NO179503B - Oral preparation - Google Patents

Description

The invention relates to an oral preparation. More specifically, it relates to an oral preparation containing a substantially water-insoluble, non-cationic, antibacterial agent which effectively inhibits plaque formation. ^

Dental plaque is a soft deposit that forms on teeth as opposed to tartar, which is a hard, calcified deposit on teeth. Unlike tartar, plaque can form on any part of the tooth surface, particularly including the gum line. In addition to being ugly, it is thus also implicated in the occurrence of gingivitis.

Accordingly, it is highly desirable to include antimicrobial agents known to reduce plaque in oral preparations. Cationic antibacterial agents have often been proposed. According to US Patent No. 4,022,880, a compound which provides zinc ions as an antitartar agent is also mixed with an antibacterial agent which is effective in retarding the growth of plaque bacteria. Many different antibacterial agents have been described with the zinc compounds, including such cationic substances as guanides and quaternary ammonium compounds, as well as non-cationic compounds, such as halogenated salicylanilides and halogenated hydroxydiphenyl ethers. The non-cationic, antibacterial, anti-plaque halogenated hydroxydiphenyl ether, triclosan, has also been described in combination with zinc citrate trihydrate in European Patent Publication No. 0161899. Triclosan is also described in European Patent Publication No. 0271332 as a toothpaste ingredient containing a solubilizing agent, such as propylene glycol.

The cationic, antibacterial substances, such as chlorhexidine, benzthonium chloride and cetylpyridinium chloride, have been the subject of the most extensive investigations as anti-bacterial, anti-plaque agents. However, they are not effective when used with anionic substances. Non-cationic antibacterial substances, on the other hand, may be compatible with anionic ingredients in an oral preparation.

However, oral preparations are usually mixtures of a large number of ingredients and even such typically neutral substances as wetting agents can affect the effectiveness of such preparations.

Moreover, even non-cationic antibacterial agents may have limited anti-plaque effectiveness with commonly used substances, such as the polyphosphate-containing anti-calculus agents described with these in British Patent Publication No. 2200551 and in EP 0251591. In US Patent Application No. 398,605, filed August 25, 1989, it has been shown that the anti-plaque effectiveness is greatly increased by including an antibacterial enhancing agent (AEA) which increases the delivery of the antibacterial agent to, and retention thereof on, oral surfaces and provides optimized amounts of, and ratio between, polyphosphate and AEA.

It is an advantage of this invention that an oral preparation is provided where a substantially water-insoluble, non-cationic, antibacterial agent and an AEA are provided to inhibit plaque formation, where the oral preparation contains an orally acceptable, liquid carrier which can have the antibacterial agent to dissolve in saliva in an effective anti-plaque amount.

It is a further advantage of the invention that AEA increases the delivery and retention of a small but effective anti-plaque amount of the antibacterial agent on teeth and on soft oral tissues.

It is a further advantage of the invention that an anti-plaque, oral preparation is provided which acts to reduce the occurrence of gingivitis.

Further advantages of this invention will become apparent upon review of the following description.

This invention relates to an oral preparation which is characterized in that it comprises: a) 0.01-5% by weight of an essentially water-insoluble, non-cationic, antibacterial agent selected from the group consisting of halogenated diphenyl ethers, halogenated salicylanilides, benzoic acid esters , halogenated carbanilides and phenolic compounds, b) 0.005-4% by weight of an antibacterial agent containing at least one release-enhancing, functional group and at least one organic retention-enhancing group for delivery and retention of the antibacterial agent on oral tooth and gum surfaces, and c) a orally acceptable carrier which causes the anti-bacterial agent to dissolve in saliva in an effective anti-plaque amount,

where the oral preparation is essentially free of polyphosphate in an antitartar quantity.

Typical examples of essentially water-insoluble, non-cationic, antibacterial agents which are particularly desirable from considerations regarding anti-plaque effectiveness, safety and composition are: Halogenated diphenyl ethers

2',4,4'-Trichloro-2-hydroxy-diphenyl ether (triclosan) 2,2'-dihydroxy-5,5'-dibromo-diphenyl ether.

Haloenated 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'-trifluoromethylsalicylanilide 5-n-octanoyl-3'-trifluoromethylsalicylanilide 3, 5-dibromo-4'-trifluoromethylsalicylanilide 3,5-dibromo-3'-trifluoromethylsalicylanilide (Flurophene).

Benzoic esters

Halogenated carbanilides

3,4,4'-trichlorocarbanilide

3-Trifluoromethyl-4,4'-dichlorocarbanilide 3,3,4'-trichlorocarbanilide.

Phenolic compounds

(including phenol and its homologues, mono- and poly-alkyl- and aromatic halogen- (e.g. F-, Cl-, Br-, I-)-

phenols, resorcinol and catechol and their derivatives and bisphenol compounds).

Phenol and its homologues

Mono- and poly-alkyl and aralkyl halophenols

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

Bisphenol compounds

bisphenol A

2,2'-methylene-bis(4-chlorophenol)

2,2'-methylene-bis(3,4,6-trichlorophenol) (hexachlorphene) 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 oral preparation in an effective anti-plaque amount, namely 0.01-5% by weight, preferably 0.03-1%, preferably 0.25-0.5% or 0.25 % to less than 0.5%, and most preferably 0.25-0.35%, e.g. about. 0.3%, in a dentifrice, or preferably 0.03-0.3% by weight, preferably 0.03-0.1%, in a mouthwash or a liquid dentifrice. The antibacterial agent is essentially water insoluble, meaning that its solubility is less than 1% by weight in water at 25°C and may be even less than 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 most preferred antibacterial, anti-plaque compound is triclosan. Triclosan is described in the previously mentioned US patent document no. 4,022,880 as an antibacterial agent in combination with an anti-plaque agent that provides zinc ions, and in BRD patent publication no. 3,532,860 in combination with a copper compound. In European patent publication no. 0278744 it is described in combination with a tooth desensitizing agent containing a source of potassium ions. It is also described as an anti-plaque agent in a dentifrice which is formulated to contain a layered liquid crystal surfactant phase with a space between the layers of less than 6.0 nm, and which may optionally contain zinc salt, in the published European patent application No. 0161898, and in a dentifrice containing zinc citrate trihydrate in published European Patent Application No. 0161899.

The antibacterial enhancing agent (AEA) which increases delivery of the antibacterial agent to, and retention thereof on, oral surfaces is used in amounts which can achieve such increase within the range of the oral preparation of 0.005% to 4%, preferably 0.1% to 3%, preferably 0.5% to 2.5%, based on weight.

AEA can be a single compound, preferably one

polymer in separable monomer, more preferably a polymer with an entirely generic designation, including e.g. oligomers, homopolymers, copolymers of two or more monomers, ionomers, block copolymers, graft copolymers, cross-linked polymers and copolymers, etc. AEA can be natural or synthetic, and water insoluble or preferably water soluble (saliva soluble)

or swellable (hydratable, hydrogel-forming). It has one

(weight)-average molecular weight of 100 to 1,000,000, preferably 1,000 to 1,000,000, most preferably 2,000 or 2,500 to 250,000 or 500,000.

AEA usually contains at least one release-enhancing group which is preferably acidic, such as sulfone, phosphone or preferably phosphone or carboxyl, or salt thereof, e.g. alkali metal or ammonium, and at least one organic retention-increasing group, preferably several of both the release-increasing and retention-increasing groups, the latter groups preferably having the formula -(X)n-R, where X is 0, N, S, SO, SO2, P, PO or Si or the like, R is hydrophobic alkyl, alkenyl, acyl, aryl, alkaryl or aralkyl, or hydrophobic heterocyclic group, or their inert substituted derivatives, and n is 0 or 1 or more. The above-mentioned "inertly substituted derivatives" are intended to include substituents on R which are generally non-hydrophilic and do not significantly affect the desired functions of AEA such as increasing the delivery of the antibacterial agent to, and retention thereof on, all surfaces, such as halogen, e.g. Cl, Br or I, and carbo etc. Illustrations of such retention-increasing groups are listed in

the table below.

As used herein, the delivery-enhancing group refers to one that attaches or firmly, adhesively, cohesively, or otherwise binds the AEA (carrying the antibacterial agent) to oral (eg, tooth and gum) surfaces, and thereby "delivering" the antibacterial agent to these surfaces. The organic retention-enhancing group, usually hydrophobic, attaches or otherwise binds the antibacterial agent to the AEA and thereby promotes retention of the antibacterial agent to the AEA and indirectly on the oral surfaces. In some cases, attachment of the antibacterial agent occurs through physical entrapment thereof by means of AEA, especially when AEA is a cross-linked polymer whose structure, according to the nature of the matter, provides an increased number of sites for such entrapment. The presence of a more hydrophobic, high molecular weight cross-linking residue in the cross-linked polymer further increases the physical entrapment of the antibacterial agent to or by the cross-linked AEA polymer.

Preferably, the AEA is an anionic polymer comprising a chain or backbone containing repeating units each preferably containing at least one carbon atom and preferably at least one direct or indirect protruding, monovalent, delivery-enhancing group, and at least one direct or indirect pendant, monovalent, retention-enhancing group geminally, vicinally or, less preferably, otherwise bonded to atoms, preferably carbon, in the chain. Less preferably, the polymer may contain release-increasing groups and/or retention-increasing groups and/or other divalent atoms or groups as links in the polymer chain instead of or in addition to carbon atoms, or as cross-linking residues.

It will be understood that all examples or illustrations of AEAs described herein, which do not contain both release-enhancing groups and retention-enhancing groups, can and preferably should be chemically modified in known manner to obtain the preferred AEAs that contain both such groups and preferably several of each such group. In the case of the preferred polymeric AEAs, it is desirable, in order to maximize substantivity and delivery of the antibacterial agent to oral surfaces, that the repeating units in the poly tag or backbone containing the acidic delivery enhancing groups comprise at least 10 %, preferably at least 50%, more preferably at least 80% and up to 95% or 100%, based on the weight of the polymer.

According to a preferred embodiment of the invention, AEA comprises a polymer containing repeating units where one or more phosphonic acid delivery-increasing groups are bound to one or more carbon atoms in the polymer chain. An example of such an AEA is poly(vinylphosphonic acid)-containing units of the formula: which, however, do not contain a retention-enhancing group. A group of the latter type will, however, be present in poly(1-phosphonopropene) with units of the formula:

A preferred phosphonic acid-containing AEA for use herein is poly(beta-styrenephosphonic acid) containing units of the formula: where Ph is phenyl, the phosphonic acid delivery-enhancing group and the phenyl retention-enhancing group are attached to vicinal carbon atoms in the chain, or a copolymer of beta-styrenephosphonic acid and vinylphosphonyl chloride with the units of formula III alternating or in the event of bonding with units of formula I above, or poly(alpha-styrenephosphonic acid) containing units of the formula:

where the delivery and retention-increasing groups are geminally bound 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 2,000 to 30,000, preferably 2,500 to 10,000. Such "inert" monomers do not significantly interfere with the intended function of any copolymer used as an AEA herein.

Other phosphonic polymers include e.g. phosphonated ethylene with units of the formula:

where n e.g. can be a whole number or have a value that gives the polymer a molecular weight of approx. 3000, and sodium poly(butene-4,4-diphosphonate) with units of the formula: poly(allyl-bis(phosphoethylamine) with units of the formula:

Other phosphonated polymers, e.g. poly(allylphosphono-acetate), phosphonated polymethacrylate etc, and the geminal di-phosphonate polymers described in EP patent publication no. 0321233, can be used here as AEAs, naturally provided that they contain or are modified to contain the above-defined organic retention enhancers groups.

In one aspect of the invention, the oral preparation comprises an orally acceptable carrier, an effective anti-plaque amount of a substantially water-insoluble, non-cationic, antibacterial agent and an antibacterial enhancing agent having an average molecular weight of 1,000 to 1,000,000, containing at least one delivery-increasing functional group and at least one organic retention-increasing group, the agent containing the groups being free of, or substantially free of, water-soluble alkali metal or ammonium salt of synthetic, anionic, straight-chain, polymeric carboxylic acid with a molecular weight of 1,000 to 1,000,000.

According to another preferred embodiment, the AEA may comprise a synthetic, anionic, polymeric polycarboxylate. Although not used in the present invention to act together with polyphosphate as an anticalculus agent, synthetic, anionic, polymeric polycarboxylate with a molecular weight of 1,000 to 1,000,000, preferably 30,000 to 500,000, has been used as an inhibitor of alkaline phosphatase enzyme to optimize -ser antitartar effectiveness of linear, molecularly dehydrated polyphosphate salts, as described in US Patent No. 4,627,977. Indeed, in the published British Patent Publication No. 2200551, the polymeric polycarboxylate is described as a possible ingredient in oral preparations containing linear, molecularly dehydrated polyphosphate salts and substantially water-insoluble, non-cationic, antibacterial agent. It has further been observed in the context of the present invention that such polycarboxylate is very effective when it comes to increasing the delivery and retention of the non-ionic, antibacterial, anti-plaque agent to tooth surfaces when another component with which the polymeric polycarboxylate interacts (i.e. molecularly dehydrated polyphosphate) is absent; e.g. when the component with which the polymeric polycarboxylate interacts in particular is the non-cationic antibacterial agent.

Synthetic, anionic, polymeric polycarboxylates and their complexes with various cationic germicides, zinc and magnesium have previously been described as antitartar agents per se in e.g. US Patent Nos. 3,429,963, 4,152,420, 3,956,480, 4,138,477 and 4,183,914. It is to be understood that the synthetic, anionic, polymeric polycarboxylates described in these various patents when they contain or are modified to contain retention increasing groups, are operative in the preparations and methods according to this invention.

The synthetic, anionic, polymeric polycarboxylates used here are well known as they are often used in the form of their free acids or preferably partially or preferably completely neutralized, water-soluble alkali metal (e.g. potassium and preferably sodium) or ammonium salts. Preferred are 1:4-4:1 copolymers of maleic anhydride or maleic acid and another polymerizable, ethylenically unsaturated monomer, preferably methyl vinyl ether/maleic anhydride with a molecular weight (m.v.) of 30,000 to 1,000,000, preferably 30,000 to 500,000. These copolymers are available e.g. such as "Gantrez", e.g. AN 139 (m.v. 500,000), AN 119 (m.v. 250,000) and preferably S-97, pharmaceutical fineness grade (m.v. 70,000).

Other AEA-operable polymeric polycarboxylates containing, or modified to contain, retention-enhancing groups include those described in US Patent No. 3,956,480 referenced above, such as the 1:1 copolymers of maleic anhydride and ethyl acrylate, hydroxyethyl methacrylate, N-vinyl-2-pyrrolidone or ethylene, the latter being available e.g. as "EMA no. 1103", etc. 10,000 and "EMA Grade 61", and the 1:1 copolymers of acrylic acid and methyl or hydroxyethyl methacrylate, methyl or ethyl acrylate, isobutyl, isobutyl vinyl ether or N-vinyl-2-pyrrolidone.

Other operative polymeric polycarboxylates described in the above cited US Patent Nos. 4,138,477 and 4,183,914 which contain, or are modified to contain, retention enhancing groups include copolymers of maleic anhydride and styrene, isobutylene or ethyl vinyl ether, polyacrylic acid, polyitaconic acid and polymaleic acid, and sulfoacrylate oligomers with m.v. as low as 1000, available as "ND-2".

Generally suitable are polymerized, olefinically or ethylenically unsaturated carboxylic acids which contain retention-enhancing groups, and which contain an activated carbon-to-carbonolefinic double bond which readily acts upon polymerization due to its presence in the monomer molecule either in the alpha-beta position of relationship to a carboxyl group, or as part of a terminal methylene group. Illustrative of such acids are acrylic, methacrylic, ethacrylic, alpha-chloroacrylic, crotonic, beta-acryloxypropionic, sorbic, alpha-chlorosorbic, cinnamic, beta-styrylacrylic, muconic, itacone, citracone, mesacone, glutacone, aconitin, alpha-phenylacrylic, 2-benzylacrylic, 2-cyclohexylacrylic, angelica, umbellic, fumaric and maleic acids, and anhydrides. Other various olefinic monomers copolymerizable with such carboxylic acid monomers include vinyl acetate, vinyl chloride, dimethyl maleate, and the like. Copolymers contain sufficient carboxylic acid salt groups for water solubility.

Also applicable here are so-called carboxyvinyl polymers described as toothpaste ingredients in US Patent Nos. 3,980,767, 3,935,306, 3,919,409, 3,911,904 and 3,711,604. They are commercially available e.g. under the trademarks "Carbopol 934", "Carbopol 940" and "Carbopol 941". These products mainly consist of a colloidal/t water-soluble polymer of polyacrylic acid cross-linked with from 0.75 to 2.0% polyallyl sucrose or polyallylpentaerythritol as cross-linking agent, the cross-linked structure and the cross-links providing the desired retention increase by means of hydrophobicity and/or physical capture of the antibacterial agent etc. "Polycarboph.il" is somewhat similar in that it is polyacrylic acid cross-linked with less than 0.2% divinyl glycol, where the lower proportion, molecular weight and/or hydrophobicity of this cross-linked agent tends to give little or no retention increase. 2,5-dimethyl-1,5-hexadiene exemplifies a more effective retention-enhancing cross-linking agent.

The synthetic anionic polymeric polycarboxylate component is essentially a hydrocarbon with any halogen or O-containing substituents and bonds present e.g. in ester, ether and OH groups, and are used in the present preparations in approximate amounts by weight of 0.05 to 4%, preferably 0.05 to 3%, and most preferably 0.1-2%.

AEA may also include natural anionic polymeric carboxylates containing retention-enhancing groups. Carboxymethyl cellulose and other binder gums and film formers that lack the above-defined release-enhancing and/or retention-enhancing groups are ineffective as AEAs.

Illustrative of AEAs containing phosphinic acid and/or sulfonic acid as delivery-enhancing groups, mention may be made of polymers and copolymers containing units or residues derived from the polymerization of vinyl or allylphosphinic and/or sulfonic acids substituted as needed on 1- or The 2- (or 3-) carbon atom with an organic retention-increasing group, e.g. with the formula -(X)n-R defined above. Mixtures of these monomers may be used, and copolymers thereof with one or more inert, polymerizable, ethylenically unsaturated monomers, such as those described above in connection with the operative synthetic, anionic, polymeric polycarboxylates. As will be noted, in these and other polymeric AEAs operative herein, typically only one acidic delivery-enhancing group is attached to any particular carbon or other atom of the polymer backbone or branch thereof. Polysiloxanes which contain, or are modified to contain, enhancing, delivery-enhancing groups and retention-enhancing groups can also be used as AEAs. Also effective as AEAs are ionomers that contain, or are modified to contain, delivery and retention enhancing groups. Ionomers are described on pages 546-573 of the Kirk Othmer Encyclopedia of Chemical Technology, 3rd Edition, Supplemental Volume, John Wiley & Sons, Inc. copyright 1984. Also effective as AEAs, provided they contain, or are modified to to contain, retention-enhancing groups, are polyesters, polyurethanes and synthetic and natural polyamides, including proteins and proteinaceous materials, such as collagen, poly(arginine) and other polymerized amino acids.

In one aspect of the present invention, the AEA, which has an average molecular weight of 1,000 to 1,000,000, contains at least one release-enhancing functional group and at least one organic, retention-enhancing group, the agent containing the groups being free of, or substantially free of, water-soluble alkali metal or ammonium salt of a synthetic, anionic, straight-chain, polymeric carboxylic acid having a molecular weight of 1,000 to 1,000,000.

In the present invention, a preferred oral preparation is a dental care agent containing approx. 0.3% by weight of the antibacterial agent (eg triclosan) and 1.5-2% by weight of the polycarboxylate as AEA.

Without being bound by theory, it is believed that AEA, particularly polymeric AEA, is generally an anionic, film-forming material, which is believed to adhere to tooth surfaces and form a cohesive film over the surfaces thereby preventing bacterial attachment to tooth surfaces. It is possible that the non-cationic antibacterial agent forms a complex or other form of connection with AEA, thereby forming a film of a complex or the like. over tooth surfaces. The film-forming property of AEA and the increased delivery and retention of the antibacterial agent on tooth surfaces due to AEA appear to make tooth surfaces unfavorable for bacterial accumulation, particularly as the direct bacteriostatic effect of the antibacterial agent regulates bacterial growth. Through the combination of three modes of action: 1) increased delivery, 2) long retention time on tooth surfaces and 3) prevention of bacterial attachment to tooth surfaces, the oral preparation is therefore effective in reducing plaque. Similar anti-plaque effectiveness is achieved on soft, oral tissue at or near the palate line.

In accordance with the present invention, the orally acceptable carrier can cause the substantially water-insoluble, non-cationic, antibacterial agent to dissolve in saliva in an effective anti-plaque amount.

In the oral preparation, an orally acceptable carrier comprises an aqueous phase with a wetting agent present. In a gel dentifrice which generally contains 5-30% by weight of a silicon-containing polish, water is usually present in an amount of at least 3% by weight, generally 3-35%, and humectant, preferably glycerol and/or sorbitol, usually a total of 6, 5-75% or 80% by weight of the oral gel dentifrice preparation. Reference to sorbitol here refers to the material which is usually available commercially in 70% aqueous solutions.

The gel dentifrices, when the amount of antibacterial agent is 0.25-0.35% by weight, do not require an additional ingredient in the oral carrier to solubilize the antibacterial agent, although the presence of such solubilizing agent is an eventuality. When the amount of antibacterial agent is below 0.25% by weight, e.g. 0.01 up to

0.25% by weight, solubilizing agent should therefore be present to ensure sufficient solubilization in saliva for anti-plaque effectiveness. When the amount of antibacterial agent is over 0.35% by weight, e.g. 0.35 to 0.5% or more, such as 5%, solubilizing agent should therefore be present as a substantial portion of the antibacterial agent would otherwise remain insoluble.

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

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

When the solubilizing agent is present in oral preparations according to the present invention, it is usually in an amount of 0.5-20% by weight, with as little as 0.5% by weight being sufficient when the amount of substantially water-insoluble, non-cationic, antibacterial agent is low, such as up to 0.3% by weight. When larger amounts, such as at least 0.5% by weight, of antibacterial agent are present, and especially when silicon-containing polishing agent is also present in an amount of 5-30% by weight, it is desirable that at least 5% by weight, usually up to 20 wt% or more of the solubilizer is present. It is noted that there may be a tendency for the dentifrice to separate into liquid and solid portions when more than 5% by weight of the solubilizing agent is present.

The agent which is, or may be, present for dissolving the antibacterial agent in saliva may be incorporated into the water humectant carrier. Such solubilizing agents include wetting polyols, such as propylene glycol, dipropylene glycol and hexylene glycol, cellosolves, such as methyl cellosolv and ethyl cellosolv, vegetable oils and waxes containing at least 12 carbon atoms in a straight chain, such as olive oil, castor oil and petrolatum, and esters, such as such as amyl acetate, ethyl acetate and benzyl benzoate. As used herein, "propylene glycol" includes 1,2-propylene glycol and 1,3-propylene glycol. Substantial amounts of polyethylene glycol, especially with 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 with triclosan at a weight ratio of 25 triclosan:1 PEG 600, reduces the antibacterial activity of triclosan by a factor of about 16 from what applies in the absence of the polyethylene glycol.

In accordance with aspects of this invention, the oral preparation dentifrice may be predominantly gel in nature, such as a gel dentifrice. Such oral gel preparations contain silicon-containing tooth polishing material. Preferred polishing materials include crystalline silica with a particle size of up to 5 µm, an average particle size of up to 1.1 µm, and a surface area of up to 50,000 cm<2>/g, silica gel or colloidal silica, and complex, amorphous alkali metal aluminum silicate.

When visually clear or opaque gels are used, a polishing agent is colloidal silica, such as those sold under the trademark "Syloid" as "Syloid 72" and "Syloid 74", or under the trademark "Santocel" as "Santocel 100", or alkali metal -aluminosilicate complexes (i.e. silica containing alumina combined in the matrix), particularly useful, as they can be combined with a gel-like structure and have refractive indices close to the refractive indices of systems of gelling agent and liquid (including water and/or wetting agent) which are usually used in dental care products.

The polishing material is usually present in the oral preparation dentifrices, such as the toothpaste or gel preparations, in concentrations by weight of 5% to 30%.

In the aspect of this invention where the oral preparation is a dentifrice, an orally acceptable carrier, including an aqueous phase with a humectant, which is preferably glycerol and/or sorbitol, is present, wherein water is present usually in an amount of 15- 35% by weight or 40% by weight, and glycerol and/or sorbitol usually together make up 20-75% by weight of the oral preparation dentifrice, usually 25-60%. Reference to sorbitol again refers to the typical material which is commercially available in 70% aqueous solutions.

In this invention, the oral dentifrice preparation may be substantially pasty in nature, such as a toothpaste (toothpaste), although it may be gel in nature when siliceous polish is used (which is not usually the case as such material is not usually used in an amount over 30% by weight. The carrier in the oral preparation dentifrice contains dentally acceptable polishing material, where examples of polishing materials are water-insoluble sodium metaphosphate, potassium metaphosphate, tricalcium phosphate, dihydrated dicalcium phosphate, anhydrous dicalcium phosphate, calcium carbonate, aluminum silicate, hydrated ^alumina, silica, bentonite and mixtures thereof with each other or with hard polishing materials, such as calcined alumina and zirconium silicate, materials including the particulate thermosetting resins described in US Patent No. 3,070,510, such as melamine-phenol and urea formaldehydes, and cross-linked polyepoxides and polyesters. Preferred polishing materials include insoluble sodium metaphosphates, dicalcium phosphate and hydrated alumina.

Many of the so-called "water-insoluble" polishing materials are anionic in nature, and they also include small amounts of soluble material. Insoluble sodium metaphosphate may thus be formed in any suitable manner, as illustrated in Thorpe's Dictionary of Applied Chemistry, vol. 9, 4th edition, pp. 510-511. The forms of insoluble sodium meta-phosphate, known as Madrell's salt and Kurrol's salt, are earlier examples of suitable materials. These metaphosphate salts exhibit only a very small solubility in water, and are therefore usually referred to as insoluble metaphosphates (IMPs). A small amount of soluble phosphate material is present as impurities, usually a few percent, such as up to 4% by weight. The amount of soluble phosphate material assumed to comprise a soluble sodium trimetaphosphate in the case of insoluble metaphosphate may be reduced or removed by washing with water if desired. The insoluble alkali metal phosphate is usually used in powder form with a particle size such that no more than 1% of the material is larger than 37 µm.

Hydrated alumina is an example of a polishing material that is essentially non-ionic in nature. It is usually small in particle size, ie at least 85% of the particles are smaller than 20 pm, and is such as is classified as gibbsite (alpha-alumina trihydrate) and is normally indicated chemically as Al203.3 H20 or Al(0H)3. The average particle size of gibbsite is generally 6-9 µm. A common variety has the following size distribution:

The polishing material is generally present in the cream paste or gel preparations in weight ratios of 30 to 75%.

Toothpastes or dental care agents in the form of toothpaste, as well as dental care agents in the form of gel, usually contain a natural or synthetic thickening or gelling agent in proportions of 0.1 to 10%, preferably 0.5 to 5%. A suitable thickener is synthetic, colloidal magnesium alkali metal silicate complex clay available e.g. as "Laponite" (eg CP, SP 2002, D). "Laponite D" analyzes show approximate values based on weight, 58.00% Si02, 25.40% MgO, 3.05% Na20, 0.98% Li20 and some water and trace metals. Its true specific gravity is 2.53 and it has an apparent bulk density (g/ml at 8% water) of 1.0.

Other suitable thickeners or gelling agents include Irish moss, iota-carrageenan, gum tragacanth, starch, polyvinylpyrrolidone, hydroxyethylpropylcellulose, hydroxybutylmethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose (e.g. available as "Natrosol"), sodium carboxymethylcellulose and especially when siliceous polishing agents are present, colloidal silica, such as those available as finely ground "Syloid 244" or "Sylodent 15".

In the aspect of the present invention where the oral preparation is a mouthwash or a liquid dentifrice, it is mainly liquid in nature, and the carrier, especially in mouthwash, is usually a mixture of water and alcohol. Generally, the weight ratio of water to alcohol is in the range of 1:1 to 20:1, preferably 3:1 to 10:1 and most preferably 4:1 to 6:1. The total amount of water/alcohol mixture in this type of preparation is usually in the range from 70 to 99.9% by weight. The alcohol is a non-toxic alcohol, such as ethanol or isopropanol. Humectants, such as glycerol and sorbitol, may be present in an amount of 10-30% by weight. Liquid dentifrices usually contain 50-85% water, may contain 0.5-20% by weight non-toxic alcohol and may also contain 10-40% by weight humectant, such as glycerol and/or sorbitol. When reference is made here to sorbitol, reference is made to the material which is usually available commercially 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, which flavor oil is also believed to do.

As indicated, the non-cationic antibacterial agent is substantially water insoluble. However, in the present invention, where AEA, such as polycarboxylate, is present in the mouthwash or liquid dentifrice, flavor oil or non-toxic alcohol is believed to help dissolve the antibacterial agent to help it reach soft oral tissue at or near the palate and the tooth surfaces. Organic surfactants and/or flavoring oils can also help to dissolve the antibacterial agents as optional ingredients in oral dental care preparations.

Organic surfactants are also used in the preparations according to the present invention to achieve an increased prophylactic effect, help to achieve thorough and complete dispersion of the anti-plaque, antibacterial agent in the oral cavity, and make the present preparations cosmetically more acceptable. The organic surface-active material is preferably anionic, non-ionic or ampholytic in nature, and it is preferred to use as the surface-active agent a cleaning material which gives the preparation cleaning and foaming properties. Suitable examples of anionic surfactants are water-soluble salts of higher fatty acid monoglyceride monosulfates, such as the sodium salt of the monosulfated monoglyceride of hydrogenated coconut oil fatty acids, such higher alkyl sulfates as sodium lauryl sulfate, such alkylaryl sulfonates as sodium dodecylbenzene sulfonate, higher alkyl sulfoacetates, higher fatty acid esters of 1,2-di- hydroxypropane sulfonate and the substantially saturated, higher aliphatic acylamides of lower aliphatic aminocarboxylic acid compounds, such as those having 12-16 carbon atoms in the fatty acid, the alkyl or acyl radicals, etc. Examples of the latter amides are N-lauroylsarcosine and the sodium, potassium and ethanolamine salts of N-lauroyl, N-myristoyl or N-palmitoylsarcosine, which should be substantially free of soap or similar higher fatty acid material. The use of these sarcosinate compounds in the oral preparations according to the present invention is particularly advantageous as these materials exhibit a long-lasting and marked effect in terms of inhibition of acid formation in the oral cavity due to carbohydrate breakdown, in addition to exhibiting some reduction in the solubility of tooth enamel in acidic solutions. Examples of water-soluble, non-ionic surfactants are condensation products of ethylene oxide and various reactive hydrogen-containing compounds that react with it, and which have long hydrophobic chains (e.g. aliphatic chains of 12-20 carbon atoms), the condensation products ("ethoxamers" ) contain hydrophilic polyoxyethylene residues, such as condensation products of poly(ethylene oxide) with fatty acids, fatty alcohols, fatty amides, polybasic alcohols (e.g. sorbitan monostearate) and polypropylene oxide (e.g. Pluronic materials).

Surfactant is usually present in an amount of 0.5-5% by weight, preferably 1-2.5% by weight.

When the oral preparation is a liquid dentifrice, the natural or synthetic thickening or gelling agent described is usually present in proportions of 0.1 to 10%, preferably 0.5 to 5%.

Generally, liquid dentifrices do not contain a polishing agent. As described in US Patent No. 3,506,757, however, 0.3-2.0% by weight of a polysaccharide with a high molecular weight above 1,000,000, which contains mannose, glucose, potassium glucuronate and acetyl residues in the approximate ratio can be used 2:1:1:1, as a suspending and thickening agent in a liquid dental care product, which may then also contain 10-20% of a polishing material, such as hydrated alumina, dicalcium phosphate dihydrate, calcium pyrophosphate, insoluble sodium metaphosphate, anhydrous dicalcium phosphate, calcium carbonate, magnesium carbonate, magnesium oxide, silica, mixtures thereof, etc.

Without being bound to a theory of how the advantages of the invention are achieved, it is assumed that an aqueous humectant carrier is normally solubilized in micelles with surfactant in the mobile phase (i.e. which do not include gelling agent and polishing agent, if such are present in the dental care product ). The solution of the mobile phase in the dentifrice can be diluted with saliva during use, causing triclosan to precipitate. Thus, it has been found that even in the absence of a special solubilizing material for triclosan, when the amount of triclosan is 0.25-0.35% by weight and AEA, such as the polycarboxylate, is present, sufficient triclosan is present to exert a excellent anti-plaque effect on the soft tissues at the palate. Similar remarks apply to other water-insoluble, non-cationic, antibacterial agents described herein.

The oral dentifrice preparation may also contain a source of fluoride ions or a fluoridating component, such as an anti-tooth decay agent in an amount sufficient to supply 25 ppm to 5000 ppm of fluoride ions. These compounds may be slightly soluble in water or may be completely water soluble. They are characterized by their ability to release fluoride ions in water with essentially no unwanted reaction with other compounds in the oral preparation. Among these materials are inorganic fluoride salts, such as soluble alkali metal and alkaline earth metal salts, e.g. sodium fluoride, potassium fluoride, ammonium fluoride, calcium fluoride-ide, a copper fluoride, such as cuprous fluoride, zinc fluoride-ide, barium fluoride, sodium fluorosilicate, ammonium fluorosilicate, sodium fluorozirconate, ammonium fluorozirconate, sodium monofluorophosphate, aluminum mono- and aluminum difluorophosphate and sodium calcium pyrophosphate . Alkali metal and stannous fluorides, such as sodium and stannous fluorides, sodium monofluorophosphate (MFP) and mixtures thereof, are preferred.

The amount of fluorinating 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 0.0005 to 3.0% of the preparation. In a dentifrice preparation, e.g. a dental gel, an amount of such a compound which releases up to 5000 ppm F ion based on the weight of the preparation is considered satisfactory. Any suitable minimal amount of such compound may be used, but is preferred

to apply sufficient compound to release 300-

2000 ppm, preferably 800 to 1500 ppm fluoride ion.

In the cases of alkali metal fluorides, this component is usually present in an amount up to 2% by weight, based on the weight of the composition, and preferably in the range of 0.05-1%. In the case of sodium monofluorophosphate, the compound may be present in an amount of 0.1-3%, usually about 0.76%.

It will be understood that the oral preparations will normally be sold or otherwise distributed in suitable, labeled packages. A dental care gel will thus usually be in a squeezable tube, usually made of aluminium, lined with lead or plastic, or another squeeze, pump or pressurized dispenser for measuring out the contents, which has a label describing it as a dental care gel or the like. Various other materials can be incorporated into the oral preparations according to the invention, such as whitening agents, preservatives, silicones, chlorophyll compounds and/or such ammonia-containing material as urea, diammonium phosphate and mixtures thereof. When these excipients are present, they are incorporated into the preparations in amounts that do not adversely affect the desired properties and characteristics to a significant extent. Significant amounts of zinc, magnesium and other metal salts and materials, which are generally soluble and would complex with the active ingredients of the present invention, must be avoided.

Any suitable flavoring or sweetening material may also be used. Examples of suitable flavoring ingredients are flavoring oils, e.g. oil of spearmint, peppermint, wintergreen, sassafras, clover, sage, eucalyptus, marjoram, cinnamon, lemon and orange, and methyl salicylate. Suitable sweeteners include sucrose, lactose, maltose, xylitol, sodium cyclamate, perill-artin, AMP (methyl ester of asparagylphenylalanine), saccharin and the like. Suitable flavoring and sweetening agents can individually or together make up from 0.1 to 5% of the preparation. Also, similarly to the surfactant, the flavor oil is believed to aid in dissolution of the antibacterial agent, together with or even in the absence of surfactant.

In the preferred practice of the invention, an oral preparation according to the invention is preferably applied regularly to tooth enamel and soft oral tissue, particularly at or near the gum line, such as every day or every second or third day, or preferably from 1-3 times a day, at a pH of 4.5 to 9 or 10, generally 5.5 to 8, preferably 6-8 and preferably 6.5 to 7.5, for at least 2 weeks and up to 8 weeks or more, up to the lifetime. Even at such a pH below 5, enamel is not decalcified or damaged in any other way. pH can be adjusted with acid (e.g. citric or benzoic acid) or base (e.g. sodium hydroxide) or buffered, such as with sodium citrate, benzoate, carbonate or bicarbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate, etc.).

The preparations according to the invention can be incorporated into lozenges or in chewing gum or other products, e.g. by stirring them into a warm rubber base or coating the outer surface of a rubber base, examples of which include jelutong, rubber latex, vinylite resins, etc., preferably together with common plasticizers or softeners, sugar or other sweeteners, or such carbohydrates as glucose, sorbitol etc.

The following examples further illustrate the present invention. All quantities and proportions referred to here and in the requirements are based on weight unless otherwise stated.

Example 1

The following dentifrice was prepared:

Toothpaste A above delivers triclosan to the teeth and soft gum tissue essentially as well as Toothpaste B, which contains a special triclosan solubilizer. In other words, a special solubilizing agent is not required for the dental care agent according to the present invention to be effective. Furthermore, a corresponding dentifrice in which the "Gantrez" polycarboxylate is absent is significantly inferior when it comes to delivering triclosan.

In the example above, improved results may also be obtained by replacing triclosan with other antibacterial agents described herein, such as phenol, thymol, eugenol, and 2,2'-methylene-bis(4-chloro-6-bromophenol), and/or by replacing "Gantrez" with other AEAs, such as a 1:1 copolymer of maleic anhydride and ethyl acrylate, sulfoacrylate oligomers, "Carbopol" (eg 934) and polymers of alpha or beta styrenephosphonic acid monomers and copolymers thereof the monomers with each other or with other ethylenically unsaturated, polymerizable monomers, such as vinylphosphonic acid.

Example 2

The following liquid phase dentifrice solutions were tested for uptake and retention of triclosan on saliva-coated HA discs, following the test procedures described in Example 3 below, with the results indicated:

Adjusted to pH 6.5 with NaOH

Triclosan uptake in ug on

saliva-coated HA discs 31.0 174.0 86.0 36.0 Retention of triclosan on

saliva-coated HA discs after:

The above results show that solution (D) containing polyvinyl alcohol, and not an AEA, gives a triclosan uptake of only 36.0, quite similar to the uptake of 31.0 in the control solution (A) without additive. In contrast, solution (C) with poly(alpha-styrenephosphonic acid) gives an uptake of 86.0, more than twice that of solutions (A) and (D), and solution (B) with poly(beta-styrenephosphonic acid) gives a recording that is approx. five times the uptake to solutions (A) and (D), which may further indicate that vicinal substitution of the delivery-enhancing group gives excellent results. The above results also show the surprisingly good retention of triclosan on the HA discs over time achieved with solution (B), which contains poly(beta-styrenephosphonic acid) (molecular weights about 3000 to about 10,000).

Example 3

The effect of synthetic, anionic, straight-chain polycarboxylate on the uptake, retention to, and release from tooth surfaces of a water-insoluble, non-cationic, antibacterial agent is determined in vitro on a saliva-coated hydroxyapatite slice and on exfoliated buccal epithelial cells. The determinations in vitro can be correlated with delivery in vivo, and retention on oral surfaces.

For the test of delivery of antibacterial agent to a saliva-coated hydroxyapatite disk, hydroxyapatite (HA) is thoroughly washed with distilled water collected by vacuum filtration, and allowed to dry overnight at 37 °C. The dried HA is ground to a powder with a mortar and pestle. 150.00 mg HA is placed in the chamber of a KBr pellet press mold and pressed for 6 min. at 4536 kg in a Carver laboratory press. The resulting 13 mm disks are sintered for 4 hours at 800 °C in a Thermo-lyne furnace. Parafilm-stimulated whole saliva is collected in an ice-cooled glass beaker. The saliva is clarified by centrifugation at 15,000 x g (times gravity) for 15 min. at 4 °C. Sterilization of the clear saliva is done at 4°C with stirring by irradiating the sample with UV light 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 salivary film is formed by incubating the slice overnight at 37°C with continuous shaking in a water bath. After this treatment, the saliva is removed and the slices are treated with 1.00 ml of a solution containing the liquid phase of a dentifrice with an antibacterial agent (triclosan ), and incubate at 37 °C with continuous shaking in the water bath. After 30 min, transfer the disc to a new tube and add 5.00 ml of water, followed by shaking the disc 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 liquid with the disc. Then 1.00 ml of methanol is added to the disc and shaken vigorously with a Vortex. The sample is left at room temperature for 30 min . to extract adsorbed triclosan in the methanol. The methanol is then aerated and clarified by centrifugation in a "Beckman Microfuge 11" at 10,000 rpm for 5 min. After this treatment, the methanol is transferred to HPLC ampoules (high-performance liquid chromatography) for the determination of antibacterial agents. Samples in triplicate are used in all experiments.

For the test of retention of antibacterial agent to a saliva-coated HA disc, a saliva-coated HA disc is treated with dentifrice slurries as described above. After incubation for 30 min. at 37°C, the HA disc is removed from the dentifrice slurry, washed twice with water and then re-incubated with parafilm-stimulated, whole human saliva that has been clarified by centrifugation. After incubation at 37°C with constant shaking for different periods of time, the HA disk is removed from the saliva and the amount of antibacterial agent (triclosan) retained on the disk, and released saliva is determined by an analytical method using HPLC.

For the analysis of delivery of antibacterial agent to buccal epithelial cells, delivery is measured to determine the effect of PVM/MA on delivery of antibacterial agent (triclosan) to soft oral tissue from a dentifrice product. Cheek epithelial cells are collected with a wooden applicator stick by gently scraping the mucosa of the mouth. The cells are resuspended in "Resting Saliva Salts" (Rss) buffer (50 nM NaCl, 1.1 nM CaCl2 and 0.6 nM KH2PO4, pH 7.0) to 5-6 x 10<5>cells/ml using a hemocytometer to count the cells, and they are kept on ice until use. 0.5 ml of the cell suspension, pre-incubated at 37 °C in a water bath, is added to 0.5 ml of the test solution of antibacterial agent and incubated at 37 °C. The solution of antibacterial agent in the incubation mixture is diluted at least 10 times to lower the surface concentration and prevent degradation of cell membranes by the surfactant. After 30 minutes of incubation, the cells are harvested by centrifugation in "Beckman Microfuge 11" at 5000 rpm for 5 minutes. The cells collected on the pellet are washed three times with Rss buffer and treated with 1.5 ml of methanol. The sample is mixed vigorously and analyzed for antibacterial agents using the HPLC method.

Dental care products are manufactured with the following compositions:

The uptake of triclosan on the saliva-coated hydroxyapatite disc and on cheek epithelial cells with and without the polymeric polycarboxylate, "Gantrez S-97", is shown in Table 1 below.

These results reveal that the "Gantrez" material (present in dentifrice B) greatly increases the delivery and uptake of triclosan on saliva-coated hydroxyapatite disc and on the desquamated cheek epithelial cells.

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

Example 4

In tests with saliva-coated hydroxyapatite discs and desquamated buccal epithelial cells different from those set forth in Example 3 above, dentifrice B, containing 2.00% "Gantrez S-97" and 0.20% triclosan, 10.00% propylene glycol and 2.00% sodium lauryl sulfate, and a similarly formulated dentifrice (B'), except for the presence of 0.30% triclosan, compared to a commercially available dentifrice (C), containing hydrated alumina as a polishing agent 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 hydrated alumina as a polishing agent, and the dentifrice below (C ) which is similar to commercial dentifrice C, except for the presence of 0.30% triclosan:

Since dentifrices C and C contain a combined 2.50% surfactant, more surfactant is available to dissolve triclosan than in dentifrices B and B', which contain 2.00%. Propylene glycol, which is present in the dental care products B and B' with silicon-containing polishing agent (but not in the dental care products C and C with hydrated alumina as polishing agent), ensures optimal dissolution of triclosan.

The advantage of dentifrices B and B' (containing propylene glycol and "Gantrez") over dentifrices C and C, in terms of triclosan uptake on saliva-coated hydroxyapatite discs and on desquamated buccal epithelial cells, is shown in Table 2 below.

Further experiments with dentifrice B' (0.3% triclosan, "Gantrez", propylene glycol) in a 50% slurry of the dentifrice to determine the retention of triclosan on the saliva-coated hydroxyapatite disc over time reveal retention of excellent levels of triclosan as shown in table 3 below:

These results indicate that dentifrices containing triclosan, "Gantrez" material and propylene glycol can provide increased delivery of triclosan to, and retention on, tooth surfaces and soft surfaces in the oral cavity, thereby providing improved anti-plaque and antibacterial effects.

Example 5

For comparison purposes, preparations a and b were prepared below:

Preparation a is a dentifrice containing a "Gantrez" polycarboxylate with 0.5% triclosan as an antibacterial, anti-plaque agent and no solubilizer. In preparation b, propylene glycol is present as a solubilizing agent.

Preparation a is poor in delivering triclosan to cheek epithelial cells, while preparation b is clearly effective.

The above results reveal excellent delivery of triclosan-containing dentifrice.

Example 6

An "in-house" study was conducted on a group of volunteers to determine the effects of specific dentifrices in affecting plaque regrowth according to the method described by Addy, Wilis and Moran, J. Clin. Perio, 1983, vol. 10, pages 89-99. The dentifrices tested included a placebo control which did not contain triclosan (i) and a dentifrice according to the invention which contained 0.3% triclosan, 10% propylene glycol (instead of 3% polyethylene glycol 600) and 2% "Gantrez S-97", and wetting agent of propylene glycol and sorbitol (ii). The compositions of the dental care products are as follows:

In terms of plaque reduction on the volunteers' teeth, the invention (ii) gave a significant reduction of ) 20% compared to placebo (i).

As 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. Similarly, the other solubilizing agents dipropylene glycol, hexylene glycol, methyl cellosolv, ethyl cellosolv, olive oil, castor oil, petrolatum, amyl acetate, glyceryl tristearate and benzyl benzoate, instead of propylene glycol, can effectively

deliver triclosan to soft, oral tissues. Similar results

further 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 were produced:

In the above examples, improved results may also be obtained by replacing triclosan with other antibacterial agents described herein, such as phenol, thymol, eugenol and 2,2'-methylene-bis(4-chloro-6-bromophenol), and/or by replacing "Gantrez" with other AEAs, such as a 1:1 copolymer of maleic anhydride and ethyl acrylate, sulfoacrylate oligomers, "Carbopol" (eg 934), polymers of monomeric alpha- or beta-styrenephosphonic acid and copolymers of these styrenephosphonic acid monomers with each other or with other ethylenically unsaturated, polymerizable monomers, such as vinylphosphonic acid.

Example 8

The following dentifrice was prepared:

The above dentifrices deliver triclosan to the teeth and soft tissue areas of the palate significantly more effectively than similar dentifrices where the "Gantrez" polycarboxylate is absent.

Example 9

The following dentifrices were produced:

The above dentifrices deliver triclosan to the saliva-coated hydroxyapatite disc more effectively than similar dentifrices where the "Gantrez" polycarboxylate is absent.

Example 10

The following anti-plaque dentifrice was prepared:

In the above examples, improved results can also be achieved when triclosan is replaced with phenol, 2,2'-methylene-bis(4-chloro-6-bromophenol), eugenol or thymol and/or when "Gantrez" is replaced with other AEAs, such as "Carbopol"

(e.g., 934) or styrenephosphonic acid polymers with molecular weights in the range of 3000-10,000, such as poly(beta-styrenephosphonic acid), copolymers of vinylphosphonic acid with beta-styrenephosphonic acid and poly(alpha-styrenephosphonic acid), or sulfoacrylic oligomers, or a 1:1- copolymer of maleic anhydride and ethyl acrylate.

in

Example 11

Dentifrice mobile phases containing triclosan

The concentration of the above ingredients is 1.33% dentifrice level to reflect the 25% level of abrasive which may be required to make a complete dentifrice.

The above-mentioned mobile phases of the specified dentifrices are tested with regard to triclosan absorption on saliva-coated HA discs. The results are reproduced in the table below:

The above results show a more than two-fold increase in triclosan uptake obtained with the B preparation containing "Gantrez" compared to the A preparation without "Gantrez".

Example 12

Concentration and uptake of triclosan by HA from supernatant of 1:1 dentifrice/water slurries

The supernatants from the 1:1 dentifrice/water slurries in the above-mentioned dentifrices were tested for concentration of triclosan in the supernatant and for triclosan uptake on saliva-coated HA discs. The results indicate that by using 50% alumina as an abrasive, triclosan is significantly increased under low (1:1) dilution conditions (from 1650 to 1905), resulting in a significant increase in triclosan uptake (from 52 to 74).

Example 13

The mouthwashes below are effective in reducing plaque by increasing the absorption and retention of triclosan on oral surfaces.

Example 14

The following liquid dentifrices are also effective in reducing plaque by increasing the absorption and retention of triclosan on oral surfaces:

In the examples above, improved results can also be achieved when triclosan is replaced with phenol, 2,2'-methylene-bis(4-chloro-6-bromophenol), eugenol or thymol and/or when "Gantrez" is replaced with other AEAs, such as "Carbopol"

(e.g., 934) or styrenephosphonic acid polymers with molecular weights in the range of 3000-10,000, such as poly(beta-styrenephosphonic acid), copolymers of vinylphosphonic acid with beta-styrenephosphonic acid and poly(alpha-styrenephosphonic acid), or sulfoacrylic oligomers, or a 1:1- copolymer of maleic anhydride and ethyl acrylate.

Claims (20)

1. Oral preparation, characterized in that it comprises: a) 0.01-5% by weight of an essentially water-insoluble, non-cationic, antibacterial agent selected from the group consisting of halogenated diphenyl ethers, halogenated salicylanilides, benzoic acid esters, halogenated carbanilides and phenolic compounds, b) 0.005 -4% by weight of an antibacterial agent containing at least one release-enhancing, functional group and at least one organic retention-enhancing group for delivery and retention of the antibacterial agent on oral tooth and gum surfaces, and c) an orally acceptable carrier that provides the antibacterial agent to be dissolved in saliva in an effective anti-plaque amount, where the oral preparation is essentially free of polyphosphate in an antitartar quantity. 2. Oral preparation according to claim 1, characterized in that the oral preparation is a dental care agent comprising 5-30% by weight of a silicon-containing polishing agent, and the antibacterial agent is present in an amount of 0.25-0.35% by weight, and at least one of a surfactant and a flavor oil is present. 3. Oral preparation according to claim 1, characterized in that the oral preparation is a dental care agent comprising 5-30% by weight of a silicon-containing polishing agent, the antibacterial agent being present in an amount of 0.01-5% by weight, and the oral preparation comprises a solubilizing material in an amount sufficient to dissolve the antibacterial agent in saliva. 4. Oral preparation according to claim 1, characterized in that the oral preparation is a dental care agent comprising 30-75% by weight of a dentally acceptable, water-insoluble polishing agent. 5. Oral preparation according to claim 1, characterized in that the oral preparation is a mouthwash or a liquid dentifrice, and the orally acceptable carrier is an aqueous carrier in which at least one surfactant, a flavor oil or a non-toxic alcohol is present. 6. Oral preparation according to any one of the above claims, characterized in that surfactant is present in an amount of 0.5-5% by weight. 7. Oral preparation according to any one of the above claims, characterized in that flavor oil is present in an amount of 0.1-5% by weight. 8. Oral preparation according to claim 8, characterized in that the preparation is a mouthwash, the aqueous carrier contains ethanol and the weight ratio between water and ethanol is from 1:1 to 20:1. 9. Oral preparation according to claim 5, characterized in that the oral preparation is a liquid dentifrice containing 0.3-2.0% by weight of a polysaccharide with a high molecular weight of over 1,000,000 which contains mannose, glucose, potassium glucuronate and acetyl residues in an approximate ratio of 2:1:1:1, as a suspending and thickening agent, and 10-20% by weight of a polishing material. 10. Oral preparation according to claim 1, characterized in that the antibacterial agent is a halogenated diphenyl ether. 11. Oral preparation according to claim 10, characterized in that the halogenated diphenyl ether is 2,4,4'-trichloro-2'-hydroxyphenyl ether. 12. Oral preparation according to any one of claims 1 and 3, characterized in that a solubilizing agent is present in an amount of 0.5-50% by weight and is selected from the group consisting of propylene glycol, dipropylene glycol, hexylene glycol, methyl cellosolv, ethyl cellosolv, vegetable oil and waxes containing at least 12 carbon atoms, amyl acetate, ethyl acetate, glyceryl tristearate and benzyl benzoate. 13. Oral preparation according to claim 12, characterized in that the solubilizing agent is propylene glycol and is present in an amount of approx. 0.5% by weight. 14. Oral preparation according to any one of claims 1 and 12, characterized in that a polishing agent selected from the group consisting of sodium meta-phosphate, tricalcium phosphate, dihydrated dicalcium phosphate, anhydrous dicalcium phosphate, calcium pyrophosphate, magnesium orthophosphate, trimagnesium phosphate, calcium carbonate, aluminum silicate, hydrated alumina, silica, bentonite and mixtures thereof is present, and the oral preparation is a dentifrice. 15. Oral preparation according to claim 14, characterized in that the polishing agent is dicalcium phosphate dihydrate or hydrated alumina. 16. Oral preparation according to any one of claims 1-5, characterized in that the antibacterial-enhancing agent has an average molecular weight of 100-1,000,000. 17. Oral preparation according to claim 16, characterized in that the release-increasing group is acidic and is selected from the group consisting of carboxylic, phosphonic, phosphinic and sulfonic acids, and the salts thereof, and mixtures thereof, that the organic retention-increasing group comprises the formula 0( X)n-R, where X is 0, N, S, SO, SO 2 , P, PO or Si, R is hydrophobic alkyl, alkenyl, acyl, aryl, alkaryl or aralkyl, or a hydrophobic heterocyclic residue, or their inert substituted derivatives, and n is 1 or 0, and that the antibacterial agent is an anionic polymer containing several of the release-increasing and retention-increasing groups, the anionic polymer comprising a chain containing repeating units each containing at least one carbon atom, where each unit contains at least one release -increasing group bonded to the same, vicinal or other atoms in the chain. 18. Oral preparation according to claim 17, characterized in that the release-increasing group is a carboxyl group or a salt thereof, that the anti-bacterial agent is a copolymer of maleic acid or maleic anhydride and another inert, ethylenically unsaturated, polymer-isable monomer, the other monomer in the copolymer is methyl vinyl ether in a 4:1-1:4 molar ratio with the maleic acid or maleic anhydride, and the copolymer has a molecular weight of 30,000-1,000,000 and is present in an amount of 0.1-2% by weight. 19. Oral preparation according to claim 18, characterized in that the copolymer has an average molecular weight of approx. 70,000. 20. Oral preparation according to claim 17, characterized in that the release-increasing group is a phosphonic group or a salt thereof, and the anti-bacterial-increasing agent is poly(beta-styrenephosphonic acid) or poly(alpha-styrenephosphonic acid) polymer or a copolymer of either styrenephosphonic acid or another ethylenically unsaturated monomer.