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WO1993011741A1 - Compositions bucco-dentaires empechant la formation de plaque et de tartre - Google Patents

Compositions bucco-dentaires empechant la formation de plaque et de tartre Download PDF

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Publication number
WO1993011741A1
WO1993011741A1 PCT/US1992/010897 US9210897W WO9311741A1 WO 1993011741 A1 WO1993011741 A1 WO 1993011741A1 US 9210897 W US9210897 W US 9210897W WO 9311741 A1 WO9311741 A1 WO 9311741A1
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WO
WIPO (PCT)
Prior art keywords
dotmp
oral composition
cpc
cyclic
water
Prior art date
Application number
PCT/US1992/010897
Other languages
English (en)
Inventor
Joseph R. Garlich
R. Keith Frank
Jaime Simon
Garry E. Kiefer
David A. Wilson
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
Priority claimed from US07/805,598 external-priority patent/US5320829A/en
Priority claimed from US07/805,600 external-priority patent/US5318772A/en
Application filed by The Dow Chemical Company filed Critical The Dow Chemical Company
Priority to FI942715A priority Critical patent/FI942715L/fi
Priority to JP5511166A priority patent/JPH07502044A/ja
Priority to BR9206910A priority patent/BR9206910A/pt
Priority to EP93901229A priority patent/EP0616521A1/fr
Publication of WO1993011741A1 publication Critical patent/WO1993011741A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/41—Amines
    • A61K8/416—Quaternary ammonium compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • A61K8/4926—Cosmetics 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/55—Phosphorus compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses

Definitions

  • the present invention relates to oral compositions containing an antiplaque agent or an anticalculus agent.
  • 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, periodontosis and gingivitis, and also to eliminate halitosis.
  • Dental calculus or tartar as it is sometimes called, is a hard mineralized material which forms on teeth that consists of inorganic and organic components.
  • the inorganic portion is largely calcium and orthophosphate arranged in a crystal lattice called
  • hydroxyapatite HAP
  • the organic portion is derived mainly from microorganisms (i.e., bacteria, yeast, etc.) as well as epithelial cells, white blood cells and food debris.
  • plaque is deposited on the teeth.
  • “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. Most of the plaque consists of dead and living bacteria surrounded by a gel-like matrix derived from the bacteria and saliva.
  • plaque undergoes calcification to form dental calculus.
  • amorphous deposits of calcium phosphate begins to appear on and withi n the matrix of the dental plaque. As the aggregates of calcium phosphate become sufficiently closely packed together, they crystallize to form HAP.
  • the amorphous calcium phosphate although related to hydroxyapatite, differs from it in crystal structure, particle morphology and stoichiometry.
  • the presence of both the bacteria and the plaque deposits is detrimental to the health of the teeth and gums. If the bacteria and the plaque formation are not checked, they may result in infected gingival tissue, the formation of dental caries and periodontal disease.
  • Chlorhexidine has been the most successful antiplaque agent and is retained in the oral cavity by binding to anionic groups mainly on the oral mucosa.
  • chlorhexidine in oral preparations suffers from the following disadvantages: (1) a prolonged bitter aftertaste lasting up to several hours; (2) after prolonged use they produce stains on the teeth, tongue, gums, oral mucosa and dental restorations; and (3) local irritation of the oral mucosa and tongue.
  • Another means to prevent plaque and calculus formation is to coat the teeth with a material to prevent the release of previously applied therapeutic agents or to coat the teeth with a material containing an antimicrobial agent.
  • HAP agents which effectively interfere with crystal growth
  • antiplaque/anticalculus agents Inhibition of crystalline HAP formation can therefore be achieved by compounds which chelate calcium ions, which prevents the calculus from forming and/or breaks down mature calculus by removing calcium.
  • water soluble hexametaphosphates, tripolyphosphates and pyrophosphates and the like are effective calcium and magnesium ion threshold agents, sequestrants and/or chelating agents
  • a threshold agent has the ability to prevent the precipitation of certain scale forming salts (e.g., calcium carbonate) at concentrations that are much lower than the amount needed for sequestration. See, for example, U.S. Patent 3,488,419 which discloses oral compositions containing polyphosphonate and U.S. Patent 4,215, 105 which discloses oral compositions containing phosphonoacetic acid.
  • the effectiveness of polyphosphonates as antiplaque agents has been limited as they are significantly hydrolyzed by salivary enzymes
  • Patent 4,808,410 It would therefore be desirable to have an oral composition containing an effective antiplaque agent to aid in the prevention of caries and gingivits which does not stain the teeth and is not subject to inactivation by enzymatic hydrolysis. It would also be desirable to provide an improved means whereby antimicrobial compound can be retained within the oral cavity for a longer period of time.
  • the present invention relates to an oral composition containing an antiplaque agent.
  • the present invention relates to oral composition comprising an orally acceptable vehicle containing therein an effective amount as an antiplaque or anticalculus agent a cyclic aikylamine or a cyclic amine selected from one or more of the compounds represented by the Formulae I to IV:
  • each R is independently selected from hydrogen, and C 1 -C 8 hydrocarbon radical, C 2 -C 6 nydroxyalkyl
  • Z is independently -PO 3 H 2 , -COOH, -H, C 1 -C 18 alkyl or a physiologically acceptable salt of the acid radicals;
  • X and Y are independently -H, C 1 -C 3 hydrocarbon radicals, with the proviso that each cyclic aikylamine or cyclic amine contain at least two Z groups which are -PO 3 H 2 or a physiologically acceptable salt thereof;
  • each n is independently 2 or 3;
  • n and m are 3 to 6, inclusive; and n and m being selected such that the total number of carbon and nitrogen atoms in the cyclic amine ring does not exceed 18.
  • alkyl means a linear or branched alkyl; and thus, secondary and tertiary amines 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.
  • hydrocarbon includes the foil owing organic radicals: alkanes, alkenes, alkynes, cycloalkanes, cycloalkenes, and benzene radicals.
  • an oral composition containing a cyclic amine and an antimicrobial quaternary ammonium compound-
  • the combination provides that the antimicrobial quaternary ammonium compound is retained within the oral cavity, especially on the tooth surface, for a longer period of time.
  • the enhanced retention of the antimicrobial quaternary ammonium compound within the oral cavity increases the time period during which the compound will be effective as an antiplaque agent and/or antigingivitis agent.
  • a further embodiment of the present invention takes the form of an oral composition containing a cyclic amine, antimicrobial quaternary ammonium compound and a metal ion for enhanced retention of the quaternary ammonium compound within the oral cavity.
  • the present invention also provides an oral composition which inhibits the transformation of amorphous calcium phosphate to the hydroxyapatite crystal structure normally associated with dental calculus.
  • the present invention further provides an improved method of inhibiting the formation of dental calculus and an improved method forthe reduction of undesirable dental plaque and/or gingivitis.
  • Figure 1 shows the inhibition of hydroxyapatite formation as observed by a decrease in the amount of titrant consumed in the presence of various concentrations of ethylenediaminetetramethylene-phosphonic acid (EDTMP).
  • ETMP ethylenediaminetetramethylene-phosphonic acid
  • Figure 2 shows the inhibition of hydroxyapatite formation as observed by a decrease in the amount of titrant consumed in the presence of various concentrations of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylenephosphonic acid (DOTMP).
  • Figure 3 shows the inhibition of hydroxyapatite formation as observed by a decrease in the amount of titrant consumed in the presence of 3.3 x 10 -5 M DOTMP,
  • HEDP hydroxyethylidenediphosphonic acid
  • EDTMP EDTMP
  • NDATMP norbomanediaminetetramethylenephosphonic acid
  • DCDATMP dicyclopentadienediaminetetramethylenephosphonic acid
  • Figure 4 shows the inhibition of hydroxyapatite formation as observed by a decrease in the amount of titrant consumed in the presence of 3.3 x 10 -5 M DOTMP over a
  • Figure 5 shows the inhibition of hydroxyapatite formation as observed by a decrease in the amount of titrant consumed in the presence of 2.71 x 10 -5 M EDTMP
  • NOTMP 1,4,7-triazacyclononanetrimethylenephosphonic acid
  • Figure 6 shows the inhibition of hydroxyapatite formation as observed by a decrease in the amount of titrant consumed in the presence of 2.73 x 10 -5 M DOTMP and DOTMP plus cetylpyridinium chloride (CPC) both present at a 2.73 x 10 -5 M concentration.
  • This invention relates to an oral composition containing in an orally acceptable vehicle an effective amount of of a cyclic aikylamine or cyclic amine as an anti calculus agent or as an antiplaque and/or antigingivitis.
  • An "orally acceptable vehicle” means a medium in which an anticalculus or an antiplaque agent may be administered to the oral cavity without substantial harmful effects to the oral cavity surfaces.
  • An "effective amount” is that which will inhibit or reduce the formation of dental calculus, plaque and/or gingivitis in the oral cavity.
  • antiplaque means antiplaque and/or antigingivitis and/or antiperiodontitis and/or anticaries.
  • an antiplaque agent will also aid in the control of oral malodor.
  • Cyclic alkylamines of the present invention are derivatives of bicycloheptadiene as given in Formula (I)
  • each R is independently -H, C 1 -C 8 hydrocarbon radical, C 2 -C 6 hydroxyalkyl or
  • Z is independently -PO 3 H 2 , -COOH, -H, C 1 -C 18 alkyl or a physiologically acceptable salt of the acid radicals;
  • X and Y are independently -H, C 1 -C 3 hydrocarbon
  • each cyclic aikylamine or cyclic amine contain at least two Z groups which are -PO 3 H 2 , or a physiologically acceptable salt thereof.
  • a physiologically acceptable salt refers to the acid addition salts, or mixtures thereof, of those bases which will form a salt which does not cause a significant adverse physiological effect when used in an oral product consistent with good pharmacological practice.
  • suitable salts include those of the alkali metal, alkaline-earth metal and mixtures thereof.
  • the cyclic alkylamines of Formulae I-III can be prepared from commercially available dicyclopentadiene (DCPD) and bicycloheptadiene (BCHD). Electrophilic addition reactions are known to form the nitrile ordinitrile by reacting the double bonds of DCPD or BCHD with hydrogencyanide (HCN). The nitrile can then be hydrolyzed to form the carboxylic acid derivative.
  • DCPD dicyclopentadiene
  • BCHD bicycloheptadiene
  • Electrophilic addition reactions are known to form the nitrile ordinitrile by reacting the double bonds of DCPD or BCHD with hydrogencyanide (HCN). The nitrile can then be hydrolyzed to form the carboxylic acid derivative.
  • the DCPD or BCHD can also be reacted with HCN followed by reduction to obtain the bis methyiamine derivative; this product in turn can be reacted with glycolonitrile in the presence of caustic to give the sodium salt of tetraacetic acid of the bisamine.
  • Cyclic amines of the present invention are macrocyclic amines of Formula (III):
  • each n is independently 2 or 3 and m is 3 to 6, inclusive, n and m being selected such that the total number of carbon and nitrogen atoms in the cyclic amine ring does not exceed 18; and each R is as defined hereinbefore.
  • Polyazamacrocycles useful as starting materials which can be derivatized to form the cyclic aminophosphonates of Formula III of the present invention include
  • Polyazamacrocycles useful as starting materials for the cyclic aminophosphonates of Formula IV of the present invention are prepared by the procedures set forth in U.S. Patent Application 07/805,551 filed December 10, 1991, filed on even date herewith and entitled "Bicydopolyazamacrocyclophosphonic Acids, and Complexes and Conjugates Thereof for Use as Contrast Agents", by Garry Kiefer, Jamie Simon and Joseph R. Garlich (Attorney Docket No. C-38,662), the disclosure of which is hereby incorporated by reference.
  • compounds of Formula IV are synthesized by the following reaction scheme.
  • Aminophosphonic acids can be prepared by a number of known synthetic techniques. Of particular importance is the reaction of a compound containing at least one reactive amine hydrogen with a carbonyl compound (aldehyde or ketone) and phosphorous acid or derivative thereof as described in U.S. Patent 3,288,846, the disclosure of which is hereby incorporated by reference, and described by Moedritzer and Irani, J.Org. Chem., 31, 1603 (1966). For example, p-nitrobenzyl ethylenediamine reacted with formaldehyde and phosphorous acid can be converted to the p-nitrobenzyl
  • Carboxymethylation of the amines of the present invention may be performed by the method of Desreux using bromoacetic acid derivatives and a suitable base [J.F. Desreux, Inorg. Chem., 19, 1319-24(1980)].
  • the cyclic alkylamines or cyclic amines of the present invention are typically present in an oral composition in a concentration of from about 0.5 millimolar (mM) to about 20 mM, preferably in the range of about 1 mM to about 10 mM, and more preferably about 1 mM to about 2 mM.
  • mM millimolar
  • the oral compositions are substantially liquid in character, such as a mouthwash or rinse.
  • the vehicle can be water or is a water-alcohol mixture, although alcohol is not required.
  • the weight ratio of water to alcohol is in the range of from about 1 : 1 to about 20: 1 , preferably about 3: 1 to 10: 1 and more preferably about 4: 1 to about 6: 1.
  • the total amount water or water-alcohol mixture in this type of preparation is typically in the range of from about 70 percent to about 99.92 percent by weight of the preparation.
  • the pH of such liquid and other preparations of the invention is generally in the range of from 4.5 to 9 and typically from about 5.5 to about 8.
  • the pH is preferably in the range of from about 6 to about 8.
  • 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 known to the art.
  • the oral composition may be substantially solid or semisolid in character, such as toothpowder, a dental tablet, a toothpaste, gel or dental cream.
  • the vehicle of such solid or semisolid oral preparations generally contains added polishing material more fully described hereinafter.
  • prophylactic agents include supplemental caries-preventing materials such as sodium fluoride, stannous fluoride, potassium fluoride, hexylamine hydrofluoride, myristylamine hydrofluoride, betaine fluoride, glycine potassium fluoride, etc.
  • 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 in the range of about
  • Suitable polishing agents include, for example, abrasive materials such as insoluble condensed phosphates such as calcium pyrophosphate, insoluble calcium
  • polishing material also known as calcium polymetaphosphate
  • highly polymerized sodium polyphosphate and water impervious cross-linked thermosetting resins.
  • suitable polishing agents will be obvious to those skilled in the art.
  • the polishing material is generally present in the solid or pasty compositions in weight concentrations of about 10 percent to about 99 percent. Preferably, it is present in amounts ranging from about 20 percent to about 75 percent in toothpaste, and from about 70 percent to about 99 percent in tooth powder.
  • Soaps, detergents or surfactants 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 of the antiplaque agent and render the 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, stearic or 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 sodium lauryl sulfate, the sulfated fatty alcohols derived from coconut oil and palm oil, etc.
  • the soaps typically comprise up to about 5 percent by weight of the dentifrice composition.
  • An example of a particularly suitable nonionic surfactant is poly(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, underthe trademark "TWEENS” (ICI American Inc., Wilmington, De.).
  • Suitable aninoic 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).
  • Surfactants typically comprise from about 0.05 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, dove, sage, eucalyptus, marjoram, cinnamon, lemon and orange and methyl salicylate.
  • suitable sweetening agents include sucrose, lactose, maltose, sorbitol, xyiitol, sodium cydamate, perillart ⁇ ne, 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 about 0.1 percent to about 10 percent, preferably 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
  • 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 10 to 90 percent by weight of the dentifrice composition.
  • the antimicrobial is therefore retained within the oral cavity for a longer period of time due to the electrostatic forces between the anionic tooth surface and the cationic antimicrobial.
  • the ability of an antimicrobial compound to be retained and remain active within the oral cavity to exert an antiplaque effort for a longer period of time is referred to as the "substantivity" of the compound.
  • the terms "antimicrobial” and “antibacterial” as used herein refer to the ability of a cationic compound to inhibit the growth, reproduction or metabolism of microorganisms.
  • the enhanced substantivity of the antimicrobial compound aids in the prevention of dental calculus by inhibiting microorganisms responsible for the initial formation of dental plaque.
  • the inhibition of microorganisms will also reduce the amount of volatile sulfur compounds produced by the putrefactive activity of the microorganisms, thus helping to control mouth malodor. It has also been surprisingly found that indusion of an antimicrobial does not affect the calculus inhibiting ability of the cyclic alkylamines or cyclic amines used in the dentifrices of the present invention.
  • Antimicrobial compounds which are particularly useful in dentifrice compositions of the present invention are compounds which contain an organic amine where the nitrogen is capable of being positively charged in an aqueous environment, preferably organic amines which are capable of being protonated in an aqueous environment and quaternary ammonium compounds.
  • antibacterial quaternary ammonium compounds used in oral compositions are cetylpyridinium chloride, benzethonium chloride, also known as Hyamine 1622 or di-isobutyl(phenoxy-ethoxyethyl dimethylbenzyl ammonium chloride) and sanguinarine.
  • Antibacterial quaternary ammonium compounds useful in the present invention include those represented by the formula
  • 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 1 to 6;
  • R 5 is -H, a C 1 -C 7 alkyl or-(CH 2 -CHOH-CH 2 -O)nH wherein n is an integer from 1 to 6;
  • X- is chloride (Cl-), bromide (Br-), iodide (I-) or fluoride (F-) ion.
  • the quaternary ammonium 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, they 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. Heterocyd. 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.
  • quaternary ammonium compounds which can be employed in dentifrices of the present invention include the following:
  • R 6 is a C 4 -C 16 alkyl or benzyl.
  • Quaternary ammonium compounds that are esters of betaine and fatty alcohols, as disclosed by Linstedt et al., Antimicrobial Agents and Chemotherapy, 39, 1949-1954 (1990), the disclosure of which is hereby incorporated by reference, the quaternary ammonium compounds having the formula
  • Sanguinarine and 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 is available in dentifrices under the trademark ViadentTM brand sanguinaria; the major active ingredient sanguinarine chloride salt having the formula
  • Dodecyltrimethylammonium bromide, benzyl dimethylstearylammonium chloride, cetylpyridinium chloride, N-tetradecyl-4-ethylpyridinium chloride, sanguinaria and 5-amino-1,3,bis(2-ethyl-hexyI)-5-methylhexahydropyrimidine are preferred quaternary ammonium antibacterial agents used in dentifrices of the present invention.
  • antibacterial organic amines which can be protonated in aqueous environments and are useful in dentifrices of the present invention include the following:
  • R 8 is a C 8 -G 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; the sum of 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 11 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.
  • R 14 -NH-R 14 wherein each R 14 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 2-5; and pharmaceutically acceptable salts thereof.
  • N'-Alkyl-N-(2-aminoethyI)piperidine compounds as disclosed by Murata et al., J. Pharm. Sci., 80, 26-28 (1991), the disclosure of which is hereby incorporated by reference, the compounds having the formula
  • R 16 is a C 10 -C 18 alkyl; and pharmaceutically acceptable salts thereof.
  • ammonium compound 4-(2-propylenepentyI)-1-piperidinoethanol having the structure
  • Alkyl-N-betaine in combination with an alkyl-N,N-dimethylamine oxide; the alkyl-N-betaine having the structure
  • R 17 is a C 10 -C 17 alkyl; the alkyl-N,N-dimethylamine having the structure
  • R 18 is a C 10 -C 18 alkyl; as disclosed in U.S. Patent 4,839, 158, the disclosure of which is hereby incorporated by reference.
  • antimicrobial agents which can be employed in the dentifrices of the present invention indude biguanides such as chlorhexidine (1,6-bis-[N 5 -(p-chlorophenyl)- -N'biguanidojhexane; N'-(4-chlorobenzyl)-N 5 -(2,4-dichlorobenzyl)biguanide;
  • Chlorhexidine being the preferred biguanide antimicrobial agent used in the dentifrices of the present invention.
  • the antibacterial agents are typically employed in amounts such that the oral product contains between about 0.001 percent and 15 percent by weight of the agent.
  • the finished oral product contains about 0.01 percent to about 5 percent and most preferably about 0.025 percent to 1.0 percent by weight of the agent.
  • the molar ratio of the quaternary ammonium compound in the oral composition to the cylicamines of the present invention is preferably from about 5: 1 to about 1 :5, more preferably from about 3: 1 to about 1 :3, and most preferably about about 1: 1.
  • the cyclic amines of Formula III are the preferred amines of the present invention to be used in oral compositions in cojjunction with cationic antimicrobial compounds.
  • the preferred cationic antimicrobial compound to be used in conjunction with the cyclic amine is cetylpyridinium chloride.
  • the dentifrices of the present invention may also be in a kit form, the kit comprising in a first compartment an orally acceptable vehicle containing one or more cyclic alkylamines or cyclic amines and in a second compartment an orally acceptable vehicle containing one or more cationic antimicrobial compounds.
  • the compounds in the separate compartments may be applied to the oral cavity sequentially or mixed prior to application. When applied sequentially, it is preferred that the cyclic aikylamine or cyclic amine be applied to the oral cavity prior to the cationic antimicrobial compounds.
  • the concentration of the cydicalkylamine, cyclic amine and cationic antimicrobial compound to which the oral cavity is exposed should be in the range given hereinbefore for their concentration in the final dentifrice product.
  • the dentifrice it is desirable for the dentifrice to contain both the antimicrobial and cyclic aikylamine or cyclic amine in one composition.
  • a variety of other ingredients may be added to the separate compartment of a dentifrice kit, such as, polishing agents, soaps or detergents, flavoring and sweetening agents, and the like as described hereinbefore.
  • a polyvalent metal ion such as, for example, calcium (Ca 2+ ), magnesium (Mg 2 + ) or mixtures thereof
  • a polyvalent metal ion such as, for example, calcium (Ca 2+ ), magnesium (Mg 2 + ) or mixtures thereof
  • the inclusion of a metal ion also does not interfere with the ability of the cyclic amine to inhibit calculus formation.
  • the molar ratio of the metal ion to cyclic amine is preferably from about 5: 1 to 1 :5, more preferably from about 3: 1 to 1 :3, and most preferably about 1 :1.
  • the metal ion is Sn + or Ca 2 + , more preferably the metal ion is Ca 2 + .
  • an oral composition according to this invention such as a mouthwash containing the cyclic amine or cyclic aikylamine and/or a cationic antimicrobial compound and/or a metal ion, may be prepared by unifying the components in conventional manner and applied to the teeth and gingiva.
  • DOTMP 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylenephosphonic acid
  • PCTMP 3,6,9,15-tetraazabicyclo[9.3.1.]pentadeca-
  • HAP hydroxyapatite
  • DCDATMP dicyclopentadienediaminetetramethylene-phosphonic acid
  • DOTMP 1 ,4,7,10-tetraazacyclododecane-1 ,4,7,10- tetramethylenephosphonic acid
  • DTPMP diethylenetriaminepentamethylenephosphonic acid
  • EDTMP ethylenediaminetetramethylenephosphonic acid
  • HAP hydroxyapatite
  • HEDP hydroxyethylidenediphosphonic acid
  • NDATMP norbornanediaminetetramethylenephosphonic acid
  • PCTMP 3,6,9,15-tetraazabicydo[9.3.1]pentadeca-
  • the water used in preparing the stock solutions and in the following examples was distilled, deionized water.
  • DOTMP 1,4,7,10-tetraazacydododecane-1,4,7,10-tetramethylenephosphonic acid
  • 0.0015 M DOTMP Twenty mL of a 0.0045 M DOTMP stock solution was loaded into a four ounce jar and then diluted with 40 mL of water to produce a 0.0015 M DOTMP solution.
  • CPC cetylpyridinium chloride
  • 0.0015 M DOTMP/CPC Twenty mL of a 0.0045 M DOTMP solution and 20 mL of a 0.0045 M CPC solution were loaded into a four ounce jar and then diluted with 20 mL of water to produce a
  • Chlorhexidine 0.0015 M Chlorhexidine.
  • a 100 mL beaker was tared and loaded with 0.0455 ⁇ .0001 g of chlorhexidine (CH) (Aldrich; FW 505.46) and 60 mL water added to give a 0.0015 M
  • PCTMP 3,6,9,15-tetraazabicydo-[9,3,1]-tetradeca- -1(15),11,13-triene-N,N',N"-trimethylenephosphonic acid
  • 0.0015 M HEDP A 0.0045 M solution of HEDP was prepared by adding 40 mL of water to a 60 mL beaker containing 0.0618 ⁇ 0.001 g of 60 percent active HEDP (MAYO Chemical Co., FW 206). This solution was adjusted to pH 7.6 using few drops of 1.0 N sodium hydroxide. A 20 mL aliquot of the solution was removed and placed in a four ounce jar where it was diluted with 40 mL of water to produce a 0.0015 M HEDP solution. The procedure for making solutions of EDTMP, NDATMP, DCDATMP, DTPMP and NOTMP were done in a similar manner as for DOTMP, PCTMP and HRDP.
  • 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 priorto 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 5 minutes, began collecting saliva for
  • testtubes 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.
  • Example 1 Prevention of bacterial adherence to HAP surfaces
  • Hydroxyapatite disks (7.5 x 2.7 mm), obtained from Calcitek, Inc. were prepared by tying a short length of chromel wire around then and placing the other end of the wire into a rubber stopper to allow the disk to be suspended within a testtube.
  • test samples were than placed into a test tube containing 8 mL of a growth medium of brain-heart infusion broth with 5 percent sucrose, the growth medium having been inoculated with 100 ⁇ L of Streptococcus mutans, ATCC #25125 (approximately 5.5 x 10 7 colony forming units).
  • the tubes were then incubated at 37°C.
  • the sample disks were transferred to a new test tube containing fresh medium and S. Mutans.
  • the samples were taken out, rinsed by dipping into water, and stained with Butler Red Coat, a dental plaque disclosing agent. The amount of plaque on each disk was determined visually and rated according to the following scale:
  • the heaviest plaque growth was found on the control disk.
  • Formulations containing an antimicrobial agent chlorhexidine, CPC, and DOTMP/CPC all showed a reduction in plaque.
  • the sample with DOTMP alone shows that the HAP surface has been modified so as to inhibit bacterial adherence without the use of an antimicrobial agent.
  • Example 2 Absorbence of DOTMP onto a HAP Surface
  • a 0.3 mM solution of DOTMP at pH 7 was prepared and injected on an HPLC (high performance liquid chromatography) system.
  • the HPLC system was a Hamilton PR-X100 anion exchange column (4.1 mm x 50 mm) with 0.016 M sulfuric acid at 1 mL/min as eluent, Dionex gradient pump, Dionex variable wavelength detector (set on 210 nm) and a VG PDP-1 1 data collection system.
  • the DOTMP at this concentration exhibited a peak with a 6.25 minute retention time and an area of 9.16.
  • a hydroxyapatite suspension (24.5 percent by weight suspension of hydroxyapatite in phosphate buffer from Sigma Chemical Co.) was washed with 20 mL of water and then mixed with 20 mL of 0.3 mM DOTMP. After a contact time of about one minute, the hydroxyapatite was removed by filtration and the filtrate analyzed by HPLC for DOTMP. The analysis showed that less than 0.7 area units could be attributed to DOTMP, indicating that 93 percent of the DOTMP left the solution to adhere to the hydroxyapatite surface.
  • Example 3 Absorbence of CaDOTMP onto a HAP surface
  • the calcium salt of DOTMP (1 mM Ca-DOTMP) was prepared by mixing DOTMP and calcium chloride in water and adjusting the pH up to 7,4 with 0.1 N NaOH.
  • a 1.1184 gram portion of hydroxyapatite suspension as described in Example 2 was washed with 12 mLof water and then resuspended in 10 mLof 1 mM Ca-DOTMP. After stirring overnight (about 16 hours) the suspension was filtered and the filtrate analyzed by HPLC as described in Example 2. This analysis showed that 98.5 percent of the DOTMP had come out of solution, presumable onto the hydroxyapatite surface.
  • Example 4 Reduction in adherence of salivary proteins to hydroxyapatite in the presence of
  • Hydroxyapatite disks (7.5 x 2.7 mm, Calciteck, Inc.) were separately placed in glass vials to which was then added either 2 mL of water (control) or 2 mL of 0.001 M DOTMP. The vials were capped and placed on an end-over-end rotator for 30 minutes. The supernatant was removed and the disks washed three times with 1 mL water used as a wash each time. Into each vial was then added 2 mL of salivary supernatant and the vials capped and placed on an end-over-end rotator for 19 hours.
  • the salivary supernatant was obtained bycentrifuging saliva, which had been collected from human volunteers who had refrained from oral hygiene after eating, at full speed on a IEC-HN-SII centrifuge (about 4,000 rpm). After the 19 hour period, the supernatant from each vial was gently removed and each disk washed gently for a brief time with 2 mL of water. The disks were then separately place in vials containing 1 mL of 0.1 N NaOH and sonicated for 2 minutes A 200 ⁇ L aliquot ofthe supernatant from each vial was then mixed with 3.0 mLof water in a quartz cuvette and the absorbence measured at 600 nm (water reference) for each sample.
  • the control showed an average absorbence reading (7 readings) of 0.0167 absorbence units and the DOTMP exposed disk (6 readings) 0.00588 absorbence units.
  • the DOTMP treated disks showed a 2.84 fold reduction in the amount of salivary material accumulated on the DOTMP treated disk versus a water treated disk.
  • Example 5 Substantivity of DOTMP/CPC versus CPC using hydroxyapatite powders.
  • the surface portion of a tooth is composed of about 97 percent inorganic substances, about 1 percent organic substances and about 2 percent water, the inorganic substances being mainly hydroxyapatite, hydroxyapatite powder was used as a model for tooth enamel.
  • a 24.5 g portion of a hydroxyapatite suspension (purchased as a 24.5 percent by weight suspension of HAP in phosphate buffer from the Sigma Chemical Co., St. Louis, MO) was weighed out and washed with 3-30 mL portions of water to remove the phosphate buffer. The solid was resuspended in 60 mL of water to give an HAP suspension in water of about 100 mg HAP/mL of water. In each of two test tubes was placed 100 ⁇ L of this suspension which contained 10 mg of solid HAP. Into tube 1 was placed 4.5 mL or 0.0015 M cetylpyridinium chloride (CPC).
  • CPC cetylpyridinium chloride
  • Example 6 Substantivity of DOTMP/CPC versus CPC using hydroxyapatite spheroids (SHAP)
  • HAP Hydroxyapatite spheroids
  • each of the "two hydroxyapatite solids from above were transferred to a disposable polypropylene column equipped with a frit (Bio-Rad Laboratories). The solution was allowed to gravity filter through the frit which holds back the solid spheroids. The last traces of solution were removed by blowing 10 mL of air through the tube which expels mostof the solution. The remaining hydroxyapatite was then exposed to 2.0 mL of water for 10 minutes by an end-over-end rotation. After 10 minutes, a 200 ⁇ L aliquot of the supernatant was taken and added to 3.0 mL of water in a quartz cuvette.
  • the UV absorption was then determined for these two solutions which corresponds to the first wash, 10 minutes exposure time.
  • the spheroid containing solutions were then mixed for an additional 4 hours, at which time another 200 ⁇ L aliquot was taken for an UV measurement.
  • a third 200 ⁇ L aliquot was taken for UV measurement after 24 hours of mixing.
  • the spheroidal hydroxyapatite was then separated from the supernatant using the disposable column method described above and placed in 2.0 mL of water for the second wash. The second wash was sampled as previously described after mixing for
  • Example 2 An 8 g sampleof a HAP suspension (as described in Example 1) was weighed out and washed with 3-20 mLportions of water using a sintered glass filter funnel. The washed- solid HAP wasthen resuspended in 20 mLof water to give a milky white suspension containing about 100 mg solid HAP permLof suspension.
  • the HAP samples labeled as "A” received 3 mL of water wash, those labeled as “B” received 11 mL of water wash, those labeled as “C” received 18.5 mL of water wash, and those labeled as "D” received 25.5 mL of water wash.
  • each containing about 0.5 mL of HAP (25 mg) suspension was added 0.5 mL of a 5 percent sucrose solution and 0.5 mL of saliva.
  • the saliva was pooled 2 hours after breakfast from four human volunteers which had refrained from oral hygiene after eating.
  • the tubes were shaken to mix the contents and the pH of each solution measured using a pH meter.
  • Table VI TABLE VI
  • a drop in pH means that there is little or no inhibition of bacteria such that the bacteria are able to metabolize the sucrose into organic acids, such as lactic acid, which then lowers the pH.
  • organic acids such as lactic acid
  • the lack of a pH drop indicates that the bacteria are either dead or unable to metabolize sucrose which is a measure of how much CPC has been carried through the water washing on the hydroxyapatie solid.
  • HAP hydroxyapatite
  • a buffer suspension 25 percent by weight solids from Sigma Chemical Co.
  • the HAP suspension was filtered through a medium glass fitted filter to obtain a HAP filter cake.
  • the HAP filter cake was washed a second time with an additional 25 mLof water.
  • the white solid filter cake containing 3.0 g of HAP without the buffer was resuspended with 30.0 mL of water to produce a 3.0 g/30.0 mLor 100 mg/mL suspension.
  • test tubes were placed in an Industrial Equipment Company
  • This sample A contains one fourth of the original 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 tubes were removed, the liquid layer decanted and 1.5 mL of water added to each tube.
  • HAP solids were resuspended to the original 100 mg/mL concentration and a 0.5 mL sample removed and placed in each of several 5 mL polystyrene test tube labeled B 1 --B n .
  • This sample B contained 50 mg HAP solids which had been treated with test solution and then washed with a total of eleven mi milliliters of water.
  • C 1 --C n .and D 1 --D n The procedure given above was repeated a third and fourth time to create a series of test tubes labeled C 1 --C n .and D 1 --D n .
  • the C samples contained HAP solids which had been treated with test solution and then washed with a total of 18.5 mL of water.
  • the D samples contained HAP solids which had been treated with the test solution and then washed with a total of 25.5 mL water.
  • a glycolysis pH test was then performed as described above by adding 0.75 mL aliquots of the saliva/sucrose/bacterial mixture to the test tubes labeled A 1 --A n , each containing 0.5 mL of the treated washed HAP suspension.
  • the following compounds were tested for HAP substantivity: water (control); CPC; chlorhexidine (CH); DOTMP; and DOTMP/CPC- All compounds being tested present as 0.0015 M aqueous solutions. The results from this trial are shown in Table VII.
  • DOTMP/CPC shows markedly better antimicrobial activity after a series of washes than the other solutions tested.
  • Example 8 Using the experimental procedure described in Example 8, the following compounds were tested for HAP substantivity: water (control); cetylpyridinium chloride (CPC); DOTMP/CPC; and PCTMP/CPC. The compounds were tested as 0.0015 M aqueous solutions.
  • DOTMP 1,4,7,10-tetraazacyclododecane-
  • PCTMP 3,6,9,15-tetrabicyclo-
  • Example 8 Using the experimental procedure described in Example 8, the following compounds were tested for HAP substantivity: water (control); cetylpyridinium chloride (CPC); DOTMP/CPC; Calcium-DOTMP (Ca-DOTMP); and Ca-DOTMP/CPC.
  • the compounds being tested present as 0.0015 M aqueous solutions and the Ca present as a .0014 M aqueous solution.
  • DOTMP 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylenephosphonic acid
  • Example 8 Using the experimental procedure described in Example 8, the following compounds were tested for HAP substantivity: water (control); cetylpryidinium chloride (CPC); Sn-DOTMP; Sn-DOTMP/CPC; Zn-DOTMP; and Zn-DOTMP/CPC.
  • the compounds being tested present as 0.0015 M aqueous sol utions and the metals present as 0.0014 M aqueous solutions.
  • CPC cetylpryidinium chloride
  • DOTMP 1,4,7,10--tetraazacyclododecane- -1,4,7,10-tetramethylenephosphonic acid
  • Sn tin
  • Zn zinc
  • Example 8 Using the experimental procedure described in Example 8, the following compounds were tested for HAP substantivity: water (control); cetylpyridinium chloride (CPC); Sr-DOTMP; Sr-DOTMP/CPC; and Mg-DOTMP/CPC.
  • the compounds being tested present as 0.0015 M aqueous solutions and the metals present as 0.0014 M aqueous solutions.
  • CPC cetylpyridinium chloride
  • DOTMP 1,4,7,10-tetraazacyclododecane-1,4,7,10- -tetramethylenephosphonic acid
  • Mg magnesium
  • Example 8 Using the experimental procedure described in Example 8, the following compounds were tested for HAP substantivity: water (control); cetylpyridinium chloride (CPC); Ca-DOTMP/CPC; Sn-DOTMP/CPC; Zn-DOTMP/CPC; Sr-DOTMP/CPC; Mg-DOTMP/CPC;
  • Fe-DOTMP Fe-DOTMP
  • Cu-DOTMP Cu-DOTMP
  • DOTMP 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylenephosphonic acid
  • CPC cetylpyridium chloride
  • the cetylpryidinium chloride and DOTMP were present at a concentration of approximately 1.5 millimolar (mM) and the metal ions, calcium and tin, at approximately 1.4 mM.
  • the CPC solution was prepared by dissolving 1.096 g CPC in 30 mL of water. The solution was transferred to a 2 0 liter volumetric flask and diluted to the mark with water. The pH ofthe final solution was approximately 5.9.
  • the Sn-DOTMP/CPC solution was prepared by initially making separate solutions of Sn-DOTMP (0.447 g stannous fluoride and 1.674 g DOTMP in one liter) and CPC (1.096 g in one liter).
  • the DOTMP was suspended in 50 m L of water and brought into solution with the addition of 50 percent by weight sodium hydroxide to bring the pH to about 7 prior to adding to the stannous fluoride solution.
  • the Sn-DOTMP and CPC solution were then combined to give approximately 1.4 mM Sn, 1.5 mM DOTMP and 1.5mM CPC.
  • the Ca-DOTMP solution was prepared by dissolving 0.419 g calcium chloride dihyrate in 50 mL of water and transferring to a two liter volumetric flask.
  • the DOTMP was prepared by suspending 1.674 g DOTMP in 50 mL of water and then adding 50 percent by weight sodium hydroxide to bring the DOTMP into solution.
  • the DOTMP solution was then added to the two liter flask and diluted to the mark with water.
  • the final pH was
  • the DOTMP/CPC solution contained 1.096 g CPC and 1.674 g DOTMP.
  • the DOTMP was prepared separately as described above, added to a two liter volumetric flask containing CPC dissoIved in 30 mLof water, and then diluting to the mark with water. The final pH was approximately 7.66.
  • DOTMP 1,4,7,10-tetraazadodecane-
  • DOTMP -1,4,7,10-tetramethylenephosphonic acid
  • Both inhibitors were prepared as 0.09 M solutions of the ammonium salts.
  • Levels of EDTMP used were 10, 15, 20, and 30 ⁇ L.
  • Levels of DOTMP used were 4, 10, 15, 20 ⁇ L (20 ⁇ L in 54 mL equals 3.3 X 10 -5 M, or on a weight basis, 14.5 ppm of EDTMP and 18.3 ppm of DOTMP). As can be seen from the Figures 1 and 2, 4 ⁇ L of DOTMP is equivalent to 10 ⁇ L of EDTMP.
  • the CPC solution was prepared by dissolving 1.096 g of cetylpyridinium chloride in
  • the DOTMP/CPC solution was prepared by adding 1.674 g of DOTMP to 50 mL of water and dissolving with the addition of 50 percent by weight sodium hydroxide to raise the pH to about 7.0. This solution was then added to 1.096 g of cetylpyridinium chloride dissolved in 30 mL of water. This solution was then diluted to 2.0 liters with the final pH being about 7.66.
  • DOTMP DOTMP was prepared as above and added to 30 mL of water containing 0.419 g of calcium chloride dihydrate or 0.477 g stannous fluoride. The solutions were then diluted to a total volume of 2 liters.
  • DOTMP 1,4,7,10-tetraazadodeane- -1,4,7,10-tetramethylene phosphonic

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

On décrit des compositions et des procédés bucco-dentaires efficaces pour favoriser l'hygiène bucco-dentaire et contenant une dose active d'au moins une alkylamine cyclique ou une amine cyclique comme agent antiplaque et/ou agent antigingivite.
PCT/US1992/010897 1991-12-10 1992-12-10 Compositions bucco-dentaires empechant la formation de plaque et de tartre WO1993011741A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
FI942715A FI942715L (fi) 1991-12-10 1992-12-10 Oraalisia koostumuksia plakin ja saostumisen syntymisen estämiseksi
JP5511166A JPH07502044A (ja) 1991-12-10 1992-12-10 歯垢及び歯石の形成を抑制するための口内組成物
BR9206910A BR9206910A (pt) 1991-12-10 1992-12-10 Composições orais para inibição da formação de placas e cálculos
EP93901229A EP0616521A1 (fr) 1991-12-10 1992-12-10 Compositions bucco-dentaires empechant la formation de plaque et de tartre

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US07/805,598 US5320829A (en) 1991-12-10 1991-12-10 Oral compositions for inhibiting plaque formation
US07/805,598 1991-12-10
US07/805,600 1991-12-10
US07/805,600 US5318772A (en) 1991-12-10 1991-12-10 Oral compositions for inhibiting calculus formation

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FI (1) FI942715L (fr)
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2322129A (en) * 1997-02-13 1998-08-19 Ciba Sc Holding Ag Polyazabicyclic compounds
EP1261349A4 (fr) * 2000-02-22 2004-09-01 Chelator Llc Composes a affinite et selectivite de chelation vis-a-vis des premiers elements des series de transition, et leur utilisation
US9717667B2 (en) 2012-12-20 2017-08-01 Colgate-Palmolive Company Oral care composition containing ionic liquids

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2452034T5 (es) * 2006-09-01 2017-09-18 Glaxosmithkline Llc Composición para el cuidado de prótesis dental

Citations (5)

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Publication number Priority date Publication date Assignee Title
US3988443A (en) * 1973-08-27 1976-10-26 Henkel & Cie G.M.B.H. Azacycloalkane-2,2-diphosphonic acids
US4508704A (en) * 1984-02-27 1985-04-02 The Dow Chemical Company Radioactive metals complexed with phosphonate derivatives of bicycloheptane bis(alkylamines)
EP0166020A1 (fr) * 1983-04-18 1986-01-02 The Dow Chemical Company Agents pour la chélation à base de dérivés de dicyclopentadiène
WO1991007911A1 (fr) * 1989-11-27 1991-06-13 Concat Ltd. Ameloration d'images d'irm d'os et de tissus apparentes a l'aide de complexes de cations paramagnetiques et de ligands de polyphosphonate
WO1991010645A2 (fr) * 1990-01-19 1991-07-25 Cockbain, Julian, Roderick, Michaelson Agents de chelation

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3988443A (en) * 1973-08-27 1976-10-26 Henkel & Cie G.M.B.H. Azacycloalkane-2,2-diphosphonic acids
EP0166020A1 (fr) * 1983-04-18 1986-01-02 The Dow Chemical Company Agents pour la chélation à base de dérivés de dicyclopentadiène
US4508704A (en) * 1984-02-27 1985-04-02 The Dow Chemical Company Radioactive metals complexed with phosphonate derivatives of bicycloheptane bis(alkylamines)
WO1991007911A1 (fr) * 1989-11-27 1991-06-13 Concat Ltd. Ameloration d'images d'irm d'os et de tissus apparentes a l'aide de complexes de cations paramagnetiques et de ligands de polyphosphonate
WO1991010645A2 (fr) * 1990-01-19 1991-07-25 Cockbain, Julian, Roderick, Michaelson Agents de chelation

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2322129A (en) * 1997-02-13 1998-08-19 Ciba Sc Holding Ag Polyazabicyclic compounds
EP1261349A4 (fr) * 2000-02-22 2004-09-01 Chelator Llc Composes a affinite et selectivite de chelation vis-a-vis des premiers elements des series de transition, et leur utilisation
US9717667B2 (en) 2012-12-20 2017-08-01 Colgate-Palmolive Company Oral care composition containing ionic liquids

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CA2125576A1 (fr) 1993-06-24
BR9206910A (pt) 1995-11-21
FI942715A7 (fi) 1994-07-27
AU3324193A (en) 1993-07-19
FI942715L (fi) 1994-07-27
JPH07502044A (ja) 1995-03-02
MX9207168A (es) 1993-12-01
FI942715A0 (fi) 1994-06-09
EP0616521A1 (fr) 1994-09-28

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