SE510832C2 - Antibacterial oral anti-plaque composition - Google Patents

Abstract

An oral composition such as a dentifrice or mouth-wash, comprises an effective antiplaque amount of a substantially water-insoluble noncationic antibacterial agents, such as 2,4, 4'-trichloro-2'-hydroxy-diphenyl other (Triclosan) and an antibacterial-enhancing agent which enhances the delivery of said antibacterial agent to and retention thereof on, oral surfaces, such as a synthetic anionic polymeric polycarboxylate having a molecular weight of about 1,000 to about 1,000,000 and an orally acceptable vehicle effective to enable said antibacterial agent to dissolve in saliva in effective antiplaque amount.

Description

'510 832 The cationic antibacterial materials, such as chlorhexidine, benstonium chloride and cetylpyridine chloride, have been the subject of extensive research as antibacterial antiplaque agents. However, they are generally not effective when used with anionic materials. Noncationic antibacterial materials, on the other hand, may be compatible with anionic components in an oral composition.

However, oral compositions are typically mixtures of innumerable components and even such typically neutral materials as humectants or humectants may affect the properties of these compositions.

Furthermore, even noncationic antibacterial agents may have limited antiplaque efficacy along with commonly used materials such as polyphosphate including antitartar agents, which are disclosed together in GB 2 200 551 (Gaffar et al.) And in EP 0 251 591 (Jackson et al.). U.S. Patent Application Serial No. 398,605, filed August 25, 1989, to the same applicant as the present application, discloses that antiplaque efficacy is greatly enhanced by the inclusion of an antibacterial effect enhancing agent (AEA) which enhances the delivery of the antibacterial agent to and retention thereof. on oral surfaces and provides optimized amounts and levels of polyphosphate and AEA.

An advantage of the present invention is that an oral composition provides, wherein a substantially water-insoluble noncationic antibacterial agent and an AEA are arranged to inhibit plaque formation, the oral composition containing an orally acceptable liquid carrier capable of allowing the antibacterial agent to dissolve in saliva in an effective amount of antiplaque. Yet another advantage of the invention is that AEA improves the delivery and retention of a small but effective amount of antiplaque of the antibacterial agent on the teeth and on soft oral tissues.

A further advantage of the invention is that an oral antiplaque composition is provided which is effective in reducing the occurrence of gingivitis.

Additional advantages of this invention will become apparent from a study of the following description.

In accordance with some of its aspects, the invention relates to an oral composition comprising an effective antiplaque amount of a substantially water-insoluble non-cationic antibacterial agent, about 0.005 to 4% by weight, of an antibacterial effect enhancing agent which enhances the release of the antibacterial agent and retention thereof on oral surfaces, and an orally acceptable carrier effective to allow the antibacterial agent to dissolve in saliva in an effective amount of antiplaque, the oral composition being substantially free of polyphosphate-containing anti-tartar agent.

Typical examples of water-insoluble non-cationic antibacterial agents which are particularly desirable in terms of antiplaque efficiency, safety and composition are: halogenated diphenyl ethers 2 ', 4,4'-trichloro-2-hydroxy-diphenyl ether (triclosan) 2,2'-dihydroxy- 5,5'-dibromo-diphenyl ether. 510,832 halogenated salicylanilides 4 ', 5-dibromosalicylanilide 3,4', 5-trichlorosalicylanilide 3,4 ', 5-tribromosalicylanilide 2,3,3', 5-tetrachlorosalicylanilide 3,3,3 ', 5-tetrachlorosalicylanilide 3,5- dibromo-3'-trifluoromethylsalicylanilide -n-octanoyl-3'-trifluoromethylsalicylanilide 3,5-dibromo-4'-trifluoromethylsalicylanilide 3,5-dibromo-3'-trifluoromethylsalicylanilide (flurophene) benzoestyl-epoxy-phenyl-ester butyl -p-hydroxybenzoester -p-hydroxybenzoester halogenated carbanilides 3,4,4'-trichlorocarbanilide 3-trifluoromethyl-4,4'-dichlorocarbanilide 3,3,4'-trichlorocarbanilide phenolic compounds (including phenol and its homologues, mono- and polyalkyl and aromatic halo (e.g.

F, Cl, Br, I) -phenols, resorcinol and catechol and derivatives thereof and bisphenol compounds) phenol and its homologues 2 methyl -phenol 3 methyl -phenol 4 methyl -phenol 4 ethyl 2,4-dimethyl 2,5-dimethyl 3,4-dimethyl 2,6-dimethyl 4-n propyl 4-n-butyl 4-n-amyl 4-tert-amyl 4-n-hexyl 4-n-heptyl 2-methoxy-4- (2-propenyl) -phenol (eugenol) -phenol -phenol -phenol -phenol -phenol -phenol -phenol -phenol -phenol -phenol -phenol 2-isopropyl-5-methyl -phenol (thymol) mono- and polyalkyl and aralkyl halophenols 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 -p- chlorophenol -p-chlorophenol -p-chlorophenol -p-chlorophenol -p-chlorophenol -p-chlorophenol -p-chlorophenol -p-chlorophenol -p-chlorophenol -o-chlorophenol -o-chlorophenol -o-chlorophenol -o-chlorophenol - o-chlorophenol -o-chlorophenol -o-chlorophenol -o-chlorophenol 510 832 510 832 p-chlorophenol o-benzyl o-benzyl-m-methyl o-benzyl-m, m-dimethyl o-phenylethyl o-phenylethyl-m- methyl 3-methyl 3,5-dimethyl 6-ethyl-3 -methyl 6-n-propyl-3-methyl 6-iso-propyl-3-methyl-2-ethyl-3,5-dimethyl 6-sec-butyl-3-methyl-β-chlorophenol-β-chlorophenol-β-chlorophenol -p-chlorophenol -p-chlorophenol -p-chlorophenol -p-chlorophenol -p-chlorophenol -p-chlorophenol -p-chlorophenol -p-chlorophenol -p-chlorophenol 2-iso-propyl-3,5-dimethyl-p- chlorophenol 6-diethylmethyl-3-methyl 6-isopropyl-2-ethyl-3-methyl-p-chlorophenol-p-chlorophenol 2-sec-amyl-3,5-dimethyl-p-chlorophenol 2-diethylmethyl-3, 5-dimethyl-p-chlorophenol 6-sec-octyl-3-methyl p-bromophenol methyl ethyl n-propyl n-butyl n-amyl sec-amyl n-hexyl cyclohexyl o-bromophenol tert-amyl n-hexyl n-propyl- m, m-dimethyl 2-phenylphenol 4-chloro-2-methylphenol 4-chloro-3-methylphenol -p-chlorophenol -p-bromophenol -p-bromophenol -p-bromophenol -p-bromophenol -p-bromophenol - p-bromophenol -p-bromophenol -p-bromophenol -o-bromophenol -o-bromophenol -o-bromophenol 4-chloro-3,5-dimethyl phenol 2,4-dichloro-3,5-dimethyl phenol 3,4,5 , 6-tetrabromo-2-methylphenol -methyl-2-pentylphenol 4-isopropyl-3-methylphenol -chloro-2-hydroxydiphenyl methane resorcinol and derivatives thereof resorcinol methyl ethyl np ropyl n-butyl n-amyl n-hexyl n-heptyl n-octyl n-nonyl phenyl benzyl phenylethyl phenylpropyl p-chlorobenzyl -chloro 4'-chloro-bromo 4 "-bromo bisphenol compounds bisphenol A -resorcinol -resorcinol -resorcinol -resorcinol - resorcinol -resorcinol -resorcinol -resorcinol -resorcinol -resorcinol -resorcinol -recorcinol -resorcinol -resorcinol 510 832 -2,4-dihydroxydiphenyl methane -2,4-dihydroxydiphenyl methane -2,4-dihydroxydiphenyl methane -2,4-dihydroxydene , 2'-methylene-bis- (4-chlorophenol) 2,2'-methylene-bis- (3,4,6-trichlorophenol) 2,2'-methylene-bis- (4-chloro-6-bromophenol) bis - (2-hydroxy-3,5-dichlorophenyl) -sulfide bis- (2-hydroxy-5-chlorobenzyl) -sulfide (hexachlorophene) 510 832 The non-cationic antibacterial agent is present in the oral composition in an effective antiplaque amount which is typically about 0 .01% - 5% by weight, preferably about 0.03% - 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%, for example about 0.3%, in a tooth care agent or preferably about 0.03 - 0.3% by weight, most preferably about 0.03 - 0.1% in a mouthwash or a liquid dentifrice. The antibacterial agent is substantially water-insoluble, which means that its solubility is less than about 1% by weight in water at 250 DEG C. and may even be lower than about 0.1%.

The preferred halogenated diphenyl ether is triclosan.

The preferred phenolic compounds are phenol, thymol, eugenol, hexylresorcinol and 2,2'-methylenebis- (4-chloro-6-bromophenol).

The most preferred antibacterial antiplaque compound is triclosan. The triclosan is disclosed in the above-mentioned US 4,022,880 as an antibacterial agent in combination with an anti-tartar agent which gives zinc ions and in DE-B 3,532,860 in combination with a copper compound. EP 0 278 744 discloses in combination with a tooth sensitivity reducing agent containing a potassium ion source.

It is also disclosed as an antiplaque agent in a dentifrice which is formulated to contain a lamellar phase comprising a liquid crystal comprising surfactant wherein the lamella spacing is less than 6.0 nm, and which optionally contains a zinc salt in the document EP 0 166 898 (Lane et al.) and in a dentifrice containing zinc citrate trihydrate, in EP 0 161 899 (Saxton et al.).

The antibacterial effect enhancing agent (AEA) which improves the delivery of the antibacterial agent to 10 510 832 and retention thereof on oral surfaces is utilized in amounts effective to achieve such improvement in the range of the oral composition of about 0.005% to about 4%, preferably about 0.1% to about 3%, more preferably about 0.5 to about 2.5% by weight.

AEA may be a simple compound, preferably a polymerizable monomer, more preferably a polymer wherein the latter term is completely generic, including for example oligomers, homopolymers, copolymers of two or more monomers, ionomers, block copolymers, graft copolymers, crosslinked polymers and copolymers and the like. AEA can be natural or synthetic and water insoluble or preferably water (saliva) -soluble or swellable (hydratable, hydrogel-forming). It has a (weight-based) 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 2,500 to about 250,000 or 500,000.

The AEA material usually contains at least one release enhancing group which is preferably acidic, such as sulfone, phosphone or more preferably phosphone or carboxyl group or salt thereof, for example alkali metal or ammonium, and at least one organic retention enhancing group, preferably a plurality of both the release enhancing and retention enhancing groups, the latter groups preferably having the formula - (X) n R wherein X is =, N, S, SO, SO 2, P, PO or Si or the like, R is hydrophobic alkyl, alkenyl , acyl, aryl, alkaryl, aralkyl, heterocylic or their inert-substituted derivatives, and n is zero or 1 or more. The above-mentioned "inert-substituted derivatives" are intended to include substituents on R which are generally non-hydrophilic and do not significantly interfere with the desired functions of AEA in improving the release of the antibacterial agent to and retaining. thereof on oral surfaces, such as halo, for example Cl, Br and I and carbo- and the like. Illustrations for such retention-enhancing groups are listed below in tabular form. n X - (X) n R 0 --- methyl, ethyl, propyl, butyl, isobutyl, t-butyl, cyclohexyl, allyl, benzyl, phenyl, chlorophenyl, xylyl, pyridyl, furanyl, acetyl, benzoyl, butyryl, terephthaloyl, etc. 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.

SO 2 butylsulfonyl, allylsulfonyl, benzylsulfonyl, phenylsulfonyl, etc. 510 832 11 n X - (X) n R P diethylphosphinyl, ethylvinylphosphinyl, ethylallylphosphinyl, ethylbenzylphosphinyl, ethylphenylphosphinyl, etc.

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

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

As used herein, the delivery enhancing group refers to one which adheres or substantially, adhesively, cohesively or otherwise binds the AEA material (which carries the antibacterial agent) to oral (e.g., tooth and gum) surfaces and thereby "releases "the antibacterial agent to these surfaces. The organic retention enhancing group, which is generally hydrophobic, attaches or otherwise binds the antibacterial agent to the AEA material, thereby promoting retention of the antibacterial agent to the AEA material and indirectly to the oral surfaces. In some cases, the attachment of the antibacterial agent takes place by physically trapping it by means of AEA, especially when the AEA material is a crosslinked polymer whose structure by its nature provides extended sites for such retention. The presence of a higher molecular weight, more hydrophobic crosslinking group in the crosslinked polymer further favors the physical retention of the antibacterial agent at or with the crosslinked AEA polymer.

Preferably, the AEA is an anionic polymer comprising a chain or back containing repeating units each preferably containing at least one carbon atom and preferably at least one directly or indirectly attached monovalent release enhancing group and at least one directly or indirectly attached monovalent retention enhancing group. which is geminally, Vicinally or less preferably otherwise attached to atoms, preferably carbon atoms, in the chain. Less preferably, the polymer may contain emission enhancing groups and / or retention enhancing groups and / or other divalent atoms or groups such as links in the polymer chain instead of or in addition to carbon atoms, or as crosslinking groups.

It should be understood that any examples or illustrations of AEA materials disclosed herein that do not contain both release enhancing groups and retention enhancing groups may and preferably should be chemically modified in a known manner to obtain the preferred AEA as contains both of these groups and preferably a plurality of each of these groups. In the case of the preferred polymeric AEA materials, it is desirable to maximize the substantivity and delivery of the antibacterial agent to oral surfaces that the repetitive moieties in the polymer chain or backbone containing the acidic delivery enhancing groups be at least about 10%. , preferably at least about 50% and more preferably at least about 80% up to 95% or 100% by weight of the polymer.

According to a preferred embodiment of this invention, AEA comprises a polymer containing repetitive moieties in which one or more phosphonic acid including release enhancing groups is attached to one or more carbon atoms in the polymer chain. An example of such an AEA 10 510 832 13 is poly (vinylphosphonic acid) containing units of the formula: I - / CH 2 T / CH / ~ PO 3 H 2 which, however, do not contain a retention enhancing group. However, a group of the latter type would exist in poly (1-phosphonopropylene) having units of the formula: II -QQH - çH / - CH3 ëo3H2 A preferred phosphonic acid-containing AEA for use herein is poly / beta-styrene phosphonic acid) containing units of the formula Wherein Ph is phenyl, the phosphonine-containing release enhancing group and the phenyline-containing retention-enhancing group are attached to vicinal carbon atoms in the chain, or a copolymer of beta-styrene phosphonic acid with vinyl phosphonyl chloride units with formula III alternating or in random association with units of formula I above or poly (alpha-styrene phosphonic acid) -containing units of formula: Iv - / cH¿ ;; f ----- / - Ph PO3H2 wherein they the release and retention promoting groups are geminally attached 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 1,000, preferably about 2,500 to about 10,000.

These "inert" monomers do not significantly interfere with the intended function of any copolymer used as an AEA herein.

Other phosphon-containing polymers include, for example, phosphonated ethylene having units of the formula: V - / CH2 / 14CHPO3H2 / n- wherein n may be, for example, an integer or have a value giving the polymer a molecular weight of About 3000; And sodium poly (butene-4,4-diphosphonate) having units of the formula: VI - / ca - cH ---- / - 2 / CH - CH <(PO Na and 2 3 2) 2 poly (allylbis (phosphonoethylamine) having units of the formula: VII '/ CH2 - / CH --- / - cnz - N <(Po3H2) 2 Other phosphonated polymers such as poly (allylphosphonoacetate), phosphonated polymethacrylate, etc. and the geminal diphosphonate polymers disclosed EP 0 321 233 can be used herein as AEA materials, provided of course that they contain or are modified to contain the above-defined organic retention enhancing groups A5 510 832 According to one aspect of the invention, the oral composition comprises an orally acceptable carrier. , an effective antiplaque amount of a substantially water-insoluble non-cationic antibacterial agent and an antibacterial effect enhancing agent having an average molecular weight of from about 1,000 to about 1,000,000, contains at least one release enhancing functional group and at least one organic retention. which agent containing these groups is free of or substantially free of water-soluble alkali metal or ammonium synthetic anionic linear polymer polycarboxylate salt having a molecular weight of from about 1000 to about 1,000,000.

According to another preferred embodiment, the AEA material may comprise a synthetic anionic polymeric polycarboxylate. Although not used in the present invention to interact with polyphosphate-containing anti-tartar agents, synthetic anionic polymeric polycarboxylate having a molecular weight of from about 1,000 to about 1,000,000, preferably from about 30,000 to about 500,000, has been used as an inhibitor of alkaline phosphatase enzyme in optimizing the antitartar efficacy of linear molecularly dehydrated polyphosphate salts, as disclosed in US 4,627,977 (Gaffar et al.). In fact, GB-A-2,200,551 discloses polymeric polycarboxylate as a freely optional ingredient in oral compositions containing linear molecularly dehydrated polyphosphate salts and substantially water-insoluble non-cationic antibacterial agent. It is further observed, in connection with the present invention, that such polycarboxylate is markedly effective in improving the release and retention of the nonionic antibacterial antiplaque agent on dental surfaces when another ingredient with which the polymeric polycarboxylate interacts (ie molecularly dehydrated polyphosphate) is absent; for example, when the ingredient with which the polymeric polycarboxylate interacts specifically is the noncationic antibacterial agent.

Synthetic anionic polymeric polycarboxylates and their complexes with various cationic germicides, zinc and magnesium have previously been disclosed as anti-tartar agents per se, for example in US 3,429,963 (Shedlovsky), US 4,152,420 (Gaffar), US 3,956,480 (Dichter et al.), U.S. 4,138,477 (Gaffar) and U.S. 4,183,914 (Gaffar et al.).

It should be understood that the synthetic anionic polymeric polycarboxylates so disclosed in these numerous patents, when containing or modified to contain retention enhancing groups, are operative in the compositions and methods of the present invention and these disclosures are incorporated into this scope herein with reference thereto.

The synthetic anionic polymeric polycarboxylates used herein are well known and are often used in the form of their free acids or preferably partially or more preferably completely 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 (etc.) of about 30,000 to about 1,000,000, most preferably about 30,000 to about 500,000. These copolymers are available, for example, such as Gantrez, for example AN 139 (mv 500,000), AN 199 (mv 250,000); and preferably S-97 Pharmaceutical Grade (including 70,000) from GAF Corporation. Other polymeric polycarboxylates operative as AEA materials containing or modified to contain retention enhancing groups include those disclosed in the aforementioned US 3,956,480, such as 1: 1 copolymers of maleic anhydride with ethyl acrylate, hydroxyethyl methacrylate, N-vinyl-2-pyrrolidone or ethylene, the latter being available, for example, as Monsanto EMA No. 1103, etc. 10,000 and EMA Grade 61 and 1: 1 copolymers of acrylic acid with methyl or hydroxyethyl methacrylate, methyl or ethyl acrylate, isobutyl, isobutyl vinyl ether or N-vinyl-2-pyrrolidone.

Additional operative polymeric polycarboxylates disclosed in the aforementioned U.S. 4,138,477 and U.S. 4,183,914 containing or modified to contain retention enhancing groups include copolymers of maleic anhydride with styrene, isobutylene or ethyl vinyl ether, polyacrylic, polyacrylic, polyacetone polymaleic acids, and sulfoacryl oligomers, etc. as far as 1000, available as Uniroyal ND-2.

Generally suitable are retention-enhancing group-containing polymerized olefinically or ethylenically unsaturated carboxylic acids, containing an activated carbon-carbon olefinic double bond which readily acts in polymerization due to its presence in the monomer molecule at either the alpha-beta position on the carboxyl group, or part of a terminal methylene group.

Illustrative of these acids are acrylic, methacrylic, ethacrylic, alpha-chloroacrylic, croton, beta-acryloxypropion, sorbin, alpha-chlorosorbine, cinnamine, beta-styrylacrylic, mucon, itacon, citracon, mesacon, glutacon, aconitine, alpha-phenylacrylic, -benzyl acrylic, 2-cyclohexylacryl, angelin, umbellin, fumar, maleic acids and anhydrides.

Other various olefin monomers that are copolymerizable with such carboxyl monomers include vinyl acetate, vinyl chloride, dimethyl maleate and the like. Copolymers contain sufficient carboxyl salt groups for water solubility.

Also useful herein are so-called carboxyvinyl polymers disclosed as toothpaste components in U.S. 3,980,767 (Chown et al.), U.S. 3,935,306 (Roberts et al.), U.S. 3,919,409 (Perla et al.), U.S. 3,911 904 (Harrison) and U.S. 3,711,604 (Colodney et al.). They are commercially available, for example, under the trademarks Carbopol 934, 940 and 941 from BF Goodrich, and these products consist essentially of a colloidal water-soluble polymer of polyacrylic acid which is crosslinked with from about 0.75% to about 2.0% of polyallyl sucrose or polyallyl pentacid. erythritol as a crosslinking agent wherein the crosslinked structure and crosslinking bonds provide the desired retention enhancement by hydrophobicity and / or physical entrapment of the antibacterial agent or the like. Polycarbophil is somewhat similar and is polyacrylic acid crosslinked with less than 0.2% divinyl glycol, the lower proportion, molecular weight and / or hydrophobicity of this crosslinking agent tending to give little or no retention improvement. 2,5-Dimethyl-1,5-hexadiene exemplifies a more effective retention enhancing crosslinking agent.

The synthetic anionic polymeric polycarboxylate component is essentially a hydrocarbon with, if desired, halogen and O-containing substituents and linkages as present in, for example, ester, ether and OH groups and is used in the present compositions in approximate amounts by weight of .05 to 4%, preferably 0.05 to 3%, more preferably 0.1 to 2%. The AEA material may also comprise natural anionic polymeric polycarboxylates containing retention enhancing groups. Carboxymethylcellulose and other binders, rubbers and film formers that are free from the above-defined release enhancing and / or retention enhancing groups are ineffective as AEA materials.

Illustrations of AEA materials containing phosphinic acid and / or sulfonic acid containing release enhancing groups include polymers and copolymers containing units or groups derived from the polymerization of vinyl or allyl phosphine and / or sulfonic acids which have been substituted as needed. one or two (or three) carbon atoms by means of an organic retention enhancing group having, for example, the formula defined above - (X) nR. Mixtures of these monomers can be utilized and the copolymer thereof with one or more inert polymerizable ethylenically unsaturated monomers such as those described above with respect to the operative synthetic anionic polymeric carboxylates. As will be noted, in these and other polymeric AEA materials operating herein, usually only one acidic release enhancing group is attached to any given carbon atom or other carbon atom in the polymer backbone or branch thereon.

Polysiloxanes containing or modified to contain the actual release enhancing groups and retention enhancing groups may also be utilized as AEA materials herein. Also effective as AEA materials herein are ionomers containing or modified to contain release and retention enhancing groups. Ionomers are described on p. 546 - 573 of the Kirk Othmer Encyclopedia of Chemical Technology, third edition, Supplement Volume, John Wiley & Sons, Inc. copyright 1984, the disclosure of which is hereby incorporated herein by reference. Also effective as AEA materials herein, provided they contain or are modified to contain retention enhancing groups, are polyesters, polyurethanes and synthetic and natural polyamides including polyamines and proteinaceous materials such as collagen, poly (arginine) and other polymerized amino acids. .

In one aspect of the present invention, the AEA having an average molecular weight of about 1,000 to about 1,000,000 contains at least one release enhancing functional group and at least one retention enhancing group, which agent containing said groups is free of or substantially free of water soluble alkali metal or ammonium polycarboxylate salt of synthetic anionic linear polymer, which salt has a molecular weight of from about 1,000 to about 1,000,000.

In the present invention, a preferred oral composition is a dentifrice containing about 0.3% by weight of the antibacterial agent (for example triclosan) and about 1.5 - 2% by weight of the polycarboxylate such as AEA.

Without being bound by theory, it is believed that the AEA material, particularly the polymeric AEA material, is generally an anionic film-forming material and is believed to adhere to the tooth surfaces and form a continuous film over the surfaces to thereby prevent bacterial attachment to the tooth surfaces. It is possible that the non-cationic antibacterial agent forms a complex or other form of association with the AEA material and thus forms a film of a complex or the like over the tooth surfaces. The film-forming property of the AEA material and the improved release and retention of the antibacterial agent on the tooth surfaces, referring to the AEA material, appear to make the tooth surfaces unfavorable for bacterial accumulation especially as the direct bacteriostatic effect of the antibacterial agent limits the bacterial growth. By the combination of three modes of action: l) improved delivery, 2) long retention time on tooth surfaces, and 3) prevention of bacterial attachment to the tooth surfaces, the oral composition is made effective in reducing plaque. Similar antiplaque efficacy is achieved on soft oral tissue at or near the gum line.

In accordance with the present invention, the orally acceptable carrier is effective in allowing the substantially water-insoluble noncationic antibacterial agent to dissolve in saliva in an effective amount of antiplaque.

In the oral preparation, an orally acceptable carrier includes an aqueous phase with humectant present. A dentifrice gel typically containing about 5 to 30% by weight of a silica-containing polish, water is typically present in an amount of at least about 3% by weight, generally about 3 to 35%, and humectant, preferably glycerin and / or sorbitol. , in a typical total amount of about 6.5-75% or 80% by weight of the oral gel-like dentifrice composition. When referring to sorbitol, the material is typically referred to as commercially available in 70% aqueous solutions.

When the amount of antibacterial agent is about 0.25 - 0.35% by weight, the dentifrice gels do not require any additional ingredient in the oral carrier to solubilize the antibacterial agent, but the presence of such solubilizing agent is freely optional. Therefore, when the amount of antibacterial agent is below about 0.25% by weight, for example about 0.01 up to about 0.25% by weight, the solubilizing agent should be present to ensure adequate salivation in saliva for antiplaque efficacy. . Therefore, when the amount of antibacterial agent is above about 0.35% by weight, for example about 0.35 to about 0.5% or more, say S%, solubilizing agent should be present because otherwise a substantial portion of the antibacterial agent is present. the agent would remain insoluble.

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

When the oral composition is a mouthwash or a liquid dentifrice, the oral carrier includes at least one of a surfactant, a flavoring oil or a non-toxic alcohol each of which helps to dissolve the antibacterial agent and again the presence of such solubilizer freely optional.

When the solubilizing agent is present in oral compositions of the present invention, it is typically present in an amount of about 0.5 to 20% by weight, with as little as about 0.5% by weight being sufficient when the amount of substantially water-insoluble non-cationic antibacterial agent is low, say up to about 0.3% by weight. When higher amounts, such as at least 0.5% by weight of antibacterial agent are present and especially when a silicic polishing agent is also present in an amount of about 5 to 30% by weight, it is desirable that at least about 5% by weight, typically up to about 20% by weight or more of the solubilizing agent is present. It can be noted that there may be a tendency of the dentifrice to separate into solid and liquid parts when more than about 5% by weight of the solubilizer is present. The agent that is or may be present for solubilizing the antibacterial agent in saliva may be incorporated into the water-humectant carrier. These solubilizers include humectants such as propylene glycol, dipropylene glycol and hexylene glycol. Cellosolv substances such as methylcellosolv and ethylcellosolv, vegetable oils and waxes containing at least about 12 carbon atoms in a straight chain, such as olive oil, castor oil and castor oils. 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, especially having a molecular weight of 600 or more, should be avoided as polyethylene glycol effectively inhibits the antibacterial activity of the non-cationic antibacterial agent. For example, polyethylene glycol (PEG) 600, when present together with triclosan in a weight ratio of triclosan PEG 600, reduces the antibacterial activity of triclosan by a factor of about 16, compared to that prevailing in the absence of polyethylene glycol.

In accordance with aspects of the present invention, the composition of the oral dentifrice may be substantially gel-like in nature, such as a dentifrice gel. Such gel-like oral preparations contain siliceous dental polishing material. Preferred polishing materials include crystalline silica having particle sizes up to about 5 microns, an average particle size of up to about 1.1 microns and a surface area of up to about 50,000 cm 2 / g, silica gel or colloidal silica and complex amorphous alkali metal aluminosilicates. gels are a polloid of colloidal silica such as those sold under the trademark SYLOID such as Syloid 72 and 510 832 24 Syloid 74 or under the trademark SANTOCEL such as Santocel 100 or alkali metal aluminosilicate complex (ie silica containing alumina combined in its food) are compatible with gel-like texture and have refractive indices which are close to the refractive index of the gelling agent and liquid systems (including water and / or humectants) commonly used in dentifrices.

The polishing material is usually present in oral dental compositions such as toothpaste or gel compositions in weight concentrations of about 5% to about 30%.

In the aspect of the present invention in which the oral preparation is a dentifrice, there is an orally acceptable carrier including an aqueous phase with humectant which is preferably glycerin and / or sorbitol, the water typically being present in an amount of about 15-35% or 40% by weight. and glycerin and / or sorbitol typically total about 20-75% by weight of the oral dentifrice formulation, with typically about 25-60%. When sorbitol is referred to herein, the material as typically available commercially in 70% aqueous solution is meant.

In the present invention, the oral dentifrice composition may be substantially pasty in nature, such as toothpaste (dental cream) but when silicic polish is used (which is not always the case as such material is typically not used in an amount above about% by weight). it be gel-like in nature. The carriers of the oral dentifrice composition contain dentally acceptable polishing material, examples of such polishing materials being water-soluble sodium metaphosphate, potassium metaphosphate, tricalcium phosphate, dihydrated dicalcium phosphate, 10 510,832 anhydrous dicalcium phosphate, aluminum silica silica, carbonate silica each other or with hard polishing materials such as calcined alumina and zirconium silicate, materials including the particulate thermosetting resins described in U.S. Pat. No. 3,070,510 (issued December 15, 1962), such as melamine phenol and urea formaldehydes, and crosslinked polyepoxides and polyesters. Preferred polishing materials include insoluble sodium metaphosphate, dicalcium phosphate and hydrogenated alumina.

Many of the so-called "water-insoluble" polishing materials are anionic in nature and also include small amounts of soluble material. Thus, insoluble sodium metaphosphate can be formed in any suitable manner as illustrated by Thorpe's Dictionary of Applied Chemistry, Volume 9, Fourth Edition, p. 510 - Sll.

The forms of insoluble sodium metaphosphate known as Madrell's salt and Kurrol's salt are further examples of suitable materials. These metaphosphate salts show only a low solubility in water and are therefore commonly referred to as insoluble metaphosphate (IMP). In these there is a small amount of soluble phosphate material as impurities, usually a few percent up to as much as 4% by weight. The amount of soluble phosphate material believed to include a soluble sodium trimetaphosphate in the case of insoluble metaphosphate can be reduced or eliminated by washing with water if desired. The insoluble alkali metal metaphosphate is typically used in powder form with a particle size so that at most 1% of the material is greater than 37 microns.

Hydrogenated alumina is an example of a polishing material that is essentially nonionic in nature. Typically, 510 832 26 has the small particle size i.e. at least about 85% of the particles are less than 20 microns and are those which are classified as gibbsite (alpha alumina trihydrate) and are normally chemically represented as Al 2 O 3 -3H 2 O or Al (OH) 3. The average particle size of gibbsite is usually about 6 to 9 microns. A typical grade has the following size distribution: Micron percent <30 94 - 99 <2O 85 - 93 <5 28 - 40 The polishing material is usually present in cream, paste or gel compositions in weight amounts of about 30 to about 75%.

Toothpaste or dental care products in the form of dental cream and dental care gels typically contain a natural or synthetic thickener or gelling agent in proportions of about 0.1 to about 10%, preferably about 0.5 to about 5%. A suitable thickener is synthetic colloidal magnesium-alkali metal silicate complex clay which is available, for example, as Laponite (eg CP, SP 2002, D) marketed by Laporte Industries Limited. The analysis for Laponite D shows, approximately on a weight basis, 58% SiO2, 25.40% MgO, 3.05% Na2O, 0.98% Li2O and some water and trace metals. Its true specific gravity is 2.53 and it has an apparent bulk density (g / ml at 8% moisture) of 1.0.

Other suitable thickeners or gelling agents include Irish moss, iota-carrageenan, tragacanth, starch, polyvinylpyrrolidone, hydroxyethylpropylcellulose, hydroxybutylmethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose (for example, sodium cellulose); when silicic polishing agent is present, colloidal silica such as those available as the fine fractions Syloid 244 or Sylodent 15.

In the aspect of the present invention in which the oral composition is a mouthwash or liquid dentifrice which is substantially liquid in nature, the carrier, especially in a mouthwash, is typically a water-alcohol mixture. Usually 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. Humectants such as glycerin and sorbitol may be present in amounts of about 10 to 30% by weight.

Liquid dentifrices typically comprise about 50-85% water, may contain about 0.5-20% by weight non-toxic alcohol and may also contain about 10-40% by weight humectant such as glycerin and / or sorbitol. When reference is made to sorbitol, this refers to a material that is typically commercially available in 70% aqueous solutions. Ethanol is the preferred non-toxic alcohol. The alcohol is believed to help dissolve the water-insoluble non-cationic antibacterial agent as it is believed to do with the flavoring oil.

As indicated, the non-cationic antibacterial agent is substantially water-insoluble. However, in the present invention, with the AEA material such as polycarboxylate present in the mouthwash or liquid dentifrice, organic surfactant, flavoring oil or non-toxic alcohol is believed to help dissolve the antibacterial agent to facilitate - take the same to reach soft oral tissue at or near the palates as well as tooth surfaces. Organic surfactants and / or flavoring oils can also help dissolve the antibacterial agents, such as freely available ingredients in oral dentifrice compositions.

Organic surfactants are also used in the compositions of the present invention to achieve increased prophylactic activity, to assist in achieving thorough and complete dispersion of the antibacterial antiplaque agent throughout the oral cavity and to make the present compositions more acceptable in cosmic from a technical point of view. The organic surfactant material is preferably anionic, nonionic or ampholytic in nature and it is preferred to use as the surfactant 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 monosulphates, such as sodium salts of monosulphated monoglyceride of hydrogenated coconut oil fatty acids, higher alkyl sulphates such as sodium lauryl sulphate, alkylaryl sulphonates such as higher sodium sulphate; 1,2-dihydroxypropanesulfonate and the substantially saturated higher aliphatic acylamides of lower aliphatic aminocarboxylic acid compounds, such as those having 12 to 16 carbon atoms in the fatty acid, alkyl or acyl radicals, and the like. Examples of the latter amides are the N-lauroyl sarcosine and the sodium potassium and ethanolamine salts of N-lauroyl, N-myristoyl or N-palmitoyl sarcosine which should be substantially free of soap or similar higher fatty acid materials. The use of these sarcosinate compounds in the oral compositions of the present invention is particularly advantageous as these materials exhibit a prolonged and marked effect with respect to the inhibition of acid formation in the oral cavity due to carbohydrate degradation, in addition to exerting some reduction in the solubility of tooth enamel in acidic solutions. Examples of water-soluble nonionic surfactants are condensation products of ethylene oxide with various reactive hydrogen-containing compounds which are reactive therewith and have long hydrophobic chains (for example aliphatic chains having about 12 to 20 carbon atoms) which condensation products ("ethoxamers) ") contains hydrophilic polyoxyethylene groups such as condensation products of poly (ethylene oxide) with fatty acids, fatty alcohols, fatty amides, polyhydric alcohols (eg sorbitan monostearate) and polypropylene oxide (eg Pluronic material).

Surfactants are typically present in an amount of 0.5 to 5% by weight, preferably about 1 to 2.5%.

When the oral composition is a liquid dentifrice, there is the natural or synthetic thickener or gelling agent as described, typically present in proportions ranging from about 0.1 to about 10%, preferably from about 0.5 to about 5%. .

Liquid dentifrices usually do not contain any polish. However, as described in US 3,506,757 (Salzmann), about 0.3 - 2.0% by weight of a high molecular weight polysaccharide exceeding 1,000,000, containing mannose, glucose, potassium glucuronate and acetyl groups in the approximate ratio 2: 1: 1: 1 as suspending and thickening agent, is used in a liquid dentifrice which can then also contain about 10 - 510 832% of a polishing material such as hydrogenated alumina, dicalcium phosphate dihydrate, calcium pyrophosphate, insoluble sodium metaphosphate, anhydrous calcium phosphate, carbonate, magnesium carbonate, magnesium oxide, silica, mixtures thereof and the like.

Without being bound by a theory as to how the benefits of the present invention are achieved, it is believed that an aqueous humectant carrier is normally solubilized in surfactant micelles in the mobile phase (ie not including gelling agents and polishes, if present in a dental prescription). During use, the dental phase agent's mobile phase solution can be diluted with saliva, which means that the triclosan precipitates. Thus, it has been found that even in the absence of special solubilizing material for the triclosan, when the amount of triclosan is about 0.25% - 0.35% by weight and the AEA material such as the polycarboxylate is present, sufficient triclosan is available to exert an excellent antiplaque effect on the soft tissues at the gum line. Corresponding remarks relate to other water-insoluble non-cationic antibacterial agents disclosed herein.

The oral dentifrice composition may also contain a fluoride ion source or fluorine-providing component such as anticarious agent, in an amount sufficient to deliver about 25 ppm to 5000 ppm fluoride ions. These compounds may be sparingly soluble in water or may be completely water-soluble. They are characterized by their ability to release fluoride ions in water and by substantial freedom from unwanted reaction with other compounds in 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 copper (I) fluoride, zinc fluoride, barium fluoride, sodium fluoride, sodium ammonium , sodium fluorosirconate, ammonium fluorosirconate, sodium monofluorophosphate, aluminum mono- and difluorophosphate and 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-giving compound depends to some extent on the type of compound, its solubility and the type of oral preparation, but it must be a non-toxic amount, generally about 0.0005 to about 3.0% in the preparation.

In a dental preparation, for example a dental gel, an amount of such a compound which gives up to about 5000 ppm F-ion on a weight basis of the preparation is considered to be satisfactory. Any suitable minimum amount of this compound can be used, but it is preferred to utilize a sufficient amount of compound to release about 300 to 2000 ppm, more preferably about 800 to about 1500 ppm fluoride ion.

In the case of alkali metal fluorides, this component is typically present in an amount of up to about 2% by weight, based on the weight of the preparation and preferably in the order 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 should be understood that, as is conventional, the oral preparations are intended to be sold or otherwise distributed in appropriately labeled packages. Thus, a dental gel will usually be in a compressible tube typically of aluminum, lined lead or plastic, or in a pressurized dispenser, pump dispenser or squeezing dispenser for dispensing the contents, the gel-containing device having a label which substantially describes it as a dental gel or the like.

Various other materials may be incorporated into the oral formulations of the present invention, such as whitening agents, preservatives, silicones, chlorophyll compounds and / or ammonized materials such as urea, diammonium phosphate and mixtures thereof. As they are present, these aids or adjuvants are incorporated into the preparations in amounts which have no significant adverse effect on the desired properties and characteristics. Significant amounts of zinc, magnesium and other metal salts and materials which are generally soluble and which would form complexes with active components of the present invention should be avoided.

Any suitable seasoning or sweetening material can also be used. Examples of suitable flavoring ingredients are flavoring oils, such as spearmint, peppermint, evergreens, sassafras, clover, sage, eucalyptus, marjoram, cinnamon, lemon and orange, and methyl salicylate. Suitable sweeteners include sucrose, lactose, maltose, xylitol, sodium cyclamate, perillartine, AMP (aspartylphenylalanine, methyl ester), saccharin and the like. Flavoring and sweetening agents may suitably each or together comprise from about 0.1% to 5% or more of the formulation. Furthermore, flavoring oil as well as the surfactant are believed to help dissolve the antibacterial agent, along with or even in the absence of surfactant.

In the preferred practice of the present invention, an oral composition of the present invention is preferably applied regularly to tooth enamel and soft oral tissues, especially at or near the gum line, such as every day or every other or every three days 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 life. Even at a pH as low as below 5, the enamel will not be decalcified or otherwise damaged. The pH can be adjusted with acid (for example citric acid or benzoic acid) or base (for example sodium hydroxide) or buffered as with sodium citrate, benzoate, carbonate or bicarbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate, etc.

The compositions of the present invention may be incorporated into tablets or chewing gums or other products, for example by stirring in a hot gum base or coating the outer surface of a gum base, illustrative examples being jelutone, gum latex, vinylite resins, etc. suitably added to conventional plasticizers or plasticizers, sugars or other sweeteners or hydrocarbons such as glucose, sorbitol and the like.

The following examples further illustrate the nature of the present invention, but it should be understood that the invention is not limited thereto. All amounts and proportions set forth herein and in the appended claims are by weight unless otherwise indicated. Example 1 The following dentifrices are prepared: glycerin propylene glycol sorbitol (70%) iota-carrageenan Gantrez S-97 sodium saccharin sodium fluoride sodium hydroxide (50%) titanium oxide silica as a polishing agent (Zeodent 113) silica as a flavonosulphate A, 00, 00 0.60 2.00 0.40 0.243 1.00 0.50, 00, 50 2.00 31.507 0.30 0.95, 00, 00 0.60 2.00 0.40 0.243 1 .00 0.50, 00 .50 2.00 31.507 0.30 0.95 The above-mentioned dentifrice A delivers the triclosan to the teeth and soft gum tissue substantially as well as the dentifrice B containing a special solubilizing agent for the triclosan. In other words, a special solubilizing agent is not required for the dentifrice of the present invention to be effective.

A corresponding dentifrice in which the Gantrez polycarboxylate is absent is also considerably worse in delivering the triclosan.

In the previous example, improved results can also be obtained by replacing the triclosan with other antibacterial agents described herein, such as phenol, thymol, eugenol and 2,2'-methylenebis (4-chloro-6-bromophenol) and or by replacing Gantrez with other AEA materials such as a 1: 1 copolymer of maleic anhydride and ethyl acrylate, sulfoacryl oligomers, Carbopoles (e.g. 934) and polymers of alpha- or beta-acid phosphonic acid monomers and copolymers of these monomers with each other or with other ethylenically compatible monomers such as vinylphosphonic acid.

Example 2 The following liquid phase dental solutions were tested for uptake and retention of triclosan on saliva-coated HA disks using the test procedures described in Example 3 below, with the results given: Ingredients parts ê. â EE sorbitol (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 Flavor oil 0.95 0.95 0.95 0.95 triclosan 0.3 0.3 0.3 0.3 water 56.507 54.507 54.507 54.507 poly (beta- styrene-phosphonic acid) 2.0 poly (alpha-styrene-phosphonic acid) 2.0 polyvinyl alcohol 2.0 adjusted to pH 6.5 with NaOH; triclosan uptake in / ug on saliva-coated HA slices 3l .0 174.0 86.0 36.0 triclosan retention on saliva-coated HA slices after: initially 183.0 minutes 136.0 l hour 105.0 3 hours 83.0 The results given above show that solution (D) containing polyvinyl alcohol, which is not an AEA material below, gives a triclosan uptake of only 36.0 which is quite similar to the uptake of 31.0 obtained with the control solution ( A) without additives. In contrast, solution (C) with poly (alpha-styrene-phosphonic acid) produces an uptake of 86.0 which is more than twice as large as that of solutions (A) and (D) and the solution (B ) with poly (beta-styrene phosphonic acid) produces an uptake that is about 5 times that of solutions (A) and (D), which tends to further indicate that the vicinal substitution of the delivery enhancing group gives superior results. The above results also show the surprisingly good retention of triclosan on the HA disks at the time perspective, obtained with the solution (B) containing poly (beta-styrene phosphonic acid) (molecular weights of about 3000 to 10,000).

Example 3 The effect of synthetic anionic linear polycarboxylate on uptake, retention and release from tooth surfaces of water-insoluble non-cationic antibacterial agent is evaluated in vitro on a saliva-coated hydroxyapatite disk and on flaked buccal epithelial cells. The in vitro evaluations are correlated to in vivo release and retention on oral surfaces.

For the test of delivery of antibacterial agent to a saliva-coated hydroxyapatite wafer, hydroxyapatite (HA) obtained from Monsanto Co. is washed. vigorously with distilled water, collected by vacuum filtration and allowed to dry overnight at 370 ° C. Dried HA is ground to a powder with a mortar and pestle. 150.00 mg of HA is placed in the chamber of a KBr-type tablet pad (Barnes Analytical, Stanford, CT.) And compacted for 6 minutes at 4500 kg in a Carver Laboratory type press. The resulting 13 mm slices are sintered for 4 hours at 800 ° C in a Thermolyne oven. Parafilm stimulated whole saliva is collected in an ice-cold glass beaker. The saliva is clarified by centrifugation at 15,000 xg (times gravity) for 15 minutes at 40 DEG C. Sterilization of the clarified saliva is carried out at 40 DEG C. with stirring by irradiating the sample with UV light for 1.0 hour.

Each sintered disk is hydrated with sterile water in a polyethylene test tube. The water is removed and replaced with 2.00 ml of saliva. A salivary membrane is formed by incubating the disc overnight at 37 ° C with continuous shaking in a water bath. After this treatment, the saliva is removed and the discs are treated with 1.00 ml of a solution containing antibacterial agent (triclosan) and a solution of the liquid phase of the dentifrice, and incubated at 37 ° C with continuous shaking in the water bath. After 30 minutes, transfer the slices to a new tube and add 5.00 ml of water followed by shaking the slice gently with a Vortex. The disc is then transferred to a new tube and the washing procedure is repeated twice. Finally, the disc is carefully transferred to a new tube to avoid simultaneous transfer of any liquid along with the disc. Then add 1.00 ml of methanol to the disc and shake vigorously with a Vortex. The sample is left at room temperature for 30 minutes to extract the absorbed triclosan into the methanol. The methanol is then aspirated and clarified by centrifugation in a Beckman Microfuge II at 100,000 rpm for 5 minutes. After this treatment, the methanol is transferred to HPLC (high performance liquid chromatography) ampoules to determine antibacterial agent. Three samples were used in all experiments.

For the test of the retention of antibacterial agent in saliva-coated HA disc, a saliva-coated HA disc is mixed with dentifrice slurries as described above. After incubation for 30 minutes at 37 DEG C., the HA disk is removed from the dentifrice slurry, washed twice with water and then re-incubated with para-film-stimulated human whole saliva which has been cleared by centrifugation. After incubation at 37 DEG C. with constant shaking for various periods of time, the HA disk is removed from the saliva and the amount of antibacterial agent (triclosan) remaining on the disk and released into the saliva is determined by analytical method using HPLC.

For the evaluation of the delivery of antibacterial agent to buccal epithelial cells, the release is measured to determine the effect of PVM / MA on the delivery of antibacterial agent (triclosan) to soft oral tissue from a dentifrice product.

Buckal epithelial cells are collected with a wooden applicator stick by gently rubbing the oral mucosa. The cells are suspended in saliva Salts (Rss) buffer (50 nM NaCl, 1.1 nM CaCl 2 and 0.6 nM KH 2 PO 4, pH 7.0) to 5 - 6 x 105 cells per ml using a hemocytometer to count the cells, and kept on ice until use. 0.5 ml of cell suspension, preincubated to 37 ° C in a water bath, is added to 0.5 ml of the antibacterial agent containing the test solution and incubated at 37 ° C. The antibacterial agent solution in the incubation mixture was diluted at least 10 times to lower the concentration of surfactant and prevent cell membranes from being destroyed by the surfactant. After incubation for 30 minutes, the cells are collected by centrifugation in a Beckman Microfuge II at 5000 rpm for 5 minutes. The cells collected, as well as the disc, are washed three times with RSS buffer and treated with 1.5 ml of methanol. The sample is mixed vigorously and analyzed for antibacterial agent by the HPLC method.

Dental care preparations are prepared which have the following prescription: propylene glycol (1,2) iota-carrageenan Gantrez S-97 titanium dioxide sorbitol (70%) sodium fluoride sodium saccharin silica thickener (Sylodent 15) silica-containing polishing agent (Zeodolocenosyl sulfate) to Parts è ä .00 10.00 0.75 0.75 - 2.00 0.50 0.50 .00 30.00 0.332 0.332 0.40 0.40 3.00 3.00 .00 20.00 0 .20 0.20 2.00 2.00 0.95 0.95 1.00 1.00 qs 100.00 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 given in Table 1 below: 510 832 41 Table 1 Denture uptake of triclosan in micrograms in micrograms at x 105, buccal saliva-coated disc epithelial cells A 25.0 38.0 B 54.0 96.0 These results reveal that the Gantrez material (which is present in dentifrice B) greatly improves the release and uptake of triclosan on saliva-coated hydroxyapatite disc and to the abraded buccal epithelial cells.

Similar results are obtained when the dental care products contain 0.30 parts of triclosan.

Example Gel 4 In tests with saliva-coated hydroxyapatite slices and abraded buccal epithelial cells different from those set forth in Example 3 above, said dentifrice B containing 2.00% Gantrez S-97 and 0.20% triclosan was compared. .00% propylene glycol and 2.00% sodium lauryl sulphate, and a dentifrice (B ') with equivalent prescription with the exception of the presence of 0.30% triclosan, with a commercially available dentifrice (C) containing a polishing agent with hydrogenated alumina and (a) 0.2% triclosan, (b) no Gantrez material, (c) no propylene glycol, (d) 0.5% zinc citrate, (e) 2.5% surfactants, (f) sodium monofluorophosphate and hydrogenated alumina as a polish; and the following dental prescription (C ') which is the same as the commercial dental preservative C except for the presence of 0.30% triclosan: Dental preservative C'% sorbitol (70%) 27.00 sodium carboxymethylcellulose 0.80 sodium monofluorophosphate , 85 zinc citrate 0.50 sodium saccharin 0.18 water 16.47 hydrogenated alumina as polish 50.00 ethanol 0.20 sodium lauryl sulphate 1,875 sodium dodecylbenzenesulfonate 0.625 triclosan 0.30 flavoring 1.20 Since dentifrices C and C 'contain a total of 2.50% surfactant more surfactant is available for dissolving the triclosan than in the dentifrices B and B 'which contain 2.00%. The propylene glycol present in dentifrices B and B 'with siliceous polishes (but not in dentifrices C and C' with hydrogenated alumina as polishing agent) ensures optimal dissolution of the triclosan.

The advantage of dentifrices B and B '(containing propylene glycol and Gantrez) compared to dentifrices C and C' with respect to triclosan uptake on salivary coated hydroxyapatite slices and on abraded buccal epithelial cells is shown in Table 2 below. 510 852 43 Table 2 buccal epithelial cells (lug) to saliva-coated hydroxyapatite disc X106 epithelial (/ ßQ_ cells dentifrice B 41.1 101.6 "B '77.4 142.0" C 20.4 61.0 "C' 42 Additional experiments with dentifrice B '(0.3% triclosan; Gantrez; propylene glycol) in a 50% slurry of dentifrice to determine the retention of triclosan on the saliva-coated hydroxyapatite wafer over a period of time reveal a retention of excellent levels of triclosan, as shown in Table 3 below: Table 3 Retention of triclosan adsorption from dentifrice slurry time retention of triclosan (min) (fig / slice) 0 70 60 60 70 120 65 180 57 240 59 510 832 These results indicate that dentifrices containing triclosan, the Gantrez material and propylene glycol can provide improved release of triclosan to and retention on tooth surfaces and soft tissues in the oral cavity and thereby provide improved antiplaque effect and antibacterial effect.

Example 5 For comparative purposes, recipes a and b are prepared below: Dental care agent glycerin propylene glycol iota-carrageenan sorbitol (70%) sodium saccharin sodium fluoride titanium dioxide Gantrez S-97 water NaOH (50%) Zeodent 113 (silica containing polishing agent) Siloxane flavoring sodium lauryl sulphate ethanol É .00 0.60 .00 0.40 0.243 0.50 2.00 29.157 2.00 .00 .50 1.10 0.50 2.00 1.00 IW HT .00 0.60, 00 0 .40 0.243 0.50 2.00 29.157 2.00 .00 .50 1.10 0.50 2.00 1.00 Recipe a is a dentifrice containing Gantrez UI 510 832 45 polycarboxylate, with 0.5% triclosan as a antibacterial antiplaque agent and no solubilizer.

In recipe b, there is a propylene glycol containing solubilizer.

Receptor a is poor in delivery of triclosan to buccal epithelial cells, while recipe b is markedly effective.

The above results reveal excellent release of triclosan dentifrice.

Example 6 An internal study was performed on a group of volunteers, to evaluate the effects of special dentifrices with respect to their effect on plaque regrowth, according to the procedure described by Addy, Willis and Moran, J. Clin. Perio, 1983, vol. 10. p. 89 - 99.

The dentifrices tested included a placebo control containing no triclosan (i) and a dentifrice in accordance with the present invention containing 0.3% triclosan, 10% propylene glycol (instead of 3% polyethylene glycol 600) and 2% Gantrez S-97 and humectant of propylene glycol and sorbitol (ii). The prescriptions of the dentifrices are as follows: 510 832 46 parts (i) (ii)% placebo invention. polyethylene glycol 600 3.00 - glycerin 25.00 - propylene glycol - 10.00 sorbitol (70%) 41.617 25.00 sodium carboxymethylcellulose 0.35 - iota-carrageenan - 0.60 sodium benzoate 0.50 - sodium saccharin 0.20 0.40 sodium fluoride 0.243 0.243 silica polish (Zeodent ll3) 18.00 20.00 silica thickener (Sylox 15) 5.50 5.50 water 8.00 28.757 Gantrez S-97 - 2.00 triclosan - 0.30 titanium dioxide 0.50 0.50 sodium lauryl sulphate 1.20 2.50 flavoring 0.89 1.10 ethyl alcohol 1.00 sodium hydroxide (50%) 2.00 With respect to plaque reduction on the teeth of the volunteers, the invention (ii) gave a significant reduction in 20% compared to placebo (i). Since smaller amounts of propylene glycol can dissolve the 0.3% triclosan present in toothpaste (ii), 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 solubilizers dipropylene glycol, hexylene glycol, methylcellosolve, ethylcellosolve, olive oil, castor oil, petrolatum, amyl acetate, glyceryl tristearate and benzyl benzoate, instead of propylene glycol, can effectively deliver triclosan to softeners. Furthermore, similar results are expected when propylene glycol or other solubilizers are omitted from toothpaste (ii) containing 0.3% triclosan. Example 7 The following dentifrices according to the invention are prepared: Parts ê glycerin - propylene glycol 10.00 sorbitol (70%) 25.00 sodium carboxymethylcellulose - iota-carrageenan 0.600 sodium saccharin 0.40 sodium fluoride 0.243 silica containing polishing agent (Zeodod silica containing thickener (Sylox 15) 5.50 water 28.757 Gantrez S-97 2.00 triclosan 0.50 titanium dioxide 0.50 'sodium lauryl sulphate 2.50 flavoring 1.0 l ethanol 1.00 sodium hydroxide (50%) 2.00 1.3. .00 0.50 19.50 l, 10 0.30 0.243, 00 3.00, 307 2.00 0.30 0.50 2.00 0.95 1.60 In the previous examples, improved results can also be obtained by replacing triclosan with other antibacterial agents described herein, such as phenol, thymol, eugenol and 2,2'-methylenebis (4-chloro-6-bromophenol) and / or by replacing Gantrez with other AEA materials such as a 1 : 1 copolymer of maleic anhydride and ethyl acrylate, sulfoacrylic oligomers, Carbopol materials (for example 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 phosphoric acid monomers.

Example gel 8 The following dentifrices are prepared: alpha-alumina trihydrate propylene glycol sorbitol (70%) Gantrez S-97 (13% solution) Gantrez S-97 (powder) sodium lauryl sulphate sodium saccharin sodium hydroxide (50%) flavoring Irish Moss sodium lucrousophylocitrose 21.70, 00 2.00 0.30 1.20 0.95 1.00 0.76 0.30 QS 100.00 Parts E 48.00 0.50 21.70 .00 2.13 0.30 1.20 0.95 1.00 0.76 0.50 0.30 to Q.S. 100.00 48.00 0.50 21.70 2.00 2.13 0.30 1.20 0.95 1.00 0.76 0.50 0.30 to Q.S. to 100.00 The above dentifrices deliver the triclosan to the teeth and the soft tissue areas of the flesh significantly more effectively than the corresponding dentifrices in which the Gantrez polycarboxylate is absent. 10 510 832 50 Example gel 9 The following dentifrices are prepared: glycerin sorbitol (70%) sodium carboxymethylcellulose Gantrez S-97 sodium saccharin sodium benzoate sodium monofluorophosphate dicalcium phosphate dihydrate triclosan sodium lauryl sulphate 2,50 76 0.30 l, 20 0.89 QS to 100.00 .00 17.00 1.00 2.00 0.20 0.50 0.76 48.76 0.30 l .20 0.89 Q.S. to 100.00 The above dentifrices deliver triclosan to saliva-coated hydroxyapatite sheets more efficiently than the corresponding dentifrices in which the Gantrez polycarboxylate is absent. 510 832 Example 10 The following antiplaquet dentifrices are prepared: Paste glycerin 15.00 propylene glycol 2.00 sodium carboxymethylcellulose 1.50 water 24.93 vinyl methyl ether / maleic anhydride copolymer (42% solution) 4.76 sodium monofluorophosphate 0.76 sodium phosphosaccharin 0.76 00 titanium dioxide 0.50 sodium lauryl sulphate 2.00 triclosan 0.30 flavoring 0.95 In the above examples, improved results are obtained even when the triclosan is replaced with each of phenol, 2,2'-methylenebis (4-chloro-6-bromophenol) , eugenol and thymol, and / or when Gantrez is replaced by other AEA materials such as Carbopoles (eg 934) or styrene phosphonic acid polymers having molecular weights in the range of about 3000 to 10,000, such as poly (beta-styrene phosphonic acid), styrene phosphonic acid, and poly (alpha-styrene phosphonic acid), or sulfoacrylic oligomers, or a 1: 1 copolymer of maleic anhydride with ethyl acrylate. 510 832 52 Example 11 Triclosan containing mobile dentifrice phases Components composition,% v / v é ä 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 sodium fluoride 0.32 0.32 flavoring oil 1.47 1.47 sodium lauryl sulphate 3.33 3.33 triclosan 0.67 0.67 The concentration of the above components is 1.33% dental care level to reflect a 25 percent level of abrasive that may be required to produce a complete dentifrice. The above-mentioned mobile phases of the indicated dental care prescriptions are tested with respect to triclosan uptake on saliva-coated HA discs. The results are given in the table below: 510 852 53 Table The triclosan uptake of saliva-coated hydroxyapatite (HA) discs from diluted and undiluted mobile phases of dentifrice. è å% triclosan 0.67 0.67 ionic strength (M / L) (calculated) 0.375 - pH 8.7 7.6 triclosan uptake (/ ug / disc) undiluted 55 122 The above results show a greater than double increase in the triclosan uptake achieved with prescription B which contains Gantrez, in comparison with the prescription A which does not contain Gantrez.

Example gel 12 Concentration and uptake of triclosan by HA from supernatant to 1: 1 dentifrice / water slurry.

Dental care products containing triclosan (/ ug / ml) triclosan-containing 0.5% in supernatant uptake triclosan, 2% nat- to 1: lpg / slice rium lauryl sulphate slurry% hydrogenated l 650 52 silica + 1.5% Gantrez S-97 50% alumina l 905 74 + 1.5% Gantrez S-97 510 832 54 Supernatants to 1: 1 dentifrice / water slurries of the above dentifrices are tested for the concentration of triclosan in the supernatant with respect to triclosan uptake on saliva-coated HA discs. The results indicate that the use of 50% alumina as an abrasive significantly increases the triclosan under low (1: 1) dilution conditions (from 160 to 1905) resulting in a significant increase in triclosan uptake (from 52 to 74).

Example gel 13 The following mouthwashes are effective in reducing plaque by increasing uptake and retention of triclosan on oral surfaces.

ABCDE parts parts parts parts parts parts Gantrez S-97 0.24 0.25 0.25 0.25 0.25 glycerin 15.00 10.00 15.00 10.00 15.00 ethanol - - l2.50 l2.50 - propylene glycol - 5.00 - 5.00 - Pluronic Fl08- (polyoxytes / - polyoxypropylene block copol.) 2.00 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 water QS Q.S. Q.S. Q.S. Q.S. to to to to to 100.00 l00.00 100.00 100.00 100.00 510 832 _55 Exemgel 14 The following liquid dentifrices are also effective in reducing plaque by increasing triclosan uptake and retention on oral surfaces.

ABC parts parts parts glycerin 20.0 20.0 - Gantrez S-97 0.3 0.3 0.3 High molecular weight polysaccharide, the molecule containing mannose, glucose, potassium glucuronate and acetyl groups in the approximate molar ratio 2: 1: 1: 1 0.8 - 1.0 sodium benzoate 0.5 0.5 0.5 saccharin, sodium 0.5 0.5 0.5 water 61.3 73.1 71.6 sodium lauryl sulfate 3.0 3.0 3.0 insoluble sodium metal phosphate 10.0 - 10.0 anhydrous dicalcium phosphate 1.0 - 2.5 flavoring oil 2.5 2.5 2.5 ethyl alcohol - - 10.0 triclosan 0.1 0.1 0.1 In the above examples, improved results can also be obtained when triclosan is replaced with each of phenol, 2,2'-methylenebis (4-chloro-6-bromophenol), eugenol and thymol, and / or when Gantrez is replaced with others. AEA materials such as Carbopoles (e.g. 934) or styrene-phosphonic acid copolymers having molecular weights in the range of about 3,000 to 10,000 such as poly (beta-styrene phosphonic acid), copolymers of vinylphosphonic acid with beta-styrene-phosphonic acid, and poly ( alpha-styrene phosphonic acid) el sulfoacrylic oligomers, or a 1: 1 copolymer of maleic anhydride with ethyl acrylate.

The present invention has been described with respect to certain preferred embodiments, and it should be understood that modifications and variations thereof which will be apparent to those skilled in the art are to be considered within the scope of the present application and the scope of the appended claims.

Claims (10)

10 20 25 510 832 57 PATENT REQUIREMENTS Oral composition, characterized in that it comprises a substantially water-insoluble non-cationic antibacterial agent, about 0.005 - 4% by weight of polyvinylphosphonate with recurring groups of the structure -cH2 - cH- in Ho-P = 0 in OH and an average molecular weight of at least about 1,000 to about 1,000,000 and an orally acceptable carrier having the ability to dissolve the antibacterial agent in saliva in an amount of plaque, the oral composition having a pH of about 4.5 to 10. An oral composition according to claim 1, characterized in that the composition is a dentifrice comprising about 5 to 30% by weight of silicon-containing polishing agent and that the antibacterial agent is present in an amount of about 0.25 to 0.35% by weight. An oral composition according to claim 1, characterized in that the composition is a dentifrice comprising from about 5 to 30% by weight of a silicon-containing polishing agent, the antibacterial agent being present in an amount of about 0.01 to 5% by weight and the The oral composition comprises a solubilizing material in an amount sufficient to support the dissolution of the antibacterial agent in saliva. lO 20 25 30 510 832 58 Oral composition according to any one of claims 1 to 3, characterized in that the composition is a tooth cleaning agent comprising from 30 to 75% by weight of a dentally acceptable water-insoluble polish. Oral composition according to any one of claims 1 to 3, characterized in that the composition is a mouthwash or a liquid dentifrice and that the orally acceptable carrier is an aqueous carrier containing a non-toxic alcohol. Oral composition according to any one of claims 1 to 5, characterized in that the antibacterial agent is selected from the group consisting of halogenated diphenyl ethers, halogenated halogenated carbanilides and the salicyl anilide, benzoic acid esters, phenolic compounds. Oral composition according to claim 6, characterized in that the antibacterial agent is a halogenated diphenyl ether. An oral composition according to claim 7, characterized in that the antibacterial agent is 2,3,4'-2'-trichloro-2'-hydroxyphenyl ether. Oral composition according to one of Claims 1 to 8, characterized in that the phosphonate is present in an amount of 0.5 to 2.5%. Use of oral composition according to any one of claims 1 to 9, treatment of plaque on the surfaces of the teeth and soft palate. for the manufacture of plaque inhibitors