AU2012204031B2 - Oral care product and methods of use and manufacture thereof - Google Patents

Abstract

This invention relates to oral care compositions comprising a basic amino acid or salt thereof, and a small particle fraction; and to methods of using and of making these compositions.

Description

1 AUSTRALIA Patents Act 1990 COLGATE-PALMOLIVE COMPANY COMPLETE SPECIFICATION STANDARD PATENT Invention Title: Oral care product and methods of use and manufacture thereof The following statement is a full description of this invention including the best method of performing it known to us:- ORAL CARE PRODUCT AND METHODS OF USE AND MANUFACTURE THEREOF [0001] This application claims the benefit of U.S. Ser. No. 61/027,435 filed February 8, 2008, U.S. Ser. No. 61/027,431 filed February 8, 2008, U.S. Ser. No. 61/027,432 filed 5 February 8, 2008 and U.S. Ser. No. 61/027,420 filed February 8, 2008, the contents of which are incorporated herein by reference. [0001a] This is a divisional of AU 2008349847, the entire contents of which are incorporated herein by reference. FIELD OF THE INVENTION 10 [0002] This invention relates to oral care compositions comprising small particles together with a basic amino acid or salt thereof, and to methods of using and of making these compositions. BACKGROUND OF THE INVENTION [0003] Arginine and other basic amino acids have been proposed for use in oral care 15 and are believed to have significant benefits in combating cavity formation and tooth sensitivity. Commercially available arginine-based toothpaste, such as ProClude@ or DenClude@, for example, contains arginine bicarbonate and calcium carbonate, but not fluoride. The carbonate ion is believed to have cariostatic properties, and the calcium is believed to form in complex with arginine to provide a protective effect. Natural 20 calcium carbonate (chalk), however, has typically a well defined crystal structure (making it very hard) and relatively large particles, as it must be milled to size. It can be highly abrasive, making such a calcium carbonate product less desirable for persons having sensitive teeth. [0004] Accordingly, there is a need for a stable oral care product that provides a basic 25 amino acid and beneficial minerals such as fluoride and calcium, while still maintaining a low radioactive dentin abrasion value (RDA) and providing optimal protection for patients suffering from hypersensitive teeth. [0004A] Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of 30 providing a context for the present invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed before the priority date of each claim of this application. [0004B] Throughout this specification the word "comprise", or variations such as 35 "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps. 1 q BRIEF SUMMARY OF THE INVENTION [0004C] One aspect relates to a method comprising applying an effective amount of the oral care composition to the oral cavity of a subject in need thereof, to a. reduce or inhibit formation of dental caries, 5 b. reduce, repair or inhibit pre-carious lesions of the enamel, c. reduce or inhibit demineralization and promote remineralization of the teeth, d. reduce hypersensitivity of the teeth, e. reduce or inhibit gingivitis, 10 f. promote healing of sores or cuts in the mouth, g. reduce levels of acid producing bacteria, h. to increase relative levels of arginolytic bacteria, i. inhibit microbial biofilm formation in the oral cavity, j. raise and/or maintain plaque pH at levels of at least pH 5.5 following 15 sugar challenge, k. reduce plaque accumulation, 1. treat, reduce, relieve or alleviate dry mouth, m. whiten teeth, n. reduce erosion, 20 o. improve systemic health, p. immunize teeth against cariogenic bacteria; and/or q. clean teeth and oral cavity; the oral care composition comprising: i) an effective amount of a basic amino acid in free or salt form; 25 ii) a small particle fraction comprising at least about 5% of the formulation by weight, wherein the particles of the small particle fraction have a d50 of less than about 5 pm. [0004D] Another aspect relates to the use of a basic amino acid, in free or salt form, in an oral care composition comprising a small particle fraction comprising at least about 30 5% of the composition by weight, wherein the particles of the small particle fraction have a d50 of less than about 5 pm, for enhancing dentinal occlusion within an oral cavity of a subject. [0004E] Another aspect relates to the use of a basic amino acid, in free or salt form, for the manufacture of a medicament which includes a small particle fraction comprising at 35 least about 5% of the medicament by weight, wherein the particles of the small particle 1h fraction have a d50 of less than about 5 Lm, for enhancing dentinal occlusion within an oral cavity of a subject. [0004F] Another aspect relates to a method of treating sensitive teeth within an oral cavity, the method comprising treating the oral cavity of a subject with an oral care 5 composition comprising a basic amino acid, in free or salt form, and a small particle fraction comprising at least about 5% of the composition by weight, wherein the particles of the small particle fraction have a d50 of less than about 5 ptm, to enhance dentinal occlusion. [0005] It is now discovered that the benefit of the basic amino acid, e.g., arginine, in 10 treatment and prophylaxis of sensitive teeth can be greatly enhanced through the addition of small particle materials, which in the presence of the basic amino acid, help block the dentinal microtubules believed to be responsible for dentinal hypersensitivity. [0006] The invention encompasses oral care compositions and methods of using the same that are effective in inhibiting or reducing the accumulation of plaque, reducing 15 levels of acid producing (cariogenic) bacteria, remineralizing teeth, inhibiting or reducing gingivitis, and in particular, reducing dentinal hypersensitivity. The invention also encompasses compositions and methods to clean the oral cavity and provide improved methods of promoting oral health 1 WO 2009/099452 PCTIUS2008/058679 and/or systemic health, including cardiovascular health, e.g., by reducing potential for systemic infection via the oral tissues. 100071 The invention thus comprises an oral care composition (a Composition of the Invention). e.g., a dentifrice, comprising i. an effective amount of a basic amino acid in free or salt form; ii. a small particle fraction comprising at least about 5%, e.g.. at least about 10 to about 40% of the formulation by weight. wherein the particles have a d50 of less than about 5 pm: and iii. optionally further comprising an effective amount of a fluoride source, e.g.. a soluble fluoride salt. 100081 The small particle fraction may be, for example, an abrasive. e.g., selected from precipitated calcium carbonate and silica and mixtures thereof. 100091 In some embodiments, the compositions may have a low radioactive dentin abrasion value (RDA). e.g., less than about 140. e.g., about 30 - about 130. e.g., about 30 - about 70. 10010] The composition optionally comprises at least about 5%, e.g., at least about 10%, e.g.. at least about 20% of an abrasive having a d50 less than about 5 micrometers, e.g., about 0.5 pm to about 5 gm. e.g., silica having a d50 of about 3 pm to about 4 ym or precipitated calcium carbonate having a d50 of about 0.5 pm to about 3 pm. 100111 For example. in one embodiment, the basic amino acid is in the form of arginine bicarbonate. the fluoride is sodium monofluorophosphate. and the abrasive comprises precipitated calcium carbonate. In another embodiment, the basic amino acid is arginine bicarbonate, the fluoride is sodium monofluorophosphate, and the abrasive comprises silica. 100121 In some embodiments. the formulation further comprises an anionic surfactant, e.g.. sodium lauryl sulfate: an anionic polymer. e.g., a copolymer of methyl vinyl ether and maleic anhydride: and/or an antibacterial agent, e.g., ticlosan. 100131 In particular embodiments, the Compositions of the Invention are in the form of a dentifrice comprising additional ingredients selected from one or more of water. abrasives, surfactants, foaming agents, vitamins, polymers. enzymes, humectants, thickeners, antimicrobial agents, preservatives, flavorings, colorings and/or combinations thereof. 100141 Without intending to be bound by a particular theory. it is believed that the presence 2 WO 2009/099452 PCT/US2008/058679 of small particles in a formulation with arginine and calcium may help plug the microtubules responsible for hypersensitive teeth and help repair precarious lesions in the enamel and dentin. 100151 In onc embodiment precipitated calcium carbonate is generally prcfened to natural calcium carbonate. Without intending to be bound by a particular theory, it is hypothesized that natural calcium carbonate has a highly crystalline structure, making it very hard, whereas precipitated calcium carbonate is amorphous and more friable, therefore having a lower abrasivity, while still maintaining adequate cleaning power. 100161 It is moreover surprisingly found that the combination of fuoridc and a basic amino acid. e.g.. arginine, in an oral care product according to particular embodiments of the present invention produces unexpected benefits beyond and qualitatively diffcrcnt from what can be observed using compositions comprising effective amounts of either compound separately. in promoting remincralization. repairing pre-carious lesions, and enhancing oral health. It has moreover been found that this action can be further enhanced by addition of a small particle abrasive, which may act to help fill microfissures in the enamel and microtubules in the dentin. 100171 The prcscncc of a basic amino acid is also surprisingly found to reduce bacterial adhesion to the tooth surface, particularly when the basic amino acid is provided in combination with an anionic surfactant. The combination of the basic amino acid and thc anionic surfactant and/or anionic polymer e.g., PVM/MA also cnhanccs delivery of antimicrobial agents. particularly triclosan. 100181 The invention thus further encompasses methods to (i) reduce or inhibit formation of dental caries, (ii) reduce, repair or inhibit pre-carious lesions of the cnancl. e.g.. as detected by quantitative light-induced fluorescence (QLF) or electrical caries measurement (ECM). (iii) reduce or inhibit demineralization and promote remineralization of the teeth. (iv) rcducc hypersensitivity of the teeth, (v) reduce or inhibit gingivitis, (vi) promote healing of sores or cuts in the mouth. (vii) reduce levels of acid producing bacteria, (viii) to increase relative levels of arginolytic bacteria. (ix) inhibit microbial biofilm formation in the oral cavity. (x) raise and/or maintain plaque pH at levels of at least pH about 5.5 following sugar challenge, (xi) reduce plaque accumulation. (xii) reduce dry mouth. (xiii) reduce erosion, (xiv) whiten the teeth. (xv) immunize or protect the teeth against cariogcnic bacteria. (xvi) clcan the tceth and oral cavity and/or (xvii) promote systemic health, including cardiovascular health, e.g.. by reducing potential for systemic infection via the oral tissues. comprising applying a Composition of the Invention to the oral cavity. e.g.. by applying a Composition of the Invention to the oral cavity of a subject in need thereof. 3 WO 2009/099452 PCT/US2008/058679 DETAILED DESCRIPTION OF THE INVENTION General Dcscription 100191 The invention thus comprises an oral care composition (Composition 1.0) comprising i. an effective amount of a basic amino acid in free or salt form; ii. a small particle fraction comprising at least about 5%. c.g., at least about 20% of the formulation by weight, wherein the particles have a d50 of less than about 5 prm; and optionally further comprising an effective amount of a fluoride source, e.g., a soluble fluoride salt: for example any of the following compositions: 1.0.1. Composition 1.0 wherein the basic amino acid is arginine. lysine. citrulline. ornithine. creatine, histidine, diaminobutanoic acid. diaminoproprionic acid. salts thereof and/or combinations thereof. 1.0.2. Composition 1.0 or 1.0.1 wherein the basic amino acid has the L-configuration. 1.0.3. Any of the preceding compositions is provided in the form ofa salt of a di- or tri peptide comprising the basic amino acid. 1.0.4. Any of the preceding compositions wherein the basic amino acid is arginine, e.g., L arginine. 1.0.5. Any of the preceding compositions wherein the basic amino acid is partially or wholly in salt form. 1.0.6. Any of the preceding compositions wherein the basic amino acid comprises arginine phosphate. 1.0.7. Any of the preceding compositions wherein the basic amino acid comprises arginine hydrochloride. 1.0.8. Any of the preceding compositions wherein the basic amino acid comprises arginine sulfate. 1.0.9. Any of the preceding compositions wherein the basic amino acid comprises arginine bicarbonate. 1.0.10. Any of the preceding compositions wherein the salt of the basic amino acid is formed in situ in the formulation by neutralization of the basic amino acid with an acid or a salt of an acid. 4 WO 2009/099452 PCT/US2008/058679 1.0.11. Any of the preceding compositions wherein the salt of the basic amino acid is formed by neutralization of the basic amino acid to fomi a premix prior to combination with the fluoride salt. 1.0.12. Any of the preceding compositions wherein the basic amino acid is prcscnt in an amount corresponding to about 0.1 wt. % to about 15 wt. %. e.g., about 1% to about 10%. e.g., about 3% to about 10% of the total composition weight, the weight of the basic amino acid being calculated as free base form. 1.0.13. Composition 1.0.11 wherein the basic amino acid is present in an amount of about 7.5 wt. % of the total composition weight. 1.0.14. Composition 1.0. 11 wherein the basic amino acid is present in an amount of about 5 wt. % of the total composition weight. 1.0.15. Composition 1.0.11 wherein the basic amino acid is present in an amount of about 3.75 wt. % of the total composition weight. 1.0.16. Composition 1.0.11 wherein the basic amino acid is present in an amount of about 1.5 wt. % of the total composition weight. 1.0.17. Any of the preceding compositions wherein the fuoride salt is stannous fluoridc. sodium fluoride. potassitim fluoride. sodium monoluorophosphate, sodium fL0uorosilicate. aiimonium fluorosilicate. amine luoride (e.g.. N'-octadecyltrimethylendiamine-N.N.N' tris(2-ethanol)-dihydrofluoride). ammonium fluoride. titanium fluoride. hexafluorosulfate. and combinations thereof. 1.0.18. Any of the preceding compositions wherein thc luoride salt is a fluorophosphate. 1.0.19. Any of the preceding composition wherein the fluoride salt is sodium monofluorophosphate. 1.0.20. Any of the preceding compositions wherein the fluoride salt is present in an amount of about 0.01 wt. % to about 2 wt. % of the total composition weight. 1.0.21. Any of the preceding compositions wherein the fluoride salt provides fluoride ion in an amount of about 0.1 to about 0.2 wt. % of the total composition weight. 1.0.22. Any of the preceding compositions wherein the soluble fluoride salt provides fluoride ion in an amount of from about 50 to about 25.000 ppm. 1.0.23. Any of the preceding compositions which is a mouthwash having 100 to about 250 5 WO 2009/099452 PCTIUS2008/058679 ppm available fluoride ion. 1.0.24. Any of which is a dcntifricc having about 750 to about 2000 ppn available fluoride ion. 1.0.25. Any of the prcccding compositions wherein the composition comprises about 750 to about 2000 ppm fluoride ion. 1.0.26. Any of the preceding compositions wherein the composition comprises about 1000 to about 1500 ppm fluoride ion. 1.0.27. Any of the preceding compositions wherein the composition comprises about 1450 ppm fluoride ion. 1.0.28. Any of the preceding compositions wherein the pH is between about 6 and about 9, e.g.. about 6.5 - about 7.4 or about 7.5 - about 9. 1.0.29. Any of the preceding compositions wherein the pH is between about 6.5 and about 7.4. 1.0.30. Any of the preceding compositions wherein the pH is approximately neutral. 1.0.31. Any of the preceding compositions wherein the pl- is about 8.5 - about 9.5. 1.0.32. Any of the prcceding compositions further comprising an abrasive or particulate. 1.0.33. The inimcdiately preceding composition wherein the abrasive or particulate is selected from sodiui bicarbonate. calcium phosphate (e.g., dicalcium phosphate dihydrate), calcium sulfate, precipitated calcium carbonate, silica (e.g.. hydrated silica), iron oxide, aluminum oxide. pcrlite. plastic particles. e.g., polyethylene. and combinations thereof. 1.0.34. The immediately preceding composition wherein the abrasive is selected from a calcium phosphate (e.g.. dicalcium phosphate dihydrate), calcium sul fate. precipitated calcium carbonate. silica (e.g.. hydrated silica). calcium pyrophosphate and combinations thereof. 1.0.35. Any of the preceding compositions comprising an abrasive in an amount of about 15 wt. % to about 70 wt. % of the total composition weight. 1.0.36. Any of the preceding compositions comprising a small particle abrasive fraction of at least about 5% having a d50 of less than about 5 pm. 1.0.37. Any of the preceding compositions having a RDA of less than about 150. 6 WO 2009/099452 PCT/US2008/058679 1.0.38. Any of the preceding compositions having a RDA of about 30 - about 130. 1.0.39. Any of the preceding compositions having a RDA of about 30 - about 70. 1.0.40. Any of the preceding compositions comprising at least about 5% small particle synthetic amorphous silica (d50 about 3 - about 4 urm). 1.0.41. Any of the preceding compositions comprising at Icast about 20% small particle precipitated calcium carbonate (d50 about 0.5 - about 3 urn). 1.0.42. Any of the preceding compositions further comprising an anti-calculus agent. 1.0.43. Any of the preceding compositions further comprising an anti-calculus agent which is a polyphosphate. e.g., pyrophosphate, tripolyphosphate. or hexametaphosphate, c.g., in sodium salt form. 1.0.44. Any of thc preceding compositions comprising at least one surfactant. 1.0.45. Any of the preceding compositions comprising at least one surfactant selected from sodium lauryl sulfate, cocamidopropyl betaine. and combinations thereof. 1.0.46. Any of the preceding compositions comprising an anionic surfactant. 1.0.47. Any of thc preceding compositions comprising sodium lauryl sulfate. 1.0.48. Any of thc preceding compositions comprising at least one humectant. 1.0.49. Any of the preceding compositions comprising at least one humcciant selected from glycerin, sorbitol and combinations thereof. 1.0.50. Any of the preceding compositions comprising at least onc polymer. 1.0.51. Any of the preceding compositions comprising at least one polymer selected from polyethylenc glycols, polyvinylmcthyl ether nialeic acid copolymcrs. polysaccharides (e.g., cellulose derivatives, for example carboxymethyl cellulose, or polysaccharide gums. for example xanthan gum or carrageenan gum), and combinations thereof. 1.0.52. Any of the preceding compositions comprising gum strips or fragments. 1.0.53. Any of the preceding compositions comprising flavoring, fragrance and/or coloring. 1.0.54. Any of the preceding compositions comprising water. 1.0.55. Any of the preceding compositions comprising an antibacterial agcnt. 1.0.56. Any of the preceding compositions comprising an antibacterial agcnt selcctcd from halogenated diphenyl ether (e.g. triclosan), herbal cxtracts and essential oils (e.g., rosemary 7 WO 2009/099452 PCT/US2008/058679 cxtract, tea extract, magnolia extract. thymol, menthol. eucalyptol. geraniol. carvacrol, citral, hinokitol. catechol, methyl salicylate. epigallocatechin gallatc. cpigallocatechin. gallic acid. miswak extract, sea-buckthorn extract). bisguanide antiscptics (e.g.. chlorhcxidinc, alexidine or octenidine), quaternary ammonium compounds (c.g.. cetylpyridinium chloride (CPC), benzalkonium chloride, tetradccylpyridinium chloride (TPC). N-tetradccyl-4-ethylpyridinium chloride (TDEPC)), phcnolic aniseptics. hcxetidine. octenidine, sanguinarine, povidone iodine, delmopinol, salifluor. mctal ions (e.g.. zinc salts, for example. zinc citrate, stannous salts. copper salts, iron salts). sanguinarinc. propolis and oxygenating agents (e.g.. hydrogen peroxide, buffered sodium peroxyborate or peroxycarbonate). plithalic acid and its salts, monoperthalic acid and its sails and esters, ascorbyl stearatc. oleoyl sarcosine. alkyl sulfate, dioctyl sulfosuccinatc. salicylanilide. domiphen bromide, delmopinol. octapinol and other piperidino derivatives. nicin preparations. chlorite salts; and mixtures of any of the foregoing. 1.0.57. Any of the preceding compositions comprising an anti-inflanmatory compound. e.g., an inhibitor of at least one of host pro-inflammatory factors sclcctcd from matrix metalloprotcinascs (MMP's), cyclooxygenases (COX). PGE 2 . intericukin I (IL-I). IL-1# converting enzyme (ICE), transforming growth factor #1 (TGF-Q I), induciblc nitric oxide synthasc (iNOS), hyaluronidase, cathepsins, nuclear factor kappa B (NF-KB). and IL-I Receptor Associatcd Kinase (IRAK). e,g, selected from aspirin, ketorolac, flurbiprofen, ibuprofen. naproxen, indomethacin, aspirin. ketoprofen. piroxicam, mcclofenamic acid. nordihydoguaiarctic acid, and mixtures thereof. 1.0.58. Any of the preceding compositions comprising an antioxidant, c.g.. selected from the group consisting of Co-enzyme QIO. PQQ. Vitamin C, Vitamin E. Vitamin A. anethole dithiothione. and mixtures thereof. 1.0.59. Any of the preceding compositions comprising triclosan. 1.0.60. Any of the preceding compositions comprising an antibacterial agent in an amount of about 0.0 1 - about 5 wt. % of the total composition weight. 1.0.61. Any of the preceding compositions comprising triclosan in anl amount of about 0.01 to about I wt. percent of the total composition weight. 1.0.62. Any of the preceding compositions comprising triclosan in an amount of about 0.3% of the total composition weight. 1.0.63. Any of the preceding compositions comprising triclosan and Zn2+ ion source c.g.. 8 WO 2009/099452 PCTIUS2008/058679 zinc citrate. 1.0.64. Any of the preceding compositions comprising a whitening agent. 1.0.65. Any of the preceding compositions comprising a whitening agent selected from a whitening active selected from thc group consisting of peroxides, metal chlorites, perborates, percarbonates, peroxyacids. hypochlorites, and combinations thercof 1.0.66. Any of the preceding compositions further comprising hydrogen peroxide or a hydrogen peroxide source, e.g., urea peroxide or a peroxide salt or cornplcx (e.g.. such as peroxyphosphate, peroxycarbonate, perborate. peroxysilicate, or persulphate salts: for example calcium peroxyphosphate. sodium perborate. sodium carbonate peroxide. sodium peroxyphosphate, and potassium persulfate). or hydrogen peroxide polymer conplexcs such as hydrogen peroxide-polyvinyl pyrrolidone polymer complexes. 1.0.67. Any of the preceding compositions further comprising a source of calcium and phosphate selected from (i) calcium-glass complexes, e.g., calcium sodium phosphosilicates, and (ii) calcium-protein complexes, e.g., casein phosphopeptide amorphous calcium phosphate. 1.0.68. Any of the preceding compositions further comprising a soluble calcium salt, e.g., selected from calcium sulfate. calcium chloride. calcium nitrate. calcium acetate, calcium lactate, and combinations thereof. 1.0.69. Any of the preceding compositions further comprising an agent that interferes with or prcvcnts bacterial attachment. e.g.. solbrol or chitosan. 1.0.70. Any of the preceding compositions further comprising a physiologically acceptable potassium salt. e.g.. potassium nitrate, potassium citrate, or potassium chloride, in an amount effective to rcducc dentinal sensitivity. 1.0.71. Any of the preceding compositions comprising from about 0.1% to about 7.5% of a physiologically acceptable potassium salt, e.g.. potassium nitrate and/or potassium chloride. 1.0.72. Any of the preceding compositions wherein the salt of a basic amino acid is argininc bicarbonate, the fluoride is sodium monofluorophosphate, and the abrasive is precipitated calcium carbonate. 1.0.73. Any of the preceding compositions wherein the salt of a basic amino acid is arginine bicarbonate, the fluoride is sodium monofluorophosphate, and the abrasive is silica. 1.0.74. Any of the preceding compositions effective upon application to the oral cavity, 9 WO 2009/099452 PCT/US2008/058679 e.g., with brushing, to (i) reduce or inhibit formation of dental carics, (ii) reduce, repair or inhibit pre-carious lesions of the enamel, e.g.. as detected by quantitative light-induced fluorescence (QLF) or electrical caries measurement (ECM). (iii) reduce or inhibit demineralization and promote remincralization of the teeth, (iv) reduce hypersensitivity of the teeth, (v) reduce or inhibit gingivitis, (vi) promote healing of sores or cuts in the mouth. (vii) reduce levels of acid producing bacteria. (viii) to increase relative levels of arginolytic bacteria. (ix) inhibit microbial biofilm formation in the oral cavity. (x) raise and/or maintain plaque p-I at levels of at least pH 5.5 following sugar challenge. (xi) reduce plaque accumulation, (xii) reduce dry mouth, (xiii) clean the teeth and oral cavity (xiv) reduce erosion, (xv) whiten teeth, and/or (xvi) immunize the teeth against cariogenic bacteria. 1.0.75. A composition obtained or obtainable by combining the ingredients as set forth in any of the preceding compositions. 1.0.76. Any of the preceding compositions in a form selected from mouthrinse. toothpaste. tooth gel, tooth powder. non-abrasive gel, mousse, foam. mouth spray, lozenge. oral tablet. dental implement. and pet care product. 1.0.77. Any of the preceding compositions wherein the composition is toothpaste. 1.0.78. Any of the preceding compositions wherein the composition is a toothpaste optionally further comprising one or more of one or more of water. abrasives. surfactants. foaming agents, vitamins, polymers, enzymes. humectants, thickeners, antimicrobial agents. preservatives, flavorings, colorings and/or combinations thereof. 1.0.79. Any of the preceding compositions 1.0 - 1.0.76 wherein the composition is a mouthwash. [00201 In another embodiment, the invention encompasses a Composition of the Invention (Composition 1.1). e.g.. according to any of the preceding Compositions 1.0 - 1.0.79. comprising i. an effective amount of a basic amino acid in free or salt form: ii. an effective amount of a fluoride source. e.g.. soluble fluoride salt: iii. an anionic surfactant, e.g.. sodium lauryl sulfate. 100211 In another embodiment, the invention encompasses a Composition of the Invention (Composition 1.2) e.g., according to any of the preceding Compositions 1.0 - 1.0.79. 10 WO 2009/099452 PCT/US2008/058679 comprising i. an effective amount of a basic amino acid in free or salt form; ii. an effective amount of a fluoride source, e.g., soluble fluoride salt: iii. an anionic surfactant. e.g.. sodium lauryl sulfate; iv. an anionic polymer, e.g., a copolymer of methyl vinyl ether and malcic anhydride; and V. an antibacterial agent, e.g.. triclosan. 100221 In another embodiment, the invention encompasses a Composition of the Invention (Composition 1.3) c.g.. according to any of the preceding Compositions 1.0 - 1.0.79, comprising i. an effective amount of a basic amino acid in free or salt form; ii. an effective amount of a fluoride source, e.g., a soluble fluoride salt: and iii. small particle abrasive having a RDA of less than about 160, e.g., about 30 - about 130. c.g., comprising at least about 5% of an abrasive having a d50 less than about 5 micrometers, c.g.. silica having a d50 of about 3 - about 4 pm or precipitated calcium carbonate having a d50 of about 0.5 - about 3 pim. 100231 In another embodiment, the invention encompasses a method ( (Method 2) to improve oral health comprising applying an effective amount of the oral composition of any of the embodiments inder Compositions 1.0. 1.1. 1.2. 1.3 or 1.4. to the oral cavity of a subject in need thereof. e.g., a method to i. reduce or inhibit formation of dental caries. ii. reduce. repair or inhibit pre-carious lesions of the enamel. e.g., as detected by quantitative light-induced fluorescence (QLF) or electrical caries measurement (ECM), iii. reduce or inhibit demineralization and promote remincralization of the teeth. iv. reduce hypersensitivity of the teeth, v. reduce or inhibit gingivitis. vi. promote healing of sores or cuts in the mouth, vii. reduce levels of acid producing bacteria, 11 WO 2009/099452 PCT/US2008/058679 viii. to increase relative levels of arginolytic bacteria. ix. inhibit microbial biofilm formation in the oral cavity. x. raise and/or maintain plaque pH at levels of at least pH1 about 5.5 following sugar challenge, xi. reduce plaque accumulation, xii. reduce crosion. xiii. whiten teeth, xiv. enhance systemic health. xv. immunize or protect teeth against cariogenic bacteria: and/or clcan the teeth and oral cavity. 100241 The invention further comprises the use of arginine in the manufacture of a Composition of the Invention, e.g., for use in any of the indications set forth in Method 2. 100251 The invention further provides an oral care composition comprising a basic amino acid. in frcc or salt form. and an abrasive material, the abrasive material including a small particle fraction comprising at least about 5 wt% of the total composition weight, whercin the particles of the small particle fraction have a d5O of less than 5 pm. for use in the treatment of sensitive teeth within an oral cavity of a subject. It has been found surprisingly that such a composition. including the combination of the basic amino acid and the small particle fraction of abrasive. exhibits enhanced dentinal occlusion of the teeth. 100261 The invention further provides an oral care composition comprising a basic amino acid, in free or salt form. and a small particle fraction comprising at least about 5% of the composition by weight. wherein the particles of the small particle fraction have a d50 of less than about 5 ym. for enhancing dentinal occlusion within an oral cavity of a subject. 100271 The invention further provides the use of a basic amino acid. in free or salt form. in an oral care composition comprising a small particle fraction comprising at least about 5% of the composition by weight. wherein the particles of the small particle fraction have a d5O of less than about 5 pm. for enhancing dentinal occlusion within an oral cavity of a subject. 100281 The invention further provides the use of of a basic amino acid. in free or salt form, for the manufacture ofa medicament which includes a small particle fraction comprising at least about 5% of the medicament by weight. wherein the particles of the sniall particle fraction have a d50 of less than about 5 pm. for enhancing dentinal occlusion within an oral cavity of a subject. 12 WO 2009/099452 PCT/US2008/058679 100291 The invention further provides a method of treating sensitive teeth within an oral cavity, the method comprising treating the oral cavity of a subject with an oral care composition comprising a basic amino acid, in free or salt form. and a small particle fraction comprising at least about 5% of the composition by weight, wherein the particles of the small paiticlc fraction have a d50 of less than about 5 pm, to enhance dentinal occlusion. [00301 It may therefore be seen by the skilled practitioner in the oral care art that a surprising technical effect and advantage of enhanced dentinal occlusion of sensitive teeth can result from the formulation, and use. of an oral care composition, for example a dcntifrice. in accordance with one or more aspects of the invention, which are directed to the provision of combinations of active components or ingredients, and preferably their respective amounts, within the composition. 100311 Levels of active ingredients will vary based on the nature of the delivery system and the particular active. For example. the basic amino acid may be present at levels from, e.g.. about 0.1 to about 20 wt expresseded as weight of free base), c.g.. about 0.1 to about 3 wt % for a mouthrinse, about I to about 10 wt % for a consumer toothpaste or about 7 to about 20 vt % for a professional or prescription treatment product. Fluoride may bc present at levels of. e.g., about 25 to about 10,000 ppm, for example about 25 to about 250 ppm for a mouthrinse, about 750 to about 2.000 ppm for a consumer toothpaste. or about 2,000 to about 10,000 ppm for a professional or prescription treatment product. Levels of antibacterial will vary similarly. with levels used in toothpaste being e.g., about 5 to about 15 times greater than used in mouthrinse. For example. a triclosan mouthrinse may contain, e.g.. about 0.03 wt % triclosan while a triclosan toothpaste may contain about 0.3 wt % triclosan. Basic Amino Acids 100321 The basic amino acids which can be used in the compositions and methods of the invention include not only naturally occurring basic amino acids, such as arginine, lysine. and histidine. but also any basic amino acids having a carboxyl group and an amino group in the molecule. which are water-soluble and provide an aqueous solution with a pH of about 7 or greater. [00331 Accordingly. basic amino acids include, but are not limited to, arginine, lysine. citrulline, ornitine, creatine, histidine, diaminobutanoic acid, diaminoproprionic acid, salts thereof or combinations thereof. In a particular embodiment. the basic amino acids are selected from arginine. citrulline. and ornithine. 13 WO 2009/099452 PCT/US2008/058679 100341 In certain embodiments, the basic amino acid is arginine. for example, l-argininc. or a salt thereof. 100351 In some cnbodiments the basic amino acid comprises at least one intermediate produced in the arginine deiminase system. The intermediates produced in the arginine dciminase system may be useful in an oral carc composition to provide plaque neutralization for caries control and/or prevention. Arginine is a natural basic amino acid that may be found in the oral cavity. Arginine in the mouth may be utilized by certain dental plaque bacterial strains such as S. sanguis. S. gordonii. S. parasanguis, S. raitus. S. miller, S. anginosus. S. faecalis, A. naeslundii, A. odonolyticus, L. cellobiosius, L. brevis, L. fermeinm. P. gingivalis. and T. denticola for their survival. Such organisms may perish in an acidic environment that may be present at areas close to the tooth surface where acidogenic and aciduric cariogenic strains may use sugars to produce organic acids. Thus. these arginolytic strains may break down argininc to ammonia to provide alkalinity to survive and. in addition, buffer the plaque and make a hostile environment for the cariogenic systems. 100361 Such arginolytic organisms may catabolize arginine by an internal cellular enzyme pathway system called the "arginine dciminase system' whereby intermediates in the pathway are fonncd. In this pathway, L-argininc may be broken down to L-eitrulline and ammonia by arginine deiminasc. L-citrullinc may then be broken down by ornithane trancarbamylase in the presence of inorganic phosphate to L-ornithine and carbamyl phosphate. Carbamate kinase may then break down carbamyl phosphate to form another molecule of ammonia and carbon dioxide. and in the process also forms ATP (adenosine 5'-triphosphate). ATP may be uscd by the arginolytic bacteria as an energy source for growth. Accordingly, when utilized. the arginine deiminase system may yield two molecules of ammonia. 100371 It has been found that, in some embodiments, the ammonia may help in neutralizing oral plaque pH to control and/or prevent dental caries. 100381 The oral care composition of some embodiments of the present invention may include intermediates produced in the arginine deiminase system. Such intennediates may include citrulline, omithine, and carbaryl phosphate. In some embodiments, the othcr care composition includes citrulline. In some embodiments, the oral care composition includes ornithinc. In sonic embodiments. the oral care composition includes carbamyl phosphate. In other embodiments, the oral care composition includes any combination of citrulline. ornithine. carbaryl phosphate, and/or other intermediates produced by the arginine deiminase system. 14 WO 2009/099452 PCT/US2008/058679 100391 The oral care composition may include the above described intermediates in an effective amount. In some embodiments. the oral care composition includes about I mmol/L to about 10 nmol/L intermediate. In other crmbodiments, the oral care composition includes about 3 mmol/L to about 7 nimol/L intermediate. In other embodiments, the oral care composition includes about 5 mmol/L intermediate. 100401 The compositions of the invention are intended for topical use in the mouth and so salts for use in the present invention should be safe for such use, in the amounts and concentrations provided. Suitable salts include salts known in the art to be pharmaceutically acceptable salts are generally considered to be physiologically acceptable in the amounts and concentrations provided. Physiologically acceptabic salts include thosc dcrived from pharmaceutically acceptable inorganic or organic acids or bases. for exampic acid addition salts formed by acids which form a physiological acceptable anion. e.g.. hydrochloride or bromide salt. and base addition salts formed by bases which form a physiologically acceptable cation. for example those derived from alkali metals such as potassium and sodium or alkaline earth metals such as calcium and magnesium. Physiologically acceptable salts may be obtained using standard procedures known in the art. for example. by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion. 100411 In various embodiments, the basic amino acid is present in an amount of about 0.5 wt. % to about 20 wt. % of the total composition weight. about I wt. % to about 10 wt. % of the total composition weight, for example about 1.5 wt. %, about 3.75 wt. %, about 5 wt. %, or about 7.5 wt. % of the total composition weight. 100421 RDA: RDA is an abbreviation for radioactive dentin abrasion. a relative measure of abrasivity. Typically, extracted human or cow teeth arc irradiated in a neutron flux. mounted in niethylmethacrylate (bonc glue). stripped of enamel, inserted into a brushing-machine. brushed by American Dental Association (ADA) standards (reference toothbrush. 150g pressure, 1500 strokes. 4-to-I water-toothpaste slurry). The radioactivity of the rinse water is then measured and recorded. For experimental control. the test is repeated with an ADA reference toothpaste made of calcium pyrophosphate. with this measurement given a value of 100 to calibrate the relative scale. Fluoride Ion Source 100431 The oral care compositions may further include one or more fluoride ion sources. e.g.. soluble fluoride salts. A wide variety of fluoride ion-yielding materials can be employed 15 WO 2009/099452 PCT/US2008/058679 as sources of soluble fluoride in the present compositions. Examples of suitable fluoride ion yielding materials are found in U.S. Pat. No. 3,535.421. to Briner et al.; U.S. Pat. No. 4.885,155. to Parran, Jr. et al. and U.S. Pat. No. 3,678.154, to Widder et al., incorporated herein by reference. 100441 Representative fluoride ion sources include, but are not limited to, stannous fluoride, sodium fluoride, potassium fluoride, sodium monofluorophosphate. sodium fluorosilicatc. ammonium fluorosilicate, amine fluoride, ammonium fluoride. and combinations thereof. In certain embodiments the fluoride ion source includes stannous fluoride, sodium fluoride. sodium monofluorophosphate as well as mixtures thereof. 100451 In certain embodiments, the oral care composition of the invention may also contain a source of fluoride ions or fluorine-providing ingredient in amounts sufficient to supply about 25 ppm to 25.000 ppm of fluoride ions. generally at least about 500 ppm, e.g., about 500 to about 2000 ppm, e.g., about 1000 to about 1600 ppm, e.g.. about 1450 ppm. The appropriate level of fluoride will depend on the particular application. A mouthwash. for example. would typically have about 100 to about 250 ppm fluoride. A toothpaste for general consumer usc would typically have about 1000 to about 1500 ppm. with pediatric toothpaste having somewhat less. A dentifrice or coating for professional application could have as much as 5.000 or even 25,000 ppm fluoride. 100461 Fluoride ion sources may be added to the compositions of the invention at a level of about 0.01 wt. % to about 10 wt. % in one embodiment or about 0.03 wt. % to about 5 wt. %. and in another embodiment about 0.1 wt. % to about I wt. % by weight of the composition in another embodiment. Weights of fluoride salts to provide the appropriate level of fluoride ion will obviously vary based on the weight of the counter ion in the salt. 100471 Where the composition comprises calcium bicarbonate. sodium monofluorophosphate is preferred to sodium fluoride for stability reasons. Abrasives 100481 The Compositions of the Invention may comprise a precipitated calcium carbonate (PCC) abrasive. calcium phosphate abrasive, e.g., tricalcium phosphate (Ca 3 (P04) 2 ). hydroxyapatite (Caio(P0 4

)

6 (OHl-)2), or dicalcium phosphate dihydrate (CaHPO4 - 2H 2 0. also sometimes referred to herein as DiCal) or calcium pyrophosphate. Alternatively. calcium carbonate. and in particular precipitated calcium carbonate. may be employed as an abrasive. 100491 The compositions may include one or more additional abrasives, for example silica 16 WO 2009/099452 PCT/US2008/058679 abrasives such as precipitated silicas having a mean particle size of up to about 20 pm. such as Zeodent 1 15*. marketed by J. M. Huber. Other useful abrasives also include sodium metaphosphate. potassium mctaphosphate. aluminum silicate, calcined alumina, bentonite or other siliceous materials, or combinations thereof. 100501 The silica abrasive polishing materials useful herein, as well as the other abrasives, generally have an average particle size of about 0.1 and about 30 pm. about 5 and about 15 pm. The silica abrasives can be from precipitated silica or silica gels, such as the silica xerogels described in U.S. Pat. No. 3,538,230, to Pader et al. and U.S. Pat. No. 3,862,307, to Digiulio, both incorporated herein by reference. Particular silica xcrogels are marketed under the trade name Syloid* by the W. R. Grace & Co.. Davison Chemical Division. The precipitated silica materials include those marketed by the J. M. Hubcr Corp. under the trade name Zcodent', including the silica carrying the designation Zeodent 115 and 119. These silica abrasives are described in U.S. Pat. No. 4.340,583. to Wason, incorporated herein by reference. 100511 In certain cmbodiments, abrasive materials useful in the practice of the oral care compositions in accordance with the invention include silica gels and precipitated amorphous silica having an oil absorption value of about less than 100 cc/100 g silica and in the range of about 45 cc/100 g to about 70 cc/100 g silica. Oil absorption values are measured using the ASTA Rub-Out Method D281. In certain embodimcnts. the silicas are colloidal particles having an average particle size of about 3 pm to about I 2 pm, and about 5 to about 10 pm. 100521 In particular embodiments, the abrasive materials comprisc a largc fraction of very small particles, e.g., having a d50 less than about 5 pm. For example small particle silica (SPS) having a d50 of about 3 - about 4 pm, for example Sorbosil AC43@ (Ineos). Such small particles arc particularly useful in formulations targeted at reducing hypersensitivity. The small particle component may be present in combination with a second largcr particle abrasive. In certain embodiments, for example, the formulation comprises about 5 to about 25% small particles e.g., SPS and about 10 to about 30% of a conventional abrasive. 100531 Low oil absorption silica abrasives particularly useful in the practice of thc invention arc marketed under the trade designation Sylodent XWA*" by Davison Chemical Division of W.R. Grace & Co., Baltimore. Md. 21203. Sylodent 650 XWA*. a silica hydrogcl composed of particles of colloidal silica having a water content of about 29% by weight averaging about 7 to about 10 pm in diameter, and an oil absorption of less than about 70 cc/l00 g of silica is an example of a low oil absorption silica abrasive useful in the practice of the present invention. The abrasive is present in the oral care composition of the present 17 WO 2009/099452 PCT/US2008/058679 invention at a concentration of about 10 to about 60% by weight, in other embodiment about 20 to about 45% by weight. and in another embodiment about 30 to about 50% by weight. 100541 In some embodiments the basic amino acid is incorporated into a dentifrice composition having a base formulation comprising calcium carbonate, and in particular precipitated calcium carbonate, as an abrasive. L-arginine and arginine salts such as arginine bicarbonate are themselves distinctly bitter in taste. and in aqueous solution can also impart a fishy taste. Consequently, it was expected that when L-arginine or arginine salts were incorporated into oral care products such as dentifrice fornulations at effective concentrations to impart anticavity efficacy and sensitivity relief. typically in an amount of from 2 to I Owt % based o the total weight of the dentifrice formulation, the taste and mouthfecl of the dentifrice formulations would be degraded as compared to the samc formulation without the addition of L-arginine or arginine salts. 100551 However, it has surprisingly been found in accordance with this aspect of the present invention that the addition of L-argininc or arginine salts to a base dentifrice formulation comprising calcium carbonate can provide a significant enhancement of taste and mouthfeel attributes to the dentifrice formulation and to an increase in the overall acceptance of the product to a consumer. Agents to Increase the Amount of Foaning 100561 The oral care compositions of the invention also may include an agent to increase the amount of foam that is produced when the oral cavity is brushed. 100571 Illustrative examples of agents that increase the amount of foam include. but are not limited to polyoxyethylene and certain polymers including. but not limited to, alginate polymers. [00581 The polyoxyethylene may increase the amount of foam and the thickness of the foam generated by the oral care carrier component of the present invention. Polyoxyethylene is also commonly known as polyethylene glycol ("PEG") or polycthylcne oxide. The polyoxyethylenes suitable for this invention will have a molecular weight of about 200,000 to about 7,000.000. In one embodiment the molecular weight will be about 600.000 to about 2.000.000 and in another cmbodiment about 800,000 to about 1,000,000. Polyox" is the trade name for the high molecular weight polyoxyethylene produced by Union Carbide. 100591 The polyoxyethylene may be present in an amount of about 1% to about 90%. in one embodiment about 5% to about 50% and in another embodiment about 10% to about 20% 18 WO 2009/099452 PCT/US2008/058679 by weight of the oral care carrier component of the oral care compositions of the present invention. The dosage of foaming agent in the oral care composition (i.e.. a single dosc) is about 0.01 to about 0.9 % by weight, about 0.05 to about 0.5% by weight, and in another embodiment about 0. 1 to about 0.2 % by weight. Sur factants 100601 Another agent optionally included in the oral care composition of the invention is a surfactant or a mixture of compatible surfactants. Suitable surfactants arc those which are reasonably stable throughout a wide pH range, for exampic. anionic, cationic, nonionic or zwitterionic surfactants. 100611 Suitable surfactants are described morc fully, for example, in U.S. Pat. No. 3.959.458. to Agricola et al.: U.S. Pat. No. 3,937,807. to Haefcle: and U.S. Pat. No. 4.051.234. to Gieske et al., which are incorporated herein by reference. 100621 In certain embodiments, the anionic surfactants useful herein include the water soluble salts of alkyl sulfates having about 10 to about 18 carbon atoms in the alkyl radical and the water-soluble salts of sulfonatcd monoglyceridcs of fatly acids having about 10 to about 18 carbon atoms. Sodium lauryl sulfate, sodium lauroyl sarcosinate and sodium coconut monoglyceride sulfonatcs are examples of anionic surfactants of this type. Mixtures of anionic surfactants may also be utilized. 100631 In another embodiment. cationic surfactants useful in the present invention can be broadly defined as derivatives of aliphatic quaternary ammonium compounds having one long alkyl chain containing about 8 to about 18 carbon atoms such as lauryl trimethylammonium chloride, cetyl pyridinium chloride, cetyl trimethylammonium bromide. di isobutylphenoxyethyldimethylbenzylammnioiun chloride, coconut alkyltrimethylammonium nitrite. cetyl pyridinium fluoride, and mixtures thereof. 100641 Illustrative cationic surfactants are the quaternary ammonium fluorides described in U.S. Pat. No. 3,535.421, to Briner et al., herein incorporated by reference. Certain cationic surfactants can also act as germicidcs in the compositions. 100651 Illustrative nonionic surfactants that can be used in the compositions of the invention can be broadly defined as compounds produced by thc condensation of alkylenc oxide groups (hydrophilic in nature) with an organic hydrophobic compound which may be aliphatic or alkylaromatic in nature. Examples of suitable nonionic surfactants include, but are not liiitcd to. the Pluronics. polyethylenc oxide condensates of alkyl phcnols. products derived 19 WO 2009/099452 PCT/US2008/058679 from the condensation of ethylene oxide with the reaction product of propylene oxide and ethylene diaminc. ethylene oxide condensates of aliphatic alcohols, long chain tertiary amine oxides, long chain tertiary phosphine oxides, long chain dialkyl sulfoxides and mixtures of such materials. 10066] In certain embodiments. zwitterionic synthetic surfactants useful in the present invention can be broadly described as derivatives of aliphatic quaternary ammonium, phosphomium, and sulfonium compounds, in which the aliphatic radicals can be straight chain or branched, and wherein one of the aliphatic substituents contains about 8 to about 18 carbon atoms and one contains an anionic water-solubilizing group. e.g.. carboxy, sulfonate. sulfate, phosphate or phosphonaic. Illustrative examples of the surfactants suited for inclusion into the composition include, but are not limited to. sodium alkyl sulfate, sodium lauroyl sarcosinate. cocoamidopropyl betaine and polysorbate 20, and combinations thereof. 100671 In a particular embodiment, the Composition of the Invention compriscs an anionic surfactant. e.g., sodium lauryl sulfate. 100681 The surfactant or mixtures of compatible surfactants can be present in the compositions of the present invention in about 0.1% to about 5.0%. in another embodiment about 0.3% to about 3.0% and in another embodiment about 0.5% to about 2.0% by weight of the total composition. Flavoring Agents 100691 The oral care compositions of the invention may also include a flavoring agent. Flavoring agents which are used in the practice of the present invention include. but are not limited to. essential oils as well as various flavoring aldehydes, csters, alcohols, and similar materials. Examples of the essential oils include oils of spearmint. peppermint, wintergreen. sassafras, clove, sage, eucalyptus, marjoram. cinnamon, lemon, limc, grapefruit, and orange. Also useful are such chemicals as menthol. carvone. and anethole. Certain embodiments employ the oils of peppermint and spearmint. 100701 The flavoring agent is incorporated in the oral composition at a concentration of about 0.1 to about 5% by weight and about 0.5 to about 1.5% by weight. The dosage of flavoring agent in the individual oral carc composition dosage (i.e.. a single dose) is about 0.00 1 to about 0.05% by weight and in another embodiment about 0.005 to about 0.015 % by weight. Chelating agents 20 WO 2009/099452 PCT/US2008/058679 100711 The oral care compositions of the invention also may optionally include one or more chelating agents able to complex calcium found in the cell walls of the bacteria. Binding of this calcium weakens the bacterial cell wall and augments bacterial lysis. [00721 Another group of agents suitable for use as chelating agents in the present invention are the soluble pyrophosphates. The pyrophosphate salts used in the present compositions can be any of the alkali metal pyrophosphate salts. In certain embodiments, salts include tetra alkali metal pyrophosphate, dialkali metal diacid pyrophosphate. trialkali metal monoacid pyrophosphate and mixtures thereof, wherein the alkali metals are sodium or potassium. The salts are useful in both their hydrated and unhydrated forms. An effective amount of pyrophosphate salt useful in the present composition is generally enough to provide at least about 1.0 wt. % pyrophosphate ions, about 1.5 w. % to about 6 wt. %, about 3.5 wt. % to about 6 wt. % of such ions. Polymers [00731 The oral care compositions of the invention also optionally include one or more polymers. such as polyethylene glycols, polyvinylmethyl ether maleic acid copolymers, polysaccharides (e.g.. cellulose derivatives, for example carboxymethyl cellulose. or polysaccharide gums, for example xanthan gum or carrageenan gum). Acidic polymers, for example polyacrylate gels. may be provided in the form of their free acids or partially or fully neutralized water soluble alkali metal (e.g., potassium and sodium) or ammonium salts. Certain embodiments include 1:4 to 4:1 copolymers of maleic anhydride or acid with another polymerizable ethylenically unsaturated monomer. for example. methyl vinyl ether (methoxyethylene) having a molecular weight (M.W.) of about 30,000 to about 1,000.000. These copolymers are available for example as Gantrez AN 139(M.W. 500,000). AN 119 (M.W. 250,000) and S-97 Pharmaceutical Grade (M.W. 70,000). of GAF Chemicals Corporation. [00741 Other operative polymers include those such as the 1:1 copolymers of maleic anhydride with ethyl acrylate, hydroxyethyl methacrylate, N-vinyl-2-pyrollidone, or ethylene, the latter being available for example as Monsanto EMA No. 1103. M.W. 10,000 and EMA Grade 61, and 1:1 copolymers of acrylic acid with methyl or hydroxyethyl methacrylate. methyl or ethyl acrylate, isobutyl vinyl ether or N-vinyl-2-pyrrolidone. 10075] Suitable generally, are polymerized olefinically or ethylenically unsaturated carboxylic acids containing an activated carbon-to-carbon olefinic double bond and at least one 21 WO 2009/099452 PCTIUS2008/058679 carboxyl group, that is. an acid containing an olefinic double bond which rcadily functions in polymerization bccausc of its presence in the monomer molecule either in the alpha-beta position with respect to a carboxyl group or as part of a terminal methylene grouping. Illustrative of such acids are acrylic, methacrylic. cthacrylic. alpha-chloroacrylic, crotonic. beta-acryloxy propionic, sorbic, alpha-chlorsorbic. cinnamic, beta-styrylacrylic, muconic, itaconic, citraconic, mesaconic, glutaconic, aconitic. alpha-phenylacrylic. 2-benzyl acrylic, 2 cyclohexylacrylic, angelic, umbellic, fumaric. malcic acids and anhydrides. Other di ffcrent olefinic monomers copolymerizable with such carboxylic monomers include vinylacetate. vinyl chloride. dimethyl nialeate and the like. Copolymers contain sufficient carboxylic salt groups for water-solubility. 100761 A further class of polymeric agents includes a composition containing homopolymers of substituted acrylamides and/or honopolymers of unsaturated sulfonic acids and salts thereof, in particular where polymers are based on unsaturated sul fonic acids selected from acrylamidoalykane sulfonic acids such as 2-acrylamide 2 methylpropane sulfonic acid having a molecular weight of about 1,000 to about 2.000,000, described in U.S. Pat. No. 4.842.847. Jun. 27, 1989 to Zahid, incorporated herein by reference. Another useful class of polymcric agents includes polyamino acids. particularly thosc containing proportions of anionic surface-activc amino acids such as aspartic acid, glutamic acid and phosphoserine, as disclosed in U.S. Pat. No. 4.866.161 Sikes et al., incorporated herein by reference. 100771 In preparing oral care compositions. it is sometimes necessary to add some thickening material to provide a desirabIc consistency or to stabilize or enhance the performance of the formulation. In certain embodiments. the thickening agents are carboxyvinyl polymers. carragcenan, hydroxyethyl cellulose and water soluble salts of cellulose ethers such as sodium carboxymethyl cellulose and sodium carboxymethyl hydroxyethyl cellulose. Natural gums such as karaya. gum arabic. and gum tragacanth can also be incorporated. Colloidal magnesium aluminum silicate or finely divided silica can be used as component of the thickening composition to further improve the composition's texture. In certain embodiments, thickening agents in an amount of about 0.5% to about 5.0% by weight of the total composition are used. Enzymes [00781 The oral care compositions of the invention may also optionally include one or more WO 2009/099452 PCT/US2008/058679 enzymes. Useful enzymes include any of the available proteases. glucanohydrolases. endoglycosidases, amylases. mutanases, lipases and mucinases or compatible mixtures thereof. In certain embodiments, the enzyme is a protease. dextranase. cndoglycosidase and mutanasc. In another embodiment., the cnzymc is papain, endoglycosidase or a mixture of dextranase and mutanase. Additional enzymes suitable for use in the present invention arc disclosed in U.S. Pat. No. 5.000.939 to Dring et al.. U.S. Pat. No. 4.992.420: U.S. Pat. No. 4.355.022: U.S. Pat. No. 4,154,815: U.S. Pat. No. 4,058,595; U.S. Pat. No. 3,991.177: and U.S. Pat. No. 3,696,191 all incorporated herein by reference. An enzyme of a mixture of several compatible enzymes in the current invention constitutes about 0.002% to about 2.0% in one embodiment or about 0.05% to about 1.5% in another embodiment or in yet another embodiment about 0.1% to about 0.5%. Water 100791 Water may also be present in the oral compositions of the invention. Water. employed in the preparation of commercial oral compositions should be deionized and free of organic impurities. Water commonly makes up the balance of the compositions and includes about 10% to about 90%, about 20% to about 60% or about 10% to about 30% by weight of the oral compositions. This amount of water includes the free water which is added plus that amount which is introduced with other materials such as with sorbitol or any components of the invention. Hunectants 100801 Within certain embodiments of the oral compositions. it is also desirable to incorporate a humectant to prevent the composition from hardening upon exposure to air. Certain humectants can also impart desirable sweetness or flavor to dentifrice compositions. The humectant, on a pure humectant basis, generally includes about 15% to about 70% in one embodiment or about 30% to about 65% in another embodiment by weight of the dentifrice composition. 100811 Suitable humectants include edible polyhydric alcohols such as glycerine, sorbitol, xylitol. propylene glycol as well as other polyols and mixtures of these humectants. Mixtures of glycerin and sorbitol may be used in certain embodiments as the humectant component of the toothpaste compositions herein. 100821 In addition to the above described components, the embodiments of this invention can contain a variety of optional dentifrice ingredients some of which arc described belov. 23 WO 2009/099452 PCT/US2008/058679 Optional ingredients include. for example. but are not limited to. adhesives, sudsing agents, flavoring agents, sweetening agents. additional antiplaque agents, abrasives, and coloring agents. These and other optional components are further described in U.S. Pat. No. 5.004.597. to Majeti: U.S. Pat. No. 3.959,458 to Agricola et al. and U.S. Pat. No. 3.937.807. to Haefele, all being incorporated herein by reference. Methods of Manufacture 100831 The compositions of the present invention can be made using methods which arc common in the oral product area. 100841 In one illustrative embodiment. the oral care composition is made by neutralizing or partially neutralizing arginine in a gcl phase with an acid, e.g., phosphoric acid, hydrochloric acid or carbonic acid, and mixing to form Premix 1. 100851 Actives such as. for example. vitamins. CPC. fluoride, abrasives, and any other desired active ingredients are added to Premix 1 and mixed to form Premix 2. 100861 Where the final product is a toothpaste. a toothpaste base, For example. dicalcium phosphate. precipitated calcium carbonate. and/or silica, is added to Premix 2 and mixed. The final slurry is formed into an oral care product. Composition Use 100871 The present invention in its method aspect involves applying to the oral cavity a safe and effective amount of the compositions described heroin. 100881 The compositions and methods according to the invention are useful to a method to protect the teeth by facilitating repair and remineralization. in particular to reduce or inhibit formation of dental caries. reduce or inhibit demineralization and promote remineralization of the teeth, reduce hypersensitivity of the teeth, and reduce, repair or inhibit pre-carious lesions of the enamel. e.g.. as detected by quantitative light-induced fluorescence (QLF) or electronic caries monitor (ECM). 100891 Quantitative Light-induced Fluorescence is a visible light fluorescence that can detect early lesions and longitudinally monitor the progression or regression. Normal teeth fluoresce in visible light: dcmineralized teeth do not or do so only to a lesser degree. The area of demineralization can be quantified and its progress monitored. Blue laser light is used to make the teeth auto fluoresce. Areas that have lost mineral have lower fluorcscencc and appear darker in comparison to a sound tooth surface. Software is used to quantify the fluoresccnce 24 WO 2009/099452 PCT/US2008/058679 from a white spot or the area/volumc associated with the lesion. Gcncrally, subjects with existing white spot lesions arc recruited as panelists. The measurements are performed in vivo with real teeth. The lcsion area/volume is measured at the beginning of the clinical. The reduction (improvement) in lesion area/volume is measured at the end of 6 months of product use. The data is often reported as a percent improvement versus baseline. 100901 Electrical Caries Monitoring is a technique used to measure mineral content of the tooth based on electrical resistance. Electrical conductance measurement exploits the fact that the fluid-filled tubules exposed upon dcmineralization and erosion of the enamel conduct electricity. As a tooth loses mineral, it becomes less resistive to electrical current due to increased porosity. An increase in the conductance of the patient's teeth therefore may indicate demineralization. Generally, studies are conducted of root surfaces with an existing lcsion. The measurements are performed in vivo with real teeth. Changes in electrical resistance before and after 6 month treatments are made. In addition, a classical caries score for root surfaces is made using a tactile probe. The hardness is classified on a three point scale: hard, leathery, or soft. In this type of study, typically the results are reported as electrical resistance (higher number is better) for the ECM measurements and an improvement in hardness of the lesion based on the tactile probe score. 100911 The Compositions of the invention are thus useful in a method to reduce pre-carious lesions of the enamel (as measured by QLF or ECM) relative to a composition lacking effective amounts of fluorine and/or arginine. 100921 The Compositions of the invention are additionally useful in methods to reduce harmful bacteria in the oral cavity, for example methods to reduce or inhibit gingivitis. reduce levels of acid producing bacteria, to increase relative levels of arginolytic bacteria, inhibit microbial biofilm formation in the oral cavity, raise and/or maintain plaque p-I at levels of at least pH 5.5 following sugar challenge. reduce plaque accumulation. and/or clean the teeth and oral cavity. 100931 Finally, by increasing the plH in the mouth and discouraging pathogenic bacteria, the Compositions of the Invention are useful to promote healing of sores or cuts in the mouth. 100941 Enhancing oral health also provides benefits in systemic health. as the oral tissues can be gateways for systemic infections. Good oral health is associated with systemic health. including cardiovascular health. The compositions and methods of the invention provide particular benefits because basic amino acids, especially arginine. are sources of nitrogen which 25 WO 2009/099452 PCT/US2008/058679 supply NO synthesis pathways and thus cnhancc microcirculation in the oral tissues. Providing a less acidic oral environment is also helpful in reducing gastric distress and creates an environment less favorable to Heliobacter. which is associated with gastric ulcers. Arginine in particular is required for high expression of specific immune ccll receptors. for example T-cell receptors. so that arginine can enhance an effective immune response. The compositions and methods of the invention are thus useful to enhance systemic health, including cardiovascular health. 100951 The compositions and methods according to the invention can bc incorporated into oral compositions for the care of the mouth and teeth such as toothpastes, transparent pastes. gels. mouth rinses, sprays and chewing gum. 100961 As used throughout. ranges arc used as shorthand for describing cach and every value that is within the range. Any value within the range can be selected as the terminus of the range. In addition, all references cited herein are hereby incorporated by reference in their entireties. In the event of a conflict in a definition in the present disclosure and that of a cited reference, the present disclosure controls. It is understood that when formulations are described, they may be described in terms of their ingredients. as is common in the art. notwithstanding that thcse ingredients may react with one another in the actual formulation as it is made, stored and used. and such products are intended to be covered by the formulations described. [00971 The following examples further describe and demonstrate ill ustrative embodiments within the scope of the present invention. The examples are given solely for illustration and are not to be construed as limitations of this invention as many variations are possible without departing from the spirit and scope thereof. Various modifications of the invention in addition to thosc shown and described herein should be apparent to those skilled in the art and arc intended to fall within the appended claims. EXAMPLES Example I - RDA test of arginine calcium carbonate formulation 100981 Natural calcium carbonate formulations show high RDA: Formulation A: Prophylactic paste: 3 1% Sylodent 756. 15% Vicron 25-11 (fine ground CaCO3. natural source), 14% Vicron 41-8 (fine ground CaCO 3 ). 26 WO 2009/099452 PCT/US2008/058679 10% Arginine Bicarbonate RDA: 230 Formulation B: Consumer sensitivity dentifrice 50% Vicron 25-11 (Fine ground CaCO3), 7%, Sylodent 15, 2% Arginine Bicarbonate RDA: /79 Example 2 - Low RDA formulations 10099] Precipitated calcium carbonate (PCC) formulations show lower RDA: RAW MATERIAL EIGHT % Deionized Water 30.260 Sorbitol 70% 23.000 Carboxymethyl cellulose 0.940 Xanthan gum 0.210 Sodium Saccharin 0.450 Sodium 1.100 Sodium bicarbonate 0.500 N-Silicate (1:3.26, 41 BE) 0.800 L-Arginine bicarbonate 5.000 Precipitated calcium 35.000 Sodium lauryl sulfate 1.620 Methyl-P-hydroxybenzoate 0.100 Propyl-P-hydroxybenzoate 0.020 Flavor 1.000 TOTAL 100.000 RDA 107 Example 3 - Low RDA formula with small particle PCC abrasive RAW MATERIAL. WEIGHT % Deionized Water 25.660 Sorbitol 70% 23.000 Carboxymethyl cellulose 0.800 Xanthan gum 0.150 Sodium Sacharin 0.250 Sodium Monofluorophosphate 1.100 27 WO 2009/099452 PCT/US2008/058679 Sodium bicarbonate 0.500 N-Silicate (1:3.26, 41 BE) 0.800 L-Arginine bicarbonate 10.000 Precipitated calcium carbonate 10.000 Small particle sizc - Precipitated calcium carbonate 25.000 Sodium lauryl sulfate 1.620 Methyl-P-hydroxybenzoate 0.100 Propyl-P-hydroxybenzoate 0.020 Flavor 1.000 TOTAL 100.000 RDA 52 Example 4 - Small particle silica formulations Prototypes are madc with incorporation of 5% and 10% small particle silica (d50 3-4 micron. Sorbosil AC43 from Ineos) in PCC base dentifrice w/ 5% arginine bicarbonate. Dentine disks are brushed with dentifrice prototypes in order to mimic three day brushing regimen, or 6 treatments. Confocal microscopy images are taken at thrce stages: prior treatment (baseline), afler dentifrice treatment and after acid challenge. Formulations containing small particic silica show better performance after acid challenge in comparison to control dentifrice. Table 1. Examples of dentifrice formulation: Ingredient Fornuila I Formula II Fornmila I1l Formula IV Formula V Sorbitol 22.25 22.25 22.25 22.25 22.25 Sodium CMC 1.00 1.00 1.00 1.00 1.00 Xanthan gum 0.25 0.25 0.25 0.25 0.25 Sodium 1.10 1.10 1.10 1.10 1.10 Monofluorophosphate Sodium Saccharin 0.50 0.50 0.50 0.50 0.50 Sodium Hydroxide 0.50 0.50 0.50 0.io 0.50 Arginine Bicarbonate 5.00 5.00 5.00 5.00 5.00 Sodium Bicarbonate 0.50 0.50 0.50 0.50 0.50 Precipitated calcium 34.00 34.00 34.00 29.00 29.00 carbonate Synthetic amorphous silica - 5.00 10.00 5.00 10.00 (d50 3-4 um) Potassium nitrate - - - 5.00 5.00 Sodium lauryl sulfate 1.50 1.50 1.50 1.50 1.50 Flavor 1.00 1.00 1.00 1.00 1.00 Water (to balance) QS QS QS QS QS Dentin Disk Preparation 1. Dentin disks are cut from extracted human tecth. 28 WO 2009/099452 PCT/US2008/058679 2. Dentin disks are then sanded with 600 grit paper and polished on magnification side. Disks are placed into fresh PBS solution. 3. Using tweezers. dentin disk is suspended in 30ml of 6% citric acid for 1 minute. then disk rinsed with PBS. 4. Dentin disk placed in 60 ml Dl water and sonicated for 60 minutes. Clean disks put in PBS for storage. 5. Baseline readings taken on Confocal microscopc- each cell in duplicate. Treatment 1. Dip toothbrush into beaker containing Deionized water. Then, "ith a 1 inch ribbon of dentifrice, brush dentin disk in one direction for 45 seconds. Rinse with PBS and agitate for I hour in PBS. repeating brushing to 6 treatments. then measure on Confocal. 2. Coke Acid Challenge: Dentin disk is suspended with tweezers for 1 minute in Coke Classic Soda. then rinsed with PBS and then with DI water. Place in PBS for storage prior to measurements. Three dentifrices arc tested in vitro for dentinal occlusion efficacy: formulas I. I1 and Ill (table 1). Confocal images arc taken of baseline, after 6 brushings and after acid challenge. The brushing treatments results in increasing dentinal occlusion with addition of small particle silica (SPS). The sample with no addition of SPS (Formula I. control) shows only modest occlusion after 6 treatments, in comparison to 5% and 10% SPS. Example 5 - Dentifrice formulation comprising precipitated calcium carbonate (PCC) 1001001 A panel of consumer testers trained in testing the sensory attributes of denti frice formulations was subjected to different dentifrice formulations which were used under double blind consumer testing conditions replicating consumer use of dentifrice forniulations. 1001011 The panel was asked to use the dentifrice formulations conventionally and then to rate various sensory characteristics. For a base dentifrice formulation comprising precipitated calcium carbonate (PCC). the known formulation acted as a placebo control, and corresponding formulations additionally comprising 1. 2. 3 or 5 wt% arginine bicarbonate were also tested. Surprisingly. it was found that the arginine bicarbonate-containing PCC formulations exhibited increases in consumer acceptance for flavor intensity, cooling and case to foam attributes, and moreover the formulation additionally comprising 2 wt% arginine bicarbonate exhibited increases in overall liking. overall liking of taste. taste while brushing and taste after brushing. In addition, the formulations additionally comprising arginine bicarbonate were perceived as 29 WO 2009/099452 PCT/US2008/058679 significantly better than the placebo control in all image attributes, including perceived efficacy, mouth/teeth feeling of clean. product suitability, taste and overall product quality. 1001021 In contrast, when formulations having dicalcium phosphate, rather than precipitated calcium carbonate (PCC). as the base were tested, the addition of arginine bicarbonate did not exhibit significantly improved sensory characteristics as compared to the same formulation without the addition of arginine bicarbonate. 1001031 The Example shows that the addition of a basic amino acid such as arginine, in particular as bicarbonate. can surprisingly enhance the sensory characteristics of dentifrice formulations, most particularly having a base formulation of precipitated calcium carbonate (PCC), when used in an oral care composition of the invention. Example 6 - Basic amino acids other than arginine [001041 An overnight culture of S. sanguis was grown at 37*C in trypticase soy broth (Becton Dickinson. Sparks, MD). The culture was centrifuged at 5.000 rpm for 5 minutes at I milliliter at a time into preweighed tubes in order to accumulate approximately 5 milligrams of wet pellet weight. The pellet was then resuspended into 20 millimolar potassium phosphate buffer (JT Baker, Phillipsburg, NJ), pH 4.0. to simulate a stressed environment for the bacterial cell where ammonia would be produced for survival. The final concentration was 5 milligram per milliliter. To this final concentration. a 5 millimolar final concentration of L-arginine. L citrulline. or L-ornithine was added along with a 0.1% final concentration of sucrose (VWR, West Chester. PA). This mixture was then incubated at 37*C in a shaking water bath for 30 minutes before ammonia production was detennined. 1001051 In order to analyze for ammonia. an Ammonia Assay kit was used from Diagnostic Chemicals Limited (Oxford. CT). The intended use of this specific kit is for the in vitro quantification of amnionia in plasma, but the procedure was modified in order to determine and quantify the ammonia production in plaque and/or bacteria. 1001061 The table below shows the ammonia production values from 6 separate trials using S. sanguis at pH 4.0 as described above. The results confirm that the intermediates produced by the arginine deiminase system can be used to produce ammonia for cell survival. L-Arginine [-Citrulline L-Ornithine Trial # Ammonia (ppm) Ammonia (ppm) Ammonia (ppm) 1 0.509 0.185 0.185 2 0.866 0.346 0.260 3 2.20 0.332 0.047 30 WO 2009/099452 PCT/US2008/058679 4 1.62 0.194 0.0 5 0.5 0.226 0.181 6 0.6790.50.3 Mean 1.06 0.951 0.134 1001071 The Example shows that basic amino acids other than arginine arc effective to produce ammonia within the oral cavity. and thus to increase plaque pH1 when used in a oral care composition of the invention. 31

Claims (14)

1. A method comprising applying an effective amount of the oral care composition to the oral cavity of a subject in need thereof, to a. reduce or inhibit formation of dental caries, 5 b. reduce, repair or inhibit pre-carious lesions of the enamel, c. reduce or inhibit demineralization and promote remineralization of the teeth, d. reduce hypersensitivity of the teeth, e. reduce or inhibit gingivitis, 10 f. promote healing of sores or cuts in the mouth, g. reduce levels of acid producing bacteria, h. to increase relative levels of arginolytic bacteria, i. inhibit microbial biofilm formation in the oral cavity, j. raise and/or maintain plaque pH at levels of at least pH 5.5 following 15 sugar challenge, k. reduce plaque accumulation, 1. treat, reduce, relieve or alleviate dry mouth, m. whiten teeth, n. reduce erosion, 20 o. improve systemic health, p. immunize teeth against cariogenic bacteria; and/or q. clean teeth and oral cavity; the oral care composition comprising: i) an effective amount of a basic amino acid in free or salt form; 25 ii) a small particle fraction comprising at least about 5% of the formulation by weight, wherein the particles of the small particle fraction have a d50 of less than about 5 pm.

2. The method of claim 1, to reduce hypersensitivity of the teeth. 30

3. Use of a basic amino acid, in free or salt form, in an oral care composition comprising a small particle fraction comprising at least about 5% of the composition by weight, wherein the particles of the small particle fraction have a d50 of less than about 5 pm, for enhancing dentinal occlusion within an oral cavity of a subject. 35 32

4. Use according to claim 3, wherein the basic amino acid is present in an amount of from 0.1 to 20 wt% of the total composition weight.

5. Use according to claim 3 or claim 4, wherein the basic amino acid comprises 5 arginine.

6. Use according to any one of claims 3 to 5, wherein the small particle fraction comprises at least about 20 wt% of the total composition weight. 10

7. Use according to any one of claims 3 to 6, wherein the small particle fraction is selected from calcium carbonate, silica, and mixtures thereof.

8. Use according to any one of claims 3 to 7, wherein the small particle fraction comprises from 15 to 70wt% of the total composition weight. 15

9. Use of a basic amino acid, in free or salt form, for the manufacture of a medicament which includes a small particle fraction comprising at least about 5% of the medicament by weight, wherein the particles of the small particle fraction have a d50 of less than about 5 pIm, for enhancing dentinal occlusion within an oral cavity of a 20 subject.

10. A method of treating sensitive teeth within an oral cavity, the method comprising treating the oral cavity of a subject with an oral care composition comprising a basic amino acid, in free or salt form, and a small particle fraction 25 comprising at least about 5% of the composition by weight, wherein the particles of the small particle fraction have a d50 of less than about 5 pm, to enhance dentinal occlusion.

11. A method of claim 1, substantially as hereinbefore described with reference to 30 the examples, excluding, if any, the comparative examples.

12. Use of a basic amino acid, in free or salt form, in an oral care composition of claim 3, substantially as hereinbefore described with reference to the examples, excluding, if any, the comparative examples. 35 33 000=g7n iA-

13. Use of a basic amino acid, in free or salt form, for the manufacture of a medicament which includes a small particle fraction of claim 9, substantially as hereinbefore described with reference to the examples, excluding, if any, the comparative examples. 5

14. A method of treating sensitive teeth within an oral cavity of claim 10, substantially as hereinbefore described with reference to the examples, excluding, if any, the comparative examples. 34 fl9r7n i rlnr