Understanding an amino acid halide complex and use of a zinc ion source together with an amino acid

专利摘要:
Summary oral gel comprising zinc-amino acid complex The present invention relates to dentifrices comprising an amino acid and zinc halide, which provide a zinc oxide precipitate upon use with dilution with water and / or saliva. methods of preparation and use of toothpastes.
公开号:BR112015014900B1
申请号:R112015014900-6
申请日:2012-12-19
公开日:2019-05-14
发明作者:Long Pan；Shaotang Yuan；Vyoma Patel；Shira Pilch；James G. Masters；Zhiqiang Liu
申请人:Colgate-Palmolive Company；
IPC主号:

专利说明:

DENTIFRICE UNDERSTANDING AN AMINO ACIDZINK HALIDE COMPLEX AND USE OF A ZINC ION SOURCE WITH AN AMINO ACID
Background [001] Dental erosion involves demineralization and damage to the tooth structure due to acid attack from non-bacterial sources. Erosion is found initially in the enamel and, if left unchecked, can proceed to the underlying 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 that 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. In general, 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 rough, spongy surface. . 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 acute local toothache in response to physical stimulation of the dentin surface, as by thermal osmotic tactile combination
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2/58 (hot or cold) of tactile, osmotic and thermal stimulus of the exposed dentin. Dentin exposure, which is usually due to gum recession, or loss of enamel, often leads to hypersensitivity. Dentin tubules open to the surface have a high correlation with dentin hypersensitivity. Dentinal tubules originate from the pulp to the cement. When the cement on the tooth root surface is corroded, the dentinal tubules are exposed to the external environment. The exposed dentinal tubules provide a path for the transmission of fluid flow to the pulp nerves, the transmission is induced by variations in temperature, pressure and ionic gradients.
[003] Heavy metal ions, such as zinc, are resistant to acid attack. The zinc rows are above hydrogen in the electrochemical series, so the metallic zinc in an acidic solution will react to release the hydrogen gas as the zinc passes through the solution to form dications, 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 dentifrice compositions, see, for example, U.S. Patent No. 6,121,315, but have several disadvantages. The zinc ions in the solution give an unpleasant astringent mouth feel, so formulations that provide effective levels of zinc and also have acceptable organoleptic properties were difficult to obtain. Finally, zinc ions will react with anionic surfactants, such as sodium lauryl sulfate, thereby interfering with foaming and cleaning. Zinc oxide and insoluble zinc salts, on the other
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3/58, they can do a bad job of distributing zinc to the teeth due to its insolubility.
[005] Although the prior art describes the use of several oral compositions for the treatment of dentin hypersensitivity, dental caries and enamel erosion and demineralization, there is still a need for additional compositions and methods that provide improved performance in such treatments.
Summary [006] It has recently been discovered that zinc ions 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 can form a salt with a halide or another anion. When placed in the formulation, this complex provides an effective concentration of zinc ions to the enamel, thus protecting against erosion, reducing bacterial colonization and the development of biofilm and providing enhanced shine to the teeth. In addition, upon use, the formulation provides a precipitate that can cover dentinal tubules, thereby reducing tooth sensitivity. Although it provides efficient distribution of zinc compared to formulations with insoluble zinc salts, formulations comprising the amino acid-zinc complex do not have a bad taste and sensation in the mouth, poor fluoride distribution, and poor foaming and cleaning, associated with conventional zinc-based oral care products using soluble zinc salts.
[007] In a particular embodiment, the amino acid-zinc complex is a zinc-lysine-HCl complex, for example
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4/58 example, the new complex called ZLC, which can be formed from a mixture of zinc oxide and lysine chloride. ZLC has the chemical structure [Zn (C6H14N2O2) 2Cl]⁺Cl and can exist in cationic cation solution ([Zn (C6H14N2O2) 2Cl]⁺) and the chloride anion, or it can be a solid salt, for example, a crystal, optionally in mono or dihydrate form.
[008] The invention thus provides oral hygiene compositions, for example, mouthwash, oral gel or dentifrice compositions, which make up an amino acid-zinc complex, for example, a lysine-zinc chloride complex, for example, a 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 suitable oral hygiene formulation, 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, flavoring and / or coloring.
[009] In a particular embodiment, the invention provides oral gel compositions, for example, comprising an amino acid-zinc complex, for example, a lysine-zinc chloride complex, for example, ZLC, which are free when formulated, but which provide a zinc oxide precipitate when diluted with water.
[0010] The invention further provides methods of using the compositions of the invention to reduce and inhibit acidic enamel erosion, clean teeth, reduce plaque and bio-film generated by bacteria, reduce gingivitis,
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5/58 inhibiting tooth decay and cavity formation and reducing dentin hypersensitivity, comprising applying a composition of the invention to teeth.
[0011] The invention further provides methods of making the compositions of the invention comprising combining a source of zinc ion (for example, ZnO), an amino acid (for example, a basic amino acid, for example, arginine or lysine) and, optionally, a halide source, for example, combining zinc oxide and lysine hydrochloride in aqueous solution, for example, at a molar ratio of Zn: amino acid from 1: 1 to 1: 3, for example, 1: 2 and Zn : halide where it is present is from 1: 1 to 1: 3, for example, 1: 2; optionally isolating the ionic complex thus formed as a solid; and mixing with an oral gel base.
[0012] Other areas of applicability of the present invention will become apparent from the detailed description provided below. It should be understood that the detailed description and 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 [0013] The following description of the preferred modality (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, an oral gel composition (Composition 1), comprising zinc in the complex with an amino acid; for example:
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1.1. Composition 1, where the amino acid is selected from lysine, glycine and arginine, in the form of a free acid addition orally acceptable salt, for example, the hydrochloride form.
1.2. Composition 1 or 1.1, where the amino acid is a basic amino acid, for example, arginine or lysine, in the form of a free or orally acceptable salt.
1.3. Any of the above compositions further comprises a halide in ionic association with zinc and the amino acid.
1.4. Any of the foregoing compositions, where the molar ratio of Zn: amino acid is 3: 1 to 1: 5, for example, about 1: 2 and the molar ratio of Zn: halide where it is present is 3: 1 to 1: 3, for example, about 1: 2.
1.5. Any of the above compositions, in which the amino acid-zinc complex is formed, in whole or in part, at the site 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, on the spot after1.7. Any of them composition be formulated. of compositions previous, wherein amino acid is lysine. 1.8. Any of them of compositions previous, in what O zinc is present in an amount of 0.05 to 10 % in
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 1-3%, for example, about 2-2.7% by weight.
1.9. Any of the previous compositions, in which the
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7/58 amino acid is present in an amount of 0.05 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 least 2, at least 3, at least 4, at least 5, at least 10, at least 15, at least 20 to 30% by weight, for example, about 1-10% by weight .
1.10. Any of the foregoing compositions, wherein a 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, 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 the amino acid, wherein the halide is selected from the group consisting of fluorine, chlorine and mixtures thereof.
1.12. Any of the foregoing compositions, wherein the amino acid-zinc complex is a lysine-zinc chloride complex (e.g., (ZnLys2Cl) ⁺ Cl ^- or (ZnLys3) ²⁺ Cl2) 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 (C6H14N2O2) 2Cl] ⁺ Cl ^- , or in the cationic cation solution (for example, [Zn (C6H14N2O2) 2Cl] ⁺ ) and the chloride anion, or in the form of a solid salt, for example, crystalline form, optionally in the mono or dihydrate form.
1.14. Any of the above compositions, in the form of a clear gel that provides a precipitated zinc oxide when diluted.
1.15. Any of the previous compositions, in the form
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8/58 of a toothpaste, for example, in which the amino acid-zinc complex is present in an effective amount, for example, in an amount of 0.5-4% by weight of zinc, for example, about 1- 3% by weight of zinc, on a toothpaste base.
1.16. Any of the foregoing compositions, in the form of a toothpaste, wherein the base of the toothpaste comprises an abrasive, for example, an effective amount of a silica abrasive, for example, from 10-30%, for example, about 20%.
1.17. Any of the foregoing compositions, in which the amino acid-zinc complex is present in an effective amount, for example, in an amount of 0.1-3% by weight of zinc, for example, about 0.2-1% by weight of zinc.
1.18. Any of the foregoing compositions, further comprising an effective amount of a fluoride ion source, for example, providing fluoride from 500 to 3000 ppm.
1.19. Any of the foregoing compositions, further comprising an effective amount of fluoride, for example, wherein fluoride is a salt selected from tin fluoride, sodium fluoride, potassium fluoride, sodium monofluorophosphate, sodium fluorosilicate, ammonium fluorosilicate, fluoride amine (eg N'-octadecyltrimethylenediamine-Ν, Ν, Ν'-tris (2-ethanol) -dihydrofluoride), ammonium fluoride, titanium fluoride, hexafluorosulfate and combinations thereof.
1.20. Any of the foregoing compositions, comprising an effective amount of one or more salts of
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9/58 alkaline phosphate, for example, sodium, potassium or calcium salts, for example, selected from alkaline dibasic phosphate and alkaline pyrophosphate salts, for example, alkaline phosphate salts selected from dibasic sodium phosphate, dibasic potassium phosphate, dicalcium phosphate dihydrate, calcium pyrophosphate, tetrasodium pyrophosphate, tetrapotassium pyrophosphate, sodium tripolyphosphate and mixtures of any of the two or more of them, for example, in an amount of 1 to 2 0%, for example 2-8 %, for example, about 5%, by weight of the composition.
1.21. Any of the foregoing compositions, comprising buffering agents, for example, sodium phosphate buffer (for example, monobasic sodium phosphate and disodium phosphate).
1.22. 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, 20-40%, for example , 25-35% glycerin.
1.23. Any of the previous compositions comprising one or more surfactants, for example, selected from anionic, cationic, zwiterionic, and non-ionic surfactants and mixtures thereof, for example, comprising an anionic surfactant, for example, a selected lauryl surfactant sodium sulfate, sodium lauryl sulfate and mixtures thereof, for example, in an amount of about 0.3% to about 4.5% by weight, for example, 1-2% sodium lauryl sulfate
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10/58 (SLS); and / or a zwitterionic surfactant, for example, a betaine surfactant, for example, cocamidopropylbetaine, for example, in an amount of about 0.1% to about 4.5% by weight, for example, 0.5-2 % cocamidopropyl betaine.
1.24. Any of the foregoing compositions, further comprising a viscosity-modifying amount of one or more polysaccharide gums, for example, xanthan or carrageenan gum, thickener silica and combinations thereof.
1.25. Any of the foregoing compositions comprising fragments or strips of gum.
1.26. Anyone further comprising a colorant.
1.27. Any of the foregoing, flavoring, fragrance and / or the foregoing compositions, comprising an effective amount of one or more antibacterial agents, for example, comprising an antibacterial agent selected from diphenyl halogenated ether (eg, triclosan), herbal extracts and essential oils (for example, rosemary extract, tea extract, magnolia extract, thymol, menthol, eucalyptol, geraniol, carvacrol, citral, hinoquitiol, catechol, methyl salicylate, epigallocatechin gallate, epigallocatechin, gallic acid, miswak extract, hawthorn antiseptics (eg chlorhexidine, alexidine or octenidine), quaternary ammonium compounds (eg cetylpyridinium chloride (CPC), benzalkonium chloride, tetra-decylpyridinium chloride (TPC), N-tetradecyl chloride -4-ethylpyridinium (TDEPC)), phenolic antiseptics, hexetidine, octenidine, sanguinarine, povidone iodine,
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11/58 delmopinol, salifluor, metal ions (for example, zinc salts, for example, 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, sarcosine oleoyl, alkyl sulfate, dioctyl sulfosuccinate, salicylanilide, domiphen bromide, delmopinol and other derivatives, octapinol nicine, chloride salts; and mixtures of any of the above; for example, comprising triclosan chloride or cetylpyridinium.
1.28. Any of the above compositions, comprising an effective antibacterial amount of triclosan, for example, 0.1-0.5%, for example, about 0.3%.
1.29. Any of the foregoing compositions, further comprising a bleaching agent, for example, one selected from the group consisting of peroxides, metal chlorites, perborates, percarbonates, peroxyacids, hypochlorites and combinations thereof.
1.30. Any of the foregoing compositions, further comprising hydrogen peroxide or a source of hydrogen peroxide, for example, urea peroxide or a peroxide complex or salt (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);
1.31. Any of the previous compositions,
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12/58 further comprising an agent that interferes with or prevents bacterial attachment, for example, solbrol or chitosan.
1.32. Any of the foregoing compositions, further comprising a source of calcium and phosphate selected from (i) calcium-glass complexes, for example, sodium calcium phosphosilicates and (ii) calcium-protein complexes, for example, casein phosphate amorphous phosphopeptide-calcium.
1.33. Any of the foregoing compositions, further comprising a soluble calcium salt, for example, selected from calcium sulfate, calcium chloride, calcium nitrate, calcium acetate, calcium lactate and combinations thereof.
1.34. Any of the foregoing compositions, further comprising a physiologically or orally acceptable potassium salt, for example, potassium nitrate or potassium chloride, in an amount effective to reduce dentin sensitivity.
1.35. Any of the compositions further comprising an anionic polymer, by synthetic anionic polymeric polycarboxylate, above, for example, one for example, in which the anionic polymer is selected from 1: 4 to 4: 1 copolymers of maleic anhydride or acid with another ethylenically polymerizable monomer unsaturated; for example, in which the anionic polymer is a maleic anhydride / vinyl methyl ether (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 15%, for example, about 2%, of the weight of the composition.
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1.36. Any of the previous compositions, including a flavoring, fragrance and / or breath freshener.
1.37. Any of the above compositions, wherein the pH of the composition is approximately neutral, for example, from pH 6 to pH 8, for example, about pH 7.
1.38. Any of the previous compositions in the form of an oral gel, where the amino acid is lysine and zinc and lysine form a lysine-zinc chloride complex, having the chemical structure [Zn (C ₆ H14N2O2) 2Cl] ⁺ Cl ^- , in an amount to provide 0.1-2%, for example, about 0.5% zinc by weight, and further comprising a humectant, for example, sorbitol, propylene glycol and mixtures thereof, for example, in an amount of 45-65%, for example, about 50-60%, thickeners, for example cellulose derivatives, for example, selected from carboxymethylcellulose (CMC), trimethylcellulose (TMC) and mixtures thereof, for example, in an amount of 0.1-2%, sweetener and / or flavoring and water, for example, an oral gel comprising:
Ingredients % by weight Sorbitol 40-60%, for example, 50-55% ZLC To provide 0.1-2% ZN, for example, about 0.5% Zn Carboxymethylcellulose (CMC) 0.5-1%, for example, about and Trimethylcellulose (TMC) 0.7% Flavoring and / or sweetening 0.01-1% Propylene glycol 1-5%, for example, about3.00%
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1.1. Any of the previous compositions for use to reduce and inhibit acidic enamel erosion, clean teeth, reduce plaque and bio-film generated by bacteria, reduce gingivitis, inhibit tooth decay and cavity formation and reduce dentin hypersensitivity .
[0015] The invention also provides methods to reduce and inhibit acid enamel erosion, clean teeth, reduce plaque and bio-film generated by bacteria, reduce gingivitis, inhibit tooth decay and the formation of cavities and reduce hypersensitivity dentin, comprising applying an effective amount of a composition of the invention, for example, any of Composition 1, et seq. to the teeth and, optionally, rinse with water or sufficient aqueous solution to trigger the precipitation of the zinc oxide of the composition.
[0016] The invention further provides a method of making an oral hygiene composition, comprising an amino acid-zinc complex, for example, any Composition 1, et seq. comprising combining a source of zinc ions with an amino acid, in free or salt form (e.g., combination of zinc oxide with lysine hydrochloride), in an aqueous medium, optionally isolating the complex thus formed as a solid salt , and combining the complex with an oral hygiene base, for example, a toothpaste or mouthwash base.
[0017] For example, in various embodiments, the invention provides methods for (i) reducing tooth hypersensitivity, (ii) reducing plaque build-up, (iii) reducing or inhibiting demineralization and
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15/58 promote the remineralization of teeth, (iv) inhibit the formation of microbial bio-films in the oral cavity, (v) reduce or inhibit gingivitis, (vi) promote the healing of wounds or cuts in the mouth, (vii) reduce levels of acid that produce bacteria, (viii) increase the relative levels of non-plaque / non-cariogenic bacteria, (ix) reduce or inhibit the formation of dental caries, (x) reduce, repair or inhibit pre-carious enamel lesions, for example, detected by quantitative light-induced 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 and / or (xvi) promote systemic health, including cardiovascular health, for example, reducing the potential for systemic infection through oral tissues, including the application of any of Compositions 1, et seq . as described above for the oral cavity of a person in need of them, for example, one or more times a day. The invention further provides Compositions 1, et seq. , for use in any of these methods.
[0018] The invention further provides for the use of zinc and an amino acid to make an oral hygiene composition, comprising an amino acid-zinc complex.
[0019] The invention also provides the use of an amino acid-zinc complex, for example, an amino acid-zinc halide, for example, a lysine-zinc chloride complex, to reduce and inhibit acidic enamel erosion, cleaning teeth, reduce plaque and bio-film generated by bacteria, reduce gingivitis, inhibit the deterioration of
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16/58 tooth and cavity formation and / or reduce dentin hypersensitivity.
[0020] Without wishing to be bound by theory, it is believed that the formation of the amino acid-zinc halide proceeds through the formation of the zinc halide then the coordination of amino acid residues around a central zinc. Using the reaction of ZnO with lysine hydrochloride in water as an example, zinc can react with lysine and / or lysine HCl to form a clear solution of the lysine-zinc 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 carboxylic acids and lysine amine groups, respectively. Zinc is also coordinated with the third lysine through its nitrogen and carboxylic oxygen, at the apical position of the metal geometry.
[0021] In another embodiment, a zinc cation is complex 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 H14N2O2) 2Cl] ⁺ Cl. 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 pyramidal geometry with the apical position occupied by a Cl ^- atom. This new structure gives rise to a positive cation portion, which a Cl ^- anion is combined to form an ionic salt.
[0022] Other zinc and amino acid complexes are possible, and the precise shape depends in part on the molar ratios of the precursor compounds, for example, if any
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17/58 limited halide, free halide complexes can form, for example, ZnOLys2, having a pyramid geometry, with the equatorial plane being the same as the compound above (Zn is linked to two oxygen atoms and two nitrogen atoms) different lysines), where the top of the pyramid is occupied by an O atom.
[0023] Mixtures of additional complexes and / or complex structures, for example, involving multiple 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.
[0024] Regardless of the precise structure of the complex or complexes, however, the interaction of zinc and amino acid converts insoluble zinc oxide or zinc salts to a highly soluble complex at approximately neutral pH. With the increase in water dilution, however, the complex disassociates, and converts the zinc ion to insoluble zinc oxide. This dynamic is unexpected, typically, the ionic compositions become more soluble at greater dilution, not inferior - and this facilitates the deposition of zinc precipitate on the teeth upon administration, in the presence of saliva and with a rinse. This precipitation hides the dentinal tubules, thus reducing hypersensitivity and also provides zinc to the enamel, which reduces acid erosion, the formation of bio-film and plaque.
[0025] It will be understood that other amino acids can be used in place of lysine in the previous scheme. It will also be understood that although zinc, an amino acid and
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18/58 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 that is currently in the complex compared to the proportion in the precursor form may vary depending on precise formulation conditions, concentration of materials, pH, presence or absence of water, presence or absence of other charged molecules, and so on.
[0026]
The assets can be distributed in the form of any oral hygiene formulations, for example, a toothpaste, gel, mouthwash, powder, cream, strip, gum or any other known in the art.
[0027] If the assets are distributed in the form of a mouthwash, a person who wants the benefits rinses with the stock solution and the natural dilution of the stock solution by the saliva will start the zinc precipitation. Alternatively, the person can mix the stock solution with an appropriate amount of an aqueous diluent (such as approximately 1 part of the stock solution and 8 parts of water for the zinc-lysine samples) and rinse with the mixture.
[0028] In another embodiment, the mixture is prepared and immediately transferred to a retention mold, such as those used in making bleaching gels, and the person can use the mold for the effective period of time. Teeth that are in contact with the mixture will be treated. For use with a retention mold, the mixture may be in the form of a low viscosity liquid or gel.
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19/58 [0029] In another embodiment, the stock solution, or a mixture of the stock solution with water, is applied to the teeth in a gel formulation, for example, where the gel can stay on the tooth for a long period of time for effective treatment.
[0030] In another modality, the asset is provided in a toothpaste. After brushing, the asset is diluted by saliva and water, leading to precipitation and the formation of deposits and particle occlusion.
[0031] The rate of precipitation from the formulation can be modulated by adjusting the concentration of the complex in the stock solution, and changing the ratio of stock to water. A more diluted formula leads to rapid precipitation and is therefore preferred when rapid treatment is desired.
[0032] The benefits of the oral hygiene compositions of the invention are numerous. By providing zinc and zinc ions containing compounds that can release zinc ions into the oral cavities, the oral hygiene compositions of the invention provide antimicrobial, anti-plaque, anti-gum, anti-odor, anti-caries and anti-calculus benefits. The occlusion particles and surface deposits are compounds containing zinc (particularly ZnO), as well as other zinc derivatives that can release zinc ions into the oral cavities and provide various benefits, as recognized above. Additional benefits include, but are not limited to, antifixation, antiperiodontitis and bone loss, as well as promoting wound healing.
[0033] A second benefit is the anti-erosion properties of zinc ions, which constitute the deposits
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20/58 anti-erosion on tooth surfaces, through oxidation and hydrolysis. Surface deposits, as well as occlusion particles, can react with and neutralize acids, thus protecting the dental surface from the erosive effects of acids. In this sense, the more depositions / surface occlusions the treatments take, they will be more effective and, therefore, zinc-arginine and zinc-lysine are preferred. It is also observed that when surface deposits and occlusion particles neutralize acids, beneficial zinc ions and amino acids (infra) can be released, providing oral hygiene benefits other than anti-erosion.
[0034] A third benefit is the anti-sensitivity benefit as a result of occlusion. Occlusion of dentinal tubules leads to relief of sensitivity.
[0035] 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 come from multiple benefits. For example, basic amino acids lead to higher pH in the plaque and can provide anti-caries benefits. In addition, it is also expected that arginine can intensify the activity of the arginolytic bacteria, leading to healthier plaque. Arginine is also known to promote wound healing and collagen integrity.
[0036] The composition may include an amino acid-zinc halide and / or its precursors. Precursors, which can react on the site with water to form the amino acid-zinc halide, include (i), zinc and an amino acid
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21/58 halide, or (ii) zinc chloride and amino acid, or (iii) a source of zinc ion, 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. On-site training provides ease of formulation. Precursors can be used instead of first having to form the amino acid and 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 into contact with the composition after application.
[0037] The amino acid-zinc halide is a water-soluble complex formed from the zinc halide acid addition salt (eg, zinc chloride) and an amino acid or the amino acid halide addition salt (eg , lysine hydrochloride) and zinc ion source and / or the combination of all three of a halogen acid, an amino acid and a zinc ion source.
[0038] 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.
[0039] As seen from the examples below, the precipitation of the zinc from the complex after dilution with water is more noticeable, when the complex is formed from a
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22/58 basic amino acid. Thus, when precipitation after dilution 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 is meant 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 about 7 or higher. Consequently, basic amino acids include, but are not limited to, arginine, lysine, citrulline, ornithine, creatine, histidine, diaminobutanoic acid, diaminopropionic acid, salts thereof or combinations thereof. In certain embodiments, the amino acid is lysine. In other embodiments, the amino acid is arginine.
[0040] The halide can be chlorine, bromine or iodine, more typically chlorine. The acid addition salt of an amino acid and a halogen acid (for example, HCl, HBr or HI) is sometimes referred to here as a halide amino acid. Thus an example of a halide acid is lysine hydrochloride. Another is glycine hydrochloride.
[0041] The source of zinc ion for combination with an amino acid halide or an amino acid, optionally more halogen in this case can be, for example, zinc oxide or zinc chloride.
[0042] In certain embodiments, the amount of amino acid-zinc halide in the composition is 0.05 to 10% by weight of the composition. In certain embodiments, the precursors, for example, zinc and halide amino acid, are present in quantities such that when combined in the
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23/58 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 both of these embodiments, the amount of the amino acid-zinc halide can be varied as to the 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 the 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 than 2, less than 1, less than 0.5 to 0.05% by weight of the composition. In other modalities, the quantities are 0.05 to 5%, 0.05 to 4%, 0.05
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 composition. [0043] In certain modalities, O zinc is
present in an amount of 0.05 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 3 , or at least 4 to 10% by weight of the composition. In other modalities, 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
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24/58 to 2%, 0.5 to 5%, 0.5 to 4%, 0.5 to 3%, or 0.5 to 2% by weight of the composition.
[0044] In certain embodiments, the halide acid is present in an amount of 0.05 to 30% by weight. In other embodiments, the amount 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, at least at least 4, at least 5, at least 10, at least 15, at least 20 to 30% by weight. In other modalities, 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 to 0.05% by weight of the composition.
[0045] Where precursor materials are present, they are preferably present in molar ratios approximately as required 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 other constituents of the formulation, to provide additional antibacterial zinc or to provide amino acid buffer. Preferably, however, the amount of halide is limited, since restricting the level of halide in some way stimulates the interaction between zinc and the amino acid.
[0046] 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 to 8% by weight of the
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25/58 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.
[0047] 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 to 1: 4, 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, 2: 1 to 1: 1 or 1: 3. Above 1: 4, zinc is expected to be fully dissolved.
[0048] In certain embodiments, the composition is anhydrous. Per anhydrous, there is less than 5% by weight in 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 in water.
[0049] When provided in an anhydrous composition, precursors, for example, TBZC and halide amino acid, will not react significantly to form the amino acid-zinc halide. When contacted 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 another dilution, will provide the precipitate containing zinc for the teeth.
[0050] The vehicle represents all other materials in the composition other than the amino acid-zinc halide complex or its precursors. The vehicle quantity is then the quantity to reach 100% by adding
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26/58 to the weight of the amino acid-zinc halide, including any precursors.
[0051] Active agents: the compositions of the invention may comprise various agents that are active to protect and enhance the strength and integrity of the enamel and tooth structure and / or to reduce associated bacteria and tooth decay and / or gum disease, including or in addition to the amino acid zinc halide complexes. The effective concentration of the active ingredients used here will depend on the particular agent and delivery system used. It is understood that a toothpaste, for example, will typically be diluted with water through use, while a mouthwash will typically not be. Thus, an effective concentration of active in a toothpaste will ordinarily be 5-15x 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 provided in the form of salt, the counterion will affect the weight of the salt, so that if the counterion is heavier, more salt by weight will be required to provide the same concentration of active ion in the final product. Arginine, where present, can be present at levels of, for example, about 0.1 to about 20% by weight (expressed as the weight of free base), for example, about 1 to about 10% by weight for a consumer toothpaste or about 7 to about 20% by weight for a professional treatment product or prescription. Fluoride where 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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2,000 to about 25,000 ppm for a professional treatment product or prescription. Levels of antibacterial agents will vary similarly with levels used in toothpaste, for example, about 5 to about 15 times higher than used in mouthwash. For example, a triclosan toothpaste can contain about 0.3% by weight of triclosan.
[0052] Fluoride ion source: Oral hygiene compositions may further include one or more fluoride ion sources, for example, soluble fluoride salts. A wide variety of materials that yield fluoride ions can be employed as sources of soluble fluoride in the present compositions. Examples of suitable materials that yield fluoride ions are found in U.S. Patent No. 3,535,421, to Briner et al .; North American Patent No. 4,885,155, to Parran, Jr. et al. and U.S. Patent No. 3,678,154, to Widder et al. Representative fluoride ion sources 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, amine fluorides, sodium monofluorophosphate, as well as mixtures thereof. In certain embodiments, the oral hygiene composition of the invention may also contain a source of fluoride ions or an ingredient that provides fluoride in sufficient quantities to provide about 50 to about 5000 ppm of fluoride ion, for example, from about 100 to about
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1000, from about 200 to about 500, or about 250 ppm of fluoride ion. The appropriate level of fluoride will depend on the particular application. A toothpaste for general consumer use would typically have about 1000 to about 1500 ppm, with pediatric toothpaste having slightly less. A toothpaste or coating for professional application could have 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% and in another embodiment about 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 obviously vary based on the weight of the counterion in the salt.
[0053] Amino acids: In some embodiments, the compositions of the invention still comprise an amino acid. In particular embodiments, the amino acid can be a basic amino acid. By basic amino acid is meant 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 about 7 or higher. Consequently, basic amino acids include, but are not limited to, arginine, lysine, citrulline, ornithine, creatine, histidine, diaminobutanoic acid, diaminopropionic acid, salts thereof or combinations thereof. In a particular modality, the basic amino acids are selected from among
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29/58 arginine, citrulline and ornithine. In certain embodiments, the basic amino acid is arginine, for example, 1-arginine, or a salt thereof.
[0054] 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% in weight of the total weight of the composition, 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 0.5-2% by weight, for example, about 1% in the case of a mouthwash.
[0055] Abrasives: The compositions of the invention, for example, Composition 1 et seq. include silica abrasives 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 phosphate of dicalcium dihydrate (CaHPO4 ^ 2H2O, in the same way 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.
[0056] Other silica abrasive polishing materials useful here, as well as the other abrasives, generally have an average particle size ranging from about 0.1 to about 30 microns, about 5 to about 15 microns. The silica abrasives can be precipitated silica or silica gels, such as
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30/58 silica described in U.S. Patent No. 3,538,230, to Pader et al. and U.S. Patent No. 3,862,307, to Digiulio. Private silica xerogels are marketed under the trademark Syloid® by WR Grace & Co., Davison Chemical Division. Precipitated silica materials include those marketed by JM Huber Corp. under the trademark Zeodent®, including the silica that receives the designation Zeodent 115 and 119. These silica abrasives are described in US Patent No. 4,340,583, to Wason. In certain embodiments, useful abrasive materials in the practice of compositions for oral hygiene according to the invention include silica gels and precipitated silica amorphous having a lower oil absorption value less than about 100 ^cm3 / 100 g silica and range of about 45 cm ^3/100 g to about 70 ^cm3 / 100 g silica. Oil absorption values are measured using the ASTA D281 rub-out method. In certain embodiments, silicas are colloidal particles having 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 by weight measuring about 7 to about 10 microns in diameter and a smaller oil absorption of about 70 ^cm3 / 100g of silica is an example of an abrasive silica with low oil absorption useful in the practice of the present invention.
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Foaming agents: The oral hygiene 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 foam-increasing agents include, but are not limited to, polyoxyethylene and certain polymers including, but not limited to, alginate polymers. Polyoxyethylene can increase the amount of foam and the foam thickness generated by the vehicle component for oral hygiene of the present invention. Polyoxyethylene is also commonly known as polyoxyethylene glycol (PEG) or polyoxyethylene 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 mode about 800,000 to about 1,000,000. Polyox® is the trademark 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 vehicle component for oral hygiene of the oral hygiene compositions of the present invention. Where present, the amount of foaming agent in the composition for oral hygiene (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 embodiment about 0.1 to about 0.2% by weight.
[0058] Surfactants: Compositions useful in the invention may contain anionic surfactants, for example:
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i. Water-soluble salts of higher fatty acid monoglyceride monoglycerides, such as the sodium salt of the monoglyceride monoglyceride of hydrogenated coconut oil fatty acids such as sodium N-methyl N-cocoyl taurate, sodium cocomonoglyceride sulfate, ii. higher alkyl sulfates, such as sodium lauryl sulfate, iii.
higher alkyl ether sulphates, for example, of the formula
CH3 (CH2) mCH2 (OCH2CH2) nOSO3X, where m is 6-16, for example,
10, n is 1-6, for example,
2, 3 or 4,
No U
K, for example sodium lauret-2 sulfate (CH3 (CH2) 10CH2 (OCH2CH2) 2OSO3Na).
iv. higher 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 (N-2-ethyl laurate potassium sulfoacetamide) and sodium lauryl sarcosinate.
[0059] By higher alkyl is meant, for example, C6-30 alkyl. In particular modalities, the anionic surfactant is selected from sodium lauryl sulfate and sodium lauryl ether sulfate. The anionic surfactant can be present in an amount that is effective, for example,> 0.01% by weight of the formulation, but not in 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, concentrations used or a mouthwash are
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33/58 typically on the order of a tenth of that used for toothpaste. In one embodiment, the anionic surfactant is present in a toothpaste at about 0.3% to about 4.5% by weight, for example, about 1.5%. The compositions of the invention may optionally contain mixtures of surfactants, for example, comprising 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 U.S. Patent No. 3,959,458, to Agricola et al; United States 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 here include the water-soluble salts of alkyl sulfates having about 10 to about 18 carbon atoms in the alkyl radical and the water-soluble salts of sulfonated monoglycerides of fatty acids having about 10 to about of 18 carbon atoms. Sodium lauryl sulfate, sodium lauroyl sarcosinate and sodium coconut monoglyceride sulfonates are examples of anionic surfactants of the type. In a particular embodiment, the composition of the invention, for example, Composition 1, et seq., Comprises sodium lauryl sulfate.
[0060] 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.
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Tartar control agents: In various embodiments of the present invention, the compositions comprise an anti-calculating agent (tartar control). Suitable anticalculating agents include without limitation phosphates and polyphosphates (e.g., pyrophosphates), polyaminopropanesulfonic acids (AMPS), hexametaphosphate salts, zinc citrate trihydrate, polypeptides, polyolefin sulfonates, polyolefin phosphates, diphosphonates. The invention thus can comprise phosphate salts. In particular embodiments, these salts are alkaline phosphate salts, i.e., alkali metal hydroxide salts or alkaline earth hydroxides, for example, sodium, potassium or calcium salts. Phosphate as used herein encompasses 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 salts of dibasic alkaline phosphate and alkaline pyrophosphate, for example, selected from sodium dibasic phosphate, dibasic potassium phosphate, dihydrated dicalcium phosphate, calcium pyrophosphate, tetrasodium pyrophosphate, pyrophosphate, pyrophosphate, pyrophosphate sodium tripolyphosphate and mixtures of any two or more of these. In a particular embodiment, for example, the compositions comprise a mixture of tetrasodium pyrophosphate (Na4P207), calcium pyrophosphate (Ca2P207), and sodium dibasic phosphate (Na2HPO4), for example, in amounts of about 3-4% of the dibasic sodium phosphate and about 0.2
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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 1-2% and STPP in about 7% at about 10%>. Such phosphates are provided in an effective amount to deduct enamel erosion, to assist in cleaning teeth, and / or to reduce the accumulation of tartar on the teeth, for example, in an amount of 2-20%, for example, about 5-15%, by weight of the composition.
[0062] Flavoring agents: The oral hygiene 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 similar materials. Examples of essential oils include mint oils, peppermint, wintergreen, sassafras, cloves, sage, eucalyptus, marjoram, cinnamon, lemon, lime, grapefruit and orange. Also useful are such chemicals as menthol, carvone and anethole. Certain modalities use peppermint and peppermint oils. The flavoring agent can be incorporated into the oral composition in a concentration of about 0.1 to about 5% by weight, for example about 0.5 to about 1.5% by weight.
[0063] Polymers: The oral hygiene compositions of the invention may also include additional polymers to adjust the viscosity of the formulation or to enhance the solubility of the other ingredients. Such additional polymers include polyoxyethylene glycols, polysaccharides
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36/58 (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 provided in the form of their free acids or partially or completely neutralized water-soluble alkali metal (eg, potassium and sodium) or ammonium salts.
[0064] Silica thickeners, which form polymeric structures or gels in the 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, since the silica thickeners are very finely divided and provide 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 caraia, gum arabic and tragacanth gum can also be incorporated. Colloidal aluminum and magnesium silicate can also 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.
[0065] The compositions of the invention can include an anionic polymer, for example, in an amount of about 0.05 to about 5%. Such agents are generally known for use in toothpaste, although not for this particular application useful in the present invention, they are
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37/58 described in U.S. Patent No. 5,188,821 and 5,192,531; and include synthetic anionic polymeric carboxylates, such as 1: 4 to 4: 1 maleic anhydride or acid copolymers with another polymerizable ethylenically unsaturated monomer, preferably methyl vinyl ether / maleic anhydride having a molecular weight (MW) of about 30,000 to 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 (MW 500,000), AN 119 (MW 250,000) and preferably S-97 Pharmaceutical Grade (MW 700,000) available from ISP Technologies, Inc., Bound Brook, NJ 08805. Intensifying agents when present are present in amounts ranging from about 0.05 to about 3% by weight. Other operational polymers include those such as 1: 1 maleic anhydride copolymers with ethyl acrylate, hydroxyethyl methacrylate, N-vinyl-2-pyrolidone or ethylene, the latter being available, for example, as Monsanto EMA No. 1103, MW 10,000 and EMA Grade 61 and 1: 1 acrylic acid copolymers with methyl or hydroxyethyl methacrylate, methyl or ethyl acrylate, isobutyl vinyl ether or N-vinyl-2-pyrrolidone. Generally suitable are polymerized olefinically or ethylenically unsaturated carboxylic acids containing an activated carbon-to-carbon olefinic double bond and at least one carboxyl group, that is, an acid containing an olefinic double bond that works readily in polymerization because its presence in the polymerization molecule monomer either in alphabetical position with respect to a carboxyl group or as part of a terminal methylene group. Illustrative are such acids
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38/58 are acrylic, methacrylic, ethacrylic, alpha-chloroacrylic, crotonic, beta-acryloxy propionic, sorbic, alpha-chlorosorbic, cinnamic, beta-styrylacrylic, muconic, itaconic, citraconic, mesaconic, glutaconic, aconitic, alpha-phenylacrylic, alpha-phenylacrylic benzyl acrylic, 2-cyclohexylacrylic, angelic, umbrellic, fumaric, maleic and anhydrides. Other different elephantine monomers copolymerizable with such carboxylic monomers include vinylacetate, vinyl chloride, dimethyl maleate and the like. Copolymers contain sufficient carboxylic salt groups for water solubility. An additional class of polymeric agents includes a composition containing substituted acrylamide homopolymers and / or unsaturated sulfonic acid homopolymers and salts thereof, in particular where polymers are based on unsaturated sulfonic acids selected from acrylamidoalkane sulfonic acids such as 2-acrylamide 2-methylpropane sulfonic acid having a molecular weight of about 1,000 to about 2,000,000, described in U.S. Patent No. 4,842,847, Jun. 27, 1989 to Zahid. Another useful class of polymeric agents includes polyamino acids containing anionic surface active amino acid ratios such as aspartic acid, glutamic acid and phosphoserine, for example as described in U.S. Patent No. 4,866,161 Sikes et al.
[0066] 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 the free water that is added
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39/58 plus that amount that is introduced with other materials.
[0067]
Humectants:
Within certain modalities of oral compositions, it is also desirable to incorporate a humectant to prevent the composition from hardening upon exposure to air.
Certain humectants can also impart desirable sweetness or flavor to 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 of greater than 25%, for example, 25-35% about 30%, with 5% or less of other humectants.
[0068] 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 antiplaque agents, abrasives and coloring agents. These and other optional components are further described in U.S. Patent No. 5,004,597, to Majeti; US patent No. 3,959,458 to Agricola et al. and U.S. Patent No. 3,937,807, to Haefele, all of which are incorporated herein by reference.
[0069] Unless otherwise stated, all percentages of components of the composition given in this
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40/58 specification is by weight based on a total weight of the composition or formulation of 100%.
[0070] Unless specifically identified otherwise, the ingredients for use in the compositions and formulations of the present invention are preferably cosmetically acceptable ingredients. Cosmetically acceptable 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 the amounts and concentrations contemplated in the formulations of this invention and includes, for example, excipients that are Generally Recognized as Safe (GRAS) by the United States Food and Drug Administration .
[0071] The compositions and formulations as provided herein are described and claimed with reference to their ingredients, as is common in the art. As would be evident to someone skilled in the art, the ingredients may, in some cases, react with each other, 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.
[0072] As used throughout this report, ranges are used as an abbreviation to describe each value that falls 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 description and
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41/58 in that of a cited reference, the present description has priority.
[0073] Unless otherwise specified, all percentages and quantities expressed here and elsewhere in the specification should be understood as referring to percentages by weight. The quantities given are based on the active weight of the material.
Examples
Example 1 [0074] The general reaction for the formation of ZLC is as follows:
ZnO + 2 (Lysine-HCl) -> [Zn (Lysine) 2Cl] Cl.2H2O (ZLC) [0075] A 2: 1 molar ratio of suspension of
ZnO: Lysine HCl is prepared with stirring at room temperature for about 12 hours. The mixture is centrifuged. 1ml of supernatant is transferred to an NMR tube. The NMR tube is then placed in a closed test tube filled with ethanol for crystal growth. Several 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 NH2 groups and O atoms of 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 positive cation portion, which a Cl anion is combined to form an ionic salt.
[0076] Synthesis of laboratory powder scheduling
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42/58 of pure ZLC: 2 moles of Lysine HCl are dissolved in 1000 ml of DI water with stirring at room temperature, 1 mole of solid ZnO is added slowly to the Lysine HCl solution with stirring and stirring is continued at RT during the night (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 5-8 ml of EtOH is required to obtain 1 g of powder. The powdered EtOH solvent is filtered and an off-white powder is obtained. The powder is placed in an oven at 50 ° C for drying and a product yield of 88% is obtained. PXRD confirms the purity of ZLC powder compared to ZLC crystal.
Example 2 [0077] Four batches of 500 g of mouthwash which contain 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 the samples with different actives. Turbidity is assessed by the percent light transmission through the solution as measured by a TurbiScan® dispersion stability analyzer. The higher the percentage transmission, the more transparent it is. Thus, a lower percentage transmission suggests that the solution is more cloudy. The concentration of zinc ions in the ZLC solution is 25300 ppm obtained by the analysis of ICP (Plasma Inductively Coupled), which corresponds to approximately 17% weight of ZLC assets in the solution. The concentration of zinc ion in all batches is controlled at the same level, ie 1.01% by weight. Among the four lots, the one that has ZnO as an active one looks milky white,
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43/58 with 0% transmission, while the other three samples are as clear as deionized water (Table 2).
Table 1
Mouthwash with NaF Ingredients % Load (g) Current (g) Sorbitol 70% sun 5.5 27.5 27.51 Sodium fluoride 0.05 0.25 0.25 Na saccharin 0.02 0.1 0.1 Propylene glycol 7 35 35 Poloxamer 407 0.4 2 2.01 Citric acid 0.2 0.1 0.1 Potassium sorbitol 0.05 0.25 0.25 Glycerin 7.5 37.5 37.5 Mint flavorchili 0.1 0.5 0.5 Deionized water 79.36 396.8 396.8 Total 100 500 500.02
Mouthwash with ZnCl2 Ingredients O,% Load (g) Current (g) Sorbitol 70% sun 5.5 27.5 27.5 ZnCl2 47.97% Zn 2.11 10.55 10.56 Na saccharin 0.02 0.1 0.1 Propylene glycol 7 35 34.98 Poloxamer 407 0.4 2 2 Citric acid 0.02 0.1 0.1 Potassium sorbitol 0.05 0.25 0.25 Glycerin 7.5 37.5 37.48
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Mint flavorchili 0.1 0.5 0.48 Deionized water 77.3 386.5 386.88 Total 100 500 500.33 Zn% 1.01
Mouthwash with ZnO Ingredients O,% Load (g) Current (g) Sorbitol 70% sun 5.5 27.5 27.55 ZnO 80.34% Zn 1.26 6.3 6.28 Na saccharin 0.02 0.1 0.1 Propylene glycol 7 35 34.98 Poloxamer 407 0.4 2 2.02 Citric acid 0.02 0.1 0.1 Potassium sorbitol 0.05 0.25 0.25 Glycerin 7.5 37.5 37.52 Mint flavorchili 0.1 0.5 0.52 Deionized water 78.15 390.75 390.62 Total 100 500 499.94 Zn% 1.01
Mouthwash with ZLC Ingredients O,% Load (g) Current (g) Sorbitol 70% sun 5.5 27.5 27.49 ZLC 2.53% Zn 40 200 200 Na saccharin 0.02 0.1 0.1 Propylene glycol 7 35 35.1 Poloxamer 407 0.4 2 2
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Citric acid 0.02 0.1 0.1 Potassium sorbitol 0.05 0.25 0.25 Glycerin 7.5 37.5 37.5 Mint flavorchili 0.1 0.5 0.5 Deionized water 39.41 197.05 196.98 Total 100 500 499.93 Zn% 1.01
Table 2
DI water NaF MW ZLC MW ZNcL2 mw ZnO MW PH 5.89 4.79 7.18 3.49 7.03 Turbidity (% ofstreaming) 88.68% 88.40% 86.23% 89.03 0.0016%
[0078] Dilution experiment: All original mouthwash lots are diluted 2 times, 4 times, 8 times, 16 times and 32 times. Turbidity measurements are performed after all solutions are prepared and thoroughly stirred. The turbidity data of the samples are shown in Tables 3, 4, 5 and 6, regarding the dilutions of mouthwash 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 (% of 89.85% 88.90% 88.44% 88.77% 88.61% streaming)
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Table 4
2X 4X 8X 16X 32X pH 7.46 7.67 7.86 7.80 7.94 Turbidity (% of 86.73% 85.99% 60.50% 59.61% 23.21% streaming)
Table 5
2X 4X 8X 16X 32X Turbidity (% of 89.63% 88.04% 87.77% 87.42% 87.99% streaming)
Table 6
2X 4X 8X 16X 32X Turbidity (% of transmission) 0% 0% 0% 0% 0%
[0079] Aging experiment: the diluted ZLC mouthwash samples are placed in an oven at 37 ° C during 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 found in 16-fold dilution. The original batch, however, is still stable and shows no precipitation even though it is aged 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)
[0080] Compared to the mouthwash lots formulated using ZnCl2 and ZnO, only the formulation with ZLC
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47/58 as active it can form a clear, stable solution, but it generates 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 buffers in the dentinal tubules, providing benefits for hypersensitivity.
Example 3 [0081] The mouthwash formulation from the previous example using ZLC as an active ingredient not only shows competitive clarity with the current commercial mouthwash product containing NaF as the active ingredient, but also exhibits precipitation capacity when diluted with water. This unique property facilitates the anti-sensitivity and anti-caries effects and it is therefore of interest to employ ZLC in a toothpaste product.
[0082] An oral gel toothpaste with ZLC as an active ingredient is formulated and compared with other formulations containing ZnCl2, ZnO, and NaF. Only the formulation with ZLC shows competitive clarity as the current gel phase containing NaF. The property of ZLC gel phase precipitation is also investigated by studying the hydrolysis reaction, providing evidence that when teeth are being brushed with toothpaste containing ZLC, insoluble particles formed during brushing can penetrate the dentinal tubules and block tubules resulting in anti-sensitivity and signal effect for the consumer.
[0083]
Four batches of 500.0 g gel phase that
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48/58 contain NaF (control), ZLC, ZnCl2 and ZnO as the active ingredient are formulated with the ingredients shown in Table 8. The clarity of the samples with different assets is compared and the ZLC gel phase precipitation characteristic by dilution is evaluated. The concentration of zinc ions in the ZLC solution is 25300 ppm obtained by ICP, which in terms offers approximately 17% by weight of ZLC assets in the solution. The zinc ion concentrations 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,% Load (g) Current(g) Sorbitol 70% sun 76.03 380.15 380.14 Aqueous ZLC solution2.53% Zn 20 100 100 Carboxymethyl cellulose(CMC) and trimethylcellulose (TMC) 0.7 3.5 3.51 Na saccharin 0.27 1.35 1.35 Propylene glycol 3 15 15 Total 100 500 500 Zn% 0.5060.5060%
Oral gel with ZnCl2 (47.97% Zn) Ingredients % Load (g) Current (g) Sorbitol 70% sun 80 400 399.99 ZnCl2 47.97% Zn 1.06 5.275 5.27 CMC TMC 0.7 3.5 3.5
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Na saccharin 0.27 1.35 1.35 Propylene glycol 3 15 14.98 DI water 14.98 74,875 74.91 Total 100 500 500 % Zn 0.5080.5056%
Oral gel with ZnO (80.34% Zn) Ingredients % Load (g) Current (g) Sorbitol 70% sun 80.2 401 400.99 ZnO 80.34% Zn 0.63 3.15 3.15 CMC TMC 0.7 3.5 3.5 Na saccharin 0.27 1.35 1.35 Propylene glycol 3 15 15 Deionized water 15.2 76 75.99 Total 100 500 499.98 % Zn 0.5500.5062%
Oral gel with NaF Ingredients O,% Load (g) Current (g) Sorbitol 70% sun 80.2 401 401 In F 0.76 3.8 3.79 CMC TMC 0.7 3.5 3.51 Na saccharin 0.27 1.35 1.35 Propylene glycol 3 15 15.01 Deionized water 15.07 75.35 75.36 Total 100 500 500.02
[0084]
The Lambda spectrometer
UV / VIS (PerkinElmer) is used to obtain absorbance information for all samples in order to compare the
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50/58 clarity of the gel phase between different assets. Absorbance is a logarithmic measure of the amount of light that is absorbed when passing through a substance. Since the particles in the gel absorb light, the more particles there are in the solution, the more light will be absorbed by the gel. Thus, a small number of absorbances of a gel indicates greater clarity. The absorbance is corrected by using deionized water (DI) as the blank solution under the wavelength of the 610 nm light source. ZnO is not dissolved and is suspended in the gel phase resulting in a high absorbance. Even though ZnCl2 is soluble in water, the gel phase containing 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 Absorbance 0.0344 0.1765 0.9204 2.4626 pH 7.63 7.37 5.25 8.30
[0085] 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 since the NaF gel, ZnCl2 gel and ZnO gel are still diluted and an increase in absorbance in the ZLC gel solution is still diluted. This observation confirms the formation of a precipitate when ZLC gel is being diluted in water. The pHs of ZLC gel solutions diluted 2 times, 4 times, 8 times, 16 times, and 32 times are 7.71, 7.91, 8.03, 8.12 and 8.14, respectively.
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Table 10
Active ingredient 2-fold dilution 4-fold dilution 8-fold dilution 16-fold dilution 32-fold dilution In F 0.0106 0.0104 0.0107 0.0075 0.0137 ZLC 0.1436 0.1887 0.1860 0.1336 0.2998 ZnCl2 0.7315 0.3700 0.1701 0.0570 0.0280 ZnO 2.4630 2.5340 2.1883 1.8638 1.0492
[0086] The gels above can be used alone or in a toothpaste having a gel phase and an abrasive paste phase. ZLC as an active ingredient in the gel phase of toothpaste formulation. Compared to the gel phase batches formulated by ZnCl2 and ZnO, only the formulation with ZLC as active shows competitive clarity and pH as that used in the commercial product (NaF as active ingredient). The dilution experiment shows that only the ZLC gel phase can form insoluble precipitate of transparent gel when it is diluted. The formation of insoluble precipitate by dilution facilitates the formation of plugs in the dentinal tubules after the use of this type of toothpaste and, in addition, it provides a sign of the white precipitate during use by the consumer.
Example 4 [0087] Dentin occlusion by an oral gel with ZLC is measured in comparison with an oral gel without ZLC for the potential anti-hypersensitivity benefit. A Flodec instrument is used to measure the flow of fluid through the dentinal tubules. A Pashley cellular method (for example, Pashley DH, O'Meara JA, Kepler EE, et al. Dentin permeability effects of desensitizing dentifrices in vitro.
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J Periodontal. 1984, -55 (9): 522-525) is used after a procedure used to measure dentinal occlusion in formulations for oral washing by S. Mello. Two 10-minute treatments of 400 pl sample are applied with a pipette to the dentin discs at 10-minute intervals. After each treatment, the discs are rinsed with phosphate buffered saline (PBS) and measured for 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 8 shows average flow of the oral gel with ZLC and reduction of the percentage flow after the application of the sample.
Table 11
Average flowwith ZLC (pl / min) of oral gel % flow reductionBasis ofreference Treatmentn ° 2 Difference (based onreference) Rep No. 1 7.51 3.47 4.05 53.87 Rep No. 2 13.02 7.20 5.82 44.68 Rep No. 3 25.74 19.79 5.95 23.13 Average 4.56 EV Standard 15.78
[0088] As shown above, the average percentage flow reduction of oral gel with ZLC triplicates is about 41% through the dentinal tubules.
[0089] Table 12 shows average flow of oral gel without ZLC (control) and reduction in percentage flow after application of the sample.
Table 12
Average flow (pl / min) of oral gel without ZLC % reduction
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(control) flowBasis of Treatment Difference (based onreference n ° 2reference) Rep No. 1 7.25 5.02 2.23 30.85 Rep No. 2 13.94 8.43 5.51 39.57 Rep No. 3 22.84 17.93 4.91 21.53 Average 30.65 EV Standard 9.02
[0090] As shown above, the average percentage flow reduction of oral gel without ZLC triplicates (control) is about 31%) through the dentinal tubules.
[0091] The oral gel with ZLC shows better performance directionally, when compared to the oral gel without ZLC (control) in an in vitro hydraulic conductance model using a FLODEC device.
Example 5 [0092] Various dilutions of ZLC are present to assess their efficiency in the production of visible precipitates and / or flocculation, which can be distributed in situ on an oral surface or in a dental opening, such as open tubules.
[0093] A pure ZLC solution is prepared by 1), reacting 0.5 mol of ZnO powder with 1 mol of lysine HCl in 1 liter of water at room temperature for about 2 hours, and 2) collecting the supernatant through centrifugation followed by filtration using a 0.45 micron membrane. The pure solution has a zinc concentration of 2.39% by weight and a pH of about 7.03.
[0094] The dilution experiment is conducted by mixing the pure solution with deionized water. The pure solution
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54/58 is diluted in 2x, 4x, 6x, 7x, 8x, 10x, 12x, 16x, 20x, 24x, 28x, and 32x, 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 kept at 37 ° C and the rates at which flocculation / precipitation occurred are monitored. Dilutions with initial zinc concentrations of 0.149% and 0.199% are capable of generating some visible flocculation within 30 minutes from the time when the stock solution is mixed with water. One hour after mixing, visible flocculation was observed at dilutions with initial zinc concentrations between 0.0854% and 0.239%. One and a half hours after mixing, visible flocculation is observed in 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 the one with the initial zinc concentration of 1.20% and those with initial zinc concentrations between 0.0747% and 0.239% exhibit most precipitates.
[0095] The pH values of diluted final samples are suitable for oral hygiene applications. Samples with initial zinc concentrations of 0.0747%, 0.0854%, 0.0996%, 0.120%, 0.149%, 0.199% by weight and 0.239% 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 hygiene formulations.
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55/58 [0096] 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 [0097] Confocal images demonstrate the efficiency of ZLC in the generation of superficial deposits and occlusion tubule openings on the dentin surface, under conditions where visible precipitation can be formed.
[0098] The deposition / occlusion test is conducted using slices of human dentin and the pure solution of Example 5. The slices of dentin were prepared by cutting human teeth into thin sections of dentin about 800 microns in thickness, choosing one side of the test, sand the said side of the test using sandpaper of about 600 grit, polishing said side of the test using a Buehler polishing cloth and 5 microns of Buehler aluminum oxide, acid conditioning of said section of dentin by 1% (by weight) of citric acid solution for about 20 seconds, ultrasounding said section of dentin for 10 minutes and storing said section of dentin in phosphate buffered saline (PBS, pH 7.4).
[0099] For the treatment, the pure solution is diluted 16 times with water, yielding 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 rinsed 4 times, each time with 1 ml of PBS. The dentin section is then dried using a paper-based tissue and examined under the
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56/58 confocal microscope in both XIZ and XIZ modes. Subsequent treatments are conducted in the same way.
[00100] Progressive deposition and occlusion can be observed through formation of confocal image. The first treatment leads to noticeable deposition. The second treatment leads to complete coverage of the surface, including blocking substantially all 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 tubule openings are observed. Surface deposits can be 25 microns or more in thickness. The deposits give a white color to the dentin surface.
[00101] Surface deposits provide several benefits, including those commonly associated with zinc and lysine, as well as protection against erosion through neutralization of erosive acids by deposits, protection of sensitivity by blocking tubules and controlled release of assets due the gradual release of zinc and lysine from the deposits, particularly through the acid challenge.
Example 7 [00102] Confocal images demonstrate the efficiency of ZLC in the generation of superficial deposits and occlusion tubule openings on the dentin surface, under conditions where no visible precipitation is observed.
[00103] Dentin sections, as prepared in Example 6, are repeatedly treated 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
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57/58 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 4 consecutive treatments, significant deposition on the surface is observed. After 12 consecutive treatments, complete coverage of the surface is observed leaving no sign of the presence of tubule openings.
[00104] Therefore, deposition on the surface and occlusion of tubules can occur under conditions, both in terms of dilution ratios and treatment durations, which do not produce visible precipitation.
Example 8 [00105] The test toothpaste comprising zincolysin, 1450 ppm fluoride, and phosphates is prepared as described in Table 13 (below).
Table 13
Ingredient % by weight PEG600 3 CMC-7 0.65 Xanthan 0.2 Sorbitol 27 Glycerin 20 Saccharin 0.3 Tetrasodium pyrophosphate 0.5 Calico pyrophosphate 0.25 Dibasic sodium phosphate 3.5 Sodium fluoride (forprovide 1450 ppm of fluoride) 0.32 Titanium dioxide 0.5
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Abrasive silica 8 Thickener silica 8 ZLC 7 Sodium lauryl sulfate 1.5 Flavor 1.2 Water Q.S.
[00106] Although the invention has been described with respect to specific examples including currently preferred ways of carrying out the invention, those skilled in the art will appreciate the fact that there are numerous variations and exchanges of the systems and techniques described above. It should be understood that other modalities 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 must be broadly constructed as presented in the appended claims.
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权利要求:
Claims (11)
[1]
1. Dentifrice characterized by the fact that it comprises an amino acid-zinc halide complex, in which the zinc is solubilized, such that the gel is substantially clear, which provides a zinc precipitate through use and dilution with saliva and / or rinse .
[2]
2. Dentifrice, according to claim 1, characterized by the fact that the amino acid-zinc halide complex is formed of precursors, optionally in which the precursors are a source of zinc ion, a source of amino acid and a source of halide .
[3]
3. Dentifrice according to claim 2, characterized by the fact that the halide source can be part of the zinc ion source, the source of amino acid or a halogen acid.
[4]
4. Dentifrice according to any one of claims 1 to 3, characterized by the fact that the amino acid is a basic amino acid, in the form of an orally acceptable or free salt, or in which the amino acid is selected from lysine, glycine and arginine in the orally acceptable or free acid addition salt form.
[5]
Dentifrice according to any one of claims 1 to 4, characterized by the fact that the amount of zinc is 0.05-4% by weight.
[6]
6. Dentifrice according to any one of claims 1 to 5, characterized in that the complex is a lysine-zinc chloride complex or an arginine-zinc chloride complex.
[7]
7. Dentifrice, according to any of claims 1 to 6, characterized by the fact that the
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2/3 amino acid-zinc halide complex is a lysine-zinc chloride complex having the chemical structure [Zn (C6H14N2O2) 2Cl] ⁺ Cl ^- , either in a cationic cation solution (for example, [Zn (C6H14N2O2) 2Cl] ⁺ ) and the chloride anion or in
solid salt form, optionally on form mono or di- hydrated.8. Dentifrice, in a deal with Any of them of claims 1 to 7, featured fur fact in what further comprises a effective amount of a source in ion fluoride.9. Dentifrice, in a deal with Any of them of claims 1 to 8, featured fur fact in what
comprises an orally acceptable base comprising ingredients selected from one or more of abrasives, buffering agents, humectants, surfactants, thickeners, strips or fragments of gum, breath fresheners, flavorings, fragrances, dyes, antibacterial agents, bleaching agents, agents that interfere with or prevent bacterial fixation, sources of calcium, sources of phosphate, orally acceptable potassium salts and anionic polymers.
[8]
10. Dentifrice according to any one of claims 1 to 9, characterized by the fact that the pH of the gel is from pH 6 to pH 8.
[9]
11. Dentifrice according to any one of claims 1 to 10, characterized by the fact that it is used to reduce and inhibit acidic enamel erosion, clean teeth, reduce bio-film and plaque generated by bacteria, reduce gingivitis, inhibit tooth decay and cavity formation and / or reduce hypersensitivity of
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3/3 dentin.
[10]
12. Use of a source of zinc ion together with an amino acid in complex, characterized by the fact that it is for the manufacture of a toothpaste.
[11]
13. Use according to claim 12, characterized by the fact that it is for preparing a toothpaste as defined in any one of claims 1 to 11, for treating or reducing erosion of tooth enamel, cleaning teeth, reducing bio-film and reducing bacteria-generated plaque, reduce gingivitis, inhibit tooth decay and cavity formation and / or reduce dentin hypersensitivity, which includes the application of dentifrice to teeth and, optionally, then rinse with sufficient water or aqueous solution to trigger the zinc oxide precipitation of the gel.

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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 8/20 (2006.01), A61K 8/4 |

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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/US2012/070513|WO2014098824A1|2012-12-19|2012-12-19|Oral gel comprising zinc - amino acid complex|

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