DK168060B1 - ORAL AND DENTAL CARE FOR INHIBITION OF DENTAL PLAQUE AND GINGIVITIS - Google Patents

Description

DK 168060 B1

The present invention relates to an oral and dental care agent for inhibiting dental plaque and gingivitis in humans, e.g. by inhibiting the attachment of Actinomyces viscosus bacteria to oral surfaces. The agent of the invention is suitable for use in the treatment, control or inhibition of both plaque and gingivitis, the latter being characterized by such symptoms as inflammation, bleeding, recession and / or swelling of the gums. Types of gingivitis include avunctional gingivitis, gingivitis marginalis, and vasculitis givitis. Gingivitis leads to periodontitis.

The gums are severely damaged 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 that can irritate the gums and cause inflammatory givitis. As the gums become increasingly irritated by this process, they tend to bleed, lose their hardness and elasticity and loosen from the teeth, leaving periodontal pockets in which deposits, secretions, more bacteria and toxins can further accumulate. It is also possible for foods to accumulate in these pockets, thereby providing nourishment for increased bacterial growth and production of endotoxins and destructive enzymes.

Actinomyces viscosus, a gram positive rod bacterium, has been identified as being implicated 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 adheres to tooth surfaces to form dental plaque.

Many different materials have been proposed and used in the past to control plaque and gingivitis, but none have been completely satisfactory. For example, some of such materials have been found to be unstable in the presence of the anionic surfactants usually present in conventional mouthpiece agents. A number of such materials, such as the cationic quaternary ammonium agents, exert an antibacterial function which undesirably tends to split or destroy the normal microflora of the mouth and / or digestive system.

In U.S. Patent No. 3,429,963, as in the present application, among a number of other water-soluble polyelectrolytes, the use of polyvinylphosphonic acid (VPA polymers) or salts thereof for complexing calcium and inhibiting tartar is suggested, but the only in vivo test described 10 therein included the supply of drinking water containing a hydrolyzed copolymer of ethylene and maleic anhydride for ad libitum drinking for rats for a period of five days. This test has the character of a stoichiometric complex of calcium and has no connection with the threshold effect of actual oral application, including treatment of tooth surfaces 1-3 times essentially daily for at least 2 weeks or for life. When subjected to such an actual use test, polyvinylphosphonic acid could not significantly inhibit tartar.

U.S. Patent No. 4,342,857 discloses antigenivitic agents containing a vinylphosphonic acid / vinylphosphonyl fluoride copolymer, but a number of scientists, authorities, and / or judicial authorities dispute the administration of fluorinated materials to humans.

It is an object of this invention to provide an antiplaque / antigenivitis agent which will not have one or more of the aforementioned shortcomings and deficiencies. Other advantages will be apparent from the following description.

The fulfillment of the above purpose is made possible by the discovery that a specially selected molecular weight VPA polymer within the range of 6,000-10,700 and its salts interferes with or inhibits the attachment of Actinomyces viscosus to salivary hydroxyapatite (HAP) beads. This is a reliable indication that the agent would interfere with the attachment of the organism to tooth surfaces, reduce plaque, and thus reduce or inhibit gingivitis. Indeed, such antigenic activity has been confirmed by an in vivo experiment on beagle dogs as described in more detail below.

Thus, this invention relates to an oral and dental care agent for the inhibition of dental plaque and gingivitis in humans peculiar to the characterizing part of claim 1.

The vinyl phosphonic acid homopolymer used herein, also referred to herein as the VPA polymer, has an average molecular weight (obtained from viscosity or light scattering measurements) of from 6,000 to 10,700, more preferably from 8,000 to 10,700, and can be prepared in known manner by polymerization of vinyl phosphonyl. chloride under substantially anhydrous conditions in the presence of a free radical catalyst, and then mixing the resulting polymer with water to hydrolytically convert the vinylphosphonyl dichloride units of the polymer into VPA units.

The resulting polymer is in the free acid form and, if desired, can be converted to salt form by treatment with any orally acceptable cation-providing base such as alkali metal (e.g., sodium or potassium), ammonium, C tri-substituted ammonium, (e.g., alkanol-substituted ammonium, such as mono-, di- and tri-ethanolammonium), organic amines, etc.

It is to 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" used for all such forms encompasses easily water-dispersible forms thereof in the usual application concentrations.

It is also to be understood that the VPA polymer may also contain smaller amounts, i. less than 50% by weight, preferably less than ca. 10% by weight, more preferably less than ca. 5% by weight and preferably less than approx. 2% by weight of units derived from other non-fluorinated ethylenically unsaturated monomers which, in type and amount, are non-toxic and do not interfere with the desired water solubility and antigenivitis activity of the polymer. Other such monomers may e.g. include defines such as ethylene, propylene, isopropylene, butylene and isobutylene, vinyl lower alkyl ethers such as vinyl methyl, ethyl and isobutyl ethers, α, β-unsaturated carboxylic acids and their lower alkyl and substituted lower alkyl ethers. alkyl esters such as acrylic, methacrylic, aconite, maleic and fumaric acids and their methyl, ethyl, isobutyl and dimethylamino ethyl esters, allyl alcohol and acetate, vinyl and vinylene 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 polymeric VPA antigenivitic agent in oral agents may vary within wide limits, typically from ca. 0.01% by weight with no upper limit, except as dictated by cost or incompatibility with the carrier. Usually, concentrations from about 0.01 to approx.

10.0% by weight, preferably approx. 0.1 to approx. 8.0% by weight, more preferably from ca. 0.5 to approx. 5.0% by weight. Oral agents which are accidentally consumed in the usual course of application preferably contain concentrations in the lower portions of the preceding ranges.

In certain highly preferred embodiments of the invention, the oral agent may be substantially liquid, such as a mouthwash or mouthwash. Such compositions usually contain a wetting agent, and the carrier is typically a water-alcohol mixture. Usually, the weight ratio of water to alcohol ranges from approx. 1: 1 to approx. 20: 1, 30 preferably from 3: 1 to 20: 1, and most preferably about 17: 3. The total amount of water-alcohol mixture in this type of preparation is typically in the range of about 70 to approx. 99.9% by weight of the composition. The pH of such a liquid and other compositions of the invention is usually in the range of about 35%. 4.5 to approx. 9 and typically from ca. The pH value is preferably in the range of from about 5 to about 8. 6 to approx. 8.0. It is worth noting that the agents of the invention can be applied orally at lower pH without substantially descaling the tooth enamel.

Such liquid oral care agents may also contain a surfactant and / or a fluorescent compound.

In certain other desirable embodiments of the invention, the oral agent may be substantially solid or paste-like in character, such as a tooth powder, a dental tablet, a toothpaste or a toothpaste. The carrier of such solid or paste-like oral care agents 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, alumina silica, zirconium silicate, zirconium Preferred polishes include crystalline silica with particle sizes of up to 5 microns, an average particle size up to 1.1 microns, and a surface area of up to 50,000 20 cm 2 / g, silica gel, complex, amorphous alkali metal aluminum silicate, hydrated alumina and dicalcium phosphate.

Alumina, and in particular the hydrated alumina sold by Alcoa as "C333", having 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 And having a density of 2.42 calculated from water at 4 ° C and such a particle size 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 used, colloidal silica polishes such as those sold under the trademark "SYLOID" as "Syloid 72" and "Syloid 74", or under the trademark "SANTO-CEL" as "Santocel 100" and alkali metal aluminum silicate com 6 DK 168060 B1 are particularly useful as they have refractive indices close to the refractive indices of the gelling and liquid systems (including water and / or wetting agent) commonly used in toothpastes.

5 Many of the so-called "insoluble" polishes are of anionic nature and also include small amounts of soluble material. Thus, insoluble sodium metaphosphate can be formed in any convenient manner, as illustrated by Thorpe's Dictionary of Applied Chemistry, Volume 9, 4th Edition, page 510-10 511. The forms of insoluble sodium metaphosphate, known as Madrell's salt and Kurrol's salt, are further examples of suitable materials.These methaphosphate salts exhibit very little solubility in water and are therefore usually referred to as insoluble methaphosphates. The amount of soluble phosphate material, which is believed to comprise a soluble sodium trimethaphosphate in the case of insoluble methaphosphate, can be reduced by washing with water. 20 if desired.The insoluble alkali metal meth Aphosphate is typically used in powder form with a particle size, so that no more than approx. 1% of the material is greater than 37 microns.

The polishing material is usually present in amounts ranging from approx. 10 to approx. 99% by weight of the oral care product. It is preferably present in amounts ranging from ca. 10 to approx. 75% in toothpaste, and from approx. 70 to approx. 99% in tooth powder.

In the manufacture of dental powders it is usually sufficient to mix mechanically, e.g. by grinding, the various solid components in appropriate amounts and particle sizes.

In paste-like mouth care agents, the above combination of antigenivitic agent and polish should be compatible with the other components of the preparation. Thus, the liquid carrier in a toothpaste may comprise water and wetting agent, typically in an amount varying from ca. 10 to approx. 90% by weight of the composition. Glycerol, sorbitol or polyethylene glycol may also be present as wetting agents or binders. Particularly advantageous liquid constituents are polyethylene glycol and polypropylene glycol. Liquid mixtures of water, glycerol and sorbitol are also advantageous.

In clear gels where the refractive index is of importance, preferably approx. 3-30% by weight water, 0 - approx. 80% by weight glycerol 10 and approx. 20-28 wt% sorbitol. A gelling agent, such as natural or synthetic rubbers or rubber-like materials, typically Irish moss, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, tragacanth, polyvinylpyrrolidone, starch and preferably hydroxypropyl methyl cellulose 9, 941), etc., is usually present in toothpaste in an amount of up to approx.

10% by weight, preferably in the range of about 0.5 to approx. 5%. In a toothpaste or gel, the fluids and solids are adapted to form a cream or jelly-like mass which can be extruded by a pressurized container or by a compressible tube, e.g. of aluminum or lead.

The solid or paste-like oral care agent, which typically has a pH, measured on a 20% slurry, of approx. 4.5 to 9, usually approx. 5.5 to approx. 8, and preferably approx. 6 to approx. 8.0, 25 may also contain a surfactant and / or a fluorine-providing compound.

It is to be understood that the oral care products, as is customary, must be sold or otherwise distributed in appropriately labeled packages. Thus, a glass of mouthwash will have a label describing it essentially as a mouthwash or mouthwash and having a instructions for use, and a toothpaste will usually be in a compressible tube, typically of aluminum or lined lead, or another collapsible dispenser for measuring the contents and 8 DK 168060 B1 having a label which essentially describes it as a toothpaste or toothpaste.

The mouthwash agents of this invention may contain a non-soap-like, synthetic, sufficiently water-soluble, organic, anionic or non-ionic surfactant at concentrations usually ranging from approx. 0.05 to approx. 10% by weight, preferably from approx. 0.5 to approx. 5% by weight to promote the wetting, cleansing 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.

In certain embodiments of this invention, a fluorine-providing compound is present in the oral care agent. These compounds may be slightly soluble in water or may be completely water soluble. They are characterized by their ability to release fluoride ions in water and by being essentially free of reaction with other components of the oral care agent. Among these materials are inorganic fluorides such as soluble alkali metal, alkaline earth metal and heavy metal salts, e.g. sodium fluoride, potassium fluoride; 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-giving compound is to some extent dependent on the type of compound, this solubility and the type of oral care agent, but it must be a non-toxic amount. In a solid oral care agent, such as toothpaste or tooth powder, an amount of such a compound which releases a maximum of approx. 1% by weight of the preparation, too satisfactory. Any suitable minimum amount of such a compound can be used, but it is preferable to use a sufficient amount to release approx. 0.005 - 1%, and preferably approx. 0.1% fluoride ions. Typically, as in the case of alkali metal fluorides and stannofluoride, this component is present in an amount of up to ca. 2% by weight, based on the weight of the composition, 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 ca. 0.76%.

Typically, in a liquid oral care agent, such as a mouthwash, the fluorine-providing compound is present in an amount sufficient to release up to approx. 0.13%, preferably from ca. 0.0013 to 0.1%, and most advantageously about 0.0013 wt% fluoride.

Various other materials may be incorporated into the oral care agents of this invention, having regard to the above. Examples are whitening agents, preservatives, silicones, chlorophyll compounds and ammoniated material such as urea, diammonium phosphate, and mixtures thereof. When these auxiliaries are present, they are incorporated into the compositions in amounts which have no significant detrimental effect on the desired properties and characteristics.

Any suitable flavoring or sweetening material may also be used, also having regard to the above. Examples of suitable flavoring ingredients are flavoring oils, e.g. oils of green mint, peppermint, evergreen, sassa-frass, clove, sage, eucalyptus, marjoram, cinnamon, lemon and orange and methyl salicylate. Suitable sweeteners include sucrose, lactose, maltose, sorbitol, sodium cyclamate, perillartin, APM (aspartylphenylalanine methyl ester) and saccharin. Conveniently, flavoring and sweetening agents may together amount to approx. 0.1 to 5% or more of the composition.

In practicing this invention, an oral care agent according to the invention, such as a mouthwash or toothpaste containing antigenivitic agent in an orally acceptable carrier, can be prepared by combining the components in the usual manner and applied to the gums and teeth at regular intervals, in all manner. -5 late daily, e.g. from approx. 1 to 3 times daily or every other or third day etc., at a pH of approx. 4.5 to approx. 9, usually from ca. 5.5 to approx. 8.5, preferably from ca. 6 to 8, and preferably for at least 2 weeks to 8 weeks or more or the rest of life.

In the case of chewing gum and other products, the active VPA constituents may be incorporated in any convenient manner during the usual manufacture of the product. For example, they can incorporated into a hot rubber base with stirring to distribute the same uniform therein. They can also be added to the outer or outer surfaces of a rubber base to coat it. The usual rubber bases can be used, and representative materials are jeluton, latex rubber, vinyl resins, etc., in addition to other conventional materials such as plastics or emollients, sugars or other suitable carbohydrates such as glucose, sorbitol etc.

The following examples further illustrate the nature of this invention. All quantities and proportions referred to herein and in the appended claims are by weight and temperatures are in degrees C unless otherwise indicated. The 25 VPA polymer used in these examples had a molecular weight (M.W.) of approx. 10,700, in the form of the disodium salt.

Example 1.

Adsorption of sodium polyvinyl phosphonate to tooth enamel:

The adsorption of the polymer to enamel surfaces was measured in vitro. Human extracted, non-caries affected and non-sealed cheek teeth were cleansed by grinding with pumice stone.

They were then polished with a rubber cap and polish. The f 11 DK 168060 B1 was placed on a rubber stopper by means of a chromium nickel wire which was bonded through a hole in the roots. A sodium salt of polymer solutions at pH 7.0 was distributed in polyethylene tubes. The teeth were immersed in the solution at 37 ° C for 1 hour under continuous stirring. Particular care was taken to avoid contact between the solution and the gums. After 1 hour of incubation, the teeth were removed and the solutions analyzed for the amount of polymer remaining in the solution. Adsorption was calculated as the difference between the initially added amount minus the remaining amount after exposure to the teeth.

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

Table 1.

results:

Wife. of poly- Amount remaining Amount of absorbed Na2VPA (mg / ml) after tooth immersion to teeth (mg / ml) _ (mg / ml) _ 25 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 30 7 3.3 3.7

The data suggested a significant adsorption of the VPA polymer to enamel surfaces.

12 DK 168060 B1

Example 2.

Effect of polymer on the adsorption of Actinomyces viscosus T14 on saliva-coated hydroxyapatite (HAP) beads: 80 mg of HAP beads were pre-coated with human saliva (blood type 5 A) for 12 hours. The beads were washed and pretreated with 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 inorganic saliva components.

10 For the adsorption studies, the mixture (1.0 ml) contained 5 x 10 7 3 H-thymidine-labeled bacteria (Actinomyces viscosus), 30 mg saliva-coated beads (S HAP) and the buffer. The mixture was shaken continuously at room temperature for 2 hours. The beads were allowed to settle for 1 minute and the supernatant containing 15 unadsorbed cells was removed. Radioactivity was measured using liquid scintillation counts. Portions of known H3-labeled cells were similarly counted so that the counts per per minute could be related to bacterial cell count. Control bacterial suspensions were incubated with S-HAP beads.

Table 2.

results:

Effects of pretreating saliva-coated HAP beads with polyvinylphosphonate on the adsorption of bacteria.

25 A. viscosus LY7 S-HAP be- Cells adsorbed (X 107)% relative to action_or. 20 mg of S-HAP_to buffer.

buffered KCl 3.88 ± 0.04 100 1% Na 2 VPA polymer 1.23 ± 0.05 32 0.1% Na 2 VPA polymer 3.54 ± 0.16 91 0.01% Na 2 VPA 3.55 ± 0, 09 92 13 DK 168060 B1

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

Example 3

5 In this study of 20 beagle dogs, the effect of a placebo and a rinse containing 1% sodium salt of polyvinylphosphonic acid on plaque / gingivitis was assessed for 4 weeks. The dogs were given complete prophylaxis to remove soft and hard deposits on the teeth. A revealing solution was applied to ensure complete removal of deposits on the teeth. The dogs were kept on a soft diet for 4 weeks. Group I (10 dogs) was then treated with the placebo softener, while group II was treated with the softener containing the polymer. The treatment was performed 1 / day / 5 days 15 per day. per week by applying 5 - 6 cubic centimeters of the rinse aid to all teeth. The study was a double-blind trial. Neither the assessor nor the persons involved in the treatments knew the allocations of fabric softeners in the respective groups. Plaque and gingivitis were assessed using the Loe and Silness index (Acta Odontoloqica Scandinavi-ca, 21: 551-555 (1963)).

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Compared to the placebo rinse, the polyvinylphosphonate rinse significantly reduced plaque / gingivitis over 4 weeks.

The following examples of oral (mouthwash and toothpaste) formulations further illustrate the invention.

Example 4

Glycerol 10.0% by weight

Ethanol 10.0% by weight "Pluronic F108" * 3.8% by weight Na-saccharin 0.03% by weight

Polyvinylphosphonate 1.0% by weight

Flavoring 0.22% by weight

Water to reach 100.00% by weight * BASF-Wyandotte block polymer, nonionic surfactant containing approx. 20% by weight polyoxypropylene chain having a molecular weight of approx. 3250 and approx. 80% by weight polyoxyethylene.

Example 5

Glycerol 25.0% by weight

Carboxymethyl 1.3 wt% cellulose

0.5% by weight

Na-saccharin 0.2 wt% Silica 30.0 wt%

Sodium lauryl 1.5 wt% sulfate

Polyvinylphosphate 3.0 wt% phonate 30 Water to 100.0 wt% reach of

Example 6 16 DK 168060 B1

The effect of the vinyl phosphonic acid homopolymer on the adsorption of Actinomyces viscosus on saliva-coated HAP beads was investigated in the same manner as described in Example 2 to assess the effect obtained with vinyl phosphonic acid homopolymers of different molecular weights. It is apparent from the results obtained in the following Table 3 that with molecular weights of 7,800, 8,800 and 12,000 a significant inhibition of the bacterial adhesion is obtained, whereas for molecular weights 10 of 14,000 or 15,000 only a slight effect is observed. .

Table 3 S-HAP- A.viscosus LY7% relative to treatment Molecular weight (x106) absorbed for control VPA-Polymers (%) _ 15 o (control) 4.16 ± 0.15 ιοο 1 2.1 ± 0.20 50 0.1 8800 2.06 ± 0.30 49 0.01 2.3 ± 0.10 55 20 1 1.95 ± 0.28 47 0.1 12000 2.35 ± 0.05 56 0.01 2, 12 ± 0.08 51 1 1.73 ± 0.09 42 25 0.1 7800 2.10 ± 0.22 50 0.01 1.96 ± 0.30 47 1 3.66 ± 0.09 88 0, 1 14000 4.50 ± 0.01 108 30 0.01 4.43 ± 0.37 106 1 4.50 ± 0.09 108 0.1 15000 4.50 ± 0.10 108 0.01 4.30 ± 0.22 103 35 (

Claims (6)

1. Oral and dental care agent for the inhibition of dental plaque and gingivitis in humans, characterized in that it contains a dental acceptable oral carrier and is essentially the only active agent an effective plague and gin-givitis inhibiting amount of vinyl phosphonic acid homopolymer having a molecular weight of 6,000-10,700, or an orally acceptable alkali metal salt or ammonium salt thereof. Agent according to claim 1, characterized in that the homopolymer has a molecular weight of from 6,000 to 8,000. An agent according to claim 1 or 2, characterized in that it contains 0.01-10% by weight of the homopolymer or an orally acceptable salt thereof. An agent according to any one of claims 1-3, characterized in that it contains 0.5-5% by weight of the homopolymer or an orally acceptable salt thereof. An agent according to one or more of the preceding claims, characterized in that it is in the form of mouthwash having a pH value of 4.5-9 and containing a water-alcohol carrier. 5 Patent claims An agent according to any one of claims 1-4, characterized in that it is in the form of a toothpaste having a pH value of 4.5-9 which contains a liquid carrier, a gelling agent and a dental acceptable. polish. 30