NL194716C - Oral preparation comprising a water-insoluble non-cationic antibacterial agent. - Google Patents

Description

1 194716

Oral preparation comprising a water-insoluble non-cationic antibacterial agent

The invention relates to an oral preparation comprising an effective anti-plaque amount of a substantially water-insoluble non-cationic antibacterial agent in an carrier acceptable for oral use which enables the antibacterial agent to dissolve in an effective anti-plaque amount in saliva.

Such an oral preparation is known from European patent application 0.161.898. This European patent application relates to toothpaste compositions for inhibiting dental plaque formation. For this purpose a substantially water-insoluble non-cationic antimicrobial agent or a zinc salt is used in this composition, while furthermore a lyotropic lamellar liquid crystal phase is present, which phase consists of alternating layers of surfactant molecules and water molecules. A preferred non-cationic antibacterial agent is Triclosan.

Dental plaque is a soft deposit forming 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, including in particular on the gum line. In addition to being an ugly face, dental plaque is involved in the occurrence of gum disease.

Cationic antibacterial materials such as chlorhexidine, benzthonium chloride and cetylpyridinium chloride have been thoroughly investigated as antibacterial anti-plaque agents. However, they are generally not effective when used with anionic materials. On the other hand, non-cationic antibacterial materials may be compatible with anionic components in an oral preparation.

Oral preparations are normally, however, mixtures of many components and even such typical neutral materials as wetting agents can affect the properties of such preparations.

In addition, even non-cationic antibacterial agents may have limited anti-plaque effectiveness with commonly used materials such as polyphosphates, which are used as anti-tartar agents and are described together in British patent publication 2,200,551 to Gaffar et al. European patent publication 0.251.591 to Jackson et al.

An advantage of this invention is that an oral preparation is provided in which a substantially water-insoluble non-cationic antibacterial agent and an antibacterial activity enhancing agent (AEA) are present for the inhibition of plaque formation, the oral preparation being an oral The use contains an acceptable liquid carrier which allows the antibacterial agent to dissolve in an effective anti-plaque amount in the saliva.

Another advantage of this invention is that the AEA improves the delivery and retention of small but effective anti-plaque amounts of the antibacterial agent on teeth and on soft tissues in the mouth.

35. Another advantage of this invention is that an oral anti-plaque preparation is provided that effectively reduces the incidence of gum disease.

The invention now relates to an oral preparation of the type mentioned in the preamble, which is furthermore characterized in that it also contains 0.05-4% by weight of an antibacterial activity-improving agent, which releases the antibacterial agent to and retains it. on surfaces in the mouth, which agent has an average molecular weight of 100 to 1,000,000, contains a release-improving group selected from the group consisting of carboxylic acids, phosphonic acids, phosphinic acids and sulfonic acid as well as salts of these acids, and the retention-improving group is satisfactory to the formula -X n-R 1, where X represents O, S, SO, SO 2, P, PO or Si, R represents a hydrophobic alkyl, alkylene, acrylic, aryl, alkaryl, or aralkyl group or a heterocyclic group as well as derivatives thereof with inert substituents, n is 0 or 1, 45 and that the oral preparation does not contain a polyphosphate anti-toothstone agent.

In a preferred embodiment, the antibacterial activity enhancing agent is an antionic polymer that contains a plurality of said release enhancing and / or retention enhancing groups.

Preferably the amount of antibacterial activity enhancing agent in the composition is 0.25-0.5% by weight.

Incidentally, a composition for oral use is known from Dutch patent application 8800206 in which polyphosphate anti-tartar agents are present. These polyphosphates can be inhibited in their degradation by adding synthetic anionic polymeric polycarboxylic acids, which polycarboxylic acids according to the present invention can be used as AEA. Furthermore, non-cationic antibacterial compounds may be present in these known compositions.

Typical examples of water-insoluble non-cationic antibacterial agents that can be used in accordance with the invention are described in NL-A-8800206.

The non-cationic antibacterial agent is present in the oral preparation in an effective anti-plaque amount of normally 0.01-5% by weight, preferably 0.03-1%, more preferably 0.25-0.5% and most preferably 0.25-0.35%, in a dental treatment agent, or preferably 0.03-0.3% by weight, most preferably 0.03-0.1%, in a mouthwash or liquid dental treatment agent.

The antibacterial agent is essentially water-insoluble, which means that its solubility is less than 1% by weight in water at 25 ° C and may even be less than 0.1%.

The preferred halogenated diphenyl ether is triclosan. The preferred phenol compounds are phenol, thymol, eugenol, hexylresorcinol and 2,2'-methylene bis (4-chloro-6 * bromophenol). Triclosan is described in U.S. Pat. No. 4,022,880 as an antibacterial agent in combination with an anti-tartar agent that provides zinc ions and in German Patent Publication No. 3,532,860, in combination with a copper compound. In European patent publication 0.278.744 it is disclosed in combination with a teeth desensitizing agent, which contains a source of potassium ions. It is also described as an anti-plaque agent in a dental treatment agent with a formulation in which a lamellar liquid crystal surfactant phase is present with a lamella spacing of less than 6.0 nm and which may optionally contain a zinc salt, in published European patent application 0.161.898 van Lane et al. and in a dental treatment agent containing zinc citrate trihydrate, in the published European patent application 0.161.899 of Saxton et al.

The antibacterial property enhancing agent (AEA) that improves the delivery of said antibacterial agent to and retention on oral surfaces is used in realizing such an improvement in effective amounts within the range in the oral preparation of 0.005 to 4 wt. %, preferably 0.1 to 3% by weight, most preferably 0.5 to 2.5% by weight.

The AEA can be a simple compound, preferably a polymerizable monomer, more preferably a polymer, the latter term being used in its fully generic sense, and e.g. oligomers, homopolymers, copolymers of two or more monomers, ionomers, block copolymers, graft copolymers, cross-linked polymers and copolymers, and the like. The AEA can be a natural or synthetic material, and can be water-insoluble or preferably water-soluble (saliva) or swellable (hydratable, hydrogel-forming). It has a (weight) average molecular weight of 100 to 1,000,000, preferably 1,000 to 1,000,000, and most preferably 2,500 to 250,000.

The AEA usually contains at least one release enhancing group, which is preferably an acidic group such as sultan, phosphone, or more preferably taston or carboxyl, or a salt thereof, e.g. alkali metal or ammonium, and at least one organic retention promoting group, preferably a plurality of both release enhancing and retention improving groups, the latter groups preferably having the formula - (X) nR, wherein X is O, N , S, SO, SO 2, P, PO or Si or the like, R is hydrophobic alkyl, alkenyl, acyl, aryl, alkaryl, aralkyl, heterocyclic or inert-substituted derivatives thereof, and n is 0 or 1 or more. The aforementioned "inert-substituted derivatives" are intended to include substituents on R 35 that are generally not hydrophilic and do not serve the desired functions of the AEA as an agent for improving the release of the antibacterial agent to and retaining it on oral surfaces significantly disturb, such as halogen, eg Cl, Br, J, and carbo and the like.

Examples of such retention enhancing groups are tabulated below: 40

η X - (X) n R

O - methyl, ethyl, propyl, butyl, isobutyl, t-butyl, cyclohexyl, ally], benzyl, phenyl, chlorophenyl, xylyl, pyridyl, furanyl, acetyl, benzoyl, butyryl, terephthaloyl, etc.

45 1 O ethoxy, benzyloxy, thioacetoxy, phenoxy, carboethoxy, carbobenzyloxy, etc.

N ethylamino, diethylamino, propylamido, benzylamino, benzoylamido, phenylacetamido, etc.

S thiobutyl, thioisobutyl, thioallyl, thiobenzyl, thiophenyl, thiopropionyl, phenylthioacetyl, thiobenzoyl, etc.

50 butyl sulfoxy, allyl sulfoxy, benzyl sulfoxy, phenyl sulfoxy, etc.

50 SO 2 butyl sulfonyl, allyl sulfonyl, benzyl sulfonyl, phenyl sulfonyl, etc.

Diethylphosphinyl, ethylvinylphosphinyl, ethylallylphosphinyl, ethylbenzylphosphinyl, ethylphenylphosphinyl, etc.

PO diethylphosphienoxy, ethylvinylphosphienoxy, methylallylphosphienoxy, methylbenzylphosphienoxy, methylphenylphosphienoxy, etc.

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

55 -----

The release enhancing group as used herein denotes a group that affixes the AEA (which carries the antibacterial agent) or binds substantively, adhesive, cohesive or otherwise to oral (e.g., tooth and gum) surfaces, the antibacterial agent being attached to such surfaces is '' issued ''. Through the organic retention enhancing group, which is generally hydrophobic, the antibacterial agent is attached or otherwise bound to the AEA, thereby promoting retention of the antibacterial agent to the AEA and indirectly to the oral surfaces. In some cases, confirmation of the antibacterial agent takes place by means of a physical capture thereof by the AEA, in particular when the AEA is a cross-linked polymer, the structure of which inherently provides additional sites for such capture. The presence of a higher molecular weight, more hydrophobic crosslinking moiety in the crosslinked polymer further promotes the physical entrapment of the antibacterial agent in or through the crosslinked AEA polymer.

The AEA is preferably an anionic polymer comprising a chain or backbone with repeating units, each of which preferably has at least one carbon atom and preferably at least one directly or indirectly pendant, monovalent release enhancing group, and at least one directly or indirectly pendant monovalent retention-enhancing group contain geminally, vicinally or less preferably, otherwise bound to atoms, preferably carbon, in the chain. The polymer, although less preferred, may contain release enhancing groups and / or retention enhancing groups and / or other divalent atoms or groups as links in the polymer chain instead of or in addition to carbon atoms, or as crosslinking moieties.

It is noted that any examples or illustrations of AEAs given herein, which do not contain both release enhancing groups and retention enhancing groups, may be chemically modified in a known manner and that are also preferred in order to obtain the preferred AEAs that include both types of groups and preferably contain a multiple of each of these groups. In the case of the preferred polymeric AEAs, for maximum substanceity and delivery of the antibacterial agent to oral surfaces, it is desirable that the repeating units in the polymer chain or backbone containing the acid release enhancing groups, at least about 10% by weight, preferably at least about 50%, more preferably at least about 60%, to 95 or 100% by weight of the polymer.

Preferably, the AEA comprises a polymer with repeating units, wherein one or more phosphonic acid release enhancing groups are attached to one or more carbon atoms in the polymer chain. An example of such an AEA is poly (vinyl phosphonic acid) with units of the formula: I - [CH 2 - CH] - PO 3 H 5 which, however, does not contain a retention-improving group. However, a group of the latter type would be present in poly (1-phosphonopropene) with units of the formula: II - [CH - CH] - 11 CH 3 PO 3 H 2

A preferred phosphonic acid containing AEA for use in the invention is poly (beta 40 styrene phosphonic acid) with units of the formula: III - [CH - CH] -

I I

Ph PO 3 H 2 wherein Ph represents phenyl, wherein the phosphonic acid release enhancing group and the phenyl retention enhancing group are linked to vicinal carbon atoms in the chain, or a copolymer of beta-styrene phosphonic acid with vinyl phosphonyl chloride, wherein the units of formula III alternate or are sometimes linked with units of formula I, or poly (alpha-pyrenerene phosphonic acid) with units of formula IV - [CH 2 - C -] - Λ 50 Ph PO 3 H 2 wherein the release and retention enhancing groups are mininally linked to the chain.

These styrene phosphonic acid polymers and their copolymers with other inert ethylenically unsaturated monomers generally have molecular weights in the range of about 2000 to about 30,000, preferably about 2500 to about 10,000. Such "inert" monomers do not significantly interfere with the intended function of copolymers used herein as an AEA.

Other phosphone-containing polymers include e.g. phosphonated ethylene with units of the formula: 194716 4 V - [CH 2) 14 CHPO 3 H 2] n - wherein n e.g. can be an integer or value, whereby the polymer has a molecular weight of about 3000; and sodium poly (butene-4,4-diphosphonate) with units of the formula: VI - [CH 2 - CH -] -

5 I

CH 2 - CH <(PO 3 Na 2) 2 and poly (allyl-bis (phosphonoethylamine) with units of the formula: VII - [CH 2 - CH -] - CH 2 -N <(PO 3 H 2) 2

Other phosphonated polymers, e.g. poly (allylphosphonoacetate), phosphonated polymethacrylate, etc., and the geminal diphosphonate polymers described in European Patent Publication 0.321.233 can be used herein as AEAs, provided they naturally contain the above-defined organic retention enhancing groups or include modification.

In an aspect of the invention, the oral preparation comprises a carrier acceptable for use in the mouth, an effective anti-plaque amount of a substantially water-insoluble non-cationic antibacterial agent, and an antibacterial property enhancing agent with an average molecular weight of 1000 up to 1,000,000 containing at least one release-enhancing functional group and at least one organic retention-enhancing group, which agent with these groups is free or substantially free of water-soluble alkali metal or ammonium synthetic anionic linear polymeric polycarboxylate salts with a molecular weight of 1,000 to 1,000,000.

According to another embodiment, the AEA may comprise a synthetic anionic polymeric polycarboxylate. Although not used in the present invention for collaboration with polyphosphate anti-tartar agent, synthetic anionic polymer polycarboxylate with a molecular weight of 1000 to 1000,000, preferably 30,000 to 500,000, has been used as an inhibitor of alkaline phosphatase enzyme to optimize the anti tartar activity of linear molecularly dehydrated polyphosphate salts, as described in U.S. Patent No. 4,627,977 to Gaffar et al. In British Patent Publication No. 2,200,551, the polymeric polycarboxylate is indeed described as an optional ingredient in oral preparations containing linear molecularly dehydrated polyphosphate salts and substantially water-insoluble non-cationic antibacterial agent. In the context of the present invention, it is further noted that such polycarboxylate pronouncedly efficaciously improves the release and retention of the non-ionic antibacterial anti-plaque agent on tooth surfaces in the case of co-action with another ingredient (ie molecularly dehydrated polyphosphate), ingredient with which the polymeric polycarboxylate interacts is absent; e.g. when the ingredient with which the polymeric polycarboxylate interacts is, in particular, the non-cationic antibacterial agent.

Synthetic anionic polymeric polycarboxylates and their complexes with various cationic germicides, zinc and magnesium, have previously been described as anti-tartar agents as such, e.g. U.S. Patent 3,429,963 to Shedlovsky; U.S. Patent No. 4,152,420 to Gaffar; U.S. Patent No. 3,956,480 to Dichter et al .; U.S. Patent No. 4,138,477 to 40 Gaffar; and U.S. Patent No. 4,183,914 to Gaffar et at. It is noted that the synthetic anionic polymeric polycarboxylates described in these patents, if they contain retention-enhancing groups or contain modification, can be used in the compositions and methods of this invention and to the extent that the publications cited herein must reference are considered.

The synthetic anionic polymeric polycarboxylates used herein are well-known products which are often used in the form of their free acids or preferably in the form of their partially or even more fully neutralized water-soluble alkali metal (e.g., potassium and most preferably sodium) ) or ammonium salts. Preferred are 1: 4 to 4: 1 copolymers of maleic anhydride or maleic acid with another polymerizable ethylenically unsaturated monomer, preferably methyl vinyl ether / 50 maleic anhydride with a molecular weight (M.W.) of 30,000 to 1,000,000, most preferably 30,000 to 500,000. These copolymers are e.g. available as Gantrez e.g. AN 139 (M.W. 500,000), AN 119 (M.W. 250,000); and preferably S-97 pharmaceutical grade (M.W. 70,000) from the GAF Corporation.

Other polymeric polycarboxylates useful as AEA that contain retention enhancing groups or include modification include the substances described in the aforementioned U.S. Patent No. 3,956,480 55, such as the 1: 1 copolymers of maleic anhydride with ethyl acrylate, hydroxyethyl methacrylate, N-vinyl 2-pyrrolidone, or ethylene, the latter copolymer e.g. is available as Monsanto EMA No. 1103, M.W. 10,000, and EMA grade 61, and 1: 1 copolymers of acrylic acid with melhyl 19 or hydroxyethyl methacrylate, methyl or ethyl acrylate, isobutyl, isobutyl vinyl ether or N-vinyl-2-pyrrolidone.

Further active polymeric polycarboxylates described in U.S. Pat. Nos. 4,138,477 and 4,183,914 mentioned above, which contain retention improving groups or contain modification, include copolymers of maleic anhydride with styrene, isobutylene or ethyl vinyl ether, polyacrylic, polyitacon and polymaleic acids, and sulfoacrylic oligomers with a molecular weight of e.g. only 1000, available as Uniroyal ND-2.

Generally suitable are retention improving groups containing polymerized olefinically or ethylenically unsaturated carboxylic acids with an activated olefinic carbon-carbon double bond that functions easily in polymerization due to its presence in the monomer molecule in the alpha-beta position relative to a carboxyl group or part of a terminal methylene group. Illustrative of such acids are acrylic, methacrylic, ethacrylic, alpha-chloroacrylic, croton, beta-acryloxypropion, sorbine, alpha-chlorosorbine, cinnamon, beta-styrylacrylic, mucon, itacon, citracon -, mesacon, glutacon, aconitine, alpha-phenylacrylic, 2-benzylacrylic, 2-cyclohexylacrylic, angelic, umbellin, fumaric, maleic acids and anhydrides. Other olefinic monomers that can be copolymerized with such carboxyl monomers include vinyl acetate, vinyl chloride, dimethyl maleate and the like. Copolymers contain sufficient carboxyl salt groups for water solubility.

Also useful in the invention are so-called carboxyvinyl polymers described as toothpaste components in U.S. Pat. No. 3,980,767 to Chown et al., U.S. Pat. No. 3,935,306 to Roberts et al., U.S. Pat. No. 3,919,409 to Perla et al. U.S. Pat. No. 3,911,904 to Harrison, and U.S. Pat. No. 3,711,604 to Colodney et al. commercially available under the trade names Carbopol 934, 940 and 941 from BFGoodrich, these products essentially consisting of a colloidal water-soluble polymer of polyacrylic acid crosslinked with about 0.75 to about 2.0% polyallyl sucrose or polyallylpentae rythritol as crosslinking agent wherein the cross-linked structure and cross-links provide the desired improvement in the retention by hydrophobicity and / or physical entrapment of the antibacterial agent and the like. Polycarbophil is somewhat similar to this in that it is a polyacrylic acid cross-linked with less than 0.2% divinyl glycol, the lower amount, lower molecular weight and / or lower hydrophobicity of this cross-linking agent tending to provide little or no improvement in retention. An example of a more effective retention-improving cross-linking agent is 2,5-dimethyl-1.5-30 hexadiene.

The synthetic anionic polymeric polycarboxylate component is essentially a hydrocarbon with optionally halogen and O-containing substituents and bonds, such as e.g. present in ester, ether and OH groups, and is used in the compositions according to the invention in amounts by weight of 0.05-4%, preferably 0.05-3%, most preferably 0.1-2%.

The AEA can also include natural anionic polymeric polycarboxylates that contain retention enhancing groups. Carboxymethyl cellulose and other binding agents, gums, and film formers that lack the above defined release enhancing and / or retention enhancing groups are not effective as AEAs.

As illustrative of AEAs containing phosphinic acid and / or sulfonic acid release enhancing groups, 40 polymers and copolymers may be mentioned which contain units or parts derived from the polymerization of vinyl or allylphosphine and / or sulfonic acids which, as required. or 2 (or 3) carbon atom are substituted by an organic retention-enhancing group, e.g. with the formula - (X) n-R defined above. Mixtures of these monomers can be used, and copolymers of one or more inert polymerizable ethylenically unsaturated monomers such as those described above with respect to the useful synthetic anionic polymeric polycarboxylates can be used. It is noted that in this and other polymeric AEAs useful herein only one acid release enhancing group is usually bound to a particular carbon atom or other atom in the polymer backbone or branch thereof. Polysiloxanes containing pendant release enhancing groups and retention enhancing groups, or by modification, may also be used herein as AEAs. Also effective herein as AEAs are ionomers that contain release and retention enhancing groups or by modification. Ionomers are described on pages 546-573 of the Kirk Othmer Encyclopedia of Chemical Technology, 3rd Edition, Supplement Volume, John Wiley & Sons, Ine., Copyright 1984, the disclosure of which is incorporated herein by reference. Also effective as AEAs herein, provided they contain retention enhancing groups or include modification, are polyesters, 55 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 having an average molecular weight of 194716 6 contains from 1000 to 1,000,000, at least one release-enhancing functional group and at least one organic retention-enhancing group, which agent, containing the 2nd groups, is free or is substantially free of water-soluble synthetic alkali metal or ammonium anionic linear polymeric polycarboxylate salts with a molecular weight of 1,000 to 1,000,000.

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

Without being bound by theory, it is believed that the AEA, in particular polymer AEA, is generally an anionic film-forming material, which is believed to bind to land surfaces and form a continuous film over the surfaces, thereby the adherence of bacteria to land surfaces is prevented. It is possible that the non-cationic antibacterial agent forms a complex or other form of association with the AEA, thereby forming a film of a complex or the like over the land surfaces. The film-forming property of the AEA and the improved release and film-forming property of the AEA and the improved release and retention of the antibacterial agent on tooth surfaces, thanks to the AEA, have been found to render tooth surfaces unfavorable for bacterial accumulation, in particular because the direct bacteriostatic effect of the antibacterial agent controls bacterial growth. As a result, the oral preparation is made effective for plaque reduction by combining three modes of action: 1) improved release, 2) long retention time on tooth surfaces, and 3) prevention of bacterial adhesion to tooth surfaces. The same anti-plaque effectiveness is achieved on soft tissue in the mouth at or near the edge of the gums.

According to the present invention, the carrier acceptable for use in the mouth is effective in the sense that the substantially water-insoluble non-cationic antibacterial agent dissolves in saliva in an effective anti-plaque amount.

In the oral preparation, a carrier acceptable for use in the mouth comprises an aqueous phase with a wetting agent present. In a gel-like dental treatment agent, typically containing 5-30% by weight of a silicon-containing polishing agent, water is normally present in an amount of at least 3% by weight, generally 3-35%, and the total amount of wetting agent is, preferably glycerin and / or sorbitol, typically 6.5-75 or 80% by weight of the oral gel-shaped dental treatment composition. Reference herein to sorbitol typically refers to the material as it is commercially available in 70% aqueous solutions.

When the amount of the antibacterial agent is 0.25-0.35% by weight, the gel-like dental treatment agents do not require any further ingredient in the oral-suitable carrier for dissolving the antibacterial agent, although the presence of such an antibacterial agent solution is optional. When the amount of the antibacterial agent is less than 0.25% by weight, e.g. 0.01% to 0.25% by weight, dissolving agent should therefore be present to ensure sufficient dissolution in the saliva for effective anti-plaque action. When the amount of the antibacterial agent is above 0.35% by weight, e.g. 0.35 to 5%, therefore, the solvent should be present because otherwise a substantial portion of the antibacterial agent would remain insoluble.

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

When the oral preparation is a mouthwash liquid or liquid dental treatment agent, the oral carrier comprises at least one ingredient from the surfactant group, flavoring oils and non-toxic alcohols, each contributing to the antibacterial agent dissolving, and again the presence of such a solubilizer is optional.

When solubilizer is present in oral compositions of the present invention, it is typically in an amount of 0.5-20% by weight, while an amount of only 0.5% by weight is already sufficient when the amount of the substantially water-insoluble non-cationic antibacterial agent is low, ie up to 0.3% by weight. When larger amounts, such as at least 0.5 wt.% Antibacterial agent, are present and especially when also a silicon-containing polishing agent is present in an amount of 5-30 wt.%, It is desirable that at least 5 wt. normally up to 20% by weight of the solvent is present. It is noted that the dental treatment agent may exhibit a tendency to separate into liquid and solid parts when more than 5% by weight of the solvent is present.

The agent that is or may be present in saliva for dissolving the antibacterial agent may be included in the water-wetting carrier. Such solubilizers include wetting polyols such as propylene glycol, dipropylene glycol and hexylene glycol, cellosolves such as methyl cellosolve and ethyl cellosolve, vegetable oils and waxes containing at least 12 straight chain carbon atoms such as olive oil, castor oil and petrolates, and esters such as amyl acetate, ethyl acetate and benzyl benzoate. When "propylene glycol" is used herein, 1,2-propylene glycol and

1,3-propylene glycol. Significant amounts of polyethylene glycol, especially with a molecular weight of 600 or more, should be avoided because polyethylene glycol effectively inhibits the antibacterial action of the non-cationic antibacterial agent. When polyethylene glycol (PEG) 600 e.g. together with triclosan present in a weight ratio of triclosan: 1 PEG 600, the antibacterial activity of triclosan is reduced by a factor of about 16 compared to the value in the absence of the polyethylene glycol. I

According to aspects of the invention, an oral dental treatment composition may have a substantially gel-like character, such as a gel-shaped dental treatment agent. Such gel-shaped oral preparations contain silicon-containing dental polishing material. Preferred polishing materials include crystalline silica with particle sizes up to about 5 µm, an average particle size up to 1.1 µm, and an area up to 50,000 cm 2 / g, silica gel or colloidal silica and complex amorphous alkali metal aluminosilicate.

When clear or opaque gels are used for the eye, colloidal silica, such as products sold under the SYLOID brand such as Syloid 72 and Syloid 74, or under the SANTOCEL brand such as Santocel 100, or alkali metal aluminosilicate complexes (ie silicon oxide) are that is combined in its matrix with alumina) is particularly useful because they are compatible with a gel-like texture and have refractive indices that are close to the refractive indices of gel agent-liquid (comprising water and / or wetting agent) commonly used in dental treatment agents) systems.

The polishing material is generally present in the oral dental treatment compositions, such as toothpaste or gel compositions, in weight concentrations of 5 to 30%.

In the aspect of this invention, wherein the oral preparation is a dental treatment agent, a carrier acceptable for use in the mouth, which comprises an aqueous phase with a wetting agent that is preferably glycerin and / or sorbitol, water normally present is in an amount of 15-40% by weight, and glycerin and / or sorbitol are typically present in a total amount of 20-75% by weight of the oral dental treatment composition, usually in an amount of 25-60%. Reference herein to sorbitol again refers to the material that is normally commercially available in 70% aqueous solutions.

In this invention, the oral dental treatment composition can be substantially pasty in nature, such as a toothpaste (dental cream), although it is used when silicon-containing polishing agent (which is not generally the case because such material is typically not used in amounts above 35 wt%) ) may be gel-like in character. The carrier of the oral dental treatment composition contains polishing material acceptable for dental purposes, examples of such polishing materials being water-insoluble sodium metaphosphate, potassium metaphosphate, tricalcium phosphate, dicalcium phosphate dihydrate, anhydrous dicalcium phosphate, calcium carbonate, silicate aluminum oxide, silicate aluminum oxide, silicate alumina phosphate with hard polishing materials, such as calcined aluminum oxide and zirconium silicate, which material comprises the powdered thermosetting resins described in U.S. Pat. No. 3,070,510, such as melamine-phenolic resins 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 also comprise small amounts of soluble material. Insoluble sodium metaphosphate, for example, can be formed in any suitable manner as described by Thorpe's Dictionary of Applied Chemistry, Vol. 9.4th edition, p. 510-511 The forms of insoluble sodium metaphosphate, known as Madrell's salt, and Kurrol's salt, are further examples of suitable materials These metaphosphate salts exhibit only very low solubility in water and are therefore commonly referred to as insoluble metaphosphates (IMP) A minor amount of soluble phosphate material is present therein as impurities, usually up to 4% by weight The amount of soluble phosphate material believed to include a soluble sodium trimetaphosphate in the case of insoluble metaphosphate can be reduced or removed by washing with water, if desired. The insoluble alkali metal metaphosphate is normally used in the form of a powder with 55 particle sizes such that no more than 1% of the material is greater than 37 µm.

Hydrated alumina is an example of a polishing material that is essentially non-ionic in nature. Normally it has a small particle size, i.e. at least 85% of the particles are less than 20 µm in 194716 and is classified as gibbsite (alpha-alumina trihydrate) that is normally chemically represented as Al 2 O 3 .3H 2 O or Al (OH) a. The average particle size of gibbsite is normally about 6-9 µm. A typical quality has the following particle size distribution: 5 ------ - size (pm) percentage <30 94-99 <20 85 - 93 10 <10 56 - 67 <5 28 - 40

The polishing material is generally present in cream-shaped, pasty or gel-like compositions in amounts of 15 to 75% by weight.

Toothpastes or dental creams, as well as gel-shaped dental agents, typically contain a natural or synthetic thickener or gel-forming agent in amounts of about 0.1 to about 10, preferably 0.5 to 5%. A suitable thickener * is synthetic colloidal magnesium alkali metal silicate complex clay, e.g. is commercially available as Laponite (e.g. CP, SP 2002, D) from Laporte Industries Limited. Laponite D analysis shows, by weight, approximately the following composition: 58.00% SiO 2, 25.40% MgO, 3.05% ββ, Ο, 0.98% U 2 O, and some water and spores metal. Its actual specific gravity is 2.53 and its apparent bulk density (g / ml at 8% moisture) is 1.0.

Other suitable thickeners or gelling agents or thickeners include Irish moss, iota-carrageenan, tragacanth gum, starch, polyvinylpyrrolidone, hydroxyethylpropylcellulose, hydroxybutylmethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose (eg available as Natrosol), sodium carboxymethylcellulose, and especially when silicon-containing polishing is present colloidal silica as materials available as the fine powders Syloid 244 or Sylodent 15.

In the aspect of the present invention, wherein the oral preparation is a mouthwash liquid or liquid dental treatment agent, which has a substantially liquid character, the carrier is normally a water-alcohol mixture especially in a mouthwash liquid. In general, the weight ratio of water to alcohol is in the range of 1: 1 to 20: 1, preferably 3: 1 to 10: 1, and more preferably 4: 1 to 6: 1. The total amount of water alcohol mixture in this type of preparation is normally in the range of 70 to 99.9% by weight. The alcohol is a non-toxic alcohol such as ethanol or isopropanol. Humectants such as glycerin and sorbitol can be present in amounts of 10-30% by weight. Liquid dentifrices typically contain 50 to 85% water, may contain 0.5-20% by weight of non-toxic alcohol, and may also contain 10-40% by weight of wetting agent such as glycerin and / or sorbitol. Reference herein to sorbitol refers to the material that is normally commercially available in 70% aqueous solutions. Ethanol is the preferred non-toxic alcohol. The alcohol is believed to contribute to the dissolution of the water-insoluble non-cationic antibacterial agent such as is believed to do the flavoring oil.

As stated, the non-cationic antibacterial agent is substantially insoluble in water. In the present invention, however, where the AEA, such as polycarboxylate, is present in the mouthwash liquid or liquid dental treatment agent, it is believed that the organic surfactant, the flavoring oil or the non-toxic alcohol help dissolve the antibacterial agent thereby this is helped to reach soft tissue in the mouth at or near the gums as well as tooth surfaces. Organic surfactants and / or flavoring oils may also help dissolve the antibacterial agents as optional ingredients in oral dental treatment compositions.

Organic surfactants are also used in the compositions of the present invention to achieve a stronger prophylactic effect, to contribute to achieving a thorough and complete dispersion of the anti-plaque antibacterial agent throughout the oral cavity, and the compositions herein make it more cosmetically acceptable. The organic surfactant material is preferably anionic, non-ionic or ampholytic in nature and it is preferred that a detergent material is used as the surfactant, which imparts detergent and foaming properties to the composition. Suitable examples of anionic surfactants are water-soluble salts of higher fatty acid monoglyceride monosulfates, 9 194716

such as the sodium salt of the monoglyceride monosulphate of hydrogenated coconut oil fatty acids, higher alkyl sulphates such as sodium lauryl sulphate, alkyl aryl sulphonates such as sodium dodecyl benzene sulphonate, higher alkyl sulphoacetates, higher fatty acid esters of 1,2-dihydroxypropane sulphonate, and the predominantly saturated higher aliphatic aliphatic amides, such as carbon atoms in the fatty acid, alkyl, or acyl groups, and the like. Examples of the latter amides are N-lauroyl sarcosine, and the sodium, potassium, and ethanolamine salts of N-lauroyl, N-myristoyl, or N-palmitoyl sarcosine, which should be essentially 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 because these materials exhibit a long-lasting and pronounced effect in inhibiting acid formation in the oral cavity due to carbohydrate degradation, in addition to the fact that they affect the solubility of dental enamel. reduce slightly in acidic solutions. Examples of water-soluble non-ionic surfactants are condensation products of ethylene oxide with various reactive hydrogen-containing compounds that can react with them and have long hydrophobic chains (e.g. aliphatic chains with about 12-20 carbon atoms), which condensation products ("ethoxamers") I

Contain hydrophilic polyoxyethylene pieces, such as condensation products of poly (ethylene oxide) with fatty acids, fatty alcohols, fatty amides, polyhydric alcohols (e.g. sorbitan monostearate) and polypropylene oxide (e.g. Pluronic materials).

Surfactant is normally present in amounts of 0.5-5% by weight, preferably 1-2.5%.

When the oral preparation is a liquid dental treatment agent, the natural or synthetic thickening or gel-forming agent as described is normally present in amounts of 0.1 to 10, preferably 0.5 to 5%.

In general, liquid dental treatment products do not contain a polishing agent. However, as described in U.S. Pat. No. 3,506,757 to Salzmann, 0.3-2.0% by weight of a high molecular weight polysaccharide may be greater than 1,000,000 comprising mannose, glucose, potassium glucuronate, and acetyl groups in a ratio of about 2 : 1: 1: 1 are used as a suspending and thickening agent in a liquid dentifrice, which is also about 10-20% of a polishing material such as hydrated alumina, dicalcium phosphate dihydrate, calcium pyrophosphate, insoluble sodium metaphosphate, anhydrous dicalcium phosphate, calcium carbonate magnesium magnesium oxide , silica, mixtures thereof and the like.

Without being bound by a theory whereby the advantages according to the invention are achieved, it is believed that an aqueous, moisturizing carrier is normally solubilized in surfactant micelles in the mobile phase (ie without gelling agent and polishing agent, if present in a dentifrice composition) . The mobile phase solution of the dental treatment agent can be diluted during use by saliva that causes a precipitate of triclosan. Thus, it is 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 provide an excellent anti - exert plaque effect on the soft tissues at the edge of the gums. The same comments apply to other water-insoluble non-cationic antibacterial agents described herein.

The oral dental treatment composition may also contain a source of fluoride ions or a fluorine-providing component as an anti-caries agent in an amount sufficient to provide 25-5000 ppm of fluoride ions. These compounds may be slightly soluble in water or may be completely soluble in water. Characteristic of these agents is their ability to release fluoride ions into water and the fact that they exhibit virtually no undesirable reaction with other compounds in the oral preparation. These materials include inorganic fluoride salts such as soluble alkali metal, alkaline earth metal salts, e.g. sodium fluoride, potassium fluoride, ammonium fluoride, calcium fluoride, a copper fluoride such as copper (I) fluoride, zinc fluoride, barium fluoride, natriumfluorosilicaat, ammoniumfluorosili silicate, natriumfluorozirkonaat, ammoniumfluorozirkonaat, sodium monofluorophosphate, sodium calcium pyrophosphate, and aluminiummono- and -difluorofosfaat. Alkali metal and tin fluorides, such as sodium and tin (11) fluorides, sodium monofluorophosphate (MFP), and mixtures thereof are preferred.

The amount of the fluorine-supplying compound is somewhat dependent on the type of compound, its solubility, and the type of oral preparation, but it must be a non-toxic amount, which generally makes up 0.0005 to 3.0% in the preparation . In a dental treatment preparation, e.g. a dental gel, an amount of such a compound that releases up to 5000 ppm of fluoride ions, based on the weight of the composition 55, is considered satisfactory. Any suitable minimum amount of such a compound can be used, but it is preferable that sufficient compound is used to release 300-2000 ppm, more preferably 800 to 1500 ppm fluoride ions.

194716 10

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

It is noted that the oral preparations, as usual, must be sold or otherwise marketed in suitably labeled packages. A gel-like dental treatment agent will usually be packaged in a compressible tube, typically made of aluminum, coated lead or plastic, or another squeezable, pump-operated or pressurized dispenser for releasing the contents, labeled whereby it is described essentially as a gel-like tooth treatment agent or the like.

Various other materials may be included in the oral compositions of the invention such as brighteners, preservatives, silicones, chlorophyll compounds and / or ammonized material such as urea, diammonium phosphate, and mixtures thereof. These adjuvants, if present, are included in the compositions in amounts that do not substantially adversely affect the desired properties and characteristics. Significant amounts of zinc, magnesium, and other metal salts and materials, which are generally soluble and would form complexes with active components of the present invention, should be avoided.

Furthermore, any suitable flavoring or sweetening material can also be used. Examples of suitable flavoring ingredients are flavoring oils, e.g. oil of hart mint, peppermint, evergreen, sassefras, clove, sago, eucalyptus, marjoram, cinnamon, lime, and orange, and methyl salicylate. Suitable sweetening agents include sucrose, lactose, maltose, xylitol, sodium cyclamate, perillartin, AMP (aspartylphenylalanine, methyl ester), saccharin and the like. Flavoring and sweetening agents can each or together preferably form 0.1-5% or more of the composition. Moreover, it is believed that the flavoring oil, as well as the surfactant, contributes to the 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 present invention is preferably applied regularly to dental enamel and soft tissues in the mouth, especially at or near the edge of the gums, such as every day or every 2nd or 3rd day, or preferably 1 to 3 times a day, at a pH of 4.5 to 10, generally 5.5 to 8, preferably 6-8 and most preferably 6.5 to 7.5, for at least 2 weeks. Even with such a pH below 5, tooth enamel is not descaled or otherwise damaged. The pH can be adjusted with acid (e.g. citric acid 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 compositions according to the invention can be included in lozenges, or in chewing gum or other products, e.g. by stirring in a hot gum base or by coating the outer surface of a gum base for which, for example, jelutong, rubber latex, vinylite resins, etc. can be added, optionally with conventional plasticizers or softeners, sugar or other sweeteners or carbohydrates such as glucose, sorbitol and the like.

The following examples further illustrate the present invention. All amounts mentioned herein and in the claims are by weight unless otherwise indicated.

Example 1

The following dental treatment agent was prepared: 45 parts

A B

glycerin 10.00 propylene glycol - 10.00 sorbitol (70%) 25.00 25.00 50 iotacarrageenan 0.60 0.60

Gantrez S-97 2.00 2.00 sodium saccharin 0.40 0.40 sodium fluoride 0.243 0.243 sodium hydroxide (50%) 1.00 1.00 55 titanium oxide 0.50 0.50 silica polishing agent (Zeodent 113) 20.00 20 00 11 194716

A B

silica thickener (Sylox 15) 5.50 5.50 sodium lauryl sulfate 2.00 2.00 water 31.507 31.507 triclosan 0.30 0.30 flavoring oil 0.95 0.95 10 The dental treatment agent A defined above supplies triclosan to the teeth and the soft gum tissue is essentially as good off as dental treatment agent B, which contains a special solvent for triclosan. M.a.w. a special dissolving agent for the effectiveness of the dental treatment agent of the present invention is not necessary. Furthermore, a corresponding dental treatment agent in which the Gantrez polycarboxylate is absent delivers much worse triclosan.

In the above example, improved results can also be achieved by replacing triclosan with other antibacterial agents described herein such as phenol, thymol, eugenol and 2,2'-methylenebis (4-chloro-6-bromophenol) and / or by replacing Gantrez by other AEAs, such as a 1: 1 copolymer of maleic anhydride and ethyl acrylate, sulfoacrylic oligomer, Carbopols (eg 934), and polymers of alpha or beta-styrene phosphonic acid monomers and copolymers of these monomers with each other or with other ethylenically unsaturated polymerizable monomeric monomeric polymeric monomeric acid .

Example 2

The following liquid phase dentifrice solutions were tested for uptake and retention of triclosan on saliva-coated HA disks according to the test procedures described in Example 1 with the reported results:

Share ingredients share

30 A B C D

sorbitol (70% solution) 30.0 30.0 30.0 30.0 glycerol 9.5 9.5 9.5 propylene glycol 0.5 0.5 0.5 0.5 SLS 20.0 20.0 20.0 20.0 35 NaF 0.243 0.243 0.243 0.243 flavoring oil 0.95 0.95 0.95 0.95 triclosan 0.3 0.3 0.3 0.3 water 56.507 54.507 54.507 54.507 poly (beta (styrene phosphonic acid) 2.0 poly (alpha styrene phosphonic acid) 2.0 polyvinyl alcohol 2.0

Adjusted to pH 6.5 with NaOH

triclosan uptake in pg on saliva coated 31.0 174.0 86.0 36.0 HA discs 45 Retention of triclosan on saliva coated HA discs after: initially 183.0 30 minutes 136.0 1 hour 105, 0 50 3 hours 83.0

The above results show that solution (D) containing polyvinyl alcohol, not an AEA below, gives a triclosan uptake of only 36.0, which is very similar to the 55 uptake of 31.0 of the control solution (A) without additive. In contrast, solution (C) with poly (alpha-styrene phosphonic acid) gives an uptake of 86.0, more than twice the uptake in the case of solutions (A) and (D), and solution (B) with poly (beta-styrene phosphonic acid) ) gives an uptake of approximately 19471612 5 * times that of solutions (A) and (D), which further appears to indicate superior results in the case of vicinal substitution of the release enhancing group. The above mentioned results also show the surprisingly good retention of triclosan on the HA disks with time, obtained with solution (B) containing poly (betastyrene phosphonic acid) (molecular weights about 3000-10,000).

5

Example 3

The effect of synthetic anionic linear polycarboxylate on the uptake, retention and release of land surfaces of water-insoluble non-cationic antibacterial agent is assessed in vitro on a saliva-coated hydroxyapatite disc and on flaked mondepitheal cells. The in vitro assays can be correlated with the in vivo release, and retention on surfaces in the mouth.

For the test of delivery of antibacterial agent to a saliva-coated hydroxyapatite disc, hydroxyapatite (HA), obtained from Monsanto Co., is washed extensively with distilled water, collected by vacuum filtration, and dried overnight at 37 ° C. The dried HA is ground into a powder with a mortar and pestle. 150.00 mg of the HA is introduced into the chamber of a KBR pill matrix (Barnes Analytical, Stanford, CT.) And compressed for 6 minutes at 10,000 pounds (4536 kg) in a Carver Laboratory press. The resulting 13 mm disks are sintered at 800 ° C for 4 hours in a Thermolyne oven. Parafilm-stimulated full saliva is collected in an ice-cooled glass beaker. The saliva is clarified by centrifugation at 15,000 x g (reverse gravity) for 15 minutes at 4 ° C. Sterilization of the clarified saliva is performed at 4 ° C with stirring by irradiating the sample for 1.0 hour with UV light.

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 skin of saliva is formed by incubating the disc overnight at 37 ° C with continuous shaking in a water bath. After this treatment, the saliva is removed and the discs are treated with 1.00 ml of a solution, contain the antibacterial agent (triclosan), dental treatment agent-liquid phase solution and are incubated in the water bath with continuous shaking at 37 ° C. After 30 minutes, the disc is transferred to a new tube and 5.00 ml of water are added, followed by gently shaking the disc with a Vortex. The disc is then transferred to a new tube and the washing procedure repeated twice. Finally, the disc is carefully transferred into a new tube, thereby avoiding the transfer of liquid together with the disc. Thereafter, 1.00 ml of methanol is added to the disk and vortexed vigorously. The sample is left at room temperature for 30 minutes, adsorbed tricloxane being extracted into the methanol. The methanol is then filtered off and clarified by centrifugation in a Beekman Microfuge 11 for 5 minutes at 10,000 rpm. After this treatment, the methanol is transferred to HPLC (high performance liquid chromatography) vials for antibacterial agent determination. All experiments use triplicate samples.

For the test of antibacterial retention on a saliva-coated HA disc, a saliva-coated HA disc as described above is treated with dentifrice suspensions. After incubation for 30 minutes at 37 ° C, the HA disk is removed from the dental treatment 40 suspension, washed twice with water, and then incubated again with parafilm-stimulated full human saliva cleared by centrifugation. After incubation at 37 ° C with constant shaking for several periods, the HA disk is removed from the saliva, and the amount of antibacterial agent (triclosan) retained on the disk and released into the saliva is analyzed by an analytical method using HPLC.

45 To determine the release of antibacterial agent to mondepitheal cells, release is measured to determine the effect of PVM / MA on the release of antibacterial agent (triclosan) to soft tissue in the mouth from a dental treatment product. Mondepitel cells are collected using a wooden applicator stick by gently rubbing the mucous membranes of the mouth. The cells are suspended in Resting Saliva Salts (RSS) Buffer (50 nM NaCl, 1.1 nM CaCl 2, and 0.6 nM 50 KH 2 PO 4, pH 7.0) to 5 - 6 x 10 * cells / ml, with a hemocytometer is used to count the cells, and are kept in ice until use. Of the cell suspension previously incubated at 37 ° C in a water bath, 0.5 ml is added to 0.5 ml of the antibacterial agent test solution and incubated at 37 ° C. The antibacterial agent solution in the incubation mixture is diluted at least 10 times to lower the surfactant concentration and prevent destruction of cell membranes by the surfactant. After a 30 minute incubation, the cells are harvested by centrifugation for 5 minutes at 5000 rpm in the Beekman Microfuge 11. The pellet collected cells are washed three times with RSS buffer and treated with 1.5 ml of methanol. The sample is mixed vigorously and 194716 is analyzed for antibacterial agent by the HPLC method.

Dental treatment agents were prepared with the following formulations: 5 parts

A B

propylene glycol (1.2) 10.00 10.00 lota-carrageenan 0.75 0.75 10 Gantrez S-97 - 2.00 titanium dioxide 0.50 0.50 sorbitol (70%) 30.00 30.00 sodium fluoride 0.332 0.332 sodium saccharin 0.40 0.40 15 silica thickener (Sylodent 15) 3.00 3.00 silica polishing agent (Zeodent 113) 20.00 20.00 triclosan 0.20 0.20 sodium lauryl sulfate 2.00 2, 00 flavoring oil 0.95 0.95 ethyl alcohol 1.00 1.00 water qs to 100.00 to 100.00

The uptake of triclosan on the saliva-coated hydroxyapatite disc and on monothelial cells with and without the polymeric polycarboxylate, Gantrez S-97, is listed in Table A below:

TABLE A

Dental Treatment Agent Triclosan Inclusion In pg x 105 mouth-in pg on saliva epithelial cells coated disc A 25.0 38.0 B 54.0 96.0 35 -

These results show that the Gantrez material (present in dental treatment agent B) greatly improves the release and uptake of triclosan on the saliva-coated hydroxyapatite disk and on the flaked monothelial cells 40 Similar results are obtained when the dental treatment agents contain 0.30 parts of triclosan .

Example 4

In tests with hydroxyapatite disks coated with saliva and with flaked mondepitheel 45 cells, which tests are different from the tests mentioned in Example 1, said dental treatment agent B was 2.00% Gantrez S-97 and 0.20% containing triclosan, 10.00% propylene glycol and 2.00% sodium lauryl sulfate and an equivalent form of dental treatment agent (BO apart from the presence of 0.30% triclosan, compared to a commercially available dental treatment agent (C) containing hydrated alumina polishing agent and (a) 0.2% triclosan, (b) no Gantrez material, (c) no 50 propylene glycol, (d) 0.5% zinc citrate, (e) 2.5% surfactants, (f) sodium monofiuorophosphate and hydrated alumina polishing agent, and the dentifrice composition below (CO corresponding to the commercially available dentifrice C except for the presence of 0.30% triclosan: 194716 14

Dental treatment agent O

5% sorbitol (70%) 27.00 sodium carboxymethyl cellulose 0.80 sodium monofluorophosphate 0.85 zinc citrate 0.50 10 sodium saccharin 0.18 water 16.47 hydrated alumina polishing agent 50.00 ethanol 0.20 sodium lauryl sulfate 1.875 15 sodium dodecylbenzene sultonate 0.625 0.30 flavor 1.20 Because the dental treatment agents C and C 'contain a total of 2.50% surfactant, more surfactant is available for dissolving triclosan than in the dental treatment agents B and B' containing 2.00%. However, the propylene glycol present in the sllicium-containing polishing agent of the dental treatment agents B and B '(which is not present in the hydrated alumina polishing agent of the dental treatment agents C and O') ensures optimum dissolution of triclosan.

The advantage of the dental treatment agents B and B '(containing propylene glycol and Gantrez) over the dental treatment agents C and C'. In the uptake of triclosan on saliva-coated hydroxyapatite disks and on flaked mondepitheal cells, table B is shown below :

TABLE B

Delivery of triclosan to saliva coated mondephithelial cells in pg x 35 hydroxyapatite disc (in pg) 10® epithelial cell dental treatment agent B 41.1 101.6 B '77.4 142.0 C 20.4 61.0 40 C' 42, 6 100.0

Further experiments with dental treatment agent B '(0.3% triclosan; Gantrez; propylene glycol) in a 50% suspension of the dental treatment agent to determine the retention of triclosan on the saliva-coated 45 hydroxyapatite disk over a period of time, allows retention of excellent levels of triclosan, as shown in Table C. below.

TABLE C

50 Retention of triclosan adsorption from dental care agent suspension Time (in minutes) Retention of triclosan (pg / disc) 0 70 55 30 60 60 70 15 194716 TABLE C (continued)

Retention of triclosan adsorption from dental care agent suspension 5 120 65 180 57 240 59 10 These results indicate that dental treatment agents containing triclosan, Gantrez material and propylene glycol have improved release of triclosan on and retention on tooth surfaces and soft surfaces in the oral cavity giving better anti-plaque and antibacterial effects.

Example 5

For comparison, the following formulations a and b were prepared:

Dental treatment agent% 20 - - ab ab glycerin 10.00 - propylene glycol - 10.00 lota-carrageenan 0.60 0.60 25 sorbitol (70%) 25.00 25.00 sodium saccharin 0.40 0, 40 sodium fluoride 0.243 0.243 titanium dioxide 0.50 0.50

Gantrez S-97 2.00 2.00 water 29.157 29.175

NaOH (50%) 2.00 2.00

Zeodent 113 (silica polishing agent) 20.00 20.00

Sylodent 15 (silica thickener) 5.50 5.50 flavoring agent 1.10 1.10 35 triclosan 0.50 0.50 sodium lauryl sulfate 2.00 2.00 ethanol 1.00 1.00 40 Formulation a is a dental treatment that Gantrez polycarboxylate, with 0.5% triclosan as an antibacterial anti-plaque agent, and does not contain any solubilizer. In formulation b, the dissolving agent is propylene glycol.

Formulation a results in poor release of triclosan on mondepitheal cells while formulation b is clearly effective.

45 The results mentioned above show an excellent release of triclosan dental treatment agent.

Example 6

A closed study was conducted on a group of volunteers to determine the effects of certain 50 dental treatment agents on their effect on the renewed growth of plaque according to the method described by Addy, Wilis and Moran, J. Clin. Perio, 1983, Vol. 10, pp. 89-99.

The dental treatment agents tested include a placebo control that did not contain triclosan (i) and a dental treatment agent according to the invention, which contains 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 contained 55 (ii). The formulations of the dental treatment agents were as follows: 194716 16 parts 5 (i) (1)% placebo invention polyethylene glycol 600 3.00 glycerin 25.00 10 propylene glycol - 10.00 sorbitol (70%) 41.617 25.00 sodium carboxymethylcellulose 0 35 lota-carrageenan - 0.60 sodium benzoate 0.50 sodium saccharin 0.20 0.40 sodium fluoride 0.243 0.243 silica polishing agent (Zeodent 113) 18.00 20.00 silica thickener (Sylox 15) 5.50 5.50 water 8.00 28.777 20 Gantrez S-97 - 2.00 triclosan - 0.30 titanium dioxide 0.50 0.50 sodium lauryl sulfate 1.20 2.50 flavor 0.89 1.10 ethyl alcohol 1.00 sodium hydroxide (50%) 2.00

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

Because smaller amounts of propylene glycol can dissolve the 0.3% triclosan present in toothpaste (ii), equal 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 can also effectively deliver dipropylene glycol, hexylene glycol, methyl cellosolve, ethyl cellosolve, olive oil, castor oil, petrolates, amylacetate, ethyl acetate, glyceryl tristearate, and benzyl benzoate to soft tissue in the mouth. Similar results are furthermore also expected when propylene glycol or other solubilizing agents are omitted from toothpaste (ii) containing 0.3% triclosan.

Example 7

The following dental treatment agents according to the invention were prepared: parts 45

A B

glycerin - 20.00 propylene glycol 10.00 0.50 sorbitol (70% * s) 25.00 19.50 50 sodium carboxymethylcellulose - 1.10 lota-carrageenan 0.600 sodium saccharin 0.40 0.30 sodium fluoride 0.243 0.243 silica polishing agent (Zeodent 113) 20.00 20.00 55 silica thickener (Sylox 15) 5.50 3.00 water 28.777 15.307 17 194716 parts 5 Gantrez S-97 2.00 2.00 triclosan 0.50 0.30 titanium dioxide 0.50 0.50 sodium auryl sulfate 2.50 2.00 flavor 1.10 0.95 ethanol 1.00 sodium hydroxide (50%) 2.00 1.60

In the above examples, better results can also be obtained by replacing triclosan with other antibacterial agents as 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, sulfoacrylic oligomers, Carbopols (eg 934), polymers of monomeric alpha or beta-styrene phosphonic acid and copolymers of these styrene phosphonic acid monomers with each other or with other ethylenically unsaturated polymerizable monomers such as vinyl phosphonic acid.

Example 8

The following dental treatment agent was prepared: 25 parts

ABC

alpha-alumina trihydrate 48.00 48.00 48.00 propylene glycol - 0.50 0.50 sorbitol (70%) 21.70 21.70 21.70

Gantrez S-97 (13% solution) 15.00 15.00

Gantrez S-97 (powder) - 2.00 sodium auryl sulfate 2.00 2.13 2.13 sodium saccharin 0.30 0.30 0.30 sodium hydroxide (50%) 1.20 1.20 1.20 flavoring agent 0, 95 0.95 0.95

Irish moss 1.00 - sodium carboxymethyl cellulose - 1.00 1.00 40 sodium monofluorophosphate 0.76 0.76 0.76 titanium dioxide - 0.50 0.50 triclosan 0.30 0.30 0.30 water q.s. up to 100.00 q.s. up to 100.00 q.s. up to 100.00 45

The aforementioned dental treatment agents deliver triclosan to the teeth and soft tissue areas of the gums to a much greater extent than corresponding dental treatment agents in which the Gantrez polycarboxylate is absent.

Example 9

The following dental treatment agents were prepared: parts 55 - glycerin 22.00 10.00 194716 18 parts 5 sorbitol (70%) - 17.00 sodium carboxymethyl cellulose 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 triclosan 0.30 0.30 sodium lauryl sulfate 1, 1.20 flavor 0.89 0.89 water qs up to 100.00 q.s. up to 100.00

The dental treatment agents mentioned above deliver triclosan to saliva coated hydroxyapatite discs much more effectively than corresponding dental treatment agents in which the Gantrez * polycarboxylate is absent.

Example 10

The following anti-plaque dentifrice was prepared: 25 parts of glycerin 15.00 propylene glycol 2.00 sodium carboxymethyl cellulose 1.50 water 24.93 vinyl methyl ether / maleic anhydride copolymer (42% solution) 4.76 sodium monofluorophosphate 0.76 35 sodium saccharin 0.30 insoluble sodium metaphosphate 47.00 titanium dioxide 0.50 sodium lauryl sulfate 2.00 triclosan 0.30 40 flavor 0.95

In the above examples, improved results can also be achieved when triclosan is replaced by phenol, 2,2'-methylene bis (4-chloro * 6-bromophenol), eugenol and thymol, and / or 45 when Gantrez is replaced by other AEAs such as Carbopols (eg 934) or styrene phosphonic acid polymers with molecular weights in the range of about 3000-10,000, such as poly (beta-styrene phosphonic acid), copolymers of vinyl phosphonic acid with beta-styrene phosphonic acid, and poly (alpha-styrene phosphonic acid), or sulfoacrylic oligomeric oligomeric oligomer or a 1: 1 copolymer of maleic anhydride with ethyl acrylate.

Example 11

Triclosan containing mobile phases of dental treatment.

Components Composition,% (w / w) 55 -----——-

A B

· ------ · 19 194716

Components Composition,% (w / w) 5 sorbitol (70% S) 53.33 40.00 water 40.48 39.15

Gantrez S (15%) - 13.33

NaOH (50%) 1.33 saccharin 0.40 0.40 sodium fluoride 0.32 0.32 flavoring oil 1.47 1.47 sodium lauryl sulfate 3.33 3.33 triclosan 0.67 0.67 15 ~~

The concentration of the above components is 1.33% dental treatment agent level in view of the 25% abrasive agent that may be required to make a complete dental treatment agent.

The above-mentioned mobile phases of the said dental treatment agent formulations are tested for triclosan incorporation on saliva-coated HA disks. The results are in the table below:

TABLE

25 Absorption of triclosan by saliva-coated hydroxyapatite discs (HA) from diluted and undiluted mobile phases of dental treatment

A B

% triclosan 0.67 0.67 30 ionic strength (M / L) (calculated) 0.375 - pH 8.7 7.6 uptake of triclosan (pg / disk), undiluted 55 122 35 The above results show more than 2-fold increase in triclosan uptake achieved with the B formulation containing Gantrez, relative to the A formulation without the Gantrez.

Example 12 40 Concentration and uptake of triclosan by HA from supernatant of 1: 1 dental treatment agent / water suspensions.

Dental treatment containing 0.5% Triclosan (pg / ml) In Triclosan incorporation 45 triclosan, 2.5% sodium lauryl sulfate supernatant of 1: 1 pg / disk suspension 25% hydrated silica + 1.5% Gantrez S-97 1,650 52 50 % alumina + 1.5% Gantrez S-97 1,905 74 50 -

Supernatants of 1: 1 dental treatment agent / water suspensions of the above-mentioned dental treatment means are tested for the concentration of triclosan in the supernatant and for the triclosan uptake on saliva coated HA disks. The results indicate that the use of 50% 55 alumina abrasive greatly increases triclosan under low 1: 1 dilution conditions (from 1650 to 1905), resulting in a significant increase in triclosan uptake (from 52 to 74).

194716 20

Example 13

The mouthwash fluids below provide effective plaque reduction by increasing the uptake and retention of triclosan on surfaces in the mouth.

5 -

ABODE

parts

Gantrez S-97 0.24 0.25 0.25 0.25 0.25 10 glycerin 15.00 10.00 15.00 10.00 15.00 ethanol - 12.50 12.50 propylene glycol - 5.00 - 5.00

Pluronic F108 2.00 (polyoxyethylene / polyoxypropylene block copolymer) sodium lauryl sulfate - - 0.20 0.20 0.20 triclosan 0.10 0.10 0.06 0.06 0.06 0.03 flavoring oil 0.40 0.40 0 40.40 0.40 20 water qstot 100.00 100.00 100.00 100.00 100.00

Example 14 The following liquid dentifrices are also effective in reducing plaque by increasing the uptake and retention of triclosan on surfaces In the mouth: 30 parts ABC glycerin 20.00 20.0 -

Gantrez S-97 0.3 0.3 0.3 35 high molecular weight 0.8 - 1.0 weight polysaccharide, the molecule containing mannose, glucose, potassium glucuronate and acetyl groups in a ratio of about 2: 1: 1: 1 40 sodium benzoate 0.5 0.5 0.5 saccharin sodium 0.5 0.5 0.5 water 61.3 73.1 71.6 sodium lauryl sulfate 3.0 3.0 3.0 insoluble sodium metaphosphate 10, 0 - 10.0 45 anhydrous dicalcium phosphate 1.0 - 2.5 flavoring oil 2.5 2.5 2.5 ethyl alcohol - - 10.0 triclosan 0.1 0.1 0.1 50

In the above examples, improved results can also be achieved when triclosan is replaced by phenol, 2,2'-methylene-bis (4-chloro-6-bromophenol), eugenol and thymol, and / or when Gantrez is replaced by other AEAs such as Carbopols (eg 934) or styrene phosphonic acid polymers with molecular weights in the range of about 3000-10,000 such as poly (beta-styrene phosphonic acid), copolymers of vinyl phosphonic acid with beta-styrene phosphonic acid, and poly (alpha-styrene phosphonic acid), or sulfoacrylic oligomers, a 1: 1 copolymer of maleic anhydride with ethyl acetate.

The invention has been described with reference to certain preferred embodiments and it will be apparent

Claims (3)

21 194716 that modifications and variations thereof, which are obvious to those skilled in the art, fall within the scope of this application and the scope of the appended claims. 5 Conclusions An oral preparation comprising an effective antiplaque amount of a substantially water-insoluble non-cationic antibacterial agent in an orally acceptable carrier which allows the antibacterial agent to dissolve in an effective antiplaque amount in saliva with the Characterized in that furthermore contains 0.05-4% by weight of an antibacterial action enhancing agent, which improves the delivery of the antibacterial agent to and retention thereof on surfaces in the mouth, which agent has an average molecular weight of 100 to 1,000,000 , contains a release-improving group selected from the group consisting of carboxylic acids, phosphonic acids, phosphinic acids and sulphonic acid as well as salts of these acids, and the retention-improving group satisfies the formula Xn-R1t where X represents O, S, SO, SO2, P, PO or Si, R represents a hydrophobic alkyl, alkylene, acrylic, aryl, alkaryl, or aralkyl group or a heterocyclic group as well as derivatives thereof with t inert substituents, n is 0 or 1, and that the oral preparation does not contain a polyphosphate anti-toothstone agent 2. The oral preparation according to claim 1, wherein the antibacterial activity enhancing agent is an anionic polymer containing a plurality of said release enhancing and / or retention enhancing groups. Oral preparation according to claim 1 or 2, characterized in that the antibacterial activity enhancing agent is present in an amount of 0.25-0.5% by weight.