SE434596B - MUNVARDS COMPOSITION CONTAINING MEDITERRIC ACID OR HEXAHYDROMELLITIC ACID FOR ANTICIPATION OF DENTAL SPOTS CAUSED BY AN INHIBITIVE NON-BREAKING HYPHEN (8209) antibacterial inhibitor - Google Patents

Description

7714727-0 of a reduction in the formation of caries and periodontal diseases.

Other cationic antibacterial agents of this type are those mentioned in e.g. U.S. Patents 2,984,639, 3,325,402, 3,431,208 and 3,703,583 and British Patents 1,319,396.

Other antibacterial plaque inhibiting quaternary ammonium compounds include those in which one or two of the substituents on the quaternary nitrogen have a carbon chain length (typically alkyl group) of about 8 to 20 and typically 10 to 18 carbon atoms, while the remaining substituents have a lower number of carbon atoms (typically alkyl or benzyl group), such as 1-7 carbon atoms and typically methyl or ethyl groups. Dodecyltrimethylammonium bromide, dodecyldimethyl- (2-phenoxyethyl), ammonium bromide, benzyldimethylylstearylammonium chloride, cetylpyridinium chloride and quaternized 5-amino-1,3-bis- (2-ethylhexyl) -5-methylhexylimenium anhydride are ammonium anhydride or

The long chain tertiary amines also possess antibacterial and plaque inhibitory activity. Such antibacterial agents include tertiary amines having a fatty alkyl group (typically 12 to 18 carbon atoms) and 2 poly (oxyethylene) groups attached to the nitrogen (typically containing a total of from 2 to 50 ethyleneoxy groups per molecule) and salts thereof with acids and compounds of the structural formula; FH 2 CH 2 O) 2 HH (CH 2 CH 2 O) x H RN-CH 2 CH 2 -N , together with salts thereof. In general, cationic agents are preferred for their plaque inhibitory efficacy. The antibacterial plaque inhibitory compound is preferably one which has an antibacterial activity of such kind that its phenolic coefficient is well above 50, more iron-rich well above 100, such as above about 200 or more for S. aureus. For example, the phenol coefficient (A.O.A.C.) for benzethonium chloride by the manufacturer is stated to be 410 for S. aureus. The cationic antibacterial agent is generally a monomeric material (or optionally a dimeric material) having a molecular weight well below 2000, such as less than about 1000. However, it is within the further scope of the invention to use a polymeric cationic antibody. bacterial agent. The cationic antibacterial agent is preferably administered in the form of an orally acceptable salt thereof, such as chloride, bromide, sulfate, alkylsulfonate such as methylsulfonate and ethylsulfonate, phenylsulfonate such as p-methylphenylsulfonate, nitrate, acetate, gluconate, etc.

The cationic antibacterial quaternary ammonium compounds and the antibacterial agents in the form of long chain tertiary amines effectively promote the hygiene, especially by removing plaque. However, it has been noted that their use leads to staining of the tooth surfaces or discoloration.

The reason for the formation of such tooth staining has not been clearly established. However, human tooth enamel contains a high content (about 95%) of hydroxyapatite, which includes Ca + 2 and PO4_3 ions. In the absence of tooth plaque, additional Ca + 2 PO 4 '3 ions, especially from saliva, may be deposited on the enamel and such deposits may include dyes which eventually stain the tooth enamel as a calcified deposit thereon. It may be that because the cationic antibacterial agents in the form of quaternary ammonium compounds or the antibacterial agents in the form of long chain tertiary amines remove plaque, they also denature protein from the saliva in the oral cavity and the denatured protein can then act as a nucleating agent. , which is deposited on and stains or discolors tooth enamel. 7714727-0 Previously used additives, which reduced tooth staining by cationic antibacterial plaque inhibitors, also generally reduced the activity of the antibacterial agents or their ability to act on dental plaque to a measurable extent.

Furthermore, it has been found that Victamide (also known as Victamine C), which is the condensation product between ammonia and phosphorus pentoxide, in fact increases staining even in the absence of a cationic antibacterial plaque inhibitor and that it and other known phosphorus-containing agents, such as disodium ethane -1-hydroxy-1,1-diphosphonic acid salt, precipitates in the presence of antibacterial agent, such as bis-biguanido compound, thereby reducing the plaque inhibitory efficacy of the antibacterial agent.

British Patent 1,319,396 and the corresponding German patent 2,161,477 recommend the use of pyromellitic acid (benzene-1,2,4,5-tetracarboxylic acid) to prevent staining and plaque buildup on the teeth, while the corresponding U.S. Pat. patent 3,671,626 strangely enough does not mention anything about a stain preventing function. These patents disclose the possible concomitant use of conventional oral care additives including preservatives and germicides, among which quaternary ammonium compounds are mentioned, but no hint is given as to the staining of teeth by plaque inhibiting antibacterial agents in the form of quaternary ammonium compounds, and even less an aid for reduce or prevent such staining.

French Patent 2,220,270 recommends the use of cyclic organic carboxylic acids, including mellitic acid and other benzenecarboxylic acids, to prevent or reduce hydroxyapatite-containing plaque, optionally together with other conventional additives including therapeutic agents, such as bis-biguanides, but without affect the staining of teeth of such bis-biguanides, let alone an aid to reduce or prevent such staining. Mellitic acid also precipitates and / or forms an insoluble complex with bis-biguanides, thereby substantially reducing the plaque inhibitory activity of the latter compounds. ..........., ...__.... . . U.S. Patent 3,920,837 discloses a method of treating the adverse effects of calcium comprising the buildup of tartar or hydroxyapatite crystals on the teeth, using cyclohexane hexacarboxylic acid, but without mentioning anti-staining functions or use in conjunction with a plaque inhibitory antibody.

An advantage of the present invention is that a nucleating inhibitor additive is provided which prevents staining of the tooth enamel without precipitation or substantially adversely affecting the antibacterial and plaque inhibitory activity of antibacterial agents in the form of cationic quaternary ammonium compounds or long chain tertiary amine amines. of the following description.

The initial oral composition is characterized according to the present invention in that it contains an addition of mellitic acid or hexahydromellitic acid to counteract tooth stains caused by the antibacterial plaque inhibitor.

The additive also comprises mixtures of mellitic acid and hexahydromellic acid, including orally acceptable salts thereof, e.g. those containing such cations as alkali metal (eg sodium and potassium), ammonium, C1-C18 mono-, di- and trisubstituted ammonium (eg alkanol substituted such as mono-, di- and triethanolammonium), amine, etc. These additives are water-soluble in their free acid form as well as their orally acceptable salts which can be used herein.

The concentration of these lactic acid additives in oral care compositions can range within wide ranges, typically from 0.005% by weight and upwards without any upper limit apart from what is prescribed by the cost or incompatibility with the carrier. Concentrations from about 0.005% to about 10% by weight and preferably from about 0.01% to about 2% by weight are generally utilized. Oral compositions, which in the usual mode of use could be inadvertently swallowed, preferably contain lower concentrations of these additives.

Thus, a mouthwash in accordance with the present invention preferably contains less than 1% by weight of the additive. Dental compositions, solutions for topical treatment and prophylactic pastes, the latter of which are intended to be administered professionally, may preferably contain about 0.1 to 2% by weight of the additive. The middle acid additive is most suitably present in a molar ratio to the amount of antibacterial plaque inhibitor (based on its free base) of about 0.2: 1 to about 6: 1, preferably about 0.5: 1 to about 4: 1 to best reduce, inhibit or prevent discoloration.

Antibacterial agents which are germicides in the form of cationic quaternary ammonium compounds or long chain amines used in the practice of the present invention are described above. They are typically used in such amounts that the oral care product contains between about 0.001% and 15% by weight of the agent.

For desired levels of the plaque inhibitory effect, the finished oral care product preferably contains about 0.01 to about 5% by weight and most preferably about 0.025 to 1.0% by weight of the antibacterial agent based on its free base form.

The staining that usually occurs on tooth enamel is significantly or completely prevented in an unexpected way when the above-mentioned intermediate acid additives or the orally acceptable water-soluble salts thereof are used. These materials are nucleating inhibitors. By themselves (even in the absence of cationic plaque-inhibiting antibacterial agents), they are effective in reducing tartar formation without unduly decalcifying the enamel.

However, not all nucleating agents are effective in preventing staining by cationic antibacterial agents. For example, Victamide actually increases staining even in the absence of an antibacterial plaque inhibitor. In certain highly preferred embodiments of the invention, the oral care composition may be substantially liquid in nature, such as a mouthwash or mouthwash. In such a preparation, the carrier is typically a water-alcohol mixture. The weight ratio of water to alcohol is generally in the range of from about 1: 1 to about 20: 1, preferably from 3: 1 to 20: 1 and most preferably about 17: 3. The total amount of the water-alcohol mixture in this type of preparation is typically in the range of from about 70% to about 99.9% by weight of the preparation. The pH of such liquids 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 is remarkable that the compositions of the invention can be applied orally at a pH below 5, 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 embodiments of the present invention, the oral care composition may be substantially solid or pasty in nature, such as a tooth powder, a tooth tablet, a toothpaste or toothpaste. The carrier of such solid or pasty oral care compounds contains polishing materials. Examples of polishing materials are water-insoluble sodium metaphosphate, potassium metaphosphate, tricalcium phosphate, calcium phosphate dihydrate, anhydrous dicalcium phosphate, calcium pyrophosphate, magnesium orthophosphate, trimagnesium phosphate, bentonium siliconium hydroxide, aluminum zirconium hydroxide, aluminum carbonate Preferred polishing materials include crystalline silica having particle sizes of up to 5 microns, an average particle size of up to 1.1 microns and a surface area of up to 50,000 cm 2 per gram of silica gel, complex amorphous alkali metal aluminosilicate and hydrated alumina. e .... 7714727-0 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% by weight, a ferric oxide content of 0.003% by weight and a moisture content of 0.37% by weight at 110 DEG C. and having a specific gravity of 2.42 and such a particle size that 100% of the particles are less than 50 microns and 84a of the particles are less than 20 microns, is particularly desirable to use.

When visually clear gels are used, a colloidal silica polish such as those sold under the SYLOID brand such as Syloid 72 and Syloid 74 or under the SANTOCEL brand such as Santocel 100, and the alkali metal aluminosilicate complexes are particularly useful because they have a refractive index close to the refractive index. in dentifrices commonly used gelling fluid-liquid systems (including water and / or wetting agents).

Many of the so-called "water-insoluble" polishing materials are anionic in nature and also include small 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 forms of insoluble sodium metaphosphate known as Madrell's salt and Kurrol's salt are further examples of suitable materials, and these metaphosphate salts have a solubility time in water of 1 minute and are therefore generally referred to as insoluble metaphosphates. these include a small amount of soluble phosphate material as impurities, usually a few percent such as up to 4% by weight.The amount of soluble phosphate material, which is considered to contain a soluble sodium metaphosphate 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 of such a particle size to tea more than 1% of the material is larger than 37 microns.

The polishing material is generally present in amounts ranging from about 20% to about 99% by weight of the oral care composition. Preferably it is present in amounts ranging from about 20% to about 75% by weight in toothpastes and from about 70% to about 99% by weight in tooth powder.

In the preparation of tooth powder, it is usually sufficient to mix together by mechanical means, e.g. by grinding, the various solids in the right quantities and particle sizes.

In pasty oral preparations, the above combination of the antibacterial plaque inhibitor and the middle acid-containing compound must be compatible with the other components of the preparation. Thus, in a toothpaste, the liquid carrier may comprise water and wetting agent typically in an amount ranging from about 10% to about 90% by weight of the composition. Glycerin, sorbitol or polyethylene glycol may also be included as wetting agents or binders. Particularly advantageous liquid constituents include mixtures of water, glycerin and sorbitol.

In clear gels, where the refractive index is an important consideration, about 3 to 30% by weight of water, 0 to about 80% by weight of glycerin and about 20 to 80% by weight of sorbitol are preferably used. A gelling agent such as natural or synthetic gums or rubber-like materials, typically carrageenan, sodium carboxymethylcellulose, methylcellulose, or hydroxyethylcellulose, may be used. Other gelling agents that can be used include gum tragacanth, polyvinylpyrrolidone and starch. They are usually included in a toothpaste in an amount of up to 10% by weight, preferably in an amount in the range of from about 0.5% to about 5% by weight. The preferred gelling agents are methylcellulose and hydroxyethylcellulose. In a toothpaste or gel, the liquids and the solid materials are proportioned so that a creamy or gel-like mass is formed, which is sprayable from a pressure vessel or from a compressible tube of e.g. aluminum or lead.

The solid or pasty oral preparations, which typically have a pH measured at a 20% slurry of about .. ... å- * ím-wwn-w-r-nwq-ïs ... _. In 7714727-0 -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 a fluorine-releasing compound.

It is to be understood that the oral care preparations are sold in a conventional manner or otherwise distributed in suitable labeled> packages. Thus, a bottle of mouthwash will have a label which essentially describes it as a mouthwash or mouthwash and which has instructions for its use, and a toothpaste will usually be present in a compressible tube, typically aluminum or lined lead, or in any other compressible dispensing device for dispensing the contents, which tube or dispensing container has a label which essentially describes the contents as a toothpaste or toothpaste.

Oral care compositions such as mouthwashes and toothpastes often include a surfactant, e.g. to promote foaming.

It is to be understood that it is preferred to use nonionic surfactants rather than their anionic counterparts. Examples of water-soluble nonionic surfactants are condensation products between ethylene oxide and various compounds which are reactive with the ethylene oxide and which have long hydrophobic chains (eg aliphatic chains having 12 to 20 carbon atoms), which condensation products ("ethoxamers") have hydrophilic polyoxyethylene moieties, such as the condensation products between ethylene oxide and fatty acids, fatty alcohols, fatty amides, including alcohols such as sorbitan monostearate or polypropylene oxide (ie Pluronic material).

In some embodiments of the present invention, a fluorine-releasing compound is included in the oral care composition. These compounds may be poorly soluble in water or may be completely water soluble.

They are characterized by their ability to release fluoride ions into water and by the substantial lack of propensity to react with other compounds of the oral care composition. Among these materials are inorganic fluoride salts, such as soluble alkali metal, alkaline earth metal and heavy metal salts, e.g. sodium fluoride, potassium fluoride, ammonium fluoride, lead fluoride, a copper fluoride such as copper (1) fluoride, zinc fluoride, a tin fluoride such as stannous fluoride or stannous fluoride, barium fluoride, sodium fluorosilicate, ammonium fluorosiliconate, sodium fluorosiliconate, sodium fluorosilicate and difluorophosphate and fluorinated sodium calcium pyrophosphate. The alkali metal and tin fluorides, such as sodium and stannous fluorides, 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 a non-toxic amount. In a solid oral care preparation, such as a toothpaste or tooth powder, it is considered satisfactory to use an amount of such a compound which releases a maximum of 1% by weight of the preparation. Any suitable minimum amount of such a compound can be used, but it is preferred to use a sufficient amount of compound to release from 0.005-1% and preferably about 0.1% fluoride ion. In the case of fluorides and stannous fluoride, such a component is typically present in an amount of up to 2% by weight, based on the weight of the preparation, and preferably in the range 0.05 - 1%.

In the case of sodium monofluorophosphate, this compound may be present in an amount of up to 7.6% by weight, more typically 0.76% by weight.

In a liquid oral care composition such as a mouthwash, the fluorine-releasing compound is typically contained in an amount sufficient to release up to 0.13% by weight, preferably 0.001-3.1% by weight and most preferably 0.003-0.05% by weight. -% fluoride ion.

A variety of other materials may be incorporated into the oral care compositions of the present invention. Examples are whitening agents, preservatives, silicones, chlorophyll compounds and ammonium-containing materials such as urea, diammonium phosphate and mixtures thereof. These additives are, where appropriate, incorporated into the preparations in amounts which do not significantly adversely affect the desired properties and characteristics. . . .- .....__ fl.-.- .. 7714727-0 12 Any suitable flavoring or sweetening agent may also be used. Examples of suitable aromatic constituents are aroma oils, e.g. oils of garden mint, peppermint, wintergreen, sassafras, cloves, sage, eucalyptus, marjoram, cinnamon, lemon and orange, and methyl salicylate. Suitable sweeteners include sucrose, lactose, maltose, sorbitol, sodium cyclamate, perillartine and sodium saccharin. The flavoring agents and sweetening agents may suitably comprise together from 0.01% to 5% or more of the preparation.

In the preparation of the oral care compositions of the present invention, which comprise the above-mentioned combination of antibacterial agent and intermediate acid-containing compound in an oral carrier, which typically comprises water, it is highly desirable, if not essential, to add it. the middle acid-containing compound after the other ingredients (with the possible exception of some of the water) is mixed or brought into contact with each other to avoid a tendency for said agent to precipitate.

A mouthwash or mouthwash can e.g. prepared by mixing ethanol and water with flavoring oil, nonionic surfactant, wetting agent, cationic antibacterial plaque inhibitor such as benzethonium chloride or cetylpyridinium chloride, sweetener, dye and then the above-mentioned intermediate acid-containing compound accompanied by additional water as desired.

A toothpaste can be prepared by preparing a gel with wetting agent, rubber or thickener such as hydroxyethylcellulose, sweetener and adding to this gel polishing agent, flavoring agent, antibacterial agent, additional water and then the above-mentioned intermediate acid-containing compound. If sodium carboxymethylcellulose is used as the gelling agent, the procedure set forth in either U.S. Patent 3,842,168 or U.S. Patent 3,843,779 is followed, but modified by the incorporation of the middle acid-containing compound. In the practice of the present invention, an oral care composition of the present invention is applied, such as a mouthwash or a toothpaste containing an antibacterial plaque inhibitor in the form of a cationic quaternary ammonium compound or a long chain amine in a amount effective to promote oral hygiene and the defined lactic acid-containing compound in an amount effective to reduce staining of tooth surfaces which otherwise results from the presence of the antibacterial plaque inhibitor, regularly on the tooth enamel, preferably from about 5 times per week to about 3 times daily, at a pH of about 4.5 to about 9, generally about 5.5 to about s, preferably about s to s. The following specific examples are further illustrative of the nature of the present invention, but it is to be understood that the invention is not limited to these examples. All amounts and proportions set forth herein and in the appended claims are by weight unless otherwise indicated. In the examples, BK means benzethonium chloride, CPK means cetylpyridinium chloride and MS means middle acid. 7714727-0 14 Table I Mouthwash formulations,% example (l) (2) (3) (4) (5) (6) placebo control control flavor 0.22 0.22 0.22 0.22 0.22 0.22 ethanol 15.0 15.0 15.0 15.0 15.0 15.0 BK - 0.075 0.075 0.075 - - cPK - - - - 0.1 0.1 Pluronic Flos * 3.0 3.0 3.0 3 .0 3.0 3.0 glycerin 10.0 10.0 10.0 10.0 10.0 10.0 10.0 MS - - 0.1 0.5 -5 0.2 water, qs to 100 100 100 100 100 100 pH 7.0 (with NaOH) appearance clear - clear clear clear clear reflection factor 56 48 52 56 31 38 reflection difference - - 4 8 - 7 É polyalkenia oxide block polymer The middle acid and about 10 parts of the water is added to the other previously mixed constituents. The properties of tooth staining are examined by suspending hydroxyapatite (Biogel) with saliva protein and acetaldehyde and a phosphate buffer -with pH 7. The mixture is shaken at 37 ° C until a light brown color is formed. Colored powder is separated, dried and color levels (in reflection units) are determined on a "Gardner Color Difference Meter" before and after the test composition is applied to the colored material.

The above results clearly establish that mellitic acid significantly reduces tooth discoloration commonly caused by quaternary ammonium compounds as antibacterial plaque inhibitors as exemplified by benzethonium chloride and cetylpyridinium chloride. Formulations adjusted to pH 5 - 8 give similar results. Orally acceptable salts of middle acid give similar results. Studies of plaque inhibitory activity against actinomyces viscosus further indicated that formulations 3 and 4 (BK and MS) were equivalent to formulation 2 (BK) and formulation 6 (CPK and MS) was equivalent to formulation 5 (CPK).

Examples 7 - 9 The use of equivalent amounts of hexahydromellic acid instead of the middle acid in Examples 3, 4 and 6 gives similar results.

Example 10 - 12 Similar results are obtained when benzethonium chloride and cetylpyridinium chloride in Examples 3, 4 and 6 are exchanged for an equivalent amount of an antibacterial plaque inhibitor in the form of a long chain tertiary amine of the formula: çH 2 CH 2 OH / I // EHZCH18ZOH alkyl - N ~ CH2CH2N \\\\ 'CHZCHZOH The following preparations are examples of toothpastes with plaque-inhibiting effect and with reduced staining: ... ,, ....__. v -._-_--- »- ~ _- 7714727-0 hydrated alumina glycerin sorbitol (70%) Pluronic F-108 hydroxyethylcellulose benzethonium chloride (BK) cetylpyridinium chloride (CPK) mellitic acid sodium saccharin flavoring water, qs to Examples (parts) 13 14 30 30 16 16 6 3, 1.2 0.5 - - 4.725 2 2 0.17 0.17 0.8 0.8 100 100 The invention has been described with respect to preferred embodiments and it is to be understood that modifications and variations of the invention, which will be apparent to those skilled in the art, fall within the spirit of the invention and the scope of the appended claims.

Claims (10)

7714727-0 I? P a t e n t k r a v An oral care composition containing an oral carrier, at least one nitrogen-containing antibacterial plaque inhibitor selected from a group consisting of cationic quaternary ammonium compounds and long chain tertiary amines containing a fatty alkyl group having 12 to 18 carbon atoms, characterized in that it counteracts of tooth stains caused by the antibacterial plaque inhibitor contains an addition of mellitic acid or hexahydromellitic acid. An oral care composition according to claim 1, characterized in that said antibacterial plaque inhibitory agent is present in an amount giving 0.001% to 15% by weight, based on the free base form of the agent, and that said tooth stain preventing additive is present in an amount of 0.005% by weight to 10% by weight. An oral composition according to claim 2, characterized in that said antibacterial plaque inhibitor is present in an amount of 0.01% to 5% by weight, based on its free base form, and that said additive is present in a molar composition. ratio of 0.2: 1 to 6: 1 relative to said agent. An oral care composition according to claim 2, characterized in that said antibacterial plague inhibitor has the formula? H CH OH CH CH OH 2 2 /, / „2 2 -alkyl-N-CH ca -N 2 2 * \\\ ° 12 '° 1a CH 2 CH 2 OH An oral care composition according to claim 2, characterized in that said antibacterial plaque inhibitor is benzethonium chloride. An oral care composition according to claim 2, characterized in that said antibacterial plaque inhibitor is 11% cetylpyridinium chloride. An oral care composition according to claim 1, characterized in that said carrier is an aqueous alcohol and that the composition is a mouthwash having a pH of 4.5 to 9. An oral care composition according to claim 1, characterized in that said carrier comprises a liquid carrier and a gelling agent and that a dentally acceptable polishing material is included, and that the composition is a toothpaste with a pH of 4.5 to 9. ' ' An oral care composition according to claim 7 in the form of a mouthwash, characterized in that the composition contains 0.01% by weight to 5.0% by weight, based on its free base form, benzethonium chloride and that said additive is included in a molar ratio of 0.2: 1 to 6: 1 relative to said benzethonium chloride. An oral care composition according to claim 7 in the form of a mouthwash, characterized in that the composition contains 0.01% by weight to 5% by weight, based on its free base form, cetylpyridinium chloride and that said additive is included in a molar ratio of 0.2: 1 to 6: 1 relative to said cetylpyridinium chloride.