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    • 专利摘要:
    Zinc Phosphate-containing Compositions The invention provides oral care compositions, for example, a toothpaste or mouthwash comprising zinc phosphate, wherein zinc phosphate is added to the toothpaste or mouthwash as a preformed salt; as well as methods for obtaining and using them.
    公开号:BR112015012921B1
    申请号:R112015012921-8
    申请日:2012-12-05
    公开日:2018-12-04
    发明作者:Aarti Rege；David F. Suriano；Richard Sullivan；Michael A. Stranick
    申请人:Colgate-Palmolive Company；
    IPC主号:
    专利说明:

    (54) Title: DENTAL PASTE, COLUTORY AND USE OF ZINC AND ARGININE PHOSPHATE IN THE PREPARATION OF THE SAME (73) Holder: COLGATE-PALMOLIVE COMPANY. Address: 300 PARK AVENUE, NEW YORK, NY, UNITED STATES OF AMERICA (US), 10022 (72) Inventor: AARTI REGE; DAVID F. SURIANO; RICHARD SULLIVAN; MICHAEL A. STRANICK.
    Validity Term: 20 (twenty) years from 12/05/2012, subject to legal conditions
    Issued on: 12/04/2018
    Digitally signed by:
    Liane Elizabeth Caldeira Lage
    Director of Patents, Computer Programs and Topographies of Integrated Circuits
    1/42
    DENTAL PASTE, MOUTHWASH AND USE OF ZINC AND ARGININE PHOSPHATE IN THE PREPARATION OF THE SAME
    BACKGROUND [0001] Dental erosion involves demineralization and damage to the dental structure due to acid attack from non-bacterial sources. Erosion is found initially in the enamel and, if left unchecked, can progress to the dentin. Dental erosion can be caused 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. Usually saliva has a pH between 7.2 to 7.4. When the pH is lowered and the hydrogen ion concentration 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 a prolonged period, then remineralization may not occur, and the teeth will continue to lose minerals, causing them to weaken and ultimately loss of structure.
    [0002] There is a need for improved products for the treatment and reduction of erosion.
    Petition 870180070625, of 8/13/2018, p. 10/56
    2/42 [0003] heavy metal ions, such as zinc, are resistant to acid attack. Zinc is above hydrogen in the electrochemical series, so that metallic zinc in an acidic solution will react to release hydrogen gas as the zinc passes into the solution to form dicatons, Zn 2+ . Zinc has demonstrated antibacterial properties in studies of plaque and caries.
    [0004] Soluble zinc salts such as zinc citrate have been used in toothpaste compositions, but they 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, are difficult to obtain. In addition, free zinc ions can react with fluoride ions to produce zinc fluoride, which is insoluble and thus reduces the availability of both zinc and fluoride. Finally, the zinc ions will react with anionic surfactants such as sodium lauryl sulfate, thus interfering with foaming and cleaning.
    [0005] Zinc phosphate (Zn3 (PO4) 2) is insoluble in water, although soluble in acidic or basic solutions, for example, solutions of mineral acids, acetic acid, ammonia or alkaline hydroxides. See, e.g., Merck Index, 13th Ed. (2001) p. 1812, monograph number 10205. In part, because it is seen in the art as a generally inert material, which is commonly used in dental cements, for example, in the cementation of fillings, crowns, bridges and orthodontic appliances, which resist inside from the mouth for many years. Dental cements
    Petition 870180070625, of 8/13/2018, p. 11/56
    3/42 zinc phosphate is generally prepared by mixing zinc oxide and magnesium oxide powders with a liquid consisting essentially of phosphoric acid, water and buffers, so that cement comprising zinc phosphate is formed in situ by reaction with phosphoric acid.
    SUMMARY [0006] It has now been discovered that zinc phosphate, when placed in the formulation, for example, in acidic or basic pH, can dissolve sufficiently as a result of use to provide an effective concentration of zinc ions in relation to the enamel, protecting thus against erosion, reducing bacterial colonization and biofilm development and providing greater shine to the teeth. In some embodiments, the formulation comprises an amino acid, for example, a basic amino acid, for example, arginine or lysine, which can impart a basic pH to the formulation. It has also been found that zinc phosphate in a formulation with a second phosphate source increases phosphate deposition. All of this is unexpected, in view of the poor solubility of zinc phosphate, and the view recognized in the technique that it is substantially inert in the conditions present in the oral cavity, as evidenced by its wide use in dental cement. At the same time, formulations containing zinc phosphate do not exhibit unpleasant taste and mouthfeel, poor fluoride release and poor foaming and cleaning associated with conventional zinc-based oral care products, which use the most effective zinc salts. soluble.
    Petition 870180070625, of 8/13/2018, p. 12/56
    [0007] The invention thus provides compositions for oral care, for example, toothpastes, which comprise zinc phosphate. In some embodiments, zinc phosphate is added to the toothpaste as a preformed salt. In one embodiment the composition further comprises an amino acid, for example, a basic amino acid. The compositions can optionally further comprise a fluoride source and an additional phosphate source. The compositions can be formulated on a conventional toothpaste or mouthwash base, for example, abrasives that comprise, for example, silica abrasives, surfactants, foaming agents, vitamins, polymers, enzymes, humectants, thickeners, antimicrobial agents , preservatives, flavorings, dyes and / or their combinations. For example, in one embodiment, the invention provides a toothpaste comprising about 2% zinc phosphate, about 5% arginine, about 5% alkaline phosphate salts and about 1,450 ppm fluoride, in one of abrasive based silica toothpaste.
    [0008] The invention further provides methods of using the compositions of the invention to reduce and inhibit acidic enamel erosion, cleaning teeth, reducing bacterially generated biofilm and plaque, reducing gingivitis, inhibiting tooth decay and inhibiting the formation of cavities , and reduction of tooth hypersensitivity, comprising brushing teeth with a composition of the invention.
    [0009] Other areas of applicability of the present invention will be evident from the detailed description
    Petition 870180070625, of 8/13/2018, p. 13/56
    5/42 provided below in this document. It should be understood that the detailed description and the specific examples, while indicating the preferred embodiment of the invention, are for illustrative purposes only and are not intended to limit the scope of the invention.
    DETAILED DESCRIPTION [00010] The following description of the preferred mode (s) is of an exemplary nature only and is in no way intended to limit the invention, its application or uses.
    [00011] As used in this document, the term preformed salt - when used with reference to zinc phosphate - means that zinc phosphate is not formed in situ in toothpaste or mouthwash, for example, through the reaction of phosphoric acid and a zinc salt.
    [00012] Therefore, the invention provides, in a first embodiment, an oral care composition for intermittent use, for example, daily use, for example, in the form of a toothpaste or mouthwash, which comprises zinc phosphate (Composition 1 ), for example:
    1.1. Composition 1 in the form of a toothpaste comprising zinc phosphate in a toothpaste base, for example, in which zinc phosphate is present in an effective amount, for example, in an amount of 0.5 to 4% in weight, for example, about 1 to 3% by weight, on a toothpaste base.
    1.2. Composition 1.1, wherein the base of the toothpaste comprises an abrasive, for example, an effective amount of a silica abrasive, for example, 10-30%, for example, about 20%.
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    6/42
    1.3. Composition 1 in the form of a mouthwash comprising zinc phosphate, for example, in an amount of 0.005-0.05% by weight, for example, about 0.01-0.03% by weight on a mouthwash base.
    1.4. Any of the preceding compositions further comprising an effective amount of a fluoride ion source, for example, providing 500-3,000 ppm of fluorine.
    1.5. Any of the preceding compositions further comprising an effective amount of fluoride, for example, where fluoride is a salt selected from stannous fluoride, sodium fluoride, potassium fluoride, sodium monofluorphosphate, sodium fluorsilicate, ammonium fluorsilicate, amine fluoride (for example, N'-octadecyltrimethylendiamine-N, Ν, N'-tris (2-ethanol) dihydrofluoride), ammonium fluoride, titanium fluoride, hexafluorsulfate and combinations thereof.
    1.6 Any of the preceding compositions comprising an amino acid in an amount sufficient to increase the solubility of zinc phosphate, for example, from about 0.5% to about 20% by weight of the total weight of the composition, from about 0.5 % by weight to about 10% by weight of the total weight of the composition, for example, about 1.5% by weight to about 3.75% by weight, 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.
    1.7 Any of the preceding compositions comprising a basic amino acid, for example, arginine or lysine or combinations thereof, for example, 1Petition 870180070625, of 13/08/2018, p. 15/56
    7/42 arginine, for example, in an effective amount, for example, in an effective amount, in combination with zinc phosphate to reduce erosion, dentin hypersensitivity and / or an accumulation of plaque, for example, in a amount of about 1-10% 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.
    1.8 Any of the preceding compositions comprising a basic amino acid, for example, arginine, in an amount sufficient to increase the pH of the formulation to a pH above 8, for example, at a pH of 8.510.
    1.9 Any of the preceding compositions further comprising additional sources of zinc ions, for example, selected from zinc citrate, zinc sulfate, zinc silicate, zinc lactate, zinc oxide and combinations thereof; for example, in one embodiment, a toothpaste comprising 1% zinc phosphate and 1% zinc citrate.
    1.10 Any of the preceding 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 alkaline phosphate selected from dibasic sodium phosphate, dibasic potassium, dicalcium phosphate dihydrate, calcium pyrophosphate, tetrasodium pyrophosphate, tetrapotassium pyrophosphate, sodium tripolyphosphate, and mixtures of any two or more of these, for example, in
    Petition 870180070625, of 8/13/2018, p. 16/56
    8/42 an amount of 1-20%, for example, 2-8%, for example, about 5%, by weight of the composition.
    1.11 Any of the preceding compositions comprising, for example, buffering agents, sodium phosphate buffer (for example, monobasic sodium phosphate and disodium phosphate).
    1.12 Any of the preceding compositions comprising a humectant, for example, selected from glycerin, sorbitol, propylene glycol, polyethylene glycol, xylitol, and mixtures thereof, for example, comprising at least 20%, for example, 20-40 %, for example, 25-35% glycerin.
    1.13 Any of the preceding compositions comprising one or more surfactants, for example, selected from anionic, cationic, zwitterionic, and non-ionic surfactants, and mixtures thereof, for example, comprising an anionic surfactant, for example, a surfactant selected from sodium lauryl sulfate, sodium lauryl sulfate ether and mixtures thereof, for example, in an amount from about 0.3% to about 4.5% by weight, for example 1-2% 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, 5-2% cocamidopropyl betaine.
    1.14 Any of the preceding compositions further comprising a modification amount and viscosity of one or more of the polysaccharide gums,
    Petition 870180070625, of 8/13/2018, p. 17/56
    9/42 for example, xanthan or carrageenan gum, silica thickener and combinations thereof.
    1.15 Any one of compositions precedent understanding strips glue or fragments. 1.16 Any one of compositions precedent understanding still flavoring, perfumes and / or i dyes. 1.17 Any one of compositions precedent
    comprising an effective amount of one or more antibacterial agents, for example, comprising an antibacterial agent selected from halogenated diphenyl ether (eg, triclosan), herbal extracts and essential oils (eg, rosemary extract, extract tea, magnolia extract, thymol, menthol, eucalyptol, geraniol, carvacrol, citral, hinokitol, catechol, methyl salicylate, epigallocatechin gaiato, gaiato, gallic acid, miswak extract, sea thorn extract), antiseptics (bisguan) e.g. chlorhexidine, alexidine or octenidine), quaternary ammonium compounds (e.g., cetylpyridinium chloride (CPC), benzalkonium chloride, tetradecylpyridinium chloride (TPC), N-tetradecyl-4-ethylpyridinium chloride (TDEPC)), phenolic antiseptics, hexetidine, octenidine, sanguinarine, povidone iodine, delmopinol, salifluor, metal ions (eg zinc salts, eg zinc citrate, stannous salts, copper salts, salts iron), blood, propolis and oxygenation agents (for example, hydrogen peroxide, buffered sodium peroxyborate or peroxycarbonate), phthalic acid and its salts, monopertallic acid and its salts and esters, ascorbyl stearate, oleoil sarcosine, sulphate of alkyl, dioctylPetition 870180070625, of 08/13/2018, p. 18/56
    10/42 sulfosucinate, salicylanilide, domiphene bromide, delmopinol, octapinol and other piperidine derivatives, nicine preparations, chloride salts; and mixtures of any of the foregoing; for example, comprising triclosan or cetylpyridinium chloride.
    1.18 Any of the preceding compositions comprising an effective antibacterial amount of triclosan, for example, 0.1-0.5%, for example, about 0.3%.
    1.19 Any of the preceding compositions additionally comprising a bleaching agent, for example, one selected from the group consisting of peroxides, metal chlorites, perborates, percarbonates, peracids, hypochlorites, and combinations thereof.
    1.20 Any of the compositions additionally comprising hydrogen peroxide or a source of hydrogen peroxide, for example, urea peroxide or a peroxide or complex salt (for example, such as peroxyphosphate, peroxycarbonate, perborate, peroxysilicate, or salts of persulfate, for example calcium peroxyphosphate, sodium perborate, sodium carbonate peroxide, sodium peroxyphosphate and potassium persulfate).
    1.21 Any of the preceding compositions additionally comprising an agent that interferes with or prevents bacterial adhesion, for example, solbrol or chitosan.
    1.22 Any of the compositions additionally comprising a source of calcium and phosphate selected from (i) calcium and glass complexes, for example, sodium, calcium phosphosilicates and (ii)
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    11/42 calcium and protein, eg casein, amorphous calcium phosphate phosphopeptide.
    1.23 Any of the compositions further comprising a soluble calcium salt, for example, selected from calcium sulfate, calcium chloride, calcium nitrate, calcium acetate, calcium lactate and combinations thereof.
    1.24 Any of the compositions additionally comprising a physiologically or orally acceptable potassium salt, for example, potassium nitrate or potassium chloride, in an amount effective to reduce dentin sensitivity.
    1.25 Any of the preceding compositions additionally comprising 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 with another polymerizable ethylenically unsaturated monomer; for example, where the anionic polymer is a copolymer of methyl vinyl ether / maleic anhydride (PVM / MA), a copolymer having an average molecular weight (MW) of about 30,000 to about 1,000,000, for example, about 300,000 to about 800,000, for example, where the anionic polymer is about 1-5%, for example, about 2%, of the weight of the composition.
    precedent perfume or
    1.26 Any of the compositions also comprising a mouth freshener, breath flavoring.
    1.27 Any of the preceding compositions, where the pH of the composition is either acidic or basic, for
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    12/42 example, from pH 4 to pH 5.5 or from pH 8 to pH
    10.
    1.28 Any of the preceding compositions, which is a toothpaste, wherein the composition comprises:
    1-3%, for example, about 2% zinc phosphate;
    2- 8%, for example, about 5% L-arginine (free base);
    2- 8%, for example, about 5% of alkaline phosphate salts, for example, selected from dibasic sodium phosphate, dibasic potassium phosphate, dicalcium phosphate dihydrate, calcium pyrophosphate, tetrasodium pyrophosphate, pyrophosphate tetrapotassium, sodium tripolyphosphate, and mixtures of any two or more of these;
    700-2,000 ppm, for example, about 1,450 ppm of fluoride, for example, 0.3-0.4%, for example, about 0.32% of sodium fluoride;
    on an abrasive silica paste base.
    1.29 Any of the preceding compositions that is a mouthwash, where the composition comprises:
    5-10%, for example, about 7.5% glycerin;
    3- 7%, for example, about 5.5% sorbitol;
    5-10%, for example, about 7% propylene glycol;
    0-0.1% TSPP;
    0.01-1% sweetener, for example, about 0.02% saccharin;
    0.01-1%, for example, about 0.05% citric acid;
    0-0.1% xanthan;
    0.005-0.05%, for example, about 0.028% zinc phosphate;
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    13/42
    0-0.01% cetyl pyridinium chloride;
    0.01-0.1%, for example, about 0.05% potassium sorbate;
    0.05-1%, for example, about 0.1-0.2% of flavorings;
    0.1-2%, for example, about 1% cocamidopropyl betaine;
    water (optionally together with any additional ingredients) to obtain the balance, for example, about 70-85%, for example, about 80% water.
    1.30. Any of the preceding compositions comprising substantially the same ingredients as in the test formulation of Example 1 or Example 4 below.
    1.31. Any of the foregoing compositions effective after application to the oral cavity, for example, with brushing, to: (i) reduce tooth hypersensitivity, (ii) reduce plaque buildup, (iii) reduce or inhibit demineralization and promote remineralization of the teeth, (iv) inhibit the formation of microbial biofilms in the oral cavity, (v) reduce or inhibit gingivitis, (vi) promote the healing of wounds or cuts in the mouth, (vii) reduce the levels of bacteria producing acid, (viii) increase the relative levels of non-cariogenic and / or non-plaque bacteria, (ix) reduce or inhibit the formation of dental caries, (x), reduce, or inhibit the repair of pre-carious enamel lesions , for example, as detected by light-induced quantitative fluorescence (QLF) or electrical cavity measurement (ECM), (xi) treating, relieving or reducing dry mouth,
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    14/42 (xii) cleaning teeth and oral cavity, (xiii) reducing erosion, (xiv) whitening teeth; and / or (XV) promoting systemic health, including cardiovascular health, for example, by reducing the potential for systemic infection through oral tissues.
    1.32. Composition obtained or obtainable by combining the ingredients as established in any of the preceding compositions.
    [00013] The invention further provides for the use of zinc phosphate in the production of an oral hygiene composition, for example, a toothpaste, and in methods for increasing the level of zinc in the enamel. In some embodiments, zinc phosphate is added to the toothpaste as a preformed salt.
    [00014] The invention further provides methods of using the compositions of the invention, to increase the levels of zinc in the enamel and to treat, reduce or control the incidence of enamel erosion, which comprises the application of a composition as described above, for example , any one of Composition 1 and teeth sequence, for example, by brushing. In several embodiments, the invention provides: (i) reduces tooth hypersensitivity, (ii) reduces plaque build-up, (iii) reduces or inhibits demineralization and promotes tooth remineralization, (iv) inhibits biofilm formation microbial in the oral cavity, (v) reduces or inhibits gingivitis, (vi) promotes the healing of wounds or cuts in the mouth, (vii) reduces the levels of acid-producing bacteria, (viii) increases the relative levels of non-cariogenic bacteria and / or not forming plaques,
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    15/42 (ix) reduces or inhibits the formation of dental caries, (x), reduces, repairs or inhibits pre-carious enamel lesions, for example, as detected by light-induced quantitative fluorescence (QLF) or electrical measurement of caries (ECM), (xi) treats, relieves or reduces dry mouth, (xii) cleans teeth and oral cavity, (xiii) reduces erosion, (xiv) whitens teeth; (xv) reduces the accumulation of tartar, and / or (xvi) promotes systemic health, including cardiovascular health, for example, by reducing the potential for systemic infection through oral tissues, including the application of any of the compositions 1 and sequences as described above to the oral cavity of a person in need, for example, by brushing the teeth one or more times a day with any of the compositions 1 and sequences. The invention further provides compositions 1 and sequences for use in any of these methods.
    [00015] Active Agents'. The compositions of the invention can comprise various agents that are active to protect and increase the strength and integrity of the enamel and teeth structure and / or to reduce tooth decay and associated bacteria and / or gum disease. The effective concentration of the active ingredients used in this document will depend on the particular agent and the delivery system used. It is understood that a toothpaste, for example, will typically be diluted with water upon use, while a mouthwash will typically not be. Thus, an effective concentration of active ingredient in a toothpaste will normally be 5 to 15 times greater than that required for a mouthwash. The concentration will also depend on the exact salt or polymer selected. Per
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    16/42 example, when the active agent is supplied 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 needed to provide the same concentration of active ion in the final product. Arginine, when present, can be present at levels, for example, from 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 for a professional treatment product or prescription. Fluoride when present can be present at levels, for example, from about 25 to about 25,000 ppm, for example, about 750 to about 2,000 ppm for a consumer toothpaste, or about 2,000 to about 25,000 ppm professional treatment product or prescription. The levels of antibacterial agents will vary in the same way, with levels used in toothpaste being, for example, about 5 to about 15 times higher than those used in mouthwashes. For example, a triclosan toothpaste can contain about 0.3% by weight of triclosan.
    [00016] Source of fluoride ions: Compositions for oral hygiene may further include one or more sources of fluoride ions, for example, soluble fluoride salts. A wide variety of materials that yield fluoride ions can be used as a source of soluble fluoride in the present compositions. Examples of suitable materials that yield fluoride ions are found in US Patent No. 3,535,421 to Briner and others; 4,885,155 by Parran, Jr. and others and 3,678,154 by Widder and others. Representative fluoride ion sources include, but are not
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    17/42 are limited to stannous fluoride, sodium fluoride, potassium fluoride, sodium monofluorophosphate, sodium fluorosilicate, ammonium fluorosilicate, amine fluoride, ammonium fluoride and their combinations.
    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 a 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 2,000 ppm, for example, about 1,000 to about 1,600 ppm, for example, about 1,450 ppm. The appropriate level of fluoride will depend on the particular application. A toothpaste for general use generally has about 1,000 to about 1,500 ppm, with the pediatric toothpaste showing 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% by weight to about 10% by weight. In one embodiment, about 0.03% by weight to about 5% by weight and in another embodiment about 0.1% by weight to about 1% by weight of the composition, in another embodiment. The weights of the fluoride salts to provide the appropriate level of fluoride ion will, of course, vary according to the weight of the counterion in the salt.
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    18/42 [00017] Amino acids: In some embodiments, the compositions of the present invention comprise an amino acid. In particular embodiments, the amino acid can be a basic amino acid. The term basic amino acid means 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. 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. In other embodiments, the amino acid is quaternized, that is, the amino group is additionally substituted to form a quaternary ammonium radical, which can form an internal salt with the carboxyl group, for example, betaine (Ν, Ν, Νtrimethylglycine).
    [00018] 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, from about 0.5% by weight to about 10% by weight of the total weight of the composition, for example, about 1.5% by weight to about 3.75% by weight, about 5% by weight or about 7.5% by weight of the total weight of the composition in the case of a toothpaste, or
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    19/42 for example, about 0.5-2% by weight, for example, about 1% in the case of a mouthwash.
    [00019] Abrasives: The compositions of the invention, for example, Composition 1 and strings can understand abrasives silica and can understand abrasives additional, for example, an abrasive of phosphate of calcium, phosphate tricalcium (Ca 3 (PO 4 ) 2 ), hydroxyapatite (Caio (PO4) 6 (OH) 2), or phosphate dihydrate dicalcic (CaHPO 4 . 2H2O, also sometimes referred to in gift document as DiCal) or pyrophosphate of calcium, abrasive carbonate calcium; or abrasives, such as metaphosphate sodium, metaphosphate potassium, aluminum silicate, alumina calcined, bentonite or other siliceous materials or combinations of the same.
    [00020] Other abrasive silica polishing materials useful herein, as well as other abrasives generally have an average particle size ranging between about 0.1 and about 30 microns, about 5 and about 15 microns. The silica abrasives can be precipitated silica or silica gels, such as the silica xerogels described in US Patent No. 3,538,230, to Pader et al. And US Patent No. 3,862,307 to Digiulio. Private silica Xerogels are marketed under the trade name Syloid® by W.R. Grace & Co.,
    Davison Chemical Division. Precipitated silica materials include those marketed by J.M. Huber Corp. under the trade name Zeodent®, including silica with the designation Zeodent 115 and 119. These silica abrasives are described in US Patent No. 4,340,583, issued to Wason. In certain modalities, materials
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    20/42 abrasives useful for the practice of the oral care compositions according to the invention include silica gels and precipitated amorphous silica having an amount of oil absorption of less than about 100 cm3 / 100 g silica and in the range of about 45 cm 3/100 g to about 70 cm3 / 100 g silica. Oil absorption values are measured using the ASTA Rub-Out D281 method. In certain embodiments, silicas are colloidal particles with an average particle size of about 3 microns and 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 silica hydrogel, compound of colloidal silica particles having a 29% water content by weight averaging about 7 to about 10 microns in diameter, and an absorption of less oil than about 70 cm3 / 100g of silica is a example of a low oil absorption silica abrasive useful in the practice of the present invention.
    [00021] Foaming agents: The oral hygiene compositions of this invention may also include an agent for increasing the amount of foam that is produced when the oral cavity is brushed. Illustrative examples of agents that increase the amount of foam include, but are not limited to, 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 oral care vehicle component of the present invention. O
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    21/42 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 mode 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 an embodiment of about 5% to about 50% and in another embodiment of about 10% to about 20% by weight, of the carrier component of the oral hygiene compositions of the present invention. When present, the amount of foaming agent in the oral care composition (i.e., a single dose) is about 0.01 to about 0.9%, by weight, about 0.05 to about 0.5% by weight, and in another embodiment from about 0.1 to about 0.2% by weight.
    [00022] Surfactants: Compositions useful in the invention may contain anionic surfactants, for example:
    i. water-soluble salts of higher fatty acid monoglyceride monosulfates, such as the sodium salt of the coconut oil fatty acid monoglyceride, such as N-methyl sodium N-cocoyl taurate, sodium cocomonoglyceride sulphate, ii . higher alkyl sulfates, such as sodium lauryl sulfate, iii. higher alkyl ether sulphates, for example, of the formula CH3 (CH2) m CH2 (OCH2CH2) n OSO3X, where m is
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    22/42
    6-16, for example, 10, n is 1-6, for example, 2, 3 or 4, and X is Na or K, for example, sodium laureth-2 sulfate (CH 3 (CH 2 ) ioCH 2 ( OCH 2 CH 2 ) 2 OSO 3 Na), iv. higher alkylarylsulfonates, 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 dihydroxypropane sulfonate, sulfocolaurate (potassium laurate sulfoacetamide Ν-2-ethyl)) and sodium lauryl sarcocinate.
    [00023] The term upper alkyl means, for example, C6-30 alkyl. In the specific modalities, the anionic surfactant is selected from sodium lauryl sulfate and sodium lauryl sulfate ether. The anionic surfactant may be present in an amount that is effective, for example,> 0.01% by weight of the formulation, but not at a concentration that is irritating to oral tissue, for example, <10%, and concentrations optimum depend on the specific formulation and the specific surfactant. For example, the concentrations used or mouthwash are typically on the order of one tenth of those used for a toothpaste. In one embodiment, the anionic surfactant is present in the toothpaste from 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,
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    23/42 cationic, zwitterionic or non-ionic. Generally, surfactants are those that are reasonably stable over a wide pH range. Surfactants are described more fully, for example, in US Patent No. 3,959,458 to Agricola and others; US patent 3,937,807 to Haefele; and US Patent No. 4,051,234 to Gieske et al., which are hereby incorporated by reference. In certain embodiments, the anionic surfactants useful for this invention 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 fatty acid monoglycerides with about from 10 to about 18 carbon atoms. Sodium lauryl sulfate, sodium lauroyl sarcosinate and sodium coconut monoglyceride sulfonates are examples of anionic surfactants of this type. In a particular embodiment, the composition of the invention, for example, Composition 1 and sequences comprise sodium lauryl sulfate.
    [00024] 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 from about 0.5% to about 2.0% by weight of the total composition.
    [00025] Tartar control agents: In the various embodiments of the present invention, the compositions comprise an anti-calculating agent (tartar control). Appropriate anticalculation agents include, without limitation,
    Petition 870180070625, of 8/13/2018, p. 32/56
    24/42 phosphates and polyphosphates (eg, pyrophosphates), acid (AMPS)], citrate zinc salts, polyamino propane-sulfonic hexametaphosphate, polypeptide trihydrate, polyolefin sulfonates, polyolefin phosphates, diphosphonates. The invention thus can comprise phosphate salts in addition to zinc phosphate. In particular embodiments, these salts are alkaline phosphate salts, that is, salts of alkali metal hydroxides or alkaline earth hydroxides, for example, sodium, potassium or calcium salts. Phosphate, as used herein, comprises orally mono- and polyphosphates orally acceptable, for example, Pi-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 the 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, dihydrated dicalcium phosphate, calcium pyrophosphate, tetrasodium pyrophosphate , tetrapotassium pyrophosphate, sodium tripolyphosphate, and mixtures of any two or more of these. In a specific embodiment, for example, the compositions comprise a mixture of tetrasodium pyrophosphate (Na4P2Ü7), calcium pyrophosphate (CazPzCb) and dibasic sodium phosphate (NazHPCU), for example, in amounts of about 3-4% of the phosphate of dibasic sodium and about 0.2-1% of each of the pyrophosphates. In another embodiment, the compositions comprise a mixture of tetrasodium pyrophosphate
    Petition 870180070625, of 8/13/2018, p. 33/56
    25/42 (TSPP) and sodium tripolyphosphate (STPP) (NasPaOio), for example, in ratios of about 1-2% TSPP and about 7% to about 10% STPP. Such phosphates are provided in an amount effective to reduce enamel erosion, to aid teeth cleaning, and / or to reduce the accumulation of tartar on the teeth, for example, in an amount of 2-20%, for example, about 5-15%, by weight of the composition.
    [00026] Flavoring agents: The oral hygiene compositions of this invention can 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 the various aldehydes, flavoring esters, alcohols and the like. Examples of essential oils include mint, peppermint, wintergreen, sassafras, cloves, sage, eucalyptus, marjoram, cinnamon, lemon, grapefruit and orange oils. Chemicals like menthol, carvone and anethole are also useful. Certain modalities use 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.
    [00027] Polymers: The oral hygiene compositions of the invention also include polymers, additional in order to adjust the viscosity of the formulation or improve 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, gum
    Petition 870180070625, of 8/13/2018, p. 34/56
    26/42 xanthan or carrageenan gum). Acid polymers, for example, polyacrylate gels can be supplied in the form of their free acids or partially soluble or completely neutralized water (eg, potassium and sodium) or ammonium salts.
    [00028] Silica thickeners, which form polymeric or gel structures in 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, such as the silica thickeners are very finely divided and offer little or no abrasive action. Other thickeners are carboxyvinyl polymers, carrageenan, hydroxyethylcellulose and water-soluble salts of cellulose ethers, such as sodium carboxymethyl cellulose and sodium carboxymethyl hydroxyethyl cellulose. Natural gums such as gum caraia, 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 are used in an amount of about 0.5% to about 5.0% by weight of the total composition.
    [00029] The compositions of the invention can include an anionic polymer, for example, in an amount of about 0.05 to about 5%. Such agents which are generally known for use in toothpaste, although not for that specific application, and useful in the present invention are disclosed in US Patent numbers 5,188,821 and 5,192,531; and include synthetic anionic polymeric polycarboxylates,
    Petition 870180070625, of 8/13/2018, p. 35/56
    27/42 such as 1: 4 to 4: 1 copolymers of maleic anhydride or acid with another ethylenically unsaturated, polymerizable monomer, preferably methyl vinyl ether / maleic anhydride having 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 (M.W. 500,000), AN 119 (M.W. 250,000) and preferably S-97 Grade
    Pharmaceutical (M..W 700,000) available from ISP Technologies, Inc., Bound Brook, NJ 08805. Reinforcing agents, when present, are present in amounts ranging from about 0.05 to about 3% by weight. Other operating polymers include those, such as 1: 1 maleic anhydride copolymers with ethyl acrylate, hydroxyethyl methacrylate, N-vinyl-2-pyrrolidone, or ethylene, the latter being available, for example, as Monsanto EMA number 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 Nvinyl-2-pyrrolidone. Generally suitable are olefinically polymerized or ethylenically unsaturated carboxylic acids containing an olefinic carbonocarbon double bond and at least one carboxyl group, that is, an acid containing an olefinic double bond that works readily in polymerization due to its presence in the monomer molecule, either in alpha-beta position relative to a carboxyl group or as part of a terminal methylene group. Illustrative of such acids are acrylic, methacrylic, ethacrylic, alpha-chloroacrylic, crotonic, beta-acryloxy-propionic acids,
    Petition 870180070625, of 8/13/2018, p. 36/56
    28/42 sorbic, alpha-chlorosorbic, cinnamic, beta-styrylacrylic, muconic, itaconic, citraconic, mesaconic, glutaconic, aconitic, alpha-phenylacrylic, 2-benzyl acrylic, 2cyclohexylacrylic, angelic, umbilic, fumaric, maleic and anhydrous. Other different olefinic monomers 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 that contains the acrylamide homopolymers and / or unsaturated sulfonic acid homopolymers and substituted salts thereof, in particular, where the polymers are based on unsaturated sulfonic acids selected from sulfonic acrylamide acids, such such as, 2-acrylamide2-methylpropane 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, incorporated herein by reference. Another useful class of polymeric agents includes polyamino acids containing proportions of anionic surface-active amino acids, such as aspartic acid, glutamic acid and phosphoserine, as disclosed in US Patent No. 4,866,161 to Sikes et al.
    [00030] Water: Oral compositions can comprise significant levels of water. The water used in the preparation of commercial oral compositions must be deionized and free from organic impurities. The amount of water in the compositions includes the free water that is added
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    29/42 plus that amount that is introduced with other materials.
    [00031] Humectants: Within certain modalities of oral compositions, it is also desirable to incorporate a humectant to prevent the composition from becoming stiff upon exposure to air. Certain humectants can also impart sweetness or desirable 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 in levels of more than 25%, for example, 25-35%, about 30% with 5% or less of other humectants.
    [00032] 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 3,959,458 to Agrícola et al. And US Patent 3,937,807 to Haefele, all of which are incorporated herein by reference.
    [00033] As used throughout the document, the ranges are used as an abbreviation for each and every value that is within the range. Any
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    30/42 value within the range can be selected as the end of the range. In addition, all references cited in this document are incorporated into this document as a reference in their entirety. In the event of a conflict of definitions between the present disclosure and that reference cited, the present invention will be preferred.
    [00034] Unless otherwise specified, all percentages and quantities expressed in this document and anywhere in the specification should be understood as referring to the percentage by weight. Quantities are provided based on the active weight of the material.
    EXAMPLES
    Example 1 [00035] Test toothpaste is prepared comprising 2% zinc phosphate in combination with 5% arginine, 1,450 ppm fluoride and phosphates. This toothpaste has a pH of 9.13, consistent with the relatively high arginine content. Toothpastes comprising 2% zinc citrate, 1% zinc citrate, 1% zinc citrate + 1% zinc phosphate, without zinc, without arginine are also prepared according to the following formulations (ingredients by weight of composition):
    Table 1
    Ingredient 2%Phosphatezinc 2%Citratezinc 1%Citratezinc 1% Phosphatezinc +1% citratezinc Withoutarginine PEG600 3.0 3.0 3.0 3.0 3.0 CMC-7 0.65 0.65 0.65 0.65 0.65 Xanthan 0.2 0.2 0.2 0.2 0.2
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    Sorbitol 27.0 27.4 28.4 28.4 28.4 Glycerin 20, 0 20, 0 20.0 20, 0 20.0 Saccharin 0.3 0.3 0.3 0.3 0.3 Pyrophosphatetetrasodium 0.5 0.5 0.5 0.5 0.5 Pyrophosphatecalcium 0.25 0.25 0.25 0.25 0.25 Sodium phosphatedibasic 3.5 3.5 3.5 3.5 3.5 Sodium fluoride(to provide 1,450fluoride ppm) 0.32 0.32 0.32 0.32 0.32 Water QS QS QS QS QS Titanium dioxide 0.5 0.5 0.5 0.5 0.5 Abrasive silica 8.0 8, 0 8, 0 8.0 8, 0 Thickenersilica 8, 0 8, 0 8.0 8, 0 8, 0 L-Arginine 5.0 5.0 5.0 5.0 - Lauryl sulfatesodium 1.5 1.5 1.5 1.5 1.5 Flavoring 1.2 1.2 1.2 1.2 1.2 Zinc Phosphate 2.0 - - 1.0 - Zinc Citrate - 2.0 1.0 1.0 1.0
    Example 2 [00036] The toothpaste of Example 1 containing 2% zinc phosphate, together with arginine and fluoride, shows superior efficacy compared to the acid challenge compared to the control toothpaste comprising 1% citrate zinc.
    [00037] An in vitro methodology is used to determine the enamel protection activity of the formulation prototypes of Example 1. Enamel substrates (N = 6/8 per cell) are prepared by incorporating bovine incisors into resin based on
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    32/42 methacrylate and polishing with 600 and 1,200 grain carbide paper consecutively. Care must be taken not to penetrate the dentin layer when polishing the enamel to a mirror finish. Before the test, all enamel substrates are pre-attacked with 5% citric acid for 30 seconds. Half the side of each substrate is coated with acid-resistant tape to protect the surface as the control surface. The model used to evaluate the products alternated treatment periods of 1 minute with product and periods of exposure to acid of 2 minutes according to the daily sequence of T-C-C-C-C-T (T = treatment with product, C = acid challenge). The acid challenge is performed with a 1% aqueous solution of citric acid (unbuffered), adjusted to pH = 3.8 with NaOH. All enamel substrates are kept in a sterile artificial saliva solution at 37 ° C, while not undergoing treatment or challenge. This regime is conducted for a total of five days, at the end of which a microhardness analysis is used to quantify the amount of enamel lost due to erosion on each enamel substrate on the protected and exposed surface. The change in percentage hardness is calculated. Without treatment, using deionized water instead of the test toothpaste, the change in the percentage of hardness is very high, around 80%, with a slight variation from experiment to experiment, depending on the specific substrate.
    [00038] The formula containing 2% zinc phosphate is effective against demineralization, in this in vitro pH cycling model designed to investigate the protective effect
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    33/42 of the treatments on the enamel at the beginning of dissolution, with a reduction in hardness followed by a repeated challenge with acid of only 24.3%, which is less than the 26.3% reduction in hardness observed for the citrate formulation of 1% zinc. A separate experiment shows that increasing the amount of zinc citrate in the formulation from 1% to 2% does not increase the effectiveness against acid challenge. The maximum effect is already reached at 1%. Thus, the effectiveness of a zinc phosphate formulation in this assay is greater or at least as good as the maximum effect achievable using a zinc citrate formulation, which is surprising in view of the belief in the art that zinc phosphate that it is relatively inert in the oral cavity.
    [00039] Further experiments are conducted to evaluate formulations that comprise zinc phosphate (ZnP) with and without arginine, and formulations that comprise 1% zinc phosphate and zinc citrate. A commercial toothpaste for enamel protection (Comercial 1), which includes sodium fluoride and potassium nitrate is included as a positive control. (NB: Preparations made from different human teeth are used for each set of experiments, so there may be some variation between sets of experiments):
    Table 2
    Withouttreatthen ZnP ZnP +citrateZnP ZnP +argininThe Comercial 1 % Reduction in hardness 67.56 34.13 44.19 31.26 32.96
    [00040] In this series of experiments, zinc phosphate with arginine is at least as good as the positive control, and unexpectedly, it is significantly
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    34/42 better than the combination of zinc phosphate and zinc citrate.
    Example 3 [00041] Electron spectroscopy, for chemical analysis (ESCA, also known as X-ray photoelectron spectroscopy or XPS) is a surface analysis technique used to obtain chemical information on the surfaces of solid materials. The material characterization method uses an x-ray beam to excite a solid sample resulting in the emission of photoelectrons. An energy analysis of these photoelectrons provides binding information for both elements and chemistry on a sample surface. The relatively low kinetic energy of the photoelectrons provides ESCA at a sampling depth of about 30 Å. ESCA is used to analyze the mineral content of enamel, before and after the use of test toothpaste vs. control toothpaste on polished and attacked enamel substrates prepared and treated as described in the previous examples, which confirms that zinc is released on the enamel surface and that zinc remains on the surface, even after acid challenges, as well as confirming the effective release of fluoride.
    [00042] The ESCA data for the enamel samples treated with the various Zn / arginine / anti-erosion phosphate pastes in Example 1 are shown in Table 3 (below), which defines the detected elements and their respective atomic concentrations. All samples are analyzed after each polishing, engraving and treatment step. For simplicity, only the average composition
    Petition 870180070625, of 8/13/2018, p. 43/56
    35/42 for all samples is presented polished and attacked. In all cases, separate samples are analyzed for each treated sample, the compositions of the as well as the average composition for presented.
    for surfaces three to four sample areas. For the individual zones, each sample is [00043] C and N are detected in the polished samples and attacked from surface organic compounds. Ca and P are detected from hydroxyapatite (PAH) in the enamel, with typical P / Ca ratios for enamel surfaces. The average P / Ca ratio for the attacked surfaces is slightly less than for the polished surfaces, indicating that there is a reduction in the phosphate of the surface in relation to Ca after etching. A low level of Zn is detected for the polished surfaces, which is removed by etching. Fluoride is also detected on both surfaces, polished and attacked at low levels. A low level of Na is also observed. In general, the polished and etched enamel surface compositions are typical for bovine enamel.
    [00044] C and N are detected on the surfaces of all samples treated from organic surface compounds. The C levels for all samples are higher than for the attacked surfaces, due to the presence of residual organic materials, most likely from the pastes. The levels of N are also higher for the treated samples in relation to the attacked surfaces.
    [00045] Ca and P are also detected on the surface of the samples, from the PAH in the enamel. The relations of
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    36/42
    P / Ca for the treated samples are higher than for the attacked surfaces, indicating an excess of phosphate in relation to Ca. For all samples, the Na concentrations are also significantly higher than for the attacked enamel. The higher levels of phosphate and Na in the treated samples suggest that the Na phosphate in the paste was deposited on the enamel surfaces. Si is also detected in low amounts in the treated enamel, due to the residual silica of the pastes.
    [00046] For enamel samples treated with pastes containing both zinc citrate and zinc phosphate, high zinc levels are observed on the surface. As with previous studies, the Zn / Ca ratios provide the best means for comparing zinc absorption on enamel surfaces. The Zn / Ca ratio for enamel treated with zinc phosphate paste is greater than that for zinc citrate pastes. This indicates that the zinc phosphate paste deposits more zinc in the enamel than zinc citrate products. On a molar basis, zinc phosphate contains more zinc than an equal weight of zinc citrate. This may explain more zinc detected in the enamel treated with the zinc phosphate paste, but it is clear that any form of zinc phosphate is effective in delivering zinc to the enamel surface. Overall, the Zn / Ca indices observed for the samples in the present study are double those for the enamel samples from the previously reported pH cycling study.
    [00047] ESCA zinc peak positions can provide information on the chemical status of zinc in the
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    37/42 enamel surfaces. The zinc peak positions for all samples treated with zinc containing pastes are the same. This suggests that the zinc present in all samples is of a similar chemical form. In addition, the peak zinc positions for samples treated with zinc paste are the same as those for the underlying zinc on the polished enamel surfaces. The underlying zinc inherently present in the enamel is likely to be in the form of a zinc PAH. Thus, the data suggest that the zinc in the treated enamel may also be in the form of a zinc PAH.
    [00048] F in the form of fluoride is detected on the surfaces of all enamel samples treated with paste. The relative fluoride absorption between samples is also best determined using the F / Ca ratios. The data indicate that enamel treated with 1% and 2% zinc citrate pastes had similar F / Ca ratios, which suggests similar F absorption. The enamel treated with pastes containing zinc citrate without arginine and Zn3 (PO4) 2 exhibited slightly lower F / Ca ratios than the other samples. The lowest fluoride absorption for the last two treatments, however, is within the normal range for this type of study.
    [00049] ESCA results indicate that zinc deposition occurs for enamel treated with pastes containing zinc citrate or zinc phosphate. The deposition of zinc is greater for the paste containing zinc phosphate compared to pastes containing zinc citrate. The data also suggest that zinc may be present on the surface in the form of zinc-PAH. High levels of
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    38/42 fluoride are also observed for all pulp treated.
    [00050] The detailed results shown in Table 3 (below).
    Table 3 the analysis samples are
    Petition 870180070625, of 8/13/2018, p. 47/56
    Cs] co
    0.055 0.059 0.058 0.057 CN LCj CO fn kO kO kO to O O O O • k O O O O LCj CN <Ti <Ti <Ti Ot • k O O O O LCj 00 r- ~ O 00 kO 00 • k i — 1 O O O 00 O <Ti Ot LCj hi • k O O O O LCj 00 00 O CO O 00 hi hi hi «K CO CO CN tn LCj CO LCj LCj LCj > n hi hi hi • k O O O O CN CN tn CO <Ti 00 O • k 00 r- ~ r- ~ 00 00 <Ti r- ~ 00 r- ~ > n hi hi hi • k 00 00 00 00 CN <Ti O 00 <Ti O Ot • k O O i — 1 O O i — 1 P i — 1 CN kO to • k kO CO CO co CO tn r- ~ LCj O LCj CO LCj 00 hi hi hi • k O CO M Treated average
    0.072 0.070 0.063 0.068 CO CN 00 00 LCj kO LCj > n O O O O • k O O O O 00 00 <Ti <Ti <Ti Ot • k O O O O r- ~ CO LCj > n CN i — 1 Ot • k CN CN i — 1 LCj i — 1 i — 1 Ot LCj LCj hi hi hi • k O O O O 00 O <Ti M 00 LCj <Ti hi hi hi «K CN CN CO tn CO LCj r- ~ M CO hi hi hi • k O O O O i — 1 O 00 i — 1 00 O Ot • k kO kO 00 Ko CO LCj CN CN i — 1 M hi hi hi • k kO r- ~ 00 CO CN tn <Tl r- ~ 00 00 • k O O O O r- ~ O O r- ~ r- ~ i — 1 M hi hi hi • k r- ~ kO r- ~ CO CO CO tn kO 00 i — 1 M O r- ~ n. n. n. • k CO CN 00 CO Treated * average
    H
    H tT
    P ε
    the o
    o o
    CN nj
    P
    O
    -P
    P
    -P
    H
    The <Ti
    ONLY
    O
    O
    LO
    LO
    O
    LO <Ti
    CN
    CN <Ti
    CO
    O
    CN r- ~
    LQ
    Γ— <Ti kO co
    CN
    Γ—
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    0.067 0.065 tstoO• kO 0.050 0.053 0.055 0.056 0.053 0.067 0.064 0.062 0.076 O00OO 0.092 0.079 0.082 03 04 .03 07 OO 97 05 .01 i — 1 i — 1 i — 1 i — 1 O i — 1 Η 83 00O .02 58 82 σι .08 O i — 1 i — 1 CN CN i — 1 Μ 55 52 .52 31 36 43 42 .38 O O O O O O O ο 60 12 ts 11 52 O00 67 .28 CN CO m ' CN CN co 09 55 51 48 r— 54 CNr— 59 58 . also detected O O O O O O O ο 8.43 8.22 8.02 6, 63 6.81 7.62 7.89 μ ·Μ• kts 22 σι tsts 21 <TiΓ— kO00 00 .09 00 r— ts kO kO r— r— ts .21 .26 .22 . 11 .07 . 91 09 .05 1—1Ο1 i — 1 i — 1 i — 1 i — 1 O i — 1 Η * 00 .28 .60 . 75  50 09 σι Μ00 CO co 33. co co O γ-γο 36, . 77 .07 ts00 06 ' .59 00O . 47 κοΟι CN CO M · ' co Γ-ΟΟ σιco * -ί * average arginine * average with 2% nj CNO0-iΓ0 Treated
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    41/42 [00051] As these data show the release of zinc into the enamel using the zinc phosphate formulation (mean 0.58) is actually greater than the release of zinc using any of the zinc citrate formulations. The incorporation of zinc into the enamel, possibly through the formation of a hydroxyapatite-zinc material is advantageous, in view of the beneficial effects of zinc to control erosion and reduce the deposition of bacterial biofilm. The fluoride release with the zinc phosphate formulation is also in an acceptable range, which shows significant fluoride deposition compared to the control, similar to the formulation comprising zinc citrate without arginine.
    Example 4 [00052] Although zinc phosphate is insoluble in water, it is soluble in acidic solutions. Formulations comprising, for example, 2% lactic acid (about pH 2.4), or even as little as 0.05% citric acid (pH about 4), with zinc phosphate at 0.01- 0.03% have no precipitation. It has been found that the solubility of zinc phosphate can be increased in a formulation comprising an amino acid and / or a betaine surfactant. A stable mouthwash formulation is provided as follows:
    Ingredient % by weight Sorbitol 5.5 Glycerin 7.5 Propylene glycol 7 Sodium saccharin 0.02
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    Citric acid (anhydrous) 0.05 Zinc Phosphate 0.028 Flavoring / coloring 0.12 Potassium sorbate 0.05 Cocoamidopropyl betaine 1 Water 0 enough Total 100
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    1/4
    权利要求:
    Claims (4)
    [1]
    1. Toothpaste characterized by the fact that it comprises (i) zinc phosphate and (ii) arginine in the form of a free or orally acceptable salt in an amount of 0.5 to 10% by weight, where zinc phosphate is a preformed salt in an amount of 0.05 to 5% by weight.
    [2]
    2. Toothpaste according to claim 1, characterized by the fact that the amount of zinc phosphate is 0.1 to 4% by weight.
    3. Toothpaste, according the claim 1, characterized by the fact that the base of the toothpaste understands an abrasive. 4. Toothpaste, according the claim 1, characterized by the fact that it comprises one or more humectants, and one or more agents surfactants, an amount effective use of a fluoride ion source, and an amount efficacy of one or more salts of alkaline phosphate • 5. Toothpaste, according the claim 4,
    characterized by the fact that it also comprises an effective amount of one or more antibacterial agents.
    6. Toothpaste according to claim 4, characterized by the fact that it also comprises a bleaching agent.
    7. Toothpaste according to claim 1, characterized by the fact that it also comprises one or more sources of zinc ion in addition to zinc phosphate.
    8. Toothpaste according to claim 1, characterized by the fact that it comprises:
    1 to 3% zinc phosphate;
    1 to 8% arginine;
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    2 to 8% of alkaline phosphate salts selected from dibasic sodium phosphate, dibasic potassium phosphate, dicalcium phosphate dihydrate, tetrasodium pyrophosphate, tetrapotassium pyrophosphate, calcium pyrophosphate, sodium tripolyphosphate, and mixtures of any of these or more;
    700 to 2,000 ppm fluoride;
    on an abrasive silica paste base.
    9. Mouthwash characterized by the fact that it comprises zinc phosphate and a basic amino acid in the form of a free or orally acceptable salt, in which zinc phosphate is a preformed salt, and in which the basic amino acid is arginine in an amount of 0.5 to 2% by weight, and zinc phosphate is added in an amount of 0.005 to 4% by weight.
    10. Mouthwash according to claim 9, characterized by the fact that the amount of zinc phosphate is 0.5 to 4% by weight.
    11. Mouthwash according to claim 10, characterized by the fact that it also comprises an effective amount of a fluoride ion source;
    an effective amount of one or more alkaline phosphate salts; and an effective amount of one or more antibacterial agents.
    12. Mouthwash according to claim 11, characterized by the fact that it also comprises a bleaching agent.
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    [3]
    3/4
    13. Mouthwash according to claim 12, characterized by the fact that it also comprises one or more sources of zinc ion in addition to zinc phosphate.
    14. Mouthwash according to claim 9, characterized by the fact that it comprises:
    0.1 to 2% zinc phosphate;
    0.1 to 3% arginine;
    2 to 8% of alkaline phosphate salts selected from dibasic sodium phosphate, dibasic potassium phosphate, dicalcium phosphate dihydrate, tetrasodium pyrophosphate, tetrapotassium pyrophosphate, calcium pyrophosphate, sodium tripolyphosphate, and mixtures of any of these or more;
    700 to 2,000 ppm fluoride;
    on an abrasive silica paste base.
    15. Mouthwash according to claim 14, characterized by the fact that the composition comprises:
    5 to 10% glycerin;
    3 to 7% sorbitol;
    5 to 10% propylene glycol;
    0 to 0.1% TSPP;
    0.01 to 1% sweetener;
    0.01 to 1% citric acid;
    0 to 0.1% xanthan;
    0.005 to 0.05% zinc phosphate;
    0 to 0.01% cetyl pyridinium chloride;
    0.01 to 0.1% potassium sorbate;
    0.05 to 1% flavoring; and
    0.1 to 2% cocamidopropyl betaine.
    Petition 870180070625, of 8/13/2018, p. 54/56
    [4]
    4/4
    16. Toothpaste, according to claim 1, or mouthwash, according to claim 9, characterized by the fact that it is for use in the treatment or reduction of erosion of tooth enamel.
    17. Use of zinc phosphate and arginine in the form of a free or orally acceptable salt characterized by the fact that it is in the preparation of a toothpaste as defined in claim 1 or mouthwash as defined in claim 9, for the treatment or reduction of enamel erosion of teeth, where zinc phosphate is a preformed salt.
    Petition 870180070625, of 8/13/2018, p. 55/56
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    RU2650609C2|2018-04-16|
    AU2012396295A1|2015-05-28|
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    IN2015DN03992A|2015-10-02|
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    TW201808256A|2018-03-16|
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    TWI605853B|2017-11-21|
    WO2014088573A1|2014-06-12|
    US20210315785A1|2021-10-14|
    HK1215158A1|2016-08-19|
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    MX360491B|2018-10-24|
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    法律状态:
    2018-05-08| B15K| Others concerning applications: alteration of classification|Ipc: A61K 8/27 (2006.01), A61K 8/24 (2006.01), A61K 8/2 |
    2018-05-15| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|
    2018-09-25| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2018-12-04| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 05/12/2012, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    PCT/US2012/068000|WO2014088573A1|2012-12-05|2012-12-05|Zinc phosphate containing compositions|
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