CA2151815A1 - Oral compositions containing antiplaque, anticalculus agents - Google Patents

Abstract

This invention involves oral-care compositions, comprising: (a) zinc oxide or zinc nitrate; a source of citrate ions; and one or more phosphorous-containing anticalculus agents selected from the group consisting of pyrophosphate, phosphonate, diphosphonate and pharmaceutically-acceptable linear condensed polyphosphates of the general formula: (PnO(3n+1)(n+2)- wherein n is an integer from 2 to 21;
wherein the molar ratio of the zinc ions:citrate ions if from about 1.01 to about 1:20; the molar ratio of the zinc ions:phosphorous-containing anticalculus agents is from about 1:1 to about 1:20; and (b) a pharmaceutically-acceptable topical oral carrier. This invention also involves methods for treating or preventing dental plaque, calculus, gingivitis, or malodor of the oral cavity comprising amdinistering to the oral cavity of a human or other animal a safe and effective amount of such compositions.

Description

2~5181~
~0 94/14406 PCT/~JS93/11786 ORAL COMPOSITIONS CONTAINING
ANTlPLAQUE, ANTICALCULUS AGENTS

This invention relates to oral colllposilio"s, such as dentifrices and oral solutions, for the treatment or prevention of dental plaque, calculus, gingivitis, and mouth malodor.
Backqround of the Invention The mouth is a habilat for microbial growth and colonization.
Within the mouth, the gums, lips, oral mucosa (cheek), palate, tongue and teeth provide surfaces for the cclo~ dliGn and accumulation of bacteria. Teeth are unique in the oral cavity be~ ~se they have hard, non-sl ,eJding surfaces where t~acleria and their products (dental plaque) can significantly accumulate, especially in ap,uro,~i,,,al areas and along the gingival crevice.
Dental plaque is a rough sticky film on the teeth that is made up of saliva, bacteria and food pa~licles which ddl,eles ten~cio!~sly to teeth at points of irregularity or disconli"uity. Within a few hours of teeth cleaning, a film of salivary mucins, co"sisli,)g primarily of proteins, forms on the teeth. Various oral ba.,leria colonize the mucins and multiply, fo""ing a layer of plaque. Carbohydrate food debris adl,eres to the mucins and is digested by some types of plaque-causing bacteria. The digestion prod(l~s both by-products which add to the plaque, and prodl~ces acid which erodes tooth enamel. The bacte,ial by-products produced in the oral cavity also include foul smelling gases which can result in r"alodor of the oral cavity.
If not prevented or removed, plaque may become embedded with mineral salts, containing calcium and ,~hospl,ate, to form a hard crusty deposit, c~lcul~ ~s or tartar, on the teeth. Calculus may be white or yellowish in color or may be slained or discolorecJ by extraneous agents. ~lcul~s tends to be more unsi!Jl,lly than plaque and much more difficult to remove from the teeth. The toxins in plaque and calculus can irritate the gingival tissoes surrounding the coated teeth, WO 94/14406 PCT/US93/1178~

2is~8l5 causing inflarr,r"alion and destruction of the gums which can lead to other complicalionc.
Zinc is an anti~lculus agent; however compositions containing zinc generally taste asll inge,)l and unpleasantly bitter. Like the chemical and biological activities the negative aesthetics of the zinc cation are dose depende"l. higher cGncenlralions of zinc exhibit poorer aesthetics; Ihere~or~ increasing the co"c~ntralion of free zinc tends to increase errica~ at the ex~pense of aesthetics. This coupled behavior between efficacy and aesU~elics has limited the utility of zinc in oral compositions. Pyrophospl-ate is also an antic~lcul~s agent and likewise has an unpleasant taste which wor~e"s with increased py, u~,l ,os~l ,ate concerlt, dlion. By carefully formulating zinc and py, uphospl ,ate~,)taining com~osilions it has been surprisingly found that the level of zinc in an oral co",posilion can be increased thus incr~asing the correspond;ng ar,licAIc~ s effect without greatly inueasing the negative aesthetics of the col"~,osilion. Applicants have SL~"~ isi, Iyly found that certain ratios of zinc:citrate:py, upl ,osphale in combination with certain formulation col"pG"ents unexpectedly provide oral cGI",cosilions which are stable for longer time periods than are other formulations.
SummarY of tne Invention This invention involves oral~are w",rosilions col"~,rising.
(a) zinc oxide or zinc nitrate; a source of citrate ions; and one or more pl,ospho"Js~"lai"ing anticalculus agents selecte~ from the group consisting of pyrophosphate pl ,osphonale dipl lospl ,Gnale and phal ",aceutically-acceptable linear condensed pol~,ul ,osphates of the general formula: (PnO(3n+1 ))(n+2)- wherein n is an inlteger from 2 to 21;
wherein a molar ratio of the zinc ions:citrate ions is from about 1:0.1 to about 1:20; the molar ratio of the zinc ions:~l,ospl,o,.ls~ontaining a, lliCAIc ~lus agents is from about 1:1 to about 1:20; and (b) the pha""~ ti~ ly-acceptable topical oral carrier.

~VO 94/14406 21 5 1 ~1 ~ PCT/US93/11786 Detailed Disclosure of the Invention This invention provides cor",oositions effective against dental plaque fo",~alion, calculus formation, gingivitis, and mouth malodor.
Such compositions coi"~,ise certain zinc salts and certain molar ratio amounts of citrate and pyro relative to zinc in a pharmaceutically-acceplable carrier.
"Pyro", as used herein, refers to pyrophosphate; phospl,G,)ale;
diphos~Jl ,onale; and pl Id~ CeU tic~lly-acceplable polyphosphales including, but not limited to, linear condensed polyphosphates of the general formula: (PnO(3n+1))(n+2)~ wherein n is an inleger from 2 to 21 .
"Pharmaceutically-acceptable topical oral carrie~', as used herein, denotes a carrier for the active co",pounds of this invention (hereinafter "Actives") co",~risi"g solid or liquid filler diluents s~it~le for use in contaot with the oral tissues of humans and other ani",als without undue. toxicity, inco"~ ibility, instability, irritation, allergic respG"se, and the like, cG",r"e"surate with a reasGI~able benefiVrisk ratio. Such topical oral carrier, when combinad with Actives of this invention, results in a composilion which is administered topic~lly to the oral cavity. r,e~rably such col"~ositions are held in the oral cavity for a period of time, and then largely eYpectorated rather than being swallowed. Such ~"~posilions include mouthwashes, mouth rinses, mouth sprays, dental llealment sol ~tions, tooU~p~stes, liquid de,ltir,ices and the like and are more fully des~ibed hereinafter.
Del,lir,ices and mouthwashes are the pr~fe"ed c~""~osilions.
"Free pyro", as used herein, refers to pyro that is not bound or chelated to the transition metal, zinc.
"Free zinc", as used herein, refers to hydlaled zinc cationic species, such as Zn(H2o)62+.
"Safe and effective amount" as used herein means an amount of co""~ound or co"~posili~" surricient to induce a significant positive ".odiricalion in the condition to be l,ealed, but low enough to avoid serious side effects (at a rea-~G"able benefiUrisk ratio), within the scope of sound medical judgment. The safe and effective amount of the ~""~ound or co,nrosi(ion will vary with the particular condition being l,ealed, the age and physical CGndi~iGIl of the patient being 2 ~S PCT/US93/1178~

treated the severity of the condition the duration of the treatment the nature of concurrent therapy the specific compound or composition employed the particular pha""aceutically-acceptable carrier utilized and like factors.
S The term col"prisil"J as used herein means that various additional cG""~onents can be conjointly employed in the compositions of this invention.
As used herein percenlages listed are weight percentage of composition unless otherwise specified.
Zinc:Citrate and Zinc:PYro Ratios The amounts of pyro and citrate are expressed in terms of a ratio to the amount of zinc in the oral colnl~osilion. On a molar basis the amount of citrate relative to zinc is at least 0.1 when the amount of zinc is 1 (i.e. the ratio of zinc:citrate is at most 1:0.1). Likewise the amount of pyro relative to to the amcunt of zinc is at least 1 when zinc is 1 (i.e. the ratio of zinc:pyro is at most 1:1). rl~relled zinc:citrate ratios are from about 1:0.1 to about 1:20 more preferdbly from about 1:0.5 to about 1:4 more ,ureferably from about 1:1 to about 1:3.
rrefe"ed zinc:pyro ratios are from about 1:1 to about 1:20 more pr~:ferably from about 1:2 to about 1:6 more prererably from about 1:3 to about 1:5. Also ~,rerer,ed is a zinc:citrate:pyro ratio wherein the sum of the ratio amounts of citrate and pyro is from about 3 to about 9 more prererdl,ly from about 4 to about 7 when the ratio amount of zinc is 1 .
The amount of zinc suitable for the purposes of this invention is from about 0.005% to about 5% Zn; more preferably from about 0.05%
to about 2% Zn; more p~efe(ably still from about 0.1% to about 0.6%
Zn. In denlir,ice co""~ositions the ~,refe"ed amounts of zinc are from about 0.1% to about 2~6 more prererably from about 0.3% to about 0.6%. In mouthwashes mouth rinses mouth sprays and dental sol~tions the ~refel,ed amount of zinc is from about 0.005% to about 1% more p~eferably from about 0.01% to about 0.75% more ~, eferably still from about 0.0~% to about 0.5%.
The amount of citrate anion suitable for the purposes of this invention is from about 0.015% to about 15% citrate. In dentifrice col"~ositions the prefer,ed amounts of citrate anion are from about ~WO 94/14406 21~1815 PCT/US93/11786 0.2 % to about 8%, more preferably from about 0.4% to about 7%, more preferably still from about 0.6% to about 6%. In mouthwashes, mouth rinses, mouth sprays and dental solutions, the prefer, ed amount of citrate anion is from about 0.01% to about 12%, more preferably from about 0.1% to about 6%, more prererably still from v about 0.15% to about 1%.
The amount of pyro anion suitable for the purposes of this invention is from about 0.5% to about 15% pyro. In dentifrice compositions, the prer~rled amounts of pyro ion are from about 1% to about 9%, more ,cr~reral,ly from about 2.5% to about 5%. In mouthwashes, mouth rinses, mouth sprays and dental solutions, the prefer,~d amount of pyro anion is from about 0.01% to about 25%, more preferably from about 0.1% to about 5%.
Suitable sources of zinc ions include zinc oxide and Zn(N03)2.
Zinc sources that are not suitable are zinc ethylenediaminetel,dacetale (ZnEDTA) and zinc nitrilot,i~cet~te (ZnNTA). The prere"ed source of zinc ions is ZnO.
Suitable sources of citrate ions include citric acid; alkali metal salts of citric acid, especi~lly sodium citrate and potassium citrate;
pharm~ce~t~ ly ~ccept~ hydrated and dehydrated salts of any of the above; and mixtures of any of the above.
Suitable sources of pyro ions are d:sclQsed in U.S. Pat. No.
4,885,155, issued Dece"lber 5, 1989 to Parran & Sakkab; U.S. Pat.
No. 3,678,154, issued July 18, 1972 to Widder et a/.; U.S. Pat. No.

3,737,522, issued June 5, 1973 to Francis et a/.; and U.S. Pat. No.

4,627,977, issued Dec~",ber 9, 1986 to Gaffar et a/.; each is inco,poratecJ herein by ,efere"ce. Suitable pyro ion sources include tell~sodi!lm pyrophospl,ale, sodium acid pyrophospl,ale (Na2H2P207), tet, apot~ssi~ ~m p~, o,GI ,osphale (K4P207); ,uhospl ,ates 3~ including, but not limited to, linear cond~"sed polyphospl ,ates of the general formula: M(n+2~PnO(3n+1) wherein M is Na or K, and n is an ? integer from 2 to 21; phospl,onates and diphosphonates, such as EHDP (ethane-1 -hydroxy-1, 1 -diphosphonate) and AHP (azacyclo-heptane-2,2-diphosphonic acid); pharmaceutically-acceptable alkali 35 metal salts of pyrophosphates, pol~,..l,osphates, phosphonates and .lipl ,osphonates; and mixtures of any of the above. Preferred WO 94/14406PCT/US93/1178~

pol~l ,osphate ions are those of the above formula wherein n is 6, 13, and 21 r,ererfed pyro ions are py,ophosphate ions. P~erer,~:d alkali metals are sodium and potassium; mixtures of alkali metal salts are accep~ble. A more preferlad source of pyro ions is a potassium salt 5 of the pyro ion.
ComPositions Components of the topical, oral carrier are suitable for administration to the oral cavity of a human or other animal and are co,l,paliL,le with one another and the other components, especially 10 with the Actives, used in an oral composition of this invention. The term "co",patiL,le" as used herein, means that the co",ponents are capable of being co-mingled with one another, in a manner such that there is no interaction wnich would sul,stA~,lially reduce the efficacy of the oral co",posilion under ordinary use condiliGr,s.
15r, efe" ed topical, oral carriers provid~ the desired characteiialics ~or mouthwashes, mouth rinses, mouth sprays, dental treatment solutions, toothp~-stes, dental gels, tooli ,powders, prophylaxis pastes, and the like. The topical, oral carriers of this invention col"~.,ise components typically used in such compositions 20 which are well known to a skilled practitioner. Such co",ponents include, but ar* not limited to, anlicaries agents, antiplaque agents, anticalculus agents, dental abrasives, su,ract~-"s, flavoring agents, sweetening.agents, binders, humectants, thickening agents, buffering agents, presel./atives, coloring agents and pig",a,lts, ethanol and 25 water.
The pH of oral co,-,~osilions of this invention is critical but can be varied to some extent. The co""~ositions must be at a pH which is safe for cG"lact with the tiss~es of the oral cavity, i.e. below a pH of about 9 for humans, ~.refe,ably below a pH of about 8.5. Otherwise, 30 the pH of the co",posilions is preferably above pH 6, more preferably above pH 7, more prt:rerably still, above pH 7.5.
During manufacture of a composition of this invention, the r conditions for addition of each component should be op~ir"i~ed such that the pH of the mixture does not drop below formulation pH at any 35 time during mixing of the ingredients. To opli"li~e stability of the final ~0 94/14406 21~ 181~ PCT/US93/11786 composition a pH of at least about 7.5 should be maintained at all times.
Water is a co",ponent of the topical oral carriers of the compositions of the subject invention. Water employed in the preparation of the commercially suitable compositions should ~.referably be of low ion col)lel ,t and free of Grgdnic impurities. Water preferably coi"~,rises from about 2% to about 99% more prererdbly from about 20% to about 95% of the cor"posilions of the subject invention. When in the form of tootl ~pasle the cor"positions prererably con,prise from about 20% to about 99.5% more prererably from about 30% to about 99% still more ,ure~eral~ly from about 35% to about 98% more preferdbly still from about 40% to about 97% water.
Mouthwashes co",prise prererably from about 2% to about 99.5%
more preferably from about 45% to about 99% more preferably still 15 from about 75% to about 98% water.
In preparing oral ~",posiliol~s of this invention, it is desirable to add binders and/or thickening agents particularly to tootl ,pasle composilions to provide a desired consistency. Suitable binders for these composilions are those which are non-ionic at the formulation pH of the co,nposiliG". By 'non-ionic" is meant not more than about 10% ionized. As used herein Yormulation pH means the pH of the final composition. Suitable binder~ include but are not limited to natural gums such as gum karaya gum arabic and gum tragaca"ll,;
polysaccha, iJe gums sùch as xantha,) gum; and other natural products such as calrageenan; chemically modihed natural products such as those based on cellulose esters that is ~I L,oxylmethylcellulose (CMC) hydroxyethylcellulose (HEC) and hydroxypropylcellulose (HPC); and synthetic binders such as polyvinylpyrrolidone; and water soluble salts of cellulose ethers such as sodium ~, boxymethyl celllJ!ose and sodium ca, Loxymethyl hydroxyethyl cellulose. Carboxyvinyl polymer binders are less desirable but may be used. Colloidal magnesium aluminum silicate or finely divided silica can be used as part of the thickening agent to further improve texture. Blends and mixtures of the suitable binders may signirica"lly improve the chara~;te,islics of compositions made therewith. r~efe"ed binders are chemically modified celluloses such ~,~S~ 8 as CMC or HEC; more prefe~-ed is HEC. Binders and thickening agents are generally present in the compositions of this invention in combined amounts of from about 0.1% to 10%, preferably from about 0.25% to about 7.5%, more preferaL)ly from about 0.5% to about 3.5%.
5 OPtional ComPonents Dental abrasives useful in the topical, oral carriers of the co""~ositions of this invention include many dirrerel,t materials. The material selectecl must be one which is coll~ iblQ with the composition of interest and does not excessively abrade dentin.
10 These include, for example, silicas, including gels and preci,.~ilates, calcium carbonate, dicalcium o, ll ,opl ,osphate dihydrate, calcium pyrophosphate, tricalcium phosphate, calcium polymeta-pl ,ospl ,dle, insoluble sodium polymeta-~Jhospl ,ate, hydrated alumina, and resinous abrasive r~alelials such as particulate condensation products 15 of urea and ~ormaldehyde, and other materials such as those disclosed by ~ooley et a/. in U.S. Pat. No. 3,070,510, issued December 25, 1962, incorporated herein by re~erence. Mixtures of abrasives may also be used.
Silica dental abrasives, of various types, can provide the unique 20 benefits of excepliGnal dental cleaning and polishing pel rOI " 'ar.ce without unduly abrading tooth enamel or dentin. For this reason they are preferred for use herein.
The silica abrasive polishi"g malerials useful herein, as well as the other abrasives, generally have an average particle size ra"~ing 25 between aboutØ1 and 30 ",icrons, preferably between about 5 and 15 "-i~or,s. The silica abrasive can be precipitated silica or silica gels such as the silica xerogels desctibed in U.S. Pat. No. 3,538,230, issued March 2, 1970 to Pader et al., and in U.S. Pat. No. 3,862,307, issued June 21, 1975 to DiGiulio, both i"c~i ~.Grdted herein by 30 reference. F~f ere~ d are the silica xetc,~els marketed under the tradename Syloid~ by the W.R. Grace & CGr"pany, Davidson Chemical Division. rfefe"ed precipitated silica materials include those marketed by the J. M. Huber C~r,uoralion under the tradename, 7essdentE9~ particularly the silica carrying the designation Zeodent 35 119~). These silica abrasives are desa ibed in U.S. Pat. No.

~0 94/14406 2~ 81~ PCT/US93/11786 4 340 583, Wason issued July 20 1982 incorporated herein by rererei ,ce.
Mixtures of abrasives may be used. The amount of abrasive in the co",posiiions desc~ibed herein ranges from about 6% to about 5 70% prt:rerably from about 15% to about 50% more preferably from about 15% to about 30% when the dentifrice is a toothpaste. Higher levels as high as 90% may be used if the composition is a tooth powder.
Flavoring agents can also be added to the oral compositions of 10 this invention to make them more p~l~t~hle. Suitable flavoring agents include menthol oil of ~inlergreen oil of peppermint oil of spearmint oil of sassarras and oil of clove. Flavoring agents are generally included in the slJhject co~,positions in amounts of from 0% to about 3% prererably from about 0.04% to about 2% by weight.
1~ Coloring agents may be added to co,nposilions of this invention to improve appearance. If present ~lori"g agents typically are incll~ded at levels of from about 0.001% to about 0.5% by weight.
Sweetening agents are also prefer,ed in the compositions of this invention to make them more l,A~ le. Sweetening agents which 20 can be used include aspa~ lame acesulfame sacchari,) salts dexlrose glucose levulose thaumatin D-tryptophan dihyd~ochalcones and cyclamate salts. Saccl,ari,l salts are prefer,ed.
Sweelenir,g agents are generally used in the subject compositions in amounts of from 0% to about 6% ,ureferably from about 0.005% to 25 about 5% by weight.
Oral colllposiliG"s can also CGI llain a su, ra~;tanl. Suitable surfactants are those which are reaso"ably stable and form suds throughout the pH range suitable for co",positions of this invention including nonsoap anionic nonionic cationic zwitterionic and 30 a"" l,oteric organic synthetic deterge"ts and cor"palible mixtures thereof. Many of these suitable su,raclanl~ are disclosed in U.S. Pat.
No. 4 051 234 issued to Gieske et al. on Septe",ber 27 1977 and in U.S. Pat. No. 3 9~9 458 issued to Agricola Briner Granger and Widder on May 25 1976 both of which are inco,~orated herein by 35 rerere,)ce. Surfactants are typically present in compositions of this invention at a level of from 0% to about 20% preferably from about 2~S~8~ 10 -0.1 more preferably from about 1% to about 4% by weight.
Surfactants may also be used as solubilizing agents to help retain sparingly soluble co" ,ponents e.g. some flavoring agents in solutions. Surfactants suitable for this purpose include polysorbales and poloxamers.
Another optional co",ponent of the oral carriers of the compositions of this invention is a hu",e~lant. The humectant serves to keep tootl"~as~e co",posilions from hardeniny upon e.Yros~re to air and to give mouthwash and tootl,paste composilions a moist feel to the mouth. Certain hume.la"ls can also impart desirable sweetness of flavor to mouthwash and tootl"~asle composilions. The humectant on a pure humectant basis generally com~rises from 0% to about 70% preferably from about 2% to about 55% by weight of the compositions herein. Suitable hume~ta,)ts for use in co",positions of this invention include edible polyhydric alcohols such as glycerin sorbitol xylitol polyethylene glycol and propylene glycol especially sorbitol and glycerin. rlere"ed humec~a"ts are sorbitol and glycerin;
more prere" ed is sorLilol.
Opacifiers may also be used in toothrA-sles of this invention to render the tooll"~as~e op~que. Suitable opacifiers include titanium dioxide and some abrasives including for exa""~le magnesium aluminum silicate. Opacifiers ge"e(ally comprise from 0% to about 4% preferably from about 0.5% to about 3% by weight of the w""Josilions herein.
Other optional co",ponenls of the compositions of this invention are preservatives. The'preservatives prevent microbial growth in the compositions. Suitable preservatives include methylpa,-a6en propyJ~arabe" ben7O~tes and ethanol. If the prese, ./ative is ethanol it generally co",prises from 0% to about 35% by weight prerer~bly from about 5% to about 15% of the co",posilions herein. Other preservatives generally coi"prise from 0% to about 5% by weight preferably from about 0.08% to about 2% of the co"~positions herein.
Anti")icrobial antiplaque agents can also Gptionally be present in the oral compositions of this invention on the condilion that they are co",~ ible with the Actives. Such agents may include but are not limited to triclosan 2 4 4'~ l ,loro-2'-hydroxydiphe, Iyl ether as 215~ 815 ~0 94/14406 ^ PCT/US93/11786 described The Merck Index. 11 th Ed. (1989), p. 1520 (entry No. 9573);
chlorhexidine, (Merck Index. No. 2090); alexidine (Merck Index, No.
222); hexetidine (Merck Index, No. 4624); sanguinarine (Merck In~ex, r No 8320); benzalkonium chloride (Merck Index. No. 1066);
salicylanilide (Merck Index. No. 8299); domiphen bromide (Merck index, No. 3411); cetylpyridinium chloride, (CPC) (Merck Index. No.
2024); tetradecylpyridinium chloride, (TPC); N-tetradecyl-4-ethylpyridinium chloride (TDEPC); octenidine; delmopinol, octapinol, and other piperidino derivatives; nicin prepardlions; antibiotics such as augmentin, amoxicillin, tetracycline, doxycycline, minocycline, and metronidazole; and peroxides, such as cylium peroxide, hy~rogen peroxide, and magnesium monoperthalate and its analogs as described in U.S. Patent No. 4,670,252; and analogs and salts of the above antimicrobial antiplaque agents. If present, the antimi~obial antiplaque agents may co"~ ise from 0% to about 6%, preferably from about 0.1 % to about 5% by weight of the compositions of this invention.
Bleaching agents can also be present in the oral compositions of this invention. Suitable bleaching agents include organic and i"orgal1ic oxidi~i"g agents such as hyd~s~en peroxi-le, alkali metal peroxides and superoxide and oryanic peroxides such as ."o"oper-oxyphthalates and pe,Le"~oic derivatives. If pr~ce"l, such bleaching agents may coi,-~,rise from 0% to about 6%, preferdbly from about 1 %
to about 5% by weight of the co",positions of this invention.
Nutrients can also be present in the oral ~,.,posi~ion of this invention, on condition that they are co,,,,ualible with the Actives. Such agents may include folate, retinoids (Vitamin A), Vitamin C, Vitamin E.
If ~Jreselll, the nutrients generally comprise from about 0.001% to about 10% by weight of the co"~posilions of this invention.
Other optional ingredients include a safe and effective amount of a fluoride ion source, which typically is in the form of a water-soluble fluoride ~I "pound. This water-soluble fluoride compound is typically present in the co",posi~ions of this invention in an amount sufficient to give a fluoride concentration of from about 3~ 0.0025~ to about 5.0% by weight, preferably from about 0.005% to about 2.0% by weight. P~efel,ed fluoride sources are sadium fluoride, -WO 94/14406 PCT/US93/1178~j_ 12 ~
~S~
acid~ ted phospl ,ate fluoride and sodium monofluorophosphate.
U.S. Pat. No. 3678154 issued July 18 1972 to Widder et al.
discloses such salts as well as others and is incorporated herein by reference.
Other optional ingredients include sy"ll,elic or natural anionic polymeric polyc:a,boxylates polysaccharides and polysulfates. The polymers may be present at a weight amount of from about 0.05% to about 3% more preferably form about 0.05% to about 2% more l~rererably still from about 0.1% to about 2%. Suitable polymers include but are not limited to copolmers of maleic acid anhydride or acid with another polymerizable ethylenically unsaturated ll,onGi"ers linear polyca, boxylates alginates pec~ins carageenans. Most prefe"ad are 1:4 to 4:1 copolymers of maleic anhydride or acid with another poly, neri~able ethylenically unsaturated " ,o"o" ,er ,c,referably methyl vinyl ether (methoyethylene) having a molcular weight (M.W.) of about 30 000 to about 1 000 000. These copolymers are available for exa",~le as Ganlre~ AN 139 (M.W. 500000) A.N. 119 (M.W.
250 000) and ~referably S-97 rl,a""aceutical Grade (M.W. 70 000) of GAF Co, ~oratiG".
Other operdli~/e polymeric polyca, 6Oxylates include those disclQsed in U.S. Pat. No. 3956480 such as the 1:1 copolymers of maleic anhydride with ethyl acrylate hydroxyethyl methacrylate N-vinyl-2-pyrrolidone or ethylene the latter being available for exa""~le as l~lqol,s~nto EMA No. 1103 M.W. 10 000 and EMA Grade 61 and 1:1 copolymers of acrylic acid with methyl or hydroxyethyl methacrylate methyl or ethyl acrylate isobutyl vinyl ether or N-vinyl 2-pyrrolidone.
~efe"eJ CGIII~OSjl;GIIS
~refe~ composilio"s of this invention are in the form of de,ltir,ices especially toothr~st~s CGIII~OneI)lS of toothr~stes generally include a dental abrasive (from about 10% to about 50%) a su,ractant (from about 0.5% to about 10%) a thickening agent (from about 0.1% to about 5%) a humectant (from about 10% to about 70%) a flavoring agent (from about 0.04% to about 2%) a sweetening agent (from about 0.1% to about 3%) a coloring agent (from about 0.01% to about 0.5%) and water (from about 2% to about ~5%).

~o 94/14406 21 S l ~ l S PCT/US93/11786 Other prefe,led compositions of this invention are mouthwashes mouth sprays and dental solutions. Components of such mouthwashes and mouth sprays include water (from about 45% to about 99%) ethanol (from O% to about 25%) humectant (from 0/O to 5 about 50%) su,r~;tanl (from about 0.01% to about 7%) flavoring agent (from about 0.04% to about 2%) sweetening agent (from about 0.1% to about 3%) and colGring agent (from about 0.001% to about 0.5~). Such mouthwashes and mouth sprays may also include an antiplaque agent (from about 0.1% to about 5%).
10 Methods of Use Another aspect of this invention involves methods of l~ealing or preventing mouth odor dental pl~ql ~e ~ s and gingivitis by application of compositions comprising a safe and effective amount of Actives to tissues of the oral cavity. Such c~ ,osilions are desc, ibed 1 5 hereinabove.
These ~lletllods involve administering a safe and effective amount of Actives ,urererably by adlllillisleri~g an oral cG""~osilion of this invention as des~ i6ed 1 ,ereinabove to the oral cavity. rl eferably ",ell,ods of this invention co",prise adminisleri"g an amount of 20 co",position ~mp~ising at least about 0.0019 of the Actives. The teeth and other oral cavity tissues are P~-osed to the Actives.
When the oral col"l~osi~ion is a too~l"~ste ~referal)ly from about 0.3 grams to about 15 grams preferably from about 0.5 grams to about 5 grams more prer~rably from about 1 to about 2 grams of 25 tooli"~asle is applied to an appli~AI;llg device e.g. a tooll,~ sh. The applicating device is then conlacled with the oral cavity surfaces in a ",anner such that the oral ~,npositiGrl is contacted with tissue of the oral cavity espqc-~lly the teeth and gums. The applicating device may be further used to effect an even distribution of the oral co"",osilion to 30 the tooth surFace for example by brushing. The application preferably lasts for a period of from about 15 secG"ds to about 10 minutes more preferably from about 30 seconds to about 3 minutes more preferably still from about 1 minute to about 2 minutes. Following arplicPtion the toothpaste residue is typically removed from the tooth surface by using 35 a liquid acceptable to the oral cavity typically water to rinse and be sxreGtora~ed from the oral cavity.

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WO 94/14406 PCT/US93/1178~

When the oral composition is a mouthwash, typically from about 1 ml. to about 20 ml., preferably from about 2 ml. to about 15 ml., most preferably from about 10 ml. to about 15 ml., of liquid mouthwash containing the antiplaque Active is introduced to the oral cavity. The liquid mouthwash is then agitated for from about 10 seconds to about 10 min., preferably from about 15 seconds to about 3 min., more preferably from about 30 seco,)Js to about 2 minutes, within the oral cavity to obtain an improved distribution of the mouthwash over the tissue of the oral cavity. Following agitation, the mouthwash is typically expectorated from the oral cavity.
Application frequency is prererably from about 3 times weekly to about 4 times daily, more ,l~refer~bly from about once daily to about 3 times daily, more preferably still from about once to about twice daily.
The period of l,edl",el,l typically ranges from about one day to a 1 5 lifetime.
ExamPles The following non-li,nilir,i~ e~amples further describe and demGnsl,dle prefer,ed e",bodi",enls within the scope of this invention.
The examples are given solely for illustration and are not to be construed as limitations of this invention as many variations are possible withou~ clel~a, ling from the spirit and scope of this invention.
The co",posilions of this invention can be made using methods which are c~l"",only used to produce oral care pro~ ct~
EXAMPLES l-VI
The ~ollowing are examples of cJenlirl ice compositions of this invention and are made using conventional processes. The numbers listed are weight peroenlages of the c~r~"~osilions. During manufacture, the pH
is maintained at a minimum of ~H 7.5.
~,~.ed ES IEL II E~ E~ EL V E~ VI
~ lV
Sonitol 31.6S 31.65 1.65 3 .6S 31.65 ~ 1.65 PEC-6 3 . ; 3 :~itr c Acid 1.4" 0.088 1 ~.91 0.433 1.0S ~ ~.44 ~d um Citrate 3.6~ 0.144 0.8S6 : .28 nc Nitrate Z.g-Z nc Oxide 0.3?4 0.407 0.407 0.407 0.407 Tc -r 7.12 7.S8 S.78 r h r ~ h~ )uS) Sodium Acid E~r~ 5~1 0.6Z 0.497 21~1815 ~VO 94/14406 ^ PCT/US93/11786 ~, ~1;.. ~-ul)h r~ 6.61 4~6 3~39 od um Fluorid~ 0."4 0.' 4 0. ~4 0 ~'4 0 "4 0 ~4 'oc wn Saccharn ~ 60.~6 0.~6 0.~6 0.~6 0.~6 Titanium Dioxice ~ .' f~ O.' O.' O.' Silica 2" 2- 2~' 22 22 2 ' Glycerin '~ ~ 2.' 1S 2.2 9 2. 5 ~ -' . S O.S 0.~
'' ~arthanGum 0.~ 0.~ 0. S 0.4 O.~
.1,~ ~u~,lh~Ilnlnt;ç o yl Sl~ te 4 ~ 4 4 4 4 (27.9% Aqueous solution~
I;lavor 1.1 1.1 1.1 1.1 1.1 1.1 KOH/HCI/watcr q.s. q.s. q.s. q.s. q.s. q.s.
to to to to to to pH pH pH pH pH ~H

7.S 8.~i 8.0 8.0 8.0 ~'.0 EXAMPLE Vll Following dental prophylaxis, a ~,er~on brushes his teeth for sixty seconcl~ twice daily using 1 9 of a fluoride, non-a"licalculus tootl "~asle. After eight weeks he receives dental prophylaxis pe~ru~ ed by his dentist. For the following eight weeks the person brushes his teeth for sixty seco"~ls twice daily with 1 9 of the co",position of Example 1. After eight weeks, the person has sigr,iricar,lly less ~Iculus on his teeth than he did after the first eight weeks.
EXAMPLE Vlll Following dental prophylaxis, a ~er~o" brushes his teeth for sixty seconds twice daily using 1 9 of a fluoride, non-anticalculus tootl ,~,asle. After one week he receives dental prophylaxis pe, rur---ed by his dentist. For the following week the person brushes his teeth for sixty seccl-ds twice daily with 1 9 of the composition of Example IV.
After one week, the person has signir,~anlly less plaque on his teeth than he did after the first week.
EXAMPLE IX
Following dental prophylaxis, a person brushes his teeth for sixty seconds twice daily using 1.5 9 of a fluoride, non-anticalculus tootl .pasle. After nine weeks he receives dental prophylaxis performed by his dentist. For the following nine weeks the person brushes his teeth for sixty seconds twice daily with 1.5 9 of the composition of Example tll. After nine weeks, the person has WO 94/14406 PCT/US93/117~_ 2~
significantly less calculus on his teeth than he did after the first nine weeks.
EXAMPLES X-XIV
The following are ex~ ples of mouthwash and dental rinse cc, l l,~ositions of this invention and ar~ made usir~g conventinal proc~ss~s The amounts listed arc weight per~"tages of the compositions. During manufacture, the pH of the following col..~osilions is lla;ntaiaed at a mininum of pH '.5.
~omponent Ex.X Ex. ~a Ex.XII Ex.XIII Ex. XIV
Glycerin 10 10 10 10 10 Ethanol 10 10 10 10 10 SodiumCitratc 0.41 3.84 1.28 Citric Acid 11.4 3.8 Zinc Cl .lorid~ 1.36 Zinc Oxide 0.081 1.63 0.81 0.41 T~t~l.ot~csi;~n 1.1 5.51 1.1 Py. v~l ,ospl late (60% Sol'n) T~r~so~ n 2.66 0.27 Py- 0~ 05l.ll'ldt~
Sodium 7.36 0.37 Tripoly,~l IGspl ,dta Sodium Add 6.66 0.22 P~ 5pl ,ata SodiumLau~yl 0.4 0.4 0.4 0.4 0.4 Sulfate Sodium Sa~l a- i~l 0.03 0.03 0.03 0.03 0 03 Flavor 0.22 o.æ 0.22 0.22 0.22 NaOH/HCL & q.s. q.s. q.s. q.s. q.s.
Water 100% 100% 100% 100% 100%
at pH at pH at pH at pH at pH
7.5 8.5 8.5 7.5 8.0 2 1 ~
~0 94/14406 PCT/US93/11786 EXAMPLE XV
Following dental prophylaxis a person rinses her mouth for twenty seconds twice daily for a period of eight weeks using 10 ml of a non-antic~lc~lus mouth rinse. After eight weeks the person received dental prophylaxis and rinses for twenty seconds twice daily with 10 ml of the cGr"posilio" of Example Xl. After eight weeks the person has significantly less C?ICI "- IS on her teeth than she did after the first eight weeks using the non-anticalculus mouth rinse.
EXAMPLE XVI
Following dental prophylaxis a persol) rinses her mouth for thirty seco"ds twice daily for a period of one week using 12 ml of a non-antiplaque mouth rinse. During this week the person does not brush her teeth. At the end of one week the per~on received dental prophylaxis and rinses for thirty seco"ds twice daily with 12 ml of the 1~ cG"~.osilion of Example Xlll. During this week the pe,~on does not brush her teeth. At the end of one week the person has significantly less plaque on her teeth than she did after the first week using the non-antiplaque mouth rinse.
EXAMPLE XVII
FollPwing dental prophylaxis a person rinses her mouth for forty-five seconds twice daily for a period of nine weeks using 15 ml of a non-anticalculus mouth rinse. After nine weeks the person received dental prophylaxis and rinses for forty-five seconds twice daily with 15 ml of the co"~posilion of Example XIV. After nine weeks the person has significantly less r-~'cul! ~s on her teeth than she did after the first nine weeks using the non-antir~lc~ s toothpaste.
While particular e"l~od;",ents of this invention have been des~ibecl it will be obvious to those skilled in the art that various changes and ",odiric~lions to these exc.,,,ples can be made without depa,ling from the spirit and scope of the invention. It is intended to cover in the appended claims all such modifications that are within the scope of this invention.

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Claims (10)

Claims

1. An oral-care composition comprising:
a) (i) zinc oxide or zinc nitrate;
(ii) a source of citrate ions; and (iii) one or more phosphorus-containing anticalculus agents selected from pyrophosphate, phosphonate, diphosphonate and pharmaceutically-acceptable linear condensed polyphosphates of the general formula:
(PnO(3n+1))(n+2)- wherein n is an integer from 2 to 21, wherein the molar ratio of the zinc ions:citrate ions is from 1:0.1 to 1:20, preferably from 1:0.5 to 1:4, more preferably from 1:1 to 1:3; the molar ratio of the zinc ions:phosphorus-containing anticalculus agents is from 1:1 to 1:20, preferably from 1:1 to 1:6, more preferably from 1:3 to 1:5; and (b) a pharmaceutically-acceptable topical oral carrier.

2. The composition of Claim 1 in the form of a dentifrice wherein the pharmaceutically acceptable topical oral carrier comprises a dental abrasive.

3. The composition of any of Claims 1-2 comprising a binder which is non-ionic at the formulation pH of the composition.

4. The composition of Claim 1 in the form of a solution selected from a mouthwash, a mouth rinse, a dental solution, and a mouth spray, wherein the pharmaceutical carrier comprises a material selected from a humectant, ethanol, and a nonionic surfactant.

5. The composition of any of Claims 1-4 wherein the pH of the composition is above pH 7; preferably above 7.5.

6. The composition of any of Claims 1-5 comprising from 0.01% to 0.75 % zinc.

7. The composition of any of Claims 1-6 wherein the anticalculus agent is selected from pyrophosphate, EHDP, AHP, and linear condensed polyphosphates of the general formula: (PnO(3n+1))(n+2)- wherein n is 6, 13, or 21, preferably the anticalculus agent is pyrophosphate, preferably a potassium salt of pyrophosphate.

8. The composition of any of Claims 1-7 comprising from 35% to 99.5 percent water.

9. The composition of any of Claims 1-8 comprising a source of fluoride ions yielding from 0.0025% to 5% by weight fluoride ions.

10. A method for treating or preventing dental plaque, calculus or malador of the oral cavity comprising administering to the oral cavity of a human or other mammal a safe and effective amount of a composition selected from Claims 1-9.