GB2027342A - Oral compositions - Google Patents

Abstract

An oral composition effective to promote oral hygiene comprising an orally acceptable vehicle containing at least one water-soluble oligomer of the formula <IMAGE> wherein M represents a water-soluble orally acceptable cation; R1, R2, R3 and R4 are the same or different and each represents hydrogen, methyl or ethyl; Y is hydrophilic and represents at least one of the groups -COOM1 wherein M1 is hydrogen or M, -CONH2 and -CH2OH; X is hydrophobic and represents at least one of the groups -CN, -COOR, -COOR5OR, -CONHR, -COONHR5COR wherein R is C1-8 alkyl and R5 is C1-4 alkylene; a is 0-7; and a+b is 4-15; and optionally at least one nitrogen-containing cationic antibacterial antiplaque agent in a proportion of up to 15% by weight based on the free base form thereof.

Description

SPECIFICATION Oral compositions This invention relates to oral compositions containing an anticalculus agent.

Calculus is a hard, mineralized formation which forms on the teeth. Regular brushing prevents a rapid build-up of these deposits; but even regular brushing is not sufficient to remove all of the calculus deposits which adhere to the teeth. Calculus is formed on the teeth when crystals of calcium phosphates begin to be deposited in the pellicle and extracellular matrix of the dental plaque and become sufficiently closely packed together for the aggregates to become resistant to deformation. There is no complete agreement on the route by which calcium and orthophosphate ultimately become the crystalline material called hydroxyapatite (HAP). It is generally agreed, however, that at higher saturations, that is, above the critical saturation limit, the precursor to crystalline hydroxyapatite is an amorphous or microcrystalline calcium phosphate.

"Amorphous calcium phosphate", although related to hydroxyapatite, differs from it in atomic structure, particle morphology and stoichiometry. The X-ray diffraction pattern of amorphous calcium phosphate shows broad peaks typical of amorphous materials, which lack the long-range atomic order characteristic of all crystalline materials, including hydroxyapatite. It is apparent, therefore, that agents which effectively interfere with crystalline growth of hydroxyapatite will be effective as anticalculus agents. A suggested mechanism by which the anticalculus agents in the oral compositions of this invention inhibit calculus formation probably involves an increase of the activation energy barrier thus inhibiting the transformation of precursor amorphous calcium phosphate to hydroxyapatite.

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

A substantial number of differenttypes of compounds and compositions have been developed for use an antibacterial, anti-plaque and anticalculus agents in oral compositions, including, for example, such cationic materials as the bisbiguanide compounds and quaternary ammonium compounds, e.g. benzethonium chloride and cetyl pyridinium chloride. These cationic materials, however, tend to stain the teeth on continued use.

This invention provides oral composition containing an anticalculus agent which has little or no tendency to stain the teeth and which inhibits the transformation of amorphous calcium phosphate to hydroxyapatite crystal structure normally associated with calculus.

According to the present invention an oral composition comprises an orally acceptable vehicle containing in an effective amount as an anticalculus agent as least one water-soluble oligomer of the formula

wherein: M represents a water-soluble orally acceptable cation; R, R2, R3 and R4 are the same or different and each represents hydrogen, methyl or ethyl; Y is hydrophilic and represents at least one of the groups -COOM, wherein Mt is hydrogen or M, -CONH2 and -CH2OH: X is hydrophobic and represents at least one of the groups -CN, -COOR, -COORsOR, -CONHR and -COONHR,COR wherein R is C18 alkyl and R5 is C,, alkylene; a is 0-7; and a +h is4-15.

Oligomers of the above formula and methods for their production are disclosed in U.S. Patents Nos.

3,646,099 and 3,859,260. These oligomers, anionic and of relatively low and accurately regulated degree of polymerization (in contrast to the conventional free radical redox polymerization conducted with an oxidative initiator such as hydrogen, alkyl or acyl peroxides, persulphates or hydroperoxides in relatively large amounts and a reductive activator such as NaHSO3, Na2S203, Na2S204 or sodium formaldehyde sulphoxylate in relatively low amounts generally added subsequently to the polymerization medium) are prepared by a reductive polymerization in which a much larger amount of a bisulphite salt, e.g. NaHSO3 (sodium bisulphite or sodium acid sulphite), a reducing agent, is the initiator charged initially with the monomer, and an oxidizing agent is added in smaller amounts as the activator during the polymerizing or oligomerizing process.

Subscript in formula I represents the number of moles of hydrophobic groups, and subscriptb the number of moles of hydrophilic groups, in the oligomer molecule. The proportion of X (i.e. the value of a) must be small enough, or even zero, to avoid the production of a too large, sticky and hydrophobic polymer molecule, and will be dependent for the most parkin any particular instance on the identity of the X and Y groups, i.e. the hydrophobiccontaining and hydrophilic-containing monomeric reactants. Mixtures of such oligomers may also be employed.

Examples of monomers containing hydrophilic Y groups are acrylic acid, methacrylic acid, alpha-ethylacrylic acid, beta-methylacrylic acid, alpha, beta-dimethylacrylic acid, orally acceptable salts (M1) of these acids, for example those containing such cations as alkali metal (e.g. sodium and potassium), ammonium, Ci-ia mono-, di-and-tri- substituted ammonium (e.g. alkanol substituted such as mono-, di- and tri-ethanol-ammonium), acrylamide, methacrylamide, ethacrylamide, and allyl alcohol.

Examples of monomers containing hydrophobic X groups are acrylonitrile, methacrylonitrile, ethacrylonitrile, methyl and ethyl and octyl acrylate and methacrylate, methoxyethyl acrylate, octoxyethyl methacrylate, ethoxybutyl methacrylate, propoxymethyl acrylate, N-ethylacrylamide, N-isopropylacrylamide, N-methylacrylamide, N-isooctylmethacrylamide, N-propylethacrylamide, vinyl acetate, propionate and octanoate and diacetone acrylamide.

The oligomerization is carried out in water in the presence of a relatively large amount of the bisul phite reducing initiator, which expressed in mols of monomer/gram formula weight (gFW) of reducing initiator is about 4 to 15, this ratio determining the degree of oligomerization.

The reducing initiator is preferably a water-soluble bisulphite salt, (M in formula 1), especially an alkali metal such as sodium or potassium salt, but bisulphite salts containing other orally acceptable cations of the type referred to above may be employed.

In practice, enough oxidative activator is used to effect 100% conversion of the monomers to oligomers. The amount of such activator, expressed as gFW activator/gFW initiator may range from 0.0001 to 0.1 but usually is from 0.001 to 0.1. Examples of these oxidative activators are ammonium, sodium and potassium persulphate, hydrogen peroxide and other water-soluble oxidants commonly employed in the polymerization art.

Following completion of the oligomerization reaction, any free carboxylic acid groups in the oligomer molecules may, if desired be partially or completely neutralized, preferably at least 60%, by treating the aqueous oligomer solution with a suitable base to convert such groups to their salts with orally acceptable cations as referred to above. These aqueous oligomer solutions have a highly desirable low viscosity, and low molecular weight range depending on the monomer units in the oligomer.

Formula I is not intended to depict the actual structure of the oligomer molecule, the bracketed units of which formula are randomly distributed in the molecule with the -SO3M group being normally bonded to a terminal carbon atom in the oligomer chain devoid of X and orYsubstituents. In the oligomers preferred for use in the compositions of the invention, a is zero, Y is -COOM1, R,-R4 are H, and M and M1 are alkali metal, e.g. sodium, b being about 10, as derived from acrylic acid. An oligomer of formula I above in the form of its sodium salt, with a molecular weight of about 1,000, containing about 10 acrylic acid monomeric units, is commercially available under the trade name ND-2 (a product of UniRoyal, U.S.A.).

The concentration of these oligomer anticalculus agents in oral compositions can range widely, typically upward from 0.01% by weight with no upper limit except as dictated by cost or incompatibility with the vehicle. Generally, concentrations of from 0.01% to 10%, preferably from 0.5% to 2%, are utilized. Oral compositions which in the ordinary course of usage could be accidentally ingested preferably contain low concentrations of these agents. Thus, a mouthwash in accordance with this invention preferably contains less than 1 weight % of the agent.

Dentifrice compositions, topical solutions and prophylactic pastes, the latter to be administered professionally, preferably contain from 0.1% to 2% of the agent.

The oligomeric anticalculus agents of formula I are antinucleating agents. Oral compositions of this invention containing such agents are effective in reducing formation of dental calculus without unduly calcifying the dental enamel, and in contrast to the above-mentioned cationic antibacterial, antiplaque and anticalculus agents, such agents and oral compositions containing them have little or no tendencyto stain the teeth.

Cationic nitrogen-containing antibacterial materials are well known in the art. See, for instance the section on "QuaternaryAmmonium 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 diisobutylphenoxyethyoxyethyl 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 Nos. 2,984,639,3,325,402, 3,431,208 and 3,703,583, and British Patent Specification No.1,319,396.

Other antibacterial antiplaque quaternary ammonium compounds include those in which one ortwo of the substituents on the quaternary nitrogen has a carbon chain length (typically an alkyl group) of 8 to 20, typically 10 to 18, carbon atoms while the remaining substituents have a lower number of carbon atoms, (typically an alkyl or benzyl group or groups), such as 1 to 7 carbon atoms, typically methyl or ethyl groups. Dodecyl trimethyl ammonium bromide, dodecyl dimethyl (2phenoxyethyl) ammonium bromide, benzyl dimethyl stearyl ammonium chloride, cetyl pyridinium chloride and quaternized 5-amino-1, 3-bis (2-ethyl hexyl)-5-methyl hexa hydropyrimidine are exemp lary of other typical quaternary ammonium antibacterial agents.

Other types of cationic antibacterial agents which may be incorporated iin oral compositions to prom ote oral hygiene by reducing plaque formation are amidines such as substituted guanidines, e.g.

chlorhexidine and the corresponding compound, alexidine, having2-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 follow- ing formula::

in which A and A' signify, as the case may be, either (1) a phenyl radical, which as substituent can contain up to 2 alkyl or alkoxy groups with 1 up to about 4C-atoms, 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 12C-atoms, X and X1, as the case may be, may represent an alkylene radical with 1-3C atoms and z' are, as the case may be, either zero or 1, R and R', as the case may be, may represent either hydrogen, an alkyl radical with 1 to about 12C-atoms or an aralkyl radical with 7 to about 1 2C-atoms, n is a whole number of 2 to 12 inclusively and the polymethylene chain (CH2) can be interrupted by up to 5 ether, thioether, phenyl- or naphthyl groups; these are available as pharmaceutically suitable 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 Np-chlorophenyl-N5-laurylbiguanide.

The long chain aliphatic tertiary amines also possess antibacterial and antiplaque activity. Such antibacterial agents include tertiary amines having one fatty alkyl group (typically 12 to 18 carbon atoms) and 2 poly(oxyethylene) groups attached to the nitrogen atom (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 andx, y andz total 3 or higher, as well as salts thereof.

Generally, cationic agents are preferred for their antiplaque effectiveness.

The antibacterial antiplaque agent is preferably one which has an antibacterial activity such that its phenol coefficient is well over 50, more preferably well above 100, such as 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 less than 1,000. It is, however, permissible to employ a polymeric cationic antibacterial agent. The cationic antibacterial agent is preferably supplied in the form of an orally acceptable saltthereof, such as the chloride, bromide, sulphate, alkyl sulphonate such as methyl sulphonate and ethyl sulphonate, phenylsulphonate such as p-methylphenyl sulphonate, nitrate, acetate or gluconate.

These nitrogen-containing cationic 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.

The reason for the formation of such dental stain has not been clearly established. However, human dental enamel contains a high proportion (about 95%) of hydroxyapatite (HAP) which includes Ca;2 and P04-3 ions. In the absence of dental plaque, additional Ca2 and P04-3, particularly from saliva, can be deposited on the enamel and such deposits can include colour bodies which ultimately stain the tooth enamel as a calcified deposit thereon. It may be that as the cationic antibacterial agents remove plaque they also denature protein from saliva in the oral environment and the denatured protein may then act as a nucleating agent which is deposited on and stains or discolours tooth enamel.

Previously employed additives which reduced dental staining by cationic antibacterial antiplaque agents also generally reduced to a measurable extent the activity of the antibacterial agents or its ability to act on dental plaque. Further, "Victamide" (also known as "Victamine C") which is the condensation product of ammonia with phosphorus pentoxide actually increases the staining even in the absence of a cationic antibacterial antiplaque agent, and it and other known phosphorous containing agents such as disodiumethane-1-hydroxy-1, 1-diphosphonic acid salt precipitate in the presence of an antibacterial agent such as bis-biguanido compound, thereby reducing the antiplaque effectiveness of the antibacterial agent.

It has now been found that the above-described oligomers unexpectedly prevent staining of dental enamel without precipitating or substantially adversely affecting the antibacterial and anti-plaque activity of the above-described cationic antibacterial antiplaque agents.

U.S. Patent No.3,934,002 discloses, among a number of alternative compounds for reducing the staining ordinarily caused by bis-biguanide antiplaque agents, homopolymers and copolymers containing units of the type present in the oligomers or oral compositions of this invention. Such polymers, however, are devoid of the essential sulphonic group of the said oligomers, and are difficu It to produce in the low 4-15 unit range and low-viscosity properties attributable to such oligomers. Such oligomers are furthermore advantageously employed in the instant oral compositions by reason of their water-solubilizing, water-dispersing sulphonic acid substituents.

Most desirably, the oligomer is present in a molar ratio relative to the amount of antibacterial antiplaque agent (based on its free base form), when such antiplaque agent is present, offrom 0.2:1 to 6:1, preferablyfrom 0.5:1 to 4:1, in order best to minimize, inhibit or prevent staining. When such antiplaque agents are present they are typically employed in amounts such that the oral composition contains from 0.001% and 15% by weight thereof. Preferably, for desired levels of antiplaque effect, the oral composition contains from 0.01% to 5%, and most preferably from 0.25% to 1.0 /O by weight of the antibacterial antiplaque agent, referring to its free base form.

In certain highly preferred forms of the invention the oral composition may be substantially liquid in character, such as a mouthwash or rinse. In such a composition the vehicle is typically a water-alcohol mixture, desirably including a humectant as described below. Generally, the ratio of water to alcohol is in the range from 1:1 to 17:3, by weight.

The total amount of water/alcohol mixture in this type of composition is typically in the range from 70% to 99.9% by weight of the composition. The pH of such liquid and other compositions of the inven tion is generally in the range from 4.5 to 9, typically from 5.5 to 8, and preferably from 6 to 8. It is noteworthythatthe compositions of the invention may be applied orally at a pH below 5 without sub stantially decalcifying dental enamel. The pH can be controlled with an acid (e.g. citric acid or benzoic acid) or a base (e.g. sodium hydroxide) or buffered (as with phosphate buffers). Such liquid oral com positions 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, a toothpaste or dental cream. The vehicle of such solid or pasty oral preparations generally contains polishing material. Examples of polishing mat erials 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 mixturesthereof.Preferred polishing materials include crystalline silica having particle sizes of up to 5 mic rons, a mean particle size of up to 1.1 microns, and a surface area of up to 50,000 cm2/g, silica gel, com plex amorphorus alkali metal aluminosilicate and hydrated alumina.

Alumina, particularly the hydrated alumina sold by Alcoa (U.S.A.) as "C333", which has 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 1 100C, 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 desirable.

When visually clear gels are employed, a polishing agent of colloidal silica, such as those sold underthe 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 com monly used in dentifrices.

Many of the so-called "water-insoluble" polishing materials are anionic in character and include small amounts of soluble material. Thus, insoluble sodium metaphosphate may be formed in any suitable man ner, as illustrated by Thorpe's Dictionary ofApp/ied Chemistry, Volume 9,4th Edition, pp. 510-511. 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 metaphosphate, may be reduced by washing with water if desired The insoluble alkali metal metaphosphateistypically-employed in powder form of a particle size such that no more than about 1% of the material is larger than 37 microns.

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

In the preparation of tooth powders, 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-defined oligomer should be compatible with the other components of the composition. Thus, in a toothpaste, the liquid vehicle may comprise water and humec tanttypically in an amount ranging from 10% to 90 /O by weight of the preparation. Glycerine, propylene glycol, sorbitol, or polyethylene glycol 400 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, from 3% to 30O/o by weight of water, up to 80% by weight of glycerine, and from 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 a amount up to 10% by weight, preferably in the range of 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.

and aluminium or lead tube.

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

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

Organic surface-active agents may be used in the compositions of the present invention to achieve increased prophylactic action, and assist in achieving thorough and complete dispersion of the anticalculus agents throughout the oral cavity. The organic surface-active material is preferably anionic, nonionic or ampholytic in nature, and it is preferred to employ as the surface-active agent a detersive material which imparts to the composition detersive and foaming properties.Suitable examples of anionic surfactants are water-soluble fatty acid monoglyceride monosulphates such as the sodium salt of the monosulphated monoglyceride of hydrogenated coconut oil fatty acids, alkyl sulphates such as sodium lauryl sulphate, alkyl aryl sulphonates such as sodium dodecyl benzene sulphonate, alkyl sulphoacetates, fatty acid esters of 1,2 dihydroxy propane sulphonate, and substantially saturated higher aliphatic acyl amides of lower aliphatic amino carboxylic acid compounds, such as those having 12 to 16 carbons in the fatty acid, alkyl or acyl radicals. Examples of the last mentioned amides are N-lauroyl sarcosine, and the sodium, potassium, and ethanolamine salts of N-lauroyl, N-myristoyl, or N-palmitoyl sarcosine which should be substantially free from soap or similar higher fatty acid material.

The use of these sarcosinate compounds in dentifrice compositions of the present invention is particularly advantageous since these materials exhibit a prolonged and marked effect in the inhibition of acid formation in the oral cavity due to carbohydrate breakdown in addition to exerting some reduction in the solubility of tooth enamel in acid solutions.

Examples of water-soluble nonionicsurfactants are condensation products of ethylene oxide with various reactive hydrogen-containing compounds reactive therewith having long hydrophobic chains (e.g. aliphatic chains of from 12 to 20 carbon atoms), which condensation products ("ethoxamers") contain hydrophilic polyoxyethylene moieties, such as condensation products of poly (ethylene oxide) with fatty acids, fatty alcohols, fatty amides, polyhydric alcohols (e.g. sorbitan monosterate) and polypropyleneoxides (e.g. "Pluronic" materials PLURONIC is a trade mark).

In certain forms of this invention a fluorineproviding 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 ingredients 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 fluorosiiicate, 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, 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 oral composition, such as toothpaste or tooth powder, an amount of such compound which releases a maximum of 1% by weight of the composition 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 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 about 0.76%.

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 0.5%, by weight, of fluoride ion.

Various other materials may be incorporated in the oral compositions of this invention such as whitening agents, preservatives, silicones, chlorophyll compounds, other anticalculus agents, antibacterial antiplaque agents, and/or ammoniated material 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 materials are flavouring oils, e.g. oils of spearmint, peppermint, wintergreen, sassafras, clove, sage, eucalyptus, marjoram, cinnamon, lemon, and orange, and methyl salicylate. Suitable sweetening agents include sucrose, lactose, maltose, sorbitol, xylitol, perillartine and saccharine. Suitably, flavour and sweetening agents may together constitute from 0.01% to 5% or more of the composition.

In preparing the oral compositions of this invention, it is preferred but not essential to add the oligomer afterthe other ingredients (except perhaps some of the water) are mixed or contacted with each otherto avoid atendencyforthe antibacterial antiplaque agent, when present, to be precipitated.

For instance, a mouthrinse or mouthwash may be prepared by mixing ethanol and water with flavouring oil, surfactant, humectant, sweetener, colour and then the above-defined oligomer, followed by 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 pol ishing agent, flavour, additional water, and then the above-defined oligomer. If sodium carboxymethyl cellulose is employed as the gelling agent the proce dure of either U.S. Patent Nos. 3,842,168 or 3,843,779, modified by the inclusion of the oligomer, is followed.

In using an oral composition of this invention such as a mouthwash or toothpaste it may be applied regularly to dental enamel, preferably from about 5 times per week to about 3 times daily, at a pH of from 4.5 to 9, generally from 5.5 to 8, preferably from 6 to 8.

The following Examples illustrate the invention.

All amounts and proportions referred to in the Examples and elsewhere in this specification are by weight unless otherwise indicated.

Example I (Part 1-Preparation of OligomerA) The procedure of Example 1 of U.S. Patent No.

3,646,099 is followed, the initial charge to the reactor being 3.129 NaHSO3 (0.03 gFW), 1 59.8g water, and 20.749 acrylic acid (0.288 mol) as the sole monomer, a correspondingly equivalent amount of the (NH4)2S2O8 activator being employed. The ratio of mols of monomerto gFW NaHSO3 is 9.6, and the oligomer, fully neutralized with 5N NaOH at the completion of the reaction, may be represented by the formula

In this case, a in formula I above is zero and b is 9.6 (average). A clear solution is obtained, this Oligomer A having a molecular weight of about 1,000.

Inhibition of Crystal Growth of HAP This is evaluated by a pH Stat method. 1.0 ml of an aqueous solution of 1x10-4M to 1 x 10-5M of the anticalculus agent being tested and 0.1 M sodium dihydrogen phosphate is placed in a reaction flask with 22 to 23 ml of distilled water with continuous stirring in an atmosphere of nitrogen. To this is added 1 ml of0.1M CaCI2 and the pH adjusted to 7At0.05 (final conc. of Ca " and PO43- = 4 x 10-3M).

Consumption of0.1N NaOH is recorded automatically by a pH Stat (Radiometer). In this test, the formation of HAP occurs in 2 distinct phases. First rapid base consumption (1-4 min) then diminishes until 15-20 minutes when second rapid uptake takes place. A delay in the time of second rapid consumption or a total absence of the second rapid consumption indicates an interference with the crystal growth of HAP. Agents which interfere with HAP crystal growth are effective anticalculus agents. When subjected to the foregoing procedure, Oligomer A above is found to delay the formation of the second phase by more than 12 hours, while Acrysol A-5 polyacrylic acid and sodium polyacrylic acid have no effect.

It is thus clear that Oligomer A effectively inhibits the crystal growth of HAP and that the inhibition is not merely due to the complexation or chelation of calcium from the system since the ratio of inhibitor to total calcium is 1:40 to 1:80.

The following Examples illustrate anticalculus mouthwash compositions according to the invention. BC refers to benzethonium chloride, and "Pluronic F108" is a polyalkene oxide block polymer.

Example 2 3 4 5 Flavour 0.22% 0.22% 0.22% 0.22% Ethanol 15.0 15.0 15.0 15.0 "Pluronic F108" 3.0 3.0 3.0 3.0 Glycerine 10.0 10.0 10.0 10.0 Na Saccharin 0.03 0.03 0.03 0.03 OligomerA 0.1 0.2 0.5 1.0 Water q.s. to 100 100 100 100 pH (with NaOH) 7.4 7.4 7 4 7 4 Appearance Clear Clear Clear Clear The following Examples illustrate anticalculus toothpastes according to the invention:: Example 6 7 Silica 30 30 Glycerine 16 16 Sorbitol (70%) 6 6 "Pluronic F-108" 3 3 Hydroxyethyl cellulose 1.2 1.2 OligomerA 2 1 Sodium saccharin 0.17 0.17 Flavour 0.8 0.8 Waterq.s.to 100 100 Significant reductions in calculus are also obtained when Oligomer A in the above Examples is replaced by any of the co-oligomers prepared by the procedures of Examples l-XIII of U.S. PatentsNos.

3,646,099 and 3,859,260 suitably adjusted to yield a co-oligomer of formula I above in which a is0-7 and a- + b is about 4-15.

Example 8 In this study on 16 beagles, a placebo mouthrinse of water at a pH of 7.0 and a 1% aqueous solution of Oligomer A as the test anticalculus mouthrinse are evaluated for effectiveness against formation of calculus for a 6 week period.

16 beagles are given thorough dental prophylaxis in order to remove existing soft and hard deposits.

Disclosing solution is used to ensure that the teeth are free of such deposits. The animals are assigned to two groups of eight animals each. The teeth of one group is sprayed with the placebo and the teeth of the other group is sprayed with the test mouth rinse twice a day, 5 days a week, for 6 weeks. At the end of this period, the teeth are scored for calculus on a scale of 1 to 3, as follows: Scale Calculus Formation 1.0 1/3 of teeth covered with calculus 2.0 2/3 of teeth covered with calculus 3.0 all teeth covered with calculus The following results are found: Mean Calculus per tooth % change Significance placebo 1.50 - Oligomer A mouthrinse 1.01 -32.6 95% * data analyzed by the analysis of variance.

The above results show that a mouthrinse containing Oligomer A is significantly effective in reducing calculus formation.

Example 9 In this study on 20 rats, a placebo of water at a pH of 7.0 and an 0.1% aqueous solution of Oligomer A as the test anticalculus mouthrinse are evaluated for effectiveness against formation of calculus for a 30 day period.

Litter matured Osborne Mendel rats are used.

They are kept on Calculogenic Diet 580F supplemented with 0.2% P as Na2PO4. From 21 days onwards, 100 microlitres of the placebo and of the test mouthrinse are each applied to the molars of a group of 10 such rats daily for a period of 30 days.

The animals are weighed at the beginning and at the end of the studyto ensure that the rats remain in otherwise normal condition. At the end of the period, calculus formation is assessed according to routine procedures and the following results are found: Mean No. Weight Calculus Animals Gain (g) Units Significance placebo 10 128 17.9 OligomerA mouthrinse 10 131 14.9 at99% level The above results establish that a mouthrinse containing OligomerA according to the invention is significantly effective in reducing calculus formation.

The following Examples illustrate the dental stain inhibiting functions of the above-described oligomers.

TABLE II- MOUTH WA SH FORMULATIONS Example Placebo Control 10 11 12 Flavour 0.22% 0.22% 0.22% 0.22% 0.22% Ethanol 15.0 15.0 15.0 15.0 15.0 "Pluronic F108" 3.0 3.0 3.0 3.0 3.0 Glycerine 10.0 10.0 10.0 10.0 10.0 Na saccharin 0.03 0.03 0.03 0.03 0.03 BC - 0.075 0.075 0.075 0.075 OligomerA - - 0.1 0.2 0.5 Water q.s. to 100 100 100 100 100 pH (with NaOH) 7.4 7.4 7.4 7.4 7.4 Appearance Clear Clear Clear Clear Clear Reflectance 55.0 46.0 53.0 54.0 54.0 Reflectance Difference - - 7.0 8.0 8.0 The OligomerA and about 10 parts of the water are added to the other previously mixed ingredients.

Tooth staining characteristics are tested by slurrying hydroxyapatite (Biogel) with salivary protein, acetaldehyde (as carbonyl source) and a pH7 phosphate buffer. The mixture is shaken at 37"C until a light brown colour is formed. Coloured powder is separated by filtration, dried and colour levels (in reflectance units) determined on a "Gardner colour difference meter" beforeandafterthetestformulation is applied to the coloured material.

The above results plainly establish that the oligomers, as exemplified by OligomerA, substantially reduce dental staining ordinarily produced by quaternary ammonium antibacterial antiplaque agents as exemplified by BC. Formulations adjusted to pH5-8 yield similar results. Other orally acceptable salts of Oligomer A yield similar results.

Further, in vitro tests for antiplaque activity against a preformed plaque on teeth (induced by Actinomyces Viscosus) establish the formulation of the Control example (0.075%BC) and a similar formu lation also containing 1.0% of OligomerAto be sub- stantially equal, indicating that these oligomer additives do not significantly affect the antiplaque activity of BC and the like.

Substitution of equivalent amounts of the following antibacterial antiplaque agents for the BC employed in Examples 10-12 yield formulations also producing unexpected reductions in dental staining: Example Antibacterial Antiplaque Agent 13 chlorhexidine diacetate 14 chlorhexidine digluconate 15 dodecyl trimethyl ammonium bromide 16 cetyl pyridinium chloride

18 alexidine dihydrochloride The following formulations exemplify toothpastes with antiplaque activity and reduced staining: : Example (Parts) 18 19 Hydrated alumina 30 30 Glycerine 16 16 Sorbitol (70%) 6 6 "Pluronic F-108" 3 3 Hydroxyethyl cellulose 1.2 Benzethonium chloride (BC) 0.5 Chlorhexidine digluconaje (20%) - 4.725 OligomerA 2 2 Sodium saccharin 0.17 0.17 Flavour 0.8 0.8 Water q.s. to 100 100 Significant reductions in dental staining are also obtained when OligomerA in the above Examples is replaced by any of the co-oligomers prepared by the procedures of Examples l-XIII of U.S. Patent Nos.

3,646,099 and 3,859,260 suitably adjusted to yield a co-oligomer of formula I above in which a is 0.7 and a + b is isabout4-15

Claims (7)

1. An oral composition comprising an orally acceptable vehicle containing as an anticalculus agent at least one water-soluble oligomer of the formula

wherein: M represents a water-soluble orally acceptable cation; R1, R2, R3 and R4 are the same or different and each represents hydrogen, methyl or ethyl; Y is hydrophilic and represents at least one of the groups -COOM1 wherein M, is hydrogen or M, -CONH2 and -CH2OH; X is hydrophobic and represents at least one of the groups-CN,-COOR,-COORsOR,-CONHR and -COONHRsCOR wherein R is C18 alkyl and R5 is C,, alkylene; a is 0-7; and a +b is 4-15.

2. An oral composition as claimed in Claim 1, wherein, in the formula df the oligomer, a is zero, a + b is aboutl0,Yis-COOM1, R1, R2, R3 and R4 are hydrogen and M and M, are sodium.

3. An oral composition as claimed in Claim 1 or Claim 2 containing from 0.01% to 10% by weight of the oligomer.

4. An oral composition as claimed in any of the preceding Claims which also contains at least one nitrogen-containing cationic antibacterial antiplaque agent in the proportion of up to 15% by weight based on the free base form thereof.

5. An oral composition as claimed in Claitn4-con- taining at least 0.001% by weight of the antiplaque agent.

6. An oral composition as claimed in Claim 1, substantially as described in any of Examples 2 to

7.

6. An oral composition as claimed in Claim 4containing from 0.0f% to 5% by weight of the antiplaque agent and whereinthe oligomeris present in a molar ratio relative to the antiplaque agent of from 0.2:1 to 6:1.

7. An oral composition as claimed in any of Claims 4 to 6 wherein the antiplaque agent is chlorhexidine or alexidine.

8. An oral composition as claimed in any of Claims 4 to 6 wherein the antiplaque agent is benzethonium chloride.

9. An oral composition as claimed in any of Claims 4 to 6 wherein the antiplaque said agent is cetyl pyridinium chloride.

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

11. An oral composition as claimed in any of Claims 1 to 9 wherein the vehicle comprises a liquid and a gelling agent, a dentally acceptable polishing material is present, and which is a toothpaste of pH in the range from 4.5 to 9.

12. An oral composition as claimed in Claim 1, substantially as described in any of Examples 2 to 7 and 10 to 19.

13. Amethod of improving oral hygiene comprising applying to the oral cavity an effective amount of an oral composition as claimed in any of the precede ing Claims.

New claims or amendments to claims filed on

16.8.79. Superseded claims 1-13. New or amended claims 1-6.

1. An oral anticalculus composition comprising an organiosurface active material which is anionic', nonionic or ampholytic in nature and an orally acceptable vehicle and containing at least one water-soluble oligomer of the formula

wherein:: M represents a water-soluble orally acceptable cation; R1, R2, R3 and R4 are the same or different and each represents hydrogen, methyl or ethyl; Y is hydrophilic and represents at least one of the groups -COOM, wherein M, is hydrogen or M, -CONH2 and -CH2OH; X is hydrophobic and represents at least one of the groups -CN, -COOR, -COORsOR, -CONHR and -COONHRsCOR wherein R is C18 alkyl and R5 is C1 aikylene; a is 0-7; and a +bis4-15; the composition being devoid of any nitrogencontaining antibacterial antiplaque agent.

2. An oral composition as claimed in Claim 1, wherein, in the formula of the oligomer, a is zero, a + b is about 10, Y is -COOM1, R1, R2, R3 and R4 are hydrogen and M and M, are sodium.

3. An oral composition as claimed in Claim 1 or Claim 2containingfrom 0.01%to 100/o by weight of the oligomer.

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

5. An oral composition as claimed in any of Claims 1 to 3 wherein the vehicle comprises a liquid and a gelling agent, a dentally acceptable polishing material is present, and which is a toothpaste of pH in the range from 4.5 to 9.