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    • 专利摘要:
    summary oral care products comprising a tetrabasic zinc amino acid halide complex are described herein as oral care compositions comprising a tetrabasic zinc halide and an amino acid; along with methods to produce and use it.
    公开号:BR112015014253B1
    申请号:R112015014253-2
    申请日:2012-12-19
    公开日:2019-04-09
    发明作者:Zhiqiang Liu；Long Pan；Ying Yang；Guofeng Xu；Michael A. Stranick
    申请人:Colgate-Palmolive Company；
    IPC主号:
    专利说明:

    ORAL HYGIENE COMPOSITION UNDERSTANDING A TETRABASIC AND AMINO ACID ZINC HALIDE COMPLEX AND BACKGROUND USES [001] Heavy metal ions, such as zinc, are resistant to acid attack. Zinc is found above hydrogen in the electrochemical series, so that the metallic zinc in an acidic solution reacts in order to release hydrogen gas, as the zinc passes through the solution to form dications, Zn 2+ . Zinc showed antibacterial properties in plaque and cavity studies.
    [002] Soluble zinc salts, such as zinc citrate, have been used in toothpaste compositions, see, for example, U.S. Patent No. 6,121,315, but have numerous disadvantages. The zinc ions in the solution convey an astringent and unpleasant mouthfeel, so formulations that provide effective levels of zinc and also have acceptable organoleptic properties were difficult to achieve. Finally, zinc ions will react with anionic surfactants such as sodium lauryl sulfate, thus interfering with foam and cleaning.
    [003] Tetrabasic zinc chloride (TBZC), is a zinc hydroxide compound with the chemical formula Zn5 (OH) 8Cl2 · H2O. It is also referred to as zinc chloride hydroxide monohydrate, basic zinc chloride, zinc hydroxychloride, or zinc oxychloride. It occurs naturally as the mineral simonkolleite. Unlike zinc chloride, TBZC is insoluble in water. TBZC has been suggested for use in oral hygiene compositions, see, for example, Document No. GB2243775A, but these formulations do not deliver zinc efficiently to patients.
    Petition 870190005760, of 01/18/2019, p. 10/14
    2/55 teeth due to TBZC insolubility.
    [004] While the prior art reveals the use of various oral compositions for the treatment of dentin hypersensitivity, tooth decay and enamel erosion and demineralization, there is still a need for additional compositions and methods that show improved performance in these treatments.
    SUMMARY [005] While TBZC is substantially insoluble in prior art formulations, it has now been revealed that tetrabasic zinc chloride can form a soluble complex with an amino acid. When placed in the formulation, this complex provides an effective concentration of zinc ions for the enamel, thus protecting against erosion, reducing bacterial colonization and the development of biofilm and perfecting the improved luster for the teeth. In addition, after use, the formulation provides a precipitate that can cover dentinal tubules, thereby reducing tooth sensitivity. This is unexpected, given TBZC's poor solubility. Although efficient delivery of zinc compared to conventional formulations with insoluble TBZC is provided, formulations comprising the TBZC amino acid complex do not exhibit poor taste and mouth feel, poor fluoride delivery and poor foam and cleanliness associated with conventional oral hygiene based on zinc with the use of soluble zinc salts.
    [006] Therefore, the invention provides oral hygiene compositions, for example, mouthwash, oral gel or dentifrice compositions comprising TBZC in combination
    3/55 with an amino acid. In one embodiment, the composition further comprises an amino acid, for example, a basic amino acid. Optionally, the compositions can additionally comprise a fluoride source and or an additional phosphate source. The compositions can be formulated in a suitable oral hygiene formulation, for example, a conventional toothpaste base, oral gel or mouthwash, for example, which comprises one or more abrasives, surfactants, foaming agents, vitamins, polymers, enzymes, humectants, thickeners, antimicrobial agents, preservatives, flavorings and / or dyes.
    [007] Additionally, the invention provides methods for using the compositions of the invention in order to reduce and inhibit acid erosion of the enamel, clean the teeth, reduce the biofilm generated by bacteria and plaque, reduce gingivitis, inhibit caries and formation cavities and reduce dentin hypersensitivity, which comprises applying a composition of the invention to teeth.
    [008] The additional areas of applicability of the present invention will be evident from the detailed description provided hereinafter. It should be understood that the detailed description and specific examples, while indicating the preferred embodiment of the invention, are designed for purposes of illustration only and are not intended to limit the scope of the invention.
    DETAILED DESCRIPTION [009] The following description of the preferred mode (s) is merely exemplary in nature and is not intended in any way to limit the invention, its order or use.
    4/55 [010] Therefore, the present invention provides, in a first embodiment, an oral hygiene composition (Composition 1) which comprises a tetrabasic zinc chloride (TBZC) in complex with an amino acid; for example:
    1.1 Composition 1, in which the amino acid is selected from lysine, glycine and arginine, in the form of a free or orally acceptable acid addition salt, for example, hydrochloride form.
    1.2 Composition 1 or 1.1, where the amino acid is a basic amino acid, for example, arginine or lysine, in the form of a free or orally acceptable salt.
    1.3 Any of the preceding compositions, in which the TBZC amino acid complex is formed, in whole or in part, in situ after the composition is applied.
    1.4 Any of the preceding compositions, in which the TBZC amino acid complex is formed, in whole or in part, in situ after the composition is formulated.
    1.5 Any of the preceding compositions, where the amino acid is lysine.
    1.6 Any of the preceding compositions, wherein the zinc amino acid halide and / or zinc amino acid halide precursors are present in an amount of 0.05 to 10% by weight of the composition, optionally at least 0.1 at least 0.2, at least 0.3, at least 0.4, at least 0.5, at least 1, at least 2, at least 3, or at least 4 to 10% by weight of the composition.
    1.7 Any of the preceding compositions, in which TBZC is present in an amount of 0.05 to 10% by weight of the composition, optionally at least 0.1, at least
    5/55
    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.
    1.8 Any of the preceding compositions, wherein the amino acid hydrohalide 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 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.
    1.9 Any of the preceding compositions, in which TBZC and amino acid hydrohalide are present in amounts, so that, if combined with zinc amino acid halide, the zinc amino acid halide would be present in an amount of 0.05 to 10 % by weight of the composition.
    1.10 Any of the preceding compositions, in which 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, or 1: 3.
    1.11 Any of the preceding compositions, wherein a total amount of zinc present in the composition is 0.05 to 10% by weight.
    1.12 Any of the preceding compositions, in which the halide is selected from the group consisting of chlorine, bromine and iodine.
    1.13 Any of the preceding compositions, wherein the zinc amino acid halide is zinc lysine chloride.
    1.14 Any of the preceding compositions, in an anhydrous carrier.
    6/55
    1.15 Any of the preceding compositions which is an anhydrous composition comprising TBZC and amino acid hydrohalide.
    1.16 Any of the preceding compositions comprising an amino acid hydrohalide which is lysine hydrochloride.
    1.17 Any of the preceding compositions comprising a zinc amino acid halide formed from TBZC and an amino acid hydrohalide.
    1.18 Any of the compositions precedents, in that the halide is chloride. 1.19 Any of them of compositions precedent in what O amino acid is lysine. 1.20 Any of them of compositions precedents, in what O amino acid halide in zinc is a chloride complex in lysine zinc (for example, (ZnLys2Cl) + Cl - or
    (ZnLys 3 ) 2+ Cl 2 ) or zinc arginine chloride complex.
    1.21 Any of the preceding compositions in the form of a toothpaste, gel, mouthwash, powder, cream, strip or gum.
    1.22 Any of the preceding compositions on an orally acceptable basis, for example, a mouthwash, gel, or toothpaste.
    1.23 Any of the preceding compositions in the form of a dentifrice, for example, in which the TBZC amino acid complex is present in an effective amount, for example, in an amount of 0.5 to 4% by weight of zinc, for example , about 1 to 3% by weight of zinc, on a toothpaste basis.
    1.24 Composition 1.1, where the dentifrice base
    7/55 comprises an abrasive, for example, an effective amount of a silica abrasive, for example, 10 to 30%), for example, about 20%.
    1.25 Composition 1 in the form of a mouthwash, for example, in which the TBZC amino acid complex is present in an effective amount, for example, in an amount of 0.5 to 4% by weight of zinc, for example, about from 1 to 3% by weight of zinc.
    1.26 Any of the foregoing compositions which further comprises an effective amount of a fluoride ion source, for example, providing 500 to 3000 ppm of fluoride.
    1.27 Any of the preceding compositions which further comprises an effective amount of fluoride, for example, wherein fluoride is a salt selected from stannous fluoride, sodium fluoride, potassium fluoride, sodium monofluorophosphate, sodium fluorsilicate, sodium fluorsilicate ammonium, amine fluoride (for example, N'-octadecyltrimethylendiamineΝ, Ν, Ν'- tris (2-ethanol) -dihydrofluoride), ammonium fluoride, titanium fluoride, hexafluorosulfate and combinations thereof.
    1.28 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 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,
    8/55 tetrasodium pyrophosphate, tetrapotassium pyrophosphate, sodium tripolyphosphate and mixtures of any of two or more of them, for example, in an amount of 20%, for example 2 to 8%, for example, ca. 5%>, by weight of the composition.
    1.29 Any of the preceding compositions comprising buffering agents, for example, sodium phosphate buffer (for example, monobasic sodium phosphate and disodium phosphate).
    1.30 Any of the preceding compositions comprising a humectant, for example, selected from glycerin, sorbitol, propylene glycol, polyethylene glycol, xylitol and mixtures thereof, for example, comprising at least 20%, for example, 20 to 40%, for example, 25 to 35% glycerin.
    1.31 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 from sodium lauryl sulfate, sodium lauryl ether sulfate and mixtures thereof, for example, in an amount of about 0.3%> to about 4.5% by weight, for example 1 to 2% lauryl sulfate sodium (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 to% > cocamidopropylbetaine.
    1.32 Any of the preceding compositions that
    9/55 further comprises a viscosity-modifying amount of one or more among polysaccharide gums, for example, xanthan or carrageen gum, silica thickener and combinations thereof.
    1.33 Any of the preceding compositions comprising strips or fragments of gum.
    1.34 Any of the preceding compositions which further comprises flavoring, fragrance and / or coloring.
    1.35 Any of the preceding compositions comprising an effective amount of one or more antibacterial agents, for example, comprising a bacterial agent selected from halogenated diphenyl ether (eg, triclosan), essential extracts (eg, tea extract, magnolia extract, thymol, herbal and rosemary oils, menthol extract, eucalyptol, geraniol, carvacrol, citral, hinokitol, catechol, methyl salicylate, epigallocatechin gallate, epigallocatechin, gallic acid, miswak extract, sea buckthorn extract) of biguanide (for example, chlorhexidine, alexidine or octenidine), quaternary ammonium compounds (for example, 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, tin salts, copper salts, iron salts), sanguinarine, propolis and oxygenating agents (eg hydrogen peroxide, buffered sodium peroxyborate or
    10/55 peroxycarbonate), phthalic acid and its salts, monopertallic acid and its salts and esters, ascorbyl stearate, oleoyl sarcosine, alkyl sulfate, dioctyl ossuccinate, salicylanilide, domiphene bromide, delmopinol, octapinol and other piperidine derivatives nicin, chlorite salts and mixtures of any of the foregoing, for example, which comprises triclosan or cetylpyridinium chloride.
    1.36 Any of the preceding compositions comprising an effective antibacterial amount of triclosan, for example, 0.1 to 0.5%, for example, about 0.3%.
    1.37 Any of the preceding compositions that further comprises a bleaching agent, for example, one selected from the group consisting of peroxides, metal chlorites, perborates, percarbonates, peroxyacids, hypochlorites and combinations thereof.
    1.38 Any of the foregoing compositions additionally comprising hydrogen peroxide or a source of hydrogen peroxide, for example, urea peroxide or a salt or peroxide complex (for example, such as peroxyphosphate, peroxycarbonate, perborate, peroxysilicate or persulfate salts; for example, calcium peroxyphosphate, sodium perborate, sodium carbonate peroxide, sodium peroxyphosphate and potassium persulfate);
    1.39 Any of the foregoing compositions that further comprise an agent that interferes with, or prevents bacterial attachment, for example, solbrol or chitosan.
    1.40 Any of the preceding compositions that
    11/55 further comprises a source of calcium and phosphate selected from (i) calcium glass complexes, for example, sodium and calcium phosphosilicates and (ii) calcium protein complexes, for example, phosphopeptide calcium phosphate amorphous casein.
    1.41 Any of the preceding compositions which further comprises a soluble calcium salt, for example, selected from calcium sulfate, calcium chloride, calcium nitrate, calcium acetate, calcium lactate and combinations thereof.
    1.42 Any of the foregoing compositions that additionally comprise a physiological or orally acceptable potassium salt, for example, potassium nitrate or potassium chloride, in an amount effective to reduce dentin sensitivity.
    1.43 Any of the preceding compositions which further comprises an anionic polymer, for example, a synthetic polymeric anionic polycarboxylate, for example, in which the anionic polymer is selected from 1: 4 to 4: 1 of maleic or acid anhydrate copolymers with another monomer polymerizable by unsaturated ethylene; for example, where the anionic polymer is a methyl vinyl ether / maleic anhydrate (PVM / MA) copolymer that has 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, wherein the anionic polymer is about 1 to 5%, for example, about 2%, of the weight of the composition.
    1.44 Any of the preceding compositions that additionally comprise a tablet to refresh the
    12/55 breath, fragrance or taste.
    1.45 Any of the preceding compositions, wherein the pH of the composition is approximately neutral, for example, pH 6 to 8, for example, about pH 7.
    1.46 Any of the preceding compositions for use in order to reduce and inhibit enamel acid erosion, clean teeth, reduce biofilm generated by bacteria and plaque, reduce gingivitis, inhibit caries and cavity formation and reduce dentin hypersensitivity.
    [011] In some embodiments, the present invention provides an oral hygiene composition comprising a tetrabasic zinc halide and an amino acid.
    [012] The invention also provides methods to reduce and inhibit enamel acid erosion, clean teeth, reduce biofilm generated by bacteria and plaque, reduce gingivitis, inhibit caries and cavity formation and reduce dentin hypersensitivity which comprise applying an effective amount composition of the invention, for
    example, any of composition 1 et seq to teeth.[013] THE invention too provides a method for to produce an composition that comprises a halide in
    zinc amino acid, for example, any one of composition 1 and following which comprises combining zinc amino acid halide precursors selected from (a) tetrabasic zinc chloride and an amino acid and / or (b) tetrabasic zinc chloride and an amino acid in a water-based material.
    [014] The invention also provides a method for producing a composition that comprises a halide of
    13/55 zinc amino acid, for example, any of composition 1 and following which comprises combining zinc amino acid halide precursors selected from (a) tetrabasic zinc chloride and an amino acid halide and / or (b) tetrabasic zinc chloride, an amino acid and a halogen acid in an aqueous-based material.
    [015] For example, in various embodiments, the invention provides methods for (i) reducing tooth hypersensitivity, (ii) reducing plaque accumulation, (iii) reducing or inhibiting demineralization and promoting remineralization of teeth, (iv ) inhibit the formation of microbial biofilm in the oral cavity, (v) reduce or inhibit gingivitis, (vi) promote wound healing or cuts in the mouth, (vii) reduce levels of acid-producing bacteria, (viii) increase relative levels of non-cariogenic and / or non-plaque forming bacteria, (ix) reduce or inhibit caries formation, (x), reduce, repair or inhibit enamel lesions before caries, for example, as detected by quantitative light-induced fluorescence (QLF ) or measurement of electrical conductance (ECM), (xi) treating, relieving or reducing dry mouth, (xii) cleaning teeth and oral cavity, (xiii) reducing erosion, (xiv) whitening teeth; (xv) reduce the formation of tartar and / or (xvi) promote systemic health, including cardiovascular health, for example, by reducing the potential for systemic infection through oral tissues, which include applying any of the compositions 1 and following, as described above, to the oral cavity of a person who needs it, for example, one or more times a day. The invention also
    14/55 provides compositions 1 and following for use in any of these methods.
    [016] The invention also provides the use of TBZC and an amino acid to produce an oral hygiene composition that comprises a zinc amino acid halide.
    [017] The invention also provides (i) the use of a zinc amino acid halide produced from TBZC (for example, produced from zinc amino acid halide precursors selected from (a) tetrabasic zinc chloride and an amino acid halide and / or (b) tetrabasic zinc chloride, an amino acid and optionally halogen acid) to reduce and inhibit acid erosion of the enamel, clean the teeth, reduce biofilm generated by bacteria and plaque, reduce gingivitis, inhibit caries and cavity formation and reduce dentin hypersensitivity; (ii) the use of a zinc amino acid halide precursor selected from (a) tetrabasic zinc chloride and an amino acid halide and / or (b) tetrabasic zinc chloride, an amino acid and optionally halogen acid in the manufacture of a composition to reduce and inhibit the erosion of enamel acid, clean clean teeth, reduce the biofilm generated by bacteria and plaque, reduce gingivitis, inhibit caries and cavity formation and reduce dentin hypersensitivity.
    [018] Without the intention of being linked to theories, it is believed that the formation of the zinc amino acid halide proceeds through a formation of the zinc halide, then a coordination of amino acid residues around a central zinc. Using the TBZC reaction with lysine hydrochloride in water as an example, TBZC
    15/55 (Zn 5 (0H) 8 Cl 2 H 2 O) can react with lysine and / or lysine HCl to form a clear solution of the Zn lysine chloride complex (ZnLys 3 Cl 2 ), where Zn 2+ is located in an octahedral center coordinated with two oxygen atoms and two nitrogen atoms in the equatorial plane that comes from two lysine carboxylic acids and amine groups, respectively. Zinc is also coordinated for the third lysine through its nitrogen and carboxylic oxygen, at the apical position of the metal's geometry.
    [019] 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 (C6H14N 2 O 2 ) 2 Cl] + Cr - . In this complex, the Zn cation is coordinated by two lysine ligands with two N atoms from NH2 groups and O atoms from carboxylic groups in an equatorial plane. This exhibits a distorted square pyramidal geometry with the apical position occupied by a CI - atom. This innovative structure gives rise to a portion of positive cation which a CI - anion is combined to form an ionic salt.
    [020] Other TBZC and amino acid complexes are possible and the precise shape depends in part on the molar proportions of the precursor compounds, for example, if there is limited halide, the free halide complexes can form, for example, ZnOLys2, which has a geometry pyramidal, with the equatorial plane which is the same as the compound above (Zn is linked to two oxygen atoms and two nitrogen atoms from different lysines), in which the top of the pyramid is occupied by an O atom.
    [021] Mixtures of complexes and / or structures of
    Additional complexes, for example, involving multiple zinc ions based on the TBZC structure, are possible and contemplated within the scope of the invention. When the complexes are in solid form, they can form crystals, for example, in hydrated form.
    [022] Regardless of the precise structure of the complex or complexes, however, the interaction of zinc and amino acid converts insoluble TBZC into a highly soluble complex. With the increase in water dilution, however, the complex disassociates and the zinc ion reverts to insoluble zinc oxide or TBZC. This dynamics is unexpected and facilitates the deposition of precipitated zinc on the teeth after administration, which acts to absorb the dentinal tubules, thus reducing hypersensitivity, and also providing zinc for the enamel, which reduces acid erosion, biofilm formation. and plate.
    [023] It should be understood that other amino acids can be used in place of lysine in the previous scheme. It will also be understood that although zinc, amino acid and halide may be mainly in the form of precursor materials or in the form of a complex, there may be a degree of equilibrium, so that the proportion of material that is currently in the complex compared to proportion in the form of precursor may vary depending on the precise formulation conditions, concentration of materials, pH, presence or absence of water, presence or absence of other charged molecules and so on.
    [024] Assets can be delivered in the form of any oral hygiene formulations, for example, a
    17/55 toothpaste, gel, mouthwash, powder, cream, strip, gum, or any other known in the art.
    [025] If the assets are delivered in the form of a mouthwash, a person who wants the benefits of washing with the stock solution and natural dilution of the stock solution by saliva will start zinc precipitation. Alternatively, the person can mix the stock solution with the appropriate amount of an aqueous diluent (such as approximately 1 part stock solution and 8 parts water for TBZC lysine samples) and wash with the mixture.
    [026] In another embodiment, the mixture is prepared and transferred immediately to a holding tray, such as those used to hold whitening gels and the person can use the tray for the effective period of time. Teeth that are in contact with the mixture will be treated. For use with this holding tray, the mixture can be in the form of a liquid or a low viscosity gel.
    [027] 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 an extended period of time for treatment effective.
    [028] In another modality, the asset is supplied in a toothpaste. After brushing the teeth, the asset is diluted by saliva and water, leading to precipitation and the formation of deposits and particles of occlusion.
    [029] The precipitation rate of the formulation can be modulated by adjusting the concentration of the complex in the stock solution and changing the proportion of the stock to water. An
    18/55 more diluted formula leads to faster precipitation and is therefore preferred when faster treatment is desired.
    [030] The benefits of the oral hygiene compositions of the invention are numerous.
    By providing zinc ions and zinc-containing compounds that can release zinc ions into the oral cavities, the oral hygiene compositions of the invention provide antimicrobial, anti-plaque, anti-gingivitis, anti-odor, anti-caries and anti-calculus benefits. Occlusion particles and surface deposits are zinc-containing compounds (in particular,
    ZnO), as well as other zinc derivatives that can release zinc ions into oral cavities and provide the various benefits, as recognized above. Additional benefits include, but are not limited to, antifixation, antiperiodontitis and anti bone loss, as well as promoting wound healing.
    [031] A second benefit is the anti-erosion properties of zinc ions that form anti-erosion deposits on dental 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 regard, the more depositions / surface occlusion due to the treatments, the more effective the treatments will be and, therefore, TBZC arginine and TBZC lysine are preferred. It is also noted that when surface deposits and occlusion particles neutralize acids, beneficial zinc ions and (infra) amino acids can be released,
    19/55 providing benefits for oral hygiene in addition to anti-erosion.
    [032] A third benefit is the anti-sensitivity benefit as a result of occlusion. Occlusion of dental tubules leads to relief of sensitivity.
    [033] A fourth benefit is the benefit associated with amino acids. The occlusion particles and surface deposits contain the corresponding amino acids, such as arginine and lysine. These amino acids provide multiple benefits. For example, basic amino acids lead to higher pH than plaque and can provide anti-caries benefits. Additionally, it is also expected that arginine can improve the activity of arginolytic bacteria, leading to healthier plaque. Arginine is also known to promote wound healing and collagen integrity.
    [034] The composition may include the zinc amino acid halide and / or precursors thereof. Precursors, which can react in situ with water to form the zinc amino acid halide, include (i) TBZC and an amino acid hydrohalide 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 zinc amino acid halide can be prepared at room temperature by mixing the precursors in a solution, such as water. In situ training provides ease of formulation. Precursors can be used instead of having to form the zinc amino acid halide first. In another modality, the water that allows the formation of the zinc amino acid halide to
    20/55 from the precursor comes from saliva and / or washing water that comes into contact with the composition after application.
    [035] Zinc amino acid halide is a water-soluble complex formed from the zinc halide acid addition salt (eg zinc chloride) and an amino acid or from the halide acid addition salt of an amino acid (eg, lysine hydrochloride) zinc ion source eg TBZC, and / or from the combination of all three of a halogen acid, an amino acid and a zinc ion source.
    [036] 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.
    [037]
    As seen from the examples below, the precipitation of zinc from the complex after dilution with water is most notable when the complex is formed from a basic amino acid.
    Thus, where precipitation after dilution is desired, a basic amino acid may be preferred.
    In some embodiments, therefore, the amino acid is a basic amino acid. Basic amino acid means natural basic amino acids, such as arginine, lysine and histidine, as well as any basic amino acid that has a carboxyl group and an amino group in the molecule that is soluble in water and provides an aqueous solution with a pH of about 7 or greater.
    21/55
    Consequently, basic amino acids include, but are not limited to, arginine, lysine, citrulline, ornithine, creatine, histidine, diaminobutanoic acid, diaminoproprionic acid, salts thereof or combinations thereof. In certain embodiments, the amino acid is lysine. In other embodiments, the amino acid is arginine.
    [038] The halide can be chlorine, bromine or iodine, more typically chlorine. The acid addition salt of an amino acid and a halogen acid (eg, HCl, HBr, or HI) is sometimes referred to herein as an amino acid hydrohalide. Thus, an example of an amino acid hydrohalide is lysine hydrochloride. Another is glycine hydrochloride.
    [039] The source of zinc ion for combination with an amino acid halide or an optionally more halogen acid in this case is tetrabasic zinc chloride. Tetrabasic zinc chloride (TBZC) or zinc chloride hydroxide monohydrate is a zinc hydroxide compound with the formula Zn 5 (OH) 8 Cl 2 · H 2 O, also referred to as basic zinc chloride, hydroxychloride zinc, or zinc oxychloride. It is a transparent crystalline solid insoluble in water. A surprising advantage of the invention is that TBZC forms complexes with the amino acid more efficiently than zinc oxide.
    [040] In certain embodiments, the amount of zinc amino acid halide in the composition is 0.05 to 30% by weight of the composition. In certain embodiments, precursors, for example, TBZC and amino acid hydrohalide, are present in amounts, so that when combined in the zinc amino acid halide, the zinc amino acid halide
    22/55 would be present in an amount of 0.05 to 10% by weight of the composition. In any of these modalities, the amount of the zinc amino acid halide may vary for the desired purpose, such as a toothpaste or mouthwash. In other embodiments, the amount of the zinc amino acid 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 30% by weight of the composition. In other embodiments, the amount of the zinc amino acid halide is less than 9, less than 8, less than 7, less than 6, less than 5, less than 4, less than 3, less than 2, less than 1, less than 0.5 to 0.05% by weight of the composition. In other modalities, the quantities are 0.05 to 5%, 0.05 to 4%,
    0.05 to 3%, 0.05 to 2%, 0.1 to 5%, 0.1 to 4%, 0.1 to 3%, 0.1 to 2%, 0.5 to 5%, 0 , 5 to 4%), 0.5 to 3%), or 0.5 to 2%> by weight of the composition.
    [041] In certain embodiments, TBZC is present in an amount of 0.05 to 10% by weight of the composition. In other embodiments, the amount of TBZC 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 others
    modalities , a amount TBZC is bottom The 9, bottom The 8, less than 7, less than 6, bottom The 5, bottom The 4, less than 3, less than 2, bottom The 1, bottom The 0.5 to 0.05%> in weight of the composition. In others
    modalities, the quantities are 0.05 to 5%>, 0.05 to 4%>,
    0.05 to 3%, 0.05 to 2%, 0.1 to 5%, 0.1 to 4%, 0.1 to 3%,
    0.1 to 2%, 0.5 to 5%, 0.5 to 4%, 0.5 to 3%, or 0.5 to 2% in
    23/55 weight of the composition.
    [042] In certain embodiments, the amino acid hydrohalide is present in an amount of 0.05 to 30% by weight. In other embodiments, the quantity 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 4, at least 5, at least 10, at least 15, at least 20 to 30%) by weight. In other embodiments, 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.
    [043] Where precursor materials are present, they are preferably present in approximately molar ratios, as required to produce the desired zinc amino acid halide, although an excess of one material or another may be desirable in certain formulations, for example, for balance the pH against other constituents of the formulation, to provide additional antibacterial zinc or amino acid buffer.
    Preferably, however, the limited amount of halide, as required by the halide level, slightly encourages the interaction between zinc and the amino acid.
    [044] 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 composition. In other embodiments, the total amount of zinc in the composition is less than 5, less than 4, less
    24/55 to 3, less than 2, or less than 1 to 0.05%> by weight of the composition.
    [045] 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 14, 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.
    [046] In certain embodiments, the composition is anhydrous. Per anhydrous, there is less than 5%) by weight of water, optionally less than 4, less than 3, less than 2, less than 1, less than 0.5, less than 0.1 to 0% by weight of water .
    [047] When supplied in an anhydrous composition, the precursors, for example, TBZC and the amino acid hydrohalide, will not react significantly to form the zinc amino acid halide. When in contact with a sufficient amount of water that may be in the form of saliva and / or water used to wash your mouth during or after applying the composition, the precursors will react to form the zinc amino acid halide, then after further dilution, they will deliver the precipitate containing zinc to the teeth.
    [048] The carrier represents all other materials in the composition besides the zinc amino acid halide complex or its precursors. The carrier amount is the amount to reach 100% by adding to the weight of the zinc amino acid halide, including any precursors.
    [049] The compositions of the invention can comprise
    25/55 various agents that are active to protect and improve the resistance and integrity of the enamel and tooth structure and / or to reduce bacteria and associated caries and / or gum disease, including or in addition to zinc amino acid halide complexes. The effective concentration of the active ingredients used in the present invention will depend on the particular agent and delivery system used. It is understood that a toothpaste, for example, will typically be diluted with water after use, while a mouth wash will typically not be. This way, an effective concentration of active in a toothpaste will ordinarily be 5 to 15x higher than necessary for a mouth wash. The concentration will also depend on the exact salt or polymer selected. For example, where the active agent is supplied in the form of salt, the counterion will affect the weight of the salt, so that if the counterion is heavier, more salt by weight will be required to provide the same concentration of active ion in the product. Final. Arginine, where it is present, can be present at levels of, for example, about 0.1 to about 20% by weight (expressed as weight of free base), for example, about 1 to about 10% by weight. weight is a toothpaste consumer or about 7 to about 20% by weight for a prescribed professional or treatment product. Fluoride, where it is 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 2,000 to about 25,000 ppm for a prescribed professional or treatment product. Levels of antibacterial agents will vary similarly, with
    26/55 levels used in toothpaste are, for example, from about 5 to about 15 times higher than those used in mouth washing. For example, a triclosan toothpaste may contain about 0.3% by weight of triclosan.
    [050] Oral hygiene compositions may additionally include one or more sources of fluoride ion, for example, soluble fluoride salts. A wide variety of fluoride ion producing materials can be employed as sources of soluble fluoride in the present compositions. Examples of suitable fluoride ion producing materials are found in US Patent Nos :: 3,535,421, to Briner et al; US 4,885,155, to Parran, Jr. et al. and US 3,678,154, to Widder et al. Representative sources of fluoride ion include, but are not limited to, stannous fluoride, sodium fluoride, potassium fluoride, sodium monofluorophosphate, sodium fluorsilicate, ammonium fluorsilicate, amine fluoride, ammonium fluoride and combinations thereof. In certain embodiments, the fluoride ion source includes stannous fluoride, sodium fluoride, sodium monofluorophosphate, and 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 apply about 25 ppm to about 25,000 ppm fluoride ions, generally at least about 500 ppm, for example, about 500 to about 2000 ppm, for example, about 1000 to about 1600 ppm, for example, about 1450 ppm. The appropriate level of fluoride will depend on the particular application. A toothpaste for general consumer use would typically have about
    27/55
    1000 to about 1500 ppm, with pediatric toothpaste that has a little less. A dentifrice or coating for professional application could have as much as 5,000 or even about 25,000 ppm of fluoride. The fluoride ion source 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, or about 0.03% by weight at 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 fluoride salts to provide the appropriate level of fluoride ion will obviously vary based on the weight of the counterion in the salt.
    [051] In some embodiments, the compositions of the invention comprise an amino acid. In particular embodiments, the amino acid can be a basic amino acid. Basic amino acid means natural basic amino acids, such as arginine, lysine and histidine, as well as any basic amino acid that has a carboxyl group and an amino group in the molecule that is soluble in water and provides an aqueous solution with a pH of about 7 or greater. Consequently, basic amino acids include, but are not limited to, arginine, lysine, citrulline, ornithine, creatine, histidine, diaminobutanoic acid, diaminoproprionic acid, salts thereof or combinations thereof. In a particular embodiment, the basic amino acids are selected from arginine, citrulline and
    ornithine. In certain modalities, the basic amino acid is arginine, per example, 1-arginine or a salt thereof.[052] In various modalities, the amino acid is gift in an amount of about 0.5% by weight The
    28/55 about 20% by weight of the total weight of the composition, about 0.5% by weight to about 10% by weight of the total weight of the composition, for example, about 1.5% by weight, about 3.75% by weight, about 5% by weight or about 7.5% by weight of the total composition in the case of a toothpaste or, for example, about 0.5 to 2% by weight, for example , about 1% in the case of a mouthwash.
    [053] The compositions of the invention, for example, composition 1 and following, include silica abrasives and may comprise additional abrasives, for example, a calcium phosphate abrasive, for example, tricalcium phosphate (Ca 3 (PO 4 ) 2 ), hydroxyapatite (Ca 40 (PO 4 ) 6 (OH) 2 ) or dicalcium phosphate dihifrate (CaHPO4 2H2O, sometimes referred to herein 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.
    [054] Other silica abrasive polishing materials useful in the present invention, as well as other abrasives, generally have an average particle size that is in the range between about 0.1 and about 30 microns, between about 5 and about 15 microns. The silica abrasive can be precipitated silica or silica gels such as the silica xerogels described in US Patent No. 3,538,230, to Pader et al. en :: US 3,862,307, for Digiulio. Private silica xerogels are marketed under the trade name Syloid® by WR Grace & Co., Davison Chemical Division. The materials of
    29/55 precipitated silica include those marketed by JM Huber Corp. under the trade name ZEODENT® including silica transmitting the designation Zeodent 115 and 119. These silica abrasives are described in US Patent No. 4,340,583, to Wason. In certain embodiments, abrasive materials useful in the practice of oral hygiene compositions according to the invention include silica gels and precipitated amorphous silica which has an oil absorption value of less than about 100 cc / 100 g of silica and located in the range of about 45 cc / 100 g to about 70 cc / 100 g of silica. Oil absorption values are measured using the D281 ASTA Rub-Out Method. In certain embodiments, silicas are colloidal particles that have an average particle size of about 3 microns to about 12 microns, and about 5 to about 10 microns. Low oil absorption silica abrasives, in particular 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 composed of colloidal silica particles that has a water content of 29% by weight of about 7 to about 10 microns in diameter and an oil absorption of less than about 70 cc / 100 g of silica is one example of a low oil absorption silica abrasive useful in the practice of the present invention.
    [055] 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 agents that increase the amount of foam include, but are not limited to
    30/55 polyoxyethylene and certain polymers that include, but are not limited to alginate polymers. Polyoxyethylene can increase the amount of foam and foam thickness generated by the oral hygiene carrier component of the present invention. Polyoxyethylene is also commonly known as polyethylene glycol (PEG) or polyethylene oxide. The polyoxyethylenes suitable for this invention will have a molecular weight of about 200,000 to about 7,000,000. In one embodiment, the molecular weight will be about 600,000 to about 2,000,000 and, in another modality, about 800,000 to about 1,000,000. Polyox® is the trade name for the 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 oral hygiene carrier component of the oral hygiene compositions of the present invention. Where 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, about 0.1 to about 0.2% by weight.
    [056] 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 hydrogenated coconut oil monoglyceride fatty acids such as sodium N-methyl N-cocoyl taurate, sodium cocomonoglyceride sulphate,
    31/55 ii. larger alkyl sulfates, such as sodium lauryl sulfate, iii. larger alkyl ether sulphates, for example, of the formula CH 3 (CH 2 ) m CH 2 (OCH 2 CH 2 ) n OSO 3 X, where m is 6 to 16, for example 10, n is 1 to 6, for example, 2, 3 or 4, and X is Na or K, for example, sodium lauret-2 sulfate (CH3 (CH2) 10CH2 (OCH2CH2) 2OSO3Na).
    iv. larger alkyl aryl sulfonates such as sodium dodecylbenzene sulfonate (sodium lauryl benzene sulfonate)
    v. larger alkyl sulfoacetates, such as sodium lauryl sulfoacetate (sodium dodecyl sulfoacetate), fatty acid esters greater than 1,2 dihydroxy propane sulfonate, sulfocolaurate (N-2-ethyl laurate potassium sulfoacetamide) and sodium lauryl sarcosinate.
    [057] For higher alkyl is meant, for example, C 6-30 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 could be irritating to oral tissue, for example, <10%, and ideal concentrations depend on the particular formulation and the particular surfactant. For example, the concentrations used or a mouthwash is typically in the order of a tenth 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, which comprise surfactants
    32/55 anionic and other surfactants that can be anionic, cationic, zwitterionic or non-ionic. Generally, surfactants are those that are reasonably stable over a wide pH range. Surfactants are described more fully in , for example, in US Pat :: 3,959,458 to Agricola et al; US 3,937,807, to Haefele; and US 4,051,234, to Gieske et al. In certain embodiments, the anionic surfactants useful in the present invention include water-soluble salts of alkyl sulfates that have about 10 to about 18 carbon atoms in the alkyl radical and water-soluble salts of sulfonated fatty acid monoglycerides that have about 10 to about 18 carbon atoms. Sodium lauryl sulfate, sodium lauroyl sarcosinate and sodium coconut monoglyceride sulfonates are examples of such anionic surfactants. In a particular embodiment, the composition of the invention, for example, composition 1 et seq., Comprises sodium lauryl sulfate.
    [058] 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.
    [059] In various embodiments of the present invention, the compositions comprise an anti-calculating agent (tartar control). Suitable anticalculating agents include, but are not limited to, phosphates and polyphosphates (eg pyrophosphates), polyaminopropanesulfonic acid (AMPS), hexametaphosphate salts, zinc citrate trihydrate,
    33/55 polypeptides, polyolefin sulfonates, polyolefin phosphates, diphosphonates. Therefore, the invention can comprise phosphate salts. In particular embodiments, these salts are alkaline phosphate salts, that is, alkali metal hydroxide salts or alkaline earth hydroxides, for example, sodium, potassium or calcium salts. Phosphate, as used herein, comprises mono and orally acceptable polyphosphates, for example, P 1 _ 6 phosphates, for example, monomeric phosphates such as monobasic, dibasic or tribasic phosphate; dimeric phosphates such as pyrophosphates and multimeric phosphates, eg sodium hexametaphosphate. In particular examples, the selected phosphate is selected from alkaline dibasic phosphate and alkaline pyrophosphate salts, for example, selected from dibasic sodium phosphate, dibasic potassium phosphate, dicalcium phosphate dihydrate, calcium pyrophosphate, tetrasodium pyrophosphate , tetrapotassium pyrophosphate, sodium tripolyphosphate and mixtures of any of two or more of them. In a particular embodiment, for example, the compositions comprise a mixture of tetrasodium pyrophosphate (Na4P2O7), calcium pyrophosphate (Ca2P2O7), and dibasic sodium phosphate (Na 5 HP 3 O 10 ), for example, in amounts of ca. 3 to 4% dibasic sodium phosphate and ca. 0.2 to 1% of each of the pyrophosphates. In another embodiment, the compositions comprise a mixture of tetrasodium pyrophosphate (TSPP) and sodium tripolyphosphate (STPP) (Na5P3O10), for example, in proportions of TSPP in about 1 to 2% and STPP in about 7% to about 10%>. These phosphates are supplied in an effective amount to
    34/55 reduce enamel erosion in order to help clean teeth and / or reduce the formation of tartar on the teeth, for example, in an amount of 2 to 20%, for example, ca. 5 to 15%, by weight of the composition.
    [060] 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 aldehydes, esters, flavoring alcohols and similar materials. Examples of oils include mint, peppermint, essential oils gualtéria, sassafras, cloves, sage, eucalyptus, marjoram, cinnamon, lemon, lime, grapefruit and orange. Chemicals are also useful 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.
    [061] The oral hygiene compositions of the invention may also include additional polymers 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, carboxymethylcellulose or polysaccharide gums, for example, xanthan gum or carrageen gum). Acid polymers, for example, polyacrylate gels, can be supplied in the form of their free acids or partially neutralized or completely neutralized water (eg, potassium and sodium) or ammonium salts.
    35/55 [062] Silica thickeners that 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 like karaya, gum arabic, and tragacanth gum can also be incorporated. Colloidal aluminum and magnesium silicate can also be used as the component of the thickener 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.
    [063] 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 dentrífico, though not for this particular application useful in the present invention are disclosed in US Patent Nos :: 5,188,821 and 5,192,531 and include synthetic anionic polymeric polycarboxylates, such as copolymers of 1: 4 to 4: 1 of maleic or acid anhydrate with another unsaturated monomer polymerizable by ethyl, preferably methyl vinyl ether / maleic anhydrate which has a molecular weight (MW) of about 30,000 to about 1,000,000, most preferably about 300,000 to fence
    36/55 of 800,000. Such copolymers are available, for example, as Gantrez., For example, A 139 (MW 500,000), A 119 (MW 250,000) and preferably S-97 Pharmaceutical Grade (MW 700,000) available from ISP Technologies, Inc., Bound Brook, NJ 08805. Auxiliary agents, when present, are present in amounts that are in the range of about 0.05 to about 3% by weight. Other operational polymers include those such as maleic anhydrate 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 copolymers of acrylic acid with methyl or hydroxyethyl methacrylate, methyl or ethyl acrylate, isobutyl vinyl ether or N-vinyl-2-pyrrolidone. Generally, unsaturated carboxylic acids polymerized by olefin or ethyl containing an activated carbon-to-carbon olefin double bond and at least one carboxyl group, that is, an acid containing an olefin double bond that works readily in polymerization, are suitable, because of its presence in the monomer molecule at any alpha to beta position relative to a carboxyl group or as part of a terminal methylene group. Illustrative of these acids are acrylic, methacrylic, ethacrylic, alpha-chloro-acrylic, crotonic, beta-acryloxy propionic, sorbic, alpha-chlorosorbic, cinnamic, betastirylacrylic, muconic, itaconic, citraconic, mesaconic, glutaconic, aconitic, alpha-phenylacrylic , 2-benzyl acrylic, 2-cyclohexylacrylic, angelic, umbelic, fumaric, maleic acids and anhydrates. Others
    37/55 different copolymerizable olefin monomers with these carboxylic monomers include vinylacetate, vinyl chloride, dimethyl maleate and similar carboxylic salt groups. Copolymers contain enough water solubility.
    [064] A class of polymeric agents includes a composition containing substituted acrylamide homopolymers and / or unsaturated sulfonic acid homopolymers salts thereof, in particular, where the polymers are based on unsaturated sulfonic acids selected from acrylamidoalonic sulfonic acids as 2 acrylamide 2 methylpropane sulfonic acid having a molecular weight of about 1,000 to about 2,000,000, described in US Patent No. 4,842,847, of June 27 , 1989 to Zahid. 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, e.g., as disclosed in US Patent No. 4,866,161 :: Sikes et al.
    [065] 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 free water that is added plus that amount that is introduced into other materials.
    [066] Within certain modalities of oral compositions, it is also desirable to incorporate a humectant to prevent the composition from hardening after exposure to air. Certain humectants can also impart desirable sweetness
    38/55 or flavor to dentifrice compositions. Suitable humectants include edible polyhydric alcohols such as glycerin, sorbitol, xylitol, propylene glycol as well as other polyols and mixtures of such humectants. In one embodiment of the invention, the main humectant is glycerin which can be present at levels greater than 25%, for example, 25 to 35% (about 30%), with 5% or less of other humectants.
    [067] In addition to the components described above, the embodiments of this invention may contain a variety of optional dentifrice ingredients, some of which are described below. Optional ingredients include, for example, but are not limited to adhesives, soap bubble 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; n :: US 3,959,458 to Agricola et al. en :: US 3,937,807, for Haefele, all of which are incorporated by reference in this document.
    [068] Unless otherwise stated, all percentages of the components of the composition provided in this specification are by weight based on a 100% total weight composition or formulation.
    [069] Unless specifically identified otherwise, the ingredients for use in the compositions and formulations of the present invention are preferred and 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 a
    39/55 excipient that is suitable for external application in the amounts and concentrations contemplated in the formulations of that invention and includes, for example, excipients that are Generally Recognized as Safe (GRAS) by the United States Food and Drug Administration.
    [070] The compositions and formulations, as provided in this document, are described and claimed with reference to their ingredients, as is usual in the art. As would be evident to a person skilled in the art, the ingredients may, in some cases, react with each other, so that the true composition of the final formulation may not correspond exactly to the ingredients listed. Thus, it should be understood that the invention extends to the product of the combination of the listed ingredients.
    [071] As used throughout the document, the strips are used as a shorthand to describe each and every value that is within the range. Any value within the range can be selected as the end of the range. In addition, all references cited in this document are incorporated into this document as a reference in their entirety. In the event of a conflict in a definition in the present disclosure and a cited reference, the present disclosure prevails.
    [072] Unless otherwise specified, all percentages and quantities expressed in this document and elsewhere in the specification should be understood as referring to weight percentages. The quantities supplied are based on the active weight of the
    40/55 material.
    EXAMPLES
    Example 1 [073] The Zn concentration of TBZC is compared to TBZC and various amino acids. The ingredients are dispersed in water, balanced for 1 h and the supernatant is analyzed for free Zn 2+ by atomic absorption. Table 1 shows the comparison of TBZC-free Zn concentration and TBZC mixed with different amino acids.
    [074] Table 1
    Free zn (ppm) TBZC + Arginine (4 + 4%) 1,819.00 TBZC + Lysine + HCl (4 + 4%) 6,000.00 TBZC + Lysine (4 + 4%) 5,000.00 TBZC (4%) 64.80
    [075] The data described in Table 1 (above) demonstrate the dramatic increase in zinc solubility when an amino acid is added. For example, solubility increases 28 times when arginine is added and close to 100 times when lysine hydrochloride is mixed with TBZC.
    Example 2 [076] The stable solutions of TBZC amino acid complexes are prepared for additional testing using lysine, glycine and arginine as the amino acids.
    [077] A. TBZC Lysine: Sample A1, TBZC Lysine is prepared as follows: at room temperature, 2.7601g (0.005 mol) of TBZC powder is added slowly in 1 M aqueous lysine solution (0.05 mole of lysine in 50 ml of
    41/55 deionized water). The mixture is stirred for 3 hours. The unreacted TBZC is removed by centrifugation followed by filtration through a 0.45 pm membrane. The zinc concentration is determined by atomic absorption spectroscopy after acid digestion.
    [078] Table 2
    TBCZLysine Quantity added 2.7601 G, 0.005 mol7.3101 g, 0.05 molfinal solution pH 10.8 Zn content of solution 1.95% reserve (w / w%) Reserve Ratio: Water 1: 8 (v / v) for treatment
    [079] The procedure is repeated to form the Sample
    A2 which has a slightly lower zinc content, due to experimental variation:
    [080] Table 3
    TBCZLysine Quantity added 2.7612 G, 0.005 mol7.3097 g, 0.05 molfinal solution pH 10.7 Zn content of solution 1.44% reserve (w / w%) Reserve Ratio: Water 1: 8 (v / v) for treatment
    [081] B. TBZC glycine: Sample B, TBZC glycine is prepared as follows: at room temperature, 2.7599g
    42/55 (0.005 mol) of TBZC powder is added slowly in 1 M of aqueous lysine solution (0.05 mol of glycine in 50 ml of deionized water). The mixture is stirred for 3 hours. Unreacted TBZC is removed by centrifugation followed by filtration through a 0.45 pm membrane. The zinc concentration is determined by atomic absorption spectroscopy after acid digestion.
    [082] Table 4
    TBCZGlycine Quantity added 2.7599 G, 0.005 mol7.3540 g, 0.05 molfinal solution pH 6.7 Zn content of solution 2.78% reserve (w / w%) Reserve Ratio: Water 1: 8 (v / v) for treatment
    [083] C. TBZC arginine: Sample C1, TBZC arginine is prepared as follows. TBZC is added in an aqueous solution of arginine (0.05 mol of arginine in 50 ml of deionized water) at about 37 ° C with stirring. The mixture is stirred for about 2 hours followed by high speed centrifugation to separate unreacted TBZC. The supernatant is filtered through a 0.45 pm membrane. The zinc concentration is determined by atomic absorption spectroscopy after acid digestion.
    [084] Table 5
    TBCZArginine
    43/55
    Quantity added 2.7608 G, 0.005 mol8.7104 g, 0.05 mol final solution pH 11.3 Reserve solution Zn content (w / w%) 2.50% Reserve Ratio: Water(v / v) for treatment 1: 8
    [085] The procedure is repeated to form the Sample
    C2, where that time uses a higher concentration of
    TBZC and also a higher final dilution of water.
    [086] Table 6
    TBCZArginine Quantity added 5.5186 G, 0.005 mol8.7145 g, 0.05 molfinal solution pH 10.4 Zn content of solution 1.53% reserve (w / w%) Reserve Ratio: Water 1:15 (v / v) for treatment
    Example 3 [087] TBZC amino acid solutions have been shown to be effective in occlusion dentinal tubules when applied to teeth and diluted to achieve precipitation. This deposition and tubular occlusion should reduce sensitivity and provide a reservoir of zinc to help protect enamel against erosion and bacterial colonization.
    [088] Dental pieces are prepared by cutting the entire human tooth into the thin dental sections of about
    44/55
    800 microns thick, designating a test side, sanding said test side using sandpaper of about 600 grit to remove any enamel on said test side, polishing said test side using a polishing cloth of Buehler and aluminum oxide of Buehler of micron 5, conditioning acid to said dental section in 1% (by weight) of citric acid solution for about 20 seconds, sonicating said dental section for 10 minutes and storing said dental section in saline buffered phosphate (PBS, pH 7.4, Gibco Cat. No. 10010).
    [089] The fine pieces of human dental sections are represented by an image on the confocal microscope for characterization. Top view images are taken in XYZ mode and side view images are taken in XZY mode. Typical images are taken with a 50x objective lens and x4 digital magnification. When a more global view is desired at a lower magnification, images are taken at x1 digital magnification.
    [090] The fine pieces of human dental sections are treated using the respective treatment solutions followed by the procedures, as set out below. The three distinct treatment procedures include A), treatments for 1 hour using the solutions of (TBZC arginine, TBZC glycine and TBZC lysine), B) treatment using an alternative method using TBZC and C lysine ) treatments with shorter durations and more repetitions. The treated fine pieces are examined with the confocal microscope for signs of occlusion and deposition on the surface. The repetition treatments are performed on the treated discs using them or substantially the
    45/55 same treatment procedure as the previous treatment, the same TBZC amino acid solution and, in most cases, treatment solutions from the same groups. Confocal images are taken to monitor the progress of occlusion and additional deposition after one or more repeat treatments.
    [091] A. One Hour Treatments Using TBZC Arginine, TBZC Lysine and TBZC Glycine: Dental discs are added after TBZC amino acid stock solutions are mixed with water. The TBZC amino acid stock solutions are mixed first in a flask with the appropriate amount of water, as set out in Tables 2, 3, 4, 5 and 6 (for example, 1 ml stock solution with 8 ml deionized water for a system with 1: 8 reserve ratio: water). In seconds, the dental piece is added to the bottle and the bottle is capped and stored in an incubator at 37 ° C for one hour for treatment. At the conclusion of the treatment, the vial is removed from the incubator and the liquid and precipitated, if any, are removed using a pipettor. The dental disc is washed 4 times, each time using 1 ml of PBS (pH = 7.4) of solution. The dental disc is dried using a tissue.
    [092] The three different complex amino acid systems of TBZC with similar zinc concentration generate different amounts of precipitation at different rates. TBZC lysine produced precipitates immediately after or seconds after the initial mixing and white precipitates are observed in the bottom of the flasks at the end of the 1 hour incubation. TBZC arginine does not produce precipitation after the initial mixing, but the
    46/55 the system is obfuscated and some precipitation can be observed at the bottom of the flasks at the end of the 1 hour incubation. TBZC glycine does not generate any precipitation and the solution remains clear and clean throughout the 1 hour incubation.
    [093] TBZC arginine substantially and completely absorbs the dental tubules and forms a substantially complete covering on the surface of the tooth piece, after 1 hour treatments. Two groups of the complex solutions (C1 and C2 from Example 2 above) do not show qualitative differences in effectiveness.
    [094] The evolution of confocal images indicates progressive deposition and occlusion. Baseline images indicate open tubules and a clean surface between the openings. After a single treatment, significant tubular occlusion is observed, as well as substantial deposition between the tubule openings. After the second and third treatments, substantially all of the tubule openings are absorbed and substantially the entire surface area between the tubule openings is covered by deposits. The side view images indicate the presence of certain deposits with a thickness above a single digit of microns or greater. The experiments are carried out on two separate dental discs and the results are qualitatively the same.
    [095] TBZC lysine is also shown to substantially absorb dental tubules and form considerable surface deposits, in particular, after repeated treatments, each for 1 hour.
    [096] Confocal images again present the
    47/55 progression. Baseline images indicate open tubules and a clean surface between the tubule openings. After treatment, some deposits are seen between openings of tubules and some tubules are at least partially occluded. After two treatments, the results are not qualitatively different from that after the first treatment. Although the two discs representing duplicate experiments show qualitatively no different results between them for the first two treatments, the results differ more significantly between the two dental discs after the third treatment. On a disc, there are substantial surface deposits with some occlusion. On the second disc, deposits cover the surface completely, as well as complete occlusion. The significant increase in deposition / occlusion with repeated treatments suggests that the surface of the disc is conditioned by previous treatments and could receive more deposits / occlusion during subsequent treatments. Similar results are seen using solutions A1 and A2 from Example 2 above.
    [097] TBZC glycine is shown by confocal images to provide limited occlusion and surface deposits after repeated treatments, each for 1 hour. Although the TBZC glycine is not without effect, the deposition is not as substantial as that for TBZC lysine or TBZC arginine. Baseline images indicate open tubules and a clean surface between the tubule openings. After a treatment, the images indicate little, if any, deposits and surface occlusion. The same is true after two treatments. After three
    48/55 treatments, both discs have some deposits.
    Therefore, TBZC glycine has a more limited ability to occlude dental tubules and form deposits on the surface, at least at the concentrations tested, compared to TBZC arginine or TBZC lysine.
    [098] B. Procedure for
    Alternative Treatment Using TBZC Lysine: In the alternative procedure, specifically for TBZC lysine samples, dental discs are added first to the lysine stock solution of
    TBZC and the appropriate amount of water added subsequently. The rest of the treatment procedure is the same as the standard one-hour treatment procedure.
    [099]
    The use of the alternative method is motivated by the observation that precipitation occurs seconds after the TBZC lysine reserve solution and the entire amount of water is mixed. In this alternative treatment method, the disc is allowed to contact the TBZC lysine stock solution before the water is subsequently added. This change should allow the disk surface to interact with the nascent precipitates, possibly leading to more significant deposition and surface occlusion.
    On the other hand, it would be conceivable that the stock solution could dissolve part of the existing surface deposits and / or particles absorbed after repeated treatments.
    [100] Confocal images for dental discs treated using this alternative method indicate the success of deposition and surface occlusion. It can be seen that significant deposition and occlusion of tubular surface
    49/55 occur after alternative treatments. This supports a regime of applying a more concentrated solution of the TBZC amino acid complex, then diluting it to initiate precipitation.
    [101] C. repeat treatments with shorter durations (one minute): In the repeat treatment with shorter durations, dental discs are treated for one minute at a time, instead of an hour. In addition, more repeat treatments are performed. Otherwise, the treatment procedure is the same as that established in section A above.
    [102] As stated earlier, precipitation occurs immediately when TBZC lysine is mixed with the appropriate amount of water. The rapid reaction in the TBZC lysine system allows for a short but effective treatment, which is more preferable than the 1-hour treatment involved in the standard and alternative treatment methods discussed above. It is contemplated that the short duration, such as 1 minute at a time, together with multiple repetitions to compensate for the possible loss of effectiveness in each treatment, can provide a typical user with a more pleasant experience and better compliance.
    [103] Confocal images of a dental disc treated 3 times and 6 times using this method confirm the value of this treatment method. Significant deposition and surface occlusion are observed after 3 treatments, each lasting 1 minute. Similar results are seen after 6 treatments. The images taken at a lower resolution indicate that the phenomena are global.
    50/55 [104] Therefore, short treatment durations can be used for TBZC lysine. The duration of treatment can be further reduced below 1 minute if desired without significant impediment to effectiveness.
    [105] While the tests above show the effectiveness of the TBZC amino acid at an adjusted concentration, several other concentrations also work to generate precipitation and produce surface deposition. It is observed that even in the absence of the formation of precipitates visible to the naked eye (due to an unfavorable concentration and / or short treatment duration), surface deposition and / or tubular occlusion can result from the formation of microscopic particles. This action may need more than 3 repeated treatments to achieve substantial or complete surface coverage and tubular occlusion. In this regard, the operable concentration of the asset and the operable treatment duration take advantage of wider ranges than can be deduced based on the above-mentioned examples and the following three paragraphs.
    [106] With the use of Sample Al (TBZC lysine), a certain precipitation can be formed in one hour with a dilution of 1: 1 (0.975% by weight of zinc) and significant amounts can be seen in 1: 2, 1 : 3, 1: 4, 1: 5, 1: 6, 1: 7, 1: 8 and 1: 9 dilutions (0.65%, 0.488%, 0.39%, 0.325%, 0.278%, 0.244%, 0.217 %, 0.195%, by weight of zinc, respectively). Larger dilutions are also expected to work and precipitation typically occurs faster at larger dilutions. Thus, TBZC lysine samples with 1: 1 dilutions and larger (with a zinc concentration of about 0.975% and less)
    51/55 will produce a precipitate and result in deposition.
    [107] Using Sample A2 (TBZC lysine), precipitation can be seen with 1: 6 and 1: 7 dilutions (0.205% and 0.18% zinc by weight) and larger dilutions are expected work too. Thus, TBZC lysine samples with zinc concentrations of 0.205% by weight and less will work to produce precipitation and deposition. The difference in Sample A1 is due to sample variation.
    [108] Using Sample C2 (TBZC arginine), precipitation can be seen with dilutions 1: 5, 1:11,
    1:12, 1:13, and 1:14 (0.255%, 0.128%, 0.118%, 0.109%, and 0.102% zinc by weight). Larger dilutions are expected to work as well. Precipitation typically happens faster at larger dilutions. Thus, TBZC arginine samples with a zinc concentration of 0.255% by weight or less will work to produce precipitation and deposition.
    [109] The precipitates contain zinc oxide and other species containing zinc (such as zinc hydroxide), as well as the corresponding amino acid. The amino acid content is high, in particular, if the precipitates are not washed with water.
    [110] Without the intention of being bound in theory, there is a hypothesis that the deposit on the dentin surface is composed of a two-component structure, as in the form of a core shell or double layer. The outer layer is composed of an amorphous zinc species that is not ZnO. The outer layer also contains amino acid. The outer layer can be readily removed by simple washing with water. What's under the layer
    52/55 external is a component that is mainly composed of ZnO as well as amino acids.
    [111] The more complex structure brings the concept of controlled release to a new level. Originally, the concept of controlled release is invoked, since zinc can be released from ZnO over time, as well as the amino acid from deposits. Now, with this new structure, there is an outer layer with more soluble zinc and amino acid and an inner layer with lower solubility.
    [112] A unique aspect of the present invention is the provision of a controlled release system and a method for continued release of zinc ions and amino acids over an extended period of time. The absorbed particles and surface deposits can release zinc ions and amino acids in saliva or plaque fluid over an extended period of time, providing benefits for oral hygiene for a much longer period of time than a typical existing formulation.
    [113] The structure of particlesabsorbed and deposits of surface, in particular, is suitable for release controlled from ions zinc and amino acids. As described above, there is a hypothesis in which these particles and deposits has a layer external what comprises species of zinc widely not ZnO and amino acid and an inner layer that comprises ZnO widely and some amino acids. The layer external can to be
    dissolved, perfecting promptly during washing, thus a source of zinc and amino acid for quick release. This is likely due to two factors. First
    53/55 non-ZnO zinc species may have a higher solubility than ZnO. Second, amino acids, such as arginine and lysine, can improve the solubility of compounds containing zinc. The inner layer can be dissolved over a long period of time, thus perfecting a source of zinc and amino acid for more controlled release.
    [114] The TBZC amino acid can promote biofilm aggregation. The aggregates do not effectively fix the dental surface and, therefore, can be removed more easily. The promotion of biofilm aggregation is an additional biologically relevant benefit.
    Example 4 [115] An exemplary dentifrice of the present invention comprising TBZC lysine, 1450 ppm fluoride and phosphates is described below in Table 7.
    [116] Table 7
    INGREDIENT WEIGHT % PEG600 3 CMC-7 0.65 Xanthan 0.2 Sorbitol 27 Glycerin 20 Saccharin 0.3 Tetrasodium pyrophosphate 0.5 Calcium pyrophosphate 0.25 Dibasic calcium phosphate 3.5 Sodium fluoride (to provide 1,450 ppm of fluoride) 0.32 Titanium dioxide 0.5 Abrasive silica 8
    54/55
    Thickener silica 8 Sodium lauryl sulfate 1.5 Flavoring 1.2 TBZC Lysine 7 (TBZC [2]+ Lysine [5]) Water QS
    Example 5 [117] An exemplary mouthwash formulation of the present invention is described in Table 8 (below).
    [118] Table 8
    INGREDIENT WEIGHT % Sorbitol 5.5 Glycerin 7.5 Propylene Glycol 7 Sodium saccharin 0.02 Citric acid (anhydrous) 0.05 TBZC 0.028 L-Lysine 0.05 Flavor / Dye 0.12 Potassium sorbate 0.05 Cocamidopropyl Betaine 1 Water QS TOTAL 100
    [119] While the invention has been described in relation to specific examples including current preferred ways of carrying out the invention, those skilled in the art will note that there are numerous variations and permutations of the systems and techniques described above. It must be understood that other modalities can be used and that
    55/55 structural and functional modifications can be made without departing from the scope of the present invention. Accordingly, the scope of the invention must be interpreted widely, as set out in the attached claims.
    权利要求:
    Claims (9)
    [1]
    1. Oral hygiene composition, characterized by the fact that it comprises a tetrabasic zinc halide and an amino acid, in which the amino acid is selected from lysine, glycine and arginine, in the form of a free or orally acceptable acid addition salt, and in which the tetrabasic zinc halide and the amino acid are in a complex.
    [2]
    2. Composition according to claim 1, characterized by the fact that the halide is selected from chloride, bromide and iodine.
    [3]
    3. Composition according to claim 1 or 2, characterized by the fact that the halide is chloride.
    [4]
    Composition 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 a free or orally acceptable salt.
    5. Composition, in a deal with any an of claims 1 to 4, characterized by the fact that the amount of zinc it's from 0.05 to 4% in Weight.6. Composition, in a deal with any an of claims 1 to 5, characterized by the fact that and on shape of a toothpaste, gel, mouthwash, powder, cream, strip or gum. 7. Composition, in a deal with any an of
    claims 1 to 6, characterized by the fact that it is an orally acceptable base, for example, a mouthwash, gel, or toothpaste base.
    8. Composition, in a deal with Any of them of claims 1 to 7, characterized by the fact in what further comprises a effective amount from a source in ion
    Petition 870190005760, of 01/18/2019, p. 11/14
    2/3 fluoride.
    [5]
    Composition according to any one of claims 1 to 8, characterized in that it comprises an orally acceptable base comprising ingredients selected from one or more of abrasives, buffering agents, wetting agents, surfactants, thickeners, strips or fragments gum, breath freshening tablets, flavoring agents, fragrance agents, coloring agents, antibacterial agents, bleaching agents, agents that interfere with or prevent bacterial fixation, calcium sources, phosphate sources, orally acceptable potassium salts and polymers anionic.
    [6]
    Composition according to any one of claims 1 to 9, characterized by the fact that the pH of the composition is 6 to 8.
    [7]
    11. Composition according to any one of claims 1 to 10, characterized by the fact that it is for use in order to reduce and inhibit the erosion of enamel acid, reduce biofilm and plaque generated by bacteria, reduce gingivitis, inhibit caries and cavities and / or reduce dentin hypersensitivity.
    [8]
    12. Use of tetrabasic zinc halide and an amino acid, characterized by the fact that it is in the manufacture of an oral hygiene composition, in which the amino acid is selected from lysine, glycine and arginine, in
    salt form in addition in acid free or orally acceptable. 13. Use, in wake upwith the claim 12, featured fur fact in what the halide in zinc
    Petition 870190005760, of 01/18/2019, p. 12/14
    3/3 tetrabásico and the amino acid are in a complex.
    [9]
    14. Use of a tetrabasic zinc halide and an amino acid, characterized in that it is in the preparation of a composition as defined in any one of claims 1 to 11 to treat or reduce enamel erosion, clean teeth, reduce biofilm and plaque generated by bacteria, reduce gingivitis, inhibit caries and cavity formation and / or reduce a subject's dentin hypersensitivity.
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    同族专利:
    公开号 | 公开日
    AR094202A1|2015-07-15|
    CA2892421C|2019-10-01|
    AU2012397266B2|2015-09-24|
    EP2934442A1|2015-10-28|
    TW201438749A|2014-10-16|
    ZA201503849B|2017-09-27|
    RU2015123679A|2017-01-23|
    CA2892421A1|2014-06-26|
    KR20150097494A|2015-08-26|
    CN104853726A|2015-08-19|
    BR112015014253A2|2017-07-11|
    US20150328111A1|2015-11-19|
    AU2012397266A1|2015-06-11|
    TWI555534B|2016-11-01|
    EP2934442B1|2016-11-30|
    MX352357B|2017-11-22|
    US9775792B2|2017-10-03|
    IL239531D0|2015-08-31|
    CN104853726B|2017-10-24|
    RU2625763C2|2017-07-18|
    PH12015501435A1|2015-09-14|
    TW201630587A|2016-09-01|
    WO2014098825A1|2014-06-26|
    MX2015007875A|2015-09-28|
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    法律状态:
    2018-10-23| B07A| Technical examination (opinion): publication of technical examination (opinion)|
    2019-01-29| B09A| Decision: intention to grant|
    2019-04-09| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 19/12/2012, OBSERVADAS AS CONDICOES LEGAIS. (CO) 20 (VINTE) ANOS CONTADOS A PARTIR DE 19/12/2012, OBSERVADAS AS CONDICOES LEGAIS |
    优先权:
    申请号 | 申请日 | 专利标题
    PCT/US2012/070521|WO2014098825A1|2012-12-19|2012-12-19|Oral care products comprising a tetrabasic zinc - amino acid - halide complex|
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