WO1992010994A1 - Oral compositions effective against plaque and gingivitis - Google Patents

Oral compositions effective against plaque and gingivitis Download PDF

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Publication number
WO1992010994A1
WO1992010994A1 PCT/US1991/009400 US9109400W WO9210994A1 WO 1992010994 A1 WO1992010994 A1 WO 1992010994A1 US 9109400 W US9109400 W US 9109400W WO 9210994 A1 WO9210994 A1 WO 9210994A1
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Prior art keywords
composition according
composition
cavity
toothpaste
oral
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Application number
PCT/US1991/009400
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French (fr)
Inventor
Edward Russell Cox
Donald James White, Jr.
Mark Matthew Crisanti
Original Assignee
The Procter & Gamble Company
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Publication of WO1992010994A1 publication Critical patent/WO1992010994A1/en

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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
    • 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

  • the present invention relates to oral compositions which provide antiplaque and antigingivitis benefits as well as being effective against other anaerobic infections of the mouth.
  • Periodontal disease affects the periodontiu , which is the investing and support ⁇ ing tissue surrounding a tooth (i.e., the periodontal ligament, the gingiva, and the alveolar bone).
  • Periodontal disease and periodontitis are inflammatory disorders of the gingiva and the periodontal ligament, respectively. Gingivosis and periodontosis are more severe conditions involving degenerative disorders of the tissue. Combinations of inflammatory and degenerative conditions are termed periodontitis complex.
  • Periodontal disease is a major cause of tooth loss in adults. Tooth loss from periodontal disease is a significant problem beginning at age 35, but even by age 15 it is estimated that about 4 out of 5 persons already have gingivitis and 4 out of 10 have periodontitis. While good oral hygiene, as achieved by brushing the teeth with a cleansing dentifrice, may help reduce the incidence of periodontal disease, it does not necessarily prevent or eliminate its occurrence. This is because microorganisms contribute to both the initiation and progress of periodontal disease. Thus, in order to prevent or treat periodontal disease, these microorganisms must be suppressed by some means other than simple mechanical scrubbing.
  • compositions contain a molecularly dehydrated polyphosphate salt.
  • the salt is stated to improve the effectiveness of the antibacterial.
  • Another reference disclosing noncationic water-insoluble antibacterials in oral compositions is U.S. 4.894.220. January 16, 1990 to Nabi et al . This reference teaches the use of solvents and polymers to enhance the antibacte ial 's effect.
  • Still another reference disclosing such antibacterials combined with polyethylene glycols in oral compositions is European Patent Application 02,220,890, May 6, 1987. All prior art references are incorporated herein by reference in total.
  • the present invention in certain aspects, embraces oral care products containing water-insoluble, noncationic antibacterial agents, and an alkali metal or ammonium zinc salt.
  • the present invention also encompasses a method for treating diseases of the oral cavity using noncationic water insoluble antibac- terial agents and an alkali metal or ammonium zinc salt.
  • oral compositions as used herein means 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.
  • safety and effective amount means sufficient amount of material to provide the desired benefit while being safe to the hard and soft tissues of the oral cavity.
  • compositions of this invention are prepared by the term “comprising”, as used herein, and/or that various additional components can be conjointly employed in the compositions of this invention as long as the listed materials perform their intended functions.
  • carrier as used herein, is meant a suitable vehicle which is pharmaceutically acceptable and can be used to apply the present compositions in the oral cavity.
  • the present invention in certain aspects involves the use of water-insoluble, noncationic antibacterials with an alkali metal or ammonium zinc salt.
  • the essential and optional components of the compositions are described in detail below.
  • Antibacterial Agents Given below are examples of antibacterial agents useful in the compositions of the present invention which are water insoluble and noncationic.
  • Halogenated Diphenyl Ethers 2' ,4,4'-trichloro-2-hydroxy-diphenyl ether (Triclosan) 2,2'-dihydroxy-5,5'-dibromo-diphenyl ether.
  • Phenolic Compounds including phenol and its homologs, mono- and poly-alkyl and aromatic halophenols, resorcinol and its derivatives, bisphenolic compounds and halogenated salicylanilides
  • the antibacterial agent is present in the oral compositions of the present invention in an effective antiplaque amount, typically about 0.01-5% by weight, preferably about 0.03-1%.
  • the antibacterial agent is substantially water-insoluble, meaning that its solubility is less than about 1% by weight in water at 25'C and may be even less than about 0.1%. If an ionizable group is present solubility is determined at a pH at which ionization does not occur.
  • the second essential component of the compositions described herein is an alkali metal or ammonium zinc salt.
  • a preferred salt is a citrate salt as described in U.S. Patent 4.325.939. April 20, 1982 to Shah incorporated herein by reference. Such salts have the empirical formula C ⁇ HsOyMZn wherein M is an alkali metal such as sodium, potass ⁇ ium or ammonium.
  • a second preferred salt is a tartrate salt of the type disclosed above for citrate salts. These salts are advantageously used in the compositions of the present invention since they surprisingly function well without relying on high levels of zinc ions for their effect. They can provide their effect in the complex form.
  • the zinc salts are used at a level of from about 0.10% to about 4%, preferably from about 0.5% to 1.5%. Water
  • Water is another essential component of this invention.
  • Water employed in the preparation of commercially suitable compositions should preferably be deionized and free of organic impurities.
  • Water generally comprises from about 10% to 50%, preferably from about 20% to 40%, by weight of the toothpaste compositions herein while mouthwashes contain from about 40% to about 95%. These amounts of water include the free water which is added plus that which is introduced with other materials as with sorbitol.
  • Optional Components include the free water which is added plus that which is introduced with other materials as with sorbitol.
  • compositions of the present invention may contain in addition to the above-listed components many others which will be somewhat dependent on the type of composition (mouthwashes, toothpastes, topical gels, prophylaxis pastes and the like). Toothpastes and mouthwashes are the preferred systems with toothpastes being the most preferred.
  • the abra ⁇ sive polishing material contemplated for use in the present invention can be any material which does not excessively abrade dentin. These include, for example, silicas including gels and precipitates, calcium carbonate, dicalcium orthophosphate dihydrate, calcium pyrophosphate, tricalcium phosphate, calcium polymetaphosphate, insoluble sodium polymetaphosphate, hydrated alumina, and resinous abrasive materials such as particulate condensation products of urea and formaldehyde, and others such as disclosed by Cooley et al . in U.S. Patent 3.070,510. December 25, 1962, incorporated herein by reference. Mixtures of abrasives may also be used.
  • Silica dental abrasives of various types, can provide the unique
  • Silica abrasive materials are also exceptionally compatible with sources of soluble fluoride and other ion sources. For these reasons they are preferred for use herein.
  • the silica abrasive polishing materials useful herein, as well as the other abrasives generally have an average particle size ranging between about 0.1 and 30 microns, preferably 5 and 15 microns.
  • the silica abrasive can be precipitated silica or silica gels such as the silica xerogels described in Pader et al., U.S. Patent 3.538,230.
  • silica xerogels marketed under the tradename "Syloid" by the W.R. Grace & Company, Davison Chemical Division.
  • Preferred precipitated silica materials include those marketed by the J.M. Huber Corporation under
  • the abrasive in the toothpaste compositions described herein is present at a level of from about 6% to about 70%, preferably from about
  • Flavoring agents can also be added to the dentifrice and other compositions of the present invention. Suitable flavoring agents include oil of wintergreen, oil of peppermint, oil of spearmint, oil of sassafras, and oil of clove. Sweetening agents are
  • Flavoring and sweetening agents are generally used in the compositions herein at levels of from about 0.005% to about 2% by weight and may be used as a solvent for the anti- bacterials hereinbefore indicated.
  • thickening agents are carboxyvinyl polymers, carrageenan, hydroxyethyl cellulose and water soluble salts of cellulose ethers such as sodium carboxy- ethyl cellulose and sodium carboxymethyl hydroxyethyl cellulose.
  • Natural gums such as gum karaya, gum arabic, and gum tragacanth and polysaccharide gums such as xanthan gum 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.
  • Thickening agents in an amount from about 0.05% to about 1.5% by weight of the total composition may be used.
  • a humectant in a toothpaste to keep it from hardening.
  • Suitable humectants include glycerin, sorbi- tol , and other edible polyhydric alcohols at a combined level of from about 10% to about 70%.
  • fluoride ion source Another optional component is a fluoride ion source.
  • the sources of fluoride ions, or fluoride-providing compounds are well known in the art as anticaries agents and also act as such agents in the practice of this invention as well as to inhibit pyrophosphatase. These compounds may be slightly soluble in water or may, preferably, be fully water-soluble. They are characterized by their ability to release fluoride ions in water and by freedom from undesired reaction with other compounds of the oral preparation.
  • inorganic fluoride salts such as soluble alkali metal, alkaline earth metal salts, for example, sodium fluoride, barium fluoride, sodium fluorosilicate, ammonium fluorosilicate, sodium fluorozirconate, sodium monofluorophosphate, aluminum mono- and di-fluorophosphate, and fluorinated sodium calcium pyrophosphate.
  • Alkali metal and tin fluo ⁇ rides such as sodium and stannous fluorides, sodium monofluorophos- phate (MFP) and mixtures thereof, are preferred.
  • the amount of fluoride-providing compound is dependent to some extent upon the type of compound, its solubility, and the type of oral preparation, but it must be a nontoxic amount, generally about 0.005 to about .3.0% in the preparation.
  • a dentifrice preparation e.g. dental gel, toothpaste (including cream)
  • an amount of such compound which releases up to about 5,000 ppm of F ion by weight of the prepara ⁇ tion is considered satisfactory.
  • Any suitable minimum amount of such compound may be used, but it is preferable to employ sufficient com ⁇ pound to release about 300 to 2,000 ppm, more preferably about 800 to about 1,500 ppm of fluoride ion.
  • this component is present in an amount up to about 2% by weight, based on the weight of the prepara ⁇ tion, and preferably in the range of about 0.05% to 1%.
  • the compound may be present in an amount of about 0.1-3%, more typically about 0.76%.
  • compositions of the present inventions are cationic antibacterials such as quaternary ammonium compounds.
  • cationic antibacterials such as quaternary ammonium compounds.
  • quaternary ammonium compounds Exemp ⁇ lary of such compounds are cetyl pyridinium chloride, lauryl dimethyl benzyl ammonium chloride, stearyl trimethyl ammonium chloride among many others.
  • Still another optional component for use in the compositions of the present invention is an anticalculus agent.
  • agents include any which are effective against calculus such as pyrophosphate salts as disclosed in U.S. Patent 4,515,772, May 7, 1985 incorporated herein by reference.
  • the preferred agents are mono, di, tri and tetra alkali metal and ammonium pyrophosphate.
  • Such agents are used in amounts sufficient to reduce calculus. These amounts are preferably in an amount of at least about 1% 2O7, most preferably at least about 1.3%, most preferably at least about 1.5%.
  • anticalculus agents are polymers such as those described in U.S. Patent 4.661.341. April 28, 1987 to Benedict and U.S. Patent 3.429.963. February 25, 1969 to Shedlovsky, both of which are incor ⁇ porated herein by reference. Such polymers are used in amounts of from about 0.01% to about 10%, preferably from about 0.1% to about 5%.
  • Particularly useful polymers for use in the compositions of this invention are anionic polymeric polycarboxylates. Such materials are well known, 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. Preferred are 1:4 to 4:1 copolymers of maleic anhydride or acid with another polymeri- zable ethylenically unsaturated monomer, preferably methyl vinyl ether (methoxyethylene) having a molecular weight (M.W.) of about 30,000 to about 1,000,000. These copolymers are available for example as Gantrez (AN 139(M.W. 500,000), A.N. 119 (M.W. 250,000) and preferably S-97 Pharmaceutical Grade (M.W. 70,000), of GAF Corporation.
  • Gantrez AN 139(M.W. 500,000
  • A.N. 119 M.W. 250,000
  • S-97 Pharmaceutical Grade M.W. 70,000
  • operative polymeric polycarboxylates can include those such as the 1:1 copolymers of maleic anhydride with ethyl acrylate, hydroxy ⁇ ethyl methacrylate, N-vinyl-2-pyrollidone, 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 hydroxy ⁇ ethyl methacrylate, methyl or ethyl acrylate, isobutyl vinyl ether or N-vinyl-2-pyrrolidone.
  • Additional operative polymeric polycarboxylates disclosed in above referred to U.S. Patent Nos. 4,138.477 and 4.183,914. incorporated herein by reference, include copolymers of maleic anhydride with styrene, isobutylene or ethyl vinyl ether, poly-acrylic, polyitaconic and polymaleic acids, and sulfoacrylic oligo ers of M.W. as low as 1,000 available as Uniroyal ND-2.
  • Suitable generally are polymerized olefinically or ethylenically unsaturated carboxylic acids containing an activated carbon-to-carbon olefinic double bond and at least one carboxyl group, that is, an acid containing an olefinic double bond which readily functions in polymeri ⁇ zation because of its presence in the monomer molecule either in the alpha-beta position with respect to a carboxyl group or as part of a terminal methylene grouping.
  • Such acids are acrylic, methacrylic, ethacrylic, alpha-chloroacrylic, crotonic, beta-acryloxy propionic, sorbic, alpha-chlorsorbic, cinnamic, beta-styrylacrylic, muconic, itaconic, citraconic, esaconic, glutaconic, aconitic, alpha- phenylacrylic, 2-benzyl acrylic, 2-cyclohexylacrylic, angelic, umbel- lie, fumaric, maleic acids and anhydrides.
  • Other different olefinic monomers copolymerizable with such carboxylic monomers include vinyl- acetate, vinyl chloride, dimethyl maleate and the like. Copolymers contain sufficient carboxylic salt groups for water-solubility.
  • the linear anionic polymeric polycarboxylate component is mainly a hydrocarbon with optional halogen and 0-containing substituents and linkages as present in for example ester, ether and OH groups, and when present is generally employed in the instant compositions in approxi ⁇ mate weight amounts of 0.05 to 3%, preferably 0.05 to 2%, more prefer ⁇ ably 0.1 to 2%.
  • Surfactants are also useful in the compositions of this invention include many different materials. Suitable surfactants include any which are reasonably stable and function over a wide pH range. Included are non-soap anionic, nonionic, cationic, zwitterionic and amphoteric organic synthetic surfactants. Many of these are disclosed by Gieske et al . in U.S. Patent 4.051.234. September 27, 1988 incor- porated herein in total by reference.
  • Preferred surfactants include alkyl sulfates, particularly Na or NH4 alkyl C12-C14 sulfate. Any surfactant used is at a level of from about 0.2% to about 4%, preferably from about 0.6% to about 2% in a toothpaste and from about 0.01% to about 5%, preferably from about 0.1% to about 0.5% in a mouthwash.
  • Polyethylene glycols are also useful in this invention and can be any of a wide range of molecular weights such as from about 100 to about 1,000, preferably from about 200 to about 600.
  • the glycol is present in an amount of from about 1% to about 10%, preferably from about 3% to about 6%.
  • Mouthwashes generally comprise from about 20:1 to about 2:1 of a water/ethyl alcohol solution and preferably other ingredients such as flavor, sweeteners, humectants and sudsing agents similar to those described for dentifrices/gels.
  • the humectants, such as glycerin and sorbitol give a moist feel to the mouth.
  • the mouthwashes of the invention comprise 5% to 60% (preferably 10% to 25%) ethyl alcohol, 0% to 20% (preferably 5% to 20%) of a humectant, 0% to 2% (preferably 0.01% to 0.15%) emulsifying agent, 0% to 0.5% (preferably 0.005% to 0.06%) sweetening agent such as saccharin, 0% to 0.3% (preferably from 0.03% to 0.3%) flavoring agent, and the balance water.
  • the pH of the present compositions and/or its pH in the mouth can be any pH which is safe for the mouth's hard and soft tissues. Such pH's are generally from about 3 to about 10, preferably from about 4 to about 9.

Abstract

Disclosed are oral compositions which are effective against plaque and gingivitis which contain a noncationic water insoluble antibacterial agent and an alkali metal or ammonium zinc salt.

Description

ORAL COMPOSITIONS EFFECTIVE AGAINST PLAQUE AND GINGIVITIS
TECHNICAL FIELD The present invention relates to oral compositions which provide antiplaque and antigingivitis benefits as well as being effective against other anaerobic infections of the mouth.
Plaque induced diseases, including periodontitis and gingivitis, are believed to involve anaerobic bacterial infections. Periodontal disease affects the periodontiu , which is the investing and support¬ ing tissue surrounding a tooth (i.e., the periodontal ligament, the gingiva, and the alveolar bone). Gingivitis and periodontitis are inflammatory disorders of the gingiva and the periodontal ligament, respectively. Gingivosis and periodontosis are more severe conditions involving degenerative disorders of the tissue. Combinations of inflammatory and degenerative conditions are termed periodontitis complex.
Periodontal disease is a major cause of tooth loss in adults. Tooth loss from periodontal disease is a significant problem beginning at age 35, but even by age 15 it is estimated that about 4 out of 5 persons already have gingivitis and 4 out of 10 have periodontitis. While good oral hygiene, as achieved by brushing the teeth with a cleansing dentifrice, may help reduce the incidence of periodontal disease, it does not necessarily prevent or eliminate its occurrence. This is because microorganisms contribute to both the initiation and progress of periodontal disease. Thus, in order to prevent or treat periodontal disease, these microorganisms must be suppressed by some means other than simple mechanical scrubbing. Towards this end, there has been a great deal of research aimed at developing therapeutic dentifrices, outhwashes, and methods of treating periodontal disease which are effective in suppressing these microorganisms. The use of noncationic, water-insoluble antibacterial agents in oral products is disclosed in a number of references. One such reference is U.S. Patent 4.022.889 to Vinson et al . Vinson describes compositions containing zinc salts and antibacterial agents such as halogenated salicy! nilides and halogenated hydroxydiphenyl ethers. Another reference disclosing noncationic water-insoluble antibac¬ terial agents is U.K. Patent Application GB 2.200,551. publ shed August 10, 1988. In addition to the antibacterial, the compositions contain a molecularly dehydrated polyphosphate salt. The salt is stated to improve the effectiveness of the antibacterial. Another reference disclosing noncationic water-insoluble antibacterials in oral compositions is U.S. 4.894.220. January 16, 1990 to Nabi et al . This reference teaches the use of solvents and polymers to enhance the antibacte ial 's effect. Still another reference disclosing such antibacterials combined with polyethylene glycols in oral compositions is European Patent Application 02,220,890, May 6, 1987. All prior art references are incorporated herein by reference in total.
It has now been found that the effectiveness of the antibacterial can be improved by incorporating the antibacterial and an alkali metal or ammonium zinc salt into the composition.
It is therefore an object of the present invention to provide improved oral care products containing specific antibacterial agents and zinc salts. It is a further object of the present invention to provide more effective products for treating diseases of the oral cavity.
It is still a further objective to provide methods for treating diseases of the oral cavity.
These and other objects will become readily apparent from the detailed disclosure which follows.
All percentages and ratios used herein are by weight unless otherwise specified. Also, all measurements referred to herein are made at 25*C in the composition unless otherwise specified.
SUMMARY OF THE INVENTION The present invention, in certain aspects, embraces oral care products containing water-insoluble, noncationic antibacterial agents, and an alkali metal or ammonium zinc salt.
The present invention also encompasses a method for treating diseases of the oral cavity using noncationic water insoluble antibac- terial agents and an alkali metal or ammonium zinc salt.
By "oral compositions" as used herein means 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.
By "safe and effective amount" as used herein means sufficient amount of material to provide the desired benefit while being safe to the hard and soft tissues of the oral cavity.
By the term "comprising", as used herein, is meant that various additional components can be conjointly employed in the compositions of this invention as long as the listed materials perform their intended functions. By the term "carrier", as used herein, is meant a suitable vehicle which is pharmaceutically acceptable and can be used to apply the present compositions in the oral cavity.
DETAILED DESCRIPTION OF THE INVENTION The present invention in certain aspects involves the use of water-insoluble, noncationic antibacterials with an alkali metal or ammonium zinc salt. The essential and optional components of the compositions are described in detail below.
Antibacterial Agents Given below are examples of antibacterial agents useful in the compositions of the present invention which are water insoluble and noncationic.
Halogenated Diphenyl Ethers 2' ,4,4'-trichloro-2-hydroxy-diphenyl ether (Triclosan) 2,2'-dihydroxy-5,5'-dibromo-diphenyl ether. Phenolic Compounds (including phenol and its homologs, mono- and poly-alkyl and aromatic halophenols, resorcinol and its derivatives, bisphenolic compounds and halogenated salicylanilides) .
Phenol and its Homologs Phenol* 2 Methyl - Phenol
3 Methyl - Phenol
4 Methyl - Phenol 4 Ethyl - Phenol 2,4-Dimethyl - Phenol 2,5-Dimethyl - Phenol
3,4-Dimethyl - Phenol
2,6-Dimethyl - Phenol
4-n-Propyl - Phenol
4-n-Butyl - Phenol
Figure imgf000006_0001
6-i so-Propyl -2-ethyl -3-methyl - p-Chlorophenol 2-sec-Amyl -3, 5-dimethyl - p-Chlorophenol 2-Di ethylmethyl -3 , 5-dimethyl - p-Chlorophenol 5-sec-0ctyl -3-methyl - p-Chlorophenol p-Bromophenol
Methyl - p-Bromophenol
Ethyl - p-Bromophenol n-Propyl - p-Bromophenol n-Butyl - p-Bromophenol n-Amyl - p-Bromophenol sec-Amyl - p-Bromophenol n-Hexyl - p-Bromophenol cyclohexyl - p-Bromophenol o-Bromophenol tert-Amyl o-Bromophenol n-Hexyl o-Bromophenol n-Propyl -m,mDimethyl o-Bromophenol
2-Phenyl Phenol
4-Chloro-2-methyl phenol 4-Chloro-3-methyl phenol
4-Chloro-3,5-dimethyl phenol
2, -dichloro-3,5-dimethylphenol
3,4,5,6-terabromo-2-methylphenol
5-methyl-2-pentylphenol 4-isopropyl-3-methylphenol
5-Chloro-2-hydroxydiphenylmethane Resorcinol and its Derivatives
Figure imgf000007_0001
Phenylethyl - Resorcinol Phenylpropyl - Resorcinol p-Chlorobenzyl - Resorcinol 5-Chloro -2, -Dihydroxydiphenyl Methane 4'-Chloro -2,4-Dihydroxydiphenyl Methane 5-Bromo -2,4-Dihydroxydiphenyl Methane 4'-Bromo -2,4-Dihydroxydiphenyl Methane
Bisphenolic Compounds 2,2'-methylene bis (4-chlorophenol) 2,2'-methylene bis (3,4,6-trichlorophenol) 2,2'-methylene bis (4-chloro-6-bromophenol) bis (2-hydroxy-3,5-dichlorophenyl) sulphide bis (2-hydroxy-5-chlorobenzyl) sulphide Halogenated Salicylanilides 4',5-dibromosalicylanilide 3,4',5-trichlorosalcylanilide 3,4',5-tribromosalicylanilide 2,3,3',5-tetrachlorosalicylani1ide 3,3',5-trichlorosalicyl nilide 3,5-dibromo-3'-trifluoromethyl salicylanilide 5-n-octanoyl-3'-trifluoromethyl salicylanilide 3,5-dibromo-4'-trifluoromethyl salicylanilide 3,5-dibromo-3'-trif1uoromethyl salicylani1ide (Fluorophene) Benzoic Esters p-Hydroxybenzoic Acid
Methyl - p-Hydroxybenzoic Acid
Ethyl - p-Hydroxybenzoic Acid
Propyl - p-Hydroxybenzoic Acid Butyl - p-Hydroxybenzoic Acid
Halogenated Carbanilides 3,4,4'-trichlorocarbaniTide 3-trif1uoromethyl- , '-dichlorocarbani1ide 3,3',4-trichlorocarbanilide The antibacterial agent is present in the oral compositions of the present invention in an effective antiplaque amount, typically about 0.01-5% by weight, preferably about 0.03-1%. The antibacterial agent is substantially water-insoluble, meaning that its solubility is less than about 1% by weight in water at 25'C and may be even less than about 0.1%. If an ionizable group is present solubility is determined at a pH at which ionization does not occur. Alakli Metal or Ammonium Zinc Salt
The second essential component of the compositions described herein is an alkali metal or ammonium zinc salt. A preferred salt is a citrate salt as described in U.S. Patent 4.325.939. April 20, 1982 to Shah incorporated herein by reference. Such salts have the empirical formula CβHsOyMZn wherein M is an alkali metal such as sodium, potass¬ ium or ammonium. A second preferred salt is a tartrate salt of the type disclosed above for citrate salts. These salts are advantageously used in the compositions of the present invention since they surprisingly function well without relying on high levels of zinc ions for their effect. They can provide their effect in the complex form. The zinc salts are used at a level of from about 0.10% to about 4%, preferably from about 0.5% to 1.5%. Water
Water is another essential component of this invention. Water employed in the preparation of commercially suitable compositions should preferably be deionized and free of organic impurities. Water generally comprises from about 10% to 50%, preferably from about 20% to 40%, by weight of the toothpaste compositions herein while mouthwashes contain from about 40% to about 95%. These amounts of water include the free water which is added plus that which is introduced with other materials as with sorbitol. Optional Components
The compositions of the present invention may contain in addition to the above-listed components many others which will be somewhat dependent on the type of composition (mouthwashes, toothpastes, topical gels, prophylaxis pastes and the like). Toothpastes and mouthwashes are the preferred systems with toothpastes being the most preferred.
Toothpastes contain as a major component an abrasive. The abra¬ sive polishing material contemplated for use in the present invention can be any material which does not excessively abrade dentin. These include, for example, silicas including gels and precipitates, calcium carbonate, dicalcium orthophosphate dihydrate, calcium pyrophosphate, tricalcium phosphate, calcium polymetaphosphate, insoluble sodium polymetaphosphate, hydrated alumina, and resinous abrasive materials such as particulate condensation products of urea and formaldehyde, and others such as disclosed by Cooley et al . in U.S. Patent 3.070,510. December 25, 1962, incorporated herein by reference. Mixtures of abrasives may also be used.
Silica dental abrasives, of various types, can provide the unique
5 benefits of exceptional dental cleaning and polishing performance without unduly abrading tooth enamel or dentin. Silica abrasive materials are also exceptionally compatible with sources of soluble fluoride and other ion sources. For these reasons they are preferred for use herein.
10 The silica abrasive polishing materials useful herein, as well as the other abrasives, generally have an average particle size ranging between about 0.1 and 30 microns, preferably 5 and 15 microns. The silica abrasive can be precipitated silica or silica gels such as the silica xerogels described in Pader et al., U.S. Patent 3.538,230.
15 issued March 2, 1970 and DiGiulio, U.S. Patent 3.862.307. June 21, 1975, both incorporated herein by reference. Preferred are the silica xerogels marketed under the tradename "Syloid" by the W.R. Grace & Company, Davison Chemical Division. Preferred precipitated silica materials include those marketed by the J.M. Huber Corporation under
20 the tradename, "Zeodent", particularly the silica carrying the desig¬ nation "Zeodent 119". These silica abrasive are described in U.S. Patent 4.340.583, July 29, 1982, incorporated herein by reference.
The abrasive in the toothpaste compositions described herein is present at a level of from about 6% to about 70%, preferably from about
25 15% to about 30%.
Flavoring agents, as was noted earlier, can also be added to the dentifrice and other compositions of the present invention. Suitable flavoring agents include oil of wintergreen, oil of peppermint, oil of spearmint, oil of sassafras, and oil of clove. Sweetening agents are
30 also useful and include aspartame, acesulfame, saccharin, dextrose, levulose and sodium cycla ate. Flavoring and sweetening agents are generally used in the compositions herein at levels of from about 0.005% to about 2% by weight and may be used as a solvent for the anti- bacterials hereinbefore indicated.
35 In preparing toothpastes, it is necessary to add some thickening material to provide a desirable consistency. Preferred thickening agents are carboxyvinyl polymers, carrageenan, hydroxyethyl cellulose and water soluble salts of cellulose ethers such as sodium carboxy- ethyl cellulose and sodium carboxymethyl hydroxyethyl cellulose. Natural gums such as gum karaya, gum arabic, and gum tragacanth and polysaccharide gums such as xanthan gum 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. Thickening agents in an amount from about 0.05% to about 1.5% by weight of the total composition may be used.
It is also desirable to include a humectant in a toothpaste to keep it from hardening. Suitable humectants include glycerin, sorbi- tol , and other edible polyhydric alcohols at a combined level of from about 10% to about 70%.
Another optional component is a fluoride ion source. The sources of fluoride ions, or fluoride-providing compounds, are well known in the art as anticaries agents and also act as such agents in the practice of this invention as well as to inhibit pyrophosphatase. These compounds may be slightly soluble in water or may, preferably, be fully water-soluble. They are characterized by their ability to release fluoride ions in water and by freedom from undesired reaction with other compounds of the oral preparation. Among these materials are inorganic fluoride salts, such as soluble alkali metal, alkaline earth metal salts, for example, sodium fluoride, barium fluoride, sodium fluorosilicate, ammonium fluorosilicate, sodium fluorozirconate, sodium monofluorophosphate, aluminum mono- and di-fluorophosphate, and fluorinated sodium calcium pyrophosphate. Alkali metal and tin fluo¬ rides, such as sodium and stannous fluorides, sodium monofluorophos- phate (MFP) and mixtures thereof, are preferred.
The amount of fluoride-providing compound is dependent to some extent upon the type of compound, its solubility, and the type of oral preparation, but it must be a nontoxic amount, generally about 0.005 to about .3.0% in the preparation. In a dentifrice preparation, e.g. dental gel, toothpaste (including cream), an amount of such compound which releases up to about 5,000 ppm of F ion by weight of the prepara¬ tion is considered satisfactory. Any suitable minimum amount of such compound may be used, but it is preferable to employ sufficient com¬ pound to release about 300 to 2,000 ppm, more preferably about 800 to about 1,500 ppm of fluoride ion. Typically, in the cases of alkali metal fluorides and stannous fluoride, this component is present in an amount up to about 2% by weight, based on the weight of the prepara¬ tion, and preferably in the range of about 0.05% to 1%. In the case of sodium monofluorophosphate, the compound may be present in an amount of about 0.1-3%, more typically about 0.76%.
Also useful in the compositions of the present inventions are cationic antibacterials such as quaternary ammonium compounds. Exemp¬ lary of such compounds are cetyl pyridinium chloride, lauryl dimethyl benzyl ammonium chloride, stearyl trimethyl ammonium chloride among many others. These and other cationic antimicrobials are disclosed in U.S. Patent 4,022,880, May 10, 1977 (Vison), incorporated herein by reference in its entirety.
Still another optional component for use in the compositions of the present invention is an anticalculus agent. These agents include any which are effective against calculus such as pyrophosphate salts as disclosed in U.S. Patent 4,515,772, May 7, 1985 incorporated herein by reference. The preferred agents are mono, di, tri and tetra alkali metal and ammonium pyrophosphate. Such agents are used in amounts sufficient to reduce calculus. These amounts are preferably in an amount of at least about 1% 2O7, most preferably at least about 1.3%, most preferably at least about 1.5%.
Other anticalculus agents are polymers such as those described in U.S. Patent 4.661.341. April 28, 1987 to Benedict and U.S. Patent 3.429.963. February 25, 1969 to Shedlovsky, both of which are incor¬ porated herein by reference. Such polymers are used in amounts of from about 0.01% to about 10%, preferably from about 0.1% to about 5%.
Particularly useful polymers for use in the compositions of this invention are anionic polymeric polycarboxylates. Such materials are well known, 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. Preferred are 1:4 to 4:1 copolymers of maleic anhydride or acid with another polymeri- zable ethylenically unsaturated monomer, preferably methyl vinyl ether (methoxyethylene) having a molecular weight (M.W.) of about 30,000 to about 1,000,000. These copolymers are available for example as Gantrez (AN 139(M.W. 500,000), A.N. 119 (M.W. 250,000) and preferably S-97 Pharmaceutical Grade (M.W. 70,000), of GAF Corporation.
Other operative polymeric polycarboxylates can include those such as the 1:1 copolymers of maleic anhydride with ethyl acrylate, hydroxy¬ ethyl methacrylate, N-vinyl-2-pyrollidone, 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 hydroxy¬ ethyl methacrylate, methyl or ethyl acrylate, isobutyl vinyl ether or N-vinyl-2-pyrrolidone.
Additional operative polymeric polycarboxylates disclosed in above referred to U.S. Patent Nos. 4,138.477 and 4.183,914. incorporated herein by reference, include copolymers of maleic anhydride with styrene, isobutylene or ethyl vinyl ether, poly-acrylic, polyitaconic and polymaleic acids, and sulfoacrylic oligo ers of M.W. as low as 1,000 available as Uniroyal ND-2.
Suitable generally are polymerized olefinically or ethylenically unsaturated carboxylic acids containing an activated carbon-to-carbon olefinic double bond and at least one carboxyl group, that is, an acid containing an olefinic double bond which readily functions in polymeri¬ zation because of its presence in the monomer molecule either in the alpha-beta position with respect to a carboxyl group or as part of a terminal methylene grouping. Illustrative of such acids are acrylic, methacrylic, ethacrylic, alpha-chloroacrylic, crotonic, beta-acryloxy propionic, sorbic, alpha-chlorsorbic, cinnamic, beta-styrylacrylic, muconic, itaconic, citraconic, esaconic, glutaconic, aconitic, alpha- phenylacrylic, 2-benzyl acrylic, 2-cyclohexylacrylic, angelic, umbel- lie, fumaric, maleic acids and anhydrides. Other different olefinic monomers copolymerizable with such carboxylic monomers include vinyl- acetate, vinyl chloride, dimethyl maleate and the like. Copolymers contain sufficient carboxylic salt groups for water-solubility.
The linear anionic polymeric polycarboxylate component is mainly a hydrocarbon with optional halogen and 0-containing substituents and linkages as present in for example ester, ether and OH groups, and when present is generally employed in the instant compositions in approxi¬ mate weight amounts of 0.05 to 3%, preferably 0.05 to 2%, more prefer¬ ably 0.1 to 2%.
Surfactants are also useful in the compositions of this invention include many different materials. Suitable surfactants include any which are reasonably stable and function over a wide pH range. Included are non-soap anionic, nonionic, cationic, zwitterionic and amphoteric organic synthetic surfactants. Many of these are disclosed by Gieske et al . in U.S. Patent 4.051.234. September 27, 1988 incor- porated herein in total by reference.
Preferred surfactants include alkyl sulfates, particularly Na or NH4 alkyl C12-C14 sulfate. Any surfactant used is at a level of from about 0.2% to about 4%, preferably from about 0.6% to about 2% in a toothpaste and from about 0.01% to about 5%, preferably from about 0.1% to about 0.5% in a mouthwash.
Polyethylene glycols are also useful in this invention and can be any of a wide range of molecular weights such as from about 100 to about 1,000, preferably from about 200 to about 600. The glycol is present in an amount of from about 1% to about 10%, preferably from about 3% to about 6%.
Another preferred embodiment of the present invention is a mouth¬ wash composition. Mouthwashes generally comprise from about 20:1 to about 2:1 of a water/ethyl alcohol solution and preferably other ingredients such as flavor, sweeteners, humectants and sudsing agents similar to those described for dentifrices/gels. The humectants, such as glycerin and sorbitol give a moist feel to the mouth. Generally, on a weight basis the mouthwashes of the invention comprise 5% to 60% (preferably 10% to 25%) ethyl alcohol, 0% to 20% (preferably 5% to 20%) of a humectant, 0% to 2% (preferably 0.01% to 0.15%) emulsifying agent, 0% to 0.5% (preferably 0.005% to 0.06%) sweetening agent such as saccharin, 0% to 0.3% (preferably from 0.03% to 0.3%) flavoring agent, and the balance water.
The pH of the present compositions and/or its pH in the mouth can be any pH which is safe for the mouth's hard and soft tissues. Such pH's are generally from about 3 to about 10, preferably from about 4 to about 9.
Given below are non-limiting examples which illustrate the composi¬ tions of the present invention. EXAMPLE I
Below is a toothpaste of the present invention.
Component Weight %
Water 26.027
Sorbitol 25.920
NaF 0.243
Figure imgf000014_0001
* Carboxyvinyl polymer offered by B. F. Goodrich Co. EXAMPLE I I
Given below is a mouthwash of the present invention.
Component Weight %
Glycerin 10.000
E+OH 10.000 Sodium Lauryl Sulfate 0.400
Na Saccharin 0.030
Zinc Chloride 0.700
Trisodium Citrate 1.507
Flavor 0.220
Triclosan 0.030
NaOH/HCl & water q.s. 100.000% pH 7.50 WHAT IS CLAIMED:

Claims

1 . An oral composition comprising a noncationic water insoluble antibacterial, an alkali metal or ammonium zinc salt and water.
2. A composition according to Claim 1 wherein said antibacterial is a phenolic compound.
3. A composition according to either of Claims 1 or 2 wherein said zinc salt is an alkali metal citrate.
4. A composition according to any of Claims 1-3 wherein said composition is a toothpaste or a mouthwash.
5. A composition according to any of Claims 1-4 wherein said composition is a toothpaste which in addition contains an abrasive and a binder.
6. A composition according to any of Claims 1-5 wherein said toothpaste also contains triclosan as the antibacterial agent and a polyethylene glycol solvent or a flavor oil.
7. A composition according to any of Claims 1 -6 wherein said toothpaste contains a soluble fluoride ion source.
8. A composition according to any of Claims 1 -7 wherein said toothpaste contains an anticalculus agent.
9. A composition according to any of Claims 1-8 wherein said anticalculus agent is a soluble pyrophosphate salt.
10. A composition according to any of Claims 1 -4 wherein the composition is a mouthwash and in addition contains a humectant.
1 1. A composition according to Claim 10 wherein the antibacterial agent is a phenolic compound.
12. A composition according to either of Claims 10 or 1 1 which in addition contains an anticalculus agent.
13. A composition according to Claim 10 wherein the antibacterial agent is triclosan.
1 . A process for treating diseases of the oral cavity by applying to said cavity an effective amount of a composition made according to Claim 1 .
1 5. A process for treating diseases of the oral cavity by applying to said cavity an effective amount of a composition made according to Claim 2.
1 6. A process for treating diseases of the oral cavity by applying to said cavity an effective amount of a composition according to Claim 5.
17. A process for treating diseases of the oral cavity by applying to said cavity an effective amount of a composition according to Claim 8.
1 8. A process for treating diseases of the oral cavity by applying to said cavity an effective amount of a composition made according to Claim 10.
PCT/US1991/009400 1990-12-18 1991-12-11 Oral compositions effective against plaque and gingivitis WO1992010994A1 (en)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993002658A1 (en) * 1991-08-06 1993-02-18 The Procter & Gamble Company Oral compositions effective against plaque and gingivitis
EP0528468A1 (en) * 1991-08-08 1993-02-24 Unilever N.V. Use of triclosan for the manufacture of a medicament for inhibiting cyclooxygenase
WO1994014407A1 (en) * 1992-12-18 1994-07-07 The Procter & Gamble Company Oral compositions containing antiplaque, anticalculus agents
WO1994026258A1 (en) * 1993-05-13 1994-11-24 Unilever N.V. Oral compositions containing triclosan for the treatment of aphthous ulcers
WO2010114546A1 (en) * 2009-04-02 2010-10-07 Colgate-Palmolive Company Dentifrice composition
WO2012060837A1 (en) 2010-11-04 2012-05-10 Colgate-Palmolive Company Dentifrice composition with reduced astringency
US9968803B2 (en) 2009-10-29 2018-05-15 Colgate-Palmolive Company Low water stannous fluoride plus zinc citrate dentifrice with improved stability, rheology, and efficacy
US20190038545A1 (en) * 2017-08-04 2019-02-07 Colgate-Palmolive Company Biphasic Oral Care Compositions

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4022880A (en) * 1973-09-26 1977-05-10 Lever Brothers Company Anticalculus composition
US4289754A (en) * 1980-11-03 1981-09-15 Richardson-Vicks Inc. Zinc derivatives and their use in mouthwash compositions
US4325939A (en) * 1980-09-22 1982-04-20 Richardson-Vicks Inc. Zinc derivatives and their use in dental compositions
US4937066A (en) * 1989-06-22 1990-06-26 David G. Vlock Zinc containing oral compositions

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4022880A (en) * 1973-09-26 1977-05-10 Lever Brothers Company Anticalculus composition
US4325939A (en) * 1980-09-22 1982-04-20 Richardson-Vicks Inc. Zinc derivatives and their use in dental compositions
US4289754A (en) * 1980-11-03 1981-09-15 Richardson-Vicks Inc. Zinc derivatives and their use in mouthwash compositions
US4937066A (en) * 1989-06-22 1990-06-26 David G. Vlock Zinc containing oral compositions

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993002658A1 (en) * 1991-08-06 1993-02-18 The Procter & Gamble Company Oral compositions effective against plaque and gingivitis
EP0528468A1 (en) * 1991-08-08 1993-02-24 Unilever N.V. Use of triclosan for the manufacture of a medicament for inhibiting cyclooxygenase
US5240696A (en) * 1991-08-08 1993-08-31 Chesebrough-Pond's Usa Co., Division Of Conopco, Inc. Treatment of periodontitis
WO1994014407A1 (en) * 1992-12-18 1994-07-07 The Procter & Gamble Company Oral compositions containing antiplaque, anticalculus agents
WO1994026258A1 (en) * 1993-05-13 1994-11-24 Unilever N.V. Oral compositions containing triclosan for the treatment of aphthous ulcers
JP2012522777A (en) * 2009-04-02 2012-09-27 コルゲート・パーモリブ・カンパニー Dentifrice composition
CN102368996A (en) * 2009-04-02 2012-03-07 高露洁-棕榄公司 Dentifrice composition
WO2010114546A1 (en) * 2009-04-02 2010-10-07 Colgate-Palmolive Company Dentifrice composition
AU2009343761B2 (en) * 2009-04-02 2013-05-09 Colgate-Palmolive Company Dentifrice composition
US9968803B2 (en) 2009-10-29 2018-05-15 Colgate-Palmolive Company Low water stannous fluoride plus zinc citrate dentifrice with improved stability, rheology, and efficacy
US10668306B2 (en) 2009-10-29 2020-06-02 Colgate-Palmolive Company Low water stannous fluoride plus zinc citrate dentifrice with improved stability, rheology, and efficacy
US10682532B2 (en) 2009-10-29 2020-06-16 Colgate-Palmolive Company Low water stannous fluoride plus zinc citrate dentifrice with improved stability, rheology, and efficacy
US11147992B2 (en) 2009-10-29 2021-10-19 Colgate-Palmolive Company Low water stannous fluoride plus zinc citrate dentifrice with improved stability, rheology, and efficacy
US11285342B2 (en) 2009-10-29 2022-03-29 Colgate-Palmolive Company Low water stannous fluoride plus zinc citrate dentifrice with improved stability, rheology, and efficacy
WO2012060837A1 (en) 2010-11-04 2012-05-10 Colgate-Palmolive Company Dentifrice composition with reduced astringency
US20190038545A1 (en) * 2017-08-04 2019-02-07 Colgate-Palmolive Company Biphasic Oral Care Compositions
US10912731B2 (en) * 2017-08-04 2021-02-09 Colgate-Palmolive Company Biphasic oral care compositions

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