CA2006718C - 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.

Description

' ~000'~18 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 plaque, wherein antiplaque effectiveness is optimized by the presence of an ,y 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 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 t:le patents to Parran et al and to Parran, water 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 plaque is a prP~~rsor of calculus. Unlike calculus, however, plaque map form on any part of the tooth surface, particularly Includi~o at the gingival margin.
_2_ ~~v~'l~..f~
Hence, besides being unsightly, it is implicated in the occurrence of gingivitis.
Accordingly, it would be highly desirable to include antimicrobial agents which have been known to reduce plaque 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 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 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 __ _ ..~ ........~..b considered to be quite surprising as polyphosphates are chelati..g 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 plaque control mouthwash containing pyrophosphate of U.S. Pat~n~ 4,323,551 to Parran and bis-biguanide antipledue agent is suggested in the anticalculus ~ pyrophosphate or~i composl!1on of U.S. Patent 4,515,772- _ Parran 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 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 antiplaque, 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 of material comprising about 0.1-3o by weight of at least one linear molecularly dehydrated polyphosphate salt as anticalculus agent, an effective antiplaque amount of a substantially water insoluble noncationic antibacterial agent and desirably up to about 4o by weight of an antibacterial-enhancing agent which enhances the delivery of the antibacterial agent to, and retention thereof on, oral surfaces, wherein typically the weight ratio of antibacterial-enhancing agent to polyphosphate ion 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 20 4a zoo~~s~
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 particularly desirable from considerations of antiplaque '_ effectiveness, safety and formulation are:
Halogenated Diphenvl Ethers 2',4,4'-trichloro-2-hydroxy-diphenyl ether (Triclosan) 2,2'-dihydroxy-5,5'-dibromo-diphenyl ether. .
Halogenated Salicvlanilides 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 ' S-n-octanoyl-3'-trifluoromethyl salicylanilide 3,5-dibromo-4'-trifluoromethyl salicylanilide 3,5-dibromo-3'-trifluoro methyl salicylanilide (Flurophene) Benzoic Esters Methyl - p-Hydroxybenzoic Ester Ethyl - p-Hydroxybenzoic Ester Propyl - p-Hydroxybenzoic Ester Butyl - p-Hydroxybenzoic Ester Halogenated Carbanilides 3,4,4'-trichlorocarbanilide 3-trifluoromethyl-4,4'-dichlorocarbanilide 3,3,4'-trichlorocarbanilide Phenolic Compounds ( ir:w 1 :ding phenol and its homologs, mono- and poly-alkyl and arcrometic halo (e. g. F, C1, Br, I.)-~,U~)f~'71~

phenols, resorcinol and catechol and their derivatives and bisphenolic compounds). Such phenolic compounds include, - :Y ~y..~
inter alias Phenol and its Homologs Phenol 2 Methyl - Phenol 3 Methyl - Phenol 4 Methyl - Phenol 4 Ethyl - Phenol 2,4-Dimethyl - Phenol 2,5-Dimethyl - Phenol 3,4-Dimethyl - Phenol 2,6-Dimethyl - Phenol 4-n Propyl - Phenol 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 Halophenols Methyl - p-Chlorophenol Ethyl - p-Chlorphenol n-Propyl - p-Chlorophenol n-Butyl - p-Chlorophenol n-Amyl - 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-c 't ; r~rophenol 2(~tlt ~'71 Ethyl - o-Chlorophenol n-Propyl - o-Chlorophenol n-Butyl - o-Chlorophenol f,~~''~~
n-Amyl - o-Chlorophenol 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-methyl - 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 n-Propyl - p-Bromophenol n-Butyl - p-Bromophenol n-Amyl - p-Bromophenol sec-Amyl - p-Bromophenol 2~OE~'~1~
n=Hexyl - p-Bromophenol cyclohexyl - p-Bromophenol 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 5-methyl-2-pentylphenol 4-isopropyl-3-methylphenol 5-chloro-2-hydroxydiphenyl methane Resorcinol and Its Derivatives - Resorcinol Methyl - Resorcinol Ethyl - Resorcinol n-Propyl - Resorcinol n-Butyl - Resorcinol n-Amyl - Resorcinol n-Hexyl - Resorcinol n-Heptyl - Resorcinol n-Octyl - Resorcinol n-Nonyl - Resorcinol Phenyl - Resorcinol Benzyl - Resorcinol Phenylethyl - Resorcinol Phenylpropyl - Resorcinol p-Chlorobenzyl - Resorcinol 5-Chloro -2,4-Dihydroxydiphenyl Methane -4'-Chloro -2,4-Dihydroxydiphenyl Methane r.- -Bromo -2, 4-Dihydroxydiphenyl Methane 4'-Bromo -2, 4-Dihydroxydiphenyl Methane Bisphenolic Compounds Bisphenol A
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 bis (2-hydroxy-5-chlorobenzyl) sulfide The antibacterial agent is present in the oral composition in an effective antiplaque amount, typically about 0.01-5% by weight, preferably about 0.03-1% and very preferably about 0.25-0.5% and most preferably about 0.25-0.35%. The antibacterial agent is substantially water insoluble, 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 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 antiplaque compound is Triclosan.
Triclosan is disclosed in aforementioned U.S. patent 4,022,880 as an antibacterial agent in combination with an anticalculus *Trade-mark 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 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.
*Trade-mark 9a The linear molecularly dehydrated polyphosphate salts operative herein as anticalculus agents are well known, 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 polyphosphates correspond to (NaP03)n where n is about 2 to 125. In the present invention, they are employed in the oral compositions in approximate weight amounts of 0.1 to 3o typically 1 to 2.5o more typically 1.5 to 20. When n is at least 3 in (NaP03)n, the polyphosphates are glassy in character.
Particularly desirable anticalculus agents are tetraalkali metal pyrophosphates, including mixtures thereof, such as tetrasodium pyrophosphate, tetrapotassium pyrophosphate and mixtures thereof. Thus, the oral composition may contain polyphosphate anticalculus agent which is substantially free from tetra sodium pyrophosphate 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. An anticalculus agent comprising about 2o by weight of the oral compositions of tetrasodium pyrophosphate is especially effective.
The antibacterial-enhancing agent (AEA) which enhances delivery of the antibacterial agent to, and retention thereof, on oral surfaces, is employed in amounts effective to achieve such enhancement within the range in the oral composition of about 0.050 to about 40, preferably about O.lo to about 30, more preferably about 0.5% to about 2.5o 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 water (saliva) soluble or swellable (hydratable, hydrogel forming). It 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 delivery-enhancing group, which is preferably acidic such as sulfonic, phosphinic, 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 retention-enhancing groups, which latter groups preferably have the formula -(X)n-R wherein X is 0, N, S, SO, SO2, P, PO or Si or the like, R is hydrophobic alkyl, alkenyl, acyl, aryl, alkaryl, aralkyl, heterocyclic or their inert-substituted 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 significantly interfere with the 2c~nf~~l~
desired functions of the AEA as enhanr_ing the delivery of the antibacterial agent to, and retention thereof on, oral surfaces such as halo, e.g. C1, Br, I, and carbo and the like. Illustrations of such retention-enhancing groups are tabulated below.
n X -(X)nR
0 --- methyl, ethyl, propyl, butyl, isobutyl, t-butyl cyclohexyl, allyl, benzyl, phenyl, chlorophenyl, xylyl, pyridyl, furanyl, acetyl, benzoyl, butyryl, terephthaloyl, etc.
1 0 ethoxy, benzyloxy, thioacetoxy, phenoxy, carboethoxy, carbobenzyloxy, etc.
N ethylamino, diethylamino, propylamido, benzylamino, benzoylamido, phenylacetamido, etc.
S thiobutyl, thioisobutyl, thioallyl, thiobenzyl, thiophenyl, thiopropionyl, phenylthioacetyl, thiobenzoyl, etc.
SO butylsulfoxy, allylsulfoxy, benzylsulfoxy, phenylsulfoxy, etc.
SOZ butylsulfonyl, allylsulfonyl, benzylsulfonyl, , phenylsulfonyl, etc.
P diethylphosphinyl, ethylvinylphosphinyl, ethylallylphosphinyl, ethylbenzylphosphinyl, . ' ethylphenylphosphinyl, etc.
PO diethylphosphinoxy, ethylvinylphosphinoxy, methylallylphosphinoxy, methylbenzylphosphinoxy, methylphenylphosphinoxy, etc.
Si trimethylsilyl, dimethylbutylsilyl, dimethyl-benzylsilyl, dimethylvinylsilyl, dimethylallyl-silyl, 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 ( a . g . tooth and gum) surfaces , 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 Y
x s 20~(~"71_t~
x 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 cross-linked polymer, the structure of which inherently provides increased sites for such entrapment. The presence of a higher molecular weight, more hydrophobic cross-linking 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 .,y,,;,:
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 retention-enhancing 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 instead of or in addition to carbon atoms, or as cross-linking moieties.
It will be understood that any examples or illustratio;.s 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 pref erred 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 tn oral sorfn~~ ~. that the repeating units in the polymer <:Inn t n «r backt":,nn containing the acidic delivery enhancing groups constitute at least about 100, preferably at least about 500, more preferably at least about 80o up to 95% or 1000 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 formula:
I - [CHZ - CH] -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 - CH] -A preferred phosphonic acid-containing AEA for use herein is poly (beta styrene phosphonic acid) containing units of the formula:
III - [CH - CH] -Ph P03H2 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 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 - [CHZ - C -----] -Ph P03H2 in which the delivery - and retention - enhancing groups are geminally bonded to the chain.
These styrene phosphonic acid polymers and their 14a 20~f,'718 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 ., ~..",~",~.~... -.
f:
example, phosphonated ethylene having units of the formula.
V -[CH2)~4CHP03H2]n-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 -[CHz ~ H____]- , CHZ - CH < (P03Na2)2 and .
poly (allyl bis (phosphonoethyl amine) having units of the formula:
. , VII -[CHz - CH-__]-C~ - N < ( P03H2 ) z ~~
Other phosphonated polymers, for example poly (allyl phosphono acetate), phosphonated polymethacrylate, etc. and the geminal diphosphonate polymers disclosed in EP Publica-tion 0321233 may be employed herein as AEA's, provided of course that they contain or are modif ied to contain the above-defined organic retention-enhancing groups.
. 15 1 r _) 2(~aE~'~1R
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 1,000,000, 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 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 ' w 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.
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, c.nly 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 con~~~n the retention-enhancing groups defined arrive are opecn~~ve as AEA's in the compositions and ~~thr~ds of ~his invention and such ___ ~ 16 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 malefic 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 malefic 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 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 retention-enhancing groups *Trade-mark include copolymers of malefic 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.
Suitable generally are polymerized retention-enhancing group-containing olefinically or ethylenically unsaturated carboxylic acids containing an activated carbon-to-carbon *Trade-mark 17a 200('; 718 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 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, 2-benzyl acrylic, 2-cyclohexylacrylic, angelic, umbellic, fumaric, malefic 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 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.Oo of polyallyl sucrose or polyallyl pentaerythritol as ' cross linking agent, the cross-linked structures and linkages providing the desired retention enhancement by hydrophcaicity and/or physical entrapment of the antibacterial agent or the like. Polycarbophil is somewhat similar, being polyacrylic acid cross-linked with less than V
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-lir,x.ing agent.
s 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 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 retention enhancing group, for example having the formula -(X)n-R defined above. Mixtures of these monomers may be employed, and copolymers thereof with one or more inert polymerizable ehtylenically 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. Polysiloxanes containing or modified to contain pendant delivery-enhancing groups and retention may also be employed as AEA's herein. Also effective as AEA's herein are ionomers containing or modified to contain delivery - and retention-enhancing groups. Ionomers are described on pages 546-573 of the Kirk-Othmer Encyclopedia of Chemical Technology, third edition, Supplement Volume, John Wiley and Sons, Inc. copyright 1984. Also 19a 20~)fi'718 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 "microemulsion". As the amount of the polycarboxylate increases such that the complete oral preparation contains ri at least about 2.2% by weight thereof, the solution becomes cloudy and may be characterized as a "macroemulsion". In ~r such "macroemulsion" type compositions, the antiplaque effect of the antibacterial agent appears to be optimized.
~. A desirable weight ratio of the substantially water-_:.r~~~'rr insoluble noncationic antibacterial agent to the 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 agents are an amount of a fluoride ion source sufficient to supply 25 ppm. to 5 , 000 ppm. of f luoride 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 so..rces of fluoride ions, or fluorine-providing ._ __ -..._.....".,...
component, as acid phosphatase and pyrophosphatase enzyme inhibitor component, are well known in the art as anti-caries 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 ~~

;~0~)1 ~ 71.8 .freedom from undesired reaction with other compounds of the .<,;r:::
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 such as cuprous fluoride, zinc fluoride, barium fluoride, sodium fluorosilicate, ammonium fluorosilicate, sodium fluorozirconate, ammonium fluorozirconate, sodium monofluorophosphate, aluminum mono- and di-fluorophosphate, and fluorinated sodium calcium pyrophosphate. Alkali metal and tin fluorides, such as sodium and stannous fluorides, sodium monofluorophosphate (MFP) and mixtures thereof, are preferred.
The amount of fluorine-providing compound is dependent h to some extent upon the type of compound, its solubility, and the type or oral preparation, but it must be a non-toxic amount, gene-rally 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 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 20~~'73.8 ion. Generally about 0.005 to about 1.0 wt. x of such :, compound is present.
In certain highly preferred forms of the invention the 1 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, pref erably 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 99.9X by weight of t:~e 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 preferably in the range of from about 6 to about 8Ø It is noteworthy that the compositions of the invention may be applied orally at a rf1 h~ 1 ow 5 w i ~ s ~ut: substantially decalcifying or oth~r~,~is~ <fama~iry~ dental enamel. The pH
can be controlled w s ~ ~~ ;ic i d ( ~ . n o itric acid or benzoic acid ) or base ( a . g . w ~~1 i um hydra ~: i <1e ) or buffered (as with sodium citrate, ben- .r e, carbonar e, or bicarbonate, disodium hydrogen p! ~~~hnte, sodium dihydrogen phsophate, etc.).
In certain other ~tesirnble form of this invention, the oral composition may he 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 2006'718 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 sized 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 trademark SYLOID as Syloid 72 and Syloid 74 or under the trademark SANTOCEL as Santocel 100, alkali metal alumino-silicate complexes are particularly useful, since they have refractive indices close to the refractive indices of gelling agent-liquid (including w.nPr and/or humectant) systems commonly moo! in ~fontif r i..s.

Many of the sue- ~ ~~ 1 1 ~~1 "wat:~ ~ i nsoluble" polishing materials are anicm, ~ i n ofrarau= f and also include small - amounts of soluble ~ ~ r ~r i al . Tl~~,~ , insoluble sodium metaphosphate may t~ t ~~rmed in any suitable manner as E illustrated by Thorti~ ' s S~ictionary of Applied Chemistry , ,~
Volume 9, 4th Editinr~; pj~. 510-511. The forms of insoluble sodium metaphosphatE~ known as Madrell's salt and Kurrol's ' salt are further examples of suitat,lc' 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 20~1~'71.~
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 site such 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, j -' 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 frwlex is an important consideration, about ? . '~- 10 wt 2 wf water, 0 to about 70 wt.% of glycerine nr,~1 ~ts«ut 20-~~ wt. % of sorbitol are preferably employrr!
Toothpastes, c r ~ gyms and gel ~, t ypically contain a natural or synthet9 =hickener or gelling agent in proportions of about ~t.i to about 10, preferably about 0.5 to about 5 wt. %. A ~>uit lhle thickener is synthetic hectorite, a synther~.~ colloidal magnesium alkali metal 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% SiOz, 25.40% MgO, 3.05% Na,O, 0.98% Li20, 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 1Ø

Other suitable thickeners include Irish moss, iota carrageenan, gum tragacanth, starch, polyvinylpyrrolidone, hydroxyethylpropylcellulose, hydroxybutyl methyl cellulose, hydroxy propyl methyl cellulose, hydroxyethyl cellulose (e. g.
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 sliceous 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 as 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.
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 *trade-mark 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 creme.
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 *Trade-mark 25a 20~6'~18 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 x 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 sodium dodecyl benzene sulfonate, higher alkylsulfo-acetates, higher fatty acid esters of 1,2-dihydroxy propane sulfonate, arid 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 a marked effect in the inhibition of p~~id formation in the oral cavity due to carhnhyclr:rt~~q ~~r w~.~kdown in addition to exerting some reduc t i ~~n i n t he sc~ i nt~ i 1 ity of tooth enamel in acid solutions. Exnr<w; ;~,~; ~,C wat.~~- soluble nonionic surfactants are concl~~~ _at.ion prociw~ is of ethylene oxide with various reactive hydr ,~n-containirsg compounds reactive therewith having long ~irnphobic chains (e. g. aliphatic chains of about 12 to .' 0 c:~ rbon atoms ) , which condensation products ("ethoxamers"~ cent:ain hydrophilic polyoxyethylene moieties, such as condensation products of polyethylene oxide) with fatty acids, fatty alcohols, fatty amides, polyhydric alcohols (e.g. sorbitan monostearate) and 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 2006'7113 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 employee. 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, ''V
AMP (aspartyl phenyl alanine, met.hvl ester), saccharine and the like. Suitably, flavs,r anti ~-~~~~~tening agents may each or together comprisr t~rc,m at,out ~ . 1'~ to 5% more of the preparation. More<~~. i ~ , f 1 avor t 1 appears to aid the dissolving of the an~ t,~ct.erial -ynnt.
In the preferre~' ~ F~ct.ice of t his invention an oral composition accorditm ~~5 .his invention such as a mouthwash or dentifrice contai~,lc,p the composition of the present invention is preferat~ ~;: aE,plied 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 ~'l 200f '7~.8 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.
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 malefic 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".
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 polycarh~fylate.

The formulations of the toothpastes evaluated are:

Parts b y Weight A B

Glycerine 10.000 10.000 Iota-carrageenan 0.750 0.750 Sorbitol (700 solution) 30.000 30.000 Propylene Glycol 0.500 0.500 Gantrez (13.020 solution) 19.000 15.500 Titanium dioxide 0.500 0.500 Water (deionized) 9.957 13.457 NaF 0.243 0.243 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 of 2.5 parts amount in toothpaste A and 2.0 parts in toothpaste B.

For the test of delivery of antibacterial agent to a saliva coated hydroxyapatite disk, hydroxyapatite (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 pellete 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 collected into an ice-chilled glass beaker.
The saliva is clarified by centrifugation at 15,000 Xg (times gravity 29a 206''718 for 15 minutes at 4°C. Sterilization of the clarified-saliva is done at 4°C with stirring by irradiation of the sample with W 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
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 t-~ 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 of antibacterial agent concent~n!ion. Triplicate samples are used in all experiments.
The Table bel«v aummnri~~~~ ttie data:
Table Delivery of TCHE to Toothpaste Saliva Coated Hydroxyapatite Disc in Micrograms The data indicatPS that with the increasing amount of Gantrpz (Toothpaste A) there is a very great increase in delivery of TCHE to saliva coated tooth minerals.
- .. . 3 0 200f'~18 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 'z Water (deionized) 2.69 Sodium Monofluorophsophate 0.76 Sodium saccharine 0.30 k x Pyrophosphate 2.00 Hydrated alumina 48.00 Flavor oil 0.95 TCHE 0.30 SLS 2.00 Example 3 y Mouthrinse Parts Tetrasodium Pyrophosphate 2.00 ' Gantrez S-97 2.50 Glycerine 10.00 Sodium Fluoride 0.05 Sodium Lauryl Sulfate 0.20 TCHE
0.06 Flavor oil 0.40 Water g.S. to 1 00.00 ~(~~~i'~~..~
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
1 to 5% Magnesium Stearate Lubricant 0.01 to 0.2% Water Example 5 Chewing Gum Parts Gum Base 25.00 Sorbitol (70$) 17.00 w TCHE 0.50 to 0.10 Tetrasodium Pyrophosphate 2.00 Gantrez 5.97 2.50 In a variant Example of the foregoing Example, Gantrez S-97 can .~e omitted.
Example 6 Chewing Gum Parts Gum Base 30.00 TCHE 0.50 Gantrez 2.00 NaF 0.05 Glycerine 0.50 Crystalline Satbitol 53.00 Tetrasodium Fjl~phosphatc~ 2.00 Flavor Oil and water Q.S. to 100.00 In the foreE>, ~ ~ r,p, Examples improved results are also achievable when T!:)tE is replaced with each of phenol, 2,2'-met~ylene bis(4-c!rloxo-6-Bromophenol), eugenol and thymol, and/or when Gantrez is replaced by other AEA's such as 2006'718 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 beta-~r-c styrenephosphonic acid, and poly (alpha-styrenephosphonic acid), or sulfoacrylic oligomers, or a 1:1 copolymer of malefic anhydride with ethyl acrylate.
.~:....~, .x__.~:
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 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 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.
~,-....,~.,.e".~
i

Claims (58)

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 linear molecularly dehydrated 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 antibacterial-enhancing agent which enhances delivery of the antibacterial agent to, and the retention thereof on, oral surfaces, the weight ratio of the antibacterial-enhancing agent to the polyphosphate ion ranging from about 1.6:1 to about 2.7:1.

2. The oral composition claimed in Claim 1, wherein the antibacterial agent is selected from the group consisting of halogenated diphenyl ethers, halogenated salcylanilides, benzoic esters, halogenated carbanilides and phenolic compounds.

3. The oral composition claimed in Claim 1, wherein the antibacterial agent is a halogenated diphenyl ether.

4. The oral composition claimed in Claim 3, wherein the halogenated diphenyl ether is 2,4,4'-trichloro-2'-hydroxyphenyl ether.

5. The oral composition claimed in Claim 1, wherein the antibacterial agent is a phenolic compound.

6. The oral composition claimed in Claim 5, wherein the phenolic compound is selected from the group consisting of phenol, thymol, eugenol and 2,2'-methylene bis(4-chloro-6-bromophenol).

7. The oral composition according to any one of Claims 2 to 6, wherein the antibacterial agent is present in amount of about 0.01-5% by weight.

8. The oral composition claimed in Claim 7, wherein the amount of antibacterial agent is about 0.25-0.5%.

9. The oral composition according to any one of Claims 1 to 8, wherein the linear molecularly dehydrated polyphosphate salt is an alkali metal pyrophosphate present in amount of about 1-2.5% by weight.

10. The oral composition claimed in Claim 9, wherein the alkali metal pyrophosphate is a tetrasodium pyrophosphate.

11. The oral composition according to any one of Claims 1 to 10, wherein the weight ratio of the antibacterial enhancing agent to polyphosphate ion is about 1.7:1 to about 2.3:1.

12. The oral composition according to any one of Claims 1-11, wherein the vehicle comprises water, humectant and a gelling agent and the oral composition contains a dentally acceptable water-insoluble polishing agent and is a dentifrice.

13. The oral composition according to any one of Claims 1-11, wherein the vehicle comprises water and a non-toxic alcohol and the oral composition is a mouthwash.

14. The oral composition according to any one of Claims 1-13, wherein the antibacterial-enhancing agent has an average molecular weight of about 1,000 to about 1,000,000.

15. The oral composition according to Claim 14, wherein the antibacterial-enhancing agent contains at least one delivery-enhancing functional group and at least one organic retention-enhancing group.

16. The oral composition according to Claim 15, wherein the delivery-enhancing group is acidic.

17. The oral composition according to Claim 16, wherein the delivery-enhancing group is selected from the group consisting of carboxylic, phosphonic, phosphinic, and sulfonic acids, and their salts, and mixtures thereof.

18. The oral composition according to Claim 17, wherein the organic retention-enhancing group has the formula -(X)n-R
wherein X is O, N, S, SO, SO2, PO, or Si, R is hydrophobic alkyl, arly, alkenyl, acyl, alkaryl, aralkyl, heterocyclic, or their inert-substituted derivative, and n is 1 or zero.

19. The oral composition according to Claim 17 or 18, wherein the antibacterial-enhancing agent is an anionic polymer containing a plurality of the delivery-enhancing and organic retention-enhancing group.

20. The oral composition according to Claim 19, wherein the anionic polymer comprises a chain containing repeating units each containing at least one carbon atom.

21. The oral composition according to Claim 20, wherein each repeating unit contains at least one delivery-enhancing group and at least one organic retention-enhancing group bonded to the same or vicinal, or other atoms in the chain.

22. The oral composition according to any one of Claims 17 to 21, wherein the delivery-enhancing group is a carboxylic group or salt thereof.

23. The oral composition according to any one of Claims 1 to 14, wherein the antibacterial-enhancing agent is a copolymer of malefic acid or anhydride with another ethylenically unsaturated polymerizable monomer or a salt thereof.

24. The oral composition according to Claim 23, wherein the other monomer is methyl vinyl ether in a 4:1 to 1:4 molar ratio with the malefic acid or anhydride.

25. The oral composition according to Claim 23 or 24, wherein the copolymer has a molecular weight of about 30,000-1,000,000.

26. A composition according to Claim 25, wherein the copolymer has an average molecular weight of about 70,000.

27. A composition according to any one of Claims 17 to 21, where the delivery-enhancing group is a phosphonic group or salt thereof.

28. A composition according to Claim 27, wherein 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 a salt thereof.

29. A composition according to Claim 27 or 28, wherein the antibacterial-enhancing agent has a molecular weight of about 2,000 to about 30,000.

30. An oral composition according to any one of Claims 1-29 containing a fluoride ion-providing source.

31. A method of controlling oral plaque comprising applying to oral surfaces a plaque-controlling amount of a composition as defined in any one of Claims 1-30

32. An oral composition comprising:
an orally acceptable vehicle, an antibacterial agent, an agent which is effective to enhance the antibacterial effect of the antibacterial agent and 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 the antibacterial effect and at least one organic group which enhances retention of the antibacterial effect, the agent containing the 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 a polyphosphate anticalculus agent, the said polyphosphate antilcalculus agent being a mixture of potassium and sodium salts, the ratio of potassium to sodium in the composition being in the range of up to less than about 3:1.

33. The oral composition claimed in Claim 32 wherein the ratio of potassium to sodium is from about 0.37:1 to about 1.04:1.

34. The oral composition claimed in Claim 32 or 33, wherein the group which enhances delivery is selected from the group consisting of phosphonic, phosphinic and sulfonic acids, and their salts, and mixtures thereof.

35. The oral composition claimed in Claim 33 or 34, wherein the organic group which enhances retention has the formula -(X)n-R wherein X is O, N, S, SO, SO2, PO, or Si, R is hydrophobic alkyl, aryl, alkenyl, acyl, alkaryl, aralkyl, heterocyclic, or their inert-substituted derivative, and n is 1 or zero.

36. An oral composition comprising:
an orally acceptable vehicle, an antibacterial agent, an agent which is effective to enhance the antibacterial effect of the antibacterial agent and 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 the antibacterial effect and at least one organic group which enhances retention of the antibacterial effect, the agent containing the 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 a polyphosphate anticalculus agent.

37. The oral composition claimed in Claim 36, wherein the delivery enhancing group is selected from the group consisting of phosphonic, phosphinic and sulfonic acids, and their salts, and mixtures thereof.

38. The oral composition claimed in Claim 36 or 37 wherein the organic retention enhancing group has the formula -(X)n-R wherein X is O, N, S, SO, SO2, PO or Si, R is hydrophobic alkyl, aryl, alkenyl, acyl, alkaryl, aralkyl,

39 heterocyclic, or their inert-substituted derivative, and n is 1 or zero.
39. 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 agent containing these 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 a polyphosphate anticalculus agent.

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

41. The oral composition claimed in Claim 40, wherein the weight ratio is from about 1:1 to about 3.5:1.

42. The oral composition claimed in Claim 40, wherein the weight ratio is from 1.6:1 to about 2.7:1.

43. An oral composition comprising:
an orally acceptable vehicle, an antibacterial agent, an agent which is effective to enhance the antibacterial effect of the antibacterial agent and 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 the antibacterial effect and at least one organic group which enhances retention of the antibacterial effect, and a polyphosphate anticalculus agent, with the proviso that the composition is free from or substantially free from tetrasodium pyrophosphate.

44. An oral composition comprising:
an orally acceptable vehicle, an antibacterial agent, an agent which is effective to enhance the antibacterial effect of an antibacterial agent and 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 the antibacterial effect and at least one organic group which enhances retention of the antibacterial effect, and a 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.

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

46. An oral composition comprising:
an orally acceptable vehicle, an effective antiplaque amount of a substantially water insoluble noncationic antibacterial agent, and a 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.

47. 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 agent containing these 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 a polyphosphate anticalculus agent, with the proviso that the composition is free from or substantially free from tetrasodium pyrophosphate.

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 agent containing these 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 a 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.

49. An oral composition comprising:
an orally acceptable vehicle, an antibacterial agent, an agent which is effective to enhance the antibacterial effect of the antibacterial agent and 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, the agent containing these groups being free from or substantially free from water soluble alkali metal or ammonium synthetic anionic linear polymer polycarboxyate salt having a molecular weight of about 1,000 to 1,000,000, and a 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.

50. The oral composition claimed in Claim 48, wherein the ratio of potassium to sodium is from about 0.37:1 to about 1.04:1.

51. 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 a polyphosphate anticalculus agent.

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 a 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.

53. The oral composition claimed in Claim 51, wherein the ratio ranges from about 0.37:1 to about 1.04:1.

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

55. An oral composition comprising:
an orally acceptable vehicle, a substantially water insoluble noncationic antibacterial agent in an amount of from 0.25% to 0.35%, and a 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.

56. 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 agent containing these 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 a 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.

57. The oral composition claimed in Claim 55, wherein the ratio is from about 0.37:1 to about 1.04:1.

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 agent containing these 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.