CA2151913A1

CA2151913A1 - Oral compositions containing antiplaque, anticalculus agents

Info

Publication number: CA2151913A1
Application number: CA 2151913
Authority: CA
Inventors: Ronald Earl Montgomery; Joseph Wasyl Pyrz; Margaret Mary Coyle-Rees
Original assignee: Individual
Current assignee: Procter and Gamble Co
Priority date: 1992-12-18
Filing date: 1993-12-06
Publication date: 1994-07-07
Also published as: AU5740094A; EP0675706A1; HU9501784D0; WO1994014407A1; HUT72041A; CZ156795A3; MX9400053A; CN1095263A; BR9307688A; JPH08505843A

Abstract

This invention involves a composition for treating or preventing dental plaque, calculus and gingivitis, or malodor of the oral cavity, comprising: (a) (i) a source of a safe and effective amount of zinc ions; (ii) a source of citrate ions; and (iii) one or more 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 zinc:citrate is at most about 1:1; the molar ratio of zinc:pyro is at most about 1:1; and (b) and a pharmaceutically-acceptable topical oral carrier. This invention also involves methods for treating or preventing dental plaque, calculus and gingivitis, or malador of the oral cavity, comprising administering to the oral cavity of a human or other animal such a composition.

Description

ORAL COMPOSITIONS CONTAINING
ANTIPLAQUE, ANTICALCULUS AGENTS

The subject invention relates to oral co",posilions, such as dentifrices and oral solutions, for the treatment or prevention of dental plaque, calculus and gingivitis, and mouth malodor.
Backqround of the Invention The mouth is a habitat for microbial growth and colo,li~dlion.
Within the mouth, the gums, lips, oral mucosa (cheek), palate, tongue and teeth provide surfaces for the colonization and accumulation of bdcleria. Teeth are unique in the oral cavity be~ ~se they have hard, non-shedding surfaces where bacteria and their products (dental plaque) can sig"iricantly accumulate, especially in apl.ro,ci",al areas and along the gingival uevice.
Dental plaque is a rough sticky film on the teeth that is made up of saliva, bacteria and food particles which adheres ter,aciously to teeth at poirits of irregularity or d;sconlinuity. Within a few hours of teeth cleaning, a film of salivary mucins, consisting primarily of proteins, forms on the teeth. Various oral bacteria colonize the mucins and multiply, ~o",)i"g a layer of plaque. Carbohydrate food debris adl,eres to the mucins and is digested by some types of plaque-causing bacleria. The digestion both prod~ ~ces by-products which add to the plaque, and pro~h~ces acid which erodes tooth enamel. The bacterial by-products prod~ced in the oral cavity also include foul smelling gases which can result in malodor of the oral cavity.
The oral Lacteria in dental plaque incl~.ldes many gram positive and gram negative ",icroorga"isms embedded in an exl,acellular matrix of insoluble polysaccharides, firmly attached to teeth and other oral surfaces. The colonization of bacteria to form dental plaque follows an ecological pallern where a few pioneer aerobic species, mostly gram-positive streptococci, colonize enamel surfaces. The plaque then progresses through stages of increasing microbial complexity. Mature plaques, often found in ,c,rolectedl regions of the 2~$~ 2 teeth such as aacks approxi",al regions and in the gingival crevice typically contain anaerobes. Saliva and crevicular fluid are a source of nutrients for the dental plaque. Local condiliG, s affect the metabolic activity and composition of dental plaque.
If not prevented or removed plaque may become embedded with mineral salts containing calcium and phosphate to forrn a hard crusty deposit calculus or tartar on the teeth. C~c~lus may be white or yellowish in color or may be stained or discolcred by e~lra"eous agents. Calculus tends to be more ~,llsi~hll~ than plaque and much more difficult to remove from the teeth. The toxins in plaque and c~lu ~ s can irritate the gingival tiss~ ~es surrounding the coated teeth causing infla,.,r~alion and destruction of the gums which can lead to other complicalions.
Zinc is an anticalculus agent; however co,.,posilions containing zinc generally taste aslr inyel ,l and unrle~5z - Itly bitter. Lik~ the chemical and bio10gi~ activities the negative aesll,etics of the zinc cation are dose depe.,de,lt. higher co"cer.l.alions of zinc exhibit poorer aesll,etics; therefore increasing the conc~nt,alion of free zinc tends to increase errica~ at the expense of aesll,etics. This coupled behavior between efficacy and aesthetics has limited the utility of zinc in oral co,.,posilions. Pyrophospl,ale is also an anti~lu~us agent and likewise has an unpleasant taste which worsens with increased py,upl.ospl.ate concer,l,alion. By carefully formulating zinc and pytu~JI ,os~l ,ale CG~ ,laining composiliG, .s applicants have surprisingly found that the level of zinc in an oral cG",posilion can be increased thus increasing the corresponding antic~luJlus effect without greatly increasing the negative aesthetics of the cG",posiliGn.
It has been su, ,u, isi, l~ly found that it is possihle to uncouple the effica~ and aesthetics of zinc contai"ing cGIllposiliGns. When zinc is formulated with citrate and pyro at certain ratios of zinc:citrate and zinc:pyro it is possible to avûid the aeslhelic negatives typically ~ssoci~tecl with the zinc ion.
It is an object of the subject invention to provide colllposilions for impeding ~lcullls for",dlion in the oral cavity.
It is also an object of the subject invention to provide compositions for impeding dental plaque formation in the oral cavity.

WO 94/14~07 2 I S 1 91 3 PCTIUS93/11781 It is a further object of the S! ~ ect invention to provide methods for impeding c~lc~ s for"~alion in the oral cavity.
It is also an object of the s~hject invention to provide methods for impeding dental plaque formation in the oral cavity.
5 Summar~ of the Invention This invention involves a CGnlpoSition for treating or preventing dental plaque calculus and gingivitis or malodor of the oral cavity co",,urising:
(a) (i) a source of a safe and effective amount of zinc ions;
(ii) a source of citrate ions; and (iii) one or more anticAlculus agents selected from the group consisting of pyrophosphate ~I osphonate diphos~l ,o"ale and pl ,a""aceutically-acceptable linear conde"sed poly-pl,ospl,ales of the general formula: (PnO(3n+1~)(n+2)~
wherein n is an integer from 2 to 21;
wherein the molar ratio of zinc:citrate is at most about 1:1; the molar ratio of zinc:pyro is at most about 1:1; and (b) and a phdr"~ceuticAlly-acceplable topical oral carrier.
This invention also involves r"etl,ocls for treating or preventing dental plaque ~-~!c~lus and gingivitis or malodor of the oral cavity con".rising ad~"inisleri"g to the oral cavity of a human or other animal such a c~l"posilion.
Detailed Disclosure of the Invention The subject invention provides co",positions effective againsl dental plaque fo""alion CAIcl Ihls fo""alion gingivitis and mouth malodor.
"rl~a""Ace~ticAIly-acceptable topical oral carrier" as used herein denotes a carrier for the active compounds of the subject invention (hereinafter"Actives") co"".risi"g solid or liquid filler diluents suitable for use in cGnlact with the oral tiss~ ~es of humans and lower ar,i",als without undue toxicity incor"patibility instability irritation allergic response and the l~ke co",n,ensurate with a reasonable benefit/risk ratio. Such topical oral carrier when combined with Actives of the su~ ject invention results in a co""~osilion which is administered topically to the oral cavity. ~leferably such compositions are held in the oral cavity for a period of time and then largely WO 94/14407 ' PCT/US93/11787 %~.S~9~3 4 expeclorated rather than being swallowed. Such composiliGns include mouthwashes, mouth rinses, mouth sprays, dental treatment solutions, tooth~astes, dental gels, tooth powders, prophylaxis pastes, lozenges, chewing gums and the like and are more fully described hereinafter.
5 Denlir~ices and mouthwashes are the prefe"ed composilions.
"Pyro", as used herein, refers to py"~l,ospl,ate; phosphonate;
diphos~l,ol)ale; and pha""~ ticAIly-acceptable polyphosphates including, but not limited to, linear condensed poly~hos,cl,dles of the general formula: (PnO(3n+1))(n+2)~wherein n is an integer from 2 to 10 21.
"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 hyd~ated zinc cationic species. such as Zn(H2o)62 15As used herein, per~e"tages listed are weight percei,lage of composition unless othenNise specified.
The amounts of pyro and citrate are e3~,u,essed in terms of a ratio to the amount of zinc in the oral co,n~.~osilion. On a molar basis, the amount of citrate relative to zinc is at least one when the molar 20 amount of zinc is one (i.e. the molar ratio of zinc:citrate is at rnost about 1:1 ); and the amount of pyro relative to zinc is at least one when the molar amount of zinc is one ~i.e. the molar ratio of zinc:pyro is at most about 1:1). r,ererably the zinc:citrate ratio is from about 1:1 to about 1:20; more p(~rerably from about 1:1 to about 1:4, more still 25 prererdl,ly from about 1:1 to about 1:3. F:~e~e"ed is a zinc:pyro ratio from about 1:1 to about 1:20 more p~ferably from about 1:1 to about 1:8, more prererably still from about 1:1.5 to about 1:6. Also pr~rer,ed is a zinc:citrate:pyro ratio wherein the sum of the molar ratio amounts of citrate ions and pyro ions is from about 2 to about 9, more 30 ~.rererably from about 3 to about 9, when the ratio amount of zinc is 1.
The amount of zinc suitable for the purposes of the sl~Qct invention is from about 0.005% to about 5% Zn; more prererably from about 0.03% to about 3% Zn; more ~)rererably still from about 0.05% to about 2% Zn. In denlirrice compositions, the prere"ed amounts of zinc 35 are from about 0.1% to about 2%, more prererably from about 0.25%
to about 1%. In mouthwashes, mouth rinses, mouth sprays and .

W094/14~7 21 S 1913 PCT~S93/11787 dental solutions, the preferred amount of zinc is from about 0.005% to about 1%, more prererdbly from about 0.05% to about 0.5%.
The amount of citrate anion suitable for the purposes of the subject invention is from about 0.015% to about 25% citrate. In dentifrice c~"~.ositions, the preferred amounts of citrate anion are from about 0.2 % to about 17%, more preferably from about 0.7% to about 12%, more ~rerer~bly still from about 1.5% to about 5%. In mouthwashes, mouth rinses, mouth sprays and dental solutions, the prefe,red amount of citrate anion is from about 0.01% to about 12%, more prefel~bly from about 0.1% to about 6%, more preferably still from about 0.15% to about 1%.
The amount of pyro anion suitable for the purposes of the subject invention is from about 0.015% to about 25% pyro. In dentifrice co,nposilio"s, the ~ refe"~ amounts of pyro ion are from about 0.25% to about 16%, more preferably from about 0.6% to about 11%. In mouthwashes, mouth rinses, mouth sprays and dental solutions, the prefer,ed amount of pyro anion is from about 0.01% to about 11%, more preferably from about 0.1% to about 5%.
Suitable sources of zinc ions include zinc oxides, zinc halides, zinc-strong acid complexes, Zn(NO3)~, Zn(C1O4)2, ZnSO4, and zinc-organic acids sources such as zinc lactate, ta,l,ate, citrate salts, zinc citrate trihydrate and sodium zinc citrate. Zinc sources that are u, .acceptable are zinc ethylenediaminetetr~cet~le (ZnEDTA) and zinc nil,ilot,iAcel~te (ZnNTA). Plefer,ed sources of zinc ions include zinc oxide (ZnO) and zinc nitrate; more prefe" ed is Znl~.
Suitable sources of citrate ions include zinc citrate; citric acid;
alkali metal salts of citric acid, especially sodium citrate and potassium citrate; ~I,arn,aceutically ~ccept~le hydrated and dehydrated salts of any of the above; and mixtures of any of the above.
Suitable sources of pyro ions are disclosed in U.S. Pat. No.
4,885,155, issued Dece",ber 5,1989 to Parran & Sakkab; U.S. Pat.
No. 3,678,154, issued July 18,1972 to Widder et al.; U.S. Pat. No.

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

4,627,977, issued December 9, 1986 to Gaffer et al.; each is incorporated herein by reference. Suitable pyro ion sources include tetrasodium pyrophosphate, sodium acid pyrophosphate WO 94/14407 PCT/US93/117~7 2~913 6 -(Na2H2P207) tel,apotassium pyrophosphale (K4P207); phosphates including but not limited to linear condensed polyphosphates of the g neral formula: M(n+2~PnO(3n ,1) wherein M is Na or K and n is an integer from 2 to 21; phosphonates and diphosphonates such as 5 EHDP (ethane-1-hydroxy-1 1-di,cllospho"ate) and AHP (azacyclo-heptane-2 2~iphosphG, lic acid); phar",aceutically-acceptable alkali metal salts of py,opl)osphales; poly~hospl,aies phospl,onales and dipl~ospl,onates; and mixtures of any of the above. r~ere"ed pyro ions are pyrophosphate ions; ~,rerened polyphosphate ions are those of the above formula wherein n is 6 13 and 21. Preferred alkali metals are sodium and potassium for solubility reasons; mixtures of alkali metal salts are acceptable.
The pH of oral co""~osilions of the subject invention is critical but can be varied to some extent. r,eferdbly the oral co",posilions are at a pH of from about 6 to about 9 more ~referably from about 6.25 to about 8.75 more ~.referably still from about 7.5 to about 8.5.
During manufacture of a cor"posiliGn of this invention the conditions for addition of each co",ponent should be optimized such that the pH of the mixture does not drop below formulation pH at any time during rnixing the indredients.
Co" "~osilions By safe and effective amount as used herein is meant an amount of co""~ound or col"posilion su~r,cie"t to induce a significant positive modirication in the condition to be treated but low enough to avoid serious side effects (at a reasonable benefiVrisk ratio) within the scope of sound medical judgment. The safe and effective amount of the co,npound or composition will vary with the particular condition being l,eale-J the age and physical condition of the patient being l,ealed the severity of the condil;o." the duration of the treatment the nature of concurrent therapy the spel~ific col"pound or composition employed the particular pha""aceutically-acceptable carrier utilized and like factors.
Bythe term comprising as used herein is meant that various additional ~mponenls can be conjointly employed in the compositions of this invention.

~15191~

Components of the topical, oral carrier are suitable for administration to the oral cavity of a human or lower animal and are c compatible with one another and the other c~mponents, especially with the Actives, used in an oral composition of the subject invention.
The term "cGmpdlible" as used herein, means that the co")ponents are ~p~hlc of being co-mingled with one another, in a rnanner such that there is no interac~ion which would subslanlially reduce the efficacy of the oral Colll~,osiliG" under ordinary use conditions.
P, efe, red topical, oral carriers provide the desired characte,istics for mouthwashes, mouth rinses, mouth sprays, dental treatment solutions, toolhpAstes, dental gels, toothpowders, prophylaxis pastes, lozenges, chewing gums, and the like. The topical, oral carriers of the subject invention comprise compGne"ts typically used in such compositions which are well known to a skilled practitioner. Such cG",pG"ents include, but are not limited to, a"licaries agentC,, antiplaque agents, anticalculus agents, dental abrasives, su,ra.,tants, flavoring agents, sweetening agents, binders, hume.,ld,)ts, thickening agents, buffering agents, preservatives, coloring agents and piy",e,lts, etl,anol and water.
Water is an optional co,n~o.,ent of the topical, oral carriers of the compositions of the subject invention. Water employed in the ~,rep~r~lion of the co"""ercially suitable cG",posilions should prereral,ly be of low ion co,~lel)t and free of orya"ic impurities. Water pre~erdbly col"p,ises from about 2% to about 99%, more prer~rably from about 20% to about 95% of the cornpositions of the sl~hject invention. When in the form of toothpaste, the compositions ~refera~ly comprise from about 2% to about 80%, more preferably from about 30% to about 60%, water, while mouthwashes comprise ~,ererdbly from about 45% to about 99%, more preferably from about 75% to about 98%, water.
Dental abrasives useful in the topical, oral carriers of the compositions of the subject invention include many dirrerenl materials.
The material selected must be one which is compatible with the cor~"~osition of i"teresl and does not excessively abrade dentin.
These include, for example, silicas, including gels and precipitates, calcium carbonate, dicalcium orthophosphate dihydrate, calcium 2iS1913 8 py, o,~ os~hate, tricalcium phosphate, calcium polymeta-phosphate, insoluble sodium polymeta-pl ,os~Jhate, hydrated alumina, and resinous abrasive materials such as partiu ~l~te con-lensa~ion products of urea and formaldehyde, and other materials such as those 5 disclosed by Cooley et al. in U.S. Pat. No. 3,070,510, issued December 25, 1962, incorporated herein by reference. Mixtures of abrasives may also be used.
Silica dental abrasives, of various types, can provide the unique benefits of exceptional dental cleaning and polishing pe,ror")a,)ce ~0 without unduly a~racJing tooth enamel or dentin. For this reason they are prefer,ed for use herein.
The silica abrasive polishing materials useful herein, as well as the other abrasives, generally have an average particle size ranging between about 0.1 and 30 microns, ~rererably between about 5 and 15 15 microns. The silica abrasive can be precipitated silica or silica gels such as the silica xerogels described 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 incorporated herein by rerere"ce. rrefer,~d are the silica xerogels marketed under the 20 tradename Syloid~19 by the W.R. Grace & Co,n~,any, Davidson Chemical Division. rrere"ed precipitated silica materials include those marketed by the J. M. Huber CG",oralion under the tradename, 7eoden~), particularly the silica carrying the designation 7eodent 119~). These silica abrasives are des~,ibed in U.S. Pat. No.
25 4,340,583, Wason, issued July 20, 1982, inc6r,Jorate-l herein by r~ference.
Mixtures of abrasives may be used. The amount of abrasive in the co""~ositions described herein ranges from about 6% to about 70%, prererably from about 15% to about 50%, when the denlir~ ice is a 30 tootl,pasle. Higher levels, as high as 90%, may be used i~ the composition is a tooth powder.
Flavoring agents can also be added to the oral compositions of the subject invention to make them more p~l~t~hle. Suitable flavoring agents include menthol, oil of w.;ntergreen, oil of peppermint, oil of 35 spearmint, oil of sassarras, and oil of clove. Flavoring agents are WO 94/14407 ^ PCT/US93/11787 generally included in the subject compositions in amounts of from 0%
to about 3%, prererdbly from about 0.04% to about 2% by weight.
Coloring agents may be added to compositions of the subject invention to improve appearance. If present, coloring agents typically 5 are included at levels of from about 0.001% to about 0.5% by weight.
Sweetening agents are also ,l~refened in the compositions of the subject invention to make them more p~l~t~hle. Sweetening agents which can be used include aspartame, acesulfame, sacchd~ salts, de~lrose, glucose, levulose thaumatin, D-tryptophan, 10 dihy-JIoc~alcones, and cyclar"ate salts. Saccharin salts are prefer,ed.
Sweeteni~g agents are generally used in the sub,ecit compositions in amounts of from 0% to about 6%, ~rererably from about 0.005% to about 5% by weight.
Oral compositions can also conlai" a sur~actant. Suitable 15 su,ractdnts are those which are r~asG"ably stable and form suds throughout a wide pH range, inciuding nonsoap anionic, nonionic, cationic, zwillerionic and a",pholeric orgdnic synthetic detergents, and compalible mixtures thereof. Many of these suitable surfactants are disclosed in U.S. Pat. No. 4,051,234, issued to Gieske et al. on 20 Seple"~ber 27, 1977, and in U.S. Pat. No. 3,959,458 issued to Agricola, Briner, Granger and Widder on May 25, 1976, both of which are incorporated herein by reference. Surfactants are typically present in composilions of the subject invention at a level of from 0%
to about 20%, prefe,ably from about 0.1, more preferdbly from about 25 1% to about 4% by weight. Surfactants may also be used as solubilizing agents to help retain spa,ingly soluble co"~pone,)ts, e.g., some flavoring agents, in solutions. Surfactants suitable for this purpose include polysG,bdles and poloxamers. rlefelled are S~ll rdc~d~ which are non-ionic at the formulation pH of the 30 compositio"~.
In prepdring oral co,nposilions of the s~ ject invention, it is desirable to add binders and/or thickening agents, particularly to tootl,paste ~"~positions to provide a desired consistency. Suitable binders for these compositions are natural gums such as gum karaya, 35 gum arabic, and gum tragacanth; polysaccharide gums such as xa, llhan gum; and other natural products such as carrageenan;

WO 94/14407 PCT/US931117$7 -~ 2i5i913 ~o chemically modified natural products such as those based on cellulose esters that is ca,boxylmethylcellulose (CMC) hydroxyethylcellulose (HEC) and hydroxypropylcell~ ~ose (HPC); and synthetic binders such as polyvinylpyrrolidone; and water soluble salts of cellulose ethers 5 such as sodium carboxymethyl ce!lulose and sodium carbokymethyl 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 10 may significantly improve the cl~ara- lerislics of con,positions made therewith. rlefe"ed binders are chemically modified celluloses such as CMC or HEC; more l.refer,ed is HEC. Binders and thickening agents are generally prese"~ in the co"~positions of the subject invention in amounts of from about 0.1% to 10% preferably from about 15 0.25% to about 7.5% more p~rerably from about 0.5% to about 3.5%.
Another optional co""~oi)ent of the oral carriers of the co""~osilions of the subject invention is a hL",.eclanl. The humectant serves to keep toothpasle compositions from hardening upon ~xros~ ~re to air and to give mouthwash and toothpaste co,--posilions a 20 moist feel to the mouth. Certain hulllecS~Ills can also impart desirable sweetness of navor to mouthwash and toothpaste c~",positions. The humectant on a pure hu",eclant basis generally comprises from 0%
to about 70% ~re~erably from about 2% to about 55% by weight of the co"".osilions herein. Suitable humectants for use in composilions 25 of the subject invention include edible polyhydric alcohols such as glycerin sorbitol xylitol, polyethylene glycol and propylene glycol especi-'ly sorbitol and glycerin.
Opacifiers may also be used in toothpastes of the subject invention to render the to.~SI ,paste op~ e. Suitable opacifiers include 30 titanium dioxide and some abrasives including for example, magnesium aluminum silic~te. Opacifiers generally comprise froM 0%
to about 4%, prerel ably from àbout 0.5% to about 3% by weight of the compositions herein.
Other optional co",ponents of the compositions of the s~l~ ect 35 invention are preservatives. The preservatives prevent microbial growth in the compositions. Suitable preservatives include 21~1913 methylparaben, propylparaben, ben~o~tes and ethanol. If the preservative is ethanol, it generally co",~,rises from 0% to about 35%
by weight, pl ~7rerably from about 5% to about 15%, of the compositions herein. Other preservatives generally coi"prise from 0% to about 5%
5 by weight, pre~rably from about 0.1% to about 2%, of the composilio"s herein.
Antimicrobial, an~ipl~ue agents can also optionally be present in the oral co",posilions of the subject invention, on lhe condition that they are compatible with the Actives. Such agents may include, but are not limited to, triclosan, 2,4,4'-trichloro-2'-hydroxydiphenyl ether, as described The Merck Index, 11th Ed. (1989), p. 1520 (entry No.
9573); chlorhexidine, (Merck Index. No. 2090); alexidine (Merck Index.
No. 222); hexetidine (Merck Index, No. 4624); sangu;.,a,i"e (Merck Index, No. 8320); benzalkonium chloride (Merck Index, No. 1066);
salicylanilide (Merck Index, No. 8299); don~iphen bro",ide (Merck Index, No. 3411); cetylpyridinium chloride, (CPC) (Merck Index. No.
2024); tetradecylpyridinium chloride, (TPC); N-telradecyl-4-ethylpyridinium chloride (TDEPC); octenidine; del~nopinol, octapinol, and other piperidino derivatives; nicin preparatio"s; antihiotics such as auy,),enlin, a",oxicillin, tetracycline, doxycycline, minocycline, and metronidazole; and peroxides, such as cylium peroxide, hydloger, ~,eroxide, and ",ag,)esium ",o, IGpei 11 ,alate and its analogs as des~il,ed in U.S. Patent No. 4,670,252; and analogs and salts of the above antimicrobial antipl^1~e agents. If presenl, the antimicrobial antirl-1ue agents may co"" ,ise from 0% to about 6%, ~referably from about 0.1% to about 5% by weight of the cornposilions of the subject invention.
Bleaching agents can also be present in the oral co",posilions of the subject invention. Suitable bleaching agents include organic and i"oryanic oxidizing agents such as hydrogen peroxide, alkali metal peroxides and su~eroxide and orydnic peroxides such as ",o"oper-oxyphthalates and perbenzoic derivatives. If present, such bleaching agents may co",~rise from 0% to about 6%, prererably from about 1% to about 5% by weight of the compositions of the subject invention.

21S ~9 l 12 PCTIUS93/11787 Nutrients can also be present in the oral composition of the subject invention, on condition that they are co"~a~ible with the Actives. Such agents may include folate, retinoids (Vitamin A), Vitamin C, Vitamin E. If pr~senl, the nutrients generally co""~,ise from about 0.001% to about 10% by weight of the com~osilions of the subject 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 cor,)pound. This water-soluble fluoride compound is typically presenl in the composilions of the subjec invention in an amount surficienl to give a fluoride co"ce"l(a~ion of from about 0.0025% to about 5.0% by weight, prererably from about 0.005% to about 2.0h by weight. rlefer,t:d fluoride sources are sodium fluoride, ~cid~ tecl phosphate fluoride, and sodium monofluorophosphate. U.S. Pat. No. 3,678,154, issued July 18, 1972 to Widder et al:, disc~oses such salts as well as others, and is incû",oraled herein by refere,)ce.
rre~er,ed cc,nposilions of the subject invention are in the form of de,)~ir,ices, especi-'ly tootbr~sles. Components of toull,pastes generally include a dental abrasive (from about 10% to about 50%), a surfactant (from about 0.5% to about 10%), a thickenirig agent (from about 0.1% to about 5%), a humectant (from about 10% to about 55%), 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 45%).
Other prefe~ed co",posilions of the s~bject invention are mouth rinses, mouthwashes and mouth sprays. Components of such mouthwashes and mouth sprays include water (from about 45% to about 95%), ethanol (from 0% to about 25%), humectant (from 0% to about 50%), sulr~.:tant (from about 0.01% to about 7%), flavoring agent (from about 0.04% to about 2%), sweetei ,ing agent (from about 0.1% to about 3%), and coloring agent (from about 0.001% to about 0.5%). Such mouth rinses, mouthwashes and mouth sprays may also include an antiplaque agent (from about 0.1% to about 5%).
Other prefe"ed compositions of the present invention are dental solutions. Components of such dental solutions generally include water (from about 90% to about 99%), preservative (from about 0.01%
to about 0.5%), thickening agent (from 0% to about 5%), flavoring agent (from about 0.04% to about 2%), sweetening agent (from about 0.1% to about 3%), and su, racldl ll (from 0% to about 5%).
Metl,ods of Use Another aspect of the subject invention involves methods of treating or preventing mouth odorj dental plaque, calculus and gingivitis, by application of cor"posilions cGIll~Jrisi~9 a safe and effective amount of Actives, to tissues of the oral cavity. Such 10 coi"positions are des.;,ibed hereinabove.
These methods involve administering a safe and effective amount of Actives, typically by adminislering an oral composition of the subject invention, as des~ibed hereinabove, to the oral cavity.
Generally an amount of con)pos;lion co",,~)rising at least about 0.0019 15 of the Actives is effective. The teeth and other oral cavity tissl ~es are exposed to the Actives.
When the oral co",position is a toothpaste, typically from about 0.3 grams to about 15 grams, prererably from about 0.5 grams to about 5 grams, more prererably from about 1 to about 2 grams, of 20 toothpasle is applied to an applicating device e.g., a tootl,b,ush. The applicating device is then contacted with the oral cavity surfaces in a manner such that the oral composition is contacted with tissue of the oral cavity, ~s~ecially the teeth and gums. The applicating device may be further used to effect an even distribution of the oral co",posilion to 25 the tooth surface, for example by brushing. The application prererably lasts for a period of from about 15 seconds to about ~0 minutes, more ~referably from about 30 seco"-Js to about 3 minutes, more prererably still from about 1 minute to about 2 minutes. Following application, the toott,paste residue is typically removed from the tooth surface by using 30 a liquid ~ccert~l~le to the oral cavity, typically water, to rinse and be expectordled from the oral cavity.
When the oral co",posilion 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 35 containing the antipl~q~e Active is introduced to the oral ca~ity. The liquid mouthwash is then agitated for from about 10 seconds to about WO 94/14407 ' PCT/US93/117~7 2~ 9 ~3 14 10 min. prererably from about 15 seconds to about 3 min. more prefel-aL,ly from about 30 seconds to about 2 minutes within the oral cavity to obtain an improved distribution of the mouthwash over the tissue of the oral cavity. Following agi~alion the mouthwash is 5 typically ex~,ectoraled from the oral cavity.
Application frequency is prererably from about 3 times weekly to about 4 times daily more p.erera~ly from about once daily to about 3 times daily more ~,rerera61y still from about once to about twice daily.
The period of such treatment typically ranges from about one day to a 1 0 lifetime.
Oral comPosition ExamPles The following non-limiting examples further describe and demonstrate pref~..ed e..,bodi.nents within the scope of the subject invention. The exd-"~les are given solely for illuslration and are not to 15 be construed as li,ilalions of the subject invention as many valia6iGr,s are ~ossi~le without Je,va. ~ing from the spirit and scope of the subject invention.
The co,.,positions of the subject invention can be made using ,............. .elho.ls which are com-~,only used to produce oral care products. EXAMPLES l-XI
The following are exa",~les of ~Jelllir.ice co-.,posilions of the subject invention and are made using convenlional processes. The numbers listed are weight pereel~lages of the co..,positions. During ~anufacture of each ~- ""~osit on a mi limum pH of 7. is main-ained.
c~ r~re~-~ Ex. Ex. Ex. Ex. Ex. Ex.
11 111 lV V Vl Sorbitol 21.17 21.17 14.2 18.3 21.17 31.65 Citric Acid 0.69 0.34 0.51 0.51 1.03 1.46 Sodium Citrate 4.84 2.42 3.63 3.63 7.25 3.68 Zinc Nitrate 2.97 Zinc Sulfate 1.61 Zinc Chloride 1.36 1.36 Zinc Oxide 0.81 0.81 WO 94/1~7 215 i 913 PCT~S93/11787 T~l,d~t~ m 5.08 12.71 10.16 7.62 2.54 11.87 P~uphosphale (60% aqueous solution) Sodium Add 1.33 3.32 2.65 1.99 0.66 ry,~phosph~te Tetrasodium 1.28 3.19 2.55 1.91 0.64 ry, uph~sp~
Sodium Fluoride 0.24 0.24 0.24 0.24 0.24 0.24 Sodium Sa~ha~ 0.46 0.46 0.46 0.46 0.46 0.46 rtanium Dioxide 0.5 0.5 0.5 0.5 0.5 0.5 Silica 22 22 22 22 22 22 Glycerin 9 9 9 9 9 9 Ca~O~"~etl,~l~e" ~CCe 1 1 0.75 0.75 0.75 Xanthan Gum 0.75 0.75 0.75 0.75 I IYdlU~etl,~;Cel UIOSe 0.75 Sodium LaurylSulfate 4 4 4 4 4 4 (27.9% Aqueous solution) Flavor 1.1 1.1 1.1 1.1 1.1 1.1 Water q.s. q.s. q.s. q;s. q.s. q.s.

Slurry pH: 7.1 to 7.3 CG~?O~Cn~ Ex. Vll Ex. Vlll Ex. IX Ex. X Ex. Xl Sorbitol 31.65 31.65 14.2 31.65 31.65 Citric Add(anhydrous or 1.44 0.91 0.73 0.88 2.94 ",onoh~ate) Sodium Citrate 3.23 0.144 4.62 ZincOxide 0.81 0.407 0.81 0.374 0.13 Te~l ~rOI~C~ n 3.3 5.09 25.33 4.22 Py. ophusphale (60% aqueous solution) Sodium Add 1.28 ry, uphosp~

WO 94/1~7 PCT~S93/11787 9~3 16 Tel,~;um 2.66 6.65 1.33 ry. u~hosp~
Sodium Fluoride 0.24 0.24 0.24 0.24 0.24 Sodium Saccl.arin 0.46 0.46 0.25 0.25 0.46 Titanium Dioxide 0.5 0.5 0.5 0.5 0.5 Silica 22 22 22 22 22 Glycerin 2.25 2.25 8 2.25 2.25 Ca.~Ay.. etl,;~e"~lose 0.5 0.5 0.75 0.75 Xanthan Gum 0.4 0.4 0.75 0.75 0.75 l Iyd,u~e~l,;l~e" ~'~se 0.75 Sodium Lauryl Sulfate 4 4 4 4 4 (27.9% Aqueous solution) Flavor 1.1 1.1 . 1 KOH/HCI and Water q.s. q.s. to q.s. q.s. q.s.
to pHpH 8.0 to pH to pH to pH
7.5 8.0 8.0 8.5 Total 100 100 100 100 100 Sluny pH: 7.5 to 8.5 EXAMPLES Xîl-XVI
The following are examples of mouthwash and dental rinse compositions of the subject invention and are made using conventinal processes. The amounts listed are weight ~ercenLages of the 5 compositio"s. During manufacture, the pH of the following co""~osilions is ~aintained at a minimum of pH '.5.
.. ron~n~ Ex. XîlEx. Ex. XIV Ex. XV Ex. XVI
Xlll Glycerin 10 10 10 10 10 Ethanol 10 10 10 10 10 Sodium Citrate 0.41 3.84 1.28 Citric Aad 11.40 3.80 Zinc Chloride 1.36 Zinc Oxide 0.081 1.63 0.81 0.41 WO 94/14407 ' 2151913 PCT/US93/11787 T~l,dl.o~ m 1.10 5.51 1.1 Py, o~hos~,hate (60% Sol'n) Tetrasodium 2.66 0.27 ry~ uphosp~d~e Sodium 7.36 0.37 Tnpolyphospl idte Sodium Acid 6.66 0.22 Pyl opl)oa~JI ,ale SodiumLauryl 0.4 0.4 0.4 0.4 0.4 Sulfate Sodium Sa~l,ann 0.03 0.03 0.03 0.03 0.03 Flavor 0.22 0.22 0.22 0.22 0.22 NaOH/HCL ~ q.s. q.s. q.s. q.s. q.s.
Water 100% 100% 100% at100% at 100% at at pH at pHpH 8.5 pH 7.5 pH 8.0 7.5 8.5 While particular embodiments of th~ subject invention have been Jes~ibed, it will be obvious to those skilled in the art that various chd,)yes and IllGdiricaliGlls to the subject invention can be made without depa, ling from the spirit and scope of the invention. It is 5 intended to cover, in the appended claims, all such l"oJiricalions that are within the scope of the subject invention.

Claims

1. A composition for treating or preventing dental plaque, calculus and gingivitis, or malodor of the oral cavity, comprising:
(a) (i) a source of a safe and effective amount of zinc ions;
(ii) a source of citrate ions; and (iii) one or more anticalculus agents selected from pyrophosphate, phosphonate, diphosphonate and pharmaceutically-acceptable linear condensed poly-phosphates of the general formula: (PnO(3n+1))(n+2)- wherein n is an integer from 2 to 21;
wherein the molar ratio of zinc:citrate is at most 1:1; the molar ratio of zinc:pyro is at most 1:1; and (b) a pharmaceutically-acceptable topical oral carrier.

2. The composition according to Claim 1 wherein the molar ratio of zinc ions:citrate ions is from 1:1 to 1:20, preferably from 1:1 to 1:5, more preferably from 1:1 to 1:4, and the molar ratio of zinc ions to the anticalculus agents is from 1:1 to 1:20, preferably from 1:1 to 1:8, more preferably from 1:1 to 1:5.

3. The composition according to any of Claims 1-2 wherein the composition is at a pH of from 6 to 9, preferably from 7.5 to 8.5 and the sum of the molar ratio amounts of citrate ions and anticalculus agents is from 3 to 9.

4. The composition of any of Claims 1-3 which is in the form of a dentifrice, preferably wherein the pharmaceutically-acceptable topical oral carrier comprises a dental abrasive.

5. The composition according to any of Claims 1-4 which comprises from 0.1% to 2%, preferably from 0.25% to 1%, by weight zinc ions.

6. A composition according to any of Claims 1-3 which is in the form of a mouth rinse, preferably wherein the pharmaceutically-acceptable topical oral carrier comprises a material selected from a humectant, ethanol, and a nonionic surfactant.

7. The composition according to any of Claims 1-3 and 6 comprising from 0.005% to 0.5% by weight zinc ions.

8. The composition according to any of Claims 1-7 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 anticalc agent is pyrophosphate.

9. The composition according to any of Claims 1-8 which comprises 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 lower mammal a safe and effective amount of a composition selected from Claims 1-9.