GB2224204A - Antiplaque/antigingivitis composition - Google Patents

Abstract

A composition for inhibiting human dental plaque and gingivitis by regular application to the oral cavity containing an amount effective to inhibit attachment to tooth surfaces of plaque-inducing Actinomyces viscosus, dental plaque and gingivitis, polyvinyl phosphonic acid or salt thereof having a number average molecular weight of 6,100 to 9,000.

Description

"ANTIPLAQUE/ANTIGINGIVITIS COMPOSITION" The present invention relates to the use of nonantibacterial agents and oral compositions for promoting human oral hygiene, and especially to a method for treating, controlling or inhibiting both plaque and gingivitis, which latter is characterized by such symptoms as inflammation, bleeding, recession, and/or swelling of the gums. Types of gingivitis include afunctional gingivitis, gingivitis marginal and cotton-roll gingivitis. Gingivitis leads to periodontitis.

The gums are seriously harmed by deposits of dental plaque, a combination of minerals and bacteria found in the mouth. The bacteria associated with plaque can secrete enzymes and endotoxins which can irritate the gums and cause an inflammatory gingivitis.

As the gums become increasingly irritated by this process they have a tendency to bleed, lose their toughness and resiliency, and separate from the teeth, leaving periodontal pockets in which debris, secretions, more bacteria and toxins further accumulate. It is also possible for food to accumulate in these pockets, thereby providing nourishment for increased growth of bacteria and production of endotoxins and destructive enzymes.

Actinomyces viscosus, a gram positive rod, has been identified as implicated in the etiology of gingivitis (Loeche et al "Bacteriology of human experimental gingivitis: effects of plaque and gingivitis sores", Infection and Immunity 21, 830-839 (1978)). This organism attaches to tooth surfaces to form the dental plaque.

A multitude of materials have been previously proposed and employed for controlling plaque and gingivitis, but none have been entirely satisfactory. For example, some of such materials have been found to be unstable in the presence of the anionic surface active agents generally present in conventional oral preparations. A number of such materials such as the cationic quaternary ammonium agents exert an antibacterial function which undesirably tends to disrupt or destroy the normal microflora of the mouth and/or the digestive system.

We have discovered that VPA polymer and its salts with an M.W.n. of about 6,100 to 9,000 effectively interfere with or inhibit the attachment of Actinomvces Viscosus and S. Mutans to saliva coated hydroxyapatite (HAP) beads.

This invention accordingly includes a composition for inhibiting human dental plaque and gingivitis by applying it to the human oral cavity, the composition containing a dentally acceptable oral vehicle and an effective plaque- and gingivitis- inhibiting amount of polyvinyl phosphonic/acid having an M.W.n of about 6,100 to 9,000, or an orally acceptable salt thereof.

The VPA polymer for use in compositions of this invention should preferably have a M.W.n., number average molecular weight, (measured by GPC-gel permeation chromatography) of 6,100 to 8,900, more preferably 6,300 to 7,300, and may be prepared in known manner by polymerizing vinyl phosphonyl dichloride under substantially anhydrous conditions in the presence of a free radical catalyst until the desired M.W.n n. is obtained, and then mixing the resulting polymer with water to hydrolytically convert the vinyl phosphonyl dichloride units in the polymer to VPA units.The resulting polymer is in free acid form and may desirably be converted to salt form by treatment with any orally acceptable cation-providing base such as alkali metal (e.g. sodium or potassium), ammonium, C1-18 mono-, di- and tri-substituted ammonium, (e.g.

alkanol substituted ammonium, such as mono-, di- and triethanolammonium), organic amines, etc. It will be understood that the mono- and di- salt forms of the polymer are the equivalent of the free acid form and that the term "water soluble" applicable to all such forms is inclusive of readily water dispersible forms thereof in the usual use concentrations.

It will also be understood that the VPA polymer may also contain minor proportions, i.e. less than 50% by weight preferably less than about 10 wt.%, more preferably less than about 5 wt.%, most preferably less than about 2 wt.%, of units derived from other nonfluorinated ethylenically unsaturated monomers which, in type and amount, are nontoxic and do not interfere with the desired water soluble and antigingivitis activities of the polymer.Other such monomers may, for example, include olefines such as ethylene, propylene, isopropylene, butylene and isobutylene, vinyl lower alkyl ethers such as vinyl methyl, ethyl and isobutyl ethers, alpha, beta unsaturated carboxylic acids and their lower alkyl and substituted lower alkyl esters such as acrylic, methacrylic, aconitic, maleic and fumaric acids and their methyl, ethyl, isobutyl and dimethylaminoethyl esters, allyl alcohol and acetate, vinyl and vinylidene halides, vinyl lower alkanoic acid esters such as vinyl acetate and butyrate, acrylamide and methacrylamide and N-lower alkyl and N,N-dilower alkyl substituted derivatives thereof, and the like.

The concentration of the VPA polymeric antiplaque agent 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%, 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 perferably contain concentrations in the lower portions of the foregoing ranges.

In certain highly preferred forms of the invention, the oral composition may be substantially liquid such as mouthwash or rinse. Such preparations generally contain a humectant and the vehicle is typically a water-alcohol mixture. Generally, the ratio of water to alcohol is in the range of from about 1:1 to about 20:1 preferably from 3:1 to 20:1 and most preferably about 17:3, 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.

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 contains polishing material. Examples of polishing materials are water-insoluble sodium metaphosphate, potassium metaphosphate, tricalcium phosphate, calcium pyrophosphate, magnesium orthophosphate, trimagnesium phosphate, calcium carbonate, alumina, hydrated alumina, aluminium silicate, zirconium silicates, silica, bentonite, and mixtures thereof. Preferred polishing materials include crystalline silica having particle sizes of up to 5 microns, a mean particle size of up to 1.1 microns, and a surface area of up to 50,000 cm2/gm, silica gel, complex amorphous alkali metal aluminosilicate, hydrated alumina, dicalcium phosphate.

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 0.037%, 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 particularly desirable.

When visually clear gels are employed, 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 par.icularly 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 "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, fourth Edition, pp. 510511. 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 believed 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 that no more than about 1% of the material is larger than 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 70 to about 99% in toothpowder.

In the preparation of toothpowders, it is usually sufficient to admix mechanically, e.g. by milling, the various solid inyredients in appropriate quantities and particle sizes.

In pasty oral preparations the above-defined combination of the antigingivitis agent and polishing material should be compatible with the other components of the preparation. 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, sorbitol, or polyethylene glycol may also be present as humectants or binders. Particularly advantageous liquid ingredients are polyethylene glycol and polypropylene glycol. Also advantageous are liquid 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 20-28% by weight of sorbitol is preferably employed. A gelling agent, such as natural or synthetic gums or gumlike materials, typically Irish moss, sodium carboxymethylcellulose, methyl cellulose, hydroxyethyl cellulose, gum tragacanth, polyvinylpyrrolidone, starch, and preferably hydroxypropyl methyl cellulose and the Carbopols (e.g. 934, 940 and 941), etcetera is usually present in toothpaste in an amount of up to about 10% by weight, preferably in the range of from about 0.5 to about 5%. 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 on 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 suitable 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, e.g. aluminium or lined lead, pump 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, detersive and foaming properties.

U.S. Patent No. 4,041,149 discloses such suitable anionic surfactants in column 4, lines 31-38, and such suitable nonionic surfactants in column 8, lines 30-68 and column 9, lines 1-12 which passages are incorporated herein by reference thereto.

In certain forms of this invention a fluorineproviding compound is present in the oral preparation.

These compounds may be slightly soluble in water or may be fully water-soluble. They are characterized by their ability to release fluoride ions in water and by substantial freedom from reaction with other components 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, Ca 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 monofluorophosphate 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 maximum 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 mono-fluorophosphate, 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% by weight, of fluoride.

Various other materials may be incorporated in the oral preparations of this invention, subject to the above. Examples are whitening agents, preservatives, silicones, chlorophyll compounds, and 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.

Any suitable flavouring or sweetening material may also be employed, also subject to the above. Examples of suitable flavouring constituents are flavouring oils, e.g. oils of spearmint, peppermint, wintergreen, sassafrass, clove, sage, eucalyptus, marjoram, cinnamon, lemon and orange, and methyl salicylate.

Suitable sweetening agents include sucrose, lactose, maltose, sorbitol, sodium cyclamate, perillartine, APM (aspartylphenylalanine, methyl ester) and saccharin.

Suitably, flavour and sweetening agents may together comprise from about 0.1 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 antiplaque agent in an orally acceptable vehicle may be prepared by unifying the components in conventional manner, and applied to the gingiva and teeth regularly, substantially daily, e.g.

from about 1 to'3 times daily or every second or third day, etc., at a pH of about 4.5 to about 9, generally about 5.5 to about 8.5, preferably about 6 to about 8, preferably for at least two weeks up to eight weeks or more or lifetime.

In the case of chewing gum and other products, the VPA active ingredients can be incorporated in any suitable manner during the usual manufacture of the product. For example, they can be incorporated in a warm gum base with stirring to distribute the same uniformly therein. They can also be added to the exterior or outer surfaces of a gum base in order to coat the base. The usual gum bases can be used, representative materials being jelutone, rubber latex, vinylite resins, etc., in addition to other usual materials such as plasticizers or softeners, sugar or other suitable carbohydrates such as glucose, sorbitol, etc.

The following examples are further illustrative of the nature of this invention but it is understood that the invention is not limited thereto. All amounts and proportions referred to herein and in the appended claims are by weight, and temperatures are in degrees C unless otherwise indicated. Table 1 gives the M.W.n and the results of tests on the efficacy of different VPA polymers. The VPA polymers employed in these examples had a range of number average molecular weights (M.W.n.). Tables 2 and 3 gives two formulations.

Effect of VPA M.W.n value on the Adsorption of Actinomyces viscosus LY7 on Saliva Coated Hydroxyapatite Beads (S-HAP): 80 mgs of HAP beads were pre-coated with human saliva (blood type A) for 12 hours. The beads were then washed and pretreated with the solution of the polymer at pH 7.0 for 5 minutes. Control examples were given no pretreatment. The beads were washed with a buffer consisting of 0.05 M KCl; 1 mM PO4, 1mM Cacti2 and 0.1 mM MgCl2 at pH 6.0. This buffer simulates saliva inorganic constituents.

For the adsorption studies the mixture (1.0 ml) contained 5 x 107 H3 thymidine labelled bacteria (Actinomyces viscosus), 30 mg saliva coated beads (S HAP) and the buffer. The mixture was continuously shaken at room temperature for 2 hours. The beads were allowed to settle for one minute and the-supernatant which contained unadsorbed cells was removed. The radioactivity was measured via liquid scintillation counts. Portions of known H3 labelled cells were counted in a similar manner so that counts per minute may be related to bacterial cell number. Control bacterial suspensions were incubated with S-HAP beads.

The results are given in Table 1.

TABLE 1 Effect of pre-treating Saliva Coated HAP Beads with Polyvinyl Phosphonate on Adsorption of Bacteria (A. Viscosus LY7) Cells absorbed S-HAP VPA. (x107) per Treatment MW n. 20 mg S-HAP Relative None 4.16 + 0.15 100 1.00% VPA1 6300 1.73 + 0.09 42 0.10% VPA2 6300 2.10 + 0.22 50 0.01% VPA 6300 1.96 + 0.30 47 1.00% VPA 7300 2.1 + 0.20 50 TABLE 1 (continued) Cells absorbed S-HAP VPA. (x107) per Treatment M.W.n 20 mg S-HAP Relative 0.10% VPA 7300 2.06 + 0.30 49 0.01% VPA 7300 2.3 + 0.10 55 1.00% VPA 8900 1.95 + 0.28 47 0.10% VPA 8900 2.35 + 0.05 56 0.01% VPA 8900 2.12 + 0.08 51 1.00% VPA 9300 3.16 + 0.09 88 0.10% VPA 9300 4.50 + 0.01 108 0.01% VPA 9300 4.43 + 0.37 106 1.00% VPA 9700 3.65 + 0.05 88 0.10% VPA 9700 4.45 + 0.05 107 0.01% VPA 9700 4.5 + 0.10 108 1.00% VPA 9900 4.50 + 0.09 108 0. 10% VPA 9900 4.50 + 0.10 108 0.018 VPA 9900 4.30 + 0.22 103 Note on Table 1 1 VPA of M.W. n. 6300 is polyvinyl phosphonic acid as the monosodium salt.

2. This and all the other VPA samples are in the form of the disodium salt.

The results show that a pre-treatment of S-HAP with the polyvinyl phosphonate of M. W. n. in t .e range 6300 to 8900 was significantly effective in inhibiting bacterial attachment.

EXAMPLES I AND II The following examples of oral (mouthwash (see Table 2) and toothpaste (see Table 3)) formulations are further illustrative of this invention.

TABLE 2 Wt. Percent Glycerin 10.0 Ethanol 10.0 Pluronic F1081 3.8 Na Saccharin 0.03 Polyvinyl phosphonate2 1.0 Flavour 0.22 Water to make 100.00 Note on Table 2 1BASF-Wyandotte block polymer nonionic surfactant containing about 20 wt.% polyoxypropylene chain of about 3250 M.W. and about 80 wt.% polyoxyethylene.

TABLE 3 Wt. Percent Glycerin 25.0 Carboxymethyl Cellulose 1.3 Sodium Benzoate ç 0.5 Na Saccharin 0.2 Silica 30.0 Sodium Lauryl Sulphate 1.5 Polyvinyl Phosphonate2 3.0 Water to make 100.0 Note on Tables 2 and 3 2 Polyvinyl phosphonate of M.W.n in the range 6,300 to 8,900 is used.

Claims (7)

1. An oral composition containing a dentally acceptable oral vehicle and in an amount effective to inhibit attachment to tooth surfaces of plaque-inducing Actinomyces viscosus, dental plaque and gingivitis, polyvinyl phosphonic acid having a number average molecular weight of 6,100 to 9,000, or an orally acceptable salt thereof.

2. A composition as claimed in Claim 1 which contains 0.01% to 10% by weight of the polyvinyl phosphonic acid or salt thereof.

3. A composition as claimed in Claim 1 or Claim 2 which contains 0.5% to 5% by weight of the polyvinyl phosphonic acid or salt thereof.

4. A composition as claimed in any one of Claims 1 to 3 in which the polyvinyl phosphonic acid has a number average molecular weight of 6,100 to 8,900.

5. A composition as claimed in any one of Claims 1 to 3 in which the polyvinyl phosphonic acid has a number average molecular weight of 6,300 to 7,300.

6. A composition as claimed in any one of the preceding claims in the form of a mouthwash having a pH of 4.5 to 9 with an aqueous-alcohol vehicle.

7. A composition as claimed in any one of Claims 1 to 5 in the form of a toothpaste having a pH of 4.5 to 9, with a liquid vehicle, a gelling agent and a dentally acceptable polishing agent.