Mouthwash Understanding Amino Acid Zinc HALOGENIDE COMPLEX AND ITS USES

专利摘要:
Abstract Amino acid zinc halide mouthwashes described herein are mouthwashes comprising an amino acid zinc ion complex. Methods of making and using the compositions are also provided.
公开号:BR112015014899B1
申请号:R112015014899-9
申请日:2012-12-19
公开日:2019-05-14
发明作者:Long Pan；Shaotang Yuan；Shira Pilch；James G. Masters；Zhiqiang Liu
申请人:Colgate-Palmolive Company；
IPC主号:

专利说明:

MUSHROOM UNDERSTANDING AMINO ACID ZINC HALOGENIDE COMPLEX AND ITS USES
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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2/62 dentin surface as per 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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3/62 anionic surfactants such as sodium lauryl sulfate, thus interfering with foaming and cleaning. Zinc oxide and insoluble zinc salts, on the other hand, can do a poor job of releasing
of zinc to the teeth because of its insolubility. [005] Although the technique previous describe usage in various compositions oral for the treatment gives hypersensitivity of dentin, tooth decay, and erosion of
enamel and demineralization, there is still a need for additional compositions and methods that provide improved performance in such treatments.
SUMMARY [006] It has now been discovered that zinc oxide can form a soluble complex with an amino acid. The complex comprising zinc and amino acid and optionally an anion and / or oxygen, forms a soluble cationic portion, which in turn forms a salt with a halide or another anion. When placed in the formulation, this complex presents an effective concentration of zinc ions for the enamel, thus protecting against erosion, reducing bacterial colonization and biofilm development, and providing better shine to the teeth. In addition, 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. Despite providing efficient zinc release compared to
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4/62 with formulations with insoluble zinc salts, formulations comprising the amino acid-zinc complex do not exhibit bad taste and mouthfeel, little fluoride release, and poor foaming and cleaning associated with oral care products. conventional zinc base using soluble zinc salts.
[007] In a particular embodiment, the zinc-amino acid complex is a zinc-lysine-HCl complex, for example, the new complex called ZLC, which can be formed from a mixture of zinc oxide and lysine hydrochloride. ZLC has the chemical structure [Zn (C ₆ Hl4N2O2) 2Cl] ⁺ Cl ^- , and can exist in a cationic cation solution [Zn (C6Hl4N2O2) 2Cl] ⁺ ) and the chloride anion, or it can be a solid salt, for example , a crystal, optionally in the form of mono- or dihydrate.
[008] The invention provides compositions for oral care, for example, mouthwash, toothpaste or oral gel compositions, which comprise a zinc-amino acid complex, for example, a zinc-lysine-chloride complex, for example, ZLC. The compositions can optionally further comprise a source of fluoride and / or an additional source of phosphate. The compositions can be formulated in 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, flavors and / or colors.
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[009] In a particular embodiment, the invention provides a mouthwash comprising a zincamino acid complex, for example, a zincolysin chloride complex, for example, ZLC.
[0010] The invention further provides methods of using the compositions of the invention to reduce and inhibit acid erosion of the enamel, clean the teeth, reduce bacterially generated biofilm and plaque, reduce gingivitis, inhibit tooth decay and cavity formation, and reduce dentin hypersensitivity, which comprises applying a composition of the invention to teeth.
[0011] The invention further provides methods of making the compositions of the invention which comprises combining a source of zinc ion (for example, ZnO), an amino acid, for example, arginine and lysine), and optionally a source of halide, for example , combining zinc oxide and lysine hydrochloride in an aqueous solution, for example, at a molar ratio of 1: 1 to 1: 3, for example, 1: 2 and Zn: halide present from 1: 1 to 1: 3, for example, 1: 2, optionally isolating the ionic complex thus formed as a solid, and mixing with a mouthwash base.
[0012] Other areas of applicability of the present 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.
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DETAILED DESCRIPTION [0013] 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.
[0014] The invention, therefore, provides, in a first embodiment, a mouthwash (Composition 1), comprising zinc in complex with an amino acid; for example,
1.1. Composition 1, in which the amino acid is selected from lysine, glycine and arginine, in the free form or orally acceptable addition salt, for example, hydrochloride form.
1.2. Composition 1 or 1.1, where the amino acid is a basic amino acid, for example, arginine or lysine, in free form or in an orally acceptable salt
1.3. Any of the previous compositions further comprising a halide, in ionic association with zinc and amino acid.
1.4. Any of the above compositions in which the molar ratio of Zn: amino acid is from 3: 1 to 1: 5, for example, about 1: 2 and the molar ratio of Zn: halide, where present, is from 3: 1 to 1: 3, for example about 1: 2.
1.5. Any of the above compositions in which the zinc-amino acid complex is formed, in whole or in part, in situ, after the composition is applied.
1.6. Any of the above compositions in which the zinc-amino acid complex is formed, in whole or in part, in situ, after the composition is formulated.
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1.7. Any of the above compositions in which the amino acid is lysine.
1.8. Any of the foregoing compositions in which zinc is present in an amount of 0.05 to 10% by weight of the composition, optionally at least 0.1, at least 0.2, at least 0.3, at least 0.4 at least 0.5, at least 1, at least 2, at least 3, or at least 4 to 10% by weight of the composition, for example, about 0.5 to 3%, for example, about 2 to 2.7% by weight.
1.9. Any of the above compositions in which amino acid is present in an amount of 0.5 to 30% by weight of the composition, optionally at least 0.1, at least 0.2, at least 0.3, at least 0.4, at least 0.5,
at least 1, at minus 2, fur any less 3, fur minus 4, at least 5, at least 10, fur any less 15, fur minus 20 up to 30% in weight, by example, fence of 1 to 10% in Weight.
1.10. Any of the foregoing compositions, in which the molar ratio of zinc to amino acid is 2: 1 to 1: 4, optionally 1: 1 to 1: 4, 1: 2 to 1: 4, 1: 3 to 1: 4 , 2: 1 to
1: 3.2: 1 to 1: 2, or 2: 1 to 1: 1, for example, about 1: 2 or 1: 3.
1.11. Any of the foregoing compositions comprising a halide in ionic association with zinc and amino acid, wherein the halide is selected from the group consisting of fluorine, chlorine, and mixtures thereof.
1.12. Any of the foregoing compositions in which the amino acid zinc complex is a lysine zinc chloride complex (for example, (ZnLys2Cl) ⁺ Cl ^- or (ZnLys3) ²⁺ Cl2)
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8/62 or an arginine zinc chloride complex.
1.13. Any of the foregoing compositions in which the amino acid zinc complex is a lysine zinc chloride complex, for example, ZLC, for example, a lysine zinc chloride complex having the chemical structure [Zn (C ₆ Hl4N2O2) 2Cl] ⁺ Cl ^- , either in cationic cation solution (for example, [Zn (C6Hl4N2O2) 2Cl] ⁺ and the chloride anion, or in the form of a solid salt, for example, crystal form, optionally in mono or dihydrate form.
1.14. Any of the above compositions which is substantially clear in the formulation, but which becomes cloudy when diluted.
1.15. Any of the foregoing compositions in which the amino acid zinc complex is present in an effective amount, for example, in an amount of 0.1 to 4% by weight of zinc, for example, about 0.1 to 1% by weight of zinc.
1.16. Any of the foregoing compositions further comprising an effective amount of a fluoride ion source, for example, providing 50 to 3000 ppm of fluoride.
1.17. Any of the foregoing compositions which further comprises an effective amount of fluoride, for example, wherein fluoride is a salt selected from stannous fluoride, sodium fluoride, potassium fluoride, sodium monofluorophosphate, sodium fluorosilicate, ammonium fluorosilicate , amine fluoride (for example, N'-octadecyltrimethylendiamine-N, N, N'-tris (2-ethanol-dihydrofluoride), ammonium fluoride, titanium fluoride, hexafluorosulfate, and combinations thereof.
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1.18. Any of the foregoing compositions comprising an effective amount of 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, dibasic potassium phosphate, dicalcium phosphate dihydrate, calcium pyrophosphate, tetrasodium pyrophosphate, tetrapotassium pyrophosphate, sodium tripolyphosphate, and mixtures of any two or more of the same, or mixtures of any of the two or more for example, in an amount of 1 to 20%, for example, 2 to 8%, for example, about 5% by weight of the composition.
1.19. Any of the foregoing compositions comprising buffering agents, for example, sodium phosphate buffer (for example, monobasic sodium phosphate and disodium phosphate).
1.20. Any of the above 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.
1.21. Any of the foregoing 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, a surfactant selected from from
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10/62 sodium lauryl sulfate, sodium lauryl sulfate ether, and mixtures thereof, for example, in an amount of from about 0.3% to about 4.5% by weight, for example, 1 to 2 % sodium lauryl sulfate (SLS); and / or a zwitterionic surfactant, for example, a betaine surfactant, for example cocamidopropyl betaine, for example, in an amount between about 0.1% to about 4.5% by weight, for example, 0.5 to 2% cocamidopropylbetaine.
1.22. Any of the foregoing compositions further comprising a viscosity modifier amount of one or more polysaccharide gums, for example xanthan or carrageen gum, thickener silica, and combinations thereof.
1.23. Any of the foregoing compositions further comprising aroma, fragrance and / or coloring.
1.24. Any of the foregoing compositions comprising an effective amount of one or more antibacterial agents, for example, comprising antibacterial selected from ether, a halogenated diphenyl agent (eg, triclosan) herbal extracts and essential oils (eg. 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 (for example, chlorhexidine, alexidine or octenidine), quaternary ammonium compounds (for example, cetylpyridinium chloride (CPC), benzalkonium chloride, chloride
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11/62 tetradecylpyridinium (TPC), N-tetradecyl-4ethylpyridinium chloride (TDEPC)), phenolic antiseptics, hexetidine, octenidine, sanguinarine, povidone iodine, delmopinol, salifluorine, metal ions (for example, zinc salts, for example, zinc salts, zinc, 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, domiphen bromide, delmopinol, octapinol and other piperidine derivatives, nicine preparations, chlorite salts; and mixtures of any of the above; for example, comprising triclosan or cetylpyridinium chloride.
1.25. Any of the foregoing compositions comprising an antibacterially effective amount of triclosan, for example, 0.1 to 0.5%, for example, about 0.3%.
1.26. Any of the foregoing compositions further comprising a bleaching agent, for example, one selected from the group consisting of peroxides, metal chlorites, perborates, percarbonates, peracids, hypochlorites, and combinations thereof.
1.27. Any of the foregoing compositions further comprising hydrogen peroxide or a source of hydrogen peroxide, for example, urea peroxide or a salt or peroxide complex (for example, such as peroxyphosphate, peroxycarbonate, perborate, peroxysilicate,
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12/62 or persulfate salts, for example, calcium peroxyphosphate, sodium perborate, sodium carbonate peroxide, sodium peroxyphosphate, and potassium persulfate);
1.28. Any of the foregoing compositions further comprising an agent that interferes with or prevents bacterial attachment, for example, chitosan or solbrol.
1.29. Any of the foregoing 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 caseinaphosphate.
1.30. Any of the above 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.
1.31. 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.
1.32. Any of the foregoing 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 4: 1 of anhydride or maleic acid copolymers with another polymerizable ethylenically unsaturated monomer; for example, where the anionic polymer is methyl vinyl
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13/62 maleic ether / 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, in which anionic polymer is about 1 to 5%, for example, about 2%, of the weight of the composition.
1.33. Any of the above compositions which further comprises mouthwash, fragrance or flavoring.
1.34. Any prior compositions in which the pH of the composition is approximately neutral, for example, from pH 6 to pH 8, for example, about pH 7.
1.35. Any of the foregoing compositions in which the amino acid is lysine and zinc and lysine form a zinc chloride-lysine complex having the chemical structure [Zn (C ₆ Hl4N2O2) 2Cl] ⁺ Cl ^- , in an amount to provide 0.5 to 2%, for example, about 1% zinc by weight, the composition further comprises a humectant, for example, sorbitol, propylene glycol and mixtures thereof, for example, in an amount of 10 to 25%, for example, about 15 at 20%, non-ionic surfactant, for example, poloxamer, for example, in an amount of 0.1 to 1%, and sweetener, flavorings, and water, for example, comprising a mouthwash.
Ingredients % Sorbitol 3 to 7%, eg about 4% ZLC To provide 0.5 to 2% Zn, foreg about 1% Zn Propylene glycol 5 to 10%, eg about 7% Polaxamer, eg 0.1 to 1%, eg about 0.4%
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Polaxamer 407Glycerin 5 to 10%, eg about 7.5% Flavoring and / orsweetener 0.01% to 1% Deionized water 70 to 85%, eg about 80%
1.36. Any of the previous 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.
[0015] The invention further provides methods for reducing and inhibiting acid erosion of the enamel, cleaning the teeth, reducing bacterially generated biofilm and plaque, reducing gingivitis, inhibiting tooth decay and cavity formation, and reducing 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.
[0016] For example, the invention provides methods to inhibit and reduce acid erosion of the enamel, clean teeth, reduce bacterially generated biofilm and plaque, reduce gingivitis, inhibit tooth decay and cavity formation, and reduce hypersensitivity dentin, which comprises applying an effective amount of a composition of the invention, for example, any of Composition 1, and following to the teeth, and then washing with sufficient water or aqueous solution to cause precipitation of the zinc oxide from the composition.
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[0017] The invention further provides a method of making an oral care composition comprising a zinc and amino acid complex, for example, any of Composition 1, et seq. comprising the combination of a source of zinc ions with an amino acid, in free or salt form (for example, the combination of zinc oxide with hydrochloride isolating that of lysine), in an aqueous medium, optionally, complex thus formed in form of solid salt, of mouthwash.
combining the complex with a base
[0018]invention For example, it provides in various embodiments, TheThe methods for (i) reduce hypersensitivity of teeth, (ii) for reduce The accumulation plate, (iii) reduce or inhibit The
of teeth, demineralization and promoting remineralization (iv) inhibit the microbial formation of oral biofilm, (v) reduce or inhibit gingivitis, (vi) in the cavity promote wound healing or cuts in the mouth, (vii) reduce levels of bacteria acid-producing, (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 example, when detected by light-induced quantitative fluorescence (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 bad oral odor, and / or (xvii) promote systemic health, including cardiovascular health, for example by reducing
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16/62 potential for systemic infection through oral tissues, comprising the application of any of the compositions 1, et segs. 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.
[0019] In some embodiments, the compositions of the present invention provide a mouthwash comprising an amino acid zinc halide. In some embodiments, the amino acid zinc halide is formed from precursors. In some embodiments, the precursors are a source of zinc ions, a source of amino acid, and a source of halide, in which the source of halide is part of the source of zinc ion, the source of amino acid, or an halogen acid.
[0020] In some embodiments, the amino acid is selected from lysine, glycine and arginine, in the free form or from an orally acceptable acid addition salt. In some embodiments, the amino acid is a basic amino acid, in the free or orally acceptable acid addition salt form.
[0021] In some embodiments, the mouthwash comprises from about 0.05% to about 4% zinc, by weight. The mouthwash of any of the preceding claims, wherein the zinc is solubilized in the formulation, but provides a zinc precipitate when used and diluted with saliva and / or rinse. In other embodiments, the source of zinc ions and the source of
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17/62 amino acids form a lysine zinc chloride complex or an arginine zinc chloride complex.
[0022] In some embodiments, the amino acid zinc complex is a lysine zinc chloride complex that has the chemical structure [Zn (C ₆ Hl4N2O2) 2Cl] ⁺ Cl ^- , either in cationic cation solution (for example, [Zn (C6Hl4N2O2) 2Cl] ⁺ and the chloride anion, or in the form of a solid salt, for example, crystal form, optionally in mono or dihydrate form.
[0023] Some embodiments still comprise an effective amount of a fluoride ion source.
[0024] Other embodiments comprise an orally acceptable base comprising selected buffering ingredients, refreshing from humectants, breath, one or more surfactants, flavorings, thickening agents, fragrances, colorants, antibacterial agents, bleaching agents, agents that interfere with or prevent bacterial fixation, calcium sources, phosphate sources, orally acceptable potassium salts, and anionic polymers.
[0025] In some embodiments, the pH of the mouthwash is between pH 4 and pH 8.
[0026] In other embodiments, the amino acid is lysine, such that zinc and lysine form a complex of zinc chloride and lysine that has the chemical structure [Zn (C6Hl4N2O2) 2Cl] ⁺ Cl, in an amount sufficient to supply 0.5 to 2% by weight of zinc from the mouthwash, the mouthwash further comprising humectant in an amount of
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18/62 to 25% by weight, non-ionic surfactant in an amount of 0.1 to 1% weight, and sweeteners, flavorings, and water.
[0027] Some embodiments provide a mouthwash for use in reducing or inhibiting acid erosion of the enamel, cleaning the teeth, reducing biofilm generated by bacteria and plaque, reducing gingivitis, inhibiting tooth decay and forming cavities, and / or reduced dentin hypersensitivity.
[0028] In some embodiments, the weight ratio of the amino acid zinc halide to water is about 1: 6 to about 1: 1. In some embodiments, the weight ratio of the amino acid zinc halide to water is from about 1: 5 to about 1: 2. In some embodiments, the weight ratio of the amino acid zinc halide to water is about 1: 4.
[0029] Some embodiments provide the use of an amino acid zinc halide, for the manufacture of a mouthwash. Other embodiments provide a method for treating or reducing tooth enamel erosion, cleaning teeth, reducing biofilm generated by bacteria and plaque, reducing gingivitis, inhibiting tooth decay and cavity formation, and / or reducing dentin hypersensitivity comprising the application of a mouthwash as described herein. Other embodiments provide methods further comprising the step of washing with sufficient water or aqueous solution to cause precipitation of zinc oxide from the mouthwash.
[0030] The invention also provides the use of zinc and
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19/62 an amino acid for making an oral hygiene composition comprising a zinc amino acid complex.
[0031] The invention further provides the use of an amino acid zinc complex, for example, an amino acid zinc halide, for example, a zinc-lysine chloride complex, to reduce and inhibit biofilm from enamel acid erosion, clean teeth, reduce bacterially generated biofilm and plaque, reduce gingivitis, inhibit the formation of tooth decay and cavities, and / or reduce dentin hypersensitivity.
[0032] Without wishing to be limited by theory, it is believed that the formation of the amino acid zinc halide proceeds through the formation of zinc halide, then the coordination of the amino acid residues around a zinc center. Using reaction of ZnO with lysine hydrochloride in water as an example, zinc can react with lysine and / or lysineHCl to form a clear solution of Zn-lysine chloride complex (ZnLys3Cl2), where Zn ++ is located in an octahedral center coordinated with two oxygen and two nitrogen atoms in the equatorial plane from two lysine carboxylic acids and the amine groups, respectively. Zinc is also coordinated with the third lysine pathway through its nitrogen and carboxylic oxygen, at the apical position of the metal's geometry.
[0033] In another embodiment, a zinc cation is complexed with two amino acid residues and two chloride residues. For example, where the amino acid is lysine, the complex has the formula [Zn (C ₆ Hl4N2O2) 2Cl] ⁺ Cl ^- .
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In this complex, the Zn cation is coordinated by two lysine ligands with two N atoms from NH2 groups and O atoms from carboxylic groups in an equatorial plane. It exhibits a distorted square-pyramidal geometry with the apical position occupied by a Cl ^- atom. This new structure gives rise to a portion of positive cation, so that a Cl ^- anion is combined to form an ionic salt.
[0034] Other zinc and amino acid complexes are possible, and their exact form is dependent, in part, on the molar ratios of the precursor compounds, for example, if it has limited halide, free halide complexes can form, for example, ZnOLys2 , which has a pyramid geometry, with the equatorial plane, which is the same as the compound above (Zn is linked to two oxygen and two nitrogen atoms from different lysines), where the top of the pyramid is occupied by an O atom.
[0035] Mixtures of complexes and / or additional complex structures, for example, involving various zinc ions based on the zinc structure, are possible and contemplated within the scope of the invention. When complexes are in solid form, they can form crystals, for example, in hydrated form.
[0036] Regardless of the precise structure of the complex or complexes, however, the interaction of zinc and amino acid converts insoluble zinc salts or zinc oxide to a highly soluble complex at about neutral pH. With the increase in water dilution, however, the complex dissociates, and the zinc ion converts to insoluble zinc oxide. This dynamic is unexpected
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21/62 typically ionic compositions become more soluble at greater dilution, not less - and this facilitates the deposition of zinc precipitate on teeth after administration, in the presence of saliva and with rinsing. This precipitation occludes the dentin tubules, thus reducing hypersensitivity, and also provides zinc to the enamel, which reduces acid erosion, and the formation of biofilm and plaque.
[0037] It should be understood that other amino acids can be used in place of lysine in the previous scheme. It will also be understood that, although the zinc, amino acid and optionally halide may be mainly in the form of precursor materials or in the form of an ionic complex, there may be some degree of equilibrium, so that the proportion of material is actually in the complex compared to the proportion in the form of precursor can vary depending on the formulation conditions, concentration of materials, pH, presence or absence of water, the presence or absence of other charged molecules, and so on.
[0038] 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.
[0039] 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 zinc precipitation. Alternatively, the person can mix the
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22/62 stock solution with an appropriate amount of aqueous diluent, and rinse with the mixture.
[0040] 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.
[0041] 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, where the gel can remain on the tooth for a long period of time. time for effective treatment.
[0042] 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.
[0043] The precipitation rate from the formulation can be modulated by adjusting the concentration of the complex in the stock solution, and changing the ratio between the material and the water. A more diluted formula leads to faster precipitation and is therefore preferred when rapid treatment is desired.
[0044] The benefits of the oral care compositions of the invention are numerous. By supplying zinc ions and zinc-containing compounds that can release zinc ions in
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23/62 oral cavity, the oral care compositions of the invention provide benefits of antimicrobials, antiplaque, anti-gingivitis, anti-odor, anti-caries and anti-calculus. Occlusion particles and surface deposits are zinc-containing compounds (particularly ZnO), as well as other zinc derivatives that can release zinc ions into oral cavities and provide the various benefits as previously recognized. Additional benefits include, but are not limited to, antifixation, antiperiodontitis and loss of antiosthesis, as well as promoting wound healing.
[0045] 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. In that case, the more depositions on the surface / occlusion the treatment leads to, the more effective the treatments are, and therefore zinoarginine and zinc-lysine are preferred. It should also be noted that when surface deposits and occlusion particles neutralize acids, beneficial zinc ions and
amino acids (infra) can be released, providing many different benefits of oral care others that anti-erosion. [0046] A third party benefit it's benefit
anti-sensitivity as a result of occlusion. Occlusion of the dentine tubules leads to relief of sensitivity.
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24/62 [0047] A fourth benefit is the benefit associated with amino acids. The occlusion particles and surface deposits contain the corresponding amino acids, such as arginine and lysine. These amino acids provide multiple benefits. For example, basic amino acids lead to a higher pH than plaque and can provide anti-caries benefits.
[0048] The composition may include the amino acid zinc halide and / or precursors thereof. Precursors, which can react in situ with water to form (i) zinc halide amino acid, include (i) zinc hydrohalide and amino acid, or (ii) zinc chloride and amino acid, or (iii) an ion source of zinc, an amino acid, and a halogen acid, or (iv) combinations of (i), (ii), and / or (iii). In one embodiment, the amino acid zinc halide can be prepared at room temperature by mixing the precursors in a solution, such as water. In situ training provides ease of formulation. Precursors can be used instead of first having to form the amino acid zinc halide. In another embodiment, the water that allows the formation of the precursor amino acid zinc halide comes from the saliva and / or rinse water that comes in contact with the composition after application.
[0049] The amino acid zinc halide is a complex formed from the zinc halide acid addition salt (eg zinc chloride) and an amino acid, or from the amino acid halide acid salt (eg example, lysine hydrochloride) and zinc ion source, and / or the combination of all three of a halogen acid, an amino acid, and a source of zinc ions.
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25/62 [0050] Examples of amino acids include, but are not limited to, common natural amino acids, for example, lysine, arginine, histidine, glycine, serine, threonine, asparagine, glutamine, cysteine, selenocysteine, proline, alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, tryptophan, aspartic acid, and glutamic acid. In some embodiments, the amino acid is a neutral or acidic amino acid, for example, glycine.
[0051] As can be seen from the examples below, the precipitation of zinc from the complex when diluted with water is most notable when the complex is formed from a basic amino acid. Thus, where dilution precipitation is desired, a basic amino acid may be preferred. In some embodiments, therefore, the amino acid is a basic amino acid. By basic amino acid means the naturally occurring basic amino acids, such as arginine, lysine and histidine, as well as any basic amino acid having a carboxyl group and an amino group in the molecule, which is soluble in water and provides an aqueous solution with a pH of about 7 or higher. Therefore, basic amino acids include, but are not limited to, arginine, lysine, citrulline, ornithine, creatine, histidine, diaminobutanoic acid, diaminoproprionic acid, their salts or combinations thereof. In certain embodiments, the amino acid is lysine. In other embodiments, the amino acid is arginine.
[0052] The halide can be chlorine, bromine, or iodine, more typically chlorine. The addition salt of an amino acid and
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26/62 of a halogen acid (for example, HCl, HBr, or HI) is sometimes referred to here as an amino acid hydrohalide.
Thus an example of an amino acid hydrohalide is lysine hydrochloride.
Another is glycine hydrochloride.
[0053]
The source of zinc ion for the combination with an amino acid halide or an amino acid, optionally plus the halogen acid in this case can be, for example, zinc oxide or zinc chloride.
[0054]
In certain embodiments, the amount of zinc halide amino acid in the composition is 0.05 to
30% by weight of the composition. In certain embodiments, for example, precursors, for example, zinc and amino acid halide, are present in amounts such that, when combined in the amino acid zinc halide, the amino acid zinc halide would be present in an amount of
0.05 to 10% by weight of the composition. In any of these embodiments, the amount of the varied for the amino acid zinc halide can be a desired purpose, such as a toothpaste or mouthwash. In other embodiments, the amount of amino acid zinc halide is at least 0.1, at least 0.2, at least 0.3, at least 0.4, at least 0.5, at least 1, at least 2, at least 3, or at least 4 to 10% by weight of the composition. In other embodiments, the amount of amino acid zinc halide is less than 9, less than 8, less than 7, less than 6, less than 5, less than 4, less than 3, less than 2, less than
1, less than 0.5 to 0.05% by weight of the composition. In others
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27/62 embodiments, the amounts are 0.05 to 5%, 0.05
at 4%, 0.05 to 3%, 0.05 to 2%, 0.1 to 5%, 0.1 to 4%, 0.1 to 3%, 0.1 to 2%, 0.5 to 5%, 0.5 to 4%, 0.5 to 3%, or 0.5 to 2% in weight of the composition. [0055] In certain forms in realization, zinc it is
present in an amount of 0.01 to 10% by weight of the composition. In other embodiments, the amount of zinc is at least 0.1, at least 0.2, at least 0.3, at least 0.4, at least 0.5, at least 1, at least 2, at least at least 3, or at least 4 to 10% by weight of the composition. In other embodiments, the amount of zinc is less than 9, less than 8, less than 7, less than 6, less than 5, less than 4, less than 3, less than 2, less than 1, less than 0 , 5 to 0.05% by weight of the composition. In other embodiments, the amounts are 0.05 to 5%, 0.05 to 4%, 0.05 to 3%, 0.05 to 2%, 0.1 to 5%, 0.1 to 4 %, 0.1 to 3%, 0.1 to 2%, 0.5 to 5%, 0.5 to 4%, 0.5 to 3%, or 0.5 to 2% by weight of the composition.
[0056] In certain embodiments, amino acid halide is present in an amount of 0.05 to 30% by weight. In other embodiments, the amount is
fur minus 0.1, at least 0.2, fur minus 0, 3, fur any less 0.4, at least 0.5 at least 1 at least 2, fur any less 3, at least 4 at least 5, fur minus 10 , fur any less 15, at least 20 to 30% in Weight. In others Forms of
realization, the quantity is less than 30, less than 25, less than 20, less than 15, less than 10, less than 5, less than 4, less than 3, less than 2, or less than 1 up to 0.05% by weight of the composition.
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28/62 [0057] Where material precursors are present, they are preferably present in molar ratios approximately as necessary to produce the desired amino acid zinc halide, although an excess of one material or another may be desirable in certain formulations, for example , to balance the pH against the other constituents of the formulation, to provide additional antibacterial zinc, or to provide amino acid buffer. Preferably, however, the amount of the halide is limited, thereby restricting the level of the halide which both stimulates the interaction between zinc and the amino acid.
[0058] 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.
[0059] In certain embodiments, a molar ratio of zinc to amino acid is at least 2: 1. In other embodiments, the molar ratio is at least 1: 1,
at least, 1: 2, at least 1: 3, at least 1: 4, 2: 1 The 1: 4, 1: 1 to 1: 4, 1: 2 to 1: 4, 1: 3 to 1: 4.2: 1 to 1: 3.2 : 1 The 1: 2.2 : 1 to 1: 1, or 1: 3. Above 1: 4, is expected what O
zinc will be completely dissolved.
[0060] In certain embodiments, the composition is
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Anhydrous 29/62. Per anhydrous, there is less than 5% by weight of water, optionally less than 4, less than 3, less than 2, less than 1, less than 0.5, less than 0.1 to 0% by weight of water .
[0061] When supplied in an anhydrous composition, precursors, for example, TBZC and amino acid hydrohalide, will not react significantly to form the amino acid zinc halide. When put in contact with a sufficient amount of water, which can be in the form of saliva and / or water used to rinse your mouth during or after applying the composition, the precursors will then react to form the amino acid zinc halide, then , after further dilution, will provide the precipitate containing zinc to the teeth.
[0062] The vehicle represents all other materials in the composition other than the amino acid zinc halide complex or its precursors. The amount of the vehicle is then the amount to reach 100%, adding to the weight of the amino acid zinc halide, including any precursors.
[0063] 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 the TMG zinc - 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
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30/62 with water upon use, while a mouthwash will typically not be. Thus, an effective concentration of active ingredient in a toothpaste will normally be 5 to 15x greater than that needed 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 a salt, the counterion will affect the weight of the salt, so that if counterion is heavier, more salt by weight will be needed to provide the same concentration of salt. active ion 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
2000 ppm for a consumer toothpaste, or about 2000 to about 25,000 ppm for 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.
[0064] Fluoride ion source: Oral care compositions may also include one or more sources of fluoride ions, for example, soluble fluoride salts. An
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31/62 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 fluoride ions, generally at least about 500 ppm, for example, about 500 to about 2000 ppm, for example, about 1000 to about 1600 ppm, for example, about 1450 ppm. The appropriate level of fluoride will depend on the particular application. A consumer toothpaste in general would typically have about 1000 to about 1500 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 from
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32/62 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 of about from 0.1% by weight to about 1% by weight, of the composition in another embodiment. The weights of fluoride salts to provide The appropriate level of fluoride ion will, of course, vary according to the weight of the salt counterion.
[0065]
Amino acids: In some embodiments, the compositions of the invention comprise an amino acid. In particular embodiments, the amino acid can be a basic amino acid. By basic amino acid means the naturally occurring basic amino acids, such as
arginine, lysine and histidine as well how any amino acid basic having one carboxyl group and a group amino na molecule, what is soluble in water and provides a solution watery with one about pH in 7 or higher.
Consequently, basic amino acids include, but are not limited to, arginine, lysine, citrulline, ornithine, creatine, histidine, diaminobutanoic acid, diaminoproprionic acid, their salts or combinations thereof. In a particular embodiment, the basic amino acids are selected from arginine, citrulline, and ornithine. In certain embodiments, the basic amino acid is arginine, for example, 1-arginine, or a salt thereof.
[0066] In various embodiments, the amino acid is present in an amount of about 0.5 by weight to about 20% by weight of the total weight of the composition, about
0.5% by weight to about 10% of the total weight of the composition,
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33/62 for example about 1.5% by weight, about 3.75% by weight, 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.
[0067] Foaming agents: The oral care compositions of the invention can also include an agent to increase 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 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
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34/62 foam 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% by weight, and in another about 0.1 to about 0.2% by weight.
[0068] 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 (CH2) mCH2 (OCH2CH2) 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 (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. [0069] By higher alkyl is meant, for example,
C6-30 alkyl. In particular embodiments, the
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35/62 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 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. Sodium lauryl sulfate, sodium lauroyl sarcosinate and sulfonates
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36/62 sodium coconut monoglycerides 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.
[0070] The surfactant or mixtures of compatible surfactants may be present in the
compositions of the present invention in fence in 0.1% about in 5.0%, in another embodiment fence in 0.3% about in 3.0% and in another embodiment fence in 0.5% about in 2.0% per weight of the total composition. [0071]Control agents Tartarus : In various
Embodiments of the present invention, the compositions comprise an anti-calculating agent (tartar control). Suitable anticalculation agents include, but are not limited to, phosphates and polyphosphates (e.g., pyrophosphates), polyaminopropanesulfonic acid (AMPS), hexametaphosphate salts, zinc citrate trihydrate, polypeptides, polyolefin sulfonates, 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, hexametaphosphate
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37/62 sodium. 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 are supplied in an amount effective to reduce enamel erosion, to assist in cleaning teeth, and / or to reduce the accumulation of tartar on the teeth, for example, in an amount of 2 to 20%, for example, about 5 to 15% by weight of the composition.
[0072] 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.
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38/62
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.
[0073]
Polymers: The oral care compositions of the invention may also include additional polymers to adjust the viscosity of the formulation or to 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 supplied in the form of free acids or partially or completely neutralized water-soluble alkali metal salts (for example, potassium and sodium) or ammonium.
[0074]
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,
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39/62 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.
[0075] 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 copolymers of anhydride or maleic acid 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. Others
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40/62 operative polymers include those such as copolymers 1:
maleic anhydride 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 from copolymers of acrylic acid 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, sorbic, alpha-chlorsorbic, cinnamic, beta-styrylacrylic, muconic, itaconic, citraconic, mesaconic, glutaconic, aconitic, alpha-phenyl, aconitic, alpha-phenyl, phenolic , 2-benzyl acrylic, 2-cyclohexylacrylic, angelic, umbelic, fumaric, maleic and anhydrides. 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
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41/62 homopolymers of unsaturated sulfonic acids and their salts, in particular, where the polymers are based on unsaturated sulfonic acids selected from sulfonic acrylamidoalkane acids such as 2acrylamide 2 methylpropane sulfonic acid 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.
[0076] 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.
[0077] 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%
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42/62 about 30% with 5% or less of other humectants.
[0078] 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.
[0079] 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%.
[0080] Unless otherwise specifically 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.
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[0081] 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.
[0082] 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.
[0083] Unless otherwise stated, all 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 [0084] The general reaction for the formation of ZLC is as follows:
ZnO + 2 (Lysine ^ HCl) -> [Zn (Lysine) 2Cl] Cl * 2H2O (ZLC)
A suspension molar ratio of 2: 1 of ZnO: Lysine <HCl is prepared with stirring at room temperature for about
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44/62 of 12 hours. The mixture is centrifuged. 1 ml of the supernatant is transferred to an NMR tube. The NMR tube is then placed in a closed test tube, filled with ethanol during the growth of the crystal. A number of colorless cubic crystals are formed after one week. The crystal structure of the ZLC crystal is determined by single crystal X-ray diffraction. The dimension of this complex molecule is 1.7nm * 7.8nm * 4.3nm. In this complex, the Zn cation is coordinated by two lysine ligands with two N atoms of the NH2 groups and O atoms of the carboxylic groups in an equatorial plane. It exhibits a distorted square pyramid geometry with the apical position occupied by a Cl atom. This new structure gives rise to a portion of positive cation, for which a Cl anion is combined to form an ionic salt.
[0085] Laboratory scale-up synthesis of pure ZLC powder: 2 moles of LisinaHCl are dissolved in 1000 ml of DI water, with stirring at room temperature, 1 mol of solid ZnO is added slowly to the LisinaHCl solution with stirring and stirring is continued overnight at RT (about 12 hours). The suspension solution is centrifuged at high speed for 15 min. The supernatant is slowly poured into EtOH. A precipitate is formed immediately. Approximately 5 to 8 ml of EtOH is required to obtain 1 g of the powder. The powdered EtOH solvent is filtered, and an off-white powder is obtained. The powder is placed in an oven at 50 ° C during drying and a yield of 88% of the product is obtained. PXRD confirms the purity of the ZLC powder compared to ZLC crystal.
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45/62 [0086] The ZLC powder can also be obtained by spray drying a ZLC solution.
Example 2 [0087] Four batches of 500 g of mouthwash containing
NaF, ZLC, ZnCl2 and ZnO as an active ingredient are formulated with the ingredients shown in Table 1. The purpose of this study is to compare the clarity of samples with different active ingredients. Turbidity is assessed by the percentage of light transmission through the solution, as measured by a TurbiScan® dispersion stability analyzer. The higher the percentage of transmission, the more transparent the composition. Thus, a lower percentage of transmission suggests that the solution is more cloudy. The concentration of zinc ions in a ZLC solution is 25,300 ppm, obtained by analysis of ICP (inductively coupled plasma), which corresponds to a weight of approximately 17% by weight of ZLC active ingredients in the solution. Concentration of zinc ions in all batches is controlled to the same level, that is, 1.01% by weight. Among the four batches, what has ZnO as active appears white milk, with 0% transmission, while the other three samples are as clear as deionized water (Table 2).
Table 1
Mouthwash with NaFIngredients O,% Load (g) Real(g)Sorbitol 70% sun. 5.50% 27.5 27.51Sodium fluoride 0.05% 0.25 0.25
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Na saccharin 0.02% 0.1 0.1Propylene glycol 7.00% 35 35Poloxomer 407 0.40% 2 2.01Citric acid 0.02% 0.1 0.1Potassium sorbitol 0.05% 0.25 0.25Glycerin 7.50% 37.5 37.5Peppermint aroma 0.10% 0.5 0.5Deionized water 79.3600% 396.8 396.8Total 100% 500 500.02
Mouthwash with ZnCl2Ingredients O,% Load (g) Real(g)Sorbitol 70% sun. 5.50% 27.5 27.5ZnCl2 47.97% Zn 2.11% 10.55 10.56Na saccharin 0.02% 0.1 0.1Propylene glycol 7.00% 35 34.98Poloxomer 407 0.40% 2 2Citric acid 0.02% 0.1 0.1Potassium sorbitol 0.05% 0.25 0.25Glycerin 7.50% 37.5 37.48Peppermint aroma 0.10% 0.5 0.48Deionized water 77,300% 386.5 386.88Total 100% 500 500.33Zn% 1.01%
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Mouthwash with ZnOIngredients O,% Load (g) Real(g)Sorbitol 70% sun. 5.50% 27.5 27.55ZnO 80.34% Zn 1.26% 6.3 6.28Na saccharin 0.02% 0.1 0.1Propylene glycol 7.00% 35 34.98Poloxomer 407 0.40% 2 2.02Citric acid 0.02% 0.1 0.1Potassium sorbitol 0.05% 0.25 0.25Glycerin 7.50% 37.5 37.52Peppermint aroma 0.10% 0.5 0.52Deionized water 78.1500% 390.75 390.62Total 100% 500 499.94Zn% 1.01%
Mouthwash with ZLCIngredients O,% Load (g) Real(g)Sorbitol 70% sun. 5.50% 27.5 27.49ZLC 2.53% Zn 40.00% 200 200Na saccharin 0.02% 0.1 0.1Propylene glycol 7.00% 35 35.01Poloxomer 407 0.40% 2 2Citric acid 0.02% 0.1 0.1
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Potassium sorbitol 0.05% 0.25 0.25Glycerin 7.50% 37.5% 37.5%Peppermint aroma 0.10% 0.5 0.5Deionized water 39.4100% 197.05 196.98Total 100% 500 499.93Zn% 1.01%
Table 2
DI water PM Naf PM ZLC PM Zn Cl2 PM ZnO pH 5.89 4.79 7.18 3.49 7.03 Turbidity (% 88.68% 88.40% 86.23% 89.03% 0.0016% instreaming)
[0088] Dilution experiment: All batches of original mouthwashes are diluted 2 times, 4 times, 8 times, 16 times and 32 times. Turbidity measurements were performed after all solutions are prepared and well stirred. The turbidity data of the samples are shown in Table 3, 4, 5 and 6, for the mouthwash dilutions containing NaF, ZLC, ZnCl2 and ZnO respectively. Precipitation is observed as the ZLC mouthwash sample is diluted, but the turbidity of the other samples is unchanged.
Table 3
2x 4x 8x 16x 32x Turbidity (% 89.85% 88.90% 88.44% 88.77% 88.61% instreaming)
Table 4
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2x 4x 8x 16x 32x pH 7.46 7.67 7.86 7.80 7.94 Turbidity (% 86.73% 85.99% 60.50% 59.61% 23.21% instreaming)
Table 5
2x 4x 8x 16x 32x Turbidity (% 88.63% 88.04% 87.77% 87.42% 87.99% instreaming)
Table 6
2x 4x 8x 16x 32x Turbidity (% ofstreaming) 0% 0% 0% 0% 0%
[0089] Aging experiment: The diluted ZLC mouthwash samples are placed in an oven at 37 ° C over the weekend (about 60 hours) for a stability study. The results are shown in Table 7. Precipitation can be observed starting from a 4-fold dilution. The greatest amount of precipitation is in a 16-fold dilution. The original batch, however, is still stable and shows no precipitation, even though it is allowed to age for 60 hours.
Table 7
0x 2x 4x 8x 16x 32x pH 7.16 7.48 7.65 7.82 7.85 7.95 Turbidity (% 86.16% 86.15% 8.33% 6.37% 0.14% 9.91% in streaming)
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50/62 [0090] Compared to the mouthwash lots formulated using ZnCl2 and ZnO, only the formulation with ZLC as active can form a clear, stable solution, but generate the precipitate when diluted. This ZLC mouthwash formulation has a neutral pH and is stable at 37 ° C. The ZLC provides a mouthwash formulation that is stable on the shelf but precipitates in the diluted solution. This formation of insoluble precipitate by dilution allows the formation of plugs in dentin tubules, providing benefits for hypersensitivity.
Example 3 [0091] The oral mouthwash formulation from the previous example using ZLC as an active ingredient not only shows the competitive clarity of a commercial mouthwash product with what contains NaF as an active ingredient, but also has the ability to precipitate when diluted with water. This unique property facilitates anti-sensitive and anti-cavity effects, and it is therefore of interest to employ ZLC in a toothpaste product.
[0092] An oral gel toothpaste with ZLC as an active ingredient is formulated and compared with other formulations containing ZnCl2, ZnO, and NaF. Only the ZLC formulation shows competitive clarity as a current gel phase containing NaF. The ZLC gel phase precipitation property is also investigated by the hydrolysis reaction study, providing evidence that when teeth are being brushed with toothpaste containing ZLC assets, the insoluble particles formed during brushing
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51/62 can penetrate the dentin tubules and block the tubules resulting in an anti-sensitive and signal effect for the consumer.
[0093] Four 500.0 g gel phase batches containing NaF (control), ZLC, ZnCl2 and ZnO as an active ingredient are formulated with the ingredients shown in Table 8. The clarity of the samples with different active ingredients is compared, and the precipitation characteristic of the ZLC gel phase is assessed by dilution. The concentration of zinc ions in the ZLC solution is 25300 ppm obtained by ICP, which in terms of weight gives about 17% of active ZLC ingredients in the solution. Concentration of zinc ions in the following batches are all prepared at a zinc level of 0.5% (w / w).
Table 8
Oral gel with ZLC (2.53% Zn)Ingredients O,% Charge(g) Real(g)Sorbitol 70% sun. 76.03% 380.15 380.142.53% ZLC aqueous solutionfrom Zn 20.00% 100 100Carboxymethyl cellulose (CMC),trimethyl cellulose (TMC) 0.70% 3.5 3.51Na saccharin 0.27% 1.35 1.35Propylene glycol 3.00% 15 15Total 100.00% 500 500% of Zn 0.50%0.5060%
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Oral gel with ZnCl2 (47.97% Zn)Ingredients O,% Charge(g) Real(g)Sorbitol 70% sun. 80.00% 400 399.99ZnCl2 47.97% Zn 1.06% 5.275 5.27CMC TMC 0.70% 3.5 3.5Na saccharin 0.27% 1.35 1.35Propylene glycol 3.00% 15 14.98DI water 14.98% 74,875 74.91Total 100.00% 500 500% of Zn 0.508%0.5056%
Oral gel with ZnO (80.34% Zn)Ingredients O,% Load (g) Real(g)Sorbitol 70% sun. 80.20% 401 400.99ZnO 80.34% Zn 0.63% 3.15 3.15CMC TMC 0.70% 3.5 3.5Na saccharin 0.27% 1.35 1.35Propylene glycol 3.00% 15 15DI water 15.20% 76 75.99Total 100.00% 500 499.98% of Zn 0.50%0.5062%
Oral gel with NaF
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Ingredients % Load (g) Actual (g)Sorbitol 70% sun. 80.20% 401 401In F 0.76% 3.8 3.79CMC TMC 0.70% 3.5 3.51Na saccharin 0.27% 1.35 1.35Propylene glycol 3.00% 15.01 15.01DI water 15.07% 75.35 75.36Total 100.00% 500 500.02
[0094] Lambda 25 UV / VIS spectrometer (Perkin Elmer) is used to obtain absorbance information for all samples in order to compare the clarity of the gel phase between the different assets. Absorbance is a logarithmic measure of the amount of light that is absorbed when it passes through a substance. Since the particles of the gel absorb light, the more particles in the solution, the greater the light absorbed by the gel. Thus, a small number of absorbances of a gel indicates greater clarity. The absorbance is corrected using deionized water (DI) as the blank solution under the 610nm wavelength light source. ZnO is not dissolved and is suspended in a gel phase resulting in a high absorbance. Although ZnCl2 is soluble in water, the gel phase that contains ZnCl2 appears cloudy. Only the gel phase formulated by ZLC forms a homogeneous solution and shows competitive clarity as the gel phase formulated by NaF. The absorbance and pH of all samples are shown in Table 9.
Table 9
In F ZLC ZnCl2 ZnO
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Absorbance 0.0344 0.1765 0.9204 2.4626 PH 7.63 7.37 5.25 8.30
[0095] Dilution experiment: All original gel phase batches are diluted 2 times, 4 times, 8 times, 16 times and 32 times. There is a decrease in absorbance when the NaF gel, ZnCl2 gel, and ZnO gel are more diluted, and an increase in absorbance in the more diluted ZLC gel solution. This observation confirms the formation of a precipitate when ZLC gel is being diluted with water. The pHs of 2 times, 4 times, 8 times, 16 times and 32 times of diluted ZLC gel solution are 7.71, 7.91, 8.03, 8.12, and 8.14, respectively.
Table 10
Ingredient Dilution Dilution Dilution Dilution Dilution active 2 times 4 times 8 times 16 times 32 times In F 0.0106 0.0104 0.0107 0.0075 0.0137 ZLC 0.1436 0.1887 0.1860 0.1335 0.2998 ZnCl2 0.7315 0.3700 0.1701 0.0570 0.0280 ZnO 2.4630 2.5340 2.1883 1.8638 1.0492
[0096] The above gels can be used alone or in a toothpaste that has a gel phase and an abrasive paste phase. ZLC as an active ingredient in the gel phase of the toothpaste formulation. Compared to the gel phase batches formulated by ZnCl2 and ZnO, only the formulation with ZLC as an active shows competitive clarity and pH as used in the commercial product (NaF as an active ingredient). The dilution experiment shows that the single phase of ZLC gel can form insoluble precipitate of transparent gel when it is diluted. The formation of a
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55/62 diluted insoluble precipitate facilitates the formation of plugs in dentin tubules after using this type of toothpaste, and in addition, it provides a white precipitate signal during consumer use.
Example 4 [0097] Dentin occlusion by an oral gel with ZLC is measured in comparison with an oral gel without ZLC for the potential benefit of anti-hypersensitivity. A Flodec instrument is used to measure the flow of fluid through the dentin tubules. A Pashley cell method (eg, Pashley DH, O'Meara JA Kepler EE, et al Dentin permeability effects of in vitro desensitizing toothpastes. J Periodontol. 1984; 55 (9): 522-525) is used following a procedure used to measure dentin occlusion in S. Mello mouthwash formulations. Two 10 minute treatments of 400 pl sample are applied with a pipette on dentin discs at 10 minute intervals. After each treatment, the disks are washed with phosphate buffered saline (PBS) and measured by flow using a FLODEC device, a device that tracks the position of a meniscus inside a capillary tube to measure small changes in volume. Table 11 shows the average flow of the oral gel with ZLC and percent flow reduction after application of the sample.
Table 11
Aging flow (pl / min) of oral gel with ZLC % reductionflowLine of Treatment Difference (from
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base n ° 2baseline) Rep No. 1 7.51 3.47 4.05 53.87 Rep No. 1 13.02 7.20 5.82 44.68 Rep No. 1 25.74 19.79 5.95 23.13 Average 40.56 Dev. 15.78 pattern
As shown above, the average percentage reduction in oral gel flow with ZLC triplicates is about 41% through dentin tubules.
[0098] Table 12 shows the average flow of oral gel without ZLC (control) and percent flow reduction after sample application.
Table 12
Average flow (pl / min) of oral gel without ZLC(control) % reductionflowLine ofbase Treatmentn ° 2 Difference (frombaseline) Rep No. 1 7.25 5.02 2.23 30.85 Rep No. 1 13.94 8.43 5.51 39.57 Rep No. 1 22.84 17.93 4.91 21.53 Average 30.65 Dev.pattern 9.02
As shown above, the average percentage reduction of oral gel flow with triplicates without ZLC (control) is about 31% through dentin tubules.
[0099] The oral gel with ZLC shows directionally better performance, compared to the oral gel without ZLC (control)
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57/62 in an in vitro hydraulic conductance model using a FLODEC device.
Example 5 [00100] Various dilutions of ZLC are prepared to evaluate their efficiency in producing visible precipitates and / or flocculation, which can be released in situ on an oral surface or in a dental opening, such as open tubules.
[00101] A pure solution of ZLC is prepared by 1), reacting 0.5 moles of powdered ZnO with 1 mole of lysine HCl in 1 liter of water at room temperature for about 2 hours, and 2) collecting the supernatant by means of centrifugation followed by filtration through a 0.45 micron membrane. The pure solution has a zinc concentration of 2.39% by weight, and a pH of about 7.03.
[00102] Dilution experiment is conducted by mixing the pure solution with deionized water. The pure solution is diluted by 2x, 4x, 6x, 7x, 8x, 10x, 12x, 16x, 20x, 24x, 28x, 32x and, corresponding to initial zinc concentrations of 1.20%, 0.598%, 0.398%, 0.341 %, 0.299%, 0.239%, 0.199%, 0.149%, 0.120%, 0.0996%, 0.0854%, 0.0747% by weight, respectively. Diluted samples are maintained at 37 ° C, and the rates at which flocculation / precipitation occurred are monitored. Dilutions with initial concentrations of zinc at 0.149% and 0.199% and is capable of generating some visible flocculation within 30 minutes from the point in time when the stock solution is mixed with water. One hour of mixing, visible flocculation is observed in dilutions with initial zinc concentrations between
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0.0854% and 0.239%. One and a half hours after mixing, visible flocculation is observed at dilutions with initial zinc concentrations between 0.0747% and 0.239%. Two hours after mixing, the additional sample with the initial zinc concentration of 0.299% also showed the presence of flocculation. After a total of 19 hours, flocculation and / or precipitation can be observed in all samples except those with an initial zinc concentration of 1.20%, and those with initial zinc concentrations between 0.0747% and 0.239 %, exhibit the majority of precipitates.
[00103] pH values of final diluted samples are suitable for oral care applications. Samples with initial zinc concentrations of 0.0747%, 0.0854%, 0.0996%, 0.120%, 0.149%, 0.199% and 0.239% by weight had a final pH value of 7.99, 8.13 , 8.11, 7.97, 7.99, 6.80, and 6.70, respectively. These pH values were well within the range of 5.5 to 10, which defines the appropriate range for oral care formulations.
[00104] Zinc is present in the precipitates mainly in the form of zinc oxide. Lysine is present in the precipitate as an integral component of it and / or as an impurity.
Example 6 [00105] Confocal images demonstrate the efficiency of ZLC in generating a surface of deposits and occlusion of tubule openings on the dentin surface, under conditions in which visible precipitation can be formed.
[00106] The deposition / occlusion test is conducted using slices of human dentin and the pure solution of Example
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5. The dentin slices were prepared by cutting human teeth into thin sections of dentin about 800 microns thick, choosing a test side, sanding said test side using sandpaper of about 600 grit, polishing the said test side using a Buehler polishing cloth and 5 micron Buehler aluminum oxide, acid conditioning of said section of dentin in 1% (by weight) of citric acid solution for about 20 seconds, sonication of said section of dentin for 10 minutes, and store that section of dentin in phosphate buffered saline (PBS, pH 7.4).
[00107] For the treatment, the pure solution is diluted 16 times with water, obtaining a treatment solution with an initial zinc concentration of about 0.149% by weight.
The dentin section is immersed in the treatment solution for 1 hour at 37 ° C. The treated dentin section is then removed from the treatment solution, and washed 4 times, each time with 1 ml of PBS. The dentin section is then dried using a paper-based tissue and examined under a confocal microscope in both XYZ and XYZ modes. Subsequent treatments are carried out in the same way.
[00108]
Progressive deposition and occlusion can be seen through confocal imaging.
first treatment leads to noticeable deposition.
The second treatment leads to complete coverage of the surface, including blocking substantially all of the tubule openings. Surface deposits can be 10 microns or more in thickness. After the third treatment, complete coverage of the surface and complete blockage of
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openings From tubules is observed. The deposits gives surface can be of 25 micron or more than thickness. The deposits confer a color white for surface in
dentin.
[00109] Surface deposits provide several benefits, including those normally associated with zinc and lysine, as well as protection against erosion through neutralization of erosive acids by deposits, protection from sensitivity by blocking the tubules and controlled release of active ingredients , due to the gradual release of zinc and lysine from the deposits,
particularly after acid challenge. Example 7[00110] Images confocal show The efficiency in ZLC on generation in surface deposits and occlusion in openings of tubules on the surface gives dentin, under
conditions where visible precipitation is not observed.
[00111] Dentin sections, as prepared in Example 6, are treated repeatedly with dilutions of ZLC with the initial zinc concentration of 0.0747% by weight. Each treatment involved 32 ml of diluted solution (1 ml of a pure solution of Example 5 and 31 ml of deionized water) and lasts for 10 minutes at 37 ° C, during which time no precipitation is observed with the naked eye. The dentin section is examined under the confocal microscope after each treatment. After four consecutive treatments, significant surface deposition is observed. After 12 consecutive treatments, complete coverage of the surface is observed leaving no sign of
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[00112] In this way, surface deposition and tubule occlusion can occur under conditions, both in terms of dilution ratios and treatment durations, which do not produce visible precipitation.
Example 8 [00113] Test toothpaste comprising zincolysin, 1450 ppm fluoride, and phosphates is prepared as follows:
Table 13
Ingredient % by weight PEG600 3.0 CMC-7 0.65 Xanthan 0.2 Sorbitol 27.0 Glycerin 20.0 Saccharin 0.3 Tetrasodium pyrophosphate 0.5 Calcium pyrophosphate 0.25 Dibasic sodium phosphate 3.5 Sodium fluoride (to provide1450ppm fluoride) 0.32 Titanium dioxide 0.5 Abrasive silica 8.0 Thickener silica 8.0 ZLC 7.0 Sodium lauryl sulfate 1.5 Flavoring 1.2
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Water QS
[00114] 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. This 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 (4)
[1]
1. Mouthwash, characterized by the fact that it comprises a soluble amino acid zinc halide complex, in which zinc is solubilized in the formulation, but provides a zinc precipitate when used and diluted with saliva and / or rinse.
[2]
2. Mouthwash according to claim 1, characterized by the fact that the amino acid zinc halide complex is formed from precursors, optionally in which the precursors are a source of zinc ion, a source of amino acid, and a source of halide , optionally wherein the halide source may be part of the zinc ion source, the amino acid source, or a halogen acid.
[3]
3. Mouthwash according to claim 1 or 2, characterized by the fact that the amino acid is a basic amino acid, in the free form or in an orally acceptable salt, or in
that the amino acid is selected from lysine, glycine, and arginine, in the form free or salt addition orally acceptable. 4. Mouthwash, in a deal with any one of claims 1 to 3, featured by the fact that The amount of zinc it's from 0.05% to 4% in Weight.5. Mouthwash, in a deal with any one of claims 1 to 4, featured by the fact that O complex is a complex chloride zinc lis ina or one chloride complex ten inco arginine. 6. Mouthwash, in a deal with any one of claims 1 to 5, featured by the fact that O halide complex in amino acid zinc is a complex in
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2/4 lysine zinc chloride having the chemical structure [Zn (C6Hi4N2O2) 2Cl] ⁺ Cl ^- , either in cationic cation solution ([Zn (C6Hi4N2O2) 2Cl] ⁺ ) and the chloride anion, or in the form of a solid salt, optionally in mono- or dihydrate form.
Mouthwash according to any one of claims 1 to 6, characterized in that it further comprises an effective amount of a fluoride ion source.
Mouthwash according to any one of claims 1 to 7, characterized by the fact that it comprises an orally acceptable base comprising ingredients selected from one or more buffering agents, humectants, surfactants, thickening agents, cooling breath, flavorings, fragrances, colorants, antibacterial agents, bleaching agents, agents that interfere with or prevent bacterial fixation, calcium sources, phosphate sources, orally acceptable potassium salts, and anionic polymers.
Mouthwash according to any one of claims 1 to
8, characterized by the fact that it also comprises cocamidopropyl betaine.
10. Mouthwash according to any one of claims 1 to 9, characterized by the fact that the pH of the mouthwash is from pH 4 to pH 8.
11. Mouthwash according to any one of claims 1 to
10, characterized by the fact that the amino acid is lysine such that zinc and lysine form a zinc chloride-lysine complex having the structure
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3/4 chemical [Zn (C6Hi4N2O2) 2Cl] ⁺ Cl, in an amount sufficient to supply 0.5 to 2% by weight of zinc to the mouthwash, the mouthwash further comprising humectant in a
amount of 10 at 25% by weight, non-ionic surfactant in a quantity of 0.1 to 1% in weight, and sweetener, flavorings, and Water. 12. Mouthwash, from wake up with any one of
claims 1 to 11, characterized by the fact that it is for use to reduce and inhibit acid erosion of the enamel, clean the teeth, reduce plaque and biofilm generated by bacteria, reduce gingivitis, inhibit tooth decay and the formation of cavities, and / or reduce dentin hypersensitivity.
Mouthwash according to any one of claims 1 to 12, characterized in that the weight ratio of the amino acid zinc halide to water is from about 1: 6 to about 1: 1.
14. Use of an amino acid zinc halide complex,
characterized by fact in be for the manufacture of one mouthwash. 15. Use, of wake up with the claim 14, characterized by fact in be for preparation of one
mouthwash as defined in any one of claims 1 to 13, for treatment or reduction of dental enamel erosion by cleaning teeth, reducing bio-film and plaque generated by bacteria, reducing gingivitis, inhibiting tooth decay and the formation of cavities and / or reduction of dentin hypersensitivity, which includes the application of mouthwash to teeth, optionally in which
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[4]
4/4 still comprises the step of rinsing with water or sufficient aqueous solution to promote precipitation of zinc oxide from the mouthwash.

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法律状态:
2018-10-09| B15K| Others concerning applications: alteration of classification|Free format text: AS CLASSIFICACOES ANTERIORES ERAM: A61K 8/27 , A61K 8/44 , A61Q 11/00 Ipc: A61K 8/27 (2006.01), A61K 8/44 (2006.01), A61K 8/2 |

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2018-10-09| B06A| Notification to applicant to reply to the report for non-patentability or inadequacy of the application according art. 36 industrial patent law|

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2019-03-19| B09A| Decision: intention to grant|

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2019-05-14| 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:

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申请号 | 申请日 | 专利标题

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PCT/US2012/070506|WO2014098822A1|2012-12-19|2012-12-19|Zinc amino acid halide mouthwashes|

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