NO179161B - Oral preparation - Google Patents

Abstract

An oral preparation, such as a dentifrice, a mouthwash, a lozenge or a chewing gum containing a polyphosphate antitartar agent, such as tetraalkali metal pyrophosphate, and an antibacterial anti-plaque agent which is compatible with the antitartar agent. The anti-plaque agent is a substantially water-insoluble, non-cationic, antibacterial agent, such as 2,4,4'-trichloro-2'-hydroxyphenyl ether (triolosan). Anti-plaque efficacy is optimized in the presence of an antibacterial agent which delivers the delivery of the antibacterial agent to, and the retention thereof on, oral surfaces.

Description

The invention relates to an oral preparation containing a carrier, an antitartar agent of polyphosphate (i.e. an antitartar agent) and a compatible antibacterial agent which acts to inhibit plaque, where the anti-plaque effectiveness is optimized by the presence of an anti-bacterial effect increasing agent which increases the delivery of the antibacterial agent to, and its retention on, oral surfaces.

US Patent Nos. 4,627,977, 4,515,772 and 4,32-3,551 describe oral preparations comprising various polyphosphate compounds. In the first-mentioned patent, a straight-chain, molecularly dehydrated polyphosphate salt is used together with a fluoride ion-giving source and a synthetic, straight-chain, polymeric polycarboxylate to inhibit calculus formation. According to European Patent Application No. 89200710.5, antitartar efficiency is optimized with a reduced amount of the straight-chain, molecularly dehydrated polyphosphate salt together with the fluoride ion-donating source and an increased amount of the synthetic, straight-chain, polymeric polycarboxylate.

According to the two latter patents, water-soluble di-alkali metal pyrophosphate is used alone or mixed with tetra-alkali metal pyrophosphate.

Oral preparations that inhibit tartar formation on tooth surfaces are highly desirable as tartar is one of the causative factors in periodontal conditions. Reduction of calculus thus promotes oral hygiene.

Dental plaque is a precursor to tartar. Unlike tartar, however, plaque can form on any part of the tooth surface, particularly at the gum line. In addition to being unsightly, plaque is thus implicated in the occurrence of gingivitis.

Accordingly, it would be highly desirable to include antimicrobial agents known to reduce plaque in oral preparations containing antitartar agents. This has actually been described in US Patent No. 4,022,550, where a compound that provides zinc ions as an antitartar agent is mixed with an antibacterial agent that can retard the growth of plaque bacteria. A large number of different antibacterial agents have been described with the zinc compounds, including cationic materials, such as guanides and quaternary ammonium compounds, as well as non-cationic compounds, such as halogenated salicylanilides and halogenated hydroxydiphenyl ethers.

To date, the cationic antibacterial materials, such as chlorhexidine, benzethonium chloride and cetylpyridinium chloride, have been the subject of the greatest investigation as antibacterial anti-plaque agents. However, despite being used with zinc-containing anti-calculus, they are not effective when used with anionic materials, such as polyphosphate-containing anti-calculus. This ineffectiveness is considered very surprising as polyphosphates are chelating agents and the chelating effect has previously been known to enhance the efficacy of cationic antibacterial agents (see, e.g., Disinfection, Sterilization and Preservation, 2nd ed., Black, 1977, p. 915 and Inhibition and Destruction of the Microbial Cell, Hugo, 1971, p. 215). Quaternary ammonium compounds are actually present in the plaque-regulating mouthwash containing pyrophosphate according to US Patent No. 4,323,551, and bis-biguanide antiplaque agent is proposed in the oral antitartar preparation with pyrophosphate according to US Patent No. 4,515,772.

In view of the surprising incompatibility between cationic antibacterial agents and polyphosphates present as antitartar agents, it was highly unexpected that other antibacterial agents would be effective.

It is an advantage of the invention that certain antibacterial agents are effective in oral calculus preparations containing a straight-chain, molecularly dehydrated polyphosphate salt, a fluoride ion-giving source and the previously mentioned antibacterial effect-enhancing agent to inhibit plaque formation.

It is a further advantage of the invention that a preparation is provided which is effective when it comes to reducing tartar formation and optimizing plaque reduction.

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

Further advantages according to the invention will be apparent from the description below.

In accordance with the aspects mentioned above, the invention relates to an oral preparation comprising:

a) an orally acceptable carrier,

b) an effective antitartar amount of material which

comprises 0.1-3% by weight of at least one straight-chain, molecular

dehydrated polyphosphate salt as an antitartar agent and

c) an effective anti-plaque amount of a substantially water-insoluble, non-cationic, antibacterial

means, characterized by the fact that it includes

d) up to 4% by weight of an antibacterial effect-enhancing agent containing at least one release-enhancing functional

group and at least one organic retention-enhancing group, which increases the delivery of the substantially water-insoluble, non-cationic, antibacterial agent to, and the retention thereof on, oral tooth and gum surfaces,

in that the weight ratio between antibacterial agent and polyphosphation is in the range from 1.6:1 to 2.7:1. For example, a highly desirable weight ratio of 1.9:1 is provided when 2% tetrasodium pyrophosphate (TSPP) is used (giving approximately 1.3% pyrophosphation) along with 2.5% of the antibacterial enhancer.

Typical examples of 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.

Halogenated salicvlanilides

4',5-dibromosalicylanilide

3,4',5-Trichlorosalicylanilide

3,4',5-tribromosalicylanilide

2,3,3',5-Tetrachlorosalicylanilide

3,3,3'5-Tetrachlorosalicylanilide

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

Benzoic acid 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), among others a.:

Phenol and its homologues

Mono- and poly-alkyl and aralkyl halophenols

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 antibacterial agent is present in the oral preparation in an effective anti-plaque amount, usually 0.01-5% by weight, preferably 0.03-1% by weight, very preferably 0.25-0.5% by weight and most preferably 0.25 -0.35% by weight. The antibacterial agent is essentially water insoluble, which means that its solubility is less than about 1% by weight in water at 25 °C and can be even less than approx. 0.1%. If an ionizable group is present, solubility is determined at a pH where ionization does not occur.

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. It is also described as an anti-plaque agent in a dentifrice which is composed so that it contains 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 the published

European Patent Application No. 0161899.

The straight-chain, molecularly dehydrated polyphosphate salts which are effective here as antitartar agents are well known as they are generally used in the form of their fully or partially neutralized, water-soluble alkali metal (e.g. potassium and preferably sodium) or ammonium salts and which any mixtures thereof. Representative examples include sodium hexametaphosphate, sodium tripolyphosphate, disodium diacid, trisodium monoacid and tetrasodium pyrophosphates, the corresponding potassium salts and the like. Straight-chain polyphosphates correspond to (NaPO3)n, where n is 2-125. In the present invention, they are used in the oral preparations in approximate amounts by weight of 0.1-3%, usually 1-2.5%, preferably 1.5-2%. When n is at least 3 in (NaPO3)n, the polyphosphates have a glassy appearance.

Particularly desirable antitartar agents are tetraalkali metal pyrophosphates, including mixtures thereof, such as tetrasodium pyrophosphate, tetrapotassium pyrophosphate and mixtures thereof. The oral preparation can thus contain a polyphosphate antitartar which is mainly free of tetrasodium pyrophosphate or mainly free of a mixture of tetrapotassium pyrophosphate and tetrasodium phosphate where the ratio between potassium and sodium pyrophosphate is 3:1 or over 3:1. An antitartar agent that comprises approx. 2% by weight of the oral preparations of tetrasodium pyrophosphate are particularly effective.

AEA can be a simple compound, preferably a polymerisable monomer, more preferably a polymer with a completely 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 a (weight)-average molecular weight of approx. 100 to approx. 1,000,000, preferably approx. 1000 to approx. 1,000,000, preferably approx. 2000 or 2500 to approx. 250,000 or 500,000.

AEA usually contains at least one release-enhancing group which is preferably acidic, such as sulfone, phosphine 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 interfere with 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, thereby " delivers" 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 the substance and delivery of the antibacterial agent to oral surfaces, that the repeating units in the polymer chain or backbone containing the acidic delivery-enhancing groups amount to at least approx. 10%, preferably at least approx. 50%, more preferably at least approx. 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 alter-

forming or in random 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 styrenephosphonic acid polymers and their copolymers with other inert, ethylenically unsaturated monomers generally have

molecular weights in the range approx. 2000 to approx. 30,000, preferably approx. 2500 to approx. 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(allylphosphonic acetate), phosphonated polymethacrylate etc, and the geminal diphosphonate polymers described in EP patent publication no. 0321233, can be used here as AEAs, of course 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 agent that can increase the antibacterial effect of an antibacterial agent having an average molecular weight of 1000-1,000,000, containing at least one functional group that increases the release of antibacterial effect, and at least one organic group that increases retention of antibacterial effects, where the agent containing the groups is free of, or essentially free of, water-soluble alkali metal or ammonium salt of synthetic, anionic, straight-chain, polymeric carboxylate with a molecular weight of 1000- 1,000,000, and polyphosphate-containing tartar agent, such as a mixture of potassium and sodium salts where the ratio between potassium and sodium in the preparation is in the range up to less than 3:1, e.g. from 0.37 to 1.04:1.

According to another preferred embodiment, AEA comprises a synthetic, anionic, polymeric polycarboxylate which is also an inhibitor of alkaline phosphatase enzyme. 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. However, only in a description essentially corresponding to US patent no. 4,627,977 are such polycarboxylates described to inhibit salivary hydrolysis of pyrophosphate antitartar agent in combination with a compound which provides a source of fluoride ion. It should be understood that the synthetic, anionic, polymeric polycarboxylates described in these patent documents are operative when they contain, or are modified to contain, the above-defined retention-increasing groups such as AEAs in the preparations and methods according to the invention.

These synthetic, anionic, polymeric polycarboxylates are often used in the form of their free acids, or preferably partially, or preferably completely, neutralized, water-soluble or water-swellable (hydratable, gel-forming) 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 approx. 30,000 to approx. 1,000,000. 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 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 sulphoacrylic oligomers with m.v. as low as 1000, available as "ND-2".

Generally suitable are polymerized, olefinically or ethylenically unsaturated carboxylic acids containing retention-enhancing groups, and containing an activated carbon-to-carbon olefinic double bond which readily acts upon polymerization due to its presence in the monomer molecule either in the alpha-beta position relative 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, itaconic, citraconic -, mesacone-, glutacone-, aconitin-, alpha-phenylacryl-, 2-benzyl-acryl-, 2-cyclohexylacryl-, 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 colloidally water-soluble polymer of polyacrylic acid cross-linked with from approx. 0.75 to approx. 2.0% polyallyl sucrose or polyallyl pentaerythritol 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 or the like. "Polycarbophil" 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 most often a hydrocarbon with any halogen- and O-containing substituents, and such bonds as are present in e.g. ester, ether and OH groups, and when present, it is usually used in the present preparations in approximate amounts by weight of up to approx. 4% (generally at least about 0.05%).

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 allyl-phosphinic 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 that contain, or are modified to contain, enhancing, release-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.

When the oral preparation is made by first dissolving the polyphosphate and antibacterial agent in wetting agent and surfactant, and adding AEA to this, especially the polycarboxylate, in gradually increasing amounts, the solution becomes clear and can be characterized as a "microemulsion". As the amount of the polycarboxylate increases so that the complete oral preparation contains at least approx. 2.2% by weight, the solution becomes cloudy and can be characterized as a "macroemulsion". In preparations of such "macroemulsion" type, the anti-plaque effect of the antibacterial agent seems to be optimized.

A desired weight ratio of the substantially water-insoluble, non-cationic, antibacterial agent to the polyphosphate-containing antitartar agent is greater than 0.72:1 to less than 4:1, e.g. from 1:1 to 3.5:1, especially from 1.6:1 to 2.7:1.

In order to optimize the antitartar effectiveness of the oral preparation, it is desirable that inhibitors against enzymatic hydrolysis of the polyphosphate are present. Such agents are an amount of a fluoride ion source sufficient to provide 25 ppm-5000 ppm fluoride ions, and up to 3% or more of the synthetic anionic polymeric polycarboxylate having a molecular weight of 1000-1,000,000, preferably 30,000-500,000.

The sources of fluoride ions, or fluoridating constituents, such as acid phosphatase and pyrophosphatase enzyme inhibitor constituents, are well known in the art as anti-tooth decay agents. 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 and by their freedom from unwanted reactions with other compounds in the oral preparation. Among these substances are inorganic fluoride salts, such as soluble alkali metal and alkaline earth metal salts, e.g. sodium fluoride, potassium fluoride, ammonium fluoride, calcium fluoride, a copper fluoride such as copper(II) fluoride, zinc fluoride, barium fluoride, sodium fluorosilicate, ammonium fluorosilicate, sodium fluorozirconate, ammonium fluorozirconate, sodium monofluorophosphate, aluminum mono- and aluminum difluorophosphate, and fluorinated 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 there must be a non-toxic amount, generally 0.005-3.0%, in the preparation. In a dental care preparation, e.g. tooth gel, toothpaste (including cream), tooth powder or dental tablet, is considered an amount of such a compound that releases up to approx. 5000 ppm F-ion based on the weight of the preparation, as satisfactory. Any suitable minimal amount of such compound may be used, but it is preferred to use sufficient compound to liberate 300-2000 ppm, preferably 800-1500 ppm, fluoride ion.

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

In oral preparations, such as mouthwash, tablets and chewing gum, the fluorinating compound is usually present

present in a sufficient amount to release up to approx.

500 ppm, preferably 25-300 ppm, based on weight of fluoride ion. Generally 0.005-1.0% by weight of such compound is present.

In certain highly preferred forms of the invention, the oral preparation may be predominantly liquid in nature, such as a mouthwash or rinse. In such a preparation, the carrier is usually a water/alcohol mixture which preferably includes a wetting agent as described below. 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 of the preparation. The alcohol is usually ethanol or isopropanol. Ethanol is preferred.

The pH in such liquid or other preparations according to the invention is generally in the range from 4.5 to 9 and usually from 5.5 to 8. The pH is preferably in the range from 6 to 8.0. It is worth noting that the preparations according to the invention can be applied orally at a pH below 5 without significant decalcification or other damage to tooth enamel. pH can be adjusted with acid (e.g. citric acid or benzoic acid) or base (e.g. sodium hydroxide) or buffered (as with sodium citrate, -benzoate, -carbonate or -bicarbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate etc).

In a certain other desirable form of the invention may

the oral preparation be mainly solid or paste-like in nature, such as tooth powder, a dental tablet or a dental care agent, i.e. a toothpaste (toothpaste) or gel dental care agent. The carrier in such solid or pasty oral preparations usually contains dentally acceptable polishing material. Examples of polishing materials are water-insoluble sodium metaphosphate, potassium metaphosphate, tricalcium phosphate, dihydrated calcium phosphate, anhydrous dicalcium phosphate, calcium pyrophosphate, magnesium orthophosphate, trimagnesium phosphate, calcium carbonate, hydrated alumina, calcined alumina, aluminum silicate, zirconium silicate, silica, bentonite and mixtures thereof. Other suitable polishing materials include the particulate, thermosetting resins described in US patent documents

No. 3,070,510, such as melamine, phenol and urea formaldehydes, and cross-linked polyepoxides and polyesters. Preferred polishing materials include crystalline silica with a particle size of up to approx. 5 pm, an average particle size of up to approx. 1.1 pm, and a surface area of up to approx.

50,000 cm<2>/g, silica gel or colloidal silica and complex, amorphous alkali metal aluminum silicate.

When visually clear gels are used, a colloidal silica polish, such as those sold under the trademark "Syloid" as "Syloid 72" and "Syloid 74", or under the trademark "Santocel" as "Santocel 100", is alkali metal aluminum -silicate complexes are particularly useful as they have refractive indices close to the refractive indices of systems of gelling agent and liquid (including water and/or wetting agent) commonly used in dentifrices.

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 metaphosphate 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 greater than 37 µm.

The polishing material is usually present in the solid or pasty preparations in weight concentrations of 10.99%. Preferably, it is present in amounts ranging from 10 to 75% in toothpaste, and from 70 to 99% in tooth powder. When the polishing material is siliceous in nature, it is usually present in an amount of 10-30% by weight. Other polishing materials are usually

present in an amount of 30-75% by weight.

In a toothpaste, the liquid carrier may comprise water and humectant, usually in an amount varying from 10 to

80% by weight of the preparation. Glycerol, propylene glycol, sorbitol and polypropylene glycol exemplify suitable wetting agents/carriers. Also advantageous are liquid mixtures of water, glycerol and sorbitol. In clear gels where the refractive index is an important

factor, preferably 2.5-30 wt% water is used, 0-70 wt%

glycerol and 20-80% by weight sorbitol.

Toothpastes, creams and gels usually contain a natural or synthetic thickening or gelling agent in proportions of 0.1-10%, preferably 0.5-5% by weight. A suitable thickener is synthetic hectorite, a synthetic colloidal magnesium alkali metal silicate complex clay available e.g. i as "Laponite" (eg CP, SP 2002, D). "Laponite D" analyzes show approximately 58.00 wt% SiO2, 25.40 wt% MgO, 3.05 wt% Na2O, 0.98 wt% Li2O and some water and trace metals. Its specific gravity is 2.53 and it has an apparent bulk density (g/ml at 8% moisture) of 1.0.

i Other suitable thickeners include Irish moss, iota-carrageenan, gum tragacanth, starch, polyvinylpyrrolidone, hydroxyethylpropylcellulose, hydroxybutylmethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose (e.g., available as "Natrosol"), sodium carboxymethylcellulose, and colloidal silica, such as finely ground "Syloid " (244). In some dentifrices produced according to the present invention, especially when more than approx. 0.35% by weight of water insoluble antibacterial agent is used and a siliceous polishing agent is present in an amount of less than approx. 30% by weight, it may be desirable to include an agent that dissolves the antibacterial agents. Such solubilizers 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 approx. 12 carbon atoms in a straight chain, such as olive oil, castor oil, and petrolatum, and esters, such as amyl acetate, ethyl acetate, and benzyl benzoate.

It will be understood that the oral preparations must be sold or otherwise distributed in suitable, labeled packages. Thus, a jar of mouthwash will have a label describing it as a mouthwash or mouthwash, and with instructions for use, and a toothpaste, cream or gel will usually be in a squeezable tube, usually of aluminium, lined with lead or plastic, or other squeeze, pump or pressurized dispenser for measuring out the contents, with a label describing it as a toothpaste, gel or toothpaste.

Organic surfactants are 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-calculus agent and the anti-plaque 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-dihydroxypropane sulfonate and the essentially 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 and the like. Examples of the latter amides are N-lauroyl sarcosine and the sodium, potassium and ethanol amine salts of N-lauroyl, N-myristoyl or N-palmitoyl sarcosine, 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 this, and which have long hydrophobic chains (e.g. aliphatic chains with approx. 12-20 carbon atoms), as 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 (eg sorbitan monostearate) and polypropylene oxide (eg Pluronic materials).

Surfactant is usually present in an amount of 0.1-5% by weight, preferably 1-2.5%. It is worth to

note that surfactant can aid in the dissolution of the non-cationic antibacterial agent and thereby reduce the amount of solubilizing wetting agent needed.

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, majoram, cinnamon, lemon and orange, and methyl salicylate. Suitable sweeteners include sucrose, lactose, maltose, sorbitol, xylitol, sodium cyclamate, perillartin, AMP (methyl ester of asparagylphenylalanine), saccharin and the like. Flavorings and sweeteners can be used as appropriate

alone or together make up from 0.1 to 5% of the preparation. Furthermore, flavoring oil appears to aid in the dissolution of the antibacterial agent.

In the preferred embodiment of the invention, an oral preparation according to the invention, such as a mouthwash or a dental care agent containing the preparation according to the present invention, is preferably added regularly to tooth enamel, such as every day or every second or third day, or preferably from 1-3 times daily, at a pH of 4.5-9, usually 5.5-8, preferably 6-8, for at least 2 weeks and up to 8 weeks or more, up to lifetime.

The preparations according to the invention can be incorporated in

tablets, 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 common plasticizers or softeners, sugar or other sweeteners such 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.

In the following examples, the agent is triclosan, 2,4,4'-trichloro-2'-hydroxydiphenyl ether, designated as "TCHE," sodium lauryl sulfate is designated as "SLS," the copolymer of maleic anhydride and methyl vinyl ether available as "Gantrez S-97 ", is identified as "Gantrez", tetrasodium pyrophosphate is identified as "pyrophosphate", and sodium fluoride is identified as "NaF".

Example 1

Adsorption to and release from dental minerals of anti-plaque/anti-cavity agents is determined by adsorption of antibacterial agent to saliva-coated dental mineral hydroxyapatite disc in the presence of pyrophosphate and various amounts of polycarboxylate.

The compositions of the evaluated toothpastes were:

"Gantrez" is present as A.I. in an amount of 2.5 parts toothpaste A and 2.0 parts toothpaste B.

For the antibacterial agent delivery test to a saliva-coated hydroxyapatite disc, hydroxyapatite (HA) was washed thoroughly with distilled water, collected by vacuum filtration and allowed to dry overnight at 37 °C. The dried HA was ground into a powder with a mortar and pestle. 150.00 mg of HA was placed in the chamber of a KBr pellet mold and compressed for 6 minutes at 4536 kg in a "Carver" laboratory press. The resulting 13 mm wafers were sintered for 4 hours at 800°C in a "Thermolyne" furnace. Parafilm-stimulated whole saliva was collected in an ice-cooled glass beaker. The saliva was cleared by centrifugation at 15,000 x g (times gravity) for 15 minutes at 4°C. Sterilization of the clarified saliva was done at 4 °C with stirring by irradiating the sample with UV light for 1.0 hour.

Each sintered disc was hydrated with sterile water in a polyethylene test tube. The water was then removed and replaced with 2.00 ml of saliva. A salivary membrane was formed by incubating the slice overnight at 37°C with continuous shaking in a water bath. After this treatment, the saliva was removed and the slices were treated with 1.00 ml of a solution containing an antibacterial agent (triclosan) in a dental care agent solution with a liquid phase and incubated at 37°C with continuous shaking in the water bath. After 30 minutes, the disc was transferred to a new tube and 5.00 mL of water was added, followed by shaking the disc gently with a Vortex. The disc was then transferred to a new tube and the washing procedure repeated twice. Finally, the disc was carefully transferred to a new tube to avoid simultaneous transfer of any liquid together with the disc. Then 1.00 ml of methanol was added to the disk, and it was shaken vigorously with a Vortex. The sample was left at room temperature for 30 minutes to extract adsorbed triclosan in the methanol. The methanol was then evaporated off, and it was clarified by centrifugation in a "Beckman" microcentrifuge 11 at 10,000 rpm for 5 minutes. After this treatment, the methanol was transferred to HPLC ampoules (high performance liquid chromatography) to determine the concentration of antibacterial agent. Samples in triplicate were used in all experiments.

The table below summarizes the data:

The data indicate that with the increasing amount of "Gantrez"

(toothpaste A) there is a very large increase in the delivery of TCHE to saliva-coated tooth minerals.

Example 2

The following toothpaste is effective as an anti-plaque and anti-tartar preparation:

Example 3

Example 4

Tablet

75-80% sugar

1-20% corn syrup

0.1-1.0% flavor oil

2% tetrasodium pyrophosphate

2.50% "Gantrez S-97"

0.01-0.05% NaF

0.01-0.1% TCHE

1-5% magnesium stearate lubricant

0.01-0.2% water

Example 5

In a variant example of the above example, "Gantrez S-97" can be omitted.

Example 6

In the above examples, improved results can also be obtained when TCHE 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 a molecular weight in the range of 3000-10,000, such as poly(beta-styrenephosphonic acid), copolymers of vinylphosphonic acid and beta-styrenephosphonic acid, and poly(alpha-styrenephosphonic acid), or sulfoacrylic oligomers, or a 1:1 copolymer of maleic anhydride and ethyl acrylate.

Likewise, similar results are obtained when pyrophosphate (tetrasodium pyrophosphate) is replaced by tetrasodium pyrophosphate and tetrapotassium pyrophosphate, the weight ratio between potassium and sodium being a) 0.37:1, b) 1.04:1, c) 3:1 and 3.5:1.

Claims (21)

1. Oral preparation comprising: a) an orally acceptable carrier, b) an effective anti-calculus amount of material comprising 0.1-3% by weight of at least one straight-chain, molecularly dehydrated polyphosphate salt as an anti-calculus agent and c) an effective anti-plaque amount of a the substantially water-insoluble, non-cationic, antibacterial agent, characterized in that it also comprises d) up to 4% by weight of an antibacterial effect-enhancing agent containing at least one delivery-enhancing functional group and at least one organic retention-enhancing group, which increases the delivery of the substantially water-insoluble, non-cationic, antibacterial agent to, and the retention hence on, oral tooth and gum surfaces, in that the weight ratio between antibacterial agent and polyphosphation is in the range from 1.6:1 to 2.7:1. 2. Oral preparation according to claim 1, characterized in that the antibacterial agent is selected from the group consisting of halogenated diphenyl ethers, halogenated salicylanilides, benzoic acid esters, halogenated carbanilides and phenolic compounds. 3. Oral preparation according to claim 2, characterized in that the halogenated diphenyl ether is 2,4,4'-trichloro-2'-hydroxyphenyl ether. 4. Oral preparation according to claim 2, characterized in that the antibacterial agent is present in an amount of 0.01-5% by weight. 5. Oral preparation according to claim 4, characterized in that the amount of antibacterial agent is 0.25-0.5% by weight. 6. Oral preparation according to claim 1, characterized in that the straight-chain, molecularly dehydrated polyphosphate salt is an alkali metal pyrophosphate which is present in an amount of 1-2.5% by weight. 7. Oral preparation according to claim 6, characterized in that the alkali metal pyrophosphate is tetrasodium pyrophosphate. 8. Oral preparation according to one of claims 1-7, characterized in that the weight ratio between antibacterial agent and polyphosphate is 1.7:1 to 2.3:1. 9. Oral preparation according to one of claims 1-8, characterized in that the carrier comprises water, wetting agent and a gelling agent, where the oral preparation contains a dentally acceptable, water-insoluble polishing agent and is a dental care agent. 10. Oral preparation according to one of claims 1-8, characterized in that the carrier comprises water and a non-toxic alcohol, and the oral preparation is a mouthwash. 11. Oral preparation according to one of claims 1-10, characterized in that the antibacterial effect-enhancing agent has an average molecular weight of 1,000-1,000,000. 12. Oral preparation according to claim 11, characterized in that the release-increasing functional group is selected from the group consisting of carboxylic, phosphonic, phosphinic and sulfonic acids, and their salts, and mixtures thereof, and the organic retention-increasing group comprises the formula -(X )n-R, where X is 0, N, S, SO, SO 2 , P, PO or Si, R is hydrophobic alkyl, aryl, alkenyl, acyl, alkaryl, aralkyl, or a hydrophobic heterocyclic residue, and their inertly substituted derivatives, and n is 1 or 0. 13. Oral preparation according to claim 12, characterized in that the antibacterial effect-enhancing agent is an anionic polymer containing a large number of release-increasing and organic retention-increasing groups, and the anionic polymer comprises a chain containing repeating units each containing at least one carbon atom. 14. Oral preparation according to claim 13, characterized in that each unit contains at least one delivery-increasing functional group and at least one organic retention-increasing group bound to the same or vicinal atom, or other atoms in the chain. 15. Oral preparation according to claim 12, characterized in that the release-enhancing functional group comprises a carboxyl group or a salt thereof. 16. Oral preparation according to claim 15, characterized in that the antibacterial agent is a copolymer of maleic acid or maleic anhydride and another ethylenically unsaturated, polymerisable monomer or a salt thereof. 17. Oral preparation according to claim 16, characterized in that the second monomer is methyl vinyl ether in a molar ratio of 4:1-1:4 with maleic acid or maleic anhydride. 18. Oral preparation according to 17, characterized in that the copolymer has a molecular weight of 30,000-1,000,000. 19. Preparation according to claim 18, characterized in that the copolymer has an average molecular weight of approx. 70,000. 20. Preparation according to claim 12, characterized in that the delivery-enhancing functional group comprises a phosphonic group or a salt thereof. 21. Preparation according to claim 20, characterized in that the antibacterial effect-enhancing agent is poly(beta-styrenephosphonic acid) or poly(alpha-styrenephosphonic acid) or a copolymer of one of the styrenephosphonic acids and the other or another inert, polymerisable, ethylenically unsaturated monomer or salts thereof.