CN104069013A - Oral nursing stannous composition - Google Patents

Abstract

The present invention discloses oral compositions comprising a source of stannous ions, a source of multivalent cations and a mineral surfactant which provide enhanced therapeutic efficacy derived from stannous fluoride and/or other stannous salts, including Antimicrobial efficacy, inhibition of bad breath, inhibition of plaque growth and metabolism, reduction of gingivitis, slowing of periodontal disease progression, reduction of dentin hypersensitivity, and reduction of crown and root caries. The mineral surfactants are agents that are substantive to mineral surfaces such as teeth and have chelating activity on the multivalent cations including stannous (Sn ⁺² ), zinc (Zn ⁺² ), copper (Cu ⁺² ), aluminum (Al ⁺³ ), iron (Fe ⁺² , Fe ⁺³ ), strontium (Sr ⁺² ), calcium (Ca ⁺² ), barium (Ba ⁺² ), magnesium ( Mg ⁺² ) and manganese (Mn ⁺² ). Preferred mineral surfactants include polymers or copolymers comprising phosphate, phosphonate or carboxyl groups. The composition also includes a source of fluoride ions and can be formulated as a single-phase or two-phase composition.

Description

Stannous oral care composition

This application is a divisional application of Chinese patent application 200680055850.5 with a filing date of October 2, 2006.

field of invention

The present invention relates to improved oral compositions comprising stannous salts such as stannous fluoride. These improved compositions have a variety of intraoral benefits derived from stannous fluoride and/or other stannous salts, including antimicrobial effects, inhibition of bad breath, inhibition of plaque growth and metabolism, reduction of gingivitis, reduction of periodontal disease progression, reduction of dentine hypersensitivity, and reduction of crown and root decay and erosion. In addition to providing the aforementioned benefits, the composition also provides significant improvements over conventional stannous compositions, including: 1) reduced tooth discoloration; 2) reduced astringency, thereby improving the composition's aesthetic properties; 3) reduced calculus formation, and 4) enhanced stability, bioavailability, thereby enhancing the efficacy of stannous as an antimicrobial, antiplaque, and antigingivitis agent. Improved stannous-containing compositions provide these benefits through the combined efficacy of stannous, a second multivalent cation, and mineral surfactants and chelating agents, preferably polymers and specifically comprising anionic polymeric substances such as condensed polyphosphates, polyphosphonates or polycarboxylates. The present invention also relates to methods of enhancing therapeutic efficacy while reducing tooth discoloration and improving the aesthetic desirability of oral compositions comprising stannous salts, such as stannous fluoride.

Background of the invention

Stannous fluoride is known for its efficacy in formulating oral products. Stannous fluoride was the first source of fluoride incorporated into toothpaste for its therapeutic efficacy in inhibiting dental caries. Since then, stannous fluoride gels, rinses, and dentifrices have been shown to provide clinical efficacy in reducing caries, dentin hypersensitivity, plaque, and gingivitis. In addition to these clinical benefits, stannous fluoride-containing formulations also help provide improved breath freshening benefits through chemical and antimicrobial actions. As stannous is lost by oxidation or precipitation during shelf storage, stannous fluoride formulations typically include a stabilization system designed to maintain bioavailable (ie soluble and active) levels of stannous. Therefore, stannous fluoride formulations are formulated with other stannous-containing ingredients, which provide a high concentration of stannous as stannous reserves to maintain clinical efficacy. Unfortunately, while stannous fluoride compositions are known to be highly effective, successful commercial utilization has been difficult to achieve due to the complexity in developing formulations that provide sufficient stannous fluoride stability and the side effects of stannous fluoride. Formulations that provide increased or improved efficacy often result in increased side effects. This limits clinical and commercial applications.

One of the most notable side effects of the routine use of stannous fluoride is yellowish-brown teeth. This discoloration results from the reaction of film, plaque and dietary components with available stannous deposited on the tooth surface during treatment with an effective stannous fluoride formulation.

A second side effect commonly encountered during use of effective stannous fluoride formulations is undesirable formulation astringency. Astringents are topically applied protein precipitants whose low cellular permeability limits action to the cell surface as well as the intercellular space. Strong astringents may cause tissue to shrink and wrinkle, and mucus secretions may settle or decrease. In oral products, these chemistries provide an unpleasant "dry" sensation in the oral cavity, such as on the tongue, gum tissue or oral epithelium. Stannous formulations containing sufficient stannous for bioavailability are often described by patients and consumers as astringent, and this property is undesirable. Astringency is most pronounced after product application.

A third side effect of the frequent use of stannous fluoride dentifrice compositions is a reduction in the effectiveness of these compositions in reducing tartar. It has been determined that stannous fluoride dentifrices, which have proven effective antimicrobial, antigingivitis, and other desirable benefits, do not always show reproducible clinical effects on the prevention of undesirable supragingival calculus buildup. Inhibition of supragingival calculus formation and other clinical benefits are desired by professionals, patients and consumers. The multifunctional activity of oral compositions can simplify health care and provide a holistic approach to maintaining therapeutic oral health.

Early attempts to develop effective and consumer acceptable stannous fluoride oral compositions to address these accumulated lesions, however, have not been entirely successful. US Patent 5,004,597 to Majeti et al. discloses oral compositions comprising stannous fluoride and gluconate. Inclusion of stannous gluconate improves formulation efficacy and stability. While effective, such formulations cause an undesirable degree of discoloration of the teeth. Furthermore, the formulation has an unacceptable aesthetic mainly due to stannous astringent properties. Likewise, US Patent 5,578,293 to Prencipe et al. discloses the use of organic acid compounds to stabilize stannous ion concentrations. In addition to stannous fluoride and citrate as an organic acid, the formulation also contained soluble pyrophosphate. US Patent 4,323,551 to Parran et al. discloses the use of pyrophosphates to provide anti-calculus benefits. Clinical studies have established the potential of mineral anionic surfactant inhibitors such as pyrophosphates in preventing the development of natural as well as antimicrobial-induced tooth discoloration. (Grossman, Bollmer, Sturzenberger, and Vick; "Journal of Clinical Dentistry" 6(4):185-187, 1995). In the Prencipe et al. patent, all examples contain sufficient citric acid and/or sodium citrate dihydrate to stabilize the stannous ion and prevent precipitation. These amounts also directly inhibit the incorporation of stannous pyrophosphate. If stannous does bind to pyrophosphate, studies have shown that this reduces the antimicrobial activity of stannous fluoride. The amount of citrate required to effectively stabilize the stannous ion against precipitation and against pyrophosphate binding also significantly detracts from the aesthetics of the stannous composition. The composition will be salty, sour and the stannous bound to the citrate will still have astringent properties which reduce the overall taste acceptability. US Patent 5,213,790 to Lukacovic et al. also discloses the use of a source of citrate ions in stannous compositions. US Patent 5,780,015 to Fisher et al. discloses the use of a two-phase dentifrice comprising a potassium salt and a stannous salt, wherein hydrogenated castor oil is used to help reduce astringency. Stannous salts are stabilized by using organic acid compounds as described in the Prencipe et al. patent. Another attempt to prepare effective stannous compositions is described in US Patent 5,716,600 to Zahradnik et al. This patent discloses low water content formulations that help prevent stannous fluoride from degrading over time. No attempt was made to reduce tooth discoloration of the formulations.

US Patent 5,017,363 to Suhonen discloses stannous ion chelating copolymers of alkyl vinyl ethers and maleic anhydride or maleic acid effective to stabilize stannous ion levels. Suhonen also discloses that due to the chelation of stannous ions in the presence of silica, soluble phosphates such as soluble pyrophosphates (e.g. tetrasodium pyrophosphate and tetrapotassium pyrophosphate), and compounds containing aldehyde groups The stabilizing effect of the polymer is ineffective, so the composition is essentially free of these ingredients.

US Patent No. 5,338,537 to White, Jr. et al. discloses the use of low molecular weight diphosphonic acids as binding agents for stannous to help reduce the tendency of the composition to discolor. Although effective in reducing the likelihood of tooth discoloration, laboratory studies have demonstrated very low antimicrobial activity of formulations comprising stannous complexed with low molecular weight bisphosphonic acids. Similar results were obtained for formulations containing soluble pyrophosphate in the absence of strong citrate chelation as described above.

Based on the foregoing, it was found that the same chemical and biochemical binding sites may be involved in the antibacterial/antiplaque activity and the reduction in stannous fluoride stability and tooth discoloration potential. Therefore, antimicrobial/antiplaque activity may be compromised in order to obtain stability and/or reduction in tooth discoloration. This makes it difficult to develop optimal stannous fluoride oral compositions and explains why there are only a few stannous fluoride compositions on the market today. In order to improve consumer acceptability and compliance with the use of stannous-containing oral compositions, there is a need for a stannous composition with high efficacy but low tooth discoloration and other negative aesthetic properties such as astringency. Furthermore, these formulations are expected to provide simultaneous efficacy in reducing and inhibiting calculus formation.

Summary of the invention

The present invention relates to oral compositions comprising a source of stannous ions, a source of multivalent cations, and a stannous-binding mineral surfactant that provide enhanced therapeutic efficacy with minimal tooth discoloration and astringent side effects. The composition provides both supragingival calculus reduction and inhibition. The mineral surfactants are agents that are direct to mineral surfaces such as teeth and also have chelating activity on multivalent cations such as stannous (Sn ⁺² ), zinc (Zn ⁺² ), copper (Cu ^{+2 2} ), Aluminum (Al ⁺³ ), Iron (Fe ⁺² , Fe ⁺³ ), Strontium (Sr ⁺² ), Calcium (Ca ⁺² ), Barium (Ba ⁺² ), Magnesium (Mg ⁺² ) and Manganese (Mn ⁺² ). The composition may also include a source of fluoride ions. The oral care compositions of the present invention can be formulated as single-phase or two-phase compositions. The present invention also provides a method of effectively delivering a stannous-containing composition by administering to a subject a stable dentifrice composition with minimal tooth discoloration or astringent side effects and effective tartar inhibition . The composition comprises a clinically effective amount of stannous fluoride and/or other stannous salts in combination with a mineral surfactant, preferably a polymer comprising phosphate, phosphonate or carboxyl groups, and a source of multivalent cations.

These and other features, aspects and advantages of the present invention will become apparent to those skilled in the art from the following detailed description.

Detailed description of the invention

While the specification concludes with claims that particularly point out and distinctly claim the invention, it is believed that the invention will be better understood from the following description.

All percentages used herein are by weight of the dentifrice composition, unless otherwise specified. Ratios used herein are molar ratios of the total composition unless otherwise indicated. All measurements are made at a temperature of 25°C unless otherwise specified.

Herein, "comprising/comprising" means that other steps and other ingredients that do not affect the end result can be added. This term includes the terms "consisting of" and "consisting essentially of".

As used herein, the word "comprising/comprises" and its variants are intended to be non-limiting, such that the recitation of an item in a list does not exclude other similar items that may also be useful in the materials, compositions, devices, and methods of the invention.

As used herein, the words "preferred," "preferably" and variations thereof refer to embodiments of the invention that afford particular benefits, under particular circumstances. However, other embodiments may also be preferred, under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, and is not intended to exclude other embodiments from the scope of the invention.

The oral compositions of the present invention may be in the form of toothpaste, dentifrice, toothpowder, topical oral gel, mouthwash, denture product, mouthspray, lozenge, oral tablet or chewing gum.

As used herein, unless otherwise indicated, the term "dentifrice" refers to a paste, gel or liquid formulation. The dentifrice composition can be in any desired form, such as deep stripes, light stripes, multiple layers, paste with gel around it, or any combination thereof.

The oral composition may be a single phase oral composition, or may be a combination of two or more oral compositions each in a separate phase. Herein, "single phase or separate phase" means that all components of each composition are combined in one mixture, which may contain liquid, solid and gaseous components. Therefore, each phase can be homogeneous or non-homogeneous. By "oral composition" is meant a product that is not swallowed intentionally for systemic administration of a particular therapeutic agent during normal administration, but which remains in the oral cavity long enough to contact substantially all of the teeth Surface and/or oral tissue to be orally active. As used herein, the term "total composition" refers to the total composition delivered to the oral cavity, whether it comprises a single phase or multiple phases.

If two-phase oral compositions are desired, each oral composition is contained in physically separate compartments of the dispenser and dispensed side-by-side. As used herein, the term "dispenser" refers to any pump, tube or container suitable for dispensing toothpaste.

As used herein, the term "orally acceptable carrier" includes safe and effective substances for use in the compositions of the present invention. The above materials are conventional additives in oral care compositions and include, but are not limited to, sources of fluoride ions, anticulus or antitartar agents, buffers, abrasives such as silica, bleaching agents such as peroxide sources, alkali metal bicarbonates Salt, thickening substances, humectants, water, surfactants, titanium dioxide, flavoring systems, sweeteners, xylitol, coloring agents, and mixtures thereof.

Herein, the terms "tartar" and "calculus" are used interchangeably and refer to the mineralized plaque biofilm.

As used herein, the term "stannous" is defined as stannous that is present in a dentifrice or other oral product and provided via sources such as stannous salts including stannous fluoride. It may involve stannous ions provided by stannous salts other than stannous fluoride added for stabilization purposes.

Active and other ingredients useful herein can be classified or described by their cosmetic and/or therapeutic benefit or their postulated mode of action or operation. It should be understood, however, that in some instances the actives and other ingredients useful herein may provide more than one cosmetic and/or therapeutic benefit or action, or function or operate via more than one mode of action. Accordingly, classification herein is for convenience only and is not intended to limit ingredients to the particular indicated application or applications listed.

The present invention relates to oral compositions comprising a source of stannous ions, a source of multivalent cations other than stannous, and a mineral surfactant having chelating activity for stannous and multivalent cations, the combination provides enhanced therapeutic efficacy derived from stannous with minimal tooth discoloration and astringent side effects. Herein, "therapeutic efficacy derived from stannous" is intended to include antimicrobial efficacy, halitosis inhibition, plaque growth and metabolism inhibition, reduction of gingivitis, slowing of periodontal disease progression, and reduction of dentin hypersensitivity. The composition preferably includes a fluoride source, which may be stannous fluoride, other fluoride salts, or combinations thereof. The composition provides both supragingival calculus reduction and inhibition. The reduction in tooth discoloration and astringency may also be enhanced by appropriate co-formulations, including the use of suitable poloxamer ingredients.

The mineral surfactant (MSA) is preferably a polymer, specifically an anionic polymer, such as a polyphosphate, polyphosphonate, or other phosphate- or phosphine-containing polymer having an average chain length of about 4 or more. Acid or carboxyl polymers. Those of ordinary skill in the art would appreciate that polymeric binders such as polyphosphates having an average chain length of about 4 or more would have similar properties to pyrophosphate or tripolyphosphate in stannous-containing dentifrice systems. effect. It has been found that chemically binding or chelating stannous with pyrophosphates, bisphosphonates or tripolyphosphates to prevent pigmentation likewise results in an unacceptable loss of therapeutic potential. However, the use of longer-chain polyphosphates and other phosphate- or phosphonate-containing polymers has been surprisingly effective in reducing tooth discoloration and astringent side effects without significantly reducing the efficacy of stannous. In fact it has been found that in oral compositions comprising stannous salts such as stannous fluoride, the inclusion of These polymeric mineral surfactants provide significant therapeutic benefits as well as reduced tooth discoloration and astringency while reducing supragingival calculus.

The oral care compositions of the present invention can be formulated as single-phase or two-phase compositions. One embodiment of the present invention provides a two-phase oral composition comprising a first composition comprising a source of stannous ions and a source of multivalent metal ions other than stannous, preferably zinc, and comprising a mineral A second composition of surfactants. The mineral surfactant in this embodiment may be a linear polyphosphate having an average chain length of about 4 or more. Compositions comprising polyphosphate preferably have a limited water content of up to about 20% to minimize hydrolysis of the polyphosphate.

Another embodiment of the present invention is directed to a single-phase oral composition comprising a source of stannous ions, a source of multivalent metal ions other than stannous, and a mineral surfactant such as an average chain length of about 4 or more Many linear polyphosphates. The single phase composition is formulated such that the linear polyphosphate is stable against hydrolytic degradation.

The present invention also relates to single-phase or two-phase compositions comprising a source of stannous ions, a source of multivalent metal ions other than stannous, and a phosphonate, diphosphonate and Anionic polymers of carboxyl functionality or combinations thereof.

The present invention also provides methods of effectively delivering stannous-containing compositions with minimal tooth discoloration or astringent side effects and effective tartar inhibition by administering to a subject a stable dentifrice composition effect, the composition comprises a clinically effective amount of stannous fluoride and/or other stannous salts in combination with a source of multivalent metal ions other than stannous and mineral surfactants and chelating agents such as polymers containing phosphate or phosphonate combination of things. One method of delivery of this improved stannous oral composition involves the application of a dentifrice comprising two dentifrice compositions contained in physically separated compartments. Another method involves administering a stable single-phase dentifrice composition to a subject. One embodiment of the stable single phase composition comprises polyphosphate or other phosphate or phosphonate containing anionic polymer, stannous fluoride as a source of stannous ions, a source of zinc ions, wherein the composition can have relatively Low total water content, depending on stability needs.

One preferred method of delivery of the improved stannous-containing compositions of the present invention involves the application of a dentifrice comprising two dentifrice compositions contained in physically separate compartments. The physical separation allows for sufficient stabilization of each dentifrice phase and the ingredients therein. When used in combination, the chemical interaction of the stannous (from stannous fluoride and/or other stannous salts) in one dentifrice phase with the mineral surfactant in the barrier dentifrice phase allows the two components to Properly delivered so as to provide full therapeutic activity and provide significant calculus reduction efficacy with significant reduction in tooth discoloration and astringent undesirable side effects. The first dentifrice composition will comprise a source of stannous ions, while the second dentifrice composition preferably comprises a polyphosphate or other anionic polymer or copolymer comprising phosphate, phosphonate, carboxyl groups, or mixtures thereof. A source of multivalent cations other than stannous may be incorporated into either the first or second composition or both, depending on the interaction with the other components.

The essential and optional components of the compositions of the present invention are described in the following paragraphs.

Stannous ion source

The present invention comprises a source of stannous ions as an essential component. The stannous ions are provided by stannous fluoride and/or other stannous salts added to the oral composition. Stannous fluoride has been found to help reduce caries, gingivitis, plaque and sensitivity, and help provide breath freshening benefits. The stannous provided in the oral composition will provide efficacy to the subject using the composition. Other stannous salts include stannous chloride dihydrate, stannous acetate, stannous gluconate, stannous oxalate, stannous sulfate, stannous lactate, and stannous tartrate. Preferred sources of stannous ions are stannous fluoride and stannous chloride dihydrate. The combined stannous salts comprise from about 0.05% to about 11% by weight of the total composition. Preferably, the content of the stannous salt is from about 0.1% to about 7%, more preferably from about 0.4% to about 3%. Formulations generally comprise stannous ions in the total composition provided by stannous fluoride and other stannous salts in a stannous content in the range of about 3,000 ppm to about 15,000 ppm.

Dentifrices containing stannous salts, especially stannous fluoride and stannous chloride, are described in US Patent 5,004,597 to Majeti et al. Additional descriptions of stannous salts can be found in US Patent 5,578,293 to Prencipe et al. and US Patent 5,281,410 to Lukacovic et al. In addition to the stannous ion source, other ingredients required to stabilize stannous, such as those described in Majeti et al. and Prencipe et al., may be included.

Mineral Surfactant (MSA)

The present invention encompasses mineral surfactants that are substantive to teeth and also have chelating or binding activity for stannous and other multivalent cations. Herein, the abbreviation "MSA" refers to such agents. The descriptor "mineral" is intended to indicate that the surface activity or substantivity of the surfactant is directed against mineral surfaces, such as calcium phosphate minerals or teeth. Preferred mineral surfactants are polymers, in particular polymers comprising anionic groups selected from the group consisting of phosphate, phosphonate, carboxyl and mixtures thereof. Such anionic functional groups provide these reagents with the ability to interact with cationic or positively charged entities.

These reagents show an affinity for stannous binding (specifically, through the chelation of stannous ions), which can be achieved by releasing fluoride ions from stannous fluoride (SnF ₂ ) and providing increased The fluoride ion form was confirmed. Effective agents also exhibit surface reactivity to calcium phosphate minerals and thus are expected to delay calculus or tartar formation. The agents may also provide plaque inhibition, surface conditioning, and anti-erosion benefits. Ideally, these agents would bind to the stannous, but still enable the combined mixture to provide the desired tartar inhibition, plaque inhibition, and surface conditioning without the inhibition of caries, oral malodor, and periodontal effects of stannous fluoride. Disease (including gingivitis) efficacy can be adversely affected.

Binding or chelating stannous with mineral surfactants provides a means of stabilizing stannous, especially in aqueous environments where stannous can form tin compounds, or can precipitate out of solution, reducing the availability of stannous ions content, thereby reducing the efficacy of the composition. For example, in US Patent 5,017,363 to Suhonen, it is reported that stannous fluoride compositions can be stabilized with copolymers of alkyl vinyl ethers and maleic anhydride or maleic acid. The copolymers are reported to have the ability to form chelates with stannous ions sufficiently strong to prevent stannous oxidation or precipitation from solution.

In addition to binding or chelating stannous, preferred polymeric mineral surfactants also have a strong affinity for the enamel surface and will deposit a polymeric layer or coating on said enamel surface and produce the desired surface protection and Adjust the effect. Suitable examples of such polymers are polyelectrolytes, such as condensed phosphorylated polymers; polyphosphonates; monomers or polymers comprising phosphate or phosphonate groups with other monomers such as ethylenically unsaturated monomers and amino acids or copolymers with other polymers such as proteins, polypeptides, polysaccharides, poly(acrylates), poly(acrylamides), poly(methacrylates), poly(ethacrylates), poly (hydroxyalkylmethacrylate), poly(vinyl alcohol), poly(maleic anhydride), poly(maleate), poly(amide), poly(vinylamine), poly(ethylene glycol), poly( propylene glycol), poly(vinyl acetate), and poly(vinylbenzyl chloride); polycarboxylates and carboxy-substituted polymers; and mixtures thereof. Suitable polymeric mineral surfactants include the carboxyl-substituted alcohol polymers described in U.S. Patents 5,292,501, 5,213,789, 5,093,170, 5,009,882, and 4,939,284, all to Degenhardt et al.; Bisphosphonate-derived polymers; and synthetic anionic polymers, including polyacrylates and copolymers of maleic anhydride or maleic acid and methyl vinyl ether, such as those described in U.S. Patent 4,627,977 to Gaffar et al. (e.g. Gantrez). A preferred polymer is bisphosphonate modified polyacrylic acid. Reactive polymers have sufficient surface binding properties to desorb and maintain thin film proteins attached to the enamel surface. For tooth surfaces, polymers with terminal or pendant phosphate or phosphonate functional groups are preferred, however other polymers with mineral binding activity may prove effective in terms of adsorption affinity.

Other examples of suitable polymeric mineral surfactants containing phosphonate groups include gem-bisphosphonate polymers disclosed as anticalculus agents in US 4,877,603 to Degenhardt et al; US 4,749,758 and GB1 to Dursch et al 290,724 (both assigned to Hoechst) for use in detergent and cleaning compositions containing phosphonate group-containing copolymers; and US 5,980,776 to Zakikhani et al. and US 6,071,434 to Davis et al. Copolymers and cotelomers useful in applications including scale and corrosion inhibition, coatings, cements and ion exchange resins. Preferred polymers include the water-soluble copolymers of vinylphosphonic acid and acrylic acid and salts thereof disclosed in GB 1,290,724, wherein the copolymer comprises from about 10% to about 90% by weight of vinylphosphonic acid and From about 90% to about 10% acrylic acid, more specifically, wherein the copolymer has a weight ratio of vinylphosphonic acid to acrylic acid of 70% vinylphosphonic acid to 30% acrylic acid; 50% vinylphosphonic acid to 50% acrylic acid; or 30% vinylphosphonic acid to 70% acrylic acid. Other preferred polymers include the water-soluble polymers disclosed by Zakikhani and Davis, which are obtained by diphosphonate or polyphosphonate monomers having one or more unsaturated C=C bonds (such as vinylidene -1,1-diphosphonic acid and 2-(hydroxyphosphinyl)ethylidene-1,1-diphosphonic acid) with at least one other compound having an unsaturated C=C bond (such as acrylates and formazan acrylate monomers), such as those having the following structure:

1. A cotelomer of acrylic acid and 2-(hydroxyphosphinyl)ethylene-1,1-diphosphonic acid having the structure:

2. Copolymers of acrylic acid and vinyl diphosphonic acid having the structure:

Suitable polymers include bisphosphonate/acrylate polymers available from Rhodia under the tradenames ITC 1087 (average molecular weight 3000 to 60,000) and Polymer 1154 (average molecular weight 6000 to 55,000).

Preferred mineral surfactants are stable in coexistence with other formulation components such as fluoride ions, and do not hydrolyze in high water content formulations, thus providing simple single phase dentifrice or mouthwash formulations. If the mineral surfactant does not possess these stabilizing properties, one option is to formulate a two-phase formulation with the mineral surfactant physically separated from the incompatible components.

Preferred polymeric mineral surfactants are polyphosphates. Polyphosphates are generally considered to consist of two or more phosphate molecules arranged primarily in a linear configuration, although some cyclic polyphosphate derivatives exist. Particularly effective are polyphosphates with an average chain length of about four or more phosphate groups, such that surface adsorption at effective concentrations can generate sufficient non-binding phosphate functional groups, which enhance the anionic surface charge and Hydrophilic properties. Pyrophosphates and tripolyphosphates are discussed separately in the additional anticulus agents. Long chain polyphosphates include, among others, tetrapolyphosphate and hexametaphosphate. Polyphosphates larger than tetrapolyphosphates generally occur as amorphous glassy materials. Examples of suitable polyphosphates are linear "glassy" polyphosphates having the formula:

XO(XPO ₃ ) _n X

wherein X is sodium, potassium or ammonium, and n has an average value of from about 6 to about 125. Preferred are the polyphosphates produced by FMC Corporation, which are known commercially as Sodaphos (n≈6), Hexaphos (n≈13) and Glass H (n≈21). The most preferred polyphosphate is Glass H. These polyphosphates can be used individually or in combination.

Polyphosphates having an average chain length greater than about 4 at ambient temperature are known to react with fluoride ions in oral compositions and, in addition to changing the pH of the composition, generate monofluorophosphate ions. This reaction compromises the efficacy of the oral composition and its ability to provide stable fluoride ions and polyphosphates to oral surfaces. Polyphosphates are also known to undergo hydrolysis. Accordingly, formulation with such polyphosphates presents some difficulties. One way to stabilize polyphosphates against hydrolysis and/or interaction with incompatible ingredients is to reduce the total water content of the dentifrice composition. Polyphosphates are further described in US Patent 5,939,052 to White, Jr. et al. Phosphate sources are also described in more detail in Kirk-Othmer's Encyclopedia of Chemical Technology, Fourth Edition, Volume 18 (Wiley-Interscience Publishers, 1996).

For compositions consisting of condensed polyphosphates having an average of 21 phosphate repeat units, it has been found that the ideal ratio of total moles of phosphate anions to total moles of stannous ions is: phosphate anions to stannous ions The molar ratio is from about 0.2:1 to about 5:1, preferably from about 0.5:1 to about 3:1, more preferably from about 0.6:1 to about 2:1, and most preferably from about 0.7:1 to about 1:1.

In addition to or as an alternative to polyphosphates, other polyphosphorylated compounds may also be used as mineral surfactants/chelating agents, specifically polyphosphorylated inositol compounds such as phytic acid, inositol (dihydrogen phosphate); inositol tetra(dihydrogen phosphate), inositol tri(dihydrogen phosphate), and their alkali metal, alkaline earth metal or ammonium salts. Preferred herein is phytic acid, also known as inositol 1,2,3,4,5,6-hexa(dihydrogen phosphate) or inositol, and its alkali metal, alkaline earth metal or ammonium salts Hexaphosphoric acid. As used herein, the term "phytic acid" includes phytic acid and its salts as well as other polyphosphorylated inositol compounds.

Other non-polymeric mineral surfactants which may also be used are chelating substances recommended in the art for the purpose of delaying calculus formation and removing calculus after it has formed. Chemical pathways for calculus inhibition generally involve chelation of calcium ions and/or crystal growth inhibition, which prevent calculus formation and/or break down mature calculus by removing calcium. These chemical chelating agents are discussed in more detail in the anticulus agents section below.

The desired amount of mineral surfactant is an effective amount to bind stannous, to have sufficient antimicrobial activity, to reduce tooth stain and to astringent the formulation, and to be able to reduce calculus. An effective amount of mineral surfactant is generally from about 0.05% to about 35%, preferably from about 1% to about 30%, more preferably from about 5% to about 25%, and most preferably From about 6% to about 20%.

In addition to effectively binding stannous ions, it has been found that some mineral surfactants/chelating agents also act as solubilizers for the water insoluble components of the composition. For example, Glass H polyphosphate has been found to dissolve insoluble stannous salts as well as stannous oxides and hydroxides.

multivalent cation source

The compositions of the present invention preferably comprise a source of multivalent cations other than stannous, including inorganic ions such as zinc (Zn ⁺² ), copper (Cu ⁺² ), aluminum (Al ⁺³ ), iron (Fe ⁺² , Fe ^{+ 3} ), strontium (Sr ⁺² ), calcium (Ca ⁺² ), barium (Ba ⁺² ), magnesium (Mg ⁺² ) and manganese (Mn ⁺² ). Such multivalent cations compete with the stannous for incorporation into the composition to stabilize the stannous mineral surfactant/chelating agent by binding or chelation. It has been found that while chelation is effective in stabilizing stannous, such chemically stable stannous ions have very limited bioavailability and thus reduced therapeutic efficacy. By having a cation competing with the stannous in the same system, overstabilization of the stannous by the chelating agent is avoided so that the stannous is available upon exchange with a competing cation. Thus, the inclusion of a second multivalent cation enables the use of chelating agents such as low molecular weight bisphosphonates, pyrophosphates and tripolyphosphates, which have the ability to chelate stannous but tend to reduce the therapeutic efficacy of stannous.

The amount of source of multivalent cations is generally sufficient to provide a molar ratio of multivalent cations to stannous, preferably 1:1 or greater. This ensures that there are sufficient concentrations of other multivalent cations to compete with the stannous for the mineral surfactant. The level of other multivalent cations will of course also depend on secondary considerations such as aesthetics and stability of the composition and may be less than the preferred 1:1 ratio. Preferred polyvalent cations are those formed from salts such as nitrate, chloride, fluoride, phosphate, pyrophosphate, polyphosphate, sulfate, carbonate, citrate, lactate and oxalate or formed from oxidized Inorganic cations provided by compounds or hydroxides. The source of multivalent cations may be water soluble, partially soluble or insoluble.

In a preferred embodiment, the composition comprises stannous fluoride as the source of stannous, zinc salt as the source of zinc ions, and polyphosphate as the mineral surfactant/chelating agent. The composition can be formulated as a single phase product or a two phase product, wherein the stannous fluoride and zinc salt are in the first composition and the polyphosphate mineral surfactant is in the second composition. In another embodiment of the two-phase composition, the second composition comprises maleic anhydride or a copolymer of maleic acid and methyl vinyl ether (Gantrez) as mineral surfactant. In these embodiments, the preferred molar ratio of zinc ions to stannous ions is in the range of about 0.5:1 to about 5:1.

In another embodiment, the composition, which may be single-phase or two-phase, comprises a calcium salt as a source of calcium ions, stannous fluoride as a source of stannous and fluorine, and polysaccharide as a mineral surfactant. Phosphate, maleic anhydride or copolymers of maleic acid and methyl vinyl ether, or mixtures thereof. The two-phase composition comprises stannous fluoride in a first composition and calcium chloride and a mineral surfactant in a second composition.

Orally acceptable carrier material

In preparing the compositions of the present invention, it may be desirable to incorporate one or more carrier materials or excipients into the composition. Such materials are well known in the art and are readily selected by those skilled in the art based on the desired physical, aesthetic and performance properties of the composition to be prepared. These carriers generally comprise from about 50% to about 99%, preferably from about 70% to about 98%, and more preferably from about 90% to about 95%, by weight of the oral compositions. Examples of such optional carriers are described in the following paragraphs.

total water content

Water used in the preparation of commercially suitable oral compositions should preferably be low in ion content and free of organic impurities. In the oral compositions, the water content is from 0% up to about 95%, and preferably from about 5% to about 50%, by weight of the compositions described herein. This water content may be present in a single-phase oral composition, or may be the resulting total water content of a two-phase oral composition. If the oral composition comprises polyphosphates having an average chain length of about 4 or more, the composition or phase comprising the polyphosphates will comprise a lower water content, generally up to about 20% total water content . The total water content is preferably from about 2% to about 20%, more preferably from about 4% to about 15%, and most preferably from about 5% to about 12%, by weight of the oral composition. The amount of water includes added free water and water introduced with other substances such as sorbitol, silica, surfactant solution and/or color solution.

buffer

The compositions of the present invention may contain buffering agents. As used herein, buffer refers to an agent that can be used to adjust the pH of the composition to a range of about 3.0 to about 10. The phases in oral compositions comprising stannous generally have a slurry pH of from about 3.0 to about 7.0, preferably from about 3.25 to about 6.0, and more preferably from about 3.5 to about 5.5. The phase comprising the mineral surfactant/chelating agent typically has a slurry pH of from about 4.0 to about 10, preferably from about 4.5 to about 8, and more preferably from about 5.0 to about 7.0. Oral compositions comprising stannous and mineral surfactant/chelating agents in a single phase generally have a pH of from about 4 to about 7, preferably from about 4.5 to about 6.5, and more preferably from about 5 to about 6.

Suitable buffers include alkali metal hydroxides, carbonates, sesquicarbonates, borates, silicates, phosphates, imidazoles, and mixtures thereof. Specific buffering agents include monosodium phosphate, trisodium phosphate, sodium benzoate, benzoic acid, sodium hydroxide, potassium hydroxide, alkali metal carbonates, sodium carbonate, imidazole, pyrophosphate, citric acid, and sodium citrate. Preferred buffers are those that adjust the pH to the target range without complexing stannous ions. Preferred buffers include acetic acid, sodium acetate, citric acid, sodium citrate, benzoic acid and sodium benzoate. Buffering agents are used in amounts of from about 0.1% to about 30%, preferably from about 1% to about 10%, and more preferably from about 1.5% to about 3%, by weight of the compositions of the present invention.

Fluoride ion source

The oral compositions of the present invention will optionally comprise a soluble fluoride source capable of providing bioavailable and available fluoride ions. Soluble fluoride ion sources include sodium fluoride, stannous fluoride, indium fluoride, amine fluoride, and sodium monofluorophosphate. Stannous fluoride is the preferred source of soluble fluorine. This ingredient can be used as a source of stannous and fluorine. Such sources of fluorine, among others, are disclosed in US Patent 2,946,725, issued July 26, 1960, to Norris et al., and US Patent 3,678,154, issued July 18, 1972, to Widder et al.

The compositions of the present invention may comprise a soluble fluoride ion source capable of providing from about 50 ppm to about 3500 ppm, and preferably from about 500 ppm to about 3000 ppm, of free fluoride ions. To deliver the desired amount of fluoride ions, the source of fluoride ions is present in the total oral composition at a level of from about 0.1% to about 5%, preferably from about 0.2% to about 1%, by weight of said total composition delivered to the oral cavity, And more preferably from about 0.3% to about 0.6%.

Anti-calculus agent

Substances known to be effective in reducing mineral deposition associated with calculus formation may also be used herein as mineral surfactants/chelating agents or stannous stabilizers. Chelating agents are able to complex with the calcium present in the bacterial cell walls and also destroy plaque by removing the calcium from the calcium bridges that help keep this biomass intact. However, it is undesirable to use chelating agents that have an excessively high affinity for calcium, as this would lead to tooth demineralization, which is contrary to the purpose and intent of the present invention. Suitable chelating agents typically have a calcium binding constant of about ¹⁰¹ to ¹⁰⁵ to provide improved cleaning with reduced plaque and calculus formation. Chelating agents also have the ability to complex with metal ions, so they can be used to stabilize stannous.

Such chelating agents useful for their anticulus activity include pyrophosphates, tripolyphosphates and bisphosphonates such as EHDP and AHP. Pyrophosphate salts useful as a source of pyrophosphate ions in the compositions of the present invention include dialkali metal pyrophosphates, tetra-alkali metal pyrophosphates, and mixtures thereof. Unhydrated and hydrated forms of disodium dihydrogen pyrophosphate (Na ₂ H ₂ P ₂ O ₇ ), tetrasodium pyrophosphate (Na ₄ P ₂ O ₇ ) and tetrapotassium pyrophosphate (K ₄ P ₂ O ₇ ) are preferred substance. In the compositions of the present invention, pyrophosphate can be present in one of three ways: substantially dissolved, substantially insoluble, or a mixture of dissolved and undissolved pyrophosphate.

A composition comprising substantially dissolved pyrophosphate refers to a composition wherein at least one source of pyrophosphate ions is present in a sufficient amount to provide at least about 1.0% free pyrophosphate ions. The content of free pyrophosphate ions may be from about 1% to about 15%, in one embodiment from about 1.5% to about 10%, in another embodiment from about 2% to about 6%. Depending on the pH of the composition, free pyrophosphate ions can exist in various protonated states.

A composition comprising substantially insoluble pyrophosphate refers to a composition comprising less than about 20%, preferably less than about 10%, of the total pyrophosphate dissolved in the composition. In these compositions, tetrasodium pyrophosphate is the preferred pyrophosphate salt. In dentifrice compositions, tetrasodium pyrophosphate can be in anhydrous or deca form, or any other species that is stable in solid form. The salt is in its solid particulate form which may be in its crystalline and/or amorphous state. The particle size of the salt is preferably small enough to be aesthetically acceptable and readily soluble in use. The amount of pyrophosphate used in preparing these compositions is any effective calculus control amount, usually from about 1.5% to about 15%, preferably from about 2% to about 15%, by weight of the dentifrice composition. About 10%, and most preferably about 3% to about 8%.

The composition may also contain a mixture of dissolved and undissolved pyrophosphates. Any of the pyrophosphates mentioned above may be used.

Pyrophosphates are described in more detail in the Kirk-Othmer Encyclopedia of Chemical Technology, Third Edition, Volume 17, Wiley-Interscience Publishers (1982).

Other examples of chelating agents useful as anticalculus agents include ethylenediaminetetraacetic acid, nitrilotriacetic acid, and related compounds disclosed in British Patent 490,384, published February 15, 1937; Polyphosphonates disclosed in U.S. Patent 3,678,154 to et al., U.S. Patent 5,338,537 issued Aug. 16, 1994 to White, Jr., and U.S. Patent 5,451,401 issued Sept. 19, 1995 to Zerby et al.; 1973 Carbonyl diphosphonates disclosed in U.S. Patent 3,737,533 issued June 5, 1979 to Francis; zinc-polymer combinations disclosed in U.S. Patent 4,138,477 issued February 6, 1979 to Gaffar, the combination consisting of zinc Formed by the reaction or interaction of compounds with anionic polymers containing carboxyl, sulfo, and/or phosphonic acid groups; Tartaric acid disclosed in 5,622,689; acid or salt forms of tartrate monosuccinic acid, tartrate disuccinic acid, and mixtures thereof disclosed in U.S. Patent 5,015,467 to Smitherman, issued May 14, 1991; published July 11, 1989 Acrylic polymers or copolymers disclosed in U.S. Patent 4,847,070 to Pyrz et al. and U.S. Patent 4,661,341 to Benedict et al., issued April 28, 1987; U.S. Patent 4,775,525 to Pera, issued October 4, 1988 Disclosed in GB741,315 published on November 30, 1955, WO99/12517 published on March 18, 1999, and US Patent 5,538,714 issued on July 23, 1996 to Pink et al. and the vinylpyrrolidones and carboxylic acids disclosed in U.S. Patent 5,670,138 issued September 23, 1997 to Venema et al. and Japanese Publication 2000-0633250 issued February 29, 2000 to Lion Corporation ester copolymers. Other chelating agents useful as anticalculus agents include gluconic acid, tartaric acid, citric acid and pharmaceutically acceptable salts thereof. Examples include sodium or potassium gluconate and sodium or potassium citrate; citric acid/alkali metal citrate combination; zinc citrate trihydrate; disodium tartrate; dipotassium tartrate; potassium sodium tartrate; hydrogen tartrate Sodium; Potassium Bitartrate. Amounts of such chelating agents suitable for use herein are from about 0.1% to about 2.5%, preferably from about 0.5% to about 2.5%, and more preferably from about 1.0% to about 2.5%.

Other anticalculus agents also suitable for use in the present invention are the polymeric polycarboxylates disclosed in U.S. Patent 4,138,477, issued February 6, 1979, and U.S. Patent 4,183,914, issued January 15, 1980 to Gaffar et al., and Copolymers of maleic anhydride or maleic acid with another polymerizable ethylenically unsaturated monomer such as methyl vinyl ether (methoxyethylene), styrene, isobutylene or ethyl vinyl ether are included. These materials are well known in the art and are employed in the form of their free acids, partially or preferably fully neutralized water-soluble alkali metal (eg potassium, and preferably sodium) or ammonium salts. An example is a 1:4 to 4:1 copolymer of maleic anhydride and methyl vinyl ether having a molecular weight (M.W.) of about 30,000 to about 1,000,000. These copolymers are available, for example, under the trade names Gantrez AN139 (M.W. 500,000), AN119 (M.W. 250,000) and S-97 pharmaceutical grade (M.W. 70,000) from GAFChemicals Corporation.

Other effective polymeric polycarboxylates include 1:1 copolymers of maleic anhydride with ethyl acrylate, hydroxyethyl methacrylate, N-vinyl-2-pyrrolidone or ethylene, which are available under trade names such as Monsanto EMA No. .1103, MW 10,000 and EMA Grade 61, and acrylic acid with methyl methacrylate or hydroxyethyl methacrylate, methyl acrylate or ethyl acrylate, isobutyl vinyl ether or N-vinyl-2-pyrrolidone 1:1 copolymer.

abrasive polishing substance

Abrasive polishing substances can also be included in oral compositions. The abrasive polishing substance contemplated for use in the compositions of the present invention may be any substance that does not excessively abrade dentin. In addition, the abrasive polishing substance should be formulated into the oral composition so that it does not compromise stannous or fluoride stability. For example, in a two-phase oral composition, the abrasive polishing substance is preferably in a phase separate from the source of fluoride ions and the source of stannous ions.

Typical abrasive polishing materials include: silica, including gels and precipitates; alumina; phosphates, including orthophosphate, polymetaphosphate, and pyrophosphate; and mixtures thereof. Specific examples include dibasic calcium phosphate dihydrate, calcium pyrophosphate, tricalcium phosphate, calcium polymetaphosphate, insoluble sodium polymetaphosphate, hydrated alumina, β-calcium pyrophosphate, calcium carbonate, and resin abrasives such as urea and Particulate condensation products of formaldehyde, among other materials, are disclosed in US Patent 3,070,510, Cooley et al., issued December 25,1962. Mixtures of abrasives may also be used. Calcium-containing abrasives and alumina are not preferred abrasives if the oral composition or particulate phase comprises polyphosphates having an average chain length of about 4 or greater. The most preferred abrasive is silica.

The various types of silica dental abrasives are preferred because of their unique benefit of polishing properties that leave the teeth exceptionally clean without excessively abrasive enamel or dentin. The silica abrasive polishing materials of the present invention, as well as other abrasives, generally have an average particle size in the range of about 0.1 to about 30 microns, and preferably about 5 to about 15 microns. The abrasive may be precipitated silica or silica gel as described in U.S. Patent 3,538,230 issued March 2, 1970 to Pader et al. and U.S. Patent 3,862,307 issued January 21, 1975 to DiGiulio Silica xerogel. Preferred is the silica xerogel sold under the trade designation "Syloid" by W.R. Grace & Company, Davison Chemical Division. Also preferred are precipitated silica materials such as those sold under the trade designation "Zeodent" by J.M. Huber Corporation, especially the silica designated "Zeodent 119". The types of silica dental abrasives useful in the toothpaste of the present invention are described in more detail in US Patent 4,340,583, issued July 29,1982 to Wason. Other suitable silica abrasives are described in US Pat. Nos. 5,589,160, 5,603,920, 5,651,958, 5,658,553, 5,716,601 to Rice and US Pat. Abrasives are generally present in the oral compositions described herein at a level of from about 6% to about 70% by weight of the composition. Oral compositions preferably comprise from about 10% to about 50%, by weight of the oral composition, of abrasives.

source of peroxide

The present invention also includes a source of peroxide in the composition. The peroxide source is selected from the group consisting of hydrogen peroxide, calcium peroxide, carbamide peroxide, and mixtures thereof. A preferred source of peroxide is calcium peroxide. To maximize stability, the peroxide source is preferably not in the same phase as the stannous ion source. The following amounts represent the amount of peroxide starting material, although the peroxide source may also contain ingredients other than peroxide starting material. The compositions of the present invention may comprise from about 0.01% to about 10%, preferably from about 0.1% to about 5%, more preferably from about 0.2% to about 3%, and most preferably from about 0.3% to about 3%, by weight of the oral composition. 0.8% peroxide source.

Alkali metal bicarbonate

The present invention may also include alkali metal bicarbonates. Alkali metal bicarbonates are water soluble. It tends to release carbon dioxide in aqueous systems unless stabilized. Sodium bicarbonate, also known as baking powder, is the preferred alkali metal bicarbonate. The alkali metal bicarbonate can also be used as a buffer. Due to the pH of the alkali metal bicarbonate buffer, the bicarbonate is preferably in a phase isolated from the source of stannous ions. The compositions of the present invention may comprise from about 0.5% to about 50%, preferably from about 0.5% to about 30%, more preferably from about 2% to about 20%, and most preferably from about 5% to about 50% by weight of the oral composition. 18% alkali metal bicarbonate.

additional vector

Compositions of the present invention may be in the form of toothpaste, dentifrice, topical oral gel, mouthwash, denture product, mouthspray, lozenge, oral tablet or chewing gum, and generally contain some thickening substance or binder to provide the desired consistency. The amount and type of thickening material will depend on the product form. Preferred thickeners are carboxyvinyl polymers, carrageenan, hydroxyethylcellulose, and water-soluble salts of cellulose ethers, such as sodium carboxymethylcellulose and sodium hydroxyethylcellulose. Natural gums such as karaya, xanthan, acacia and tragacanth can also be used. Colloidal magnesium aluminum silicate or finely divided silica can be used as part of the thickener to further improve texture. Thickening agents are used in amounts of from about 0.1% to about 15% by weight of the oral compositions.

Another optional component of the compositions contemplated herein is a humectant. Humectants can be used to prevent hardening of oral compositions due to exposure to air, and certain humectants can also impart desirable sweetness to toothpaste compositions. Humectants suitable for use in the present invention include glycerin, sorbitol, polyethylene glycol, propylene glycol, xylitol and other edible polyols. The humectants generally comprise from about 0% to 70%, and preferably from about 15% to 55%, by weight of the oral compositions.

The compositions of the present invention may also comprise surfactants, which are also commonly referred to as sudsing agents. Suitable surfactants are those which have moderate stability and foam over a broad pH range. Surfactants can be anionic, nonionic, amphoteric, zwitterionic, cationic, or mixtures thereof. Anionic surfactants useful in the present invention include water-soluble salts of alkyl sulfates containing 8 to 20 carbon atoms in the alkyl group (such as sodium alkyl sulfate) and sulfonated monoacids of fatty acids containing 8 to 20 carbon atoms Water-soluble salt of glycerides. Examples of such anionic surfactants are sodium lauryl sulfate and sodium cocoyl monoglyceride sulfonate. Other suitable anionic surfactants are sarcosinates such as sodium lauroyl sarcosinate, taurate, sodium lauryl sulfoacetate, sodium lauroyl isethionate, sodium laureth carboxylate and sodium dodecylbenzenesulfonate. Mixtures of anionic surfactants may also be used. A number of suitable anionic surfactants are disclosed in US Patent 3,959,458, Agricola et al., issued May 25,1976. Nonionic surfactants useful in the compositions of the present invention can be broadly defined as compounds resulting from the condensation of alkylene oxide groups (hydrophilic in nature) with organic hydrophobic compounds which may in themselves be aliphatic or alkylaromatic . Examples of suitable nonionic surfactants include poloxamers (sold under the trade name Pluronic), polyoxyethylene, polyoxyethylene sorbitan esters (sold under the trade name Tweens), Polyoxyl 40 hydrogenated castor oil, fatty alcohol ethyl alcohol Oxylates, condensation products of alkylphenols with polyethylene oxide, condensation products derived from the reaction product of ethylene oxide with propylene oxide and ethylenediamine, ethylene oxide condensation products of fatty alcohols, long chain tertiary Amine oxides, long chain tertiary phosphine oxides, long chain dialkyl sulfoxides, and mixtures of these. The nonionic surfactant Poloxamer 407 is a most preferred surfactant since it has been found that poloxamers help reduce the astringency of stannous. Amphoteric surfactants useful in the present invention can be broadly described as derivatives of aliphatic secondary and tertiary amines, wherein the aliphatic group may be straight or branched and wherein one of the aliphatic substituents contains from about 8 to About 18 carbon atoms, and one contains a water-soluble anionic group such as carboxylate, sulfonate, sulfate, phosphate, or phosphonate. Other suitable amphoteric surfactants are betaines, in particular cocamidopropyl betaine. Mixtures of amphoteric surfactants may also be used. Among the suitable nonionic and amphoteric surfactants are many disclosed in US Patent 4,051,234, Gieske et al., issued September 27,1977. The compositions of the present invention generally comprise one or more surfactants, each at a level of from about 0.25% to about 12%, preferably from about 0.5% to about 8%, and most preferably From about 1% to about 6%.

Titanium dioxide may also be incorporated into the compositions of the present invention. Titanium dioxide is a white powder that provides opacity to the composition. Titanium dioxide is generally present at from about 0.25% to about 5% by weight of the composition.

Colorants may also be incorporated into the compositions of the present invention. The colorant may be in the form of an aqueous solution, preferably an aqueous solution containing 1% colorant. Colored solutions generally comprise from about 0.01% to about 5% by weight of the composition.

Flavor systems may also be incorporated into the compositions. Suitable flavor components include oil of wintergreen, oil of peppermint, oil of spearmint, oil of clove bud, menthol, p-propenyl anisole, methyl salicylate, eucalyptol, cinnamon, 1-menthyl acetate, Grasswort, Eugenol, Parsley Oil, Hydroxyphenyl Butanone, Alpha-Ionone, Oregano, Lemon, Orange, Propyl Ethyl Guaiac, Cinnamon, Vanillin, Ethyl Pandan Hedione, 4-cis-heptenal, diacetyl, methyl 4-tert-butylphenylacetate, and mixtures thereof. Coolants may also be part of the flavor system. Preferred coolants in the compositions of the present invention are p-mentane carbamoyl reagents such as N-ethyl-p-mentane-3-carboxamide (commercially known as "WS-3") and mixtures thereof. Flavor systems are generally present in the compositions at levels of from about 0.001% to about 5% by weight of the composition.

Sweetening agents can be added to the compositions. These include saccharin, glucose, sucrose, lactose, xylitol, maltose, fructose, aspartame, sodium cyclamate, D-tryptophan, dihydrochalcone, acesulfame, and mixtures thereof. Various colorants may also be incorporated into the present invention. Sweetening and coloring agents are generally used in toothpaste at levels of from about 0.005% to about 5% by weight of the composition.

In addition to stannous, the present invention also includes other agents to provide antimicrobial benefits. The content of these reagents does not interfere with the interaction between stannous and mineral surfactants. Included in this class of antimicrobial agents are water insoluble non-cationic antimicrobial agents such as halogenated diphenyl ethers, phenolic compounds (including phenol and its homologues), mono- and polyalkyl and aromatic halophenols , resorcinol and its derivatives, bisphenol compounds and halogenated N-salicylanilides, benzoin esters and halogenated N-carbanilides. Water-soluble antimicrobial agents also include quaternary ammonium salts and bis-biguanide salts, among others. Triclosan monophosphate is an additional water-soluble antimicrobial agent. Quaternary ammonium reagents include wherein one or two substituents on the quaternary nitrogen have a carbon chain length (usually an alkyl) of about 8 to about 20, usually about 10 to 18 carbon atoms, while the remaining substituents (usually an alkyl or benzyl) have a lower number of carbon atoms, such as from about 1 to about 7 carbon atoms, typically those of methyl or ethyl. Typical examples of quaternary ammonium antibacterial agents are dodecyltrimethylammonium bromide, tetradecylpyridinium chloride, domiphene, N-tetradecyl-4-ethylpyridinium chloride, dodecyl Alkyldimethyl(2-phenoxyethyl)ammonium bromide, benzyldimethylstearylammonium chloride, cetylpyridinium chloride, quaternized 5-amino-1,3-bis (2-Ethylhexyl)-5-methylhexahydropyrimidine, alkylbenzyldimethylammonium chloride, benzethonium chloride, and methylbenzethonium chloride. Other compounds are the bis[4-(R-amino)-1-pyridinium alkanes disclosed in US Patent 4,206,215, issued June 3,1980 to Bailey. Other antimicrobial agents may also be included, such as copper bisglycinate, copper glycinate, zinc citrate, and zinc lactate. Also useful are enzymes, including endoglycosidase, papain, dextranase, mutanase, and mixtures thereof. Such agents are disclosed in US Patent 2,946,725, issued July 26, 1960 to Norris et al. and US Patent 4,051,234 to Gieske et al. Specific antimicrobial agents include chlorhexidine, triclosan, triclosan monophosphate, and flavor oils such as thymol. Triclosan and other agents of this type are disclosed in US Patent 5,015,466 to Parran, Jr. et al. and US Patent 4,894,220 to Nabi et al. If two phases are present, the water insoluble antimicrobial agent, water soluble agent and enzyme may be present in either the first or second oral composition. These agents are present at levels of from about 0.01% to about 1.5% by weight of the oral compositions.

The dentifrice composition can be a paste, a gel, or any configuration or combination thereof. If a two-phase dentifrice is desired, the first and second dentifrice compositions will be located physically separate in the dentifrice dispenser. It is generally preferred that the first dentifrice composition is a paste and the second dentifrice composition is a gel. The dispenser may be a tube, pump, or any other container suitable for dispensing toothpaste. Dual chamber packages suitable for this purpose are described in US Patents 4,528,180, 4,687,663 and 4,849,213, all to Shaeffer. The dispenser will deliver approximately equal amounts of each dentifrice composition through the openings. The compositions can be mixed upon dispensing. Alternatively, the oral formulation may be delivered by a kit comprising two separate dispensers for delivering two simultaneous dentifrice compositions.

Efficacy assay

The overall performance of the compositions of the invention can be specified in terms of the ratio Efficacy Score/Spot Score, where efficacy is measured using the in vitro plaque glycolysis and regeneration model (i-PGRM) and the in vitro thin film tea rust model ( i-PTSM) to measure stains. Compositions of the invention provide a ratio of efficacy score to stain score of at least 1.2, which represents a real improvement in which sufficient therapeutic efficacy is maintained while achieving a reduction in tooth discoloration. Improvement in formulation astringency is defined as a greater than 50% increase in formulation mouthfeel parameters such as dry mouth and oral cleansing indices as defined in controlled consumer tests. Efficacy in inhibiting supragingival calculus is defined by activity against plaque calcification as determined using a modified plaque growth and mineralization assay.

antimicrobial activity

The concentration and bioavailability of stannous ions required to provide a therapeutic effect may vary for different clinical effects, eg caries versus gingivitis. However, it is important to determine the minimum antimicrobial activity level, below which the therapeutic activity of stannous may be impaired. Maintaining efficacy is especially important in compositions where stannous binding occurs, since stannous binding tends to lead to loss of antimicrobial activity. Herein, the minimum efficacy provided by stannous ion sources is defined in terms of efficacy in causing metabolic inhibition of plaque bacterial biofilms, which are responsible for numerous undesirable intraoral diseases. Efficacy was therefore defined in terms of a significant and substantial reduction in in situ plaque metabolism measured using the in vitro plaque glycolysis and regeneration model (i-PGRM) developed in our laboratory. i-PGRM has been shown to provide excellent correlation with the bioavailability of stannous fluoride required for clinical antimicrobial, antigingivitis and antiplaque activity of oral compositions comprising stannous fluoride. For stannous-containing dentifrice formulations such as those described in U.S. 5,004,597 to Majeti et al., or for the commercially available stannous fluoride-containing dentifrice Crest Gum Care, direct comparisons of stannous-containing compositions against Efficacy for gingivitis.

i-PGRM is a technique in which dental plaque is generated from human saliva and treated with agents designed to develop various antimicrobial activities. The goal of this technique is to provide a simple and rapid method to determine whether a compound has a direct effect on the metabolic pathways that plaque microbes use to produce toxins that can adversely affect gum health. Specifically, the model is for the production of organic acids, including lactic acid, acetic acid, propionic acid, and butyric acid. This method employs plaque grown on ground glass rods soaked in saliva overnight, soaked in soy broth and sucrose for 6 hours, and soaked in saliva overnight. The plaque growing on the glass rod was then treated with a 3:1 ratio of water to dentifrice slurry for 1 minute. Then, the plaques were placed in the soybean broth/sucrose solution for 6 hours, and the pH of the broth was measured at the end of 6 hours. Therefore, for both the test preparation and the control, the pH before incubation and the pH after incubation were measured. Typically, this test is performed in multiple replicates to minimize experimental variance, and the average pH is calculated from the replicates. Due to the strong reactivity with saccharolytic organisms, compositions comprising high levels of bioavailable stannous produced a significant inhibitory effect on the formation of plaqueic acid in the i-PGRM assay. This enables easy comparison of stannous stability and bioavailability of various formulations.

Stannous fluoride and/or other stannous salts are present in the oral compositions described herein in an effective amount to provide the desired i-PGRM score. The expected i-PGRM score is determined relative to a formulation not containing stannous (negative control) and relative to a formulation containing stannous (positive control), such as described in U.S. 5,004,597 to Majeti et al. The most preferred i-PGRM scores were significantly different from placebo controls and theoretically similar to those provided by conventional stannous fluoride compositions proven effective in reducing plaque and gingivitis. Studies have demonstrated that for compositions containing at least about 60%, preferably at least about 70%, and more preferably at least about 80% of an effective stannous-containing dentifrice as shown in the comparative example of Example II below, predictably effective effect on gingivitis.

Calculate the i-PGRM score according to the following formula:

The average pH refers to the pH of the culture medium obtained after the treatment and sucrose competition involved. The stannous-free control plaque samples produced a large amount of acid, so their pH was lower than that of the plaque samples treated with the positive control (stabilized stannous fluoride dentifrice as shown in Example II Comparative Example ). Formulations made from the combination of stannous ion source and mineral surfactant are theoretically as effective as the stannous containing control, so the theoretical i-PGRM score should be close to 100%.

reduce tooth discoloration

Tooth discoloration is a common undesirable side effect when using stannous fluoride compositions. The improved stannous fluoride dentifrices described herein can reduce the formation of tooth stains due to the more effective delivery of stannous by combining the stannous with mineral surfactants. Discoloration of the tooth surface, usually caused by stannous, can be measured in a clinical setting by using a stain index such as the Lobene or Meckel index described in the literature. An in vitro tooth discoloration model was also developed that provides a quantitative assessment of the tooth discoloration potential of stannous fluoride formulations that correlates closely with clinical observations. Therefore, using these methods, formulations can be assayed prior to clinical examination.

The in vitro thin film tea rust model (i-PTSM) is a technique in which in vitro plaque biomass is grown on glass rods from accumulated human stimulated saliva over a three-day period. Plaque biomass was treated with a 3:1 ratio of water to dentifrice supernatant, in which abrasives and insoluble solids had been removed by centrifugation, to determine the degree of potential tooth discoloration of each agent. The purpose of this technique is to provide a simple and quick method to determine whether a compound has a direct effect on plaque stain weight. This method employs plaque growth from accumulated human saliva on ground glass rods, which are treated for 5 minutes each, followed by 10 minutes of tea. The treatment protocol was repeated at least three times before plaque biomass was eluted from the glass rods, filtered and the absorbance at 380 nm was measured. Typically this test is repeated several times to minimize experimental variance, and the average absorbance is calculated from the replicates.

It has been found that by mixing stannous fluoride with one of the above-discussed mineral surfactants or mixtures thereof, the staining normally produced by effective stannous fluoride can be reduced. The beneficial effect of reducing tooth discoloration caused by stannous can be obtained with the compositions of the present invention without significantly compromising the efficacy of stannous, fluoride and mineral surfactants. The degree of tooth discoloration produced by the oral compositions of the present invention is significantly lower than that produced by typical stannous-containing dentifrices. As used herein, the term "reduction" refers to a statistically significant reduction. Thus, reduced stannous mottling refers to a statistically significant reduction in the amount of stannous mottling relative to a positive control comprising stannous. No reduction in stannous potency means no statistically significant reduction in stannous potency relative to a stannous containing positive control. Alternatively, staining can be measured relative to a typical oral composition that does not contain stannous fluoride or another antimicrobial agent known to stain. Accordingly, the compositions were determined to have relatively very little to no mottling.

The i-PTSM score was calculated from this tooth discoloration detection assay according to the following formula:

The mean absorbance values refer to the colorimetric values of dissolved plaque obtained after dentifrice treatment and tea competition. The stannous control used was typically a highly pigmented stannous fluoride formulation, as shown in the Comparative Example II below. The stannous control sample caused a substantial amount of tea absorption and thus an increase in the colorimetric absorbance. Thus, the i-PTSM score is a measure of relative coloration. The lower the score, the less pigmented. The combination of stannous ion source and mineral surfactant provides a reduction in staining and will ideally have an i-PTSM score of less than about 75%, preferably less than 60%, more preferably less than 50%, most preferably less than 25%.

Ratio of i-PGRM score to i-PTSM score

A key improvement descriptor for the stannous compositions provided herein is the ratio of stannous efficacy to coloring potential, which is of great concern to consumers. The efficacy of the oral compositions of the present invention can be measured by the ratio of the i-PGRM score to the i-PTSM score.

The ratio of i-PGRM score to i-PTSM score was calculated according to the following formula:

Ratio = i-PGRM score/i-PTSM score

According to the present invention, the ratio obtained using these methods should be at least about 1.2 due to the significant improvement in stannous formulation efficacy versus tooth discoloration side effects. The ratio is preferably above about 1.3, more preferably above about 1.5, and most preferably above about 2.0. If almost no mottling is generated, the ratio approaches infinity, which is preferable.

Binding of stannous

As noted above, effective stabilization of stannous (effective with reduced side effects) can be achieved by in situ binding or complexing of stannous ions with mineral surfactants. In mixed compositions containing stannous fluoride, signs of stannous incorporation will readily be observed by potentiometric measurements of available fluoride ions. For example, binding of stannous to polyphosphate mineral surfactant ligands results in the exchange of fluorine from stannous fluoride and release into solution as fluoride ions. Since fluorine is the strongest ligand in the system after mineral surfactant binders, relative measurements of stannous binding can be assessed by this technique. Therefore, fluorine release is exemplified by the binding of stannous to MSA under these conditions.

This method was used to determine the complexation of stannous and zinc ions with polyphosphate mineral surfactants. Since stannous ions can be complexed by polyphosphate anions, a fluorine release detection assay using an ion-selective fluorine electrode can be used to monitor the release and complexation of fluorine by stannous ions. In a stannous fluoride solution, Glass H polyphosphate is added to generate free fluoride ions due to the formation of a stannous-polyphosphate complex and the subsequent release of fluoride ions from the stannous fluoride complex. Since zinc ions have a higher affinity for polyphosphate anions than stannous ions, adding zinc salts to the mixture of stannous fluoride and polyphosphate will facilitate the formation of zinc-polyphosphate complexes and release The stannous ion subsequently complexed with free fluorine. Therefore, the addition of zinc ions will reduce the content of free fluoride ions.

A solution containing stannous fluoride alone and a solution containing stannous fluoride and a zinc salt were prepared. Glass H polyphosphate solution was added incrementally to these solutions and fluoride ions were monitored via a fluoride ion selective electrode. Prepare the following two solutions.

Solution 1: _SnF2 0.454%

Solution 2: SnF ₂ 0.454%+ZnCl ₂ 1.25% (6000ppm zinc ions)

To each of these solutions, 0.1M Glass H polyphosphate (22% w/v) was titrated and the fluoride ion was determined. The data are plotted as the concentration of free fluorine as a function of titrated dose added. The results of this in vitro metal-ligand complexation study are presented in the table below. The theoretical fluorine release amount of 0.454% stannous fluoride will be 1100ppm free fluorine. Since most of the fluorine in a solution containing stannous fluoride is complexed with stannous ions, very little free fluorine is present. With the addition of polyphosphate, free fluoride ions increased significantly and approached the theoretical value of 1100 ppm. This is due to the coordination of stannous fluoride and polyphosphate anions to form a stannous-polyphosphate complex, while releasing fluoride ions from the stannous fluoride complex. Adding zinc ions to the stannous fluoride solution reduces the content of free fluoride ions while increasing the content of polyphosphate. This suggests that zinc ions contribute to the release of stannous ions from the stannous-polyphosphate complex by competing for the binding of polyphosphate anions.

Solution composition Free fluoride ion (ppm) _SnF2 (0.454%) 29 SnF ₂ (0.454%) mixed with polyphosphate (6.2%) 669 SnF ₂ (0.454%)+ZnCl ₂ (1.2%)+polyphosphate (6.2%) 355

reduce convergence

Astringency, an additional side effect of many stannous containing compositions, is significantly improved in compositions of the present invention comprising a mineral surfactant in combination with stannous and a second multivalent cation. The astringency of the formulations was determined in an oral panel format in which subjects rated the condition of the oral cavity before and after brushing with the test formulation. In these studies, a time-dependent study may be constituted of the effect of the dentifrice on the consumer's subjective response. In one protocol, panelists begin a series of conditioning by cleaning teeth with intensive self-oral oral hygiene, including brushing twice for three minutes each, flossing and developing to ensure complete removal of plaque. The subjects were then assigned their test products and instructed to routinely brush their teeth twice a day. For these tests, subjects reported to the clinical department in the morning before any oral hygiene or ingestion of food or beverages, and panelists were then asked to complete individual taste assessment questionnaires, including questions on tooth cleanliness, tooth smoothness, and mouth cleanliness and assessment of oral moistness. Then, panelists brushed their teeth for one minute with the assigned oral product. At this time, before lunch and before dinner (evening), the subjects filled out the personal taste questionnaire again. The results of these tests show that formulations of the invention comprising stannous salts in combination with mineral surfactants such as Glass H polyphosphate provide a significant improvement in the astringency of the formulation after brushing. Reduced astringency compared to conventional stannous formulations without mineral surfactants. The acceptability of the formulations of the present invention was comparable to conventional sodium fluoride (NaF) and tartar inhibiting dentifrices, respectively.

Reduce and inhibit dental calculus

Providing an anti-calculus benefit is another essential aspect of the stannous fluoride formulations of the present invention. Anti-calculus activity can be predicted from mineral surface activity measurements and the use of plaque growth and mineralization assays. The compositions of the present invention comprise a mineral surfactant, such as a stannous ion bound polyphosphate. A preferred composition comprises a mineral surfactant phosphate polymer having a pronounced affinity for tooth surfaces, consisting of hydroxyapatite. Preferred mineral surfactants include phosphate polymers which achieve a significant reduction in calcium phosphate mineralization as determined in a controlled calcium mineral detection assay. It has been found that polyphosphates (specifically, linear polyphosphates with an average chain length greater than about 4) produce better activity and direct contact with oral surfaces relative to pyrophosphate and certain other commonly used tooth cleaning ingredients. sex. The increase in activity and immediacy translates into a marked improvement in the prevention of dental stains and supragingival calculus as well as the non-abrasive removal of dental stains. Without being bound by theory, it is believed that polyphosphates prevent supragingival calculus formation by essentially disrupting the mineralization process that forms hard calcium phosphate mineral deposits on tooth enamel. By binding to the tooth surface, polyphosphates disrupt the mineral accumulation process because their structure does not fit well into the growing mineral lattice that becomes calculus.

treatment method

The present invention also relates to a method of treating gingivitis and plaque while reducing tooth discoloration by using a composition of the present invention comprising a source of stannous ions, a source of multivalent metal ions other than stannous and a mineral surfactant/ Chelating agents such as linear polyphosphates having an average chain length of about 4 or more. A source of fluoride ions is preferably included in the composition, especially where the source of stannous ions does not comprise stannous fluoride or stannous fluorophosphate. Also provided are methods of providing oral care compositions having anti-caries, anti-gingivitis, anti-plaque, anti-tartar, anti-stain, anti-allergy, aesthetics, breath freshening, mouthfeel and cleaning benefits. The beneficial effects of these compositions may increase over time when the compositions are used repeatedly. In particular, the method of treatment will include reducing gingivitis and plaque as measured by i-PGRM while reducing tooth discoloration caused by stannous containing oral compositions as measured by i-PTSM. The ratio of i-PGRM score to i-PTSM shading model score is higher than about 1.2.

The present invention also relates to methods of reducing the appearance of calculus on tooth enamel and methods of providing desirable oral aesthetic benefits, including reduced astringency and oral surface conditioning. The beneficial effects of these compositions may increase over time when the compositions are used repeatedly.

The method of treatment includes preparing an oral composition comprising a source of stannous ions, a source of multivalent cations other than stannous, and a mineral surfactant (MSA) to a subject and administering the composition to a subject. Administration to a subject can be defined as contacting the oral care composition to the surface of a subject's teeth by brushing with a dentifrice or rinsing with a dentifrice slurry. It can also be administered by contacting a topical oral gel, mouthwash, denture product, mouth spray, oral tablet, lozenge, or chewing gum to the tooth surface. The subject can be any human or animal in need of treatment or prevention of oral diseases including dental plaque, gingivitis, tartar, stains and allergies. Specifically, "animal" is intended to include household pets or other livestock or animals in cages.

For example, a method of treatment may involve a person brushing a dog's teeth with a dentifrice composition. Another example involves rinsing the cat's mouth with the oral composition long enough to see a beneficial effect. Pet care products, such as chews and toys, can be formulated to include the present oral compositions. Compositions comprising stannous, a second cationic and a mineral surfactant are incorporated into softer but strong and durable materials such as hides, ropes made of natural or synthetic fibers, and ropes made of nylon, polyester or Polymer articles made of thermoplastic polyurethane. When an animal chews, licks or bites the above product, the active ingredients contained are released into the saliva matrix in the animal's oral cavity, which corresponds to effective brushing or rinsing.

Example

The following examples and descriptions further illustrate embodiments within the scope of the present invention. These examples are given for the purpose of illustration only and should not be considered as limitations of the invention, since many changes can be made therein without departing from the spirit and scope of the invention.

Example I

Example I shows a two-phase dentifrice composition that incorporates stannous fluoride and/or other stannous salts in a first dentifrice composition and Mineral surfactants such as sodium polyphosphate (Glass H supplied by FMC Corporation, n=21, condensed phosphate polymer) or maleic anhydride or copolymers of maleic acid and methyl vinyl ether (Gantrez ). A second source of multivalent cations is incorporated into either composition. These compositions are suitably prepared by conventional methods at the option of the formulator.

first dentifrice composition

Element 1a 2a 3a 4a 5a stannous fluoride 1.062 1.062 1.062 1.062 - stannous chloride 1.500 - - - 1.500 zinc lactate - - 5.000 - zinc carbonate - - 5.000 - - sodium fluoride -- - - - 0.486 27.9% Sodium Lauryl Sulfate Solution - - 2.500 2.500 7.500 sodium gluconate 3.290 1.300 2.940 1.840 4.135 50% sodium hydroxide solution 0.600 0.600 0.600 0.280 0.900 sodium saccharin 0.400 0.400 0.400 0.300 0.400 flavoring agent 1.500 1.300 1.300 1.200 1.100 1% FD&C Blue No. 1 Dye Solution 0.300 0.300 0.300 0.100 0.500 polyethylene glycol - - - - 6.000 Poloxamer 407 15.500 15.500 17.500 16.500 7.000 70% sorbitol solution 23.000 23.000 - - 36.879 glycerin 31.008 31.008 22.000 22.000 20.000 xanthan gum - - 0.850 - 1.100 Hydroxyethyl cellulose - - - - 0.500 polyoxyethylene - - 0.200 - - water 21.840 25.530 45.348 49.218 12.000

Second dentifrice composition

Element 1b 2b 3b 4b 5b Glass H polyphosphate 25.800 20.800 26.000 - 18.000 Gantrez - 5.000 - 5.000 - zinc lactate - - - - 5.000 calcium chloride 1.712 1.712 - - - carboxymethyl cellulose 0.500 0.500 0.200 0.200 0.300 water 2.210 2.210 - 32.150 1.400 flavoring agent 1.500 1.500 1.100 1.100 1.100 glycerin 28.178 28.178 45.550 20.550 34.850 polyethylene glycol 1.500 1.500 - - 6.000 Propylene Glycol 8.000 8.000 - - - polyoxyethylene 0.200 0.200 - - - 27.9% Sodium Lauryl Sulfate Solution 10.000 10.000 8.000 10.000 6.000 silica 15.000 15.000 18.150 30.000 26.000 Polyoxyl40 Hydrogenated Castor Oil 2.500 2.500 - - -

benzoic acid 0.600 0.600 - - 0.300 sodium benzoate 0.600 0.600 - - 0.300 sodium saccharin 0.400 0.400 0.400 0.400 0.350 Titanium dioxide 1.000 1.000 0.500 0.500 0.400 xanthan gum 0.300 0.300 0.100 0.100 -

Example II

Example II shows a single-phase dentifrice composition incorporating a stannous salt as a source of stannous ions, a source of multivalent cations, and Glass H sodium polyphosphate or Gantrez® as a mineral surfactant. . The composition can be prepared using conventional methods.

The dimensions and values disclosed herein are not intended to be understood as strictly limited to the precise values recited. Instead, unless otherwise specified, each such dimension refers to both the recited value and a functionally equivalent range surrounding that value. For example, a dimension disclosed as "40 mm" is intended to mean "about 40 mm."

All documents cited in the Detailed Description of the Invention are, in relevant part, incorporated herein by reference. Citation of any document should not be construed as an admission that it is prior art with respect to the present invention. To the extent that any meaning or definition of a term in this writing conflicts with any meaning or definition of the term in a document incorporated by reference, the meaning or definition assigned to that term in this writing shall govern.

While particular embodiments of the present invention have been illustrated and described, it would be obvious 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, the appended claims are intended to cover all such changes and modifications that are within the scope of this invention.

Claims (7)

1. An oral care composition having antimicrobial activity effective in reducing plaque and gingivitis, said composition comprising: A. stannous ion source, wherein said stannous ion source is selected from stannous fluoride, stannous chloride dihydrate, stannous acetate, stannous gluconate, stannous oxalate, stannous sulfate, stannous lactate, Stannous tartrate and mixtures thereof; b. A source of multivalent cations other than stannous selected from zinc (Zn ⁺² ), copper (Cu ⁺² ), iron (Fe ⁺² , Fe ⁺³ ), strontium (Sr ⁺² ), barium (Ba ⁺² ), magnesium (Mg ⁺² ), manganese (Mn ⁺² ) and their mixtures; c. Mineral surfactants, wherein the mineral surfactants comprise maleic anhydride or a copolymer of maleic acid and methyl vinyl ether; and d. Abrasive polishing substances containing silica, The compositions provide enhanced stannous stability and therapeutic efficacy. 2. The oral care composition of claim 1 comprising from about 0.05% to about 35% condensed phosphorylated polymer. 3. The oral care composition of claim 2, wherein the phosphorylated polymer is a linear polyphosphate having an average chain length of about 2 to about 125. 4. The oral care composition of claim 1, further comprising a material selected from the group consisting of a fluoride ion source, an antibacterial agent, a surfactant, a thickening material, a humectant, a buffer, Titanium dioxide, flavor systems, sweeteners, colorants and mixtures thereof. 5. The oral care composition of claim 4, wherein the fluoride ion source is selected from the group consisting of sodium fluoride, stannous fluoride, indium fluoride, amine fluoride, sodium monofluorophosphate and the like mixture. 6. The oral care composition of claim 4, wherein the thickening material is selected from the group consisting of carboxyvinyl polymers, carrageenan, hydroxyethyl cellulose, carboxymethyl cellulose Sodium, sodium hydroxyethylcellulose, karaya gum, xanthan gum, acacia gum, tragacanth gum, magnesium aluminum silicate, silicon dioxide, and mixtures thereof. 7. An oral care composition comprising: (a) a first composition comprising a source of stannous ions, wherein the source of stannous ions is selected from the group consisting of stannous fluoride, stannous chloride dihydrate, stannous acetate, stannous gluconate, stannous oxalate, sulfuric acid Stannous, stannous lactate, stannous tartrate and mixtures thereof; (b) a second composition comprising a mineral surfactant, wherein the mineral surfactant comprises maleic anhydride or a copolymer of maleic acid and methyl vinyl ether; and (c) a source of multivalent cations other than stannous present in either or both of said first and second compositions selected from the group consisting of zinc (Zn ^{+ 2} ), copper ( Cu ⁺² ), iron (Fe ⁺² , Fe ⁺³ ), strontium (Sr ⁺² ), barium (Ba ⁺² ), magnesium (Mg ⁺² ), manganese (Mn ⁺² ) and their mixtures, wherein the mineral surfactant chelates the stannous ions when the first composition and the second composition are contacted in the oral cavity, and wherein the oral care composition comprises an abrasive polishing material comprising silica .