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    • 专利摘要:
    Summary Oral care products comprising zinc oxide and trimethylglycine described herein are oral care compositions comprising a mixture of zinc oxide and trimethylglycine, in free or orally acceptable salt form. Methods of making and using the compositions are also provided.
    公开号:BR112015014758B1
    申请号:R112015014758-5
    申请日:2012-12-19
    公开日:2019-04-09
    发明作者:Guofeng Xu；Zhiqiang Liu；Long Pan；LaTonya Kilpatrick-Liverman；Ying Yang；Michael A. Stranick；Zhigang Hao
    申请人:Colgate-Palmolive Company；
    IPC主号:
    专利说明:

    ORAL CARE PRODUCTS UNDERSTANDING ZINC OXIDE AND TRIMETHYLGLYCIN
    FUNDAMENTALS [001] Dental erosion involves demineralization and damage to the dental structure due to acid attack from non-bacterial sources. Erosion is initially seen in the enamel and, if left unchecked, can progress to the dentin. Dental erosion can be caused or aggravated by acidic foods and drinks, exposure to chlorinated pool water and gastric acid regurgitation. Tooth enamel is a negatively charged surface, which naturally tends to attract positively charged ions such as hydrogen and calcium ions, while resisting negatively charged ions such as fluoride ions. Depending on the relative pH of the surrounding saliva, tooth enamel will lose or gain positively charged ions such as calcium ions. Generally saliva has a pH between 7.2 to 7.4. When the pH is lowered and the concentration of hydrogen ions becomes relatively high, the hydrogen ions will replace the calcium ions in the enamel, forming hydrogen phosphate (phosphoric acid), which damages the enamel and creates a porous surface, like rough sponge. If saliva remains acidic for an extended period, then remineralization may not occur, and the tooth will continue to lose minerals, causing the tooth to weaken and ultimately lose its structure.
    [002] Dentin hypersensitivity is localized toothache, acute in response to physical stimulation of
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    2/49 dentin surface as by thermal osmotic (hot or cold), thermal tactile combination, osmotic and tactile stimulation of exposed dentin. Dentin exposure, which is usually due to receding gums, or loss of enamel, often leads to hypersensitivity. Dentin tubules open to the surface have a high correlation with dentin hypersensitivity. Dentin tubules lead from the pulp to the cementum. When the superficial cementation of the tooth root is eroded, the dentin tubules are exposed to the external environment. The exposed dentin tubules provide a pathway for the transmission of fluid flow to the pulp nerves, the transmission induced by changes in temperature, pressure and ionic gradients.
    [003] Heavy metal ions, such as zinc, are resistant to acid attack. Zinc is above hydrogen in the electrochemical series, so that the metallic zinc in an acidic solution will react to release the hydrogen gas when the zinc passes into the solution to form di-cations, Zn 2+ . Zinc has been shown to have antibacterial properties in plaque and caries studies.
    [004] Soluble zinc salts, such as zinc citrate, have been used in toothpaste compositions, see, for example, US patent No. 6,121,315, but have several disadvantages. Zinc ions in solution impart an unpleasant astringent taste, so formulations that provide effective levels of zinc, and also have acceptable organoleptic properties, have been difficult to achieve. Finally, the zinc ions will react with
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    3/49 anionic surfactants such as sodium lauryl sulfate, thus interfering with foaming and cleaning.
    [005] Zinc oxide has been used as an ingredient for toothpaste. Although several oral care efficacies have been shown, their performance is limited by the limited solubility of zinc oxide. Zinc oxide has a low solubility, about 0.16 mg per 100 ml of water at 30 ° C. Therefore, the zinc oxide that can be effectively supplied as a soluble species is limited in quantity. Zinc oxide, supplied in the form of conventional powder, does not have a strong affinity for the dental or mucosal surface within the oral cavity. Therefore, the released zinc oxide will be washed at the conclusion of the treatment period when the user spits out toothpaste, mouthwash, etc.
    [006] N, N, N-trimethylglycine (TMG or betaine glycine) has a quaternary ammonium structure. At neutral pH, the compound exists in the form of a zwitterion, forming an internal salt between the quaternary ammonium and the carboxy portions of the molecule. In the presence of strong acids, it will form acid addition salts, for example, hydrochloride. The compound is originally isolated from sugar beet, and is used as a dietary supplement, in animal feed and as a laboratory reagent stabilizer, for example, in polymerase chain reactions. There are reports of its use in oral care products to treat dry mouth, for example, US 6,156,293, and in products
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    4/49 antiperspirants, for example, US 6,969,510.
    [007] Although the prior art describes the use of various oral compositions for the treatment of dentin hypersensitivity, tooth decay, and enamel erosion and demineralization, there is still a need for additional compositions and methods that provide improved performance in such treatments.
    SUMMARY [008] While zinc oxide is present with limited solubility in prior art formulations, it has now been discovered that zinc oxide can form a soluble complex with TMG, both in its free form and in the form of acid addition. When placed in the formulation, this complex has an effective concentration of zinc ions for the enamel and / or dentin surface, thus protecting against erosion, reducing colonization and biofilm development, and providing better shine to the teeth. In addition, when diluted during use, the formulation provides a precipitate that can clog dentin tubules, thereby reducing tooth sensitivity. In addition, when diluted during use, the formulation provides a coating of solid material, mainly zinc salts and some TMG on the teeth surface. The strong affinity of solid material for the surface of the teeth allows for better substantivity, and allows controlled release of the active principles of the teeth. This is unexpected, at least partially because better solubilization is generally expected with dilution.
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    5/49 [009] Despite providing efficient zinc release compared to conventional zinc oxide formulations, formulations comprising zinc oxide and TMG do not exhibit bad taste and mouthfeel, little fluoride release, and poor foaming and cleaning associated with conventional zinc-based oral care products that use soluble zinc salts.
    [0010] The soluble complex formed from zinc oxide and TMG in its acid addition form is particularly effective. The acid can be any acid, preferably a hydrohalide. TMG in its acid addition form can be provided as a pre-existing entity, such as TMG hydrochloride, or it can be formed in situ by mixing TMG with acid, in various proportions, for example, from 1: 5 to 5 : 1 (moles of TMG against moles of protons resealable from acid). The soluble complex formed from zinc oxide and TMG in its acid addition form can lead to precipitation by dilution with water. The precipitates may be in the form of free floating solids and / or be attached to the surfaces of the teeth and mucous membranes for subsequent release. In contrast, the soluble complex formed from zinc oxide and TMG in its free form is less capable of producing precipitation by diluting with water.
    [0011] The invention thus provides, in one embodiment, a complex comprising zinc oxide and TMG in its free or acid addition form, for example, a zinc-TMG-HCl complex, for example, formed by combination of zinc oxide and hydrochloride
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    6/49 trimethylglycine in aqueous solution.
    [0012] In another embodiment, the invention provides compositions for oral care, for example, mouthwash, toothpaste or oral gel, which comprise zinc oxide in combination with TMG in its free form or with acid addition, for example, that comprise a complex as described above. The compositions can optionally further comprise a source of fluoride and / or an additional source of phosphate. The compositions can be formulated from a formulation for oral care, for example, suitable, for example, a conventional toothpaste, oral gel or mouthwash, for example, comprising one or more abrasives, surfactants, foaming agents, vitamins, polymers, enzymes, humectants, thickeners, antimicrobial agents, preservatives, flavorings and / or dyes.
    [0013] The invention also provides methods of using the compositions of the invention to reduce and inhibit acid enamel erosion, clean teeth, reduce bacterially generated biofilm and plaque, reduce gingivitis, reduce oral odor, provide relief from dry mouth , inhibits tooth decay and caries formation, and reduce dentin hypersensitivity, which comprises applying a composition of the invention to teeth. The invention further provides methods of using the compositions of the invention to whiten teeth by imparting a coating on the teeth, where the coating is whiter than native teeth.
    [0014] Other areas of applicability of this
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    7/49 invention will become apparent from the detailed description provided hereinafter. It should be understood that the detailed description and the specific examples, while indicating the preferred embodiment of the invention, are intended for purposes of illustration only and are not intended to limit the scope of the invention.
    DETAILED DESCRIPTION [0015] The following description of the preferred embodiment (s) is merely exemplary in nature and is in no way intended to limit the invention, its application or uses.
    [0016] As used herein, trimethylglycine refers to N, N, N-trimethylglycine; and the terms can be used interchangeably here.
    [0017] The invention therefore provides, in a first embodiment, an oral care composition (Composition 1), comprising or prepared from a mixture of zinc oxide and trimethylglycine (TMG) in the free or orally acceptable form. its salt corresponding to the added acid; for example,
    1.1. Composition 1, in which the zinc level in the formulation, by weight, on an elementary basis is 0.05 to 4%, for example, 1 to 2%, for example, from 0.5 to 1.5%, for example, about 1%.
    1.2. Composition 1 or 1.1 in which TMG is provided in the form of the correspondingly added orally acceptable acid salt, for example, hydrochloride salt form, or where TMG is formed in situ, providing TMG and acid (such as HCl) as entities separated in molar ratios between 1: 5 to
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    8/49
    5: 1 (moles of TMG vs. moles of protons released from the acid).
    1.3. Any of the preceding compositions in which the molar ratio of zinc oxide to TMG is from 1: 1 to 1:10, for example, about 1: 5.
    1.4. Any of the preceding compositions in which the molar ratio of zinc to TMG is 5: 1 to 1: 2, for example, about 1: 1.
    1.5. Any of the preceding compositions in which the pH is between pH 5 and pH 6.
    1.6. Any of the preceding compositions in which the formulation includes the step of combining zinc oxide and trimethylglycine hydrochloride in aqueous solution.
    1.7. Any of the preceding compositions in which TMG is supplied in the form of a hydrohalide salt, and zinc oxide and TMG form soluble complexes, selected from zinc-TMG-halide complexes, zinc-halide complexes, and their mixtures, for example, in which the halide is selected from fluoride, chloride, bromide and their mixtures.
    1.8. Any of the preceding compositions in which TMG is supplied in the form of a hydrohalide salt and zinc oxide and TMG form two soluble complexes, one having the chemical composition Zn2O8H6X2 and the other having the chemical composition Zn2O8H5X2-TMG, where X is selected from Cl, F, Br, and their mixtures.
    1.9. Any of the preceding compositions in which TMG is supplied as the hydrochloride salt, and zinc oxide and TMG form soluble complexes selected from
    Petition 870190007122, of 01/23/2019, p. 16/61
    9/49 of zinc-TMG-chloride complexes, zinc chloride complexes, and mixtures thereof.
    1.10. Any of the preceding compositions in which TMG is supplied as the hydrochloride salt, and zinc oxide and TMG form two soluble complexes, one having the chemical composition Zn2O8H6Cl2 and the other having the chemical composition Zn2O8H5Cl2-TMG.
    1.11. Any of the preceding compositions in which a complex comprising zinc oxide and TMG is formed, in whole or in part, in situ, after the composition is applied.
    1.12. Any of the foregoing compositions in which a complex comprising zinc oxide and TMG is formed, in whole or in part, in situ, after the composition is formulated.
    1.13. Any of the preceding compositions comprising an acid, for example, hydrochloric acid, for example, such that the pH of the mixture is between 5 and 6.
    1.14. Any of the preceding compositions which further comprises a basic amino acid, for example, lysine or arginine.
    1.15. Any of the foregoing compositions, in a substantially anhydrous vehicle, for example, a vehicle comprising less than 10% water.
    1.16. Any of the preceding compositions in the form of a toothpaste, gel, mouthwash, powder, cream, strip or gum.
    1.17. Any of the previous compositions on a
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    10/49 orally acceptable, for example, a mouthwash, gel or toothpaste base.
    1.18. Any of the preceding compositions in the form of a dentifrice, for example, in which zinc oxide and TMG are present in an effective amount, for example, in an amount of 0.05 to 4% by weight of zinc, for example, about 0 , 5 to 3%, for example, about 1% zinc by weight, on a toothpaste base.
    1.19. Composition 1.1, wherein the base of the toothpaste comprises an abrasive, for example, an effective amount of a silica abrasive, for example, 10 to 30%, for example, about 20%.
    1.20. Composition 1 in the form of a mouthwash, for example, in which zinc oxide is present in an effective amount, for example, in an amount of 0.05 to 4% zinc by weight, for example, about 1% zinc in Weight.
    1.21. Any of the preceding compositions further comprising an effective amount of a fluoride ion source, for example, supplying 500 to 3000 ppm of fluorine.
    1.22. Any of the preceding compositions further comprising an effective amount of fluoride, for example, where fluoride is a salt selected from stannous fluoride, sodium fluoride, potassium fluoride, sodium monofluorophosphate, sodium fluorosilicate, ammonium fluorosilicate, amine fluoride (eg, octadecyltrimethylondiamine-N, N, N'-tri (2-ethanol) dihydrofluoride), ammonium fluoride, titanium fluoride,
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    11/49 hexafluorosulfate, and combinations thereof.
    1.23. Any of the preceding compositions comprising an effective amount or one or more alkaline phosphate salts, for example, sodium, potassium or calcium salts, for example, selected from dibasic alkaline phosphate and alkaline pyrophosphate salts, for example, salts of alkaline phosphate selected from dibasic sodium phosphate salts, dibasic potassium phosphate, dicalcium phosphate dihydrate, calcium pyrophosphate, tetrasodium pyrophosphate, tetrapotassium pyrophosphate, sodium tripolyphosphate, and mixtures of any of two or more of these two or more example, in an amount of 1 to 20%, for example, 2 to 8% for example, about 5% by weight of the composition.
    1.24. Any of the foregoing compositions comprising buffering agents, for example, sodium phosphate buffer (for example, sodium monobasic phosphate and disodium phosphate).
    1.25. Any of the preceding compositions comprising a humectant, for example, selected from glycerin, sorbitol, propylene glycol, polyethylene glycol, xylitol, and mixtures thereof, for example, comprising at least 20%, for example, 20 to 40%, for example, 25 to 35% glycerin.
    1.26. Any of the preceding compositions comprising one or more surfactants, for example, selected from anionic, cationic, zwitterionic, and non-ionic surfactants, and mixtures thereof, for example, comprising an anionic surfactant, for example
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    12/49 example, a surfactant selected from sodium lauryl sulfate, sodium lauryl sulfate ether, and mixtures thereof, for example, in an amount from about 0.3% to about 4.5% by weight , for example, 1 to 2% sodium laurel sulfate (SLS); and / or a zwitterionic surfactant, for example, a betaine surfactant, for example, cocamidopropylbetaine, for example, in an amount between about 0.1% to about 4.5% by weight, for example, 0.5 to 2% cocamidopropyl betaine.
    1.27. Any of the foregoing compositions which further comprises a viscosity-modifying amount of one or more polysaccharide gums, for example, xanthan or carrageenan gum, silica thickener, and combinations thereof.
    1.28. Any of the foregoing compositions which comprise gum strips or fragments.
    1.29. Any of the preceding compositions further comprising flavoring, flavoring and / or coloring.
    1.30. Any of the preceding compositions comprising an effective amount of one or more antibacterial agents, for example, comprising an antibacterial agent selected from halogenated diphenyl ether (eg, triclosan), extracts based on
    plants and essential oils (for example, extract of Rosemary, tea extract, magnolia extract, thymol,
    menthol, eucalyptol, geraniol, carvacrol, citral, hinocytol, catechol, methyl salicylate, epigallocatechin gallate, epigallocatechin, gallic acid, miswak extract, sea buckthorn extract), bisguanide antiseptics (eg
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    13/49 chlorhexidine, alexidine or octenidine), quaternary ammonium compounds (for example, cetylpyridinium chloride (CPC), benzalkonium chloride, tetradecylpyridinium chloride (TPC), N-tetradecyl-4ethylpyridinium chloride (TDEPC)), phenolic antiseptics, hexetidine, octenidine, sanguinarine, povidone iodine, delmopinol, salifluor, metal ions (eg zinc salts, eg zinc citrate, tin salts, copper salts, iron salts), sanguinarine, propolis and oxygenating agents (for example, hydrogen peroxide, buffered sodium peroxyborate or peroxycarbonate), phthalic acid and its salts, monopertallic acid and its salts and esters, ascorbyl stearate, oleoyl sarcosine, alkyl sulfate, dioctyl sulfosuccinate, salicylanilide, bromide domifene, delmopinol, octapinol and other piperidine derivatives, nicine preparations, chlorite salts; and mixtures of any of the above; for example, comprising triclosan or cetylpyridinium chloride.
    1.31. Any of the preceding compositions comprising an antibacterially effective amount of triclosan, for example, 0.1 to 0.5%, for example, about 0.3%.
    1.32. Any of the preceding compositions which further comprises a bleaching agent, for example, one selected from the group consisting of peroxides, metal chlorites, perborates, percarbonates, peracids, hypochlorites, and combinations thereof.
    1.33. Any of the preceding compositions which further comprises hydrogen peroxide or a source of
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    14/49 hydrogen peroxide, for example, urea peroxide or a salt or peroxide complex (for example, such as peroxyphosphate, peroxycarbonate, perborate, peroxysilicate, or persulfate salts, for example, calcium peroxyphosphate, sodium perborate, sodium carbonate peroxide, sodium peroxyphosphate, and potassium persulfate);
    1.34. Any of the foregoing compositions further comprising an agent that interferes with or prevents bacterial attachment, for example, chitosan or solbrol.
    1.35. Any of the preceding compositions further comprising a source of calcium and phosphate selected from (i) calcium-glass complexes, for example, calcium and sodium phosphosilicates, and (ii) protein-calcium complexes, for example, phosphopeptide of amorphous calcium phosphate casein
    1.36. Any of the preceding compositions which further comprises a soluble calcium salt, for example, selected from calcium sulfate, calcium chloride, calcium nitrate, calcium acetate, calcium lactate, and combinations thereof.
    1.37. Any of the foregoing compositions which further comprises a physiologically or orally acceptable potassium salt, for example, potassium nitrate or potassium chloride, in an amount effective to reduce dentin sensitivity.
    1.38. Any of the preceding compositions which further comprises an anionic polymer, for example, a synthetic anionic polymeric polycarboxylate, for example, in which the anionic polymer is selected from 1: 4 to
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    15/49
    4: 1 copolymers of anhydride or maleic acid with another ethylenically unsaturated polymerizable monomer; for example, in which the anionic polymer is a methyl vinyl ether / maleic anhydride (PVM / MA), copolymer having an average molecular weight (MW) of about 30,000 to about 1,000,000, for example, about 300,000 to about 800,000, for example, where the anionic polymer is about 1 to 5%, for example, about 2%, of the weight of the composition.
    1.39. Any of the preceding compositions which further comprises a mouthwash, aroma or flavoring.
    1.40. Any of the above compositions for use to reduce and inhibit acid erosion of the enamel, clean teeth, reduce biofilm generated by bacteria and plaque, reduce gingivitis, inhibit tooth decay and cavity formation, and reduce dentin hypersensitivity.
    1.41. Any of the above compositions produced by a process comprising the step of mixing zinc oxide and trimethylglycine hydrochloride in aqueous media.
    1.42. Any of the foregoing compositions in which upon dilution with water, for example, to a level of 1% less zinc compared to water, a zinc precipitate is formed.
    [0018] The invention also provides methods to reduce and inhibit acid erosion of the enamel, cleaning the teeth, reducing bacterially generated biofilm and plaque, reducing gingivitis, providing relief from dry mouth,
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    16/49 reduce halitosis, inhibit tooth decay and cavity formation, improve whitening, and reduce dentin hypersensitivity, which comprises applying an effective amount of a composition of the invention, for example, any of Composition 1, et seq . for the teeth.
    [0019] The invention further provides a method of manufacturing a composition comprising zinc oxide and TMG, for example, any of Composition 1, et seq. comprising the step of combining zinc oxide and an orally acceptable acid addition salt of TMG, for example, TMG-HCl, in aqueous medium.
    [0020] For example, in many forms of achievement, The invention provides methods for (i) reduce The hypersensitivity of teeth, (ii) for reduce The accumulation of plaque, (iii) reduce or inhibit The demineralization and promoting remineralization of teeth,
    (iv) inhibit microbial biofilm formation in the oral cavity, (v) reduce or inhibit gingivitis, (vi) promote wound healing or cuts in the mouth, (vii) reduce levels of acid-producing bacteria, (viii) to increase relative levels of non-plaque and / or cariogenic bacteria, (ix) reduce or inhibit the formation of tooth decay (x) reduce, repair or inhibit enamel precarious lesions, for example, when detected by induced quantitative fluorescence by light (QLF) or electrical caries measurement (ECM), (xi) treating, relieving or reducing dry mouth, (xii) cleaning teeth and oral cavity, (xiii) reducing erosion, (xiv) whitening teeth; (xv) reduce the accumulation of tartar, (xvi) reduce the bad odor
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    17/49 oral, and / or (xvii) promote systemic health, including cardiovascular health, for example by reducing the potential for systemic infection through oral tissues, comprising the application of any of the compositions 1, et secs. as described above, for the oral cavity of a person in need of it, for example, one or more times a day. The invention further provides compositions 1, et secs. for use in any of these methods.
    [0021] The invention further provides for the use of zinc oxide and TMG in the form of a free or orally acceptable salt, for example, trimethylglycine hydrochloride, to prepare an oral care composition, for example, any of Compositions 1, et. seq ..
    [0022] In some embodiments, the compositions of the present invention provide relief of dentin sensitivity after 5 seconds. In some embodiments, the compositions of the present invention provide relief from dentin sensitivity after 10 seconds. In some embodiments, the compositions of the present invention provide relief from dentin sensitivity after 15 seconds. In some embodiments the compositions of the present invention provide relief from dentin sensitivity after 30 seconds. In some embodiments, the compositions of the present invention provide relief from dentin sensitivity after 60 seconds.
    [0023] The invention also provides the use of zinc oxide in conjunction with TMG in the form of free salt or
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    18/49 orally acceptable (ie the acid addition form), to reduce and inhibit acid erosion of the enamel, clean the teeth, reduce bacterially generated biofilm and plaque, reduce gingivitis, inhibit tooth decay and the formation of cavities, and reduce dentin hypersensitivity; (ii) the use of amino acid zinc halide precursors selected from (a) zinc oxide and an amino acid halide, and / or (b) zinc oxide, an amino acid and optionally halogen acid in the manufacture of a composition to reduce and inhibit acid erosion of enamel, clean teeth, reduce bacterially generated biofilm and plaque, reduce gingivitis, reduce bad oral odor, provide relief from dry mouth, inhibit tooth decay and caries formation, and reduce dentin hypersensitivity.
    [0024] It was discovered that the interaction of zinc and TMG converts zinc oxide to a highly soluble complex. Preferably, TMG is in the form of the salt corresponding to the added acid, for example, hydrochloride form. The complex is highly soluble at concentrations in water, for example, levels corresponding to about 1% or more of zinc. But with increasing dilution in water, for example, in concentrations of 0.1 to 1%, for example, about 0.5%, of zinc in water, the complex dissociates, and the zinc ion in the complex reverts to insoluble forms, which is substantially free of zinc oxide. In experiments where complexes are formed using zinc oxide and an amino acid, such as lysine, precipitation by dilution is also observed, but the
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    19/49 precipitate is zinc oxide, so the formation of a precipitate substantially free of zinc oxide is unexpected.
    [0025] Without wishing to be limited by theory, it is noted that at least two types of complexes exist in solution. At least one complex is derived from zinc without interaction with TMG, and at least one complex is derived from zinc in interaction with TMG. One complex has the structure of Zn2O8H5Cl2, and the other has the structure of Zn2O8H5Cl2-TMG.
    [0026] This dynamic - reduced solubility due to increased dilution - is unusual and unexpected. Dilution under brushing or rinsing or combining with saliva facilitates the deposition of zinc precipitate on teeth with administration, which acts to occlude the dentin tubules, thereby reducing hypersensitivity, and also providing zinc to the enamel, which reduces acid erosion, biofilm and plaque formation.
    [0027] It should be understood that, although zinc and TMG may be essentially in the form of precursor materials (for example, zinc oxide and TMG-HCl) or in the form of a complex, there may be some degree of balance, so that the proportion of material that is actually in the complex compared to the proportion in the form of precursor can vary depending on the precise conditions of the formulation, concentration of materials, pH, presence or absence of water, presence or absence of other charged molecules , and so on.
    [0028] It should be understood that the complex may also be in the form of a mixture. Zinc oxide and TMG
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    20/49 can form one type of complex, while zinc oxide and TMG in one form of acid addition can form another. These complexes can be present in different proportions, particularly when TMG and acid protons are supplied in unequal molar quantities.
    [0029] The assets can be administered in the form of any oral care formulations, for example, a toothpaste, gel, mouthwash, powder, cream, strip, gum, or any other known in the art.
    [0030] If the assets are administered in the form of a mouthwash, a person who wants the benefits of rinsing with the stock solution and the natural dilution of the stock solution by saliva will start the zinc precipitation. Alternatively, the person can mix a stock solution with an appropriate amount of an aqueous diluent (for example, to provide a zinc to water concentration of about 0.1 to 1%), and rinse with the mixture.
    [0031] In another embodiment, the mixture is prepared and immediately transferred to a holding tray, such as those used in making bleaching gels, and the person can use the tray for the effective period of time. Teeth that are in contact with the mixture will be treated. For use with the holding tray, the mixture can be in the form of a low viscosity liquid or gel.
    [0032] In another embodiment, the stock solution, or a mixture of stock solution with water, is applied to the teeth of a gel formulation, for example,
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    21/49 where the gel can remain on the tooth for a long period of time for effective treatment.
    [0033] In another embodiment, the asset is provided in a toothpaste. After brushing, the active substance is diluted by saliva and water, leading to precipitation and the formation of deposits and particles of occlusion.
    [0034] The precipitation rate from the formulation can be modulated by adjusting the concentration of the complex in the stock solution, and changing the relationship between the material and water. A more diluted formula leads to faster precipitation and is therefore preferred when rapid treatment is desired.
    [0035] The advantages of the oral care compositions of the invention are numerous. By providing zinc ions and zinc-containing compounds that can release zinc ions into the oral cavity, the oral care compositions of the invention provide benefits of antimicrobials, anti-plaque, anti-gingivitis, anti-odor, anti-caries and anti-calculus. Occlusion particles and surface deposits are compounds containing zinc salts that can release zinc ions in oral cavities and provide the various benefits as previously recognized. The coating formed on tooth surfaces due to deposition can improve the whiteness of the tooth surface, thereby providing whitening benefits. Additional benefits include, but are not limited to, antifixation, antiperiodontitis and loss of antiosthesis, as well as promoting wound healing.
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    22/49 [0036] A second benefit is the anti-erosion properties of zinc ions, which form anti-erosion deposits on tooth surfaces through oxidation and hydrolysis. Surface deposits, as well as occlusion particles, can react with and neutralize acids, thus protecting the tooth surface from the erosive effects of acids. It should also be noted that when surface deposits and occlusion particles neutralize acids, beneficial zinc ions can be released, providing different oral care benefits other than anti-erosion.
    [0037] A third benefit is anti-sensitivity benefit as a result of occlusion. Occlusion of the dentin tubules leads to relief of sensitivity.
    [0038] A fourth benefit is the associated benefit with TMG. TMG, due to its zwitterionic character, provides a buffering effect, neutralizing the acid that can damage your teeth and so can
    provide anti-caries benefits. In addition, TMG has been
    recognized to provide relief from dry mouth. [0039] In a particular embodiment, the invention provides a ionic complex comprising zinc oxide,
    TMG and an anionic species, for example, a halide, for example chloride. In a particular embodiment, the invention provides a complex formed by combining zinc oxide and TMG HCl in an aqueous medium to form a complex conveniently referred to as a ZnOTMG HCl complex.
    [0040] In another embodiment, the invention
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    23/49 provides oral care formulations that comprise a ZnO-TMG HCl complex, for example, compositions according to Composition 1, and following, comprising a ZnO-TMG HCl complex, for example, in the form of a mouthwash , a gel, a toothpaste, a cream, a powder, a strip, or a gum.
    [0041] In one embodiment, if the desired formulation in the form of a mouthwash, a two-component libation system is contemplated. The first component is a concentrated solution of the ZnO-TMG HCl complex, and the second component is substantially water. The two components are mixed by the administrator / user immediately before treatment. Alternatively, a single component release system in the form of a mouthwash is contemplated, in which the system comprises a concentrated solution of the ZnO-TMG HCl complex and the diluent is supplied by the administrator / user either in the form of naturally involved water in a typical oral care treatment and / or saliva generated by the user.
    [0042] The invention is also directed, in other embodiments, to a controlled release system and a method of supplying zinc ions and TMG over an extended period of time within oral cavities, comprising administering a composition of accordance with Composition 1 and following.
    [0043] In particular embodiments, compositions 1 and following have provided zinc oxide and TMG complexes, for example zinc-TMG-chloride complexes, and / or zinc oxide and TMG in the form or addition salt of
    Petition 870190007122, of 23/01/2019, p. 31/61
    24/49 acid, for example, TMG-HCl, as complex precursors, which can react in situ with water to form the complexes. In situ training provides ease of formulation. In another embodiment, the water, allowing the formation of the complex from the precursor, comes from the saliva and / or rinse that comes into contact with the composition after application.
    [0044] In a particular embodiment, TMG is supplied in the form of an acid addition salt, for example a hydrohalide, for example, trimethylglycine hydrochloride, which forms a complex complex in the aqueous medium with the oxide of zinc.
    [0045] As the number of moles or weight percent of various zinc salts and complexes here will vary according to the particular salt or form of complex, which is often referred to here for the amount of total zinc in the formulation by weight or of molar quantity, regardless of its salt or complex form. In some embodiments, the total amount of zinc in the composition is 0.05 to 8% by weight of the composition. In other embodiments, the total amount of zinc is at least 0.1, at least 0.2, at least 0.3, at least 0.4, at least 0.5, or at least 1 up to 8% by weight of the composition. In other embodiments, the total amount of zinc in the composition is less than 5, less than 4, less than 3, less than 2, or less than 1 to 0.05% by weight of the composition. For example, in some embodiments, the total amount of zinc in the composition can be about 1%.
    Petition 870190007122, of 23/01/2019, p. 32/61
    25/49 [0046] Active agents: The compositions of the invention may comprise various agents that are active to protect and improve the strength and integrity of the enamel and teeth structure and / or to reduce bacteria and associated tooth decay and / or gum disease, including or in addition to zinc TMG - halide complexes. Effective concentration of the active ingredients used here will depend on the particular agent and the delivery system used. It is understood that a toothpaste, for example, will typically be diluted with water upon use, while a mouthwash will typically not be. Thus, an effective concentration of active ingredient in a toothpaste will normally be 15x greater than that required for a mouthwash.
    The concentration will also depend on the exact salt or polymer selected.
    For example, where the active agent is supplied in the form of salt, the counterion will affect the weight of the salt, so that if counterion is heavier, more salt by weight same concentration will be needed to provide that of the ion. active in the final product. Arginine, when present, can be present at levels of, for example, about 0.1 to about 20% by weight (expressed as free base weight), for example, about 1 to about 10% by weight of a consumer toothpaste or about 7 to about 20% by weight of a treatment or professional or prescription product. Fluoride when present can be present at levels of, for example, about 25 to about 25,000 ppm, for example about 750 to about
    2,000 ppm for a consumer toothpaste, or about
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    26/49 from 2,000 to about 25,000 ppm of a treatment or professional product or prescription. Levels of antibacterial agents will vary similarly, with levels used in toothpaste being, for example, about 5 to about 15 times higher than that used in rinse solution. For example, a triclosan toothpaste can contain about 0.3% by weight of triclosan.
    [0047] Fluoride ion source: Oral care compositions may also include one or more sources of fluoride ions, for example, soluble fluoride salts. A wide variety of materials, giving rise to fluoride ions can be used as sources of soluble fluoride in the present compositions. Examples of materials giving rise to suitable fluoride ions are found in US Patent No. 3,535,421, to Briner et al .; US patent No. 4,885,155, to Parran, Jr. et al. and US patent No. 3,678,154, Widder et al. Representative sources of fluoride ions include, but are not limited to stannous fluoride, sodium fluoride, potassium fluoride, sodium monofluorophosphate, sodium fluorosilicate, 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. In certain embodiments, the oral care composition of the invention may also contain a source of fluoride ions or fluoride-providing ingredient in amounts sufficient to provide about 25 ppm to about 25,000 ppm of fluoride ions, generally at
    Petition 870190007122, of 23/01/2019, p. 34/61
    27/49 minus about 500 ppm, for example, about 500 to about 2,000 ppm, for example, about 1,000 to about 1,600 ppm, for example, about 1,450 ppm. The appropriate level of fluoride will depend on the particular application. A general consumer toothpaste would typically have about 1,000 to about 1,500 ppm, with pediatric toothpaste having slightly less. A professional toothpaste or coating could contain as much as about 5,000 or even about 25,000 ppm of fluoride. Fluoride ion sources can 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% weight, and in another embodiment from about 0.1% by weight to about 1% by weight, of the composition in another embodiment. Weights of fluoride salts for
    provide O level appropriate in fluoride ion will, obviously, vary according with the counter-ion weight of the salt. [0048] In various forms in realization, the amino acid is present in a amount in about 0.5% by weight at
    about 20% by weight of the total weight of the composition, about 0.5% by weight to about 10% by weight of the total weight of the composition, for example about 1.5% by weight to about 3.75% by weight at about 5% by weight, or about 7.5% by weight of the total weight of the composition in the case of a toothpaste, or for example about 0.5 to 2% by weight, for example, about 1 % in the case of a mouthwash.
    [0049] Abrasives: Compositions of the invention, for example, Composition 1 et seq. include silica abrasives,
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    28/49 and may comprise additional abrasives, for example, a calcium phosphate abrasive, for example, tricalcium phosphate (Ca3 (PO4) 2), hydroxyapatite (Ca10 (PO4) 6 (OH) 2), or dihydrate dicalcium phosphate (CaHPO4 * 2H2O, also sometimes referred to here as DiCal) or calcium pyrophosphate; calcium carbonate abrasive; or abrasives, such as sodium metaphosphate, potassium metaphosphate, aluminum silicate, calcined alumina, bentonite or other siliceous materials or combinations thereof.
    [0050] Other silica abrasive polishing materials useful here, as well as the other abrasives, generally have an average particle size ranging between about 0.1 and about 30 microns, about between 5 and about 15 microns. The silica abrasives can be precipitated silica or silica gels, such as the silica xerogels described in US Patent No. 3,538,230, by Pader et al. and US Patent No. 3,862,307, to Digiulio. Private silica Xerogels are marketed under the trade name Syloid® by WR Grace & Co., Davison Chemical Division. Precipitated silica materials include those marketed by JM Huber Corporation under the trade name Zeodent®, including silica under the designation Zeodent 115 and 119. These silica abrasives are described in Wason US Patent No. 4,340,583. In certain embodiments, useful abrasive materials in the practice of compositions for oral care in accordance with the invention include silica gels and precipitated silica amorphous having a value of less oil absorption of about 100 cm3 / 100 g silica and in the range of about 45 cm3 / 100g
    Petition 870190007122, of 23/01/2019, p. 36/61
    29/49 to about 70 cm3 / 100 g silica. Oil absorption values are measured using the ASTA Rub-out Method D281. In certain embodiments, silicas are colloidal particles with an average particle size of about 3 microns to about 12 microns and about 5 to about 10 microns. Low oil absorption silica abrasives particularly useful in the practice of the invention are marketed under the trade name Sylodent XWA® by Davison Chemical Division of WR Grace & Co., Baltimore, Md. 21203. Sylodent 650 XWA®, a compound silica hydrogel colloidal silica particles having a 29% water content average weight of about 7 to about 10 microns in diameter and an oil absorption of less than about 70 cm3 / 100g of silica is an example of a low oil absorption silica abrasive useful in the practice of the present invention.
    [0051] Foaming agents: The oral care compositions of the invention may also include an agent for increasing the amount of foam that is produced when the oral cavity is brushed. Illustrative examples of agents that increase the amount of foam include, but are not limited to certain polyoxyethylene polymers and including, but not limited to, alginate polymers. Polyoxyethylene can increase the amount of foam and the foam thickness generated by the oral care vehicle component of the present invention. Polyoxyethylene is also commonly known as polyethylene glycol (PEG) or polyethylene oxide. The polyoxyethylenes suitable for this invention will have a molecular weight of about 200,000 to
    Petition 870190007122, of 23/01/2019, p. 37/61
    30/49 about 7,000,000. In one embodiment the molecular weight will be about 600,000 to about 2,000,000 and in another embodiment about 800,000 to about 1,000,000. Polyox® is the trade name for high molecular weight polyoxyethylene produced by Union Carbide. Polyoxyethylene can 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% by weight of the component of the oral care vehicle of the oral care compositions of the present invention. When present, the amount of foaming agent in the oral care composition (i.e., a single dose) is about 0.01 to about 0.9% by weight, about 0.05 to about 0, 5 wt%, and in another embodiment about 0.1 to about 0.2 wt%.
    [0052] Surfactants: Compositions useful in the present invention may contain anionic surfactants, for example:
    i. water-soluble salts of higher fatty acid monoglyceride monosulfates, such as the sodium salt of the monoglyceride monoglyceride of hydrogenated coconut oil fatty acids, such as sodium N-methyl-Ncocoyl taurate, cocomonoglyceride sodium sulfate, ii. higher alkyl sulfates, such as sodium lauryl sulfate, iii. higher alkyl ether sulfates, for example, of the formula CH3 (CH 2 ) mCH2 (OCH2CH 2 ) nOSO3X, where m is 6 to 16, for example, 10, n is 1 to 6, for example, 2, 3 or 4, and X is Na or K, for example, sodium laureth-2 sulfate
    Petition 870190007122, of 23/01/2019, p. 38/61
    31/49 (CH3 (CH2) 10CH2 (OCH2CH2) 2OSO3Na).
    iv. upper alkyl aryl sulfonates, such as sodium dodecyl benzene sulfonate (sodium lauryl benzene sulfonate)
    v. higher alkyl sulfoacetates, such as sodium lauryl sulfoacetate (sodium dodecyl sulfoacetate), higher fatty acid esters of 1,2-dihydroxy propane sulfonate, sulfocolaurate (potassium N-2-ethylamine) sulfoacetamide and lauryl sarcosinate sodium. [0053] By higher alkyl is meant, for example,
    C6-30 alkyl. In particular embodiments, the anionic surfactant is selected from sodium lauryl sulfate and sodium laurel sulfate ether. The anionic surfactant can be present in an amount that is effective, for example,> 0.01% by weight of the formulation, but not at a concentration that would be irritating to oral tissue, for example, <10%, and optimal concentrations depend on the particular formulation and the particular surfactant. For example, the concentrations used or a mouthwash are typically on the order of a tenth of that used for a toothpaste. In one embodiment, the anionic surfactant is present in a toothpaste from about 0.3% to about 4.5% by weight, for example, about 1.5%. The compositions of the invention can optionally contain mixtures of surfactants, for example, which comprise anionic surfactants and other surfactants which can be anionic, cationic, zwitterionic or non-ionic. Generally, surfactants are those that are reasonably stable over a
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    32/49 wide pH range. Surfactants are more fully described, for example, in patent No. 3,959,458, Agrícola et al .; US patent No. 3,937,807, to Haefele; and US Patent No. 4,051,234, to Gieske et al. In certain embodiments, the anionic surfactants useful for this invention include the water-soluble salts of alkyl sulfates having from about 10 to about 18 carbon atoms in the alkyl radical and the water-soluble salts of sulfonated fatty acid monoglycerides having about 10 to about 18 carbon atoms 0. Sodium lauryl sulfate, sodium lauroyl sarcosinate and sodium coconut monoglyceride sulfonates are examples of anionic surfactants of this type. In a particular embodiment, the composition of the invention, for example, Composition 1, and following, comprises sodium laurel sulfate.
    [0054] 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.
    [0055] Tartar control agents: In various embodiments of the present invention, the compositions comprise an anti-calculating agent (tartar control). Suitable anti-calculating agents include, but are not limited to, phosphates and polyphosphates (eg, pyrophosphates), polyaminopropanesulfonic acid (AMPS), hexametaphosphate salts, zinc citrate trihydrate, polypeptides, sulfonates
    Petition 870190007122, of 23/01/2019, p. 40/61
    33/49 polyolefin, polyolefin phosphates, diphosphonates. The invention can therefore comprise phosphate salts. In particular embodiments, these salts are alkaline phosphate salts, that is, alkali metal hydroxide salts or alkaline earth hydroxides, for example, sodium, potassium or calcium salts. Phosphate, as used herein, orally acceptable mono- and polyphosphates, for example, P1-6 phosphates, for example, monomeric phosphates such as monobasic, dibasic or tribasic phosphate; dimeric phosphates such as pyrophosphates; and multimeric phosphates, for example, sodium hexametaphosphate. In particular examples, the selected phosphate is selected from alkaline dibasic phosphate and alkaline pyrophosphate salts, for example, selected from dibasic sodium phosphate, dibasic potassium phosphate, dicalcium phosphate dihydrate, calcium pyrophosphate, tetrasodium pyrophosphate, tetrapotassium pyrophosphate, sodium tripolyphosphate, and mixtures of any of two or more of these. In a particular embodiment, for example, the compositions comprise a mixture of tetrasodium pyrophosphate (Na4P2O7), calcium pyrophosphate (Ca2P2O7), and dibasic sodium phosphate (Na2HPO4), for example, in amounts of about 3 to 4% of dibasic sodium phosphate and about 0.2 to 1% of each of the pyrophosphates. In another embodiment, the compositions comprise a mixture of tetrasodium pyrophosphate (TSPP) and sodium tripolyphosphate (STPP) (Na5P3O10), for example, in proportions of TSPP in about 1 to 2% and STPP in about 7% about 10%. Such phosphates
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    34/49 are provided in an amount effective to reduce enamel erosion, to aid teeth cleaning, and / or to reduce the accumulation of tartar on the teeth, for example, in an amount of 2 to 20%, for example, about from 5 to 15% by weight of the composition.
    [0056] Flavoring agents: The oral care compositions of the invention may also include a flavoring agent. Flavoring agents that are used in the practice of the present invention include, but are not limited to, essential oils, as well as various flavoring aldehydes, esters, alcohols, and the like. Examples of essential oils include mint, peppermint, wintergreen, sassafras, cloves, sage, eucalyptus, marjoram, cinnamon, lemon, lime, grapefruit and orange oils. Also useful are chemicals like menthol, carvone and anethole. Certain embodiments employ peppermint and peppermint oils. The flavoring agent can be incorporated into the oral composition at a concentration of about 0.1 to about 5% by weight, for
    example, about 0.5 to about 1.5% by weight. [0057] Polymers: The oral care compositions of invention may also include additional polymers for adjust viscosity of the formulation or increase the
    solubility of other ingredients. Such additional polymers include polyethylene glycols, polysaccharides (for example, cellulose derivatives, for example carboxymethyl cellulose, or polysaccharide gums, for example, xanthan gum or carrageenan gum). Acid polymers, for example, polyacrylate gels, can be
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    35/49 supplied in the form of free acids or partially or completely neutralized water-soluble alkali metal salts (eg potassium and sodium) or ammonium. [0058] Silica thickeners, which form polymeric structures or gels in an aqueous medium, may be present. Note that these silica thickeners are physically and functionally distinct from the particulate silica abrasives also present in the compositions, as the silica thickeners are very finely divided and offer little or no abrasive action. Other thickening agents are polymers of carboxyvinyl, carrageenan, 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, gum arabic, and tragacanth gum can also be incorporated. Colloidal magnesium aluminum silicate can be used as a component of the thickening composition to further improve the texture of the composition. In certain embodiments, thickening agents in an amount of about 0.5% to about 5.0% by weight of the total composition are used.
    [0059] The compositions of the invention can include an anionic polymer, for example, in an amount of from about 0.05 to about 5%. Such agents are generally known for use in dentifrice, although not for this particular application, useful in the present invention are disclosed in US Patent Nos. 5,188,821 and 5,192,531; and include synthetic anionic polymeric polycarboxylates, such as 1: 4 to 4: 1 anhydride or acid copolymers
    Petition 870190007122, of 23/01/2019, p. 43/61
    36/49 maleic with another ethylenically unsaturated polymerizable monomer, preferably methyl vinyl ether / maleic anhydride with a molecular weight (MW) of about 30,000 to about 1,000,000, more preferably about 300,000 to about 800,000. These copolymers are available, for example, as Gantrez., For example, AN 139 (PM 500,000), AN 119 (PM 250,000) and preferably S-97 Pharmaceutical Grade (PM 700,000) available from ISP Technologies, Inc., Bound Brook, NJ 08805. Breeding agents when present are present in amounts ranging from about 0.05 to about 3% by weight. Other operating polymers include those such as 1: 1 maleic anhydride copolymers with ethyl acrylate, hydroxyethyl methacrylate, N-vinyl-2-pyrrolidone, or ethylene, the latter being available, for example, as Monsanto EMA No. 1103, PM 10,000 and EMA Grade 61, and 1: 1 of acrylic acid copolymers with methyl or hydroxyethyl methacrylate, methyl or ethyl acrylate, isobutyl vinyl ether or Nvinyl-2-pyrrolidone. Generally suitable, they are olefinically or ethylenically unsaturated polymerized carboxylic acids that contain an activated carbon-carbon olefinic double bond and at least one carboxyl group, that is, an acid containing an olefinic double bond that works readily in polymerization due to their presence in the molecule of the monomer, either in the alpha-beta position in relation to a carboxyl group or as part of a terminal methylene group. Illustrative of such acids are acrylic, methacrylic, ethacrylic, alpha-chloroacrylic, crotonic, beta-acryloxy-propionic acids,
    Petition 870190007122, of 23/01/2019, p. 44/61
    37/49 sorbic, alpha-chlorsorbic, cinnamic, beta-styrylacrylic, muconic, itaconic, citraconic, mesaconic, glutaconic, aconitic, alpha-phenylacrylic, 2-benzyl acrylic, 2-cyclohexylacrylic, angelic, umbilic, fumaric, maleic and anhydrous. Other olefinic monomers other than copolymerizable with these carboxylic monomers include vinyl acetate, vinyl chloride, dimethyl maleate and the like. Copolymers contain sufficient carboxylic salt groups for water solubility. Another class of polymeric agents includes a composition containing the substituted acrylamide homopolymers and / or unsaturated sulfonic acid homopolymers and their salts, in particular, where the polymers are based on unsaturated sulfonic acids selected from acrylamido sulfonic acids such as acid 2 sulfonic methylpropane 2 having a molecular weight of about 1,000 to about 2,000,000, described in US Patent No. 4,842,847, June 27, 1989 to Zahid. Another useful class of polymeric agents includes polyamino acids that contain proportions of anionic surfactant amino acids, such as aspartic acid, glutamic acid and phosphoserine, for example, as disclosed in US Patent No. 4,866,161 Sikes et al.
    [0060] Water: Oral compositions can comprise significant levels of water. The water used in the preparation of commercial oral compositions must be deionized and free of organic impurities. The amount of water in the compositions includes free water that is added plus the amount that is introduced with other materials.
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    38/49 [0061] Humectants: Within certain embodiments of oral compositions, it is also desirable to incorporate a humectant to prevent the composition from hardening by exposure to air. Certain humectants can also impart desirable sweetness or flavor to toothpaste compositions. Suitable humectants include edible polyhydric alcohols such as glycerin, sorbitol, xylitol, propylene glycol, as well as other polyols and mixtures of these humectants. In one embodiment of the invention, the main humectant is glycerin, which can be present at levels greater than 25%, for example, 25 to 35%, about 30% with 5% or less of other humectants.
    [0062] Other optional ingredients: In addition to the components described above, the embodiments of this invention may contain a variety of optional toothpaste ingredients some of which are described below. Optional ingredients include, for example, but are not limited to, adhesives, foaming agents, flavoring agents, sweetening agents, additional anti-plaque agents, abrasives and coloring agents. These and other optional components are further described in US Patent No. 5,004,597, to Majeti; US patent No. 3,959,458 to Agricola et al. and US patent No. 3,937,807, to Haefele, all of which are incorporated herein by reference.
    [0063] Unless otherwise stated, all percentages of components of the composition given in this specification are by weight based on a composition or formulation with a total weight of 100%.
    [0064] Unless otherwise specifically
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    39/49 identified, the ingredients to be used in the compositions and formulations of the present invention are preferably cosmetically acceptable ingredients. By cosmetically acceptable it means suitable for use in a formulation for topical application to human skin. A cosmetically acceptable excipient, for example, is an excipient that is suitable for external application in amounts and concentrations contemplated in the formulations of the present invention, and includes, for example, excipients that are generally recognized as safe (GRAS) by United States Food and Drug Administration.
    [0065] The compositions and formulations, as provided herein, are described and claimed with reference to their ingredients, as is customary in the art. As would be apparent to one skilled in the art, the ingredients may in some cases react with one another, so that the actual composition of the final formulation may not correspond exactly to the listed ingredients. Thus, it should be understood that the invention extends to the product of the combination of the listed ingredients.
    [0066] As used throughout, bands are used as an abbreviation to describe each and every value that is within the range. Any value within the range can be selected as the end of the range. In addition, all references cited herein are hereby incorporated by reference in their entirety. In the event of a conflict in a definition in this disclosure and that of a cited reference, this disclosure controls.
    [0067] Unless otherwise specified, all
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    40/49 percentages and quantities here and elsewhere expressed in the specification should be understood as referring to percentages by weight. The quantities given are based on the weight of the active material.
    EXAMPLES
    Example 1 [0068] Sample 1, ZnO-TMG, is prepared as follows. At room temperature, 50 ml of deionized water is added slowly to a flask containing 4.0712g (0.05003mol) of zinc oxide powder, and 5.8595g (0.05002 mol) of TMG in its free form (CAS # 107-43-7). The mixture is stirred overnight for about 20 hours. Unreacted zinc oxide is removed by centrifugation followed by filtration through a 0.45 micron membrane. The final product is a transparent solution.
    Table 1
    SAMPLE 1 ZnO TMG Amountadded 4.0712 g, 0.05003 mol 5.8595 g, 0.05002 mol solution pHFinal 7.77
    [0069] Sample 2, ZnO-TMG-HCl, is prepared as follows. At room temperature, 50 ml of deionized water is added slowly to a flask containing 4.0712 g (0.05003 mol) of zinc oxide powder, and 7.6832 g (0.05002 mol) of TMG-HCl (CAS # 590-46-5). The mixture is stirred overnight for about 20 hours. Unreacted zinc oxide is removed by centrifugation followed by filtration through a 0.45 micron membrane. The final product is
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    41/49 a transparent solution.
    Table 2
    SAMPLE 2 ZnO TMG-HCl Quantity added 4.0712 g, 0.05003 mol 7.6832 g, 0.05002 mol solution pHFinal 6.02
    [0070] Sample 3, ZnO-TMG-HCl, is prepared as follows. 1M TMG-HCl solution is prepared by dissolving 7.68 g (0.0500 mol) of TMG-HCl (CAS # 590-46-5) in 50 ml of deionized water. At room temperature, 4.07 g (0.0500 mol) of zinc oxide powder is slowly added to the TMG-HCl solution. The mixture is stirred overnight for about 20 hours. Unreacted zinc oxide is removed by centrifugation followed by filtration through a 0.45 micron membrane. The final product is a transparent solution.
    Table 3
    SAMPLE 3 ZnO TMG-HCl Amountadded 4.07 g, 0.0500 mol 7.68 g, 0.0500 mol solution pHFinal 5.56
    [0071] Each sample is evaluated for its capacity and rate to form precipitation or flocculation after dilution. For this analysis, samples with different dilution ratios (for example, through 2x to 32x) are prepared and maintained at 37 ° C. The samples are periodically monitored and their generation efficiency
    Petition 870190007122, of 23/01/2019, p. 49/61
    42/49 precipitation / flocculation are recorded.
    [0072] Dilution experiments indicate that ZnO-TMGHCl (samples 2 and 3) generates precipitation / flocculation, and is therefore preferred for the deposition of solid particles on the dentin surface. Flocculation / precipitation rate depends on the dilution ratio, which is related to the initial zinc concentration at the time the water is mixed with the stock solutions in desired proportions.
    [0073] A first dilution experiment is performed using sample 2 of ZnO-TMG-HCl 2. Dilutions are prepared by mixing the stock solution with water in different ratios based on volume, producing samples with 2x dilutions (1 : 1 stock and water), 4x, 8x, 16x and 32x. Diluted samples are maintained at 37 ° C, and the rates at which flocculation / precipitation occurs are monitored. One hour of mixing, visible precipitations are observed in systems with dilutions of 2x, 4x and 8x.
    [0074] A second dilution experiment is performed using sample 3 of ZnO-TMG-HCl. The dilutions are again prepared by mixing the stock solution with water in different ratios based on volume, producing samples with dilutions of 2x (1: 1 stock and water), 4x, 8x, 16x and 32x. Diluted samples are maintained at 37 ° C, and the rates at which flocculation / precipitation occurs are monitored. Twenty-four hours from the mixture, visible precipitations are observed in systems with dilutions of 2x, 4x and 8x. The pH values of the diluted systems are measured at the end of the treatment period of 24
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    43/49 hours, and they are 5.57, 5.69, 5.89, 6.06, 6.28 for systems with dilutions of 2x, 4x, 8x, 16x and 32x, respectively. These pH values are well within the range of 5.5 to 10 suitable for oral care applications. [0075] A third dilution experiment is performed using ZnO-TMG sample 1. The dilutions are again prepared by mixing the stock solution with water in different ratios based on volume, producing samples with dilutions of 2x (1: 1 stock and water), 4x, 8x, 16x and 32x. Diluted samples are kept at 37 ° C, and the rates at which flocculation / precipitation occurred are monitored. One hour of mixing, visible precipitations cannot be observed in all samples.
    [0076] Preparations that generate flocculation / precipitation can be used to deposit active agents on oral surfaces, including the surfaces of teeth and mucous membranes. In this regard, dilutions from 2x to 8x can be used. In the event that the stock solution is prepared at a different concentration, dilutions that produce the same effective zinc fillers can be used. In a real formulation, in fact, the zinc concentration in the formulation would be less than the dilution concentration in relation to water, because of the total formulation comprising components in addition to water. Preparations with low and high ends of the concentration spectrum tend to require more hours of treatment and are not among the most reliable in producing precipitation / flocculation.
    [0077] Preparations that do not generate
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    44/49 flocculation / precipitation discernible to the naked eye can also be used for the deposition of active agents on oral surfaces. The inability to generate noticeable flocculation / precipitation may be due to the unfavorable dilution ratio or inadequate treatment duration. However, the preparations may still be able to generate particles, such as colloidal particles. While these particles do not form precipitates during the duration of treatment, they can form deposits on the surface on oral surfaces. In this regard, the operable ranges of dilution ratios and / or treatment durations are broader than what can be directly inferred from the aforementioned dilution experiments.
    [0078] In some embodiments, the precipitates or particles formed by dilution comprise one or more types of zinc salts, as well as TMG. In some embodiments, the zinc salts are essentially free of zinc oxide, and are in a form that can be at least partially solubilized in the oral cavity. In some embodiments, one type of zinc salts is zinc hydroxide. In some embodiments, TMG is also present in precipitates or particles, either as an integral component of them, or as an impurity.
    [0079] ZnO-TMG-HCl provides relatively high levels of solubilized zinc compared to what can be released from ZnO alone, and furthermore provides for localized and enriched release to dental surfaces (such as
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    45/49 as dentin and enamel surfaces) under dilution. The released material exists in the form of a solid coating. The coating improves the whiteness of the tooth surface. The coating can block dentin tubules providing relief from sensitivity. The coating can neutralize acids that provide anti-erosion benefits. The coating can disintegrate in saliva and / or over the acid challenge, and release zinc and TMG ions over an extended period of time, providing all the benefits associated with zinc and TMG.
    Example 2 [0080] Test dentifrice comprising ZnO-TMG HCl,
    1450 ppm of fluoride, and phosphates is prepared as follows:
    Table 4
    Ingredient % by weight PEG 600 3 CMC-7 0.65 Xanthan 0.2 Sorbitol 27 Glycerin 20 Saccharin 0.3 Tetrasodium pyrophosphate 0.5 Calcium pyrophosphate 0.25 Dibasic sodium phosphate 3.5 Sodium fluoride 0.32 Titanium dioxide 0.5 Abrasive silica 8 Thickener silica 8 TMG-HCl 5
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    46/49
    Sodium lauryl sulfate 1.5 Flavoring 1.2 ZnO 2 Water QS
    Example 3 [0081] A stable mouthwash formulation is provided as follows:
    Table 5
    Ingredient % by weight Sorbitol 7.5 Glycerin 7.5 Propylene glycol 7 Sodium saccharin 0.02 Citric acid (anhydrous) 0.05 ZnO 2 TMG HCl 5 Flavoring / coloring 0.12 Potassium sorbate 0.05 Cocoamidopropyl betaine 1 Water QS
    Example 4 [0082] Sample 4, ZnO-TMG-HCl, is prepared as follows. 15.3604 g (0.1000 mol) of TMG-HCl (CAS # 590-46-5) is dissolved in 100 ml of deionized water with stirring. At room temperature, 8.1370 g (0.09999 mol) of zinc oxide powder is slowly added to the TMG-HCl solution. The mixture is stirred overnight for about 16 hours. Unreacted zinc oxide is removed by centrifugation followed by filtration through a membrane
    Petition 870190007122, of 23/01/2019, p. 54/61
    47/49 of 0.45 micron. The final product is a transparent solution. Table 6
    SAMPLE 4 ZnO TMG-HCl Amountadded 8.1370 g, 0.09999 mol 15.3604 g, 0.1000 mol solution pHFinal 6.02
    [0083] A dilution experiment with Sample 4 is performed to assess its ability to form precipitation and / or flocculation over dilution within a short period of time.
    [0084] Before dilution, the stock solution of Sample 4 and deionized water are preheated to 37 ° C. Dilutions are prepared by mixing the stock solution with water in different ratios based on volume, producing samples with dilutions of 1.5x (1 ml of stock and 0.5 ml of water), 2x (1 ml of stock and 1 ml of water), 4x (1 ml of stock and 3 m of water), 8x (1 ml of stock and 7 ml of water), 16x (0.5 ml of stock and 7.5 ml of water) and 32x (0.5 ml of stock and 15.5 ml of water). After the initial mixing, the samples are manually shaken to maintain effective mixing under ambient conditions (air temperature at about 24 ° C). The rates at which flocculation / precipitation occurred are monitored.
    [0085] Dilutions have been found to produce precipitation and / flocculation at different rates. The 1.5x dilution produced discernible flocculation with the naked eye within about 20 seconds from the initial mixture. Dilution in 2x produced flocculation within about 5
    Petition 870190007122, of 23/01/2019, p. 55/61
    48/49 seconds. Dilutions in 4x and 8x require about 10 seconds before flocculation is discernible to the naked eye. The 16x dilution requires about 1 minute. The 32x dilution does not produce discernible flocculation with the naked eye until 2 minutes of initial mixing.
    [0086] It has also been found that similar rates can be acquired at temperatures below 37 ° C, which is the case in the initial phase of use by a typical user. For this, dilutions in 1.5x and 2x are prepared by mixing the stock solution of Sample 4 (preheated to 37 ° C) and water (at room temperature, about 24 ° C) in volumes as specified above. Dilution temperatures are lower than 37 ° C. The dilutions produced flocculations within the same structure 20 seconds and 5 seconds of time, respectively.
    [0087] The flocculation generated from these short treatments can also bond to the surfaces of teeth and mucous membranes, releasing compounds containing zinc and TMG to the target surface. All benefits discussed with reference to the above mentioned ZnO-TMG-HCl samples (samples 2 and 3) apply.
    [0088] Short-term treatments are exceptionally suitable for oral care applications, especially when the release is made through toothpaste and mouthwash. A typical user will brush or rinse for less than 2 minutes. User compliance with the regimen will be greatly improved, compared to situations where prolonged treatment periods are required.
    Petition 870190007122, of 23/01/2019, p. 56/61
    49/49 [0089] Efficacy with short treatment durations is also expected with the other ZnOTMG-HCl samples, ie samples 2 and 3.
    [0090] Although the invention has been described with respect to specific examples including presently preferred ways of carrying out the invention, those skilled in the art will appreciate that there are numerous variations and permutations of the systems and techniques described above. It is to be understood that other embodiments can be used and structural and functional modifications can be made without departing from the scope of the present invention. Thus, the scope of the invention should be interpreted widely as set out in the appended claims.
    权利要求:
    Claims (15)
    [1]
    1. Oral care composition characterized by comprising zinc oxide, trimethylglycine (TMG), in free form or orally acceptable salt, on an orally acceptable basis, where the composition comprises zinc oxide in an amount to provide 0.05 to 4% by weight of zinc in the composition, and TMG in an amount to provide a molar ratio of zinc oxide to TMG of 1: 1 to 1:10.
    [2]
    2. Composition according to claim 1, characterized by the fact that zinc oxide and trimethylglycine form a complex with a halide, in which the halide is selected from chloride, bromide and fluoride.
    [3]
    3. Composition according to claim 2, characterized by the fact that the halide is chloride.
    [4]
    Composition according to any one of claims 1 to 3, characterized in that TMG is supplied in the form of the salt corresponding to the orally acceptable acid added.
    [5]
    5. Composition, according to claim 4, characterized by the fact that TMG is supplied in the form of hydrochloride salt.
    [6]
    Composition according to any one of claims 1 to 5, characterized in that the amount of zinc is 1 to 2% by weight of the composition.
    [7]
    Composition according to any one of claims 1 to 6, characterized in that the zinc oxide is solubilized in the formulation, but provides a precipitate of zinc when used and diluted with the
    Petition 870190007122, of 23/01/2019, p. 58/61
    2/3 saliva and / or rinse.
    [8]
    8. Composition according to any one of claims 1 to 7, characterized in that the mixture of zinc oxide and TMG is prepared before its incorporation into the oral care composition.
    [9]
    Composition according to any one of claims 1 to 8, characterized in that it is in the form of a toothpaste, gel or mouthwash.
    [10]
    Composition according to any one of claims 1 to 9, characterized in that it further comprises an effective amount of a fluoride ion source.
    [11]
    11. Composition according to any one of claims 1 to 10, characterized in that the orally acceptable base comprises ingredients selected from an abrasive, a buffering agent, a humectant, a surfactant, a thickener, a breath freshener, a flavor, an aroma, a dye, an antibacterial agent, a bleaching agent, an agent that interferes with or prevents bacterial fixation, a source of calcium, a source of phosphate, an orally acceptable potassium salt, an anionic polymer, and combination of two or more of them.
    12. Composition, according to any an of claims 1 to 11, characterized by the fact of pH gives composition be 5 to 8. 13. Composition, according to any an of
    claims 1 to 12, characterized for being for use to reduce and inhibit acid erosion of the enamel, cleaning the teeth, whitening the teeth, reducing the biofilm and the plaque
    Petition 870190007122, of 23/01/2019, p. 59/61
    3/3 bacterially generated, reduce gingivitis, inhibit tooth decay and caries formation, and / or reduce dentin hypersensitivity.
    [12]
    14. Ionic complex characterized by comprising zinc oxide, TMG and an anionic species selected from fluoride, chloride or bromide.
    [13]
    15. Use of zinc oxide together with TMG, in the form of a free or orally acceptable salt, characterized by being in the manufacture of an oral care product.
    [14]
    16. Complex characterized by being zincotrimethylglycine oxide.
    [15]
    17. Use of a mixture of zinc oxide and trimethylglycine (TMG) characterized in that it is used in the preparation of a composition, as defined in any one of claims 1 to 12, to treat or reduce erosion of tooth enamel, clean teeth, whiten teeth, reduce bacterially generated biofilm and plaque, reduce gingivitis, inhibit tooth decay and cavity formation, reduce oral odor and / or reduce dentin hypersensitivity.
    类似技术:
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    同族专利:
    公开号 | 公开日
    RU2015123707A|2017-01-26|
    JP2016506405A|2016-03-03|
    IL239122D0|2015-07-30|
    KR20150097492A|2015-08-26|
    AR094193A1|2015-07-15|
    EP2934446A1|2015-10-28|
    AU2012397270A1|2015-06-11|
    BR112015014758A2|2017-07-11|
    CA2892422A1|2014-06-26|
    IL239122A|2018-07-31|
    PH12015501439A1|2015-09-14|
    MX352556B|2017-11-29|
    CN104853727A|2015-08-19|
    US20150328112A1|2015-11-19|
    US9901523B2|2018-02-27|
    TWI507210B|2015-11-11|
    WO2014098829A1|2014-06-26|
    CN104853727B|2018-04-20|
    AU2012397270B9|2015-08-13|
    JP5976955B2|2016-08-24|
    TW201503906A|2015-02-01|
    MX2015007675A|2015-09-07|
    CA2892422C|2019-10-01|
    RU2628540C2|2017-08-18|
    ZA201503690B|2017-09-27|
    AU2012397270B2|2015-08-06|
    EP2934446B1|2016-12-07|
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    法律状态:
    2018-10-30| B06A| Notification to applicant to reply to the report for non-patentability or inadequacy of the application according art. 36 industrial patent law|
    2019-02-12| B09A| Decision: intention to grant|
    2019-02-12| B15K| Others concerning applications: alteration of classification|Free format text: AS CLASSIFICACOES ANTERIORES ERAM: A61K 8/27 , A61K 8/44 , A61Q 11/00 , C07F 3/06 Ipc: A61K 8/27 (2006.01), A61K 8/44 (2006.01), A61Q 11/ |
    2019-04-09| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 19/12/2012, OBSERVADAS AS CONDICOES LEGAIS. (CO) 20 (VINTE) ANOS CONTADOS A PARTIR DE 19/12/2012, OBSERVADAS AS CONDICOES LEGAIS |
    优先权:
    申请号 | 申请日 | 专利标题
    PCT/US2012/070537|WO2014098829A1|2012-12-19|2012-12-19|Oral care products comprising zinc oxide and trimethylglycine|
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