DK148898B - ANTIBACTERIAL ORAL CARE - Google Patents

Description

in 148898

The present invention relates to an antibacterial mouthpiece comprising an oral carrier, at least one nitrogen containing antibacterial antiplaque agent of the group consisting of cationic antibacterial antiplaque agents and long chain amines containing an alkyl group of 12 to 18 carbon atoms as antibacterial antiplaque agents and agent. , which removes discoloration, formed by these non-faithful antibacterial antiplaque agents.

Cationic antibacterial materials are well known. See, e.g. the section on "Quaternary Ammonium and Related Compounds" in the article on "Antiseptics and Disinfectants" in the Kirk-Othmer Encyclopedia of Chemical Technology, 2nd edition (Vol. 2, pages 632-635). Cationic materials that have antibacterial action (i.e., are germicides) are used against bacteria and have been used in oral care agents to counteract the formation of tartar caused by bacteria in the oral cavity.

Among the most common of these antibacterial antiplaque quaternary ammonium compounds are benzethonium chloride, also called Hyamine 1622 or diisobutylphenoxyethoxyethyldimethylbenzylammonium chloride.

In an oral care agent, this material is very effective in promoting oral hygiene by reducing the formation of plaque and tartar, which is usually accompanied by a reduction in caries formation and periodontal disease. Other cationic antibacterial agents of this type are those mentioned e.g. U.S. Patent Nos. 2,984,639; 3,325,402; 3,431,208; and 3,703,583;

1319396.

Other antibacterial antiplaque quaternary ammonium compounds include that in which one or two of the substituents on the quaternary nitrogen have a carbon chain length (typically alkyl group) of approx. 8-20, typically 10-18 carbon atoms, while the remaining substituents have a lower number of carbon atoms (typically alkyl or benzyl group), such as 1-7 carbon atoms, typically methyl or ethyl groups. Dodecyl = trimethylamraonium bromide, benzyldimethylstearylammonium chloride, cetyl = pyridinium chloride and quaternized 5-amino-1,3-bis (2-ethylhexyl) -5-methylhexahydropyrimidine are typical quaternary antibacterial ammonium compounds.

Other types of cationic antibacterial agents which are conveniently incorporated into oral care agents to promote oral hygiene by reducing plaque formation are the amidines such as the substituted guanidines, e.g. chlorhexidine, and the corresponding compound alexidine having 2-ethylhexyl groups in place of chlorophenyl groups, and other bis-biguanides such as those disclosed in German Publication No. 2,332,383 which disclose the following formula RNH NH NH NH R '

f ti II tt II I

A- (X) -NC-NH-C-NH (CH) -NH-C-NH-CN- (X ')' -A 'z 2 ri z where A and A' denote either (1) a phenyl radical, which may contain as substituents up to 2 alkyl or alkoxy groups of 1 to about 4 carbon atoms, a nitro group or a halogen atom; (2) an alkyl group containing 1 to about 12 carbon atoms, or (3) alicyclic groups of 4 to ca. 12 carbon atoms, X and X 'can represent an alkylene radical of 1-3 carbon atoms, z and z' can be either 0 or 1, R and R 'can represent either hydrogen, an alkyl radical of 1 to about 12 carbon atoms or an aralkyl radical of 7 to approx. 12 carbon atoms, n is an integer of 2 to 12 inclusive, and the polymeric chain (CH 2) n may be interrupted by up to 5 ether groups, thioether groups, phenyl groups or naphthyl groups. These are available as pharmaceutically useful salts. Other substituted guanidines are: N '- (4-chlorobenzyl) -N ~ * - (2,4-dichlorobenzyl) biguanide, p-chlorobenzylbi = 5 guanide, 4-chlorobenzhydryl guanylurea, N-3-lauroxypropyl-N-p-chlorobenzylbiguanide, 5,6-dichloro-2-guanidobenzimidazole and Np-chlorophenyl-N5-lauryl biguanide.

The long-chain tertiary amines also have antibacterial and antiplaque action. Such antibacterial agents include tertiary amines having a fatty alkyl group (typically 12 to 18 carbon atoms) and 2 poly (oxyethylene) groups bonded to the nitrogen (typically containing from 2 to 50 ethenoxy groups per molecule) and salts thereof with acids and compounds. with structure:

(CH 2 CH 2 O) zH ______— (CH 2 CH-O) H

r-n-ch2ch2ch2n ----- 1

---- (CH2CH20) y H

Wherein R is a fatty alkyl group containing 12-18 carbon atoms, and X, y and z are in total 3 or more, and salts thereof. In general, cationic agents are preferred because of their antiplaque efficiency.

Preferably, the antibacterial antiplaque compound is one having an antibacterial effect such that its phenol coefficient is slightly above 50, preferably above 100, such as above about 100. 200 or more, for S.aureus. Eg. the phenol coefficient (A.O.A.C.) of benzethonium chloride of the manufacturer is set at 410 to S.aureus. The cationic antibacterial agent will generally be a monomeric (possibly dimeric) material having a molecular weight slightly below 2000, such as less than about 100 mg. However, a polymeric cationic antibacterial agent may also be used. The cationic antibacterial agent is preferably administered in the form of an orally acceptable salt thereof such as the chloride, bromide, sulfate, alkylsulfonate such as methylsulfonate and ethylsulfonate, phenylsulfonate such as p-methylphenylsulfonate, nitrate, acetate or gluconate.

The cationic antibacterial agents and antibacterial long-term tertiary amines effectively promote oral hygiene, especially by removing plaque. However, their use has been found to lead to discoloration of tooth surfaces or discoloration beyond that occurring in normal contact of tooth surfaces with food, beverages, tobacco, etc.

The reason for the formation of such tooth discoloration in the presence of antibacterial antiplaque agent has not been clearly established. Human tooth enamel is usually covered by a proteinaceous membrane (derived from saliva protein) over which there may be a layer of bacterial plaque. The enamel contains a high amount (about 95%) of hydroxyapatite, which contains +2 in [- 2 der Ca and PO. ions. In the absence of dental plaque, additional Ca -3 4 and PO 2, especially from saliva, may be deposited on the enamel of the enamel, and these deposits may contain coloring agents which eventually discolor the tooth as a calcified deposit thereon. It may be that while the cationic or long chain tertiary amines as antibacterial agents remove plaque, they also denature saliva protein in the environment found in the mouth, and the denatured +2 -3 protein may then act as a nucleating agent, wherein Ca and PO 2 ions are deposited and then crystallized as hydroxyapatite. Small crystals of hydroxyapatite provide a large surface area on which tooth discoloration or stains are retained.

4 148598

Previously used additives which reduced tooth discoloration of cationic antibacterial antiplaque agents generally also decreased the activity of the antibacterial agents or their ability to act on tooth plaque to a measurable extent. Thus, this applies to the additives known from German publication no. 2,332,383, of which Victamid (Victamine C), which is the condensation product of ammonia with phosphorus pentoxide, actually increases the discoloration even in the absence of a cationic antibacterial antiplaque agent, and this substance and other Known phosphorus-containing agents, such as disodium ethane-1-hydroxy-1,1-diphosphonic acid (EHDP) salt, are known from said German application to precipitate in the presence of antibacterial agent such as bisguanido compound, thereby reducing the antiplaque effectiveness of the antibacterial agent.

It has now been found that the phosphonic acid compounds defined in the characterizing portion of claim 1 constitute an anti-nucleating additive which prevents discoloration of the tooth enamel due to the use of the cationic or long chain tertiary amines as antibacterial agents without causing any significant deterioration of the antibacterial agent. and antiplaque effect of these agents. Other advantages will be apparent from the following description.

The oral care agent of the invention is characterized in that the agent which removes discoloration formed by said nitrogen-containing antibacterial antiplaque agent is selected from the group consisting of (A) a water-soluble quaternary aminoalkylene phosphone compound of the formula R_ - N + - R "por Mi, 3-nn 2n-1 wherein R is to C2q alkyl, alkenyl, cycloalkyl or aralkyl, R 'is C1 to C2q alkyl or alkenyl, R "is to C8 alkylene or alkenyl, n is an integer from 1 to 3 and M is an orally acceptable cation, (B) a water-soluble diphosphone pyrrolidone compound of the formula

R \, / R

R—— C-C R

i

= 0

x2o3p /. IN

wherein the R's are independently H, C1-6 alkyl or C2-6 hY = droxyalkyl, and X is an orally acceptable cation, (C) a water-soluble N-methylene phosphonate compound of the formula al / N-CH2 PO3X2 \ A "where A" is -CH2CH2OH, -CH2COOX or -CH2PO3X2, A "is -CH2CH2OH or -CH2COOX, and X is an orally acceptable cation, (D) phosphonic acetic acid (PAA) of the formula in O-jP-CI2 -COOH or an orally acceptable salt thereof, and (E) a water-soluble phosphone-containing compound of the formula

COOH COOH

I I 2

H-C - C R

II 11

ΈΓ R

Wherein R is hydrogen, C · to alkyl or (CH₂) C₂COOH, and R is

PO3B2 and PO3H2 COOH

-ΡΟ, ,,., -C-R1, -C — ΡΟ, Η,, -C — R1 \ \! COOH R CH 2 PO 2 H 2 and mixtures thereof and preferably of formula CHO - CH R 2 / PO

COOH COOH where R 2 is -PO H 2 CH

And mixtures thereof or an orally acceptable salt thereof.

Typically orally acceptable cations include H, metal (e.g., sodium and potassium), ammonium or C C-C ^ g mono-, di- and trisubstituted ammonium (e.g., alkanol substituted such as mono-, di- and triethanol-ammonium). Niura).

The preferred compounds of group (A) are those in which n = 3, R 1 is lower alkyl of to C 9, preferably to and most preferably methyl, and R "is methylene. These compounds have the formula CH 2 P ° 3 H 2 In the above formulas, the cation M may be, for example, hydrogen, alkali metal (e.g., sodium, potassium, lithium), ammonium or substituted ammonium such as C1 (g) mono-, di- or trisubstituted ammonium (f. e.g., alkanol substituted such as mono-, di- and triethanolammonium).

Examples of active polyphonic carboxylic acids of the above formula (s) include; (a J 1-phosphonetha, nl, 2-dicarboxylic acid, (b) 2-phosphonopropane-2,3-dicarboxylic acid, (c) 2-phosphonobutane-2,3-dicarboxylic acid, (d) 1-phosphonopropane-1,2 dicarboxylic acid, (e) 1-phosphone propane-1,2,3-tricarboxylic acid, (f) 1-phosphonbutane-2,3,4-tricarboxylic acid, (g) 2-phosphonobutane-2,3,4-tricarboxylic acid, (h) 1 * phosphonobutane-1,2,3-tricarboxylic acid (i) 2-phosphonepentane-2,3,4-tricarboxylic acid, (j) 1,1-diphosphone propane-2,3-dicarboxylic acid, (k) 1,1 -diphosphonbutane-2,3-dicarboxylic acid, (1) 2,2-diphosphonbutane-3,4-dicarboxylic acid and (m) 1,1-diphosphone-2-methylpropane-2,3-dicarboxylic acid.

The above compounds (a) and (j) are preferred,

Antibacterial agents which are cationic germicides or long chain amine germicides which can be used according to the invention are described above. They are typically used in amounts such that the oral product contains between about 0.001% and 15% by weight of the agent. Preferably, to obtain the desired degree of antiplaque effect, the finished oral product contains approx. 0.01% to about 5% and most conveniently about 0.25% to 1.0% by weight of the agent. These amounts refer to the amount of the free base form of the agent.

The discoloration commonly found on tooth enamel is unexpectedly prevented when using the quaternary aminoalkylene phosphonic acid or a water-soluble salt thereof. These materials are antigen-forming agents. In themselves (even in the absence of cationic antiplaque antibacterial agents) they are effective in reducing the formation of tartar without descaling the enamel. However, not all anticancer agents are effective in preventing discoloration of cationic antibacterial agents while allowing these agents to retain the antiplaque effect.

U.S. Patent No. 3,934,002 discloses combining the bis-biguanide antiplaque agents described above with various antitanking agents, some of which contain phosphone groups, but none corresponding to the phosphone-containing additives used in the present invention.

The most preferred group (A) additives are N-methylamino = tri (methylene phosphonic acid) (hereinafter referred to as QUIVJATMP) and its water-soluble salts (e.g., sodium, potassium and ammonium salts). Other preferred compounds include: N-ethylaminotri (methylene = phosphonic acid), N-n-propylaminotri (methylene phosphonic acid), N-methylamino = tri (ethylene phosphonic acid), and the water-soluble salts of these acids, e.g., sodium, potassium and ammonium salts.

148898 8

Mixtures of any of the foregoing may be used in accordance with the invention.

These quaternary aminoalkylene phosphonates can be prepared in any convenient manner, e.g. as disclosed in U.S. Patent No. 3,925,453.

The most preferred phosphone compound of group (B) is pyrrolidone-5,5-diphosphonic acid and its water-soluble salts (e.g., sodium, potassium and ammonium salts). Other compounds include; N-methyl = pyrrolidone. 5,5-diphosphonic acid, N-ethylpyrrolidone-5,5-diphosphonic acid, N-isopropylpyrrolidone-5,5-diphosphonic acid, N-2-hydroxyethylpyrrolidone-5,5-diphosphonic acid, and the water-soluble salts of these acids, e.g. -, potassium and ammonium salts.

Mixtures of any of the foregoing diphosphone pyrrolidones can be used in accordance with the invention. These diphosphone pyrrolidone compounds can be prepared in any convenient manner, e.g. as described in German Publication No. 2,343,147.

The most preferred N-methylene phosphone compounds of group (C) are iminodiacetic acid N-methylene phosphonic acid (hereinafter referred to as IDANMPA) and its water-soluble salts (e.g., sodium, potassium and ammonium salts). Other N-methylene phosphonate compounds include; N-carboxymethylamino-dimethylene phosphonic acid, monoethanolamino dimethylphosphonic acid, diethanolamino methylene phosphonic acid and the water-soluble salts of these acids, e.g. sodium »potassium and ammonium = salts.

Mixtures of any of the foregoing may be used in accordance with the invention. .

These N-methylene phosphonic acid compounds can be prepared in any convenient manner, e.g. as disclosed in British Patent No. 1,394,035.

The phosphonecarboxylic acids of group (E1 and suitable salts thereof used in the invention can be prepared in any convenient manner, for example, as described in British Patent No. 1,394,172.

The concentration of the agent which removes discoloration caused by the nitrogen-containing antibacterial antiplaque agent in the oral care agents can vary widely, typically from about 0.01% by weight. There is no upper limit to the amount that can be used except that which can be dictated by cost and incompatibility with the carrier. Generally, concentrations from about 0.01% to about 10% by weight. Mouthwash agents which, by conventional use, could be ingested by accident, preferably contain lower concentrations of the discoloration reducing agent. Thus, a mouthwash liquid according to the invention preferably contains less than 3% by weight of the discoloration reducing agents, dental care products, topical solvents and prophylactic pastes, the latter of which must be professionally administered, may contain from 0.01 to 10% by weight, preferably from 0.1 to 5% by weight. % of the discoloration reducing agent. Most suitably, the discoloration reducing agent is present in a molar excess relative to the amount of antibacterial antiplaque agent (calculated on its free base) to best prevent discoloration of the antibacterial antiplaque agent.

In certain particularly preferred embodiments of the invention, the oral agent may be substantially liquid in character such as a mouthwash or rinse liquid. In such a preparation, the carrier is typically a mixture of water and alcohol. , 1: 1 to approx. 20: 1, preferably from 3: 1 to 20; 1 and most conveniently about 17: 3 by weight. The total amount of mixture of water and alcohol in this type of composition is typically in the range of from about 70% to about 99% by weight of the composition. The pH of such liquid compositions is generally in the range of from about 4.5 to about 9, and typically from about 10 to about 10. The pH is preferably in the range of from about 6 to about 6. 8.0, It is noteworthy that the agent of the invention permits the use of these phosphone compounds at a pH below 5 without substantially descaling the tooth enamel.

These liquid oral preparations may also contain a surfactant and / or a compound which provides fluoride.

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 tooth tablet or a toothpaste or toothpaste.

The carrier in such solid or paste-like oral preparations contains polishing materials. Examples of polishing materials are water-insoluble sodium metaphosphate, potassium metaphosphate, tricalcium phosphate, dihydrated calcium phosphate, anhydrous calcium phosphate, calcium pyrophosphate, maghium orthophosphate, trimagnium phosphate, calcium carbonate, aluminum oxide silica, aluminum oxide / hydrated alumina Preferred polishing materials include crystalline silica with particle sizes. up to 5 microns, an average particle size up to 1.1 microns 2 and a surface area up to 50,000 cm / g, silica gel, complex amorphous alkali metal aluminum silicate, and hydrated alumina (e.g., α-alumina trihydrate].

Alumina, in particular α-alumina trihydrate marketed 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 0.37% at 110 ° C , and having a density of 2.42 and a particle size such that 100% of the particles are less than 50 microns and .84% of the particles are less than 20 microns, is particularly suitable.

When visually clear gels are used, a colloidal silica polishing agent such as those traded under the trademark Syloid such as Syloid 72 and Syloid 74 or under the trademark Santocel such as Santocel 100 and alkali metal aluminum silicate complexes is particularly useful because they have refractive indexes near the refractive systems. of gelling agent and liquid (including water and / or moisture-binding agent) commonly used in dentifrices.

"Many of the so-called water-insoluble polishing materials are of anionic nature and also contain small amounts of soluble material. Thus, insoluble sodium metaphosphate can be formed in any suitable manner as shown in Thorpe's Dictionary of Applied Chemistry, Vol. 9, 4th edition, pages 510-511. forms of insoluble sodium metaphosphate, called Madrell's salt and Kurrol's salt, are other examples of suitable materials.These metaphosphate salts exhibit very little solubility in water, and are generally referred to as insoluble metaphosphates, containing a small amount of soluble phosphate materials as impurities, As a rule, a few percent such as up to 4% by weight The amount of soluble phosphate material which is believed to contain a soluble sodium trimetaphosphate in the case of insoluble sodium metaphosphate can be reduced by washing with water if desired. alkali metal metaphosphate is typically used in powder form with such a particle size that no more than 1% of the material is greater than 37 microns,

The polishing material is typically found in amounts ranging from approx. 20 to about 99% by weight of the oral composition. Preferably, it is present in amounts ranging from approx. 20% to approx. 75% in toothpaste and approx. 70 to approx. 99% in tooth powder.

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

In paste-like oral preparations, the above-described combination of antibacterial antiplaque agent and phosphone compound must be compatible with the other components of the preparation.

Thus, in a toothpaste, the liquid carrier may comprise water and moisture-binding agent, typically in an amount of from 10% to about 90% by weight of the composition. Glycerin, sorbit or polyethylene glycol may also be present as moisture-binding agents or binders. Particularly advantageous liquid constituents include mixtures of water, glycerine and sorbit.

In clear gels where the refractive index is of importance, preferably approx. 3 to 30% by weight water, 0 to approx. 80% by weight glycerine and approx.

20 to 80% by weight sorbit. A gelling agent such as natural or synthetic rubbers or rubbery materials, typically Irish moss, sodium carboxymethyl cellulose, methyl cellulose or hydroxyethyl cellulose may be used. Other gelling agents which may be used include tragacanth, polyvinylpyrrolidone and starch. They are usually found in toothpaste in an amount up to 10% by weight, preferably in the range of from about. 0.5 to approx. 5%. The preferred gelling agents are methyl cellulose and hydroxyethyl cellulose. In a toothpaste or gel, the amounts of liquid and solids are adjusted to form a creamy or gelled mass which can be extruded by a pressure vessel or by a compressible tube, e.g. of aluminum or lead.

148898 12

The solid or paste-like oral preparation, typically having a pH value measured on a 20% slurry of approx. 4.5 to about «9, usually about 5.5 to approx. 8 and preferably approx. 6 to approx. 8.0 may also contain a surfactant and / or a compound which gives fluorine.

In mouth care agents such as mouthwashes and toothpastes, there is often a surfactant, e.g. to promote foaming. It will be appreciated that it is preferred to use nonionic surfactants instead of the corresponding anionic agents. Examples of water-soluble non-ionic surfactants are condensation products of ethylene oxide with various compounds which are reactive therewith and which have long hydrophobic chains (e.g., aliphatic chains of 12 to 20 carbon atoms) which have condensation products ("ethoxamers"). hydrophilic polyoxyethylene units such as condensation products of ethylene oxide and fatty acids, fatty alcohols, fatty amides, including alcohols such as sorbitan monostearate or polypropylene oxide (ie Pluronics).

In certain embodiments of the invention, a fluorine-providing compound is found in the oral composition. These compounds may be slightly soluble in water or may be completely water soluble. They are characteristic of their ability to release fluoride ions in water and to be essentially free of reaction with other compounds in the oral composition. Among these materials are inorganic fluorides such as soluble alkali metal salts, alkaline earth metal salts and heavy metal salts, e.g. sodium fluoride, potassium fluoride, ammonium fluoride, blyfluorid, a copper fluoride such as cuprous fluoride, zinc fluoride, a tin fluoride such as stannic fluoride or stannous chlorofluoride, barium fluoride, sodium fluorosilicate, ammonium fluorosilicate, natriumfluorzirconat, sodium monofluorophosphate, and aluminiummono- difluorphosphat and fluorescence right sodium calcium pyrophosphate. Alkali metal and tin fluorides such as sodium and stannofluorides, sodium monofluorophosphate and mixtures thereof, especially sodium fluoride and sodium monofluorophosphate, are preferred.

The amount of the fluorine-giving compound depends to some extent on the type of compound, its solubility, and the type of the oral preparation, but it must be a non-toxic amount. In a solid oral preparation such as a toothpaste or a powder is an amount of such compound. which releases a maximum of about 1% by weight of the composition, considered satisfactory. Any suitable minimum amount of such a compound can be used, but it is preferred to use sufficient compound to release from about 0.005% to 1% and preferably about 0.1% fluoride ion. In the case of alkali metal fluorides and stannous fluoride, this component is typically present in an amount up to 2% by weight based on the weight of the composition and preferably in the range of 0.05 to 1%. In the case of sodium monofluorophosphate, this compound may is present in an amount up to 7.6% by weight, more typically o, 76%.

When in admixture, the ratio of sodium monofluorophosphate to sodium fluoride is conveniently about 1: 1 to approx. 3: 1 calculated on the amount of fluorine supplied by each.

In liquid mouth care agent such as a mouthwash liquid, the fluorine-giving compound is typically present in an amount sufficient to release up to 0.13%, preferably from 0.0013% to 0.1% and most conveniently from 0.0013% to 0.05% by weight fluoride ion.

Various other materials may be incorporated into the oral compositions of the invention. Examples are laundering agents, preservatives, silicones, chlorophyll compounds and ammoniated materials such as urea, diammonium phosphate and mixtures thereof. When these additives are present, they are incorporated into compositions in amounts which have no significant detrimental effect on the desired properties.

t

Any suitable flavoring or sweetening material may also be used. Examples of aromatic ingredients are aromatic oils, such as oils of garden mint, peppermint, evergreen, sassafras, clove, sage, eucalyptus, marjoram, cinnamon, lemon and orange and methyl salicylate. Suitable sweeteners include sucrose, lactose, maltose, sorbit, sodium cyclamate, perillarytin and sodium saccharin. Conveniently, aroma and sweeteners may together constitute from 0.01 to 5% or more of the composition.

In preparing oral care compositions of the invention that contain a carrier which typically contains water, it is highly desirable not to add substantially the phosphone additive after the other ingredients (except perhaps some of the water) are mixed or brought into contact with each other to avoid a tendency to form a precipitate.

For example, a mouthwash or mouthwash can be prepared by mixing ethanol and water with aromatizing oil, non-ionic surfactant, moisturizing agent, cationic antibacterial antiplaque agent such as benzethonium chloride, cetylpyridinium chloride or chlorhexidine, and chlorhexidine set. discoloration reducing agent and additional water as needed.

A toothpaste may be prepared by forming a gel with a moisture-binding agent, rubber or thickening agent such as hydroxyethyl cellulose, sweetening agent, and adding polish, aroma, antibacterial agent such as benzethonium chloride, cetylpyridinium chloride or chlorhexidine and additional water followed by the addition of the discolouring agent. If sodium carboxymethyl cellulose is used as a gelling agent, the procedure of either U.S. Patent

No. 3,842,168 or U.S. Patent No. 3,843,779 modified by including the quaternary aminoalkylene phosphone compound.

In carrying out the invention, an oral composition of the invention such as a mouthwash or toothpaste containing cationic or long-chain amine as antibacterial antiplaque agent in an amount effective to promote oral hygiene and the discolouring reducing agent in an amount effective to reduce discoloration of tooth surfaces, becomes effective. would appear in the presence of the anti-bacterial antiplaque agent applied regularly to tooth enamel, preferably from ca. 5 times a week to approx. 3 times daily, at a pH of approx. 4.5 to 9, generally approx. 5.5 to approx. 8, preferably approx. 6 to 8.

The following examples further illustrate the nature of the invention, but it will be understood that the invention is not limited thereto. The compositions are prepared in the usual manner and all quantities and proportions referred to in the specification and claims are by weight, unless otherwise stated.

Examples 1-3

The following mouthwash fluid is prepared and tested:

Parts

Flavored alcohol 15

Pluronic F-108 (polyalene oxide block polymer) 3

Glycerin 10

Benzethonium chloride (BC) 0.075

Sodium saccharin 0.03

QMATMP X

Water to 100 pH 7.0 (adjusted with 5 N sodium hydroxide).

All funds are clear with no visible sign of precipitation. QMATMP (N-methylaminotri (methylene phosphonic acid)) and ca. 10 parts of the water are added to the other pre-mixed ingredients.

The in vitro discoloration properties of the agent are tested as follows in this and other examples: 250 mg of oxalbumin (crystallized 3 times) is added to 2 g of hydroxyapatite (HAP) powder (Biogel) which serves as a substrate for a discoloration while the proteins simulate tooth decay and give a amine source. The mouthwash is added to the mixture followed by a 7.5% buffered acetaldehyde serving as a carbonyl source. The mixture is shaken at 37 ° C for 18 hours. The colored HAP is separated from the solution by filtration and dried at 37 ° C. The color of the powder is read on a Gardner color difference meter. The color levels are determined on a Gardner color difference meter before and after test agents are applied to the colored material.

The following Table I shows the anti-staining results when the indicated quantities (x) of QMATMP are used in the above-mentioned detergent.

Table I - Anti-staining

Ex. Parts (x) QMATMP Reflectance Reflectance Difference 1 0 41.0 0 2 0.1 56.0 15.0 3 0.2 58.0 17.0

The above results clearly show that these quaternary aminoalkylene phosphonic acid compounds exemplified by QMATMP substantially reduce tooth discoloration usually caused by BC. These tests are carried out with the pH set to approx. 7.0, the pH before setting being from approx. 4 to 4.8. Preparations adjusted to pH ranging from approx. 5 to 8 give similar results.

Example 4.5 The following compositions exemplify toothpastes having antiplaque effect and reduced discoloration.

Ex.4 Ex.5

Hydrated alumina 30 (parts) 30

Glycerin 16 16

Sorbit (70%) 6 6

Pluronic F-108 3 3

Hydroxyethyl cellulose 1,2 1,2

Benzethonium chloride 0.5 ---

Chlorhexide indigluconate (20%) --- 4.725 QMATMP 2 2

Sodium saccharin 0.17 0.17. Aroma 0.8 0.8

Water for 100 to 100

Examples 6-12

A mouthwash preparation is prepared and tested as follows:

Mouthwash Parts

Flavored alcohol 15

Pluronic F108 (polyalene oxide block polymer) 3

Glycerin 10

Benzethonium chloride (BC) 0.075

Sodium saccharin 0.03

Pyrrolidone-5,5-diphosphonic acid (PYDP) x

Water to 100 pH 7.0 (adjusted with 5N NaOH)

Appearance, stability ready 148898 17 PYDP and approx. 10 parts of the water are added to the other pre-mixed ingredients.

The following Table I shows the anti-staining results in vitro when the indicated amounts of (x) PYDP are used in the above mouthwash preparation.

Table I - Anti-staining

Phosphon Reflectance

Ex. compound Parts (x) Reflectance difference 6-0 40.0 0 7 PYDP 0.1 52.0 12.0 8 PYDP 0.2 55.0 15.0 9 PYDP 0.3 50.0 10.0 10 PYDP 0 , 4 54.0 14.0 11 PYDP 0.5 52.0 12.0 12 PYDP 1.0 51.0 11.0

The above results clearly show that the pyrrolidone diphosphonic acid additives of the invention exemplified by PYDP substantially reduce the tooth discoloration usually produced by BC. These tests are performed with the pH of the preparation set to approx. 7.0, which pH before the setting is from approx. 3.5 to 4.6. Preparations adjusted to pH ranging from approx. 5 to 8 give similar results.

Example 13.14

The following compositions exemplify toothpastes with anti-plaque activity and reduced discoloration:

Ex.

13 14

Hydrated alumina 30 parts 30

Glycerin 16 16

Sorbit (70%) 6 6

Pluronic F-108 3 3

Hydroxyethyl cellulose 1,2 1,2

Benzethonium Chloride 0.5

Chlorhexide indigluconate (20%) - 4,725 PYDP 2 2

Sodium saccharin 0.17 0.17

Aroma 0.8 0.8

Water to 100 100

Examples 15-21

A mouthwash is prepared and tested as follows:

Parts

Flavored alcohol 15

Pluronic F-108 (polyalene oxide block polymer) 3

Glycerin 10

Benzethonium chloride (BC) 0.075

Sodium saccharin 0.03

IDANMPA X

Water to 100 pH 7.0 (adjusted with 5 N sodium hydroxide).

All compositions are clear with no visible sign of precipitation.

IDANMPA and approx. 10 parts of the water are added to the other pre-mixed ingredients. The color gradient is determined in vitro on a Gardner color difference meter before and after the experimental composition is applied to the colored material. The following Table I shows the anti-staining results when the indicated quantities (x) of IDANMPA are used in the aforementioned mouthwash liquid.

Table I - Anti-staining

Ex. Parts (x) IDANMPA Reflectance Reflectance Difference 15 0 40.0 0 16 0.1 52.0 12.0 17 0.2 56.0 16.0 18 0.3 57.0 17.0 19 '0.4 51, 0 11.0 20 0.5 58.0 18.0 21 1.0 57.0 17.0 148898 19

The above results clearly show that the N-methylene phosphonate additives of the invention exemplified by IDANMPA significantly reduce tooth discoloration normally produced by BC. These tests are carried out with the pH set to approx. 7.0, with the pH before setting being from approx. 3.5 to 4.8. Preparations set to a pH value ranging from approx. 5 to 8, give similar results.

Examples 22, 23

Ex.

22 23

Hydrated alumina 30 (parts) 30

Glycerin 16 16

Sorbit (70%) 6 6

Pluronic F-108 3 3

Hydroxyethyl cellulose 1,2 1,2

Benzethonium chloride 0.5 ---

Chlorhexide indigluconate --- 4,725 IDANMPA 2 2

Sodium saccharin 0.17 0.17

Aroma 0.8 0.8

Water for 100 to 100

Examples 24-30

The following mouthwash fluid is prepared and tested:

Mouthwash Parts

Flavored alcohol 15

Pluronic F 108 (polyalkene oxide block polymer) 3

Glycerin 10

Benzethonium chloride (BC) 0.075

Sodium saccharin 0.03

Phosphonic acetic acid (PAA) x

Water to 100 pH 7.0 (adjusted with 5N NaOH)

Appearance, stability clear PAA and approx. 10 parts of the water are added to the other pre-formed components.

The following Table I shows the anti-staining results in vitro when the amounts (x) of PAA shown are used in the aforementioned mouthwash.

Table X - Anti-staining

Parts (x)

Ex. PAA Reflectance Reflectance Difference 24 0 39.0 0 25 0.1 56.0 17.0 26 0.2 54.0 15.0 27 0.3 56.0 17.0 28 0.4 53.0 14.0 29 0.5 55.0 16.0 30 1.0 53.0 14.0

The above results clearly show that PAA for all sizes of x significantly and appreciably reduces the tooth discoloration usually induced by BC. These tests are carried out with the pH set to approx. 7.0, since the pB value before the setting was from approx.

3.5 to 4.6. Compositions set to a pH value ranging from approx. 5 to 8, give similar results.

Example 31.32 The following compositions exemplify toothpastes having antiplaque effect and reduced discoloration:

Ex.

31 32

Hydrated alumina 30 (parts) 30

Glycerin 16 16

Sorbit (70%) 6 6

Pluronic F-108 3 3

Hydroxyethyl cellulose 1,2 1,2

Benzethonium chloride 0.5 ---

Chlorhexide indigluconate (20%) --- 4.725

Phosphonic acetic acid 2 2 148898 21

Sodium saccharin 0.17 0.17

Aroma 0.8 0.8

Water for 100 to 100

Examples 33-46 In the following examples, a mouthwash is prepared and tested as follows:

Mouthwash peel

Flavored alcohol 15>

Pluronic P 108 (polyalkene oxide block polymer) 3

Glycerin 10

Benzethonium chloride (BC) 0.075

Sodium saccharin 0.03

Phosphone-containing compound x

Water to 100 pH 7.0 (adjusted with 5N NaOH)

Appearance ;, stability clear

The phosphone-containing compound and ca. 10 parts of the water are added to the other pre-mixed ingredients.

The following Table I shows the anti-staining results in vitro when the amounts (x) of the phosphone-containing compound shown are used in the above detergent.

Table I - Anti-staining

phosphonic

Ex. Component Parts (x) Reflectance Reflectance Difference 33 0 40.0 0 34 DPPD * 0.1 45.0 5.0 35 "0.2 49.0 7.0 36" 0.3 53.0 13.0 37 * ' 0.4 60.0 20.0 38 "0.5 53.0 13.0 39" 1.0 56.0 16.0 .40 PEDAXX 0.1 43.0 3.0 148898 22 41 PEDA J® 0 , 2 54.0 14.0 42 "0.3 58.0 18.0 43 0.4 52.0 12.0 44" 0.5 54.0 14.0 45 "0.6 60.0 20, 0 46 "1.0 51.0 11.0 1, 1-diphosphone propane-2,3-dicarboxylic acid 1-phosphonethane-1,2-dicarboxylic acid

The above results clearly show that the phosphonal alkane polycarboxylic acid additives of the invention exemplified by DPPD and PEDA substantially reduce the tooth discoloration normally produced by BC. The tests are carried out with the pH of the preparation set to approx. 7.0, the pH before the setting being from about 3.5 to 5.0. Preparations adjusted to pH from approx. 5 to 8 give similar results.

Example 47

In vivo tests for antiplaque and anti-staining effect are carried out on beagles with the mouthwash preparation of Example 1 containing 0.075 parts BC, 0.5 parts DPPD and 0.1 part N-ethylaminotri (ethylene phosphonic acid) instead of QMATMP, the control composition of Example 1 containing 0.075 parts BC and no DPPD and a placebo containing neither BC nor DPPD. The beagles are first subjected to dental prophylaxis to remove existing soft and hard tooth deposits. A revealing solution is used to ensure complete removal. Applications are done by gentle spraying twice a day, 5 days a week for 6 weeks. The discoloration is judged relatively by visual observation of the oral cavity. Plaque is assessed after spraying the teeth with the revealing solution. The results are as follows:

Number Average Average Discoloration difference dogs plaque discoloration compared to _ _ _ placebo_

Placebo 8 2.4 0.38 0

Control (+ BC) 7 1.8 0.53 + 39.4% + BC + DPPD 8 1.8 0.32 -42.3%

Claims (3)

It is clear from the above results that the phosphone-containing additives of the invention exemplified by DPPD substantially reduce tooth discoloration (by 42.3%) caused by antibacterial antiplaque agents exemplified by the cationic BC and actually reduce the discoloration to less than placebo. These results also show that these added compounds do not affect the antiplaque effect of the antibacterial antiplaque agents that cause discoloration. Example 48.49 The following compositions exemplify toothpastes having antiplaque effect and reduced discoloration: Ex. 48 49 Hydrated alumina 30 30 Glycerin 16 16 Sorbit (70%) 6 6 Pluronic F-108 3 3 Hydroxyethyl cellulose 1,2 1,2 Benzethonium chloride 0.5 Chlorhexide indigluconate (20%) - 4,725 DPPD 2 2 Sodium saccharin 0.17 0.17 Aroma 0.8 0.8 Water for 100 to 100 Patent claims. An oral care agent comprising an oral carrier, at least one nitrogen-containing antibacterial antiplaque agent of the group consisting of cationic antibacterial antiplaque agents and long chain amines containing an alkyl group of 12 to 18 carbon atoms as antibacterial antiplaque agents and a discolouring agent formed by these nitrogen-containing antibacterial antiplaque agents, characterized in that the agent which removes discoloration is selected by the group consisting of (A) a water-soluble quaternary aminoalkylene phosphone compound of formula R 'I + R3-n-N - R "Γ0Γ M $ n-1 Wherein R is to C2Q alkyl, alkenyl, cycloalkyl or aralkyl, R 'is to C2Q alkyl or alkenyl, R "is to C8 alkylene or alkenylene, n is an integer from 1 to 3 and M is an orally acceptable cation, (B) a water-soluble diphosphone pyrrolidone compound of the formula RR \ / R-CC-RIIX ~ 0, P-CC = 0 and / h / X2 ° 3P IR wherein the Rs are independently H, C1-6 alkyl or C2_g hydroxy alkyl, and X is an orally acceptable cation, (C) a water-soluble N-methylene phosphonate compound of formula A 'n -— ch 2 po 3 x 2 A "where A" is -CH 2 CH 2 OH, -CH 2 CO 2 X, or -CH 2 PO 3 X 2, A "is -CH 2 CH 2 and X is an orally acceptable cation. (D) phosphonic acetic acid (PAA) of the formula ^ O ^ P-CE ^ -COOH or an orally acceptable salt thereof, and (E) a water-soluble phosphone-containing compound of the formula COOH COOH HC-C-R2 ^ 1 * 1 RR 1. wherein R is hydrogen, for alkyl or (C ^) COCOOH, and R is PO, H0 PO, H0 COOH / I / 3 2 / -PO, H0, -C-R or -CR \ \ 1 \ COOH R CH2 PO3H2 and mixtures thereof and preferably of the formula CH1 -CH-R2 II COOH COOH PO2H2-3 where R2 is -PO3H2 or CH Xpo3H2 and mixtures thereof or an orally acceptable salt thereof . Mouth care agent according to claim 1, characterized in that the antibacterial antiplaque agent is present in an amount which gives approx. 0.001% to approx. 15% by weight based on the free base form of the agent and that the quaternary aminoalkylene phosphone compound is present in an amount of approx. 0.01% to approx. 10% by weight. Mouth care agent according to claim 2, characterized in that the antibacterial antiplaque agent is present in an amount of approx. 0.01% to approx. 5% by weight based on the free base form of the agent and that the quaternary aminoalkylene phosphone compound is present in a molar excess relative to said agent.