WO2000000166A2 - Compositions orales ameliorees d'elimination et de prevention du tartre, de la fetidite, de la plaque et de la gengivite - Google Patents

Compositions orales ameliorees d'elimination et de prevention du tartre, de la fetidite, de la plaque et de la gengivite Download PDF

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WO2000000166A2
WO2000000166A2 PCT/US1999/009135 US9909135W WO0000166A2 WO 2000000166 A2 WO2000000166 A2 WO 2000000166A2 US 9909135 W US9909135 W US 9909135W WO 0000166 A2 WO0000166 A2 WO 0000166A2
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zinc
amount
weight
present
composition
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PCT/US1999/009135
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WO2000000166A3 (fr
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Mona Kesavan Nair
Pauline C. Pan
Lori Dee Kumar
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Warner-Lambert Company
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Publication of WO2000000166A3 publication Critical patent/WO2000000166A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N59/00—Biocides, pest repellants or attractants, or plant growth regulators containing elements or inorganic compounds
    • A01N59/16—Heavy metals; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—Compounds containing heavy metals
    • A61K31/315—Zinc compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • A61K8/27—Zinc; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/34—Alcohols
    • A61K8/347—Phenols

Definitions

  • This invention relates to oral compositions for treating and/or preventing diseases of the mouth, and more particularly to oral compositions for treating and/or preventing tartar, oral malodor, plaque and gingivitis. More specifically, this invention is directed to the use of zinc and essential oils in a mouthwash that has long lasting breath freshening, inhibits tartar and is effective against the microbes that cause plaque and gingivitis.
  • Thymol is a well known essential oil that has been used in mouthwash for many years for its antimicrobial properties. Thymol is one ingredient in Listerine® brand mouthwash. However, thymol is also well known for its very unpleasant, harsh taste.
  • U.S. Patent No. 4,945,087 provides one solution to thymol's taste problem by masking the taste with a combination of sugar alcohol and anethole.
  • Zinc salts have been used over the years in several oral care products, primarily to limit or prevent malodor.
  • oral care products include AIM® toothpaste, Breath Savers® mints, Lavoris® mouthwash, Viadent® mouthrinse, and Listermint®.
  • Zinc has also been shown to have antimicrobial efficacy. Here, its mode of action is believed to result from surfactant charge activity, resulting in disruption of membranes. Verran, J. Int. J. Cosmet. Sci., 13: 29-42, 1991. Zinc is also believed to inhibit essential enzymes in glucose transport and catabolism. Cummins D. J. Clin. Periodontol, 18: 455-461, 1991; and Marsh, PD, J. Clin. Periodontal, 18(6); 462-467, 1991.
  • Antiplaque and antigingivitis efficacy is another attribute of zinc salts. Part of this activity may be a direct consequence of its antimicrobial efficacy. Further, zinc may reduce the rate of bacterial adherence to teeth. Harrap, GJ, Saxton, CA, Best, JS,
  • Zinc is also said to prevent the toxic effects that volatile sulfur compounds have on membrane permeability by preventing VSC penetration into epithelial cells. Pader, M, Oral Hygiene Products and Practice, Chapter 10, pg. 351-352.
  • U.S. Patent No. 4,022,880 to Vinson et al. teaches oral compositions including mouthwash that retard the development of dental calculus that contain 0.05% to about 4% zinc ions.
  • U.S. Patent No. 5,095,035 to Eby teaches zinc acetate containing oral products to which saccharin is added as a super sweetener.
  • Listerine® brand mouthwash has been sold in the United States for approximately 100 years. Listerine® contains thymol, menthol, eucalyptol and methyl salycilate.
  • the present invention is directed to mouthwash compositions that contain zinc salts and thymol that provide antitartar, antiplaque, antigingivitis efficacy and long lasting breath freshening, yet have high consumer acceptability in spite of the presence of two ingredients, thymol and a zinc salt, that are known to taste bad.
  • the present invention is directed to a mouthwash composition comprising thymol and a zinc salt in combination with a sweetener.
  • BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1. is a graph of the induction time for precipitation of hydroxyapatite vs. percent zinc chloride in both mouthwash and aqueous solution using 3.0 ml of sample.
  • Fig. 2. is a graph of the induction time for precipitation of hydroxyapatite vs. percent zinc chloride in both mouthwash and aqueous solution using 1.5 ml of sample.
  • Fig. 3. is a graph of the induction time for precipitation of hydroxyapatite vs. percent zinc acetate in aqueous solution using 1.5 ml of sample.
  • Fig. 4. is a photograph (at 29x) of a crystal of dicalcium phosphate dihydrate
  • Fig. 5. is a photograph (at 29x) of a crystal of DCPD formed in the presence of 0.01% Zn.
  • Fig. 6. is a photograph (at 29x) of a crystal of DCPD formed in the presence of 0.09% Zn.
  • Fig. 7. is a photograph (at 29x) of a crystal of DCPD formed in the presence of 0.15% Zn.
  • Fig. 8. is a photograph (at 29x) of a crystal of DCPD formed in the presence of 0.20% Zn.
  • Fig. 9. is a photograph (at 29x) of a crystal of DCPD formed in the presence of
  • Fig. 10 is a graph showing the effect on a cysteine VSC response of rinsing with a mouthwash without zinc.
  • Fig. 11 is a graph showing the effect on the cysteine VSC response of rinsing with mouthwash with 0.1% ZnCl 2 .
  • Fig. 12 is a graph showing the effect on the cysteine VSC response of rinsing with mouthwash with 0.21% zinc sulfate.
  • Fig. 13 is a graph showing the effect on the cysteine VSC response of rinsing with Viadent®, which contains 0.2% ZnCl 2 .
  • the oral compositions of this invention contain thymol.
  • the thymol is usually present in amounts of not more than about 0.1 % by weight, based on the weight of the total composition, with about 0.02 to about 0.1% by weight being preferred, and about 0.05 to about 0.075% by weight being most preferred.
  • Suitable zinc salts for use in the present invention are well known in the art, and are those which freely ionize in an aqueous or hydroalcohol base. Suitable salts include inorganic, organic and water insoluble and water soluble zinc salts. Nonlimiting examples of suitable zinc salts that may be employed include:
  • Zinc tartarate Preferred salts are zinc chloride, zinc citrate, zinc oxide, zinc acetate, zinc stearate, zinc methionine sulfate, zinc phenol sulfonate, zinc sulfate, and zinc gluconate.
  • the most preferred salts are zinc chloride, zinc sulfate, and zinc citrate.
  • the zinc salt is added to the composition in an amount sufficient to provide zinc ions in amount from about 0.005 to about 0.095 % w/v of the composition.
  • the amount of zinc salt added to the composition is sufficient to provide zinc ions in an amount from about 0.02 to about 0.09 % w/v of the composition. More preferably, the amount of zinc salt added to the composition is sufficient to provide zinc ions in an amount from about 0.03 to about 0.085 % w/v of the composition. Even more preferably, the amount of zinc salt added to the composition is sufficient to provide zinc ions in an amount from about 0.03 to about 0.043 % w/v of the composition. Additionally, the amount of zinc ions can be from about 0.045 to about 0.075% w/v of the composition.
  • compositions of this invention may, in addition to the thymol and zinc salt, include effective amounts of other essential oils such as those selected from the group consisting of eucalyptol, menthol, methyl salicylate, and the like, and mixtures thereof.
  • the total amount of essential oils present in a composition, exclusive of the thymol can be from about 0.05 to about 0.35% by weight, based on the weight of the composition, with about 0.12 to about 0.28% by weight being preferred.
  • the compositions, as stated above can contain eucalyptol, menthol, and methyl salicylate.
  • the eucalyptol is present in amounts of about 0.07 to about 0.11% being preferred and most preferably about 0.08 to about 0.10%; preferably menthol is present in amounts of about 0.03% to about 0.06% by weight and most preferably about 0.04 to about 0.05%; and preferably methyl salicylate is present in amounts of about 0.03 to about 0.08% by weight and most preferably about 0.04 to about 0.07%. All of the percent amounts of essential oils are of the total composition.
  • compositions of the present invention include liquid oral preparations such as a mouthwash, spray or rinse.
  • vehicle i.e. the carrier for the ingredients of the mouthwash, such as the essential oils, and the like
  • the vehicle i.e. the carrier for the ingredients of the mouthwash, such as the essential oils, and the like
  • the carrier for the ingredients of the mouthwash is typically a water-alcohol mixture.
  • reduced alcohol mouthwashes can be formulated with same taste properties as higher alcohol mouthwashes.
  • the mouthwashes with no alcohol can be made with the same or similar properties as alcohol containing mouthwashes.
  • the oral compositions according to the present invention include reduced alcohol and no alcohol mouthwashes.
  • the ratio of water to alcohol is in the range of from about 1 : 1 to about 20:1, preferably about 3:1 to about 20:1 and most preferably about 3:1 to about 10:1 by weight.
  • the total amount of water-alcohol mixture in a mouthwash preparation is typically in the range from about 50% to about 99.9% by weight of the composition.
  • the pH value of such mouthwash preparations is generally from about 3.5 to about 8.0 and preferably from about 4 to about 6.0. A pH below 3.5 would be irritating to the oral cavity and soften tooth enamel. A pH greater than 8 would result in an unpleasant mouth feel.
  • the oral compositions according to the present invention may also contain surface active agents —i.e. surfactants— in amounts up to about 5%.
  • surface active agents are organic materials that aid in the complete dispersion of the preparation throughout the oral cavity.
  • the organic surface active material may be anionic, non-ionic, ampholytic, or cationic.
  • Suitable anionic surfactants are water-soluble salts of higher fatty acid monoglyceride monosulfates, such as the sodium salt of the monosulfated monoglyceride of hydrogenated coconut oil fatty acids; higher alkyl sulfates, such as sodium lauryl sulfate; alkyl aryl sulfonates, such as sodium dodecyl benzene sulfonate; higher alkyl sulfonacetates; higher fatty acid esters of 1,2-dihydroxy propane sulfonates; and substantially saturated higher aliphatic acyl amides of lower aliphatic amino carboxylic acids such as those having 12 to 16 carbons at the fatty acid, alkyl or acyl radicals.
  • higher alkyl sulfates such as sodium lauryl sulfate
  • alkyl aryl sulfonates such as sodium dodecyl benzene sulfonate
  • amides are N-lauroyl sarcosine, and the sodium, potassium, and ethanolamide salts of N-lauroyl, N-myristyl or N- palmitoyl sarcosine.
  • non-ionic surfactants employed are poly(oxyethylene)-poly(oxypropylene) block copolymers. Such copolymers are known commercially as poloxamers and are produced in a wide range of structures and molecular weights with varying contents of ethylene oxide and propylene oxide.
  • the non-ionic poloxamers according to the invention are non-toxic and acceptable as direct food additives. They are stable and readily dispersible in aqueous systems and are compatible with a wide variety of formulating ingredients for oral preparations. These surfactants should have an HLB (Hydrophilic-Lipophilic Balance) of between about 10 and 30 and preferably between 10 and 25.
  • HLB Hydrophilic-Lipophilic Balance
  • these polymers should constitute from 0.1% to 2% by weight of total volume of liquid oral preparation (% w/v) and preferably from 0.2% to 1% w/v.
  • a particularly preferred poloxamer is Poloxamer 407 having an HLB of about 18-23.
  • Pluronic F-127 BASF-WYANDOTTE
  • the molecular weight distribution of Poloxamer 407 is reported to be approximately 11,800-12,600.
  • Non-ionic surfactants useful in this invention are ethoxylated hydrogenated castor oils.
  • Such surfactants are prepared by hydrogenating castor oil and treating the so-formed product with from about 10 to 200 moles of ethylene glycol. They are designated as PEG (numeral) hydrogenated castor oil in accordance with the dictionary of the Cosmetics, Toiletries and Fragrance Association, 3rd Ed. wherein the numeral following PEG indicates the degree of ethoxylation, i.e. the number of moles of ethylene oxide added.
  • PEG hydrogenated castor oils include PEG 16, 20, 25, 30, 40, 50, 60, 80, 100 and 200.
  • the ethoxylated hydrogenated castor oils are used in the same concentrations as the above described poly(oxyethylene)-poly(oxypropylene) block co-polymers.
  • non-ionic surface active agents include condensates of sorbitan esters of fatty acids with from 20 to 60 moles of ethylene oxide (e.g., "Tweens” a trademark of ICI United States, Inc.), and amphoteric agents such as quaternized imidazole derivatives.
  • Additional non-ionic surfactants that may be suitable are the condensation products of an alpha-olefin oxide containing 10 to 20 carbon atoms, a polyhydric alcohol containing 2 to 10 carbons and 2 to 6 hydroxyl groups and either ethylene oxide or a heteric mixture of ethylene oxide and propylene oxide.
  • the resultant surfactants are polymers having a molecular weight in the range of 400 to about 1600 and containing 40%o to 80% by weight of ethylene oxide, with an alpha-olefin oxide to polyhydric alcohol mole ratio in the range of about 1:1 to 1:3.
  • Cationic surface active agents that may be suitable are molecules that carry a positive charge such as cetylpyridinium chloride, domiphen bromide, benzylkonium chloride, and dequalinium chloride.
  • Fluorine providing compounds may be present in the oral preparations of this invention. These compounds may be slightly water soluble or may be fully water soluble and are characterized by their ability to release fluoride ions or fluoride containing ions in water.
  • Typical fluorine providing compounds are inorganic fluoride salts such as soluble alkali metal, alkaline earth metal, and heavy metal salts, for example, sodium fluoride, potassium fluoride, ammonium fluoride, cuprous fluoride, zinc fluoride, stannic fluoride, stannous fluoride, barium fluoride, sodium fluorosilicate, ammonium fluorosilicate, sodium fluorozirconate, sodium monofiuorophosphate, aluminum mono- and difluorophosphate and fluorinated sodium calcium pyrophosphate.
  • inorganic fluoride salts such as soluble alkali metal, alkaline earth metal, and heavy metal salts, for example, sodium fluoride, potassium fluoride, ammonium fluor
  • the fluorine providing compound is generally present in an amount sufficient to release up to about 0.15%, preferably about 0.001% to about 0.1% and most preferably from about O.OOP/o to about 0.05% fluoride by weight of the preparation.
  • the present invention also includes a high intensity sweetener.
  • the sweetener is used is small amounts but is present in amounts sufficient to make the composition acceptable to most consumers in spite of the presence of two ingredients, thymol and a zinc salt, that are known to taste unpleasant.
  • the high intensity sweeteners useful in the compositions of the present invention include water-soluble artificial sweeteners such as the soluble saccharin salts, i.e. sodium or calcium saccharin salts, cyclamate salts, the sodium, ammonium or calcium salt of 3,4-dihydro-6-methyl-l,2,3-oxathiazine-4-one-
  • the amount of sweetener needed in composition is dependent on the sweetening profile of the particular sweetener. The amounts can be readily determined by those skilled in the art.
  • a preferred high intensity sweetener is saccharin.
  • the saccharin can be added in granular or spray dried form.
  • the amount of saccharin useful in the compositions of the present invention is from about 0.001 to about 0.25 percent by weight of the composition, preferably from about 0.01 to about 0.2 percent by weight of the composition and even more preferably from about 0.05 to about 0.15 percent by weight of the composition.
  • auxiliary sweeteners may be utilized in the compositions of this invention.
  • Suitable natural and artificial sweeteners are known in the art.
  • the sweetening agent (sweetener) used may be selected from a wide range of materials including water-soluble sweetening agents, water-soluble artificial sweeteners, water-soluble sweetening agents derived from naturally occurring water-soluble sweeteners and mixtures thereof.
  • sweeteners include monosaccharides, disaccharides and polysaccharides such as xylose, ribose, glucose (dextrose), mannose, galactose, fructose (levulose), sucrose (sugar), maltose, invert sugar (a mixture of fructose and glucose derived from sucrose), partially hydrolyzed starch, corn syrup solids, dihydrochalcones, monellin, steviosides, and glycyrrhizin; and protein based sweeteners such as thaumatoccous danielli (Thaumatin I and II).
  • monosaccharides such as xylose, ribose, glucose (dextrose), mannose, galactose, fructose (levulose), sucrose (sugar), maltose, invert sugar (a mixture of fructose and glucose derived from sucrose), partially hydrolyzed starch, corn syrup solids, dihydrochalcone
  • flavoring agents include those known to the skilled artisan, such as, natural and artificial flavors. These flavorings may be chosen from synthetic flavor oils and flavoring aromatics, and/or oils, oleo resins and extracts derived from plants, leaves, flowers, fruits and so forth, and combinations thereof.
  • Representative flavor oils include: spearmint oil, cinnamon oil, oil of wintergreen (methyl salicylate), peppermint oil, clove oil, bay oil, eucalyptus oil, thyme oil, cedar leaf oil, oil of nutmeg, oil of sage, and oil of bitter almonds.
  • vanilla and citrus oil, including lemon, orange, grape, lime and grapefruit and fruit essences including apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot and so forth.
  • sweetenings may be used individually or in admixture.
  • Commonly used flavors include mints such as peppermint, menthol, artificial vanilla, cinnamon derivatives, and various fruit flavors, whether employed individually or in admixture.
  • Flavorings such as aldehydes and esters including cinnamyl acetate, cinnamaldehyde, citral, diethylacetal, dihydrocarvyl acetate, eugenyl formate, p- methylanisole, and so forth may also be used.
  • any flavoring or food additive such as those described in Chemicals Used in Food Processing, pub 1274 by the National Academy of Sciences, pages 63-258 may be used.
  • aldehyde flavorings include, but are not limited to acetaldehyde (apple); benzaldehyde (cherry, almond); cinnamic aldehyde (cinnamon); citral, i.e., alpha citral (lemon, lime); neral, i.e. beta citral (lemon, lime); decanal (orange, lemon); ethyl vanillin (vanilla, cream); heliotropine, i.e.
  • trans-2 (berry fruits); tolylaldehyde (cherry, almond); veratraldehyde (vanilla); 2,6- dimethyl-5-heptenal, i.e. melonal (melon); 2-6-dimethyloctanal (green fruit); and 2- dodecenal (citrus, mandarin); cherry; grape; mixtures thereof; and the like.
  • the amount of flavoring employed is normally a matter of preference subject to such factors as flavor type, individual flavor, and strength desired. Thus, the amount may be varied in order to obtain the result desired in the final product. Such variations are within the capabilities of those skilled in the art without the need for undue experimentation. In general, amounts of about 0.01% to about 2.0% by weight of the composition are useable with amounts of about 0.025% to about 1.5% being preferred.
  • compositions of this invention may also contain coloring agents or colorants.
  • the coloring agents are used in amounts effective to produce the desired color.
  • the coloring agents (colorants) useful in the present invention include the pigments such as titanium dioxide, which may be incorporated in amounts of up to about 2% by weight of the composition, and preferably less than about 1% by weight.
  • Colorants may also include natural food colors and dyes suitable for food, drug and cosmetic applications. These colorants are known as F.D. & C. dyes and lakes.
  • the materials acceptable for the foregoing spectrum of use are preferably water-soluble, and include indigoid dye, known as F. D. & C. Blue No. 2, which is the disodium salt of 5,5-indigotindisulfonic acid.
  • the dye known as Green No. 1 comprises a triphenylmethane dye and is the monosodium salt of4-[4-N-ethyl-p-sulfobenzylamino)diphenylmethylene]-[l-N-ethyl-N- p-sulfoniumbenzyl)-2,5 -cyclohexadiemmine]. Additional examples include the yellow dye, known as D&C Yellow No. 10, the dye known as F.D.& C. Green No. 3 that comprises a triphenylmethane dye and fhe dye F.D. & C. Blue No.
  • the present invention may include a preservative in concentration ranges of from about 0.05% to about 2.0% by weight.
  • preservatives include benzoic acid and sodium benzoate, among others.
  • any pharmaceutically or orally acceptable preservative may be used to prepare the present invention.
  • Sodium benzoate is typically present in amount of about 0.01-1% by weight, preferably about 0.025-0.8%.
  • compositions according to the present invention can also include an alcohol having 3 to 6 carbon atoms.
  • Preferred alcohols having 3 to 6 carbon atoms are aliphatic alcohols.
  • a particularly preferred aliphatic alcohol having 3 carbons is 1-propanol.
  • the amount of 3 to 6 carbon alcohol in the composition is from about 0.1 to about 1.5% by weight of the composition.
  • a preferred amount of 3 to 6 carbon alcohol in the composition is from about 0.3 to about 1.0% by weight of the composition.
  • a more preferred amount is from about 0.5 to about 0.75% by weight of the composition.
  • Human dental calculus consists of inorganic or mineral and organic phases.
  • the mineral phase is composed of a mixture of calcium phosphates, namely, dicalcium phosphate dihydrate (DCPD), octacalcium phosphate (OCP), magnesium-substituted beta-tricalcium phosphate ( ⁇ -TCMP) and carbonate hydroxyapatite (CHA).
  • DCPD dicalcium phosphate dihydrate
  • OCP octacalcium phosphate
  • ⁇ -TCMP magnesium-substituted beta-tricalcium phosphate
  • CHA carbonate hydroxyapatite
  • anti- calculus agents such as pyrophosphates, statherins, gantrez, magnesium salts and zinc salts have been proposed to retard the formation of calculus on tooth surfaces. These agents are usually compounds that inhibit the formation of calcium phosphate, mainly apatite.
  • the stock solution was mixed and used to make three mouthwash compositions.
  • the pH of the three formulas was adjusted with NaOH to 4.19 to 4.20.
  • Zinc chloride solutions at concentrations of 0.09, 0.15, and 0.20% were prepared.
  • Zinc acetate solutions at concentrations of 0.0, 0.09, 0.15 and 0.20% were prepared.
  • a calcium phosphate metastable solution (CPMS) was prepared by mixing 20 ml of 0.225 M NaCl; 80 ml of 4.185 mM CaCl 2 and 50 ml, 2.805 mM Na 2 HPO 4 in a 250 ml beaker. The solution was adjusted to pH 7.4.
  • a beaker containing the continuously stirred CPMS was immersed in a waterbath maintained at 37°C.
  • This CPMS was prepared to give a one (1) minute induction time before the initial precipitation of calcium phosphate.
  • the precipitation signals a Dosimat to add drops of a 0.012 M NaOH solution.
  • Samples containing zinc ions were added to the CPMS (150 ml) in 1.5 and 3.0 ml volumes.
  • the starting pH of fhe metastable solution after addition of the sample was recorded. Formation of calcium phosphate was indicated by the change in the pH and the observation of suspensions of microparticles shown by Tyndall effect.
  • Induction time was established as the time required for fhe initial precipitation to occur without (control) and with fhe addition of the zinc- containing samples. Measurements were made in duplicates or triplicates and results presented as the average values.
  • the results obtained with the mouthwash samples containing ZnCl 2 at various levels and using 1.5 and 3.0 ml samples are summarized in Table 3.
  • the results obtained with the aqueous solutions containing ZnCl 2 at various levels and using 1.5 and 3.0 ml samples are summarized in Table 4.
  • the results obtained with aqueous solutions containing ZnAc at various levels and using 1.5 ml samples are summarized in Table 5.
  • Tables 3-5 the original and actual concentration of zinc is reported.
  • the original zinc concentration is the amount of zinc salt in the mouthwash or aqueous solution.
  • the actual concentration of zinc is the amount of zinc after it is added to the 150 ml of CPMS.
  • Fig. 1 The effect of zinc on induction time using ZnCl 2 with a 3.0 ml sample in both the mouthwash and aqueous solution is summarized in Fig. 1.
  • Fig. 2 The effect of zinc on induction time using ZnCl 2 with a 1.5 ml sample in both the mouthwash and aqueous solution is summarized in Fig. 2.
  • Fig. 3. The effect of zinc on induction time using ZnAC with a 1.5 ml sample in aqueous solution is summarized in Fig. 3.
  • the zinc chloride solutions were observed to have sediment at the bottom of the bottles.
  • the higher the Zn concentration the greater the amount of the sediment, due to high pH.
  • ZnCl 2 hydrolyzes to Zn (OH) 2 and ZnO.
  • results obtained from the Zn solutions prepared with ZnAc demonstrated a dose response, as shown in Fig. 3.
  • the difference in results obtained from the ZnCl 2 solution compared to the mouthwash, at 0.15% ZnCl 2 using 1.5 ml of the solution, may be due to the buffer capacity and greater acidity of the mouthwash, causing the Zn 2+ ions to stay in solution.
  • a difference in induction time is observed between metastable calcium phosphate solution CPMS (control) and the Zn-containing solutions. For example, time induction of 4 min observed for mouthwash or Zn acetate solutions indicate that such solution would take 4 time longer than the control before precipitation of apatitic calcium phosphate to appear.
  • Photographs of crystalline dicalcium phosphate dihydrate were taken to show the effect of ZnCl 2 on the growth of the crystals.
  • the crystals were prepared as follows. A 5% solution of sodium meta silicate, 9-hydrate is prepared. While stirring, sodium phosphate monobasic, monohydrate is added to make a 0.3M phosphate solution. The pH of the phosphate/silica solution is adjusted to 6.0 using acetic acid. Thirty mL of solution is poured into 25x150mm size test tubes and covered. The gel completely solidifies in 2- 3 days at room temperature. A 0.3M calcium acetate solution with fhe indicated amount of zinc chloride is prepared and the pH of the calcium/zinc solutions is adjusted to 4.2 using acetic acid.
  • the zinc chloride solutions were prepared in the stock solution described above. Ten ml of the calcium/zinc solution is added to the top of the solidified gels. The tubes are incubated at 25 C.
  • the photos of fhe dicalcium phosphate dihydrate (DCPD) crystals in the gels were taken with a Mamiya medium format camera, equipped with a 55mm lens.
  • Fig. 4 is a photograph of a crystal of dicalcium phosphate dihydrate (DCPD).
  • Figs. 5-9 are photographs of crystals of dicalcium phosphate dihydrate formed in the presence of 0.01, 0.09, 0.15, 0.20 and 0.40% ZnCl 2 , respectively. As the amount of zinc increases, the size and quantity of DCPD changes.
  • the four treatment groups were 1) a moufhrinse within the scope of the present invention that contained 0.09% zinc chloride and 0.064% thymol and regular Crest® toothpaste, 2) a moufhrinse within fhe scope of the present invention that contained 0.15%) zinc chloride and 0.064% thymol and regular Crest® toothpaste, 3) a placebo moufhrinse and regular Crest® toothpaste and 4) a placebo rinse and tartar control Crest® toothpaste.
  • Cysteine VSC response is measured using a halimeter.
  • the subject rinses with 5 ml of 6 mM of Cysteine rinse or the subject mouthwash for thirty seconds at 20 minute intervals.
  • the halimeter measures the amount of volatile sulfur compounds (VSC) in ppm of H 2 S.
  • Each graph represents the results from one subject.
  • Fig. 10 shows the cysteine VSC response rinsing with a control mouthwash without any zinc.
  • Fig. 11 shows the cysteine VSC response rinsing with Formula 7.
  • Fig. 12 shows the cysteine VSC response rinsing with Formula 8.
  • the amount of zinc sulphate added is higher than zinc chloride to provide approximately equal amounts of zinc ions.
  • Fig. 13 shows the cysteine VSC response of rinsing with Viadent®, which the inventors believe has approximately 0.2% ZnCl 2 .
  • the formulas used in this study are summarized in Table 7. Control and Test Formulas
  • the ingredients were mixed.
  • the ingredients are mixed.
  • Mouthwash formulas based on one liter were made as follows:
  • the cysteine VSC response graphs show that rinsing with control mouthwashes without zinc does not provide extended breath protection. Mouthwash formulas with zinc ions including as low as 0.1 % ZnCl 2 or 0.21% ZnSO 4 provide significant breath protection that is comparable to a commercial mouthwash with twice as much ZnCl 2 . Hedonic Malodor Studies
  • the purpose of this test was to measure the overnight efficacy in reducing and controlling intrinsic oral malodor using hedonic methodology.
  • the test was an observer- blind, parallel design using 99 subjects.
  • Post treatment hedonic rating were taken on day 1, 9 hours after a single use (in morning) and on Day 4 after 5 uses (in morning).
  • Formulas 9 and 10 are significantly superior (p ⁇ 0.001) to water control at all time intervals from 30 minutes through 5 hours.
  • Control C was significantly superior (p ⁇ 0.016) to water at 30, 60, and 90 minutes and 2, 3 and 5 hours.
  • Formulas 9 and 10 were significantly superior (p ⁇ 0.012) to Control C at all times through 4 hours.
  • the adjusted hedonic ratings are summarized in Table 10.
  • the overnight and long term efficacy of mouthrinses in reducing and controlling intrinsic oral malodor with daily use using a halimeter was measured.
  • the test used a observer-blind, parallel design with 47 subjects.
  • a baseline halimeter reading was taken on day 0 in the morning, the subjects rinsed with a single use in the evening on day 0 and then used the moufhrinse twice daily usage for 28 days.
  • Post-treatment halimeter reading were taken on day 1 after a single 9 hour use (in morning), on day 7 after 13 uses (in morning) and on day 28 after 55 uses (in morning).
  • compositions according to the present invention contain at least two ingredients that are known to taste bad, thymol and zinc salt, yet they provide superior taste.
  • a taste test was performed using Formula 11 , which contains

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Abstract

L'invention concerne une composition à administration par voie orale contenant du thymol, un sel de zinc ainsi qu'un édulcorant. La composition à administration par voie orale présente une efficacité anti-tartre, anti-plaque, anti-gingivite, elle procure un rafraîchissement de l'haleine durable et est acceptée par le consommateur en dépit de la présence de deux ingrédients, le thymol et un sel de zinc, connus pour leur mauvais goût.
PCT/US1999/009135 1998-06-29 1999-04-28 Compositions orales ameliorees d'elimination et de prevention du tartre, de la fetidite, de la plaque et de la gengivite WO2000000166A2 (fr)

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AU37659/99A AU3765999A (en) 1998-06-29 1999-04-28 Improved oral compositions for control and prevention of tartar, oral malodor, plaque and gingivitis

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US60/091,119 1998-06-29
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Cited By (18)

* Cited by examiner, † Cited by third party
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WO2002058469A1 (fr) * 2001-01-23 2002-08-01 Van Beek, Ron Composes et compositions pesticides
EP1262110A2 (fr) * 2001-04-26 2002-12-04 Nutrinova Nutrition Specialties & Food Ingredients GmbH Sel non-métallique de l'acesulfam
US6759544B2 (en) 2001-06-22 2004-07-06 Nutrinova Nutrition Specialties & Food Ingredients Gmbh Antimicrobially active acesulfame complexes, process for their preparation and their use
EP1587477A2 (fr) * 2003-01-03 2005-10-26 Epien Medical, Inc. Formulation non odorante pour le traitement de discontinuites des muqueuses
EP2415473A1 (fr) * 2006-11-10 2012-02-08 The Procter & Gamble Company Compositions d'hygiène buccale contenant des combinaisons d'agents antibactériens et de modulation de réponse hôte
US20120148506A1 (en) * 2009-08-20 2012-06-14 Tomas Bernardo Galvan Gonzalez Antiseptic pharmaceutical composition for oral hygiene and the treatment of oral diseases of microbial origin
WO2012076310A1 (fr) 2010-12-07 2012-06-14 Unilever Nv Composition de soin buccal
WO2014056824A3 (fr) * 2012-10-12 2014-10-09 Unilever N.V. Composition de soins de bouche
CN104837469A (zh) * 2012-10-12 2015-08-12 荷兰联合利华有限公司 口腔护理组合物
EP2918261A1 (fr) * 2014-03-13 2015-09-16 Imarko Research S.A. Dérivés d'acides gras pour le traitement de maladies infectieuses
WO2016036341A1 (fr) * 2014-09-01 2016-03-10 Colgate-Palmolive Company Compositions à base de zinc et contenant des huiles essentielles
US9693941B2 (en) 2011-11-03 2017-07-04 Conopco, Inc. Liquid personal wash composition
AU2013406783B2 (en) * 2013-12-02 2017-08-31 Colgate-Palmolive Company Oral care zinc compositions
US9801916B2 (en) 2013-02-07 2017-10-31 Tomás Bernardo Galvan Gonzalez Oral antiseptic composition useful for treating oral mucositis
WO2018114121A1 (fr) * 2016-12-20 2018-06-28 Unilever N. V. Composition antimicrobienne comprenant un métal oligodynamique
US10543155B2 (en) * 2011-07-26 2020-01-28 Wm. Wrigley Jr. Company Compositions containing zinc salts and isothiocyanates for reduction of oral volatile sulfur compounds (VSCs)
US10682298B2 (en) 2014-08-06 2020-06-16 Conopco, Inc. Process for preparing an antimicrobial particulate composition
US11529295B2 (en) 2019-09-25 2022-12-20 Church & Dwight Co., Inc. Oral care composition

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010046238A1 (fr) 2008-10-20 2010-04-29 Unilever Nv Composition antimicrobienne
WO2011036048A1 (fr) 2009-09-24 2011-03-31 Unilever Nv Agent désinfectant comprenant de l'eugénol, du terpinéol et du thymol

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WO1996011694A2 (fr) * 1994-10-13 1996-04-25 Gombert, Bernard COMPOSITION AROMATIQUE A BASE D'OLIBAN EN COMBINAISON AVEC UN AGENT SYNERGIQUE (e.g. EUCALIPTOL, BANEOL, SEL DE ZINC, SEL DE CUIVRE) ET SON UTILISATION
WO1997040812A1 (fr) * 1996-04-26 1997-11-06 Warner-Lambert Company Composition buccale amelioree contenant du zinc

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Publication number Priority date Publication date Assignee Title
WO1996011694A2 (fr) * 1994-10-13 1996-04-25 Gombert, Bernard COMPOSITION AROMATIQUE A BASE D'OLIBAN EN COMBINAISON AVEC UN AGENT SYNERGIQUE (e.g. EUCALIPTOL, BANEOL, SEL DE ZINC, SEL DE CUIVRE) ET SON UTILISATION
WO1997040812A1 (fr) * 1996-04-26 1997-11-06 Warner-Lambert Company Composition buccale amelioree contenant du zinc

Cited By (32)

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US6844369B2 (en) 2001-01-23 2005-01-18 Van Beek Global, Llc Pesticidal compounds and compositions
WO2002058469A1 (fr) * 2001-01-23 2002-08-01 Van Beek, Ron Composes et compositions pesticides
EP1262110A2 (fr) * 2001-04-26 2002-12-04 Nutrinova Nutrition Specialties & Food Ingredients GmbH Sel non-métallique de l'acesulfam
EP1262110A3 (fr) * 2001-04-26 2002-12-18 Nutrinova Nutrition Specialties & Food Ingredients GmbH Sel non-métallique de l'acesulfam
US6759544B2 (en) 2001-06-22 2004-07-06 Nutrinova Nutrition Specialties & Food Ingredients Gmbh Antimicrobially active acesulfame complexes, process for their preparation and their use
EP1587477A2 (fr) * 2003-01-03 2005-10-26 Epien Medical, Inc. Formulation non odorante pour le traitement de discontinuites des muqueuses
EP1587477A4 (fr) * 2003-01-03 2008-09-10 Epien Medical Inc Formulation non odorante pour le traitement de discontinuites des muqueuses
EP2415473A1 (fr) * 2006-11-10 2012-02-08 The Procter & Gamble Company Compositions d'hygiène buccale contenant des combinaisons d'agents antibactériens et de modulation de réponse hôte
US8865136B2 (en) * 2009-08-20 2014-10-21 Tomas Bernardo Galvan Gonzalez Antiseptic pharmaceutical composition for oral hygiene and the treatment of oral diseases of microbial origin
US20120148506A1 (en) * 2009-08-20 2012-06-14 Tomas Bernardo Galvan Gonzalez Antiseptic pharmaceutical composition for oral hygiene and the treatment of oral diseases of microbial origin
CN103354741B (zh) * 2010-12-07 2016-01-13 荷兰联合利华有限公司 口腔护理组合物
WO2012076310A1 (fr) 2010-12-07 2012-06-14 Unilever Nv Composition de soin buccal
CN103354741A (zh) * 2010-12-07 2013-10-16 荷兰联合利华有限公司 口腔护理组合物
EA022986B1 (ru) * 2010-12-07 2016-04-29 Юнилевер Нв Композиция для ухода за полостью рта
US10543155B2 (en) * 2011-07-26 2020-01-28 Wm. Wrigley Jr. Company Compositions containing zinc salts and isothiocyanates for reduction of oral volatile sulfur compounds (VSCs)
US9693941B2 (en) 2011-11-03 2017-07-04 Conopco, Inc. Liquid personal wash composition
EA027276B1 (ru) * 2012-10-12 2017-07-31 Юнилевер Н.В. Композиция для ухода за полостью рта
CN104837469A (zh) * 2012-10-12 2015-08-12 荷兰联合利华有限公司 口腔护理组合物
CN104837469B (zh) * 2012-10-12 2017-09-26 荷兰联合利华有限公司 口腔护理组合物
WO2014056824A3 (fr) * 2012-10-12 2014-10-09 Unilever N.V. Composition de soins de bouche
US9801916B2 (en) 2013-02-07 2017-10-31 Tomás Bernardo Galvan Gonzalez Oral antiseptic composition useful for treating oral mucositis
AU2013406783B2 (en) * 2013-12-02 2017-08-31 Colgate-Palmolive Company Oral care zinc compositions
EP2918261A1 (fr) * 2014-03-13 2015-09-16 Imarko Research S.A. Dérivés d'acides gras pour le traitement de maladies infectieuses
FR3018447A1 (fr) * 2014-03-13 2015-09-18 Imarko Res S A Derives d'acide gras dans le traitement de maladies infectieuses
US10682298B2 (en) 2014-08-06 2020-06-16 Conopco, Inc. Process for preparing an antimicrobial particulate composition
WO2016036341A1 (fr) * 2014-09-01 2016-03-10 Colgate-Palmolive Company Compositions à base de zinc et contenant des huiles essentielles
CN106794120A (zh) * 2014-09-01 2017-05-31 高露洁-棕榄公司 具有精油的含锌组合物
AU2014405603B2 (en) * 2014-09-01 2018-03-29 Colgate-Palmolive Company Zinc-containing compositions with essential oils
WO2018114121A1 (fr) * 2016-12-20 2018-06-28 Unilever N. V. Composition antimicrobienne comprenant un métal oligodynamique
CN110113945A (zh) * 2016-12-20 2019-08-09 荷兰联合利华有限公司 包含微动金属的抗微生物组合物
EA038526B1 (ru) * 2016-12-20 2021-09-10 ЮНИЛЕВЕР АйПи ХОЛДИНГС Б.В. Противомикробная композиция, содержащая олигодинамический металл
US11529295B2 (en) 2019-09-25 2022-12-20 Church & Dwight Co., Inc. Oral care composition

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WO2000000166A3 (fr) 2000-02-10
PE20000650A1 (es) 2000-08-10
CO4840514A1 (es) 1999-09-27
AR019722A1 (es) 2002-03-13
AU3765999A (en) 2000-01-17
UY25591A1 (es) 1999-09-27

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