GB2092000A - Oral composition - Google Patents

Oral composition Download PDF

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GB2092000A
GB2092000A GB8139057A GB8139057A GB2092000A GB 2092000 A GB2092000 A GB 2092000A GB 8139057 A GB8139057 A GB 8139057A GB 8139057 A GB8139057 A GB 8139057A GB 2092000 A GB2092000 A GB 2092000A
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oral composition
copolymer
units
ranging
ratio
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Colgate Palmolive Co
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Priority claimed from US06/221,664 external-priority patent/US4339430A/en
Priority claimed from US06/221,665 external-priority patent/US4339431A/en
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    • 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
    • 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
    • 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
    • A61K8/40Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/43Guanidines
    • 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
    • A61K8/72Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/84Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
    • 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
    • A61K8/72Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/84Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
    • A61K8/88Polyamides

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Birds (AREA)
  • Epidemiology (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Cosmetics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

An oral composition effective to promote oral hygiene contains a copolymer of glutamic acid, tyrosine and optionally alanine and at least one nitrogen containing cationic antibacterial antiplaque agent in an amount of 0 to about 15% by weight based on its free base form.

Description

SPECIFICATION Oral composition The present invention relates to oral compositions containing an anticalculus agent.
Calculus is a hard, mineralized formation which forms on the teeth. Regular brushing prevents a rapid build-up of these deposits, but even regular brushing is not sufficient to remove all of the calculus deposits which adhere to the teeth. Calculus is formed on the teeth when crystals of calcium phosphates begin to be deposited in the pellicle and extracellular matrix of the dental plaque and become sufficiently closely packed together for the aggregates to become resistant to deformation. There is no complete agreement on the route by which calcium and orthophosphate ultimately become the crystalline material called hydroxyapatite (HAP). It is generally agreed, however, that at higher saturations, that is, above the critical saturation limit, the precursor to crystalline hydroxyapatite is an amorphous or microcrystalline calcium phosphate.
"Amorphous calcium phosphate" although related to hydroxyapatite differs from it in atomic structure, particle morphology, and stoichiometry. The X-ray diffraction pattern of amorphous calcium phosphate shows broad peaks typical of amorphous materials, which lack the longrange atomic order characteristic of all crystalline materials, including hydroxyapatite. It is apparent therefore that agents which effectively interfere with crystalline growth of hydroxyapatite will be effective as anticalculus agents. Whilst the invention is not dependent on the accuracy or otherwise of the following theory, a suggested mechanism by which the anticalculus agents of this invention inhibit calculus formation probably involves an increase of the activation energy barrier thus inhibiting the transformation of precursor amorphous calcium phosphate to hydroxyapatite.
Studies have shown that there is a good correlation between the ability of a compound to prevent hydroxyapatite crystalline growth in vitro and its ability to prevent calcification in vivo.
A substantial number of different types of compounds and compositions have been developed for use as antibacterial, and antiplaque and anticalculus agents in oral compositions, including for example such cationic materials as the bisbiguanide compounds and quaternary ammonium compounds, e.g. benzethonium chloride and cetyl pyridinium chloride, disclosed in U.S.
4,1 0,429. These cationic materials however tend to stain the teeth with continued use.
Further, they exert an antibacterial function which undesirably tends to disrupt or destroy the normal microflora of the mouth and/or the digestive system. Other such materials have been found to be unstable in the presence of anionic surface active agents often present in conventional oral compositions.
This invention aims to provide an oral anticalculus composition which will be less subject to one or more of the above deficiencies.
This invention also aims to provide an improved anticalculus oral composition which will have relatively little or no tendency to stain the teeth.
The invention further aims to provide an oral composition which inhibits the transformation of amorphous calcium phosphate to hydroxyapatite crystal structure normally associated with calculus.
This invention further aims to provide an improved method for inhibiting the formation of calculus and/or staining of teeth N-containing cationic antibacterial antiplaque agents.
The invention also aims to provide an oral composition containing a nitrogen-containing cationic antibacterial antiplaque agent, which composition has a reduced tendency to stain the teeth.
In accordance with certain of its aspects, this invention relates to an oral composition comprising an orally acceptable vehicle containing in an effective amount as an anticalculus agent a copolymer consisting essentially of: A) n units have the molecular configuration of units derived from glutamic acid, B) m units having the molecular configuration of units derived from alanine, and C) p units have the molecular configuration of units derived from tyrosine, the ratio of (n + m): p ranging from about 5:1 to about 9.5:1 and the ratio of m:n ranging from 0:1 to about 0.6:1, the molecular weight of the copolymer ranging from about 5,000 to about 150,000.
The afore-mentioned copolymers may be prepared in well known manner, as for example by the procedure disclosed in Chase and Williams ''lmmunochemistry", Vol. 2, pp 168, 1 69 (1978) Academic Press. In general, the copolymers are prepared by randomn copolymerization of the N-carboxyanhydrides of glutamic acid, tyrosine and alanine in the required molar proportions in the form of a mixture in an organic solvent such as dioxane, benzene, dimethyl formamide or N-methyl pyrrolidone and in the presence of an initiator such as an organic amine (e.g. triethylamine) or sodium methoxide.
The (A) units in the copolymer may be depicted as having the structural formula:
n being a numerical value representing the number of (A) units of glutamic acid in the copolymer.
The (B) units in the copolymer may be depicted as having the structural formula:
m being a numerical value representing the number of (B) units of alanine in the copolymer.
The (C) units in the copolymer may be depicted as having the structural formula:
p being a numerical value representing the number of (C) units of tyrosine in the copolymer.
As defined above, the ratio of (n + m): p ranges from about 5:1 to about 9.5:1, the ratio of m:n ranges up to about 0.6:1 and the values of m, n and p are such that the copolymer has a molecular weight of about 5,000 to about 150,000, preferably about 17,000 to about 100,000.
Especially preferred copolymers are a two component copolymer containing glutamic (A) units and tyrosine (B) units in a ratio of about 9:1 and having a molecular weight of about 17,000 to about 21,000, and a three component copolymer containing glutamic (A) units, alanine (B) units and tyrosine (C) units in a ratio of about 6:3:1 and having a molecular weight of about 80,000 to about 100,000.
It will be understood that the free acid form of the copolymers employed herein may be converted to, and employed, in their equivalent salt form by treatment with any base containing an orally acceptable cation such as alkali metal (e.g. sodium or potassium), ammonium, C, ,8 mono-, di- or tri- substituted ammonium (e.g. alkanol substituted such as mono-, di- or triethanolammonium), or organic amine. It will also be understood that when referring to these copolymers as being water soluble such copolymers should be water soluble or readily water dispersible in the concentration employed in conventional oral compositions such as mouthwashes, toothpastes and the like.
The copolymers employed in accordance with this invention are peculiarly advantageous oral anticalculus agents. Bearing in mind that human saliva contains natural inhibitors of calcium and phosphate precipitation including glutamic acid and tyrosine, the copolymers of the present invention are relatively safe to use even if ingested since they are readily hydrolyzed in the stomach by chymotyprin, a proteolytic enzyme known to hydrolyze tyrosine. In contrast, other non-hydrolyzable anticalculus agents when absorbed in the gastrointestinal tract could cause changes in the bone. These copolymers are additionally advantageous in being substantive to oral surfaces.
The concentration of these copolymer anticalculus agents in oral compositions can range widely, typically upwards of about 0.01% by weight with no upper limit except as dictated by cost or incompatibility with the vehicle. Generally, concentrations of about 0.01% to about 10.0%, preferably about 0.1% to about 8.0% more preferably about 0.5% to about 5.0% by weight are utilized. Oral compositions which in the ordinary course of usage could be accidentally ingested preferably contain concentrations in the lower portions of the foregoing ranges.
Cationic nitrogen-containing antibacterial materials are well known in the art. See, for instance the section on "Quaternary Ammonium and Related Compounds" in the article on "Antiseptics and Disinfectants" in Kirk-Othmer Encyclopedia of Chemical Technology, second edition (Vol. 2, p. 632-635), incorporated herein by reference. Cationic materials which possess antibacterial activity (i.e. are germicides) are used against bacteria and have been used in oral compositions to counter plaque formation caused by bacteria in the oral cavity.
Among the most common of these antibacterial anti-plaque quaternary ammonium compounds is benzethonium chloride, also known as Hyamine 1 622 diisobutyl-phenoxyethoxyethyl dimethyl benzyl ammonium chloride. In an oral preparation this material is highly effective in promoting oral hygiene by reducing formation of dental plaque and calculus, which is generally accompanied by a reduction in caries formation and periodontal diseases. Other cationic antibacterial agents of this type are those mentioned, for instance, in U.S. Patent Nos, 2,984,639, 3,325,402, 3,431,208 and 3,703,583 and British Patent No. 1,319,396.
Other antibacterial antiplaque quaternary ammonium compounds include those in which one or two of the substituents on the quaternary nitrogen has a carbon chain length (typically provided by an alkyl group) of some 8 to 20, typically 10 to 18, carbon atoms while the remaining substituents have a lower number of carbon atoms (typically provided by an alkyl or benzyl group), such as 1 to 7 carbon atoms, typically methyl or ethyl groups. Dodecyl trimethyl ammonium bromide, dodecyl dimethyl (2-phenoxyethyl) ammonium bromide, benzyl dimethyl stearyl ammonium chloride, cetyl pyridinium chloride and quaternized 5-amino-1,3-bis (2-ethylhexyl)-5-methyl hexa hydropyrimidine are exemplary of other typical quaternary ammonium antibacterial agents.
Other types of cationic antibacterial agents which are desirably incorporated in oral compositions to promote oral hygiene by reducing plaque formation are the amidines such as the substituted guanidines e.g. chlorhexidine and the corresponding compound, alexidine, having 2ethylhexyl groups instead of chlorophenyl groups and other bis-guanides such as those described in German patent application No.P 2,332,383 published January 10, 1974, which sets forth the following formula:
in which A and A' signify as the case may be (1) a phenyl radical, which can be substituted with up to 2 alkyl or alkoxy groups having 1 up to about 4 carbon atoms, a nitro group or a halogen atom, (2) an alkyl group which contains 1 to about 1 2 carbon atoms, or (3) alicyclic groups with 4 to about 1 2 carbon atoms, X and X' as the case may be may represent an alkylene radical with 1 to 3 carbon atoms, z and z' are as the case may be either zero or 1, R and R', as the case may be, may represent either a hydrogen atom or an alkyl radical with 1 to about 1 2 carbon atoms or an aralkyl radical with 7 to about 1 2 carbon atoms, n is a whole number of 2 to 1 2 inclusive and the polymethylene chain (CH2)n can be interrupted by up to 5 ether, thioether, phenyl or naphthyl groups; these are available as pharmaceutically suitable salts.
Additional substituted guanidines are: N '-(4-chlorobenzyl)-N5-(2,4-dichlorobenzyl) biguanide; pchlorobenzyl biguanide, 4-chlorobenzhydryl guanylurea; N-3-lauroxypropyl-N5-p-chlorobenzyl biguanide; 5,6-dichloro-2-guanidobenzimidazole; and N-p-chlorophenyl-N5-laurylbiguanide.
The cationic aliphatic tertiary amines also possess antibacterial and antiplaque activity. Such antibacterial agents include tertiary amines having one fatty alkyl group (typically containing 1 2 to 1 8 carbon atoms) and 2 poly(oxyethylene) groups attached to the nitrogen (typically containing a total of from 2 to 50 ethenoxy groups per molecule) and salts thereof with acids and compounds of the structure:
where R represents a fatty alkyl group containing 1 2 to 1 8 carbon atoms and x, y and z total 3 or higher, as well as salts thereof. Generally, cationic agents are preferred for their antiplaque effectiveness.
The antibacterial antiplaque compound is preferably one which has an antibacterial activity such that its phenol co-efficient is well over 50, more preferably well above 100, such as above about 200 or more for S, aureus (staphylococcus aureus); for instance the phenol coefficient (A.O.A.C.) of benzethonium chloride is given by the manufacturer as 410, for S. aureus. The cationic antibacterial agent will generally be a monomeric (or possibly dimeric) material of molecular weight well below 2,000, such as less than about 1,000. It is, however, within the broader scope of the invention to employ a polymeric cationic antibacterial agent.The cationic antibacterial agent is preferably supplied in the form of an orally acceptable salt thereof, such as the chloride, bromide, sulphate, alkyl sulphonate such as methyl sulphonate or ethyl sulphonate, phenylsulphonate, such as p-methylphenyl sulphonate, nitrate, acetate, or gluconate.
The nitrogen-containing cationic antibacterial agents (including the tertiary amine) antibacterial agents effectively promote oral hygiene, particularly by removing plaque. However, their use has been observed to lead to staining of dental surfaces or discolouration.
The reason for the formation of such dental stain has not been clearly established. However, human dental enamel contains a high proportion (about 95%) of hydroxyapatite (HAP) which includes Ca2+ and P043- ions. In the absence of dental plaque additional Ca2+ and P033particularly from saliva, can be deposited on the enamel and such deposits can include colour bodies which ultimately stain the tooth enamel as a calcified deposit thereon. It can be that as the cationic (including the tertiary amine) antibacterial agents remove plaque they also denature protein from saliva in the oral environment and the denatured protein can then act as a nucleating agent which is deposited on and stains or discolours tooth enamel.
Previously employed additives which reduced dental staining by cationic antibacterial antiplaque agents also generally reduced the activity of antibacterial antiplaque agents such as bisbiguanido compounds, as by forming a precipitate with such agents.
It is a further advantage of this invention that the above-described copolymers are antinucleating agents which unexpectedly inhibit, prevent or remove, the staining of dental enamel caused by such cationic (including the tertiary amine) antibacterial agents without precipitating or substantially adversely affecting their antibacterial and antiplaque activity. In themselves (even in the absence of such antibacterial agents), these copolymer additives are effective to reduce formation of dental calculus without unduly decalcifying dental enamel, in addition to effectively inhibiting gingivitus. However, not all anti-nucleating agents are effective to prevent staining by such antibacterial agents. Victamide (also known as Victamine C) which is a condensation product of ammonia with phosphoruspentoxide, actually increases staining even in the absence of such antibacterial agents.
Cationic nitrogen-containing antibacterial antiplaque agents optionally employed in the practice of this invention are described above. When such agents are present they are typically employed in amounts such that the oral product contains between about 0.001 and 15% by weight of the agent. Preferably for desired levels of antiplaque effect, the finished oral product contains about 0.01 to about 5%, and most preferably about 0.25 to 1.0% by weight of the antibacterial antiplaque agent, referring to its free base form.
In certain highly preferred forms of the invention the oral composition may be substantially liquid in character, such as a mouthwash or rinse. In such a preparation the vehicle is typically a water-alcohol mixture desirably including a humectant as described below. Generally, the 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 most preferably about 4:1 to about 5:1 by weight. The total amount of water-alcohol mixture in this type of preparation is typically in the range of from about 70% to about 99.9% 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 typically from about 5.5 to 8. The pH is preferably in the range of from about 6 to about 8.0.It is noteworthy that the compositions of the invention may be applied orally at a lower pH without substantially decalcifying dental enamel. The pH can be controlled with acid (e.g. citric acid or benzoic acid) or base (e.g. sodium hydroxide) or buffered (as with phosphate buffers). Such liquid oral preparations may also contain a surface active agent and/or a fluorine-providing compound.
In certain other desirable forms of this invention, the oral composition may be substantially solid or pasty in character such as toothpowder, a dental tablet, a toothpaste or dental cream.
The vehicle of such solid or pasty oral preparations generally contains polishing material.
Examples of polishing materials are water-insoluble sodium metaphosphate, potassium metaphosphate, tricalcium phosphate, dihydrated calcium phosphate, anhydrous dicalcium phosphate, calcium pyrophosphate, magnesium orthophosphate, trimagnesium phosphate, calcium carbonate, alumina, hydrated alumina, aluminium silicate, zirconium silicate, silica, bentonite, and mixtures thereof. Preferred polishing materials include Dical (calcium dihydrogen phosphate), colloidal silica, silica gel, complex amorphous alkali metal aluminosilicate and hydrated alumina.
Alumina, particularly the hydrated alumina sold by Alcoa as C333, which has an alumina -content of 64.9% by weight, a silica content of 0.008%, a ferric oxide content of 0.003%, and a moisture content of 0.37%, at 110"C, and which has a specific gravity of 2.42 and a particle size such that 100% of the particles are less than 50 microns and 84% of the particles are less than 20 microns, is very effective.
When visually clear gels are desired, a polishing agent of colloidal silica, such as those sold under the trademark SYLOID as Syloid 72 and Syloid 74 or under the trademark SANTOCEL as Santocel 100 and alkali metal aluminosilicate complexes are particularly useful, since they have refractive indices close to the refractive indices of gelling agent-liquid (including water and/or humectant) systems commonly used in dentifrices.
Many of the so-called "water-insoluble" polishing materials are anionic in character and also include small amounts of soluble material. Thus, insoluble sodium metaphosphate may be formed in any suitable manner, as illustrated by Thorpe's Dictionary of Applied Chemistry, Volume 9, 4th Edition, pp. 510-511. The forms of insoluble sodium metaphosphate known as Madrell's salt and Kurrol's salt are further examples of suitable materials. These metaphosphate salts exhibit a minute solubility in water, and therefore are commonly referred to as insoluble metaphosphates. There is present therein a minor amount of soluble phosphate material as impurities, usually a few percent such as up to 4% by weight.The amount of soluble phosphate material, which is beleived to include a soluble sodium trimetaphosphate in the case of insoluble metaphosphate, may be reduced by washing with water if desired. The insoluble alkali metal metaphosphate is typically employed in powder form of a particle size such than no more than about 1 % of the material is larger than about 37 microns.
The polishing material is generally present in amounts ranging from about 10% to about 99% by weight of the oral preparation. Preferably, it is present in amounts ranging from about 10% to about 75% in toothpaste, and from about 99% in toothpowder.
In the preparation of tooth powders, it is usually sufficient to admix mechanically, e.g. by milling, the various solid ingredients in appropriate quantities and particle sizes.
In pasty oral preparations the copolymer should be compatible with the other components of the preparations. Thus, in a toothpaste, the liquid vehicle may comprise water and humectant typically in an amount ranging from about 10% to about 90% by weight of the preparation.
Glycerine, propylene glycol, sorbitol, or polyethylene glycol 400 may also be present as humectants. Particularly advantageous liquid ingredients comprise mixtures of water, glycerine and sorbitol.
In clear gels where the refractive index is an important consideration, about 3-30% by weight of water, 0 to about 80% by weight of glycerine, and about 20-80% by weight of sorbitol is preferably employed. A gelling agent, such as natural or synthetic gums or gum-like materials, typically Irish moss, sodium carboxymethylcellulose, methyl cellulose, or hydroxy-ethyl cellulose, may be employed. Other gelling agents which may be employed include gum tragacanth, polyvinylpyrrolidone and starch. They are usually present in toothpaste in an amount up to about 10% by weight, preferably in the range of from about 0.5% to about 5%. The preferred gelling agents are methyl cellulose and hydroxyethyl cellulose.In a toothpaste or gel, the liquids and solids are proportioned to form a creamy or gelled mass which is extrudable from a pressurized container or from a collapsible, e.g. aluminium or lead, tube.
The solid or pasty oral preparation which typically has a pH measured as a 20% slurry of about 4.5 to 9, generally about 5.5 to about 8 and preferably about 6 to about 8.0, may also contain a surface active agent and/or a fluorine-providing compound.
It will be understood that, as is conventional, the oral preparations are to be sold or otherwise distributed in suitably labelled packages. Thus a jar of mouthrinse will have a label describing it, in substance, as a mouthrinse or mouthwash and having directions for its use; and a toothpaste will usually be in a collapsible tube, typically aluminium, lined lead or plastic, or other squeeze dispenser for metering out the contents, having a label describing it, in substance, as a toothpaste or dental cream.
The oral compositions of this invention may contain a non-soap synthetic sufficiently water soluble organic anionic or nonionic surfactant in concentrations generally ranging from about 0.05 to about 10, preferably about 0.5 to about 5, weight percent, to promote wetting, detersiveand foaming properties. U.S. Patent No. 4,041,149 discloses such suitable anionic surfactants in col. 4, 31-38, and such suitable nonionic surfactants in col. 8, lines 30-68 and col. 9, lines 1-12, which passages are incorporated herein by reference thereto.
In certain forms of this invention a fluorine-providing compound is present in the oral preparations. These compounds may be slightly soluble in water or may be fully water-soluble.
They are characterised by their ability to release fluoride ions in water and by substantial freedom from reaction with other compounds of the oral preparation. Among these materials are inorganic fluoride salts, such as soluble alkali metal, alkaline earth metal and heavy metal salts, for example, sodium fluoride, potassium fluoride, ammonium fluoride, calcium fluoride, a copper fluoride such as cuprous fluoride, zinc fluoride, a tin fluoride such as stannic fluoride or stannous chlorofluoride, barium fluoride, sodium fluorosilicate, ammonium fluorosilicate, sodium fluorozirconate, sodium monofluorophosphate, aluminium mono- and di-fluorophosphate, and fluorinated sodium calcium pyrophosphate. Alkali metal and tin fluorides, such as sodium and stannous fluorides, sodium mono-fluorophosphate and mixtures thereof, are preferred.
The amount of the fluorine-providing compound is dependent to some extent upon the type of compound, its solubility, and the type of oral preparation, but it must be a nontoxic amount. In a solid oral preparation, such as toothpaste or toothpowder, an amount of such compound which releases a maximun of about 1 % by weight of the preparation is considered satisfactory.
Any suitable minimum amount of such compound may be used, but it is preferable to employ sufficient compound to release about 0.005% to 1%, and preferably about 0.1% of fluoride ion. Typically, in the cases of alkali metal fluorides and stannous fluoride, this component is present in an amount up to about 2% by weight, based on the weight of the preparation, and preferably in the range of about 0.05% to 1%. In the case of sodium monofluorophosphate, the compound may be present in an amount up to 7.6% by weight, more typically about 0.76%.
In a liquid oral preparation such as a mouthwash, the fluorine-providing compound is typically present in an amount sufficient to release up to about 0.13%, preferably about 0.0013% to 0.1% and most preferably about 0.0013% to 0.5%, by weight, of fluoride ion.
Various other materials may be incorporated in the oral preparations of this invention such as whitening agents, preservatives, silicones, chlorophyll compounds, other anticalculus agents, antibacterial antiplaque agents, and/or ammoniated material such as urea, diammonium phosphate, and mixtures thereof. These adjuvants, where present, are incorporated in the preparations in amounts which do not substantially adversely affect the properties and characteristics desired.
In preparating the oral compositions of this invention comprising the above-defined combination of anti-bacterial agent and additive in an oral vehicle which typically includes water, it is highly preferred if not essential to add the additive after the other ingredients (except perhaps some of the water) are mixed or contacted with each other to avoid a tendency for the said agent to be precipitated.
Any suitable flavouring or sweetening material may also be employed. Examples of suitable flavouring or sweetening material may also be employed. Examples of suitable flavouring constituents are flavouring oils, e.g. oils of spearmint, peppermint, wintergreen, sassafras, clove, sage, eucalyptus, majoram, cinnamon, lemon, and orange, and methyl salicylate. Suitable sweetening agents include sucrose, lactose, fructose, maltose, sorbitol, xylitol, sodium cyclamate, perillartine, APM (aspartyl phenyl alanine, methyl ester), and saccharin. Suitably, flavour and sweetening agents may together comprise from about 0.01% to 5% or more of the preparation.
In the practice of this invention an oral composition according to this invention such as a mouthwash or toothpaste containing the defined copolymer in an amount effective to inhiit calculus on dental surfaces is applied regularly to dental enamel, preferably from about 5 times per week to about 3 times daily, at a pH of about 4.5 to about 9, generally about 5.5 to about 8, preferably about 6 to 8.
The invention may be put into practice in various ways and a number of specific embodiments will be described to illustrate the invention with reference to the accompanying examples. All amounts and proportions referred to herein and in the appended claims are by weight unless otherwise indicated.
EXAMPLES 1 to 13 Inhibition of Crystal Growth of HAP This was evaluated by a pH Stat method. 1.0 ml of an aqueous solution of 1 X 10-4M to 1 X 1032-5M of the anticalculus agent being tested and 0.1 M sodium dihydrogen phosphate was placed in a reaction flask with 22 to 23 ml of distilled water with continuous stirring in an atmosphere of nitrogen. To this was added 1 ml of 0.1 M calcium chloride (CaC12) and the pH adjusted to 7.4 + 0.05 with sodium hydroxide (NaOH) (final conc. of Ca2+ and P033- = 4 X 10-3M). Consumption of 0.1 N sodium hydroxide (NaOH) was recorded automatically by a pH Stat (Radiometer). In this test, the formation of HAP occurs in 2 distinct phases.
In the first stage there is rapid consumption of base (1-4 mins) which then diminishes until after 15-20 minutes when a second stage of rapid uptake of base takes place. A delay in the onset of the second rapid consumption of base or a total absence of the second stage of rapid consumption of base indicates an interference with the crystal growth of HAP. Agents which interfere with HAP crystal growth are effective anticalculus agents. When tested by the foregoing procedure, the results obtained are given in Table I below.
TABLE I Delay (Min.) for second Time (Min.) stage of Anticalculus for HAP HAP Example Agent Type conc. Formation Formation 1 Water(Conrol) 21.0 2 copolymer 9/1 (20 ppm) 30.0 9.0 3 copolymer 9/1 (21 ppm) 40.0 19.0 4 copolymer 9/1 (27 ppm) 87.0 66.0 5 copolymer 9/1 (32 pp) 117.0 96.0 6 Copolymer 6/3/1 (40 ppm) 31.0 10.0 7 Copolymer 7/3 (40 ppm) 21.0 0 8 Copolymer 1/1 (1 x 10-4 21.0 0 9 Copolymer 3/7 (40 ppm) 21.0 0 10 Copolymer G/L/T (32 ppm) 21.0 0 11 Glu/Tyr/l/l (2x 10-4 18.0 0 12 Glu/Ala/Tyr 1/1/1 (32 --m) 21.0 0 13 Tyr (32 ppm) 18.0 0 The copolymers referred to in Table I were prepared by copolymerization of alpha-amino acid anhydride mixtures by the procedure described in "Immunochemistry" (see above).
Copolymer 9/1 (Examples 2-5), illustrative of the invention, was prepared from a 9:1 molar mixture of glutamic acid and tyrosine, and was determined by centrifugation to have a molecular weight of about 1 9,300.
Copolymer 6/3/1 (Example 6), also illustrative of the invention, was prepared from a 6:3:1 molar mixture of glutamic acid, alanine and tyrosine, and was determined to have a molecular weight of about 90,800.
The remaining copolymers were comparative.
Thus, copolymers 7/3 (Example 7), 1/1 (Example 1) and 3/7 (Example 9) were prepared from mixtures containing proportions of glutamic acid to tyrosine outside those required herein, i.e. in molar ratios of 7:3, 1:1 and 3:7.
Copolymer G/L/T (Example 10) was prepared from a 1:1:1 molar mixture of glutamic acid, lysine and tyrosine.
The agents tested in Examples 11, 1 2 and 13 were monomers or monomer mixtures including glutamic acid, tyrosine and/or alanine, the mixtures containing equal molar proportions of monomer components.
The results shown in TABLE I plainly show the effective inhibition by the copolymers of this invention, in Examples 2 to 5 and 6, of crystal growth of HAP in vitro, and that the inhibition is not due to complexation or chelation of calcium since substoichiometric ratios of copolymer:calcium were employed. The failure of the comparative agents of Examples 7 to 1 3 to inhibit HAP formation emphasises the criticality of the copolymers of the present invention, with respect to components and ratios of such components therein, for achieving the unexpectedly improved HAP inhibition of this invention.
EXAMPLES 14 to 17 In the following examples 1 4 to 1 7 are illustrative of mouthwash formulations according to the invention; the material identified as Pluronic F108 being a polyoxalkylene block polymer.
The components of these examples are listed in Table 2 below, the amounts being percentages.
TABLE 2 Example 14 15 16 17 Flavour 0.22 0.22 0.22 0.22 Ethanol 15.0 15.0 15.0 15.0 Pluronic F108 3.0 3.0 3.0 3.0 Glycerine 10.0 10.0 10.0 10.0 Sodium Saccharin 0.03 0.03 0.03 0.03 Copolymer 6/3/1 0.1 0.2 0.5 1.0 (see Example 6) Water q.s. to 100 100 100 100 EXAMPLE 18 This is an example of a toothpaste formulation in accordance with the invention, the inredients and proportions (weight percentages) are given in Table 3 below.
TABLE 3 Ingredient Proportions Glycerin 25.0 Carboxymethylcellulose 1.3 Sodium benzoate 0.5 Sodium saccharin 0.2 Silica 30.0 Sodium lauryl sulphate 1.5 Flavour 1.0 Copolymer 9/1 (see Examples 2 to 5) 3.0 Water to make 1 00 EXAMPLES 19 to 22 Mouthwash formulations according to the present invention and the antistaining activity of the copolymer additive therein are illustrated in Examples 21 and 22 by comparison with comparative Examples 1 9 (a placebo) and 20 (a control). The tooth staining characteristics of the formulations were evaluated by slurrying hydroxyapatite (Biogel), a specific salivary protein, a carbonyl source (e.g. acetaldehyde), and a pH 7 phosphate buffer, with and without the mouthwash formulations being tested. The mixture was shaken at 37"C for 18 hours.The coloured HAP powder was separated by filtration, dried and the colour levels (in reflectance units) determined on a Gardner colour difference metre.
TABLE 4 Example 19 20 21 22 Ethanol 10% 10% 10% 10% Glycerine 10 10 10 10 Flavour 0.146 0.146 0.146 0.146 Saccharin 0.03 0.03 0.03 0.03 Pluronic F1081 3.0 3.0 3.0 3.0 CPC(2) 0.1 0.1 0.1 Copolymer 9/1(3) 0.1 0.2 Water, q.s. to 100 100 100 100 pH (with 1N NaOH) 7.0 7.0 7.0 7.0 Reflectance 70.7 41.8 57.7 56.0 Difference + 28.9 -15.9 -14.2 Rd relative to (2) Notes on Table 4 1. Polyoxyalkylene block polymer (BASF; Wyandotte) 2. Cetyl pyridinium chloride 3. Prepared by the procedure described in "Immunochemistry" supra for copolymerizing a 9:1 molar mixture of glutamic acid and tyrosine, the copolymer being determined by centrifugation to have a molecular weight of about 19,300 (see Examples 2-5).
The above results plainly establish that the copolymer additives of the present invention substantially reduce dental staining ordinarily produced by cationic quarternary ammonia antibacterial antiplaque agents as exemplified by cetyl pyridinium chloride.
Further, in vitro tests established that the antiplaque activity of examples 20 and 21 were substantially equal, indicating that the copolymer additives of this invention do not significantly effect the anti plaque activity of cetyl pyridinium chloride.
EXAMPLES 23 to 28 Substitution of equivalent amounts of the antibacterial antiplaque agents given in Table 5 below for the cetyl pyridinium chloride employed in Examples 21 and 22 yield formulations also producing an unexpected reduction in dental staining.
TABLE 5
Example Antibacterial Antiplaque Agent 23 benzethonium chloride (BC) 24 Chlorhexidine diacetate 25 chlorhexidine digluconate 26 dodecyl trimethyl ammonium bromide CH2CH2OH CH2CH2OH 27 Cr2- ,8alkyl-N-CH2CH2N CH2CH2OH 28 alexidine dihydrochloride EXAMPLES 29 to 31 Further formulations exemplifying toothpastes with antiplaque activity and reduced staining are listed in Table 6 below.
TABLE 6 Example 29 30 31 Ingredient proportions (% by weight) Hydrated alumina 30 30 30 Glycerine 16 16 16 Sorbitol (70% aqueous solution) 6 6 6 Pluronic F-108 3 3 3 Hydroxyethyl cellulose 1.2 1.2 1.2 Benzethonium chloride (BC) 0.5 - - Chlorhexidine digluconate (20%) - 4.725 Cetyl pyridinium chloride - - Copolymer 6/3/1 (see Example 6) 0.08 0.5 1.0 Sodium saccharin 0.17 0.17 0.17 Flavour 0.8 0.8 0.8 Water q.s. to 100 100 100 As referred to above by reference to U.S.P. 4041149 suitable anionic surfactants include, for example, the water-soluble salts of higher fatty acid monoglyceride monosulphate detergent (e.g. sodium coconut fatty acid monoglyceride monosulphate), higher alkyl sulphates (e.g.
sodium lauryl sulphate), alkyl aryl sulphonate (e.g. sodium dodecyl benzene sulphonate), and higher fatty acid esters of 1 ,2-dihydroxypropane-sulphonate), and suitable nonionic surfactants include, water-soluble products which are derived from the condensation of an alkylene oxide or equivalent reactant and a reactive-hydrogen hydrophobe. The hydrophobic organic compounds may be aliphatic, aromatic or heterocyclic, although the first two classes are preferred. The preferred types of hydrophobes are higher aliphatic alcohols and alkyl phenols, although others may be used such as carboxylic acid, carboxamides, and sulphoamides. The ethylene oxide condensates with higher-alkyl phenols represent a preferred class of nonionic compounds.
Usually the hydrophobic moiety should contain at least about 6 carbon atoms, and preferably at least about 8 carbon atoms, and may contain as many as about 50 carbon atoms or more. The amount of alkylene oxide will vary considerably, depending upon the hydrophobe, but as a general guide and rule, at least about 5 moles of alkylene oxide per mole of hydrophobe should be used. The upper limit of alkylene oxide will vary also, but no particular criticality can be ascribed thereto. As much as 200 or more moles of alkylene oxide per mole of hydrophobe may be employed. While ethylene oxide is the preferred and predominating oxyalkylating reagent, other lower alkylene oxides such as propylene oxide, butylene oxide, and the like, may also be used or substituted in part of the ethylene oxide.Other nonionic compounds which are suitable are the polyoxyalkylene esters of the organic acids such as the higher fatty acids, the rosin acids, tall oil acids, and acids from petroleum oxidation products. These esters will usually contain from about 10 to about 22 carbon atoms in the acid moiety and from about 12 to about 30 moles of ethylene oxide or its equivalent.
Still other non ionic surfactants are the alkylene oxide condensates with the higher fatty acid am ides. The fatty acid group will generally contain from about 8 to about 22 carbon atoms and this will be condensed with about 10 to about 50 moles of ethylene oxide as the preferred illustration. The corresponding carboxamides and sulphonamides may also be used as substantial equivalents.
Still another class of nonionic products are the oxyalkylated higher aliphatic alcohols. The fatty alcohols should contain at lest 6 carbon atoms, and preferably at least about 8 carbon atoms.
The most preferred alcohols are lauryl, myristyl, cetyl, stearyl and oleyl alcohols and the said alcohols should be condensed with at least about 6 moles of ethylene oxide, and preferably about 10 to 30 moles of ethylene oxide. A typical nonionic product is oleyl alcohol condensed with 1 5 moles of ethylene oxide.

Claims (16)

1. An oral composition comprising an orally acceptable vehicle, and a copolymer consisting essentially of: (A) n units having the molecular configuration of units derived from glutamic acid, (B) m units having the molecular configuration of units derived from alanine, and (C) p units having the molecular configuration of units derived from tyrosine, the ratio of (n + m):p ranging from about 5:1 to about 9.5:1 and the ratio of m:n ranging from 0:1 to about 0.6:1, the molecular weight of the copolymer ranging from about 5,000 to about 1 50,000.
2. An oral composition comprising an orally acceptable vehicle, at least one cationic nitrogen-containing antibacterial antiplaque agent, and a copolymer consisting essentially of: (A) n units having the molecular configuration of units derived from glutamic acid, (B) m units having the molecular configuration of units derived from alanine, and (C) p units having the molecular configuration of units derived from tyrosine, the ratio of (n + m):p ranging from about 5:1 to about 9.5:1 and the ratio of m:n ranging from 0:1 to about 0.6:1, the molecular weight of the copolymer ranging from about 5,000 to about 150,000.
3. An oral composition comprising an orally acceptable vehicle, at least one cationic nitrogen-containing antibacterial antiplaque agent in an amount of up to 15% by weight based on its free base form and 0.01 to 10% by weight, a copolymer consisting essentially of: (A) n units having the molecular configuration of units derived from glutamic acid, (B) m units having the molecular configuration of units derived from alanine, and (C) p units having the molecular configuration of units derived from tyrosine, the ratio of (n + m):p ranging from about 5:1 to about 9.5:1 and the ratio of m:n ranging from 0:1 to about 0.6:1, the molecular weight of the copolymer ranging from about 5,000 to about 150,000.
4. An oral composition as claimed in any one of Claims 1 to 3 in which the copolymer consists of (A) and (C) and has a molecular weight of about 17,000 to 21,000.
5. An oral composition as claimed in Claim 4 in which the ratio of n:m:p in the copolymer is about 9:0:1.
6. An oral composition as claimed in any one of Claims 1 to 3 in which the copolymer consists of (A), (B) and (C) and has a molecular weight of about 80,000 to 100,000.
7. An oral composition as claimed in Claim 6 in which the ratio of n:m:p in the copolymer is about 6:3:1.
8. An oral composition as claimed in any one of Claims 2 to 7 in which the said antibacterial antiplaque agent is present in an amount of about 0.001 to about 15% by weight based on its free base form.
9. An oral composition as claimed in any one of Claims 2 to 8 in which the said antibacterial antiplaque agent is present in an amount of about 0.01 to about 5% by weight, based on its free base form.
1 0. An oral composition as claimed in any one of Claims 2 to 9 in which the said antibacterial antiplaque agent is substituted guanidine.
11. An oral composition as claimed in Claim 10 in which the said antibacterial antiplaque agent comprises a pharmaceutically acceptable water soluble salt of chlorhexidine or alexidine.
1 2. An oral composition as claimed in any one of Claims 2 to 9 in which the said antibacterial antiplaque agent is benzethonium chloride.
1 3. An oral composition as claimed in any one of Claims 2 to 9 in which the said antibacterial antiplaque agent is a quaternary ammonium compound containing 1 to 2 alkyl groups of 8 to 20 carbon atoms.
1 4. An oral composition as claimed in Claim 1 2 in which the said antibacterial antiplaque agent is cetyl pyridinium chloride.
1 5. An oral composition as claimed in any one of Claims 1 to 14 in which form of a mouthwash having a pH of about 4.5 to about 9, and in which the orally acceptable vehicle is an aqueous-alcohol vehicle.
16. An oral composition as claimed in any one of Claims 1 to 14 in the form of a toothpaste having a pH of about 4.5 to about 9, and incorporating a liquid vehicle, a gelling agent, and a dentally acceptable polishing agent.
1 7. A method of preparing a composition as defined in any one of Claims 1 to 1 6 comprising adding the copolymer to a mixture of the other ingredients thereof optionally except for some water.
1 8. A composition as claimed in Claim 1 substantially as specifically described herein with reference to any one of Examples 2 to 6, 14 to 17,18,21,22, 23 to 28, or 29 to 31.
GB8139057A 1980-12-31 1981-12-30 Oral composition Expired GB2092000B (en)

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US06/221,664 US4339430A (en) 1980-12-31 1980-12-31 Antibacterial oral composition
US06/221,665 US4339431A (en) 1980-12-31 1980-12-31 Anticalculus oral composition

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5000943A (en) * 1989-05-30 1991-03-19 Nabisco Brands, Inc. Canine biscuits containing an inorganic pyrophosphate
US5000973A (en) * 1989-05-30 1991-03-19 Nabisco Brands, Inc. Nutritionally-balanced canine biscuits containing an inorganic pyrophosphate
US5000940A (en) * 1989-05-30 1991-03-19 Nabisco Brands, Inc. Devices, compositions and the like having or containing an inorganic pyrophosphate
US5011679A (en) * 1989-05-30 1991-04-30 Nabisco Brands, Inc. Raw hide having a coating containing an inorganic pyrophosphate
US5015485A (en) * 1989-05-30 1991-05-14 Nabisco Brands, Inc. Dog biscuits having a coating containing an inorganic pyrophosphate
US5047231A (en) * 1989-05-30 1991-09-10 Nabisco Brands, Inc. Raw hide containing an inorganic pyrophosphate
US5094870A (en) * 1989-05-30 1992-03-10 Nabisco Brands, Inc. Canine biscuits containing an inorganic pyrophosphate
US5114704A (en) * 1989-05-30 1992-05-19 Nabisco Brands, Inc. Raw hide having a coating containing an inorganic pyrophosphate

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Publication number Priority date Publication date Assignee Title
KR100785232B1 (en) 2006-06-15 2007-12-11 남두석 Antifungal gypsum composite for dental surgery

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2015510A1 (en) * 1970-04-01 1971-10-21 ESPE Fabrik pharmazeutischer Präparate GmbH, 8031 Seefeld Dishwashing and cleaning agents for mucous membranes
US3939261A (en) * 1974-08-30 1976-02-17 Colgate-Palmolive Company Flavored dentifrice
ZA773318B (en) * 1976-06-18 1978-04-26 I Kleinberg Means and method for improving natural defenses against caries
US4110429A (en) * 1976-12-30 1978-08-29 Colgate-Palmolive Company Antibacterial oral composition
US4225579A (en) * 1979-02-27 1980-09-30 Israel Kleinberg Means and method for improving defenses against caries

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5000943A (en) * 1989-05-30 1991-03-19 Nabisco Brands, Inc. Canine biscuits containing an inorganic pyrophosphate
US5000973A (en) * 1989-05-30 1991-03-19 Nabisco Brands, Inc. Nutritionally-balanced canine biscuits containing an inorganic pyrophosphate
US5000940A (en) * 1989-05-30 1991-03-19 Nabisco Brands, Inc. Devices, compositions and the like having or containing an inorganic pyrophosphate
US5011679A (en) * 1989-05-30 1991-04-30 Nabisco Brands, Inc. Raw hide having a coating containing an inorganic pyrophosphate
US5015485A (en) * 1989-05-30 1991-05-14 Nabisco Brands, Inc. Dog biscuits having a coating containing an inorganic pyrophosphate
US5047231A (en) * 1989-05-30 1991-09-10 Nabisco Brands, Inc. Raw hide containing an inorganic pyrophosphate
US5094870A (en) * 1989-05-30 1992-03-10 Nabisco Brands, Inc. Canine biscuits containing an inorganic pyrophosphate
US5114704A (en) * 1989-05-30 1992-05-19 Nabisco Brands, Inc. Raw hide having a coating containing an inorganic pyrophosphate

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ES508439A0 (en) 1982-12-16
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NO814477L (en) 1982-07-01
NO155527B (en) 1987-01-05
FR2497097B1 (en) 1986-05-02
CH651204A5 (en) 1985-09-13
PT74225B (en) 1983-05-30
NZ199305A (en) 1984-07-31
CA1175358A (en) 1984-10-02
KR830007064A (en) 1983-10-14
DK575881A (en) 1982-07-01
KR880001750B1 (en) 1988-09-12
FR2497097A1 (en) 1982-07-02
DE3151217A1 (en) 1982-08-05
ATA563081A (en) 1984-09-15
NO155527C (en) 1987-04-15
AU7886781A (en) 1982-07-08
SE8107611L (en) 1982-07-01
GB2092000B (en) 1984-06-27
NL8105896A (en) 1982-07-16
ES8302033A1 (en) 1982-12-16
GR76968B (en) 1984-09-04
AU555654B2 (en) 1986-10-02
AR228295A1 (en) 1983-02-15

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