FI84021C - Oral composition for preventing human dental plaque and gingivitis - Google Patents

Description

84021

This invention relates to a non-antibacterial oral composition for preventing human dental plaque and gingivitis for the purpose of promoting human oral hygiene. Gingivitis is characterized by symptoms such as gingivitis, bleeding, withdrawal and / or swelling. Types of gingivitis include functional gingivitis, marginal gingivitis, and cotton-roll gingivitis. Gingivitis leads to periodontitis.

The gums are severely damaged due to a layer of dental plaque, which is a combination of bacteria and minerals present in the mouth. Bacteria associated with dental plaque can secrete enzymes and endotoxins that can irritate the gums and cause inflammatory gingivitis. As the gums become increasingly irritated as a result of this process, they tend to begin to bleed, lose their hardness and elasticity, and separate from the teeth, forming periodontal pockets into which organic matter wastes, secretions, more bacteria, and toxins continue to accumulate. Food may also accumulate in these pockets, thus providing nutrition for increased bacterial growth and production of endotoxins and degrading enzymes.

Actinomyces viscosus, a gram-positive rod, has been identified as reported in the etiology of gingivitis by 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 the tooth surfaces, forming a dental plaque.

Several agents have been proposed and used in the past to control dental plaque and gingivitis, but none have been completely satisfactory. For example, some such substances have been found to be unstable in the presence of anionic surfactants commonly contained in conventional oral preparations. Many such agents, such as cationic quaternary ammonium compounds, produce antibacterial functions that undesirably seek to degrade or destroy the normal microflora of the mouth and / or digestive system.

U.S. Patent No. 3,429,963 proposes, in addition to many other water-soluble polyelectrolytes, the use of polyvinylphosphonic acid (VPA polymer) or its salts to complex calcium and prevent oral tartar, but in the only in vivo test described therein, the above substance was added to drinking water. a hydrolyzed copolymer of ethylene and maleic anhydride which was water soldered to the rats ad libitum for five days. This test is a stoichiometric calcium complexation in nature and is not related to the threshold reaction that occurs during actual oral use, where tooth surfaces are treated 1-3 times substantially daily for at least 2 weeks or a lifetime. When polyvinylphosphonic acid was put into such an actual use test, it was not able to significantly inhibit oral tartar.

U.S. Patent No. 4,342,857 discloses and claims anti-gingivitis compositions containing a vinylphosphonic acid / vinylphosphonyl fluoride copolymer, but several scientists, authorities, and / or litigants oppose the administration of fluorinated agents to humans.

The object of the present invention is to provide an oral composition for preventing human dental plaque and gingivitis which does not have the above-mentioned drawbacks.

This object is achieved by the present invention, as the VPA polymer and its salts interfere with or prevent the attachment of Actinomyces viscosus to saliva-coated hydroxyapatite (HAP) beads. This is a reliable indication that the substance interferes with the adhesion of the organism 3 84021 to tooth surfaces, reduces dental plaque, and thus reduces or prevents gingivitis. In fact, such gingivitis activity has been confirmed by an in vivo test in beagles, as described in more detail below.

The present invention therefore relates to an oral composition for preventing human dental plaque and gingivitis by preventing the bacterium Actinomyces viscosus from adhering to tooth surfaces, characterized in that it comprises a dentally acceptable oral excipient and an effective amount of about 6,000 plaque and gingivitis , or an orally acceptable salt thereof.

The VPA polymer used in this invention has a molecular weight of about 6,000 to 10,700, e.g., about 6,000 to 8,000 (obtained by viscosity or light scattering measurements), and can be prepared by a known method by polymerizing vinylphosphonyl dichloride under substantially anhydrous conditions in the presence of a free radical catalyst. with water, whereby the vinylphosphonyl dichloride units in the polymer are hydrolytically converted to VPA units. The resulting polymer is in the form of the free acid and can be converted to the salt form, if desired, by treatment with any orally acceptable cation - by the addition of a base such as an alkali metal (e.g. sodium or potassium), ammonium, C 1-8 mono-, α- and tri-substituted ammonium ions (e.g. alkanol-substituted ammonium, such as mono-, di- or tri-ethanolammonium), organic amines, etc. It will be appreciated that the mono- and di-salt forms of the polymer are equivalent to the free acid form and the term "water soluble" in all of these forms is generally at the concentrations used.

It will also be appreciated that the VPA polymer may further contain small amounts, i.e. less than 50% by weight, preferably less than about 10% by weight, even more preferably less than about 4,84021% by weight. most preferably less than about 2% by weight, units derived from other non-fluorinated ethylenically unsaturated ronomers that are non-toxic in type and amount and do not interfere with the desired water solubility and gingivitis activities of the polymer. Other such monomers may, for example, contain olefins such as ethylene, propylene, isopropylene, butylene and isobutylene, vinyl lower alkyl ethers such as vinylmethyl ethyl and isobutyl ethers, alpha, beta unsaturated and their lower unsaturated carboxylic acids 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 such as vinyl acid ester, vinyl lower alkanoic acid -butyrate, acrylamide and methacrylamide and N-lower alkyl and N, N-dipower alkyl substituted derivatives thereof, and the like.

The content of the anti-gingivitis VPA polymeric agent in the oral compositions can vary widely, typically upwards of about 0.01% by weight, without an upper limit, taking into account the limitations of cost and incompatibility with the excipient. In general, concentrations of from about 0.01% to about 10%, preferably from about 0.1% to about 0.8%, even more preferably from about 0.5% to about 5% by weight are used. Oral compositions which may be accidentally swallowed in normal use preferably contain concentrations below the limits described above.

In certain highly preferred embodiments of the invention, the oral composition may be a substantially liquid, such as a mouthwash or rinse aid. Such preparations generally contain a wetting agent and the excipient is typically a water-alcohol mixture. In general, the ratio of water to alcohol is from about 1: 1 to about 20: 1, preferably 3: 1 to 20: 1, and most preferably about 17: 3, by weight. The total amount of aqueous alcohol mixture in this type of preparation 5,84021 is typically between about 70% and about 99.9% by weight of the preparation. The pH of such a liquid and other preparations of the invention is usually between about 4.5 and about 9, and typically between about 5.5 and 8. Preferably, the pH is between about 6 and about 8.0. It is noteworthy that the compositions of this invention can be used orally at lower pH without significant decalcification of tooth enamel.

Such liquid oral compositions may also contain a surfactant and / or a fluorinated compound.

In certain other desired forms of this invention, the oral composition may be fairly hard or pasty in nature, such as a tooth powder, tooth tablet, toothpaste or toothpaste. Excipients for such solid or pasty oral preparations contain polishing agents. Examples of polishing agents are water-insoluble sodium metaphosphate, potassium metaphosphate, tricalcium phosphate, calcium pyrophosphate, magnesium orthophosphate, trimagnesium phosphate, calcium carbonate, alumina, hydrogenated alumina, zirconium silicate, aluminosilicate, aluminosilicate. Preferred polishes contain crystalline silica with a particle size of up to 5 microns, with an average particle size of 1.1 microns.

up to 50,000 cm / g, silica gel, complex amorphous alkali metal aluminosilicate, hydrogenated aluminum, dicalcium phosphate.

Particularly desirable is alumina, especially the hydrogenated alumina C333 sold by Alcoa, which has an aluminum content of 64.9% by weight, a silica content of 0.008%, an iron (III) oxide content of 0.003% and a moisture content of 0.037% at 110 ° C and a specific gravity of 2.42 and a particle size such that 100% of the particles are smaller than 50 microns and 84% of the particles are smaller than 20 microns.

When using visually transparent gels, colloidal polishing agents containing colloidal silica, such as those sold under the trademark SYLOID, such as Syloid 72 and Syloid 74, or under the trademark SANTOCEL, such as Santocel 100, and alkali metal aluminosilicate, are particularly useful. refractive indices of the gelling liquid-liquid (including water and / or wetting agent) systems used.

Many of the so-called "insoluble" polishes are anionic in nature and also contain small amounts of soluble material. Thus, sodium metaphosphate can be prepared in any suitable manner, as described in Thorpen Dictionary of Applied Chemistry, Volume 9, Fourth Edition, p. 510-511. Further examples of suitable materials are insoluble forms of sodium metaphosphate known as the Madrell salt and the Kurrol salt. These metaphosphate salts are only sparingly soluble in water and are therefore generally considered to be insoluble metaphosphates. They contain small amounts of soluble phosphate as an impurity, usually a few percent, such as up to 4% by weight. The soluble phosphate material believed to contain soluble sodium metaphosphate in the case of insoluble metaphosphate can be reduced, if desired, by washing with water. The insoluble alkali metal metaphosphate is typically added in powder form, with a particle size such that no more than about 1% of the material is greater than 37 microns.

The polish 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 toothpastes and from about 70 to about 99% in tooth powders.

It is usually sufficient, in the case of toothpowder preparations, to mix the solid ingredients mechanically, e.g. by grinding, in suitable amounts and particle sizes.

? 84021

In pasty oral preparations, the combination of anti-ging agent and glidant described above should be compatible with the other components in the preparation. Thus, in toothpaste, the liquid excipient may comprise water and a wetting agent in amounts ranging from about 10 to about 90% by weight of the preparation. Glycerin, sorbitol or polyethylene glycol may also be present as wetting agents or binders. Particularly preferred liquid ingredients are polyethylene glycol and polypropylene glycol. Liquid mixtures of water, glycerin and sorbitol are also preferred.

For transparent gels with a refractive index important factor, 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 natural or synthetic rubber or gummy material, typically Irish moss, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, tragacanth gum, in the presence of polyvinylpyrrolidone, e.g. in an amount of up to 10% by weight, preferably in the range of about 0.5 to about 5%. In toothpaste or gel, the liquid and solid substances are distributed so as to form a creamy or gel-like mass which can be extruded from a pressure vessel or a compressible tube, e.g. aluminum or lead.

A solid or pasty oral preparation having a pH, typically measured from a 20% slurry, of typically about 4.5 to 9, generally about 5.5 to about 8, and preferably about 6 to about 8.0, may also contain a surfactant and / or or a fluorine-containing compound.

Understandably, as is customary, oral preparations should be sold or otherwise distributed in appropriate labeled packages. Thus, there is a label on the mouthwash bottle which describes it essentially as a mouthwash or mouthwash and with instructions for its use; and the toothpaste is usually in a compressible tube, typically aluminum or coated lead, or some other compressible dispensing device for measuring the contents, having a label describing it as a toothpaste or toothpaste.

The oral preparations of this invention may contain an unsaponifiable synthetic sufficiently water-soluble organic anionic or nonionic surfactant in concentrations usually ranging from about 0.05 to about 10, preferably about 0.5 to about 5 weight percent, to promote wetting, cleaning and foaming properties. U.S. Patent 4,041,149 describes 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 paragraphs are incorporated herein by reference.

In certain embodiments of this invention, a fluorinated compound is present in oral preparations. These compounds may be sparingly soluble in water or completely soluble in water. They are characterized by their ability to release fluorine ions in water and their considerable ability not to react with other components in the oral preparation. These substances include inorganic fluorine salts such as soluble alkali metal, alkaline earth metal and heavy metal salts, for example sodium fluoride, potassium fluoride, ammonium fluoride, Ca fluoride, copper fluoride such as cuprofluoride, zinc fluoride, stannous fluoride such as stannous fluoride or stannous chloride. fluoride, sodium fluorosilicate, ammonium fluorosilicate, sodium fluorozirconate, sodium monofluorophosphate, luminium mono- and difluorophosphate, and fluorinated sodium calcium pyrophosphate. Preferred are alkali metal and tin fluorides such as sodium and stannofluorides, sodium monofluorophosphate and mixtures thereof.

The amount of fluorinated compound depends to some extent on the type of compound, its solubility and the type of oral preparation, but the amount should be non-toxic. In solid oral preparations, such as toothpaste or tooth powder, 5,84021 is considered satisfactory in an amount that releases up to about 1% by weight of the preparation. Any minimum amount of such a compound may be used, but it is preferred to use sufficient compound to release about 0.005-1%, and more preferably about 0.1% fluorine ions. Typically, in the case of alkali metal fluorides and stannofluoride, this compound is present in amounts up to about 2% by weight, based on the weight of the preparation, and preferably between about 0.05-1%. In the case of sodium monofluorophosphate, the compound may be present in amounts up to 7.6% by weight, more typically about 0.76%.

In a liquid oral preparation, such as a mouthwash, the fluorinated compound is typically present in amounts sufficient to release up to about 0.13%, preferably about 0.0013-0.1%, and most preferably about 0.0013% by weight fluorine.

Several other materials may be included in the oral preparations of this invention, subject to the foregoing. Examples are bleaches, preservatives, silicones, chlorophyll compounds and ammonized materials such as urea, diammonium phosphate and mixtures thereof. These additives, if present, are included in the preparations in amounts that do not substantially adversely affect the desired properties and characteristics.

Any suitable flavoring or sweetening agent may also be added, also taking into account the above. Examples of suitable flavoring agents are spice oils, e.g. spearmint oil, peppermint oil, winter oil, 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, the flavoring and sweetening agents may together comprise from about 0.1% to about 5% or more of the preparation.

According to the practice of the present invention, an oral composition of the present invention, such as a mouthwash or toothpaste, containing an anti-ging agent in an orally acceptable excipient may be prepared by combining the components in a conventional manner and applied to the gums and teeth regularly, substantially daily, e.g. once a day or every other 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 to eight weeks or longer or lifetime.

In the case of chewing gum or other product, the active ingredients of VPA may be added in any suitable manner during the conventional preparation of the product. For example, they can be added to the warm chewing gum base while stirring to distribute the substance evenly therein. They can also be applied to the outer surfaces of the chewing gum base or to the outer surfaces to coat the base. Conventional chewing gum bases may be used, with representative materials being jelutone, rubber latex, vinyl resins, etc., in addition to other common materials such as plasticizers or plasticizers, sugar or other suitable carbohydrate such as glucose, sorbitol, etc.

The following examples further illustrate the nature of this invention, but it is to be understood that the invention is not limited thereto. All amounts and proportions given herein and in the appended claims are by weight and temperatures are in degrees C unless otherwise indicated. The VPA polymer used in these examples had a molecular weight (M.P.) of about 10,700 in the form of the disodium salt.

Example 1

Adsorption of sodium polyvinyl phosphonate on tooth enamel The adsorption of the polymer on the enamel surface was measured in vitro. Human-derived, caries-free and unrepaired cheek teeth were cleaned by rubbing with pumice. They were then polished with a rubber cup and polish. They were attached to rubber caps with nichrome wire tied through a hole in the root. The sodium salt of the polymer solution at pH 7.0 was dispensed into polyethylene tubes. The teeth were immersed in the solution at 37 ° C for 1 hour with constant stirring. Particular care was taken to ensure that the roots of the teeth did not come into contact with the solution. After one hour of incubation, the teeth were removed and the solutions were analyzed for the amount of polymer remaining in solution. Adsorption was calculated as the difference between the amount originally added and the amount remaining after exposure to the teeth.

The concentration of polymer in the solution was determined by turbidimetric measurements using 5M CaCl 2 solution at pH 4.5. 1 ml of CaCl 2 was added to 1 ml of polymer solution. The turbidity of the resulting colloidal suspension at 500 nm was found to be proportional to the polymer concentration between 1 and 8 mgs / ml. The calibration curve was prepared with a known amount of polymer.

table 1

Score

Residual Amount of Poly-Na ~ VPA Tooth Adsorbs Conc. fmg / ml) treated amount after tooth implantation _ (mg / ml) _ (mg / ml) _ 2 0.4 1.6 3 0.7 2.3 4 1.1 2.9 5 1.6 3.4 6 2.4 3.6 7 3.3 3.7

The results show considerable adsorption of the VPA polymer on mica surfaces.

Example 2

Effect of polymer from Actinomyces viscosus T14 on adsorption to saliva-coated hydroxyapatite (HAP) beads: 80 mg of HAP beads were precoated with human saliva (blood type A) for 12 hours. The beads were washed and pretreated with a solution of polymer 12,84021 at pH 7.0 for 5 minutes. The treated beads were washed with a buffer solution containing 0.05 M KCl, 1 mM PO 2, 1 mM CaCl 2 and 0.1 mM MgCl 2 at pH 6.0. This buffer mimics the inorganic constituents of saliva.

7 3

For adsorption experiments, the mixture (1.0 ml) contained 5 x 10 H-thymidine-labeled bacteria (Actinomyces viscosus), 30 mg of saliva-coated beads (S HAP) and buffer. The mixture was stirred continuously at room temperature for 2 hours. The beads were allowed to settle for one minute and the supernatant containing non-adsorbed cells was removed. Radioactivity was measured by liquid scintillation 3 ...

calculator. Known proportions of H-labeled cells were measured in a similar manner so that scintillation per minute could be related to bacterial cells. Control bacterial suspensions were incubated with HAP beads.

Table II

Score

Effect of salivary-coated HAP beads pretreated with polyvinyl phosphonate on bacterial adsorption____ A. Viscosus LY7 7 S-HAP Adsorbed cells (X 10)% relative to buffer treatment per 20 mg S-HAP__course_

Buffered KCl 3.88 + 0.04 100

1% Na VPA

polymer 1.23 + 0.05 32

0.1% Na2VPA

polymer 3.54 + 0.16 91 0.01% Na 2 VPA 3.55 + 0.09 92

The results show that pretreatment of S-HAP with 1% polyvinyl phosphonate was significantly effective in inhibiting bacterial adhesion.

Example 3 This experiment in 20 beagle dogs illustrates the effect of placebo and the effect of a rinsing agent containing 1% sodium salt of polyvinylphosphonic acid on dental plaque / gingivitis over 4 weeks.

Dogs were given complete prophylaxis to remove soft and hard tooth deposits. Beagles were kept on a light diet for 4 weeks. Group 1 (10 dogs) was then treated with a placebo rinse aid, while group 2 was treated with a polymer-containing rinse aid. The treatment was performed once a day for 5 days a week by applying 5-6 ml of rinsing agent to the entire dentition. The experiment was a double-blind test. Neither the evaluator nor the people involved in the treatment knew the compositions of the rinse aids in the corresponding groups. Dental coverage and gingivitis were determined using the Loe and Silness Index / Acta Odontologica Scandinavica, 21: 551-555 (1963JT7-

Table III

Score:

Mouthwash N Group Dental plaque index /% Gingivitis% tooth - 4 weeks change index 4 change after treatment weeks after treatment - - - - - _

Placebo 10 I 0.99 + 0.23 --- 0.91 + 0.10 --- 1% Na2 VPA polymer 10 II 0.68 + 0.23 -31 0.73 + 0.29 -20

Compared to placebo flushing, polyvinyl phosphonate flushing significantly reduced plaque / gingivitis for 4 weeks.

The following examples of oral (mouthwash and toothpaste) compositions further illustrate this invention.

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Example 4

weight Percent

Glycerin 10.0

Ethanol 10.0

Pluronic F108 3.8

Na-saccharin 0.03

Polyvinyl phosphonate 1.0

Flavoring agent 0.22

Water to give 100.00 *. , BAS F-Wyandotte is a large nonionic surfactant polymer containing about 20% by weight of polyoxypropylene chain, m.p. about 3250 and about 80% by weight polyoxyethylene.

Example 5

weight Percent

Glycerin 25.0

Carboxymethylcellulose 1.3

Sodium benzoate 0.5

Na-saccharin 0.2

Silica 30.0

Sodium lauryl sulphate 1.5

Polyvinyl phosphonate 3.0

The present invention has been disclosed in connection with preferred embodiments, and it is to be understood that their applications and variations, which will be apparent to those skilled in the art, are included within the spirit and scope of this application and the scope of the appended claims.

Claims (6)

15 84021 An oral composition for preventing human dental plaque and gingivitis by preventing bacteria Actinomyces viscosus from adhering to tooth surfaces, characterized in that it contains a dentally acceptable oral excipient and an effective amount of dental plaque and anti-gingivitis polyvinylphosphonic acid having a molecular weight of about 6,000. orally acceptable salt. Composition according to Claim 1, characterized in that the polyvinylphosphonic acid has a molecular weight of about 6,000 to 8,000. Composition according to Claim 1 or 2, characterized in that it contains about 0.01 to 10% by weight of polyvinylphosphonic acid or a salt thereof. Composition according to Claim 1 or 2, characterized in that it contains about 0.5 to 5% by weight of polyvinylphosphonic acid or a salt thereof. 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 9 and containing an aqueous-alcoholic excipient. 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 9 and containing a liquid excipient, a gelling agent and a dentally acceptable polishing agent. 16 84021