WO1993011739A1 - Oral compositions for suppressing mouth odors - Google Patents

Oral compositions for suppressing mouth odors Download PDF

Info

Publication number
WO1993011739A1
WO1993011739A1 PCT/US1992/010662 US9210662W WO9311739A1 WO 1993011739 A1 WO1993011739 A1 WO 1993011739A1 US 9210662 W US9210662 W US 9210662W WO 9311739 A1 WO9311739 A1 WO 9311739A1
Authority
WO
WIPO (PCT)
Prior art keywords
copper
compound
percent
oral
oral composition
Prior art date
Application number
PCT/US1992/010662
Other languages
French (fr)
Inventor
Joseph R. Garlich
Tipton T. Masterson
Jaime Simon
Vidyadhar B. Hegde
Original Assignee
The Dow Chemical Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The Dow Chemical Company filed Critical The Dow Chemical Company
Priority to EP93901382A priority Critical patent/EP0616519A1/en
Priority to BR9206908A priority patent/BR9206908A/en
Priority to JP5511066A priority patent/JPH07501826A/en
Publication of WO1993011739A1 publication Critical patent/WO1993011739A1/en
Priority to FI942713A priority patent/FI942713A0/en

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q15/00Anti-perspirants or body deodorants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/66Phosphorus compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00Medicinal preparations containing inorganic active ingredients
    • A61K33/24Heavy metals; Compounds thereof
    • A61K33/34Copper; Compounds thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/19Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/41Amines
    • A61K8/416Quaternary ammonium compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4906Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • A61K8/4926Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having six membered rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/55Phosphorus compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q11/00Preparations 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 compositions for the control of volatile compounds associated with oral malodor.
  • Oral composition means a composition for topical applications to the oral . cavity to clean and care for the teeth as well as the oral cavity surfaces.
  • Representatives of such compositions are oral hygiene products and dentifrices such as mouthwashes or rinses, toothpaste, dental gels, tooth powder, chewing gum, lozenges, and similar products.
  • oral hygiene preparations In addition to cleaning teeth to remove dental plaque, the function of oral hygiene preparations is to stop the formation of dental calculus, to prevent dental disorders such as caries, periodontitisand gingivitis, and also to eliminate halitosis.
  • Dental plaque is a deposit which forms on teeth and consists of inorganic and organic components derived from saliva, food and bacteria which are present in the oral cavity. When plaque undergoes calcification it forms dental calculus, or tartar as it is sometimes called. Dental calculus is largely calcium and orthophosphate arranged in a crystal lattice called hydroxyapatite (HAP).
  • HAP hydroxyapatite
  • Oral malodor, or halitosis is caused by the putrefactive activity of microorganisms on appropriate substrate components of dental plaque, debris adhering to mucous membranes and salivary cellular elements to produce volatile sulfur compounds
  • These sulfur volatiles primarily consists of hydrogen sulfide (H 2 S), methyl mercaptan (CH 3 SH) and traces of dimethyl sulfide (CH 3 ) 2 S.
  • Volatile sulfur compounds, aromatic amines, ammonia and urea have also been shown to increase in the mouth of patients suffering from periodontal disease, see, for example, J. Periodontal Res., 15, 185-192 (1980), Clin. Chem., 27, 842-845 (1981), Intl. Den. J., 28, 309-319 (1978).
  • chlorhexidine has been used for centuries as a medicinal plant.
  • side effects associated with chlorhexidine such as a bitter taste and staining of the teeth, tongue, gums and oral mucosa, precludes the use of chlorhexidine in oral compositions.
  • Copper compounds including copper chlorophyllin, copper gluconate, copper citrate and copper long chain alkyloyl sarcosine have been used to reduce mouth odors. See, for example, U.S. Patents 3,044,939; 3,565,933 and 4,112,066 and Nippon Shishyubyo Gakkai Kaishi, 490-498 (1981) for oral compositions containing such compounds. These copper compounds, however, do notfully exert their mouth odor reducing effect when blended in relatively small amounts. As copper is astringent, the amount of these copper compounds required to assure their effect in reducing mouth odor makes such oral compositions unpleasant in taste.
  • the present invention relates to oral compositions for controlling mouth malodor comprising: (a) from about 0-0002 to about 1 percent by weight of one or more copper salts; (b) from about 0-001 to about 10 percent by weight of one or more compounds having C-O-P bonds wherein the compound having C-O-P bonds is myo-inositol hexakis(dihydrogen phosphate), myo-inositol tetrakis(dihydrogen phosphate), myo-inositol pentakis(dihydrogen phosphate) or physiologically acceptable salts thereof;
  • the remaining percent by weight is an orally acceptable vehicle.
  • the addition of the quaternary ammonium compound reduces the amount of bacteria which are responsible for production of volatile sulfur compounds.
  • the inclusion of a quaternary ammonium compound also aids in reducing the formation of dental plaque and/or gingivitis and/or periodontitis and/or dental caries.
  • the oral compositions of the present invention provide for improved mouth malodor suppression by combining in an orally-acceptable vehicle at least one copper (II) salt and phytic acid or derivatives thereof.
  • the oral composition can also contain an antimicrobial agent for killing bacteria in the oral cavity thereby reducing the level of plaque and/or gingivitis formed along with mouth malodor suppression.
  • An "orally-acceptable vehicle” means a medium in which the copper (II) salt and phytic acid may be administered to the oral cavity surfaces without substantial harmful effects to the surfaces thereof and also is pleasant in taste.
  • the term “copper” refers to the cupricion.
  • the retention of the copper ion within the oral cavity can be substantially enhanced if the copper salt is used in combination with a hydroxyapatite seeking agent, such as phytic acid or a derivative thereof.
  • a hydroxyapatite seeking agent such as phytic acid or a derivative thereof.
  • the ability of the copper to remain in contact with the tooth surface is referred to as the "substantivity" of the agent.
  • a compatibilizing agent in addition to the copper saltand phytic acid, a cationic antimicrobial compound can be added to the oral composition to control dental plaque, gingivitis, periodontitis and oral malodor without the components precipitating.
  • Copper compounds useful in the present invention are any copper salt, or combination thereof, which has a stability constant less than that of copper phytate, such as, copper acetate, copper gluconate, copper sulfate, copper chloride, and the like.
  • Other copper compounds useful in the present invention include copper succinate and copper tartrate
  • the preferred copper salts are copper acetate and copper gluconate.
  • the copper salts are preferably present in the oral composition of the present invention in an amount of from about 0.0002 to about 1 percent by weight of the total composition, preferably from about 0.0002 to about 0.5 percent by weight.
  • the tooth surface seeking agent of the present invention are compounds which contain a carbon atom covalently bonded to an oxygen atom, the oxygen being covalently bonded to a phosphate atom, hereinafter referred to as C-O-P bonds.
  • the compounds of the present invention which contain C-O-P bonds are phosphate esters of myo-inositol, such as phytic acid, also known as myo-inositol hexakis(dihydrogen phosphate), inositol
  • phytic acid means the hexakis phosphate ester of myo-inositol, myo-inositol hexakis(dihydrogen phosphate) and the lesser substituted tetrakis and pentakis phosphate esters of myo-inositol, myo-inositol tetrakis(dihydrogen phosphate) and myo-inositol pentakis(dihydrogen phosphate) respectively, and physiologically acceptable salts thereof, such as alkali metal, alkaline earth metal, ammonium salts or mixtures thereof.
  • Phytin which isthe calcium magnesium salt of phytic acid, represented by the formula Ca 5 Mg(C 6 H 12 O 24 P 6 3H 2 O) 2 , can also be used in the present invention in addition to or for replacement of the phytic acid. These phytic acid compounds may be used singly or in combination.
  • Phytic acid is present in the oral composition of the present invention in an amount of from about 0.001 to about 10 percent by weight of the total composition.
  • the phytic acid or salt thereof is typically present in an amount of from about 0.005 to about 5 percent, and preferably from about 0.01 to about 1 percent by weight.
  • the molar ratio of cupric ion to phytic acid in the oral composition of the present invention is from about 1 :100 to about 1:1, preferably from about 1 :50 to about 1 :1 and more preferably about 1 :20 to about 1 :1.
  • the composition is substantially liquid in character, such as a mouthwash or rinse.
  • the vehicle can be water or a water-alcohol mixture.
  • the weight ratio of water to alcohol is generally in the range of from about 1 :1 to about 20:1, preferably from about 3:1 to about 10:1 and more preferably from about 4:1 to about 6:1.
  • the total amount of waterbuffer or water-alcohol mixture in this type of preparation is typically in the range of from about 70 percentto about99.9 percent by weight of the preparation.
  • the pH of such liquid and other preparations of the invention is generally in the range of from about 4.5 to about 9, and preferably from about 5.5 to about 8, more preferably in the range of from about 6 to about 8.
  • the oral composition may be substantially solid or semisolid in character, such astoothpowder, a dental tablet, a toothpaste, gel or dental cream.
  • the vehicle of such solid or semisolid oral preparation generally contains added polishing material more fully described hereinafter.
  • the oral composition of the present invention can contain one or more cationic antimicrobial compounds.
  • a "cationic antimicrobial compound” refers to an organic amine where the nitrogen is capable of being positively charged in an aqueous environment, and is represented by one or more of the following general formulae from A.J.
  • R 1 is a C 8 -C 20 alkyl
  • R 2 is benzyl or C 1 -C 12 alkyl
  • R 3 and R 4 are independently a C 1 -C 7 alkyl or -(CH 2 -CHOH-CH 2 -O) n H wherein n is an integer from 1 to 6;
  • R 5 is -H, a C 1 -C 7 alkyl or -(CH 2 -CHOH-CH 2 -O) n H wherein n is an integer from 1 to 6;
  • X- is chloride (CI-), bromide (Br-), iodide (I-) or fluoride (F-) ion;
  • X is as defined herein before and X 1 is oxygen or sulfur;
  • R 6 is a C 4 -C 16 alkyl or benzyl
  • R 7 ⁇ s a C 10 -C 18 aIkyl; and physiologically acceptable salts thereof;
  • R 8 is a C 8 -C 16 alkyl at the 2 or 3 position of the morpholino ring
  • R 9 is a C 2 -C 10 alkyl substituted with a hydroxy group at other than the alpha- -position
  • R 8 and R 9 being greater than or equal to 10 and preferably 10-20; and physiologically acceptable salts thereof;
  • R 10 is a C 10 -C 18 alkyl
  • each R 1 1 is independently C 8 H 17 or C 10 H 21 ;
  • R 13 is a C 9 -C 17 alkyl
  • each R 13 is independently C 7 H 15 or C 9 H 19 ; and physiologically acceptable salts thereof, (G) Dialkyl amines and N,N'-dialkylpolymethylene-diamines as disclosed in J. Antibacterial and Antifungal Agents, 17, 579 (1989), the disclosure of which is hereby incorporated by reference, having the formula
  • each R 1 4 is independently C 8 H 17 or C 12 H 25 ; or formula
  • each R 15 is independently a C 7 -C 10 alkyl
  • n is an integer from 2 to 5; and physiologically acceptable salts thereof;
  • R 16 is a C 10 -C 18 alkyl; and physiologically acceptable salts thereof;
  • R 18 is a C 10 -C 18 alkyl
  • alkyl means a linear or branched alkyl and thus secondary and tertiary alkyls are included.
  • the alkyl terms up to C 20 include, for example, t-butyl, sec-butyl, isobutyl, and in like manner all such branched or straight chain alkyls.
  • Preferred quaternary ammonium antibacterial agents include dodecyl trimethyl ammonium bromide, benzyl dimethyl stearyl ammonium chloride, N-tetradecyl-
  • antibacterial and antimicrobial mean the ability to inhibit growth, metabolism or reproduction of
  • quaternary ammonium compounds may be produced by reacting alkyl halides with ammonia or primary amines, or by reacting a tertiary amine, pyridine or pyridine derivative with an alkyl halide. See, for example, Zoltewicz and Deady, Adv. Heterocycl. Chem., 22, 71-121 (1978); U.S. Patents 2,446,792; 2,295,504 and 4,994,199, the teachings of which are hereby incorporated by reference.
  • One or more cationic antimicrobial compounds are employed in amounts such that the oral product contains from about 0.001 to about 10 percent by weight of the antimicrobial compound.
  • the finished oral product contains from about 0.01 to about 5 percent, and preferably from about0.025to 1.0 percent by weight of the antimicrobial compound.
  • a singular antimicrobial compound is employed in the oral product.
  • the oral composition When the oral composition is essentially liquid in nature, to maintain the copper ion, phytic acid and cationic antimicrobial compound in solution, it is desirable for the composition to contain a sufficient amount of a compatibilizing agent to keep the phytic acid, copper ion and cationic antimicrobial compound in solution.
  • a compatibilizing agent to keep the phytic acid, copper ion and cationic antimicrobial compound in solution.
  • Compatibilizing agents in the present invention are those which do not have a detrimental effect on the substantivity of the phytic acid, copper ion and cationic antimicrobial compound in solution and maintain the components in solution such that the composition does not visually become turbid after standing for 12 to 15 hours at room temperature.
  • a detrimental effect on substantivity means the retention of the antimicrobial compound nearthe tooth surface is the presence of phytic acid is not substantially different than that of the antimicrobial compound in the absence of phyticacid. It is therefore possible that a compound or combination of compounds may combatibilizethe phyticacid and antimicrobial compound, i.e., keep them in solution, but adversely affect the substantivity of the antimicrobial/phytic acid solution.
  • compatibilizing agents of the present invention reduce the interaction between the phytic acid and cationic antimicrobial compound, reducing or preventing the formation of a precipitate when these two compounds are exposed to each other in an aqueous environment.
  • Particularly useful compatibilizing agents in the present invention are acids and their alkali metal or alkalineearth metal salts, or mixtures thereof, designated herein as anionic buffers.
  • Suitable anionic buffers are, for example, phosphate, acetate, borate, citrate, bicarbonate, gluconate, tartrate, sulfate, and the like, or mixtures thereof.
  • the preferred anionic buffers being phosphate and/or bicarbonate.
  • the amount of anionic buffer in the oral compositions of the present invention is from about 0.1 to about 20 percent by weight, preferably from about 0.1 to about 10 percent by weight of the total composition.
  • the anionic buffer is present in a concentration of about 0.1 M to about 1.0 M, preferably from about 0.25 M to about 0.75 M.
  • compatibilizing agents useful in the present invention are surfactants which maintain the phyticacid and antimicrobial compound in solution and does not interfere with enhanced substantivity due to the presence of phytic acid.
  • An example of a particularly suitable nonionic surfactant is pofy(oxyethylene), poly(oxpropylene) block polymers known as poloxamers and available, for example, under the trademark "PLURONICS" (BASFWyandotte Co., Parsippany, NJ).
  • Suitable nonionic surfactant is polyethylene oxide sorbitan esters, available for example, under the trademark "TWEENS” (ICI American Inc., Wilmington, De.)
  • Suitable amnoic surfactants include, for example, anionic surfactants produced from fatty acids and the amino acid sarcosine, such as N-lauroyl sarcosine, available for example, under the trademark "HAMPOSYL” by W.R. Grace and Co. (CT).
  • compatibilizing agent When utilizing a combination of compatibilizing agents, it is desirable that the total amount of compatibilizing agent in the oral composition remain from about 0.1 to about 20 weight percent.
  • concentration of compatibilizing agent or agents for use in the present invention can be readily determined by those of ordinary skill in the art based upon the teachings herein.
  • compatibilizing agent for phytic acid and an antimicrobial compound such as N-tetradecyl-4-ethylpyridinium bromide
  • concentration of compatibilizing agent can be reduced below 0.1 weight percent, and about 0.05 weight percent can be used.
  • Preparation of the oral compositions of the present invention can be done by using customary procedures for unifying components applied to the teeth and gingiva. It has been found that when the oral compositions of the present invention contain the
  • the compositions are advantageously prepared by (a) dissolving the metal ion, phytic acid and compatibilizing agent in water, and then (b) adding the cationic antimicrobial compound or cationic antimicrobial solution to the solution obtained from step (a).
  • the pH of the oral composition is adjusted to between about 6 and about 8 either before or after the addition of the cationic antimicrobial compound or cationic antimicrobial solution.
  • Other components such as sweetening and flavoring agents as described more fully herein, can then be added if desired.
  • the dentifrices of the present invention may also be in a kit form for treating the oral cavity, the kit comprising one or more compounds having C-O-P bonds wherein the compound having C-O-P bonds is myo-inositol hexakis(dihydrogen phosphate), myo-inositol tetrakis(dihydrogen phosphate), myo-inositol pentakis(dihydrogen phosphate) or
  • physiologically acceptable salts thereof a copper salt, a compatibilizing agent and at least one cationic antimicrobial compound, the compound having C-O-P bonds, copper salt,
  • antimicrobial compound and compatibilizing agent each being in an orally-acceptable vehicle; and a means to contain the compound having C-O-P bonds separately from the cationic antimicrobial.
  • antimicrobial compound include placing them in separate containers or placing them in a compartmentalized container.
  • the copper salt is preferably mixed with the compound having C-O-P bonds; the compatibilizing agent may be mixed with the compound having C-O-P bonds, with the cationic antimicrobial, or is placed in a separate container.
  • the separate components i.e., compound having C-O-P bonds, copper salt, compatibilizing agent and cationic antimicrobial compound
  • the concentration of the individual compounds to which the oral cavity is exposed should be in the range given hereinbefore fortheir concentration in the final dentifrice product.
  • ingredients may be added to the dentifrices of the present invention.
  • prophylactic agents, polishing agents, soaps or detergents, flavoring and sweetening agents, thickening agents and humectants may be included using techniques which are know to the art.
  • prophylactic agents include supplemental caries-preventing materials such as, for example, sodium fluoride, stannous fluoride, potassium fluoride, hexylamine hydrofluoride, myristylamine hydrofluoride, betaine fluoride, glycine potassium fluoride.
  • a particularly preferred fluoride is sodium fluoride.
  • prophylactic agents are present in sufficient concentrations so as to provide an available fluoride ion concentration of up to about 2 percent by weight, and preferably from about 0.5 percent to about 2 percent by weight, of the dentifrice composition.
  • Suitable polishing agents include, for example, abrasive materials such as insoluble condensed phosphates such as calcium pyrophosphate, insoluble calcium
  • polyphosphate also known as calcium polymetaphosphate
  • highly polymerized sodium polyphosphate and highly polymerized sodium polyphosphate; and water impervious cross-linked thermosetting resins such as the
  • condensation products of melamine and urea with formaldehyde condensation products of melamine and urea with formaldehyde.
  • Other suitable polishing agents will be obvious to those skilled in the art.
  • the polishing material is generally present in the solid or semisolid compositions in weight concentrations of from about 10 to about 99 percent. Preferably, it is present in amounts ranging from about 20 to about 75 percent in toothpaste, and from about 70 percent to about 99 percent in tooth powder.
  • Soaps or detergents may also be employed in the present invention to lower the surface tension to achieve increased prophylactic action, assist in achieving thorough and complete dispersion ofthe anticalculus agent and renderthe instant compositions more cosmetically acceptable.
  • Suitable soaps include, for example, the soaps of high.molecular weight fatty acids such as sodium and potassium soaps of myristic, stearicor palmitic acids and fatty acids mixtures of palm oil and coconut oil.
  • Typical synthetic detergents include alkyl sulfates and sulfonates having alkyl groups of from about 8 to about 18 carbon atoms, such as, for example, sodium lauryl sulfate, the sulfated fatty alcohols derived from coconut oil and palm oil.
  • the soaps typically comprise up to about 5 percent by weight of the dentifrice composition.
  • flavoring or sweetening material may also be employed.
  • suitable flavoring constituents are flavoring oils, e.g., oil of spearmint, peppermint, wintergreen, sassafras, clove, sage, eucalyptus, marjoram, cinnamon, lemon and orange and methyl salicylate.
  • suitable sweetening agents include sucrose, lactose, maltose, sorbitol, xylitol, sodium cyclamate, perillartine, APM (aspartylphenylalanine, methyl ester), saccharine and the like.
  • flavor and sweetening agents may together comprise from about 0.1 percent to 5 percent of the preparation.
  • creams and gels typically contain a natural or synthetic thickener or gelling agent in proportions of from about 0.1 to about 10 percent, preferably from about 0.5 to about 5 percent by weight.
  • Suitable gelling or thickening agents include for example, water-soluble salts of cellulose ethers such as sodium carboxymethyl cellulose and sodium carboxymethyl hydroxyethyl cellulose; natural gums such as gum karaya, gum arabic, and gum tragacanth; and colloidal magnesium aluminum silicate or finely divided silica.
  • Suitable humectants which may be employed in compositions of the invention include glycerine, propylene glycol, sorbitol, polypropylene glycol and/or polyethylene glycol and other polyhydric alcohols.
  • the humectants may comprise from about 10 to 90 percent by weight of the dentifrice composition.
  • CPC cetylpyridinium chloride
  • a 0.0045 M Cu-phytic acid A 0.0045 M solution of phytic acid and copper metal ion was prepared by adding 0.2042 ⁇ 0.0001 g of D-gluconic acid, Cu(ll) salt, (Aldrich Chemical Co., Inc.) to a 60 mL beaker. To this was added 0.5847 ⁇ 0.0001 g of 50 percent by weight phytic acid (Jonas Chemical Co.) and approximately 20 mL of water. This solution was transferred to a 100 mL volumetric flask and diluted to the mark with water. The final pH was approximately 3.0.
  • 1.5 M sodium phosphate A 1.5 M solution of sodium phosphate was prepared by adding 20.70 ⁇ 0.01 g of NaH 2 PO 4 ⁇ H 2 O (J.T. Baker Co.) to a beaker and dissolving in approximately 40 mL of water. The pH of this solution was adjusted to approximately 6.3 with the dropwise addition of 25 percent by weight sodium hydroxide solution. This solution wasthen transferred quantitatively to a 100 mL volumetric flask and diluted to the mark with water.
  • 1.5 M sodium bicarbonate A 1.5 M bicarbonate solution was prepared by adding 16.6 ⁇ 0.01 g of NaHCO 3 (J.T. BakerCo.) to a 100 mL volumetric flask and diluting to the mark with water. The pH of the sodium bicarbonate solution was approximately 8.4.
  • sucrose solution was prepared by loading 1.0 g of sucrose (Imperial Pure Cane Sugar) into a 60 mL beaker and then adding 20 mL of water. To this solution was added 8.0 mL of pooled whole human saliva. The saliva was collected from donors who had been permitted to eat or drink anything prior to the collection period, but had foregone any oral hygiene on the day of collection. Prior to the collection, each donor rinsed their mouth for thirty seconds with approximately 30 mL water, and after waiting about 5 minutes, began collecting saliva for 30-40 minutes, keeping the collected saliva on ice.
  • sucrose Imperial Pure Cane Sugar
  • test tubes containing various washed HAP suspensions. These test tubes were capped and attached to a tube rotator and placed in a 37°C incubator for sixteen hours. Following this incubation period, the rotator was removed from the oven and allowed to cool to ambient temperature. The pH of the solutions were checked with a pH meter using a pH electrode calibrated with pH 4, 7 and 10 buffers. The pH of each test tube was recorded and plotted in graphic format.
  • a 60 mL beaker was loaded with 6.0 g of hydroxyapatite (HAP) in a buffer suspension (25 percent by weight solids from Sigma Chemical Co.) and washed with 30 mLof water.
  • the HAP suspension was filtered through a medium glass fitted filter to obtain a HAP filter cake.
  • the white solid filter cake containing 1.5 g of HAP was transferred to a dry 60 mL beaker and the total weight brought up to 15 grams with water to produce a 100 mg HAP/mL suspension.
  • sterile-disposable polystyrene 5 mLtest tubes labeled D 1 --D n (where n identity number of the test solution).
  • n identity number of the test solution.
  • test tubes were placed in an Industrial Equipment Company (lEC) model K centrifuge and spun at setting 25 (mid-range) for ten minutes. The tubeswere removed and the liquid layer decanted. A macropipettorwasthen used to add 3.0 mL of water to each test tube containing the centrifuged hydroxyapatite. The HAP sol ids were resuspended by vigorous in-and-out flowing action through the pipette and then placed on an end-over- end rotator for ten minutes. The tubes were again centrifuged at setting 25 for ten minutes and the liquid layer decanted.
  • lEC Industrial Equipment Company
  • HAP solids were resuspended in 4.0 mLof water.
  • Two separate 0.5 mL samples (containing 25 mg HAP) of each HAP suspension was removed from each test suspension and placed in test tubes labeled A 1 --A n or A 1 '--- A n ' for the duplicate samples.
  • a group of samples each contain one-eighth of the original treated HAP suspension which has been washed with three milliliters of water.
  • test tubes labeled D 1 --D n were centrifuged for ten minutes, the test tubes removed, and the liquid layer decanted. Three milliliters of water were added to these test tubes and the HAP solids resuspended/washed using disposable pipettes. The tubes were centrifuged for ten minutes, the tubes removed and the liquid layer decanted. An additional three milliliters of water were added to these tubes and the HAP solids resuspended/washed by pipette. These tubes were again placed in the centrifuge and spun for ten minutes. The tubeswere removed, the liquid layer decanted and 3.0 mL of water added to each tube.
  • HAP solids were resuspended and a 0.5 mL sample removed and placed in each of several 5 mL polystyrene test tubes labeled B 1 -- B n or B 1 '--B n '. These samples contained approximately 25 mg HAP solids which had been treated with test solution and then washed with a total of 13 milliliters of water.
  • the procedure given above was repeated a third and fourth time to create a series of test tubes labeled C 1 --C n or C 1 '--C n ' and D 1 - D n or D 1 '--D n ', with the exception that after the second three milliliter wash to give the C samples, the HAP was resuspended in 2 mL of water a nd f or the D samples, 1 mL of water.
  • the C and C samples contained approximately 25 mg of HAP solids which had been treated with test solution and then washed with a total of 21 mLof water.
  • the D and D' samples contained approximately 25 mg of HAP solids which had been treated with the test solution and then washed with a total of 31 mL water.
  • a glycolysis pH test was then performed as described above by adding 0.75 mL aliquots of the saiiva/sucrose/bacterial mixture to the test tubes labeled A 1 -- D n , each containing 0.5 mL of the treated washed HAP suspension.
  • the A 1 ' --- D n ' samples were duplicates that could be tested for deodorizing power. Measurement of deodorizing power
  • the ability of the oral compositions to reduce malodor was determined by placing 2 mL of the composition in a sample tube and bubbling a standard mixture of hydrogen sulfide (H 2 S) and methyl mercaptan (CH SH) through the test solution for 1 minute and measuring the reduction of the H 2 S/CH 3 SH.
  • H 2 S hydrogen sulfide
  • CH SH methyl mercaptan
  • the H 2 S (542 ng/min) and CH 3 SH (735 ng/min) standards were obtained from permeation tube standards (Thermedics Inc.) and carried through the test samples by a 30 mlJmin flow of nitrogen.
  • the testing apparatus was fitted with a tee to allow diversion of a portion of the gas stream from the standards to obtain a linear response by the detector.
  • the gas stream from the sample tube was analyzed using a Hewlett Packard 5890A gas
  • the ability of Cu-phytic acid to adsorb to a hydroxyapatite surface and retain deodorizing power was measured by treating 1 mL of a hydroxyapatite (HAP) suspension with 1 mLof a test solution and then subjecting the HAP to several washing steps.
  • HAP hydroxyapatite
  • the HAP suspension was prepared by washing a 24.5 g portion of HAP (Sigma Chemical Co., 24.5 percent solids in phosphate buffer, 0.001 M, pH 6.8) with three 30 mL portions of water. The washed hydroxyapatite powder (approximately 6 g) was then suspended in 60 mL of water with vigorous stirring to give a 100 mg/mL homogeneous white HAP suspension.
  • test solutions were as follows:
  • Solution A 0.0015 M copper acetate, 0.0015 M phytic acid and 0.05 M phosphate buffer at pH 6.8;
  • Solution B 0.0015 M copper acetate and 0.05 M phosphate buffer at pH 7.05;
  • Solution C water (control).
  • Solutions A and B were prepared as described in Example 1 and the solutions filtered through a 0.22 micron syringe filter immediately before use.
  • compositions were evaluated for retention on a HAP surface after washing as measured by the ability of the treated and washed HAP to reduce malodor and inhibit microorganisms:
  • cetylpyridinium chloride and phytic acid being at a concentration of 0.0015 M and phosphate at 0.5 M.
  • the second set of the split hydroxyapatite samples (A 1 ' ---A n ', B 1 '---B n ' , etc.) were suspended in 2.0 mLof phosphate buffer and evaluated by the procedure given in
  • the ability of phytic acid to enhance the substantivity of an antimicrobial to HAP was measured by treating HAP with a test solution, washing the HAP as described under general experimental and measuring retention of antimicrobial activity by the glycolysis pH test described above.
  • the HAP was treated with the following test solutions:
  • CPC cetylpyridinium chloride
  • the cetylpyridinium chloride and phytic acid concentration being 0.0015 M, phosphate 0.5 M and copper ion 0.5 millimolar.
  • Samples B, Cand E were prepared by mixing the appropriate amount of required stock solutions and diluting with water when necessary to give the indicated concentrations.
  • Sample D was prepared by placing 0.0102 g of D-gluconic acid, Cu(II) salt, into a jar and dissolving with the addition of 15 mLof a 0.0045M phyticacid solution. Fifteen mL of a 1.5 M phosphate buffer solution was added to the jar and the pH adjusted to about 7 with the dropwise addition of a 50 percent sodium hydroxide solution. A 15 mL aliquot of water was then added to give the final concentrations listed above. For Sample F, a 15 mL aliquot of a 0.0045 M cetylpyridinium chloride solution was used to replace the final water addition as described for sample D.
  • aCPC cetylpyridinium chloride (Control);
  • bPaP phytic acid and phosphate (Control);
  • CPC cetylpyridinium chloride
  • Cu-PaB copperion, phyticacid, sodium bicarbonate
  • CPCB bicarbonate
  • TDEP N-tetradecyl-4-ethylpyrid ⁇ nium bromide
  • G phyticacid, sodium bicarbonate, cetylpyridinium chloride (PaBC);
  • the concentration of the components being 0.0015 M except sodium bicarbonate at 0.5 M.
  • Solutions B, C, D, 1 and 2 were prepared by mixing the appropriate amount of stock solutions and diluting with water when necessary to give the indicated concentrations.
  • Sample E was prepared by adding 0.0173 ⁇ 0.0001 g of N-tetradecyl-4- ethylpyridinium bromide to a 10 mL volumetric flask and diluting to mark with water. A 4 mL aliquot of this 0.0045 M solution was diluted with 8 mLof water to produce a final
  • Sample 3 was prepared by adding a 4 mLaliquot of 1.5 M sodium bicarbonate to 4 mLof a 0.0045 M Cu + + /phytic acid stock solution and then adding 4 mL of a 0.0045 M
  • N-tetradecyl-4-ethylpyr ⁇ dinium bromide stock solution The pH of this formulation was about 8.3.
  • CPC cetylpyridinium chloride
  • CuPaB copper, phytic acid and sodim bicarbonate
  • CPCB cetylpyridinium chloride and sodim bicarbonate
  • Cu-PaBC copper, phytic acid, sodim bicarbonate and cetylpyridinium chloride
  • PaBC phytic acid, sodim bicarbonate, and cetylpyridinium chloride

Abstract

An oral composition for suppressing mouth odors comprising from about 0.001 to about 10 percent by weight of a copper salt and from about 0.001 to about 10 percent by weight phytic acid or a physiologically acceptable salt thereof. A cationic antimicrobial compound is added to the oral composition to aid in the prevention of plaque formation and gingivitis provided the oral composition contains from about 0.01 to about 20 percent by weight of a compatibilizing agent.

Description

ORAL COMPOSITIONS FOR SUPPRESSING MOUTH ODORS
BACKGROUND OF THE INVENTION
The present invention relates to oral compositions for the control of volatile compounds associated with oral malodor.
"Oral composition" means a composition for topical applications to the oral . cavity to clean and care for the teeth as well as the oral cavity surfaces. Representatives of such compositions are oral hygiene products and dentifrices such as mouthwashes or rinses, toothpaste, dental gels, tooth powder, chewing gum, lozenges, and similar products. In addition to cleaning teeth to remove dental plaque, the function of oral hygiene preparations is to stop the formation of dental calculus, to prevent dental disorders such as caries, periodontitisand gingivitis, and also to eliminate halitosis.
Dental plaque is a deposit which forms on teeth and consists of inorganic and organic components derived from saliva, food and bacteria which are present in the oral cavity. When plaque undergoes calcification it forms dental calculus, or tartar as it is sometimes called. Dental calculus is largely calcium and orthophosphate arranged in a crystal lattice called hydroxyapatite (HAP).
Oral malodor, or halitosis, is caused by the putrefactive activity of microorganisms on appropriate substrate components of dental plaque, debris adhering to mucous membranes and salivary cellular elements to produce volatile sulfur compounds These sulfur volatiles primarily consists of hydrogen sulfide (H2S), methyl mercaptan (CH3SH) and traces of dimethyl sulfide (CH3)2S. Volatile sulfur compounds, aromatic amines, ammonia and urea have also been shown to increase in the mouth of patients suffering from periodontal disease, see, for example, J. Periodontal Res., 15, 185-192 (1980), Clin. Chem., 27, 842-845 (1981), Intl. Den. J., 28, 309-319 (1978).
Methods of inhibiting volatile sulfur compounds to reduce the production of mouth odor have included the use of dentifrices containing antimicrobials, such as,
chlorhexidine. However, the side effects associated with chlorhexidine, such as a bitter taste and staining of the teeth, tongue, gums and oral mucosa, precludes the use of chlorhexidine in oral compositions.
Copper compounds including copper chlorophyllin, copper gluconate, copper citrate and copper long chain alkyloyl sarcosine have been used to reduce mouth odors. See, for example, U.S. Patents 3,044,939; 3,565,933 and 4,112,066 and Nippon Shishyubyo Gakkai Kaishi, 490-498 (1981) for oral compositions containing such compounds. These copper compounds, however, do notfully exert their mouth odor reducing effect when blended in relatively small amounts. As copper is astringent, the amount of these copper compounds required to assure their effect in reducing mouth odor makes such oral compositions unpleasant in taste.
An oral composition containing copper gluconate, a fluorine compound, and an alkali metal salt of an alkyl sulfate having 8to 18 carbon atoms is reported in published European Patent Application 0321180. It was reported that these components act in a synergistic manner so that mouth odor suppression is accomplished when each ingredient is contained in a low concentration.
While the use of copper compounds in oral compositions for controlling mouth malodor is known, none of the references provide a means by which the copper can be retained in the oral cavity to control mouth odorovera period of time. In addition, many copper compounds are unstable at biological pH (about 7.0) resulting in undesirable cloudiness and precipitation of insoluble by-products.
It istherefore desirable when using copper in an oral composition to control mouth malodor, to have an oral composition in which the copper compound is effective at a relatively low concentration, can be maintained in the oral cavity over a prolonged period of time, and remains soluble when used in liquid compositions. It would also be desirable to prepare an oral composition capable of controlling mouth malodor in addition to the prevention of plaque and calculus formation.
SUMMARY OF THE INVENTION
The present invention relates to oral compositions for controlling mouth malodor comprising: (a) from about 0-0002 to about 1 percent by weight of one or more copper salts; (b) from about 0-001 to about 10 percent by weight of one or more compounds having C-O-P bonds wherein the compound having C-O-P bonds is myo-inositol hexakis(dihydrogen phosphate), myo-inositol tetrakis(dihydrogen phosphate), myo-inositol pentakis(dihydrogen phosphate) or physiologically acceptable salts thereof;
(c) from about 0.001 to about 10 percent by weight of one or more cationic antimicrobial compounds;
(d) from about 0.1 to about 20 percent by weight of one or more compatibilizing agents; and
(e) the remaining percent by weight is an orally acceptable vehicle. The addition of the quaternary ammonium compound reduces the amount of bacteria which are responsible for production of volatile sulfur compounds. The inclusion of a quaternary ammonium compound also aids in reducing the formation of dental plaque and/or gingivitis and/or periodontitis and/or dental caries.
It has also been found that the addition of phytic acid to a liquid composition containing a copper (II) salt prevents the undesirable cloudiness and precipitation of insoluble by-products associated with the instability of copper compounds at about pH 7.2
DETAILED DESCRIPTION OF THE INVENTION
The oral compositions of the present invention provide for improved mouth malodor suppression by combining in an orally-acceptable vehicle at least one copper (II) salt and phytic acid or derivatives thereof. In the presence of a compatibilizing agent, the oral composition can also contain an antimicrobial agent for killing bacteria in the oral cavity thereby reducing the level of plaque and/or gingivitis formed along with mouth malodor suppression. An "orally-acceptable vehicle" means a medium in which the copper (II) salt and phytic acid may be administered to the oral cavity surfaces without substantial harmful effects to the surfaces thereof and also is pleasant in taste. As used herein, the term "copper" refers to the cupricion.
To enhance the control of mouth malodor by copper salts, it has been unexpectedly found that the retention of the copper ion within the oral cavity can be substantially enhanced if the copper salt is used in combination with a hydroxyapatite seeking agent, such as phytic acid or a derivative thereof. The ability of the copper to remain in contact with the tooth surface is referred to as the "substantivity" of the agent. It has now also been unexpectedly found that in the presence of a compatibilizing agent, in addition to the copper saltand phytic acid, a cationic antimicrobial compound can be added to the oral composition to control dental plaque, gingivitis, periodontitis and oral malodor without the components precipitating.
Copper compounds useful in the present invention are any copper salt, or combination thereof, which has a stability constant less than that of copper phytate, such as, copper acetate, copper gluconate, copper sulfate, copper chloride, and the like. Other copper compounds useful in the present invention include copper succinate and copper tartrate The preferred copper salts are copper acetate and copper gluconate. The copper salts are preferably present in the oral composition of the present invention in an amount of from about 0.0002 to about 1 percent by weight of the total composition, preferably from about 0.0002 to about 0.5 percent by weight.
The tooth surface seeking agent of the present invention are compounds which contain a carbon atom covalently bonded to an oxygen atom, the oxygen being covalently bonded to a phosphate atom, hereinafter referred to as C-O-P bonds. The compounds of the present invention which contain C-O-P bonds are phosphate esters of myo-inositol, such as phytic acid, also known as myo-inositol hexakis(dihydrogen phosphate), inositol
hexaphosphoric acid, and 1,2,3,4,5,6-cyclohexanehexolphosphoric acid. As used herein "phytic acid" means the hexakis phosphate ester of myo-inositol, myo-inositol hexakis(dihydrogen phosphate) and the lesser substituted tetrakis and pentakis phosphate esters of myo-inositol, myo-inositol tetrakis(dihydrogen phosphate) and myo-inositol pentakis(dihydrogen phosphate) respectively, and physiologically acceptable salts thereof, such as alkali metal, alkaline earth metal, ammonium salts or mixtures thereof. Phytin, which isthe calcium magnesium salt of phytic acid, represented by the formula Ca5Mg(C6H12O24P63H2O)2, can also be used in the present invention in addition to or for replacement of the phytic acid. These phytic acid compounds may be used singly or in combination.
Phytic acid is present in the oral composition of the present invention in an amount of from about 0.001 to about 10 percent by weight of the total composition. When the oral composition is essentially liquid in nature, the phytic acid or salt thereof is typically present in an amount of from about 0.005 to about 5 percent, and preferably from about 0.01 to about 1 percent by weight.
The molar ratio of cupric ion to phytic acid in the oral composition of the present invention is from about 1 :100 to about 1:1, preferably from about 1 :50 to about 1 :1 and more preferably about 1 :20 to about 1 :1.
In certain preferred forms of the invention, the composition is substantially liquid in character, such as a mouthwash or rinse. In such a preparation the vehicle can be water or a water-alcohol mixture. When alcohol is used in the mixture, the weight ratio of water to alcohol is generally in the range of from about 1 :1 to about 20:1, preferably from about 3:1 to about 10:1 and more preferably from about 4:1 to about 6:1. The total amount of waterbuffer or water-alcohol mixture in this type of preparation is typically in the range of from about 70 percentto about99.9 percent by weight of the preparation.
The pH of such liquid and other preparations of the invention is generally in the range of from about 4.5 to about 9, and preferably from about 5.5 to about 8, more preferably in the range of from about 6 to about 8.
In certain other desirable forms of this invention, the oral composition may be substantially solid or semisolid in character, such astoothpowder, a dental tablet, a toothpaste, gel or dental cream. The vehicle of such solid or semisolid oral preparation generally contains added polishing material more fully described hereinafter.
To aid in the prevention of dental plaque and/or gingivitis as well as controlling oral malodor, the oral composition of the present invention can contain one or more cationic antimicrobial compounds. As used herein, a "cationic antimicrobial compound" refers to an organic amine where the nitrogen is capable of being positively charged in an aqueous environment, and is represented by one or more of the following general formulae from A.J.
(A) Quaternary ammonium compounds represented by Formula I or Formula II
Figure imgf000007_0002
wherein:
R1 is a C8-C20 alkyl;
R2 is benzyl or C1-C12 alkyl;
R3 and R4 are independently a C1-C7 alkyl or -(CH2-CHOH-CH2-O)nH wherein n is an integer from 1 to 6;
R5 is -H, a C1-C7 alkyl or -(CH2-CHOH-CH2-O)nH wherein n is an integer from 1 to 6; and
X- is chloride (CI-), bromide (Br-), iodide (I-) or fluoride (F-) ion;
(B) Pyridinium chlorides containing alkylthiomethyl or alkoxymethyl hydrophobic groups as disclosed by Weglowski et al., J. Phar. Sci., 80, 91-85 (1991 ), the disclosure of which is hereby incorporated by reference, having the formula
O
Figure imgf000007_0001
wherein
X is as defined herein before and X1 is oxygen or sulfur; and
R6 is a C4-C16 alkyl or benzyl;
(C) Quaternary ammonium compounds that are esters of betaine and fatty alcohols, as disclosed by Lϊnstedt et al., Antimicrobial Agents and Chemotherapy, 39, 1949-1954 (1990), the disclosure of which is hereby incorporated by reference, having the formula
(CH3)3N-CH2C(O)OR7
wherein R7 ϊs a C10-C18 aIkyl; and physiologically acceptable salts thereof;
(D) Sanguinarine and sanguinaria, sanguinaria being an extract from the bloodroot plant Sanguinaria candensis, the extract containing benzophenanthridine alkaloids such as sanguinarine, chelerythrine, protopine, homochelidonine and physiologically acceptable salts thereof as disclosed in U.S. Patents 4,145,412 and 4,406,881, the disclosures of which are hereby incorporated by reference, sanguinaria being available in dentifrices under the trademark Viadent™ brand sanguinaria; the major active ingredient sanguinarine chloride salt having the formula
Figure imgf000008_0001
(E) Morpholine compounds as disclosed in U.S. Patent 4,894,221, the disclosure of which is hereby incorporate by reference, the morpholine compounds having the formula
Figure imgf000008_0002
wherein R8 is a C8-C16 alkyl at the 2 or 3 position of the morpholino ring; R9 is a C2-C10 alkyl substituted with a hydroxy group at other than the alpha- -position;
the sum of R8 and R9 being greater than or equal to 10 and preferably 10-20; and physiologically acceptable salts thereof;
(F) Antibacterial secondary amines and amides as disclosed in J. Antibacterial and
Antifungal Agents, 17, 371 (1989), the disclosure of which is hereby incorporated by reference, wherein the antibacterial compounds have the following formulae
VV
Figure imgf000009_0001
wherein R10 is a C10-C18 alkyl;
Figure imgf000009_0002
wherein each R1 1 is independently C8H17 or C10H21 ;
Figure imgf000009_0003
wherein R13 is a C9-C17 alkyl;
or
Figure imgf000009_0004
wherein each R13 is independently C7H15 or C9H19; and physiologically acceptable salts thereof, (G) Dialkyl amines and N,N'-dialkylpolymethylene-diamines as disclosed in J. Antibacterial and Antifungal Agents, 17, 579 (1989), the disclosure of which is hereby incorporated by reference, having the formula
R14-NH-R14
wherein each R1 4 is independently C8H17 or C12H25; or formula
R15-NH(CH2)nNH-R15
wherein each R15 is independently a C7-C10 alkyl;
n is an integer from 2 to 5; and physiologically acceptable salts thereof;
(H) N'-Alkyl-N-(2-aminoethyl) piperidine compounds as disclosed by Murata et al., J. Pharm. Sci., 80, 26-28 (1991), the disclosure which is hereby incorporated by reference, the compounds having the formula
Figure imgf000010_0001
wherein R16 is a C10-C18 alkyl; and physiologically acceptable salts thereof;
(I) The quaternary ammonium compound 4-(2-propytenepentyl)- -1-piperidinoethanol having the structure
Figure imgf000010_0002
wherein X- is as defined hereinbefore; described in the literature as Octapinal™ brand
4-(2-propylenepentyI)-1-piperidinoethanol (Ferrosan AB, Sweden); and
(J) Alkyl-N-betaine in combination with an alkyl-N,N-dimethylamine; the alkyl-N-betaine having the structure
Figure imgf000011_0002
wherein R17 is a C10-C18 alkyl;
the alkyl-N,N-dimethylamine having the structure
Figure imgf000011_0001
wherein R18 is a C10-C18 alkyl;
asdisclosed in U.S. Patent 4,839, 158, the disclosure of which is hereby incorporated by reference.
As used herein, the term "alkyl" means a linear or branched alkyl and thus secondary and tertiary alkyls are included. The alkyl terms up to C20 include, for example, t-butyl, sec-butyl, isobutyl, and in like manner all such branched or straight chain alkyls.
Preferred quaternary ammonium antibacterial agents include dodecyl trimethyl ammonium bromide, benzyl dimethyl stearyl ammonium chloride, N-tetradecyl-
-4-ethylpyridinium chloride and cetyl pyridinium chloride. The terms antibacterial and antimicrobial mean the ability to inhibit growth, metabolism or reproduction of
microorganisms.
The cationic antimicrobial compounds useful in the present invention are commercially available or may be obtained by those of ordinary skill in the art without undue experimentation. For example, quaternary ammonium compounds may be produced by reacting alkyl halides with ammonia or primary amines, or by reacting a tertiary amine, pyridine or pyridine derivative with an alkyl halide. See, for example, Zoltewicz and Deady, Adv. Heterocycl. Chem., 22, 71-121 (1978); U.S. Patents 2,446,792; 2,295,504 and 4,994,199, the teachings of which are hereby incorporated by reference.
One or more cationic antimicrobial compounds are employed in amounts such that the oral product contains from about 0.001 to about 10 percent by weight of the antimicrobial compound. Preferably, for desired levels of antiplaque and antigingivitis effect, the finished oral product contains from about 0.01 to about 5 percent, and preferably from about0.025to 1.0 percent by weight of the antimicrobial compound. Typically a singular antimicrobial compound is employed in the oral product.
When the oral composition is essentially liquid in nature, to maintain the copper ion, phytic acid and cationic antimicrobial compound in solution, it is desirable for the composition to contain a sufficient amount of a compatibilizing agent to keep the phytic acid, copper ion and cationic antimicrobial compound in solution. Compatibilizing agents in the present invention are those which do not have a detrimental effect on the substantivity of the phytic acid, copper ion and cationic antimicrobial compound in solution and maintain the components in solution such that the composition does not visually become turbid after standing for 12 to 15 hours at room temperature. A detrimental effect on substantivity means the retention of the antimicrobial compound nearthe tooth surface is the presence of phytic acid is not substantially different than that of the antimicrobial compound in the absence of phyticacid. It is therefore possible that a compound or combination of compounds may combatibilizethe phyticacid and antimicrobial compound, i.e., keep them in solution, but adversely affect the substantivity of the antimicrobial/phytic acid solution.
While not wishing to be bound by theory, it is believed the compatibilizing agents of the present invention reduce the interaction between the phytic acid and cationic antimicrobial compound, reducing or preventing the formation of a precipitate when these two compounds are exposed to each other in an aqueous environment. Particularly useful compatibilizing agents in the present invention are acids and their alkali metal or alkalineearth metal salts, or mixtures thereof, designated herein as anionic buffers. Suitable anionic buffers are, for example, phosphate, acetate, borate, citrate, bicarbonate, gluconate, tartrate, sulfate, and the like, or mixtures thereof. The preferred anionic buffers being phosphate and/or bicarbonate. The amount of anionic buffer in the oral compositions of the present invention is from about 0.1 to about 20 percent by weight, preferably from about 0.1 to about 10 percent by weight of the total composition. When the oral composition is essentially in the liquid form, the anionic buffer is present in a concentration of about 0.1 M to about 1.0 M, preferably from about 0.25 M to about 0.75 M.
Other examples of compatibilizing agents useful in the present invention are surfactants which maintain the phyticacid and antimicrobial compound in solution and does not interfere with enhanced substantivity due to the presence of phytic acid. An example of a particularly suitable nonionic surfactant is pofy(oxyethylene), poly(oxpropylene) block polymers known as poloxamers and available, for example, under the trademark "PLURONICS" (BASFWyandotte Co., Parsippany, NJ). Another example of a particularly suitable nonionic surfactant is polyethylene oxide sorbitan esters, available for example, under the trademark "TWEENS" (ICI American Inc., Wilmington, De.) Suitable amnoic surfactants include, for example, anionic surfactants produced from fatty acids and the amino acid sarcosine, such as N-lauroyl sarcosine, available for example, under the trademark "HAMPOSYL" by W.R. Grace and Co. (CT).
When utilizing a combination of compatibilizing agents, it is desirable that the total amount of compatibilizing agent in the oral composition remain from about 0.1 to about 20 weight percent. The concentration of compatibilizing agent or agents for use in the present invention can be readily determined by those of ordinary skill in the art based upon the teachings herein.
In a further embodiment, it has been found that when a polyethylene oxide sorbitan ester is used as a compatibilizing agent for phytic acid and an antimicrobial compound such as N-tetradecyl-4-ethylpyridinium bromide, the concentration of compatibilizing agent can be reduced below 0.1 weight percent, and about 0.05 weight percent can be used.
Preparation of the oral compositions of the present invention can be done by using customary procedures for unifying components applied to the teeth and gingiva. It has been found that when the oral compositions of the present invention contain the
compatibilizing agent and the cationic antimicrobial compound, in addition to polyvalent metal ions and the phytic acid, the compositions are advantageously prepared by (a) dissolving the metal ion, phytic acid and compatibilizing agent in water, and then (b) adding the cationic antimicrobial compound or cationic antimicrobial solution to the solution obtained from step (a). The pH of the oral composition is adjusted to between about 6 and about 8 either before or after the addition of the cationic antimicrobial compound or cationic antimicrobial solution. Other components, such as sweetening and flavoring agents as described more fully herein, can then be added if desired.
The dentifrices of the present invention may also be in a kit form for treating the oral cavity, the kit comprising one or more compounds having C-O-P bonds wherein the compound having C-O-P bonds is myo-inositol hexakis(dihydrogen phosphate), myo-inositol tetrakis(dihydrogen phosphate), myo-inositol pentakis(dihydrogen phosphate) or
physiologically acceptable salts thereof; a copper salt, a compatibilizing agent and at least one cationic antimicrobial compound, the compound having C-O-P bonds, copper salt,
antimicrobial compound and compatibilizing agent each being in an orally-acceptable vehicle; and a means to contain the compound having C-O-P bonds separately from the cationic antimicrobial. Means to separate the compound having C-O-P bonds and cationic
antimicrobial compound include placing them in separate containers or placing them in a compartmentalized container. The copper salt is preferably mixed with the compound having C-O-P bonds; the compatibilizing agent may be mixed with the compound having C-O-P bonds, with the cationic antimicrobial, or is placed in a separate container. When the dentifrice of the present invention is in a kit form, the separate components (i.e., compound having C-O-P bonds, copper salt, compatibilizing agent and cationic antimicrobial compound) are mixed prior to application.
When mixing the components prior to application to the oral cavity, it may be necessary to increase the concentration of the compounds to account for dilution effects which can occur upon mixing. When applying the compound having C-O-P bonds, copper salt, compatibilizing agentand cationic antimicrobial in a kitform by mixing prior to use, the concentration of the individual compounds to which the oral cavity is exposed should be in the range given hereinbefore fortheir concentration in the final dentifrice product.
A variety of other ingredients may be added to the dentifrices of the present invention. Thus for example, prophylactic agents, polishing agents, soaps or detergents, flavoring and sweetening agents, thickening agents and humectants may be included using techniques which are know to the art.
Representative prophylactic agents include supplemental caries-preventing materials such as, for example, sodium fluoride, stannous fluoride, potassium fluoride, hexylamine hydrofluoride, myristylamine hydrofluoride, betaine fluoride, glycine potassium fluoride. A particularly preferred fluoride is sodium fluoride. Typically these prophylactic agents are present in sufficient concentrations so as to provide an available fluoride ion concentration of up to about 2 percent by weight, and preferably from about 0.5 percent to about 2 percent by weight, of the dentifrice composition.
Suitable polishing agents include, for example, abrasive materials such as insoluble condensed phosphates such as calcium pyrophosphate, insoluble calcium
polyphosphate (also known as calcium polymetaphosphate) and highly polymerized sodium polyphosphate; and water impervious cross-linked thermosetting resins such as the
condensation products of melamine and urea with formaldehyde. Other suitable polishing agents will be obvious to those skilled in the art.
The polishing material is generally present in the solid or semisolid compositions in weight concentrations of from about 10 to about 99 percent. Preferably, it is present in amounts ranging from about 20 to about 75 percent in toothpaste, and from about 70 percent to about 99 percent in tooth powder.
Soaps or detergents may also be employed in the present invention to lower the surface tension to achieve increased prophylactic action, assist in achieving thorough and complete dispersion ofthe anticalculus agent and renderthe instant compositions more cosmetically acceptable. Suitable soaps include, for example, the soaps of high.molecular weight fatty acids such as sodium and potassium soaps of myristic, stearicor palmitic acids and fatty acids mixtures of palm oil and coconut oil. Typical synthetic detergents include alkyl sulfates and sulfonates having alkyl groups of from about 8 to about 18 carbon atoms, such as, for example, sodium lauryl sulfate, the sulfated fatty alcohols derived from coconut oil and palm oil. The soaps typically comprise up to about 5 percent by weight of the dentifrice composition.
Any suitable flavoring or sweetening material may also be employed. Examples of suitable flavoring constituents are flavoring oils, e.g., oil of spearmint, peppermint, wintergreen, sassafras, clove, sage, eucalyptus, marjoram, cinnamon, lemon and orange and methyl salicylate. Suitable sweetening agents include sucrose, lactose, maltose, sorbitol, xylitol, sodium cyclamate, perillartine, APM (aspartylphenylalanine, methyl ester), saccharine and the like. Suitably, flavor and sweetening agents may together comprise from about 0.1 percent to 5 percent of the preparation.
Toothpastes, creams and gels typically contain a natural or synthetic thickener or gelling agent in proportions of from about 0.1 to about 10 percent, preferably from about 0.5 to about 5 percent by weight. Suitable gelling or thickening agents include for example, water-soluble salts of cellulose ethers such as sodium carboxymethyl cellulose and sodium carboxymethyl hydroxyethyl cellulose; natural gums such as gum karaya, gum arabic, and gum tragacanth; and colloidal magnesium aluminum silicate or finely divided silica.
Suitable humectants which may be employed in compositions of the invention include glycerine, propylene glycol, sorbitol, polypropylene glycol and/or polyethylene glycol and other polyhydric alcohols. The humectants may comprise from about 10 to 90 percent by weight of the dentifrice composition.
The invention will be further clarified by a consideration of the following examples, which are intended to be purely exemplary of the present invention.
GENERAL EXPERIMENTAL
Preparation of Stock Solutions
0.0045 M CPC. A 0.0045 M solution of cetylpyridinium chloride (CPC) was prepared by adding 0.3222 ± 0.0001 g of CPC (Aldrich Chemical Co., Inc.) to a 200 mL volumetric flask and diluting to the mark with water. The final pH was approximately 6.9.
0.0045 M phytic acid. A 0.0045 M solution of phytic acid was prepared by adding
0.5847 ± 0.0001 g of phytic acid (50 percent by weight, Jonas Chemical Co.) to a 100 mL volumetric flask and diluting to the mark with water. The pH of this solution was
approximately 2.5.
0.0045 M Cu-phytic acid. A 0.0045 M solution of phytic acid and copper metal ion was prepared by adding 0.2042 ± 0.0001 g of D-gluconic acid, Cu(ll) salt, (Aldrich Chemical Co., Inc.) to a 60 mL beaker. To this was added 0.5847 ± 0.0001 g of 50 percent by weight phytic acid (Jonas Chemical Co.) and approximately 20 mL of water. This solution was transferred to a 100 mL volumetric flask and diluted to the mark with water. The final pH was approximately 3.0.
1.5 M sodium phosphate. A 1.5 M solution of sodium phosphate was prepared by adding 20.70 ± 0.01 g of NaH2PO4●H2O (J.T. Baker Co.) to a beaker and dissolving in approximately 40 mL of water. The pH of this solution was adjusted to approximately 6.3 with the dropwise addition of 25 percent by weight sodium hydroxide solution. This solution wasthen transferred quantitatively to a 100 mL volumetric flask and diluted to the mark with water. 1.5 M sodium bicarbonate. A 1.5 M bicarbonate solution was prepared by adding 16.6 ± 0.01 g of NaHCO3 (J.T. BakerCo.) to a 100 mL volumetric flask and diluting to the mark with water. The pH of the sodium bicarbonate solution was approximately 8.4.
Glycolysis pH Test
A sucrose solution was prepared by loading 1.0 g of sucrose (Imperial Pure Cane Sugar) into a 60 mL beaker and then adding 20 mL of water. To this solution was added 8.0 mL of pooled whole human saliva. The saliva was collected from donors who had been permitted to eat or drink anything prior to the collection period, but had foregone any oral hygiene on the day of collection. Prior to the collection, each donor rinsed their mouth for thirty seconds with approximately 30 mL water, and after waiting about 5 minutes, began collecting saliva for 30-40 minutes, keeping the collected saliva on ice.
To the saliva/sucrose solution was added 1.0 mLof brain/heart infusion broth containing Streptococcus mutants (American Type Culture Collections No. 25175, ATCC) and 1.0 mLof brain/heart infusion broth containing Streptococcus sanguis (ATCC#10556). These cultures had been inoculated into 40 mLof broth and grown at 37°C for sixteen hours priorto adding to the saliva/sucrose solution. (Each broth contained approximately 60 million colony forming units atthetime of addition.)
Aliquots of 0.75 mL of the above saliva/sucrose/bacterial solution were added to the test tubes containing various washed HAP suspensions. These test tubes were capped and attached to a tube rotator and placed in a 37°C incubator for sixteen hours. Following this incubation period, the rotator was removed from the oven and allowed to cool to ambient temperature. The pH of the solutions were checked with a pH meter using a pH electrode calibrated with pH 4, 7 and 10 buffers. The pH of each test tube was recorded and plotted in graphic format.
Treating and Washing Hydroxyapatite
To determine the substantivity of phytic acid and CPC either alone or in combination with copper ions, the following washing procedure of the hydroxyapatite was done priorto performing a glycolysis pH test:
A 60 mL beaker was loaded with 6.0 g of hydroxyapatite (HAP) in a buffer suspension (25 percent by weight solids from Sigma Chemical Co.) and washed with 30 mLof water. The HAP suspension was filtered through a medium glass fitted filter to obtain a HAP filter cake. The white solid filter cake containing 1.5 g of HAP was transferred to a dry 60 mL beaker and the total weight brought up to 15 grams with water to produce a 100 mg HAP/mL suspension.
Two mLof the HAP suspension was transferred to each of several
sterile-disposable polystyrene 5 mLtest tubes labeled D1--Dn (where n = identity number of the test solution). Four mL of a test solution were then added to each test tube. The tubes containing the HAP and test solution were capped and attached to a Tube Rotator and rotated end-over-end to allow the test solutions to contact the HAP for a total of ten minutes.
After mixing, the test tubes were placed in an Industrial Equipment Company (lEC) model K centrifuge and spun at setting 25 (mid-range) for ten minutes. The tubeswere removed and the liquid layer decanted. A macropipettorwasthen used to add 3.0 mL of water to each test tube containing the centrifuged hydroxyapatite. The HAP sol ids were resuspended by vigorous in-and-out flowing action through the pipette and then placed on an end-over- end rotator for ten minutes. The tubes were again centrifuged at setting 25 for ten minutes and the liquid layer decanted.
Following the three milliliter wash step, the HAP solids were resuspended in 4.0 mLof water. Two separate 0.5 mL samples (containing 25 mg HAP) of each HAP suspension was removed from each test suspension and placed in test tubes labeled A1--An or A1'--- An' for the duplicate samples. A group of samples each contain one-eighth of the original treated HAP suspension which has been washed with three milliliters of water.
The remaining 3.5 mL in test tubes labeled D1--Dn were centrifuged for ten minutes, the test tubes removed, and the liquid layer decanted. Three milliliters of water were added to these test tubes and the HAP solids resuspended/washed using disposable pipettes. The tubes were centrifuged for ten minutes, the tubes removed and the liquid layer decanted. An additional three milliliters of water were added to these tubes and the HAP solids resuspended/washed by pipette. These tubes were again placed in the centrifuge and spun for ten minutes. The tubeswere removed, the liquid layer decanted and 3.0 mL of water added to each tube. The HAP solids were resuspended and a 0.5 mL sample removed and placed in each of several 5 mL polystyrene test tubes labeled B1-- Bn or B1'--Bn'. These samples contained approximately 25 mg HAP solids which had been treated with test solution and then washed with a total of 13 milliliters of water.
The procedure given above was repeated a third and fourth time to create a series of test tubes labeled C1--Cn or C1'--Cn' and D1- Dn or D1'--Dn', with the exception that after the second three milliliter wash to give the C samples, the HAP was resuspended in 2 mL of water a nd f or the D samples, 1 mL of water. The C and C samples contained approximately 25 mg of HAP solids which had been treated with test solution and then washed with a total of 21 mLof water. The D and D' samples contained approximately 25 mg of HAP solids which had been treated with the test solution and then washed with a total of 31 mL water.
A glycolysis pH test was then performed as described above by adding 0.75 mL aliquots of the saiiva/sucrose/bacterial mixture to the test tubes labeled A1-- Dn, each containing 0.5 mL of the treated washed HAP suspension. The A1' --- Dn' samples were duplicates that could be tested for deodorizing power. Measurement of deodorizing power
The ability of the oral compositions to reduce malodor was determined by placing 2 mL of the composition in a sample tube and bubbling a standard mixture of hydrogen sulfide (H2S) and methyl mercaptan (CH SH) through the test solution for 1 minute and measuring the reduction of the H2S/CH3SH.
The H2S (542 ng/min) and CH3SH (735 ng/min) standards were obtained from permeation tube standards (Thermedics Inc.) and carried through the test samples by a 30 mlJmin flow of nitrogen. The testing apparatus was fitted with a tee to allow diversion of a portion of the gas stream from the standards to obtain a linear response by the detector. The gas stream from the sample tube was analyzed using a Hewlett Packard 5890A gas
chromatograph equipped with a flame photometric detector and a 11 meter x 0.125 cm (i.d.) fluorinated ethylene propylene teflon column packed with 5 percent polyphenyl (6 ring) ether and 0.5 percent phosphonic acid on a 40/60 mesh chromosorb T. The samples were
chromatographed isothermally at 80°C with the flame photometric detector at 130°C using an ultra pure air gas flow of 30 cc/min.
Example 1
To determine the ability of the copper ion to remove malodor components in the presence of phytic acid, the following compositions were tested as described for measuring deodorizing power:
(A) water (control)
(B) copper (II) acetate, (control);
(C) copper (II) gluconate, (control);
(D) copper (II) acetate and phytic acid; and
(E) copper (II) gluconate and phytic acid.
All samples were 0.0015 M prepared in 0.05 M phosphate at about pH 7.0
The 0.0015 M solutions of copper acetate and copper gluconate (Aldrich Chemical Co.) were prepared by adding 0.029 g and 0.068 g respectively to 100 mLof water. Samples D and Ewere prepared by adding 0.029 g of copper acetate or 0.068 g of copper gluconate to 100 mLof a 0.0015 M solution of phyticacid, prepared by diluting a 0.0045 M stock solution, and stirring until all the solids disappeared. The results of this evaluation are summarized in Table 1.
Figure imgf000019_0001
*evaluation was performed immediately after the preparation of the composition as a precipitate forms after 2-3 hours following the sample preparation.
The results show that in the presence of an anionic buffer, the copper ion and phytic acid both remain in solution and that the phytic acid does not interfere with the ability of copper to remove hydrogen sulfide or methyl mercaptan from a gas stream.
Example 2
The ability of Cu-phytic acid to adsorb to a hydroxyapatite surface and retain deodorizing power was measured by treating 1 mL of a hydroxyapatite (HAP) suspension with 1 mLof a test solution and then subjecting the HAP to several washing steps.
The HAP suspension was prepared by washing a 24.5 g portion of HAP (Sigma Chemical Co., 24.5 percent solids in phosphate buffer, 0.001 M, pH 6.8) with three 30 mL portions of water. The washed hydroxyapatite powder (approximately 6 g) was then suspended in 60 mL of water with vigorous stirring to give a 100 mg/mL homogeneous white HAP suspension.
The test solutions were as follows:
Solution A: 0.0015 M copper acetate, 0.0015 M phytic acid and 0.05 M phosphate buffer at pH 6.8;
Solution B: 0.0015 M copper acetate and 0.05 M phosphate buffer at pH 7.05;
Solution C: water (control).
Solutions A and B were prepared as described in Example 1 and the solutions filtered through a 0.22 micron syringe filter immediately before use.
Into separate tubes labeled 1, 2, and 3 were added 1 mLof the HAP suspension and into tube 1 , one mL of solution A; into tube number 2, one mL of solution B; and into tube number 3, one mLof solution C Thetubeswere immediately capped and placed on an end-over-end rotator for 5 minutes. The suspensions were then centrifuged in a IEC HN-SII table top model centrifuge at full speed (4,000 rpm). The supernatant from each tube was removed and 3.0 mLof water added and the solids suspended by vigorous pipette action. The suspensions were then centrifuged again as above and the supernatant discarded. The solids were then washed with 3 mL portions of water in this manner an additional three times so the total water wash volume was 12 mL (from 4 three-mL washes). After the last wash the supernatant was removed and the moist solid washed HAP samples were suspended in two mL of phosphate buffer (0.05 M, pH 7.0) and their ability to deodorize was performed as described under general experimental. The results of this evaluation are given in Table II.
Figure imgf000021_0001
aHAP treated with copper acetate , phytic acid
and
phosphate
bHAP treated with copper acetate and phosphate
CHAP washed with water
The results show that the presence of phytic acid and a phosphate buffer does not interfere with the ability of Copper (II) to be adsorbed onto hydroxyapatite and to adsorb volatile sulfur compounds.
Example 3
The following compositions were evaluated for retention on a HAP surface after washing as measured by the ability of the treated and washed HAP to reduce malodor and inhibit microorganisms:
Sample 1: water;
Sample 2: cetyl pyridinium chloride;
Sample 3: 0.0015 M Cu + + metal ion, phytic
acid, phosphate buffer and
cetyl pyridinium chloride;
Sample 4: 0.00021 M Cu+ + metal ion, phytic
acid, phosphate buffer and
cetylpyridinium chloride;
Sample 5: phytic acid, phosphate buffer and
cetylpyridinium chloride.
The cetylpyridinium chloride and phytic acid being at a concentration of 0.0015 M and phosphate at 0.5 M.
All samples were prepared by mixing the appropriate amount of required stock solutions and diluting with water when necessary to give the indicated concentrations. The Cu+ + metal ion, phytic acid and phosphate buffer were mixed and adjusted to approximately pH 6.9 with 1.0 N sodium hydroxide prior to the addition of cetylpyridinium chloride.
These solutions were used to treat hydroxyapatite powder which was then washed according to the procedure listed in General Experimental. One set of the split hydroxyapatite samples (A1---An, B1---Bn, etc.) along with their water and cetylpyridinium chloride controls were subjected to the glycolysis test to give the results in Table III.
Figure imgf000022_0001
*Sample 1 = Water
Sample 2 = Cetylpyridinium chloride
Sample 3 = 0.0015 M copper (II), phytic acid,
phosphate and cetylpyridinium chloride Sample 4 = 0.00021 M copper (II), phytic acid,
phosphate and cetylpyridinium chloride
Sample 5 = phytic acid, phosphate and
cetylpyridinium chloride
The second set of the split hydroxyapatite samples (A1' ---An', B1'---Bn' , etc.) were suspended in 2.0 mLof phosphate buffer and evaluated by the procedure given in
measurement for deodorizing power described under general experimental. The results are shown in Table IV.
Figure imgf000023_0001
* Sample 3 = 0.0015 M copper (II), phytic acid,
phosphate and cetylpyridinium
chloride
Sample 4 = 0.0021 M copper (II), phytic acid,
phosphate and cetylpyridinium
chlroide
Sample 5 = phytic acid, phosphate and
These results indicate that the addition of copper/phytic acid to CPC enhances the substantivity of CPC to hydroxyapatite to the same degree as phytic acid alone. These results also show that the addition of copper to a mixture of phytic acid/CPC improves their ability to remove volatile sulfur compounds from a gas stream while adsorbed on a hydroxyapatite surface.
Example 4
The ability of phytic acid to enhance the substantivity of an antimicrobial to HAP was measured by treating HAP with a test solution, washing the HAP as described under general experimental and measuring retention of antimicrobial activity by the glycolysis pH test described above.
The HAP was treated with the following test solutions:
A. Water (control);
B. cetylpyridinium chloride (CPC);
C. phytic acid, phosphate (PaP);
D. Cu + + metal ion, phytic acid, phosphate
buffer (Cu-PaP);
E. phytic acid, phosphate buffer and
cetylpyridinium chloride (PaPC);
F. metal ion, phytic acid, phosphate buffer
and cetylpyridinium chloride (Cu-PaPC).
The cetylpyridinium chloride and phytic acid concentration being 0.0015 M, phosphate 0.5 M and copper ion 0.5 millimolar. Samples B, Cand E were prepared by mixing the appropriate amount of required stock solutions and diluting with water when necessary to give the indicated concentrations.
Sample D was prepared by placing 0.0102 g of D-gluconic acid, Cu(II) salt, into a jar and dissolving with the addition of 15 mLof a 0.0045M phyticacid solution. Fifteen mL of a 1.5 M phosphate buffer solution was added to the jar and the pH adjusted to about 7 with the dropwise addition of a 50 percent sodium hydroxide solution. A 15 mL aliquot of water was then added to give the final concentrations listed above. For Sample F, a 15 mL aliquot of a 0.0045 M cetylpyridinium chloride solution was used to replace the final water addition as described for sample D.
The results of this substantivity trial are given in Table V.
Figure imgf000025_0001
aCPC = cetylpyridinium chloride (Control);
bPaP = phytic acid and phosphate (Control);
cCu-PaP = copper (II), phytic acid and phosphate (Control); dPaPC = phytic acid, phosphate and cetylpyridinium chloride; eCu-PaPC = Copper (II), phytic acid, phosphate and
cetylpyridinium chloride
The results show that phytic acid enhances the substantivity of cetylpyridinium chloride to the HAP and that copper phytate without CPC is ineffective. In addition, the results show that the addition of copper does not interfere with the substantivity enhancement of CPC with phytic acid. Increasing the copper ion concentration to 0.0015 M did not alter the improved substantivity of CPC in the presence of phytic acid.
Example 5
In this trial, the preparation of HAP and the treatment of HAP with the test solutions were as previously described under general experimental. The following solutions were tested for HAP substantivity as measured by the glycolysis pH test:
A. Water (control);
B. cetylpyridinium chloride (CPC);
C. copperion, phyticacid, sodium bicarbonate (Cu-PaB);
D. cetylpyridinium chloride, sodium
bicarbonate (CPCB);
E. N-tetradecyl-4-ethylpyridϊnium bromide (TDEP);
F. copperion, phyticacid, sodium bicarbonate, cetylpyridinium chloride
(Cu-PaBC);
G. phyticacid, sodium bicarbonate, cetylpyridinium chloride (PaBC);
H. copper ion, phytic acid, sodium bicarbonate, N-tetradecyl-4-ethylpyridinium bromide (Cu-PaBT).
The concentration of the components being 0.0015 M except sodium bicarbonate at 0.5 M.
Solutions B, C, D, 1 and 2 were prepared by mixing the appropriate amount of stock solutions and diluting with water when necessary to give the indicated concentrations.
Sample E was prepared by adding 0.0173 ± 0.0001 g of N-tetradecyl-4- ethylpyridinium bromide to a 10 mL volumetric flask and diluting to mark with water. A 4 mL aliquot of this 0.0045 M solution was diluted with 8 mLof water to produce a final
concentration of 0.0015 molar N-tetradecyl-4-ethyl pyridinium bromide.
Sample 3 was prepared by adding a 4 mLaliquot of 1.5 M sodium bicarbonate to 4 mLof a 0.0045 M Cu + + /phytic acid stock solution and then adding 4 mL of a 0.0045 M
N-tetradecyl-4-ethylpyrϊdinium bromide stock solution. The pH of this formulation was about 8.3.
The results from thistrial are given in Table VI.
Figure imgf000027_0001
1CPC = cetylpyridinium chloride (CPC);
2CuPaB = copper, phytic acid and sodim bicarbonate;
3CPCB = cetylpyridinium chloride and sodim bicarbonate;
4ETDP = N-tetradecyl-4-ethylpyridinium bromide
5Cu-PaBC = copper, phytic acid, sodim bicarbonate and cetylpyridinium chloride;
6PaBC = phytic acid, sodim bicarbonate, and cetylpyridinium chloride;
7Cu-PaBT = copper, phytic acid, sodim bicarbonate and 4-ethyltetra- decylpyridinium bromide
The results show that sodium bicarbonate buffer works as effectively in combination with phytic acid and cetylpyridinium chloride as does the phosphate buffer. In addition N-tetradecyl-4-ethyI pyridinium bromide works as well as cetylpyridinium chloride as an antimicrobial in combination with phytic acid, copper and bicarbonate buffer.
Other embodiments of the invention will be apparent to those skilled in the art from a consideration of this specification or practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with the true scope and spirit of the invention being indicated by the following claims.

Claims

WHAT IS CLAIMED IS:
1. An oral composition comprising: (a) from 0.0002 to 1 percent by weight of one or more copper salts;
(b) from 0.001 to 10 percent by weight of one or more compounds having C-O-P bonds wherein the compound having C-O-P bonds is myo-inositol hexakis(dihydrogen phosphate), myoinositol tetrakis(dihydrogen phosphate), myo-inositol pentakis(di hydrogen phosphate) or physiologically acceptable salts thereof;
(c) from 0.001 to 10 percent by weight of one or more cationic antimicrobial corn pounds;
(d) from 0.1 to 20 percent by weight of one or more compatibilizing agents; and
(d) the remaining percent by weight is an orally acceptable vehicle.
2. The oral composition of Claim 1 wherein the cationic antimicrobial compound is one or more quaternary ammonium compounds of Formula I
Figure imgf000029_0001
Formula lI
Figure imgf000030_0001
or a mixture thereof;
wherein
R1 is a C8-C20 alkyl,
R2 is benzyl or C1-C12 alkyl,
R3 and R4 are independently a C1-C7 alkyl or-(CH2-CHOH-CH2-O)nH wherein n is an integer from 1 to 6 inclusive,
R5 is-H, a C1-C7 alkyl or-(CH2-CHOH-CH2-O)nH wherein n is an integer from 1 to 6 inclusive, and
X- is chloride, bromide, iodide or fluoride ion.
3. The oral composition of Claim 1 wherein the compatibilizing agent is an anionic buffer.
4. The oral composition of Claim 3 wherein the anionic buffer is phosphate, acetate, borate, citrate, bicarbonate, gluconate, tartrate, sulfate or mixtures thereof.
5. The oral composition of Claim 4 wherein the quaternary ammonium compound is cetylpyridinium chloride.
6. The oral composition of Claim 5 wherein the copper salt is copper gluconate, copper acetate or a mixture thereof; the anionic buffer is phosphate, bicarbonate or a mixture thereof; the compound having C-O-P bonds is myo-inositol hexakis(dihydrogen phosphate) or a physiologically acceptable saltthereof; and the orally acceptable vehicle is 70 to 99.9 percent by weight water or an alcohol-water mixture.
7. A method of inhibiting oral malodor in mammals comprising administering to the oral cavity an oral composition according to any one of Claims 1 to 6.
8. The method of Claim 7 wherein the mammal is a human.
9. The method of Claim 7 wherein the mammal is a dog.
10. A process for preparing an oral composition asdefined in Claim 1 comprising the steps of
(a) dissolving the metal salt, phyticacid and compatibilizing agent in water, and (b) dissolving the cationic antimicrobial compound or cationic antimicrobial solution in the solution obtained from step a;
wherein the pH of the oral composition isadjusted to between about 6 and about 8 prior to or after the addition of the cationic antimicrobial compound or cationic antimicrobial solution.
11. A kit for controlling oral malodor comprising one or more copper salts in an orally-acceptable vehicle, one or more compounds having C-O-P bonds wherein the compound having C-O-P bonds is myo-inositol hexakis(dihydrogen phosphate), myo-inositol tetrakis(dihydrogen phosphate), myo-inositol pentakis(di hydrogen phosphate) or
physiologically acceptable salts thereof, one or more compatibilizing agents in an
orally-acceptable vehicle, and a cationic antimicrobial compound in an orally-acceptable vehicle; and a means to contain the compound having C-O-P bonds separate from the cationic antimicrobial compound.
12. The use of a composition according to any one of Claims 1 to 6 for use as a dentifrice.
13. The use of a composition according to any one of Claims 1 to 6 for the manufacture of an oral composition for the treatment of oral malodor in mammals.
14. A commercial package comprising a copper salt, a compound having C-O-P bonds and a compatibilizing agent together with instructions for adding an antimicrobial compound wherein the resulting dentifrice composition is as defined in any one of Claims 1 to 6.
15. A commercial package comprising an antimicrobial compound together with instructions for adding a copper salt, a compound having C-O-P bonds and a
compatibilizing agent wherein the resulting dentifrice composition is an defined in any one of Claims 1 to 6.
PCT/US1992/010662 1991-12-10 1992-12-10 Oral compositions for suppressing mouth odors WO1993011739A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP93901382A EP0616519A1 (en) 1991-12-10 1992-12-10 Oral compositions for suppressing mouth odors
BR9206908A BR9206908A (en) 1991-12-10 1992-12-10 Oral compositions to suppress mouth odors
JP5511066A JPH07501826A (en) 1991-12-10 1992-12-10 Oral composition for suppressing bad breath
FI942713A FI942713A0 (en) 1991-12-10 1994-06-09 Oral compositions for reducing oral odors

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US07/805,599 1991-12-10
US07/805,599 US5286479A (en) 1991-12-10 1991-12-10 Oral compositions for suppressing mouth odors

Publications (1)

Publication Number Publication Date
WO1993011739A1 true WO1993011739A1 (en) 1993-06-24

Family

ID=25192004

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1992/010662 WO1993011739A1 (en) 1991-12-10 1992-12-10 Oral compositions for suppressing mouth odors

Country Status (9)

Country Link
US (1) US5286479A (en)
EP (1) EP0616519A1 (en)
JP (1) JPH07501826A (en)
AU (1) AU3275193A (en)
BR (1) BR9206908A (en)
CA (1) CA2125575A1 (en)
FI (1) FI942713A0 (en)
MX (1) MX9207169A (en)
WO (1) WO1993011739A1 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0650720A1 (en) * 1993-10-28 1995-05-03 Sanwa Kagaku Kenkyusho Co., Ltd. Skin care and deodorant compositions
WO1999013888A1 (en) * 1997-09-12 1999-03-25 Westfalia-Surge, Inc. Germicidal compositions for the treatment of animal infectious diseases of the hoof, comprising a copper salt, a quaternary ammonium compound and a peroxide
WO2009130608A2 (en) * 2008-04-24 2009-10-29 Uti Limited Partnership Combination of copper cations with peroxides or quaternary ammonium compounds for the treatment of biofilms

Families Citing this family (75)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5389360A (en) * 1993-05-13 1995-02-14 The Procter & Gamble Company Oral compositions
US5496539A (en) * 1993-07-22 1996-03-05 The Procter & Gamble Company Oral compositions
US5578294A (en) * 1994-05-13 1996-11-26 The Procter & Gamble Company Oral compositions
US5560905A (en) * 1994-05-13 1996-10-01 The Proctor & Gamble Company Oral compositions
CA2199818A1 (en) * 1994-09-15 1996-03-21 Hooman Shahidi Oral compositions
US5534243A (en) * 1994-09-26 1996-07-09 The Procter & Gamble Company Aqueous oral compositions
US5849271A (en) * 1995-06-07 1998-12-15 The Procter & Gamble Company Oral compositions
ES2132033B1 (en) * 1997-11-06 2000-03-01 Dentaid Sa ORAL COMPOSITION FOR THE TREATMENT OF HALITOSIS.
US5888479A (en) * 1997-12-31 1999-03-30 Carlin; Edward J. Method for deterring smoking
US6132701A (en) * 1998-12-17 2000-10-17 Perez; Narciso C. Method for reducing oral malodor
NO307168B1 (en) * 1999-03-01 2000-02-21 Orix As Oral preparation effective against halitosis
JP2001097984A (en) * 1999-09-28 2001-04-10 Nisshinbo Ind Inc Novel near infrared-absorbing compound
US7592304B2 (en) * 1999-10-01 2009-09-22 Dmi Life Sciences, Inc. Metal-binding compounds and uses therefor
US7632803B2 (en) 1999-10-01 2009-12-15 Dmi Life Sciences, Inc. Metal-binding compounds and uses therefor
US20030158111A1 (en) * 1999-10-01 2003-08-21 David Bar-Or Methods and products for oral care
US8283135B2 (en) * 2000-06-30 2012-10-09 The Procter & Gamble Company Oral care compositions containing combinations of anti-bacterial and host-response modulating agents
US6919364B2 (en) * 2001-06-28 2005-07-19 Solution Biosciences, Inc. Microbiological control in animal processing
US6986910B2 (en) * 2001-06-28 2006-01-17 Albemarle Corporation Microbiological control in poultry processing
US20030077365A1 (en) * 2001-06-28 2003-04-24 Howarth Jonathan N. Environmentally-friendly microbiological and microbiocidal control in aqueous systems
CA2462898C (en) * 2001-10-09 2012-03-27 Albemarle Corporation Control of biofilms in industrial water systems
JP5204947B2 (en) 2002-11-27 2013-06-05 ディーエムアイ バイオサイエンシズ インコーポレイテッド Use of phosphate receptor compounds and pharmaceutical compositions, skin care compositions and kits containing phosphate receptor compounds
US20060073216A1 (en) * 2002-12-26 2006-04-06 Solution Biosciences, Inc. Compositions and methods for control of bovine mastitis
WO2004108091A2 (en) * 2003-06-06 2004-12-16 Board Of Regents, The University Of Texas System Antimicrobial flush solutions
US20040265445A1 (en) * 2003-06-24 2004-12-30 Liimatta Eric W. Microbiocidal control in the processing of poultry
US7901276B2 (en) 2003-06-24 2011-03-08 Albemarle Corporation Microbiocidal control in the processing of meat-producing four-legged animals
US20040265446A1 (en) * 2003-06-24 2004-12-30 Mcnaughton James L. Microbiocidal control in the processing of poultry
CN1886126A (en) * 2003-09-25 2006-12-27 Dmi生物科学公司 Methods and products which utilize N-acyl-L-aspartic acid
US9241885B2 (en) * 2004-01-29 2016-01-26 The Procter & Gamble Company Oral care compositions comprising increased bioavailable levels of quaternary ammonium antimicrobials
ES2432140T3 (en) * 2004-08-06 2013-11-29 Syneron Beauty Ltd. Therapy device
US20060047281A1 (en) * 2004-09-01 2006-03-02 Syneron Medical Ltd. Method and system for invasive skin treatment
US20110015549A1 (en) * 2005-01-13 2011-01-20 Shimon Eckhouse Method and apparatus for treating a diseased nail
WO2007065113A1 (en) * 2005-12-01 2007-06-07 Solution Biosciences, Inc. Microbiocidal control in the processing of meat-producing four-legged animals
CA2535276A1 (en) * 2006-02-06 2007-08-06 John Kennedy Therapy device and system and method for reducing harmful exposure to electromagnetic radiation
ES2280136B1 (en) * 2006-02-17 2008-08-16 Universitat De Les Illes Balears FIXED AND ZINC FIXED DOSE ASSOCIATION.
AU2009205297A1 (en) 2008-01-17 2009-07-23 Syneron Medical Ltd. A hair removal apparatus for personal use and the method of using same
EP2237732A4 (en) 2008-01-24 2011-06-01 Syneron Medical Ltd A device, apparatus, and method of adipose tissue treatment
EP2303026B1 (en) 2008-06-17 2020-09-09 Brigham Young University Cationic steroid antimicrobial diagnostic, detection, screening and imaging methods
US20100017750A1 (en) * 2008-07-16 2010-01-21 Avner Rosenberg User interface
US9314293B2 (en) * 2008-07-16 2016-04-19 Syneron Medical Ltd RF electrode for aesthetic and body shaping devices and method of using same
AU2009294227B2 (en) * 2008-09-21 2012-07-19 Syneron Medical Ltd. A method and apparatus for personal skin treatment
JP4674633B2 (en) * 2008-12-03 2011-04-20 パナソニック電工株式会社 Manufacturing method of near-infrared absorber
US8606366B2 (en) 2009-02-18 2013-12-10 Syneron Medical Ltd. Skin treatment apparatus for personal use and method for using same
JP2012518459A (en) 2009-02-25 2012-08-16 トランスファーマ メディカル リミテッド Electrical skin regeneration
AU2010325682B2 (en) 2009-12-06 2014-09-11 Gilead Bar - Ilan A method and apparatus for personal skin treatment
RU2012156842A (en) 2010-06-01 2014-07-20 Белле-Эйр Фрейгренсиз, Инк. METHOD AND PRODUCT FOR COMBATING ODOR WITH MOUTH
CA2842460C (en) 2011-07-20 2019-08-20 Brigham Young University Hydrophobic ceragenin compounds and devices incorporating same
RU2652308C2 (en) 2011-09-13 2018-04-25 Брайем Янг Юниверсити Methods and products for healing tissue wounds
US9694019B2 (en) 2011-09-13 2017-07-04 Brigham Young University Compositions and methods for treating bone diseases and broken bones
US9603859B2 (en) 2011-09-13 2017-03-28 Brigham Young University Methods and products for increasing the rate of healing of tissue wounds
CA2852989C (en) 2011-09-13 2021-06-29 Brigham Young University Compositions for treating bone diseases and broken bones
CN104379120A (en) * 2011-12-21 2015-02-25 布莱阿姆青年大学 Oral care compositions
US9533063B1 (en) 2012-03-01 2017-01-03 Brigham Young University Aerosols incorporating ceragenin compounds and methods of use thereof
CA2872399C (en) 2012-05-02 2021-01-12 Brigham Young University Ceragenin particulate materials and methods for making same
US9314472B2 (en) 2012-10-17 2016-04-19 Brigham Young University Treatment and prevention of mastitis
JP6294352B2 (en) 2013-01-07 2018-03-14 ブリガム・ヤング・ユニバーシティBrigham Young University Methods for reducing cell proliferation and treating certain diseases
KR102282183B1 (en) * 2013-03-15 2021-07-26 브라이엄 영 유니버시티 Methods for treating inflammation, autoimmune disorders and pain
US10568893B2 (en) 2013-03-15 2020-02-25 Brigham Young University Methods for treating inflammation, autoimmune disorders and pain
US11524015B2 (en) 2013-03-15 2022-12-13 Brigham Young University Methods for treating inflammation, autoimmune disorders and pain
US9387215B2 (en) 2013-04-22 2016-07-12 Brigham Young University Animal feed including cationic cholesterol additive and related methods
US11690855B2 (en) 2013-10-17 2023-07-04 Brigham Young University Methods for treating lung infections and inflammation
US20150203527A1 (en) 2014-01-23 2015-07-23 Brigham Young University Cationic steroidal antimicrobials
CA2844321C (en) 2014-02-27 2021-03-16 Brigham Young University Cationic steroidal antimicrobial compounds
US10220045B2 (en) 2014-03-13 2019-03-05 Brigham Young University Compositions and methods for forming stabilized compositions with reduced CSA agglomeration
US9867836B2 (en) 2014-03-13 2018-01-16 Brigham Young University Lavage and/or infusion using CSA compounds for increasing fertility in a mammal
US9931350B2 (en) 2014-03-14 2018-04-03 Brigham Young University Anti-infective and osteogenic compositions and methods of use
US9686966B2 (en) 2014-04-30 2017-06-27 Brigham Young University Methods and apparatus for cleaning or disinfecting a water delivery system
US10238665B2 (en) 2014-06-26 2019-03-26 Brigham Young University Methods for treating fungal infections
US10441595B2 (en) 2014-06-26 2019-10-15 Brigham Young University Methods for treating fungal infections
US10227376B2 (en) 2014-08-22 2019-03-12 Brigham Young University Radiolabeled cationic steroid antimicrobials and diagnostic methods
US10155788B2 (en) 2014-10-07 2018-12-18 Brigham Young University Cationic steroidal antimicrobial prodrug compositions and uses thereof
US10370403B2 (en) 2015-04-22 2019-08-06 Brigham Young University Methods for the synthesis of ceragenins
WO2016172553A1 (en) 2015-04-22 2016-10-27 Savage Paul B Methods for the synthesis of ceragenins
US9434759B1 (en) 2015-05-18 2016-09-06 Brigham Young University Cationic steroidal antimicrobial compounds and methods of manufacturing such compounds
US10226550B2 (en) 2016-03-11 2019-03-12 Brigham Young University Cationic steroidal antimicrobial compositions for the treatment of dermal tissue
US10959433B2 (en) 2017-03-21 2021-03-30 Brigham Young University Use of cationic steroidal antimicrobials for sporicidal activity

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0011663A1 (en) * 1978-12-01 1980-06-11 Unilever Plc Toilet and dental preparations and their use for oral and dental hygiene
DE2940460A1 (en) * 1979-07-31 1981-07-23 Lion Corp., Tokio ORAL USE FOR CARIES PROPHYLAXIS
EP0038868A1 (en) * 1980-04-29 1981-11-04 Blendax-Werke R. Schneider GmbH & Co. Toothpaste
US4335102A (en) * 1979-09-20 1982-06-15 Lion Corporation Oral composition for caries prophylaxis
US4370314A (en) * 1975-12-08 1983-01-25 Colgate-Palmolive Company Oral composition containing antibacterial agent
EP0229375A1 (en) * 1986-01-07 1987-07-22 Blendax GmbH Oral hygiene composition

Family Cites Families (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3044939A (en) * 1959-02-26 1962-07-17 American Chicle Co Copper gluconate oral deodorant composition
US4193988A (en) * 1971-04-29 1980-03-18 Beecham Group Limited Oral hygiene compositions
GB1384375A (en) * 1971-04-29 1975-02-19 Beecham Group Ltd Oral hygiene compositions
US3934002A (en) * 1972-06-30 1976-01-20 The Procter & Gamble Company Oral compositions for plaque, caries and calculus retardation with reduced staining tendencies
US4039653A (en) * 1974-01-23 1977-08-02 Defoney, Brenman, Mayes & Baron Long-acting articles for oral delivery and process
US4041149A (en) * 1976-01-12 1977-08-09 Colgate-Palmolive Company Composition and method of controlling and preventing mouth odor
US4138477A (en) * 1976-05-28 1979-02-06 Colgate Palmolive Company Composition to control mouth odor
GB1573727A (en) * 1978-05-19 1980-08-28 Colgate Palmolive Co Dentifrices
JPS55122709A (en) * 1979-03-13 1980-09-20 Asama Kasei Kk Stench remover from mouth
JPS5679797A (en) * 1979-11-30 1981-06-30 Weyerhaeuser Co Bleaching of cellulose fiber
US4430323A (en) * 1980-04-29 1984-02-07 Jules Silver Method for controlling oral mal odors and dental plaque
EP0038867B1 (en) * 1980-04-29 1983-09-28 Blendax-Werke R. Schneider GmbH & Co. Toothpaste
DE3110882C2 (en) * 1981-03-20 1983-07-07 Mannesmann AG, 4000 Düsseldorf Method and device for bleaching chemically produced pulp with ozone
GB2095991B (en) * 1981-04-07 1985-01-03 Colgate Palmolive Co Dentifrice preparations containing phytic acid
US4469674A (en) * 1981-09-03 1984-09-04 Richardson-Vicks Inc. Stable oral compositions containing zinc and fluoride compounds
US4597959A (en) * 1982-04-30 1986-07-01 Arthur Barr Sustained release breath freshener, mouth and palate coolant wafer composition and method of use
US4512968A (en) * 1982-11-30 1985-04-23 Lion Corporation Oral compositions
IL68027A (en) * 1983-03-03 1986-09-30 Univ Ramot Dental preparation for preventing bacterial adherence to the tooth surface
US4472373A (en) * 1983-05-09 1984-09-18 The Procter & Gamble Company Oral compositions
US4528181A (en) * 1984-02-01 1985-07-09 Colgate-Palmolive Company Dentifrice containing dual sources of fluoride
EP0152836B1 (en) * 1984-02-20 1990-06-20 Blendax GmbH Oral hygiene composition
GB8411731D0 (en) * 1984-05-09 1984-06-13 Unilever Plc Oral compositions
JPH0742219B2 (en) * 1984-07-26 1995-05-10 ライオン株式会社 Oral composition
US4837009A (en) * 1986-03-31 1989-06-06 Ratcliff Perry A Method and composition for prevention of plaque formation and plaque dependent diseases
US4689215A (en) * 1984-07-30 1987-08-25 Ratcliff Perry A Method and composition for prevention and treatment of oral disease
DE3437679C1 (en) * 1984-10-15 1985-08-29 Richardson GmbH, 6080 Groß-Gerau Preparation against bad breath
JPS61200908A (en) * 1985-03-04 1986-09-05 Mitsui Seito Kk Glucide transfusion
US4689214A (en) * 1985-04-16 1987-08-25 Colgate-Palmolive Company Composition to counter breath odor
DE3686135T2 (en) * 1985-05-28 1993-03-18 Pcr Group Inc POLYMERS MODIFIED BY SILANE.
DE3532860C1 (en) * 1985-09-14 1987-03-12 Blendax Werke Schneider Co Oral hygiene products
US4740368A (en) * 1985-12-11 1988-04-26 Plevy Donald J Amylase containing breath cleansing confection
US4814163A (en) * 1986-03-10 1989-03-21 Colgate-Palmolive Company Solid antitartar mouth deodorant
US4814164A (en) * 1986-03-10 1989-03-21 Colgate-Palmolive Company Solid antitartar mouth deodorant composition
JP2540895B2 (en) * 1987-12-17 1996-10-09 ライオン株式会社 Oral composition
GB8729564D0 (en) * 1987-12-18 1988-02-03 Unilever Plc Oral compositions
US4826675A (en) * 1988-02-17 1989-05-02 Colgate-Palmolive Company Anticalculus oral composition
EP0343567A3 (en) * 1988-05-25 1991-01-09 Hitachi, Ltd. Multi-processing system and cache apparatus for use in the same
FI89516B (en) * 1989-05-10 1993-06-30 Ahlstroem Oy Foerfarande Foer blekning av cellulosamassa med Otson
GB8922594D0 (en) * 1989-10-06 1989-11-22 Unilever Plc Oral compositions
US5037633A (en) * 1990-08-16 1991-08-06 Chesebrough-Pond's Usa Co., Division Of Conopco, Inc. Microbiologically stabilized phase for bicarbonate toothpaste manufacture
US5037634A (en) * 1990-08-16 1991-08-06 Chesebrough-Pond's Usa Co., Division Of Conopco, Inc. Oral compositions containing stabilized copper

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4370314A (en) * 1975-12-08 1983-01-25 Colgate-Palmolive Company Oral composition containing antibacterial agent
EP0011663A1 (en) * 1978-12-01 1980-06-11 Unilever Plc Toilet and dental preparations and their use for oral and dental hygiene
DE2940460A1 (en) * 1979-07-31 1981-07-23 Lion Corp., Tokio ORAL USE FOR CARIES PROPHYLAXIS
US4335102A (en) * 1979-09-20 1982-06-15 Lion Corporation Oral composition for caries prophylaxis
EP0038868A1 (en) * 1980-04-29 1981-11-04 Blendax-Werke R. Schneider GmbH & Co. Toothpaste
EP0229375A1 (en) * 1986-01-07 1987-07-22 Blendax GmbH Oral hygiene composition

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0650720A1 (en) * 1993-10-28 1995-05-03 Sanwa Kagaku Kenkyusho Co., Ltd. Skin care and deodorant compositions
WO1999013888A1 (en) * 1997-09-12 1999-03-25 Westfalia-Surge, Inc. Germicidal compositions for the treatment of animal infectious diseases of the hoof, comprising a copper salt, a quaternary ammonium compound and a peroxide
WO2009130608A2 (en) * 2008-04-24 2009-10-29 Uti Limited Partnership Combination of copper cations with peroxides or quaternary ammonium compounds for the treatment of biofilms
WO2009130608A3 (en) * 2008-04-24 2009-12-30 Uti Limited Partnership Combination of copper cations with peroxides of quaternary ammonium compounds for the treatment of biofilms

Also Published As

Publication number Publication date
FI942713A (en) 1994-06-09
CA2125575A1 (en) 1993-06-24
MX9207169A (en) 1994-06-30
BR9206908A (en) 1995-11-21
US5286479A (en) 1994-02-15
EP0616519A1 (en) 1994-09-28
AU3275193A (en) 1993-07-19
JPH07501826A (en) 1995-02-23
FI942713A0 (en) 1994-06-09

Similar Documents

Publication Publication Date Title
US5286479A (en) Oral compositions for suppressing mouth odors
EP0616520B1 (en) Phytate-antimicrobial compositions in oral care products
WO1992008441A1 (en) Improved anti-plaque compositions comprising a combination of morpholinoamino alcohol and metal salts
JPH05124944A (en) Sanguinaria containing gargling liquid excellent in antibacterial power and stability
US5320829A (en) Oral compositions for inhibiting plaque formation
US4559223A (en) Silver sulfadiazine and/or zinc sulfadiazine-containing toothpaste or oral medicament
EP2399576B1 (en) Use of antibacterial compounds for the oral cavity hygiene
US6110445A (en) Oral composition exhibiting improved uptake and retention of antibacterial compounds on dental tissue surfaces
CA2754213C (en) Desensitizing dentifrice exhibiting dental tissue antibacterial agent uptake
US20050180927A1 (en) Novel anti-bacterial compositions
JP3117086B2 (en) Oral liquid preparation
KR20030009578A (en) Oral composition for inhibiting the halitosis
WO1993011741A1 (en) Oral compositions for inhibiting plaque and calculus formation
JP3821553B2 (en) Liquid dentifrice
JP3877412B2 (en) Liquid oral composition
KR101816638B1 (en) Oral composition comprising saponin extracted from the root of Camellia sinensis
EP1019015B1 (en) Oral composition exhibiting improved antibacterial uptake and retention
AU2003213864B2 (en) Novel anti-bacterial compositions
KR100759518B1 (en) Oral Composition for suppressing oral malodor
JP2848696B2 (en) Oral liquid preparation
JPH05331032A (en) Composition for oral cavity

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU BR CA FI JP KR NZ US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
ENP Entry into the national phase

Ref document number: 1994 244465

Country of ref document: US

Date of ref document: 19940602

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2125575

Country of ref document: CA

Ref document number: 942713

Country of ref document: FI

WWE Wipo information: entry into national phase

Ref document number: 246430

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 1993901382

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1993901382

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1993901382

Country of ref document: EP