IE894196A1 - Antibacterial antiplaque, anticalculus oral composition - Google Patents

Abstract

An oral composition such as a dentifrice, mouthwash, lozenge or chewing gum containing a polyphosphate anticalculus agent, such as tetraalkali metal pyrophosphate and antibacterial antiplaque agent compatible therewith. The antiplaque agent is a substantially water-insoluble noncationic antibacterial agent such as 2,4,4'-trichloro-2'-hydroxydiphenyl ether (Triclosan). Antiplaque effectiveness is optimized by the presence of an antibacterial-enhancing agent which enhances delivery of said antibacterial agent to, and retention thereof on, oral surfaces. Suitable enhancing agents are anionic polymers such as a maleic acid-methyl vinyl ether copolymer or a polymer containing phosphonic groups. Also disclosed are compositions comprising (1) the noncationic antibacterial agent and the enhancing agent, (2) the polyphosphate anticalculus agent and the noncationic antibacterial agent and (3) the enhancing agent and polyphosphate anticalculus agent effective against any antibacterial agent.

Description

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 antibacterial agent effective to inhibit plague, wherein antiplaque effectiveness is optimized by the presence of an antibacterial-enhancing 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 2θ 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 3° 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 P1 4958 soluble dialkali 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 causative factors in periodontal conditions. Thus, its reduction promotes oral hygiene.

Dental plague is a precursor of calculus. Unlike 10 calculus, however, plague may form on any part of the tooth surface, particularly including at the gingival margin.

Hence, besides being unsightly, it is implicated in the 15 occurrence of gingivitis.

Accordingly, it would be highly 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 effective to retard the growth of plaque bacteria. A wide 25 variety of antibacterial agents are described with the zinc compounds including cationic materials such as guanides and quaternary ammonium compounds as well as non-cationic compounds such as halogenated salicylanilides and halogenated hydroxydiphenyl ethers.

Hitherto, the cationic antibacterial materials such as chlorhexidine, benzethonium chloride and cetyl pyridinium P1 4958 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 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 . · been known to increase the efficacy of cationic antibacterial agents. (see e.g. Disinfection, sterilization and Preservation,, 2nd Ed., Black, 1977, Page 915 and Inhibition and Destruction of the Microbial Cell, Hugo, 1971, Page 215). Indeed, quaternary ammonium compound is present in the plague control mouthwash containing pyrophosphate of U.S. Patent 4,323,551 to Parran and bis20 biguanide antiplague 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 dehydrated polyphosphate salt, a fluoride-ion-providing source and the P1 4958 aforementioned antibacterial-enhancing agent to inhibit plague formation.

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

It is a further advantage of this invention that an antiplaque, anticalculus oral composition is provided which 10 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 of material preferably comprising about 0.1-3% by weight of at 2Q least one, preferably linear molecularly dehydrated, polyphosphate salt as anticalculus agent, an effective antiplaque amount of a substantially 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 £ 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% P14958 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 effectiveness, safety and formulation are: Halogenated Diphenyl Ethers 2', 4,4'-trichloro-2-hydroxy-diphenyl ether (Triclosan) 2,2'-dihydroxy-5,5’-dibromo-diphenyl ether.

Halogenated Salicylanilides 20 4',5-dibromosalicylanilide 3,4',5-trichlorosalcylanilide 3,4',5-tribromosalicylanilide 2,3,3',5-tetrachlorosalicylanilide 3,3,3',5-tetrachlorosalicylanilide 3.5- dibromo-3'-trifluoromethyl salicylanilide 5-n-octanoyl-3'-trifluoromethyl salicylanilide 3.5- dibromo-4'-trifluoromethyl salicylanilide 0 3, 5-dibromo-3'-trifluoro methyl salicylanilide (Flurophene) P14958 Benzoic Esters Methyl - p-Hydroxybenzoic Ester Ethyl - p-Hydroxybenzoic Ester Propyl - p-Hydroxybenzoic Ester Butyl - p-Hydroxybenzoic Ester Halogenated Carbanilides 3,4,4'-trichlorocarbanilide 1 θ 3-trifluoromethyl-4,4’-dichlorocarbanilide 3,3,4'-trichlorocarbanilide Phenolic Compounds (including phenol and its homologs, mono- and poly-alkyl and aromatic halo (e.g. F, Cl, Br, I.)1 5 phenols, resorcinol and catechol and their derivatives and bisphenolic compounds). Such phenolic compounds include, inter alia: Phenol and its Homologs Phenol Methyl - Phenol Methyl - Phenol Methyl - Phenol Ethyl - Phenol 4-Dimethyl - Phenol 5-Dimethyl - Phenol 4-Dimethyl - Phenol 6-Dimethyl - Phenol n Propyl - Phenol Phenol P1 4958 4-n-Butyl - Phenol 4-n-Amyl - Phenol 4-tert-Amyl - Phenol 4-n-Hexyl - Phenol 4-n-Heptyl - Phenol 2-Methoxy-4-(2-Propenyl)-Phenol (Eugenol) 2-Isopropyl-5-Methyl - Phenol (Thymol) Mono- and Poly-Alkyl and Aralkyl Halophenol Methyl - p-Chlorophenol Ethyl - p-Chlorphenol n-Propyl - p-Chlorophenol n-Butyl - p-Chlorophenol n-Arnyl - p-Chlorophenol sec-Amyl - p-Chlorophenol n-Hexyl - p-Chlorophenol cyclohexyl - p-Chlorophenol n-Heptyl - p-Chlorophenol n-Octyl - p-Chlorophenol O-Chlorophenol Methyl - o-Chlorophenol Ethyl - o-Chlorophenol n-Propyl - o-Chlorophenol n-Butyl - o-Chlorophenol n-Amyl - o-Chlorophenol P14958 tert-Amyl - o-Chlorophenol n-Hexyl - o-chlorophenol n-Heptyl - o-Chloropenol p-Chlorophenol o-Benzyl - p-Chlorophenol o-Benzyl-m-methyl - p-Chlorophenol o-Benzyl-m, m-dimethyl - p-Chlorophenol o-Phenylethyl - p-Chlorophenol o-Phenylethyl-m-methyl - p-Chlorophenol 3-Methyl - p-Chlorophenol 3,5-Dimethyl - p-Chlorophenol 6-Ethyl-3-methyl - p-Chlorophenol 6-n-Propyl-3-me thy1 - p-Chlorophenol 6-iso-propyl-3-methyl - p-Chlorophenol 2-Ethyl-3,5-dimethyl - p-Chlorophenol 6-sec Butyl-3-methyl - p-Chlorophenol 2-iso-Propyl-3, 5-dimethyl - p-Chlorophenol 6-Diethylmethyl-3-methyl - p-Chlorophenol 6-iso-Propyl-2-ethyl-3-methyl - p-Chlorophenol 2-sec Amyl-3,5-dimethyl - p-Chlorophenol 2-Diethylmethyl-3,5-dimethyl - p-Chlorophenol 6-sec Octyl-3-methyl - p-Chlorophenol p-Bromophenol Methyl - p-Bromophenol Ethyl - p-Bromophenol P1 4958 n-Propyl n-Butyl n-Amyl sec-Amyl n-Hexyl cyclohexyl - p-Bromophenol - p-Bromophenol - p-Bromophenol - p-Bromophenol - p-Bromophenol - p-Bromophenol 0 o-Bromophenol tert-Amyl - o-Bromophenol n-Hexyl - o-Bromophenol n-Propyl-m,m-Dimethyl - o-Bromophenol 2-Phenyl Phenol 4-Chloro-2-methyl phenol 4- chloro-3-methyl phenol 4-chloro-3,5-dimethyl phenol 2, 4-dichloro-3, 5-dimethyl phenol 3,4,5,6-tetrabromo-2-methylphenol - methyl-2-pentylphenol 25 4-isopropyl-3-methylphenol -chloro-2-hydroxydiphenyl methane Resorcinol and Its Derivatives Resorcinol - Resorcinol - Resorcinol Methyl Ethyl n-Propyl Resorcinol P14958 n-Butyl - Resorcinol n-Amyl - Resorcinol n-Hexyl - Resorcinol 5 n-Heptyl - Resorcinol n-Octyl - Resorcinol n-Nonyl - Resorcinol Phenyl - Resorcinol 1 0 Benzyl - Resorcinol Phenylethyl - Resorcinol Phenylpropyl - Resorcinol p-Chlorobenzyl - Resorcinol 1 5 5-Chloro -2,4-Dihydroxydiphenyl Methane 4’-Chloro -2,4-Dihydroxydiphenyl Methane 5-Bromo -2,4-Dihydroxydiphenyl Methane 20 4’-Bromo -2,4-Dihydroxydiphenyl Methane Bisphenolic Compounds Bisphenol A 25 2,2'-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 30 bis (2-hydroxy-5-chlorobenzyl) sulfide The antibacterial agent is present in the oral P14958 composition in an effective antiplaque amount, preferably about 0.01-5% by weight, more preferably about 0.03-1% and very preferably about 0.25-0.5% and most preferably about 0.255 0.35%. 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 0 determined at a pH at which ionization does not occur.

The preferred halogenated diphenyl ether is Triclosan.

The preferred phenolic compounds are phenol, 2,2’methylene bis (4-chloro-6-bromophenol), thymol and eugenol. The most preferred antibacterial antiplague compound is Triclosan. Triclosan is disclosed in aforementioned U.S. Patent 4,022,880 as an antibacterial agent in combination with an anticalculus agent which provides zinc ions and in German Patent Disclosure 35 32 860 in combination with a copper compound. It is also disclosed as an antiplaque agent in a dentifrice formulated to contain a lamellar liquid crystal 25 surfactant phase having a lamellar 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 European Patent Application 0161899 to Saxton.

The, preferably linear molecularly dehydrated, polyphosphate salts operative herein as anticalculus agents are well known, P14958 being generally employed in the form 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 10 polyphosphates correspond to (NaPO3)„ where n is about 2 to about 125. In the present invention, 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 NaPO3)„, said polyphosphates are glassy in character.

Particularly desirable anticalculus agents are 2q tetraalkali metal pyrophosphates, including mixtures thereof, such as tetrasodium pyrophosphate, tetrapotassium pyrophosphate and mixtures thereof. Thus, the oral composition may preferably contain polyphosphate anticalculus agent which is substantially free from tetra sodium pyrophosphate or substantially free from combinaion of tetra potassium pyrophosphate and tetra sodium pyrophosphate in which the ratio of potassium to sodium pyrophosphate is 3-.1 or in 0 excess of 3:1. An anticalculus agent comprising about 2% by weight of the oral compositions of tetrasodium pyrophosphate is especially effective.

P14958 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 ionomers, block copolymers, graft copolymers, cross-linked polymers and copolymers, and the like. The AEA may be natural or synthetic, and water insoluble or preferably 20 water (saliva) soluble or swellable (hydratable, hydrogel forming). It preferably has an (weight) average molecular weight of about 100 to about 1,000,000, preferably about 1,000 to about 1,000,000, more preferably about 2,000 or 2,5000 to about 250,000 or 500,000.

The AEA ordinarily-contains at least one deliveryenhancing group, which is preferably acidic such as sulfonic, phosphonic, or more preferably 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 P1 4958 retent ion-enhancing groups, which latter groups preferably have the formula -(X)„-R wherein X is 0, N, S, SO, S02 , 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 non1 0 hydrophilic and do not significantly 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. η X (X)„R --- methyl, ethyl, propyl, butyl, isobutyl, t-butyl cyclohexyl, allyl, benzyl, phenyl, chlorophenyl, xylyl, pyridyl, furanyl, acetyl, benzoyl, butyryl, terephthaloyl, etc. 0 ethoxy, benzyloxy, thioacetoxy, phenoxy, carboethoxy, carbobenzyloxy, etc.

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

S thiobutyl, thioisobutyl, thioallyl, thiobenzyl, thiophenyl, thiopropionyl, phenylthioacetyl, tbiobenzoyl, etc.

IE 834136 P1 4958 butylsulfoxy, allylsulfoxy, benzylsulfoxy, phenylsulfoxy, etc.

S02 butylsulfonyl, allylsulfonyl, benzylsulfonyl, phenylsulfonyl, etc.

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

PO diethylphosphinoxy, ethylvinylphosphinoxy, methylallylphosphinoxy, methylbenzylphosphinoxy, methylphenylphosphinoxy, etc. 0 trimethylsilyl, dimethylbutylsilyl, dimethylbenzylsilyl, dimethylvinylsilyl, dimethylallylsilyl, etc.

As employed herein, the delivery-enhancing group refers to one which attaches or substantively, adhesively, cohesively or otherwise bonds the AEA (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 AEA, especially when the AEA is a cross30 linked polymer, the structure of which inherently provides increased sites for such entrapment. The presence of a higher molecular weight, more hydrophobic cross-linking P14958 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 delivery-enhancing group and at least one directly or 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 delivery-enhancing groups and/or retention-enhancing groups and/or other divalent atoms or groups as links in the polymer chain 2Q instead of or in addition to carbon atoms, or as crosslinking moieties.

It will be understood 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 preferably a plurality of each such groups. In the case of the preferred polymeric AEA’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 P14958 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 deliveryenhancing 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 formula: I -[CHZ - CH]/ po3h2 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]- A preferred phosphonic acid-containing AEA for use herein is poly (beta styrene phosphonic acid) containing units of the formula: III -[CH-CH]- wherein Ph is phenyl, the phosphonic delivery-enhancing 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 P14958 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: ]10 IV -ICH2 /C — Ph PO3H2 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 AEA herein.

Other phosphonic-containing polymers include, for example, phosphonated ethylene having units of the formula.

V -[CH2)1ACHPO3H2J„where n may for example be an integer or have a value giving the polymer a molecular weight of about 3,000; and sodium poly (butene-4,4-diphosphonate) having units of the formula VI -[CH2 -/.CH----JCH2 - CH < (P03Na2)2 and poly (allyl bis (phosphonoethyl amine) having units of the formula: VII -[CH2 -.CH---)CH2 -N < (PO3H2)2 P14958 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-defined organic retention-enhancing groups.

In an aspect of this invention the oral 10 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 1,000,000, contains at least one functional group which enhances delivery of antibacterial effect and at least one organic group which enhances retention of antibacterial effects, said agent containing 2Q 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 sodium 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. from 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.

P14958 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 2Q 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 25 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 P1 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. 0 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 1 5 anhydride with ethyl acrylate, hydroxyethyl methacrylate, Nvinyl-2-pyrollidone, or ethylene, the latter being available for example as Monsanto EMA No. 1103, M.W. 10,000 and EMA 2Q 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, 3θ polyitaconic and polymaleic acids, and sulfoacrylic oligomers of M.W. as low as 1,000, available as Uniroyal ND2.

P14958 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 1 θ respect to a carboxyl group or as part of a terminal methylene grouping. Illustrative of such acids are acrylic, methacrylic, ethacrylic, alpha-chloroacrylic, crotonic, beta-acryloxy propionic, sorbic, alpha-chlorosorbic, cinnamic, beta-styrylacrylic, muconic, itaconic, citraconic, mesaconic, glutaconic, aconitic, alpha-phenylacrylic, 2benzyl acrylic, 2-cyclohexylacrylic, 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 P14958 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 0 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-l,5- hexadiene exemplifies a more effective retention-enhancing cross-linking agent.

The synthetic anionic polymeric polycarboxylate component is most often a hydrocarbon with optional halogen and O-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 polycarboxylates containing retention-enhancing groups. Carboxymethyl cellulose and other binding agents, gums and film-formers devoid of the above-defined delivery-enhancing P14958 and/or retention-enhancing groups are ineffective as AEA’s As illustrative of AEA's containing phosphinic acid and/or sulfonic 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 retention10 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 20 acidic delivery-enhancing group is bonded to any given carbon or other atom in the polymer backbone or branch thereon. Polysiloxanes containing or modified to contain pendant delivery-enhancing groups and retention enhancing groups may also be employed as AEA's herein. 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 P14958 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 surface active agent and adding thereto the AEA, especially the polycarboxylate, incrementally, the solution becomes clear and may be characterized as a 1 5 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 2θ cloudy and may be characterized as a macroemulsion. In such macroemulsion type compositions, the antiplaque effect of the antibacterial agent appears to be optimized.

A desirable weight ratio of the substantially water25 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 P14958 agents are an amount of a fluoride ion source sufficient 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, preferably 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 1 5 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 fluorosilicate, ammonium fluorosilicate, sodium fluorozirconate, ammonium fluorozirconate, sodium monofluorophosphate, aluminum mono- and difluorophosphate, and fluorinated sodium calcium pyrophosphate. Alkali metal and tin fluorides, such as sodium and stannous fluorides, sodium monofluorophosphate (MFP) and mixtures thereof, are preferred.

P1 4958 The amount of fluorine-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 ϊθ 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, 2Q 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 mouthwashes, 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 3θ ion. Generally about 0.005 to about 1.0 wt. % of such compound is present.

P14958 In certain highly preferred forms 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 2θ about 9 and typically from about 5.5 to 8. The pH is preferably in the range of from about 6 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 (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 .).

P1 4958 In certain other desirable form 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. 3,070,510, issued Dec. 15, 1962, such as melamine-, phenolic, and urea-formaldehydes, 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.2/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 P1 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 agent-liquid (including water and/or humectant) systems commonly used in dentifrices.

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 formed 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. The amount of 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 P14958 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 P14958 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% SiO2, 25.40% MgO, 3.05% Na2O, 0.98% Li2O, 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.

Other suitable thickeners include Irish moss, iota carrageenan, gum tragacanth, starch, polyvinylpyrrolidone, hydroxyethylpropylcellulose, hydroxybutyl methyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose (e.g. 1 5 available as Natrosol), sodium carboxymethyl cellulose, and colloidal silica such as finely 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 include an agent which dissolves the antibacterial agent. Such 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 .

P14958 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 0 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 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 which 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 P14958 sodium dodecyl benzene sulfonate, higher alkylsulfoacetates, higher fatty acid esters of 1,2-dihydroxy propane sulfonate, 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 effect in the inhibition of acid formation in the 2Q oral cavity due to carbohydrates 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 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 P1 4958 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 8 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 material may also be employed. Examples of suitable flavoring constituents are flavoring oils, e.g. oil of spearmint, peppermint, Wintergreen, sassafras, clove, sage, eucalyptus, marjoram, 30 cinnamon, lemon, and orange, and methyl salicylate.

Suitable sweetening agents include sucrose, lactose, maltose, sorbitol, xylitol, sodium cyclamate, perillartine, P14958 AMP (aspartyl phenyl alanine, methyl ester), saccharine and the like. Suitably, flavor and sweetening agents may each or together comprise frctn 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 0 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 20 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 25 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 30 the invention is not limited thereto. All amounts and proportions referred to herein and in the appended claims are by weight unless otherwise indicated.

P14958 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 from GAF Corporation as Gantrez S-97 is identified as Gantrez; tetrasodium pyrophosphate is identified as pyrophosphate; and sodium fluoride is identified as NaF. 1θ Example 1 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 pyrophosphate and differing amounts of polycarboxylate.

The formulations of the toothpastes evaluated are: Parts by Weight A B Glycerine Iota-carrageenan 25 Sorbitol (70% solution) Propylene Glycol Gantrez (13.02% solution) Titanium dioxide Water (deionized) NaF 000 10.000 750 0.750 000 30.000 500 0.500 .000 15.500 .500 0.500 .957 13.457 .243 0.243 38 P14958 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 mm disks are sintered for 4 hours at 800°C in a Thermolyne furnace. Parafilm stimulated whole saliva is collected into a ice-chilled glass beaker. The saliva is clarified by centrifugation at 15,000 Xg (times gravity) P14958 for 15 minutes at 4°C. Sterilization of the clarifiedsaliva 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 0 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 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 2Q 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 HPLCChigh performance liquid chromatography) vials for determination P1 4958 of antibacterial agent concentration. Triplicate samples are used in all experiments.

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

T, 7 n Example 2 The following toothpaste is effective as an antiplaque and anticalculus composition: Parts by Weight Sorbitol (70%) 22.00 Irish Moss 1.00 Sodium Hydroxide (50%) 1.00 Gantrez (13.02% solution) 19.00 Water (deionized) 2.69 Sodium Monofluorophsophate 0.76 Sodium saccharine 0.30 Pyrophosphate 2.00 Hydrated alumina 48.00 Flavor oil 0.95 TCHE 0.30 SLS 2.00 P14958 Example 3 Mouthrinse 5 Tetrasodium Pyrophosphate Gantrez S-97 Glycerine Sodium Fluoride Sodium Lauryl Sulfate TCHE Flavor oil ί ς Water Parts 2.00 2.50 .00 0.05 0.20 0.06 0.40 Q.S. to 100.00 Example 4 Lozenge 75-80% Sugar 1-20% Corn Syrup 0.1-1.0 Flavor Oil 2% Tetrasodium Pyrophosphate 2.50% Gantrez S-97 0.01 to 0.05% NaF 0.01 to 0.1% TCHE to 5% Magnesium Stearate Lubricant 30 0.01 to 0.2% Water P1 4958 Example 5 Chewing Gum Gum Base 5 Sorbitol (70%) TCHE Tetrasodium Pyrophosphate Gantrez S.97 Parts .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.

Example 6 Chewing Gum Gum Base TCHE Gantrez NaF Glycerine Crystalline Sorbitol Tetrasodium Pyrophosphate Flavor Oil and Water Parts .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 30 achievable when TCHE is replaced with each of phenol, 2,2'metjiylene bis( 4-chloro-6-Bromophenol), eugenol and thymol, and/or when Gantrez is replaced by other AEA’s such as P14958 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-styrenephosphonic acid), copolymers of vinyl phosphonic acid with betastyrenephosphonic acid, and poly (alpha-styrenephosphonic acid), or sulfoacrylic oligomers, or a 1:1 copolymer of maleic anhydride with ethyl acrylate.

Likewise similar results are achieved when pyrophosphate (tetrasodium pyrophosphate) is replaced by tetrasodium pyrophosphate and tetrapotassium pyrophosphate, with the weight ratio of potassium to sodium being a) 0.37:1 1 5 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 2Q modifications and variations thereof obvious to those skilled in the art are to be included within the purview of this application and the scope of the appended claims.

Claims (43)

1. An oral composition comprising in an orally 5 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 -] q about 4% by weight of an antibacterial-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. 1 5

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 2 0 carbanilides and phenolic compounds.

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

4. An oral composition as claimed in Claim 3 wherein the said halogenated diphenyl ether is 2,4,4'trichloro-2'-hydroxyphenyl ether. 2Q 5. An oral composition as claimed in Claim 1 in which the said antibacterial agent is a phenolic compound. 45 P1 4958 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 2,2*methylene 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. 10 8. An oral composition as claimed in Claim 7 in which the said amount of antibacterial agent is about 0.25-0.5%. 9. An oral composition as claimed in any one of 15 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 any one of Claims 1 to 9 in which the polyphosphate salt is a 20 linear molecularly dehydrated polyphosphate salt. 11. An oral composition 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. 2Q 13. An oral composition as claimed in any one of Claims 1 to 12 in which the weight ratio of polyphosphate ion to antibacterial enhancing agent is about 1.7:1 to about 2.3:1 . P14958 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

5. 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

6. 10 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 antibacterial15 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 antibacterial-enhancing agent contains 20 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 delivery-enhancing group is acidic. 19. An oral composition as claimed in Claim 18 in which the said delivery-enhancing group is selected from the group consisting of carboxylic, phosphonic, phosphinic, and sulfonic acids, and their salts, and 30 mixtures thereof. 20. An oral composition as claimed in any one of Claims 17 to 19 in which the said organic retentionIE 894196 47 P14958 enhancing group comprises the formula -(X) n -R wherein X represents 0, N, S, SO, SO2, PO or Si, R represents a hydrophobic alkyl, aryl, alkenyl, acyl, 5 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 antibacterial10 enhancing agent is an anionic polymer containing a plurality of delivery-enhancing and organic retentionenhancing groups. 22. An oral composition as claimed in Claim 21 in

7. 15 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

8. 20 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.

9. 25 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 30 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. P14958

10. 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 5 anhydride.

11. 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. 1 0

12. 28. An oral composition as claimed in Claim 27 in which the copolymer has an average molecular weight of about 70,000. 15

13. 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.

14. 30. An oral composition as claimed in Claim 29 in 2Q which the antibacterial-enhancing agent is poly (betastyrenephosphonic 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.

15. 31. An oral composition as claimed in Claim 30 in which the said antibacterial-enhancing agent has a molecular weight of about 1,000 to about 30,000. 20

16. 32. An oral composition as claimed in any one of Claims 1 to 31 containing a fluoride ion-providing source. 49 P14958

17. 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 5 1 ,000 to about 1 ,000,00 0 , 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 10 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 anticalculus agent being a 15 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.

18. 34. An oral composition as claimed in Claim 33 in 20 which the said ratio of potassium to sodium is from about 0.37:1 to about 1.04:1.

19. 35. An oral composition as claimed in Claim 33 in which the said group which enhances delivery is 25 selected from the group consisting of phosphonic, phosphinic and sulfonic acids, and their salts, and mixtures thereof.

20. 36. An oral composition as claimed in Claim 33, 30 34 or 35 in which the said organic group which enhances retention comprises the formula -|X) n -R wherein X represents Ο, N, S, SO, S02i PO or Si, R 50 P14958 represents a hydrophobic alkyl, aryl, alkenyl, acyl, alkaryl, aralkyl, or heterocyclic group, or their inert-substituted derivatives, and n is 1 or zero. 5

21. 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 10 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 15 anionic linear polymer polycarboxylate salt having a molecular weight of about 1,000 to about 1,000,000, and polyphosphate anticalculus agent.

22. 38. An oral composition as claimed in Claim 37 in 20 which the said delivery enhancing group is selected from the group consisting of phosphonic, phosphinic and sulfonic acids, and their salts, and mixtures thereof.

23. 39. An oral composition as claimed in Claim 36 or 25 Claim 37 in which the said organic retention enhancing group comprises the formula -(X) n -R wherein X represents Ο, N, S, SO, SO 2 , PO or Si, R represents a hydrophobic alkyl, aryl, alkenyl, acyl, 30 alkaryl, aralkyl or heterocyclic group, or their inertsubstituted derivatives, and n is 1 or zero.

24. 40. An oral composition comprising an orally 51 P1 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 5 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 1Q linear polymer polycarboxylate salt having a molecular weight of about 1,000 to about 1,000,000, and polyphosphate anticalculus agent.

25. 41. An oral composition comprising an orally 15 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 antibac2q 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 polycarboxy25 late 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 30 than 4:1.

26. 42. An oral composition as claimed in Claim 41 in which the said weight ratio is from about 1:1 to about P14958 3.5:1.

27. 43. An oral composition as claimed in Claim 41 or Claim 42 in which the said weight ratio is from 1.6:1 5 to about 2.7:1.

28. 44. An oral composition comprising an orally acceptable vehicle, an agent which is effective to enhance the antibacterial effect of an antibacterial 10 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 15 polyphosphate anticalcul-us agent, with the proviso that the composition is free from or substantially free from tetrasodium pyrophosphate.

29. 45. An oral composition comprising an orally 20 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 antibac25 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 30 sodium pyrophosphate in which the ratio of potassium to sodium pyrophosphate is 3:1 or in excess of 3:1.

30. 46. An oral composition comprising an orally 53 P14958 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 substan5 tially free from tetrasodium pyrophosphate.

31. 47. An oral composition comprising an orally acceptable vehicle, an effective antiplaque amount of a substantially water insoluble noncationic antibacterial 1θ agent and polyphosphate anticalculus agents, 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. 1 5

32. 48. 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, with the proviso that the composition is free from or substantially free from 30 tetrasodium pyrophosphate.

33. 49. An oral composition comprising an orally 54 P1 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 5 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 10 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 combination of tetra potassium pyrophosphate and tetra ,1 1 5 sodium pyrophosphate in which the ratio of potassium to sodium pyrophosphate is 3:1 or in excess of 3:1.

34. 50. An oral composition comprising an orally acceptable vehicle and an agent which is effective to 20 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 25 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 30 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. P1 4958

35. 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.

36. 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.

37. 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, If 15 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. 20

38. 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.

39. 55. An oral composition comprising an orally 25 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.

40. 56. An oral composition comprising an orally acceptable vehicle, a substantially water insoluble noncationic antibacterial agent in an amount of from 56 P14958 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 5 the ratio of potassium to sodium pyrophosphate is 3:1 or in excess of 3:1.

41. 57. An oral composition comprising an orally acceptable vehicle, an effective antiplaque amount of a 10 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 I 15 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 polyphos20 phate 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 .

42. 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 30 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 P1 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 5 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 . 1 0 60. An oral composition as claimed herein substantially as specifically described herein with reference to the accompanying examples.

43. 61. A method of controlling oral plague 15 comprising applying to oral surfaces a plaquecontrolling amount of a composition as claimed in any one of Claims 1 to 60.