosphate, tetrapolyphosphate, alkali metal dibasic dibasic salts (e.g., disodium), alkali metal monobasic trisubstituted salts (e.g., trisodium), potassium hydrogen phosphate, sodium hydrogen phosphate, and alkali metal hexametaphosphate (e.g. , sodium) and mixtures thereof. Polyphosphates larger than tetrapolyphosphate usually occur as amorphous glassy materials. In one embodiment, these are polyphosphates manufactured by FMC Corporation, which are commercially known as Sodaphos (n ≈ 6), Hexaphos (n ≈ 13) and Glass H (n ≈ 21, sodium hexametaphosphate) and mixtures thereof. The pyrophosphate salts useful in the present invention include alkali metal pyrophosphates, di-, tri- and monopotassium or sodium pyrophosphates, dibasic alkali metal pyrophosphate salts, alkali metal pyrophosphate salts, and mixtures thereof. In one embodiment, the pyrophosphate salt is selected from the group consisting of trisodium pyrophosphate, sodium dihydrogen phosphate (Na ₂ H ₂ P ₂ O ₇ ), dipotassium pyrophosphate, sodium pyrophosphate (Na ₄ P ₂ O ₇ ), potassium pyrophosphate (K ₄ P ₂ O ₇ ) and their mixtures. Polyolefin sulfonates include those in which the olefin group contains 2 or more carbon atoms and their salts. Polyolefin phosphonates include those in which the olefin group contains 2 or more carbon atoms. Polyvinylphosphonates include polyvinylphosphonic acid. Diphosphonates and their salts include azocycloalkane-2,2-diphosphonic acids and their salts, azocycloalkane-2,2-diphosphonic acid ions and their salts, azacyclohexane-2,2-diphosphonic acid, azacyclopentane-2,2-diphosphonic acid, N-methyl-azacyclopentane-2,3-diphosphonic acid, EHDP (ethane-1-hydroxy-1,1-diphosphonic acid), AHP (azacycloheptane-2,2-diphosphonic acid), ethane-1-amino-1, 1-diphosphonate, dichloromethanediphosphonate, etc. Phosphonoalkanecarboxylic acid or its alkali metal salts include PPTA (phosphonopropane tricarboxylic acid), PBTA (phosphonobutane-1,2,4-tricarboxylic acid), each as an acid or alkali metal salts. Polyolefin phosphates include those in which the olefin group contains 2 or more carbon atoms. Polypeptides include polyaspartic and polyglutamic acids.

In certain embodiments, zinc salts, such as zinc chloride, zinc acetate, or zinc citrate, may be added as an astringent to create an "antiseptic cleansing" sensation, as a breath freshening enhancing agent, or as an anti-tartar agent. stone, in an amount of about 0.0025% wt./about. up to about 0.75% wt./about. compositions.

Any of a variety of additional surfactants can be used in the present invention. Suitable surfactants may include anionic, nonionic, cationic, amphoteric, zwitterionic surfactants, and combinations of two or more of these. Examples of suitable surfactants are described, for example, in US patent No. 7,417,020, Fevola et al, which is fully incorporated herein by reference.

In certain embodiments, the compositions of the present invention contain a non-ionic surfactant. Those skilled in the art will appreciate that any of a variety of one or more non-ionic surfactants includes, without limitation, compounds obtained by the condensation of alkylene oxide groups (hydrophilic in nature) with a hydrophobic organic compound, which may be aliphatic or alkylated aromatic. Examples of suitable non-ionic surfactants include, without limitation, alkyl polyglucosides; alkylglucosamines, block copolymers such as ethylene oxide and propylene oxide copolymers such as poloxamers; ethoxylated hydrogenated castor oils, commercially available, for example, under the tradename CRODURET (Croda Inc., Edison, New Jersey); alkylpolyethylene oxide, for example polysorbates and/or fatty alcohol ethoxylates; polyethylene oxide condensates of alkylphenols; products resulting from the condensation of ethylene oxide with the reaction product of propylene oxide and ethylenediamine; ethylene oxide condensates of aliphatic alcohols; long chain tertiary amine oxides; long chain oxides of tertiary phosphines; long chain dialkyl sulfoxides; and their mixtures.

Representative non-ionic surfactants are selected from the group known as poly(oxyethylene)-poly(oxypropylene) block copolymers. Such copolymers are known commercially as poloxamers and are available in a wide range of structures and molecular weights with various ethylene oxide contents. These non-ionic poloxamers are non-toxic and are acceptable as direct food additives. They are stable and readily dispersed in aqueous systems and are compatible with a wide variety of formulations and other ingredients in oral formulations. Such surfactants should have an HLB (hydrophilic-lipophilic balance) of about 10 to about 30, and preferably about 10 to about 25. By way of example, non-ionic surfactants useful in the present invention include poloxamers identified as poloxamers 105, 108, 124, 184, 185, 188, 215, 217, 234, 235, 237, 238, 284, 288, 333, 334, 335, 338, 407, and combinations of two or more of them In certain preferred embodiments implementation, the composition contains poloxamer 407.

In certain embodiments, the compositions of the claimed invention contain less than about 9% non-ionic surfactant, less than 5%, or less than 1.5%, or less than 1%, or less than 0.8, less than 0.5%, less than 0. 4% or less than 0.3% non-ionic surfactants. In certain embodiments, the composition of the present invention is free of non-ionic surfactants.

In certain embodiments, the compositions of the present invention also contain at least one alkyl sulfate surfactant. In certain embodiments, suitable alkyl sulfate surfactants include, without limitation, sulfated C ₈ -C ₁₈ , optionally sulfated C ₁₀ -C ₁₆ even carbon chain alcohols neutralized with a suitable basic salt such as sodium carbonate or sodium hydroxide; and mixtures thereof, such that the alkyl sulfate surfactant has an even number of chain atoms, C ₈ -C ₁₈ , optionally C ₁₀ -C ₁₆ . In certain embodiments, the alkyl sulfate is selected from the group consisting of sodium lauryl sulfate, sodium hexadecyl sulfate, and mixtures thereof. In certain embodiments, commercially available mixtures of alkyl sulfates are used. A typical percentage distribution of alkyl sulfates with different alkyl chain lengths in commercially available sodium lauryl sulfate (SLS) is as follows:

Percentages of alkyl

circuit components

different lengths in SLS

_C12 > 60%

C ₁₄ 20%-35%

_C16 <10%

_C10 <1%

_C18 <1%

Another suitable surfactant is one selected from the group consisting of sarcosinate surfactants, isethionate surfactants and taurate surfactants. Preferred for use in the present invention are the alkali metal or ammonium salts of these surfactants, such as the sodium and potassium salts of the following compounds: lauroyl sarcosinate, myristoyl sarcosinate, palmitoyl sarcosinate, stearoyl sarcosinate and oleoyl sarcosinate. The sarcosinate surfactant may be present in the compositions of the present invention in an amount of from about 0.1% to about 2.5%, or from about 0.5% to about 2% by weight of the total composition.

In certain embodiments, the compositions of the present invention are substantially free of sodium lauryl sulfate. The term "substantially free of" as used herein means less than 2% by weight of the composition, preferably less than 1%, less than 0.5%, less than 0.1%, less than 0.05% by weight of the composition. In certain embodiments, the composition of the present invention is free of sodium lauryl sulfate.

The zwitterionic synthetic surfactants useful in the present invention include derivatives of aliphatic quaternary ammonium, phosphonium and sulfonium compounds in which the aliphatic radicals may be linear or branched and wherein one of the aliphatic substituents contains from about 8 to 18 carbon atoms, and one contains an anionic water-soluble group, for example a carboxyl group, a sulfonate, a sulfate, a phosphate, or a phosphonate.

Amphoteric surfactants useful in the present invention include, without limitation, derivatives of aliphatic secondary and tertiary amines, in which the aliphatic radical may be linear or branched, and one of the aliphatic substituents contains from about 8 to about 18 carbon atoms, and one contains an anionic water-soluble group, for example a carboxylate, sulfonate, sulfate, phosphate or phosphonate. Examples of suitable amphoteric surfactants include, without limitation, alkyl iminodipropionates, alkylamphoglycinates (mono- or di-), alkylamphopropionates (mono- or di-), alkylamphoacetates (mono- or di-), N-alkyl[3-aminopropionic acids, alkylpolyaminocarboxylates, phosphorylated imidazolines, alkylbetaines, alkylamidobetaines, alkylamidopropylbetaines, alkylsultaines, alkylamidosultaines and mixtures thereof. In certain embodiments, the amphoteric surfactant is selected from the group consisting of alkylamidopropyl betaines, amphoacetates such as sodium lauroamphoacetate, and mixtures thereof. Mixtures of any of the aforementioned surfactants may also be used. A more detailed discussion of anionic, nonionic, and amphoteric surfactants can be found in US Patent No. 7,087,650 to Lennon; U.S. Patent No. 7,084,104 to Martin et al.; US Pat. No. 5,190,747 to Sekiguchi et al. and US Patent No. 4,051,234 to Gieske, et al., each of which is hereby incorporated by reference in its entirety.

In certain embodiments, the compositions of the claimed invention contain less than about 9% amphoteric surfactant, less than 5%, or less than 1.5%, or less than 1%, or less than 0.8, less than 0.5%, less than 0. 4% or less than 0.3% amphoteric surfactants. In certain embodiments, the compositions of the present invention are free of amphoteric surfactants.

Additional surfactants may be added in addition to the alkyl sulfate surfactant to improve the solubility of essential oils, provided that said surfactants do not interfere with the bioavailability of the essential oils. Suitable examples include additional anionic surfactants, nonionic surfactants, amphoteric surfactants, and mixtures thereof. However, in certain embodiments, the total concentration of surfactants (including an alkyl sulfate surfactant alone or in combination with other surfactants) in the mouthwashes of the present invention must not exceed or be about 9% or less, optionally, the total concentration of surfactants should be about 5% or less, optionally about 1% or less, optionally about 0.5% or less % wt./mass. active surfactant based on the weight of the composition.

In certain embodiments, a sugar alcohol (humectant) is also added to the oral compositions of the present invention. The solvent(s) from the class of sugar alcohols may(s) be selected from those multi-hydroxy functional compounds commonly used in oral and ingestible products. In certain embodiments, the sugar alcohol(s) used must be non-metabolizable and non-fermentable sugar alcohol(s). In specific embodiments, sugar alcohols include, without limitation, sorbitol, glycerin, xylitol, mannitol, maltitol, inositol, allitol, altritol, dulcitol, galactitol, glucitol, hexitol, iditol, pentitol, ribitol, erythritol, and mixtures thereof. Optionally, the sugar alcohol is selected from the group consisting of sorbitol and xylitol, or mixtures thereof. In some embodiments, the sugar alcohol is sorbitol. In certain embodiments, the total amount of sugar alcohol(s) that is(are) added to effectively assist in dispersing or dissolving the mouthrinse ingredients or other ingredients should not exceed about 50% w/w of the total composition. Or the total amount of sugar alcohol should not exceed about 30% wt./about. overall composition. Or the total amount of sugar alcohol should not exceed 25% wt./about. overall composition. The sugar alcohol may be present in an amount of from about 1.0% to about 24% w/v, or from about 1.5% to about 22% w/v, or from about 2.5% to about 20% w/v. ./about. overall composition.

In certain embodiments, a solvent with a polyol is added to the composition. The polyol solvent contains a polyol or a polyhydric alcohol selected from the group consisting of polyhydric alkanes (such as propylene glycol, glycerol, butylene glycol, hexylene glycol, 1,3-propanediol); polyhydric esters of alkanes (dipropylene glycol, ethoxydiglycol); polyalkene glycols (such as polyethylene glycol, polypropylene glycol) and mixtures thereof. In certain embodiments, the polyol solvent may be present in an amount of 0% to about 40% w/v, or about 0.5% to about 20% w/v, or about 1.0% to about 10% w/v compositions.

Sweeteners such as aspartame, sodium saccharin (saccharin), sucralose, stevia, acesulfame K, and the like can be added to improve taste in amounts from about 0.0001% w/v. up to about 1.0% wt./about. In certain preferred embodiments, the sweetener contains sucralose.

In certain embodiments, the composition further comprises flavoring agents or flavors to correct or enhance the taste of the composition, or to reduce or mask the harsh "burning" or "tingling" effect of ingredients such as thymol. Possible flavorings suitable for administration include, without limitation, flavor oils such as anise oil, anethole, benzyl alcohol, spearmint oil, citrus oils, vanillin, and the like. Other flavors such as citrus oils, vanillin, and the like, may be added to provide additional flavor variation. In these embodiments, the amount of flavor oil added to the composition can be from about 0.001% to about 5% w/v. or from about 0.01% to about 0.3% wt./about. overall composition. The specific flavors or flavors and other flavoring ingredients used will vary depending on the particular taste and feel desired. Those skilled in the art can select and tailor these types of ingredients to achieve the desired results.

In certain embodiments, acceptable approved food colors may be used to provide a pleasing color to the compositions of the invention. They may be selected, without limitation, from an extensive list of acceptable food colors. Suitable dyes for this purpose include FD&C Yellow No. 5, FD&C Yellow No. 10, FD&C Blue No. 1, and FD&C Green No. 3. . up to about 0.0008% wt./about. or from about 0.000035% wt./about. up to about 0.0005% wt./about. compositions.

Other conventional ingredients, including those known and used in the art, may be used in the liquid or mouthrinse compositions of the present invention. Examples of such ingredients include thickeners, suspending agents and softeners. Guidance on thickeners and suspending agents used in the compositions of the present invention can be found in US Patent No. 5,328,682 to Pullen et al., incorporated herein in its entirety by reference. In certain embodiments, they are introduced in amounts from about 0.1% wt./about. up to about 0.6% wt./about. or about 0.5% wt./about. compositions.

In some embodiments, antimicrobial preservatives may be added to the composition. Some antimicrobial preservatives that may be used include, without limitation, cationic antibacterials such as sodium benzoate, polyquaternium polycationic polymers (i.e., polyquaternium-42:poly[oxyethylene(dimethylimino)ethylene (dimethylimino)ethylene dichloride]) , quaternary ammonium salts or quaternary ammonium compounds, parabens (i.e. parahydroxybenzoates or parahydroxybenzoic acid esters), hydroxyacetophenone, 1,2-hexanediol, caprylyl glycol, chlorhexidine, alexidine, hexetidine, benzalkonium chloride, domiphen bromide, cetylpyridinium chloride (CPC) , tetradecylpyridinium chloride (TPC), N-tetradecyl-4-ethylpyridinium chloride (TDEPC), octenidine, bisbiguanides, zinc or ionic tin agents, grapefruit extract, and mixtures thereof. Other antibacterial and antimicrobial agents include, without limitation: 5-chloro-2-(2,4-dichlorophenoxy)-phenol, commonly referred to as triclosan; 8-hydroxyquinoline and its salts, copper II compounds, including, without limitation, copper (II) chloride, copper (II) sulfate, copper (II) acetate, copper (II) fluoride, and copper (II) hydroxide; phthalic acid and its salts, including but not limited to those described in US Pat. No. 4,994,262, including magnesium monopotassium phthalate; sanguinarine; salicylanilide; iodine; sulfonamides; phenols; delmopinol, octapinol and other piperidine derivatives; niacin preparations; nystatin; apple extract; thyme oil; thymol; antibiotics such as augmentin, amoxicillin, tetracycline, doxycycline, minocycline, metronidazole, neomycin, kanamycin, cetylpyridinium chloride and clindamycin; analogues and salts of the above; methyl salicylate; hydrogen peroxide; metal chlorites; pyrrolidone ethyl cocoylarginate; lauroyl ethyl arginate monochloride; and mixtures of all of the above. In another embodiment, the composition contains phenolic antimicrobial compounds and mixtures thereof. The antimicrobial components may be present in an amount of from about 0.001% to about 20% by weight of the oral care composition. In another embodiment, antimicrobial agents typically comprise from about 0.1% to about 5% by weight of the oral care compositions of the present invention.

Other antibacterial agents may be basic amino acids and salts. Other embodiments may contain arginine.

In certain embodiments, the compositions may include bleaches, oxidizing agents, anti-inflammatory agents, chelating agents, abrasives, combinations thereof, and the like.

The bleach may be included in the present compositions as an active agent. Active agents suitable for bleaching are selected from the group consisting of alkali metal and alkaline earth metal peroxides, metal chlorites, polyphosphates, perborates including mono- and tetrahydrates, perphosphates, percarbonates, peroxyacids and persulfates such as ammonium, potassium, sodium and lithium, and combinations thereof. Suitable peroxide compounds include hydrogen peroxide, urea peroxide, calcium peroxide, carbamide peroxide, magnesium peroxide, zinc peroxide, strontium peroxide, and mixtures thereof. In one embodiment, the peroxide compound is carbamide peroxide. Suitable metal chlorites include calcium chlorite, barium chlorite, magnesium chlorite, lithium chlorite, sodium chlorite and potassium chlorite. Additional whitening actives may be hypochlorite and chlorine dioxide. In one embodiment, the chlorite is sodium chlorite. In another embodiment, the percarbonate is sodium percarbonate. In one embodiment, the persulfates are oxones. The level of these substances depends on the available oxygen or chlorine, respectively, which the molecule can provide to whiten the pigment spot. In one embodiment, bleaches may be present at levels from about 0.01% to about 40%, in another embodiment from about 0.1% to about 20%, in another embodiment from about 0.5% to about 10%. % and in another embodiment, from about 4% to about 7% by weight of the oral care composition.

The compositions of this invention may contain an oxidizing agent, such as a peroxide source. The peroxide source may contain hydrogen peroxide, calcium peroxide, carbamide peroxide, or mixtures thereof. In some embodiments, the peroxide source is hydrogen peroxide. Other peroxide actives may include those which produce hydrogen peroxide when mixed with water, such as percarbonates, eg sodium percarbonates. In certain embodiments, the peroxide source may be in the same phase as the tin ion source. In some embodiments, the composition contains from about 0.01% to about 20% of a peroxide source, in other embodiments, from about 0.1% to about 5%, in certain embodiments, from about 0.2% to about 3%. and in another embodiment, from about 0.3% to about 2.0% peroxide source by weight of the oral composition. The peroxide source may be provided as free ions, salts, complex or encapsulated form. It is desirable that the peroxide in the composition be stable. The peroxide can provide a reduction in the formation of pigment spots when measured by the cyclic test for pigment spots or other appropriate methods.

Anti-inflammatory agents may also be present in the compositions of the present invention. Such agents may include, without limitation, non-steroidal anti-inflammatory drugs (NSAIDs), oxicams, salicylates, propionic acids, acetic acids, and fenamates. Such NSAIDs may include, without limitation, ketorolac, flurbiprofen, ibuprofen, naproxen, indomethacin, diclofenac, etodolac, indomethacin, sulindac, tolmetin, ketoprofen, fenoprofen, piroxicam, nabumetone, aspirin, diflunisal, meclofenamate, mefenamic acid, oxyphenbutazone, phenylbutazone and acetaminophen. The use of NSAIDs such as ketorolac is claimed in US Pat. No. 5,626,838. It describes methods for the prevention and/or treatment of primary and recurrent oral or oropharyngeal squamous cell carcinoma by topical administration of an effective amount of an NSAID to the oral cavity or oropharynx. Suitable steroidal anti-inflammatory drugs include corticosteroids such as fluccinolone and hydrocortisone.

The present compositions may optionally contain chelating agents, also referred to as chelating agents or sequestrants, many of which also prevent tartar formation or have activity on dental tissues. An advantage of using chelating agents in oral care products is their ability to form complexes with calcium, such as found in bacterial cell walls. Chelating agents can also break down plaque by removing calcium from the calcium bridges that help keep the biomass intact. Chelating agents also have the ability to form complexes with metal ions and thus help to prevent their adverse effect on the stability or appearance of the products. Chelation of ions, such as iron or copper ions, helps slow down the oxidative deterioration of finished products. In addition, chelating agents can in principle remove stains by binding to tooth surfaces and thus displacing stains or chromagens. The retention of such chelating agents also helps to prevent the accumulation of age spots due to the destruction of stain binding sites on tooth surfaces. Thus, chelating agents can help reduce age spots and improve cleansing. A chelating agent can help improve cleaning since fused silica and abrasives are mechanically cleaned, while a chelating agent can help provide chemical cleaning. Because fused silica is a good mechanical cleanser, more stains can be removed, so a chelating agent may be desirable to hold, suspend, or complex with the stain so that it cannot recontaminate the tooth surface. In addition, the chelating agent can coat the surface of the tooth, helping to prevent the formation of a new pigment spot. Chelating agents may be desirable to be added to formulations containing cationic antibacterial agents. It may be desirable to add chelating agents to tin formulations. The chelating agent can help stabilize the tin and allow more tin to be bioavailable. The chelating agent can be used in tin formulations with a pH greater than about 4.0. In some formulations, tin may be stable without the use of a chelating agent because tin is more stable with fused silica than with precipitated silica.

Suitable chelating agents include soluble phosphate compounds such as phytates and linear polyphosphates having two or more phosphate groups, including but not limited to tripolyphosphate, tetrapolyphosphate, and hexametaphosphate. Preferred polyphosphates are those that have a number of phosphate groups n averaging from about 6 to about 21, such as the polyphosphates commercially available as Sodaphos (n ≈ 6), Hexaphos (n ≈ 13) and Glass H (n ≈ 21). Other polyphosphorylated compounds can be used in addition to or instead of polyphosphate, in particular polyphosphorylated inositol compounds such as phytic acid, myo-inositol pentakis(dihydrogen phosphate); myo-inositol tetrakis(dihydrogen phosphate), myo-inositol trikis(dihydrogen phosphate), and an alkali metal, alkaline earth metal or ammonium salt thereof. Preferred in this context is phytic acid, also known as myo-inositol 1,2,3,4,5,6-hexakis (dihydrogen phosphate), or inositol hexaphosphoric acid, and its alkali metal, alkaline earth metal or ammonium salts. As used herein, the term "phytate" includes phytic acid and its salts, as well as other polyphosphorylated inositol compounds. The amount of chelating agent in the compositions will depend on the chelating agent used and will typically be from at least about 0.1% to about 20%, preferably from about 0.5% to about 10%, and more preferably from about 1. 0% to about 7%.

However, other phosphate compounds that are used in this context, due to their ability to bind, solubilize and transport calcium, are the above-described surface-active organophosphate compounds used as agents acting on dental tissues, including organic phosphate mono-, di- or triesters.

Other suitable chelating agents for use in controlling plaque, tartar and pigmentation include the polyphosphonates described in U.S. Pat. No. 3,678,154, Widder et al., U.S. Pat. carbonyl; polymer or copolymer of acrylic acid in US patent No. 4,847,070, July 11, 1989, Pyrz et al., and US patent No. 4,661,341, April 28, 1987, Benedict et al.; sodium alginate in US Pat. No. 4,775,525 issued October 4, 1988 to Pera; polyvinylpyrrolidone in GB 741,315, WO 99/12517 and US Pat. No. 5,538,714 to Pink et al.; and copolymers of vinylpyrrolidone with carboxylates in US Pat. No. 5,670,138 to Venema et al.

However, other chelating agents suitable for use in the present invention are anionic polymeric polycarboxylates. Such materials are well known in the art and are used in the form of free acids or partially or preferably completely neutralized water soluble alkali metal salts (eg potassium and preferably sodium) or ammonium salts. Examples are copolymers of maleic anhydride or acid with another polymerizable ethylenically unsaturated monomer, preferably methyl vinyl ether (methoxyethylene), in a ratio of 1:4 to 4:1, having a molecular weight (MW) of from about 30,000 to about 1,000,000. These copolymers are available , for example, as Gantrez® AN 139 (MM 500,000), AN 119 (MM 250,000) and S-97 pharmaceutical grade (MM 70,000) manufactured by GAF Chemicals Corporation. Other working polymeric polycarboxylates include 1:1 copolymers of maleic anhydride with ethyl acrylate, hydroxyethyl methacrylate, N-vinyl-2-pyrrolidone, or ethylene, the latter being available, for example, as Monsanto EMA No. 1103, MM 10,000 and EMA Grade 61, and 1 : 1 copolymers of acrylic acid with methyl or hydroxyethyl methacrylate, methyl or ethyl acrylate, isobutyl vinyl ether or N-vinyl-2-pyrrolidone. Additional working polymeric polycarboxylates are described in US Pat. No. 4,138,477, Feb. 6, 1979, Gaffar, and US Pat. No. 4,183,914, Jan. 15, 1980, Gaffar et al., and include copolymers of maleic anhydride with styrene, isobutylene, or ethyl vinyl ether; polyacrylic, polyitaconic and polymaleic acids; and sulfoacrylic oligomers with only 1000 MW available as Uniroyal ND-2. Other suitable chelating agents include the polycarboxylic acids and their salts described in US Pat. No. 5,015,467 to Smitherman, US Pat. Nos. 5,849,271 and 5,622,689, both Lukacovic; such as tartaric acid, citric acid, gluconic acid, malic acid; succinic acid, succinic acid and their salts such as sodium or potassium gluconate and citrate; a combination of citric acid/alkali metal citrate; disodium tartrate; dipotassium tartrate; sodium potassium tartrate; sodium hydrotartrate; potassium hydrotartrate; acid or salt form sodium monosuccinate tartrate, potassium disuccinate tartrate, and mixtures thereof. In some embodiments, mixtures or combinations of chelating agents may be present.

Suitable abrasives for use in the present invention may include, without limitation: perlite, silica such as sand or quartz, ground glass, silicon carbide, ilmenite (FeTiO ₃ ), zircon oxide, zircon silicate, topaz, TiO ₂ , precipitated lime, chalk, ground pumice, zeolites, talc, kaolin, kieselguhr, aluminum oxide, silicates, zinc orthophosphate, sodium bicarbonate (baking soda), plastic particles, alumina, aluminum hydroxide, calcium carbonate, calcium pyrophosphate and mixtures thereof. The silica-based abrasive may be natural amorphous silica, including diatomaceous earth; or synthetic amorphous silica such as precipitated silica; or silica gel such as a silica xerogel; or mixtures thereof.

As such, the amount of abrasive suitable for use in the composition of the invention will be determined empirically to provide an acceptable level of cleaning and polishing in accordance with techniques known in the art. In one embodiment, the composition of the present invention includes an abrasive. In one embodiment, the composition includes a silica abrasive. In one embodiment, the silica abrasive is present in an amount of 0.001% by weight. up to 30 wt.%. In one embodiment, the silica abrasive is present in an amount of 1 wt.% to 15 wt.%. In one embodiment, the silica abrasive is present in an amount of 4 wt.% to 10 wt.%.

Data on other active and/or inactive oral care ingredients used and further examples thereof can be found in US Pat. No. 6,682,722 to Majeti et al. and US Pat. No. 6,121,315 to Nair et al. document by reference.

The compositions of the present invention can be made in accordance with any of the many methods described herein and known in the art. In general, the compositions described can be prepared by combining the desired components in a suitable container and mixing them under ambient conditions by any conventional agitation means well known in the art, such as a propeller mechanical agitator, a paddle agitator, and the like.

The compounds and compositions of the present invention may be used in the oral cavity. In accordance with certain embodiments, the present invention provides for the inhibition, prevention and/or treatment of tooth demineralization by bringing the tooth surface into contact with a composition of the present invention. In certain embodiments, the implementation of the present invention provides for the inhibition or prevention of demineralization of teeth by bringing the surface of the tooth into contact with the composition of the present invention.

In each of the above methods, the composition according to the claimed method can be applied to the tooth surface by any of a variety of methods. In certain embodiments, the composition is administered by the user to the oral cavity and applied to the surface of the tooth as a mouthwash or mouthrinse. In certain embodiments, the composition is administered to the oral cavity and applied to the tooth surface as a toothpaste on a dentifrice product, such as a toothbrush. The compositions of the present invention may additionally be administered orally and applied to the surface of the tooth in the form of a chewing gum, lozenge, dissolvable wafer, or the like.

Moreover, the step of bringing into contact within the methods of the present invention may include bringing the surface of the tooth into contact with the composition for any suitable period of time. In certain embodiments, the contacting step includes bringing the surface into contact for less than thirty seconds. In certain embodiments, the contacting step includes bringing the surface into contact with the composition for thirty seconds or more, such as for about thirty seconds, for about forty seconds, for about one minute, or for more than one minute.

EXAMPLES

EXAMPLE 1

Cationic vinylpyrrolidone copolymer (cationic PVP copolymer) was prepared by copolymerizing n-vinylpyrrolidone (VP) monomer with n-vinylphthalimide (VPA) monomer followed by hydrazinolysis of VPA to vinylamine. The resulting copolymer is called PVP-PVAmine.

Briefly, a mixture of isopropyl alcohol (IPA, 105 g) and acetic acid (0.05 g) was heated to about 82°C in a round bottom flask under nitrogen and with gentle agitation. An initiator solution consisting of IPA (125 g) and a mixture of VPA (30 g), VP (70 g) and VAZO 67 (0.4 g, Chemours Inc.) was added gradually over 90 minutes. The temperature of the reaction mixture was allowed to rise during the polymerization to 85-86°C and the mixture was held at this temperature for another hour before being cooled to 80°C. Hydrazine hydrate (200 g) was then added to the reaction mixture and the temperature was maintained at 80°C for another 2.5 hours. The solution was diluted with methanol (600 g) and the phthalhydrazine solids were removed by vacuum filtration. The extract was distilled for concentration to obtain approximately 100 g of the final solution. The polymer was then precipitated from tetrahydrofuran, filtered and dried under vacuum for several hours. The expected polymer composition is 64.8 wt% VP/35.2 wt% VPA based on titration to a pH 5.0 endpoint (2.03 meq/g titer). All chemicals were purchased from Sigma-Aldrich unless otherwise noted.

EXAMPLE 2

The anti-erosion performance of the PVP-PVAmine synthesized in Example 1 was compared to commercially available PVP homopolymers (Sigma-Aldrich - cat. no. PVP10, PVP4, PVP360) by measuring the change in pH due to the dissolution of hydroxyapatite (HAP) powder in a solution of citric acid. . Experimental solutions were prepared by dissolving PVP homopolymers or PVP-PVAmine copolymer in water and adjusting the pH with hydrochloric acid or sodium hydroxide.

Briefly, before treatment, 100 mg ceramic hydroxyapatite type I, 20 µm (Bio Rad Laboratories, Inc. - cat. no. 158-2000) was incubated for 2 hours at 37°C in artificial saliva (Northeast Laboratory, Waterville, Maine). - Cat. No. T0300) to ensure the formation of a salivary film. The film-coated HAP powder was subjected to one ten minute mixing treatment by inverting from the bottom to the lid with 10 ml of the designated experimental solution. Subsequently, the treated particles were filtered using a polycarbonate membrane filter, pore size 5 μm, diameter 25 mm (Whatman® Nuclepore™ Track-Etched Membranes - cat. no. 110613), and washed with deionized water, after which they were dispersed in 25 ml of a 1 wt.% solution citric acid at pH 3.8. The pH value in the mass of the citric acid solution was recorded every 30 seconds for 10 minutes. Erosion prevention performance was measured by the magnitude of the increase in pH from baseline, with a smaller increase in pH indicating slower dissolution and higher efficiency.

Tables 1 and 2 show the compositions of various experimental solutions. Table 1 lists solutions with PVP homopolymers and Table 2 lists solutions with PVP-PVAmine copolymers. Sodium fluoride (NaF) or sodium tripolyphosphate (PPi) was added to some solutions to determine if synergistic effects could be seen with the presence of fluoride or phosphate ions in the test solution. The tables also show positive controls (100 ppm NaF in water) and negative controls (water).

Table 1. PVP Homopolymer Experimental Blends Used in a Manual Erosion Prevention Study. Concentrations are indicated in % wt./mass.

Ingredient A2 B2 C2 D2 E2 F2 G2 H2 PVP (average mol. wt. 10,000) - - 2,000 2,000 - - - - PVP (average mol. wt. 40,000) - - - - 2,000 2,000 - - PVP (average mol. wt. 360,000) - - - - - - 2,000 2,000 sodium fluoride - 0.0221 - - - - - - Water, pH regulator 100 Ven. quantity Ven. quantity Ven. quantity Ven. quantity Ven. quantity Ven. quantity Ven. quantity pH N/A 4.2 4.2 7.0 4.2 7.0 4.2 7.0

Note: the concentration was converted to % wt./mass. taking into account the bulk density of the product 1,000 g/ml.

A2=water (negative control)

B2=100 ppm F, pH=4.2 (positive control)

C2=PVP-10K, pH 4.2

D2=PVP-10K, pH 7.0

E2=PVP-40K, pH 4.2

F2=PVP-40K, pH 7.0

G2=PVP-360K, pH 4.2

H2=PVP-360K, pH 7.0

Table 2. PVP-PVAmine Test Blends Used in the Manual Erosion Prevention Study. Concentrations are indicated in % wt./mass.

Ingredient A2 B2 I2 J2 K2 L2 M2 PVP-PVAmine - - 3.086 3.086 - 3.086 3.086 Sodium tripolyphosphate (PPi) - - - - 1.266 1.266 1.266 sodium fluoride - 0.0221 - 0.0221 - - 0.0221 Water, pH regulator 100 Ven. quantity Ven. quantity Ven. quantity Ven. quantity Ven. quantity Ven. quantity pH N/A 4.2 6.8 6.8 - 6.8 6.8

Note: the concentration was converted to % wt./mass. taking into account the bulk density of the product 1,000 g/ml.

A2=water (negative control)

B2=100 ppm F, pH 4.2 (positive control)

I2=PVP-PVAmine, pH 6.8

J2=PVP-PVAmine+100 ppm F, pH 6.8

K2=PPi

L2=PVP-PVAmine+PPi, pH 6.8

M2=PVP-PVAmine+PPi+100 ppm F, pH 6.8

Table 3 summarizes the erosion prevention performance for the test solutions in Tables 1 and 2.

Table 3. Manual Erosion Prevention Test Results for Test Blends of PVP Homopolymers and PVP-PVAmine Copolymers Expressed as Increase in Bulk Solution pH From Baseline (ΔpH)

Compound ΔpH A2 0.29 B2 0.09 C2 0.26 D2 0.29 E2 0.28 F2 0.28 G2 0.30 H2 0.28 I2 0.23 J2 0.04 K2 0.22 L2 0.13 M2 0.04

Table 3 shows that experimental solutions containing only PVP (C2 to H2) provide little erosion prevention compared to pure water (ΔpH 0.29 for water versus 0.26-0.30 for experimental PVP solutions). An experimental solution containing only PVP-PVAmine (I2) was superior to pure water in preventing erosion, while a solution of PVP-PVAmine with sodium tripolyphosphate (PPi), solution L2, was superior in preventing erosion of PPi alone. The highest erosion prevention efficiency was demonstrated by experimental solutions in which PVP-PVAmine was combined with fluoride (J2) or both fluoride and phosphate ions (M2). These experimental solutions outperformed the positive control (B2).

Thus, in general, experimental solutions containing cationic PVP copolymer PVP-PVAmine are better suited for erosion prevention than solutions containing PVP polymers.

EXAMPLE 3

A second cationic vinylpyrrolidone copolymer (cationic PVP copolymer) was obtained by copolymerizing n-vinylpyrrolidone (VP) monomer with n-vinylformamide (VF) monomer followed by deprotection by aqueous alkaline hydrolysis. The resulting copolymer is also called PVP-PVAmine.

Briefly, a solution of isopropyl alcohol (IPA, 80 g) and water (360 g) was heated to approximately 82°C in a round bottom flask under nitrogen and with gentle stirring. A stock solution of VAZO 56 initiator (1 g, Chemours Inc.) in water (20 g) was added. The monomer/initiator solution consisting of VF (60 g), VP (340 g), VAZO 56 (3 g) and water (36 g) was then gradually added over 120 minutes. The pH of the solution was checked periodically and a solution of sodium monophosphate (~20% in water) was added as needed to maintain the pH at 6-6.5. During polymerization, the temperature was allowed to rise to 83-84°C and the mixture was held at this temperature for another 30 minutes before being cooled to 73°C. Thereafter, a solution of the promoter with FeSO4 heptahydrate (0.01 g) in water (5 g) was added, followed by the addition of a solution to remove the initiator, 70% T-butyl hydroperoxide (0.75 g) dissolved in water (5 g). The temperature of the reaction mixture was maintained at 77°C for 20 min. A second solution was then added to remove the initiator, followed by the addition of an activating solution of isoascorbic acid (1 g) in water (10 g). The temperature was maintained for another 20 minutes and then the mixture was allowed to cool. The polymer solution was then diluted with water (900 g) and purified using overnight dialysis (Slide-A-Lyzer G2 dialysis cassette, MWCO=2k) against an equal weight of water. VF was hydrolyzed by adding sodium bisulfite (2 g diluted in 5 g water) and heating to 80°C for 4 hours in a round bottom flask. The polymer solution was then cooled and purified again by overnight dialysis. The final polymer was isolated by precipitation in acetone and vacuum drying at 50°C overnight. The theoretical polymer composition was 85 wt% VP/15 wt% VF, corresponding to 2.11 meq/g titer when titrated to a pH 5.0 endpoint. The actual titer required was 1.2 meq/g. All chemicals were purchased from Sigma-Aldrich unless otherwise noted.

EXAMPLE 4

The effect of the PVP-PVAmine synthesized in Example 3 on hydroxyapatite remineralization was evaluated using a constant composition based automatic titration method. Experimental solutions containing PVP-PVAmine were compared with experimental solutions containing commercially available PVP homopolymer. Experimental solutions were prepared by dissolving the PVP homopolymer or PVP-PVAmine copolymer in water and adjusting the pH to 4.2 with hydrochloric acid or sodium hydroxide.

Briefly, prior to treatment, 50 mg ceramic hydroxyapatite type I, 20 µm (Bio Rad Laboratories, Inc. - cat. no. No. T0300) to form a film layer. The film-coated hydroxyapatite was then subjected to a single treatment for ten minutes, filtered, washed and added to a solution of artificial saliva (1 mM CaCl ₂ , 0.6 mM KH ₂ PO ₄ , pH=7.4). pH and calcium activity were measured and kept constant by automatic titration (Metrohm Titrando). Higher remineralization efficiency correlated with higher volumes of titrant added to maintain a constant composition.

Table 4 shows the compositions of various experimental solutions. Sodium fluoride (NaF) was added to some solutions to determine if synergistic effects could be detected in the presence of fluoride ions in the experimental solution. The tables also show positive controls (0.0221 NaF in water) and negative controls (water).

Table 4. PVP-PVAmine test blends used in constant composition experiments. Concentrations are indicated in % wt./mass. * Plasdone K-29/32 polymer from Ashland, a commercially available water-soluble n-vinyl-2 pyrrolidone homopolymer with a typical molecular weight of 58,000 daltons

Ingredient A2 B2 C4 D4 E4 F4 G4 H4 PVP-PVAmine - - - - 1,000 1,000 5,000 5,000 PVP* - - 0.850 0.850 - - - - sodium fluoride - 0.0221 - 0.0221 - 0.0221 - 0.0221 Water, pH regulator 100 Ven. quantity Ven. quantity Ven. quantity Ven. quantity Ven. quantity Ven. quantity Ven. quantity pH N/A 4.2 4.2 4.2 4.2 4.2 4.2 4.2

Table 5 summarizes the results of experiments with constant composition for the experimental solutions from Table 4.

Table 5. The results of experiments with constant composition are presented as the final volume of titrant (in ml) after 30 min of automatic titration.

Compound Final volume of titrant
(mean ± SEM, ml) A2 8.3±0.6 B2 25.0±2 C4 9.4 ± 0.09 D4 26.8±0.6 E4 12.2±0.4 F4 31.0±2 G4 12.1±0.7 H4 25.3±0.7

The table shows that the final volume of titrant for experimental solutions containing only PVP (C4) reflects a negligible remineralization efficiency compared to pure water (8.3 ml for water vs. 9.4 ml for experimental PVP solutions). In the case of experimental solutions with only PVP-PVAmine (E4, G4), the total titrant volume increases to about 12 ml. When fluoride is added to experimental solutions with PVP-PVAmine, the remineralization efficiency increases already by 24% compared to the experimental solution with only fluoride (B2).

EXAMPLE 5

The effectiveness of remineralization for experimental mixtures with PVP-PVAmine was evaluated in vitro during five-day cycles of remineralization - demineralization. The PVP-PVAmine used in this example was synthesized in example (3).

Briefly, twenty-four crushed and polished samples of human tooth enamel were demineralized to create artificial lesions without the formation of cavities. Artificial lesions were formed by immersing samples in a demineralization solution, and the initial surface of the lesions had a range of 25-45 in units of Vickers hardness number (VHN). For each sample, the initial microhardness of the surface was measured using a Shimadzu Micro Hardness Tester. Twenty-four samples were divided into four groups of six, and these four groups were balanced by the initial microhardness of the surface of the samples.

These four experimental groups were subjected to a series of treatments followed by remineralization and demineralization steps. The four experimental groups used formulations C4, D4, E4 and F4 from Table 4 in Example 4. Briefly, C4 was PVP homopolymer 0.85%, D4 was PVP 0.85% with 100 ppm F, E4 was was PVP-PVAmine 1% and F4 was PVP-PVAmine 1% with 100 ppm F.

The remineralization step used artificial saliva (130 mM KCl, 1.5 mM CaCl ₂ , 0.9 mM KH ₂ PO ₄ , 25 mM BTP buffer, 2.2 g/l porcine mucin, pH=7), while the demineralization used lactic acid (0.1 M lactic acid, 0.2 wt.% carbopol, saturation with hydroxyapatite 50%, pH=5.0%). The daily regimen, which was carried out for five days, is shown in Table 6.

Table 6. Daily schedule for a five-day study with cyclic remineralization - demineralization. *At the start of the study, the first treatment was preceded by soaking in artificial saliva for one hour. ** On the fifth day of the study, the final treatment was followed by a one-hour soak in artificial saliva.

00:02 Treatment* 01:28 Soaking in artificial saliva 00:02 Treatment 01:28 Soaking in artificial saliva 02:00 Exposure to lactic acid 01:30 Soaking in artificial saliva 00:02 Treatment 01:28 Soaking in artificial saliva 00:02 Treatment 15:58 Soak overnight in artificial saliva**

After five days, the samples were evaluated for change in surface microhardness (ΔSMH), measured using a Shimadzu Micro Hardness Tester in units of Vickers hardness number (VHN). Higher remineralization efficiency correlated with a greater increase in surface microhardness. Table 7 shows the change in surface microhardness after five days of treatment.

Table 7. Change in surface microhardness after five-day cyclic remineralization/demineralization

Treatment ∆SMH(VHN) C4 1 ± 2 D4 13 ± 11 E4 2 ± 2 F4 36±10

Table 7 shows that after 20 treatments for five days, there was an increase in surface microhardness of enamel samples treated with PVP-Amine with 100 ppm F. Treatment with 1 wt% PVP-PVAmine and fluoride (F4) resulted in an ∆SMH of 1.8 times higher than when treated with PVP homopolymer and fluoride (D4).

EXAMPLE 6

Solutions of 1 wt % PVP-PVAmine synthesized in Example 3 and diluted in commercially available or experimental mouthwash formulations were prepared and tested for stability after (i) equilibration at room temperature, (ii) equilibration at 40°C and (iii) performing freeze-thaw cycles. The formulations tested are listed in Table 8 and are formulations with and without fluoride, formulations with and without alcohol, and alcohol-free formulations with and without anionic surfactants. All solutions were initially homogeneous throughout the volume. The loss of stability was defined as the loss of uniformity, for example due to the formation of sediment. After at least 22 weeks of storage at room temperature or 40°C, only formulations containing sodium lauryl sulfate surfactant lost stability. In addition, all solutions prepared from commercially available formulations, including containing and anionic surfactant, were tested for stability after three freeze-thaw cycles of 24 hours at -10°C and 24 hours at 25°C.

Table 8. Commercially Available Mouthwash Used for PVP-PVAmine Stability Testing

The product's name Country of origin Contains alcohol Contains fluoride Contains a surfactant based on sodium lauryl sulfate LISTERINE ZERO mouthwash USA Not Not Yes LISTERINE ZERO mouthwash Germany Not Yes Yes Mouthwash LISTERINE COOL MINT USA Yes Not Not LISTERINE TOTAL CARE ENAMEL GUARD Mouthwash Great Britain Yes Yes Not Experimental mouthwash N/A Not Not Not

Claims (11)

1. A composition for inhibiting tooth demineralization, comprising an orally acceptable carrier and a cationic copolymer having repeat units derived from n-vinylpyrrolidone (VP) and repeat units derived from monomers containing amines or guanidine selected from the group consisting of n-vinylphthalimide, 2-N-morpholinoethyl acrylate, 2-N-morpholinoethyl methacrylate, 2-diisopropylaminoethyl methacrylate, 2-aminoethyl methacrylate, methacryloyl-L-lysine, N-(2-aminoethyl)methacrylamide, 2-(tert-butylamino)ethyl methacrylate, 2- acryloxyethyltrimethylammonium, 3-guanidinopropyl methacrylate, N-(3-guanidinopropyl)methacrylamide, arginine methacrylamide, N-(diaminomethylene)-2-methylprop-2-enamide, 1-(2-aminoethyl)-1H-pyrrole-2,5-dione and 1 -(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethyl)guanidine, spermidine and 1-(4-aminobutyl)guanidine. 2. The composition of claim 1 wherein the repeating units are derived from a monomeric n-vinylphthalimide compound. 3. The composition according to claim 1, containing from 0.01 to 5% of the specified cationic copolymer. 4. The composition of claim 1, which is in a form selected from the group consisting of mouthwash, mouthrinse, mouth spray, toothpaste, tooth gel, gingival gel, mousse, foam, for the care of dentures, dentifrices, lozenges for resorption, concentrate and chewable tablets. 5. The composition according to claim 4, which is a mouthwash containing water and at least one surfactant selected from the group consisting of anionic, cationic, nonionic, zwitterionic surfactants and combinations of two or more of them. 6. The composition of claim 4 further comprising at least one essential oil selected from the group consisting of menthol, thymol, eucalyptol, methyl salicylate, and combinations of two or more of these. 7. Composition according to any one of claims 1 or 6, additionally containing fluoride. 8. Composition according to any one of claims 1 or 6, additionally containing sodium tripolyphosphate. 9. The composition of claim 1, wherein said copolymer has a weight average molecular weight of 10,000 to 1,000,000. 10. Composition according to any one of claims 1 or 5, which essentially does not contain sodium lauryl sulfate. 11. A composition according to any one of the preceding claims for use in a method for inhibiting tooth demineralization by bringing the tooth surface into contact with said composition.