LU88191A1 - Anti-bacterial antibacterial buccal composition and method of use - Google Patents

Description

Anti-bacterial antibacterial buccal composition and method of use

The present invention relates to an antibacterial, anti-plaque toothpaste composition for oral use. More particularly, the invention relates to a dentifrice composition for buccal use containing a non-cationic antibacterial agent substantially insoluble in water, effective for inhibiting dental plaque.

Dental plaque is a soft deposit that forms on the teeth, unlike tartar which is a hard mineral formation deposited on the teeth. Unlike tartar, plaque can form anywhere on the surface of the teeth, including in particular at the gingival margin. As a result, in addition to its unsightly appearance, dental plaque is involved in the appearance of gingivitis.

It is therefore very desirable to include antimicrobial agents, which are already known to reduce plaque, in compositions for oral use. Cationic type antibacterial agents have often been proposed. In addition, in the U.S. patent No. 4,022,880, a compound providing zinc ions serving as an anti-scale agent is mixed with an effective antibacterial agent to retard the development of the bacteria responsible for dental plaque. A wide variety of antibacterial agents are described with zinc compounds, including cationic substances such as guanides and quaternary ammonium compounds / as well as non-cationic compounds such as halogenated salicylanilides and halogenated hydroxydiphenyl ethers. A halogenated hydroxydiphenyl antibacterial, antiplaque / non-cationic ether namely Triclosan / has also been proposed in combination with zinc citrate trihydrate in European patent publication No. 0 161 899. Triclosan is also proposed in patent publication European No. 0 271 332 as a component of a toothpaste containing a solubilizing agent such as propylene glycol.

Cationic antibacterial substances such as chlorhexidine, benzethonium chloride and cetyl-pyridinium chloride have been the subject of the most important research on antibacterial antiplaque agents. However, they are generally ineffective when used with anionic substances. Non-cationic antibacterial substances can, on the other hand, be compatible with the anionic components of a composition for oral use.

However, compositions for oral use are generally mixtures of many components and even typically neutral substances such as humectants can affect the behavior of these compositions.

In addition, even non-cationic antibacterial agents can have limited anti-plaque efficacy with these commonly used substances such as polyphosphate type anti-scale agents which are described in British Patent Publication No. 2,200,551 and in European Patent No. 0 251 591-

An advantage of the present invention is that it provides a composition for oral use in which a non-cationic antibacterial agent substantially insoluble in water and an antibacterial stimulating agent (ASA) are provided to inhibit the formation of dental plaque. , the composition for buccal use containing a liquid vehicle acceptable for buccal use, effective for allowing said antibacterial agent to dissolve in saliva in an amount effective against dental plaque.

Another advantage of the present invention is that 11ASA improves the distribution and retention of a small but effective antiplaque amount of the antibacterial agent on the teeth and on the soft tissues of the oral cavity.

Another advantage of the present invention is that it provides an antiplaque composition for oral use which is effective in reducing the appearance of gingivitis. Other advantages of the present invention will become apparent from the following description.

In some of its aspects, the present invention relates to a composition for oral use comprising an amount effective against dental plaque of a non-cationic antibacterial agent substantially insoluble in water, approximately 0.005 to 4% by weight of a stimulating agent antibacterial agent which improves the distribution and retention of said antibacterial agent on the surfaces of the oral cavity and an acceptable vehicle for oral use, effective in allowing said antibacterial agent to dissolve in saliva in an amount effective against dental plaque, said composition oral use being substantially free of anti-scale agent of the pyrophosphate type in an effective anti-scale proportion.

Representative examples of water-insoluble non-cationic antibacterial agents, which are particularly advantageous from the viewpoints of efficacy against dental plaque, safety in use and formulation, are the following:

Halogenated diphenyl ethers 2 ', 4,4'-trichloro-2-hydroxy (diphenyl ether) (Triclosan) 2,2'-dihydroxy-5,5'-dibromo (diphenyl ether) Halogenated salicvlanilides 4', 5- dibromosalicylanilide 3,4 ', 5-trichlorosalicylanilide 3,4', 5-tribromosalicylanilide 2,3,3 ', 5-tetrachlorosalicylanilide 3,3,3', 5-tetrachlorosalicylanilide 3.5- dibromo-3'-trifluoromethyl-salicylanilide -octanoyl-3'-trifluoromethyl-salicylanilide 3.5- dibromo-4'-trifluoromethyl-salicylanilide 3.5- dibromo-3'-trifluoromethyl-salicylanilide (Flurophene)

Benzo esters methyl p-hydroxybenzoate ethyl p-hydroxybenzoate propyl p-hydroxybenzoate butyl p-hydroxybenzoate

Halogenated carbanilides 3,4,4'-trichlorocarbanilide 3-trifluoromethyl-4,4'-dichlorocarbanilide 3,3,4'-trichlorocarbanilide

Phenolic compounds (including phenol and its counterparts, halogenated mono- and polyalkyl- and aryl-phenols (e.g., F, Cl / Br, I), resorcinol, pyrocatechol and their derivatives, and bisphenolic compounds)

Phenol and its counterparts Phenol 2- methylphenol 3- methylphenol 4- methylphenol 4-ethylphenol 2.4- dimethylphenol 2.5- dimethylphenol 3,4-dimethylphenol 2.6- dimethylphenol 4-n-propylphenol 4-n-butylphenol 4-n-amylphenol 4-tert. -amylphenol 4-n-hexylphenol 4-n-heptylphenol 2-methoxy-4- (2-propenyl) phenol (eugenol) 2-isopropyl-5-methylphenol (thymol)

Mono- and poly-alkyl- and aralkyl-halogenophenols_ Methyl-p-chlorophenol Ethyl-p-chlorophenol n-propyl-p-chlorophenol n-butyl-p-chlorophenol n-amyl-p-chlorophenol sec.-amyl-p-chlorophenol n-hexyl-p-chlorophenol Cyclohexyl-p-chlorophenol n-heptyl-p-chlorophenol n-octyl-p-chlorophenol o-chlorophenol Methyl-o-chlorophenol

Ethyl-o-chlorophenol n-propyl-o-chlorophenol n-butyl-o-chlorophenol n-amyl-o-chlorophenol tert.-amyl-o-chlorophenol n-hexyl-o-chlorophenol n-heptyl-o-chlorophenol p- chlorophenol o-benzyl-p-chlorophenol o-benzyl-m-methyl-p-chlorophenol o-benzyl-m / m-dimethyl-p-chlorophenol o-phenylethyl-p-chlorophenol o-phenylethyl-m-methyl-p-chlorophenol 3-methyl-p-chlorophenol 3,5-dimethyl-p-chlorophenol 6-ethyl-3-methyl-p-chlorophenol 6-n-propyl-3-methyl-p-chlorophenol 6-isopropyl-3-methyl-p- chlorophenol 2-ethyl-3,5-dimethyl-p-chlorophenol 6-sec.-butyl-3-methyl-p-chlorophenol 2-isopropyl-3,5-dimethyl-p-chlorophenol 6-diethylmethyl-3-methyl-p -chlorophenol 6-isopropyl-2-ethyl-3-methyl-p-chlorophenol 2-sec.-amyl-3,5-dimethyl-p-chlorophenol 2-diethylmethyl-3,5-dimethyl-p-chlorophenol 6-sec. -octyl-3-methyl-p-chlorophenol p-bromophenol Methyl-p-bromophenol

Ethyl-p-bromophenol n-propyl-p-bromophenol n-butyl-p-bromophenol n-amyl-p-bromophenol sec.-amy1-p-bromophenol n-hexyl-p-bromophenol

Cyclohexyl-p-bromophenol o-bromophenol tert.-amyl-o-bromophenol n-hexyl-o-bromophenol n-propyl-m, m-dimethyl-o-bromophenol 2-phenylphenol 4-chloro-2-methylphenol 4-chloro- 3-methylphenol 4- chloro-3,5-dimethylphenol 2,4-dichloro-3,5-dimethylphenol 3,4 / 5/6-tetrabromo-2-methylphenol 5- methyl-2-pentylphenol 4- isopropyl-3-methylphenol 5- chloro-2-hydroxydiphenylmethane Resorcinol and its derivatives Resorcinol Methylresorcinol Ethylresorcinol n-propylresorcinol n-butylresorcinol n-amylresorcinol n-hexylresorcinol n-heptylresorcinol n-octylresorcinol n-nonylresorcinol

Phenylresorcinol

Benzylresorcinol

Phenylethyl resorcinol

Phenylpropyl-resorcinol p-chlorobenzyl-resorcinol 5-chloro-2,4-dihydroxydiphenylmethane 41-chloro-2,4-dihydroxydiphenylmethane 5-bromo-2,4-dihydroxydiphenylmethane 4'-bromo-2,4-dihydroxydiphenylmethane

Bisphenolic compounds Bisphenol A 2,2'-methylene-bis (4-chlorophenol) 2,2'-methylene-bis (3,4,6-trichlorophenol) (hexachlorophene) 2,2'-methylene-bis (4-chloro- 6-bromophenol)

Bis (2-hydroxy-3,5-dichlorophenyl) sulfide

Bis (2-hydroxy-5-chlorobenzyl) sulfide The non-cationic antibacterial agent is present in the composition for oral use in an amount effective against dental plaque / which is typically about 0/01 to 5% by weight / preferably from about 0/03 to 1% / more preferably from about 0/25 to 0/5% or from about 0/25 to less than 0/5%, and at best from about 0/25 to 0/35% / for example about 0/3% / in a toothpaste / or preferably about 0/03 to 0/3% by weight and at best about 0/03 to 0/1% in mouthwash or liquid toothpaste. The antibacterial agent is substantially insoluble in water / which means that its solubility is less than about 1% by weight in water at 25 ° C and may even be less than about 0/1%. The preferred halogenated diphenyl ether is Triclosan. The preferred phenolic compounds are phenol / thymol / eugenol / hexylresorcinol and 2,2'-methylene-bis (4-chloro-6-bromophenol) · The anti-bacterial compound antiplaque prefers above all is Triclosan. Triclosan is proposed in the U.S. patent. No. 4,022,880 mentioned above as an antibacterial agent in combination with a scale inhibitor which provides zinc ions and in R.F.A. patent No. 3,532,860 in combination with a copper compound. In European Patent No. 0 278 744 / it is proposed in combination with a tooth desensitizing agent containing a source of potassium ions. It is also proposed in the published European patent application No. 0 161 898 as an antiplaque agent in an oentiirice formulated so as to contain a lamellar phase of an agent i_ensio-actij-before the structure of a liquid crystal, the Interlamellar spacing is less than 6.0 nm and which may optionally contain a zinc salt as well as in published European patent application No. 0 161 899 in a toothpaste containing zinc citrate trihydrate. The antibacterial stimulating agent (ASA) which improves the distribution and retention of said antibacterial agent on the oral surfaces / is used in amounts effective to achieve this improvement which are in the range of about 0.005% to about 4% , preferably from about 0.1% to about 3% and more preferably from about 0.5% to about 2.5% by weight in the composition for oral use. ASA can be a simple compound, preferably a polymerizable monomer, better still a polymer, the latter term being taken in a completely generic sense and including for example oligomers, homopolymers, copolymers of two or more monomers, ionomers, block copolymers, graft copolymers, crosslinked polymers and copolymers, etc. ASA can be natural or synthetic, and insoluble in water or, preferably, soluble or swellable (hydra-table, forming a hydrogel) in water (saliva). It has an average molecular weight (by weight) of about 100 to about 1,000,000, preferably from about 1,000 to about 1,000,000 and more preferably from about 2,000 or 25,000 to about 250,000 or 500,000. ASA ordinarily contains at least one distribution enhancing group, which is preferably acidic, for example of a sulfonic, phos-phonic, or more preferably phosphinic or carboxylic acid, or a salt thereof / for example of an alkali metal or of ammonium / and at least one organic group improving the retention / preferably several of each of the groups improving the distribution and improving the retention / these latter groups preferably corresponding to the formula - (X) -R where X is 0 / N / S, SO / S0_, P / PO / Π ^

If, etc., R is a hydrophobic alkyl, alkenyl, acyl, arvle, alkarvy, aralkyl, heterocyclic group or their derivatives with inert substituents, and n is zero or 1. The above-mentioned "derivatives with inert substituents" have substituents on R which are generally non-hydrophilic and do not substantially disturb the functions which the ASA must fulfill to improve the distribution and the retention of the antibacterial agent on the oral surfaces, for example halogeno substituents, in particular Cl, Br, I, and carbo, etc. Representative examples of such retention enhancing groups are presented in a table below. η X - (X) n 0 --- methyl, ethyl, propyl, butyl, isobutyl, t-butyl, cyclonexyl, allyl, benzyl, phenyl, chlorophenyl, xylyl, pyridyl, furannyl, acetyl, benzoyl, butyryl, terephthaloyl, etc. . Ethoxy, benzyloxy, thioacetoxy, phenoxy, carbethoxy, carbobenzyloxy, etc. N ethylamino, diethylamino, propylamido, benzylamino, benzoylamido, phenylacetamido, etc. S thiobutyl, thio-isobutyl, thioallyl, thiobenzyl, thiophenyl, thiopropionyl, phenylthioacetyl, thiobenzoyl, etc. SO butylsulfoxy, allylsulfoxy, benzylsulfoxy, phenylsulfoxy, etc. SC> 2 butylsulfonyl, allylsulfonyl / benzylsulfonyl / phenylsulfonyl, etc. p diethylphosphinyl, ethylvinylphosphinyl / ethylallylphosphinyl / ethylbenzylphosphinyl, ethylphenylphosphinyl, etc. PO diethylphophinoxy, ethylvinylphosphinoxy / methylallylphosphinoxy, methylbenzylphosphinoxy, methylphenylphosphinoxy / etc.

If trimethylsilyl, dimethylbutylsilyl, dimethylbenzylsilyl, dimethylvinylsilyl / diraéthylallylsilyl / etc.

As used herein / the term "distribution enhancing group" refers to a group which substantively fixes or binds, adhesive or cohesively or in some other way ASA (carrying the antibacterial agent) to surfaces from the oral cavity (eg teeth and gums), thereby "delivering" or "distributing" the antibacterial agent to these surfaces. The organic group improving retention, generally hydrophobic, fixes or otherwise binds the antibacterial agent to ASA, thereby improving the retention of the antibacterial agent to ASA and, indirectly, to the surfaces of the cavity buccal. In some cases, the fixing of the antibacterial agent is carried out by its physical encroachment by ASA, in particular when the ASA is a crosslinked polymer, the structure of which offers by nature more sites suitable for such encroachment. The presence of a more hydrophobic crosslinking fragment, of higher molecular weight, in the crosslinked polymer further promotes the physical encroachment of the antibacterial agent by the crosslinked polymer forming the ASA.

Preferably, the ASA is an anionic polymer comprising a chain or skeleton having repeating units which each preferably contain at least one carbon atom and, preferably, at least one monovalent group improving the distribution attached laterally directly or indirectly and at least one monovalent group improving the retention attached laterally directly or indirectly, which are linked in twin, vicinal or, less preferably, in other ways to atoms of the chain, preferably carbon atoms. Less preferably, the polymer may contain distribution improving groups and / or retention improving groups and / or other divalent atoms or groups as links in the polymer chain in place of or in addition to carbon atoms, or as moieties crosslinkers.

It will be understood that all of the examples or illustrations of ASAs presented herein which do not contain both distribution improving groups and retention improving groups can, and preferably must, be chemically modified in a known manner to form ASAs preferred containing these two types of groups, and preferably more than one of each type of these groups. In the case of preferred polymeric ASAs, it is advantageous, in order to maximize the substantive fixation and the distribution of the antibacterial agent to the surfaces of the oral cavity, that the recurring units of the polymer chain or skeleton comprising the acid groups improving the distribution constitute at least 10%, preferably at least about 50%, and more preferably at least about 80% to 95% or 100% by weight of the polymer.

According to a preferred embodiment of the present invention, the ASA consists of a polymer containing repeating units in which one or more distribution improving phosphonic acid groups are linked to one or more carbon atoms of the polymer chain. An example of such an ASA is a vinylphosphonic polyacid) having units of formula:

which, however, does not contain a retention enhancing group. A group of the latter type is however present in a poly- (1-phosphonopropene) having units of formula:

An ASA containing phosphonic acid which is preferred to be used here is a poly (beta-styrene-phos-phonic acid) having units of formula.

where Ph is the phenyl group, the phosphonic group improving the distribution and the phenyl group improving the retention being linked to vicinal carbon atoms of the chain, or a copolymer of beta-styrene-phosphonic acid with vmyl-phos chloride -phonyl containing the units of formula III alternately or in statistical association with units of formula I above, or alternatively an alpha-styrene-phosphonic polyacid) having units of formula:

where the groups improving the distribution and the groups improving the retention are linked in female relation to the chain.

These styrene-phosphonic acid polymers and their copolymers formed with other ethylenically unsaturated inert monomers generally have molecular weights in the range of about 2000 to about 30,000, preferably about 2,500 to about 10,000. These "inert" monomers do not significantly disturb the function assigned to any copolymer used here as ASA. Other polymers containing phosphonic groups include, for example, a phosphonated ethylene polymer having units of formula:

where n can, for example, be an integer or have a value giving the polymer a molecular weight of approximately 3000; and a poly (sodium butene-4,4-diphosphonate) having units of formula:

and a poly (allyl-bis (phosphonoethyl) amine) having units of formula:

Other phosphonated polymers, for example a poly (allyl-phosphono-acetate), a phosphonated polymethacrylate, etc., and the polymers with two feminine phosphonate groups described in European Patent No. 0 321 233 may be. used here as ASA, provided of course that they contain or are modified to contain the organic groups improving the retention defined above.

In one aspect of the invention, the composition for oral use comprises a vehicle acceptable for oral use, an amount effective against dental plaque of a non-cationic antibacterial agent substantially insoluble in water and an anti-bacterial stimulating agent, the molecular weight is approximately 1000 to approximately 1,000,000 and which contains at least one functional group improving the distribution and at least one organic group improving the retention, said agent containing said groups being devoid or substantially devoid of any synthetic anionic linear polymeric polycarboxylate water-soluble alkali metal or ammonium having a molecular weight of about 1000 to about 1,000,000.

According to another preferred embodiment, the ASA may contain a synthetic anionic polymeric polycarboxylate. Although not used in the present invention to act in concert with a polyphosphate type anti-scale agent, a synthetic anionic polymeric polycarboxylate having a molecular weight of from about 1000 to about 1,000,000, preferably from about 30,000 at about 500,000, has been used as an alkaline phosphatase inhibitor to optimize the anti-scale activity of linear saline polyphosphates with molecular dehydration, as described in the US patent No. 4,527,977. In fact, in the British patent published under No. 2,200,551, the polymeric polycarboxylate is proposed as an optional ingredient in compositions for oral use containing linear saline polyphosphates with molecular dehydration and a non-antibacterial agent. cationic substantially insoluble in water. It has also been observed, in the context of the present invention, that this polycarooxyl = ie, is very effective in improving the distribution and the retention of the non-ionic antibacterial antiplaque agent on the dental surfaces when there is no another ingredient with which the polymeric polycarboxylate is capable of reacting (that is to say a molecularly dehydrated polyphosphate); for example / when the ingredient with which the polymeric polycarboxylate acts in concert is in particular the non-cationic antibacterial agent.

Synthetic anionic polymeric polycarboxylates and their complexes formed with various cationic germicides / zinc and magnesium have previously been proposed as scale inhibitors by themselves / for example in U.S. patents. No. 3,429,963, 4,152,420, 3,956,480, 4,138,477 and 4,183,914. It will be understood that the synthetic anionic polymeric polycarboxylates thus proposed in these various patents, when they contain or are modified to contain groups improving the retention, are usable in the compositions and methods of the present invention and, to that extent, the relevant disclosures of these patents are incorporated herein by reference to them.

The synthetic anionic polymeric polycarboxylates used herein are well known, since they are often used in the form of their free acids or their alkali metal salts (e.g. potassium and preferably sodium) or preferably partially hydrolubied ammonium or, better yet, totally neutralized. Preferred are 1: 4 to 4: 1 copolymers of maleic anhydride or acid with another ethylenically unsaturated polymerizable monomer, preferably a methyl ether / vinyl / maleic anhydride copolymer having a molecular weight (PM) of about 30 000 to approximately 1,000,000 and better still from approximately 30,000 to approximately 500,000. These copolymers are available, for example, under the Gantrez product designations, for example AN 139 (PM 500,000), AN 119 (P-Μ - 250,000) and preferably S-97 Pharmaceutical Grade (PM 70,000) from GAF Corporation. Other polymeric polycarboxylates usable as ASA, containing or modified to contain retention improving groups include those proposed in the U.S. Patent. No. 3,956,480 cited above, such as 1: 1 copolymers of maleic anhydride with ethyl acrylate, hydroxyethyl methacrylate, N-vinyl-2-pyrrolidone or ethylene, the latter type of copolymer being available, for example, under the designations EMA No. 1103, PM 10,000, and EMA Grade 61 from Monsanto, and 1: 1 copolymers of acrylic acid with methyl or hydroxyethyl methacrylate, acrylate methyl or ethyl, isobutyl vinyl ether or N-vinyl-2-pyrro-lidone. Other usable polymeric polycarboxylates proposed in US patents. Nos. 4,138,477 and 4,183,914, supra, containing or modified to contain retention enhancing groups, include copolymers of maleic anhydride with styrene, isobutylene or ethyl vinyl ether, polyacrylic acids , polyitaconic and polymaleic, and sulfoacrylic oligomers of PM as low as 1000, available under the designation ND-2 from Uniroyal.

Generally suitable monomers are the olefinically or ethylenically unsaturated carboxylic acids containing a retention-improving group, which have an activated carbon-carbon olefinic double bond which easily polymerizes because it is present in the molecule. monomer either in the alpha-beta position relative to a carboxyl group, or as part of a terminal methylene group. Representative examples of such acids are acrylic, methacrylic, ethacrylic, alpha-chloracrylic, crotonic, beta-acryl-oxypropionic, sorbic, alpha-chlorosorbic, cinnamic, beta-styrylacrylic, muconic, itaconic, citraconic, mesaconic acids. , glutaconic, aconitic, alpha-phenylacrylic, 2-benzylacrylic, 2-cyclohexyl-acrylic, angelic, umbellic, fumaric, maleic and their anhydrides. Other different olefinic monomers copolymerizable with these carboxylic monomers include vinyl acetate, vinyl chloride, dimethyl maleate, etc. The copolymers contain enough salified carboxylic groups to ensure their solubility in water.

Substances also useful here are so-called carboxyvinyl polymers proposed as components of toothpaste in U.S. patents. N ° 3,980,767, 3,935,306, 3,919,409, 3,911,904 and 3,711,604. These polymers are commercially available, for example under the trade names Carbo-poi 934, 940 and 941 from BF Goodrich, these products essentially consisting of a colloidally water-soluble polymer of polyacrylic acid crosslinked with about 0.75% to about 2.0% polyallyl-saccha-rose or polyallyl-pentaerythritol as a crosslinking agent, the crosslinked structure and the crosslinking bonds ensuring the desired retention improvement by hydrophobicity and / or physical overlapping of the antibacterial or other agent. A carbophilic polymer is quite similar in the case of a polyacrylic acid crosslinked with less than 0.2% of divinylglycol, the proportion, the molecular weight and / or the hydrophobicity lower of this crosslinking agent tending to offer only little or no improvement in retention. 2,5-dimethyl-1,5-hexadiene is an example of a more effective cross-linking agent which improves retention.

The synthetic anionic polymeric polycarboxylate component is mainly a hydrocarbon comprising optional halogen and oxygenated substituents and bonds, such as for example ester, ether and OH groups, and it is generally used in the compositions of the invention in approximate weight proportions of 0.05 to 4%, preferably 0.05 to 3%, and more preferably 0.1 to 2%. The ASA can also include natural anionic polymeric polycarboxylates containing retention enhancing groups. Carboxymethylcel lulose and other binding agents, gums and film-forming agents lacking the above-defined distribution and / or retention improving groups are ineffective as ASAs. As representative examples of ASA containing phosphinic acid and / or sulfonic acid groups improving the distribution, mention may be made of polymers and copolymers containing units or fragments originating from the polymerization of vinyl- or allyl-phosphinic acids and / or sulfonic substituted, as necessary, on the carbon atom in 1 or 2 (or 3) by an organic group improving retention, corresponding for example to the formula - (X) n ~ R defined above. Mixtures of these monomers and their copolymers formed with one or more ethylenically unsaturated inert polymerizable monomers such as those described above with respect to the usable synthetic anionic polycarboxylates can be used. As will be noted, in these polymeric ASAs as well as others usable here, there is generally only one acid group improving the distribution bound to any given carbon or other atom of the polymer backbone or an offshoot of it. Polysiloxanes containing or modified to contain side groups improving distribution and side groups improving retention can also be used here as ASA. Ionomers containing or modified to contain distribution and retention enhancing groups are also effective here as ASA. These ionomers are described on pages 546-573 of the supplemental volume of "Kirk Othmer Encyclopedia of Chemical Technology", third edition, John Wiley & Sons, Inc., copyright 1984, the description of which is incorporated herein by reference. Substances also effective here like ASA are synthetic and natural polyesters, polyurethanes and polyamides, including proteins and proteinaceous materials such as collagen, poly (arginine) and other polymerized amino acids, provided that they contain or be modified to contain groups improving retention.

In one aspect of the present invention, ASA which has an average molecular weight of about 1000 to about 1,000,000 contains at least one functional group improving distribution and at least one organic group improving retention, said agent containing said groups being free or substantially free of anionic linear water-soluble synthetic alkali metal or ammonium polycarboxylate having a molecular weight of about 1000 to about 1,000,000.

In the present invention, a preferred composition for oral use is a toothpaste containing 0j-jyfj-Qn 0.3% by weight of the antibacterial agent (for example Triclosan) and about 1.5 to 2% by weight of the polycarboxylate serving from ASA.

Without wishing to be bound by theory, it is considered that ASA, in particular a polymeric ASA, is generally a film-forming anionic substance and it is believed that it attaches to dental surfaces and forms a continuous film on the surfaces, thus preventing bacterial fixation on the surface of the teeth. The non-cationic antibacterial agent may form a complex or some other kind of association with ASA, thereby forming a film of a complex or the like on dental surfaces. It appears that the film-forming property of ASA and the better distribution and retention of the antibacterial agent on dental surfaces under the effect of ASA make dental surfaces not receptive to bacterial accumulation, in particular because direct bacteriostatic action of the antibacterial agent inhibits bacterial growth. Consequently, by the combination of the three modes of action, namely 1) the best distribution, 2) the long retention time on the dental surfaces and 3) the prevention of bacterial attachment to the dental surfaces, the composition for use buccal is made effective in reducing dental plaque. Similar anti-plaque efficacy is obtained on the soft tissues of the mouth at or near the gingival margin.

According to the present invention, the vehicle acceptable for oral use is effective in allowing the non-cationic antibacterial agent substantially insoluble in water to dissolve in saliva in an amount effective against dental plaque.

In the preparation for oral use, an acceptable vehicle for oral use comprises an aqueous phase in the presence of a humectant. In a gel toothpaste, typically containing about 5 to 30% by weight of a siliceous polishing agent, water is usually present in an amount of at least about 3% by weight, generally about 3 to 35% , and the humectant, preferably clycerol and / or sorbitol, generally constitutes in total approximately 6.5 to 75% or 80% by weight of the composition of toothpaste for oral use. The sorbitol in question here designates the product generally commercially available in 70% aqueous solutions.

When the amount of antibacterial agent is about 0.25 to 0.35% by weight, the gel toothpastes do not require any other ingredient in the oral vehicle to dissolve the antibacterial agent, although the presence of such a solubilizing agent is optional. When the amount of antibacterial agent is less than about 0.25% by weight, for example from about 0.01 to about 0.25% by weight, the solubilizing agent must therefore be present to ensure sufficient solubilization in the saliva to produce antiplaque activity. When the amount of antibacterial agent is more than about 0.35% by weight, for example from about 0.35 to about 0.5% or more, for example 5%, the solubilizing agent must therefore be present because, otherwise, a significant part of the antibacterial agent would remain insoluble.

When the composition for oral use is a toothpaste containing about 30 to 75% by weight of a polishing agent acceptable for the teeth, the presence of such a solubilizing agent is also optional.

When the composition for oral use is a mouthwash or a liquid toothpaste, the vehicle for oral use contains at least one of a surfactant, a flavoring essence or a non-toxic alcohol, each helping dissolving the antibacterial agent and, here again, the presence of the solubilizing agent is optional.

When a solubilizing agent is present in the oral compositions of the present invention, its amount is generally from about 0.5 to 20% by weight, an amount as low as about 0.5% by weight being sufficient when the non-cationic antibacterial agent substantially insoluble in water is present in a small amount, namely about 0.3% by weight. When the antibacterial agent is present in greater amounts such as at least about 0.5% by weight and, in particular, when a siliceous polishing agent is also present in an amount of about 5 to 30% by weight , it is desirable that there is at least about 5% by weight, and up to 20% by weight or more, of the solubilizing agent. Note that the toothpaste may tend to separate into liquid and solid parts when there is more than about 5% by weight of the solubilizing agent. The agent which is optionally present to dissolve the antibacterial agent in saliva can be incorporated into the water-humectant vehicle. These solubilizing agents include humectants of the polyol type such as propylene glycol, dipropylene glycol and hexylene glycol, products of the Cellosolve type such as methylcellosolve and ethylcellosolve, vegetable oils and waxes containing at least about 12 carbon atoms in a straight chain configuration, such as olive oil, castor oil and petrolatum, and esters such as amyl acetate, ethyl acetate and benzyl benzoate. As used herein, the term "propylene-clycol" includes 1,2-propylene glycol and 1,3-pro? Ylene glycol. Large quantities of polyethylene glycol, in particular with a molecular weight equal to or greater than 600, are to be avoided since polyethylene glycol strongly inhibits the antibacterial activity of the non-cationic antibacterial agent. For example, polyethyleneglycol (PEG) 600, when present with

Triclosan in a weight ratio Triclosan: PEG 600 of 25: 1 / reduces the antibacterial activity of Triclosan by a factor of about 16 compared to that which is exerted in the absence of polyethylene glycol.

In certain aspects of the present invention, the dentifrice composition for buccal use can have substantially the nature of a gel, being for example a toothpaste gel. These gel preparations for oral use contain a siliceous material for dental polishing. Preferred polishing materials include crystalline silica having a particle size limited to a maximum of about 5 microns, an average particle size limited to a maximum of about 1.1 microns and a specific surface area limited to a maximum of 50 000 cm / g, a silica gel or a colloidal silica, and an amorphous aluminosilicate complex of alkali metal.

When using visually transparent or opacified gels, colloidal silica such as those sold under the trademark SYLOID, such as Syloid 72 and Syloid 74, or under the trademark SANTOCEL, such as Santocel 100, or aluminosilicate complexes of alkali metals ( that is to say silica containing alumina combined in its matrix) are particularly useful as polishing agents because they are compatible with the texture of a gel and their index of refraction is close to the index of refraction of the celifying-liquid systems (comprising water and / or a humectant) commonly used in toothpastes.

The polishing material is generally present in dentifrice compositions for oral use, such as paste compositions or toothpaste gel, in weight concentrations of about 5% to about 30%.

In the aspect of the present invention in which the preparation for oral use is a toothpaste / this preparation contains an acceptable vehicle for oral use comprising an aqueous phase with a humectant which is preferably glycerol and / or sorbitol / in which the water is generally present in an amount of about 15 to 35% or 40% by weight and the glycerol and / or sorbitol generally constitute in total about 20 to 75% by weight / and more typically 25 to 60% / of the toothpaste preparation for oral use. The mention of sorbitol again designates the product generally available commercially in aqueous solutions at 70%.

In the present invention / the dentifrice composition for oral use can be of a substantially pasty nature / being for example a toothpaste (dental cream) / although if a siliceous polishing agent is used (which is not generally not the case since this material is not usually used in an amount greater than about 30% by weight) / it may have the nature of a gel. The carrier of the oral use toothpaste composition contains a polishing material acceptable for the teeth. Examples of polishing materials are the water insoluble varieties of sodium metaphosphate and potassium metaphosphate / tricalcium phosphate, dicalcium phosphate dihydrate, anhydrous dicalcium phosphate / calcium carbonate / aluminum silicate / l alumina / silica / bentonite and mixtures thereof or with hard polishing materials such as calcined alumina and zirconium silicate / a material containing the particulate thermosetting resins described in the US Patent No. 3,070,510 / such as melamine-phenol and urea-formaldehyde resins, and crosslinked polyepoxides and polyesters. Preferred polishing materials include insoluble sodium metaphosphates / dicalcium phosphate and hydrated alumina.

Many of the so-called "water-insoluble" polishes are anionic in character and also contain small amounts of soluble material. Thus / an insoluble sodium metaphosphate can be prepared by any suitable method as explained / for example / in the work "Dictionary of Applied Chemistry" by Thorpe / Volume 9, 4th edition / pages 510-511. Other examples of suitable materials are the insoluble sodium metaphos-phate forms known as Madrell salt and Kurrol salt. These saline metaphosphates show only a minute solubility in water and are therefore commonly called insoluble metaphosphates (MPI). There is found / as impurities / a minor proportion of soluble phosphate materials / usually a few percent / for example 4% by weight at most. The amount of soluble phosphate material / which is assumed to include a soluble sodium trimetaphos-phate in the case of an insoluble metaphosphate / can optionally be reduced or removed by washing with water. The insoluble alkali metal metaphosphate is typically used in the form of a powder whose particle size is such that a maximum of 1% of the material is larger than 37 micrometers. Hydrated alumina is an example of a polishing material of essentially nonionic nature. In general / its particle size is small, that is 3 ^ _ (3ij7e that at least about 85% of the particles measure less than 20 micrometers / and it is classified as gibbsite (alpha-alumina trihydrate) and normally represented chemically by Α1203 · 3Η20 or Al (OH) 3 · The average particle size of gibbsite is generally around 6 to 9 micrometers. A typical quality has the following particle size distribution:

Micrometers Percent <30 94-99 <20 85-73 <10 56-67 <5 28-40

The polishing material is generally present in gel or paste or cream compositions in weight concentrations of from about 30% to about 75%.

Toothpaste / creams and gels typically contain a natural or synthetic gelling or thickening agent in proportions of about 0.1 to about 10%, preferably about 0.5 to about 5%. A suitable thickener is a synthetic colloidal clay formed by a complex silicate of alkali metals and magnesium, available for example under the designation Laponite (for example CP, SP, 2002, D), these products being marketed by Laporte Industries Limited. Analysis of Laponite D indicates, approximately, by weight, 58.00% of Si02, 25.40% of MgO, 3.05% of Na20, 0.98% of Li2C, water and traces of metals. Its real density is 2.53 and its apparent density (at 8% humidity) of 1.0g / ml. Other suitable thickeners or gelling agents include Irish moss, iota-carrageenan, tragacanth, starch, polyvinylpyrrolidone, hydroxyethylpropylcellulose, hydroxybutylmethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose (available for example under Here designation Natrosol), the. sodium carboxy methylcellulose and, in particular when a siliceous polishing agent is present / a colloidal silica such as the finely ground silicas available under the designations Syloid 244 and Sylodent 15.

In the aspect of the present invention in which the composition for oral use is a mouthwash or a liquid toothpaste / of a substantially liquid nature / the vehicle is typically a water-alcohol mixture / in particular in a mouthwash. Generally / the weight ratio of water to alcohol is in the range of 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 generally in the range of about 70 to about 99.9% by weight. The alcohol is a non-toxic alcohol such as ethanol or isopropanol. A humectant such as glycerol or sorbitol can be present in an amount of about 10 to 30% by weight. Liquid toothpastes generally contain about 50 to 85% water, they can contain about 0.5 to 20% by weight of non-toxic alcohol and can also contain about 10 to 40% by weight of a humectant such as g ^ y (-. gj-Ql st / or sorbitol. The mention made here to sorbitol designates the product which is generally commercially available in 70% aqueous solutions. Ethanol is the preferred non-toxic alcohol. that alcohol facilitates the dissolution of the non-cationic antibacterial agent insoluble in water and it is also thought that a flavoring essence acts in the same way.

As noted, the non-cationic antibacterial agent is substantially insoluble in water.

However, in the present invention, it is believed that with ASA, such as a polycarboxylate, which is present in the mouth or liquid toothpaste bath, an organic surfactant, a flavoring essence or a non-toxic alcohol facilitate the dissolution of the antibacterial agent by helping it reach the soft oral tissues at or near the gums as well as the dental surfaces. Organic surfactants and / or flavoring essences which can also facilitate the dissolution of antibacterial agents are optional ingredients of toothpaste compositions for oral use.

Organic surfactants are also used in the compositions of the present invention to produce increased prophylactic action, to help achieve complete and uniform dispersion of the anti-plaque antibacterial agent throughout the oral cavity, and to make the present compositions more acceptable from a cosmetic point of view. The organic surface-active substance is preferably of anionic, nonionic or ampholytic character, and it is preferred to use as a surface-active agent a detersive substance which gives the composition detergent and foaming properties. Examples of suitable anionic surfactants are the water-soluble salts of higher fatty acid monoglyceride monosulphates, such as the sodium salt of the monoglyceride monosulphate of hydrogenated coconut oil fatty acids, higher alkyl sulphates such as lauryl sulphate sodium, alkylarylsulfonates such as sodium dodecylbenzene sulfonate, higher alkylsulfoacetates, higher fatty acid esters of 1,2-dihydroxypropane sulfonates, and substantially saturated higher aliphatic acylamides formed with lower aliphatic aminocarboxylic acids / such than those whose fatty acid / alkyl or acyl radicals have 12 to 16 carbon atoms / etc. Examples of the last mentioned amides are N-lauroylsarcosine / and the sodium / potassium and ethanolamine salts of N-lauroyl- / N-myristoyl- or N-palmitoyl-sarcosine which must be substantially free from soap or similar derivatives of higher fatty acids. The use of these sarcosinates in the compositions for buccal use of the present invention is particularly advantageous because these substances exert a marked and prolonged effect of inhibiting the formation of acids by decomposition of carbohydrates in the buccal cavity / and additionally exert a certain reduction in the solubility of dental enamel in acid solutions. Examples of water-soluble nonionic surfactants are condensation products of ethylene oxide with various labile hydrogen compounds reactive with ethylene oxide which have long hydrophobic chains (e.g., aliphatic chains of about 12 to 20 carbon atoms) / these condensation products ("ethoxamers") containing hydrophilic polyoxyethylene fragments / for example the condensation products of poly (ethylene oxide) with fatty acids / fatty alcohols / fatty amides / polyalcohols (for example sorbitan monostearate) and poly (propylene oxide) (for example the products of the pluronic series). The surfactant is generally present in an amount of about 0/5 to 5% by weight / preferably about 1 to 2/5% by weight.

When the composition for oral use is a liquid toothpaste / the thickener or natural or synthetic gelling agent as described is generally present in proportions of approximately 0/1 to approximately 10% / preferably of approximately 0/5 to approximately 5%.

In general / liquid toothpaste does not contain a polishing agent. However / as described in the U.S. patent. No. 3,506,757 / about 0.3 to 2.0% by weight of a polysaccharide having a high molecular weight greater than 1,000,000, containing fragments of mannose, glucose, potassium glucuronate and acetyl, can be used in the approximate ratio of 2: 1: 1: 1, as a suspending and thickening agent, in a toothpaste which may then also contain approximately 10 to 20% of a polishing material such as hydrated alumina, dical phosphate- cic dihydrate, calcium pyrophosphate, an insoluble sodium meta-phosphate, anhydrous dicalcium phosphate, calcium carbonate, magnesium carbonate, magnesium oxide, silica, mixtures thereof, etc.

Without wishing to be bound by any theory concerning the manner in which the advantages of the present invention are obtained, it is believed that an aqueous humectant vehicle is normally solubilized in the micelles of surfactant in the mobile phase (i.e. n '' not including the gelling agent and the polishing agent if they are present in a toothpaste formula). The mobile phase solution of the toothpaste can, in use, be diluted with saliva, which causes the precipitation of Triclosan. Thus, it can be seen that even in the absence of a special solubilizing agent for Triclosan, when the amount of Triclosan is approximately 0.25 to 0.35% by weight and an ASA such as the polycarboxylate is there is enough Triclosan present to exert an excellent anti-plaque effect on soft tissue at the gingival margin. Similar observations apply to the other water-insoluble non-cationic antibacterial agents described here.

The oral toothpaste composition may also contain a source of fluoride ions or a fluorine donor component as an anti-caries agent in an amount sufficient to provide about 25 x 10% to 5000 x 10 4% fluoride ions. These compounds may be slightly soluble in water or may be completely soluble in water. They are characterized by their ability to release fluoride ions in water and by their virtual absence of adverse reaction with the other compounds contained in the composition for oral use. Among these substances, there are mineral saline fluorides, such as soluble salts of alkali metals and alkaline earth metals, such as for example sodium fluoride, potassium fluoride, ammonium fluoride, calcium fluoride, a copper fluoride such as cuprous fluoride, zinc fluoride, barium fluoride, sodium fluorosilicate, ammonium fluorosilicate, sodium fluorozirconate, ammonium fluorozirconate, sodium monofluorophosphate, mono- and aluminum difluorophosphates, and sodium and calcium pyrophosphate. Preferred are alkali metal and tin fluorides, such as sodium and stannous fluorides, sodium monofluorophosphate (MFP) and mixtures thereof.

The amount of fluorine-providing compound depends to some extent on the type of compound, its solubility and the type of oral preparation, but it should be a non-toxic amount, generally from about 0.0005 to about 3.0 % in the preparation. In a preparation of toothpaste, for example a dental gel, an amount of such a compound is considered satisfactory which releases a maximum of approximately 5000 × 10 −4% by weight of F ions, relative to the weight of the preparation. . Any lesser proportion of this compound can be used, but it is preferable to use enough to liberate about 300 to 2000 x 10- ^% and more preferably about 800 to about 1500 x 10-4% fluoride ions.

In the case of alkali metal fluorides, this component is typically present in an amount limited to about 2% by weight, relative to the weight of the preparation, and preferably in the range of about 0.05% to 1% . In the case of sodium monofluorophosphate, this compound may be present in an amount of about 0.1 to 3%, more commonly about 0.76%.

It will be understood that, as is usual, preparations for oral use must be sold or otherwise distributed in suitably labeled packages. Thus, a toothpaste gel is usually packaged in a compressible tube, typically aluminum, lead coated internally or in plastic, or in another compressible dispenser, pump or pressure, intended to deliver its content in a metered manner and bearing a label describing it essentially as a toothpaste gel, etc.

Various other substances can be incorporated into the oral preparations of the present invention, such as bleaches, preservatives, silicones, chlorophyll compounds and / or ammoniated substances such as urea and diammonium phosphate , and mixtures thereof. These adjuvants, if present, are incorporated into the preparations in amounts which do not substantially affect the desired properties and characteristics. Large proportions of generally soluble salts and substances containing zinc, magnesium and other metals which would form complexes with the active components of the preparations of the present invention should be avoided.

Any suitable flavoring or sweetening substance may also be used. Examples of suitable flavoring constituents are flavoring essential oils, for example, spearmint, peppermint, wintergreen, sassafras, cloves, sage, eucalyptus, marjoram, cinnamon, lemon and orange, and methyl salicylate. Suitable sweetening agents include sucrose, lactose, maltose, xylitol, sodium cyclamate, perillartine, AMP (aspartylphenyl-alanine methyl ester), saccharin, etc. The flavoring and sweetening agents may suitably constitute together about 0.1% to 5% or more of the preparation. In addition, like the surface-active agent, the flavoring essence is supposed to facilitate the dissolution of the antibacterial agent, in the presence or even in the absence of surface-active agent.

In the preferred practical application of the present invention, a composition for buccal use according to the invention is preferably applied at regular intervals to the dental enamel and the soft tissues of the buccal cavity, in particular at or near the gingival margin, for example every day or every two or three days, or preferably 1 to 3 times a day, at a pH of approximately 4.5 to approximately 9 or 10, generally approximately 5.5 to approximately 8, preferably from about 6 to 8 and, at best, from about 6.5 to about 7.5, for at least 2 to 8 weeks or more, or even for life. Even at pH below 5, the enamel is not decalcified or otherwise damaged. The pH can be adjusted with an acid (for example citric acid or benzoic acid) or a base (for example sodium hydroxide) or buffered for example with sodium citrate, benzoate, carbonate or bicarbonate Disodium hydrogen phosphate, sodium dihydro-phosphate, etc.).

The compositions of the present invention can be incorporated into lozenges or into chewing gum or other products, for example by stirring them in a hot gum base or by applying them to the exterior surface of a gum base of which representative examples which may be mentioned are jelutong, rubber latex, vinylite resins, etc., advantageously combined with conventional plasticizers or softeners, sugar or other sweeteners or carbohydrates such as glucose , sorbitol, etc.

The following examples further illustrate the nature of the present invention without, however, limiting it. All the quantities and proportions mentioned therein are expressed by weight unless otherwise specified. EXAMPLE 1

The following toothpaste is prepared:

Parts A J3

Glycerol 10.00 propylene glycol "10.00

Sorbitol (70%) 25.00 25.00

Iota-carrageenan 0.60 0.60

Center S-97 2.00 2.00

0.40 ° '40 sodium saccharinate

Sodium fluoride 0.243 0.243

Sodium hydroxide (50%) 1.00 1.00

Titanium oxide 0.50 0.50

Polishing agent (silica) (Zeodent 113) 20.00 20.00

Thickener (silica) (Sylox 15) 5.50 5.50

Sodium lauryl sulfate 2.00 2.00

Water 31.507 31.507

Triclosan 0.30 0.30

Flavoring essence 0.95 0.95

Toothpaste A above distributes Triclosan to teeth and soft gum tissue essentially as effectively as Toothpaste B containing a special solubilizing agent for Triclosan. In other words, for the toothpaste of the present invention to be effective, no special solubilizing agent is required. In addition, a corresponding toothpaste from which the Gantrez polycarboxylate is absent distributes Triclosan substantially less well.

In the example above, better results can also be obtained by replacing Triclosan with other antibacterial agents described here such as phenol, thymol, eugenol and 2,2'-methylene-bis ( 4-chloro-6-bromophenol) and / or by replacing Gantrez with other ASAs such as a 1: 1 copolymer of maleic anhydride and ethyl acrylate, a sulfoacrylic oligomer, one of the products of the Carbopol series (for example 934) and polymers of alpha- or beta-styrene-phosphonic acids monomers and copolymers of these monomers with each other or with other ethylenically unsaturated polymerizable monomers such as vinylphosphonic acid. EXAMPLE 2

The following liquid phase toothpaste solutions are subjected to tests to determine the fixation and retention of Triclosan on saliva-coated HA disks, following the procedures described in Example 3, which gives the results indicated:

Ingredients PARTIES

A B C D

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

Sodium lauryl sulfate 20/0 20/0 20/0 20.0

NaF 0/243 0.243 0/243 0.243

Flavoring essence 0.95 0.95 0.95 0.95

Triclosan 9/9 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 _ _ _ -

Adjusted to pH 6.5 with NaOH

Fixation of Triclosan in micrograms on saliva-coated discs 31.0 174.0 86.0 36.0 Retention of Triclosan on HA saliva-coated discs after:

Initial 183.0 30 minutes 136.0 1 hour 105.0 3 hours ^ 3.0

The above results show that solution (D) containing polyvinyl alcohol, not an ASA below / produces a Triclosan binding of only 36.0, quite similar to the binding of 31.0 produced with the control solution (A) without additive. In contrast, solution (C) containing a poly (alpha-styrene-phosphonic acid) produces a fixation of 86.0, more than twice that of solutions (A) and (D), and solution (B) containing poly (beta-styrene-phosphonic acid) produces a fixation equal to approximately 5 times that of solutions (A) and (D) / which tends to demonstrate further that vicinal substitution of the group improving the distribution gives superior results. The above results also demonstrate the surprisingly good retention over time of Triclosan on the HA disks obtained with solution (b) containing poly (beta-styrene-phosphonic acid) (molecular weight of approximately 3000 to 10,000). EXAMPLE 3 The effect of the synthetic anionic linear polycarboxylate on the fixation, retention and release of the water-insoluble non-cationic antibacterial agent on and from the dental surfaces is evaluated "in vitro" on a hydroxyapatite disc. coated with saliva and on epithelial cells exfoliated from the oral cavity. "In vitro" assessments can be correlated with "in vivo" distribution and retention on the surfaces of the oral cavity.

To test the distribution of the antibacterial agent on a hydroxyapatite disc coated with saliva, hydroxyapatite (HA) supplied by Monsanto Co. is abundantly washed with distilled water, collected by vacuum filtration and dry overnight at 37 ° C. The dried HA is ground to a powder using a mortar and pestle. 150.00 mg of HA are placed in the cavity of a KBr pellet matrix (Barnes Analytical, Stanford, CT.) And compressed for 6 minutes under a pressure of 4540 kg in a Carver laboratory press. The resulting 13 mm discs are sintered for 4 hours at 800 ° C in a Thermolyne oven. Whole saliva produced by parafilm stimulation is collected in an ice-cold glass beaker. The saliva is clarified by centrifugation at 15,000 x £ for 15 minutes at 4 ° C. Sterilization of the clarified saliva is carried out, with stirring at 4 ° C., by irradiation of the sample with a UV lamp for 1.0 hour.

Each sintered disc is hydrated with sterile water in a polyethylene test tube. The water is then removed and replaced with 2.00 ml of saliva. A saliva film is formed by incubating the disc overnight at 37 ° C in a water bath with continuous shaking. After this treatment, the saliva is removed and the discs are treated with 1.00 ml of a solution containing the liquid phase solution of toothpaste containing the antibacterial agent (Triclo-san) and incubated at 37 ° C. in the bain-marie with continuous shaking by shaking. After 30 minutes, transfer the disc to a new tube and add 5.00 ml of water, then gently shake the disc with a Vortex machine. The disc is then transferred to a new tube and the washing operation is repeated twice. Finally, the disc is carefully transferred to a new tube to avoid simultaneous transfer of any liquid with the disc. Then add 1.00 ml of methanol to the disc and shake vigorously with a Vortex machine. The sample is left at room temperature for 30 minutes to extract the adsorbed Triclosan by passing it through methanol. The methanol is then removed by suction and clarified by centrifugation in a Beckman Microfuge 11 apparatus at 10,000 rpm for 5 minutes. After this treatment, the methanol is transferred into CEHP (high performance liquid chromatography) flasks for the determination of the antibacterial agent. Triplicate samples are used in all experiments.

For the antibacterial agent retention test on a saliva coated HA disc # treat a saliva coated HA disc with toothpaste suspensions as described above. After incubation for 30 minutes at 37 ° C, the HA disk is removed from the toothpaste suspension # washed twice with 1 water # and then incubated again with whole human saliva produced by parafilm stimulation, having been clarified by centrifugation. After incubation at 37 ° C with constant shaking for various periods of time, the HA disc is removed from the saliva and the amount of antibacterial agent (Triclosan) retained on the disc is determined and released into the saliva. an analytical method using HPLC.

For the test of distribution of the antibacterial agent on the epithelial cells of the oral cavity, the distribution is measured in order to determine the effect of the methyl ether / vinyl / maleic anhydride copolymer on the distribution of the antibacterial agent. (Triclosan) to the soft tissues of the oral cavity from a toothpaste. Epithelial cells are collected from the oral cavity using a wooden applicator stick by gently rubbing the oral mucosa. The cells are suspended in a Saliva Resting Buffer (SSR) (NaCl 50nM # CaC ^ 1 # InM and F ^ PO ^ 0.6nM # pH 7.0) at a rate of 5-6 X 105 cells / ml using a hematiometer to count the cells and keep them in ice until use. 0.5 ml of cell suspension, previously incubated at 37 ° C. in a water bath, is added to 0.5 ml of the solution of antibacterial agent under test and the mixture is incubated at 37 ° C. The solution of antibacterial agent is diluted at least to the tenth in the incubation mixture in order to lower the concentration of surfactant and to prevent destruction of the cellular membranes by the surfactant. After 30 minutes of incubation, harvest the cells by centrifugation in a Beckman Microfuge 11 device at 5000 rpm for 5 minutes. The cells collected in the form of the pellet are washed 3 times with SSR buffer and treated with 1.5 ml of methanol. The sample is thoroughly mixed and analyzed by the HPLC method to determine its content of antibacterial agent.

Toothpastes are prepared having the following formulas:

Parts A B

Propylene glycol (1.2) 10.00 10.00

Iota-carrageenan 0.75 0.75

Gantrez S-97 "2.00

Titanium dioxide 0/50 0.50

Sorbitol (70%) 30 '° 30.0

Sodium fluoride 0.332 0.332

Sodium saccharin ° '40 0.40

Thickener (silica) (Sylodent 15) 3.00 3.00

Polishing agent (silica) (Zeodent 113) 20'00 20 '00

Triclosan 0.20 0.20

Sodium lauryl sulfate 2.00 2.00

Flavoring essence 0.95 0.95

Ethyl alcohol 1.00 1.00

Water, q.s. for 100.00 100.00

Table 1 below shows the fixation of Triclosan on the saliva-coated hydroxyapatite disc and on the epithelial cells of the oral cavity, with and without the Gantrez S-97 polycarboxylate polymer: TABLE 1

In micrograms Fixation of Triclosan x 10 cells in micrograms on the epithelial cells

Disc toothpaste coated with oral saliva_ A 25.0 38.0 B 54.0 96.0

These results reveal that the Gantrez product (present in Toothpaste B greatly improves the distribution and fixation of Triclosan on the saliva-coated hydroxyapatite disc and on the exfoliated oral epithelial cells.

Similar results are obtained when toothpaste contains 0.30 parts of Triclosan. EXAMPLE 4

In tests with saliva-coated hydroxyapatite discs and exfoliated mouth epithelial cells different from those presented in Example 3 above, said Toothpaste B containing 2.00% Gantrez S-97 and 0.20% Triclosan, 10.00% propylene glycol and 2.00% sodium lauryl sulfate, and an equivalent formulated toothpaste (B '), except for the presence of 0.30% Triclosan, are compared to a commercial toothpaste (C) containing hydrated alumina as a polishing agent and (a) 0.2% Triclosan, (b) no Gantrez, (c) no propylene glycol, (d) 0.5 % zinc citrate, (e) 2.5% surfactants, (f) sodium monofluorophosphate and hydrated alumina as a polishing agent, and a formulation of Toothpaste (C) ci below which is similar to commercial toothpaste except for the presence of 0.30% of Triclosan.

Toothpaste C '-%

Sorbitol (70%) 27.00

Carboxyraethylcellulose sodium 0/80

Sodium monofluorophosphate 0.85

Zinc citrate 0.50

Sodium Saccharinate 0/18 "16.47

Water

Hydrated alumina (polishing agent) 50.00 0/2 °

Ethanol

Sodium lauryl sulfate 1.875

Sodium dodecylbenzenesulfonate 0.625. . 0.30

Triclosan A 1.20

Aroma

Since Toothpastes C and C contain a total of 2.50% surfactant, there is more surfactant available to dissolve Triclosan than in Toothpastes B and B which contain 2, 00%. However, the propylene glycol present in Toothpastes B and B 'containing a siliceous polishing agent (but not in toothpastes C and C containing hydrated alumina as polishing agent) ensures optimal dissolution of Triclosan. The advantage of Toothpastes B and B '(containing propylene glycol and Gantrez) over Toothpastes C and C' with regard to the fixation of Triclosan on the saliva-coated hydroxyapatite discs and on the exfoliated oral epithelial cells appears on the Table 2 below: TABLE 2

Distribution of Triclosan_ to the disc to cells έριά 1 oral thelial hydroxyapatite g coated with saliva in micrograms x 10 (micrograms) epithelial cells

Toothpaste B 41/1 101/6 B '77.4 142.0 C 20.4 61/0 C' 42.6 100.0 Other experiments with Toothpaste B '(0.3% Triclosan; Gantrez; propylene glycol) in a 50% suspension of toothpaste to determine the retention of Triclosan on the saliva-coated hydroxyapatite disc for a certain period of time reveal excellent retention rates of Triclosan as shown in Table 3 below. below: TABLE 3 Retention of Adsorption of Triclosan from the Toothpaste Suspension

Triclosan Retention Time (in minutes) (micrograms / disc) 0 70 30 60 60 70 120 65 180 57 240 59

These results show that the toothpastes containing Triclosan, Gantrez and propylene glycol can ensure better distribution and retention of Triclosan on dental surfaces and soft tissue surfaces of the oral cavity, thereby ensuring better antiplaque and antibacterial effects. EXAMPLE 5 By way of comparison / the formulas a and b are prepared below:

Toothpaste a b%

Glycerol 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 ° '50 0.50

Gantrez S-97 2/00 2/00

Water 29,157 29,157

NaOH (50%) 2.00 2.00

Polishing agent (silica) (Zeodent 113) 20'00 20.00

Thickener (silica) (Sylodent 15) 5/50 5/50. ~ 1.10 1/10

Aroma. , 0.50 0.50

Triclosan '

Sodium lauryl sulfate 2.00 2.00

Ethanol 1.00 1/00

Formula a is a toothpaste containing a Gantrez polycarboxylate with 0.5% Triclosan as an anti-bacterial anti-plaque agent and containing no solubilizing agent. Formula b contains propylene glycol as a solubilizing agent.

Formula a has poor distribution of Triclosan on the oral epithelial cells, while Formula b is clearly effective.

The above results show the excellent distribution of toothpaste with Triclosan. EXAMPLE 6

A "home" study is conducted on a group of volunteers to evaluate the effects of particular toothpastes on new growth of dental plaque according to the method described by Addy / Wilis and Moran, J. Clin. Perio. 1983, Vol. 10, pages 89-99. The toothpastes tested include a placebo control not containing Triclosan (i) and a toothpaste according to the present invention containing 0.3% of Triclosan, 10% of propylene glycol (instead of 3% of polyethylene glycol 600) , 2% Gantrez S-97 and a humectant consisting of propylene glycol and sorbitol (ii). The formulas of the toothpastes are as follows: _Parties__ (i) _ (ü)% _

Placebo Invention

Polyethylene glycol 600 3.00

Glycerol 25.00

Propylene glycol - 10.00

Sorbitol (70%) 41.617 25.00

Carboxymethylcellulose sodium 0.35 -

Iota-carrageenan - 0.60

Sodium benzoate 0.50

Sodium saccharin 0.20 0.40

Sodium fluoride 0.243 0.243

Polishing agent (silica) (Zeodent 113) 18.00 20.00

Thickener (silica) (Sylox 15) 5.50 5.50 left 3.00 28.757

Gantrez S-97 - 2.00

Triclosan - 0.30

Titanium dioxide 0.50 0.50

Sodium lauryl sulfate 1.20 2.50

Aroma 0.89 1.10

Ethyl alcohol 1.00

Sodium hydroxide (50%) 2.00

With regard to the reduction of dental plaque, on the teeth of volunteers, compared to placebo (i), the invention (ü) produces a significant reduction of 20%.

Since lower amounts of propylene glycol can dissolve the amount of 0.3% Triclosan present in toothpaste (ii), similar results are expected if the amount of propylene glycol is reduced to 0.5 parts and the amount of sorbitol is increased to 39.5 parts. Similarly, the other solubilizing agents, namely dipropylene glycol, hexylene glycol, methylcel-losolve, ethylcellosolve, olive oil, castor oil, petrolatum, acetate amyl, ethyl acetate, glyceryl tristearate and benzyl benzoate, in place of propylene glycol, can effectively distribute Triclosan to the soft tissues of the oral cavity. In addition, similar results are expected if propylene glycol and other solubilizers are omitted from toothpaste (n) containing 0.3% Triclosan. EXAMPLE 7

The following toothpastes of the invention are prepared: _Parties_ A J3

Glycerol - 20/00

Propylene glycol 10/00 0/50

Sorbitol (70%) 25.00 19.50

Carboxymethylcellulose sodium - 1.10

Iota-carrageenan 0.600 -

Sodium saccharin 0.40 0.30

Sodium fluoride 0.243 0.243

Polishing agent (silica) (Zeodent 113) 20.00 20.00

Thickening agent (silica) (Sylox 15) 5.50 3.00

Water 28,757 15,307

Gantrez S-97 2.00 2.00 'Triclosan 0.50 0.30

Titanium dioxide 0.50 0.50

Sodium lauryl sulfate 2.50 2.00

Aroma 1.10 0.95

Ethanol 1.00

Sodium hydroxide (50%) 2.00 1.6

In the previous examples, the best results can also be obtained by replacing Triclosan with other antibacterial agents described here such as phenol, thymol, eugenol and 2,2-methylene-bis (4-chloro-6 -bromophenol) and / or by replacing Gantrez with other ASAs such as a 1: 1 copolymer of maleic anhydride and ethyl acrylate, sulfoacrylic oligomers, Carbopol products (for example 934), polymers of alpha- or beta-styrene-phosphonic acid monomer and copolymers of these styrene-phosphonic acid monomers with each other or with other polymerizable ethylenically unsaturated monomers such as vinylphosphonic acid. EXAMPLE 8

The following toothpaste is prepared:

Parts

ABC

Alpha-alumina trihydrate 48/00 48.00 48.00

Propylene glycol "0.50 0.50

Sorbitol (70%) 21.10 21.70 21.70

Gantrez S-97 (13% solution) 15.00 15.00

Gantrez S-97 (powder) "" 2.00

Sodium lauryl sulfate 2.00 2.13 2.13

Sodium saccharin 0.30 0.30 0.30

Sodium hydroxide (50%) 1.20 1.20 1.20

Aroma 0.95 0.95 0.95

Irish Moss 1.00

Carboxymethylcellulose sodium - 1/00 1.00

Sodium monofluorophosphate 0.76 0.76 0.76

Titanium dioxide "0.50 0.50

Triclosan 0.30 0.30 0.30

Water, q.s. for 100.00 100.00 100.00

The above toothpaste distributes Triclosan to the teeth and soft tissue of the gums significantly more effectively than the corresponding toothpaste which does not contain the Gantrez polycarboxylate. EXAMPLE 9

The following toothpastes are prepared:

Parts

Glycerol 22-00 10 '00

Sorbitol (70%) - 17.00

Carboxymethylcellulose sodium 1.00 1.00

Gantrez S-97 2'00 2 '00

Sodium saccharin 0/20 0.20

Sodium benzoate 0.50 0.50

Sodium monofluorophosphate 0.76 0.76 dicalcium phosphate dihydrate 48.76 48.76, 0.30 0.30

Triclosan '

Sodium lauryl sulfate 1/20 1.20

Aroma 0.89 0.89

Water, q.s. for 100.00 100.00

The above toothpaste distributes Triclosan to the saliva-coated hydroxyapatite disc more effectively than the corresponding toothpaste not containing the Gantrez polycarboxylate. EXAMPLE 10

The following anti-plaque toothpaste is prepared:

Parts

Glycerol 15.00

Propylene glycol 2.00

Carboxymethylcellulose sodium 1.50

Water 24.93

Methyl vinyl ether / maleic anhydride copolymer (42% solution) 4.76

Sodium monofluorophosphate 0.76

Sodium saccharin 0.30 Insoluble sodium metaphosphate 47.00

Titanium dioxide 0.50

Sodium lauryl sulfate 2.00

Triclosan 0.30

Aroma 0.95

In the previous examples, the best results can also be obtained by replacing Triclosan with phenol, 2,2'-methylene-bis (4-chloro-6-bromophenol), eugenol or thymol and / or replacing Gantrez with other ASAs such as Carbopol products (for example 934) or styrene-phosphonic acid polymers having molecular weights in the range of approximately 3000 to 10,000, for example a poly (beta acid -styrene-phosphonic), copolymers of vinyl phosphonic acid and beta-styrene-phosphonic acid, and a poly (alpha-styrene-phosphonic acid), or sulfoacrylic oligomers, or a 1: 1 copolymer of maleic anhydride and ethyl acrylate. EXAMPLE 11

Movable Phases of Toothpaste Containing Triclosan Components Composition,% by weight

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

Sodium fluoride 0.32 0.32

Flavoring essence 1.47 1.47

Sodium lauryl sulfate 3.33 3.33

Triclosan 0.67 0.67

The concentration of the above components is a rate of toothpaste of 1.33% to reflect a rate of 25% of abrasive which may be necessary to constitute a complete toothpaste.

The above mobile phases of the indicated toothpaste formulations are tested to determine the fixation of Triclosan on saliva coated HA disks. The results are presented in the table below.

BOARD

Fixation of Triclosan by hydroxyapatite (HA) discs coated with saliva from mobile phases of diluted and undiluted toothpaste.

__A _B

Triclosan,% 0.67 0.67

Ionic strength (m / l) (calculated) 0.375 - pH 8'7 7 '6

Fixation of undiluted Triclosan (pg / disc) 55 133

The above results show an increase of a factor greater than 2 in the fixation of Triclosan obtained with formulation B containing Gantrez compared to formulation A without Gantrez. EXAMPLE 12

Concentration and Fixation of Triclosan by HA from the Supernatant of 1: 1 Toothpaste / Water Suspensions.

Toothpaste containing Triclosan (pg / ml) Fixation 0.5% of Triclosan, in the supernatant of Triclosan 2.5% of lauryl- of the suspension pg / sodium sulfate disk _ at 1: 1 _ _. 25% hydrated silica +1.5% Gantrez S-97 1650 52 50% alumina + 1.5% Gantrez S-97 1905 74

The supernatants of the 1: 1 toothpaste / water suspensions of the above toothpaste are tested for the concentration of Triclosan in the supernatant and the fixation of Triclosan on HA discs coated with saliva. The results show that the use of 50% of abrasive alumina appreciably increases the Triclosan under conditions of low dilution of 1: 1 (from 1650 to 1905), which results in a significant increase in the fixation of Triclosan (from 52 to 74). EXAMPLE 13

The mouthwashes below effectively reduce dental plaque by increasing the fixation and retention of Triclosan on the surfaces of the oral cavity.

A B £ D E

Parties Parties Parties Parties Parties

Gantrez S-97 0.24 0.25 0.25 0.25 0.25

Glycerol 15.00 10.00 15.00 10.00 15.00

Ethanol - "12.50 12.50

Propylene glycol - 5.00 - 5.00

Pluronic F108 (polyoxyethylene / polyoxopropylene block copolymer) 2.00

Laurylsulfate. sodium - "0/20 0.20 0.20

Triclosan 0.10 0.10 0.06 0.06 0.03 flavoring 0.40 0.40 0.40 0.40 0.40

Water, q.s. for 100.00 100.00 100.00 100.00 100.00 EXAMPLE 14

The following liquid toothpastes are also effective in reducing plaque by increasing the fixation and retention of Triclosan on the oral surfaces. abc Parties Parties Parties

Glycerol 20 '° 20.0

Gantrez S-97 ° '3 °' 3 0/3

High molecular weight polysaccharide, the molecule containing fragments of mannose, glucose, potassium glucuronate and acetyl in a molar ratio

approximate 2: 1: 1: 1 0.8 - -L / C

Sodium benzoate 0.5 0.5 0.5

Sodium saccharinate 0.5 0.5 0.5

Water 61'3 73/1 71/6

Sodium lauryl sulfate 3.0 3.0 3.0 insoluble sodium phosphate 10.0 - 10.0

Anhydrous dicalcium phosphate 1/0 - 2,5 Flavoring essence 2,5 2,5 2,5 Ethyl alcohol - "10,0 Triclosan 0Ί ^ / 1

In the previous examples, the improved results can be obtained by replacing Triclosan with one or the other of phenol, 2,2'-methylene-bis (4-chloro-6-bromophenol), eugenol or thymol and / or by replacing Gantrez with other ASAs such as products of the Carbopol series (for example 934) or polymers of styrene-phosphonic acid whose molecular weights are in the range of approximately 3000 to 10,000 such as a poly (beta-styrene-phosphonic acid), copolymers of vinylphosphonic acid and beta-styrene-phosphonic acid, and a poly (alpha-styrene-phosphonic acid), or oligomers sulfo-acrylics or a 1: 1 copolymer of maleic anhydride and ethyl acrylate.

It goes without saying that the invention is not limited to the embodiments described and that various variants and modifications can be made thereto without departing from its scope.

Claims (3)

1. Composition for buccal use according to any one of claims X to 5, characterized in that the antibacterial agent is chosen from the group formed by halogenated diphenyl ethers, isalogenated salicylanilides, benzoic esters, halo carbanalides -jénés and phenolic compounds. 7. Composition for oral use according to claim 5, characterized in that the antibacterial agent is a halogenated diphenyl sther. 3. Composition for buccal use according to claim 7, characterized in that the halogenated diphenyl ether 2st 2,4,4'-trichloro-2'-hydroxyphenyl ether. 1. Composition for buccal use, characterized in that it comprises an effective dental antiplaque proportion of an antibacterial agent, non-cationic, substantially insoluble in water, approximately 0.05 to 4% by weight of a polyvinylphosphonate comprising recurring radicals

and having an average molecular weight of about 1000 to about 1 million and an orally acceptable vehicle, effective in allowing the above-mentioned antibacterial agent to dissolve in saliva in an effective dental antiplaque proportion, wherein said oral composition has a pH from around 4.5 to around 10. 2. Composition for oral use according to claim 1, characterized in that it is a toothpaste comprising from approximately 5 to 30% by weight of a siliceous polishing agent and in that the above-mentioned antibacterial agent is present in a proportion of about 0.25 to 0.35% by weight. 3. Composition for oral use according to claim 1, characterized in that it is a toothpaste comprising from approximately 5 to 30% by weight of a siliceous polishing agent and the abovementioned antibacterial agent is present in a proportion of about 0.01 to 5% by weight and this composition comprises a solubilizing material in a proportion such that it facilitates the dissolution of the above-mentioned antibacterial agent in saliva. 4. Composition for oral use according to any one of claims 1 to 3, characterized in that it is m toothpaste comprising from about 30 to 75% by weight, one polishing agent insoluble in water and acceptable in the dental field. j. Composition for oral use according to any one of Claims 1 to 3, characterized in that it is a mouthwash or a liquid toothpaste and in that the orally-acceptable vehicle is an aqueous vehicle in which an atoxic alcohol is present. 3. Composition for oral use according to any one of claims 1 to 8, characterized in that the phosphonate is present in an amount of about 0.5 to 2.5% by weight. LO. Method for inhibiting dental plaque, characterized in that the composition for oral use according to any one of claims 1 to 9 is applied to the surfaces of the teeth and gums.