NL8004619A - MOUTH TREATMENT MIX AND METHOD FOR IMPROVING THE MOUTH HYGIENE. - Google Patents

Description

t 4 I vo 0827

Oral handling mixture and method for improving oral hygiene.

The invention relates to a mouth treatment mixture, as well as to a method for improving oral hygiene.

More particularly, the invention relates to oral treatment mixtures containing an anti-tartar agent and to the use thereof.

Tartar (Calculus) is a hard mineralized batter formed on the teeth. Regular brushing prevents a rapid build-up of these deposits, but even regular brushing is not sufficient to completely remove the tartar deposits which adhere to the teeth. Tartar is formed on the teeth when calcium phosphate crystals begin to deposit in the skin and the extracellular matrix of the dental plaque and are packed tightly enough that the aggregates become resistant to deformation. There is no complete agreement about the route by which calcium and orthophosphate finally produces the crystalline material, which is called hydroxyapatite (HAP). It is generally agreed, however, that at higher saturations, i.e. above the critical saturation limit, the precursor of crystalline hydroxyapatite is an amorphous or microcrystalline calcium phosphate. Although "amorphous calcium phosphate" is related to hydroxyapatite, it differs in atomic structure, particle morphology and stoichiometry. The X-ray diffraction pattern of amorphous calcium phosphate exhibits broad peaks characteristic of amorphous materials lacking the long-range atomic order characteristic of all crystalline materials, including hydroxyapatite. It is therefore evident that agents which effectively interfere with the crystalline growth of hydroxyapatite will be effective as anti-calculus agents. A proposed mechanism by which the anti-calcium agents of the invention counteract the formation of tartar probably entails an increase in the activation energy barrier, preventing the conversion of the amorphous calcium phosphate to be considered precursor to hydroxyapatite.

Studies have shown that there is a good correlation between the ability of a compound to prevent crystalline 8004619 2 line growth Tan hydroayapatite in vitro and its ability to prevent calcification in vivo.

Cationic nitrogen-containing antibacterial substances are gate end. See e.g. the section on "Quaternary Ammonium and 5 Eelated Compounds" in the article on "Antiseptics and Disinfectants" in Kirk-Qthmer: Encyclopedia, of Chemical Technology, second edition (volume 2, p. 632 - 635) · Cationics, which have antibacterial activity (i.e. germicides are), are used against bacteria and have been used in oral treatment mixtures to prevent plaque formation caused by bacteria in the oral cavity.

The best known representatives of these anti-plaque antibacterial quaternary ammonium compounds include benzethonium chloride, which is also known as. Hyamine 1622 or di-isobutylphenoxyethoxyethyldimethylbenzylammoniimimchloride ·. When used in an oral treatment formulation, this compound is very effective in promoting oral hygiene by reducing plaque and tartar formation, which is generally accompanied by a reduction in caries formation and periodontal disease. Other cationic antibacterial agents of this type are those which, e.g. are listed in. U.S. Pat. Nos. 2,998,639 * 3 * 325. 02, 3. -31,208 and 3,703,583, as well as British Patent 1,319,396.

Other quaternary ammonium compounds with. anti-bacterial anti-plaque activity include those wherein 1 or 2 of the substituents on quaternary nitrogen have a carbon chain length (e.g., an alkyl group) of about 8-20, e.g. 10-18 carbon atoms, while the remaining substituents have a lower number of carbon atoms Cb.v. an alkyl or benzyl group), such as 1-7 carbon atoms, e.g. methyl or ethyl groups. Dodecyl trimethyl ammonium broxnide, dodecyl dimethyl- (2-phenoethyl) ammonium bramide, benzyl dimethyl stearyl ammonium chloride, cetyl pyridinium chloride and quaternized 5-amino-1,3-bis- (2-ethylhexyl-1-methylhexahydropyrimidine) quaternary ammonium compounds.

Other types of cationic antibacterial agents, the inclusion of which in oral treatment mixtures is desired to promote oral hygiene by reducing plaque formation, are the amine 8004619 L * 3 dines, such as the substituted guanidines, e.g. chlorhexidine and the corresponding compound, alexidine, which contains 2-ethylhexyl groups in place of chlorophenyl groups, and other bis-guanidines, such as those described in German patent application P 2,332,383 »published January 5, 1971 *» in which compounds according to the formula 1, wherein A and A 'according to the circumstances either: (1) a phenyl radical, which as substituent may contain at most 2 alkyl or alkoxy groups with 1 to about b carbon atoms, a nitro group or a halogen atom either: (2) an alkyl group containing 1 to about 12 carbon atoms, or: (3) alicyclic groups having U to about 12 carbon atoms; X and X, depending on the conditions, may represent an alkylene-15 moiety with 1 to 3 carbon atoms; z and z are equal depending on the circumstances, as either 0 or 1; Depending on the conditions, R and R 'may represent either hydrogen or an alkyl group of 1 to about 12 carbon atoms or an arallyl group of 7 to about 12 carbon atoms; n is an integer from 2 to 12; and the polymethylene chain (CHg) may be interrupted by at most 5 ether, thioether, phenyl or naphthyl groups.

These compounds are available in the form of pharmaceutically acceptable salts. Other substituted guanidines are: - - (h-chlorobenzyl) -3r - (2, U-dichlorobenzyl) biguanidine; p-chlorobenzyl biguanidine, k-chlorobenzhydrylguanylurea; R-3-lauroxypropyl-R 1 -p-chlorobenzylbiguanidine; 5> 6-dichloro-2-guanidobenzimidazole; and R-p-30 chlorophenyl-R 1 -laurylbi guanidine.

The long chain tertiary amines also have anti-bacterial and anti-plaque activity. Such antibacterial agents include tertiary amines with T fatty alkyl group (eg, with 12-18 carbon atoms) and 2 poly (oxyethylene) groups, bonded to the nitrogen atom (eg, containing a total of 2-50 ethenoxy groups per molecule) and salts thereof with acids and compounds, the structure of which is represented by Formula 2, wherein B represents a fatty alkyl group having 12 to 18 carbon atoms and x, y and z total 3 or more ", and salts thereof. cationic agents due to their effective action as anti-plaque agent, are preferred.

The anti-bacterial anti-plaque compound is preferably a compound which has an antibacterial activity, so that its phenol coefficient for jS, aureus is clearly more than 50, in particular clearly more than 100, e.g. is greater than about 200 or greater; 10, e.g. the phenol coefficient (A.O.A.C.) of benzethonium chloride declared by the manufacturer as klO, for £ 3. aureus The cationic antibacterial agent will generally be a monomeric (or optionally drier) compound having a molecular weight well below 2,000, e.g. less than about 1,000. However, the invention also relates to the use of a polymeric cationic antibacterial agent. The cationic antibacterial agent is preferably provided in the form of a salt acceptable for oral use, such as the chloride, bromide, sulfate, alkyl sulfonate, such as methyl sulfonate and ethyl sulfonate, phenyl sulfonate, such as p-methylphenyl-20 sulfonate, nitrate, acetate, glu <? onaat, etc.

The nitrogen-containing cationic antibacterial agents and long-chain tertiary amine antibacterial agents effectively promote oral hygiene, in particular, by removing plaque. However, it has been found that their use leads to the formation of stains on the surface of the teeth or to discoloration.

The reason for the formation of such staining or discoloration of the teeth has not been clearly established. Human tooth enamel, however, contains a large amount (about 95%) of +2 -3 hydroxyapatite (HAP), which includes Ca and POvions, among others. In the absence of dental plaque, additional Ca and PO, especially saliva, may be deposited on the enamel and such deposits may contain dyes which eventually stain the enamel in the form of a calcified deposit thereon . It may be that while the cationic antibacterial agents or the antibacterial agents based on long chain tertiary amines remove plaque, they also denature protein from saliva in the vicinity of the mouth, after which the denatured protein as a nucleating agent can act, which is deposited on the tooth enamel and stains or discolours this enamel.

Previously used additives that reduce tooth discoloration by cationic antibacterial anti-plaque agents also generally reduce the activity of the antibacterial anti-plaque agents, such as bis-biguanido compounds, e.g. because a precipitate is formed with such means.

The invention relates inter alia to an oral treatment mixture containing an oral (orally acceptable) carrier, which carrier as an anti-tartar agent an effective amount of a 2-fo-phono-but-1,2,4-tr ic arbonic acid (PBTA) compound of the formula 3 wherein R represents hydrogen, lower alkyl or carboxyl and R 15 represents hydrogen or methyl, or an orally acceptable salt thereof, which is preferably water-soluble, such as a salt with an alkali metal (eg, sodium and potassium), ammonium, C 1 -C 4 g-mno, dien tri-substituted ammonium (eg substituted by alkanol, such as mono-, di- and triethanolammonium) cation.

Compounds of the above formula and methods for their preparation are described in U.S. Pat. Nos. 3,386,204 and 3,886,205. The preferred PBTA compound according to the invention is the unsubstituted compound of formula 3 above, wherein R and R 1 each represent hydrogen. When R is a lower alkyl group, it preferably contains 1 to 4 carbon atoms, especially the methyl group.

The concentration of the PBTA compound (or salt) in the oral treatment mixtures can vary within wide limits, e.g. more than about 0.01 percent by weight, with no need to observe an upper limit as to the amount to be used, except that dictated by cost or incompatibility with the carrier. Generally, concentrations of from about 0.01 to about 10, and preferably from about 0.1-6 wt.% Are used. Mouth treatment mixtures, which could accidentally enter the stomach during normal use, preferably contain low concentrations of the PBTA compound. For example, a mouthwash according to the invention at 8004619 6 preferably contains less than about 2% by weight of the PBTA compound, preferably about 0.1-1.5% by weight. Other dental treatment mixtures, topically applied solutions and prophylactic pastes, the latter of which are to be professionally administered, may preferably contain about 0.1-3% by weight of the PBTA compound.

The PBTA dressings of the invention are anti-germinating agents, wherein oral treatment compositions of the invention containing these compounds are effective in reducing tartar build-up without over-decalcifying the enamel 10, while in contrast to the Nitrogen-containing antibacterial anti-plaque agents, such PBTA compounds and mixtures described above, except that they effectively prevent gingivitis, have little or no tendency to discolour the teeth.

The invention further provides the advantage that these anti-germinating anti-tartar PBIA compounds unexpectedly prevent, prevent or remove the discoloration of dental enamel caused by the above-described nitrogen-containing anti-plaque antibacterial agents. without precipitating or without significantly affecting their antibacterial and anti-plaque activity. Not all anti-germinating agents are effective in preventing discoloration from such antibacterial agents. Victamide (also known as Vicatamine C), which is a condensation product of ammonia with phosphorus pentoxide, actually increases discoloration even in the absence of such antibacterial agents.

When present, these antibacterial anti-plaque agents, which normally cause discoloration, e.g. used in amounts that are normally effective, e.g. so that the mouth treatment product thereof contains between about 0.001 and 15% by weight. To achieve desired concentrations of the anti-plaque effect, the oral treatment end product contains about 0.01 to about 5, and in particular about 0.25, 1.0% by weight of the anti-bacterial anti-plaque agent, based on the free base form. It is highly desirable that the ΡΒΈΑ-35 compound be present in a molar excess over the amount of antibacterial anti-plaque agent (based on the free base 8004619 7 * X.

shape) to minimize, prevent or prevent discoloration.

In certain highly preferred forms of the invention, the mouth treatment mixture may be substantially liquid, such as in a mouthwash or mouthwash. In such a preparation, the carrier is e.g. a mixture of water and alcohol, preferably containing a humectant as described below. Generally, the water to alcohol weight ratio is about 1: 1 to about 20: 1, preferably about 3: 1 to 10: 1, and especially about k: 1 to about 5: 1. The total amount of water -alcohol mixture for this type of preparation is e.g. about 70 to about 99% by weight of the composition. The pH of such a liquid and of other compositions of the invention is generally from about kt5 to about 9, e.g. about 5.5-15. The pH is preferably between about 6 and about 8.0. It is to be remembered that the mixtures according to the invention can be used orally at a pH below 5, without decalcifying the enamel significantly. The pH can be adjusted with acid (e.g. citric acid or benzoic acid) or base (e.g. sodium hydroxide) or buffered (such as with phosphate-20 buffers). Such liquid oral treatment preparations may also contain a surfactant and / or a fluorine-providing compound.

In certain other desirable forms of the invention, the mouth treatment mixture may be substantially solid or pasty, such as with dental powder, a dental treatment tablet, a toothpaste or a dental cream. The carrier of such solid or pasty mouth treatment compositions generally contains a polishing agent . Examples of polishing agents are: water-insoluble sodium metaphosphate, potassium metaphosphate, tricalcium phosphate ,. dihydrated calcium phosphate, anhydrous dicalcium phosphate, calcium pyrophosphate, magnesium orthophosphate, trimagnesium phosphate, calcium carbonate, alumina, hydrated alumina, aluminum silicate, zirconium silicate, silicon oxide, bentonite and mixtures thereof. Preferred polishing agents include silica gel or colloidal silica, complex amorphous alkali metal aluminosilicate and hydrated alumina.

Aluminum oxide, in particular the hydrated aluminum oxide 8004619 8, which is marketed by Alcoa as C-333, which has an alumina content of 6.9 wt.%, A silica oxide content of 0.008 wt.%, An iron oxide content of 0.003 gsv.% and a moisture content of 0.37 wt.%, it has 110 ° C, and has a specific gravity of 2.1 (-2 and a particle size such that 100% of the particles are smaller than 50 micrometers and Qh% of the particles smaller than 20 micrometers is very effective.

When visually clear anti-tartar gels are used, a colloxal silica polishing agent such as those commercially available under the trade name SYLOID as

Syloid 72 and syloid jk or under the tradename SANTO CEL as Santocel 100 and alkali metalaluminosilicate complexes are particularly useful as they have refractive indices close to the refractive indices of gelling liquid (including water and / or wetting agent) systems , which are commonly used with dental treatments. For the same reasons, alkali metal aluminosilicate complexes are particularly suitable as polishes in visually clear gels containing the PBTA compound in combination with the described nitrogen-containing antibacterial anti-plaque agents.

Many of the so-called "water-insoluble" polishes are anionic in nature and also contain small amounts of soluble material. For example, insoluble sodium metaphosphate can be formed in any suitable manner, as noted in Thorpe's Dictionnary of Applied Chemistry, Volume 9, fourth edition, pp. 510-511. The forms of insoluble sodium metaphosphate, known as Madrell's salt and Kurrol's salt, are other examples of suitable substances. These metaphosphate salts exhibit very low water solubility and are therefore commonly referred to as insoluble metaphosphates. Therein a very small amount of soluble phosphate is present as impurities, usually a few percent, such as at most 4 percent. The amount of soluble phosphate material believed to comprise a soluble sodium trimetaphosphate in the case of insoluble metaphosphate can be reduced by water washing if desired. The insoluble alkali metal metaphosphate is e.g. in powder form having such a particle size that no more than about λ% of the material has a larger diameter than about 37 micrometers.

i

The polishing material is generally present in 8004619 9 amounts from about 10 to about 99 weight percent of the oral treatment composition. It is preferably present in amounts from about 10 to about 15% as far as the toothpaste, and from about 70% to about 99% as far as the tooth powder is concerned.

In dental powder formulations, it is usually sufficient to mechanically mix the various solid ingredients in appropriate amounts and particle sizes, e.g. by grinding »

In pasty oral treatment compositions, the PBTA compound should be compatible with the other components of the composition. For example, in a toothpaste, the liquid carrier may contain water and a wetting agent, e.g. in an amount from about 10 to about 90% by weight of the composition. Glycerol, propylene glycol, sorbitol or polyethylene glycol ol h-00 may also be present as wetting agents or binders. Particularly suitable liquid ingredients include mixtures of water, glycerol and sorbitol.

Clear gels, where the refractive index is an important point, use about 3-30 wt% water, 0 to about 80 wt% glycerol and about 20-80 wt% sorbitol. A gelling agent, such as natural or synthetic gums or gummy substances, e.g. Irish moss, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, the Carbopoles (e.g. 93 ^, 9k0 and 9 ^ + 1), gum tragacanth, polyvinylpyrrolidone or starch or mixtures thereof or the like, are usually present in toothpaste in an amount of at most about 10% by weight, preferably from about 0.5 to about 5%. With a toothpaste or gel, such amounts of liquids and solids are used that a creamy gelled mass is formed which can be extruded from a pressurized container or from a compressible tube, e.g. is made of aluminum or lead.

The solid or pasty mouth treatment composition whose pH, measured on a 20% slurry, e.g. about 0.5 to 9, generally about 5.5 to about 8, and preferably about 6 to about 8.0, may also contain a surfactant and / or a fluorine-providing compound.

It will be appreciated that, as usual, the mouth treatment compositions are marketed in suitable labeled packages in 8004619, or are otherwise distributed. For example, a bottle of mouthwash will have one. have a label that describes it primarily as a mouthwash or mouthwash, with directions for its use; whereas a toothpaste will usually be contained in a collapsible tube, eg of aluminum, lined with lead or plastic, or in another squeezable container with which the Infyoud can be dosed, on which tube or container a label is applied, on which the contents are mainly described as a toothpaste or a dental cream.

In the mixtures according to the invention, organic surfactants are used to effect an increased prophylactic effect, to effect an intensive and complete dispersion of the EBiEL agent through the oral cavity and to make the ready-to-use mixtures cosmetically more acceptable. The organic surfactant material is preferably anionic, nonionic or ampholytic in nature, while it is preferable to use as the surfactant a detersive material which imparts detergent and foam-forming properties to the mixture. Suitable examples of anionic surfactants 20 are: water-soluble salts of. high fatty acid monoglyceride monosulfates, such as the sodium salt of the mono-sulfated mono glyceride of hydrogenated coconut oil fatty acids, high alkyl sulfates, such as sodium lauryl sulfate alkylarylsulfonates, such as sodium dodecylbenzenesulfonate, high alkyl sulfoacetates, high sulfuric acid esters of 1,2-fatty acid esters of 1,2-fatty acid esters the substantially saturated high aliphatic acyls of low aliphatic aminocarboxylic acid compounds, such as those having 12 to 16 carbon atoms in the fatty acid, alkyl or acyl groups, and the like. Examples of the latter amides are N-lauroyl sarcosine and the sodium, potassium and ethanolamine salts of N-lauroyl, N-myristo-30 yl or N-palmitoyl sarcosine, which should be essentially free of soap or similar high fatty acid material. The use of these sarcosinate compounds in dental treatment compositions according to the invention is particularly advantageous, since this material exerts a longer and characteristic effect in counteracting acid formation in the oral cavity as a result of the breakdown of carbohydrate, while at the same time reducing some of the solubility of the tooth enamel in acidic solutions 8004619 11.

Examples of water-soluble nonionic surfactants are condensation products of ethylene oxide with various compounds which contain and can react with reactive hydrogen and which have long hydrophobic chains (eg aliphatic chains with about 12 to 20 carbon atoms), which condensation products ("ethoxamers") hydrophilic polyoxyethylene moieties, such as condensation products of poly (ethylene oxide) with fatty acids, fatty alcohols, fatty amides, polyhydric alcohols (eg sorbitan monostearate) and polypropylene enoxide (that is, material called "Pluronics", is indicated).

In certain forms of the invention, a fluorine-providing compound is present in the oral treatment composition. These compounds can be slightly or completely soluble in water. They are characterized by their ability to release fluorine ions in water and by a considerable freedom of reaction with other compounds of the mouth treatment composition. These compounds include inorganic fluoride salts such as soluble alkali metal, alkaline earth metal heavy metal salts, e.g. sodium fluoride, potassium fluoride, ammonium fluoride, a copper fluoride, such as cuprofluoride, zinc fluoride, a tin fluoride, such as stannous fluoride or stannous chlorofluoride, barium fluorine, sodium fluorosulfonate fluorosulfonate, sodium fluorosulfonate, sodium fluorosulfonate, sodium fluorosulfonate, sodium calcium pyrophosphate. Alkali metal and tin fluorides, such as sodium and stannous fluoride, sodium monofluorophosphate and mixtures thereof, are preferred.

The amount of the fluorine-providing compound depends to some extent on the type of the compound, its solubility and the type of the oral treatment composition, but it must be a non-toxic amount. In a solid mouth treatment composition, such as toothpaste or dental powder, an amount of such a compound, which is a maximum of about 1 wt. $ of the preparation is considered satisfactory. Any suitable minimum amount of such a compound may be used, but it is preferable to use sufficient compound to. about 0.005 / ¾ to% and preferably about 0.1% to release fluoride ion. In the cases of using alkali metal fluorides and stannous fluoride, this compound is e.g. present in an amount of up to about 2% by weight, based on the weight of the composition, preferably using about 0.05% - 1%. In the case of sodium 5 monofluorophosphate, the compound may be present in an amount of up to 7.6% by weight, for example, about 0.76%.

In a liquid mouth treatment composition, such as a mouthwash, the fluorine-providing compound is e.g. present in an amount sufficient to make up to about 0.13 wt.%, preferably about 0.0013 wt.% to 0.1 wt.%, and in particular about 0.0013 wt.% to 0.1. To release 5 wt.% Fluoride ion.

Various other substances can be included in the oral treatment preparations according to the invention, such as whitening agents, preservatives, silicones, chlorophyll compounds, other anti-calculating agents, antibacterial anti-plaque agents and / or ammonium derivatives, such as urea , diammonium phosphate and mixtures thereof. These additives, when present, are included in the compositions in amounts that do not significantly affect the desired properties and characteristics.

Eli suitable material to improve the smell or taste or whether any sweetener can be used. Examples of suitable taste and / or odor improving ingredients are taste and / or odor improving oils, e.g. oils of spearmint, peppermint, wintergreen, sassafras, cloves, sage, eucalyptus, marjoram, cinnamon, lemon and orange and methyl salicylate. Suitable sweeteners include sucrose, lactose, maltose, sorbitol, xylitol, sodium cyclamate, perillaratin, APM (aspartylphenylalanine, methyl ester), saccharin and the like. A suitable amount of flavor, fragrance and sweeteners together is about 0.01-5% or more of the composition.

In preparing oral treatment mixtures according to the invention, it is preferable, without being essential, however, to add the PBTA after the other ingredients (perhaps with the exception of part of the water) have been mixed or contacted, in order to avoid a tendency of the PBTA to be precipitated.

For example, e.g. a mouthwash or mouthwash is prepared by mixing ethanol and water with odor and / or flavor enhancing oil, surfactant, wetting agent, optionally anti-bacterial anti-plaque agent, such as cetylpyridinium chloride, benzethium chloride or chlorhexidine, sweetener, colorant and then adding to the above defined PBTA compound, optionally followed by addition of additional water.

A toothpaste can be prepared by mixing a gel with humectant, gum, thickener or gelling agent, such as hydroxyethyl cellulose, sweetener and adding a polishing agent, a taste or / or odor improving agent, if desired antibacterial anti-plaque agent, additional water and then the PBTA compound described above. If sodium carboxymethyl cellulose is used as the gelling agent, together with an antibacterial anti-plaque agent of the bis-biguanide type, the procedure described in either U.S. Pat. No. 3,842,168 or in U.S. Pat. Patent 3,8-3,779, modified by also incorporating the PBTA compound.

In the practice of the use of the invention, a mouth treatment mixture of the invention, such as a mouth wash or a toothpaste, is regularly applied to the enamel, preferably about 1 to about 3 times a day at a pH of about 4.5 to about 9, generally about 5.5 to about 8, preferably about 6 to 8.

The invention is further illustrated by the following examples, in which all amounts and ratios are weight ratios, unless otherwise indicated.

Example I

Inhibition of crystal growth from HAP

This was evaluated by a pH-Stat method. 1.0 ml aliquot of an aqueous solution of 1 x 10 M to 1 x 10 µ M of the anti-tartar agent to be tested and 0.1 M sodium dihydrogen phosphate were placed in a reaction flask with 22 - 23 ml of distilled water , with continuous stirring in a nitrogen atmosphere. To this 1 ml of 0.1 M CaClp was added and the pH using HaOH

I | 73 —O

35 set at T, h + 0.05 (final concentration of Ca and PO = 1 * x 10 M).

The consumption of 0.1 n NaOH was automatically recorded by a pH-8004619

1U

Stat (Radiometer). In this experiment, the formation of HAP occurred in two separate phases. First a fast consumption of base (1 - k minutes) took place and then this consumption decreased until 15-20 minutes had elapsed, after which a second fast recording took place. A delay in time went from the second rapid consumption or a complete absence. of the second rapid consumption, indicates a staring of the crystal growth of HAP. Agents that interfere with the crystal growth of HAP are effective anti-calculus agents. When PBTA was tested according to the method just described, the following results were obtained.

TABLE A

10 Anticalculus- Time for Delay at Medium (conc.) HAP Vapor HAP Vapor

Water (control) 15 min - PBTA (4 ppm) 25 min 10 min PBTA (8 ppm) T5 min 60 min 15 PBTA (10 ppm) 129 min 11 ^ min PBTA (20 ppm) 33.8 hours

The above results demonstrate that PBTA effectively inhibits crystal growth of HAP in vitro and that the inhibition is not due to complexation or chelation of calcium, since sub-stoichiometric ratios of PBTA: calcium have been used.

Examples II - V

In the following examples, which relate to mouthwash compositions of the invention, Pluronic 25 F108, a polyalkylene oxide block polymer, was used.

Example _II III IV V_

Fragrance and / or flavoring 0.22% 0.22% 0.22% 0.22%

Ethanol 15.0 15.0 15.0 15.0 30 Pluronic F108 3.0 3.0 3.0 3.0

Glycerol 10.0 10.0 10.0 10.0

Ha-saccharin 0.03 0.03 0.03 0.03 PBTA 0.1 0.2 0.5 1.0

Water, make up to 100 100 100 100 8004619 15

Example (Continued) _II III IV V_

pH (with NaOH) - 7 Λ 7Λ 7Λ 7, U

Appearance bright clear clear clear

5 Examples VI and VII

The following examples serve to illustrate anti-calculus toothpastes according to the invention.

Example

VI_VII

10 Silicon dioxide 30 30

Glycerol _ 16 16

Sorbitol (70 $) 6 6

Pluronic F-108 3 3

Hydroxyethyl cellulose 1.2 1.2 15 PBTA 2 2

Hatrium saccharin 0.1T 0.17

Fragrance and / or flavoring 0.8 0.8

Water, make up to 100 100

Examples VIII-XIV

Table B further clarifies compositions of mouth vases according to the invention and the anti-discoloration action of the preferred PBTA additive used therein. The tooth staining characteristics of the compositions were evaluated by slurrying hydroxyapatite (Biogel), a particular saliva protein, a carbonyl source (eg, ac eats aldehyde) and a pH = 7-phosphate buffer with and without testing the mouth fat mixes. process. The colored HAP powder was separated by filtration and dried, while the color levels (in reflectance units) were determined using a Gardner color and diff er meter.

8004619 16 M3 _ js co * - οτ-Ο’-ο o o \ on, |> ^ A ft A A A ^ Λ Λ Λ 11 HOOCOOOO'— Ot— LAVO ^ r- r- Ο ΙΛ »“

* - I.

VO

-3- CO „

H O O W

(-1¾¾ αααααϊϊϊϊ, ααα HOOCOOOOOOt— t— CO X * - 1- 0-4-1 r— fd Ö,.

i Ω (U O’-O'-CO O W VO Ό Η · & 5- Λ »ΛΛ ·» ^ «**« Η <D HOOCOOOOOOC— VOVO Tue 5 X * - * - 0-3-10 0 a

O.

m o w a> 03

ο vo -P

be -3 "co aj

O h C O * - O <- CM ovoo S

Ο · Η H ΛηΛΛΟ ^ ΛΛΛ pqoca txjoocoooooot — coj- a t »CD r- O -3" I 03 pa -¾ a> «

Aj 4) H

bO 43 tl Ö vo _ bo • rl -3- CO! h H O'- O'— O LA 03 H> 5. «Λ» ** ^ *** J>

03 IxjOOCOOOOOOt— CM CM

+3 r ~ f— O -3 "1 4

03 ’“ I

a -1— «3 vo

CQ -3- CO

0 ^ 0 * “O VO OJ

Λ Λ Λ Λ Λ ^ Λ χοογοοοο ο t- σι h · Η r- r- Ο CO «- r- +

VO

-3- CO _ Ο * - Ο O CO in I— (ft ft ft ^ ft ft I 4) HOOCOOO O t— vo I 0 Η T- T- Ο ΙΑ I a> 0 ft <u M * 0 Ο · A H a P 0

ft J, H

Or Φ P

+3 0 Ό υ aft £ § pa ο · η a <u a a T- a a h <u -π CO 03 a h „<u Ό o v_- a '' ο Η · Η r—? μ3 Η 0) ί * ϊ a ftoo a o ft · η -id> »a a a a ft Hft h Hoa-H a a a an an 03 Η Ο · Η 03 a ft>? > »Ο o a 3 a« a o a Q h ft P a ο ο ι p ^ a * - o> ® «oo aaoa ^ ocvjpowHft ft o op >> 33 00 ^ + 5 ^ ¾1 ^ _ ofTHH a a ffi p a a <u-h

> WOftKCQOftSftKQ 'CM

8004619 17

The results listed in Table B clearly demonstrate that the additives of the invention, such as PB1A, tooth discoloration usually caused by antibacterial anti-plaque agents, e.g. by CPC, significantly reduce. A PBIA concentration of about 1.0 # appears to give excellent results. Such additives also reduced or inhibited calculus gingivitis, while not significantly reducing the anti-plaque activity of the indicated anti-plaque agents.

Examples XV-XX

By replacing the CPC used in Examples X-XIV with equivalent amounts of the following antibacterial anti-plaque agents, compositions were obtained which also brought about an unexpected reduction in tooth discoloration and calculus.

Example Antibacterial Anti-plaque Agent XV Benzethonium Chloride (BC) XVI Chlorhexidine Diacetate XVH Chlorhexidine Digluconate XVIII Dodecylt Rimet Hylammnium Bride 20 XIX Compound of Formula 1 * XX Alexidin Dihydrochloride

Examples XXI - XXIII

The following compositions are examples of anti-plaque action toothpastes with reduced discoloration and reduced calculus.

Example (share)

XXI_ΧΧΓΕ_XXIII

Hydrated aluminum oxide 30 30 30

Polyethylene glycol 600 22 22 22 30 Pluronic F-108 3 3 3

Hydroxypropyl methylcellulose 1.2 1.2 1.2 BC 0.5 - -

Hibitan - 725 CPC - - 0.5 35 PBTA. 1.0 1.0 1.0

Hatrium saccharin 0.17 0.17 0.17 8004619 18 (Continued) Example (parts)

XXI_XXII_XXIII

Fragrance and / or flavoring 0.8 0.8 0.8

Water, make up to 100 100 100 5 Significant reductions in tooth discoloration, plaque, calculus and gingivitis were also obtained according to the invention when the PBTA in the above examples was replaced by any other representative of the PBTA compounds disclosed in U.S. Patents 3,886 .20b and 3,886,205 have been described.

·. t 8004619

Claims (13)

An oral treatment mixture with an orally acceptable carrier containing about 0.01-10% by weight "of a 2-phosphono-butane-1,2,4-tricarboxylic acid compound of the formula 3, wherein R is hydrogen, lower alkyl or carboxyl and R 2 hydrogen or methyl, 5 or an orally acceptable salt thereof, and 0-15% of at least one usually discolouring nitrogen-containing antibacterial anti-plaque agent based on the free base. form of this medicine. An oral treatment mixture according to claim 1, wherein in formula 3 R and H1 represent hydrogen. Mouth treatment mixture according to claim 1 or 2, characterized in that the antibacterial anti-plaque agent is cationic and is present in an amount of at least about 0.001% by weight. Mouth treatment mixture according to any one of claims 1 to 3, characterized in that the compound is present in an amount of from about 0.1 to about 6% by weight. Mouth treatment mixture according to any one of claims 1 to 4, characterized in that the antibacterial anti-plaque agent is a substituted guanidine. Mouth treatment mixture according to claim 5, characterized in that the antibacterial anti-plaque agent is a pharmaceutically acceptable water-soluble salt of chlorhexidine or alexidine. Mouth treatment mixture according to any one of claims 1 to 4, characterized in that the antibacterial anti-plaque agent is benzethonium chloride. Mouth treatment mixture according to any one of claims 1 to 4, characterized in that the antibacterial anti-plaque agent is a quaternary ammonium compound containing 1 to 2 alkyl groups of 8 to 20 carbon atoms. Mouth treatment mixture according to any one of claims 1 to 4, characterized in that the antibacterial anti-plaque agent is cetylpyridinium chloride. Mouth treatment mixture according to any one of claims 1 to 9, characterized in that the carrier is an aqueous alcohol and the mixture is a mouthwash with a pH of about 4.5 to about 9,800 4 6 19 Mouth treatment mixture according to any one of claims 1 to 9, characterized in that the carrier consists of a liquid carrier and a gelling agent, which further comprises a dentally acceptable polishing material and the mixture is a toothpaste with a pH of about 5 k, 5 to about 9 » An oral fat mixture according to any one of claims 1 to 11, characterized in that the mixture contains about 0.01 to about 5.0 gs% of the agent. 13. A method for improving oral hygiene, characterized in that an effective amount of an oral treatment mixture according to any one of the preceding claims is administered to the oral cavity. * 8004619