BE1004240A4 - ANTIBACTERIAL COMPOSITION, AND antiplaque anticalculus USE ORAL AND METHOD OF USE. - Google Patents

Abstract

The invention relates to an antibacterial composition for oral use effective against dental plaque and tartar. The composition contains an anti-scale agent of the polyphosphate type, such as a tetra pyrophosphate (alkali metal), and an anti-plaque antibacterial agent compatible with the latter. The anti-plaque agent is a non-cationic antibacterial agent that is substantially insoluble in water, such as 2,4,4'-trichloro-2'-hydroxy (diphenyl ether) (Triclosan). The effectiveness against dental plaque is optimized by the presence of an antibacterial stimulating agent, such as an anionic polymer, which improves the distribution and retention of said antibacterial agent on the surfaces of the oral cavity.

Description

       

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  Antibacterial, anti-plaque and anti-tartar composition for oral use and method of use
The present invention relates to a composition for oral use antibacterial, anti-plaque and anti-tartar. More particularly, the invention relates to a composition for oral use containing a polyphosphate as an anti-scale agent and a compatible antibacterial agent effective for inhibiting dental plaque, the antiplaque activity being optimized by the presence of an antibacterial stimulating agent which improves the distribution and retaining said antibacterial agent on the surfaces of the oral cavity.



   U.S. Patents No. 4,627,977, 4,515,772 and 4,323,551 describe compositions for oral use which contain various polyphosphates.



  According to the aforementioned patent NI 4,627,977, a linear saline polyphosphate with molecular dehydration is used jointly with a source of fluoride ions and with a synthetic linear polycarboxylate to inhibit the formation of tartar. In the simultaneously pending European patent application NI 89 200 710.5, the anti-scale activity is optimized with a smaller proportion of the linear molecularly dehydrated salt polyphosphate used jointly with the source of fluoride ions and a greater proportion of the synthetic linear polymeric polycarboxylate.

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   According to patents Nos. 4,515,772 and 4,323,551, use is made of a water-soluble di (alkali metal) pyrophosphate, alone or as a mixture with a tetra pyrophosphate (alkali metal).



   The compositions for buccal use which inhibit the formation of tartar on the dental surfaces are very interesting, because tartar is one of the factors responsible for periodontal diseases. Therefore, its reduction promotes oral hygiene.



   Plaque is a precursor to tartar. Unlike tartar, however, plaque can form anywhere on the surface of the tooth, including in particular at the gingival margin.



  As a result, in addition to its unsightly appearance, dental plaque is involved in the appearance of gingivitis.



   Consequently, it would be very desirable to include antimicrobial agents. already known to reduce dental plaque, in compositions for oral use containing anti-tartar agents. In fact, this has been described in U.S. Patent No. 4,022,550, in which a compound providing zinc ions is mixed as a scale inhibitor with an antibacterial agent effective in retarding the development of bacteria in dental plaque. A wide variety of antibacterial agents are described with zinc compounds, including cationic substances such as guanides and quaternary ammonium compounds, as well as non-cationic compounds such as halogenated salicylanilides and halogenated hydroxydiphenyl ethers.



   So far, cationic antibacterial substances such as chlorhexidine, benzethonium chloride and cetylpyridinium chloride have been the most important.

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 a lot of research on anti-bacterial anti-plaque agents. However, although used in conjunction with a zinc scale inhibitor, they are ineffective when used with anionic substances such as a polyphosphate type scale inhibitor.

   This ineffectiveness is considered to be entirely surprising, given that polyphosphates are chelating agents and that it has been previously recognized that the chelating effect increases the effectiveness of cationic antibacterial agents (see, for example, Disinfection, Sterilization and Preservation, 2nd ed., Black, 1977, page 915, and Inhibition and Destruction of the Microbial Cell, Hugo, 1971, page 215). In fact, a quaternary ammonium compound is present in the anti-plaque pyrophosphate mouthwash from US Patent No. 4,323,551, and a bisbiguanide is suggested as an anti-plaque agent in the oral anti-scale pyrophosphate composition of US Patent No. NI 4,515,772.



   Given the surprising incompatibility of cationic antibacterial agents with the polyphosphates present as anti-scale agents, it was completely unpredictable that other antibacterial agents would be effective.



   An advantage of the present invention is that it offers certain antibacterial agents effective in inhibiting the formation of dental plaque in anti-scaling compositions for oral use containing a linear saline polyphosphate with molecular dehydration, a source providing fluoride ions and the agent. of the above-mentioned antibacterial stimulation.



   Another advantage of the present invention is that it provides a composition which is effective in reducing the formation of dental calculus and optimizing the reduction of dental plaque.

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   Another advantage of the present invention is that it provides an anti-plaque anti-plaque composition for oral use which is effective in reducing the appearance of gingivitis.



   Other advantages of the present invention will emerge from the description which follows.



   In certain aspects, the present invention relates to a composition for oral use comprising, in an acceptable vehicle for oral use, an effective amount against dental calculus of a material comprising about 0.1 to 3% by weight of at least a linear saline polyphosphate with molecular dehydration as an anti-scale agent, an amount effective against dental plaque of a non-cationic antibacterial agent substantially insoluble in water and, advantageously, up to about 4% by weight of an antibacterial stimulating agent which improves the distribution and retention of said antibacterial agent on the surfaces of the oral cavity, in which the weight ratio of the antibacterial stimulating agent
 EMI4.1
 alien to polyphosphate ions being more than 0.72: 1 to less than 4:

   1, for example from about 1: 1 to about 3.5: 1, especially from about 1.6: 1 to about 2.7: 1, preferably from about 1.7: 1 to about 2.3 : 1, and even better from about 1.9: 1 to about 2: 1. For example, when using tetrasodium pyrophosphate (PPTS) (providing about 1.3% of pyrophosphate ions) with 2.5% of the antibacterial stimulating agent, a very advantageous weight ratio of approximately 1.9: 1 is obtained.



   Representative examples of antibacterial agents which are particularly advantageous for considerations of efficacy against dental plaque, safety of use and formulation are as follows:

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Halogenated diphenyl ethers 2 ', 4, 4'-trichloro-2-hydroxy (diphenyl ether) (Triclosan) 2, 2'-dihydroxy-5, 5'-dibromo (diphenyl ether)
Halogenated salicylanilides 4 ', 5-dibromosalicylanilide 3, 4', 5-trichlorosalicylanilide
 EMI5.1
 3, 4 ', 5-tribromosalicylanilide 2, 3, 3', 5-tetrachlorosalicylanilide 3, 3, 3 ', 5-tetrachlorosalicylanilide 3, 5-dibromo-3'-trifluoromethyl-salicylanilide 5-n-octanoyl-3'-trifluoromethyl -salicylanilide 3,5-dibromo-4'-trifluoromethyl-salicylanilide 3,5-dibromo-3'-trifluoromethyl-salicylanilide (Flurophene)

  
Benzo esters methyl p-hydroxybenzoate ethyl p-hydroxybenzoate propyl p-hydroxybenzoate butyl p-hydroxybenzoate
Halogenated carbanilides 3, 4, 4'-trichlorocarbanilide
 EMI5.2
 3-trifluoromethyl-4,4'-dichlorocarbanilide 3,3,4'-trichlorocarbanilide
Phenolic compounds (including phenol and its counterparts, halogenated mono- and polyalkyl- and aryl-phenols (e.g., F, Cl, Br, I), resorcinol, pyrocatechol and their derivatives, and bisphenolic compounds).

   These phenolic compounds include among others:
Phenol and its counterparts Phenol 2-methylphenol 3-methylphenol 4-methylphenol

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 4-ethylphenol 2, 4-dimethylphenol 2, 5-dimethylphenol 3, 4-dimethylphenol 2, 6-dimethylphenol 4-n-propylphenol 4-n-butylphenol 4-n-amylphenol 4-tert.-amylphenol 4-n-hexylphenol 4 -n-heptylphenol
 EMI6.1
 2-methoxy-4- (2-propenyl) phenol (eugenol) 2-isopropyl-5-methylphenol (thymol)

   Mono- and poly-alkyl- and aralkyl-halophenols Methyl-p-chlorophenol Ethyl-p-chlorophenol n-propyl-p-chlorophenol n-butyl-p-chlorophenol n-amyl-p-chlorophenol dry.-amyl-p-chlorophenol n-hexyl-p-chlorophenol Cyclohexyl-p-chlorophenol n-heptyl-p-chlorophenol n-octyl-p-chlorophenol o-chlorophenol Methyl-o-chlorophenol Ethyl-o-chlorophenol n-propyl-o-chlorophenol n-butyl- o-chlorophenol n-amyl-o-chlorophenol tert.-amyl-o-chlorophenol n-hexyl-o-chlorophenol n-heptyl-o-chlorophenol p-chlorophenol o-benzyl-p-chlorophenol

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   o-benzyl-m-methyl-p-chlorophenol o-benzyl-m,

   m-dimethyl-p-chlorophenol o-phenylethyl-p-chlorophenol o-phenylethyl-m-methyl-p-chlorophenol 3-methyl-p-chlorophenol 3,5-dimethyl-p-chlorophenol 6-ethyl-3-methyl-p -chlorophenol 6-n-propyl-3-methyl-p-chlorophenol 6-isopropyl-3-methyl-p-chlorophenol 2-ethyl-3, 5-dimethyl-p-chlorophenol 6-sec. -butyl-3-methyl-p-chlorophenol 2-isopropyl-3, 5-dimethyl-p-chlorophenol 6-diethylmethyl-3-methyl-p-chlorophenol 6-isopropyl-2-ethyl-3-methyl-p-chlorophenol 2 -dry. -amyl-3, S-dimethyl-p-chlorophenol 2-diethylmethyl-3, 5-dimethyl-p-chlorophenol 6-sec. -octyl-3-methyl-p-chlorophenol p-bizomophenol.



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

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 3, 4, S,

   6-tetrabromo-2-methylphenol 5-methyl-2-pentylphenol 4-isopropyl-3-methylphenol 5-chloro-2-hydroxydiphenylmethane
Resorcinol and its derivatives Resorcinol Methylresorcinol Ethylresorcinol n-propylresorcinol n-butylresorcinol n-amylresorcinol n-hexylresorcinol n-heptylresorcinol
 EMI8.1
 n-octylresorcinol n-nonylresorcinol Phenylresorcinol Benzylresorcinol Phenylethyl-resorcinol Phenylpropyl-resorcinol p-chlorobenzyl-resorcinol 5-chloro-2, 4-dihydroxydiphenylmethane 4'-chloro-2, 4-dihydroxiphenyl 4-dihydroxypheniphenyl 2,4-bromo-dihydroxydiphenylmethane
Bisphenolic compounds Bisphenol A 2, 2'-methylene-bis (4-chlorophenol) 2, 2'-methylene-bis (3, 4, 6-trichlorophenol) (hexachlorophene) 2,

   2'-methylene-bis (4-chloro-6-bromophenol) Bis (2-hydroxy-3,5-dichlorophenyl) sulfide Bis (2-hydroxy-5-chlorobenzyl) sulfide
The antibacterial agent is present in the composition for oral use in an amount effective against dental plaque, generally of about 0.01

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 to 5% by weight, preferably from about 0.03 to 1%, most preferably from about 0.25 to 0.5% and, most preferably from about 0.25 to 0.35%. The antibacterial agent is substantially insoluble in water, which means that its solubility is less than about 1% by weight in water at 250C and can even be less than about 0.1%. If an ionizable group is present, the solubility is determined at a pH at which no ionization occurs.



   The preferred halogenated diphenyl ether is Triclosan. The preferred phenolic compounds are phenol-, thymol, eugenol, and 2,2'-methylene-bis (4-chloro-6-bromophenol). The most preferred anti-bacterial anti-bacterial compound is Triclosan. Triclosan is proposed in U.S. Patent No. 4,022,880 mentioned above as an antibacterial agent in combination with a scale inhibitor which provides zinc ions and in R.F.A. NI 3,532,860 in association with a copper compound. In European patent NI 0 278 744, it is proposed in combination with a tooth desensitizing agent containing a source of potassium ions.

   It is also proposed in the published European patent application NI 0 161 898 as an antiplaque agent in a toothpaste formulated so as to contain a lamellar phase of a lamellar liquid crystal surfactant whose interlamellar spacing is less than 6, 0 nm and which can optionally contain a zinc salt, as well as in the European patent application published NO 0 161 899 in a toothpaste containing zinc citrate trihydrate.



   The linear saline polyphosphates with molecular dehydration which are effective here as anti-scale agents are well known compounds, generally used in the form of hydro-

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 soluble, totally or partially neutralized, of alkali metals (for example potassium, and preferably sodium) or ammonium, and any mixtures of them. Representative examples include sodium hexametaphosphate, sodium tripolyphosphate, pyrophosphates diacid disodium, mono trisodium and tetrasodium, corresponding potassium salts, etc. Linear polyphosphates have the formula (Nap03) n where n is from about 2 to about 125.

   In the present invention, they are used in compositions for buccal use in weight proportions due-0.1 to 3%, typically from 1 to 2.5%, and more typically from 1.5 to 2%. When n is equal to or greater than 3 in (Nap03) n 'these polyphosphates are vitreous in nature.



   Particularly advantageous anti-scale agents are the tetra (alkali metal) pyrophosphates, including their mixtures, such as tetrasodium pyrophosphate, tetrapotassium pyrophosphate, and their mixtures. Thus, the composition for oral use can contain a polyphosphate type anti-scale agent which is substantially free of tetrasodium pyrophosphate or substantially free of a combination of tetrapotassium pyrophosphate and tetrasodium pyrophosphate where the ratio of potassium pyrophosphate to sodium pyrophosphate is equal to or greater than 3: 1.



  An anti-scale agent comprising approximately 2% by weight of tetrasodium pyrophosphate, relative to the weight of the compositions for oral use, is particularly effective.



   The antibacterial stimulating agent (ASA) which improves the distribution and retention of said antibacterial agent on the oral surfaces, is used in effective amounts to achieve this improvement which are in the range of about

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 0.005% to about 4%, preferably from about 0.1% to about 3% and more preferably from about 0.5% to about 2.5% by weight in the composition for oral use.



   ASA can be a simple compound, buccal rence a polymerizable monomer, better still a polymer, the latter term being taken in a completely generic sense and including for example oligomers, homopolymers, copolymers of two or more monomers, ionomers , block copolymers, graft copolymers, crosslinked polymers and copolymers, etc. ASA can be natural or synthetic, and insoluble in water or, preferably, soluble or swellable (hydratable, forming a hydrogel) in water (saliva). It has an average molecular weight (by weight) of about 100 to about 1,000,000, preferably from about 1,000 to about 1,000,000 and more preferably from about 2,000 or 2,500 to about 250,000 or 500,000.



   The ASA ordinarily contains at least one distribution enhancing group, which is preferably acidic, for example of a sulfonic, phosphonic, or more preferably phosphinic or carboxylic acid, or a salt thereof, for example of an alkali metal or of ammonium, and at least one organic group improving the retention, preferably several of each of the groups improving the distribution and improving the retention, the latter groups preferably corresponding to the formula- (X) -R where X is 0, N , S, SO, SO, P, PO, Si, etc., R is a hydrophobic alkyl, alkenyl, acyl, aryl, alkaryl, aralkyl, heterocyclic group or their derivatives with inert substituents, and n is zero or 1 or more.

   The above-mentioned "derivatives with inert substituents" have substituents on R which are generally non-hydrophilic and do not substantially disturb the functions which the ASA must fulfill to improve the distribution and retention of the antibacterial agent on the

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 EMI12.1
 buccal surfaces, for example halot substituents in particular Cl, Br, Il and carboi etc.

   Representative examples of such retention enhancing groups are presented in a table below.
 EMI12.2
 
 <tb>
 <tb> n
 <tb> 0 <SEP> --- <SEP> methyl, <SEP> ethyl, <SEP> propyle, <SEP> butyl, <SEP> isobutyle,
 <tb> t-butyl, <SEP> cyclohexyl, <SEP> allyle, <SEP> benzyl,
 <tb> phenyl, <SEP> chlorophenyl, <SEP> xylyle, <SEP> pyridyle,
 <tb> furannyle, <SEP> acetyl, <SEP> benzoyl, <SEP> butyryl,
 <tb> terephthaloyl, <SEP> etc.
 <tb>



  1 <SEP> 0 <SEP> ethoxy, <SEP> benzyloxy, <SEP> thioacetoxy, <SEP> phenoxy,
 <tb> carbethoxy, <SEP> carbobenzyloxy, <SEP> etc.
 <tb>



  NOT <SEP> ethylaminot <SEP> diethylaminot <SEP> propylamido,
 <tb> benzylamino, <SEP> benzoylamido, <SEP> phenylacetamido,
 <tb> etc.
 <tb>



  5 <SEP> thiobutyle, <SEP> thio-isobutyl, <SEP> thioallyle,
 <tb> thiobenzyle, <SEP> thiophenyl, <SEP> thiopropionyl,
 <tb> phenylthioacetyl, <SEP> thiobenzoyle, <SEP> etc.
 <tb>



  SO <SEP> butylsulfoxy, <SEP> allylsulfoxy, <SEP> benzylsulfoxy,
 <tb> phenylsulfoxy, <SEP> etc. <SEP>
 <tb>



  502 <SEP> butylsulfonyl, <SEP> allylsulfonyl, <SEP> benzylsulfonyl, <SEP> phenylsulfonyl, <SEP> etc.
 <tb>



  P <SEP> diethylphosphinyl, <SEP> ethylvinylphosphinyl,
 <tb> ethylallylphosphinyl, <SEP> ethylbenzylphosphinyl, <SEP> ethylphenylphosphinyl, <SEP> etc.
 <tb>



  PO <SEP> diethylphophinoxy, <SEP> ethylvinylphosphinoxy,
 <tb> methylallylphosphinoxy, <SEP> methylbenzylphosphinoxy, <SEP> methylphenylphosphinoxy, <SEP> etc.
 <tb>



  Yes <SEP> trimethylsilyl, <SEP> dimethylbutylsilyl,
 <tb> dimethylbenzylsilyl, <SEP> dimethylvinylsilyl,
 <tb> dimethylallylsilyl, <SEP> etc.
 <tb>
 

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   As used herein, the term "distribution enhancing group" refers to a group that substantially or adhesively fixes or binds ASA (carrying the antibacterial agent) to the surfaces of the oral cavity (eg teeth and gums), thereby "delivering" or "distributing" the antibacterial agent to these surfaces. The organic group improving retention, generally hydrophobic, fixes or binds in another way
 EMI13.1
 the ASA antibacterial agent, thereby improving the retention of the ASA antibacterial agent and, indirectly, to the surfaces of the oral cavity.

   In some cases, the fixing of the antibacterial agent is carried out by its physical encroachment by ASA, in particular when the ASA is a crosslinked polymer, the structure of which offers by nature more sites suitable for such encroachment. The presence of a more hydrophobic crosslinking fragment, of higher molecular weight, in the crosslinked polymer further promotes the physical encroachment of the antibacterial agent by the crosslinked polymer forming the ASA.



   Preferably, ASA is an anionic polymer comprising a chain or skeleton having repeating units which each preferably contain at least one carbon atom and, preferably, at least one monovalent group improving the distribution attached laterally directly or indirectly and at least one monovalent retention improving group laterally attached directly or indirectly, which are linked in twin, vicinal or, less preferably, in another way to atoms of the chain, preferably carbon atoms.

   Less preferably, the polymer may contain distribution improving groups and / or retention improving groups and / or other divalent atoms or groups such as mail-

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 Ions of the polymer chain in place of or in addition to carbon atoms, or as crosslinking fragments.



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



   According to a preferred embodiment of the present invention, the ASA consists of a polymer containing repeating units in which one or more phosphonic acid groups improving the distribution are linked to one or more carbon atoms of the polymer chain. An example of such an ASA is a poly (vinylphosphonic acid) having units of formula:
 EMI14.1
 which, however, does not contain a retention enhancing group.

   A group of the latter type is however present in a poly (l-phosphonopropene) having units of formula:
 EMI14.2
 

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 An ASA containing phosphonic acid which it is preferred to use here is a poly (beta-styrenephosphonic acid) having units of formula:
 EMI15.1
 where Ph is the phenyl group, the phosphonic group improving the distribution and the phenyl group improving the retention being linked to vicinal carbon atoms of the chain, or a copolymer of betastyrene-phosphonic acid with vinylphosphonyl chloride containing the units of formula III alternately or in statistical association with units of formula I above, or alternatively a poly (alphastyrene-phosphonic acid) having units of formula:

   
 EMI15.2
 where the groups improving the distribution and the groups improving the retention are linked in female relation to the chain.



   These styrene-phosphonic acid polymers and their copolymers formed with other inert ethylenically unsaturated monomers generally have molecular weights in the range of about 2000 to about 30,000, preferably about 2,500 to about 10,000. These "inert" monomers do not significantly disturb the function assigned to any copolymer used here as ASA.



   Other polymers containing phosphonic groups include 1, for example, a phosphonated ethylene polymer having units of formula:
 EMI15.3
 where n can, for example, be an integer or have

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 a value giving the polymer a molecular weight of approximately 3000; and a poly (sodium butene-4, 4-diphosphonate) having units of formula:
 EMI16.1
 and a poly (allyl-bis (phosphonoethyl) amine) having units of formula:

   
 EMI16.2
 Other phosphonated polymers, for example a poly (allyl-phosphono-acetate), a phosphonated polymethacrylate, etc., and the polymers with two feminine phosphonate groups described in European patent NO 0 321 233 can be used here as ASA, provided of course that they contain or are modified to contain the organic groups improving the retention defined above.



   In one aspect of the present invention, the composition for oral use comprises an acceptable vehicle for oral use, an agent which is effective in stimulating the antibacterial effect of an antibacterial agent, which has an average molecular weight of about 1000 to about 1,000,000, contains at least one functional group improving the distribution of the antibacterial effect and at least one organic group improving the retention of the antibacterial effect, said agent containing said groups being free or substantially free of synthetic water-soluble synthetic anionic linear polycarboxylate of an alkali metal or of ammonium, having a molecular weight of approximately 1000 to 1,000,000, and an anti-scale agent of the polyphosphate type, for example a mixture of potassium and sodium salts,

   the ratio of potassium to sodium in the-

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 said composition being in the range of up to less than about 3: 1, for example from about 0.37 to about 1.04: 1.



   In another preferred embodiment, the ASA comprises a synthetic anionic polymeric polycarboxylate which is also an alkaline phosphatase inhibitor. Synthetic anionic polymeric polycarboxylates and their complexes formed with various cationic germicides, zinc and magnesium have been previously proposed as scale inhibitors by themselves, for example in U.S. patents.



  NO 3,429,963.4 152,420.3 956,480.4 138,477 and 4,183,914. However, it is only in one disclosure which essentially corresponds to the U.S. Patent.



  No. 4,627,977, the use of these polycarboxylates is described to inhibit the hydrolysis by saliva of an anti-scale agent of the pyrophosphate type in association with a compound providing fluoride ions. It will be understood that the synthetic anionic polymeric polycarboxylates thus proposed in these various patents, when they contain or are modified to contain retention-improving groups, can be used in the compositions and methods of the present invention and, to this extent, the relevant presentations of these patents are incorporated herein by reference to them.



   These synthetic anionic polymeric polycarboxylates are often used in the form of their free acids or, preferably, their alkali metal (for example potassium and preferably sodium) or ammonium salts, partially or, better still, completely neutralized , water-soluble or swellable with water (hydratable, forming a gel). 1: 4 to 4: 1 copolymers of maleic anhydride or acid with another polymerizable monomer are preferred

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 ethylenically unsaturated, preferably a methyl ether / vinyl / maleic anhydride copolymer having a molecular weight (MW) of from about 30,000 to about 1,000,000 and more preferably from about 30,000 to about 500,000.

   These copolymers are available, for example, under the Gantrez product designations, for example AN 139 (PM 500,000), AN 119 (PM 250,000) and, preferably, S-97 Pharmaceutical Grade (PM 70,000) from GAF Corporation .



   Other polymeric polycarboxylates usable as ASA, containing or modified to contain retention improving groups include those proposed in the aforementioned US Patent No. 3,956,480, such as 1: 1 copolymers of maleic anhydride with acrylate d ethyl, hydroxyethyl methacrylate, N-vinyl-2-pyrrolidone or ethylene, the latter type of copolymer being available, for example, under the designations EMA NO 1103, PM



  10,000, and EMA Grade 61 from Monsanto, and 1: 1 copolymers of acrylic acid with methyl or hydroxyethyl methacrylate, methyl or ethyl acrylate, isobutyl vinyl ether or N-vinyl-2-pyrrolidone.



   Other usable polymeric polycarboxylates proposed in the aforementioned US Pat. Nos. 4,138,477 and 4,183,914, containing or modified to contain retention improving groups, include maleic anhydride copolymers with styrene, isobutylene or ethyl vinyl ether, polyacrylic, polyitaconic and polymaleic acids, and sulfoacrylic oligomers with PM as low as 1000, available under the designation ND-2 from Uniroyal.



   Generally suitable monomers are olefinically or ethylenically carboxylic acids.

  <Desc / Clms Page number 19>

 nically unsaturated containing a group improving the retention, which comprise an activated carbon-carbon olefinic double bond easily operating a polymerization owing to the fact that it is present in the molecule of monomer either in position alpha-beta compared to a carboxyl group, or like part of a terminal methylene group.

   Representative examples of such acids are acrylic, methacrylic, ethacrylic, alpha-chloracrylic, crotonic, beta-acryloxypropionic, sorbic, alpha-chlorosorbic, cinnamic, beta-styrylacrylic, muconic, itaconic, citraconic, mesaconic, glutaconic, aconitic acids. -phenylacrylic, 2-benzylacrylic, 2-cyclohexylacrylic, angelic, umbellic, fumaric, maleic and their anhydrides. Other different olefin monomers copolymerizable with these carboxylic monomers include vinyl acetate, vinyl chloride, dimethyl maleate, etc. The copolymers contain enough salified carboxylic groups to ensure their solubility in water.



   Substances also useful here are so-called carboxyvinyl polymers proposed as components of toothpaste in U.S. patents.



  NO 3,980,767.3 935 306.3 919,409.3 911,904 and 3,711,604. These polymers are commercially available, for example under the trade names Carbopol 934,940 and 941 from BF Goodrich, these products being essentially composed of a colloidally water-soluble polymer of polyacrylic acid crosslinked with about 0.75% to about 2.0% of polyallyl-sucrose or polyallyl-pentaerythritol as crosslinking agent, the crosslinked structure and the crosslinking bonds ensuring the desired retention improvement by hydrophobia and / or physical encroachment of the antibacterial agent, or the like.

   A carbophilic polymer is quite similar)

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 being a polyacrylic acid crosslinked with less than 0.2% of divinylglycol, the proportion, the molecular weight and / or the hydrophobicity lower of this crosslinking agent tending to offer little or no improvement retention. 2,5dimethyl-1,5-hexadiene is an example of a crosslinking agent which improves retention and is more effective.



   The synthetic anionic polymeric polycarboxylate component is most often a hydrocarbon bearing optional halogenated and oxygenated substituents and bonds, as it exists for example in ester, ether and OH groups, and, when it is present, it is generally used in the present compositions in approximate weight proportions of up to about 4% (generally at least about 0.05%).



   The ASA may also include natural anionic polymeric polycarboxylates containing retention enhancing groups. Carboxymethylcellulose and other binding agents, gums and film-forming agents lacking the distribution improving and / or retention improving groups defined above are ineffective as ASAs.



   As representative examples of ASA containing phosphinic acid and / or sulfonic acid groups improving the distribution, mention may be made of polymers and copolymers containing units or fragments originating from the polymerization of vinyl- or allyl-phosphinic acids and / or sulfonic substituted, as necessary, on the carbon atom in 1 or 2 (or 3) by an organic group improving retention, for example corresponding to the formula- (X) nR defined above. Mixtures of these monomers and their copolymers formed with one or more ethylenically inert polymerizable monomers can be used.

  <Desc / Clms Page number 21>

 unsaturated such as those described above with respect to the usable synthetic anionic polymer polycarboxylates.

   As will be noted, in these polymeric ASAs as well as others usable here, there is generally only one acid group improving the distribution bound to any given carbon or other atom of the polymer backbone or an offshoot of it. Polysiloxanes containing or modified to contain side groups improving distribution and side groups improving retention can also be used here as ASA. Ionomers containing or modified to contain distribution and retention enhancing groups are also effective here as ASA. These ionomers are described on pages 546-573 of the supplemental volume of "Kirk Othmer Encyclopedia of Chemical Technology", third edition, John Wiley & Sons, Inc., copyright 1984, the description of which is incorporated herein by reference.

   Substances also effective here like ASA are synthetic and natural polyesters, polyurethanes and polyamides, including proteins and proteinaceous materials such as collagen, poly (arginine) and other polymerized amino acids, provided that they contain or be modified to contain groups improving retention.



   When the composition for oral use is prepared by first dissolving the polyphosphate and the antibacterial agent in a humectant and a surfactant and adding ASA, in particular the polycarboxylate, in successive portions, the solution becomes clear and can be characterized as a "microemulsion". As the proportion of polycarboxylate increases so that the finished preparation contains at least about 2.2% by weight, the solution becomes cloudy and can be characterized as

  <Desc / Clms Page number 22>

   a "macroemulsion". In these "macroemulsion" type compositions, the antiplaque effect of the antibacterial agent turns out to be optimized.



   An advantageous weight ratio of the non-cationic antibacterial agent substantially insoluble in water to the anti-scale agent of the polyphosphate type is between more than about 0.72: 1 and less than about 4: 1, for example d '' about 1: 1 to about 3.5: 1, especially about 1.6: 1 to about 2.7: 1.



   In order to optimize the anti-tartar efficacy of the composition for oral use, it is desirable that inhibitors are present which prevent the enzymatic hydrolysis of polyphosphate. These agents consist of a proportion of a source of fluoride ions sufficient to provide 25 to 5000 x 10-4% of fluoride ions, and. up to 3% or more of the synthetic anionic polymeric polycarboxylate having a molecular weight of about 1000 to about 1,000,000, preferably about.



  30,000 to about 500,000.



   Sources of fluoride ions, or fluorine-providing compounds, used as a pyrophosphatase and acid phosphatase inhibitor component, are well known in the art as anti-caries agents.



  These compounds may be slightly soluble in water or may be completely soluble in water.



  They are characterized by the ability to release fluoride ions into water and by their absence of undesirable reaction with the other compounds contained in the composition for oral use. Among these substances are mineral saline fluorides, such as soluble salts of alkali metals and alkaline earth metals such as, for example, sodium fluoride, potassium fluoride, ammonium fluoride, calcium fluoride, a copper fluoride such as copper fluoride, zinc fluoride, fluoride

  <Desc / Clms Page number 23>

 barium, sodium fluorosilicate, ammonium fluorosilicate, sodium fluorozirconate, ammonium fluorozirconate, sodium monofluorophosphate, aluminum mono and difluorophosphates, and sodium and fluorinated calcium pyrophosphate.

   Preferred are alkali metal and tin fluorides, such as sodium and stannous fluorides, sodium monofluorophosphate (MFP) and mixtures thereof.



   The proportion of fluorine-providing compound depends to some extent on the type of compound, its solubility and the type of oral preparation, but this should be a non-toxic proportion, generally from about 0.005 to about 3.0% in the preparation. In a preparation of toothpaste, for example a toothpaste gel, a toothpaste (including a cream), a toothpaste or a dental tablet, a proportion of such a compound is considered satisfactory which releases a maximum of about 5000 x 10-4% by weight of F ions, relative to the weight of the preparation. Any lower proportion of this compound can be used, but it is preferable to use it
 EMI23.1
 enough to release about 300 to 2000 x 10%, and more preferably about 800 to about 1500 x 10%, of fluoride ions.



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



   In preparations for oral use such as mouthwashes, lozenges and chewing gums, the fluorine-providing compound is typically

  <Desc / Clms Page number 24>

 
 EMI24.1
 present in sufficient quantity to release a maximum. about 500 x 10-4% / preferably 25 to 300 x 10-4% by weight of fluoride ions. In general, this compound is present in an amount of 0.005 to 1.0% by weight.



   In certain embodiments of the invention which are very particularly preferred, the composition for oral use may be of a substantially liquid nature, being for example a bath for washing or rinsing the mouth. In such a preparation, the vehicle is typically a water-alcohol mixture advantageously containing a humectant as described below. In general, the weight ratio of water to alcohol is in the range of from about 1: 1 to about 20: 1, preferably from about 3: 1 to 10: 1, and more preferably, from about 4: 1 to about 6: 1. The total amount of water-alcohol mixture in this type of preparation is typically in the range of from about 70 to about 99.9% by weight of the preparation.



  The alcohol is typically ethanol or isopropanol.



  Ethanol is preferred.



   The pH of these liquid preparations and the other preparations of the invention is generally in the range of about 4.5 to about 9, and typically about 5.5 to 8. The pH is preferably in the range range from about 6 to about 8.0. It is interesting to note that the compositions of the invention can be applied to the oral cavity at a pH below 5 without substantially decalcification or otherwise damaging the enamel dental. The pH can be adjusted by an acid (e.g. acid
 EMI24.2
 citric or benzoic acid) or by a base (for example sodium hydroxide), or be buffered (as by citrate, benzoate, carbonate or sodium bicarbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate , etc.).

  <Desc / Clms Page number 25>

 



   In certain other advantageous embodiments of the present invention, the composition for oral use can be of a substantially solid or pasty nature, being for example a toothpaste, a dental tablet or a toothpaste, it ie toothpaste (dental cream) or toothpaste gel. The vehicle for these solid or pasty oral preparations generally contains an acceptable polishing material for the teeth.

   Examples of polishing materials are water-insoluble sodium metaphosphate, potassium metaphosphate, tricalcium phosphate, calcium phosphate dihydrate, 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 U.S. Patent No. 3,070,510, such as melamine, phenolic and urea formaldehyde resins, and crosslinked polyesters and polyepoxides.

   Preferred polishing materials include crystalline silica having a particle size of about 5 micrometers maximum, an average particle size of about 1.1 micrometers maximum and a specific surface of about 50,000
 EMI25.1
 o cm2 / g maximum, a silica gel or a colloidal silica, and an amorphous alkali metal aluminosilicate.



   When using gels with a transparent appearance, particularly useful polishing agents are colloidal silicas, such as the products sold under the trademark SYLOID such as Syloid

  <Desc / Clms Page number 26>

 72 and Syloid 74 or under the trademark SANTOCEL such as Santocel 100, or complex aluminosilicates of alkali metals, because their refractive index is close to the refractive index of gelling agent-liquid systems (comprising water and / or a humectant) commonly used in toothpaste.



   Many of the so-called "water-insoluble" polishes are anionic in character and also contain small amounts of soluble material. Thus, an insoluble sodium metaphosphate can be prepared by any suitable method as explained, for example, in the book "Dictionary of Applied Chemistry" by Thorpe, Volume 9, 4th edition, pages 510-511. Other examples of suitable materials are the forms of insoluble sodium metaphosphate known as Madrell salt and Kurrol salt. These saline metaphosphates show only a minute solubility in water and are therefore commonly called insoluble metaphosphates (MPI).

   There are found, as impurities, a minor proportion of soluble phosphates, usually a few percent, for example 4% by weight at most. The amount of soluble phosphate material, which is assumed to include a soluble sodium trimetaphosphate in the case of an insoluble metaphosphate, can optionally be reduced or removed by washing with water. The insoluble alkali metal metaphosphate is typically used in the form of a powder whose particle size is such that a maximum of 1% of the material is larger than 37 micrometers.



   The polishing material is generally present in solid or pasty compositions in weight concentrations of about 10 to about 99%. Preferably, this material is present in pro-

  <Desc / Clms Page number 27>

 portions ranging from about 10% to about 75% in a toothpaste, and from about 70% to about 99% in a tooth powder. In toothpaste, when the polishing material is siliceous in nature, it is generally present in a proportion of about 10 to 30% by weight. The other polishing materials are typically present in an amount of about 30 to 75% by weight.



   In a toothpaste, the liquid vehicle may include water and a humectant, typically in an amount of from about 10% to about 80% of the weight of the preparation. Representative examples of suitable vehicles / humectants are glycerol, propylene glycol, sorbitol and polypropylene glycol.



  Liquid mixtures of water, glycerol and sorbitol are also advantageous. In transparent gels where the refractive index is an important criterion, preferably between about 3 and 30% by weight of water, 0 to about 70% by weight of glycerol and about 20 to 80% by weight of sorbitol are used. .



   Toothpastes, creams and gels typically contain a gelling or thickening agent
 EMI27.1
 natural or synthetic in proportions of from about 0.1 to about 10%, preferably from about 0.5 to about 5%, by weight. A suitable thickener is synthetic hectorite, a synthetic colloidal clay consisting of a silicate complex of alkali metals and magnesium, commercially available under the designation Laponite (for example CP, SP, 2002, D), these products being marketed by Laporte Industries Limited. Analysis of Laponite D indicates, by weight, approximately 58.00% of Si02'25, 40% of MgO, 3.05% of Na20, 0.98% of Li20 and traces of metals.



  Its real density is 2.53 and its apparent density (at 8% humidity) is 1.0.

  <Desc / Clms Page number 28>

 



   Other suitable thickeners include Irish moss, iota-carrageenan, tragacanth, starch, polyvinylpyrrolidone, hydroxyethylpropylcellulose, hydroxybutylmethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose (available for example under the designation Natrosol, sodium carboxymethylcellulose and a colloidal silica such as Syloid (for example 244) finely ground In certain toothpastes prepared according to the present invention, in particular when more than about 0.35% by weight of the antibacterial agent insoluble in water and a siliceous polishing agent is present in an amount less than about 30% by weight, it may be advantageous to include an agent which dissolves the antibacterial agent.

   Such solubilizers include humectant polyols such as propylene glycol, dipropylene glycol and hexylene glycol, Cellosolve products such as Methylcellosolve and Ethylcellosolve, vegetable oils and waxes containing at least about 12 carbon atoms in a chain configuration
 EMI28.1
 straight, such as olive oil, castor oil and petroleum jelly and esters such as amyl acetate, ethyl acetate and benzyl benzoate.



   It will be understood that, as is usual, preparations for oral use must be sold or otherwise distributed in suitably labeled packages. Thus, a mouthwash bottle must bear a label which essentially describes it as such and gives indications for its use; and a toothpaste, gel or dental cream is usually packaged in a compressible tube, typically aluminum, coated lead or plastic, or in another compressible dispenser, pump or pressure, intended to deliver its contents

  <Desc / Clms Page number 29>

 in a metered manner and bearing a label essentially describing it as a toothpaste, a gel or a dental cream.



   Organic surfactants are used in the compositions of the present invention to exert an increased prophylactic action, to help achieve a complete and uniform dispersion of the anti-scale agent and the anti-plaque agent throughout the oral cavity, and present compositions more acceptable from the cosmetic point of view. The organic surface-active substance is preferably of anionic, nonionic or ampholytic character, and it is preferred to use as a surface-active agent a detersive substance which gives the composition detergent and foaming properties.

   Examples of suitable anionic surfactants are the water-soluble salts of monoglycerides of higher fatty acid monoglycerides, such as the sodium salt of monoglyceride monosulfate of hydrogenated coconut oil fatty acids, higher alkyl sulfates such as sodium lauryl sulfate, alkylarylsulfonates such as sodium dodecylbenzene sulfonate, higher alkylsulfoacetates, higher fatty acid esters of 1,2-dihydroxypropane sulfonates, and substantially saturated higher aliphatic acylamides formed with lower aliphatic aminocarboxylic acids, such as those of which fatty acid, alkyl or acyl radicals have 12 to 16 carbon atoms, etc.

   Examples of the last mentioned amides are N-lauroylsarcosine, and the sodium, potassium and ethanolamine salts of N-lauroyl-, N-myristoylou N-palmitoyl-sarcosine which must be substantially free from soap or derivatives similar to higher fatty acids. The use of these sarcosinates in the compositions for oral use of the present invention

  <Desc / Clms Page number 30>

 is particularly advantageous because these substances exert a marked and prolonged effect of inhibiting the formation of acids by decomposition of carbohydrates in the oral cavity, and moreover exert a certain reduction in the solubility of dental enamel in the acid solutions.

   Examples of water-soluble non-ionic surfactants are condensation products of 1 1 ethylene oxide with various labile hydrogen compounds reactive with ethylene oxide which have long hydrophobic chains (e.g. aliphatic chains of about 12 to 20 carbon atoms), these condensation products ("ethoxamers") containing hydrophilic polyoxyethylene fragments, for example the condensation products of poly (ethylene oxide) with fatty acids, fatty alcohols, fatty amides, polyalcohols (for example sorbitan monostearate) and poly (propylene oxide) (for example the products of the Pluronic series).



   The surfactant is generally present in an amount of about 0.1 to 5% by weight, preferably about 1 to 2.5%. It is interesting to note that the surfactant can promote the dissolution of the non-cationic antibacterial agent and thus reduce the amount of solubilizing humectant required.



   Various other substances can be incorporated into the oral preparations of the present invention, such as bleaches, preservatives, silicones, chlorophyll compounds and / or ammoniated substances such as urea and diammonium phosphate, and their mixtures. These adjuvants, if present, are incorporated into the preparations in amounts which do not substantially affect the desired properties and characteristics. Important pro-

  <Desc / Clms Page number 31>

 portions of salts and substances, generally soluble, containing zinc, magnesium and other metals, which would form complexes with the active components of the preparations of the present invention.



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



   In the preferred practical application of the present invention, a composition for buccal use according to the invention, for example a mouthwash or a toothpaste containing the composition of the present invention, is preferably applied at regular intervals to the dental enamel. , for example every day or every two or three days, or preferably 1 to 3 times a day, at a pH of about 4.5 to about 9, generally from about 5.5 to about 8 and of preferably about 6 to 8, for at least 2 to 8 weeks or more, or even for life.



   The compositions of the present invention can be incorporated into lozenges or into chewing gum or other products, for example by shaking them in a hot gum base or by applying them to the outer surface of a gum base.

  <Desc / Clms Page number 32>

 representative examples of which may be mentioned are jelutong, rubber latex, vinylite resins, etc., advantageously combined with conventional plasticizers or softeners, sugar or other sweeteners or carbohydrates, such as glucose, sorbitol, etc.



   The following examples further illustrate the present invention without, however, limiting it. All the quantities and proportions mentioned therein are expressed by weight.



   In the following examples, the anti-
 EMI32.1
 Bacterial Triclosan, that is to say 2, 4, 4'-trichloro-2'-hydroxy (diphenyl ether) is designated by "TCHE" 7 sodium lauryl sulfate is designated by "L88": the copolymer d maleic anhydride and methyl vinyl ether available from GAF Corporation
 EMI32.2
 under the designation "Gantrez S-97" is identified by "Gantrez" 7 tetrasodium pyrophosphate is identified by "pyrophosphate": and sodium fluoride is identified by "NaF".



   Example 1
The adsorption and release by the mineral constituents of the teeth are evaluated to determine the anti-plaque / anti-scale effectiveness of the agents. proceeding by adsorption of the antibacterial agent on a dental mineral hydroxyapatite disk, coated with saliva, in the presence of pyrophosphate and various amounts of polycarboxylate.



   The formulations of the toothpastes evaluated are as follows:

  <Desc / Clms Page number 33>

 
 EMI33.1
 Parts by weight
 EMI33.2
 
 <tb>
 <tb> A <SEP> B
 <tb> Glycerol <SEP> 10,000 <SEP> 10,000
 <tb> Iota-carrageenan <SEP> 0.750 <SEP> 0.750
 <tb> Sorbitol <SEP> (solution <SEP> to <SEP> 70 <SEP>%) <SEP> 30, <SEP> 000 <SEP> 30,000
 <tb> Propylene glycol <SEP> 0.500 <SEP> 0, <SEP> 500
 <tb> Gantrez <SEP> (solution <SEP> to <SEP> 13.02 <SEP>%) <SEP> 19,000 <SEP> 15,500
 <tb> Dioxide <SEP> from <SEP> titanium <SEP> 0, <SEP> 500 <SEP> 0.500
 <tb> Water <SEP> (deionized) <SEP> 9, <SEP> 957 <SEP> 13,457
 <tb> NaF <SEP> 0, <SEP> 243 <SEP> 0.243
 <tb> Saccharinate <SEP> from <SEP> sodium <SEP> 0.300 <SEP> 0.300
 <tb> Pyrophosphate <SEP> 2,000 <SEP> 2, <SEP> 000
 <tb> Hydroxide <SEP> from <SEP> sodium <SEP> (50 <SEP>% <SEP> 1, <SEP> 000 <SEP> 1,

    <SEP> 000
 <tb> Agent <SEP> from <SEP> polishing <SEP> (silica)
 <tb> (Zeodent <SEP> 113) <SEP> 20,000 <SEP> 20, <SEP> 000
 <tb> Thickener <SEP> (silica) <SEP> (Sylodent <SEP> 15) <SEP> 2,500 <SEP> 2, <SEP> 500
 <tb> Essence Flavoring <SEP> <SEP> 0, <SEP> 950 <SEP> 0, <SEP> 950
 <tb> TCHE <SEP> 0.300 <SEP> 0, <SEP> 300
 <tb> LSS <SEP> 2,000 <SEP> 2,000
 <tb>
 The Gantrez product is present as
 EMI33.3
 active ingredient in an amount of 2.5 parts in toothpaste A and 2.0 parts in toothpaste B.



   For the antibacterial agent distribution test on a hydroxyapatite disc coated with saliva, hydroxyapatite (HA) supplied by Monsanto Co. is abundantly washed with distilled water, collected by vacuum filtration and the dry overnight at 37 C. The dried HA is ground to a powder using a mortar and pestle. 150.00 mg of HA are placed in the cavity of a KBr pellet matrix (Barnes Analytical, Stanford, CT.) And compressed for 6 minutes under a pressure of 4540 kg in a Carver laboratory press. The resulting 13 mm discs are sintered for 4 hours at 800 C in

  <Desc / Clms Page number 34>

 a Thermolyne oven. Whole saliva produced by parafilm stimulation is collected in a beaker in
 EMI34.1
 ice-cold glass.

   The saliva is clarified by centrifugation at 15,000 x g for 15 minutes at 4 C.



  Sterilization of the clarified saliva is carried out, with stirring at 4 ° C., by irradiation of the sample with a UV lamp for 1.0 hour.



   Each sintered disc is hydrated with sterile water in a polyethylene test tube. The east water is then removed and replaced with 2.00 ml of saliva. A saliva film is formed by incubating the disc overnight at 370C in a water bath with continuous shaking. After this treatment, the saliva is removed and the discs are treated with 1.00 ml of a solution containing the antibacterial agent (Triclosan) in a liquid phase solution of toothpaste and incubated at 370C in the bain-marie with stirring. continues by shaking. After 30 minutes, the disc is transferred to a new tube and 5.00 ml of water are added, then the disc is gently shaken with a Vortex device.

   The disc is then transferred to a new tube and the washing operation is repeated twice. Finally, the disc is transferred to a new tube carefully to avoid simultaneous transfer of any liquid with the disc.



  Then add 1.00 ml of methanol to the disc and shake vigorously with a Vortex machine. The sample is left at room temperature for 30 minutes to extract the adsorbed Triclosan by passing it through methanol. The methanol is then removed by aspiration and clarified by centrifugation in a Beckman Microfuge 11 apparatus at 10,000 rpm for 5 minutes. After this treatment, methanol is transferred into flasks of HPLC (high performance liquid chromatography) for the

  <Desc / Clms Page number 35>

 dosage of the antibacterial agent. Triplicate samples are used in all experiments.



   The table below summarizes the results:
Board
 EMI35.1
 
 <tb>
 <tb> Distribution <SEP> from <SEP> TCHE <SEP> on <SEP> a
 <tb> disk <SEP> of hydroxyapatite
 coated <tb> <SEP> from <SEP> saliva
 <tb> Dough <SEP> toothpaste <SEP> (micrograms)
 <tb> A <SEP> 130
 <tb> B <SEP> 30
 <tb>
 
The results show that with the increase in the amount of Gantrez (Toothpaste A), there is a very large increase in the distribution of TCHE on dental minerals coated with saliva.



   Example 2
The following toothpaste is effective as an anti-plaque and anti-scale composition:
 EMI35.2
 
 <tb>
 <tb> Parties <SEP> in <SEP> weight
 <tb> Sorbitol <SEP> (70 <SEP>%) <SEP> 22.00
 <tb> Foam <SEP> from Ireland <SEP> 1, <SEP> 00
 <tb> Hydroxide <SEP> from <SEP> sodium <SEP> (50 <SEP>%) '""' - <SEP> 1, <SEP> 00
 <tb> Gantrez <SEP> (solution <SEP> to <SEP> 13, <SEP> 02 <SEP>%) <SEP> 19, <SEP> 00
 <tb> Water <SEP> (deionized) <SEP> 2, <SEP> 69
 <tb> Monofluorophosphate <SEP> from <SEP> sodium <SEP> 0, <SEP> 76
 <tb> Saccharinate <SEP> from <SEP> sodium <SEP> 0, <SEP> 30
 <tb> Pyrophosphate <SEP> 2, <SEP> 00
 <tb> Alumina <SEP> hydrated <SEP> 48, <SEP> 00
 <tb> Essence Flavoring <SEP> <SEP> 0, <SEP> 95
 <tb> TCHE <SEP> 0, <SEP> 30
 <tb> LSS <SEP> 2,

    <SEP> 00
 <tb>
 

  <Desc / Clms Page number 36>

 Example 3
 EMI36.1
 
 <tb>
 <tb> Bath <SEP> from <SEP> mouth <SEP> Parties
 <tb> Pyrophosphate <SEP> tetrasodium <SEP> 2, <SEP> 00
 <tb> Gantrez <SEP> S-97 <SEP> 2, <SEP> 50
 <tb> Glycerol <SEP> 10, <SEP> 00
 <tb> Fluoride <SEP> from <SEP> sodium <SEP> 0, <SEP> 05
 <tb> Laurylsulfate <SEP> from <SEP> sodium <SEP> 0, <SEP> 20
 <tb> TCHE <SEP> 0, <SEP> 06
 <tb> Essence Flavoring <SEP> <SEP> 0, <SEP> 40
 <tb> Water, <SEP> q. <SEP> s.

    <SEP> for <SEP> 100, <SEP> 00
 <tb>
 Example 4
 EMI36.2
 
 <tb>
 <tb> Pastilles <SEP> For <SEP> hundred
 <tb> Sugar <SEP> 75-80
 <tb> Syrup <SEP> from <SEP> glucose <SEP> 1-20
 <tb> Essence Flavoring <SEP> <SEP> 0, <SEP> 1-1, <SEP> 0
 <tb> Pyrophosphate <SEP> tetrasodium <SEP> 2
 <tb> Gantrez <SEP> S-97 <SEP> 2.50
 <tb> NaF <SEP> 0, <SEP> 01-0, <SEP> 05
 <tb> TCHE <SEP> 0, <SEP> 01-0, <SEP> 1
 <tb> Stearate <SEP> from <SEP> magnesium <SEP> (lubricant) <SEP> 1-5
 <tb> Water <SEP> 0, <SEP> 01-0, <SEP> 2
 <tb>
 Example 5
 EMI36.3
 
 <tb>
 <tb> Chewing gum <SEP> Parties
 <tb> Basic <SEP> from <SEP> eraser <SEP> 25, <SEP> 00
 <tb> Sorbitol <SEP> (70 <SEP>%) <SEP> 17.00
 <tb> TCHE <SEP> 0, <SEP> 50-0, <SEP> 10
 <tb> Pyrophosphate <SEP> tetrasodium <SEP> 2.00
 <tb> Gantrez <SEP> S-97 <SEP> 2.50
 <tb>
 In a variant of the Example above, we can omit Gantrez S-97.

   

  <Desc / Clms Page number 37>

 Example 6
 EMI37.1
 
 <tb>
 <tb> Chewing gum <SEP> Parties
 <tb> Basic <SEP> from <SEP> eraser <SEP> 30, <SEP> 00
 <tb> TCHE <SEP> 0.50
 <tb> Gantrez <SEP> 2.00
 <tb> NaF <SEP> 0, <SEP> 05
 <tb> Glycerol <SEP> 0, <SEP> 50
 <tb> Sorbitol <SEP> crystalline <SEP> 53.00
 <tb> Pyrophosphate <SEP> tetrasodium <SEP> 2, <SEP> 00
 <tb> Essence Flavoring <SEP> <SEP> and <SEP> water, <SEP> q. <SEP> s.

    <SEP> for <SEP> 100.00
 <tb>
 
In the above examples, the best results can also be achieved when TCHE is replaced by either phenol, 2,2'-methylene-bis (4-chloro-6-bromophenol), l eugenol and thymol, and / or when Gantrez is replaced by other ASAs such as Carbopol products (for example 934), or polymers of styrene-phosphonic acid having molecular weights falling within the range d '' about 3000 to 10 000, such as a poly (beta-styrene-phosphonic acid), copolymers of vinylphosphonic acid and beta-styrene-phosphonic acid and a poly (alpha-styrene-phosphonic acid), or sulfoacrylic oligomers, or a 1: 1 copolymer of maleic anhydride and ethyl acrylate.



   Similar results are also obtained by replacing pyrophosphate (tetrasodium pyrophosphate) with tetrasodium pyrophosphate and tetrapotassium pyrophosphate, the weight ratio of potassium to sodium being a) 0.37: 1, b) 1.04: 1, c ) 3: 1, and d) 3.5: 1.



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


    

Claims (58)

 CLAIMS 1. Composition for oral use, characterized in that it comprises, in a vehicle acceptable for oral use, an effective amount against dental calculus of a material comprising approximately 0.1 to 3% by weight of at least one polyphosphate linear salt with molecular dehydration as an anti-scale agent, an amount effective against dental plaque of a non-cationic antibacterial agent substantially insoluble in water and up to about 4% by weight of an antibacterial stimulating agent which improves the distribution and the retention of said antibacterial agent on the surfaces of the oral cavity, the weight ratio of the antibacterial stimulating agent to polyphosphate ions being part of. the range from about 1.6: 1 to about 2.7: 1.  2. Composition for oral use according to claim li characterized in that said antibacterial agent is chosen from the group formed by halogenated diphenyl ethers, halogenated salicylanilides, benzoic esters, halogenated carbanilides and phenolic compounds.  3. Composition for oral use according to claim If characterized in that said antibacterial agent is a halogenated diphenyl ether.  4. Composition for oral use according to claim 3, characterized in. that said halogenated diphenyl ether is 2,4,4'-trichloro-2'-hydroxy- (diphenyl ether).  5. Composition for oral use according to the. claim li characterized in that said antibacterial agent is a phenolic compound.  6. Composition for oral use according to claim 5, characterized in that said phenolic compound is chosen from phenol, thymol, eugenol  <Desc / Clms Page number 39>  and 2,2'-methylene-bis (4-chloro-6-bromophenol).  7. Composition for oral use according to claim 2, characterized in that said antibacterial agent is present in an amount of about 0.01 to 5% by weight.  8. Composition for oral use according to claim 7, characterized in that the amount of the antibacterial agent is approximately 0.25 to 0.5%.  9. Composition for buccal use according to claim li characterized in that said linear saline polyphosphate with molecular dehydration is an alkali metal pyrophosphate present in an amount of about 1 to 2.5% by weight.  10. Composition for oral use according to claim 9 ,. characterized in that said alkali metal pyrophosphate is tetrasodium pyrophosphate.    11. Composition for oral use according to any one of claims 1 to 10, characterized in that the weight ratio of the antibacterial stimulating agent to polyphosphate ions is from about 1.7: 1 to about 2.3: 1 .  12. Composition for oral use according to one  EMI39.1  any of claims 1 to 11, characterized in that said vehicle comprises water, a humectant and a gelling agent, and said composition is a toothpaste and contains a water-insoluble polishing agent acceptable for teeth.  EMI39.2   13. Composition for oral use according to any one of claims 1 to 11, characterized in that said vehicle comprises water and a non-toxic alcohol and said composition is a mouthwash.  14. Composition for oral use according to any one of claims 1 to 15, characterized in  <Desc / Clms Page number 40>  that said antibacterial stimulating agent has an average molecular weight of about 1000 to about 1,000,000.  15. Composition for buccal use according to claim 14, characterized in that said antibacterial stimulation agent contains at least one functional group improving the distribution and at least one organic group improving the retention.  16. Composition for oral use according to claim 15, characterized in that said group improving the distribution is an acid group.  17. Composition for oral use according to claim 16, characterized in that said group improving the distribution is chosen from carboxylic, phosphonic, phosphinic and sulfonic acids, their salts and their mixtures.  18. Composition for oral use according to the  EMI40.1  claim 17, characterized in that the organic group improving the retention corresponds to the formula - (X) nR where X is 0, S / SO / SO PO or Si, R is an alkyl, aryl, alkenyl, acyl, alkaryl group, hydrophobic aralkyl or heterocyclic, or one of their derivatives with inert substituents, and n is 1 or zero.  19. Composition for oral use according to claim 17, characterized in that said antibacterial stimulating agent is an anionic polymer containing several of said distribution improving groups and organic groups improving retention.  20. Composition for oral use according to claim 19, characterized in that said anionic polymer comprises a chain containing recurring units each having at least one carbon atom.  21. Composition for oral use according to claim 20, characterized in that each motif contains at least one group improving the distributior  <Desc / Clms Page number 41>  and at least one organic group improving retention linked to the same atom or to vicinal atoms or to other atoms of the chain.  22. Composition for oral use according to claim 17, characterized in that the group improving the distribution comprises a carboxylic group or a salt thereof.  23. Composition-for oral use according to claim 22, characterized in that the antibacterial stimulating agent is a copolymer of maleic acid or anhydride and another polymerizable ethylenically unsaturated monomer, or a salt thereof.  24. Composition for oral use according to claim 23, characterized in that said other monomer is methyl ether of vinyl in a molar ratio of 4: 1 to 1: 4 with maleic acid or anhydride.  25. Composition for oral use according to the. claim 24, characterized in that said copolymer has a molecular weight of about 30,000 to 1,000,000.  26. Composition for oral use according to claim 25, characterized in that the copolymer has an average molecular weight of approximately 70,000.  27. Composition for oral use according to claim 17, characterized in that the group improving the distribution comprises a phosphonic group or a salt thereof.  28. Composition for buccal use according to claim 27, characterized in that the antibacterial stimulating agent is a poly (beta-styrene-phosphonic acid), a poly (alpha-styrene-phosphonic acid) or a copolymer formed between these two acids or with another inert polymerizable ethylenically unsaturated monomer, or a salt thereof.  <Desc / Clms Page number 42>    29. Composition for oral use according to claim 28, characterized in that said antibacterial stimulating agent has a molecular weight of approximately 1000 to approximately 30,000.  30. Composition for oral use according to one of claims 1 to 29, characterized in that it contains a source of fluoride ions.  31. A method for fighting against dental plaque, characterized in that it consists in applying to the buccal surfaces an amount capable of fighting plaque of a composition as defined in any one of claims 1 to 30.  32. Composition for oral use, characterized in that it comprises an acceptable vehicle for oral use, an agent which is effective in stimulating the antibacterial effect of an antibacterial agent, the average molecular weight of which is approximately 1000 to approximately  EMI42.1  1,000,000, and which contains at least one functional group improving the distribution of the antibacterial effect and at least one organic group promoting the retention of the antibacterial effect, said agent containing said groups being free or substantially free of saline polycarboxylate a water-soluble synthetic anionic linear polymer of alkali metal or ammonium having a molecular weight of about 1000 to about 1,000,000, and a polyphosphate type anti-scale agent, said polyphosphate type anti-scale agent being a mixture of potassium and sodium salts ,  the ratio of potassium to sodium in said composition being in the range of less than about 3: 1.  33. Composition for oral use according to claim 32, characterized in that the ratio of potassium to sodium is approximately 0.37: 1 to approximately 1.04: 1.  <Desc / Clms Page number 43>    34. Composition for oral use according to claim 32, characterized in that the said group improving the distribution is chosen from phosphonic, phosphinic and sulfonic acids, their salts, and their mixtures.  35. Composition for oral use according to claim 33, characterized in that said group  EMI43.1  organic retention promoting agent has the formula - (X) nR, where X is 0, N, S, SO, SO2, PO or Si, R is an alkyl, aryl, alkenyl, acyl, alkaryl, aralkyl or heterocyclic group hydrophobic, or one of their derivatives with inert substituents, and n is 1 or zero.  36. Composition for oral use, characterized in that it comprises an acceptable vehicle for oral use, an agent which is effective in stimulating the antibacterial effect of an antibacterial agent, including the weight. average molecular is from about 1,000 to about 1,000,000 and which contains at least one functional group improving the distribution of the antibacterial effect and at least one organic group improving the retention of the antibacterial effect, said agent containing said groups being free or substantially free of water-soluble synthetic alkali metal or ammonium anionic linear polymeric saline polycarboxylate having a molecular weight of about 1000 to about 1,000,000, and a scale inhibitor of the polyphosphate type.  37. Composition for oral use according to claim 36, characterized in that the said agent improving the distribution is chosen from phosphonic, phosphinic and sulfonic acids, their salts and their mixtures.  38. Composition for oral use according to claim 37, characterized in that said organic retention-improving group corresponds to the formula - (X) -R, where X is 0, N, S, SO, SO2, PO or Si, R is a  <Desc / Clms Page number 44>  hydrophobic alkyl, aryl, alkenyl, acyl, alkaryl, aralkyl or heterocyclic group or one of their derivatives with inert substituents, and n is 1 or zero.  39. Composition for oral use, characterized in that it comprises an acceptable vehicle for oral use, an effective amount against dental plaque of a non-cationic antibacterial agent substantially insoluble in water, an antibacterial stimulating agent which has a average molecular weight of approximately 1000 to approximately 1,000,000 and contains at least one functional group improving the distribution and at least one organic group improving the retention, said agent containing said groups being free or substantially free of water-soluble synthetic anionic linear polymeric saline polycarboxylate of alkali metal or ammonium having a molecular weight of about 1000 to about 1,000,000, and a scale inhibitor of the polyphosphate type.  40. Composition for oral use, characterized in that it comprises an acceptable vehicle for oral use, an agent which is effective in stimulating the antibacterial effect of an antibacterial agent, the average molecular weight of which is approximately 1000 to approximately 1,000,000 and which contains at least one functional group improving the distribution of the antibacterial effect and at least one organic group improving the retention of the antibacterial effect, said agent containing said groups being free or substantially free of synthetic anionic linear polymer polycarboxylate water-soluble alkali metal or ammonium having a molecular weight of approximately 1000 to approximately 1,000,000, and an anti-scale agent of the polyphosphate type,  the weight ratio of said agent which is effective in stimulating the antibacterial effect of an antibacterial agent to the polyphosphate of the anti-scale agent of the polyphosphate type being greater than 0.72: 1 and less than 4: 1.  <Desc / Clms Page number 45>    41. Composition for oral use according to claim 40, characterized in that said weight ratio is from approximately 1: 1 to approximately 3.5: 1.  42. Composition for oral use according to claim 40, characterized in that said weight ratio is from 1.6: 1 to about 2.7: 1.  43. Composition for oral use, characterized in that it comprises an acceptable vehicle for oral use, an agent which is effective in stimulating the antibacterial effect of an antibacterial agent, the average molecular weight of which is approximately 1000 to approximately 1000000 and which contains at least one functional group improving the distribution of the antibacterial effect and at least one organic group improving the retention of the antibacterial effect, and a scale inhibitor of the polyphosphate type, provided that the composition is free or substantially free of tetrasodium pyrophosphate.  44. Composition for oral use, characterized in that it comprises an acceptable vehicle for oral use, an agent which is effective in stimulating the antibacterial effect of an antibacterial agent, the average molecular weight of which is approximately 1000 to approximately 1000000 and which contains at least one functional group improving the distribution of the antibacterial effect and at least one organic group improving the retention of the antibacterial effect, and a scale inhibitor of the polyphosphate type, provided that the composition is free or substantially free a combination of tetrapotassium pyrophosphate and tetrasodium pyrophosphate in which the ratio of potassium pyrophosphate to sodium pyrophosphate is 3: 1 or more.  45. Composition for oral use, characterized in that it comprises an acceptable vehicle for oral use, an amount effective against plaque  <Desc / Clms Page number 46>  with a non-cationic antibacterial agent substantially insoluble in water and an anti-scale agent of the polyphosphate type, provided that the composition is free or substantially free of tetrasodium pyrophosphate.  46. Composition for oral use, characterized in that it comprises an acceptable vehicle for oral use, an effective amount against dental plaque of a non-cationic antibacterial agent substantially insoluble in water and an anti-scale agent of the polyphosphate type, under provided that the composition is free or substantially free from a combination of tetrapotassium pyrophosphate and tetrasodium pyrophosphate in which the ratio of potassium pyrophosphate to sodium pyrophosphate is equal to or greater than 3: 1.  47. Composition for oral use, characterized in that it comprises an acceptable vehicle for oral use, an effective amount against dental plaque of a non-cationic antibacterial agent substantially insoluble in water, an antibacterial stimulating agent whose weight average molecular is from about 1000 to about 1,000,000 and which contains at least one functional group improving the distribution and at least one organic group improving the retention, said agent containing said groups being free or substantially free of synthetic anionic linear polymeric saline polycarboxylate water-soluble alkali metal or ammonium having a molecular weight of about 1000 to about 1,000,000, and a scale inhibitor of the polyphosphate type, provided that the composition is free or substantially free of tetrasodium pyrophosphate.  48. Composition for oral use, characterized in that it comprises an acceptable vehicle for oral use, an amount effective against dental plaque  <Desc / Clms Page number 47>  a non-cationic antibacterial agent substantially insoluble in water, an antibacterial stimulating agent whose average molecular weight is from approximately 1000 to approximately 1,000,000 and which contains at least one functional group improving the distribution and at least one group organic retention-improving agent, said agent containing said groups being free or substantially free of saline polycarboxylate, anionic linear polymer, water-soluble synthetic of alkali metal or ammonium having a molecular weight of approximately 1000 to approximately 1,000,000, and an anti-scale agent of the type polyphosphate,  with the proviso that the composition is free or substantially free from a combination of potassium pyrophosphate and tetrasodium pyrophosphate in which the ratio of potassium pyrophosphate to sodium pyrophosphate is equal to or greater than 3: 1.  49. Composition for oral use, characterized in that it comprises an acceptable vehicle for oral use and an agent which is effective in stimulating the antibacterial effect of an antibacterial agent, the average molecular weight of which is approximately 1000 to approximately 1,000,000 and which contains at least one functional group improving the distribution of the antibacterial effect and at least one organic group improving the retention of the antibacterial effect, said agent containing said groups being free or substantially free of anionic linear polymeric polycarboxylate salt water-soluble synthetic of alkali metal or ammonium having a molecular weight of approximately 1000 to approximately 1,000,000, and an anti-scale agent of the polyphosphate type, said composition containing potassium or sodium salts or ions,  the ratio of potassium to sodium in said composition being in the range of less than 3: 1.  <Desc / Clms Page number 48>    50. Composition for oral use according to claim 48, characterized in that said potassium to sodium ratio is from approximately 0.37: 1 to approximately 1.04: 1.  51. Composition for buccal use, characterized in that it comprises an acceptable vehicle for buccal use, a non-cationic antibacterial agent substantially insoluble in water in an amount of 0.25% to 0.35% and an anti-scale agent of polyphosphate type.  52. Composition for oral use, characterized in that it comprises an acceptable vehicle for oral use, a non-cationic antibacterial agent substantially insoluble in water in an amount of 0.25 to 0.35% and an anti-scale agent of the type polyphosphate, the anti-scale agent of the polyphosphate type being a mixture of potassium and sodium salts, the ratio of potassium to sodium in said composition being in the range of less than about 3: 1. 53. Composition for oral use according to claim 52, characterized in that said ratio is from approximately 0.35: 1 to approximately 1.04: 1.  54. Composition for buccal use, characterized in that it comprises an acceptable vehicle for buccal use, a non-cationic antibacterial agent substantially insoluble in water in an amount of 0.25 to 0.35% and an antitartar agent of the type polyphosphate, provided that the composition is free or substantially free of tetrasodium pyrophosphate.  55. Composition for buccal use, characterized in that it comprises an acceptable vehicle for buccal use, a non-cationic antibacterial agent substantially insoluble in water in an amount of 0.25 to 0.35% and an antitartar agent of the type polyphosphate, provided that the composition is free or substantially free from a combination of pyrophosphate  <Desc / Clms Page number 49>  tetrapotassium and tetrasodium pyrophosphate in which the ratio of potassium pyrophosphate to sodium pyrophosphate is 3: 1 or more.  56. Composition for oral use, characterized in that it comprises an acceptable vehicle for oral use, an effective amount against dental plaque of a non-cationic antibacterial agent substantially insoluble in water, an antibacterial stimulating agent whose weight average molecular is from about 1000 to about 1,000,000 and which contains at least one functional group improving the distribution and at least one organic group improving the retention, said agent containing said groups being free or substantially free of synthetic anionic linear polymeric saline polycarboxylate water-soluble alkali metal or ammonium having a molecular weight of approximately 1000 to approximately 1,000,000, and an anti-scale agent of the polyphosphate type,  said polyphosphate type anti-scale agent being a mixture of potassium and sodium salts, the ratio of potassium to sodium in said composition being in the range of less than about 3: 1.  57. Composition for oral use according to the  EMI49.1  claim 55, characterized in that said ratio is from about 0.37: 1 to about 1.04: 1.  58. Composition for buccal use, characterized in that it comprises an acceptable vehicle for the buccal route, an effective amount against dental plaque of a non-cationic antibacterial agent substantially insoluble in water and an antibacterial stimulating agent, the weight average molecular weight is from about 1,000 to about 1,000,000 and which contains at least one functional group improving distribution and at least one organic group improving retention, said agent containing said groups  <Desc / Clms Page number 50>  being free or substantially free from alkaline metal or ammonium-soluble synthetic anionic linear anionic polycarboxylate saline having a molecular weight of about 1000 to about 1,000,000, said composition containing potassium or sodium salts or ions,  the ratio of potassium to sodium in said composition being in the range of 0.37: 1 to 1.04: 1.