GB2259856A - Antiplaque antibacterial oral composition - Google Patents

Description

I - c ' f' 0 c, r -A 1 ANTIPLAQUE ANTIBACTERIAL ORAL COMPOSITION This

invention relates to antibacterial antiplaque oral compositions such as dentifrices and mouthwashes. More particularly, it relates to oral compositions containing a substantially water-insoluble noncationic antibacterial agent effective to inhibit plaque.

Dental plaque is a soft deposit which forms on teeth as opposed to 6alculus which is a hard calcified deposit on teeth. Unlike calculus, plaque may form on any part of the tooth surface, particularly including at the gingival margin. Hence, beside being unsightly, it is implicated in the occurence of gingivitis.

Accordingly, it is highly desirable to include antimicrobial agents which have been known to reduce plaque in oral compositions. Frequently, cationic antibacterial agents have been suggested. Moreover, in U.S. Patent 4,022,880 to Vinson et al, 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 c&' 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 hvdroxydiDhenvl ethers. The nor-cationic antibacterial antiplaque halogenated hydroxydiphenyl ether, triclosan, has also been described in combination with zinc citrate trihydrate in European Patent Publication 0161,899 2 K1 4956 to Saxton et al. Triclosan is also disclosed in European Patent Publication 0271,232 to Davis as a toothpaste comnonent containing a solubilizing agent such as propylene glycol.

The cationic antibacterial materials such as chlorhexidine, benzthanium chloride and cetyl pyridinium chloride have been the subject of greatest investigation as antibacterial antiplaque agents. However., they are generally not effective when used with anionic materials.

Noncationic antibacterial materials, on the other hand, can be compatible with anionic components in an oral composition.

However, oral compositions typically are mixtures of numerous components and even such typically neutral materials as humectants can affect performance of such compositions.

Moreover, even noncationic antibacterial agents may have limited antiplaque effectiveness with commonly used materials such as polyphosphate anticalculus agents which are disclosed togethei British Patent Publication 22 00551 of Gaffar et al and in EP 0251591 of Jackson et al.

In commonly assigned U.S.S.N. 398,605, filed on August 25, 1989, corresponding to G.B. Application No. Serial No.

it is shown that the antiplacrue effectiveness is greatly enhanced by including an antibacterial-enhancing agent (AEA) which enhances the delivery of said antibacterial agent to, and retention thereof on, oral 3 V,1 4956 surfaces and providing optimized amounts and ratios of polyphosphate and AEA.

It is an advantage of this invention that an oral composition is provided wherein a substantially waterinsoluble nancationic antibacterial agent and an AEA is provided to inhibit plague formation, wherein the oral composition contains an orally acceptable liquid vehicle effective to'enable said antibacterial agent to dissolve in saliva in effective antiplaque amount.

it is a further advantage of. this invention that the AEA enhances the delivery and retention of small but effective antiplaque amount of the antibacterial agent on teeth and on soft oral tissues.

it is a further advantage of this invention that an antiplaque oral composition is provided which is effective to reduce the occurence 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 an effective antiplaque amount of a substantially water insoluble noncationic antibacterial agent, about 0. 005-4% by weight of an antibaceri al - enhancing agent which enhances the delivery of said antibacterial' agent to, and retention thereon, oral surfaces and an orally acceptable vehicle effective to enable said antibacterial agent to dissolve in 4 K1 4956 saliva in effective antiplaque amount, said oral composition being substantially f ret of polyphosphate anticalculus agent.

Typical examples of water insoluble noncationic antibacterial agents which are particularly desirable from considerations of antiplaclue effectiveness, safety and formulation are:

Halogendted Diphenvl Ethers 21,4,41-trichloro-2-hvdroxy-dipheny1 ether (Triclosan) 2,21dihydroxy-5,51-dibroma-dipheny1 ether.

Haloaenated Salicylanilides 41,5-dibromosalicylanilide 3,41,5trichlorosalcylanilide 3,41,5-tribromosalicylanilide 2,3,31,5-tetrachlorosalicylanilide 3,3,31,5-tetrachlorosalicylanilide 3,5dibromo-31-trifluaromethyl salicylanilide 5-n-octanoyl-3'-trifluoromethyl salicylanilide 3,5dibromo-41-trifluoromethyl salicylanilide salicylanilide (Flurophene) Benzoic Esters Methyl - p-Hydroxybenzoic Ester Ethyl p-Hydroxybenzoic Ester Propyl - D- Hydroxybenzoic Ester Butyl p-Hydroxybenzoic Ester t i K1 4956 Halocenated Carbanilides 3,4,4'-tr4-chlorocarbaniz..I...4..A"e 3trifluaromethyl-4,4'-dichlorocarbanilide 3,3,4'-trichlorccarbanilide Phenolic Commounds (including phenol and its homologs, and polir-alkyl and aromatic halo (e.g. F, Cl, Br, I.)phenols, resorcinol and catechol. and their derivatives and bisphenolic compounds) Phenol and its Homoloas Phenol 2 Methyl 3 Methyl 4 Methyl 4 Ethyl 2,4-Dimethyl 2,5-Dimethyl 3,4-Dimethyl 2,6-Dimethyl 4-n Propyl 20 4-n- Butyl 4-n-Amyl 4-tert-AmyI.

Phenol Phenol Phenol Phenol Phenol Phenol Phenol Phenol Phenol Phenol Phenol Phenol 4-n-Hexyl - Phenol 4-n-Heptyl - Phenol 2-Methoxy-4-(2-Propenyl)-Phenol 2 -Met"tnrl - (Eugenol) 6 K1 4956 Monoand Polv-Alkyl and Aralkyl Halophenols - p-Chlorophenol p- Chlorphenol p-Chlorophenol p-Chlorophenol p-Chlorophenol p-Chlorophenol pChlorophenol p-Chlorophenol p-Chlorophenol p-Chlorophenol Methyl Ethyl n-Propyl n-Butyl n-Amyl sec-Amyl n-Hexyl cyclohexyl n-Heptyl n-Octyl O-Chlorophenol Methyl Ethyl n-Propyl n-Butyl n-Amyl tert-Amyl n-Hexyl n-Heptyl p-Chlorophenol o-Benzyl o-lenzyl-m-methyl o-Benzyl-m, m-dimethyl o-Phenylethyl o-Phenylethyl-m-methyl 3-Methyl 3,5-Dimethyl t o-Chlorophenol o-Chlorophenol o-Chlorophenol o-Chlorophenol o-Chlorophencl o-Chlorophenol o-chloraphencl --Chloropenol .i p-Chlorophenol p-Chlorophenol p-Chlorophenol p-Chlorophenal p- Chlorophenol p-Chlorophenol p-Chlorophenol 7 6-Ethyl-3-methyl 6-n-Propyl-3-methyl 6-iso-propyl-3-methyl 2-Ethyl-3,5- dimethyl 6-sec Butyl-3-methyl 2-iso-Propyl-3,5-dimethyl 6-Diethylmethyl-3- methyl 6-iso-Propyl-i-ethyl-3-methyl 2-sec Amy1-3,5-dL-nethyl 10 2Diethylmethyl-3,5-dimethyl 6-sec Octyl-3-methyl p-Bromophenol Methyl Ethyl n-Propyl n-Butyl n-Amyl sec-Amyl n-Hexyl 20 cyclohexyl o- Bromophenol tert-Amyl n-Hexyl n-Propylm,m-Dimethyl 25 2-Phenyl Phenol 4Chloro-2-methyl phenol 4-chloro-3-methyl phenol K14956 p-Chlcrophencl p-Chlorophenol p-Chlorophenol p-Chlorophenol p- Chlorophenol p-Chlorophenol p-Chlorophenol p-Chlorophenol p-Chlorophenol p-Chlorophenol p-Chlorophenol p-Bromophenol p-Bromophenol p-Bromophenol p-Bromophenol p-Bromophenol p- Bromophenol p-Bromophenol p-Bromophenol o-Bromophencl o-Bromophenol o-BromoDhenol 8 4-chloro-3,5-dimethyl phenol 2,4-dichloro-3,5-dimethyl'phenol 3,4,5,6- tetrabromo-2-methylphena1 5-methyl-2-pentylphenol 4-isopropyl-3- methylphenol 5-chlarc-2-hydroxydiphenyl methane Resorcinol and Its Derivatives Resorcinol Methyl 10 Ethyl n-Propyl n-Butyl n-Amyl n-Hexyl 15 n-Heptyl n-Octyl n-Nonyl Phenyl Benzyl 20 Phenylethyl Phenylpropyl p- Chlorobenzyl 5-Chloro 4'-Chloro 5-Bromo 4"-Bromo Y, 14956 Resorcinol Resorcinol Resorcinol Resorcinol Resorcinol Resorcinol Resorcinal Resorcinol Resorcinol Resorcinol Resorcinol Inol Resorcinol Resorcinol -2,4-Dihydroxydiphenyl Methane -2,4- Dihvdroxvdiphenyl Methane -2,4-Dihydroxydiphenyl Methane -2,4- Dihydroxydiphenyl Methane c I 1. 111 9 K1 4956 Bisphenolic Compounds Bisphenol A 2,21-methylene bis (4-chlorophenol) 2,21-methylene bis (3,4,6-trichlorophenol) (hexachlorophene) 2,21-methylene bis (4-chloro-6-bromophenol) bis (2-hydroxy-3,5- dichlorophenyl) sulfide bis (2-hydroxy-5-chlorobenzyl) sulfide The nonationic antibacterial agent is present in the oral composition in an effective antiplaque amount preferably about 0. 01 %-5% by weight, more preferably about 0. OR-1 %, more preferably about 0.25-0.5% or about 0.25% to less than 0.5% and most preferably about 0.25-0.35%, e.g. about 0.3%, in a dentifrice or preferably about 0.03-0.3% by weight, most preferably about 0.03-0.1% in a mouthwash or liquid dentifrice. 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%.

The preferred halogenated diphenyl ether is triclosan.

The preferred phenolic compounds are phenol, thymol, eugenol, hexyl resorcinol and 2,2'methylene bis (4-chloro-6 bromophenol). 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 agent which provides zinc ions and in German Patent Disclosure 3532860

K14956 in combination with a copper compound. In European Patent Disclosure 0278744 it is disclosed in combination with a tooth desensitizing agent containing a source of potassium ions. 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 m and which may optionally contain a zinc salt in published European Patett Application 0161898 of Lane et al and in a dentifr-ice containing zinc citrate trihydrate in published European Patent Application 0161899 to Saxton et al.

Ihe antibacterial-enhancing agent (AEA) which enhances delivery of said antibacterial agent to, and retention thereof on, oral surf aces, is employed in amounts effective to achieve such enhancement preferably within the range in the oral carposition of about 0.005% to about 4%, preferably about 0. 1% to about 3%, more pref erably 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 oligamers, homopolymers, copolymers of two or more monamers, 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, hydragel forming). It- preferably has an (wei#,t) average molecular weight t t 71.1 K1 4956 of about 100 to about 1,000,000, preferably about 1,000 to about 1, 000, 000, more pref erably about 2, 000 or 2, 5000 to about 250,000 or 500,000.

The AEA ordinarily contains at least one delivery- enhancing group, which'is preferably acidic such as sulf onic, phosphonic, or more pref erably phosphonic or carboxylic, or salt thereof, e.g. alkali metal or ammonium, and at least 1Dne organic retention- enhancing group, preferably a plurality of both the delivery- enhancing and retention-enhancing groups, which latter groups preferably have the f ormula - (X),,-R wherein X is 0, N, S, SO, SO,, P, PO or Si or the like, R is hydrophobic alkyl, alkenyl, acyl, aryl, alkaryl, aralkyl, heterocyclic or their inertsubstituted derivatives, and n is zero or 1 or more. The aforesaid "inert -substituted derivatives", are intended to include substituents on R which are generally nonhydrophilic and do not significantly interfere with the desired functions of the AF-A as enhancing the delivery of the antibacterial agent to, and retention thereof on, oral 20 surfaces such as halo, e.g. Cl, Br, I, and carbo and the 0 like. Illustrations of such retention-enhancing groups are tabulated below.

12 K1 4956 n X - (V),D 0 --- is 1 0 N methyl, ethyl, propyl, butyl, isobutyl, t-butyl cycloexyl, allyl, benzyl, phenyl, chlorophenyl, xylyl, pyridyl, furanyl, acetyl, benzoyl, butyryl, terephthaloyl, etc.

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

ethylamino, diethylamino, propylamido, benzylamino, benzoylamido, phenyl ace tamido, etc.

S thiobutyl, thioisobutyl, thioallyl, thiobenzvl, thiophenyl, thiopropionyl, phenyithicacetyl,thiobenzoyl, etc.

SO butylsulf oxy, allylsulf oxy, benzylsulf oxy, phenylsulfoxy, etc.

SO, butylsulf anyl, allylsulf onyl, benzyIsulf anyl, phenyIsulfonyl, etc.

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

PO diethylphosphinoxy, ethylvinylphosphinoxy, methyl al lylpho sphinoxy, methylbenzylphosphinoxy, methylphenylphosphinoxy, etc.

Si trimethylsilyl, dimethylbutylsilyl, dimethylbenzylsilyl, dimethylvinylsilyl, dimethylallylsilyl, etc.

As einployed herein, the delivery-enhancing group refers to one which attaches or substantively, adhesively, cohesively or otherwise bands the AF. A (carrying the antibacterial agent) to oral (e.g. tooth and gum) surfaces. thereby "delivering" the antibacterial agent to such surfaces. The organic re tent ion- enhancing group, generally K1 4956 hydrophobic, attaches or otherwise bonds the antibacterial agent to the AEL, thereby promoting retention of the antibacr-erial agent to the ARA 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 crosslinked polymer, the structure of which inherently provides increased sies for such entrapment. The presence of a higher molecular weight, more hydrODhobic 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 AF.A 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 bonde%-&' to atoms, pref erably carbon, in the chain. Less preferably, the polymer may contain delivery-enhancing groups andlor retention-enhancing groups andlor other divalent atoms or groups as links in the polymer chain instead of or in addition to carbon a-toms, or as crosslinking moieties.

It will be understood that any examples or illustrations of ARA's disclosed herein which do not contain 14 K1 4956 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 surf aces, that the repeating units in the olymer chain or backbone containing the acidic delivery enhancing groups constitute at least about 10%, preferably at least about 50%, more preferably at least about 80% up to 95% or 100% by weight of the polymer.

According to a preferred embodiment of this invention, the AEA comprises a polymer containing repeating units in which one or more phosphonic acid delivery- enhancing groups are banded 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 -[CH, CHI P03H, whirh howevw d= nrt a rc.--ltion-enh=ing g=up. A group of the latter type would however be present in poly (1-phasphonopropene) with units of the formula:

-[CH CHI CH3 P03H, A preferred phosphonic acid-containing AEA for use herein z z is K1 4956 is poly (beta styrene phosphonic acid) containing units of the formula:

III -[CH - CHIPh A3H2 wherein Ph is phenyl, the phosphonic deliveryenhancing group and the phenyl retention-enhancing group being bonded on vicinal carbon atoms in the chain, or a copolymer of beta styrene phoshonic acid with vinyl phosphonyl chloride 1 having the units of formula III alternating or in random association with units of f armula I above, or poly (alpha styrene phosphonic acid) containing units of the f armula:

iv -[CH2 C ----- IPh P03H2 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, f or example, phosphonated ethylene having units of the f armula.

v -[CH2)14CHP03H23._ where n may f or example be an integer ar have a value giving 16 K1 4956 the polymer a molecular weight of about 3,000; and sodium poly (butene-4, 4-diphosphonate) having units of the formula.

VI CH2 - CH ---- 1 - c, - CH < (P03Na2)2 and poly (allyl bis (phosphonoethyl amine) having units of the f ormula:

Vii -[CH2 - CH--- 1 c2 - N < (P03H2) 2 other phosphonated polymers, for example poly (allyl phosphono acetate), phosphonated polymethacrylate, etc. and the geminal diphosphonate polymers disclosed in EP Publication 0321233 may be employed herein as AEA' s, provided of course that they contain-or are modified to contain the above-def ined organic retent ionenhancing groups. In an aspect of the invention, the oral composition comprises 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 20 weight or about 1,1w%rbolr-l tc about 1,000,000, contains at least one delivery enhancing functional group and at least one organic retention enhancing group,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 about 1,000,000.

1 K1 4956 According to another prefferred embodiment, the AF-A may comprise a synthetic anionic polymeric polycarboxylate. Although not used in the present invention to coact with polyphosphate anticalculus agent, 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, has been used as an inhibitor of alkaline phosphatase enzyme in optimizing anticalculus effectiveness of linear molecularly dehydrated polyphosphate saltes, as disclosed in U.S. Patent 4,627,977 to Gaffar et al. indeed, in published British Patent Publication 22 00551, the polymeric polycarboxylate is disclosed as an optional ingredient in oral compositions containing linear molecularly dehydrated polyphosphate salts and substantially water- insoluble noncationic antibacterial agent. It is further observed, in the context of the present invention that such polycarboxylate is markedly effective to enhance delivery and retention of the nonionic antibacterial, antiplaque agent to dental surfaces when another ingredient 2 (that is, molecularly dehydrated polyphosphate) with which the polymeric polycarboxylate coacts is absent; for instance, when the ingredient with which the polymeric polycarboxylate coacts is especially the noncationic antibacterial agent.

Synthetic anionic polymeric polycarboxylates and their complexes with various cationic germicides, zinc and 18 K14956 magnesium have been previously disclosed asanticalculus 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.

it is to be understood that the synthetic anionic polymeric pol,,,.carbo.-.ylates so _in these several patents when containing ot modified to contain retention-enhancing groups are operative in the compositions and methods of this invention and such disclosures are to that extent incorporated herein by reference thereto.

The synthetic anionic polymeric polycarboxylates employed herein are well known, being often employed in the form of their free acids or preferably partially or more preferably fully neutralized water soluble alkali metal (e.g. potassium and preferably sodium) or ammonium salts. Preferred are 1:4 to 4:1 copolymers of 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, most preferably about 30,000 to about 500,000. 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.

19 K1 4956 other AEA operative polymeric polycarboxylates containing or modified to contain retention-enhancing groups include those disclosed in U.S. Patent No. 3,956,480 ref erred to above, such as the 1: 1 copolymers of maleic anhydride with ethyl acrylate, hydroxyethyl methacrylate, Nvinyl-2- pyrallidone, 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 10 acrylate, isobutyl, isobutyl vinyl ether or N-vinyl-2pyrrolidone.

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 retention15 enhancing groups include copolymers of maleic anhydride with styrene, isobutylene or ethyl vinyl ether, polyacrylic, polyitaconic and polymaleic acids, and sulfoacrylic oligomers of M.W. as low as 1,000, available as Uniroyal ND- Suitable generally are retent.,&.cn-enhanc-4ng group containing polymerized olefinically or ethylenically unsaturated carboxylic acids containing an activated carbon to-carbon 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 a part of a terminal methylene grouping.

Illustrative ethacrylic, K1 4956 of such acids are acrylic, methacrylic, alpha-chloroacrylic, crotonic, propionic, sarbic, alphachlorsorbic, cinnamic, betastyrylacrylic, muconic, itaconic, citraconic, mesaconic, glutaconic, aconitic, alpha-phenylacryllc, 2-benzyl acrylic, 2cyclohexylacrylic, angelic, umbellic, fumaric, maleic acids and anhydrides. Other d Iffe-rent ole -An-4c monomer copolymerizable with such carboxylic monomers include vinylacetate, vinyl chloride, dimethyl maleate and the like.

Copolymers contain sufficient carboxylic salt groups for water-solubility.

Also usef ul 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.F. Goodrich, these products consisting essentially of a colloidally water-soluble polymer of polyacrylic acid crosslinked with from about 0.75% 1= abcu. 2.0% of polvallyl sucrose or polyallyl pentaerythritol as cross linking agent, the cross-linked structure and crosslinkages providing the desired retention enhancement by hydrophobicity and/or physical efitrapment of the antibacterial agent or the like. Polycarbophil is somewhat similar, being poly acrylic acid cross-l-inked with less than beta-acryloxy c 21 K1496 0.2% of divinyl glycol, the lower proportion, molecular weight andlor hydrophobicity of this cross-linking agent tending to provide little or no retention enhancement. 2,5dimethyl-1,5-hexadiene exemplifies a more effective retention-enhancing cross-linking agent.

The synthetic anionic polymeric polycarboxylate exponent is mainly a hydrocarbon with optional halogen and 0containing substituents and linkages as present in, for example ester, ether and OH grcups, and is employed in the instant c=positions in apprcximte weight amomts of 0.05 to 4%, preferably 0.05 to 3%, more preferably 0.1 to 2%.

The AEA may also comprise natural anionic polymeric polycarboxylates containing retention-enhancing groups. Carboxymethyl cellulose and other binding agents gums and f ilm- formers devoid of the above-def ined delivery-enhancing andlor retention- enhancing groups are inef f ective as AEA' s.

As illustrative of AEA' s containing phosphinic acid andlor sulf anic acid delivery enhancing groups, there may be mentioned polymers and copolymers containing units or moieties derived from the polymerization of or allyl phosphinic andlor sulf onic acids substituted as needed on the 1 or 2 (or 3) carbon atom by an organic retention-enhancing group, for example having the f ormula - (X),, -R def ined 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 22 K1 4956 polymeric polycarboxylates. As will be noted. in these and other polymeric AEA's operative herein, usually only one acidic del ivery- enhancing group is bonded to any given carbon or other atom in the polymer backbone or branch thereon. Polysilaxanes containing or modified to contain pendant delivery-enhancing groups and retention enhancing groups may also be employed as AEA ' s herein. Also ef f ective as AEA's herein are ionamers containing or modif ied to contain delivery-and retentionenhancing groups. Ionamers are described on pages 546-573 of the Kirk Othmer Encyclopedia of Chemical Technology, third edition, Supplement Volume, John Wiley & Sons, Inc. copyright 1984, which description is incorporated herein by ref erence. Also effective as AEA's herein, provided they contain or are modified to contain retention- enhancing groups, are polyesters, polyurethanes and synthetic and natural polyamides including proteins and proteinaceous materials such as collagen, poly (arginine) and other polymerized amino acids.

in an aspect of the present invention the AEA which has an average molecular weight of about 1,000 to about 1,000.000, contains at least one delivery enhancing functional group and at least one organic retention enhancing group, 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 about 1; 000,000.

:' 23 is Y,l 4956 In the present invention a preferred oral composition is a dentifrice containing about 0.3% by weighof the antibacterial agent (e.g. triclosan) and about 1.5-2% by weight of the polycarboxylate as AEA.

Without being bound to a theory, it is believed that the AEA, especially polymeric AEA, is generally an anionic f iLm f orming material and is thought to attach to tooth surfacds and form a continuous film over the surfaces, thereby preventing bacterial attachment to tooth surf aces.

it is possible that the noncationic antibacterial agent f orms a complex or other f orm of association with the AEA, thus f orming a film of a complex or the like over tooth surfaces. The film forming property of the AEA and the enhanced delivery and retention of the antibacterial agent on tooth surfaces due to the AEA appears to make tooth surfaces unfavourable for bacterial accumulation particularly since the direct bacteriostatic action of the antibacterial agent controls bacterial growth. Therefore, through the combination of three modes of actions: 1) enhanced deliver y,2) long retention time on tooth surfaces, and 3) prevention of bacterial attachment to tooth surfaces, the oral c omposition is made efficacious for reducing plaque. Similar antiplaque effectiveness is" attained on soft oral tissue at or near the gum line.

in accordance with the present invention, the orally acceptable vehicle is effective to enable the substantially 24 K1 495.6 water-insoluble noncationic antibacterial agent to dissolve in saliva in an effective antiplaque amount.

In the oral preparation, an orally acceptable vehicle includes a waterphase with humectant present. In a gel dentifrice, typically containing about 5-30% by weight of a siliceous polishing agent, water is typically present in amount of at least about 3% by weight, generally about 335%, and hurdectant, preferably glycerine andlor sorbitol typically total about 6.5-75% or 80% by weight of the oral gel dentifrice composition. Reference hereto to sorbitol refers to the material typically as available commerically in 70% aqueous solutions.

The gel dentifrices, when the amount of antibacterial agent is about 0.250.35% by weight, do not require a further ingredient in the oral vehicle to solubilize the antibacterial agent, although the presence of such solubilizing agent is optional. When the amount of antibacterial agent is below about 0.25% by weight, e.g. about 0.01 up to about 0.25% by weight, solubilizing agent therefore should be Dresent in order to assure sufficient solubilization in saliva for antiplaque effectiveness. When the amount of antibacterial agent is above about 0.35% by weight, e.g. about 0.35 to about 0.5% or more, say 5%, solubilizing agent therefore should be present since otherwise a substantial part of the antibacterial agent would remain insoluble.

2 K1 4956 When the oral composition is a dentifrice containing about 30-75% by weight of a dentally acceptable polishing agent, the presence of such solubilizing agent is also optional.

when the oral composition is a mouthwash or liquid dentifrice, the oral vehicle includes at 'Least one of a surface-active agent, a flavoring oil or a non-toxic alcohol each of which assists in dissolving the antibacterial agent and again the presence of such -4ng agent is solubilioptional.

when solubilizing agent is present in oral compositions of the instant invention, it is typically in amount of about 0.5-20% by weight, with as little as about 0.5% by weight being sufficient when the amount of substantially waterinsoluble non-cationic antibacterial agent is low, say up to about 0.3% by weight. When higher amounts such as least about 0.5% by weight of antibacterial agent are present and particularly when siliceous polishing agent is also present in amount of about 5-30% by weight, it is desirable that at least about 5% by weight, typically up to about 20% or more by weight, of the solubilizing agent be present. It is noted that there may be a tendency f or the dentifrice o separate into liquid and solid portions when more than about 5% bv we-4--h-- of the solubiliZing agent is present.

26 K1 4956 The agent which is or may be present to assist solubilization of the antibacterial agent in saliva may be incorDorated in the water-humectant vehicle. Such solubilizing agents include humectant polyois such as propylene glycol, dipropylene glycol and hexylene glycol, cellosolves such as methyl cellosolve and ethyl cellosolve, vegetable oils and waxes containing at leasz about 12 carbons in a straight chain such as olive oil, castor oil and petrolatum and esters suc'4,4 as amyl acetate, ethyl acetate and benzyl benzoate. As used herein, "propylene glycol" includes 1,2-propylene glycol and 1,3-propylene glycol. Significant amounts of polyethylene glycol particularly of molecular weight of 600 or more should be avoided since polyethylene glycol effectively inhibits the antibacterial activity of the noncationic antibacterial agent. For instance, polyethylene glycol (PEG) 600 when present with triclosan in a weight ratio of 25 triclosan:l PEG 600 reduces the antibacterial activity of triclosan by a factor of about 16 from that prevailing in the absence of 2C.1 the polyetl&-.,-lene gl.. ^1 In accordance with aspects of this invention, oral compositions may be substantially gel in character, such as a gel dentifrice. Such gel oral preparations may contain siliceous dentally polishing material Preferred polishing materials include crystalline silica having particle sizes of up to about 5 microns, a mean 27 K1 4956 particle size of up to about 1.1 microns, and a surface area of up to about 50,000 cm.l/gm., silica gel or colloidal silica and complex amorphous alkali metal aluminosillcate.

When visually clear or opacified gels are s employed, a polishing agent of colloidal silica, such as those sold under the trade-mark SYLOID as Syloid 72 and Syloid 74 or under the trademark. SANTOCEL as Santocel 100 or alkali metal aluminosilicate complexes (that is, silica containing alumina combined in its matrix) are particularly useful, since they are consistant with gel-like texture and have refractive indices close to the refractive indices of gelling agent- liquid (including water and/or humectant) systems commonly used in dentifrices.

The polishing material is generally present in the oral composition dentifrices such as toothpaste or gel compositions in weight concentrations of about 5% to about 30%.

In the aspect of this invention wherein the oral preparation is a dentifrice, an orally acceptable vehicle including a water-phase with humectant which is preferably glycerine andlor sorbitol is present, wherein water is present typically in amount of about 15-35% or 40% by weight and glycerine andlor sorbitol typically total about'20-75% by weight of the oral preparation dentifrice, more typically about 25-60%. Reference hereto to sorbitol again refers to the material typically as available commercially in 70% aqueous solutions.

28 K1 4956 in this invention, the oral dentifrice composition may be substantially pasty in character, such as a toothpaste (dental cream), although when siliceous polishing agent is employed (which is not generally the case, since such material is typically not employed in amount above about 30% by weight) it can be gel in character. The vehicle of the oral composition dentifrice contains dentally acceptable polishing material, examples of which polishing mater:i:a71s are water-lnsoluble sodium metaphosphate, potassium mataphosphate, tricalcium phosphate, dihydrated dicalcium phosphate, anhydrous dicalcium phosphate, calcium carbonate, aluminum silicate, hydrated alumina, silica, bentonite, and mixtures thereof with each other or with hard polishing materials such as calcined alumina and zirconium silicate, material including 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 insoluble sodium metaphosphates, ate and h.. rat d alumina.

20,.z d ta Many of the so-called "water-insoluble" polishing materials are anionic in character and also include small amounts of soluble material. Thus, insoluble sodium meraphosphate may be formed in any suitable manner as I'llustated by Thorpels Dictionary of Applied Chemistry, 29 IC 4956 9, 4th Edition, pp. 510-511. The forms of insoluble sodium metaphosphate known as Madrell's salt and Y=ol's salt are further examples of suitable materials. These metaphosphate salts exhibit only a minute solubility in 5 water, and therefore are commonly referred to as insoluble metaphosphates (IMP). There is present therein a minor a =r- of soluble phosphate material as impurities, usually a f ew 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 cage 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 that no more than 1% of the material is larger than 37 microns.

Hydrated alumina is an example of a polishing material which is essentially nonionic in nature. Typically, it is small in particle size, i.e., at least about 85% of the particules are smaller than 20 microns and is such as that &V classified as (alpha alumina trihydrate) and no rma lly represented chemically as A1203.3H20 or Al(OH)3.

The average particle size of gibbsite is generally about 6 to 9 microns. A typical grade has the following size distribution:

Micron <30 <20 <10 < 5 K1 4956 Percent 94-99 85-93 56-67 28-40 The polishing material is generally present in the cream paste or g1 csitions in weight contents of about 30% to about 75%.

Toothpastes or dental cream dentifrices as well as gel dentifrices typically contain a natural or synthetic thickener or gelling agent in proportions of about 0.1 to about 10%, pref erably about 0. 5 to about 5%. A suitable thickener is synthetic colloidal magnesium alkali metal is 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% Si02, 25.40% MgO, 3.05% NA20, 0. 98% W20, and some water and trace metals. Its true specific gravity is 2 J. 1 &.53 and -J- has an apparent bulk density 'g./ml. at 8% moisture) of 1.0. other suitable thickeners or gelling agents or thickeners include Irish moss, iota-carrageenan, gum tragacanth, starch, polvvinvlDvrralidone, hydroxyethpropylcellulose, hydroxybutyl methyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose (e.g. available as 31 K1 4956 Natrosol), sodium carboxymethyl cellulose, and particularly when siliceous olishing agent is present, colloidal silica such as those available as finely gromd Sylold 244 or Sylodent 15.

In the aspect of the present invention wherein the oral composition is a mouthwash or liquid dentifrice, substantially liquid in character, the vehicle, parti cularly in a mouthwash, is typically a water-alcohol mixture. 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. The alcohol is a non- toxic alcohol such as ethanol or isopropanol. Humectant such as glycerine and sorbitol may be present in amount of about 10-30% by weight. Liquid dentifrices typically contain about 50-85% of water, may contain about 0. 5-20% by weight of non-toxic alcohol and may also contain about 10-40% by weight of humectant such as glycerine and/or sorbitol. Reference here to sorbitol refers to the material typically as available commercially in 70% aqueous solutions. Ethanol is the preferred non-toxic alcohol. The alcohol is believed to assist in dissolving the water-insoluble non-cationic antibacterial agent as, it is believed also does flavoring oil.

32 K1 496 As indicated, the noncationic antibacterial agent is substantially water - insoluble. However, in the present invention, with the AEA, such as polycarboxylate, present in the mouthwash or liquid dentifrice, organic surface-active s agent, flavoring oil or non-toxic alcohol are believed to aid dissolving the antibacterial agent to assist it to reach sof t oral tissue at or near the gums as well as tooth surfaces. organic surf ace- active agents andlor f lavoring oils may also assist dissolving the antibacterial agents as optional ingredients in oral dentifrice compositions.

organic surface-active agents are also used in the compositions of the present invention to achieve increased prophylactic action, assist in achieving thorough and complete dispersion of the anti-plaque antibacterial agent throughout the oral cavity, and render the instant compositions more cosmetically acceptable. The organic surf ace-active material is pref erably anionic, nonionic or ampholytic in nature, and it is preferred to employ as the surf ace-active agent a detersive material which imparts to the composition detersive and f oaming properties. Suitable examples of anionic surf actants are water-soluble salts of higher f atty acid monoglyceride monosulf ates, such as the sodium salt of the monosulfated monoglyceride of hydrogenated coconut oil f atty acids, higher alkyl sulf ates such as sodium lauryl sulfate, alkyl aryl sulfonates such as sodium dodecyl benzene sulfanate, higher alkyl 33 K1 4956 sulfoacetates, higher fatty acid esters of 1,2-dihydroxy propane sulforiate, 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-laurayl, 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 oral cavity due to carbohydrate breakdown in addition to exerting some reduction in the solubility of tooth enamel in acid solutions. Examples of water-soluble nonionic surfactants are condensation products of ethylene oxide with various reactive hydrogen- connaining compounds reactive therewith having long hydrophobic chains (e. g. aliphatic chains of about 12 to 20 carbon atoms), which condensation products (Ilethoxamers") 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 polypropyleneoxide (e.g. Pluronic materials)- Surface active agent is typically present in amount of about 0.5-5% by weight, preferably about 1-2.5%.

34 K14956 When the oral composition is a liquid dentifrice the natural or synthetic thickener or gelling agent as described is typically present in proportions of about 0. 1 to about 10%, preferably about 0.5 to about 5%.

Generally liquid dentifrices do not contain a polishing agent. However, as described in U.S. Patent 3,506,757 to Salzmann, about 0.3-2.0% by weight of a polysaccharide of high molecular weight in excess of 1,000, 000 containing mannose, glucose, potassium glucuronate and acetyl moieties in the approximate ratio of 2:1:1:1, as suspending and thickening agent can be employed in a liquid dentifrice, which then may also contain about 10-20% of a polishing material such as hydrated alumina, dicalcium phosphate dihydrate, calcium pyrophosphate, insoluble sodium metaphosphate, anhydrous dicalclum phosphate, calcium carbonate, magnesium carbonate, magnesium oxide, silica, mixtures thereof, and the like.

Without being bound to a theory whereby the advantages of this invention are achieved, it is believed that an aqueous, humectant vehicle is normally solubilized in surfactant micelles in the mobile phase (that is, not including gelling agent and polishing agent, if present in a dentifrice formula). The mobile phase solution of dentifrice during use can become diluted with saliva which causes triclosan to precipitate. Thus, it is f ound that even in the absence of a spec-i-=-' SolUbili-4nmaterial for j 1 K14956 triclosan, when the amount of triclosan is about 0.25%-0.35% by weight and AEA such as the polycarboxylate is present, sufficient triclosan is present to exert an excellent antiplaque effect on the soft tissues at the gum line.

Similar remarks apply to other water-insoluble noncationic antibacterial agents herein described.

The oral composition dentifrice may also contain a source of fluoride ions or fluorine-providing component, as anticaries agent in amount sufficient to supply about 245 ppm to 5000 ppm of fluoride ions. 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 substantial 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 flourosilicate, ammonium flourosilicate, sodium fluorozirconate, ammonium fluorozirconate, sodium monofluorophosphate, aluminum mono-and di-fl uorophosphate and sodium calcium pyrophosphate. Alkali metal and tin fluorides, such as sodium and stannous fluorides, sodium monofluorophosphate (MFP) and mixtures thereof, are preferred.

36 K1 4956 The amount of fluorine-providing compoundis dependent to some extent upon the type of compound, its solubility, and the type of oral prepartion, but it must be a non-toxic amount, generally about 0.0005 to about 3.0% in the preparation. In a dentifrice preparation, e.g. dental gel an amount of such compound which releases up to about 5,000 ppm of F ion by weight of the preparation is considered iatisfactory. Any suitable minimum amount of such compound may be used, but it is preferable to employ sufficent 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%.

it will be understood that, as is conventional, the oral preparations are to be sold or otherwise distributed in suitable labelled Dackaaes. Thus a dentifrice gel will usually be in a collapsible tube typically aluminum, lined lead or plastic, or other squeeze, pump or pressurized dispenser for metering out the contents, having a label describing it, in substance, as a dentifrice gel or the like.

37 K1 4956 Various other materials may be incorporated in the oral preparations of this invention such as whitening agents, preservatives, silicones, chlorophyll compounds andlor ammoniated material such as urea, diammonium.

phosphate, and mixtures thereof. These adjuvants, where present, are incorporatd in the preparations in amounts which do not substantially adversely af fect the properties and charactristics desired. Significant amounts of zinc, magnesium and other metal salts and materials, which are generally soluble and which would complex with active components of the instant invention are to be avoided.

Any suitable f lavoring or sweetening material may also be employed. Examples of suitable flavoring constituents are flavoring oils, e.g. oil of spearmint, is peppermint, wintergreen, sassafras, clove, sage, euclyptus, majoram, cinnamon, lemon, and orange, and methyl salicylate. Suitable sweetening agents include sucrose, lactose, maltose, xylitol, sodium cyclamate, perillartine, AMP (aspartyl phenyl alanine, methyl ester), saccharine and the like. Suitably, f lavor and sweetening agents may each or' together comprise from about 0.1% to 5% or more of the preparation. Moreover, like the surface-active agent, flavoring oil is believed to aid the dissolving of the antibacterial agent, together with or even in the absence of 25 surface-active agent.

38 K1 4956 In the preferred practice of this invention an oral composition of the present invention is preferably applied regularly to dental enamel and soft oral tissues, particularly at or near the gum line, 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 or 10, generally about 5.5 to about 8, preferably about 6 to 8 and most preferably about 6.5 to about 7.5, for at least 2 weeks up to 8 weeks or more up to lifetime. Even at such pH below 5 enamel is not decalcified or otherwise damaged. 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.).

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

39 EXAMPLE 1

The following dentifrice is prepared:

K1 4956 -Parts Glycerine 10.00 Propylene Glycol - 10.00 Sorbit.ol (70%) 25.00 25.00 Iota crrageenan 0.60 0.60 Gantrez S-97 2.00 2.00 Sodium Saccharin 0.40 0.40 Sodium Fluoride 0.243 0.243 Sodium Hydroxide (50%) 1.00 1.00 Titanium oxide 0.50 0.50 Silica Polishing Agent (Zeodent 113) 20.00 20.00 Silica Thickener (Sylox 15) 5.50 5.50 Sodium Lauryl Sulfate 2.00 2.00 Water 31.507 31.507 Triclosan 0.30 0.30 Flavor 011 0.95 0.95 The above dentifrice A delivers Triclosan to the teeth and soft gum tissue essentially as well as dentifrice B containing a special solubilizing agent for Triclosan. In other words, a special solubili--- 4ng agent is not required f or the dentifrice of the present invention to be effective. Further, a corresponding dentifrice in which the Gantrez polycarboxylate is absent is substantially poorer in delivering Triclosan.

K1 4956 in the foregoing example, improved results may also be obtained by replacing Triclosan with other antibacterial agents herein described such as phenol, tlivml, eugenol and 2,2'methylene bis (4-chloro-6-bromophenol) and/or by replacing Gantrez with other AEA's such as a 1:1 copolymer of maleic' anhydride and ethyl acrylate, sulfoacrylic oligomer, Carbopols (e.g. 934), and polymers of alpha or beta-styrenephosphonic acid monomers and copolymers of these monomers with each or with other ethylenically unsaturated polymerizable monomers such as vinyl phosphonic acid.

EXAMPLE 2

The following liquid phase dentifrice solutions are tested for uptake and retention of triclosan on saliva coated HA disks following the test procedures described in Ebomple 3 below with the indicated results: Ingredients PARTS A B c D Sorbital (70% solution) 30.0 30.0 30.0 30.0 Glycerol 9.5 9.5 9.5 9.5 Propylene Glycol 0.5 0.5 0.5 0.5 SLS 20.0 20.0 20.0 20.0 NaF 0.243 0.243 0.243 0.243 Flavar oil 0.95 0.95 0.55 0.95 Triclosan 0.3 0.3 0.3 0.3 Water 56.507 54.507 54.507 54.507 1 41 Poly (beta-styrenephosphonic acid) Poly (alpha-styrenephosphonic acid) Polyvinyl Alcohol Adjusted to pH 6.5 with NaOH Triclosan UDtake in Micrograms on Saliva Coated HA Disks Retention of Triclosan on Saliva Coatqd HA Disks After: initial minutes 1 hour 3 hours K1 4956 1). n 31.0 174.0 183.0 136.0 105.0 83.0 2.0 2.0.

86.0 36.0 The above results show that solution (D) containing polyvinyl alcohol, not an AEA hereunder, produces a triclosan uptake of only 36.0, quite similar to the 31.0 uptake of the control solution (A) without additive. In contrast, solution (C) with poly (alpha- styrenephosphonic acid) produces an uptake of 86.0, more than double that of solutions (A) and (D), and soluion (B) with poly (beta- styrenephosphonic acid) produces an uptake about 5 times that of solutions (A) and (D), tending.to indicate further that vicinal substitution of the delivery- enhancing group yields superior results. The above results also show the surprisingly good retention of triclosan. on the HA disks over time obtained with solution (B) containing poly 25 (beta-styrenephosphonic acid (M.Wls about 3,000 to 10,000).

42 K14956 EXAMPLE 3

The effect of synthetic anionic linear polycarboxylate on the uptake, retention to and release f rom tooth surfaces of water-insoluble noncationic antibacterial agent is assessed in vitro on a saliva coated hydroxyapatite disk and on exfoliated buccal epithelial cells. The in vitro assessments are correlatable to in vivo delivery, and retention on oral surfaces.

For the test of delivery of antibacterial agent to a 10 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 RA are placed into the chamber of a KBr pellet die (Barnes Analytical, Stanford, CT.) and ccmpressed for 6 minutes at 10,000 pound in a Carver laboratory press. The resulting 13 mm disks are sintered f or 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) for 15 minutes at 4'C. Sterilization of the clarified-saliva is done at 4c2C with stirring by irradiation of the sample with UV light for 1.0 hour.

Each sintered disk is hydrated with sterile water in a 25 polyethylene test tube. The water is then removed and replaced with 2.00 ml of saliva. A salivary pellicle is formed by 43 K14956 incubating the disk overnight at 37C 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) dentifrice liquid phase solution and incubated at 37cC with continuous shaking in the water bath. After 30 minutes, the disk is transferred into a new tube and 5.00 ml of water are added followed by shaking the disk gently with a Vortex. The disk is then transferred into a new tube and the washing procedure repeated twice. Finally, the disk is transferred carefully into a new tube to avoid co-transfer of any liquid along with the disk. Then 1.00 ml of methanol is added to the disk and shaken vigorously with a vortex. The sample is left at room temperature for 30 minutes to extract adsorbed Triclosan into the methanol. The methanol is then aspirated and clarified by centrifugation in a Beckman Microfuge 11 at 10,000 rpm to 5 minutes. After this treatment, the methanol is transferred into HPLC (high performance liquid chromatography) vials for determination of antibacterial agent. Triplicate samples are used in all experiments.

"or the test o"c retention of antibacterial agent to a saliva coated HA disk, a saliva coated HA disk is treated with dentifrice slurries as described above. After incubation or 30 minutes at 370C, the HA disk is removed frcm the dentifrice slurry, washed twice with water, and then reincubated with parafilm stimulated human whole saliva which had been clarified by centrifugation. After incubation at 37'C with constant 44 K1 4956 shaking for various periods, the HA disk is removed f rom the saliva, and the amount of antibacterial agent (Triclosan) retained onto the disk and released into saliva is determined by analytical method using HPLC.

For the assay of delivery of antibacterial agent to buccal epithelial cells, the delivery is measured in order to determine the effect of PVM/MA on the delivery of antibacterial agent Triclosan) to soft oral tissue from a dentifrice product.

Buccal epithelial cells are collected with a wooden applicator stick by gently rubbing the oral mucosa. The cells are suspended in Resting Saliva Salts (Rss) Buffer (50 r1M NaCl, 1.1 riM CaC12, and 0.6 nM M2M4 pH 7.0) to 5-6x105 cells/ml using a hemocytometer to enumerate the cells and kept in ice until use.

0.5 ml of cell suspension, preincubated to 37"C in a waterbath, is added with 0.5 ml of the test antibacterial agent solution and incubated at370C. The antibacterial agent solution in the incubation mixture is diluted at least 10 times in order to lower the surfactant concentration and prevent destruction of cell membranes by the surfactant. After 30 minutes of incubation, the cells are harvested by centrifugation in Beckman Microfuge 11 at 5,000 rpm for 5 minutes. The cells, collected as the pellet, are washed 3 times with RSS buffer and treated with 1.5 ml of methanol. The sample is mixed vigorously and is analyzed for antibacterial agent by the HPLC method.

Y,l 4956 Dentifrices are prepared having the following formulas:

Parts A 10.00 0.75 B 10.00 0.75 2.00 0.50 30.00 0.332 0.40 3.00 Propylene Glycol (1,2) Iota Carrageenan Gantrez S-97 Ticanium. Dioxide 0.50 30.00 0.332 Sodium saccharin 0.40 Silica Thickener(Sylodent 15) 3.00 Sorbi-Ltol (70%) Sodium Fluoride Silica Polishing Agent (Zeodent 113) 20.00 20.00 Triclosan 0.20 0.20 Sodium Lauryl Sulfate 2.00 2.00 Flavor oil Ethyl Alcohol Water 0.95 0.95 i. 00 1.00 Q.S. to 100.00 Q.S. to 100.00 The uptake of Triclosan on the saliva coated hydroxyapatite disk and on buccal epithelial cells with and without the polymeric polycarboxylate, Gantrez S-97, is set forth in Table 1 below:

46 K1 4956 TABLE 1

Uptake of Triclosan In Micrograms in micrograms. x 10' Buccal Dentifrice On Saliva Coated Disk Epithelial Cells A 25.0 38.0 B 54.0 96.0 These results reveal that the Gantrez material (present in 'Dentifrice B) greatly enhances the delivery and _tRti" of Triclosan to saliva coated hyd=wyapat:Lte disk and to the exfoliated buccal epithelial cells.

Similar results are obtained when the dentifrices contain 0.30 parts of triclosan.

EXAMPLE 4

In tests with saliva coated hydroxyapatite disks and exf oliated buccal epithelial cells dif f erent f rom those set forth in Example 3 above, said dentifrice B containing 2.00% Gantrez S-97 and 0.20% of Triclosan, 10.00% of propylene glycol and 2.00% of sodium lauryl sulfate and an equivalently formulated Dentifrice (B'), except for the presence of 0.30% of triclosan were compared with a commercially available Dentifrice (C) containing hydrated alumina polishing agent and (a) 0.2% of Triclosan, (b) no Gantrez material, (c) no propylene glycol, (d) 0.5% zinc citrate, (e) 2.5% of surface active agents (f) sodium monof luorophasphate and hydrated alumina polishing agent; and 47 Y,1 4956 the dentifrice formulation below (cl) which is similar to commercial Denlfrice C except for the presence of 0.30% of Triclosan:

DENTIFRICE Cl % Sorbital (70%) 27.00 Sodium Carboxymethyl Cellulose 0.80 Sodiuin Monofluorophosphate 0.85 Zinc Citrate 0.50 Sodium Saccharin 0.18 Water 16.47 Hydrated Alumina Polishing Agent 50.00 Ethanol 0.20 Sodium Lauryl Sulfate 1.875 is Sodium Dodecyl Benzene Sulfanate '0.625 Triclosan 0.30 Flavor 1.20 since Dentifrices C and C' contain a total of 2.50% of surface active agent, more surface active agent is available to dissolve Tl-closan tIm m Dentifrice B and B I which contain 2.00%. However, propylene glycol present in siliceous polishing agent Dentifrices B and B' (but not in hydrated alumina polishing agent Dentifrices C and Cl) insures optimum dissolutimof Triclosan.

The advantage of Dent -4fr ices B and B' (containing propylene glycol and Gantrez) over Dentifrices C and C' in 48 M 4956 Triclosan uptake m saliva coated hydmryapatite disks and m Table 2 exfoliated buccal epithelial cells 4.s shown below:

TABLE 2 Delivery of Triclosan To Saliva Coated To Buccal Epithelial Hydroxyapatite Disk Cells (in micrograms) in micrograms X106 Emlithelial Cell Dentifri6e B 41.1 101.6 BY 77.4 142.0 c 20.4 61.0 V. 42.6 100.0 Additional experiments with Dentifrice B' (0.3% Triclosan; Gantrez; Propylene Glycol) in a 50% slurry of the dentifrice to determine the retention of Triclosan on the saliva coated hydroxyapatite disk over a period of time reveals retention of excellent levels of triclosan as shown in Table 3 below:

TABLE 3

Retention of Triclosan Adsorption from Dentifrice Slurry Time (in Minutes) 0 "0.i 240 Retention of Triclosan (Microc;rams/Disk) 57 59 49 Y, 14956 These results indicate that dentifrices containing Triclosan, Gantrez material and propylene glycol can provide enhanced delivery of Triclosan to, and retention on, tooth surfaces and soft surfaces in the oral cavity, thereby providing improved antiplaque and antibacterial effects. EXAMPLE 5 For purpose of comparison formulas a and b below are 1 prepared:

Dentifrice Glycerin 10.00 - Propylene Glycol - 10.00 Iota Carrageenan 0.60 0.60 Sorbitol (70%) 25.00 25.00 Sodium saccharin 0.40 0.40 Sodium Fluoride 0.243 0.243 Titanium Dioxide 0.50 0.50 Gantrez S-97 2.00 2.00 Water 29.157 29.157 NaOW50%) 2.00 2.00 Zeodent 113 (silica polishing Agent) 20.00 20.00 Sylodent 15 (Silica Thickener) 5.50 5.50 Flavor 1.10 1.10 Triclosan 0.50 0.50 Sodium Lauryl Sulfate 2.00 2.00 Ethancl 1.00 1.00 so K1 4956 Formula a is a dentifrice containing a Gantraz poly=b=late, with 0.5% TriClOSan as an antibacterial antiplaque agent and no solubilizing agent. In Formula b, propylene glycol solubilizing agent.is present.

Fo=mila a is poor in delivery of Triclosan on buccal epithel-Jal cells while Formula b is markedly effective.

The foregoing results reveal excellent delivery of Triclosan dentifrice.

EXAMPLE 6

An "in-house" study was conducted on a group of volunteers to assess the effects of particular dentifrices in influencing plaque regrowth in accordance with the method described by Addy, Wills and Moran, J. Clin. Perio, 1983, Vol. 10, Pages 89-99. The dentifrices tested included a placebo control containing no Triclosan (i) and a dentifrice in accordance with this invention containing 0.3% of Triclosan, 10% propylene glycol (instead of 3% polyethylene glycol 600) and 2% of Gantrez S-97 and humectant of propylene glycol and sorbitol (ii). The fornulas of the dentifrices are as follows:

Parts (i)- (ii) Placebo invention 1 Polyethylene Glycol 600 3.00 Glycerine 25.00 Propylene Glycol 10.00 51 Sorbitol (70%) Sodium CArboxyThdthyl Cellulose Iota Carrageenan Sodium BEnzoate Sodium Saccharin sodium Fluoride Silica Polishing Agent (Zeodent 113) Silica Thickeher (Sylox 15) Water Gantrez S-97 Triclosan Titanium Dioxide Sodium Lauryl Sulfate K1 4956 41.617 0.35 0.50 0.20 0.243 18.00 5.50 1.00 0.50 1.20 25.00 0.60 0.40 0.243 20.00 5.50 28.757 2.00 0.30 0.50 2.50 Flavor 0.89 1.10 Ethyl Alcohol 1.00 Sodium Hydroxide (50%) 2.00 With regard to plaque reduction, on the teeth of the volunteers, compared to placebo (i), invention (ii) provided a significant decrease of 20%.

Since lesser amounts of propylene glycol can dissolve the 0.3% of Triclosan present in Tbothpaste (A), similar results are expected when the amount of propylene glycol is reduced to 0.5 parts and the amount of sorbitol is increased to 39.5 parts. Likewise, the other solubilizing agents dipropylene glycol, hexylene glycol, methyl cellosolve, ethyl cellosolve, olive oil, castor oil, petrolatum, amyl acetate, 52 K1 496 ethyl acetate, glyceryl tristearate and benzyl benzoate, in place of prcWlene glycol, can effectively deliver Triclosan to soft oral tissues. Further, similar results are expected when propylene glycol or other solubilizing agents are omitted f rom toothpaste (ii) containing 0.3% triclosan.

EXAMPLE 7 The following dentifrices of the invention are prepared:

Glycerine Propylene Glycol Sorbital (70%) Sodium Carboxymethyl Cellulose Iota Carrageenan Sodium Saccharin Sodium Fluoride Silica Polishing Agent 20 (Zeodent 113) Silica thickener (Sylox 15) Water Gantrez S-97 Triclosan Titanium Dioxide Parts A 10.00 25.00 0.600 0.40 0.243 20.00 5.50 28.757 2.00 0.50 0.50 20.00 0.50 19.50 1.10 0.30 0.243 20.00 3.00 15.307 4.00 0.30 0.50 53 Alpha Alumina Trihydrate Propylene Glycol Sorbitol (70%) Gantrez S-97 (13% solution) Gantrez S-97 (powder) K1 4956 Sodium Lauryl Sulfate 2.50 2.00 Flavor 1.10 0.95 Et-h.anol 1.00 - Sodium Hydroxide (50%) 2.00 1.60 In the foregoing examples, improved results may also be obtained by replacing Triclosan with other a tibacterial agents herein described such as phenol, thymol, eugenol and 2,21methylene bis (4-chlorc-6-bromophenol) andlor by replacing Gantrez with other AEA's such as a 1:1 copolymer of maleic anhydride and ethyl acrylate, sulfoacrylic ollgomers, Carbopols (e.g. 934), polymers of monomeric alpha- or beta-styrene phosphonic acid and copolymers of these styrene phosphonic acid monomers with each other or with other ethylenically unsaturated polymerizable monomers such as vinyl phosphonic acid. Exam,Ple 8 The following dentifrice is prepared:

A Parts B 48.00 48.00 48.00 0.50 0.50 21.70 21.70 15.00 21. 7 0 15.00 C 2.00 54 Sodium Lauryl Sulfat Sodium Saccharihe, Sodium Hyroxide (50%) Flavor Irish Moss Sodium carboxymethyl celluose C-d4= monofluorophosphate Titanium Dioxide Triclosan 10 Water K1 4956 2.00 0.30 1.20 0.95 1.00 0.76 2.13 0.30 1.20 0.95 1.00 0.76 0.50 0.30 2.13 0.30 1.20 0.95 1.00 0.76 0.50 0.30 0.30 Q.S. to Q.S. to Q.S. to 100.00 100.00 100.00 The foregoing dentifrices deliver Triclosan to the teeth and sof t tissue. areas of the gums substantially more 15 ef f ectively than corresponding dentif rices in which the Gantrez polycarboxylate is absent.

=AMPLE 9 The following dent- Ity Glycerine Sorbitol (70%) Sodium Carboxymethyl cellulose Gantrez S-97 25 Sodium Saccharin are prepared:

Parts 22.00 1.00 2.00 0.20 10.00 17.00 1.00 2.00 0.20 7 Sodium Benzoate sodium Monofluorophsophate. Dicalcium Phosphate Dihydrate Triclosah Sodium Lauryl Sulfate Flavor Water 1 K1496 0.50 0.76 48.76 0.30 1.20 0.89 Q.S. to-100.00 0.50 0.76 48.76 0.30 1.20 0.89 Q.S. to 100.00 The foregoing dentifrices deliver Triclosan to saliva coated hydroxyphate disk more effectively than corresponding dentifrices in which the Gantrez polycarboxylate is absent.

EXAMPLE 10

The following antiplaque dentifrice is prepared:

Glycerine Propylene Glycol Sodium Carboxymethyl cellulose Water Vinyl Methyl Ether/Maleic Anhydride (42% solution) Sodium Monofluorophosphate Sodium Saccharin Insoluble Sodium Metaphosphate copolymer Parts 15.00 2.00 1.50 24.93 4.76 0.76 0.30 47.00 56 Titanium Dioxide Sodium La:uryl Sulfat Triclosan Flavor Y,l 4956 0.50 2.00 0.30 0.95 In the foregoing examples improved results are also achievable when Triclosan is replaced with each of phenol, 2,21-methylene bis (4-chloro-6-Bromophenol), eugenol and thymol, and/or when Gantrez is replaced by other AEA's such as 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. EXAMPLE 11 Dentifrice Mobile Phases containing Triclosan ComDonents ------- ?---Composition, %wlw --------- 20. A- B Sorbitol (70%) 53.33 40.00 Water 40.48 39.15 Gantrez S (15%) ---- 13.33 NaOH (50%) 1.33 Saccharin 0.40 0.40 57 K14956 Sodium Fluoride 0.32 0.32 Flavor Oil 1.47 1.47 Sodium Lauryl Sulfate 3.33 3.33 Triclosan 0.67 0.67 is The concentration of the above components are 1.33% dentifrice level to reflect 25% level of ive which may be needed to make a complete dentifrice.

The above mobile phases of the indicated dentifrice f=11 ations;g tested for Triclosan uptake m saliva coated BA disks. Results are in the Table below:

TABLE

Uptake of Triclosan by Saliva Coated Hydroxyapatite (HA) Disks from Diluted and Undiluted Dentifrice mobile Phases. A B % Triclosan 0.67 0.67 Ionic Strength (M/L) (calculated) 0.375 -- PH 8.7 7.6 Triclosan Uptake (ug/disk) 55 122 Undiluted The above results show a greater th&i two fold increase in Triclosan uptake achieved with the B forzulation containing Gantrez relative to the A formulation without the 25 Gantrez.

58 1 X1 4956 FXAMPLE 12 Concentration and Uptake of Tr-4--l---san by HA from Supernatant. of 1:1 Dentifrice/Water Slurries.

Dentifrice Containing Triclosan (uglml) in Triclosan Uptake 0.5% Triclosan, 2.5% Supernatant of 1:1 pg/disk Sodium Lauryl Slurry Sulfate 25% Hydrated silica +1.5% Gantrez S-97 50% Alumina +1.5% Gantrez S-97 1,905 74 Supernatants of 1: 1 Dentif rice/Water slurries of the above dentifrices are tested for -- of the Triclosan in the supernatant and for Triclosan uptake m saliva coated HA disks. The results indicate that using 50% alumina abrasive increases the Triclosan substantially under low 1:1 dilution conditions (from 1,650 to 1,905), resulting in a substantial increase in the Triclosan uptake (fr= 52 to 74).

1,650 EXAMPLE 13

The mouthrinses below are effective in reducing plaque by increasing the uptake and retention of Triclosan on oral surfaces.

A B c D E Parts Parts Parts Parts Parts Gantrez S-97 0.24 0.25 0.25 0.25 0.25 Glycerine 15.00 10.00 15.00 10.00 15.00 Ethanol - - 12.50 12.50 Propylene Glycol 5.00 - 5.00 59 14956 Pluronic F108- 2.00 (Polyoxye-thylene/Polyoxypropylene Block Copolymer) Sodium Lauryl Sulfate - - 0.20 0.20 0.20 Triclosan 0.10 0.10 0.06 0.06 0.03 Flavoring Oil 0.40 0.40 0.40 0.40 0.40 Q.S. to Q.S. to Q.S. to Q.S. to Q.S. to 100.00 100.00 100.00 100.00100.00 Water is Glycerine Gantrez S-97 Polysaccharide of high molecular weight, the molecule containing mannose, glucose, potassium glucuronate and acetyl moieties in the approximate molar ratio 20of 2:1:1:1 Sodium benzoate Saccharine sodium Water Sodium lauryl sulfate Insoluble sodium metaphosphate EXAMPLE 14

The following liquid dentifrices are also effective in reducing plaque by increasing the uptake and retention of Triclosan m oral surfaces:

c Parts Parts Parts 20.0 20.0 - 0.3 0.3 0.3 A B 0.8 0.5 0.5 61.3 3.0 10.0 0.5 0.5 - 73.1 3.0 1.0 0.5 0.5 71.6 3.0 10.0 Anhydrous dicalcium phosphate Flavoring 011 Ethyl alcohol Triclosan In the forgoing Examples, improved results are also achievable when Triclosan is replaced with each of 19, 2,V- methylene bis (4-chloro-6-Bromophenol), eugenol and thymol, and/or when Gantrez is replaced by other AEA's such as Carbopols (e.g. 934) or styrene phosphonic acid polymers having molecular weights within tie range of about 3,000 to 10,000 such as poly (beta- styrenephosphonic acid), copolymers of vinyl phosphonic acid with beta- styrenephosphonic acid, and poly (alphastyrenephosphonic acid), or sulf oacrylic oligomers, or a 1: 1 copolymer of maleic anhydride with ethyl acrylate.

This invention has been described with respect to certain preferred embadiments 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 20 application and the scope of the appended claims.

K1456 1.0 2.5 - 0.1 0.1 2.5 -).5. 5 10.0 0.1 z 61

Claims (23)

1. CLAIMS < 14956 1. An oral composition comprising an effective antiplaque

   amount of a substantially water insoluble noncationic antibacterial agent, about 0.005-4% by weight of antibacterial enhancing agent which enhances delivery of said antibacterial agent to, and retention on, oral surfaces and an orally acceptable vehicle effective to enable the said antibacterial agent to dissolve 'in saliva in effective antiplaque amount. the said oral composition being substantially free of polyphosphate anticalculus agent.

   is
2. 2. An oral composition as claimed in Claim 1. in which the said oral composition is a dentifrice comprising about 5-30% by weight of a siliceous polishing agent and the said antibacterial agent is present In amount of about 0.25-0.35% by weight and there is present at least one of a surface-active agent and a flavouring oil.
3. 3. An oral composition as claimed in Claim 1. in which the said oral composition is a dentifrice.

   comprising about 5-30% by weight of a siliceous polishing agentr the said antibacterial agent is present in amount of about 0.01-5% by weight and the said oral composition comprises a solubilizing material in amount sufficient to dissolve the said antibacterial agent in saliva.
4. 4. An oral composition as claimed in Claim 3r in which the said antibacterial agent is present in amount 62 of about 0.05% up to below about 0.25% by weight.

   K1 4956
5. 5. An oral composition as claimed in Claim 3, in' which the said antibacterial agent is present in amount of above about 0.35% up to about 5% by weight.
6. 6. An oral composition as claimed in Claim 5, in which the said antibacterial agent is present in amount of above about 0.35% up to about 0.5% by weight.
7. 7. An oral composition as claimed in any one of Claims 1 to 6 in which the said oral composition is a dentifrice comprising about 30-75% by weight of a dentally acceptable water-insoluble polishing agent.
8. 8. An oral composition as claimed in Claim 1. in which the said oral composition is a mouthwash or liquid dentifrice and the said orally acceptable vehicle is an aqueous vehicle wherein there is present at least one of a surface-active agent, a flavouring oil o:t a non-toxic alcohol.
9. 9. An oral composition as claimed in any one of the preceding claims in which there is present surface- active agent in amount of about 0.5-5% by weight.
10. 10. An oral composition as claimed in any one of the preceding claims in which there is present flavouring oil in amount of about 0.1-5% by weight.
11. 11. An oral composition as claimed in Claim 8 in which the said composition is a mouthwash and the said aqueous vehicle contains ethanol and the weight ratio 63 of water to dhanol is from about 1:1 to about 20:1.

    K1 4956
12. 12. An oral composition as claimed in Claim 8 or Claim 11 in which the said oral composition is a liquid dentifrice containing about 0.3-2.0% by weight of a polysaccharide of high molecular weight in excess of 1,,000,000 containing mannose, glucose, potassium glucuronate and acetyl moieties in the approximate ratio of 2:1:1:1, as suspending and thickening agent and about 10-20% by weight of a polishing material.
13. 13. An oral composition as claimed in any of Claims 1 to 12 in which the said antibacterial agent is selected from the group consisting of halogenated diphenyl ethers,, halogenated salicylanilides, benzoic esters, halogenated carbanilides and phenolic compounds.
14. 14. An oral composition as claimed In Claim 13 In which the said antibacterial agent is a halogenated diphenyl ether.

    1 25
15. 15. An oral composition as claimed in Claim 14 in which the said halogenated diphenyl ether is 2,4,,41trichlaro-2'-hydroxyphenyl ether.
16. 16. An oral composition as claimed in any one of Claims 1 to 15 in which a solubilizing agent Is present in amount of about 0.5 to 50% by weight and is selected 30 from the group consisting of propylene glycole dipropylene glycol, hexylene glycol, methyl cellosolve, eth9P, cellosolve, vegetable oil and wax containing at least about 12 carbon atoms, amyl acetate, ethyl 64 acetate, glyceryl tristearate and benzyl benzoate.

    K1 4956
17. 17. An oral compos Ltion dentifrice as claimed in Claim 16 in which the solubilizing agent is propylene glycol and is present in amount of about 0.5% by weight.
18. 18. An oral composition in Cke- -. form of a dentifrice as claimed in any one of Claims 1 to 17 wherein a polishing agent is present which is selected from the group consisting of sodium metaphosphate, tricalcium phosphate, dihydrated dicalcium phosphate, anhydrous dicalcium phosphate, anhydrous dicalcium phosphate, calcium pyrophosphate, magnesium orthophosphate, trimagnesium phosphate, calcium carbonate, aluminum. silicate, hydrated alumina, silica, bentonite and mixtures thereof.
19. 19. An oral - composition dentifrice as claimed in Claim 18 wherein said polishing agent is dicalcium phosphate dihydrate or hydrated alumina.
20. 20. An oral composition as claimed in any one of Claims 1 to 19 which contains an antibacterial- enhancing agent which has an average molecular weight of about 100 to about 1,000,000.
21. 21. An oral composition in the form of a dentifrice as claimed in any one of Claims 1 to 20 wherein a polishing agent is present which is selected from the group consisting of sodium metaphosphate, tricalcium phosphate, dihydrated dicalcium phosphate, anhydrous dicalcium phosphate. calcium pyrophosphate, 1 '1 L K14956 magnesium orthophosphate, trimagnesium phosphate, 2 calcium carbonate, aluminum silicate, hydrated alumina, 3 silica, bentonite and mixtures thereof.

    4
22. 22. An oral composition dentifrice as claimed in 6 Claim 21 wherein said polishing agent is dicalcium 7 phosphate dihydrate or hydrated alumina.

    8
23. 23. An oral composition as claimed in any one of Claims 1 to 22 in which the antibacterial -enhancing agent has an average molecular weight of 1000 to 1,000,000.

    11 12 13 14 15 16 17 is 19 20 21 22 23 24 25 26 27 28 29 31 32 33

    21. An oral composition as claimed in Claim 20 in which the said antibacterial -enhancing agent contains at least one delivery-enhancing functional group and at least one organic retention-enhancing group.

    22. An oral comDosition as claimed in Claim 21 in which the said delivery-enhancing group is acidic.

    K14956 23. An oral composition as claimed in Claim 22 in which the said delivery- enhancing group is selected from the group consisting of carboxylic, phosphonic, phosphinic, and sulfonic acids,. and their salts, and mixtures thereof.

    24. An oral composition as claimed in Claim 23 in which the said organic retention-enhancing group comprises. the formula O(X)n-R wherein X"represents 0. N, S, So, S021 P, PO or SI, R represents a hydrophobic alkyl, alkylene, acyl, aryl, alkaryl, aralkyl, or heterocyclic group. or their inert- substituted derivatives# and n is 1 or zero.

    25. An oral composition as claimed in any one of Claims 20-24 wherein the said antibacterial-enhancing agent is an anionic polymer containing a plurality of the said delivery-enhancing and retention-enhancing groups.

    26. An oral composition as claimed in Claim 25 in which the said anionic polymer comprises a chain containing repeating units each containing at least one carbon atom.

    27. An oral composition as claimed in Claim 26 in which each unit contains at least one delivery- enhancing group bonded to the same, vicinal, or other atoms in the chain.

    28. An oral composition as claimed in any one of 1 66 )l 4956 Claims 23 to 27 in which the delivery-enhancing group is a carboxylic group of salt thereof.

    29. An oral composition as claimed in Claim 28 in which the antibacterialenhancing agent is a copolymer of maleic acid or anhydride with another inert ethylenically unsaturated polymerizable monomer.

    - 30. An oral composition as claimed in Claim 29 in i o which the said other monomer of the said copolymer is methyl vinyl ether in a 4:1 to 1:4 molar ratio with the maleic acid or anhydride.

    31. An oral composition as claimed in Claim 30 in which the said copolymer has a molecular weight of about 30,000-1 p000,000 and is present in amount of about 0.2-2% by weight.

    32. A composition as claimed in Claim 31 in which the copolymer has an average molecular weight of about 70p000.

    33. A composition as claimed in any one of Claims 23 to 27 in which the delivery-enhancing group is a phosphonic group or salt thereof.

    34. A composition as claimed in Claim 33 in which the antibacterialenhancing agent is poly (betastyrenephosphonic acid) or poly (alphastyrenephos- phonic acid) polymer or a copolymer of either styrenephosphonic acid with another ethylenically unsaturated monomer.

    67 lc,l 4956 35. An oral composition comprising an orally acceptable vehicle, an effective antiplaque amount of a substantially water insoluble noncationic antibacterial agent and an antibacterial-enhancing agent which has an average molecular weight of about 1 000 to about 1,000,000, and contains at least one delivery enhancing functional group and at least one organic retention enhancing group, the said agent containing the said 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 1p000 to about 1p000,000.

    36. An oral composition as claimed in Claim 35 in which the said antibacterial agent is present in amount of from about 0. 25% to less than 0.5% by weight.

    37. An oral composition as Claimed In-Claim 35An which the said antibacterial agent is present in amount of from about 0.25% to about 0.35% by weight.

    38. An Pral composition as claimed in Claim 351.36 or 37 in which the said oral composition contains a siliceous polishing agent.

    39. -An oral composition as claimed in any one of the preceding claims substantially as specifically described herein with reference to the accompanying Examples.

    40. A method of controlling oral plaque comprising applying to oral surfaces an effective plaque-controlling amount of a composition as claimed in any one of the preceding claims.

    /1r - r_ bo Amendments to the claims have been filed as follows 1 2 3 4 6 7 11 12 13 14 15 16 17 is 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 1. An oral composition comprising an effective antiplaque amount of a substantially water insoluble non-cationic antibacterial agent. 0.005 to 4% by weight of an antibacterial-enhancing agent which enhances the delivery of the said antibacterial agent to,, and retention on. oral surfaces, and an orally acceptable vehicle effective to enable the said antibacterial agent to dissolve in saliva in an effective antiplaque amount, the said oral composition being free of polyphosphate anticalculus agent, the antibacterial enhancing agent being a poly(vinylphosphonic acid) containing units of the formula CH2-CH-J, 1 P03H2 the composition having a pH in the range 4.5-10.

    2. An oral composition as claimed in Claim 1 in which the antibacterial enhancing agent has a molecular weight of from 100 to 1,000,000.

    3. An oral composition as claimed in claim 1 or Claim 2 in which the orally acceptable vehicle comprises at least one of a surface active agent or a flavouring oil effective to enable the said antibacterial agent to dissolve in saliva in an effective antiplaque amount.

    4. An oral composition as claimed in any one of Claims 1 to 3 in which the antibacterial enhancing agent is present in an amount of 0.5 to 2.5% by weight.

    I- 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 is 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 K14956 5. An oral composition as claimed in claim 4 in which the antibacterial enhancing agent is poly(vinyl-phosphonate).

    6. An oral composition as claimed in any one of Claims 1 to 5 in which the said oral composition is a dentifrice comprising 5-30% by weight of a siliceous polishing agent and the said antibacterial agent is present in amount of 0.25-0.35% by weight.

    7. An oral composition as claimed in any one of Claims 1 to 5, in which the said oral composition is a dentifrice comprising 5-30% by weight of a siliceous polishing agent, the said antibacterial agent is present in an amount of 0.01-5% by weight and the said oral composition comprises a solubilizing material in amount sufficient to dissolve the said antibacterial agent in saliva.

    8. An oral composition as claimed in Claim 7, in which the said antibacterial agent is present in amount of 0.25% up to below 0.5% by weight.

    9. An oral composition as claimed in Claim 7, in which the said antibacterial agent is present in amount of 0.25% to 0.35% by weight.

    10. An oral composition as claimed in any one of Claims 1 to 9 in which the said oral composition is a dentifrice comprising 30-75% by weight of a dentally acceptable water-insoluble polishing agent.

    - 1 2 3 4 5 6 7 8 9 11 12 13 14 15 16 17 is 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 K14956 11. An oral composition as claimed in Claim 1, in which the said oral composition is a mouthwash or liquid dentifrice and the said orally acceptable vehicle is an aqueous vehicle wherein there is present at least one of a surf ace-active agent, a f lavouring oil or a non-toxic alcohol.

    12. An oral composition as claimed in any one of the preceding claims in which there is present surfaceactive agent in amount of 0.5-5 by weight.

    13. An oral composition as claimed in any one of the preceding claims in which there is present flavouring oil in amount of 0.1-5 by weight.

    14. An oral composition as claimed in Claim 11 in which the said composition is a mouthwash and the said aqueous vehicle contains ethanol and the weight ratio of water to ethanol is from 1:1 to 20:1.

    15. An oral composition as claimed in Claim 11 or Claim 14 in which the said oral composition is a liquid dentifrice containing 0.3-2.0% by weight of a polysaccharide of high molecular weight in excess of 1,000, 000 containing mannose, glucose, potassium glucuronate and acetyl moieties in the approximate ratio of 2: 1: 1: 1, as suspending and thickening agent and 10-20% by weight of a polishing material.

    16. An oral composition as claimed in any of Claims 1 to 15 in which the said antibacterial agent is selected from the group consisting of halogenated 7 ( - K14956 1 diphenyl ethers, halogenated salicylanilides, benzoic 2 esters, halogenated carbanilides and phenolic compounds.

    4 5 6 7 8 9 11 12 13 14 15 16 17 is 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 17. An oral composition as claimed in Claim 16 in which the said antibacterial agent is a halogenated diphenyl ether.

    18. An oral composition as claimed in claim 17 in which the said halogenated diphenyl ether is 2,4,41trichloro-21-hydroxyphenyl ether.

    19. An oral composition as claimed in any one of Claims 1 to 18 in which a solubilizing agent is present in amount of 0.5 to 20% by weight and is selected from the group consisting of propylene glycol, dipropylene glycol, hexylene glycol, methyl cellosolve, ethyl cellosolve, vegetable oil and wax containing at least 12 carbon atoms, amyl acetate, ethyl acetate, glyceryl tristearate and benzyl benzoate.

    20. An oral composition dentifrice as claimed in Claim 19 in which the solubilizing agent is propylene glycol and is present in mount of 0.5 by weight.