GB2263066A - Antibacterial, antiplaque, anticalculus, oral composition comprising poly(vinylphosphonic acid) and polyphosphate salt - Google Patents

Description

1 ANTIBACTERIAL ANTIPLAQUE, ANTICALCULUS ORAL COMPOSITION is 1 2263066

This invention relates to an antibacterial antiplaque anticalculus oral composition. More particularly, it relates to an oral composition containing a polyphosphate anticalculus (that is, antitartar) agent and a compatible 10 antibacterial agent effective to inhibit plaque, wherein antiplaque effectiveness is optimized by the presence of an antibacterialenhancing agent which enhances the delivery of said antibacterial agent to, and retention thereof on, oral surfaces.

In U.S. Patents 4,627,977 to Gaffar et al; 4,515,772 to Parran et al; and 4,323,551 to Parran, oral compositions are described which include various polyphosphate compounds. In the patent to Gaffar et al, a linear molecularly dehydrated polyphosphate salt is employed in conjunction with a fluoride ion-providing source and a synthetic linear polymeric polycarboxylate to inhibit calculus formation. in copending European Patent Application 89 200 710.5, anticalculus effectiveness is optimized with a reduced amount of the linear molecularly dehydrated polyphosphate salt in conjunction with the fluoride ion-providing source and increased amount of the synthetic linear polymeric polycarboxylate.

In the patents to Parran et al and to Parran, water 2 J 14958 soluble dialkali metal pyrophosphate alone or mixed with tetraalkall metal pyrophosphate is employed.

Oral compositions which inhibit calculus formation on dental surf aces are highly desirable since calculus is one of the causative f actors in periodontal conditions. Thus, its reduction promotes oral hygiene.

Dental plague is a precursor of calculus. Unlike calculus, however, plaque may f orm on any part of the tooth surface, particularly including at the gingival margin.

Hence, besides being unsightly, it is implicated in the 1. occurrence of gingivitis.

Accordingly, it would be high ly desirable to include antimicrobial agents which have been known to reduce plague in oral compositions containing anticalculus agents.

Indeed, this has been described in U.S. Patent 4,022,550 to Vinson et al, wherein a compound providing zinc ions as an anticalculus agent is admixed with. an antibacterial. agent ef f ective to retard the growth of plaque bacteria. A wide variety of antibacterial agents are describ ed with the zinc compounds including cationic materials such as guanides and ammonium compounds as well as non-cationic halogenated salic lanilides and quaternary compounds such as 30 halogenated hydroxydiphenyl ethers.

Hitherto, the cationic antibacterial materials such as chlorhexidine, benzethonium chloride and cetyl pyridin-Jum j_ 11 3 5714958 chloride have been the subject of greatest investigation as antibacterial antiplaque agents. However, in spite of their being used in conjunction with zinc anticalculus agent, they 5 are not effective when used with anionic 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 10 been known to increase the efficacy of cationic antibacter.ial agents. (see e. g. Disinfection, sterilization and Preservation,, 2nd Ed., Black, 1977, Page 915 and Inhibition and Destruction of the Microbial Cell, Hugo, 5 1971, Page 215). Indeed, quaternary ammonium compound is present in the plaque control mouthwash containing pyrophosphate of U.S. Patent 4,323, 551 to Parran and bis20 biguanide antiplaque agent is suggested in the anticalculus pyrophosphate oral composition of U.S. Patent. 4,515, 772Parran et al.

In view of the surprising incompatibility of cationic antibacterial agents with polyphosphates present as anticalculus agents, it was quite unexpected that other antibacterial agents would be effective.

It is an advantage of this invention that certain antibacterial agents are effective in anticalculus oral compositions containing a linear molecularly dehydra:ted polyphosphate salt, a fluoride-ion-providing source and the 4 71 4950 aforementioned antibacterial-enhancing agent to inhibit plaque formation.

It is a further advantage of this invention that a composition is provided which is effective to reduce calculus formation and optimize plaque reduction.

It is a further advantage of this invention that an dntiplaque, anticalculus oral composition is provided which is effective to reduce the occurrence of gingivitis.

Additional advantages of this invention will be apparent from consideration of the following specification.

In accordance with certain of its aspects this invention relates to an oral composition comprising in an orally acceptable vehicle, an effective anticalculus amount 1 of material preferably comprising about 0.1-3% by weight of at least me, preferably linea molecularly dehydrated, polyphosphate salt as anticalculus agent, an effective antiplaque amount of a subs tantl. al ly water insoluble noncationic antibacterial agent and desirably, up to preferably about 4% by weight of, an antibacterial-enhancing agent which enhances the delivery of said antibacterial to, and retention thereof on, oral surfaces. Preferably the weight ratio of polyphosphate ion to antibacterial-enhancing agent ranges 30 from in excess of 0.72:1 to less than 4:1, e.g. from about 1:1 to about 3.5:1, especially from about 1.6:1 to about 2.7:1, preferably about 1.7:1 to about 2.3:1 and most preferably about 1.9:1 to about 2:1 For instance, when 2% 1 r, J1 4958 tetrasodium pyrophosphate (TSPP) is employed (providing about 1.3% of pyrophosphate ion) with 2. 5% of the antibacterial -enhancing agent, a highly desirable weight ratio of about 1. 9: 1 is provided.

Typical examples of antibacterial agents which are 10 particularly desirable from considerations of antiplaque effectivegess, safety and formulation are:

is Halocienated DiDhenyl Ethers 21,4,41-trichloro-2-hydroxy-diphenyl ether (TriClosan) 2,21-dihydroxy-5,51-dibromo-diphenyl ether. Halogenated Salicylanilides 20 41,5-dibromosalicylanilide.3,4',5trichlorosalcylanilide 3,41,5-tribromosalicylanilide 2,3,31,5-&-etrachlorosalicylanilide 3,3,31,5-tetrachlorosalicylanilide 3,5-dibromo31-trifluoromethyl salicylanilide 5-n-octanoyl-31-trifluoromethyl salicylanilide 3,5-dibromo-41-trifluoromethyl salicylanilide 30 3,5dibromo-31-trifluoro methyl salicylanilide (Flurophene) 6 Benzoic Esters Methyl - p-Hydroxybenzoic Ester Ethyl - p-Hydroxybenzoic Ester Propyl p-Eydroxybenzoic Ester Butyl - p-Hydroxybenzoic Ester Halogenated Carbanilides 3,4,41-trichlorocarbanilide 3-trifluoromethyl-4,41-dichlorocarbanilide 3,3,41-trichlorocarbanilide Phenolic Compounds (including phenol and its homologs, mono- and poly-alkyl and aromatic halo (e.g. F, Cl, Br, I.) phenols, resorcinol and catechol and their derivatives and bisphenolic compounds). Such phenolic compounds include, inter alia:

Phenol and its Homologs Phenol 2 Methyl 3 Methyl 4 Methyl 4 Ethyl 2,4-Dimethyl 2,5-Dimethyl 3,4-Dimethyl 2,6-Dimethyl 4-n Propyl is J1 4958 Phenol Phenol Phenol Phenol Phenol Phenol Phenol Phenol Phenol 7 4-n-Butyl 4-n-Amyl 4-tert-Amyl 4-n-Hexyl J1 4958 Phenol - Phenol - Phenol Phenol 4-n-Heptyl - Phenol 2-Methoxy-4-(2-Propenyl)-Phenol (Eugenol) 2-Isopropyl-5-Methyl - Phenol (Thymol) Mono- and Poly-Alkyl and Aralkyl HaloiDhenols Methyl Ethyl n-Propyl n-Butyl n-Amyl sec-Amyl n-Hexyl cycloheryl n-Heptyl n-Octyl O-Chlorophenol Methyl Ethyl n-Propyl n-Butyl n-Amyl p-Chlorophenol p-Chlorphenol p-Chlorophenol p-Chlorophenol p-Chlorophenol p-Chlorophenol p- Chlorophenol p-Chlorophenol p-Chlorophenol - p-Chlorophenol - o-Chlorophenol O-Chlorophenol O-Chlorophenol - o-Chlorophenol - o-Chlorophenol p m is 1 tert-Amyl n-Hexyl n-Heptyl p-Chlorophenol o-Benzyl o-Benzyl-m-methyl o-Benzyl-m, m-dimethyl o-Phenylethyl o-Phenylethyl-m-methyl 3-Methyl,5-Dimethyl 6-Ethyl-3-methyl 6-n-Propyl-3-methyl 6-1so-propyl-3- methyl 20 2-Ethyl-3,5-dimethyl 6-sec Butyl-3-methyl 2.;-iso-Propyl-3,5- dimethyl 6-Diethylmethyl-3-methyl 25 6-iso-Propyl-2-ethyl-3-methyl 2-sec Amy1-3,5-dimethyl 2-Diethylmethyl-3,5-dimethyl 6-sec octyl-3-methyl 30 pBromophenol Methyl Ethyl 714958 - o-Chlorophenol o-chlorophenol o-Chloropenol p-Chlorophenol p-Chlorophenol p-Chlorophenol p-Chlorophenol p- Chlorophenol p-Chlorophenol p-Chlorophenol p-Chlorophenol p-Chlorophenol p-Chlorophenol p-Chlorophenol p-Chlorophenol p-Chlorophenol p- Chlorophenol p-Chlorophenol p-Chlorophenol p-Chlorophenol p-Chlorophenol p-Bromophenol p-Bromophenol 9 n-Propyl n-Butyl n-Amyl 5 sec-Amyl n-Hexyl cyclohexyl o-Bromophenol tert-Amyl n-Hexyl n-Propyl-m,m-Dimethyl 2-Phenyl Phenol 4- Chloro-2-methyl phenol 4-chloro-3-methyl phenol 4-chloro-3,5-dimethy.lphenol 2,4-dichloro-3,5-dimethyl phenol t.

JI 4958 p-Bromophenol p-Bromophenol p-Bromophenol p-Bromophenol p-Bromophenol p- Bromophenol o-Bromophenol o-Bromophenol o-Bromophenol 3,4,5,6-tetrabromo-2-methylphenol 5-methyl-2-pentylphenol 4-isopropyl-3methylphenol 5-chloro-2-hydroxydiphenyl methane Resorcinol and Its Derivatives Resorcinol Methyl Ethyl n-Propyl Resorcinol Resorcinol Resorcinol 1 () 1 is n-Butyl n-Amyl n-Hexyl 5 n-Heptyl n-octyl n-Nonyl Phenyl 10 Benzyl Phenylethyl Phenylpropyl p-Chlorobenzyl 5-Chloro 4'-Chloro 5-Bromo 20 4' -Bromo 714958 Resorcinol Resorcinol Resorcinol Resorcinol Resorcinol Resorcinol Resorcinol Resorcinol Resorcinol Resorcinol Resorcinol -2, 4Dihydroxydiphenyl Methane -2,4-Dihydroxydiphenyl Methane -2,4-Dihydroxydiphenyl Methane -2,4-Dihydroxydiphenyl Methane Bisr)henolic Comounds Bisphenol A 7,21-methylene bis (4-chlorophenol) 2,2'-methylene bis (3,4,6-trichlorophenol) (hexachlorophene) 2,2'-methylene bis (4-chloro-6-bromophenol) bis (2-hydroxy-3,5-dichlorophenyl) sulfide bis (2-hydroxy-5-chlorobenzyl) sulfide The antibacterial agent is present in the oral J1 4958 1 composition in an effective antiplaque amount, preferably cut 0.01-5% by weight, more preferably about 0.03-1% and very preferably about 0.25-0.5% and most preferably about 0.250.35%. The antibacterial agent is substantially waterinsoluble, meaning that its solubility is less than about 1% by weight in water at 25'C and may be even less than about 0.1%. If an ionizable group is present solubility is 10 determined at a pH at which ionization does not occur.

is The preferred halogenated diphenyl ether is Triclosan. The preferred phenolic compounds are phenol, 2,21methylene bis (4-chloro-6-bromophenol), thymol and eugenol. The most preferred antibacterial antiplaque compound is Triclosan. Triclosan is disclosed in aforementioned U.S. Patent 4,022, 880 as an antibacterial agent in combination with an 20 anticalculus agent which provides zA-nc ions and in German Patent Disclosure 35 32 86. 0 in combination with a copper compound. it is also disclosed as an antiplaque agent in a lamellar liquid crystal spacing-of less than 6.0 nm and which may optionally contain a zinc salt in published European Patent Application 0161898 of Lane et al and in a dentifrice containing zinc citrate trihydrate in published 30 European Patent Application 0161899 to Saxton.

dentifrice formulated to contain a surfactant phase having a lamellar t.

The, preferably linear molecularly dehydrated, polyphosphate salts operative herein as anticalculus agents are well known, 1 1 J1 4955 being generally employed in the f orm of their wholly or partially neutralized water soluble alkali metal (e.g. potassium and preferable sodium) or ammonium salts, and any mixtures thereof. Representative examples include sodium hexametaphosphate, sodium tripolyphosphate, disodium diacid, trisodium monoacid and tetrasodium pyrophosphates, the corresponding potassium salts and the like. Linear polyphosphates correspond to (NaPO3),, where n is about 2 to about 125. In the present irmention, they are preferably employed in the oral compositions in approximate weight amounts of 0.1 to 3% typically 1 to 2.5% more typically 1.5 to 2%. When n is at least 3 in NaPO.),,., said polyphosphates are glassy in character.

Particularly desirable anticalculus agents are tetraalkali - metal pyrophosphates, including mixtures thereof, such as tetrasodium pyrophosphate, tetrapotassium 1 pyrophosphate and mixtures thereof. Thus, the oral csi- tion may preferably contain polyphosphate anticalculus agent which is substantially free f rom tetra sodium pyrophosphate or substantially f ree from combinalon of tetra portassium pyrophosphate and tetra sodium pyrophosphate in which the ratio of potassium to sodium pyrophosphate is 3:1 or in excess of 3:1. An anticalculus agent comprising about 2% by weight of the oral compositions of tetrasodium pyrophosphate is especially effective.

13 714958 The antibacterial -enhancing agent (.AEA) which enhances delivery of said antibacterial agent to, and retention thereof on, oral surfaces, is employed in amounts effective to achieve such enhancement, preferably within the range in the oral composition of about_0.05% to about 4%, preferably about 0. 1% to about 3%, more preferably about 0. 5% to about 2.5% by weight.

The AEA may be a simple compound, preferably a polymerizable monomer, more preferably a polymer, which latter term is entirely generic, including for example oligomers, homopolymers, copolymers of two or more monomers, is ionomers, block copolymers, graft copolymers, cross-linked polymers and copolymers, and the like. The AF.A may be natural or synthetic, and water insoluble or preferably water (saliva) soluble or swellable (hydratable, hydrogel foruting). It preferably has an (weight) average molecular weight of about loo to about 1,000,000, preferably about 1,000 to about 1, 000, 000, more pref erably about 2, 000 or 2, 5000 to about 250,000 or 500,000.

The AF-A ordinarily- contains at least one deliveryenhancing group, which is preferably acidic such as sulf onic, phosphonic, or more pref erably phosphonic or carboxylic, or salt thereof, e.g. alkali metal or -ammonium, and at least one organic retention- enhancing group, preferably a plurality of both the delivery- enhancing and 14 -rl dQrQ j --- - ret ention- enhancing groups, which latter groups preferably have the formula - (X),-R wherein X is 0, N, S, SO, SO.,, P, PO or Si or the like, R is hydrophobic alkyl, alkenyl, acyl, aryl, alkaryl, aralkyl, heterocyclic or their inertsubstituted derivatives, and n is zero or 1 or more. The aforesaid "inert-substituted derivatives", are intended to include substituents on R which are generally non- hydrophilic and do not s ignif icantly interfere with the desired functions of the AEA as enhancing the delivery of the antibacterial agent to, and retention thereof on, oral surfaces such as halo, e.g. Cl, Br, I, and carbo and the like. Illustrations of such retention- enhancing groups are tabulated below.

n X - (X),,R methyl, ethyl, propyl, butyl, isobutvl, t-butyl cyclohexyl, allyl, benzyl, phenyl, chlorophenyl, xylyl, pyridyl, furanyl, acetyl, benzovl, butyryl, terephthaloyl, etc.

0 ethoxy, benzyloxy, thioacetoxy, phenoxy j carboethoxy, carbobenzyloxy, etc.

N ethylamino, diethylamino, propylamido, benzylamino, benzoylamido, phenylacetamido, etc.

S thiobutyl, thioisobutyl, thioallyl, thiobenzyl, thiophenyl, thiopropionyl, phenyl thioacetyl, thiobenzoyl, etc.

J1 l 4958 p si so butylsulf oxy, allylsulf oxy, benzylsulf oxy, phenylsulf oxy, etc.

So. butylsulfonyl, allylsulfonyl, benzy1sulfonyl, phenylsulf onyl, etc.

diethylphosphinyl, ethylvinylphosphinyl, ethylallylphosphinyl, ethylbenzylphosphinyl, ethylphenylphosphinyl, etc.

PO diethylphosphinoxy, ethylvinylphosphinoxy, methylallylphosphinoxy, methylbenzylphosphinoxy, methylphenylphosphinoxy, etc.

trimethylsilyl, dimethylbutylsilyl, dimethylbenzylsilyl, dimethylvinylsilyl, dimethylallyls.ilyl, etc.

As employed herein, the delivery-enhancing group refers to one which attaches or substantively, adhesively, cohesively or otherwise bonds the AFKA (carrying the antibacterial agent) to oral (e.g. tooth and gum) surfaces, 20. thereby "delivering" the antibacterial agent to such surfaces. The organic retention-enhancing group, generally hydrophobic, attaches or otherwise bonds the antibacterial agent to the AEA, thereby promoting retention of the.

antibacterial agent to the AEA and indirectly on the oral surfaces. In some instances, attachment of the antibacterial agent occurs through physical entrapment thereof by the AFRA, especially when the AEA is a crosslinked polymer, the structure of which inherently provides increased sites for such entrapment. The presence of a higher molecular weight, more hydrophobic cross-linking 1 f; 714958 moiety in the cross-linked polymer still further promotes the physical entrapment of the antibacterial agent to or by the cross-linked AEA polymer.

Preferably, the AEA is a anionic polymer comprising a chain or backbone containing repeating units each preferably containing at least one carbon atom and preferably at least one directly or indirectly pendent, monovalent del ivery- enhancing group and at least one directlyor indirectly pendent monovalent retentionenhancing group geminally, vicinally or less preferably otherwise bonded to atoms, preferably carbon, in the chain.

Less preferably, the polymer may contain de livery- enhancing groups and/or retention- enhancing groups and/or other divalent atoms or groups as links in the polymer chain instead of or in addition to carbon atoms, or as cross- linking moieties.

It will be underttood that any examples or illustrations of AEA' s disclosed herein which do not contain both delivery-enhancing groups and retention. enhancing groups may and preferably should be chemically modified in known manner to obtain the preferred AEA's containing both such groups and pref erablY a plurality of each such groups. In the case of the preferred polymeric ARA's, it is desirable, for maximizing substantivity and delivery of the antibacterial agent to oral surfaces, that the repeating units in the polymer chain or backbone containing the 17 3-14958 acidic delivery enhancing groups constitute at least about 10%, preferably at least about 50%, more preferably at least about 80% up to 95% or 100% by weight of the polymer.

According to a preferred embodiment of this invention, the AEA comprises a polymer containing repeating units in which one or more phosphonic acid delivery enhancing groups are bonded to one or more carbon atoms in the polymer chain. An example of such an AEA is poly (vinyl phosphonic acid) containing units of the f ormula:

I -[CH., CHI P03H2 which however does not contain a retention-enhancing group. A group of the latter type would however be present in poly (1-phosphonopropene) with units of the formula:

II -[CH H 4:3 10 - 0 3H., A preferred phosphonic acid-containing AFIA for use herein is poly (beta styrene phosphonic acid) containing units of 25 the f ormula:

III -[CH - CHI Ph P/0,H, wherein Ph is phenyl, the phosphonic deliveryenhancing group and the phenyl retention-enhancing group being bonded on vicinal carbon atoms in the chain, or a copolymer of beta styrene phosphonic acid with vinyl phosphonyl chloride 18 3-14958 having the units of formula III alternating or in random association with units of formula I above, or poly (alpha styrene phosphonic acid) containing units of the formula:

IV -ICH,- - C ----- I Ph P03H,.,, in which the delivery - and retention enhancing groups are geminally bonded to the chain.

These styrene phosphonic acid polymers and their copolymers with other inert ethylenically unsaturated monomers generally have molecular weights in the range of about 2,000 to about 30,000, preferably about 2,500 to about 10, 000. Such "inert" monomers do not significantly interfere with the intended function of any copolymer employed as an ALA herein.

Other phosphonic- containing polymers include, for exampld, phosphonated ethylene having units of the f o=ula.

V - [ CH2) m4CHPO,H., I,,, where n may f or example be an integer or have a value giving the polymer a molecular weight of about 3, OOD; and sodium poly (butene-4, 4-diphosphonate) having units of the formula.

VI -ICH2 - CH ---- I- CH2 - CH < (P03Na2)2 and poly (allyl bis (phosphonoethyl amine) having units of the f ormula:

VII -[CH2 CH-- C2 - N < (PO.H.,)2 19 ."rl 495P other phosphonated polymers, for example poly (allyl phosphono acetate), phosphonated polymethacrylate, etc. and the geminal diphosphonate polymers disclosed in EP Publica5 tion 0321233 may be employed herein as AEA's, provided of course that they contain or are modified to contain the above-def ined organic retention-enhancing groups. In an aspect of this invention the oral composition comprises an orally acceptable vehicle, an agent which is,' effective to enhance the anti-bacterial effect of an antibacterial agent which has an average molecular weight of about 1,000 to about 1,()00,000, contains at least one functional group which enhances delivery of antibacterial effect and at least one organic group which enhances retention of antibacterial effects, said agent containing said groups being free from or substantially free from water soluble alkali metal or ammonium synthetic anionic linear polymer polycarboxylate salt having a molecular weight of about 1,000 to 1,000,000, and polyphosphate anticalculus agent, such as a mixture of potassium and todium salts, the ratio of potassium to sodium in the said composition being in the range of up to less than about 3: 1, e. g. f rom about 0.37 to about 1.04:1.

According to another preferred embodiment, the AEA comprises a synthetic anionic polymeric polycarboxylate ' which is also an inhibitor of alkaline phosphatase enzyme.

---c1.1 C) r, 8 1 111 - Synthetic anionic polymeric polycarboxylates and their complexes with various cationic germicides, zinc 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. Patent No. 4,138,477 to Gaffar; and U.S. Patent No. 4,183,914 to Gaffar et al.

However, only in disclosure essentially corresponding to U.S. Patent 4, 627,977 to Gaffar et al is there described use of such polycarboxylates for inhibiting salivary hydrolysis of pyrophosphate anticalculus agents in combination with a compound providing a source of fluoride ion. It is to be understood that the synthetic anionic polymeric polycarboxylates so disclosed in these several patents when containing or modified to contain the retention-enhancing groups defined above are operative as AEA's in the compositions and methods of this invention and such disclosures are to that extent incorporated herein by reference thereto.

These synthetic anionic polymeric polycarboxylates are often employed in the form of their free acids or preferably partially or more preferably fully neutralized water soluble or water swellable (hydratable, gel/forming) alkali metal (e.g. potassium and preferably sodium) or ammonium salts. Preferred are 1:4 to 4:1 copolymers of 21 T1 4958 maleic anhydride or acid with another polymerizable ethylenically unsaturated monomer, preferably methyl vinyl ether/maleic anhydride having a molecular weight (M.W.) of about 30,000 to about 1,000,000. These copolymers are available for example as Gantrez e.g. AN 139 (M.W. 500,000), AN 119 (M.W. 250,000); and preferably S-97 Pharmaceutical Grade (M.W. 70,000), of GAF Corporation.

Other AEA-operative polymeric polycarboxylates containing or modified to contain retention-enhancing groups include those disclosed in U.S. Patent No. 3,956,480 referred to above, such 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 -20 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-pyrollidone.

Additional operative polymeric polycarboxylates.

disclosed in above referred to U.S. Patent No. 4,138,477 and 4,183,914, containing or modified to contain retentionenhancing groups include copolymers of maleic anhydride with styrene, isobutylene or ethyl vinyl ether, polyacrylic, polyitaconic and polymaleic acids, and sulfoacrylic oligomers of M.W. as low as 1,000, available as Uniroyal ND- 2.

ZZ :F 14958 Suitable generally are polymerized retention-enhancing group-containing olefinically or ethylenically unsaturated carboxylic acids containing an activated carbon-to-carbon olefinic double bond and at least one carboxyl group, that is, an acid containing an olefinic double bond which readily functions in polymerization because of its presence in the monomer molecule either in the alpha-beta position with respect to a carboxyl group or as part of a terminal methylenegrouping. Illustrative of such acids are acrylic, methacrylic, ethacrylic, alpha- chloroacrylic, crotonic, beta-acryloxy propionic, sorbic, alpha-chlorosorbic, 15 cinnamic, beta-styrylacrylic, muconic, itaconic, citraconic, mesaconic, glutaconic, aconitic, alpha-phenylacrylic,.2benzyl acrylic, 2cyclohexylacrylic, angelic, umbellic, fumaric, maleic acids and anhydrides. Other different olefinic monomers copolymerizable with such carboxylic monomers include vinylacetate, vinyl chloride, dimethyl maleate and the like. Copolymers ordinarily contain sufficient carboxylic salt groups for water-solubility.

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 commercially available for example under the trademarks Carbopol 934, 940 2 J14958 and 941 of B. V. Goodrich, these products consisting essentially of a colloidally water-soluble polymer of polyacrylic acid crosslinked with from about 0.75% to about 2.0% of polyallyl sucrose or polyallyl pentaerythritol as cross linking agent, the cross-linked structures and linkages providing the desired retention enhancement by hydrophobicity and/or physical entrapment of the antibacterial agent or the like. Polycarbophil is somewhat similar, being polyacrylic acid cross-linked with less than 0.2% of divinyl glycol, the lower proportion, molecular weight, and/or hydrophobicity of this cross-linking agent tending to provide decreased, or no, retention enhancement. 2,5-dimethyl- 1,5- hexadiene exemplifies a more effective retention-enhancing cross- linking agent.

The synthetic anionic polymeric.polydarboxylate -ional halogen component is most often a hydrocarbon with opt and 0-containing substituents and linkages as present in for example ester, ether and OH groups, and when present is generally employed in the instant compositions in approximate weight amounts of up to about 4% (generally at least about 0.05%).

The AEA may also comprise natural anionic polymeric 30 polycarboxylates containing retention-enhancing groups. Carboxymethyl cellulose and other binding agents, gums and filmformers devoid of the above-defined deliveryenhancing 14 is 714055.0 and/or retention-enhdncing groups are ineffective as ARA's.

As illustrative of AEA's containing phosphinic acid and/or sulf onic acid delivery enhancing groups, there may be mentioned polymers and copolymers containing units or moieties derived from the polymerization of vinyl or allyl phosphinic and/or sulfonic acids substituted as needed on the 1 or 2 (or 3) carbon atom by an organic retention- enhancing group, for example having the formula -(X),-R defined above. Mixtures of these monomers may be employed, and copolymers thereof with one or more inert polymerizable ethylenically unsaturated monomers such as those described above with respect to the operative synthetic anionic polymeric polycarboxylates. As will be noted, in these and other polymeric AEA's operative herein, usually only one acidic delivery- enhancing group is bonded to any given carbon or other atom in the polymer backbone or branch thereon. Polysilaxanes containing or modified to contain pendant delivery-enhancing groups and retention enhancing groups may also be employed as AEA'sherein. - Also effective as AEA's herein are ionomers containing or modified to contain delivery- amd retention-enhancing groups. Ionomers are described on pages 546-573 or the Kirk-Othmer Encyclopedia of Chemical Technology, third edition, Supplement Volume, John Wiley and Sons, Inc. copyright 1984, which description is incorporated herein by reference. Also

114958 is effective as AEA's herein, provided they contain or are modified to contain retention-enhancing groups, are polyesters, polyurethanes and synthetic and natural polyamoides including proteins and proteinaceous materials such as collagen, poly (argenine) and other polymerized amino acids.

When the oral preparation is made by initially dissolving the polyphosphate and the antibacterial agent in humectant and surf ace active agent and adding thereto the AEA, especially the polycarboxylate, incrementally, the solution becomes clear and may be characterized as a "microemulsion". As the amount of the polycarboxylate increases such that the complete oral preparation contains at least about 2. 2% by weight thereof, the solution becomes cloudy and may be characterized as a "macroemulsion". In such "macroemuls.-Lon" type compositions, the antiplaque dffect of the antibacterial agent appears to be optimized.

A desirable weight ratio of the substantially water- insoluble noncationic antibacterial agent to the polyphosphate anticalculus agent is in excess of about 0,72:1 to less than about 4:1, e.g. from about 1:1 to about 3.5:1, especially from about 1.6:1 to about 2.7:1.

In order to optimize the anticalculus effectiveness of the oral composition, inhibitors against enzymatic hydrolysis of the polyphosphate are desirably present. Such 26 J1 4958 agents are an amount of a f luoride ion source suf f icient to supply 25 ppm. to 5, 000 ppm. of fluoride ions, and up to 3% or more of the synthetic anionic Polymeric polycarboxylate having a molecular weight of about 1, 000 to about 1, 000, 000, pref erably about 30, 000 to about 500, 000.

The sources of fluoride ions, or fluorine -providing component, as acid phosphatase and pyrophosphatase enzyme inhibitor component, are well known in the art as anticaries agents These compounds may be slightly soluble in water or may be fully water-soluble. They are characterized by their ability to release fluoride ions in water and by freedom from undesired reaction with other compounds of the oral preparation. Among these materials are inorganic fluoride salts, such as soluble alkali metal, alkaline earth metal salts, for example., sodium fluoride, potassium fluoride, ammonium fluoride, calcium fluoride, a copper fluoride such as cuprous. fluoride, zinc fluoride, barium fluoride, sodium f luorosilicate, ammonium f luorosilicate, sodium fluorozirconate, ammonium fluorozirconate, sodium monof luorophosphate, aluminum mono- and difluorophosphate, and fluorinated sodium calcium pyrophosphate. Alkali metal and tin fluorides, such as sodium and stannous f luorides, sodium monof luorophosphate (MFP) and mixtures thereof, are preferred.

77 3 14958 The amount of f luorine -providing compound is dependent to some extent upon the type of compound, its solubility, and the type of oral preparation, but it must be a non-toxic amount, generally about 0.005 to about 3.0% in the preparation. In a dentifrice preparation, e.g. dental gel, toothpaste (including cream), toothpowder, or dental tablet, an amount of such compound which releases up to about 5,000 ppm of F ion by weight of the preparation is considered satisfactory. Any suitable minimum amount of such compound may be used, but it is preferable to employ sufficient compound to release about 300 to 2,000 ppm, more preferably about 800 to about 1,500 ppm of fluoride ion.

Typically, in the cases of alkali metal fluorides, this component is present in an amount up to about 2% by weight, based on the weight of the preparation, and preferably in the range of about 0. 05% to 1%. In the case of sodium monofluorophosphate, the compound may be present in an amount of about 0.1-3%, more typically about 0.76%.

In oral preparations such as mouthwashe, lozenges and chewing gum, the fluorine -providing compound is typically present in an amount sufficient to release up to about 500 ppm, preferably about 25 to 300, ppm by weight of fluoride ion. Generally about' 0.005 to about 1.0 wt. % of compound is present.

28 -114958 In certain highly preferred f orms of the invention the oral 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 of from about 1:1 to about 20:1, preferably about 3:1 to 10:1 and more preferably about 4:1 to about 6:1. The total amount of water-alcohol mixture in this type of preparation is typically in the range of from about 70 to about 99.9% by weight of the preparation. The alcohol is typically ethanol or isopropanol. Ethanol is preferred.

The pH of such liquid and other preparations of the invention is. generally in the range of from about 4.5 to about 9 and typically from about 5.5 to 8. The pH is.-20 preferably in the range of from about 6 to about 8.0. 1Lt is noteworthy that the compositions of the invention may be applied orally at a pH below 5 %ithout substantially decalcifying or otherwise damaging dental adamel. The pH can be controlled with acid (e.g. citric acid or benzoic acid) or base (e.g. sodium hydroxide) or buffered (as with sodium citrate, benzoate.. carbonate, or bicarbonate, 'disodium hydrogen phosphate, sodium dihydrogen phosphate, etc.).

29 _Xl 4958 In certain other desirable f orm of this invention, the oral composition may be substantially solid or pasty in character, such as toothpowder, a dental tablet or a dentifrice, that is a toothpaste (dental cream) or gel dentifrice. The vehicle of such solid or pasty oral preparations generally contains dentally acceptable polishing material. Examples of polishing materials are water-insoluble sodium metaphosphate, potassium metaphosphate, tricalcium phosphate, dihydrated calcium phosphate, anhydrous dicalcium phosphate, calcium pyrophosphate, magnesium orthophosphate, trimagnesium phosphate, calcium carbonate, hydrated alumina, calcined alumina, aluminum silicate, zirconium silicate, silica, bentonite,-and mixtures thereof. Other suitable polishing material include the particulate thermosetting resins described in U.S. Pat. No. 3,070,519, issued Dec. 15, 1962, such as melamine-, phenolic, and urea - f ormaldehydes, and cross-linked polyepoxides and polyesters. Preferred polishing materials include crystalline silica having particle sizes of up to about 5 microns, a mean particle size of up to about 1.1 microns, and a surface area of up to about 50, 000 cm. '/gm., silica gel or colloidal silica, and complex amorphous alkali metal aluminosilicate.

When visually clear gels are employed, a polishing agent of colloidal silica, such as those sold under the J-1 4958 trademark SYLOID as Syloid 72 and Syloid 74 or under the trademark SANTOCEL as Santocel 100, alkali metal aluminosilicate complexes are particularly useful, since they have refractive indices close to the refractive indices of gelling agentliquid (including water and/or humectant) systems commonly used in dentif rices.

Many of the so-called "water- insoluble" polishing materials are anionic in character and also include small amounts of soluble material. Thus, insoluble sodium metaphosphate may be f ormed in any suitable manner as illustrated by Thorpe's Dictionary of Applied Chemistry, Volume 9, 4th Edition, pp. 510-511. The forms of insoluble sodium metaphosphate known as Madrell's salt and Kurrol's salt are further examples of suitable materials. These metaphosphate salts exhibit only a minute solubility in water, and therefore are commonly referred to as insoluble metaphosphates (IMP). There is present therein a minor amount of soluble phosphate material as impurities, usually a few percent such as up to 4% by weight. Th. e amount (f soluble phosphate material, which is believed to include a soluble sodium trimetaphosphate in the case of insoluble metaphosphate, may be reduced or eliminated by washing with water if desired. The insoluble alkali metal metaphosphate is typically employed in powder form of a particle size such 31 J 14958 that no more than 1% of the material is larger than 37 microns.

The polishing material is generally present in the solid or pasty compositions in weight concentrations of about 10% to about 99%. Preferably, it is present in amounts ranging from about 10% to about 75% in toothpaste, and from about 70% to about 99% in toothpowder. In toothpastes, when the polishing material is silicious in nature, it is generally present in amount of about 10-30% by weight. Other polishing materials are typically present in amount of about 30-75% by weight.

In a toothpaste, the liquid vehicle may comprise water and humectant typically in an amount ranging from about 10% to about 80% by weight of the preparation. Glycerine, propylene glycol, sorbitol and polypropylene glycol exemplify suitable humectants /carriers. Also advantageous are liquid mixtures of water, glycerine and sorbitol. In clear gels where the refractive index is an important consideration, about 2.5-30 wt. % of water,- 0 to about 70 wt.% of glycerine and about 20-80 wt. % of sorbitol are preferably employed.

Toothpastes, creams and gels typically contain a natural or synthetic thickener or gelling agent in proportions of about 0. 1 to about 10, preferably about 0.5 to about 5 wt. %. A suitable thickener is synthetic hectorite, a synthetic colloidal magnesium alkali metal 1 32 J'1 4958 silicate complex clay available for example as Laponite (e.g. CP, SP 2002, D) marketed by Laporte Industries Limited. Laponite D analysis shows, approximately by weight, 58.00% SiO, 25-40% MgO, 3.05% Na,,O, 0.98% LiO, and some water and trace metals. Its true specific gravity is 2.53 and it has an apparent bulk density (g./ml. at 8% moisture) of 1.0.

is Other suitable thickeners include Irish moss, iota carrageeri an, gum tragacanth, starch, polyvinylpyrrolidone, hydroxyethylpropylcellulose, hydroxybutyl methyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose (e.g. available as Natrosol), sodium carboxymethyl cellulose, and colloidal silica such as f inely ground Syloid (e.g. 244). In some dentifrices prepared in accordance with the present invention particularly when more than about 0.35% by weight of the water insoluble antibacterial agent is employed and a Siliceous polishing agent is present in amount of less than about 30% by weight, it may be desirable to includg an agent which dissolves the antibacterial agent. Stich solubilizing agents include humectant polyols such propylene glycol, dipropylene glycol and hexylene glycol, cellosolves such as methyl cellosolve and ethyl cellosolve, vegetable oils and waxes containing at least about 12 carbons in a straight chain such as olive oil, castor oil and petrolatum and esters such as amyl acetate, ethyl acetate and benzyl benzoate.

33 3 1 495R is It will be understood that, as is conventional, the oral preparations are to be sold or otherwise distributed in suitable labelled packages. Thus, a jar of mouthrinse will have a label describing it, in substance, as a mouthrinse or mouthwash and having directions for its use; and a toothpaste, cream or gel will usually be in a collapsible tube, typically aluminum, lined lead or plastic, or other squeeze, pump or pressurized dispenser for metering out the contents,- having a label describing it, in substance, as a toothpaste, gel or dental cream. organic surface-active agents are used in the compositions of the present invention to achieve increased prophylactic action, assist in achieving thorough and complete dispersion of the anticalculus agent and antiplaque agent throughout the oral cavity, and render the instant compositions more cosmetically acceptable. The organic I surface-active material is preferably anionic, nonionic or ampholytic in nature, and it is preferred to employ as the surface-active agent a detersive material wh'ich imparts to the composition detersive and foaming properties. Suitable examples of anionic surfactants are water-soluble salts of higher fatty acid monoglyceride monosulfates, such as the sodium salt of the monosulfated monoglyceride of hydrogenated coconut oil fatty acids, higher alkyl sulfates such as sodium lauryl sulfate, alkyl aryl sulfonates such as 34 -714958 sodium dodecyl benzene sulf onate, higher alkYlsulf oacetates, higher fatty acid esters of 1,2-dihydroxy propane sulf onate, and the substantially saturated higher aliphatic acyl amides of lower aliphatic amino carboxylic acid compounds, such as those having 12 to 16 carbons in the fatty acid, alkyl or acyl radicals, and the like. Examples of the last mentioned amides are N-lauroyl sarcosine, and the sodium, potassium, and ethanolamine salts of N-lauroyl, N-myristoyl, or N-palmitoyl sarcosine which should be substantially free from soap or similar higher fatty acid material. The use of these sarcosinate compounds in the oral compositions of the present invention is particularly advantageous since these materials exhibit a prolonged and marked ef f ect in the inhibition of acid f ormation in the oral cavity due to carbohydrates breakdown in addition to exerting some reduction in the solubility of tooth enamel in acid soiutions. Examples of water-soluble nonionic surf actants are condensation products of ethylene oxide with various reactive hydrogencontaining compounds reactive therewith 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. sorbitan monostearate) and - 5 J 14958 polypropyleneoxide (e.g. Pluronic materials).

Surface active agent is typically present in amount of about 0.1-5% by weight, preferably about 1-2.5%. It is noteworthy, that surface active agent may assist in the dissolving of the noncationic antibacterial agent and thereby diminish the amount of solubilizing humectant needed.

Various other materials may be incorporated in the oral 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 mat'erial may also be employed. Examples of suitable flavoring constituents are flavoring oils, e.g. oil of spearmint, peppermint, wintergreen, sassafras, clove, sage, eucalyptus, marjoram, cinnamon, lemon, and orange, and methyl salicylate.

Suitable sweetening agents include sucrose, lactose, maltose, sorbitol, xylitol, sodium cyclamate, perillartine, R6 -714958 AMP (aspartyl phenyl alanine, methyl ester), saccharine and the like. Suitably, flavor and sweetening agents may each or together comprise from about 0.1% to 5% or more of the preparation. Moreover, flavor oil appears to aid the dissolving of the antibacterial agent.

In the preferred practice of this invention an oral composition according to this invention such as a mouthwash or dentifrice containing the composition of the present invention is preferably applied regularly to dental enamel, such as every day or every second or third day or preferably from 1 to 3 times daily, at a pH of about 4.5 to about 9, generally about 5.5 to about 8, preferably about 6 to 8, for at least 2 weeks up to 8 weeks or more up to lifetime.

The compositions of this invention can be incorporated in lozenges, or in chewing gum or other products, e.g. by stirring into a warm gum base or coating the outer surface of a gum base, illustrative of which may be mentioned jelutong, rubber latex, vinylite resins, etc., desirably with conventional plasticizers or softeners, - sugar or.other sweeteners or such as glucose, sorbitol and the like.

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 the appended claims are by weight unless otherwise indicated.

37 -T 14 9.S 8 In the following Examples, the agent Triclosan, 2,4,4'trichloro-2'- hydroxydiphenyl ether is indicated as "TCHE"; sodium lauryl sulfate is indicated as "SLS"; the copolymer of maleic anhydride and methyl vinyl ether available f rom GAF Corporation as "Gantrez S-97" is identified as "Gantrez"; tetrasodium pyrophosphate is identified as 11pyrophosphate"; and sodium fluoride is identified as "NaF" Example I The adsorption to and release from tooth minerals for antiplaque/antitartar efficacy of agents is assessed by adsorption of antibacterial agent to saliva coated tooth mineral hydroxyapatite disk in the presence of pyrophosphat and differing amounts of polycarboxylate.

The f ormulations of the toothpastes evaluated are:

Parts bv Weiaht A B Glycerine 10.000 10.000 Iota-carrageenan 0.750 0.750 Sorbitol (70% solution) 30.'000 30.000 t.

Propylene Glycol 0.500 0.500 Gantrez (13.02% solution) 19.000 15.500 Titanium dioxide 0.500 0.500 Water (deionized) 9.957 13.457 NaF 0.243 0.243 38:7 14 955 8 Sodium Saccharine 0.300 0.300 Pyrophosphate 2.000 2.000 Sodium hydroxide (50%) 1.000 1.000 Silica polishing agent (Zeodent 113) 20.000 20.000 Silica Thickener (Sylodent 15) 2.500 2.500 Flavor oil 0.950 0.950 TCHE 0.300 0.300 SLS 2.000 2.000 Gantrez is present as A. I. in amount of 2.5 parts in toothpaste A and 2. 0 parts in toothpaste B. For the test of delivery of antibacterial agent to a saliva coated hydroxyapatite disk.. hydroxtapatite (HA) obtained from the Monsanto Co. is washed extensively with distilled water, collected by vacuum filtration, and permitted to dry overnight at 37'C. The dried HA is ground into a powder with a mortar and pestle. 150. 00 mgs of HA are placed into the chamber of a KBr pellet die (Barnes Analytical, Stanford, CT.) and compressed for 6 minutes at 10,000 pounds in a Carver Laboratory press. The resulting 13 mm disks are sintered for 4 hours at 800'C in a Thermolyne furnace. Parafilm stimulated whole saliva is collecped into a ice-chilled g1ass beaker. The saliva is clarified by centrifugation at 15, 000 Xg (times gravity) 39 -rl lIQCP for 15 minutes at 4'C. Sterilization of the clarif iedsaliva is done at 4'C with stirring by irradiation of the sample with UV light for 1. 0 hour.

Each sintered disk is hydrated with sterile water in a polyethylene test tube. The water is then removed and replaced with 2.00 ml of saliva. A salivary pellicle is formed by incubating the disk overnight at 37'C with continuous shaking in a water bath. After this treatment, the saliva is removed and the disks are treated with 1. 00 ml of a solution containing antibacterial agent (triclosan) in a dentifrice liquid phase solution and incubated at 37'C is with continuous shaking in the water bath. After 30 minutes, the disk is transferred into a new tube and 5.00 ml of water are added followed by shaking the disk gently with a Vortex. The disk is then transferred into a new tube and the washing procedure repeated twice. Finally, the disk is transferred carefully into a new tube to avoid co-transfer of any liquid along with the disk. Then 1.00 ml of methanol is added to the disk and shaken vigorously with a Vortex.

The sample is left at room temperature for 30 minutes to extract adsorbed triclosan in the methanol. The methanol is then aspirated and clarified by centrifugation in a Beckman Microfuge 11 at 10,000 rpm for 5 minutes. After this treatment, the methanol is transferred into HPLC(high performance liquid chromatography) vials for determination -rl 4958 of antibacterial agent concentration. Triplicate samples are used in all experiments.

The Table below siimmarizes the data: Table ToothRaste A is B Delivery of TCHE to Saliva Coated Hydroxyapatite Disc in Micrograms 130 30 The data indicates that with the increasing amount of Gantrpz (Toothpaste A) there is a very great increase in delivery of TCHE to saliva coated tooth minerals.

ExamDle 2 The following toothpaste is effective as an antiplaque and anticalculus composition:

Parts by Weiaht Sorbitol (70%) Irish Moss Sodium Hydroxide (56%) Gantrez (13.02% solution) Water (deionized) Sodium Monofluorophsophate sodium saccharine Pyrophosphate Hydrated alumina Flavor oil TCHE SLS 22.00 1.00 1.00 19.00 2.69 0.76 0.30 2.00 48.00 0.95 0.30 2.00 1 Mouthrinse Tetrasodium Pyrophosphate Gantrez S-97 Glycerine Sodium Fluoride Sodium Lauryl Sulfate TCHE Flavor oil Water ExamDle 4 Example 3

Lozenge 75-80% Sugar 1-20% Corn Syrup 0.1-1.0 Flavar Oil 2%. Tetrasodium Pyrophosphate 2.5051. Gantrez S-97 0.01 to 0.05% NaF 0.01 to 0.1% TCHE 1 to 5% Magnesium Stearate Lubricant 0.01 to 0.2% Water J5-1 4958 Q. S. to Parts 2.00 2.50 10.00 0.05 0.20 0.06 0.40 100.00 42 ExamDle 5 Chewing Gum Gum Base Sorbitol (70%) TCHE Tetrasodium Pyrophosphate Gantrez S.97 Chewina Gum Gum Base TCHE Gantrez NaF Glycerine Crystalline Sorbitol Tetrasodium Pyrophosphate Flavor Oil and Water 514958 Parts 25.00 17.00 0.50 to 0.10 2.00 2.50 In a variant Example of the foregoing Example, Gantrez S-97 can be omitted.

ExamDle 6 Parts 30.00 0.50 2.00 0.05 0.50 53.00 2.00 Q.S. to 100.00 In the foregoing Examples improved results are also achievable when TCHE is replaced with each of phenol, 2,2' methylene bis(4-chloro-6- Bromophenol), eugenol and thymol and/or when Gantrez is replaced by other AEA's such as 43 714958 Carbopols (e.g. 934), or styrene phosphonic acid polymers having molecular weights within the range of about 3,000 to 10,000 such as poly (beta - s tyrenephosphoni c acid), 5 copolymers of vinyl phosphonic acid with betastyrenephosphonic acid, and poly (alpha- s tyrenephosphoni c acid), or sulfoacrylic oligomers, or a 1:1 copolymer of maleic anhydride with ethyl acrylate.

Likewise similar results are achieved when pyrophoshate (tetrasodium. pyrophosphate) is replaced by tetrasodium, pyrophosphate and tetrapotassium, pyrophosphate, with the weight ratio of potassium to sodium being a) 0.37:1 is b) 1. 04: 1; c) 3: 1; and 3.5: 1.

This invention has been described with respect to certain preferred embodiments and it will be understood that 20 modifications and variations thereof obvious to those -skilled in the art are to be included within the purview of this application and thb scope of the appended claims.

44 T1 4958

Claims (11)

1. An oral composition comprising in an orally acceptable vehicle, an effective anticalculus amount of material comprising about 0.1-3% by weight of at least one polyphosphate salt as anticalculus agent, an effective antiplaque amount of a substantially water insoluble noncationic antibacterial agent and up to about 4% by weight of an ant ibacterial-enhancing agent which enhances delivery of said antibacterial gent to, and the retention thereof on, oral surfaces, the weight ratio of polyphosphate ion to antibacterial - enhancing agent ranging from about 1.6:1 to about 2.7:1.

2. An oral composition as claimed in Claim 1 in which the said antibacterial agent is selected from the group consisting of halogenated diphenyl ethers, halogenated salicylanilides, benzoic esters, halogenated carbanilides and phenolic compounds.

3. An oral comp9sition as claimed in Claim 1 in which the said antibacterial agent is a halogenaed diphenyl ether.

4. An oral composition as claimed in Claim 3 wherein the said halogenated diphenyl ether is 2,4,Vtrichloro-2'-hydroxyphenyl ether.

5. An oral composition as claimed in Claim 1 in which the said antibacterial agent is aphenolic compound.

71 inr,8 X.' -

6. An oral composition as claimed in Claim 5 in which the said phenolic compound is selected from the group consisting of phenol, thymol, eugenol and 2,Vmethylene bis(4-chloro-6-bromophenol).

7. An oral composition as claimed in any one of Claims 1 to 6 in which the said antibacterial agent is present in amount of about 0.01-5% by weight.

8. An oral composition as claimed in Claim 7 in which the said amount of antibacterial agent is about 0.25-0.5i.

9. An oral composition as claimed in any one of Claims 1 to 8 in which the anticalculus polyphosphate is present in an amount of about 1-2.5% by weight.

10. An oral composition as claimed in Claim -7 wherein the said halogenated diphenyl ether is 2,4,41trichloro-21-hydroxyphenyl ether.

(00 4 J14958

11. An oral composition as claimed in any one of Claims 1 to 10 in which the said antibacterial enhancing agent is present in an amount of about 0. 5-2.5% by weight.

t.

10. An oral composition as claimed in any one of Claims 1 to 9 in which the polyphosphate salt is a 20 linear molecularly dehydrated polyphosphate salt.

11. An oral compc?sition as claimed in Claim 10 in which the polyphosphate salt is an alkali metal pyrophosphate.

12. An oral composition as claimed in Claim 11 in which the said alkali metal pyrophosphate is tetrasodium pyrophosphate.

13. An oral composition as claimed in any one of Claims 1 to 12 in which the weight ratio of polyphos phate ion to antibacterial enhancing agent is about 1.7:1 to about 2.3:1.

46 j71 4958 14. An oral composition as claimed in any one of Claims 1 to 13 in which the said vehicle comprises water, humectant and a gelling agent, the said oral composition contains a dentally acceptable waterinsoluble polishing agent and is a dentifrice.

15. An oral composition as claimed in any one of Claims 1 to 13 in which the said vehicle comprises water and a non-toxic alcohol and the said oral composition is a mouthwash.

16. An oral composition as claimed in any one of Claims 1 to 15 in which the said antibacterial- enhancing agent has an average molecular weight of about 1000 to about 1, 000,000.

17. An oral composition as claimed in Claim 16 in which the said ant ibacteria 1 -enhancing agent contains at least one delivery-enhancing functional group and at least one organic retention-enhancing group.

18. An oral composition as claimed in Claim 17 in which the said deliveryenhancing group is acidic.

19. An oral composition as claimed in Claim 18 in which the said deliveryenhancing group is selected from the group consisting of carboxylic, phosphonic, phosphinic, and sulfonic acids, and their salts, and mixtures thereof.

20. An oral composition as claimed in any one of Claims 17 to 19 in which the said organic retention- i 47 J1 4958 enhancing group comprises the formula -(X)n-R wherein X represents 0, N, S, SO, S02, PO or S i, R represents a hydrophobic alkyl, aryl, alkenyl, acyl, alkaryl, aralkyl, or heterocyclic group, or their inert-substituted derivatives, and n is 1 or zero.

21 An oral composition as claimed in any one of Claims 17 to 20 in which the said antibacterial- enhancing agent is an anionic polymer containing a plurality of delivery- enhancing and organic retentionenhancincl groups.

22. An oral composition as claimed in Claim 21 in which the said anionic polymer comprises a chain containing repeating units each containing at least one carbon atom.

23. An oral composition as claimed in Claim 22 in which. each unit contains at least one deliveryenhancing group and at least one organic retentionenhancing group bonded to the same or vicinal, or other atoms in the chain.

24. An oral composition as claimed in any one of Claims 17 to 23 in which the delivery-enhancing group comprises a carboxylic group or salt thereof.

25. An oral composition as claimed in any one of Claims 17 to 24 in which the antibacterial-enhancing agent is a copolymer of maleic acid or anhydride with another ethylenically unsaturated polymerizable monomer. or a salt thereof.

A R J1 4958 26. An oral composition as claimed in Claim 25 in which the said other monomer is methyl vinyl ether in a 4:1 to 1:4 molar ratio with the maleic acid or anhydride.

27. An oral composition as claimed in Claim 25 or Claim 26 in which the said copolymer has a molecular weight of about 30,000-1,000,000.

is 28. An oral composition as claimed in Claim 27 in which the copolymer has an average molecular weight of about 70,000.

29. An oral composition as claimed in any one of Claims 17 to 28 in which the delivery -enhancing group comprises a phosphonic group or salt thereof.

30. An oral composition as claimed in Claim 29 in which the antibacterial-enhancing agent - is poly (beta styrenephosphonic acid), poly (alpha - styrenephosphonic acid) or a copolymer of either styrenephosphonic acid with the other or with another inert polymerizable ethylenically unsaturated monomer or the salts thereof.

31. An oral composition as claimed in Claim 30 in which the said ant ibac teria 1 -enhancing agent has a molecular weight of about 1,000 to about 30,000.

32. An oral composition as claimed in any one of Claims 1 to 31 containing a fluoride ion-providing source.

4 -9 J14958 33. An oral composition comprising an orally acceptable vehicle, an agent which is effective to enhance the antibacterial effect of an antibacterial agent which has an average molecular weight or about 1,000 to about 1,000,000, contains at least one functional group which enhances delivery of antibacterial effect and at least one organic group which enhances retention of antibacterial effect, the said agent containing the said groups being free from or substantially free from water soluble alkali metal or ammonium. synthetic anionic linear polymer polycarboxylate salt having a molecular weight of about 1,000 to about 1r000,000, and polyphosphate anticalculus agent, the said polyphosphate anticalculus agent being a mixture of potassium and sodium salts, the ratio of potassium to sodium in the said composition being in the range of up to less than about 3:1.

34. An oral composition as claimed in Claim 33 in which the said ratio of potassium to sodium is from about 0.37:1 to about 1.04:1.

35. An oral composition as claimed in Claim 33 in which the said group which enhances delivery is selected from the group consisting of phosphonic, phosphinic and sulfonic acids, and their salts, and mixtures thereof.

36. An oral composition as claimed in Claim 33, 34 or 35 in which the said organic group which enhances retention comprises the formula (X)n-R wherein X represents 0, N, S, So, S021 PO or Si, R so J1 4958 represents a hydrophobic alkyl, aryl, alkenyl, acyl, alkaryl, aralkyl, or heterocyclic group, or their inert-substituted derivatives, and n is 1 or zero.

is t.

j 37. An oral composition comprising an orally acceptable vehicle, an agent which is effective to enhance the antibacterial effect of an antibacterial agent which has an average molecular weight of about 1,000 to about 1,000,000, and contains at least one group which enhances delivery of antibacterial effect and at least one organic group which enhances retention of antibacterial effect, the said agent containing the said groups being free from or substantially free from water soluble alkali metal or ammonium synthetic anionic linear polymer polycarboxylate salt having a molecular weight of about 1,000 to about 1,000,000, and polyphosphate anticalculus agent.

38. An oral composition as claimed in Claim 37 in which the said delivery enhancing group is selected from the group consisting of phosphonic, phosphinic and sulfonic acids, and their salts, and mixtures thereof.

39. An oral composition as claimed in Claim 36or Claim 37 in which the said organic retention enhancing group comprises the formula -(X)n-R wherein X represents 0, N, S, SO, S021 PO or Si, R represents a hydrophobic alkyl, aryl, alkenyl, acyl, alkaryl, aralkyl or heterocyclic group, or their inertsubstituted derivatives, and n is 1 or zero.

40. An oral composition comprising an orally '1 -514958 acceptable vehicle, an effective antiplaque amount of a substantially water insoluble noncationic antibacterial agent, an a ntibacter ia 1 - enhancing agent which has an average molecular weight of about 1 000 to about 1,000,000, and contains at least one delivery enhancing functional group and at least one organic retention enhancing group, the said agent containing the said groups being free from or substantially free from water soluble alkali metal or ammonium synthetic anionic linear polymer polycarboxylate salt having a molecular weight of about 1, 000 to about 1,000,000, and polyphosphate anticalculus agent.

41. An oral composition comprising an orally acceptable vehicle, an agent which is effective to enhance the antibacterial effect of an antibacterial agent which has an average molecular weight of about 1,000 to about 1,000,000, contains at least one functional group which enhances delivery of antibac- terial effect and at least one organic group which enhances retention of antibacterial effect, the said agent containing the said groups being free from or substantially free from water soluble alkali metal or ammonium synthetic anionic linear polymer polycarboxylate salt having a molecular weight of about 1,000 to about 1, 000, 000, and polyphosphate anticalculus agent where the weight ratio of polyphosphate from the said polyphosphate anticalculus agent to the said antibacterial agent range from in excess of 0.72:1 to less than 4:1.

42. An oral composition as claimed in Claim 41 in. which the said weight ratio is from about 1: 1 to about n.14 T 14958 43. An oral composition as claimed in Claim 41 or Claim 42 in which the said weight ratio is f rom 1. 6:1 to about 2.7:1.

44. An oral composition comprising an orally acceptable vehicle, an agent which is effective to enhance the antibacterial effect of an antibacterial agent which has an average molecular weight of about 1,000 to. about 1, 000,000, and contains at least one functional group which enhances delivery of antibacterial effect and at least one organic group which enhances retention of antibacterial effect, and polyphosphate anticalculus agent, with the proviso that the composition is free from or substantially free from tetrasodium pyrophosphate.

45. An oral composition comprising an orally acceptable vehicle, an agent which is effective to enhance the antibacterial effect of an antibacterial agent which has an average molecular weight of about 1,000 to about 1,000,000, and contains at least one functional group which enhances delivery of antibac- terial effect and at least one organic -group which enhances retention of antibacterial effect, and polyphosphate anticalculus agent, with the proviso that the composition is free from or substantially free from combination of tetra potassium pyrophosphate and tetra sodium pyrophosphate in which the ratio of potassium to sodium pyrophosphate is 3:1 or in excess of 3:1.

46. An oral composition comprising an orally 53 314958 acceptable vehicle, an effective antiplaque amount of a substantially water insoluble noncationic antibacterial agent and polyphosphate anticalculus agent, with the proviso that the composition is free from or substantially free from tetrasodium pyrophosphate.

47. An oral composition comprising an orally acceptable vehicle, an effective antiplaque amount of a substantially water insoluble noncationic antibacterial agent and polyphosphate anticalculus agents, with the proviso that the composition is free from or substantially -kree from combination of tetra potassium pyrophosphate and tetra sodium pyrophosphate in which the ratio of potassium to sodium pyrophosphate is 3:1 or in excess of 3:1.

is 48. An oral composition comprising an orally acceptable vehicle, an effective antiplaque amount of a substantially water insoluble noncationic antibacterial agent, an aptibacteria 1 -enhancing agent which has an average molecular weight of about 1 #000 to about 1,000,000, and contains at least one delivery enhancing functional group and at least one organic retention 6nhancing group,, the said agent containing the said groups being free from or substantially free from water soluble alkali metal or ammonium synthetic anionic linear polymer polycarboxylate salt having a molecular weight of about 1,000 to about 1,000,000, and polyphosphate anticalculus agent, with the proviso that the composition is free from or substantially free from tetrasodium pyrophosphate.

49. An oral composition comprising an orally 54 J1 4958 acceptable vehicle, an effective antiplaque amount of a substantially water insoluble noncationic antibacterial agent, an antibacterial - enhancing agent which has an average molecular weight of about 1, 000 -to about 1,000,000, and contains at least one delivery enhancing functional group and at least one organic retention enhancing group, the said agent containing the said groups being free from or substantially free from water soluble alkali metal or ammonium synthetic anionic linear polymer polycarboxylate salt having a molecular weight of about 1, 000 to about 1,000,000, and polyphosphate anticalculus agent with the proviso that thecomposition is free from or substantially free from combination of tetra potassium pyrophosphate and tetra sodium pyrophosphate in which the ratio of potassium to sodium pyrophosphate is 3:1 or in excess of 3:1.

50. An oral composition comprising an orally acceptable vehicle and an agent which is effective to enhance the antibacterial effect of an antibacterial agent which has an average molecular weight of about 1,000 to about 1,000,000, and contains at leat one functional group which enhances delivery of antibacterial effect and at least one organic group which enhances retention of antibacterial effect,, the said agent containing the said groups being free from or substantially free from water soluble alkali metal or ammonium synthetic anionic linear polymer polycarboxylate salt having a molecular weight of about 1,000 to 1,000,000, and polyphosphate anticalculus agent, the said composition containing potassium and sodium salts or ions, the ratio of potassium to sodium in the said composition being in the range of up to less than 3:1.

J1 4958 51. An oral composition as claimed in Claim 50 in which the said ratio of potassium to sodium is from about 0.37:1 to about 1.04:1.

52. An oral composition comprising an orally acceptable vehicle, a substantially water insoluble non-cationic antibacterial agent in an amount of from 0.25% to 0.35% and polyphosphate anticalculus agent.

53. An oral composition comprising an orally acceptable vehicle, a substantially water insoluble non-cationic antibacterial agent in an amount of from 0.25% to 0.35% and polyphosphate anticalculus agent, the said polyphosphate anticalculus agent being a mixture of potassium and sodium salts, the ratio of potassium to sodium in the said composition being in the range of up to less than about 3:1.

54. An oral composition as claimed in Claim 53 in which the said ratio is from about 0.35:1 to about 1.04:1.

55. An oral composition comprising an orally 2,5 acceptable vehicle, a substantially water insoluble noncationic antibacterial agent in an amount of from 0.25% to 0.35% and polyphosphate anticalculus agent, with the proviso that the composition is free from or substantially free from tetrasodium pyrophosphate.

56. An oral composition comprising an orally acceptable vehicle, a substantially water insoluble noncationic antibacterial agent in an amount of from 56 -S14958 0.25% to 0.35% and polyphosphate anticalculus agent, with the proviso that the composition is free from or substantially free from a combination of tetrapotassium pyrophosphate and tetrasodium pyrophosphate in which the ratio of potassium to sodium pyrophosphate is 3:1 or in excess of 3:1.

57. An oral composition comprising an orally acceptable vehicle, an effective antiplaque amount of a substantially water insoluble noncationic antibacterial agent, An antibacterial -enhancing agent which has an average 'molecular weight of about 1 000 to about 1,000,000, and contains at least one delivery enhancing functional group and at least one organic retention enhancing group, the said agent containing the said groups being free from or substantially free from water soluble alkali metal or ammonium synthetic anionic linear polymer polycarboxylate salt having a molecular weight of about 1,000 to about 1,000,000, and polyphosphate anticalculus agent, the said polyphosphate anti calculus agent being a mixture of potassium and sodium salts, the ratio of potassium to sodium in the said composition being in the range of up to less than about 3:1.

58. An oral composition comprising an orally acceptable vehicle, an effective antiplaque amount of a substantially water insoluble noncationic antibacterial agent, and an antibacterial -enhancing agent which has an average molecular weight of about 1,000 to about 1,000,000, and contains at least one delivery enhancing functional group and at least one organic retention enhancing group, the said agent containing the said 57 T1 4958 groups being free from or substantially free from water soluble alkali metal or ammonium synthetic anionic linear polymer polycarboxylate salt having a molecular weight of about 1,000 to about 1,000,000, the said composition containing potassium and sodium salts or ions, the ratio of potassium to sodium in the said composition being in the range of from 0. 37:1 to 1.04:1.

60. An oral composition as claimed herein substantially as specifically described hereinwith reference to the accompanying examples.

61. A method of controlling oral plaque comprising applying to oral surfaces a plaquecontrolling amount of a composition as claimed in any one of Claims 1 to 60.

f 1 6% Amendments to the claims have been filed as follows J14958 r, 1. An oral composition comprising in an orally acceptable vehicle, an effective anticalculus amount of polyphosphate salt as anticalculus agent, an effective antiplaque amount of a substantially water insoluble noncationic antibacterial agent and an antibacterialenhancing agent which enhances delivery of the said antibacterial to, and retention thereof on, oral surfaces, the said antibacterial-enhancing agent being a poly(vinylphosphonic acid) containing units of the formula P03H2 the composition having a pH of 4.5-9.

2. An oral composition as claimed in claim 1 in which the antibacterial-enhancing agent has a molecular weight of from 1000 to 1,000,000.

3. An oral composition as claimed in claim 1 or claim 2 in which the orally acceptable vehicle comprises a surface active agent or a flavouring oil to assist in t. the dissolving of the non-cationic antibacterial agent.

4. An oral composition as claimed in Claim 1, 2 or 3 in which the said oral composition is a dentifrice comprising about 5-30% by weight of a siliceous polishing agent and the said antibacterial agent is present in an amount of about 0.25-0.35% by weight.

59 t.

J14958 5. An oral composition as claimed in Claim 1 or Claim 2 in which the said oral composition is a dentifrice comprising about 5-30% by weight of a siliceous polishing agent. the said antibacterial agent is present in amount of about 0.01-5% by weight and the said oral composition comprises a solubilizing material in amount to assist dissolving the said antibacterial agent in saliva.

6. An oral composition as claimed in any one of Claims 1 to 5 in which the said oral composition is a dentifrice comprising about 60-75% by weight of a dentally acceptable water-insoluble polishing agent.

7. An oral composition as claimed in any one of Claims 1 to 5 in which the said oral composition is a mouthwash or liquid dentifrice and the said orally acceptable vehicle is an aqueous vehicle wherein there is present a non-toxic alcohol.

8. An oral cpmposition as claimed in any one of Claims 1 to 5 in which the said antibacterial agent is selected from the group consisting of halogenated diphenyl ethers, halogenated salicylanilides, benzoic esters, halogenated carbanilides and phenolic compounds.

9. An oral composition as claimed in Claim 6 in which the said antibacterial agent is a halogenated diphenyl ether.