FI100691B - Antibacterial oral antibacterial composition - Google Patents

Description

100691

This invention relates to an antibacterial dental plaque-inhibiting oral composition. In particular, it relates to an oral dentifrice composition comprising a substantially water-insoluble non-cationic antibacterial agent which effectively inhibits plaque.

Dental plaque is a soft deposit that forms on the tooth as opposed to tartar, which is a hard calcified deposit on the tooth surface. However, unlike tartar, plaque can form on any part of the tooth surface, especially including the gingival margin. Thus, in addition to being ugly, it is involved in developing gingivitis.

Therefore, it would be highly desirable to include antimicrobial agents known to reduce plaque in oral compositions. Indeed, cationic antibacterial agents have often been proposed. In addition, in U.S. Patent 4,022,880 to Vinson et al., A compound that provides zinc ions as an anti-calculus agent is mixed with an antibacterial agent that is effective in retarding the growth of plaque bacteria. A large number of antibacterial agents have been described with zinc compounds with cationic materials such as guanides and quaternary ammonium compounds, as well as non-cationic compounds such as halogenated salicylanilides and halogenated hydroxydiphenyl ethers. A non-cationic antibacterial anti-plaque halogenated hydroxydiphenyl ether, trisacan, is also described in conjunction with zinc citrate trihydrate in European Patent Publication No. 0 161 899 to Saxton et al. Triclosan is also disclosed in European Patent Publication 0 271 332, Davis, as a toothpaste component having a solubilizing agent such as propylene glycol.

* * ··: Cationic antibacterial materials such as chlorhexidine, benzethonium chloride and cetylpyridine chloride have been extensively studied as antibacterial anti-plaque agents. However, they are not effective when used with anionic materials. On the other hand, non-cationic antibacterial agents may be compatible with anionic components in oral compositions.

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However, oral compositions are typically mixtures of numerous components, and even such typically neutral materials, such as wetting agents, can affect the effectiveness of such compositions.

In addition, even non-cationic antibacterial agents may have limited dental plaque inhibitory efficacy with commonly used materials such as tartar-inhibiting polyphosphate disclosed in British Patent 2,200,551 to Gaffar et al. And EP-0 251 591 to Jackson et al. Oh.

According to the invention, there is provided an oral composition comprising an effective anti-plaque amount of about 0.01 to 5% by weight of a water-insoluble non-cationic antibacterial agent (AAA) selected from the group consisting of halogenated diphenyl ethers, halogenated salicylanilides, benzoic acid esters, halogenated carbanilides and phenols, an orally acceptable excipient capable of dissolving said AAA in saliva in an effective anti-plaque amount, and about 0.005-4% by weight of an antibacterial enhancer (AEA) having an average molecular weight of about 100-1 And comprising a polyvinyl phosphonate or an organic compound containing at least one partitioning group which increases the partitioning of said AAA on the oral surfaces and comprising a carboxylic, phosphonic, phosphinic or sulfonic acid group or a salt thereof or a mixture thereof, and ain one retention-enhancing organic group which enhances the retention of said AAA on oral surfaces and has the formula - (X) nR, wherein X is O, N, S, SO, SO2, P, PO or Si, R is a hydrophobic al- alkyl, alkenyl, acyl, aryl, alkaryl, aralkyl or heterocyclic group and n is' 0 or 1, or an inertly substituted derivative thereof, which AEA comprises natural and synthetic polymerizable monomers, oligomers, homopolymers, copolymers of two or more monomers, ionomers, block copolymers, graft copolymers or crosslinked polymers or copolymers including styrenephosphonic acid polymers, phosphonated polymerized ethylenically unsaturated compounds, polyesterified ethylenically unsaturated carboxylic acids, carboxyvinyl polymers; polysiloxanes, polyesters, polyurethanes or synthetic polyamides, and which is free of anti-calculus polyphosphate.

• *,: "It is an advantage of the present invention to provide an oral composition comprising substantially; a water-insoluble non-cationic antibacterial agent and AEA that inhibit plaque; the formation, wherein the oral composition comprises an orally acceptable liquid excipient capable of dissolving said an effective amount of an antibacterial agent in saliva to prevent dental plaque.

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In addition, the present invention has the advantage that AEA increases the distribution and retention of a small but effective anti-plaque amount of the antibacterial agent in teeth and soft oral tissues.

A further advantage of the present invention is that an anti-plaque anti-plaque composition is obtained which effectively reduces the incidence of gingivitis.

Additional advantages of the present invention will become apparent upon consideration of the following detailed explanations.

Typical examples of water-insoluble non-cationic antibacterial agents which are particularly desirable in view of their anti-plaque efficacy, safety and formulation are:

Halogenated diphenyl ethers 2 ', 4,4'-trichloro-2-hydroxydiphenyl ether (Triclosan) 2,2'-dihydroxy-5,5'-dibromodiphenyl ether.

Halogenated Salicylanilides 4 ', 5-dibromosalicylanilide 3,4', 5-trichlorosalicylanilide ': "· 3,4', 5-tribromosalicylanilide: 2,3,3 ', 5-tetrachlorosalicylanilide 3,3,3', 5-tetrachlorosalicylanilide 3,5-Dibromo-3'-trifluoromethylsalicylanilide 5-n-octanoyl-3'-trifluoromethylsalicylanilide 3,5-Dibromo-4'-trifluoromethylsalicylanilide 3,5-Dibromo-3'-trifluoromethyl salicylanilide (Flurophene)

Esters of benzoic acid

Methyl p-hydroxybenzoic acid ester

Ethyl p-hydroxybenzoic acid ester

Propyl p-hydroxybenzoic acid ester

Butyl p-hydroxybenzoic acid ester

Halogenated carbanilides: '. · 3,4,4'-trichlorocarbanilide 3-trifluoromethyl-4-4'-dichlorocarbanilide 3,3,4'-trichlorocarbanilide 4,100691

Phenol compounds (including phenol and its homologues, mono- and polyalkyl and aromatic halo (e.g. F, Cl, Br, I.) phenols, resorcinol and catechol and their derivatives and bisphenol compounds).

Phenol and its homologues

Phenol 2-methylphenol 3-methylphenol 4-methylphenol 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 2-methoxy-4- (2-propenyl) phenol (eugenol) 2-Isopropyl-5-methyl-phenol (thymol)

Mono- and polyalkyl and aralkyl 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-chlorophenol • · n-heptyl-p-chlorophenol n-octyl-p-chlorophenol.: O-chlorophenol

Methyl-o-chlorophenol

Ethyl-o-chlorophenol n-propyl-o-chlorophenol 5 100691 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 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- -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-sec-amyl-3,5-dimethyl-p-chlorophenol '··' · '2-diethylmethyl-3 .5-dimethyl-p-chlorophenol 6-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 6,100691 4-chloro-2-methylphenol 4-chloro-3-methylphenol 4-chloro -3,5-Dimethylphenol 2,4-dichloro-3,5-dimethylphenol 3,4,5,6-tetrabromo-2-methylphenol 5-methyl-2-pentylphenol 4-isopropyl-3-methylphenol 5-chloro-2 -hydroksidifenyylimetaani

Resorcinol and its derivatives

resorcinol

Methyl resorcinol

Ethyl resorcinol n-propyl resorcinol n-butyl resorcinol n-amyl resorcinol n-hexyl resorcinol n-heptyl resorcinol n-octyl resorcinol n-nonyl resorcinol ... Phenyl resorcinol •; Benzyl resorcinol

Phenylethyl resorcinol · Phenylpropyl resorcinol p-chlorobenzyl resorcinol 5-chloro -2,4-dihydroxydiphenylmethane 4'-chloro -2,4-dihydroxydiphenylmethane 5-bromo -2,4-dihydroxydiphenylmethane 4'-bromo -2,4- dihydroxydiphenylmethane • · • ·

bisphenol compounds

Bisphenols 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 7,100691

The antibacterial agent is present in the oral composition in an effective anti-plaque amount of about 0.01 to 5% by weight, preferably about 0.03 to 1%, and more preferably about 0.25 to 0.5%, or from about 0.25% to less. than 0.5% and most preferably about 0.25-0.35%, e.g. about 0.3% in dentifrice or preferably about 0.03-0.3% by weight, most preferably about 0.03-0.1% in mouthwash or liquid tooth powder. The antibacterial agent is substantially insoluble in water, meaning that it has a solubility of less than about 1% by weight in water at 25 ° C and may even be less than about 0.1%.

The preferred halogenated diphenyl ether is triclosan. Preferred phenol compounds are phenol, 2,2'-methylene-bis- (4-chloro-6-bromophenol), thymol and eugenol, hexyl-resorcinol and 2,2'-methylene-bis- (4-chloro-6-bromophenol) . The most preferred antibacterial anti-plaque compound is triclosan. Triclosan is disclosed in the aforementioned U.S. Patent 4,022,880 as an antibacterial agent together with an anticalculus agent which produces zinc ions, and in German Patent Publication No. 35,328,860 together with a copper compound. It is also disclosed in European Patent Publication 0 278 744 together with a dental anesthetic having a source of potassium ions. It is also disclosed as an anti-plaque agent in a dentifrice formulated to contain a layered liquid crystal surfactant phase having a layer spacing of less than 6.0 nm and which may alternatively contain a zinc salt, published in European Patent Application 0 161 898 to Lane et al. is zinc citrate trihydrate, published in European Patent Application 0 161 899, Saxton.

An antibacterial agent (AEA) which increases the distribution of said antibacterial agent and its retention on oral surfaces is used in amounts effective to effect such an increase, i.e. about 0.005-4% by weight, preferably about 0.1-3% by weight, most more preferably in the range of about 0.5-2.5% by weight in oral compositions.

AEA may be a polymerizable monomer, more preferably a polymer, the latter term being completely common, including, for example, oligomers, homopolymers, copolymers of two or more monomers, ionomers, block polymers, graft copolymers, network polymers and copolymers and the like.

• AEA can be natural or synthetic and insoluble in water or preferably soluble or swellable in water (saliva) (hydratable, hydrogel-forming). It has a (weight) average molecular weight of about 100 to 1,000,000, preferably about 1,000 to 1,000,000, most preferably about 2,000 or 2,500 to 250,000 or 500,000.

8 100691 AEA has at least one partition enhancing group, which is preferably a phosphonic or carboxylic acid group or a salt thereof, e.g. alkali metal or ammonium, and at least one organic retention enhancing group, preferably numerous both partition enhancing and retention enhancing groups, the latter groups having the formula is - (X) n R, wherein X is O, N, S, SO, SO 2, P, PO or Si, R is hydrophobic alkyl, alkenyl, acyl, aryl, alkaryl, aralkyl, heterocyclic or their inertly substituted derivatives and n is zero or 1. The aforementioned "inertly substituted derivatives" are intended to include substituents in which R is generally non-hydrophilic and does not significantly interfere with the desired functions of AEA, such as the distribution and retention of the antibacterial agent on oral surfaces, such as halo, e.g., Cl, Br, I, and carbon and the like. Descriptions of such retention enhancing groups are tabulated below.

n X - (X) n R

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

Ethoxy, benzyloxy, thioacetoxy, phenoxy, carboethoxy, carbobenzyloxy, etc.

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

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

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

SO2 butylsulfonyl, allylsulfonyl, benzylsulfonyl, phenylsulfonyl, etc.

• · • # * »P diethylphosphinyl, ethyl vinylphosphinyl, ethylallylphosphinyl, ethylbenzylphosphinyl, ethylphenylphosphinyl, etc.

PO diethylphosphineoxy, ethyl vinylphosphineoxy, methylallylphosphineoxy, methylbenzylphosphineoxy, methylphenylphosphineoxy, etc.

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

As used herein, a distribution enhancing group refers to one that adheres or tightly, adhesively, cohesively, or otherwise binds AEA (having an antibacterial agent) to the oral (e.g., tooth and gum) surfaces, thereby "distributing" the antibacterial agent to such surfaces. The organic retention enhancing group, usually hydrophobic, attaches or otherwise binds the antibacterial agent to the AEA, thereby promoting the retention of the antibacterial agent in the AEA and indirectly on the oral surfaces. In some cases, the attachment of the antibacterial agent occurs by the physical capture of the AEA, especially when the AEA is a network polymer whose structure inherently provides increased sites for such capture. The presence of a high molecular weight, more hydrophobic crosslinking moiety in the network polymer further enhances the physical entrapment of the antibacterial agent in the network AEA polymer.

AEA is preferably an anionic polymer having a chain or backbone containing repeating units, each of which preferably has at least one carbon atom and preferably at least one directly or indirectly open monovalent cleavage enhancing group and at least one directly or indirectly open monovalent retention enhancing group geminally. , at a side position or less preferably otherwise bonded to an atom, preferably carbon, in the chain. Less preferably, the polymer may have partition enhancing groups and / or retention enhancing groups. and / or other divalent atoms or groups as a bond in the polymer chain instead of or in addition to carbon atoms or as crosslinking moieties.

It is to be understood that any examples or descriptions of AEA presented herein that do not have both a partition enhancing group and a persistence enhancing group should be chemically modified in a known manner to provide an AEA having both such groups and preferably numerous for each such group. group. In the case of the preferred polymeric AEA, it is desirable to maximize the persistence and distribution of the antibacterial agent on the oral surfaces. The repeating units in the polymer chain or backbone having acidic addition groups are at least about 10%, preferably at least about 50%, more preferably at least about 80-95 or 100% by weight of the polymer.

According to a preferred embodiment of the present invention, the AEA comprises a polymer having repeating units in which one or more phosphonic acid distribution enhancing groups are attached to one or more carbon atoms in the polymer chain. An example of such an AEA is poly- (1-phosphonopropylene) having units of the formula: I - [pH -CH] -ch3 po3h2

The preferred phosphonic acid-containing AEA for use herein is poly- (beta-styrenephosphonic acid) having units of the formula: II - [pH - CH] -Ph PO 3 H 2 wherein Ph is phenyl, wherein the phosphonium enhancing group and the phenyl retention enhancing group are attached to adjacent carbon atoms in the chain or a copolymer of beta-styrenephosphonic acid with vinylphosphonyl chloride having units of formula II alternating or randomly associated with units of formula - [CH2 - CH] - po3h2, or poly (alpha-styrenephosphonic acid) units of formula : III - [CH2 ^ C -----] -

Ph PO3H2 where the groups that increase distribution - and persistence - are geminally bound in the chain.

These styrenophosphonic acid polymers and their copolymers with other inert, ethylenically unsaturated monomers generally have a molecular weight in the range of about 2,000 to 30,000, preferably in the range of about 2,500 to 10,000. Such "inert" monomers do not significantly interfere with the function of any of the AEA polymers used herein.

100691 π

Other phosphonium-containing polymers that can be modified to contain the organic retention enhancing groups described above include, for example, phosphonated ethylene having units of the formula.

IV - [(CH2) 14CHPO3H2] n- where, for example, n may be an integer or may have a value which gives the polymer a molecular weight of about 3000; and sodium poly (butene-4,4-diphosphonate) having units of the formula: V- [CH2-CH-] -CH, -CH <(PO, N2) 2 and poly- (allyl-bis- (phosphonoethylamine)) with units of the formula: VI - [CH2 - CH- ~] - ch2 - N <(POjH2) 2

Other phosphonated polymers, for example poly (allylphosphonoacetate), phosphonated polymethacrylate, etc. and the geminal diphosphonate polymers disclosed in EP 0 321 233, may be used herein as AEA, provided, of course, that they contain or are modified to contain those described above. organic survival groups.

In one embodiment, the AEA is free or substantially free of a water-soluble alkali metal or ammonium salt of a synthetic anionic linear polymeric polycarboxylate having a molecular weight of about 1,000 to 1,000,000.

According to another preferred embodiment, the AEA may contain a synthetic anionic polymeric polycarboxylate. Although not used in this invention to interact with tartar-inhibiting polyphosphate, a synthetic anionic polymeric polycarboxylate having a molecular weight of about • 1,000 to 1,000,000, preferably about 30,000 to 500,000, has been used as an alkaline phosphatase enzyme inhibitor for linear linear optimization. *. ' the anticalculus efficacy of polyphosphate salts, as disclosed in U.S. Patent 4,627,977 to Gaffar et al. Indeed, in a published British patent publication; · 2,200,551 is a polymeric polycarboxylate disclosed as an alternative ingredient: in oral compositions comprising linearly molecularly dehydrated polyphosphonate salts and a substantially water-insoluble non-cationic antibacterial agent. In addition, it has been found in the context of the present invention that such a polycarboxylate 12 100691 is remarkably effective in increasing the distribution and retention of a nonionic antibacterial anti-plaque agent on dental surfaces (i.e., molecularly dehydrated polyphosphate) when the other agent with which the polymeric polycarboxylate interacts; for example, when the substance with which the polymeric polycarboxylate interacts is in particular a non-cationic antibacterial agent.

Synthetic anionic polymeric polycarboxylates and their complexes with various cationic germicides, zinc and magnesium have been previously disclosed as anticalculus agents, for example, U.S. Patent 3,429,963 to Shedlovsky; U.S. Patent 4,152,420 to Gaffar; and U.S. Patent 3,956,480 to Dichter et al .; U.S. Patent 4,138,477 to Gaffar; and U.S. Patent 4,183,914 to Gaffar et al. It should be noted that the synthetic anionic polymeric polycarboxylates disclosed in these various patents, when present or modified to have retention enhancing groups, are functional in the compositions of this invention and such disclosures are incorporated herein by reference.

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

Other AEA-functional polymeric polycarboxylates having or modified to contain retention enhancing groups are disclosed in U.S. Patent 3,956,480 and referenced above, such as 1: 1 copolymers of maleic anhydride with ethyl acetate. with hydroxyethyl methacrylate, N-vinyl-2-pyrrolidone or ethylene, the latter being available, for example, as Monsanto EMA no. 1103, M.W.

: V · 10,000 and EMA as Grade 61 and 1: 1 copolymers of acrylic acid methyl or hydroxy; diethyl methacylate, methyl or ethyl acrylate, isobutyl vinyl ether or N-. ; with vinyl-2-pyrrolidone.

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Other functional polymeric polycarboxylates disclosed in the aforementioned U.S. Patents 4,138,477 and 4,183,914, which have or are modified to contain retention enhancing groups, include copolymers of maleic anhydride with styrene, iso-butylene or ethyl vinyl ether, polyacrylic ether, polyacrylonitrile and sulfoacrylic oligomers with MW is as low as 1000, available as Uniroyal ND-2.

Suitable in general are a stability-enhancing group polymerized with olefinically or ethylenically unsaturated carboxylic acids having an activated olefinic carbon-carbon double bond which acts readily in polymerization because it is present in the monomeric molecule either in the alpha-beta position relative to the carboxyl group or as part of the thermoxyl group . Exemplary such acids include acrylic, methacrylic, ethacrylic, alpha-chloroacrylic, crotonic, beta-acryloxypropionone, sorbic, alpha-chlorosorbine, cinnamon, beta-styrylacrylic, muconic, itaconic, citraconic, mesaconic, glutaconic, aconitine, alpha-phenylacrylic, 2-benzylacrylic, 2-cyclohexylacrylic, angelic, umbellic, fumaric, maleic and anhydrides. Other various olefin monomers that copolymerize with such carboxyl monomers include vinyl acetate, vinyl chloride, dimethyl maleate, and the like. The copolymers have sufficient carboxylic salt groups for water solubility.

., .. · Also useful here are the so-called carboxyvinyl polymers, which are pre- ·. . as components of toothpaste in U.S. Pat. No. 3,980,767 to Chown et al .; U.S. Pat. No. 3,935,306 to Roberts et al .; U.S. Pat. No. 3,919,409 to Peria et al .; In U.S. Pat. No. 3,911,904; Harrison, and U.S. Pat. No. 3,711,604 to Colodney et al. They are commercially available pre-; '' Under the trade marks Carbopol 934, 940 and 941, B.V. Goodrich, and these •• V products consist essentially of a colloidally water-soluble polyacrylic acid polymer crosslinked at about 0.75% -2.0% with polyallyl sucrose or polyallyl pentaerythritol as the crosslinking agent, the crosslinkable structure and crosslinks provide the desired increase in hydrophobic persistence and / or physical entrapment of an antibacterial agent or the like. Polycarbophil is somewhat similar, with less than 0.2% polyacrylic acid cross-linked to divinyl glycol, the lower proportion, molecular weight, and / or hydrophobicity of this cross-linking material tend to provide little or no increased persistence. 2,5-Dimethyl-1,5-hexadiene is an example of a more effective cross-linking agent.

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The synthetic anionic polymeric polycarboxylate component is most often a hydrocarbon having additional halogen and O-containing substituents and bonds present in, for example, ester, ether and OH groups and is used in these configurations in approximate weight amounts of about 0.05-4%, preferably about 0.05 -3%, more preferably 0.1-2%.

The AEA may also contain natural anionic polymeric polycarboxylates with retention enhancing groups. Carboxymethylcellulose and other binders, gums and film formers which do not have the above-mentioned distribution-enhancing and / or persistence-enhancing groups are ineffective as AEA

As it is illustrative for AEAs having phosphinic acid and / or sulfonic acid partitioning groups, polymers and copolymers having units or moieties derived from vinyl or allylphosphinic and / or sulfonic acids which are substituted may also be mentioned. as required for the polymerization of an 1- or 2- (or 3-) carbon atom with an organic retention enhancing group, for example of the formula - (X) nR as defined above. Mixtures of these monomers can be used and copolymers thereof with one or more inert polymerizable ethylenically unsaturated monomers, as described above, for operative synthetic anionic polymeric polycarboxylates. Like ; . ·. it is noted that in these and other polymeric AEAs operating herein, usually only one acid addition enhancing group is attached to any given: ·, carbon or other atom in the polymer backbone or branch thereof. Polysiloxanes,! having or modified to include open distribution enhancing groups and persistence enhancing groups may also be used herein as AEAs. Also effective as ‘<’ in this AEA are ionomers having or modified to contain a splitter * · ’. and retention groups. The ionomers are described on pages 546-573

Othmer Encyclopedia of Chemical Technology, Third Edition, Supplement, Copyright John Wiley and Sons, Inc. 1984, which description is incorporated herein by reference. Also effective as AEAs herein, provided that they have or are modified to contain retention enhancing groups, are polyesters, polyurethanes, and synthetics; *: · and natural polyamides, proteins, and proteinaceous materials such as collagen, poly (arginine), and other polymerizable amino acids.

": In an aspect of the present invention, an AEA having an average molecular weight of about 1000-1000,000 contains at least one partition enhancing functional; group and at least one organic retention enhancing group, said substance '·': containing groups having no or no a substantially water-soluble alkali metal or an anionically linear anionic linear polymeric polycarboxylate salt having a molecular weight of about 1,000 to 1,000,000.

In the present invention, the preferred oral composition is a dentifrice having about 0.3% by weight of an antibacterial agent (e.g., triclosan) and about 1.5-2% by weight of polycarboxylate as AEA.

Without wishing to be bound by theory, it is believed that AEA, especially polymeric AEA, is generally an anionic film-forming material and is thought to adhere to tooth surfaces and form a uniform film over surfaces, thus preventing bacteria from adhering to tooth surfaces. It is possible that the non-cationic antibacterial agent forms a complex or other form of association with the AEA, thus forming a complex membrane or the like over the tooth surfaces. The film-forming property of AEA and the increased distribution and retention of the antibacterial agent on tooth surfaces due to AEA appear to make tooth surfaces unfavorable for bacterial accumulation, especially since the direct bacteriostatic action of the antibacterial agent controls bacterial growth. Therefore, a combination of three modes of action makes the oral composition effective in reducing dental plaque: 1) increased distribution, 2) long residence time on the tooth surface, and 3) inhibition of bacterial adhesion to the tooth surfaces. Similar anti-dental plaque efficacy is achieved with soft oral tissues or near the gum.

In an oral preparation, the orally acceptable excipient comprises an aqueous phase with a wetting agent. The gel dentifrice typically contains about 5-30% by weight of a quartz-containing polishing agent, water typically in an amount of at least 3% by weight,: Y generally about 3-35%, and a wetting agent, preferably glycerin and / or sorbitol, typically totaling about 6.5-75%. % by weight of the oral gel dentifrice composition. Reference herein to sorbitol refers to a material that is typically obtained commercially as 70% aqueous solutions.

• ·! Gel dentifrices, in an amount of about 0.25 to 0.35% by weight of the antibacterial agent, do not require other additives in the oral excipient to dissolve the antibacterial agent, although the presence of such a solubilizing agent is optional. When the amount of antibacterial agent is less than about 0.25% by weight, e.g., about 0.01-0.25% by weight, there should be a solubilizing agent to ensure adequate dissolution for saliva to be effective against dental plaque. When antibak-; the amount of active substance is more than about 0.35% by weight, e.g. about 0.35-0.5% or more, e.g. 5%, there should be a solubilizing agent for this, otherwise the antibacterial substance would remain essential. part insoluble.

When the oral composition is a dentifrice having about 30-75% by weight of an acceptable polishing agent for the teeth, such a solubilizing agent is also optional.

When the oral composition is a mouthwash or liquid dentifrice, the oral excipient contains at least one surfactant, flavoring or non-toxic alcohol, each of which helps to dissolve the antibacterial agent, and again the presence of such a solubilizing agent is optional.

When the oral compositions of this invention contain a solubilizing agent, it is typically present in an amount of about 0.5 to 20% by weight, with less than 0.5% by weight being sufficient when the amount of substantially water-insoluble non-cationic antibacterial agent is low, e.g. about 0.3% by weight. When higher amounts are present, such as at least about 0.5% by weight of antibacterial agent, and especially when the quartz-containing polishing agent is present in an amount of about 5-30% by weight, it is desirable that at least about 5% by weight, typically about 20% by weight. % or more, a solubilizing agent is present. It has been found that tooth powder may tend to separate into a liquid and a solid when more than about 5% by weight of solubilizer is present.

A substance which is or may be present in dissolving an antibacterial substance in saliva may be:, '. add a water-wetting agent to the excipient. Such solubilizers are wetting; polyols such as propylene glycol, dipropylene glycol and hexylene glycol, cello. v solvents such as methylcellosolve and ethylcellosolve, vegetable oils and waxes having up to 12 carbons in the straight chain, such as olive oil, castor oil and petrolatum, and esters such as amyl acetate, ethyl acetate and benzyl benzoate. As used herein, "propylene glycol" includes 1,2-propylene glycol and 1,3-propylene glycol.

Significant amounts of polyethylene glycol, especially one with a molecular weight. . . 600 or more should be avoided, as polyethylene glycol effectively inhibits the antibacterial activity of a non-cationic antibacterial agent. For example, polyethylene glycol (PEG) 600, when present with triclosan in a weight ratio of 25 triclosan: 1 PEG 600, reduces the antibacterial activity of triclosan by a factor of about 16 from that in the absence of polyethylene glycol.

4 I, 1 »17 100691 In an embodiment of the present invention, the oral dentifrice composition may be substantially gel in nature, such as a gel dentifrice. Such gel-like oral preparations contain a quartz-containing dental polishing material. Preferred polishing materials include crystalline silica having a particle size of about 5 microns, a mean particle size of about 1.1 microns and a surface area of about 50,000 cm 2 / gm, silica gel or colloidal silica, and complex amorphous alkali metal aluminosilicate.

When clear or opaque gels are used, colloidal silica polishes such as those sold under the trademark SYLOID, such as Syloid 72 and Syloid 74, or under the trademark SANTOCEL, such as Santocel 100, include alumina silicate complexes (i.e., alkali metal aluminosilicate). ), are particularly useful because they are in a tightly gel-like structure and have a refractive index close to that of gelling fluid systems (including water and / or wetting agent) commonly used in dentifrices.

The polish is generally present in oral dentifrices, such as toothpaste or gel compositions, in concentrations of about 5-30% by weight.

In an embodiment of the present invention, wherein the oral preparation is a tooth powder, there is an orally acceptable excipient having an aqueous phase with a wetting agent, typically about 15-35% by weight of water and typically a total of about 20-75% by weight of glycerin and / or sorbitol. oral gel dentifrice composition, more typically about 25-60%. Reference herein to sorbitol refers to a material that is typically obtained commercially as 70% aqueous solutions.

In the present invention, the oral dentifrice composition may be substantially pasty in nature, such as toothpaste (toothpaste), although when a quartz-containing polish is used (which is generally not the case as such material is not typically used in an amount greater than about 30% by weight), it may be a gel. in nature. The excipient for the oral dentifrice composition usually contains a polishing material acceptable to the tooth, examples of the polishing material include water-insoluble sodium metaphosphate, potassium metaphosphate, tricalcium phosphate, hydrazide toactone, dihydrated dicalcium phosphate, dicalcium phosphate, anhydrous dicalcium, · T: or with hard polishing materials such as calcined alumina and grit. ·. : sodium silicate, a material comprising the particulate thermosetting resins described in U.S. Patent 3,070,510, issued December 15, 1962, 18,100,691, such as melamine, phenol and urea formaldehydes, and crosslinked polyepoxides and polyesters. Preferred polishing materials are insoluble sodium metaphosphates, dicalcium phosphate and hydrogenated alumina.

Many of the so-called "water-insoluble" polishes are anionic in nature and contain small amounts of soluble material. Thus, insoluble sodium metaphosphate may be formed by any suitable means as described in the Thorpen Dictionary of Applied Chemistry, Volume 9, 4th Edition, pp. 510-511. Further examples of suitable materials are the forms of insoluble sodium metaphosphate known as the Madrell salt and the Kurrol salt. These metaphosphate salts have only a slightly low water solubility and are therefore commonly referred to as insoluble metaphosphates (IMPs). They contain a small amount of soluble phosphate material as impurities, usually a few percent, such as 4 weight percent. The amount of soluble phosphate material believed to contain porous sodium trimetaphosphate in the case of insoluble metaphosphate can be reduced or eliminated by washing with water, if desired. Insoluble alkali metal metaphosphate is typically used in powder form with a particle size such that no more than 1% of the material is larger than 37 microns.

Aluminum hydroxide is an example of a polishing agent that is substantially non-ionic in nature. Typically it is small in particle size, i. at least about 85% of the particles are smaller than 20 microns and are classified as gibbsite (alpha-aluminum trihydroxide) and are normally chemically represented as Al2O3.3H2O or Al (OH) 3 · Gibbsite has an average particle size of about 6-9 microns. Typical quality has the following size distribution:

Micron Percent <30 94-99 <20 85-93 <10 56-67 <5 28-40 • · • · · ’·· The polishing material is generally present in the cream paste or gel compositions in about 30-75% by weight of the contracts.

· ... · ‘Toothpastes or dentifrices, as well as gel powders, contain : naturally occurring natural or synthetic thickener or gelling agent, in proportions: about 0.1-10%, preferably about 0.5-5%. A suitable thickener is synthetic colloidal magnesium alkali metal silicate complex alumina available, for example, as Laponite (e.g. CP, SP 2002, D) marketed by Laporte Industries Limited. Laponite D analysis shows approximately 58.00% by weight S1O2, 25.40% MgO, 3.05% Na2O, 0.98% L12O and some water and trace elements. It has a true specific gravity of 2.53 and an apparent bulk density (g / ml at 8% humidity) of 1.0.

Other suitable thickeners or gelling agents include carrageenan, iota-carrageenan, gum tragacanth, starch, polyvinylpyrrolidone, hydroxyethylpropylcellulose, hydroxybutylmethylcellulose, in the presence of quaternary cellulose, hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, hydroxyethylcellulose, hydroxyethylcellulose Syloid 244 or Sylodent 15.

In an embodiment of the present invention where the oral composition is a mouthwash or liquid tooth powder, substantially liquid in nature, the excipient, especially in the mouthwash, is typically a water-alcohol mixture. In general, the weight ratio of water to alcohol is in the range of about 1: 1 to 20: 1, preferably in the range of about 3: 1 to 10: 1, and more preferably in the range of about 4: 1 to 6: 1. The total amount of aqueous alcohol mixture in such a preparation is typically in the range of about 70-99.9% by weight. The alcohol is a non-toxic alcohol such as ethanol or isopropanol. A wetting agent such as glycerin and sorbitol may be present in an amount of about 10-30% by weight. Liquid dentifrices typically contain about 50-85% water, may contain about 0.5-20% by weight of non-toxic alcohol, and may also contain about 10-40% by weight of a wetting agent such as glycerin and / or sorbitol. Reference herein to sorbitol refers to a material that is typically commercially available as 70% aqueous solutions. Ethanol is the preferred non-toxic alcohol. Alcohol is believed to help dissolve a water-insoluble: Y: non-cationic antibacterial agent, so it is also believed to flavor the oil.

As shown, the non-cationic antibacterial agent is substantially insoluble in water. However, in the present invention, when AEA is present as a polycarboxylate in mouthwash or liquid dentifrice, an organic surfactant, flavoring oil or non-toxic alcohol is believed to help dissolve the antibacterial agent by helping it to reach the soft mouth tissue in or near the gums. gums, as well as on the tooth surface. Organic surfactants and / or flavoring oils may help to dissolve antibacterial agents as alternative ingredients in oral dentifrice compositions.

20 100691

Organic surfactants are used in the compositions of this invention to provide an increased pre-protective effect, to help achieve a thorough and complete distribution of the anti-plaque antibacterial agent throughout the oral cavity, and to make these compositions more cosmetically pleasing. The organic surfactant is preferably anionic, nonionic or ampholytic in nature and it is preferred to use the detergent material as a surfactant which imparts detergent and foaming properties to the composition. Suitable examples of anionic surfactants are water-soluble salts of higher rasvahappomonoglyseridimonosulfaattien, such as hydrogenated kookosöljyrasvahapon monosulfonated monoglyceride sodium salt, higher alkyl sulfates such as sodium lauryl sulfate, alkyl aryl sulfonates such as sodium dodecyl benzene sulphonate, higher alkyylisulfoasetaatit, 1,2-dihydroxy higher fatty acid and lower aliphatic amino carboxylic acid-critical-outlined saturated higher aliphatic acyl, such as those having 12 to 16 carbons in a fatty acid, alkyl or acyl radicals and the like. Examples of the latter amides are N-lauroyl sarcosine and the sodium, potassium and ethanolamine salts of N-lauroyl, N-myristoyl or N-palmitoyl sarcosine, which should be substantially free of soap or similar higher fatty acid material. The use of these sarcosinized compounds in the oral compositions of this invention is particularly advantageous because these materials show a long-lasting, clear effect in inhibiting acid formation in the oral cavity due to carbohydrate degradation, in addition to providing some reduction in tooth enamel solubility under acidic conditions. Examples of water-soluble nonionic surfactants are the condensation products of ethylene oxide with various reactive hydrogen-containing compounds which are reactive after having long hydrophobic chains (e.g. aliphatic chains having about 12 to 20 carbon atoms) in which the condensation thio products ("ethoxamers") have hydrophilic polyoxyethylene moieties, such as condensation products of poly (ethylene oxide) with fatty acids, fatty alcohols, fatty amides, polyhydride alcohols (e.g. sorbitan monostearate) and polypropylene oxide: e.g.

«· · • · • ·»

The surfactant is typically present in an amount of about 0.5 to 5% by weight, preferably about 1-2.5%.

When the oral composition is a liquid dentifrice, natural or synthetic; ; the thickener or gelling agent, as described, is typically present in proportions of about 0.1 to 10%, preferably about 0.5 to 5%.

21 100691

Usually, liquid dentifrices do not contain a polishing agent. However, as described by Salzmann in U.S. Patent 3,506,757, about 0.3-2.0% by weight of a high molecular weight polysaccharide (greater than 1,000,000) contains mannose, glucose, potassium glucuronate, and acetyl moieties in an approximate ratio of 2: 1: 1: 1, can be used as a suspending and thickening agent in a liquid dentifrice which may then contain about 10-20% of a polishing material such as aluminum hydroxide, dicalcium phosphate dihydrate, calcium pyrophosphate, insoluble sodium metaphosphate, magnesium carboxate, calcium carboxate, anhydrous dicalcium phosphate, dicalcium phosphate, like that.

Without wishing to be bound by theory, whereby the advantages of this invention are achieved, it is believed that the aqueous wetting aid normally dissolves in the surfactant micelles in the mobile phase (i.e., it does not contain a gelling agent or polishing agent if included in the dentifrice formula). The mobile phase solution of the dentifrice can be diluted with saliva, which causes the precipitation of triclosan. Thus, it has been found that even in the absence of a specific triclosan solubilizing material, when the amount of triclosan is about 0.25-0.35% by weight and AEA, such as polycarboxylate, is present, there is enough triclosan to provide excellent anti-dental plaque activity in soft tissues. the gum line. Similar considerations apply to the other water-insoluble, non-cationic antibacterial agents described herein.

The oral dentifrice composition may also contain fluoride ions or a fluoride ion donating component as an anti-rot agent in an amount sufficient to provide 25 ppm to 5000 ppm fluoride ions. These compounds may be to some extent soluble in water or may be completely soluble in water. They are described by their ability to release fluoride ions into water and by the fact that they do not have undesired reactions with other compounds in oral preparations. These materials include fluoride salts such as soluble alkali metal, alkaline earth metal salts, e.g. sodium fluoride, potassium fluoride, ammonium fluoride, calcium fluoride, copper fluoride such as cuprofluoride, zinc fluoride, barium fluoride, sodium fluorosilicate, sodium fluorosilicate, ammonium fluorosilicate, ammonium fluorosilicate , sodium monofluorophosphate, aluminum mono- and difluorophosphate and sodium ***, calcium calcium pyrophosphate. Alkali metal and tin fluorides such as sodium and tin (2) fluorides, sodium monofluorophosphate (MFP) and mixtures thereof are preferred.

The amount of fluorine-releasing compound depends to some extent on the type of compound, its solubility and the type of oral preparation, but it must be non-toxic; amount, usually about 0.005-3.0% in the preparation. In a dentifrice preparation, e.g.

dental gel, the amount of compound that releases about 5000 ppm F ions 22 100691 per weight of the preparation is considered satisfactory. Any suitable minimum amount of such a compound may be used, but it is preferred to use sufficient compound to release about 300-2000 ppm, more preferably about 800-1500 ppm of fluoride ions.

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

It is clear that oral preparations must be sold or otherwise distributed in appropriately labeled packages. Thus, a dentifrice gel is usually contained in a flexible tube, typically aluminum, lined lead, or plastic, or in another compression, pump, or pressure dispenser that dispenses content and has a label that describes it substantially as a dentifrice gel or the like.

A variety of other materials can be incorporated into the oral preparations of this invention, such as bleaching agents, preservatives, silicones, chlorophyll compounds, and / or ammonia-containing material, such as urea, diammonium phosphate, and mixtures thereof. These excipients, when present, are incorporated into the preparations in amounts that do not substantially adversely affect the desired properties and characteristics. Significant amounts of zinc, magnesium, and other metal salts and materials, generally soluble, that could complex with the active components of this invention must be avoided.

‘’ Any suitable flavoring or sweetening material may also be used.

Examples of suitable flavoring ingredients are flavoring oils, e.g., green mint, peppermint, winter, sassafras, clover, sage, eucalyptus, marjoram, cinnamon, lemon and orange oil, and methyl salicylate. Suitable sweeteners include sucrose, lactose, maltose, xylitol, sodium cyclamate, perillartine, AMP: * ·. (asparatylphenylalanine, methyl ester), saccharin and the like. Flavorings and. *: · The sweeteners may suitably each comprise from about 0.1% to about 5% or more of the preparation. In addition, like a surfactant, the seasoning oil is believed to help dissolve the antibacterial agent, with or without a surfactant.

In a preferred embodiment of the present invention, the oral composition of the present invention is preferably applied regularly to tooth enamel and soft oral tissues, especially at or near the gum line, such as every day or every two or three days or preferably 1-3 times daily, at a pH of about 4, 5-9-10, generally about 5.5-8, preferably about 6-8, most preferably about 6.5-7.5, at least 2-8 weeks or more depending on the person. Even at a pH of less than 5, the lime does not descale or is otherwise damaged. The pH can be controlled with an acid (e.g., citric acid or benzoic acid) or a base (e.g., sodium hydroxide) or buffered, such as with sodium citrate, benzoate, carbonate or bicarbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate, etc.).

The compositions of this invention may be applied to lozenges or chewing gum or other products, e.g., by mixing with a warm gum base or covering the outer surface of the gum base, exemplified by Jelutong, rubber latex, vinylite resins, etc., if desired with suitable plasticizers or plasticizers, sugar or other sweeteners. with glucose, sorbitol and the like.

The following examples further illustrate the nature of this invention, but it is to be understood that the invention is not limited thereto. All amounts and ratios referred to herein and in the appended claims are by weight unless otherwise indicated.

• * *

Example 1

The following tooth powder is prepared:

parts

: Y A B

Glycerin 10.00

Propylene glycol - 10.00

Sorbitol (70%) 25.00 25.00 .. Iota carrageenan 0.60 0.60 * * Gantrez S-97 2.00 2.00

Sodium saccharin 0.40 0.40

Sodium fluoride 0.243 0.243

Sodium hydroxide (50%) 1.00 1.00

Titanium oxide 0.50 0.50

Silica polishing agent (Zeodent11) 20.00 20.00 24 100691

Silica thickener (Sylox 15) 5.50 5.50

Sodium lauryl sulphate 2.00 2.00

Water 31,507 31,507

Triclosan 0.30 0.30

Spice oil 0.95 0.95

From the above dentifrice A, Triclosan for tooth and soft gingival tissue is obtained substantially, as well as tooth powder B, which contains a special Triclosan solubilizer. In other words, no special solubilizer is required for the dentifrice of the present invention to be effective. In addition, the corresponding dentifrice lacking Gantrez polycarboxylate is substantially inferior to delivering Triclosan.

In the above example, improved results can be obtained by replacing Triclosa with other antibacterial agents described herein, such as phenol, thymol, eugenol, and 2,2'-methylene-bis- (4-chloro-6-bromophenol), and / or by replacing Gantrez with other AEA: such as a 1: 1 copolymer of maleic anhydride and ethyl acrylate, a sulfoacrylic oligomer, Carbopol (e.g. 934) and polymers of alpha- or beta-styrenephosphonic acid monomers and copolymers of these monomers with each other or other ethylenically unsaturated polymerizable monomers.

Example 2

The following liquid phase dentifrice solutions have been tested for Triclosan recovery and retention on saliva-covered HA plates, following the • · ‘* test methods in Example 3; results shown in the following: • «• ·« · · • »•« 25 100691

Ingredients Parts

A B C D

Sorbitol (70%) 30.0 30.0 30.0 30.0

Glycerol 9.5 9.5 9.5 9.5

Propylene glycol 0.5 0.5 0.5 0.5 SLS 20.0 20.0 20.0 20.0

NaF 0.243 0.243 0.243 0.243

Spice oil 0.95 0.95 0.95 0.95

Triclosan 0.3 0.3 0.3 0.3

Water 56,507 56,507 56,507 56,507

Poly- (beta-styrene-phosphonic acid) 2.0

Poly- (alpha-styrene-phosphonic acid) 2.0

Polyvinyl alcohol 2.0 Adjusted to pH 6.5 with NaOH Uptake of triclosan into microorganisms covered with saliva 31.0 174.0 86.0 36.0

Retention of triclosan on saliva-covered HA plates, Start 183.0 · *: * after 30 min 136.0 1 h 105.0 3 h "83.0

The above results show that the AEA of solution (D) with polyvinyl alcohol is not included, the uptake of triclosan is only 36.0, quite similar to that of • · '· ’control solution (A) without additive, 31.0. In contrast, the uptake of solution (C) with poly- (alpha-styrenephosphonic acid) is 86.0, more than double that of solutions (A) and (D) and solution (B) with poly- (beta-styrenephosphonic acid). -poa), the uptake is about 5 times the uptake of solutions (A) and (D), indicating further, '; ‘· That the substitution of adjacent distribution-enhancing groups ai- 1 · '! brings first-class results. The above results also show a surprisingly good retention of triclosan 26 100691 on HA plates for the time obtained with solution (B) with poly- (beta-styrenephosphonic acid) (M.W. about 3000-10,000).

Example 3

The effect of synthetic anionic linear polycarboxylate on the uptake, retention, and release of a non-water-soluble, non-cationic antibacterial agent on tooth surfaces is evaluated in vitro by saliva-covered hydroxyapatite plates and scaly cheek epithelial cells. In vitro estimates correlate with in vivo distribution and persistence on oral surfaces.

For an assay examining the distribution of antibacterial agent on a saliva-covered hydroxyapatite plate, hydroxyapatite (HA) obtained from Monsanto Co evening was washed with well-distilled water, collected by vacuum filtration, and allowed to dry overnight at 37 ° C. The dried HA is ground to a powder with a mortar and pestle. 150.00 mg of HA is placed in a KBr pill pad chamber (Barnes Analytical, Stanford, CT.) And compressed for 6 min at 10,000 pounds Carver Laboratory weight. The obtained 13 mm plates are sintered for 4 h at 800 ° C in a Thermolyne furnace. Total saliva stimulated with parafilm is collected in an ice-cooled glass vessel. Saliva is clarified by centrifugation at 15,000 Xg (times gravity) for 15 min at 4 ° C. Sterilization of clarified saliva is performed at 4 ° C by stirring the sample under UV light for 1.0 h.

Each sintered plate is hydrogenated with sterile water in a polyethylene test tube. The water is then removed and replaced with 2.00 milliliters of saliva. A salivary film is formed when incubated overnight at 37 ° C with constant shaking in a water bath. After this treatment, the saliva is removed and the plates are treated with 1.00 ml of a solution containing; . antibacterial agent (triclosan) in the liquid phase solution of the dentifrice and ‘incubated at 37 ° C with constant shaking in a water bath. After 30 min, transfer the plate to a new tube and add 5.00 ml of water and then gently shake with a vortex. The plate is then transferred to a new tube and the washing procedure is repeated twice. Finally, carefully transfer the plate to a new tube and avoid fluid transfer with the plate. Then add 1.00 ml of methanol on top of the plate and shake vigorously with a vortex. Allow the sample to stand at room temperature for 30 min to extract the adsorbed triclosan into methanol. The methanol is aspirated off and clarified by centrifugation in a Beckman Microfuge 1 at 10,000 rpm for 5 min. After this treatment, the methanol is transferred to HPLC (high pressure liquid chromatography) vials to determine the antibacterial agent. In all: ‘. In my experiments, triplicate samples were used.

27 100691

To test the persistence of the antibacterial agent on the saliva-covered HA plate, the saliva-covered HA plate is treated with dentifrice suspensions as described above. After incubation or after 30 min at 37 ° C, the HA plate is removed from the dentifrice suspension, washed twice with water, and re-incubated with parafilm-stimulated total human saliva clarified by centrifugation. After incubation at 37 ° C with constant shaking for various periods of time, the HA plate is removed from the saliva and the amount of antibacterial agent (Triclosan) remaining on the plate and released into the saliva is determined by analytical methods using HPLC.

To determine the distribution of antibacterial agent to buccal epithelial cells, the distribution is measured to determine the efficacy of PVM / MA in the distribution of antibacterial agent (Triclosan) to soft oral tissue from a dentifrice product. Cheek epithelial cells are collected with a wooden applicator stick by gently rubbing the oral mucosa. The cells are resuspended in Resting Saliva Salts buffer (Rss) (50 nM NaCl, 1.1 nM CaCl2 and 0.6 nM KH2PO4 pH 7.0) so that the cells are 5-6x10 6 cells / ml using a hemocytometer to count the cells and keep on ice. until used. Add 0.5 ml of the cell suspension pre-incubated in a 37 ° C water bath with 0.5 ml of the test antibacterial agent and incubate at 37 ° C. The solution of the antibacterial agent in the incubation mixture is diluted at least 10 times to lower the surfactant concentration and prevent surfactant-induced destruction of cell membranes. After 30 min of incubation, cells are harvested by centrifugation on a Beckman Microfuge 11 at 5000 rpm for 5 min. Cells collected as pellets are washed 3 times with RSS buffer and treated with 1.5 ml of methanol. The sample is mixed vigorously and analyzed for antibacterial activity by HPLC. . by.

* · ·

Tooth powders are prepared having the following formulas:

parts

i · A B

Propylene glycol 10.00 10.00

Iota-carrageenan 0.75 0.75

Gantrez S-97 - 2.00. . : Titanium dioxide 0.50 0.50 i Sorbitol (70%) 30.00 30.00

Sodium fluoride 0.332 0.332 28 100691

Sodium saccharin 0.40 0.40

Silica Thickener (Sylodent 15) 3.00 3.00

Silica polish (Zeodent 113)

Triclosan 0.20 0.20

Sodium lauryl sulphate 2.00 2.00

Spice oil 0.95 0.95

Ethyl alcohol 1.00 1.00

Water is added up to 100.00 100.00

The uptake of triclosan into saliva-covered hydroxyapatite plate and cheek epithelial cells with or without a polymeric polycarboxylate, Gantrez S-97, is shown in Table 1:

table 1

Ingestion of triclosan Micrograms in microorganisms syl- x 10 ^ cheek

Epithelial cell A 25.0 38.0 B 54.0 96.0 on a plate covered with toothpowder These results reveal that the Gantrez material (present in dentifrice (B) greatly increases the distribution and uptake of triclosan to salivary-coated hydroxyapatite plate and scaly buccal epithelial cells .

Similar results have been obtained when the tooth powder contains 0.30 parts of triclosan.

Example 4:. In tests with saliva-covered hydroxyapatite plates and scaly cheek epithelial cells different from those used in Example 3 above, said dentifrice B containing 2.00% Gantrez S-97 and 0.20% triclosan, 10.00% propylene glycol and 2.00% sodium lauryl sulfate and a correspondingly formulated dentifrice (B '), except in the presence of 0.30% triclosan, with a commercially available dentifrice (C) containing aluminum hydroxide-4j polish and (a) 0.2% triclosan, (b) no Gantrez material, (c) no propylene glycol, (d) 0.5% zinc citrate, (e) 2.5% surfactants (f) sodium monofluorophosphate and aluminum hydroxide polish; and dentifrice formulation (C) below, which is similar to commercial dentifrice C, except that 0.30% triclosan is present:

Tooth powder C

%

Sorbitol (70%) 27.00

Sodium carboxymethylcellulose 0.80

Sodium monofluorophosphate 0.85

Zinc citrate 0.50

Sodium saccharin 0.18

Water 16.47

Aluminum hydroxide polish 50.00

Ethanol 0.20

Sodium lauryl sulphate 1,875

Sodium dodecylbenzenesulphonate 0.625

Triclosan 0.30

Spices 1.20

Since dentifrices C and C contain a total of 2.50% surfactant, more surfactant is available to dissolve triclosan than dentifrices B and B 'with 2.00%. However, the propylene glycol present in the quartz-containing polish in dentifrices B and B '(but not in the aluminum hydroxide-polish in dentifrices C and C) ensures optimal dissolution of triclosan.

• ·

The advantage of dentifrices B and B '(containing propylene glycol and Gantrez) over dentifrices C and C in triclosan uptake by salivary-covered hydroxyapatite plates and scaly cheek epithelial cells is shown in Table 2 below: • · • · * · 1 · 30

Table 2

Distribution of triclosan

For saliva-covered Posse epithelial hydroxyapatite plates in micrograms (micrograms) x10 2 epithelial cells

Tooth powder B 41.1 101.6 B '77.4 142.0 C 20.4 61.0 C 42.6 100.0

Additional experiments with dentifrice B '(0.3% triclosan; Gantrez; propylene glycol) in a 50% dentifrice suspension to determine persistence on a hydroxyapatite plate covered with triclosan saliva over a period of time reveal excellent levels of triclosan persistence, as shown in Table 3 below:

Table 3

Persistence of Triclosa adsorption from dentifrice suspension

Time Persistence of Triclosan '· (min) (micrograms / plate) i 0 70 30 60:; 60 70: *: * · 120 65 180 57 240 59 .. These results indicate that dentifrices containing triclosan, Gantrez- * ..] material, and propylene glycol can produce increased triclosan. distribution and retention on tooth surfaces and soft surfaces in the oral cavities, thus providing enhanced anti-plaque and antibacterial effects.

31

Example 5 100691

For the comparison of formulas (a) and (b) below, prepare:

Tooth powder a b%

Glycerin 10.00

Propylene glycol - 10.00

Iota-carrageenan 0.60 0.60

Sorbitol (70%) 25.00 25.00

Sodium saccharin 0.40 0.40

Sodium fluoride 0.243 0.243

Titanium dioxide 0.50 0.50

Gantrez S-97 2.00 2.00

Water 29,157 29,157

NaOH (50%) 2.00 2.00

Zeodent 113 20.00 20.00 (Silica polish)

Sylodent 15 5.50 5.50 (Silica Thickener)

Spices 1.10 1.10

Triclosan 0.50 0.50

Sodium lauryl sulphate 2.00 2.00

Ethanol 1.00 1.00 • ·

Formula a is a dentifrice with Gantrez polycarboxylate, 0.5% triclosan as an antibacterial anti-plaque agent and not a solubilizer. In formula b, propylene glycol, a solubilizing agent, is present.

.. Formula a poorly delivers triclosan to cheek epithelial cells, while formula b is * ... * * Significantly more effective.

• · «·

The above examples reveal the excellent delivery of Triclosa dentifrice.

«T * 32

Example 6 100691 An "in-house" study was performed on a group of volunteers to evaluate the effects of certain dentifrices that affect plaque regrowth according to the method described by Addy, Wilis, and Moran, J. Clin. Perio, 1983, vol. 10, pages 89-99. The dentifrices tested included a placebo control without triclosan (i) and a dentifrice containing 0.3% triclosan, 10% propylene glycol (3% polyethylene glycol instead of 600) and 2% Gantrez S-97 and propylene glycol and sorbitol as a wetting agent. The formulas of these dentifrices are as follows:

Parts (0 (H)%

Placebo Invention

Polyethylene glycol 600 3.00

Glycerin 25.00

Propylene glycol - 10.00

Sorbitol (70%) 41.617 25.00 N atrium carboxymethyl. · Cellulose 0.35

Iota carrageenan - 0.60 ... Sodium benzoate 0.5 •; Sodium saccharin 0.20 0.40 '- · Sodium fluoride 0.243 0.243 •. ‘Silica polishing agent (Zeodent11) 18.00 20.00

Silica thickener (Sylox 15) 5.5 5.50

Water 3.00 28.757

Gantrez S-97 - 2.00 ♦ · [·: · Triclosan - 0.30

Titanium dioxide 0.50 0.50

Sodium lauryl sulphate 1.20 2.50

Spices 0.89 1.10

Ethyl alcohol 1.00

Sodium hydroxide (50%) 2.00 33 100691

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

Since smaller amounts of propylene glycol can be dissolved in 0.3% triclosan present in this toothpaste (ii), similar results are expected when the amount of propylene glycol is reduced to 0.5 parts and the amount of sorbitol is increased to 39.5 parts. Similarly, other solubilizers, dipropylene glycol, hexylene glycol, methylcellosolve, ethylcellosolve, olive oil, castor oil, petrolatum amyl acetate, glyceryl tristearate, and benzyl benzoate for propylene glycol instead of softme glycol can effectively distribute. In addition, similar results are expected when propylene glycol or other solubilizers are omitted from toothpaste (ii) containing 0.3% triclosan.

Example 7

The following dentifrices of the invention are prepared:

Some of

A B

Glycerin - 20.00

Propylene glycol 10.00 0.50: Sorbitol (70%) 25.00 19.50

Sodium carboxymethylcellulose - 1.10

Iota carrageenan 0.600

Sodium saccharin 0.40 0.30

Sodium fluoride 0.243 0.243 f ·

Silica polishing agent (Zeodent 113) 20.00 20.00

Silica thickener (Sylox 15) 5.50 3.00

Water 28.757 15.307: T Gantrez S-97 2.00 2.00

Triclosan 0.50 0.30

Titanium dioxide 0.50 0.50

Sodium lauryl sulphate 2.50 2.00

Spices 1.10 0.95

Ethanol 1.00

Sodium hydroxide (50%) 2.00 2.00 34 100691

In the above examples, improved results can also be obtained by replacing triclosan with other antibacterial agents described herein, such as phenol, eugenol and 2,2'-methylene-bis- (4-chloro-6-bromophenol) and / or by replacing Gantrez with other AEAs. such as a 1: 1 copolymer of maleic anhydride and ethyl acrylate, sulfoacrylic oligomers, Carbopoles (e.g. 934), monomeric polymers of alpha and beta-styrenic phosphonic acid, and copolymers of these styrenic phosphonic acid monomers, such as copolymers of other styrenic phosphonic acid monomers, phosphonic acid.

Example 8

The following dentifrice is prepared:

Some of

ABC

Alpha-aluminum trihydrate 48.00 48.00 48.00

Propylene glycol - 0.50 0.50

Sorbitol (70%) 21.70 21.70 21.70

Gantrez S-97 (13% solution) 15.00 15.00

Gantrez S-97 (powder) - - 2.00

Sodium laurilsulfate 2.00 2.13 2.13 '·' ·· Sodium saccharin 0.30 0.30 0.30: Sodium hydroxide (50%) 1.20 1.20 1.20 | , Spice 0.95 0.95 0.95: Carrageenan 1.00: Sodium carboxymethylcellulose - 1.00 1.00

Sodium monofluorophosphate 0.76 0.76 0.76

Titanium dioxide - 0.50 0.50

Triclosan 0.30 0.30 0.30 ,, Water is added up to 100.00 100.00 100.00 «· rt» · »• · * · * The above dentifrices give triclosan to the teeth and soft tissue of the gums substantially more effectively than the corresponding dentifrices lacking Gantrez polycarboxylate.

35

Example 9 100691

The following dental cleanings are prepared:

Some of

Glycerin 22.00 10.00

Sorbitol (70%) - 17.00

Sodium carboxymethylcellulose 1.00 1.00

Gantrez S-97 2.00 2.00

Sodium saccharin 0.20 0.20

Sodium benzoate 0.50 0.50

Sodium monofluorophosphate 0.76 0.76

Dicalcium phosphate dihydrate 48.76 48.76

Triclosan 0.30 0.30

Sodium lauryl sulphate

Spices 0.89 0.89

Water is added up to 100.00 100.00

The above dentifrices deliver triclosan to the saliva-covered hydroxyapatite plate more efficiently than the corresponding dentifrices, of which Gantrez- •: · ·; polycarboxylate is absent.

Example 10

Prepare the following anti-plaque dentifrice:

Some of

Glycerin 15.00

Propylene glycol 2.00

Sodium carboxymethylcellulose 1.50

Water 24.93 · “Vinyl Methyl Ether /

Maleic anhydride copolymer 4.76: Y · (42% solution)

Sodium monofluorophosphate 0.76 ·; Sodium saccharin 0.30; Insoluble sodium metaphosphate 47.00 36 100691

Titanium dioxide 0.50

Sodium lauryl sulphate 2.00

Triclosan 0.30

Spices 0.95

In the above examples, improved results are also obtained when triclosan is replaced by each phenol, 2,2'-methylene-bis- (4-chloro-6-bromophenol), eugenol and thymol and / or when Gantrez is replaced by other AEAs such as Carbopoles (e.g., 934) or with styrenephosphonic acid polymers having molecular weights in the range of about 3,000 to 10,000, such as copolymers of poly (beta-styrenephosphonic acid), vinylphosphonic acid with beta-styrenephosphonic acid and poly- (alpha-styrene) sulfone or phosphonic acid Copolymer of 1 maleic anhydride with ethyl acrylate.

Example 11

Dental cleaning mobile phases with triclosan

Components Composition,% w / w

A B

Sorbitol (70%) 53.33 40.00

Water 40.48 39.15

Gantrez S (15%) - 13.33

NaOH (50%) 1.33

Saccharin 0.40 0.40

Sodium fluoride 0.32 0.32

Spice oil 1.47 1.47

Sodium lauryl sulphate 3.33 3.33

Triclosan 0.67 0.67

The concentrations of the above components are 1.33% dentifrice level i ·: · reflecting the 25% abrasion level that may be required to replenish the dentifrice.

»·

From the above mobile phases of the indicated formulations, the uptake of triclosan into a saliva-covered HA plate has been tested. The results are in the following table: 37 100691

Table

Triclosan uptake from saline-coated hydroxyapatite (HA) plates from diluted and undiluted dentifrice mobile phases:

A B

% Triclosan 0.67 0.67

Ion strength (M / L) (calculated) 0.375 pH 8.7 7.6

Triclosa uptake (pg / plate) 55,122 undiluted

The above results show a greater than twofold increase in triclosan uptake achieved with Formulation B with Gantrez compared to Formulation A without Gantrez.

Example 12

Triclosan concentration and uptake by HA 1: 1 dentifrice / aqueous suspension from supernatant.

Dental cleaner with Triclosan (pg / ml) Triclosan is 0.5% Triclosan, 1: 1 suspension uptake in 2.5% sodium lauryl supernatant pg / plate sulfate 25% hydrogenated silicon 1,650 52 oxide + 1.5% Gantrez S-97 50% aluminum + 1,905 74 1.5% Gantrez S-97 ·: · The supernatants of the 1: 1 dentifrice / water suspensions of the above dentifrices are tested for triclosan concentration in the supernatant and triclosan uptake into saliva-covered plates. The results show that the use of 50% aluminum abrasive increases triclosan under substantially low (1: 1) dilution conditions (from 1,650 to 1,905), leading to a substantial increase in triclosan uptake from 52 to 74 : reads).

Example 13 38 100691

The mouth rinses below are effective in reducing plaque by increasing triclosan uptake and retention on oral surfaces.

A B C D E

Osaa Osaa Osaa Osaa Osaa

Gantrez S-97 0.24 0.25 0.25 0.25 0.25

Glycerin 15.00 10.00 15.00 10.00 15.00

Ethanol - - 12.50 12.50

Propylene glycol - 5.00 - 5.00

Pluronic F108 2.00 (Polyoxyethylene / polyoxypropylene block copolymer)

Sodium lauryl sulphate - - 0.20 0.20 0.20

Triclosan 0.10 0.10 0.06 0.06 0.03

Spice oil 0.40 0.40 0.40 0.40 0.40

Water lis. up to 100.00 100.00 100.00 100.00 100.00

Example 14

The following liquid dentifrices are also effective in reducing plaque. ·. - by increasing the uptake and retention of triclosan on the surface of the mouth: ABC Part Part Part

Glycerin 20.00 20.00: * ·. · Gantrez S-97 0.3 0.3 0.3: T High molecular weight polysaccharide, molecule with mannose, glucose, potassium glucuronate and acetyl moieties in an approximate molar ratio of 2: 1: 1: 1 0.8 - 1.0

Sodium benzoate 0.5 0.5 0.5 39 100691

Saccharin sodium

Water 61.3 73.1 71.6

Sodium lauryl sulphate

Insoluble sodium metal phosphate 10.0 to 10.0

Anhydrous dicalcium phosphate 1.0 to 2.5

Spice oil

Ethyl alcohol - - 10.0

Triclosan 0.1 0.1 0.1

In the above examples, improved results are also obtained when triclosan is replaced by each phenol, 2,2'-methylene-bis- (4-chloro-6-bromophenol), eugenol and thymol and / or when Gantrez is replaced by other AEAs, such as Carbopoles (e.g., 934) or with styrenephosphonic acid polymers having molecular weights in the range of about 3,000 to 10,000, such as copolymers of poly (beta-styrenephosphonic acid), vinylphosphonic acid with beta-styrenephosphonic acid and poly- (alpha-styrene) sulfone or phosphonic acid Copolymer of 1 maleic anhydride with ethyl acrylate.

The present invention has been described in terms of certain preferred embodiments, and it is to be understood that modifications and variations thereof which will be apparent to those skilled in the art are intended to be included within the scope of this application and the appended claims.

I * • * • · «• · 9 9« · * 1 »• * * ·» «« t * »» «

Claims (28)

100691 An oral composition, characterized in that it contains an effective anti-plaque amount of about 0.01 to 5% by weight of a water-insoluble non-cationic antibacterial agent (AAA) selected from the group consisting of halogenated diphenyl ethers, halogenated salicylanilides, benzoic acid esters, halogenated carbanilides and phenols, an orally acceptable excipient capable of dissolving said AAA in saliva in an effective amount of anti-plaque anti having an average molecular weight of about 100 to 1,000,000 and comprising a polyvinyl phosphonate or an organic compound containing at least one partition enhancing group that increases the partitioning of said AAA on the oral surfaces and comprising a carboxyl, phosphone, phosphine or sulfone an acid group or a salt thereof or a mixture thereof, and at least one an organic group which increases the stability of said AAA on the surfaces of the mouth and has the formula - (X) nR, wherein X is O, N, S, SO, SO2, P, PO or Si, R is hydrophobic alkyl , alkenyl, acyl, aryl, alkaryl, aralkyl or heterocyclic group and n is 0 or 1, or an inertly substituted derivative thereof, which AEA comprises natural and synthetic polymerizable monomers, oligomers, homopolymers, copolymers of two or more monomers, ionomers, block copolymers polymers or cross-linked polymers or copolymers, including styrenic phosphonic acid polymers, phosphonated polymerized ethylenically unsaturated compounds, polymerized ethylenically unsaturated carboxylic acids \ V * An oral composition according to claim 1, characterized in that it is a dentifrice comprising about 5-30% by weight of a quartz-containing polishing agent and in that about 0.25-0.35% by weight of antibacterial agent is present and that the surface is present. -active substance and / or flavoring oil. An oral composition according to claim 1, characterized in that it is a dentifrice comprising about 5 to 30% by weight of a quartz-containing polishing agent and that it contains a solubilizing material in an amount sufficient to dissolve said antibacterial agent in saliva. An oral composition according to claim 1, characterized in that the antibacterial agent is present in an amount of about 0.05 to 0.25% by weight. 100691 An oral composition according to claim 1, characterized in that the antibacterial agent is present in an amount of about 0.35 to 5% by weight. An oral composition according to claim 5, characterized in that the antibacterial agent is present in an amount of about 0.35 to 0.5% by weight. An oral composition according to claim 1, characterized in that it is a dentifrice comprising about 30 to 75% by weight of a water-insoluble polishing agent acceptable for teeth. An oral composition according to claim 1, characterized in that it is a mouthwash or a liquid dentifrice and that the orally acceptable excipient is an aqueous excipient with at least one surfactant, flavoring oil or non-toxic alcohol. Oral composition according to one of the preceding claims, characterized in that about 0.5 to 5% by weight of surfactant is present. Oral composition according to one of the preceding claims, characterized in that a flavoring oil is present in an amount of about 0.1 to 5% by weight. An oral composition according to claim 8, characterized in that it is a mouthwash and that the aqueous excipient contains ethanol and the weight ratio of water to ethanol is about 1: 1 to 20: 1. An oral composition according to claim 8, characterized in that it is a liquid dentifrice containing about 0.3-2.0% by weight of high molecular weight; . liposome polysaccharide having a molecular weight greater than 1,000,000, containing mannose, glucose, potassium glucuronate and acetyl moieties in an approximate ratio of 2: 1: 1: 1, as a suspending and thickening agent, and about 10-20% by weight of polishing material . ·. An oral composition according to claim 1, characterized in that the antibacterial agent is a halogenated diphenyl ether. • · Oral composition according to Claim 13, characterized in that the halogenated diphenyl ether is 2,4,4'-trichloro-2'-hydroxydiphenyl ether. Oral composition according to any one of claims 1 and 3 to 6, characterized in that the solubilizing agent is present in an amount of about 0.5 to 50% by weight and is selected from the group consisting of propylene glycol, dipropylene glycol, hexylene glycol, methylcellosolve, ethylcellosolve, vegetable oil and wax having at least 12 carbon atoms, amyl acetate, ethyl acetate, glyceryl tristearate and benzyl benzoate. An oral composition according to claim 15, characterized in that the solubilizing agent is propylene glycol present in about 0.5% by weight. An oral composition according to claim 1 or 15, characterized in that the polishing agent is present and is selected from the group consisting of sodium metaphosphate, tricalcium phosphate, dihydrated dicalcium phosphate, anhydrous dicalcium phosphate, aluminate phosphate, calcium pyrophosphate, magnesium orthophosphate, magnesium silica, bentonite and mixtures thereof and that the oral composition is a dentifrice. Oral composition according to Claim 17, characterized in that the polishing agent is dicalcium phosphate dihydrate or aluminum hydroxide. An oral composition according to claim 1, characterized in that the antibacterial agent is an anionic polymer having a plurality of said distribution and persistence enhancing groups. An oral composition according to claim 19, characterized in that the anionic polymer contains a chain with repeating units, each of which contains at least one carbon atom. An oral composition according to claim 20, characterized in that each unit contains at least one distribution-enhancing group attached to the same, adjacent or other atoms in the chain. An oral composition according to claim 1, characterized in that the partition enhancing group is a carboxylic acid group or a salt thereof. • · «·« · An oral composition according to claim 22, characterized in that the antibacterial agent is a copolymer of maleic acid or maleic anhydride with another inert ethylenically unsaturated polymerizable monomer. An oral composition according to claim 23, characterized in that said monomer is methyl vinyl ether in a molar ratio of 4: 1 to 1: 4 with maleic acid or maleic anhydride. 100691 An oral composition according to claim 24, characterized in that the copolymer has a molecular weight of about 30,000 to 1,000,000 and is present in an amount of about 0.1 to 2% by weight. An oral composition according to claim 25, characterized in that the copolymer has an average molecular weight of about 70,000. An oral composition according to claim 1, characterized in that the partition enhancing group is a phosphonic acid group or a salt thereof. An oral composition according to claim 27, characterized in that the antibacterial agent is a polymer of poly- (beta-styrenephosphonic acid) or poly- (alpha-styrenephosphonic acid) or a copolymer of one of the styrenic phosphonic acids with another ethylenically unsaturated monomer.