NZ238146A

NZ238146A - Dentifrice composition including an alkali metal or ammonium phosphate salt and a water insoluble non cationic antibacterial agent

Info

Publication number: NZ238146A
Application number: NZ23814688A
Authority: NZ
Inventors: Abdul Gaffar; Brian S Jannone; Nuran Nabi
Original assignee: Colgate Palmolive Co
Priority date: 1987-01-30
Filing date: 1988-01-07
Publication date: 1992-02-25
Also published as: NZ236645A; NZ236642A; NZ236644A; NZ236641A; NZ236643A

Description

<div id="description" class="application article clearfix"> New Zealand Paient Spedficaiion for Paient Number £38146 2 "3 8 '1 4 6 Under the provisions of Regulation 23 (1) the Specification has been ante-dated 19 * _ i' . : f- - t » C ' ' »+»»■ imM********""""*"""""""' *1 Patents Form No. 5 Number Initials PATENTS ACT 1953 Dated ; y' V 1 ' I W ,4MAYt99l. "Divided out of N.Z. Patent 223125" Vf,. COMPLETE SPECIFICATION rOML ANTIBACTERIAL ANTIPLAQUE ANTICALCULUS'COMPOSITION We, COLGATE-PALMOLIVE COMPANY of 300 Park Avenue, New York, New York 10022, United States of America, a corporation under the laws of the State of Delaware, United States of America do hereby declare the invention for which I/we pray that a Patent may be granted to me/us, and the method by which it is to be performed, to be particularly described in and by the following statement: 2 3 8 14 6 j This invention r < ■ I a; 's to an ant.ibactorial nntiplaquo ant. i oil cuius I dentifrice cuqxisit ion. More ;vu t iculat ly, it relator, to a dent i 1 ricc 11 compos! t Ion containing a polyphosphate ar.t icalculus (that is, , antitartar) agent am! a compatible ant 1 bacteria 1 agent effective to I inhibit plaque. II ■ I ; In N.7.. Pat-n' Sp^oi' i to Gaffar c-t a1. ; 4 , 1 S, 7 T 2 j to Parran et al; and •' ,''.23, rr~' to Pis-ran, oral cv/u x~r, i r ions are d^scriiyxl which include various wo 1 ypims: h i t ■■ ';opu j'ui.-'.ds . In the ratc-nt to Gaffar et al, a linear polyphosphate salt, is etrp!oyed ;n • conjunction with a fluoride ion-providing source and a synthetic linear I polymeric polycarboxylate to inhibit calculus formation. In the patents to Parran et al and to Parran water soluble II . I ijdialkali metal pyrophosphate alone or mixed with tetraalkali metal : pyrophosphate is employed. Oral compositions which inhibit calculus formation on dental surfaces are highly desirable since calculus is one of the causitive ; factors in periodontal conditions. Thus, its reduction promotes oral jj hygiene. i1 i| Dental plaque is a precursor of calculus. Unlike calculus, !| ,, however, plaque may form on any part of the tooth surface, particularly jj including at the gingival margin. Hence, besides being unsightly, it I !' is implicated in the occurence of gingivitis. i; Accordingly, it would be highly desirable to include j} antimicrobial agents which have been known to reduce plaque in oral •compositions containing anticalculus agents. Indeed, this has been 'described in U.S. Patent "• ,0?."', iid') to Vinson et al, wherein a compound (providing zinc ions as an anticalculus agent is admixed with an I :antibacterial agent effective to retard the growth of plaque bacteria. :A wide variety of antibacterial agents are described with the zinc -2- 238146 j cxjnpounds including cationic iiut dials such as quanicier, and quat.einary : i nmraonium compounds as well as non-catio:ii o compounds such as h.iiogenated 1 salicylanilides and hal ogena ted hydroxyd iphenyl others. I | Hitherto, the cationlc antibacterial materials 6uch as ; chlorhexidine, benzthonlura chloride and cefyl pyridinium chloride have I i i been the subject of greatest investigation as antibacterial ant 1 plaque II ■jagents. However, in spite of their being used in conduction with zinc •anticalculus agent, they are not effective when used with anionic ; i materials such as polyphosphate anticalculus agent. This ,! ineffectiveness is considered to be quite surprising as polyphosphates ! ■;are chelating agents and the chelating effect has previously been known i 11to increase the efficacy of cationic antibacterial agents.(6ee e.g. !; ij Disinfection, Sterilization and Preservation, 2nd Ed., Black, 1977, page ! 915 and Inhibition and Destruction of the Microbial Cell, Hugo, 1971, I .jpage 215). Indeed, quaternary ammonium compound is present in the j:plaque control mouthwash containing pyrophosphate of U.S. Patent A,323,551 and bis-biguanide antiplaque agent is suggested in the I ^anticalculus pyrophosphate oral composition of U.S. Patent 4,515,772. ij In view of the surprising incompatibility of cationic I:antibacterial agents with polyphosphates present as anticalculus agents, ' t • t it was quite unexpected that other antibacterial agent would be I ' effective. i j It is an advantage of this invention that certain antibacterial ! i agents are effective in anticalculus dontiiri.ce eoiTpositions to inhibit •! plaque formation. l| It is a further advantage of this invention that a composition , is provided which Is effective to reduce plaque and calculus formation. l | It is a further advantage of this invention that an antiplaque, j| anticalculus dentifrice cau(x;sition is provided which is effective to ^ reduce the occurence of cjinyivilJ-S. ' i Additional advantages of this invention will be apparent from I i; consideration of tho following specification. j In accordance with certain of its aspects this invention :j relates to a dentifrice cxinposit ion (as heroin defined) comprising in ii '! an orally acceptable vohicle, an effective anticalculus amount of material 'j conprising at least one wholly or partially neutralized alkali metal jj or aimonium tripolyphosphate or hexametaphosphate salt as essential •' anticalculus agent and an effective antiplaque amount of a substantially water insoluble noncationic antibacterial agent selected from the group | consisting of halogenated diphenyl ethers, phenolic compounds, and halogenated carbanilides. :| ■ ' In this specification and claims ''dentifrice'1 and ''dentifrice 1 : | composition' ' mean any toothpaste or cream or dental gel, mouthwash j or rinse, toothpowder, chewing gum, or tablet or lozenge or any other | preparation or comjxisition for cleansing teeth. '! Typical exanples of antibacterial agents which are particularly ( 1 i :j desirable from considerations of antiplaque effectiveness, safety and ' formulation are: !| I Halogenated Diphenyl Ethers 2,4,4' -trichloro- >.1 -hydroxy-diphenyl ether (Triclosan) '! 2,2' -dihydroxy-5,5' -dibrcmo-diphenyl ether. Phenolic Compounds (including phenol and its hcmologs, mono- and jj poly-<ilkyl and aromatic haloplienols, resorcinol and its derivatives, ; bisphenolic compounds and halogenated salicylanilides). i ! Phenol and its Hcmologs Phenol , 2 Methyl - Phenol 3 Methyl - Phenol 1 4 Methyl - Phenol 4 Ethyl - Phenol 2,4-Dimethyl - Phenol I 2,5-Dimethyl - Phenol i 3,4-Dimethyl - Phenol 238 1 4 6 12,6-Dimethyl - Phenol 'I • i ■ | 4-n-Frupyl - Phenol |4-n-Butyl i !4-n-Amyl 4-tert-Amyl 4-n-Hexyl 4-n-Heptyl •i Methyl lEthyl i I In-Propyl - Phenol - Phenol - Phenol - Phenol - Phenol Mono- and Poly-AIkyl and Aromatic Halophenols - p-Chlorophenol - p-Chlorophenol - p-Chlorophenol J n-Butyl - P~ ■Chlorophenol 1n-Arayl - P" ■Chlorophenol 'sec-Anyl P" ■Chlorophenol i n-Hexyl - P" ■Chlorophenol i j Cyclohexyl - P" -Chlorophenol 1 J n-Heptyl P- -Chlorophenol i n-Octyl P- -Chlorophenol |O-Chlorophenol Methyl - o- -Chlorophenol > 1 Ethyl 1 o- -Chlorophenol I ' n-Propyl - o- -Chlorophenol ! n-Butyl , \ o- -Chlorophenol •\ |n-Amyl o- -Chlorophenol tert-Amyl o' -Chlorophenol • 1 ri-Kexyl - o' -Chlorophenol i n-Heptyl - o -Chlorophenol 11 p-Ch] orophenol 11 o-Benzyl - p-Chl I I II -5- - p-Chlorophenol - p-Chlorophenol - p-Chlorophenol - p-Chlorophenol - p-Chlorophenol - p-Chlorophenol - p-Chlorophenol - p-Chlorophenol - p-Chlorophenol - p-Chlorophenol - p-Chlorophenol J, 2~lso-Propyl-3,5-dimethyl - p-Chlorophenol •i jj6-Diethyloethyl-3-methyl - p-Chlorophenol :! 6-iso-Propyl-2-ethyl-3-methyl - p-Chlorophenol 4 I 2-sec Amyl-3,5-dimethyl - p-Chlorophenol :| ji2-Plethylmethyl-3.5-dlmethyl - p-Chlorophenol 'j 6-sec Octyl-3-oethyl - p-Chlorophenol '• p-Bronophenol j Methyl , Ethyl i! |n-Propyl ;i n-Butyl ■ i i • J n-Arayl sec-Amyl . in-Hexyl cyclohexyl Jj o-Bromophenol li tert-Anyl jj n-Hexyl ■ i ' I •J o-Benzyl-o-methyl |! j)o-Benzyl-o, n-dlaethyl |j o-Phenylethyl i j If o-Phenylethyl-m-nethyl 1 j 3-Methyl j 3,5-Ditoethyl • i •6-fcthyl-3-nethyl 6-n-Propyl-3-methyl j 6-iso-Propyl-3-methyl |l2-Ethyl-3,5-dlmethyl ij 6-sec Butyl-3-methyl - p-Bromophenol - p-Bromophenol - p-Bromophenol - p-Bromophenol - p-Bromophenol - p-Bromophenol - p-Bromophenol - p-Bromophenol - o-Bromophenol - o-Bromophenol it n-Propyl-m jiD-Dlmethyl - o-Bromophenol . |2-Phenyl Phenol ''4-chloro-2-methyl phenol ■4-chloro-3-methyl phenol . I 4-chloro-3,5-dlmethyl phenol I ! 2,4-dichloro-3,5-dlraethylphenol I .3,4,b,6-terabromo-2-methy1 phenol jj 5-nethyl-2-pentylphenol II i4-isopropyl-3-methylphenol • 5-chloro-2-hydroxydiphenyliEthane • l ! 'i Resorcinol and Its Derivatives •Resorcinol •'Methyl ■! Ethyl : n-Propyl ■| jj r;-Butyl 1n-Amyl !| n-Hcxyl il - Resorcinol - Resorcinol - Resorcinol - Resorcinol - Resorcinol - Resorcinol - Resorcinol - Resorcinol - Resorcinol - Resorcinol - Resorcinol - Resorcinol - Resorcinol p-C'niurobenzyl - Resorcinol 5-Chloro -2,4-Dihydroxydiphenyl Methane A'-Chloro -2,4-Dihydroxydiphenyl Methane 5-Bromo -2,4-Dihydroxydiphenyl Methane n-Heptyl n-Octyl ,| n-Nonyl Phenyl I Benzyl J | Phenylethyl ;Phenylpropyl ^ 3 j * 4 ^ i J X.' A'-Bromo -2,4-Dihydroxv.M phenvl Methane i i : Btsphenolic Compound's I 2 ,2 '-methylene bis (^-chlorophenol ) i I 2,2'-methylene bis (3,4,6-trichlorophenol) 2,2'-methylene bis (4-ch!oro-6-bromophenol) bis (2-hydroxy-3,5-dichlorophenyl) sulfide I M s (2-hydroxy-5-chlorobenzvl) sulfide j Halogenated Sa11cylanil1des i4',5-dibromosalicylanilide '3,A',5-trichlorosalcylanllido I .3,A',5-tribromosalicylnnllide !2,3,3 ' , 5-tetrachlorosalicvlanilide I I 3,3' ,5- t r icii loro.->a 1 i cv 1 an i I i do :3,5-dibromo-3'-tri fluoromethyl salicylaniiide j 5-n-octanoyl-3'-trifluoromethyl salicylaniiide I j ;!3,5-dibromo-4'-trifluoromethyl salicvlanilide !i 3,5-dibromo-3'-trifluoro methyl salicylaniiide (lluorophene) ! ii : I II it i| 11 i! ii Jj Halogenated Carbanllldes ,j 3,4,4'-trichlorocarbanilide I i II 3-t rifluorome thyl-4,4'-dichlorocarbanilide ! 3,3',4-trichlorocarbanilide •I The antibacterial agent is present in the dentifrice conposition in ;jan effective antiplaque amount, typically about 0.01-5% by weight, -8- 2 3 8 1 j!preferably about 0.03-12. The antibacterial agent 1b substantially 1 !■water-insoluble, meaning that lt6 solubility is less than about 1Z by • i i!weight in water at 25°C and may be even less than about 0.1Z. If I 1 anionizable group is present solubility Is determined at a pH at which i I '! ionization does not occur. ■ i J j The preferred halogenated diphenyl ether is Triclosan. The ,jpreferred phenolic compound are hexyl resorcinol, 2,2'-methylene ,jbis(A-chloro-6-bromophenol) and Fluorophene. The most preferred ||antibacterial antiplaque compound is Triclosan. Triclosan is disclosed in aformentioned U.S. Patent A,022,880 as an antibacterial agent in I • i "combination with an anticalculus agent which provides zinc ions. It is i jalso disclosed 86 an antiplaque agent in a dentifrice formulated to '!contain a lamellar liquid crystal surfactant phase having a lamellar !|spacing of less than 6.0 mm and which may optionally contain a zinc salt i . 5j in published European Patent application 0161898 of Lane et al and in a i jjdentifrice containg zinc citrate trlhydrate in published European Patent 'Application 0161899 to Saxton. '! The linear polyphosphate salts operative 'I herein as anticalculus agents are well known, being generally employed j! 'I in the form of their wholly or partially neutralized water soluble I I ljalkali metal (e.g. potassium and preferable sodium) or ammonium salts, l I Hand any mixtures thereof. Representative examples include sodium '.! hexametaphosphate, sodium tripolyphosphate, disodium diacid, trisodium i I i|monoacid and tetrasodium pyrophosphates and the like. Linear ..polyphosphates correspond to (NaP03)n where n is about 2 to about 125. I .They are generally employed in the instant oral compositions in ! •[approximate weight amounts of 0.1 to 7% preferably 0.1 to 7Z, more i 'preferably 2 to 7Z. When n is at least 3 in (NaP03)n, said !|polyphosphates are glassy in character. 27R1 Aft \ IVirt ieulnrly desi rablo ant . ic.ilcuius agont s dn; t.otrnulkal i 'pyrophosphate, toirapntassiin pvro^hosph*Le «nd mixtures thereof. An ' nntlral cuius agent comprising about A.3". to about 7* by weight of the oral compositions whore In the weight ratio of tct rapotas6 ium ipyrophosphate to tetrasodiuni pyrophosphate is from about 4.3:2.7 to I I about 6:1 is especially preferred. ; In order to optimize the anticalculus effectiveness of the dcnt.it rice j jcomposition, inhibitors against enzymatic hydrolysis of the polyphosphate are desirably present. Such, agents are an amount of a I |fluoride ion source sufficient to supply 25 ppn. to 5,000 ppm. of I ;fluoride ions, and 0% to 37. of a synthetic anionic polymeric Ipolycarboxylate having a molecular weight of about 1,000 to about Ij 1,000,000, preferably about 30,000 to about 500,000. 1 The sources of fluoride ions, or fluorine-providing component, !i ■ias acid phosphatase and pyrophosphatase enzyme inhibitor component, are ! j ''well known in the art as anti-caries agents. These compounds may be jjslightly soluble in water or may be fully water-soluble. They are i i • i ^characterized by their ability to release fluoride ions in water and by |freedom from undeslred reaction with other compounds of the oral , t : t preparation. Among these materials are inorganic fluoride salts, 6uch II ■I ;as soluble alkali metal, alkaline earth metal salts, for example, sodium ! I 'jfluoride, potassium fluoride, ammonium fluoride, calcium fluoride, a j I '!copper fluoride such as cuprous fluoride, zinc fluoride, barium ;ifluoride, sodium flourosilicate, ammonium florosilicate, sodium : i !! fliiorozirconate , sodium fluorozirconate , sodium monofluorophosphate, ;]aluminum mono- and di-fluorophosphate, and fluorinated sodium calcium i | 1 •pyrophosphate. Alkali metal and tin fluorides, such as sodium and Jjstannous fluorides, sodium monofluorophosphate (MFP) and mixtures thereof, are preferred. -10- li ■ The amount of fluorine-providing compound is dependent to some iextent upon the type of compound, its solubility, and the type or oral |Jpreparation, but it must be a non-toxic amount, generally abut 0.005 to :|about 3.02 in the preparation. In a dentifrice preparation, e.g. dental jjgel, toothpaste (including cream), toothpowder, or dental tablet, an 'I jjamount of such compound which releases up to about 5,000 ppm of F ion by I , weight of the preparation is considered satisfactory. Any suitable 'I ^minimum amount of such compound may be used, but it is preferable to ,jemploy sufficient compound to release about 300 to 2,000 ppm, more preferable about 800 to about 1,500 ppm of fluoride ion. ■I i Typically, in the cases of alkali metal fluorides, this .'component is present in an amount up to about 22 by weight, based on the i! i|weight of the preparation, and preferably in the range of about 0.05% to '!12. In the case of sodium monofluorophosphate, ! the compound may be present in an amount of about 0.1-32, more typically i j about 0.762. In dentifrice preparations such as lozenges and chewing gum, l!the fluorine-providing compound is typically present in an amount sufficient to release up to about 500 ppm, preferably about 25 to 300 |jppm by weight of fluoride ion. Generally about 0.005 to about 1.0 wt. 2 i! !|of such compound is present. II Ij The synthetic anionic polymeric polycarboxylate is an inhibitor ,;of alkaline phosphatase enzyme. Synthetic anionic polymeric jjpolycarboxylates and their complexes with various cationic germicides, ijzinc and magnesium have been previously disclosed as anticalculus agents .per se in, for example U.S. Patent No. 3,429,963 to Shedlovsky; U.S. Patent ,| No 4,152,420 to Gaffar; U.S. Patent No. 3,956,480 to Dichter et al; U.S. ; I 'Patent No. 4,138,477 to Gaffar; and U.S. Patent No. 4,183,914 to Gaffar et ||al. However, only in aforementioned N.Z. Patent Specification No. 217558 'I II ' I i i 11 23 8 1 \ ! I! ! * to Gaffar et al is there disclosed use of such polycarboxylates alone i | for inhibiting salivary hydrolysis of pyrophosphate anticalculus agents, ijrauch less in combination with a compound providing a source of fluoride I; ;|ion. It i6 to be understood that the synthetic anionic polymeric ''polycarboxylates so disclosed in these several patents are operative in the compositions and methods of this Invention and such disclosures are to that extent incorporated herein by reference thereto. II The synthetic anionic polymeric polycarboxylates optionally but preferably employed herein are, as indicated above, well known, being often employed in the form of their free acids or preferably partially or more preferably fully neutralized water soluble alkali metal (e.g. jpolassiura and preferably sodium) or ammonium salts. Preferred are 1:4 jto 4:1 copolymers of maleic anhydride or acid with another polymerizable i J :ethylenically unsaturated monomer, preferably methyl vinyl ether jCraaleic anhydride) having a molecular weight (M.W.) of about 30,000 to about 1,000,000. These copolymers are available for example as Gantrez ' j(AN 139 (M.W. 500,000), A.N. 119 (M.W. 250,000); and preferably S-97 ;(pharmaceutical Grade (M.W. 70,000), of GAF Corporation. The term ii 11"synthetic" is intended to exclude known thickening or gelling agents ' i j comprising carboxymethylcellulose and other derivatives of cellulose and i natural gums. Other operative polymeric polycarboxylates include those disclosed in U.S. Patent No. 3,956,480 referred to above, 6uch as the 1:1 copolymers of maleic anhydride with ethyl acrylate, hydroxyethyl methacrylate, N-vinyl-2-pyrollidone, or ethylene, the latter being available for example as Monsanto EMA No. 1103, M.W. 10,000 and EMA [iGrade 61, and 1:1 copolymers of acrylic acid with methyl or hydroxyethyl ! I Imethacrylate, methyl or ethyl acrylate, isobutyl vinyl ether or N-vinyl-2-pyrrolidone. -12- ii 23 8 1 i! Additional operative polymeric polycarboxylates disclosed in .above referred to U.S. Patent No. 4,138,477 and 4,183,914, include ;jcopolymers of maleic anhydride with styrene, isobutylene or ethyl vinyl ' I 'ether, polyacrylic, polyitaconic and polymaleic acids, and sulfoacrylic joligomers of M.W. as low as 1,000, available as Uniroyal ND-2. 11 l| Suitable generally are polymerized olefinically or ,etii>lenically unsaturated carboxylic acids containing an activated i icarbon-to-carbon olefinic double bond and at least one carboxyl group, 'I .that is, an acid containing an olefinic double bond which readily I i ifunctlons in polymerization because of its presence in the monomer l ijmolecule either in the alpha-beta position with respect to a carboxyl jgroup or as part of a terminal methylene grouping. Illustrative of such i i iHcids are acrylic, nethacrylic, ethacrylic, alpha-chloroacrylic, |crotonic, beta-acryloxy propionic, sorbic, alpha-chlorsorbic, cinnamic, •bfeta-styrilacrylic, muconic, itaconic, citraconic, mesaconic, i I Mplutaconic, aconitic, alpha-phenylacrylic, 2-benzyl acrylic, '12-cyclohexylacrylic, angelic, umbellic, fumaric, maleic acids and ' I anhydrides . Other different olefinic monomers copolymerizable with such !|carboxylic monomers include vinylacetate, vinyl chloride, dimethyl !|maleate and the like. Copolymers contain sufficient carboxylic salt I jgroups for water-solubility. il ! Also useful herein are so-called carboxyvinyl polymers disclosed as toothpaste components in U.S. 3,980,767 to Chown et al; ^U.S. 3,935,306 to Roberts et al; U.S. 3,919,409 to Perla et al; U.S. ..3,911,904 to Harrison, and U.S. 3,711,604 to Colodney et al. They are j cf.runercially available for example under the trademarks Carbopol 934, 1940 and 941 of B. F. Goodrich, these products consisting essentially of ia colloidally water-6oluble polymer of polyacrylic acid crosslinked with |from about 0.75% to about 2.0% of polyallyl sucrose or polyallyl pentaerythritol as cross linking agent. I I II ij j| -13- \ 2 3 8 14 6 'rtio synLhct ic anionic polymeric polycarboxylate cuapanent is , mainly a hydrocarbon with option.1.! ha'open and 0—containing subs i i tuciit s and linkages as present i r. fur example ester, ether and OH groups, and i when present is generally employed in the instant compositions in 'approximate weight amounts of l", .05 to 3%, preferably 0.05 to 22, more I 'preferably 0.1 to 27.. Amounts in the upper portions of these ranges arc jtypically employed in dentifrice compositions typically containing a ;dental abrasive and used in conjunction with brushing of the teeth, e.g. I j tooth pastes (including creams), gels, powders and tablets. Amounts in excess of these ranges nay be employed for thickening or gelling 11 ! purposes, ! As indicated above, these polvmeric polycarboxylates have been 11 » I ijfound to be effective inhibitors of alkaline phosphatase enzyme. Since l! this enzyme has little activity (for hydrulyzing pyrophosphate) at about pH 7.0 or below, the polymeric polycarboxylate component nay, if desired, be omitted from oral preparations formulated to operate at such " pH of 7.0 or below. Such omission however could reduce the versatility !|and anticalculus effectiveness of the present oral compositions over the H broad pH range of about A.5 to about 10. j| In dentifrice preparation:; such a:; ru:ut hwashes, lozenges and chewing il gum, the fluorine-providing compound may be typically present in an ii ''amount sufficient to release up to about 500 ppm, preferably about 25 to '! about 300 ppm by weight of fluoride ion. Generally about 0.005 to about n 1.0 wt.7. of such compound is present. i In certain highly preferred forms of the invention the dentifrice :i composition may be substantially liquid in character, such as a mouthwash or rinse. In such a preparation the vehicle is typically a 'water-alcohol mixture desirably including a humectant as described below. Generally, the weight ratio of water to alcohol is in the range -14- 238146 of from about 1:1 to aoout 20:], pn-i t-r.itu v about 3:1 to 10:1 and more ' I preferably about 4:1 to about 6:1. The total amount of water-alcohol j mixture in this type of preparation is typically in the range of from i '! ab-jut 70 to about 99.9*. by vvlplt of the preparation. The alcohol is |j typically ethanol or isopropanol. Ethanol is preferred. ,i The pH of such liquid and other preparations of the invention I p ,! is generally in the range of froa about 4.5 to about 9 and typically ' from about 5.5 to 8. The pH is preferably in the range of from about 6 |j to about 8.0. It is noteworthy that the compositions of the invention , may be applied orally at a pH below 5 without substantially decalcifying !! or otherwise damaging dental enamel. The pH can be controlled with acid ij (e.g. citric acid or benzoic acid) or base (e.g. sodium hydroxide) or i I J |j buffered (as with sodium citrate, benzoate, carbonate, or bicarbonate, j| disodium hydrogen phosphate, sodium dihvdrogen phosphate, etc.). t i In certain other desirable forms of this invention, the dentifrice i ;! composition may be substantially solid or pasty in character, such as toothpowder, a dental tablet or a dentifrice, that is a toothpaste 1 (dental cream) or gel dentifrice. The vehicle of such solid or pasty j oral preparations generally contains dentally acceptable polishing material. Examples of polishing materials are water-insoluble sodium metaphosphate, potassium metaphosphate, tricalciuni phosphate, dihydrated ! I I I calcium phosphate, anhydrous dicalcium phosphate, calcium pyrophosphate, • I ' » 'j magensium orthophosphate , trimagnesiura phosphate, calcium carbonate, aluminum silicate, zirconium silicate, silica, bentonite, and mixtures . thereof. Other suitable polishing material include the particulate i i ' thermosetting resins described in U.S. Pat. No. 3,070,510 of Dec. 15, I 1962 such as raelamine-, phenolic, and urea-formaldehydes, and .j cross-linked polyepoxides and polyesters. Preferred polishing materials jj include crystalline silica having particle sized of up to about 5 -15- »I 2 3 8 1 4 \ 'I ijmicrons, a mean particle size or up to about 1.1 microns, and a surface i1 2 ,jarea of up to about 50, 000 cm. /gm., silica gel or colloidal silica, '{and complex amorphous alkali metal alurninosilicate. . i !l When visually clear gels are employed, a polishing agent of colloidal silica, such as those sold under the trademark SYLOID as Syloid 72 and Syloid 74 or under the trademark SANTOCEL as Santocel 100 ..alkali metal almuino-sllicate complexes are particularly useful, since they have refractive indices close to the refractive indices of gelling . i jjagent-liquid (including water and/or humectant)systems commonly used in :dentifices. ij Many of the so-called "water-insoluble" polishing materials are ,1 anionic in character and also include small amounts of soluble material. ii ijThus, insoluble 6odium metaphosphate may be formed in any suitable •jmanner as illustrated by Thorpe's Dictionary of Applied Chemistry, i!Volume 9, 4th Edition, pp. 510-511. The forms of insoluble sodium ( I ;!metaphosphate known as Madrell's salt and Kurrol's salt are further I I examples of suitable materials. These metaphosphate salts exhibit only .la minute solubility in water, and therefore are commonly referred to as • I • i !| insoluble metaphosphates (IMP). There i6 present therein a minor amount of soluble phosphate material as impurities, usually a few percent such as up to 42 by weight. The amount of soluble phosphate material, which • is believed to include a soluble sodium trimetaphosphate in the case of 11 i| insoluble metaphosphate, may be reduced or eliminated by washing with ■ i !l water if desired. The insoluble alkali metal metaphosphate is typically ; employed in powder form of a particle size such that no more than 1% of j | .the material is larger than 37 microns. The polishing material is generally present in the solid or 11 : pasty compositions in weight concentrations of about 10% to about 99%. i, Preferably, it is present in amounts ranging from about 10% to about 75% -16- | in toothpaste, and from about 703: to about 99% in toothpowder. In a toothpaste, the liquid vehicle ciav comprise water and j jhumectant typically in an amount ranging from about 10% to about 80% by j I weight of the preparation. Glycerine, propylene glycol, sorbitol, 'polypropylene glycol and/or polyethylene glycol (e.g. 400-600) exemplify !|suitable humectants/carriers. Also advantareuus are liquid mixtures of jwater, glycerine and sorbitol. In clear gels where the refractive index is an important consideration, about 3-30 wt. X of water, 0 to about 70 ' i ;jwt.% of glycerine and about 20-80 wt. % of sorbitol are preferably enploved. i' Toothpastes, creams and gels typically contain a natural or ijsynthetic thickener or gelling agent in proportions of about 0.1 to !j about 10, preferably about 0.5 to about 5wt.%. A suitable thickener is synthetic hectorite, a synthetic colloidal magnesium alkali metal i I ;jsilicate complex clay available for example as Laponite (e.g. CP, SP f J :12002,D) marketed bv Laporte Industries Limited. Laponite D analysis i! ''shows, approximately by weight, 58.00% Si0o, 25.40% MgO, 3.05% Na^O, ,0.98% Li„0, and some water and trace metals. Its true specific gravity ! I C is 2.53 and it has an apparent bulk density (g./tnl. at 8% moisture) of i i 1'0* ! i jj Other suitable thickeners include Irish moss, gum tragacanth, '! starch, polyvinylpyrrolidone, hydroxyethypropylcellulose, hydroxybutyl l! methyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose (e.g. available as Natrosol), sodium carboxymethyl. cellulose, and colloidal silica such as finely ground Syloid (e.g. 244). It will be understood that, as Is conventional, the dentifrice ,preparations are to be sold or otherwise distributed in suitable I i 1 labelled packages. Thus a jar of mouthrinse will have a label |jdescribing it, in substance, as a mouthrinse or mouthwash and having 238 14 6 I directions for its use; an! a toothpaste, crem- or gel will usuallv bo in n collapsible tube, typic.illv aluminum, lined lead or plastic, or • >thcr squct.'" , pur.;' or pr<-j"sur ! red <ii sponsor for petering i>i;r the .-or.tprtK, having a label describing it, in substance, as n toothpaste, gel or dental crcan. Organic surface-active agents art- used in the compositions of the present invention to achieve increase: prophylactic action, assist ! 1 in achieving thorough and complete disporsion of the anticalculus agent ij throughout the oral cavity, and render the Instant compos it ions more cosmetically acceptable. The orivnio surf ace-act i v«- material is preferably anionic, nonionic or amphulytlc in nature, and it is |i preferred to employ as the surface-active agent a detersive material : t Ij which imparts to the composition detersive and foaming properties. ;; Suitable examples of anionic surfactants are water-soluble salts of j higher fatty acid monoglyceride monosuifates, such as the sodium salt of .! ■i the monosulfated raonoglyceride of hydrogenated coconut oil fatty acids, higher alkyl sulfates such as sodium lauryl sulfate, alkyl aryl sulfonates such as sodium dodocyl benzene sulfonate, higher alkyl sulfoacetates , higher fatty acid esters of 1,2-dihydroxy propane ■ i j| sulfonate, and the substantially saturated higher aliphatic acyl amides \ j of lower aliphatic amino carboxylic acid compounds, such as those having ! 12 to 16 carbons in the fatty acid, alkyl or acyl radicals, and the Ij like. Examples of the last mentioned amides are H-lauroyl sarcosine, j and the sodium, potassium, and ethanolainine salts of N-lauroyl, ,I N-myristoyl, or N-palmitoyl sarcosine which should be substantially free i I from soap or similar higher fatty acid material. The use of these : sarcoBinate compounds in the dentifrice-! cciiifxir.itions of the present invention I is particularly advantageous since these materials exhibit a prolonged ,j and marked effect in the inhibition of acid formation in the oral cavity 23 8 1 4 due Co carbohydrate breakdown in addition to exerting some reduction in the solubility of tooth enamel in acid solutions. Examples of water-soluble nonionic surfactants are condensation products of ethylene oxide with various reactive hydrogen-containing compounds reactive there-« with having long hydrophobic chains (e.g. aliphatic chains of about 12 to 20 carbon atoms), which condensation products ("ethoxamers") contain hydrophilic polyoxyethylene moieties, such as condensation products of poly(ethylene oxide) with fatty acids, fatty alcohols, fatty amides, polyhydric alcohols (e.g. sobitan monosterate) and polypropyleneoxide (e.g. Pluronic materials). It is preferred to use from about 0.05 to 5% by weight and preferably about 0.5 to 5% of the foregoing surface active materials in the instant composition. Various other materials may be incorporated in the dentifrice preparations of this invention such as whitening agents, preservatives, silicones, chlorophyll compounds and/or ammoniated material such as urea, diammonium phosphate, and mixtures thereof. These adjuvants, where present, are incorporated in the preparations in amounts which do not substantially adversely affect the properties and characteristics desired. Significant amounts of zinc, magnesium and other metal salts and materials, generally soluble, which would complex with active components of the instant invention are to be avoided. Any suitable flavoring or sweetening material may also be employed. Examples of suitable flavoring constituents are flavoring oils, e.g. oil of spearmint, pepperment, wintergreen, sassafras, clove, sage, eucalyptus, marjoram, cinnamon, lemon, and orange, and methyl salicylate. Suitable sweetening agents include sucrose, lactose, maltose, sorbitil, xylitol, sodium cyclamate, perillartine, AMP (aspartyl phenyl alanine, methyl ester), saccharine and the like. Suitably, flavor and sweetening agents may together comprise from about 0.1% to 5% more of the prepara-t ion. In the preferred practice of this invention an dentifrice composition -19- 238 14 6 according to this invent ion cx)iit .1 in 1 riq , the composition of the present Invention is preferably applied regularly ' to dental enanel, such as every dnv or every second or third day or I preferably from 1 to 3 times daily, at a pH of about A.5 to about 9, 'generally about 5.5 to about 8, preferably about 6 to 8, for at least 2 i 1 weeks up to 8 weeks or more up to lifetime. The compositions of this invention can be incorporated in | 'lozenges, or in chewing guc or other products, e.g. by stirring into a ! warm gura base or coating the outer suri'.'icf of « gum base, illustrative of which may be mentioned jelutone, rubber latex, vinylite resins, etc., desirably with conventional plasticizers or softeners, sugar or other : sweeteners or carbohwirates such as glucose, sorbitol and the like. 1 i The following examples are further illustrative of the nature of the present invention, but it Is understood that the invention is not ;limited thereto. All amounts and proportions referred to herein and in 1 the appended claims are bv weight. I t i 1 ii -20- 238146 Example 1 Slurries and solutions described below are prepared to determine 1 ;of fectiveness in terms of minimum inhibitory concentration (MIC) of jvarious antibacterial agents against a variety of oral bacterial organises implicated In formation of plaque and leading to gingivitis on dental surfaces. Soft plaque contains about 1.7 >: 10"' organ i sm/gm. J(net weight). The antibacterial agents are admixed with anionic materials, particularly anionic surface active acent often commonly employed in oral compositions and polyphosphate anticalculus agent. | Minimum inhibitory concentration (MIC) of antibacterial agent i i jis used to evaluate the efficacy of the agent in vitro. MIC is defined as the minimum concentration in micrograms/ml of antibacterial agent at jwhich the growth of bacteria is completely inhibited by the agent. The smaller the MIC value the greater is the efficacy of the antibacterial I agent to inhibit the growth of the bacteria. The in vitro MIC data is !related to the efficacy of the dentifrice In vlvo since retention and I release of antibacterial agent into the oral cavity after toothbrushing is in the range of mcg/nl. 5 In the Tables, following disclosure and following Examples, the I jagent Triclosan, 2,A,A'-trichloro-2 '-hydroxydiphenyl ether is indicated j I as "TCilE" ; the quaternary ammonium antibacterial agents benzthonium 'chloride is indicated as "BTC"; The biguanide chlorhexidine digluconate :is indicated as "CH", sodium lauryl sulfate is indicated as "SLS"; the copolymer of maleic anhydride and raethyl vinyl ether available from GAF I 11corporation as "Gantrez S-97" is identified as "Gantrez"; tetrasodium j '1 pyrophosphate is identified as "pyrophosphate"; and sodium fluoride is ||identified as "NaF". 2 5 8 1 / 4 6' TABLE 1 j Test |Solution Minimum Inhibition Concentration (MIC) In mcg/ml Bacteriodes Bacteriodes Art itiubaci 1 lu6 St rep I ococcu; gingival is 1 n t ermcd 1 us actinomyceten- mutans comi tans !1. 0.52 TCHE and 2.5 12 SLS in j water , 2. 0.55! TCHE, 2.5 I 12 SLS, I 12 Gantrez, ■ 22 Pyrophosphate I and 0.22 NaF in | water j 3. 12 SLS in NF. water :4. 12 SLS, NE 12 Gantre2 and 22 Pyrophosphate tn water 2.5 NE NE 5.0 5.0 NE 25.0 25.0 N'E N'E I inote: NE « not effective The results indicate that TCHE in the presence of anionic surfactant inhibited four dental plaque organisms, Bacteriodes i gingivalls, Bacteroides intermedins, Actlnobac111 us ! !actinomycetemcomitans and Strep. mutans at 2.5 mcg/ml and 2.5 mcg/ml, I j 5.0 mcg/ml and 25.0 mcg/ml respectively(1). Similar antibacterial "ffecr is seen in the presence of Gant re r./pyrophosphate/f luor ide( 2). jSLS per se and a combination of SLS/Gantrez/pyrophosphate/fluoride was !ineffective(3 and 4). |j It is noteworthy that in human clinical tests with cationic I antibacterial agents, 0.075/1 BTC dissolved in water is effective in reducing plaque formation while 0.0752 BTC and 12 pyrosphosphate dissolved in water is not. Similarly, 0.012 CH dissolved in water is [effective in reducing plaque formation while 0.012 CII and 12 sodium '[N-lauroyl sarcosinate dissolved in water is not. il -22- !l 23 8 1 4 6 11 Example 2 The adsorption to and release from tooth minerals for ' i .iantiplaque/ antitartar efficacy of agents is assessed by adsorption of M i antibacterial agent to saliva coated tooth mineral hydroxyapnt i te in the j presence and the absence of pyrophosphate (soluble tetraBodium , j pyrophosphate)/Gantrez/NaF. 'j 200 mg. of hydroxyapatite (HA) is treated with human saliva for :2 hours. The excess sal iv.i is v;i>n.vl otf v.th a b;::ii-:' ntul sj I iv.i coated HA ■ I is used for adsorption studies. Various concentrations of TCHE in SLS |or in SLS/pyrophospha t e/Gant re z/N'.nF are mixed with the coated HA and ,Incubated at 37° for 3 hours tinder continuous agitation. At the end of j t !incubation period, the mixtures are centrifuged, HA separated and the 11 amounts of TCHE adsorbed determined by estimating TCHE in the I i . I supernatant at 283nM in a Gilford spectrophotometer. The amounts I i;adsorbed are calculated by the difference between the amount added and : the amount left in the supernatant after the incubation with coated HA. • t The table below summarizes the data, \ i i . i |l .i ii • i • i I I !! TABLE 2 238146 , (-proponents and Concentrations 2 of TCHE Adsorbed to Coated HA j j 0.0C5S TCHE In 12 SLS 802 0.017. TCHE In IX SLS 85% jj 0.0152 TCHE In It SLS 85% 0.02% TCHE in IX SLS 88% : 0.0052 TCHE in 12 SLS; 0.52 80% ' Gantrez; 22 pyrophosphate/ '0.242 NaF '10.012 TCHE " 852 ,0.0152 TCHE " 862 ,0.022 TCHE " 8 7% I » The data indicates that the addition of pyrophosphate/ il Gantrez/NaF does not impair adsorption of TCHE to saliva coated tooth ul^erals. .1 ;! i h ii i \ Example 3 c d c> 1 ' c- u i!Dentifrice Compositions Glyccrlnp i ! Polyethylene Glycol 600 , ioi.« Carrageenan ■ i Sodium Carboxymet Jiyl Cellulose , jSodium Saccharin '! •Sodium Cyclamate i i • ] ;Sodium Fluoride ■ I Deionized water t ,'iTitanium Dioxide 'Sodium Benzoate ,FDiC Blue No. 1(12 Solution) i i ''Sorbitol (702) I ! ;IGantrez S-97 |jTetrasodium Pyrophosphate i I Tetrapotasslum Pyrophosphate Parts 15.00 5.00 0.60 0.40 0.243 15.08 0.400 19.807 8.330(*) 1.50 4.50 •Preciphated Amorph. Hydrated Silica 16.00 1 1 t IPreciphated Amorp. Silica U containing combined alumina Silica Thickener ! |Flavor ii Sodium Lauryl Sulfate 1 TCHE 7.00 1.10 1.20 0.50 Parts 15.00 5.00 0.60 0.40 0.243 23.657 0.50 22.50 1.00(**) 1.50 4.50 16.00 5.50 1.10 1.20 0.50 * liquid ** powder -25- \ 238 146 Example 4 The dentifrice described in Example 3A is compared with the same composition except without any TCHE and with added 0.50 parts of water. Aqueous extracts of each dentifrice are prepared as follows: 50 j ml of distilled water is added to 1.0 gm of each dentifrice, mixed well , for a couple of hours with stirring bar and centrifuged, after which the 'supernatant is collected as aqueous extract. Antibacterial activity of ||the dentifrice extracts are evaluated on Bacteriodes glnglvalls. Results are summarized below. I I I ■ I TABLE 3 11 II II Inhibition of Growth of Bacteriodes Glnglvalls ji Treatment X i|Extract from dentifrice containing 100.0 TCHE (1:500) I Extract from dentifrice without 0.0 TCHE (1:500) •I 'TCHE (5.0 mcg/ml) by itself 100.0 II 1 i ; These results indicate that TCHE antibacterial antiplaque agent is ! i 'compatible in a dentifrice composition containing anionic surfactant jjplus pyrophosphate anticalculus ingredients with enzyme inhibitors i I iGantrez and NaF. Similar comparable effects prevail when each of hexyl resorcinol, 2,2'-methylene bis(4-chloro-6-bromophenol) and Flourophene ,replace TCHE. -26- \ Exainpl e !i' ] Mou tlirlrise 1'Tetrasodium Pyrophosphate i!Gantrez S-97 iIG1ycerlne ■ i Sodium Fluoride Fluronic F108 (Polyoxyethylene/Polyoxypropylene Block Copolymer) TCHE Flavor Wa t e r -• t s 2,00 0.25 10.00 0.05 2.00 0.10 0.40 O.S. to 100.00 i Example 6 Lozenge ■ 75-80% Sugar 1-20? Corn Syrup .i 0.1-1.0 Flavor < ] 2% Tetrasodium Pyrophosphate 11 i! 0.252 Gantrez S-97 II '0.01 to 0.052 NaF 0.01 to 0.12 TCHE 'j 1 to 52 Magnesium Stearnte Lubricant i 0.01 to 0.22 Water 233146 !| t . i i! -27- </div>

Claims

<div id="claims" class="application article clearfix printTableText"> ?38M ~x i ;i Example 7 II '. Chewing Gum Parts Gum base 25.00 , Sorbitol (70X) 17.00 i TCHE 0.50 to 0.10 Ij • Tetrasodium Pyrophosophate 2.00 ij j Gantrez S.97 0.25 NaF 0.05 ;Glycerine 0.50 j Crystalline Sorbitol 53.00 ;;Flavor and Water Q.S. to 100.00 •I This invention has been described with respect to certain jpreferred embodiments and it will be understood that modifications and variations thereof obvious to those skilled in the art are to be I included within the purview of this application and the scope of the ;l ,iappended claims. Hr»e Ccmmissioner considers that the inventions described in j this specification cannot be performed without substantial risk of infringement of New Zealand Patent Nos: 223125, 236641, 236642, jj 236643, 236644 and 236645. ' l ! I / / J -28- ? 3 8 ! 4 6 WHAT WE rr,ATM TS

1. A dentifrice composition comprising in an orally acceptable vehicle, an effective anticalculus amount of material comprising at least one wholly or partially neutralized alkali metal or ammonium tripolyphosphate or hexametaphosphate salt as anticalculus agent and an effective antiplaque amount of a substantially water insoluble noncationic antibacterial agent selected from the group consisting of halogenated diphenyl ethers, phenolic compounds and halogenated carbanilides.

2. The dentifrice composition of claim 1 wherein sodium tripolyphosphate is present as an anticalculus agent.

3. The dentifrice composition claimed in claim 2 wherein sodium tripolyphosphate is present in amount of substantially 0.1-7% by weight and as anticalculus agent and said antibacterial agent is present in amount of substantially 0.01-5% by weight.

4. The dentifrice composition claimed in either one of claims 2 or 3 wherein said antibacterial agent comprises 2,4,4'-trichloro-2'-hydroxy-diphenyl ether.

5. The dentifrice composition claimed in Claim 1 wherein sodium hexametaphosphate is present as anticalculus agent.

6. The dentifrice composition claimed in Claim 5 wherein sodium hexametaphosphate is present in amount of substantially 0.1-7% by weight and said antibacterial agent is present in amount of substantially 0.01-5% by weight.

7. The dentifrice composition claimed in Claim 6 wherein said antibacterial agent comprises 2,4,4'-trichloro-2'-hydroxy-diphenyl ether.

8. The dentifrice composition claimed in Claim 1 wherein the phenolic compound is present as an antibacterial agent, said phenolic compound being selected from the group consisting of - 29 - ? 3 8 1 4 6 phenol and homologs thereof (as herein defined - Page 4), mono-alkyl phenols, poly-alkyl phenols, halophenols, resorcinol and its derivatives (as herein defined - Page 7) and bisphenolic compounds.

9. The dentifrice composition as claimed in any one of the preceding claims, wherein the composition is a toothpowder, dental tablet or toothpaste.

10. The dentifrice composition claimed in Claim 8 wherein the composition contains 10-80% by weight of a liquid phase comprising water and humectant and 0.1-10% by weight of a gelling agent and the composition is a toothpaste or dental gel.

11. The dentifrice composition claimed in any one of claims 1 to 8 wherein the composition contains 7 0-99.9% by weight of a mixture of water and alcohol in a weight ratio of from 1:1 to 20:1 and the composition is a mouth rinse.

12. The dentifrice composition claimed in Claim 11 wherein the alcohol is ethanol.

13. The dentifrice composition claimed in tiny one of claims 1 to 8 wherein the dentifrice composition is a lozenge.

14. The dentifrice composition claimed in any one of claims 1 to 8 wherein the dentifrice composition is a chewing gum.

15. The dentifrice composition claimed in any one of the preceding claims wherein said composition further includes a fluoride ion source sufficient to supply 25 to 5,000 ppm. of fluoride ions.

16. The dentifrice compositions claimed in any one of claims 1 to 14 wherein said composition further includes 0-3% by weight of a synthetic anionic polymeric polycarboxylate having a molecular weight of substantially 1000 to substantially 1,000,000. WEST-WALKER, McCA.BE per: ^ ATTORNEYS FOB THE APPUCAlif - 30 - </div>