SK750989A3 - Oral composition - Google Patents

Abstract

An oral composition such as a dentifrice, mouthwash, lozenge or chewing gum containing a polyphosphate anticalculus agent, such as tetraalkali metal pyrophosphate and antibacterial antiplaque agent compatible therewith. The antiplaque agent is a substantially water-insoluble noncationic antibacterial agent such as 2,4,4'-trichloro-2'-hydroxydiphenyl ether (Triclosan). Antiplaque effectiveness is optimized by the presence of an antibacterial-enhancing agent which enhances delivery of said antibacterial agent to, and retention thereof on, oral surfaces. Suitable enhancing agents are anionic polymers such as a maleic acid-methyl vinyl ether copolymer or a polymer containing phosphonic groups. Also disclosed are compositions comprising (1) the noncationic antibacterial agent and the enhancing agent, (2) the polyphosphate anticalculus agent and the noncationic antibacterial agent and (3) the enhancing agent and polyphosphate anticalculus agent effective against any antibacterial agent.

Description

Technical field

The invention relates to an oral composition, in particular a composition for oral administration having antibacterial action and against plaque and calculus formation. The oral composition comprises a pyrophosphate (or pyrophosphate) anti-tartar compound and a compatible antibacterial agent effective in inhibiting plaque, the antiplaque efficacy being optimized by the presence of an antibacterial efficacy enhancing agent that promotes the release of the antibacterial agent and its retention on the oral cavity surface.

BACKGROUND OF THE INVENTION

U.S. Pat. Nos. 4,627,977 (Gaffar et al.), 4,515,772 (Parran et al.) And 4,323,551 (Parran) disclose oral compositions containing various polyphosphates. In Gaffar et al. Linear dehydrated polyphosphate salts are used in conjunction with a fluoride ion source and a synthetic linear polymeric polycarboxylate to prevent calculus formation. In European patent application no. 89 200 710.5 discloses an increase in anti-tartar efficacy by using a small amount of a linear, molecularly dehydrated polyphosphate salt in conjunction with a fluoride ion source and an increased amount of a synthetic linear polymeric polycarboxylate.

U.S. Pat. 4,515,772 and 4,323,551 use a water-soluble alkali metal pyrophosphate (pyrophosphate) as such or in admixture with tetraalkalic metal pyrophosphate.

Oral agents that prevent the formation of tartar on the tooth surface are highly desirable, since tartar is one of the causes of malfunctions

-et.w.iggr periondontal structures. Reducing tartar therefore improves oral hygiene.

Dental coatings are a prior stage of tartar formation. However, unlike tartar, plaque can form on any part of the tooth, especially on the edge of the tooth and gum. Since the coating is virtually invisible, it remains adhering to the dental surface and becomes the cause of gum inflammation.

Accordingly, it would be highly desirable to use antimicrobial agents known to reduce the formation of coatings in oral anti-tartar compositions. U.S. Pat. No. 4,022,550 (Vinson et al.) Discloses the use of a zinc ion-releasing compound as an antioxidant and at the same time antibacterial agents for retarding bacterial growth in dental plaques. Described herein is the use of a variety of antibacterial agents together with zinc compounds, for example, cationic materials such as guanides and quaternary ammonium compounds, as well as non-cationic materials such as halogenated salicylamilides and halogenated hydroxydiphenyl ethers.

Until now, cationic antibacterial materials such as chlorhexidine and benzethonium chloride and acetylpyridinium chloride have been thoroughly investigated in which they have been tested as anti-dental agents. However, even though they have been used with zinc containing compounds that prevent the formation of tartar, they are not effective when used concurrently with anionic materials such as anti-tartar polyphosphates. This ineffectiveness is considered very surprising since polyphosphates are chelating agents and it is known that chelation usually increases the effectiveness of cationic antibacterials as described in the publication; Disinfection, Sterilization and Preservation, 2nd Edition, Black, 1977, p. 215. The quaternary ammonium compound is a mouthwash component for suppressing a dental plaque containing pyrophosphate (pyrophosphate) according to U.S. Pat. No. 4,323,551 (Parran) and the use of bisbiguanide as a dental plaque is suggested in oral

-V376 / 94II --- 3 pyrophosphate-containing composition according to U.S. Pat. No. 4,515,772 (Parran et al.).

Due to the unexpected incompatibility of antibacterial compounds of cationic nature with polyphosphates used when anti-tartar agents have been completely unexpected, other antibacterial agents not yet tested could be effective in this regard.

SUMMARY OF THE INVENTION

The invention is based on the discovery that certain antibacterial compounds are effective in oral anti-tartar formulations comprising a linear, molecularly dehydrated pyrophosphate (pyrophosphate) salt, a fluoride ion source and the aforementioned antibacterial agent, whereby inhibiting the formation of dental plaque (or plaque).

SUMMARY OF THE INVENTION It is an object of the present invention to provide a composition which effectively reduces the formation of tartar and, at the same time, optimizes the formation of dental plaques.

It is an object of the present invention to provide an oral composition which suppresses the formation of dental plaque and calculus, while at the same time effectively reducing the incidence of gum inflammation.

Other advantages of the oral composition of the invention will be described in more detail in the following description and example of the invention.

The essence of the oral composition of the present invention comprises:

- an orally acceptable vehicle,

-1 to 2.5 wt. % of a substance containing 0.1 to 3 wt. of at least one linear molecularly dehydrated polyphosphate salt as an anti-tartar agent, " v376 / 94H - = - 4

0.01 to 5 wt. a non-cationic antibacterial agent, and

up to about 4% by weight of an antibacterial agent, wherein the weight ratio of said antibacterial agent to said polyphosphate ion is in the range of from 1.6: 1 to 2.7: 1.

Said antibacterial agent is selected from the group consisting of halogenated diphenyl ethers, halogenated salicylanilides, benzoic acid esters, halogenated carbanilides and phenolic compounds. The halogenated diphenyl ether may be 2,4,4'-trichloro-2'-hydroxyphenyl ether. The phenolic compound may be a compound selected from phenol, thymol, eugenol, and 2,2'-methylene-bis (4-chloro-6-bromophenol). The amount of antibacterial agent ranges from 0.25% to 0.5% by weight.

The linear molecular dehydrated polyphosphate salt may be an alkali metal pyrophosphate, for example, tetrasodium pyrophosphate.

The weight ratio of polyphosphate ion to antibacterial enhancer ranges from 1.7: 1 to 2.3: 1.

As the vehicle, the oral composition may contain water, a humectant and a gelling agent, and further a dentally acceptable water-insoluble polishing agent.

In the form of a mouthwash, the composition may contain water and a non-toxic alcohol as a vehicle.

The antibacterial enhancer may have an average molecular weight ranging from about 100 to about 1,000,000, comprising at least one acidic functional group promoting the delivery of the substance, selected from the group consisting of carboxylic, phosphonic, phosphinic, sulfonic, salts of these substances and mixtures of these substances and at least one organic retention promoting function of the general formula:

- (X) n-R • V 3 76/9411, in which:

X is oxygen, nitrogen, sulfur, SO, SO2, PO or Si,

R represents a hydrophobic alkyl group, an aryl group, an alkenyl group, an acyl group, an alkaryl group, an aralkyl group, a heterocyclic group or derivatives thereof with inert groups, and n is 1 or zero.

The antibacterial promoting agent may be an anionic polymer comprising a series of release promoting groups and organic retention groups containing a chain of repeating units, each containing at least one carbon atom, each unit containing at least one release promoting group and at least one organic retention promoting group attached to the same atom, or to an adjacent atom or to another atom in the chain. The release promoting group may comprise a carboxyl group or a salt thereof.

Further, the antibacterial enhancing agent may be a copolymer of maleic acid or maleic anhydride with another ethylenically unsaturated polymerizable monomer or salt thereof. The other monomer may be methyl vinyl ether in a molar ratio with maleic acid or maleic anhydride in a ratio of from 4: 1 to 1: 4a with an average molecular weight of about 30,000 to 1,000,000, preferably 70,000.

Further, the release promoting moiety may comprise a phosphonic group or a salt thereof and may be poly-p-styrene phosphonic acid, poly-astyrene phosphonic acid, or a copolymer of any styrene phosphonic acid with another styrene phosphonic acid or other inert polymerizable ethylenically unsaturated monomer or salts thereof. it has a molecular weight ranging from about 1,000 to about 30,000.

The oral composition of the invention may further comprise a fluoride ion source.

In one embodiment, the invention relates to an oral composition comprising a vehicle acceptable for oral administration of an effective amount of at least > ≥7% of a linear molecular dehydrated pyrophosphate salt as an anti-tartar agent in an amount ranging from about 1% up to 3% by weight of an effective amount of a substantially insoluble, non-cationic, water-insoluble antibacterial agent effective against dental plaque formation and up to 4% by weight of an agent promoting bacterial activity and improving delivery and retention of the agent to the oral cavity surface wherein, in typical embodiments, the weight ratio of pyrophosphate ions to antibacterial agent enhancing agent ranges from greater than 0.72: 1 to less than 4: 1, for example in the range of 1: 1 to 3.5: 1, in particular v rozmed from 1.7: 1 to 2.3: 1 and most preferably in the range

1.9: 1 to 2: 1. For example, when tetrasodium pyrophosphate (TSPP) is used, which releases about 1.3% by weight of the pyrophosphate ion, it is simultaneously used with 2.5% by weight of an antibacterial promoting agent, thereby reaches a highly preferred value of the above weight ratio of 1.9: 1.

The following are typical examples of non-cationic antibacterial agents that are particularly advantageous in terms of plaque formation, efficacy, safety in use and ease of formulation. Halogenated diphenyl ethers

2 ', 4,4'-trichloro-2-hydroxydiphenyl ether (triclosan),

2,2'-dihydroxy-5,5'-dibromodiphenyl ether,

Halogenated salicylamides

4 ', 5 - dibromosalicylanilide,

3,4 ', 5-trichlorosalicylanilide,

3,4 ', 5-tribromosalicylanilide, 2,3,3', 5-tetrachlorosalicylanilide, 3,3,3 ', 5-tetrachlorosalicylanilide,

3,5-dibromo-3 * - trifluoromethylsalicylanilide,

- n - octanoyl - 3 '- trifluoromethylsalicylanilide, no. 04.1995

-V375794H 7

3,5-dibromo-4'-trifluoromethylsalicylanilide,

3,5-dibromo-3'-trifluoromethylsalicylanilide (fluorophene).

Benzoic acid esters methyl p - hydroxybenzoic acid ester, p - hydroxybenzoic acid ethyl ester, p - hydroxybenzoic acid propyl ester, and p - hydroxybenzoic acid butyl ester.

Halogenated carbanilides

3,4,4'- trichlorocarbanilide,

- trifluoromethyl-4,4´- dichlorocarbanilide,

3,3,4'-trichlorocarbanilide.

Phenol compounds (including phenol and its homologues, mono- and polyalkylated and aromatic halogenated, that is, fluorinated, chlorinated, brominated and iodine, phenols, resorcinol and catechol and their derivatives and bisphenolic compounds). These phenolic compounds include, but are not limited to: phenol,

- methylphenol,

- methylphenol,

- methylphenol,

- ethylphenol,

2.4 - dimethylphenol,

2.5 - dimethylphenol,

3,4-dimethylphenol,

2.6 - dimethylphenol,

- n-propylphenol,

- n-butylphenol,

- n-amylphenol,

- tert-amylphenol,

- n-hexylphenol,

V376 / 94H.

. ^ ni η / i mnn 8

- η - heptylphenol,

- methoxy -4- (2-propenyl) phenol (eugenol),

isopropyl-5-methylphenol (thymol).

Mono - and polyalkyl - and arylalkyl halophenols methyl - p - chlorophenol, ethyl - p - chlorophenol, n - propyl - p - chlorophenol, n - butyl - p - chlorophenol, n - amyl - p - chlorophenol, sec - amyl - p - chlorophenol , n - hexyl - p - chlorophenol, cyclohexyl - p - chlorphenol, n - heptyl - p - chlorphenol, n - octyl - p - chlorphenol, o - chlorphenol, methyl - o - chlorphenol, ethyl - o - chlorphenol, n - propyl - o - chlorophenol, n - butyl - o - chlorphenol, n - amyl - o - chlorphenol, t - amyl - o - chlorphenol, n - hexyl - o - chlorphenol, n - heptyl - o - chlorphenol, p - chlorophenol, o - benzyl - p - chlorophenol, o - benzyl - m - methyl - p - chlorophenol, o - benzyl - m, m - dimethyl - p - chlorophenol, o - phenylethyl - p - chlorophenol, o - phenylethyl - m - methyl - p - chlorophenol,

- methyl p-chlorophenol,

V376 / 94H ui.w.iyyy

3,5-dimethyl-p-chlorophenol,

- ethyl-3-methyl-p-chlorophenol,

- n-propyl-3-methyl-p-chlorophenol,

- isopropyl-3-methyl-p-chlorophenol,

- ethyl 3,5-dimethyl-p-chlorophenol,

- sec-butyl-3-methyl-p-chlorophenol,

- isopropyl-3,5-dimethyl-p-chlorophenol,

- dimethyl-3-methyl-p-chlorophenol,

- dimethyl-2-ethyl-3-methyl-p-chlorophenol, 2-sec-amyl-3,5-dimethyl-p-chlorophenol, 2-diethylmethyl-3,5-dimethyl-p-chlorophenol,

- sec - octyl - 3 - methyl - p - chlorophenol, p - bromophenol, methyl - p - bromophenol, ethyl - p - bromophenol, n - propyl - p - bromophenol, n - butyl - p - bromophenol, n - amyl - p - bromophenol, sec-amyl - p - bromophenol, n - hexyl - p - bromophenol, cyclohexyl - p - bromophenol, o - bromophenol, tert - amyl - o - bromophenol, n - hexyl - o - bromophenol, n - propyl - m , m - dimethyl - o - bromophenol, 2 - phenylphenol,

- chloro-2-methylphenol,

- chloro-3-methylphenol,

- chloro-3,5-dimethylphenol,

2,4-chloro-3,5-dimethylphenol,

3,4,5,6-tetrabromo-2-methylphenol, & UMJ999

- methyl-2-pentylphenol,

- isopropyl-3-methylphenol,

- chloro - 2 - hydroxydiphenylmethane.

Resorcinol and its derivatives resorcinol, methylresorcinol, ethylresorcinol, n-propylresorcinol, n-butylresorcinol, n-amylresorcinol, n-hexylresorcinol, n-heptylresorcinol, n-octylresorcinol, n-nonylresorcinol, phenylresorcinol, phenylresorcinol, benzylresorcinol, benzylresorcinol, benzylresorcinol, benzylresorcinol, benzylresorcinol chloro - 2,4 - dihydroxydiphenylmethane, 4'- chloro - 2,4 - dihydroxydiphenylmethane, 5 - bromo - 2,4 - dihydroxydiphenylmethane, 4'- bromo - 2,4 - dihydroxydiphenylmethane. Bisphenyl compounds Bisphenol A, 2,2'-methylenebis (4-chlorophenol), 2,2'-methylenebis (3,4,6-trichlorophenol) (hexachlorophene), 2,2'-methylenebis (4-chloro-6-bromophenol) , bis (2-hydroxy-3,5-dichlorophenyl) sulfide, bis (2-hydroxy-5-chlorobenzyl) sulfide.

'01 .04.1999

The antibacterial agent is present in the oral composition in an amount effective against dental plaque formation, usually in the range of from 0.01% to 5% by weight, in particular in the range of 0.03% to 1% by weight, preferably in the range of 0% 25% to 0.5% by weight, and most preferably in the range of 0.25% to 0.35% by weight. The antibacterial agent should be substantially insoluble in water, which means that its solubility in water is less than about 1% by weight at 25 ° C, and may be less than 0.1% by weight. If an ionizable group is present, the solubility of such a substance is determined at a pH at which no ionization occurs.

Of the halogenated diphenyl ethers, the preferred compound is triclosan. Among the phenolic compounds, phenol, 2,2'-methylenebis (4-chloro-6-bromophenol), thymol and eugenol are particularly preferred. However, the most preferred antibacterial agent effective against plaque formation is triclosan. This triclosan is described in the aforementioned U.S. Pat. No. 4,022,880 as an antibacterial agent which can be used in combination with a tartaric agent that provides zinc ions. In addition, triclosan is also mentioned in DE 3,532,860 as a substance which can be combined with copper-containing compounds. Triclosan is also referred to as a dentifrice in a dentifrice composition comprising a lamellar liquid crystal surfactant in which the gaps between the individual lamellae are less than 6.0 nm and can also be used in a zinc salt composition as described in European Patent No. 161,988 (Lane et al.) and in a dentifrice composition containing zinc citrate trihydrate, which composition is described in European Patent No. 3,980,519. 161,899 (Saxton et al.).

Linear molecular dehydrated pyrophosphate (and generally polyphosphate or polyphosphate) salts for use as anti-tartar agents are known substances which are generally used in the form of their wholly or partially neutralized water-soluble alkali metal salts, for example potassium, preferably sodium salts or ammonium salts and mixtures thereof. Examples of such materials are sodium hexametaphosphate, disodium pyrophosphate, trisodium and tetrasodium, corresponding to the potassium salt and the like. Linear polyphosphates can be represented by the general formula (NaPO ₃ ) _n , wherein n is 2 to about 125. The oral compositions of the present invention may be used in an amount of about 0.1% to 3% by weight, usually in an amount of % to 2.5% by weight, preferably in the range from 1.5% to 2% by weight. When n has a value of at least 3, said polyphosphates are of glassy nature.

Particularly suitable anticalculus agents are tetraalkali metal pyrophosphates (or pyrophosphates) and mixtures thereof, for example tetrasodium pyrophosphate (or pyrophosphate), tetrapotassium pyrophosphate and mixtures thereof. Thus, the oral composition may comprise an anti-tartaric agent of the pyrophosphate (and generally polyphosphate) type, which is substantially free of dipotassium pyrophosphate or substantially free of a mixture of dipotassium pyrophosphate and potassium pyrophosphate wherein the ratio of potassium or sodium pyrophosphate to diphosphate is 3: higher. Particularly effective is an anti-tartar agent comprising about 2% by weight of tetrasodium pyrophosphate based on the total weight of the oral composition.

The antibacterial agent (AEA), which enhances the delivery and retention of the agent to the surface of the oral cavity, is used in an amount sufficient to achieve this effect, which is typically an amount ranging from 0.05% to 4% by weight. % by weight, preferably from 0.1% to 3% by weight, in particular from 0.5% to 2.5% by weight.

The AEA may be a single compound, preferably a polymerizable monomer, even more preferably a polymer, and the term is quite general and includes, for example, oligomers, homopolymers, copolymers of two or more monomers, ionomers,

01/04/1999

VT76 / 94H

block copolymers, graft copolymers, crosslinked polymers and copolymers, and the like. The AEA may be of natural or synthetic origin, may be water insoluble or preferably water soluble (i.e., saliva), or may be swellable (hydratable, hydrogen-forming). The molecular weight of these compounds may generally be in the range of about 100 to about 1,000,000, preferably about 1,000 to about 1,000,000, particularly preferably in the range of about 2000 or about 2,500 to about 250,000 or about 500,000 .

These AEAs usually contain at least one group to aid in the delivery of an active agent that is acidic in nature, such as a sulfonic, phosphonic or, preferably, phosphonic or carboxylic acid residue, or an acid salt such as an alkali metal salt or an ammonium salt. , and at least one organic group promoting the retention (or retention) of the active agent on the mucosal surface, wherein preferably the substance comprises a plurality of both kinds of the above groups. The following retention-promoting groups can be expressed with the general formula:

- (X) n - R in which:

X represents oxygen, nitrogen, sulfur, SO, SO ₂ , phosphorus, PO or SI, and the like,

R represents a hydrophobic alkyl group, an alkenyl group, an acyl group, an aryl group, an alkaryl group, a heterocyclic group, or an inertly substituted derivative thereof, and n is 0,1 or above.

By the term "inertly substituted derivatives" is meant substituents on the R group, which are generally non-hydrophilic and which do not substantially affect the desired AEA function in promoting the delivery of the antibacterial agent to the oral mucosal surface and retention of the agent on the oral mucosal surface. the "inertly substituted derivatives" can be groups substituted with a halogen atom such as chlorine, bromine, iodine, or a carbocycle and the like.

Examples of such groups promoting delivery of the antibacterial agent to the surface of the oral cavity and its retention on the surface of the oral cavity will be described below.

n X - (X) _n R

methyl, ethyl, propyl, butyl, isobutyl, tert. butyl group, cyclohexyl group, allyl group, benzyl group, phenyl group, chlorophenyl group, xylyl group, pyridyl group, furanyl group, acetyl group, benzoyl group, butyryl group, terephthaloyl group, etc.

O ethoxy, benzyloxy, thioacetoxy, phenoxy, carbethoxy, carbobenzyloxy, etc.

N ethylamino, diethylamino, propylamido, benzylamino, benzoylamino, phenylacetamide, etc.

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

SO butylsulfoxy, allylsulfoxy, benzylsulfoxy, phenylsulfoxy, etc.

SO ₂ butylsulfonyl, allylsulfonyl, benzylsulfonyl, phenylsulfonyl, etc.

P diethylphosphinyl, ethylvinylphosphinyl, v376j

01.04Λ999 ethylallylphosphinyl, ethylbenzylphosphinyl ethylphenylphosphinyl, etc.

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

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

When used in an oral formulation, the group promoting the delivery of an antibacterial agent to the oral cavity surface, i.e., the tooth and gum surfaces, is a substance that associates with adhesion, cohesion or otherwise with AEA (containing the antibacterial agent) to achieve "delivery" an antibacterial agent to this surface. The organic group that promotes retention of the antibacterial agent on this surface is generally a hydrophobic group that binds or otherwise attaches the antibacterial agents to the AEA, thereby promoting the retention of the antibacterial agent to the AEA and thus indirectly on the oral cavity surface. In some cases, the capture of the antibacterial agent is achieved by physically attaching the agent to the AEA, particularly in cases where the AEA is a crosslinked polymer, the structure of which itself increases the number of sites to effect this binding, respectively. connection. The presence of higher molecular weight moieties and the presence of multiple moieties with hydrophobic crosslinked moieties in the crosslinked polymer further enhance the possibility of physical attachment of the antibacterial agent to the crosslinked AEA polymer or the crosslinked polymer.

In a preferred embodiment, the AEA is an anionic polymer consisting of a chain or backbone containing repeating units, each containing at least one carbon atom and preferably at least one directly bonded or indirectly bonded attachment monovalent group to promote the delivery of the active antibacterial agent, and at least one directly or indirectly coupled trailer v37i

01XM999 is a monovalent moiety promoting retention of an effective antibacterial agent, i.e. geminally, vicinally or less preferably by other means, to atoms in the chain, preferably carbon atoms. It is less preferred that the polymer comprises antibacterial delivery promoting groups and / or antibacterial retention group 4 and / or other divalent atoms or groups as linkers in the polymer chain instead of or in addition to the carbon atoms as crosslinking moieties.

It is contemplated that all of the AEA ingredients mentioned herein that do not contain both antibacterial agent and retention groups may be, and in a preferred embodiment, are indeed chemically modified in such a way that such types of AEA agents are obtained. which preferably comprise both of these types of groups and more preferably a full range of these types of groups. In the case of preferred polymeric AEAs, in order to maximize the effect and promote the delivery of the antibacterial agent to the oral cavity surface, the repeating units in the polymer chain or backbone of the polymer containing the acidic groups promoting the antibacterial agent are at least about 10% by weight of the polymer. at least about 50% by weight, even more preferably at least about 80% by weight to about 95% by weight or even 100% by weight of the polymer.

Preferably, the AEA comprises a polymer comprising repeating units in which one or more phosphonic acid-based groups promoting the delivery of an antibacterial agent is bound to one or more carbon atoms in the polymer molecule. An example of these AEAs are poly (vinylphosphonic) acid containing units of formula I:

1999

- [CH ₂ - CH] PO ₃ H ₂ (O

However, this group does not contain a group which promotes retention of the antibacterial on the surface of the oral cavity. However, a group of this type is present in poly (1-phosphonopropene) having the formula II:

- [CH-CH] I (ii) ch ₃ for ₃ h ₂

A preferred type of AEA phosphonic acid-containing substance for use according to the invention is poly (β-styrenephosphonic acid) of formula III:

- [CH-CH] II (in)

Ph PO ₃ H wherein pH is a phenyl group, wherein the phosphonic group promoting the antibacterial agent and the phenyl group promoting the antibacterial agent are bonded to vicinal carbon atoms in the chain, or a β-styrene-phosphonic acid copolymer with vinylphosphonyl chloride having units of formula III with units of formula I, cf. above in alternating or statistical ordering, or a poly (and styrenephosphonic) acid comprising units of formula IV:

ph

I

- [CH ₂ -C -I (iv) after ₃ h ₂ in which both the feeder and the retention groups of the antibacterial are bonded to the same carbon atom in the chain.

These polymers of styrene phosphonic acid and their copolymers with other inert, ethylenically unsaturated monomers have, as mentioned above, a molecular weight ranging from about 2000 to about 30,000, wherein

In a preferred embodiment, their molecular weight is in the range of about 2500 to about 10,000. These "inert" monomers do not adversely affect the function of any polymer used in the AEA of the invention.

Other polymers containing phosphonic acid residues include, for example, phosphonated ethylene compounds having units of formula V:

- [(CH ₂ ) ₁₄ CHPO ₃ H ₂ ] _n - (V) wherein n can be, for example, an integer with a value such that the polymer of formula V has a molecular weight of approximately 3000, and sodium (poly (butene-4), 4-diphosphonate) with units of formula VI:

- [CH ₂ - CH] I (VI)

CH ₂ -CH <(PO ₃ Na ₂ ) ₂ (VI) and poly (allyl-bis (phosphonomethylamine)) with units of formula VII:

- [CH ₂ - CH] I (VII)

CH ₂ -N? (C ₂ H ₄ PO ₃ H ₂ ) ₂

Other phosphonated polymers such as poly (allylphosphone acetate), phosphonated polymethacrylate, etc. as well as the geminal diphosphonate polymers disclosed in European patent no. 321233, can be used as AEAs, provided they contain both types of the above groups or are modified to contain both types of the above groups.

According to one aspect of the present invention, the oral composition comprises an orally acceptable vehicle, an agent effective to promote the antibacterial effect of the antibacterial agent used, which has an

V376 / 94H 704.1999, an average molecular weight in the range of about 1000 to about 1,000,000, comprises at least one functional group that promotes the release and delivery of an antibacterial effect and at least one organic group that promotes retention of antibacterial effects, said agent comprising said groups being without or substantially free of an alkali metal synthetic anionic linear polymeric polycarboxylate or an ammonium salt of the polycarboxylate having a molecular weight ranging from about 1000 to about 1,000,000, and a pyrophosphate (or pyrophosphate) anti-tartar agent, such as a mixture potassium and sodium salts, wherein the ratio of potassium to sodium in said composition is in the range of up to about 3: 1 or less, such as in the range of about 0.37 to about 1.04: 1.

According to another preferred embodiment, said AEA may comprise a synthetic anionic polymeric polycarboxylate which is also an inhibitor of the alkaline phosphatase enzyme. Synthetic anionic polymeric polycarboxylates and their complexes with various cationic disinfectants, zinc and magnesium are known in the art as anti-tartar agents per se, for example, U.S. Pat. 3,429,963 (Shedlovsky), 4,152,420 (Gaffar), 3,956,480 (Dichter et al.), 4,138,477 (Gaffar), and 4,183,914 (Gaffar et al.). However, only U.S. Pat. No. 4,627,977 (Gaffar et al.) Discloses the use of these polycarboxylates to inhibit the hydrolysis of pyrophosphate (or pyrophosphate) anti-tartar agents by combination with a fluoride ion source compound. It should be noted, however, that the synthetic anionic polymeric polycarboxylates cited in several patents when they contain or are not modified by the retention-enhancing groups are active AEAs that can thus be used in the oral compositions and preparation processes of the invention. These publications are reference materials in the context of the present invention.

v376 / 94H 01.04.1999

Said synthetic anionic polymeric polycarboxylates are used many times in the form of free acids or preferably in the form of partially neutralized salts or even more preferably in the form of completely neutralized salts which are water-soluble or water-swellable (hydratable form, gel-forming form). o alkali salts (such as potassium salt, or preferably sodium salt) or ammonium salts. Preferred are copolymers of maleic anhydride or maleic acid with another polymerizable ethylenically unsaturated monomer in a ratio of 1: 4 to 4: 1, preferably a methyl vinyl ether / maleic anhydride copolymer having a molecular weight ranging from These copolymers are available under the designation Gantrez, such as AN 139 (molecular weight 500,000), AN 119 (molecular weight 250,000) and preferably S-97 with a pharmaceutical grade (molecular weight 70,000). ), manufactured by GAF Corporation.

Other AEA active polymeric polycarboxylates which contain or are modified by retention-enhancing groups include, for example, those disclosed in U.S. Pat. No. 3,956,480 mentioned above, in particular copolymers of maleic anhydride with ethyl acrylate in a ratio of 1: 1, further with hydroxyethyl methacrylate, N-vinyl-2-pyrrolidone or ethylene, the latter being for example the commercially available product Monsanto EMA no. . 1103 with a molecular weight of 10,000 and EMA Grad 61, and copolymers of acrylic acid with methyl or hydroxyethyl methacrylate, methyl or ethyl acrylate, isobutyl vinyl ether or N - vinyl - 2 pyrrolidone in a 1: 1 ratio.

Other useful polymeric polycarboxylates disclosed in U.S. Pat. Nos. 4,138,477 and 4,183,914 and containing or modified to contain antibacterial agent retention groups consisting of copolymers of maleic anhydride with styrene, isobutylene or

V376 / 94H 01.04.1999 ethyl vinyl ether, polyacrylic acid, polyitaconic acid and polymaleic acid and sulfoacrylic oligomers, the molecular weight of which is very low, about 1000, these products being available under the designation Uniroyal ND - 2.

In general, retention-promoting groups which contain polymerizable olefinically or ethylenically unsaturated carboxylic acids containing an activated olefinic carbon-carbon double bond and at least one carboxyl group, i.e. an olefinic double bond, which is readily functional in polymerization due to its presence in the monomer molecule either at the α - β position relative to the position of the carboxyl group or as part of the terminal methylene group. Illustrative examples of such acids include acrylic acid, methacrylic acid, etacrylic acid, α-chloroacrylic acid, crotonic acid, β-acryloxypropionic acid, sorbic acid, α-chlorosorbic acid, cinnamic acid, mucylic acid, itacrylic acid, itacrylic acid. , citraconic acid, mesaconic acid, glutaconic acid, aconitic acid, α phenylacrylic acid, 2 - benzylacrylic acid, 2 - cyclohexylacrylic acid, angelic acid, umbelic acid, fumaric acid, maleic acid and anhydrides of these acids. Other different olefinic monomers copolymerizable with said carboxyl monomers include vinyl acetate, vinyl chloride, dimethyl maleate and the like. The copolymers usually contain a sufficient number of carboxylic acid salt groups to achieve water solubility of these compounds.

For the above purposes, the so-called carboxyvinyl polymers, referred to as toothpaste components in U.S. Pat. 3,980,767 (Chown et al.), 3,935,306 (Roberts et al.), 3,919,409 (Perla et al.), 3,911,904 (Harrison), and 3,711,604 (Colodney et al. ). These substances are commonly marketed, for example, under the tradenames Carbopol 934, 940 and 941 by B.F. Goodrich

Wherein the products consist essentially of a colloidal water-soluble polyacrylic acid polymer crosslinked by the addition of 0.75% to about 2.0% polyallylsaccharose or polyallylpentaerythritol as crosslinking agent, wherein the crosslinked structures and crosslinking bonds provide the desired retention enhancement due to the hydrophobic nature of these structures and / or due to the physical attachment of the antibacterial agent and the like. Polycarbophil is a similar substance, being a polyacrylic acid cross-linked with less than 0.2% divinyl glycol, with the lower proportion, molecular weight and / or hydrophobicity of the cross-linking agent providing little or no improvement in retention. In contrast, for example, 2,5-dimethyl-1,5 hexadiene is a more effective crosslinking agent promoting retention of the antibacterial agent.

Synthetic anionic polymeric polycarboxylates as a component of the compositions of the invention are most often of the hydrocarbon type, optionally containing halogen and O-containing substituents and residues, such as ester, ether and hydroxyl groups, as substituents, usually present in these compositions in an approximate amount up to 4% by weight (usually at least about 0.05% by weight).

The AEA may also include natural anionic polymeric polycarboxylates containing antibacterial retention-promoting groups. Carboxymethylcellulose and other binders and film-forming agents which do not contain the abovementioned antibacterial agent-promoting groups and / or retention-promoting groups of the antibacterial agent are ineffective as AEAs.

Illustrative examples of AEAs containing phosphinic acid and / or sulfonic acid groups that promote the delivery of an antibacterial agent include polymers and copolymers containing units or moieties derived from the polymerization of vinylphosphonic or allylphosphonic acid and / or sulfonic acid substituted as necessary on one or two (or three) carbon atoms by organic retention groups, such as those mentioned above

V376 / 94H 01.04.1999 formula - (X) _n - R as defined above. It is also possible to use mixtures of these monomers and copolymers of these with one or more inert polymerizable ethylenically unsaturated monomers, such as those mentioned above in connection with active synthetic anionic polymeric polycarboxylates. As will be noted, in these agents and other polymeric AEA agents suitable for the purposes of the present invention, usually only one acid group promoting the introduction of the antibacterial agent is bound to any carbon atom or to another atom in the polymer backbone or to branching this backbone. It is also possible to use polysiloxanes containing pendant groups to promote the delivery of the antibacterial agent and the retention of the agent or modified to contain these groups as AEAs. The ionomers containing the abovementioned groups promoting the retention of the antibacterial agent and the retention of the antibacterial agent or modified to contain these groups are also effective as AEAs. These ionomeric materials are described in Kirk Orhmer's Encyclopedia of Chemical Technology, Third Edition, Supplement Volume, John Wiley &amp; copyright, 1984, p. 546-573, the disclosures of which are incorporated herein by reference. Also polyesters, polyurethanes and synthetic and natural polyamides, including proteins and protein materials such as collagen, poly (arginine) and other polymerizable amino acids, are also effective as AEAs if they contain or have been modified to contain retention-promoting groups.

When the oral composition is manufactured by first dissolving the pyrophosphate (generally polyphosphate) and the antibacterial in a solvent with a wetting agent, and then gradually adding AEA, especially polycarboxylate, the solution becomes clear and can be characterized as a "microemulsion" . By increasing the amount of polycarboxylate so that the finished oral composition contains at least 2.2% by weight of the latter, the solution becomes cloudy and can be characterized as a "macroemulsion". In compositions of this type, the anti-bacterial effect of anti-coatings achieves an optimum degree.

V376 / 94H 01.04.1999

The desired weight ratio of the substantially water-insoluble non-cationic antibacterial agent to the anti-tartar polyphosphate agent is greater than 0.72: 1 to less than 4: 1, for example about 1: 1 to about 3.5: 1, s preferably about 1.6: 1 to about 2.7: 1.

In order to optimize the anti-calculus effect of the oral composition, it is desirable to include inhibitors against the enzymatic hydrolysis of pyrophosphate (generally polyphosphate). These agents are typically a source of fluoride ions, the amount of which is sufficient to dispense 25 ppm to 5000 ppm of fluoride ions, and about 3% or more of the synthetic anionic polymeric polycarboxylate having a molecular weight ranging from about 1000 to about 1,000,000, in a preferred embodiment of about 30,000 to about 500,000.

The fluoride ion source or fluorine-providing component, such as the acid phosphatase and pyrophosphatase inhibitor component, are generally known anti-tartar agents. These compounds may be sparingly soluble in water or may be completely soluble in water. These substances are characterized by their ability to release fluoride ions into water and are not intended to have a substantially undesirable effect on the action of the other components of the formulation. These include, for example, inorganic fluorides, for example, soluble alkali metal and alkaline earth metal salts such as sodium fluoride, potassium fluoride, ammonium fluoride, calcium fluoride, copper fluoride such as copper fluoride, zinc fluoride, barium fluoride, sodium fluorosilicate or ammonium fluorosilicate, sodium fluorosilicate or ammonium fluorosilicate, sodium monofluorophosphate, aluminum mono and difluorophosphate and calcium pyrophosphate. Alkali metal tin fluorides such as sodium and stannous fluoride, sodium monofluorophosphate (MFP) and mixtures thereof are more preferred.

The amount of fluorine-providing compound depends to some extent on the type of compound, its solubility, and the type of final oral composition, but it must be a non-toxic amount, usually in the range of

V376 / 94H April 1, 1999 ranges from about 0.0005% to about 3.0% by weight. In a dentifrice composition, such as tooth gel, toothpaste (including creams), tooth powder or dental tablets, an amount of said substance that releases about 5,000 ppm of fluoride ion based on the weight of the composition is acceptable. In the present case, any minimum amount of this substance may be used, but it is preferred to use an amount that releases about 300 to about 2000 ppm, preferably 800 ppm to 1500 ppm of fluoride ion.

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

In oral compositions such as mouthwashes, sublingual lozenges and chewing gums, the fluorine-releasing compound is usually present in an amount sufficient to release up to about 500 ppm of fluoride ions, preferably 25 to 300 ppm of fluoride ions. Typically, the compound is used in an amount ranging from about 0.005% to about 1.0% by weight.

In certain highly preferred embodiments of the oral composition of the invention, the composition is of a substantially liquid nature, for example, a mouthwash or a composition used to rinse the oral cavity. In such compositions, the vehicle is usually a mixture of water and an alcohol, optionally containing a humectant, as described above. The weight ratio of water and alcohol is generally in the range of 1: 1 to 20: 1, preferably in the range of 3: 1 to 10: 1, and in particular in the range of 4: 1 to 6: 1. in preparations of this type it is in the range of 70% by weight to about 99.9% by weight. A typical alcohol is ethanol or isopropanol, ethanol is preferred.

V376 / 94H 01.04.1999

A liquid composition of this type or other composition of the invention typically has a pH in the range of about 4.5 to about 9, usually in the range of about 5.5 to about 8. A preferred pH range is from 6 to 8.0. It should be noted that the composition of the invention can also be used orally at a pH of less than 5 without substantial decalcification or other damage to the enamel. The pH can be controlled with an acid (such as citric or benzoic acid), bases (such as sodium hydroxide) or buffers (such as sodium citrate, sodium benzoate, sodium carbonate or sodium bicarbonate, sodium hydrogen phosphate, dihydrogen phosphate sodium and the like).

In other preferred embodiments, the oral form of the present invention may be a substantially solid or pasty substance, such as a dentifrice, dental tablet, or dentifrice, i.e., a toothpaste (dental cream) or gel dentifrice. The vehicle for such solid or pasty oral dentifrices comprises a dentally acceptable polishing material, such as water insoluble sodium or potassium metaphosphate, calcium phosphate, anhydrous calcium phosphate, calcium pyrophosphate, magnesium orthophosphate, magnesium phosphate, calcium carbonate, alumina, calcined alumina, aluminum silicate, zirconium silicate, silica, bentonite and mixtures thereof. These suitable polishing materials also include the thermosetting resins described in U.S. Pat. No. 3,070,510 of December 15, 1962, such as melamine-, phenol- and urea-formaldehyde resins and crosslinked polyepoxides and polyesters. A preferred polishing material is crystalline silica with a particle size of up to about 5 µm, medium size

Íc particles up to about 1.1 µm and having a surface area of up to about 50,000 cm / g, which may be silica gel or colloidal silica gel and complex amorphous alkali metal aluminosilicates.

In the case where clear gels are used, it is particularly suitable to use colloidal silicon dioxide as a polishing material, such as those supplied under v376 / 94H 01.04.1999

TJ by Syloid, such as Syloid 72 and Syloid 74, or by Santocel, such as Santocel 100, or may be alkali aluminosilicate complexes which are particularly suitable or have a refractive index close to that of liquid gelling agent systems (including water and / or wetting or dissolving agents) generally used in dentifrices.

Many of the so-called "water-insoluble" polishing materials are anionic in nature and, moreover, contain a small amount of soluble material. Insoluble sodium metaphosphate can be obtained by any suitable method, for example according to: Thorpes Dictionary of Applied Chemistry, Vol. 9, 4 ^{, h} Edition, p. Another example of suitable materials are some forms of insoluble sodium metaphosphate, known as Madrell's salt and Kurrol's salt. These metaphosphate salts have only low solubility in water, so they are usually referred to as insoluble metaphosphates (IMP). Small amounts of soluble phosphate material are usually present as impurities, usually up to 4% by weight. The amount of soluble phosphate, which includes probably soluble sodium trimetaphosphate, can be reduced or removed if necessary by washing with water. Insoluble alkali metal metaphosphates are usually used in the form of powders, their particle size being such that only a maximum of 1% of the material has a particle size greater than 37 µm.

The polishing material is usually present in the solid or pasty compositions of the invention in an amount of 10% to 99% by weight, preferably 10% to 75% by weight in the toothpaste and 70% to 99% by weight in the tooth powder. In the case of a silicon-based polishing material, it is usually present in the toothpaste in an amount ranging from 10% to 30% by weight. Other polishing materials are typically comprised in the toothpastes in the range of 30% to 70% by weight.

In a toothpaste, the liquid vehicle may contain water and an additional humectant, usually in an amount ranging from 10% to 80% by weight.

V376 / 94H 01.04.1999 Examples of humectants / carriers are preferably glycerol, propylene glycol, sorbitol and polypropylene glycol. Also preferred are liquid mixtures of water, glycerol and sorbitol. In clear gels where refractive index is an important value, about 2.5% to 30% by weight of water, 0 to 70% by weight of glycerol and 20 to 80% by weight of sorbitol are preferably used.

Toothpastes, creams or gel cleansers generally contain a natural or synthetic thickener or gel-forming agent in an amount of about 0.1% to about 10% by weight, preferably about 0.5% to about 5% by weight. A preferred thickener is, for example, synthetic hectorite, a synthetic colloidal magnesium alkali metal silicate complex, which is available, for example, as Laponite (e.g., CP, SP 2002 or D, Laporte Industries Limited). Laponite D analysis gave a composition (in% by weight) of 58.00% SiO ₂ , 25.40% MgO, 3.05% Na ₂ O, 0.98% Li ₂ O and a small amount of water and a trace of metal. The density of this material is 2.53 g / cm ³ and the bulk density at a moisture content of 8% by weight is 1.0 g / ml.

Other suitable thickeners are Irish moss, carrageenan, iota carageenan, tragacanth yarn, starch, polyvinylpyrrolidone, hydroxyethylpropylcellulose, hydroxybutylmethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, such as the carboxymethylcellulose, such as the carboxymethyl cellulose; fine crushed Syloid (for example, product under the name 244). In some dentifrice compositions of the invention, particularly when more than 0.35% by weight of the water-insoluble antibacterial agent and silica polishing agent are used in an amount of less than 30% by weight, it may be appropriate to add a substance to dissolve the antibacterial agent . These dissolving agents, including humectants, may be some polyols such as propylene glycol, dipropylene glycol and hexylene glycol, celluloses such as methylcellulose and ethylcellulose, vegetable oils and waxes with

V376 / 94H 01.04.1999 containing at least 12 straight-chain carbon atoms such as olive oil, castor oil and petrolatum, and esters such as amyl acetate ethyl acetate and benzyl benzoate.

It is understood that the oral compositions of the invention will be sold or otherwise delivered in a suitably labeled package. For example, a mouthwash bottle will be labeled with a description of the use and instructions for use, the toothpaste, cream or gel will usually be stored in a tube, usually aluminum, coated in lead or plastic or other material from which the paste can be made If the paste can also be supplemented with a pump or dispensing device under pressure to dispense the contents, the tube will also bear a label that it is a toothpaste, cream or gel.

To enhance the prophylactic effect, organic surfactants are also used in the compositions of the invention to assist in the complete dispersion of the antibacterial anti-plaque and tartar throughout the oral cavity, while also making the composition more cosmetically acceptable. The organic surfactant material is preferably of an anionic, nonionic or ampholytic nature, and in this connection it is preferred to use a surfactant as a surfactant which simultaneously has a cleaning and foaming effect. Suitable examples of anionic surfactants are the water-soluble salts of higher fatty acids with monoglyceride monosulfates, e.g. with 1,2-dihydroxypropanesulfonate and substantially saturated higher aliphatic acylamides derived from lower aliphatic aminocarboxylic acids, e.g. containing 12 to 16 carbon atoms in the fatty acid, alkyl or acyl residue, and the like. Examples of said amides are N-lauroyl-sarcosine and the sodium or potassium salt of N-lauroyl-, N-myristoyl- or N-palmitoyl sarcosine, or a salt of these with ethanolamine, which should be substantially free of soaps; or

V376 / 94H 01.04.1999 Similar materials containing higher saturated aliphatic acids. The use of these sarcosinate compounds is particularly advantageous since these materials have a long-lasting and significant effect in inhibiting the formation of acids in the oral cavity in the breakdown of carbohydrates, and furthermore reduce the solubility of enamel in acidic solutions. Examples of water-soluble nonionic surfactants are the condensation products of ethylene oxide with various reactive compounds containing hydrogen with a long hydrophobic chain, for example an aliphatic chain containing 12 to 20 carbon atoms, these condensation products ("etoxamers") containing hydrophilic polyoxyethylene moieties, i.e. for example, polyethylene oxide condensation products with fatty acids, fatty alcohols, fatty amides, polyhydric alcohols such as sorbitan monostearate and polypropylene oxides (e.g., the product available under the name Pluronic).

The surfactant is usually present in an amount of from about 0.1% to about 5% by weight, preferably from 1% to 2.5% by weight. In this regard, it should be noted that the surfactant may assist in dissolving the non-cationic antibacterial agent and thereby reduce the amount of dissolving humectant required.

Other materials may be incorporated into the oral compositions of the invention, for example, bleaching agents, preservatives, silicones, chlorophyll compounds and / or ammonia-derived materials such as urea, ammonium hydrogen phosphate, and mixtures thereof. These auxiliary components, when used, are incorporated into the composition in an amount that does not substantially adversely affect the desired properties and effects of the composition. Larger amounts of zinc, magnesium and other metal salts, which are usually soluble and could form a complex with the active ingredient of the composition, should not be used.

It is also possible to use suitable flavorings or sweeteners. Examples of such flavoring or flavoring agents include some essential oils (flavoring oils), such as spearmint,

Peppermint), menthol, sassfras, clove, sage, eucalyptus, marjoram, cinnamon, lemon or orange or methyl salicylate. Suitable sweeteners are, for example, sucrose, lactose, maltose, xylitol, sodium cyclamate, perillartin, AMP (asparylalanine methyl ester), saccharin and the like. Flavoring or flavoring agents and sweeteners may individually or together comprise from about 0.1% to about 5% by weight of the composition. In addition, these flavoring agents (or essential oils) are likely to aid in the dissolution of the antibacterial agent with or in the absence of the surfactant.

In a preferred embodiment of the composition of the invention, these oral preparations, such as mouthwash or dentifrice containing the composition of the invention, are applied regularly to the enamel, such as every day, or every second or third day, or preferably one to three times. daily, at a pH of about 4.5 to about 9, usually about 5 to about 8, preferably about 6 to about 8, for example at least two weeks to 8 weeks or more, until the end of life.

The composition of the invention may be incorporated in the form of lozenges for sublingual use in chewing gum or other similar products by, for example, being mixed into a warm gum base or applied to the exterior surface of chewing gum, for which purpose jelutong may be used. , rubber latex, vinyl resin and the like, preferably these are used together with conventional plasticizers or plasticizers, sugar or other sweeteners or carbohydrates such as glucose, sorbitol and the like.

DETAILED DESCRIPTION OF THE INVENTION

The oral composition of the invention and its use will now be described in more detail by way of specific examples, which are, however, illustrative only and not limiting of the scope of the invention. All parts and amounts referred to herein as in the foregoing description and claims are

V376 / 94H 01.04.1999 is intended to be by weight unless otherwise indicated or expressly stated otherwise.

In the following examples, triclosan, which is 2,4,4-trichloro-2 hydroxydiphenyl ether, referred to as (TCHE), sodium lauryl sulfate will be referred to as SLS, maleic anhydride copolymer and methyl vinyl ether, sold under the name Gantrez S-97 (GAF Corporation). such as Gantrez, tetrasodium pyrophosphate (or pyrophosphate) will only be referred to as pyrophosphate (or pyrophosphate) and sodium fluoride will be referred to under its chemical brand NaF.

Example 1

Adsorption to the tooth surface and the release of minerals to determine the effectiveness of certain anti-tartar and plaque agents have been investigated for the adsorption of antibacterial agents to a hydroxyapatite disc containing minerals coated with saliva in the presence of pyrophosphate and varying amounts of polycarboxylates.

The toothpaste to be evaluated had the following composition:

component Weight parts A B glycerol 10.00 10.00 lota - carragenan 0,750 0,750 Sorbitol (70% solution) 30,000 30,000 propylene 0,500 0,500 Gantrez (13.02% solution) 19,000 19,000 Titanium dioxide 0,500 0,500 Water (deionized) 9,957 9,957 NaF 0,243 0,243 Saccharin sodium 0,300 0,300 pyrophosphate 2,000 2,000 Sodium hydroxide (50%) 1,000 1,000 Base polishing agent silicon dioxide (Zeodent 113) 20,000 20,000 Oxide-based thickener Silodent 15) 2,500 2,500 Aromatic silica 0,950 0,950 TCHE 0,300 0,300 SLS 2,000 2,000

V376 / 94H 01.04.1999

Gantrez is present as an active ingredient in an amount of 2.5 parts by weight in toothpaste A and an amount of 2.0 parts by weight in toothpaste B.

Hydroxyapatite (HA), obtained from Monsato Co., was thoroughly washed with distilled water, filtered in vacuo and then dried overnight at 37 ° C to test the delivery of antibacterial agent to saliva-coated hydroxyapatite disks. The dried hydroxyapatite was ground in a mortar. Then 150 milligrams of HA were placed in a chamber for production of potassium bromide pellets (Barnes Analytical, Stanford, CT) and the material was compressed for 6 minutes at a pressure of approximately 5000 kg in a laboratory press (Carver Laboratory). The resulting 13 mm diameter discs were sintered for 4 hours at 800 ° C in an oven (Thermolyne). Saliva was collected in an ice-cooled glass vial, clarified by centrifugation for 15 minutes at 15,000 x g at 4 ° C. They were then sterilized at the same temperature of 4 ° C and under agitation by irradiating the sample with ultraviolet light for 1 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 saliva. Incubation of the disc overnight at 37 ° C and continuous shaking in a water bath created a saliva coating. The saliva was then removed and the discs were placed in a 1.0 ml solution containing antibacterial agent (Triclosan) for a liquid phase dental cleaner, and then the discs were incubated at 37 ° C with stirring in a water bath. After 30 minutes, the discs were transferred to a new tube, 5 ml of water was added and the disc was gently shaken (Vortex). The disc was then transferred to a new tube and the wash was repeated two more times. Finally, the disc was carefully transferred to a new tube so that no liquid was transferred. 1 ml of methanol was then added to the disc and the disc was vigorously shaken (Vortex). The sample was then left at room temperature for 30 minutes to extract the absorbed triclosan into methanol. The methanol was aspirated and clarified by centrifugation for 5 minutes in a microcentrifuge

V376 / 94H 01.04.1999 (Backman Microfuge 11) at 10,000 rpm. The methanol was then transferred to high pressure liquid chromatography vials to determine the antibacterial content. Each assay in all experiments was performed in triplicate.

The results are summarized in the following table:

TABLE

Toothpaste A B Supply of TCHE to a saliva-coated hydroxyapatite disc in pg 130 30 The data show that with an increasing amount of Gantrez (toothpaste A) occurs the increase of the TCHE supply to the minerals with coated with saliva. Example 2 According to this example a toothpaste was prepared with the following a composition which is effective as a dental plaque agent; and tartar. component Weight parts Sorbitol (70%) 22,00 carrageenan 1.00 Sodium hydroxide (50%) 1.00 Gantrez (13.02% solution) 19,00 Water (deionized) 2.69 Sodium monofluorophosphate 0.76 Saccharin sodium 0.30 diphosphate 2.00 Hydrated alumina 48,00 Aromatic silica 0.95 TCHE 0.30 SLS 2.00 Example 3 According to this example an oral rinse solution was prepared

cavity, which consisted of the following components:

V376 / 94H 01.04.1999

component Weight parts Tetrasodium diphosphate 2.00 Gantrez S-97 2.50 glycerol 10.00 Sodium fluoride 0.05 Sodium lauryl sulphate 0.20 TCHE 0.06 Aromatic silica 0.40 Water supplement to 100.00

Example 4

According to this example, pill dissolution pills were prepared having the following composition:

component % by weight sugar 75-80 Corn syrup 1 -20 Aromatic silica 0.1-1.0 Tetrasodium diphosphate 2.0 Gantrez S-97 2.50 Sodium fluoride 0.01-0.05 TCHE 0.01-0.1 Magnesium stearate 1.0-5.0 Water 0.01-0.2

Example 5

Chewing gum parts basis 25.00 Sorbitol (70%) 17,00 TCHE 0.50 to 0.10 Tetrasodium diphosphate 2.00 Gantrez S-97 2.50

Alternatively, the Gantrez component may be omitted.

Example 6

Chewing gum Base

TCHE

Gantrez

Weight parts 30,00 0,50 2,50

V376 / 94H 01.04.1999

NaF

glycerol

Crystalline sorbitol Tetrasodium diphosphate Aromatic silica and water:

0.05

0.50 53.00 2.00

Supplement up to 100,00

In the previous examples, improved results can also be obtained by replacing the TCHE component with phenol, 2,2-methylene bis (4-chloro-6-bromo-phenol), eugenol or thymol and / or replacing Gantrez with another type of substance AEA, for example by one of the Carbopol agents, for example 934 (which is a cross-linking polycarboxylate having a molecular weight of 3,000,000), or polymers of styrene and phosphonic acid having a molecular weight of 3,000 to 10,000, such as poly (β styrenephosphonic acid), vinylphosphonic acid copolymers with β styrenephosphonic acid or poly (alpha - styrenephosphonic acid) or sulphoacrylic acid oligomers or copolymers of maleic anhydride with ethyl acrylate in a 1: 1 ratio by weight.

Similar results can be obtained if the pyrophosphate (or pyrophosphate) used, in this case tetrasodium, is replaced by a mixture of tetrasodium and tetrasodium pyrophosphate at a potassium to sodium weight ratio of (a) 0.37: 1, (b) 1.04: 1 , (c) 3: 1: 3.5: 1.

The invention has been described in connection with various preferred embodiments, and it will be understood that various other simple modifications and variations may be made by those skilled in the art and are within the scope of the invention.

V376 / 94H

Claims (29)

PATENT CLAIMS Oral anti-dental plaque and tartar in the form of a gel-like or pasty dentifrice, liquid dentifrice, mouthwash, lozenge or chewing gum, characterized in that it contains an orally acceptable vehicle, 1 to 2.5% by weight a substance containing from 0.1 to 3% by weight of at least one linear molecular dehydrated polyphosphate salt as an anti-tartar, 0.01 to 5% by weight of a non-cationic antibacterial agent, and up to about 4% by weight of an antibacterial enhancer improving the antibacterial effect on said polyphosphate ion is in the range from 1.6: 1 to 2.7: 1. The oral composition of claim 1, wherein said antibacterial agent is selected from the group consisting of halogenated diphenyl ethers, halogenated salicylanilides, benzoic acid esters, halogenated carbanilides, and phenolic compounds. Oral composition according to claim 1, characterized in that the antibacterial agent is a halogenated diphenyl ether. 4. An oral formulation according to claim 3 wherein said halogenated diphenyl ether is 2,4,4 &apos; -trichloro-2 &apos; -hydroxyphenyl ether. The oral composition of claim 1, wherein said antibacterial agent is a phenolic compound. 6376 / 94ΙΙ * 01.04.1999 6. The oral composition according to claim 5, characterized in that the said phenolic compound is a compound selected from the group consisting of phenol, thymol, eugenol and ^2,2, -methylene-bis- (4-chloro-6-bromophenol). The oral composition of claim 2, wherein the amount of antibacterial agent is in the range of 0.25% to 0.5% by weight. The oral composition of claim 1, wherein said linear molecular dehydrated polyphosphate salt is an alkali metal pyrophosphate. The oral composition of claim 8, wherein said alkali metal pyrophosphate is tetrasodium pyrophosphate. The oral composition of any one of claims 1 to 7, wherein the weight ratio of polyphosphate ion to antibacterial enhancer is in the range of from about 1.7: 1 to about 2.3: 1. Oral composition according to any one of claims 1 to 10, characterized in that it contains water, a humectant and a gelling agent as the vehicle, and the oral composition comprises a dentally acceptable water-insoluble polishing agent. Oral composition according to any one of claims 1 to 11, characterized in that it comprises water and a non-toxic alcohol as the vehicle and the composition is a mouthwash. The oral composition of any one of claims 1 to 12, wherein said antibacterial enhancing agent has an average molecular weight ranging from about 100 to about 1,000,000. C-V37Ú / 91II Ol.Olilflf10— The oral composition of claim 13, wherein said antibacterial agent comprises at least one functional group promoting delivery of said substance and at least one organic functional group promoting retention. The oral composition of claim 14, wherein said delivery promoting group is of an acidic nature. The oral composition of claim 15, wherein the antibacterial delivery promoting group is selected from the group consisting of residues derived from carboxylic, phosphonic, phosphinic, sulfonic acid, salts thereof, and mixtures thereof. The oral composition of claim 16, wherein said organic retention aid group has the general formula: - (X) n-R in which: X is oxygen, nitrogen, sulfur, SO, SO2, PO or Si, R represents a hydrophobic alkyl group, an aryl group, an alkenyl group, an acyl group, an alkaryl group, an aralkyl group, a heterocyclic group or derivatives thereof with inert groups, and n is 1 or zero. The oral composition of claim 16, wherein said antibacterial enhancing agent is an anionic polymer comprising a series of release promoting groups and organic retention promoting groups. V376 / 94H - PfcfrHm The oral composition of claim 18, wherein the anionic polymer comprises a chain of repeating units each containing at least one carbon atom. The oral composition of claim 19, wherein each unit comprises at least one release promoting group and at least one organic retention promoting group attached to the same atom or adjacent atom or to another atom in the chain. The oral composition of claim 16, wherein the release promoting group comprises a carboxyl group or a salt thereof. The oral composition of claim 21, wherein the antibacterial enhancing agent is a maleic acid or maleic anhydride copolymer with another ethylenically unsaturated polymerizable monomer or salt thereof. 23. The oral composition of claim 22 wherein said additional monomer is methyl vinyl ether in a molar ratio with maleic acid or maleic anhydride in a ratio of from 4: 1 to 1: 4. The oral composition of claim 23, wherein said copolymer has a molecular weight of about 30,000 to 1,000,000. The oral composition of claim 24, wherein said copolymer has an average molecular weight of about 70,000. The oral composition of claim 16, wherein said release promoting group comprises a phosphone group or a salt thereof. -vj / 6 / 94H-o .04. i yyy The oral composition of claim 26, wherein said antibacterial enhancing agent is poly-β-styrene phosphonic acid, poly-α-styrene phosphonic acid, or a copolymer of any styrene phosphonic acid with another styrene phosphonic acid or other inert polymerizable ethylenically unsaturated, ethylenically unsaturated salt. of these substances. The oral composition of claim 27, wherein said antibacterial enhancing agent has a molecular weight in the range of about 1,000 to about 30,000. Oral composition according to any one of claims 1 to 28, characterized in that it comprises a fluoride ion source.