GB1562979A

GB1562979A - Oral compositions

Info

Publication number: GB1562979A
Application number: GB34022/77A
Authority: GB
Original assignee: Colgate Palmolive Co
Current assignee: Colgate Palmolive Co
Priority date: 1976-08-16
Filing date: 1977-08-12
Publication date: 1980-03-19
Also published as: AU511034B2; AU2738477A; PH14683A; DK148898C; CA1095414A; SE8900372A; SE7708553L; FR2361865B1; IT1079817B; JPH02323B2; SE431285B; SE8900372A0; JPS5341437A; SE8900372D0; BR7705395A; DE2736155A1; DK365077A; DK148898B; FR2361865A1; DE2736155C2

Abstract

An oral hygiene composition contains at least one nitrogen-containing antibacterial plaque-preventing compound from the group consisting of the cationic antibacterial plaque-preventing compounds and long-chain amines having an alkyl radical of 12 to 18 carbon atoms. The oral hygiene composition additionally contains, for reducing stains which are caused by the nitrogen-containing plaque-preventing compound, one or more of the following compounds: water-soluble, quaternary aminoalkylenephosphorus compounds, water-soluble N-methylenephosphonate compounds, phosphoracetic acid or orally tolerable salts thereof and one or more water-soluble phosphorus compounds or an orally tolerable salt of these compounds; the formulae of the said group of compounds are given in Claim 1. The oral hygiene composition described can be used as a powder, paste or liquid preparation.

Description

(54) ORAL COMPOSITIONS (71) We, COLGATE-PALMOLIVE COMPANY, a Corporation organised under the laws of the State of Delaware, United States of America, of 300 Park Avenue, New York, New York 10022, United States of America, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to antibacterial oral compositions which promote oral hygiene. The compositions embodying the invention include an antibacterial antiplaque agent which may be any of those set forth below.

Cationic antibacterial materials are well known in the art. See, for instance the section on "Quaternary Ammonium and Related Compounds" in the article on "Antiseptics and Disinfectants" in Kirk-Othmer Encyclopedia of Chemical Technology. 2nd edition (Vol. 2, p. 632-635). Cationic materials which possess antibacterial activity (i.e. are germicides) are used against bacteria and have been used in oral compositions to counter plaque formation caused by bacteria in the oral cavity.

Among the most common of these antibacterial antiplaque quaternary ammonium compounds is benzethonium chloride, also known as Hyamine 1622 or diisobutylphenoxyethoxyethyl dimethyl benzyl ammonium chloride. In an oral composition this material is highly effective in promoting oral hygiene by reducing formation of dental plaque and calculus, which is generally accompanied by a reduction in caries formation and periodontal diseases. Other cationic antibacterial agents of this type are those mentioned, for instance, in U.S. Patents 2,984,639, 3,325,402, 3,431,208 and 3,703,583, and British Patent 1,319,396.

Other antibacterial antiplaq ue quaternary ammonium compounds include those in which one or each of two of the substituents on the quaternary nitrogen has a carbon chain length (typically alkyl group) of 8 to 20, typically 10 to 18, carbon atoms while each of the remaining substituents (typically an alkyl or benzyl group) has a lower number of carbon atoms such as 1 to 7 carbon atoms, typically a methyl or ethyl group. Dodecyl trimethyl ammonium bromide, benzyl dimethyl stearyl ammonium chloride, cetyl pyridinium chloride and quaternized 5-amino1,3-bis (2-ethylhexyl)-5-methyl hexa hydro-pyrimidine are typical quaternary ammonium antibacterial agents.

Other types of cationic antibacterial agents which may be incorporated in oral compositions to promote oral hygiene by reducing plaque formation are amidines such as the substituted guanidines, e.g. chlorhexidine and the corresponding compound, alexidine, having 2-ethylhexyl groups instead of chlorophenyl groups and other bis-biguanides such as those described in published German patent application P 2,332,383 which sets forth the following formula:

in which A and A' independently represent (1) a phenyl radical, which as substituents can contain up to 2 alkyl or alkoxy groups with 1 up to about 4 Catoms, a nitro group or a halogen atom, (2) an alkyl group which contains 1 to about 12 C-atoms, or (3) alicyclic groups with 4 to about 12 C-atoms; X and X' independently represent an alkylene radical with 1-3 C-atoms, z and z' are either zero or 1; R and R' independently represent hydrogen, an alkyl radical of 1 to about 12 C-atoms or an aralkyl radical of 7 to about 12 C-atoms; n is a whole number of 2 to 12 inclusively; and the polymethylene chain (CH2)n can be interrupted by up to 5 ether, thioether, phenyl- or naphthyl groups; these are available as pharmaceutically acceptable salts. Additional substituted guanidines are: N'-(4-chlorobenzyl)-N5-(2,4-dichlorobenzyl) biguanide; p-chlorobenzyl biguanide; 4-chlorobenzhydryl guanylurea: N-3-lauroxypropyl-N5-p-chlorobenzyl biguanide: 5,6-dichloro-2-guanidobenzimidazole: and N-p-chlorophenyl-N5 laurylbiguanide.

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

where R is a fatty alkyl group containing 12 to 18 carbon atoms and x, y and z total 3 or higher, as well as salts thereof. Generally, cationic agents are preferred for their antiplaque effectiveness.

The antibacterial antiplaque compound is preferably one which has an antibacterial activity such that its phenol coefficient is well over 50, more preferably well above 100, such as above about 200 or more for S. aureus; for instance the phenol coefficient (A.O.A.C.) of benzethonium chloride is given by the manufacturer as 410, for S. aureus. The cationic antibacterial agent will generally be a monomeric (or possibly dimeric) material of molecular weight well below 2,000, such as about 1,000 or less. However, higher polymeric cationic antibacterial agents may be used. The cationic antibacterial is preferably supplied in the form of an orally acceptable salt thereof, such as the chloride, bromide sulphate, alkyl sulphonate such as methyl sulphonate or ethyl sulphonate, phenylsulphonate such as p-methylphenyl sulphonate, nitrate, acetate or gluconate.

The cationic antibacterial agents and long chain tertiary amine antibacterial agents effectively promote oral hygiene, particularly by removing plaque.

However, their use has been observed to lead to staining of dental surfaces or discoloration other than that which occurs from normal contact of dental surfaces with certain foods, beverages and tobacco.

The reason for the formation of such dental stain in the presence of antibacterial antiplaque agent has not been clearly established. Human dental enamel is normally covered by a proteinaceous pellicle (derived from saliva protein) over which there may be a layer of bacterial plaque. The enamel contains a high proportion (about 95%) of hydroxyapatite which includes Ca+2 and PO4-3 ions.

In the absence of dental plaque additional Ca+2 and PO4-3, particularly from saliva, can be deposited on tooth pellicle on the enamel and such deposits can include colour bodies which ultimately stain the tooth as a calcified deposit thereon. It may be that as the cationic or long chain tertiary amine antibacterial agents remove plaque they also denature protein from saliva in the oral environment and the denatured protein can then act as a nucleating agent in which Ca+2 and P04-3 ions are deposited and then crystallized as hydroxyapatite. Small crystals of hydroxyapatite provide a high surface area upon which tooth stain or discoloration is retained.

Previously employed additives which reduced dental staining by cationic antibacterial antiplaque agents also generally reduced the activity of the antibacterial agents or their ability to act on dental plaque to measurable degrees.

Further Victamide (Victamine C) which is the condensation product of ammonia with phosphorus pentoxide actually increases staining even in the absence of a cationic antibacterial antiplaque agent and it and other known phosphoruscontaining agents such as disodium-ethane- 1 -hydroxy- 1,1 -diphosphonic acid (EHDP) salt precipitate in the presence of antibacterial agents such as bisbiguanido compounds thereby reducing the antiplaque effectiveness of the antibacterial agent.

It is an object of this invention to provide an antibacterial oral composition containing an anti-nucleating additive which inhibits (prevents, removes or reduces) the staining of dental enamel resulting from the use of cationic or long chain tertiary amine antibacterial agents without substantially adversely affecting the antibacterial and antiplaque activity of such agent.

In accordance with this invention an oral composition comprises an oral vehicle, at least one nitrogen-containing antibacterial antiplaque agent selected from cationic antibacterial antiplaque agents of the amidme and quaternary ammonium types and long chain tertiary amine antibacterial antiplaque agents containing a fatty alkyl group of 12 to 18 carbon atoms, and an agent which inhibits stain formation by the nitrogen containing antibacterial antiplaque agent selected from water-soluble quaternary aminoalkylene phosphonic compounds of the formula:

wherein R represents C, to C20 alkyl, alkenyl, cycloalkyl or aralkyl; R' represents C, to C20 alkyl or alkenyl; R" represents C, to C6 alkylene or alkenylene; n is 1,2 or 3; and M is an orallv acceptable cation; (B) water-soluble diphosphono pyrrolidone compounds of the formula:

wherein the R's independently represent hydrogen, C16 alkyl or C26 hydroxyalkyl and X is an orally acceptable cation; (C) water-soluble N-methylene phosphonate compounds of the formula

wherein A' represents -CH2CH2OH, -CH2COOX or CH2PO3X2; A" represents -CH2CH2OH or -CH2COOX; A' is the same as A" when A' is not -CH2PO3X2; and X is an orally acceptable cation; (D) phosphonoacetic acid (PAA), of the formula H2O3P-CH2-COOH, and orally acceptahle salts thereof; and (E) water-soluble phosphono-containing compounds of the formula:

wherein R' represents hydrogen, C, to C4 alkyl or (CH2)12COOH; and R2 represents:

preferably of the formula:

wherein R2 is -PO3H2 or

and orally acceptable salts thereof.

Typical orally acceptable cations include hydrogen, metal (e.g. sodium and potassium), ammonium, C1-C18 mono-, di and tri-substituted ammonium (e.g.

alkanol substituted such as mono-, di and tri-ethanolammonium).

The preferred compounds of formula (A) are those having three -PO-2 groups and wherein R' is lower alkyl of C, to C6, more preferably C, to C4, and most preferably methyl; and R" is methylene. Such compounds have the formula:

In the above formulae, the cation M may for example be hydrogen, alkali metal (e.g. sodium, potassium or lithium), ammonium or substituted ammonium such as C,~,6 mono-, di or tri-substituted ammonium (e.g. alkanol substituted such as mono-, di- and tri-ethanolammonium).

Illustrative operative phosphonocarboxylic acids of formula (A) above include: (a) 1 -phosphonoethane- 1 ,2-dicarboxylic acid; (b) 2-phosphonopropane-2,3-dicarboxylic acid: (c) 2-phosphonobutane-2,3-dicarboxylic acid; (d) I-phosphonopropane-1,2-dicarboxylic acid: (e) I-phosphonopropane-1,2.3,-tricarboxylic acid; (f) I-phosphonobutane-2,3,4-tricarboxylic acid; (g) 2-phosphonobutane-2,3,4-tricarboxylic acid: (h) 1 -phosphonobutane- 1 ,2,3-tricarboxylic acid; (i) 2-phosphonopentane-2,3,4-tricarboxylic acid; (j) 1,1 -diphosphonopropane-2,3-dicarboxylic acid; (k) 1,1 -diphosphonobutane-2,3-dicarboxylic acid; (1) 2,2-diphosphonobutane-3,4-dicarboxylic acid; and (m) 1,1 -diphosphono-2-methylpropane-2,3-dicarboxylic acid.

Compounds (a) and (j) above are preferred.

Antibacterial agents which are cationic or long chain amine germicides which may be employed in the practice of this invention are described above. They are typically employed in amounts such that the oral composition contains between 0.001An and 15Sd by weight of the agent. Preferably for desired levels of antiplaque effect, the finished oral composition contains from 001An to 5%, and most preferably from 0.25?n' to 1.0? by weight of the agent. These amounts refer to the quantity of the free base form of the agent.

The stain which generally occurs on dental enamel is unexpectedly inhibited when the quaternary aminoalkylene phosphonic acid or water-soluble salt thereof is employed. These materials are anti-nucleating agents. In themselves (even in the absence of cationic antiplaque antibacterial agents) they are effective to reduce formation of dental calculus without unduly decalcifying enamel. However, not all anti-nucleating agents are effective to prevent stain by cationic antibacterial agents while permitting such agents to retain the antiplaque activity.

U.S. Patent 3,934,002 discloses combining the above-described bis-biguanide antiplaque agents with various anti-calculus agents, some of which contain phosphono groups, but none corresponding to the phosphono-containing additives employed herein.

The compounds of formula (A) most preferred are N-methyl aminotri (methylene phosphonic acid) (hereafter QMATMP) and its water-soluble salts (e.g.

sodium, potassium and ammonium salts). Other preferred compounds of formula (A) include: N-ethyl aminotri (methylene phosuhonic acid). N-n-oropvl aminotri (methylene phosphonic acid), N-methyl amid tri (ethylene phosphonic acid), and the water soluble salts of these acids, e.g. sodium, potassium and ammonium salts.

Mixtures of any of the foregoing can be used in the practice of this invention.

These quaternary aminoalkylene phosphonates can be prepared in any convenient manner, for example, according to the teachings of U.S. Patent 3,925,453.

The phosphono compounds of formula (B) which are most preferred are pyrrolidone-5,5-diphosphonic acid, N-2 hydroxyethyl pyrrolidone-5,5-diphosphonic potassium and ammonium salts).

Other compounds of formula (B) includes: N-methyl pyrrolidone-5,5diphosphonic acid, N-ethyl pyrrolidone-5,5 disphosphonic acid, N-isopropyl pyrrolidone-5,5-diphosphonic aid, N-2 hydroxyethyl pyrrolidone-5.5-diphosphonic acid and the water soluble salts of these acids, e.g. sodium, potassium and ammonium salts.

Mixtures of any of the foregoing diphosphono pyrrolidones can be used in the practice of this invention. These diphosphono pyrrolidone compounds can be prepared in any convenient manner, for example, according to the teachings of published German Patent Specification No. 2,343,147.

The N-methylene phosphonic compounds of formula (C) which are most preferred are iminodiacetic-N-methylene phosphonic acid (hereinafter IDANMPA) and its water-soluble salts (e.g sodium, potassium and ammonium salts). Other N-methylene phosphonate compounds of formula (C) include: Ncarboxymethyl-amino-di-methylene phosphonic acid: monoethanol-amino-dimethylene phosphonic acid; diethanol-amino-methylene phosphonic acid and the water soluble salts of these acids, e.g., sodium, potassium and ammonium salts.

Mixtures of any of the foregoing can be used in the practice of this invention.

These N-methylene phosphonic acid compounds can be prepared in any convenient manner, for example, according to the teachings of British Patent 1,394,035.

The phosphonocarboxylic acids of formula (E) and suitable salts thereof which may be employed can be prepared in any convenient manner. for example, according to the teachings of British Patent 1,394,172.

The concentration of the agent which removes stain caused by the nitrogencontaining antibacterial antiplaque agent in the oral compositions can range widely, typically upward from 0.01 q by weight. There is no upper limit on the amount that can be utilized except as dictated by cost or incompatibility with the vehicle of the composition. Generally, concentrations from 0.01 En to 10? by weight are utilized. Oral compositions which in the ordinary course of usage could be accidentally ingested preferably contain lower concentrations of the stain inhibiting agent. Thus, a mouthwash in accordance with this invention preferably contains less than 30 by weight of the stain inhibiting agents. Dentifrice compositions, topical solutions and prophylactic pastes, the latter to be administered professionally, can contain from 0.01An to 10% by weight, preferably from 0.1non to 59, by weight, of the stain inhibiting agent. Most desirably, the stain inhibiting agent is present in a molar excess relative to the amount of antibacterial antiplaque agent (based on the free base thereof), in order best to inhibit staining by the antibacterial antiplaque agent.

In certain highly preferred forms of the invention the oral composition is substantially liquid in character, such as a mouthwash or rinse. In such a composition the vehicle is typically a water-alcohol mixture. Generally, the ratio of water to alcohol is in the range from 1:1 to 20:1 preferably from 3:1 to 20:1 and most preferably about 17:3, by weight. The total amount of water-alcohol mixture in this type of composition is typically in the range from 700;, to 99.9An by weight of the composition. The pH of such liquid compositions is generally in the range from 4.5 to 9 and typically from 5.5 to 8. The pH is preferably in the range of from 6 to 8. It is noteworthy that the composition of the invention permits the use of the phosphono compounds at a pH below 5 without substantially decalcifying dental enamel.

Such liquid oral compositions may also contain a surface active agent and/or a fluorine-providing compound.

In certain other desirable forms of this invention, the oral composition may be substantially solid or pasty in character, such as a toothpowder, a dental tablet or a toothpaste or dental cream. The vehicle of such solid or pasty oral preparations contains polishing material. Examples of polishing materials 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, aluminium silicate, zirconium silicate, silica, bentonite, and mixtures thereof. Preferred polishing materials include crystalline silica having particle sizes of up to 5 microns, a mean particle size of up to 1.1 microns, and a surface area of up to 50,000 cm2/gm silica gel, complex amorphous alkali metal alumino-silicate and hydrated alumina (e.g. alpha-alumina trihydrate).

Alumina, particularly the alpha-alumina trihydrate sold by Alcoa (U.S.A.) as C333, which has an alumina content of 64.9% by weight, a silica content of 0.008An, a ferric oxide content of 0.0039h, and a moisture content of 0.370/;, at 110"C. and which has a specific gravity 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 employed, a polishing agent of colloidal silica, such as those sold under the trademark Syloid as "Syloid 72" and "Syloid 74" or under the trademark Santocel as "Santocel 100" and alkali metal aluminosilicate complexes are particularly useful, since they have refractive indices close to the refractive indices of gelling agent-liquid (including water and/or humectant) systems commonly used in dentifrices.

Many of the so-called "water-insoluble" polishing materials are anionic in character and also include small amounts of soluble material. Thus, insoluble sodium metaphosphate may be formed in any suitable manner, as illustrated by Thorpe's Dictionary of Applied Chemistry, Volume 9,4to Edition, pp. 51e511.The forms of insoluble sodium metaphosphate known as Madrell's salt and Kurrol's salt are further examples of suitable materials. These metaphosphate salts exhibit a minute solubility in water, and therefore are commonly referred to as insoluble metaphosphates. There is present therein a minor 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 believed to include a soluble sodium trimetaphosphate in the case of insoluble sodium metaphosphate, may be reduced by washing with water if desired. The insoluble alkali metal metaphosphate is typically employed in powder form of a particle size such that no more than 1 ', of the material is larger than 37 microns.

The polishing material is generally present in amounts ranging from 20% to 990 by weight of the oral preparation. Preferably, it is present in amounts ranging from 200,, to 75?,,,, in toothpaste, and from 70% to 99% in toothpowder.

In the preparation of toothpowders it is usually sufficient to admix mechanically, e.g. by milling, the various solid ingredients in appropriate quantities and particle sizes.

In pasty oral compositions the above described combination of the antibacterial antiplaque agent and phosphonic compound should be compatible with the other components of the composition. Thus, in a toothpaste, the liquid vehicle may comprise water and humectant typically in an amount ranging from 10% to 90% by weight of the composition. Glycerine, sorbitol or polyethylene glycol may also be present as humectants or binders. Particularly advantageous liquid ingredients comprise mixtures of water, glycerine and sorbitol.

In clear gels where the refractive index is an important consideration, 3 to 30 /n by weight of water, 0 to 800',,' by weight of glycerine, and 20 to 80?,,' by weight of sorbitol is preferably employed.

A gelling agent, such as natural or synthetic gums or gum-like materials, typically Irish moss, sodium carboxymethylcellulose, methyl cellulose or hydroxyethyl cellulose, may be employed. Other gelling agents which may be employed include gum tragacanth, polyvinylpyrrolidone and starch. They are usually present in toothpaste in an amount up to 10% by weight, preferably in the range from 0.5% to 5%. The preferred gelling agents are methyl cellulose and hydroxyethyl cellulose. In a toothpaste or gel, the liquids and solids are proportioned to form a creamy or gelled mass which is extrudable from a pressurized container or from a collapsible tube. e.g. an aluminium or lead tube.

The solid or pasty oral composition which typically has a pH measured on a 20% slurry of from 4.5 to 9, generally 5.5 to 8 and preferably 6 to 8, may also contain a surface active agent and/or a fluorine-providing compound.

As is conventional, the oral composition will usually be sold or otherwise distributed in suitably labelled packages. Thus a jar of mouthrinse will have a label describing it, in substance, as a mouthrinse or mouthwash and having directions for its use; and a toothpaste will usually be in a collapsible tube, typically an aluminium or lined lead tube, or other squeeze dispenser for metering out the contents, having a label describing it, in substance as a toothpaste or dental cream.

In oral compositions such as mouthrinses and toothpastes, a surfactant is often present, e.g. to promote foaming. It is preferable to employ nonionic surfactants rather than their anionic counterparts. Examples of water-soluble nonionic surfactants are condensation products of ethylene oxide with various compounds reative therewith having long hydrophobic chains (e.g. aliphatic chains of 12 to 20 carbon atoms) which condensation products ("ethoxamers") have hydrophilic polyoxyethylene moieties, such as condensation products of ethylene oxide and fatty acids, fatty alcohols or fatty amides, including alcohols such as sorbitan monostearate or polypropyleneoxide (that is, materials such as are sold under the trade mark Pluronic).

In certain embodiments of this invention a fluorine-providing compound is present in the oral composition. These compounds may be slightly soluble in water or may be fully water-soluble. They are characterized by their ability to release fluoride ions in water and by substantial freedom from reaction with other compounds of the oral composition. Among these materials are inorganic fluoride salts, such as soluble alkali metal, alkaline earth metal and heavy metal salts, for example, sodium fluoride, potassium fluoride, ammonium fluoride, lead fluoride, 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, sodium fluorozirconate, sodium monofluorophosphate, aluminium mono-and di-fluorophosphate, and fluorinated sodium calcium pyrophosphate. Alkali metal and tin fluorides, such as sodium and stannous fluorides, sodium monofluorophosphate and mixtures thereof, particularly of sodium fluoride and sodium monofluorophosphate, are preferred.

The amount of the fluorine-providing compound is dependent to some extent upon the type of compound, its solubility, and the type of oral composition, but it must be a nontoxic amount. In a solid or partially solid oral composition, such as a toothpaste or toothpowder, an amount of such compound which releases a maximum of 1% by weight of the preparation is considered satisfactory. Any suitable minimum amount of such compound may be used, but it is preferable to employ sufficient compound to release from 0.005% to 1%, preferably about 0.1% of fluoride ion. Typically, in the cases of alkali metal fluorides and stannous fluoride, this component is present in an amount up to 2% by weight, based on the weight of the composition, preferably in the range of from 0.05% to 1%. In the case of sodium monofluorophosphate, the compound may be present in an amount up to 7.6% by weight, more typically 0.76%. When present in mixture the ratio of sodium monofluorophosphate to sodium fluoride is desirably in the range from 1:1 to 3:1, based on fluorine provided by each.

In a liquid oral composition such as a mouthwash, the fluorine-providing compound is typically present in an amount sufficient to release up to 0.13%, preferably from 0.0013% to 0.1% and most preferably from 0.0013% to 0.05%, by weight, of fluoride ion.

Various other materials may be incorporated in the oral compositions of this invention. Examples are whitening agents, preservatives, silicones, chlorophyll compounds and ammoniated materials such as urea, diammonium phosphate, and mixtures thereof. These adjuvants, where present, are incorporated in the compositions in amounts which do not substantially adversely affect the properties and characteristics desired.

Any suitable flavouring or sweetening material may also be employed.

Examples of suitable flavouring constituents are flavouring oils, e.g. oils or spearmint, peppermint, wintergreen sassafras, clove, sage, eucalyptus. marjoram, cinnamon, lemon and orange, and methyl salicylate. Suitable sweetening agents include sucrose, lactose. maltose, sorbitol, perillartine and sodium saccharin.

Suitably, flavour and sweetening agents may together constitute from 0.010 to 5 " or more of the composition.

In preparing the oral compositions of this invention having an oral vehicle which typically includes water, it is highly desirable if not essential to add the phosphono additive after the other ingredients (except perhaps some of the water) are mixed or contacted with each other, for instance to avoid a tendency towards formation of a precipitate.

For example, a mouthrinse or mouthwash may be prepared by mixing ethanol and water with flavouring oil, nonionic surfactant, humectant, cationic antibacterial antiplaque agent, such as benzethonium chloride, cetyl pyridinium chloride or chlorhexidine, sweetener and colour and then adding the stain inhibiting agent compound and additional water as desired.

A toothpaste may be prepared by forming a gel with humectant, gum or thickener such as hydroxyethyl cellulose, sweetener and adding thereto polishing agent, flavour, antibacterial agent, such as benzethonium chloride, cethyl pyridinium chloride or chlorhexidine, and additional water, followed by addition of the stain inhibiting agent. If sodium carboxymethyl cellulose is employed as the gelling agent the procedure of either U.S. Patent 3,842,168 or U.S. Patent 3,843,779, modified by the inclusion of the quaternary aminoalkylene phosphonic compound, is followed.

An oral composition according to the invention, such as a mout

TABLE I Antistain Parts (x) Reflectance Example QMATMP Reflectance Difference 0 0 41.0 0 2 0.1 56.0 15.0 3 0.2 58.0 17.0 The above results plainly establish that these quaternary aminoalkylene phosphonic acid compounds, as exemplified by QMATMP, substantially and significantly reduce dental staining ordinarily caused by BC. These tests are conducted with the pH adjusted to about 7.0, the pH prior to adjustment ranging from about 4 to 4.8. Formulations adjusted to pH ranging from about 5 to 8 yield similar results.

EXAMPLES 4--7 Substitution of equivalent amounts of the following phosphono-containing compounds for the QMATMP employed in Examples 2 and 3 yields formulations also producing reductions in dental staining: Example Quaternary aminoalkylene phosphonate 4 N-ethyl aminotri (methylene phosphonic acid) 5 N-isobutyl aminotri (methylene phosphonic acid) 6 N-ethyl aminotri (ethylene phosphonic acid) 7 N-methyl aminotri (butylene phosphonic acid) EXAMPLES 8-14 Substitution of equivalent amounts of the following antibacterial antiplaque agents for the BC employed in Examples 2-7 yields formulations also producing reductions in dental staining: Example Antibacterial Antiplaque Agent 8 chlorhexidine diacetate 9 chlorhexidine digluconate 10 alexidine dihydrochloride 11 dodecyl trimethyl ammonium bromide 12 benzyl dimethyl stearly ammonium chloride 13 cetyl pyridinium chloride 14 Ci2is alkyl

It is further notable that the antiplaque activities of the above-exemplified formulations containing the indicated quaternary aminoalkylene phosphonic compounds are substantially equal to those of corresponding formulations omitting these compounds.

EXAMPLES 15, 16 The following formulations exemplify toothpastes with antiplaque activity and reduced staining.

Example 15 16 Parts Parts Hydrated alumina 30 30 Glycerine 16 16 Sorbitol (70%) 6 6 "Pluronic F-l08" 3 3 Hydroxyethyl cellulose 1.2 1.2 Benzethonium chloride 0.5 Chlorhexidine digluconate (20 a) 4.725 QMATMP 2 2 Sodium saccharin 0.17 0.17 Flavour 0.8 0.8 Water Q.S. to 100 Q.S. to 100 EXAMPLES 1723 A basic mouthwash formulation is prepared and tested as follows: Mouthwash Formulation Parts Flavoured alcohol 15 "Pluronic F108" (polyalkene oxide blockpolyer) 3 Glycerine 10 Benzethonium chloride (BC) 0.075 Sodium saccharin 0.03 Pyrrolidone-5,5-diphosphonic acid (PYDP) x Water q.s to 100 pH 7.0 (adjusted with 5N NaOH) Appearance, stability clear The PYDP, and about 10 parts of water, are added to the other previously mixed ingredients.

The following Table II shows the in vitro antistain results when the indicated amounts (x) of PYDP are employed in the above mouthwash formulation.

TABLE II Antistain Phosphono Parts Reflectance Example Compound (x) Reflectance Difference 17 - 0 40.0 0 18 PYDP 0.1 52.0 12.0 19 PYDP 0.2 55.0 15.0 20 PYDP 0.3 50.0 10.0 21 PYDP 0.4 54.0 14.0 22 PYDP 0.5 52.0 12.0 23 PYDP 1.0 51.0 11.0 The above results plainly establish that the pyrrolidone diphosphonic acid compounds, as exemplified by PYDP, substantially reduce dental staining ordinarily produced by BC. These tests are conducted with the pH of the formulation adjusted to about 7.0, the pH prior to adjustment ranging from 3.5 to 4.6. Formulations adjusted to pH ranging from about 5 to 8 yield similar results.

EXAMPLES 24-30 Substitution of equivalent amounts of the following phosphono-containing compounds for the PYDP employed in Examples 18 to 23 yield formulations also producing reductions in dental staining: Example Phosphono Compound 24 N-methyl pyrrolidone-5,5-diphosphonic acid 25 N-ethyl pyrrolidone-5,5-diphosphonic acid 26 N-butyl pyrrolidone-5,5-diphosphonic acid 27 N-(2-hydroxyethyl)pyrrolidone-5,5-diphosphonic' acid 28 3-butyl pyrrolidone-5,5-diphosphonic acid 29 3,4-tetramethyl pyrrolidone-5,5-diphosphonic acid 30 4,4-diethyl pyrrolidone-5,5-diphosphonic acid EXAMPLES 31-36 Substitution of equivalent amounts of the following antibacterial antiplaque agents for the BC employed in Examples 18-30 yield formulations aiso producing reductions in dental staining: Example Antibacterial Antiplaque Agent 31 chlorhexidine diacetate 32 chlorhexidine digluconate 33 dodecyl trimethyl ammonium bromide 34 cetyl pyridinium chloride

CH2CH3OH CH2CH2OH 35 C12~,8 alkyl-N-CH2CH2N-CH2CH2OH 36 alexidine dihydrochloride EXAMPLES 37-38 The following formulations exemplify toothpastes with antiplaque activity and reduced staining: Example 37 38 Parts Parts Hydrated alumina 30 30 Glycerine 16 16 Sorbitol (70) 6 6 "Pluronic F-l08" 3 3 Hydroxyethyl cellulose 1.2 1.2 Benzethonium chloride 0.5 Chlorhexidine digluconate (20,,') 4.725 PYDP 2 2 Sodium saccharin 0.17 0.17 Flavour 0.8 0.8 Water q.s. to 100 100 EXAMPLES 39 "5 A mouthwash formulation is prepared and tested as follows: Parts Flavoured alcohol 15 "Pluronic F-108" (polyalkene oxide block power) 3 Glycerine 10 Benzethonium chloride (BC) 0.075 Sodium saccharin 0.03 IDANMPA x Water Q.S. to 100 pH 7.0 (adjusted with 5 N sodium hydroxide) All compositions are clear without visible evidence of precipitation. The IDANMPA, and about 10 parts of water, are added to the other previously mixed ingredients. Colour levels are determined in vitro on a Gardner Color Difference Meter before and after the test composition is applied to the coloured material.

The following Table III shows the antistain results when the indicated amounts (x) of IDANMPA are employed in the above mouthwash formulation.

TABLE III Antistain Parts (x) Reflectance Example IDANMPA Reflectance Difference 39 0 40.0 0 40 0.1 52.0 12.0 41 0.2 56.0 16.0 42 0.3 57.0 17.0 43 0.4 51.0 11.0 44 0.5 58.0 18.0 45 1.0 57.0 17.0 The above results plainly establish that the N-methylene phosphonate compounds, are exemplified by IDANMPA, substantially reduce dental staining ordinarily produced by BC. These tests are conducted with the pH adjusted to about 7.0, the pH prior to adjustment ranging from 3.5 to 4.8. Formulations adjusted to pH ranging from 5 to 8 yield similar results.

Examples 4648 Substitution of equivalent amounts of the following phosphono-containing compounds for the IDANMPA employed in Examples 4o--45 yield formulations also producing reductions in dental staining.

Example N-methylene phosphonate 46 N-carboxymethyl-amino-di-methylene phosphonic acid 47 N-hydroxyethyl-amino-di-methylene phosphonic acid 48 N,N-dihydroxyethyl-amino-methylene phosphonic acid EXAMPLES 49-55 Substitution of equivalent amounts of the following antibacterial antiplaque agents for the BC employed in Examples 40-48 yield formulations also producing unexpected reductions in dental staining: Example Antibacterial Antiplaque Agent 49 chlorhexidine diacetate 50 chlorhexidine digluconate 51 alexidine dihydrochloride 52 dodecyl trimethyl ammonium bromide 53 benzyl dimethyl stearyl ammonium chloride 54 cetyl pyridinium chloride

CH2CH2OlI CH2CH2OH 55 C12~, alkyl-N-CH2CH2N-CH2CH2OH It is further notable that the antiplaque activities of the above-exemplified formulations containing the indicated phosphono-containing compounds are substantially equal to those of corresponding formulations omitting these compounds.

EXAMPLES 56-57 Example 56 57 Parts Parts Hydrated alumina 30 30 Glycerine 16 16 Sorbitol (70%) 6 6 "Pluronic F-108" 3 3 Hydroxyethyl cellulose 1.2 1.2 Benzethonium chloride 0.5 Chlorhexidine digluconate (200/,) 4.725 IDANMPA 2 2 Sodium saccharin 0.17 0.17 Flavour 0.8 0.8 Water Q.S. to 100 Q.S. to 100 EXAMPLES 58-64 The following mouthwash formulation is prepared and tested: Mouthwash Formulation Parts Flavoured alcohol 15 "Pluronic F-108" (polyalkene oxide block polymer) 3 Glycerine 10 Benzethonium chloride (BC) 0.075 Sodium saccharin 0.03 Phosphonoacetic acid (PAA) x Water Q.S. to 100 pH 7.0 (adjusted with 5N NaOH) Appearance, stability Clear The PAA, and about 10 parts of the water, are added to the other previously mixed ingredients.

The following Table IV shows the in vitro antistain results when the indicated amounts (x) of PAA are employed in the above mouthwash formulation.

TABLE IV A ntistain Parts (x) Reflectance Example PAA Reflectance Difference 58 0 39.0 0 59 0.1 56.0 17.0 60 0.2 54.0 15.0 61 0.3 56.0 17.0 62 0.4 53.0 14.0 63 0.5 55.0 16.0 64 1.0 53.0 14.0 The above results plainly establish that PAA, at all levels of x, substantiallv and signficantly reduces dental staining ordinarily produced by BC. These tests are conducted with the pH adjusted to about 7.0, the pH prior to adjustment ranging from about 3.5 to 4.6. Formulations adjusted to pH ranging from about 5 to 8 yield similar results.

EXAMPLES 65-71 Substitution of equivalent amounts of the following antibacterial antiplaque agents for the BC employed in Examples 59 to 64 yield formulations also producing reductions in dental staining.

Example Antibacterial Antiplaque Agent 65 Chlorhexidine diacetate 66 Chlorhexidine digluconate 67 Alexidine dihydrochloride 68 Dodecyl trimcthyl ammonium bromide 69 Benzyl dimethyl stearyl ammonium chloride 70 Cetyl pyridinium chloride

CH2CH2OH /CH2CH2OH 71 C,2~18 alkyl-N-CH2CH2N-CH2CH2OH It is further notable that the antiplaque activities of the above-exemplified formulations containing PAA are substantially equal to those of corresponding formulations without the PAA.

The following formulations exemplify toothpastes with antiplaque activity and reduced staining: Example 72 73 Parts Parts Hydrated alumina 30 30 Glycerine 16 16 Sorbitol (70,,) 6 6 "Pluronic F-108" 3 3 Hydroxyethyl cellulose 1.2 1.2 Benzethonium chloride 0.5 Chlorhexidine digluconate (209) 4.725 Phosphonoacetic acid 2 2 Sodium saccharin 0.17 0.17 Flavour 0.8 0.8 Water Q.S. to 100 Q.S. to 100 EXAMPLES 74-99 In the following Examples, a basic mouthwash formulation is prepared and tested as follows: Mouthwash Formulation Parts Flavoured alcohol 15 "Pluronic F108" (polyalkene oxide block polymer) 3 Glycerine 10 Benzethonium chloride (BC) 0.075 Moutwash Formulation Parts Sodium saccharin 0.03 Phosphono-containing compound x Water Q.S. to 100 pH 7.0 (adjusted with 5N NaOH) Appearance, stability clear The phosphono-containing compound, and about 10 parts of the water, are added to the other previously mixed ingredients.

The following Table V shows the in vitro antistain results when the indicated amounts (x) of the indicated phosphono-containing compound are employed in the above mouthwash formulation.

TABLE V Antistain Phosphono Parts Reflectance Example Compound (x) Reflectance Difference 74 - 0 40.0 0 75 DPPD* 0.1 45.0 5.0 76 " 0.2 49.0 7.0 77 ,, 0.3 53.0 13.0 78 " 0.4 60.0 20.0 79 " 0.5 53.0 13.0 80 " 1.0 56.0 16.0 81 PEDA** 0.1 43.0 3.0 82 " 0.2 54.0 14.0 83 " 0.3 58.0 18.0 84 ,, 0.4 52.0 12.0 85 " 0.5 54.0 14.0 86 " 0.6 60.0 20.0 87 " 1.0 51.0 11.0 * I, I-diphosphonopropane-2,3-dicarboxylic acid.

** 1 -phosphonoethane- 1 ,2-dicarboxylic acid.

The above results plainly establish that the phosphono-alkane polycarboxylic acid compounds, as exemplified by DPPD and PEDA, substantially reduce dental staining ordinarily produced by BC. These tests are conducted with the pH of the formulation adjusted to about 7.0, the pH prior to adjustment ranging from 3.5 to 5.0. Formulations adjusted to pH ranging from 5 to 8 yield similar results.

Substitution of equivalent amounts of the following phosphono-containing compounds for those employed in Examples 75-87 yield formulations also producing reductions in dental staining: Example Phosphono-Containing Compound 88 2-phosphonopropane-2,3-dicarboxylic acid 89 2-phosphonobutane-2,3-dicarboxylic acid 90 1,1 -diphosphonobutane-2,3-dicarboxylic acid 91 1 -phosphonopropane- 1,2,3-tricarboxylic acid 92 2-phosphonobutane-2,3,4-tricarboxylic acid Substitution of equivalent amounts of the following antibacterial antiplaque agents for the BC employed in Examples 75-92 yield formulations also producing reductions in dental staining: Example Antibacterial Antiplaq ue Agent 93 chlorhexidine diacetate 94 chlorhexidine digluconate 95 dodecyl trimethyl ammonium bromide 96 cetyl pyridinium chloride

CH2CH2OH CH2CH2OH 97 Cm12~,8 alkyl-N-CH2CH2N-CH2CH2OH 98 alexidine dihydrochloride It is further notable that the in vitro antiplaque activities of the aboveexemplified formulations containing the indicated phosphono-containing additive compounds are substantially equal to those of corresponding formulations omitting these compounds.

EXAMPLE 99 In vivo tests for antiplaque and antistain activity are conducted on beagles with the mouthwash formulation of Example 80 containing 0.075 parts of BC and 0.5 parts of DPPD the control formulation of Example 74 containing 0.075 parts of BC and no DPPD, and a placebo devoid of both BC and DPPD. The beagles are first subjected to dental prophylaxis to remove existing soft and hard dental deposits. A disclosing solution is used to ensure complete removal. Applications are made by gentle spraying twice a day, 5 days a week for 6 weeks. Stain is evaluated relatively by visual observation of the oral cavityf Plaque is evaruated after spraying the teeth with disclosing solution. The results are as follows: Stain No. Mean Difference of Plaque Mean Compared to Dogs Score Stain Placebo Placebo 8 2.4 0.38 0 Control(+BC) 7 1.8 0.53 +39.4An +BC+DPPD 8 1.8 0.32 -42.3", It is clear from the above results that the phosphono-containing compounds.

as exemplified by DPPD, significantly and substantially reduce dental staining (by 42.3?f) caused by antibacterial antiplaque agents as exemplified by BC, in fact reducing staining to less than the placebo. These results also show that such compounds do not affect the antiplaque activity of the stain-producing antibacterial antiplaque agents.

EXAMPLES 100--101 The following formulations exemplify toothpastes with antiplaque activity and reduced staining: Example 101 102 Parts Parts Hydrated alumina 30 30 Glycerine 16 16 Sorbitol (70 /,) 6 6 "Pluronic F-108" 3 3 Hydroxyethyl cellulose 1.2 1.2 Benzethonium chloride 0.5 Chlorhexidine digluconate (20 ,')) - 4.725 DPPD 2 2 Sodium saccharin 0.17 0.17 Flavour 0.8 0.8 Water q.s. 100 100 WHAT WE CLAIM IS: 1. An oral composition comprising an oral vehicle, at at least one nitrogencontaining antibacterial antiplaque agent selected from cationic antibacterial antiplaque agents of the amidine and quaternary ammonium types and long chain tertiary amine antibacterial antiplaque agents containing a fatty alkyl group of 12 to 18 carbon atoms, and an agent which inhibits stain formation by the nitrogencontaining antibacterial antiplaque agent selected from water-soluble quaternary aminoalkylene phosphonic compounds of the formula:

wherein R represents C, to C20 alkyl, alkenvl cycloalkyl or aralkyl: R' represents C, to C20 alkyl or alkenyl: R" represents C, tci C6 alkylene or alkenylene; n is 1. 2 or 3: and M is an orally acceptable cation:

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **.

It is further notable that the in vitro antiplaque activities of the aboveexemplified formulations containing the indicated phosphono-containing additive compounds are substantially equal to those of corresponding formulations omitting these compounds.

EXAMPLE 99 In vivo tests for antiplaque and antistain activity are conducted on beagles with the mouthwash formulation of Example 80 containing 0.075 parts of BC and 0.5 parts of DPPD the control formulation of Example 74 containing 0.075 parts of BC and no DPPD, and a placebo devoid of both BC and DPPD. The beagles are first subjected to dental prophylaxis to remove existing soft and hard dental deposits. A disclosing solution is used to ensure complete removal. Applications are made by gentle spraying twice a day, 5 days a week for 6 weeks. Stain is evaluated relatively by visual observation of the oral cavityf Plaque is evaruated after spraying the teeth with disclosing solution. The results are as follows: Stain No. Mean Difference of Plaque Mean Compared to Dogs Score Stain Placebo Placebo 8 2.4 0.38 0 Control(+BC) 7 1.8 0.53 +39.4An +BC+DPPD 8 1.8 0.32 -42.3", It is clear from the above results that the phosphono-containing compounds.

as exemplified by DPPD, significantly and substantially reduce dental staining (by 42.3?f) caused by antibacterial antiplaque agents as exemplified by BC, in fact reducing staining to less than the placebo. These results also show that such compounds do not affect the antiplaque activity of the stain-producing antibacterial antiplaque agents.

EXAMPLES 100--101 The following formulations exemplify toothpastes with antiplaque activity and reduced staining: Example

101 102 Parts Parts Hydrated alumina 30 30 Glycerine 16 16 Sorbitol (70 /,) 6 6 "Pluronic F-108" 3 3 Hydroxyethyl cellulose 1.2 1.2 Benzethonium chloride 0.5 Chlorhexidine digluconate (20 ,')) - 4.725 DPPD 2 2 Sodium saccharin 0.17 0.17 Flavour 0.8 0.8 Water q.s. 100 100 WHAT WE CLAIM IS: 1. An oral composition comprising an oral vehicle, at at least one nitrogencontaining antibacterial antiplaque agent selected from cationic antibacterial antiplaque agents of the amidine and quaternary ammonium types and long chain tertiary amine antibacterial antiplaque agents containing a fatty alkyl group of 12 to

18 carbon atoms, and an agent which inhibits stain formation by the nitrogencontaining antibacterial antiplaque agent selected from water-soluble quaternary aminoalkylene phosphonic compounds of the formula:

wherein R represents C, to C20 alkyl, alkenvl cycloalkyl or aralkyl: R' represents C, to C20 alkyl or alkenyl: R" represents C, tci C6 alkylene or alkenylene; n is 1. 2 or 3: and M is an orally acceptable cation:

(B) water-soluble diphosphono pyrrolidone compounds of the formula:

wherein the R's independently represent hydrogen, C,~6 alkyl or C26 hydroxyalkyl and X is an orally acceptable cation: (C) water-soluble N-methylene phosphonate compounds of the formula:

wherein A' represents -CH2CH2OH, -CH2COOX or -CH2PO3X2: A" represents -CH2CH9OH or -CH2COOX: A' is the same as A" when A' is not CH2PO2X2: and X is an orally acceptable cation; (D) phosphonoacetic acid (PAA), of the formula H2O3P-CH2-COOH, and orally acceptable salts thereof: and (E) water-soluble phosphono-containing compounds of the formula:

wherein R' represents hydrogen, C, to C4 alkyl or (-CH2)12 COOH: and R2 represents -PO2H2,

and orally acceptable salts thereof.

2. An oral composition as claimed in Claim 1 wherein the antibacterial antiplaque agent is present in amount to provide from 0.001An to 150,, by weight based on the free base form of the agent, and the quaternary aminoalkylene phosphonic compound is present in amount of from 0.01?',, to 10% by weight, 3. An oral composition as claimed in Claim 2 wherein the antibacterial antiplaque agent is present in amount of from 0.019, to 5?:' by weight based on the free base form of the agent and the quaternary aminoalkylene phosphonic compound is present in a molar excess relative to the agent.

4. An oral composition of any of the preceding Claims wherein the antibacterial antiplaque agent is a substituted guanidine.

5. An oral composition as claimed in Claim 4 wherein the antibacterial antiplaque agent is a pharmaceutically acceptable water-soluble salt of chlorhexidine or alexidine.

6. An oral composition as claimed in Claim 5 wherein the antibacterial antiplaque agent is a pharmaceutically acceptable water-soluble salt of chlorhexidine.

7. An oral composition as claimed in any of Claims I to 3 wherein the antibacterial antiplaque agent is benzethonium chloride.

8. An oral composition as claimed in any of Claims 1 to 3 wherein the antibacterial antiplaque agent is a quaternary ammonium compound containing 1 or 2 alkyl groups each of 8 to 20 carbon atoms.

9. An oral composition as claimed in Claim 8 wherein the antibacterial antiplaque agent is cetyl pyridinium chloride.

I U. An oral composition as claimed in any of the preceding Claims wherein the stain inhibiting agent has the formula:

II. An oral composition as claimed in any of Claims I to 9 wherein the stain inhibiting agent is pyrrolidone-5,5-diphosphonic acid or an orally acceptable salt thereof.

12. An oral composition as claimed in any of Claims 1 to 9 wherein the stain inhibiting agent has the formula:

wherein X is an orally acceptable cation.

13. An oral composition as claimed in any of Claims 1 to 9 wherein the stain inhibiting agent is phosphono acetic acid or an orally acceptable salt thereof.

14. An oral composition as claimed in any of Claims 1 to 9 wherein the stain inhibiting agent is l.l-diphosphonopropane-2,3-dicarboxylic acid or 1phosphonoethane-l.2-dicarboxylic acid or an orally acceptable salt thereof.

15. An oral composition as claimed in any of the preceding Claims wherein the vehicle is an aqueous-alcohol and the composition is a mouthwash of pH in the range from 4.5 to 9.

16. An oral composition as claimed in any of the preceding Claims wherein the vehicle comprises a liquid vehicle and a gelling agent, a dentally acceptable polishing material is present, and the composition is a toothpaste of pH in the range from 4.5 to 9.

17. An oral composition as claimed in Claim 15 which is a mouthwash containing from 0.0l,,' to 5,, based on its free base weight of benzethonium chloride and, relative thereto, a molar excess in the range from 0.1", to 50,, by weight of the stain inhibiting agent.

18. An oral composition as claimed in Claim 15 which is a mouthwash containing from 0.01 " to 5 " based on its free base weight of a water-soluble pharmaceutically acceptable salt of chlorhexidine and, relative thereto, a molar excess in the range from 0.1 ,', to 5,, by weight of the stain inhibiting agent.

19. An oral composition as claimed in Claim 1 and substantially as described in any of Examples 2 to 16, 18 to 38, 40 to 57, 59 to 73 and 75 to 101.

20. A method of preparing an oral composition as defined in any of Claims I to 8 wherein the stain inhibiting agent is added to the remaining components of the composition after the components have been contacted with each other.

21. An oral composition as claimed in any of Claims 1 to 18 which has been prepared by a method as claimed in Claim 20.