SE502745C2 - Oral composition for preventing human dental plaque and gingivitis - Google Patents

Abstract

Toothpastes and mouthwashes that inhibit plaque formation and gangivitis contain an orally acceptable vehicle, a polyvinylphosphonic acid (I) or its orally acceptable salts. with mol. wt. 6000-100,000. Compns. contg. 0.01-10 wt.% (I) are formulated as mouthwashes contg. an aq. alcoholic vehicle and as toothpaste contg. gelling and polishing agents, pref. with pH 4.5-9. A fluoride-contg. cpds., fragrance, and sweetener can be added to the formulations. (I) inhibits attachment of actinomyces viscosus to the teeth.

Description

UI 10 15 20 25 30 5Ü2 745 l \) exerts an antibacterial function, which in an undesirable manner tends to dissolve or destroy the normal microflora in the mouth and / or in the digestive system.

U.S. Patent No. 3,429,963 proposes, among a number of other water-soluble polyelectrolytes, the use of polyvinylphosphonic acid (VPA polymer) or salts thereof for complexing calcium and preventing oral calculus, but the only in vivo test described herein includes of drinking water containing a hydrolysed copolymer of ethylene and maleic anhydride for ad libitum drinking of rats for a period of five days. This test is by nature a stoichiometric complex formation of calcium and is not related to the threshold effect that occurs during actual oral use, including treatment of the dental surfaces one to three times in principle daily for at least two weeks or for a lifetime. When polyvinylphosphonic acid was subjected to such an actual use test, it was not found to appreciably prevent oral calculus.

U.S. Patent No. 4,342,857 discloses and protects anti-inflammatory compositions containing a vinylphosphonic acid / vinylphosphonyl fluoride copolymer, but a number of scientists, authorities and / or jurisdictions object to the administration of fluorinated materials to humans.

The object of the present invention is to provide an oral composition for preventing plaque and gingivitis which does not suffer from any of the above shortcomings and objections. Other objects and advantages will be apparent from the following detailed description.

The achievement of the above objects has been made possible by my discovery that VPA polymer and its salts interfere with or prevent the adhesion of actinomyces viscosus to salivary hydroxyapatite (4HAP) beads. This is a reliable indication that the agent would interfere with the organism of tooth surfaces, would reduce plaque and thus reduce or prevent the onset of gingivitis. Such anti-gingivitis activity has been confirmed in an in vivo test on beagles, which is discussed in more detail below. The invention thus comprises an oral composition of the type indicated in the introduction, which is characterized according to the features stated in the characterizing part of claim 1.

The oral composition according to the invention is thus characterized by a molecular weight of approx. 6,000 to approx. 10,700 or even better to about 8,000 to approx. It can be prepared in a known manner by polymerizing vinylphosphonyl dichloride under substantially anhydrous conditions in the presence of a free radical catalyst, and then mixing the resulting polymer with water to hydrolyze the vinylphosphonyl dichloride units in the polymer to VPA units.

The resulting polymer is in its free acid form and can, if desired, be converted to salt form by treatment with an orally tolerable cation-releasing base such as alkali metal (eg sodium or potassium), ammonium, C1-18 mono, di- and trisubstituted ammonium, (e.g. alkanol-substituted ammonium, such as mono-, di- and triethanolammonium), organic amines, etc. It is understood that the mono- and disalt forms of the polymer are equivalent to the free acid form and that the term "water-soluble" as is applicable to all such forms includes readily water-dispersible forms thereof in the commonly used concentrations.

The VPA polymer may also be present in minor amounts, i.e. less than 5+% by weight, preferably less than about 10% by weight, more preferably less than about 5% by weight and most preferably less than about 2% by weight of units derived from other non fluorinated ethylenically unsaturated monomers, which are non-toxic in type and amount and do not interfere with polymeric water solubility and antigengine effect. Other such monomers may include, for example, olefins such as ethylene, propylene, isopropylene, butylene and isobutylene, vinyl lower alkyl ethers such as vinyl methyl, ethyl and isobutyl ethers, alpha and beta unsaturated carboxylic acids and their lower alkyl and substituted lower alkyl esters such as acrylic, methacrylic, aconite, maleic and fumaric acids and their methyl, ethyl, isobutyl and dimethylaminoethyl esters, alyl 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-di-lower alkyl-substituted derivatives thereof and the like.

The concentration of the VPA polymer-containing anti-gingival agent in oral compositions can vary within wide limits, typically from about 0.01% by weight and upwards without any upper limit except for that dictated by the cost or intolerance of the vehicle. In general, concentrations of about 0.01 - about 10.0% by weight, preferably about 0.1 - 8.0% by weight, more preferably about 0.5 - 5.0% by weight, are used. Oral compositions, which can be swallowed by normal use by mistake, preferably contain concentrations within the lower parts of the above ranges.

According to certain highly preferred forms of the invention, the oral composition may be substantially liquid, such as a mouthwash or mouthwash. Such preparations generally contain a humectant and the vehicle is typically a water-alcohol mixture. Usually the ratio of water to alcohol is in the range 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 composition is typically in the range of from about 70% to about 99.9% by weight of the composition. The pH of such a liquid and other formulations 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 should be noted that the compositions of the invention can be applied orally at a lower pH without substantially decalcifying the tooth enamel.

Such liquid oral preparations may also contain a surfactant and / or a fluorine-releasing compound.

In certain other desirable forms of the present invention, the oral composition may have a substantially solid or pasty character such as tooth powder, a dental tablet, a toothpaste or dental cream. The vehicle for such pastes or pasty oral preparations contains polishes. Examples of polishing materials are water-insoluble sodium metaphosphate, potassium metaphosphate, tricalcium phosphate, calcium pyrophosphate, magnesium orthophosphate, trimagnesium phosphate, calcium carbonate, alumina, hydrated alumina, aluminosilicate, zirconia and silicates, zirconium silicates. Preferred polishing materials include crystalline silica with particle sizes up to 5 μm, an average particle size of up to 1.1 μm and a surface area of up to 50,000 cm 2 / g, silica gel, complex amorphous alkali metal aluminosilicate, hydrated alumina, dicalcium phosphate.

Alumina, in particular the hydrated alumina sold by Alcoa as C333, which has an alumina content of 64.9% by weight, a silica content of 0.008%, an iron oxide content of 0.003% and a moisture content of 0,037% at 110 ° C, and having 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 preferred.

CT 1 CT.) 10 15 20 25 30 35 * Q 4> 01 When visually clear gels are used, a polishing agent containing colloidal silica, such as that sold under the trademark SYLOID as Syloid 72 and Syloid 74 or under the trademark SANTOCEL as Santocel 100 and alkali metal-aluminosilicate complexes, as they have refractive indices close to the refractive index of the gelling fluid systems (including water and / or humectant) commonly used in dentifrices.

Many of the so-called "insoluble" polishing materials are anionic in nature and also include minor amounts of soluble material. Thus, insoluble sodium metaphosphate can be prepared in any suitable manner, as illustrated in Thorpe's Dictionary of Applied Chemistry, Volume 9, Fourth Edition, pages 510 - 511. The types of insoluble sodium metaphosphate known as Mandrell's salt and Kurrol's salt are further examples of suitable materials. These metaphosphate salts show very low solubility in water and are therefore usually attributed to insoluble metaphosphates. In these there is present a small amount of soluble phosphate material as impurities, usually a few% such as up to 4% by weight. The amount of soluble phosphate material believed to include a soluble sodium trimetaphosphate in the case of insoluble metaphosphate can be reduced by washing with water if desired. The insoluble alkali metal metaphosphate is typically used in powder form with a particle size such that no more than about 1% of the material has a particle size in excess of 37 Åpm.

The polishing material is usually present in amounts from about 10 to 99% by weight of the oral preparation. Preferably, the polishing material is present in amounts from about 10 to about 75% in toothpaste and from about 70 to about 99% in tooth powder.

In the tooth powder preparation, it is usually sufficient to mechanically mix in, for example by grinding, the various solid ingredients in suitable quantities and particle sizes.

In pasty oral formulations, the above combination of the antiging agent and the polishing material shall be compatible with the other components of the formulation.

Thus, in a toothpaste, the liquid vehicle may comprise water and humectant typically in an amount of from about 10% to about 90% by weight of the formulation. Glycerin, sorbitol or polyethylene glycol may also be present as humectants or binders. Particularly advantageous liquid ingredients are polyethylene glycol and polypropylene glycol. Liquid mixtures of water, glycerin and sorbitol are also advantageous.

In clear gels, where refractive index is an important aspect, about 3 to 30% by weight of water, 0 to about 80% by weight of glycerin and about 20 to 28% by weight of sorbitol are preferably used.

A gelling agent, such as a natural or synthetic rubber or rubber-like material, typically carrageenan, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, gum tragacanth, polyvinylpyrrolidone, starch and preferably hydroxypropylmethylcellulose and carbopoles (e.g. 941, 9), 9 in toothpaste in an amount of up to about 10% by weight, preferably in the range of from about 0.5 to about 5% by weight. In a toothpaste or gel, the liquids and the solid particles are proportioned to form a creamy or gelled mass which is extrudable from a pressurized container or from a compressible, eg aluminum 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, usually about 5.5 to about 8 and preferably about 6 to 8, 0 may also contain a surfactant and / or a fluorine-releasing compound.

The oral preparations must be sold or distributed in another conventional way in suitably labeled packaging. Thus, a can of mouthwash should have a label describing it as a mouthwash or mouthwash and with instructions for its use and a toothpaste is usually arranged in a compressible tube, typically made of aluminum or lined lead, or any other squeeze container for removal. feeding the contents, with a label describing it as a toothpaste or dental cream.

The oral compositions of the invention may contain a non-soap synthetic and sufficiently water-soluble organic anionic or nonionic surfactant in concentrations generally between about 0.05 and about 10% by weight, preferably about 0.5 to about 10% by weight. 5% by weight, to promote wetting, and detersive and foaming properties. U.S. Patent No. 4,041,149 discloses such suitable anionic surfactants in column 4, rows 31-38 and such suitable nonionic surfactants in column 8, rows 30-68 and column 9, rows 1-12, which are to be considered as part of the present description.

According to certain aspects of the present invention, a fluorine-releasing compound is present in the oral preparation. These compounds may be slightly soluble in water or completely water soluble. They are characterized by their ability to release fluoride ions in water and the significant inability to react with other components in the oral preparation. Among these materials may be mentioned organic fluoride salts, such as soluble alkali metal, alkaline earth metal and heavy metal salts, for example h) sodium fluoride, potassium fluoride, ammonium fluoride, calcium fluoride, a copper fluoride such as copper (I) fluoride, zinc fluoride, a tin fluoride such as stannous fluoride or stannous fluoride, barium fluoride, sodium fluorosilicate, ammonium fluorosilicate, sodium fluorosirconate, sodium monofluorophosphate, aluminum mono- and difluorophosphate, and fluorinated sodium calcium pyrophosphate. Alkali metal and tin fluorides, such as sodium and stannofluorides, sodium monofluorophosphate and mixtures thereof, are preferred.

The amount of the fluorine-releasing compound depends to some extent on the type of compound, its solubility and the type of oral preparation, but it must be present in a non-toxic amount. In a solid oral preparation, such as a toothpaste or a tooth powder, an amount of such a compound which releases a maximum of about 1% by weight of the preparation is considered satisfactory. Any suitable minimum amount of such a compound may be used, but preferably the compound is used in an amount sufficient to release about 0.005-1% and preferably about 0.1% of fluoride ion.

Typically in the case of alkali metal fluorides and stannous fluorides, the component is present in an amount of up to 2% by weight, based on the weight of the preparation, and preferably in the range of about 0.05 - 1%. In the case of sodium monofluorophosphate, the compound may be present in an amount of up to 7.6% by weight. more typically about 0.76%.

In a liquid oral preparation such as a mouthwash, the fluorine-releasing 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. fluoride.

Various other materials may be incorporated into the oral formulations of the present invention as defined above.

Examples are whitening agents, preservatives, silicones, chlorophyll compounds, and ammonia-treated materials such as urea, diammonium phosphate and mixtures thereof. These aids are incorporated when they are present in the preparations in amounts which do not significantly adversely affect the desired properties and characteristics.

Any seasoning or sweetener can also be used. Examples of suitable aromatic constituents are aromatic oils, such as oils of green mint, peppermint, evergreens, sassafras, cloves, sage, eucalyptus, marjoram, cinnamon, lemon and orange and methyl salicylate. Suitable sweeteners include sucrose, lactose, maltose, sorbitol, sodium cyclamate, perillartine, APM (aspartylphenylalanine, methyl ester) and saccharin. Suitably, flavoring and sweetening agents together constitute about 0.1 to 5% or more of the preparation.

In the practice of the present invention, an oral composition of the invention such as a mouthwash or a toothpaste containing the antiging agent in an orally tolerable vehicle may be prepared by combining the components in a conventional manner, and applied to the gingivitis sites and to the teeth regularly, substantially daily. from one to three times daily or every other or every third day, etc., at a pH of about 4.5 to about 9, usually about 5.5 to about 8.5, preferably about 6 to about 8, preferably at least two weeks up to eight weeks or more or for life.

In the case of chewing gum and other products, the active VPA ingredients may be incorporated in any suitable manner during the normal manufacture of the product. For example, they can be incorporated into the hot rubber base with stirring to uniformly distribute it therein. They can also be added to the outer casing or the outer surface of the rubber base for coating the base. Normal rubber bases can be used, wherein representative materials are jeluton, rubber latex, vinylite resins etc. in addition to other common materials such as plasticizers or plasticizers, sugars or other suitable carbohydrates such as glucose, sorbitol etc.

The following examples further illustrate the invention, but this is of course not limited thereto. All amounts and proportions herein and in the appended claims are by weight, and temperatures are given in OC unless otherwise indicated. The VPA polymer used in these examples had a molecular weight (M.W.) of about 10,700 and was used in the form of the disodium salt.

Example I Adsorption of sodium powder vinyl phosphonate on tooth enamel: The adsorption of the polymer on enamel surfaces was measured in vitro.

Cheek teeth without caries and without human fillings were cleaned by pumice grinding. They were then polished with a rubber cap and polish. They were applied to a rubber plug with a micron wire, which was tied through a hole in the roots. A sodium salt of polymer solutions at pH 7.0 was filled into polyethylene tubes. The teeth were immersed in the solution at 37 ° C for 1 hour with continuous stirring.

Special care was taken to avoid the solution coming into contact with the roots of the teeth. After one hour of incubation, the teeth were removed and the solutions were analyzed for residual polymer in the solution.

The adsorption was calculated as a difference between the amount initially added amount minus the remaining amount after exposure to teeth.

The concentration of the polymer in the solution was determined by turbidimetric measurements using a SM CaCl2 solution at pH 4.5. 1 cm 3 of CaCl 2 was added to 1 cm 3 of the polymer solution. The turbidity of the resulting colloidal suspension at 500 nanometers was found to be proportional to the polymer concentration in the range of 1 to 8 mg / ml. A calibration curve was established with the known amount of polymer.

Table I Results: Amount adsorbed to the teeth Remaining amount after tooth dip- Concentration of poly- Na VPA (mg / ml) 2 ning (mg / ml) (mg / ml) 2 0.4, 3 0.7, 4 1.1 .6 1.6, 6 2.4, 7 3.3, The data obtained show a significant adsorption of the VPA polymer on enamel surfaces.

Example II Effect of polymer on the adsorption of Actinomyces Viscosus T 14 on salivary hydroxyapatite (HAP) beads: 80 mg of HAP beads were precoated with human saliva (blood group A) for 12 hours. The beads were washed and pretreated with the polymer solution at pH 7.0 for 5 minutes.

The treated beads were washed with a buffer consisting of 0.05 M KCl, 1 mM PO 4, 1 mM CaCl 2 and 0.1 mM MgCl 2 at pH 6.0. This buffer simulates the inorganic constituents of saliva. For the adsorption studies, the mixture (1.0 ml) contained 5 x 107 3 30 mg of saliva-coated beads (S HAP) and the buffer. The mixture was shaken continuously at room temperature under 2 H thymidine-labeled bacteria (Actinomyces Viscosus), hours. The beads were allowed to settle for one minute and the supernatant containing non-adsorbed cells was removed. Radioactivity was measured via liquid scintillation measurements. Known amounts of H3-labeled cells were similarly counted so that numbers per minute could be related to bacterial cell units. Control bacterial suspensions were incubated with S-HAP beads.

Table II Results: Effect of pretreatment of saliva-coated HAP beads with polyvinylphosphonate on adsorption of bacteria.

A. Viscosus LY7 S-HAP- Adsorbed Cells (x 107)% relative treatment per 20 mg S-HAP buffer Buffered Kci 3.88 ï 0.04 100 1% Na VPA + polymer year 1.23 - 0.05 32 0, 1% Na VPA polymer 3.54 - 0.16 91 0.01% Naz VPA 3.55 - 0.09 92 The results show that a pretreatment of S-HAP with 1% polyvinylphosphonate was significantly effective in preventing bacterial adhesion.

Example III This study in 20 beagle dogs evaluated the effect of a placebo and a rinse containing 1% sodium salt of polyvinylphosphonic acid on plaque / gingivitis for 4 weeks. 10 15 20 25 30 [12 14 The dogs were given complete prophylaxis to remove soft and hard dental deposits. A control solution was used to ensure complete removal of dental deposits. The beagles were kept on a soft diet for 4 weeks. Group I (10 dogs) was then treated with the placebo rinse while Group II was treated with the polymer-containing rinse. The treatment was carried out once a day for 5 days a week by applying 5 - 6 cm3 of the rinse aid to all tooth surfaces. The study was doubly blind, and neither the evaluator nor the people involved in the treatments knew about the allocation of fabric softeners in the respective groups. Plaque and gingivitis were determined via the Loe and Silness index (Acta Odontologica Scandinavica, 21: 551-555 (1963)).

Table III Result: Mouthwash- N Group Plaque index /% pre- Gingival% pre-average tooth - 4 V change index 4 v change after treatment- after be- ling action Placebo 1o I 0.99 ï 0.23 --- 0, 91 3 o fl o --- 1% Na VPA påly- + + Compared to the placebo rinse aid, the polyvinyl phosphonate rinse aid significantly reduced plaque / gingivitis for 4 weeks.

The following examples of oral preparations (mouthwash and toothpaste) further illustrate the invention. Example IV Weight% Glycerin 10.0 Ethanol 10.0 Pluronic F108 * 3.8 Na-saccharin 0.03 Polyvinylphosphonate 1.0 Flavor 0.22 water ad 100.00 * BASE F-Wyandotte block polymer nonionic surfactant containing about 20% by weight of polyoxypropylene chain of about 3250 molecular weight and about 80% by weight of polyoxyethylene.

Example V Weight% Glycerin 25.0 Carboxymethylcellulose 1.3 Sodium benzoate 0.5 Sodium saccharin 0.2 Silica 30.0 Sodium lauryl sulphate 1.5 Polyvinylphosphonate 3.0 water ad 100.0 The present invention has been described with reference to preferred embodiments and it is implied that modifications and variations obvious to those skilled in the art are included within the scope of the present application and within the scope of the appended claims.

Claims (6)

502 745 10 15 20 25 30 P a t e n t k r a v An oral composition for preventing human dental plaque and gingivitis by inhibiting the adhesion of Actinomyces Viscosus bacteria to dental surfaces, containing a dentally compatible oral vehicle and an effective plaque and gingivitis-preventing amount of polyvinylphosphonic acid or an orally tolerable salt thereof, e.g. The polyvinylphosphonic acid shown has a molecular weight of about 6,000 - about 10,700. 2. A composition according to claim 1, characterized in that the polyvinylphosphonic acid has a molecular weight of about 6,000 - about 8,000. 3. A composition according to claim 1 or 2, characterized in that it contains about 0.01 - about 10% by weight of the polyvinylphosphonic acid or the salt thereof. 4. A composition according to claim 1, 2 or 3, characterized in that it contains about 0.5 - about 5% by weight of the polyvinylphosphonic acid or the salt thereof. A composition according to any one of claims 1 to 4, characterized in that it is a mouthwash having a pH of about 4.5 to about 9 and a water-alcohol vehicle. A composition according to any one of claims 1 to 4, characterized in that it is a toothpaste having a pH of about 4.5 to about 9, a liquid vehicle, a gelling agent and a dental pullable polish.