CA1150151A - Oral compositions containing 2-phosphono -butane-1,2,4-tricarboxylic acid - Google Patents

Abstract

ABSTRACT

An oral composition effective to promote oral hygiene containing a 2-phosphono-butane-1,2,4-tricarboxylic acid compound or an orally acceptable salt thereof as an anti-calculus agent and, in combination with normally staining antibacterial, antiplaque agents, as an antistain additive to reduce such staining.

Description

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This inventlon relates to oral compositions containing an anticalcul~s agent~
Calculus is a har~, mineralized formation which forms on the teeth. Regular brushing prevents a rapid ; 5 build-up of these deposits, but even regular brushing is not sufficien-t 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 ma-trix of the dental plaque and become sufficiently closely packed together for the `aggregates to become resistant to deforma~lon. There is no complete agreement on the route by which calcium and orthophosphate ultimately become the c:rystalline material - oalled hydroxyapatite (~AP). It is generally agreed, however, that at higher satura-tions, 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, ., 0 particle morpholo~y, 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.
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A suggested mech~mism by which the anticalculus agents 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 hydroxyapati~e.
` Studies have shown that there is a good correlation between the ability of a compound to preven~ hydroxyapatite crystalline growth in vitro and its ability to prevent :`
~ calcification in vivo.
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;~ 10 Cationic nitrogen-containing antibacterlal materials are well known in the art. See, for instance the section on "Quaternary Ammonium and Related Compounds" in ~he articLe on "Antiseptics and Disinfectants" in Kirk-Othmer Encyclopedia : .:
`~ of Chemical Tec}mology, second edition ~Vol. 2, pp. 632-635).
Cationic materials which possess antib3cterial activity ~i.e. are germicides) are used against bacteria and have been used in oral compositions to co~mter pIaque formation caused by bacteria in the oral cavity.
Among the most common of these antibacterial anti-plaque quaternary ammonium compounds is benzethonium chloride, also known as Hyamine* 1622 or di-isobutylphenoxy-ethoxyethyl dimethyl benzyl ammonium chloride. In an oral preparation this material is highly effective in promoting oral hygiene by reducing formation of dental plaque and *Trademark - 3 -~1 Sl calculus, which is generally accompanied by a. reduction in caries :~o~mation and periodontal diseaseæ~ Other cationic antibacterial agents o~ this type are those mentioned, -for instance, in U.S. Patent Nos. 2,984~639, 3,3259402, 3,431,208 and 3,703~583 and British Patent ~o. 1,319,396.
;~- Other antiba.cterial anti-plaque ~uate rnary ammonium compounds lnclude those in which one or two of the sub-stituents on the quaternary nitrogen has a carbon chaln length (typically alkyl group~ of some ','',' ..
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~ ~o 20, ty~ically 10 to 18, carbon atoms while the remainillg substituellts have a lower number of carbon atollls (typically alkyl or benzyl group), such as 1 to 7 caLbon atoms, typically methyl or ethyl groups. Dodecyl trimetllyl ammonium bromide, dodecyl dimethyl ~2-- phenoxyethyl) ammonium bromide, benzyl dimethyl st.earyl ammollium chloride, cetyl pyridinium chloride and , ~lu.lterni7.e~1 5-amino-1,3-bis (2-ethyl-hexyl)-5-methyl ;
hexa hydro~)yrimidine are exemplary of other typical l~ clu;lterllary allllnollium antibacterial agents.

Other types of cationic antibacterial agents which are desirably incorporated in oral compositions to promote oral hygiene by reducing plaque formation are ` the amidines such as the substituted guanidines e.g.
lS chlorhexidine and the corresponding compound, alexidine, havin~ 2-ethylhexyl groups instead of `~ chlorophenyl groups and other bis-biguanides such as those described in German patent application No. P
~; 2,332,383 published ~anuary 10, 1974, which sets forth the ~ollowing formula:

1~ NEI N~l NH N~ R ' A- tX) z-N C-NH-C-NH (C1~2) n-NH-~-NH-C- N- (X ' ) zl A' in whicl- 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 12C-atoms, or ~3) alicyclic groups with 4 to about 12C-atoms, X and X' as the case may be may represent an alkylene radical with 1-3C atoms, z and ; z' are as the case ~'.' .
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may be eithec zero or 1, R and R' as the case may be may répresent either hydrogenr an alkyl radical with 1 to about 12C-atollls or an aralkyl radical with 7 to about 12C-atoms, n is a whole number of 2 to inclusively 12 ancl 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-chloroben7yl)-N5-(2,4-dichlorobenzyl) biguanide; p-chlorobenzyl biguanide, 4 chlorobenzhydryl guanylurea;
N-3-lauroxypropyl-N -p-chlorobenzyl biguanide; 5,6-dichloro-2-guanidobenzimidazole; and N-p-chlorophenyl-N -laurylbiguanide.

The long chain tertiary amines also possess

2~ antibacterial and antiplaque activity. Such an~ibacterial agents include tertiary amines having one fatty alkyl group (typically 12 to 18 carbon atoms) and 2 poly(oxyethylene) groups attached to the nitrogen :
- (typically containing a total of from 2 to 50 ethenoxy groups per molecule) and sal~s thereof with acids and compounds of the structure:

/(CH2CH20)zH (CH2CH20)XH
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where R is a fatty alkyl group containing 12 to 18 carbon atoms and x, y and 2 total 3 or higher, as well as salts thereof. Generally, cationic agents are preferred for their antiplaque ef~ectiveness.
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~lh~ ~n~ibact~Li~l antiplaque compound is preferably one which has an antibacterial activity such ~h~l~ its phel)ol co-e~ficient 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.~.C.) of benzethonium chloride is given by the manut`acturer as 410, for S. aureus. The cationic antibacterial agent will generally be a monomeric (or ~, ~ o~
-~ possibly dimeric) materia~ ~olec~lar weight well below 2,000, such as less than about 1,000 It is, however, within the broader scope o~ the invention to employ a polymeric cationic antibacterial agent. The c:ationic antibacterial is pref~rably supplied in the form of an orally acceptable salt thereof, such as the chloride, bromide, sulfate, alkyl sulfonate such as methyl sul~onate and ethyl sulfonate, phenylsulfonate, such as I
; . p-methylphenyl sulfonate, nitrate, acetate, gluconate, etc.

The nitrOgen-CQntaining 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 sur~aces 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 PO4 3 ions.
~ In the absence of dental plaque additional Ca+2 and PO4 3, - particularly from saliva, can be deposited on the enamel and such deposits can include color ~odies which ultimately stain the tooth enamel as a calcified deposit thereon. It can be that as the cationic or long chain tertiary amine antibacterial agents remove plaque they also denature protein from saliva -in the oral environ-ment and the denatured protein can then act as a nucleating agent which is deposited on and stains or discolors tooth enamel.
P~eviously employed additives which reduced dental staining by cationic antibacterial antiplaque agents also generally reduced the activity - of antibacterial antiplaque agents such as bis-biguanido compounds, as by forming a precipitate with such agents.
; 10 In accordance with certain of its aspects, this invention relates to an oral composition comprising an orally acceptable vehicle containing approximately by weight GoOl% to 10% of a 2-phosphono-butane-1,2,4-tricarboxylic acid (PBTA) compound of the formula ':~. O CH2-COOH
HO ¦¦ ¦
(I~ \ P-C - COOH
HO ¦ R
R-CH- ff H-COOH
~ wherein R is hydrogen, lower alkyl or carboxyl, and R is hydrogen or methyl, or an orally acceptable salt thereof, preferably water soluble, such as with ~ an alkali metal (e.g. sodium and potassium), ammonium, Cl-C18 mono-, di- and ; tri-substituted ammonium (e.g. alkanol substituted such as mono-, di- and tri-ethanolammonium) cation, and 0 to 15% of at least one normally staining nitrogen-containing antibacterial antiplaque agent based on the free base form of said agent.
Compounds of the above formula, and methods Eor their production are disclosed in United States Patent Nos. 3,886,204 and 3,886,205. The preferred PBTA compound for use in the present invention is the unsubstituted compound of the above formula (I) in which R and p~l are each hydrogen. When R is lower alkyl, it preferably contains 1 to 4 carbon atoms, especially methyl.

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:~ The concentration ~ the PBTA compound (or salt) in the oral composition~ can range widely, typically upward ~rom about O.01~ by weight, with no upper limit on the amount that can be utilized except as dlctated by cost or incompatibility with the : "

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vehicle. Generally, concentrations of ab~ut 0.01~ to about 10~ and preferably about .1% to 6% by weight are utilized Oral compo~itions which in the ordinary course of usage could be accldentally inge~ted pre~erabl~ contain lower - 5 concentrations of the P~TA compound Thus~, a mo~thwash in accordande with this invention preferably contains less than about 2 weight ~ o~ the PBTA compound, preferably about 0.1 - 1.5 wt. ~. Other dentifrice compo~itions, topical solutions and prophylactic pastes~ the latter to be administer-IO ed profesgionally~ can preferably contain about 0.1 to 3 weight % o~ the PBTA compound.
The PBT~ compounds of this invention are anti-nucleating agents, oral composition~ of this invention con-taining them are effective in reducing formation of dental . .
calculus without unduly decalcifyin~ the dental enamel3 and in contrast to the above descrlbed nltrogen-contalning anti-bacterial, antip~aque agents, such PBTA compounds and - ~ compositions have little or no tendency to stain the teeth, in addition to e~fectively inhibiting gingivitis.
It is a further advantage of this lnvention th&t these anti-nucleating antlcalculus PBTA compounds unexpect-edly inhibit, l e. prevent or remove, the staining of dental enamel caused by the above-described nitrog~n-contalning antiplaque, antibacterial agent~ without preclpit&ting or substantially adversely a~ectlng their antibacterial and antiplaque activity. Not all anti-nucleatirig agents are effective t~ prevent ~tainlng by such antibacterial agents.
Victamide (also known as Victamine C) which is a condensa-tion product of ammonia with phosphoruspentoxide, actually ; ~ 30 increase~ staining even ln the absence of such antibacterial ' agents.

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~8-When pre~ent, these normally staining antibacter-i~l antiplaque agents are typically employed in normally effective amountsg e.g., such that the ora]. product contAins between about 0.001 and 15~ by weight thereof. Preferably : 5 for desired levels o~ antiplaque efrect, t~le ~inished oral .

product contains about 0.01 to about 5%, and most preferably ~.~ ab~ut 0.25 to 1.0% by weight of the antibacteria.l antlp~que .~ . agent, re.ferring to lts free base form. Most de~irably the ; PBTA compound is present in a molar exce~s relative to the : 10amount of antlbacter~al antiplaque agent (based on it~ ~ree ., .
:~ base form) in order to best minimize~ inhibit or prevent staining.
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ln certain highly preferred forms of the invention the oral composition may be substan~ially liquid in character, -~ such as a mouthwash or rinse. In such a preparation the ~ vehicle is typically a water-alcohol mixture desirably . .
including a humectan-t as described below. Generally, the ratio of water to alcohol i6 in the range of ~rom about 1l1 to a~out 20~1, pre~erably about 311 to lOsl and most preferably about 411 to about 5-1, by weight. The to-tal amount o~ water-.:
alcohol mixture in this type o~ preparation is typically ~.
in the range of from about 70% to about 99.9% by weight of the preparation. The pH of such liquid and other preparations ~` of the inverltion i5 generally in the range o~ from ~bout 4.5 .
to about 9 and typically ~rom about 5.5 to 8, The pH is prererably in the range of from about 6 t~ about 8,0, It is noteworthy that the composi-tions of the invention may . ., ~ be applied orally at a pH below 5 without substan-tially `~ decalcifying dental enamel. The pH can be controlled with acid (e.g. citric acid or benzoic acid) or base (e.g.
sodium hydroxide) or buffered (as with phosphate buffers).
Such ~liquid oral preparations may also oontain 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 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 materials are water-insoluble sodium metaphosphate, potassium metaphosphate, -tricalcium phosphate, dihydrated calcium phosphate, anhydrous dicalcium phosphate, calcium pyrophosphate, magnesium orthophosphate. trimagnesium , ~ -~s~

Phospha.te, calclum carbonate~ alumina~ hydrated alumina, :` aluminum silicateg zirconium silicate, silica, bentoniteg .. and mixtures thereof~ Preferred polishing materials include silica gel or colloidal silica~ complex amorphous alkali ~ 5 metal aluminosilicate and hydrated al~ina.
: Alumina, particularly the hydrated alumina sold by Alcoa as C333, which has an alumina content of 64.9~ by weight, a silica content of o.oo8~, a ferric oxide content o~ 0.003~, and a moisture content o~ 0 37%, at 110C., and which has a specific gravity of 2 ~2 and a particle slæe such tha.t 100 : of the particles are 1~9s than 50 microns and 84% o~ the particles are less than 20 microns, is very erfective.
When visually clea.r antlcalculus gels are employed, a polishing agent of colloidal siIica, ~uch e~s those sold under the trademark SYLOID as Syloid 72 and Syloid 74 or under the trademark SANTOCEL as Santocel 100 and alkali metal alumino-silicate c~mplexes 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. For similar reasons~ alkali metal aluminosilicate complexes are particularly useful as polishing agents in visually clear gels contalning the PBTA
compound in comblnation with the described nitrogen-containing antibacterial antiplaque agents~
Many o~ the so-called "water-insoluble" polishing : materials are anionic in character and also include small amounts of soluble material. Thus, insoluble sodium meta-phosphate may be formed in any sultable manner, as illustrat-ed by Thorpe's ~lctionary of A~lied Chemistry, Volume 9, 4th Edition, pp. 510 - 511. The forms of insoluble ~ r~

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;odium metaphosphate kno~l ~s Madrell~s sal-t an~ 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 metaphosphatcs. There is present therein a minor amount of soluble phosphate material as impurities, usually a - ~ew percent such as up to 4yO by weight. The amount ofsoluble phosphate material, whic~ is believed to include a soluble sodium trimetaphosphate in the case of insoluble ~etaphosljhate~ may be reduced by washing with wa-ter if desired. The insoluble al}cali metal metapho~phate .is typicc~lly employed in powder form of a particle~size such that no more than about 1% of the material is larger than about 37 microns.
The polishing material is general].y present in amounts ranFin~ from about lO~ to about 99% by weight of the oral preparation. Preferably, it is present in amounts ranging from about lO~ to about 7~ in toothpaste, and from about 70~0 to about 99% in toothpowder.
In the preparation of toothpowders, i-t is usually sufficient -to admix mechanically, e.g., by milling, the various solid ingredients in appropriate quantities and particle sizes.
In pasty oral preparations thc PBTA compound should be compatible with the other components of the preparation, Thus, in a too-thpastej the liquid vehicle may comprise water and humectant typically in an amoun-t ranging fram about 10% to about 90% by weight of the preparation. Glycerine, propylene glycol, sorbitol, or polyethylene glycol 400 may also be present as humectants or binders. Particularly advantageous liquid in~redients comprise mixtures of water, glycerine and sorbitol.
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In clear gel~ where the refractive index ls ~n important consideration, about 3-30% by we.ight of water, O to about 80~ by weight of glycerine, and about 20 - 80 by weight of sorbitol is preferably employed. A gelling agent~ such as natural or synthetic gums or gum-like mater-ials, typically Irish~moss~ sodium carboxymethylcellulose, methylcellulose~ hydroxyethylcellulose~ hydroxypropylmethyl-cel1ulose, the Carbopols(e g., 934, 9~0 and 941), gum tragacanth, polyvinylpyrrolidone or starch or mixtures there-of or the like is usually pres~nt in toothpaste ln an ~nountup to about 10% by weight, pre-~erably in the range of ~:r.om about 0.5~ to aOout 5%. In a toothpaste or gel3 the liquids and solids are proportioned to ~orm a creamy or gelled mass which is extrudable from a pressurized container or ~rom a collapsible, e.g., aluminum or lead, tube The solid or pasty ora.l preparation whlch typically has a pH measured on a 20~ slurry o~ about 4.5 to 9, generally about 5.5 to about 8 and pre.~erably about 6 to about 8.o, may also contain a surface active agent and/or a ~luorine-providing compound.
It will be understood that, as is conventiona.l, : the oral preparatlons are to be sold or otherwise distrubuted in suitable labelled packages. Thus a ~ar o~ mouthrinse will have a label describing it, in substance~ as a mouth-rinse or mouthwash and having dlrections .~or its use; and a toothpaste will usually be in a collapsible tube, typically aluminu~, lined lead or plastic, or other squeeze dispenser for metering out the contents, having a label describing it, in substance, as a toothpaste or dental cream.

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1~ S~S:l - ~rganic surf'ace-ac-tive a~ents are used in the composi-tions of the present invention to achieve increased prophylactic action, assist in achieving thorough and complete dispersion of the PBTA ' agent -throughout the oral cavity, and render the instant compositions more cosmetically acceptable. The organic surface-ac-tive ma-terial is preferably anionic, nonionic or ampholytic in nature, and it is preferred to employ as the surface active agent a de-tersive material which imparts to the composition detersive and foaming properties. Suitable examples of anionic surf.~ctants are water-soluble salts of higher. fatty acid mono~lyceride monosulfates, such as the sodium salt of the monosulfated monoglyceride of hydrogenated coconut oil fatty acids, higher alkyl sulfates, such as sodium lauryl ~ 15 sulfate, alkyl aryl sulfonates, such as sod.ium dodecyl benzene sulfonate, higher alkyl sulfoace-ta-tes, higher fatty `~ acid esters of` 1,2 dihydroxy propane sulfonate, and the substantially saturated higher aliphatic acyl amides of lo'wer aliphatic amino carboxylic acid compounds, such as : 20 those having 12 to 16 carbons in the f'at-ty acid, alkyl, or acyl radicals, and the like. Examples of the last mentioned amides are N-lauroyl sarcosine, and the sodium, potassium, and ethanolamine salts of N-lauroyl, N-myris-toyl, or N-palmitoyl sarcosine which should be substantially ~ree from soap or '~ 25 similar higher fatty acid material. The use of these s~-~rcosinate compounds in dentif'rice compositions of the present invention is particularly advantageous since these materials exhibit a prolonged and marked effect in the inhibi-tion of acid formation in the oral cavity due to carbohydrate breakdown in addition to exerting some reduction in thc solubility of tooth enamel in acid solutions.

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~xample~, of water--soluble nonionic surfactants are condensat,iorl products o~ ethyl~ne oxide wl th variou~ reactiv~
hydrog~n-containin~ compounds reactive therewith having long hydrophobic chains (e,~, alipha-tic chains of about 12 to 20 S carbon a-toms), which condensation products ("ethoxamers") contain hydrophilic polyoxyethylene moieties, such as condensation products of poly (ethylene oxide) with fatty acids, fat-ty alcohols, Xatty amides~ polyhydric alcohols (e.g. sorbi-tan monos-~arate)and polypropyleneoxide (i,e, - ~ 10 Pluronic ma-terials).
~ In certain forms of this invention a fluorine- ' providing compound is present in the oral preparation, I
These compounds may be slightly soluble in water or may be fully water-soluble, They are characterized by their ~, abili-ty to release fluoride ions in water and by substantial freedom from reaction with other compounds of -the oral prepara-tion~ Amon~ these materials are inorganic fluoride salts, such as soluble alkali metal~ alkaline earth me-tal and heavy metal salts, for example, sodium fluoride, I
potassium fluoride, ammonium fluoride, a copper fluoride such as cuprous fluoride, zinc fluoride, a tin fluoride such as stannic fluoride or stannous chloro-fluoride, barium fluoride, sodium fluorsilicate, ammonium fluorosilicate, sodium fluorozirconate, sodium monofluoro-phosphate, aluminum 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, 3Q The amount of the fluorine-providing compound is dependent to some extent upon the type of compound, its solubility, and the type of oral preparation, bu-t it must Tf~de /i1ar,K

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bc a non-toxic amo-lnt. In a solid oral preparation, such as toothpa~te or toot}lpowder, an amount of such compound which releases a maximum of abou-t l~o by weight of the preparation is considered sa-tisfactory. Any suitable minimum c~nount of such compound may be used, but it is prt~fer.lbly to cmF)loy sufficient compound -to release about 0.005~ to 1~" and prefcrably about O.l~o of fluoride ion.
Typica11y, in -the cases of a~kali metal fluorides and stannous iluoride, this componen-t is present in an amount up to abou-t 2~ by weif~)lt, based on -the weight of the preparation, and preferab1y in the range of about 0.05~0 to 1%. In the cac,e ol~ sodium mono~luorophospha-te, the eompound may be present in an amoun-t up to 7.65~ by weigh-t, more typlcally abollt o.7G%.
~; 15 In a liquid oral preparation such as a mouthwash, -the fluorine-providing compound is typically present in an amount sufficient to release up to about 0,13%, preferably abou-t 0.0013% to 0.1% and most preferably about 0,0013% to 0.5~, by weight, of fluoride ion, Various other materials may be incorporated in the oral prepara-tions of this invention such as whitening agents, preservatives, silicones, chlorophyll compounds, ~; otheF anticalculus agents, antibacterial antiplaque agents9 and/or ammonia-ted material such as urea, diammonium phosphate, and mixtures thereof, These adjuvan-ts, where present, are incorporated in the preparations in amounts which do not substantially adversely affect the properties and characteristics desired.
~ny suitable flavoring or sweetening material may also be employed. Examples of ' 1L5~

suitable flavoring constituents are ~lavorlng oils, e.g., oil of spearmint, peppermint, wintergreen, sassa~ras~ clove, sage, eucalyptws, mar~oram, cinnamon, lemon, and orange, and methyl salicylate. Suitable sweetening agents include sucrose~ lactose, maltose, sorbitol, xylitol, sodium cycla-mate, perillartine, APM (aspartyl phenyl alanine, methyl ester) 3 saccharine and the like. Suitably, ~lavor and sweetening agents may together comprise ~rom about 0.01% to 5~ or more o~ the preparat~on.
In preparing the oral compositions of this invention, it 1s preferred but not essential to add the PBTA after the other ingredients (except perhaps some o~ the water) ars mixed or contacted with each other to avoid a tendency ~or the PBTA to be precipitated.
For instance, a mouthrinse or mouthwash may be prepared by mixing ethanol and water with flavoring oil, surfactant~ humectant, optional antibacterial antiplaque agent, such as cetyl pyrid1nium chloride, benzethonlum chloride or chlorohexidine~ swee~ener~ colo-r and then the above-de~ined PBTA compound followed by additional water as desired.
A toothpaste may be prepared by ~orming a gel with humectant, gum, thickener or gelling agent such as hydroxy-ethyl cellulose, sweetener and adding thereto polishing ag0nt3 flavor, optional antibacterial antiplaque agent~
additional water, and then the above-defined PBTA compound.
~f sodium carboxymethylcellulose is employed as the gelling agent together with a bis-biguanide type antibacterial .

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antiplaque agent~ the procedure of ei-ther.U.S. Patent No.

3,84~168 or U.S. Patent No. 3~843,7793 modi:fied by the inclusion of the PBTA compound i~ followed.
In the pra,ctice o' this invention an oral composi-tion according to this invention such as a mouthwash or toothpaste is applied regularly to dental ena,mel, preferably from about 1 to about 3 times daily, at a pH of about 4.5 to about 9, generally about 505 to about 8, preferably about - 6 to 8.
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The follo/in~ exaulpleo are further illu trative of t;he naturc of the present inventiQn, but it i~ understood that tlle invention i6 no-t limited thereto. All amounts and lroportions referred to herein and in the appended claim~ are by weight unless otherwise indicated. I

1, ll) This is evaluated by a pH Stat method. 1.0 ml an nqucou3 solution of lX10 4M to lX10 5M of the anti-calculus agent being tested and O.l M sodium dihydrogen phosphate is placed in a reaction flask with 22 to 23 ml.
o~ distilled water with continuous stirring in an atmosphere Or nitrogen. To this is added 1 ml. o~ O.lM CaCl2 and the pH adjusted -to 7.4 ~ 0.05 with NaOH (final conc. of Ca and ; Pol~3 =4X10 3~). Consumption of O.lN NaOH is recorded automa-tically 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 }~P. Agents which interfere with HAP
crystal growth are effective anticalculus agents. When PBTA is tested by the foregoing procedure, the following results are obtained.

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TABLE I

Anticalculus Time for Delay in Agent (conc)HAP Formation HAP Formation ~` Water (control~15 min. --PBTA ~4 ppm) 25 min. 10 min.
PBTA ~8 ppm) 75 min. 60 min.
`-~ PBTA (10 ppm)129 min. 114 min.
:~ PBTA (20 ppm)33.8 hrs.

... The above results show that PBTA effectively inhibits crystal . 10 growth of HAP in vitro and that the inhibition is not due to complexation or chelation of calcium since sub-stoichiometric ratios of PBTA:calcium ~; are employed.
; In the following examples illustrative of mouthwash formulat~ons ~ according to the invention~ Pluronic F108 is a polyalkylene oxide block ;~ polymer and a Trade Mark.
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2 , 3 4 5 .
;~ Flavor 0.22% 0.22% 0.22% 0.22%
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; Ethanol 15.0 15.0 15.0 15.0 Pluronic F108 3.0 3.0 3.0 3.0 ~i Glycerine 10.0 10.0 10.0 10.0 ~:: Na Saccharin 0.03 0.03 0.03 0.03 PBTA 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 ~lear... . Clear , , . . .

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The following examples are illustrative of anticalculus tooth-pastes according to the invention:
Example 6 Silica 30 Glycerine 16 Sorbitol ~70%) 6 Pluronic F--108 3 Hydroxyethyl cellulose1.2 Sodium saccharin 0.17 Flavor 0.8 Water q.s. to 100 Table II below is illustrative of mouthwash formulations according to the inven~ion and the antistaining activity of the preferred PBT~ additive therein. The tooth staining characteristics of the formulations are evaluated by slurrying hydroxyapatite ~Biogel), a specific salivary protein, a carbonyl source ~e.g. acetaldehyde)l and a pH 7 phosphate buffer, with and without the mouthwash formulations being tested. The mixture is shaken at 37C. for 18 hours. The colored HAP powder is separated by filtration, dried and the color levels ~in reflectance units) determined on a Gardner color difference meter.

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., Sl 1. Polyal~ylene oxide block polymer 2. Cetyl pyridinium chloride.
The above results plainly establish that the additives of the present inven~ion, as exemplified by PBTA, substantially reduce dental staining ordinarily produced by antibacterial antiplaqu~ agents as exemplified by CPC. A PBTA concentration of about 1.0% appears to yield excellent results. Such additives also reduce or inhibit calculus m gingivitis and do not significantly reduce the antiplaque activity ; 10 of the indicated antiplaque agents.
Substitution of equivalent amounts of the following anti-- bacterial antiplaque agents for the CPC employed in Examples g -13 yield formulations also producing an unexpected reduction in dental staining and calculus.

Example tibacterial Antiplaque Agent 14 benzethonium chloride (BC) chlorhexidine diacetate 16 chlorhexidine digluconate 17 dodecyl trimethyl ammonium bromide 2CH2H ~ C~l2CH2OH
C12 18 Alkyl-N-CH2CH2N ~ CH CH OH

19 alexidine dihydrochloride ., ' ''~.

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' 1 . . .

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`- ~15~151 The follo~ing formulations cxemplify toothpastcs with antiplaquc activity and recluced stainin~ and calculus.

Example (Parts~
~; 20 21 22 I{ydrated alumina 30 30 30 , , Polyethylene glycol 600 22 22 22 : Pluronic F-108 3 3 3 ~Iydro~ypropyl methyl cellulose 1.2 1.2 1.2 ~ ~ BC o.5 __ __ ::~ lO Hibitane -~ 4.725 --. j CPC 0 5 ;: I .
PBTA 1~0 1.0 1.0 :~ , ~ Sodium saccharin 0.17 0.170.17 .~ FIavor 0.8 0.8 0.8 ,` y. ~.
~ Water_~_s~ to lO0 ~ 100 100 ~-, , ,` Signi~icant reductions in dental staining, plaque, calculus ~3~ and gingivitis are also obtained according to the present invention ~j when the PBTA in the above e~amples is replaced by any of the , other PBTA compounds disclosed in United States Patent No. 3~886,20 and 3,886,205.
: This invention has been described with respect to pre-ferred embodiments and it will be understood that modifications and variations thereof obvious to those skilled in the art are to be included within the spirit and purview of this application and the scope of the appended claims.

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Claims (12)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. An oral composition comprising an orally acceptable vehicle con-taining approximately by weight 0.01% to 10% of a 2-phosphono-butane-1,2,4-tricarboxylic acid compound of the formula wherein R is hydrogen, lower alkyl or carboxyl, and R1 is hydrogen or methyl, or an orally acceptable salt thereof, and 0 to 15% of at least one normally staining nitrogen-containing antibacterial antiplaque agent based on the free base form of said agent.

2. The oral composition of Claim 1 wherein R and R1 are hydrogen.

3. The oral composition of Claim 1 wherein said antibacterial anti-plaque agent is cationic and is present in an amount of at least about 0.001%
by weight.

4. The oral composition of claim 1, 2 or 3 wherein said compound is present in an amount of about 0.1% to about 6% by weight.

5. The oral composition of Claim 1, 2 or 3 wherein said antibacterial antiplaque agent is a substituted guanidine.

6. The oral composition of Claim 1, 2 or 3 wherein said antibacterial antiplaque agent is a pharmaceutically acceptable water soluble salt of an agent selected from the group consisting of chlorhexidine and alexidine.

7. The oral composition of Claim 1, 2 or 3 wherein said antibacterial antiplaque agent is benzethonium chloride.

8. The oral composition of Claim 1, 2 or 3 wherein said antibacterial antiplaque agent is a quaternary ammonium compound containing 1 to 2 alkyl groups of 8 to 20 carbon atoms.

9. The oral composition of Claim 1, 2 or 3 wherein said antibacterial antiplaque agent is cetyl pyridinium chloride.

10. The oral composition of Claim 1, 2 or 3 wherein said vehicle is an aqueous-alcohol and said composition in a mouthwash of pH of about 4.5 to about 9.

11. The oral composition of Claim 1, 2 or 3 wherein said vehicle com-prises a liquid vehicle and a gelling agent and a dentally acceptable polish-ing material is present and said composition is a toothpaste of pH of about 4.5 to about 9.

12. The oral composition of Claim 1, 2 or 3 containing about 0.01 to about 5.0% by weight of said agent.