Classifications

• • 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
  • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
  • A61K8/20—Halogens; 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
  • A61K8/55—Phosphorus compounds
• • 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

Definitions

• the present invention relates to oral care compositions comprising an essentially water- insoluble zinc compound and a phytate compound.
• Zinc has been used for its ability to neutralize oral malodor and to provide antimicrobial, antiplaque and anticalculus activities.
• the activity of zinc compounds is generally attributed to zinc ions, in particular divalent zinc ions (Zn +2 ).
• zinc ions in particular divalent zinc ions (Zn +2 ).
• Zn +2 divalent zinc ions
• water-soluble and highly ionized zinc compounds such as zinc chloride that readily provide active zinc ions have found utility in oral compositions, which are typically aqueous based.
• the soluble zinc compounds have the disadvantages of leaving an unpleasant astringent and metallic taste in the mouth as well as having short-lived efficacy against plaque, calculus and as an odor inhibitor.
• Sparingly water-soluble salts such as zinc citrate and zinc lactate have thus been used to moderate the release of zinc ions, thereby reducing astringency and providing slow dissolution of the zinc compound by saliva for longer activity in the oral cavity.
• the sparingly soluble characteristic of these zinc compounds promotes longevity of action at the expense of initial or immediate efficacy.
• the use of zinc compounds of varying solubility has been disclosed for example, in U.S. Patent Nos.
• the present invention is directed to oral care compositions and their use, comprising in an orally acceptable carrier:
• a compound having C-O-P bonds selected from polyphosphorylated inositol compounds such as phytic acid, myo-inositol pentakis(dihydrogen phosphate); myo-inositol tetrakis(dihydrogen phosphate), myo-inositol trikis(dihydrogen phosphate), and an alkali metal, alkaline earth metal or ammonium salt thereof.
• compositions are effective in preventing and controlling oral cavity conditions including plaque, calculus, caries, periodontal disease and mouth malodor and have acceptable aesthetics without the unpleasant astringent and metallic taste associated with the use of zinc.
• the word "include,” and its variants, are intended to be non-limiting, such that recitation of items in a list is not to the exclusion of other like items that may also be useful in the materials, compositions, devices, and methods of this invention.
• oral care composition or “oral composition” is meant a product, which in the ordinary course of usage, is not intentionally swallowed for purposes of systemic administration of particular therapeutic agents, but is rather retained in the oral cavity for a time sufficient to contact substantially all of the dental surfaces and/or oral tissues for purposes of oral activity.
• oral care compositions function to prevent the formation of dental calculus and disorders such as caries, periodontitis and gingivitis, and also to eliminate and prevent oral malodor or halitosis and staining.
• oral care product forms include toothpaste, dentifrice, tooth gel, subgingival gel, mouthrinse, mouthspray, mousse, foam, denture product, lozenge, chewable tablet or chewing gum and strips or films for direct application or attachment to oral surfaces.
• dentifrice means paste, gel, or liquid formulations unless otherwise specified.
• the dentifrice composition may be a single phase composition or may be a combination of two or more separate dentifrice compositions.
• the dentifrice composition may be in any desired form, such as deep striped, surface striped, multilayered. having the gel surrounding the paste, or any combination thereof.
• Each dentifrice composition in a dentifrice comprising two or more separate dentifrice compositions may be contained in a r physically separated compartment of a dispenser and dispensed side-by-side.
• dispenser means any pump, tube, or container suitable for dispensing compositions such as dentifrices.
• teeth refers to natural teeth as well as artificial teeth or dental prosthesis.
• tartar and “calculus” are used interchangeably and refer to mineralized dental plaque bioi ⁇ lms.
• orally acceptable carrier includes any safe and effective materials for use in the compositions of the present invention.
• materials include conventional additives in oral care compositions including but not limited to fluoride ion sources, anti-calculus or anti-tartar agents, desensitizing agents, teeth whitening agents such as peroxide sources, abrasives such as silica, herbal agents, chelating agents, buffers, anti-staining agents, alkali metal bicarbonate salts, thickening materials, humectants, water, surfactants, titanium dioxide, flavor system, sweetening agents, xylitol, coloring agents, and mixtures thereof.
• Active and other ingredients useful herein may be categorized or described herein by their cosmetic and/or therapeutic benefit or their postulated mode of action or function. However, it is to be understood that the active and other ingredients useful herein can, in some instances, provide more than one cosmetic and/or therapeutic benefit or function or operate via more than one mode of action. Therefore, classifications herein are made for the sake of convenience and are not intended to limit an ingredient to the particularly stated application or applications listed.
• the present oral care compositions comprise as essential ingredients an essentially water-insoluble zinc compound and a complexing agent selected from polyphosphorylated inositol compounds such as phytic acid, myo-inositol pentakis(dihydrogen phosphate); myoinositol tetrakis(dihydrogen phosphate), myo-inositol trikis(di hydrogen phosphate), and an alkali metal or ammonium salt thereof.
• polyphosphorylated inositol compounds such as phytic acid, myo-inositol pentakis(dihydrogen phosphate); myoinositol tetrakis(dihydrogen phosphate), myo-inositol trikis(di hydrogen phosphate), and an alkali metal or ammonium salt thereof.
• Phytic acid also known as myo-inositol 1,2,3,4,5,6-hexakis (dihydrogen phosphate) or inositol hexaphosphoric acid, and its alkali metal, alkaline earth metal or ammonium salts are the preferred compounds containing C-O-P bonds, functioning as complexing agent to aid in solubilizing the essentially water-insoluble zinc compound to provide a supply of divalent zinc ions (Zn +2 ), which function as antimicrobial, antiplaque, anticalculus and deodorizing agent.
• the term "phytate” includes phytic acid and its salts as well as the other polyphosphorylated inositol compounds. Phytates also act as anticaries agent and as inhibitor of hydroxyapatite or calculus formation.
• essentially water-insoluble as employed herein in reference to zinc compounds, means that the zinc-containing compound has a solubility in water that is less than about 0.1 gram per 100 milliliters of water at 25° C.
• essentially water insoluble zinc compounds useful herein include zinc carbonate, zinc oxide, zinc silicate, zinc phosphate, zinc pyrophosphate, and zinc-containing minerals such as smithsonite, hydrozincite (zinc carbonate hydroxide), aurichalcite and rosasite.
• a preferred zinc compound is zinc carbonate, which term as used herein includes various forms including a crystalline form also referred to as basic zinc carbonate, which is commercially available as Zinc Carbonate Basic (Cater Chemicals: Bensenville, IL, USA), Zinc Carbonate (Shepherd Chemicals: Norwood, OH, USA), Zinc Carbonate (CPS Union Corp.: New York, NY, USA), Zinc Carbonate (Elementis Pigments: Durham, UK), and Zinc Carbonate AC (Bruggemann Chemical: Newtown Square, PA, USA).
• Basic zinc carbonate is a synthetic version consisting of materials similar to naturally occurring hydrozincite.
• the idealized stoichiometry is represented by Zn S (OH) G (CCb) 2 but the actual stoichiometric ratios can vary slightly and other impurities may be incorporated in the crystal lattice.
• oral care compositions comprising in an orally acceptable carrier, from about 0.01 to about 10% by weight of a phytate compound and from about 0.01 % to about 10 % by weight of one or a mixture of essentially insoluble zinc compounds
• the essentially insoluble zinc compound is zinc carbonate, zinc oxide or zinc pyrophosphate and the phytate compound is phytic acid or its alkali metal or ammonium salt.
• the level of insoluble zinc compound in these embodiments is up to about 10%, typically from about 0.01 % to about 5 %.
• the level of phytate compound is up to about 10%, typically from about 0.01 % to about 5%.
• the divalent zinc ions generally possess the activities beneficial for oral cavity treatment, an important consideration in this respect is that the final product must not be so excessively astringent or unpleasant tasting as to be unacceptable to the user.
• Many soluble or sparingly soluble zinc compounds including zinc chloride, zinc acetate, zinc sulfate and zinc citrate that readily provide active zinc ions are known to be highly astringent when incorporated in aqueous oral compositions.
• the present invention utilizes essentially insoluble zinc compounds which tend to be significantly less astringent than the soluble or sparingly-soluble zinc compounds.
• the phytate compounds are present in the compositions to provide a solubilizing function by complexing with zinc and providing a source of active divalent zinc ions.
• the oral care composition of the present invention may be in various forms including toothpaste, dentifrice, tooth gel, subgingival gel, mouthrinse, mouthspray, mousse, foam, denture product, lozenge, chewable tablet or chewing gum.
• the oral care composition may also be incorporated onto strips or films for direct application or attachment to oral surfaces.
• the present compositions will optimally have a pH ranging from about 4.0 to about 10.0.
• the pH of the compositions is from about 6.0 to about 9.0.
• the pH of a dentifrice composition is measured from a 3: 1 aqueous slurry of the dentifrice, e.g., 3 parts water to 1 part toothpaste.
• compositions may comprise additional optional components collectively referred to as orally acceptable carrier materials, which are described in the following paragraphs.
• the orally acceptable carrier comprises one or more compatible solid or liquid excipients or diluents which are suitable for topical oral administration.
• compatible is meant that the components of the composition are capable of being commingled without interaction in a manner which would substantially reduce the composition's stability and/or efficacy.
• the carriers or excipients of the present invention can include the usual and conventional components of dentifrices, non-abrasive gels, subgingival gels, mouthwashes or rinses, mouth sprays, chewing gums, lozenges and breath mints as more fully described hereinafter.
• Carrier materials for toothpaste, tooth gel or the like include abrasive materials, sudsing agents, binders, humectants, flavoring and sweetening agents, etc. as disclosed in e.g., U.S. Pat. No. 3,988,433 to Benedict.
• Carrier materials for biphasic dentifrice formulations are disclosed in U.S. Pat. Nos. 5,213,790 issued May 23, 1993; 5,145,666 issued September 8, 1992; and 5,281,410 issued January 25, 1994 all to Lukacovic et al. and in U. S. Patents 4,849,213 and 4,528,180 to Schaeffer.
• Mouthwash, rinse or mouth spray carrier materials typically include water, flavoring and sweetening agents, etc., as disclosed in, e.g., U.S. Pat. No. 3,988,433 to Benedict.
• Lozenge carrier materials typically include a candy base; chewing gum carrier materials include a gum base, flavoring and sweetening agents, as in, e.g., U.S. Pat. No. 4,083,955 to Grabenstetter et al.
• Sachet carrier materials typically include a sachet bag, flavoring and sweetening agents.
• a "subgingival gel carrier" is chosen as disclosed in, e.g. U.S. Pat.
• compositions of the present invention may be in the form of non-abrasive gels and subgingival gels, which may be aqueous or non-aqueous.
• Aqueous gels generally include a thickening agent (from about 0.1% to about 20%), a humectant (from about 10% to about 55%), a flavoring agent (from about 0.04% to about 2%), a sweetening agent (from about 0.1% to about 3%), a coloring agent (from about 0.01% to about 0.5%), and the balance water.
• the compositions may comprise an anticaries agent (from about 0.05% to about 0.3% as fluoride ion), and an anticalculus agent (from about 0.1% to about 13%).
• compositions of the subject invention are in the form of dentifrices, such as toothpastes, tooth gels and tooth powders.
• Components of such toothpaste and tooth gels generally include one or more of a dental abrasive (from about 6% to about 50%), a surfactant (from about 0.5% to about 10%), a thickening agent (from about 0.1% to about 5%), a humectant (from about 10% to about 55%), a flavoring agent (from about 0.04% to about 2%), a sweetening agent (from about 0.1% to about 3%), a coloring agent (from about 0.01% to about 0.5%) and water (from about 2% to about 45%).
• a dental abrasive from about 6% to about 50%
• a surfactant from about 0.5% to about 10%
• a thickening agent from about 0.1% to about 5%
• a humectant from about 10% to about 55%)
• a flavoring agent from about 0.04% to about 2%
• Such toothpaste or tooth gel may also include one or more of an anticaries agent (from about 0.05% to about 0.3% as fluoride ion) and an anticalculus agent (from about 0.1% to about 13%). Tooth powders, of course, contain substantially all non-liquid components.
• mouthwashes or rinses and mouth sprays are mouthwashes or rinses and mouth sprays.
• Components of such mouthwashes and mouth sprays typically include one or more of water (from about 45% to about 95%), ethanol (from about 0% to about 25%), a humectant (from about 0% to about 50%), a surfactant (from about 0.01% to about 7%), a flavoring agent (from about 0.04% to about 2%), a sweetening agent (from about 0.1% to about 3%), and a coloring agent (from about 0.001% to about 0.5%).
• Such mouthwashes and mouth sprays may also include one or more of an anticaries agent (from about 0.05% to about 0.3% as fluoride ion) and an anticalculus agent (from about 0.1% to about 3%).
• compositions of the subject invention may also be in the form of dental solutions and irrigation fluids.
• Components of such dental solutions generally include one or more of water (from about 90% to about 99%), preservative (from about 0.01% to about 0.5%), thickening agent (from 0% to about 5%), flavoring agent (from about 0.04% to about 2%), sweetening agent (from about 0.1% to about 3%), and surfactant (from 0% to about 5%).
• Chewing gum compositions typically include one or more of a gum base (from about 50% to about 99%), a flavoring agent (from about 0.4% to about 2%) and a sweetening agent (from about 0.01 % to about 20%).
• the term "lozenge” as used herein includes: breath mints, troches, pastilles, microcapsules, and fast-dissolving solid forms including freeze dried forms (cakes, wafers, thin films, tablets) and compressed tablets.
• fast-dissolving solid form means that the solid dosage form dissolves in less than about 60 seconds, preferably less than about 15 seconds, more preferably less than about 5 seconds, after placing the solid dosage form in the oral cavity.
• Fast-dissolving solid forms are disclosed in commonly-assigned WO 95/33446 and WO 95/11671; U.S. 4,642,903; U.S. 4,946,684; U.S. 4,305,502; U.S. 4,371 ,516; U.S. 5,188,825; U.S. 5,215,756; U.S. 5,298,261; and U.S. 4,687,662.
• Lozenges include discoid- shaped solids comprising a therapeutic agent in a flavored base.
• the base may be a hard sugar candy, glycerinated gelatin or combination of sugar with sufficient mucilage to give it form.
• Lozenge compositions compressed tablet type typically include one or more fillers (compressible sugar), flavoring agents, and lubricants.
• Microcapsules of the type contemplated herein are disclosed in U.S. 5,370,864 to Peterson et al., issued Dec. 6, 1994.
• the invention provides a dental implement impregnated with the present composition.
• the dental implement comprises an implement for contact with teeth and other tissues in the oral cavity, said implement being impregnated with the present composition.
• the dental implement can be impregnated fibers including dental floss or tape, chips, strips, films and polymer fibers.
• a water-soluble fluoride compound present in dentifrices and other oral compositions in an amount sufficient to give a fluoride ion concentration in the composition, and/or when it is used of from about 0.0025% to about 5.0% by...weight,..preferably.. from about 0.005% to about 2.0% by weight, to provide anticaries effectiveness.
• fluoride ion-yielding materials can be employed as sources of soluble fluoride in the present compositions. Examples of suitable fluoride ion-yielding materials are found in U.S. Patent No. 3,535,421, October 20, 1970 to Briner et al. and U.S. Patent No. 3,678,154, July 18, 1972 to Widder et al.
• Representative fluoride ion sources include: stannous fluoride, sodium fluoride, potassium fluoride, sodium monofluorophosphate, indium fluoride, amine fluoride and many others. Stannous fluoride and sodium fluoride are preferred, as well as mixtures thereof.
• Dental abrasives useful in the topical, oral carriers of the compositions of the subject invention include many different materials.
• the material selected must be one which is compatible within the composition of interest and does not excessively abrade dentin.
• Suitable abrasives include, for example, silicas including gels and precipitates, insoluble sodium polymetaphosphate, hydrated alumina, calcium carbonate, dicalcium orthophosphate dihydrate, calcium pyrophosphate, tricalcium phosphate, calcium polymetaphosphate, and resinous abrasive materials such as particulate condensation products of urea and formaldehyde.
• abrasives for use in the present compositions is the particulate thermosetting polymerized resins as described in U.S. Pat. No. 3,070,510 issued to Cooley & Grabenstetter on Dec. 25, 1962.
• Suitable resins include, for example, melamines, phenolics, ureas, melamine-ureas, melamine-formaldehydes, urea-formaldehyde, melamine-urea- formaldehydes, cross-linked epoxides, and cross-linked polyesters.
• Silica dental abrasives of various types are preferred because of their unique benefits of exceptional dental cleaning and polishing performance without unduly abrading tooth enamel or dentine.
• the silica abrasive polishing materials herein, as well as other abrasives generally have an average particle size ranging between about 0.1 to about 30 microns, and preferably from about 5 to about 15 microns.
• the abrasive can be precipitated silica or silica gels such as the silica xerogels described in Pader et al., U.S. Patent 3,538,230, issued Mar. 2, 1970, and DiGiulio, U.S. Patent 3,862,307, issued Jan. 21, 1975.
• silica xerogels examples include the silica xerogels marketed under the trade name "Syloid" by the W.R. Grace & Company, Davison Chemical Division and precipitated silica materials such as those marketed by the J. M. Huber Corporation under the trade name, Zeodent®, particularly the silicas carrying the designation Zeodent® 119, Zeodent® 1 18, Zeodent® 109 and Zeodent® 129.
• Zeodent® particularly the silicas carrying the designation Zeodent® 119, Zeodent® 1 18, Zeodent® 109 and Zeodent® 129.
• the types of silica dental abrasives useful in the- toothpastes of the present invention are described. in more detail in Wasan ⁇ U-S. _Patent_ 4,340,583, issued July 29, 1982; and in commonly-assigned US Pat. Nos. 5,603,920, issued on Feb. 18, 1997; 5,589,160, issued Dec. 31, 1996; 5,
• abrasives can be used such as mixtures of the various grades of Zeodent® silica abrasives listed above.
• the total amount of abrasive in dentifrice compositions of the subject invention typically range from about 6% to about 70% by weight; toothpastes preferably contain from about 10% to about 50% of abrasives, by weight of the composition.
• Dental solution, mouth spray, mouthwash and non-abrasive gel compositions of the subject invention typically contain little or no abrasive.
• the present compositions may optionally include an additional anticalculus agent, such as a pyrophosphate salt as a source of pyrophosphate ion.
• a pyrophosphate salt as a source of pyrophosphate ion.
• the pyrophosphate salts useful in the present compositions include the dialkali metal pyrophosphate salts, tetraalkali metal pyrophosphate salts, and mixtures thereof. Disodium dihydrogen pyrophosphate (Na2H2P2 ⁇ 7), tetrasodium pyrophosphate (Na4P2 ⁇ 7), and tetrapotassium pyrophosphate (K4P2O7) in their unhydrated as well as hydrated forms are the preferred species.
• the pyrophosphate salt may be present in one of three ways: predominately dissolved, predominately undissolved, or a mixture of dissolved and undissolved pyrophosphate.
• compositions comprising predominately dissolved pyrophosphate refer to compositions where at least one pyrophosphate ion source is in an amount sufficient to provide at least about 1.0% free pyrophosphate ions.
• the amount of free pyrophosphate ions may be from about 1 % to about 15%, from about 1.5% to about 10% in one embodiment, and from about 2% to about 6% in another embodiment.
• Free pyrophosphate ions may be present in a variety of protonated states depending on the pH of the composition.
• compositions comprising predominately undissolved pyrophosphate refer to compositions containing no more than about 20% of the total pyrophosphate salt dissolved in the composition, preferably less than about 10% of the total pyrophosphate dissolved in the composition.
• Tetrasodium pyrophosphate salt is the preferred pyrophosphate salt in these compositions.
• Tetrasodium pyrophosphate may be the anhydrous salt form or the decahydrate form, or any other species stable in solid form in the dentifrice compositions.
• the salt is in its solid particle form, which may be its crystalline and/or amorphous state, with the particle size of the salt preferably being small enough to be aesthetically acceptable and readily soluble during use.
• amniint rtf nvrnnhnsnhate salt useful in making these comnositions is. anv tartar control effective amount, generally from about 1.5% to about 15%, preferably from about 2% to about 10%, and most preferably from about 3% to about 8%, by weight of the dentifrice composition.
• Compositions may also comprise a mixture of dissolved and undissolved pyrophosphate salts. Any of the above mentioned pyrophosphate salts may be used.
• Optional agents to be used in place of or in combination with the pyrophosphate salt include such known materials as synthetic anionic polymers, including polyacrylates and copolymers of maleic anhydride or acid and methyl vinyl ether (e.g., Gantrez), as described, for example, in U.S. Patent 4,627,977, to Gaffar et al., as well as, e.g., polyamino propane sulfonic acid (AMPS), polyphosphates (e.g., tripolyphosphate and hexametaphosphate), diphosphonates (e.g., EHDP; AHP), polypeptides (such as polyaspartic and polyglutamic acids), and mixtures thereof.
• synthetic anionic polymers including polyacrylates and copolymers of maleic anhydride or acid and methyl vinyl ether (e.g., Gantrez), as described, for example, in U.S. Patent 4,627,977, to Gaffar et al., as
• Examples of phosphonate copolymers include the diphosphonate-derivatized polymers in U.S. Patent 5,011,913 to Benedict et al, such as diphosphonate modified polyacrylic acid.
• Other suitable phosphonate-containing polymers are described in U.S. Patent 5,980,776 to Zakikhani, et al. and U.S. Patent 6,071,434 to Davis et al.
• Polyphosphates may also be included in the present compositions.
• a polyphosphate is generally understood to consist of two or more phosphate groups arranged primarily in a linear configuration, although some cyclic derivatives may be present.
• pyrophosphates and tripolyphosphate which are technically polyphosphates
• polyphosphates having an average of about four or more phosphate groups i.e., tetrapolyphosphate and hexametaphosphate, among others.
• Polyphosphates larger than tetrapolyphosphate usually occur as amorphous glassy materials, the linear "glassy" polyphosphates having the formula:
• XO(XPO3) n X wherein X is sodium or potassium and n averages from about 6 to about 125.
• Preferred polyphosphates are manufactured by FMC Corporation which are commercially known as Sodaphos (n«6), Hexaphos (n ⁇ 13), and Glass H (n«21). These polyphosphates may be used alone or in combination thereof. Chelating agents
• a chelating agent also called sequestrants, such as gluconic acid, tartaric acid, citric acid and pharmaceutically-acceptable salts thereof.
• Chelating agents are able to comolex calcium found in the cell walls of the bacteria. Chelating agents can also disrupt plaque by removing calcium from the calcium bridges which help hold this biomass intact. However, it is not desired to use a chelating agent which has an affinity for calcium that is too high, as this may result in tooth demineralization, which is contrary to the objects and intentions of the present invention. Suitable chelating agents will generally have a calcium binding constant of about 10 1 to 10 5 to provide improved cleaning with reduced plaque and calculus formation. Chelating agents also have the ability to complex with metallic ions and thus aid in preventing their adverse effects on the stability or appearance of products. Chelation of ions, such as iron or copper, helps retard oxidative deterioration of finished products.
• Suitable chelating agents are sodium or potassium gluconate and citrate; citric acid/alkali metal citrate combination; disodium tartrate; dipotassium tartrate; sodium potassium tartrate; sodium hydrogen tartrate; potassium hydrogen tartrate; sodium, potassium or ammonium polyphosphates and mixtures thereof.
• the amounts of chelating agent suitable for use in the present invention are about 0.1% to about 2.5%, preferably from about 0.5% to about 2.5% and more preferably from about 1.0% to about 2.5%.
• Still other chelating agents suitable for use in the present invention are the anionic polymeric polycarboxylates.
• Such materials are well known in the art, being employed in the form of their free acids or partially or preferably fully neutralized water soluble alkali metal (e.g. potassium and preferably sodium) or ammonium salts.
• Examples are 1 :4 to 4: 1 copolymers of maleic anhydride or acid with another polymerizable ethylenically unsaturated monomer, preferably methyl vinyl ether (methoxy ethylene) having a molecular weight (M. W.) of about 30,000 to about 1,000,000.
• M. W. molecular weight
• These copolymers are available for example as Gantrez AN 139 (M.W. 500,000), AN 119 (M. W. 250,000) and S-97 Pharmaceutical Grade (M.W. 70,000), of GAF Chemicals Corporation.
• operative polymeric polycarboxylates include the 1: 1 copolymers of maleic anhydride with ethyl acrylate, hydroxyethyl methacrylate, N-vinyl-2-pyrrolidone, or ethylene, the latter being available for example as Monsanto EMA No. 1103, M.W. 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.
• ⁇ Teeth whitening actives may be included in the oral care compositions of the present invention.
• the actives suitable for whitening include the peroxides, metal chlorites, perborates, percarbonates, peroxyacids, persulfates, and combinations thereof.
• Suitable peroxide compounds include hydrogen peroxide, urea peroxide, calcium peroxide, and mixtures thereof.
• Suitable metal chlorites include calcium chlorite, barium chlorite, magnesium chlorite, lithium chlorite, sodium chlorite, and potassium chlorite.
• a preferred chlorite is sodium chlorite.
• Additional whitening actives may be hypochlorite and chlorine dioxide.
• a preferred percarbonate is sodium percarbonate.
• Other suitable whitening agents include potassium, ammonium, sodium and lithium persulfates and perborate mono- and tetrahydrates, and sodium pyrophosphate peroxyhydrate.
• Other Active Agents include potassium, ammonium, sodium and lithium persulfates and perbor
• the present invention may optionally include other agents, such as antimicrobial agents.
• agents such as water insoluble non-cationic antimicrobial agents such as halogenated diphenyl ethers, phenolic compounds including phenol and its homologs, mono and poly-alkyl and aromatic halophenols, resorcinol and its derivatives, bisphenolic compounds and halogenated salicylanilides, benzoic esters, and halogenated carbanilides.
• the water soluble antimicrobials include quaternary ammonium salts and bis-biquanide salts, among others. Triclosan monophosphate is an additional water soluble antimicrobial agent.
• the quaternary ammonium agents include those in which one or two of the substitutes on the quaternary nitrogen has a carbon chain length (typically alkyl group) from about 8 to about 20, typically from about 10 to about 18 carbon atoms while the remaining substitutes (typically alkyl or benzyl group) have a lower number of carbon atoms, such as from about 1 to about 7 carbon atoms, typically methyl or ethyl groups.
• antimicrobial agents include chlorhexidine, triclosan, triclosan monophosphate, and flavor oils such as thymol.
• Triclosan and other agents of this type are disclosed in Parran, Jr. et al., U.S. Patent 5,015,466, issued May 14, 1991, and U.S. Patent 4,894,220, Jan. 16, 1990 to Nabi et al. These agents, which provide anti-plaque benefits, may be present at levels of from about 0.01% to about 5.0%, by weight of the dentifrice composition.
• compositions may also comprise surfactants, also commonly referred to as sudsing agents.
• Suitable surfactants are those which are reasonably stable and foam throughout a wide pH range.
• the surfactant may be anionic, nonionic, amphoteric, zwitterionic, cationic, or mixtures thereof.
• Anionic surfactants useful herein include the water-soluble salts of alkyl sulfates having from 8 to 20 carbon atoms in the alkyl radical (e.g., sodium alkyl sulfate) and the water-soluble salts of sulfonated monoglycerides of fatty acids having from 8 to 20 carbon atoms.
• Sodium lauryl sulfate (SLS) and sodium coconut monoglyceride sulfonates are examples of anionic surfactants of this type.
• anionic surfactants are sarcosinates, such as sodium lauroyl sarcosinate, taurates, sodium lauryl sulfoacetate, sodium lauroyl isethionate, sodium laureth carboxylate, and sodium dodecyl benzenesulfonate. Mixtures of anionic surfactants can also be employed. Many suitable anionic surfactants are disclosed by Agricola et al., U.S. Patent 3,959,458, issued May 25, 1976. The present composition typically comprises an anionic surfactant at a level of from about 0.025% to about 9%, from about 0.05% to about 5% in some embodiments, and from about 0.1% to about 1% in other embodiments.
• Another suitable surfactant is one selected from the group consisting of sarcosinate surfactants, isethionate surfactants and taurate surfactants.
• Preferred for use herein are alkali metal or ammonium salts of these surfactants, such as the sodium and potassium salts of the following: lauroyl sarcosinate, myristoyl sarcosinate, palmitoyl sarcosinate, stearoyl sarcosinate and oleoyl sarcosinate.
• the sarcosinate surfactant may be present in the compositions of the present invention from about 0.1% to about 2.5%, preferably from about 0.5% to about 2.0% by weight of the total composition.
• Cationic surfactants useful in the present invention include derivatives of aliphatic quaternary ammonium compounds having one long alkyl chain containing from about 8 to 18 carbon atoms such as lauryl trimethylammonium chloride; cetyl pyridinium chloride; cetyl trimethylammonium bromide; di-isobutylphenoxyethyl-dimethylbenzylammonium chloride; coconut alkyltrimethylammonium nitrite; cetyl pyridinium fluoride; etc.
• Preferred compounds are the quaternary ammonium fluorides described in U.S. Patent 3,535,421, October 20, 1970, to Briner et al., where said quaternary ammonium fluorides have detergent properties.
• cationic surfactants can also act as germicides in the compositions disclosed herein.
• Cationic surfactants such as chlorhexidine, although suitable for use in the current invention, are not preferred due to their capacity to stain the oral cavity's hard tissues. Persons skilled in the art are aware of this possibility and should incorporate cationic surfactants with this limitation in mind.
• Nonionic surfactants that can be used in the compositions of the present invention include compounds produced by the condensation of alkylene oxide groups (hydrophilic in nature) with an organic hydrophobic compound which may be aliphatic or alkylaromatic in nature.
• suitable nonionic surfactants include the Pluronics, polyethylene oxide condensates of alkyl phenols, products derived from the condensation of ethylene oxide with the reaction product of propylene oxide and ethylene diamine, ethylene oxide condensates of aliphatic alcohols, long chain tertiary amine oxides, long chain tertiary phosphine oxides, long chain dialkyl sulfoxides and mixtures of such materials.
• Zwitterionic synthetic surfactants useful in the present invention include derivatives of aliphatic quaternary ammonium, phosphonium, and sulfonium compounds, in which the aliphatic radicals can be straight chain or branched, and wherein one of the aliphatic substituents contains from about 8 to 18 carbon atoms and one contains an anionic water-solubilizing group, e.g., carboxy, sulfonate, sulfate, phosphate or phosphonate.
• Suitable betaine surfactants are disclosed in U.S. Patent 5,180,577 to Polefka et al., issued January 19, 1993.
• Typical alkyl dimethyl betaines include decyl betaine or 2-(N-decyl-N,N- dimethylammonio) acetate, coco betaine or 2-(N-coc-N, N-dimethyl ammonio) acetate, myristyl betaine, palmityl betaine, lauryl betaine, cetyl betaine, cetyl betaine, stearyl betaine, etc.
• the amidobetaines are exemplified by cocoamidoethyl betaine, cocoamidopropyl betaine, lauramidopropyl betaine and the like.
• the betaines of choice are preferably the cocoamidopropyl betaine and, more preferably, the lauramidopropyl betaine.
• thickening agents are added to provide a desirable consistency to the composition, to provide desirable active release characteristics upon use, to provide shelf stability, and to provide stability of the composition, etc.
• Suitable thickening agents include one or a combination of carboxyvinyl polymers, carrageenan, hydroxyethyl cellulose (HEC),. natural and synthetic clays (e,g., Veegum and laponite) and w ⁇ ater soluble salts of cellulose ethers such as sodium carboxymethylcellulose (CMC) and sodium carboxymethyl hydroxyethyl cellulose.
• Natural gums such as gum karaya, xanthan gum, gum arabic, and gum tragacanth can also be used.
• Colloidal magnesium aluminum silicate or finely divided silica can be used as part of the thickening agent to further improve texture.
• Suitable carboxyvinyl polymers useful as thickening or gelling agents include carbomers which are homopolymers of acrylic acid crosslinked with an alkyl ether of pentaerythritol or an alkyl ether of sucrose.
• Carbomers are commercially available from B.F. Goodrich as the Carbopol® series, including Carbopol 934, 940, 941 , 956, and mixtures thereof.
• Copolymers of lactide and glycolide monomers are useful for delivery of actives into the periodontal pockets or around the periodontal pockets as a "subgingival gel carrier.” These polymers are described in U.S. Pat. Nos. 5,198,220, and 5,242,910, issued March 30, 1993 and Sept. 7, 1993, respectively both to Damani, and 4,443,430, issued April 17, 1984 to Mattei.
• Thickening agents are typically present in an amount from about 0.1% to about 15%, preferably from about 2% to about 10%, more preferably from about 4% to about 8%, by weight of the total toothpaste or gel composition, can be used. Higher concentrations may be used for chewing gums, lozenges and breath mints, sachets, non-abrasive gels and subgingival gels. Humectants
• humectant serves to keep toothpaste compositions from hardening upon exposure to air, to give compositions a moist feel to the mouth, and, for particular humectants, to impart desirable sweetness of flavor to toothpaste compositions.
• the humectant on a pure humectant basis, generally comprises from about 0% to about 70%, preferably from about 5% to about 25%, by weight of the compositions herein.
• Suitable humectants for use in compositions of the subject invention include edible polyhydric alcohols such as glycerin, sorbitol, xylitol, butylene glycol, polyethylene glycol, propylene glycol and trimethyl glycine. Flavoring and Sweetening Agents
• Flavoring agents may also be added to the compositions. Suitable flavoring agents include oil of wintergreen, oil of peppermint, oil of spearmint, clove bud oil, menthol, anethole, methyl salicylate, eucalyptol, cassia, 1-menthyl acetate, sage, eugenol, parsley oil, oxanone, alpha-irisone, marjoram, lemon, orange, propenyl guaethol, cinnamon, vanillin, thymol, linalool, cinnamaldehyde glycerol acetal known as CGA, and mixtures thereof. Flavoring agents are generally used in the compositions at levels of from about 0.001% to about 5%, by weight of the composition.
• Sweetening agents which can be used include sucrose, glucose, saccharin, sucralose, dextrose, levulose, lactose, mannitol, sorbitol, fructose, maltose, xylitol, saccharin salts, thaumatin, aspartame, D-tryptophan, dihydrochalcones, acesulfame and cyclamate salts, especially sodium cyclamate, sucralose and sodium saccharin, and mixtures thereof.
• a composition preferably contains from about 0.1% to about 10% of these agents, preferably from about 0.1% to about 1%, by weight of the composition.
• coolants in addition to flavoring and sweetening agents, coolants, salivating agents, warming agents, and numbing agents can be used as optional ingredients in compositions of the present invention. These agents are present in the compositions at a level of from about 0.001% to about 10%, preferably from about 0.1% to about 1%, by weight of the composition.
• the coolant can be any of a wide variety of materials. Included among such materials are carboxamides, menthol, ketals, diols, and mixtures thereof.
• Preferred coolants in the present compositions are the paramenthan carboxyamide agents such as N-ethyl-p-menthan-3- carboxamide, known commercially as "WS-3", N,2,3-trirnethyl-2 ⁇ isopropylbutanamide, known as "WS-23,” and mixtures thereof.
• Additional preferred coolants are selected from the group consisting of menthol, 3-l-menthoxypropane-l,2-diol known as TK-10 manufactured by Takasago, menthone glycerol acetal known as MGA manufactured by Haarmann and Reimer, and menthyl lactate known as Frescolat® manufactured by Haarmann and Reimer.
• menthol and menthyl as used herein include dextro- and levorotatory isomers of these compounds and racemic mixtures thereof.
• TK-10 is described in U.S. Pat. No. 4,459,425, Amano et al., issued 7/10/84.
• WS-3 and other agents are described in U.S. Pat. 4,136,163, Watson, et al
• Suitable salivating agents of the present invention include Jambu® manufactured by Takasago.
• warming agents are capsicum and nicotinate esters, such as benzyl nicotinate.
• Suitable numbing agents include benzocaine, lidocaine, clove bud oil, and ethanol. Miscellaneous Carrier Materials
• Water employed in the preparation of commercially suitable oral compositions should preferably be of low ion content and free of organic impurities.
• Water generally comprises from about 5% to about 70%, and preferably from about 20% to about 50%, by weight of the aqueous compositions herein. These amounts of water include the free water which is added plus that which is introduced with other materials, such as with sorbitol. . . . .
• the present invention may also include an alkali metal bicarbonate salt, which may serve a number of functions including abrasive, deodorant, buffering and adjusting pH. Alkali metal bicarbonate salts are soluble in water and unless stabilized, tend to release carbon dioxide in an aqueous system.
• Sodium bicarbonate also known as baking soda, is a commonly used alkali metal bicarbonate salt.
• the present composition may contain from about 0.5% to about 30%, preferably from about 0.5% to about 15%, and most preferably from about 0.5% to about 5% of an alkali metal bicarbonate salt.
• Buffering agents refer to agents that can be used to adjust the pH of the compositions to a range of about pH 4.0 to about pH 10.0. Buffering agents include sodium bicarbonate, monosodium phosphate, trisodium phosphate, sodium hydroxide, sodium carbonate, sodium acid pyrophosphate, citric acid, and sodium citrate. Buffering agents are typically included at a level of from about 0.5% to about 10%, by weight of the present compositions.
• Poloxamers may be employed in the present compositions.
• a poloxamer is classified as a nonionic surfactant and may also function as an emulsifying agent, binder, stabilizer, and other related functions.
• Poloxamers are difunctional block-polymers terminating in primary hydroxyl groups with molecular weights ranging from 1,000 to above 15,000. Poloxamers are sold under the tradename of Pluronics and Pluraflo by BASF. Suitable poloxamers for this invention are Poloxamer 407 and Pluraflo L4370.
• emulsifying agents that may be used in the present compositions include polymeric emulsifiers such as the Pemulen® series available from B.F. Goodrich, and which are predominantly high molecular weight polyacrylic acid polymers useful as emulsifiers for hydrophobic substances.
• Titanium dioxide may also be added to the present composition. Titanium dioxide is a white powder which adds opacity to the compositions. Titanium dioxide generally comprises from about 0.25% to about 5% by weight of the dentifrice compositions.
• dimethicone copolyols selected from alkyl- and alkoxy-dimethicone copolyols, such as Cl 2 to C20 alkyl dimethicone copolyols and mixtures thereof. Highly preferred is cetyl dimethicone copolyol marketed under the trade name Abil EM90.
• the dimethicone copolyol is generally present in a level of from about 0.01% to about 25%, preferably from about 0.1% to about 5%, more preferably from about 0.5% to about 1.5% by weight.
• the dimethicone copolyols aid in providing positive tooth feel benefits.
• a dentinal desensitizing agent to control hypersensitivity such as salts of potassium, calcium, strontium and tin including nitrate, chloride, fluoride, phosphates, pyrophosphate, polyphosphate, citrate, oxalate and sulfate.
• the present invention also relates to methods for cleaning teeth and preventing undesirable oral cavity conditions including caries, microbial infection, plaque, calculus, stain and oral malodor and dental erosion.
• the method of use herein comprises contacting a subject's dental enamel surfaces and oral mucosa with the oral compositions according to the present invention.
• the method of use may be by brushing with a dentifrice, rinsing with a dentifrice slurry or mouthrinse, or chewing a gum product.
• Other methods include contacting the topical oral gel, mouthspray, or other form with the subject's teeth and oral mucosa.
• the present invention relates not only to methods for delivering the present compositions to the oral cavity of a human, but also to methods of delivering these compositions to the oral cavity of other animals, e.g., household pets or other domestic animals, or animals kept in captivity.
• a method of use may include brushing a dog's teeth with one of the dentifrice compositions.
• Another example would include the rinsing of a cat's mouth with an oral composition for a sufficient amount of time to see a benefit.
• Pet care products such as chews and toys may be formulated to contain the present oral compositions.
• the composition is incorporated into a relatively supple but strong and durable material such as rawhide, ropes made from natural or synthetic fibers, and polymeric articles made from nylon, polyester or thermoplastic polyurethane.
• the animal chews,. licks or gnaws the product the incorporated active elements are released into the animal's oral cavity into a salivary medium, comparable to an effective brushing or rinsing.
• Dentifrice compositions according to the present invention (IA - IF) and comparative examples (IG and IH) are shown below with amounts of components in weight %. These compositions are made using conventional methods.
• Antimicrobial efficacy of the present compositions is measured using the in vitro Plaque Glycolysis and Regrowth Model (i-PGRM). Effectiveness for control of supragingival calculus is defined by activity in prevention of plaque calcification using the Modified Plaque Growth and Mineralization assay. Effectiveness to prevent staining of formulations that contain ingredients associated with staining such as stannous and copper ions is measured using the in vitro Pellicle Tea Stain Model (i-PTSM). Acceptability of formulation aesthetics, such as reduction in astringency, taste acceptability and in-use experience, is measured in controlled consumer testing. Antimicrobial Activity
• the zinc ion concentration and bioavailability required for the provision of therapeutic actions may differ for different clinical actions, for example, antiplaque vs. gingivitis.
• it is critical to establish a minimum antimicrobial activity level since the therapeutic activity of zinc can be compromised below this level.
• To maintain antimicrobial efficacy it is important to derive a sufficient concentration of zinc ions from the insoluble zinc compound used in the present compositions.
• the minimum efficacy provided by the zinc ion source is defined in terms of effects in producing metabolic inhibition of dental plaque bacterial biof ⁇ lms, which are responsible for numerous undesirable intraoral conditions.
• Antimicrobial efficacy is thus defined in terms of a noticeable and significant reduction in in situ plaque metabolism as measured using the in vitro Plaque Glycolysis and Regrowth Model (i-PGRM), developed in the Procter & Gamble laboratories.
• the i-PGRM is a technique where plaque is grown from human saliva, and treated with agents designed to produce various levels of antimicrobial activity.
• the purpose of this technique is to provide a simple and quick method for determining if compounds have a direct effect on the metabolic pathways that plaque microorganisms utilize for the production of toxins which adversely affect gingival health.
• the model focuses on the production of organic acids including lactic, acetic, propionic, and butyric.
• This method utilizes plaque grown on polished glass rods which have been dipped in saliva overnight, soy broth and sucrose for 6 hours, and saliva again overnight. The plaque mass grown on the glass rods is then treated for 1 minute with a 3:1 water to dentifrice slurry.
• i-PGRM Score 100% x (Test product mean pH - Non-Zinc Control mean pH)
• the mean pH values refer to incubation media pH's obtained following treatment and sucrose challenge.
• the negative or non-Zinc control plaque samples produce large amounts of acid, and hence their pH's are lower than that of plaque samples treated with the positive control.
• the pH difference between the positive and negative controls would typically be a minimum of about 0.6 pH unit, ideally at least about 1.0 pH unit.
• the negative or non-Zinc control used is a sodium fluoride toothpaste marketed as Crest® Cavity Protection and the positive control is a formulation containing relatively high levels of stannous shown as comparative example IH above and described in U.S. 5,004,597 to Majeti et al. Such high stannous compositions have been shown to produce significant inhibition of plaque acid generation in the i-PGRM assay.
• a composition as shown in comparative example IG above containing zinc lactate (a soluble zinc compound) was also tested for comparison with the present compositions containing an insoluble zinc compound.
• the present compositions comprising insoluble zinc salts and phytate also provide protection against the initiation and progression of dental erosion, as demonstrated in a study using an in vitro erosion cycling model.
• dental erosion herein is meant a permanent loss of tooth substance from the surface by the action of chemicals, such as harsh abrasives and acids, as opposed to subsurface demineralization or caries caused by bacterial action.
• Dental erosion is a condition that does not involve plaque bacteria and is therefore distinct from dental caries, which is a disease caused by acids generated by plaque bacteria. It is believed the present compositions deposit on the tooth surface a barrier film or coating thereby protecting teeth from the action of erosive agents on contact.
• Enamel specimens were prepared by cutting 3-mm cores from extracted, human teeth using a diamond core drill. The teeth, collected by local surgeons, were stored in 5% thymol at room temperature. Enamel cores were mounted in 1 A inch diameter Lucite rods using dental acrylic (Dura Base, Reliance Mfg. Co.) covering all sides except the surface. Polishing with 600 grit silicon carbide-water slurry is used to remove approximately 50 microns of the outer enamel. Following this, specimens are polished for 90 minutes with gamma alumina (Linde No. 3, AB Gamma Polishing Alumina). Enamel specimens found to have surface imperfections are rejected. Following this preparation, nail polish was applied to approximately 2/3 of the surface, 1/3 on each side leaving the center portion exposed as a treatment window. Specimens were randomly assigned to one of the treatment groups (5 specimens/group).
• each group of specimens was placed into 20 ml of fresh, pooled human saliva to initiate the formation of a pellicle layer on the enamel surfaces.
• dentifrice slurries were prepared by mixing 5 grams of dentifrice with 15 grams of fresh, pooled human saliva for a period of not less than 4 or more than 5 minutes prior to use. Fresh slurry was prepared for each treatment.
• Each treatment cycle consisted of: dentifrice slurry (1 min) —> rinse in deionized distilled water (ddiH ⁇ O) — » saliva (5 min) — » erosion challenge (15 min) — > rinse in ddiH 2 O. There were 7 treatments per day for a total of five treatment days.
• Dentifrice treatments consisted of immersing the specimens into the dentifrice slurry for one minute while rotating at 75 rpm.
• the erosion challenge consisted of soaking each treatment group in 20 ml of Cola (at room temperature). A fresh volume of cola was used for each treatment cycle. Saliva was refreshed 3X/day, during the 1 st , 4 th and 7 th treatment cycles. At any time specimens were not in treatment, they remained in 20 ml of pooled, human saliva (stirred). At night, each group of specimens remained immersed in saliva (stirred at room temperature).
• specimens were rinsed well in ddiH 2 O and stored refrigerated in a humid environment until analysis.
• a layer of nail polish was applied to the entire surface of each specimen to seal the surface and protect the fragile eroded areas.
• Specimens were cut piano-parallel using a hard tissue sectioning saw. Each section was cut to allow the control and treated portion to be represented for analysis.
• a thin section ( ⁇ 100 ⁇ m) was removed from each specimen and placed flat on a specially designed holder that fits into a camera mounted to an X-ray generator. These sections were then exposed to CuKa radiation. Radiographs were taken using Kodak SO253 Holographic film. The film was processed using standard black and white film developing methods.
• Radiographic images were then analyzed using TMR, a computer based image analysis system (Inspektor Research). By comparing the original surface, based on the control (untreated) area, to the post treatment surface, the depth of the eroded area can be measured ( ⁇ M of mineral lost).

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