Anti-bacterial, anti-bacterial filth and anti-tartar compound for oral cavity

(54) (56) (57)

REPRESENTATIVE TITLE

Colgate-Palmolive Co, New York Abdul Gaffar, Princeton NJ US, NJ US, John Afflitto, Yardley PA US

HW Barnieske patent agency AB Antibacterial oral composition with plaque- and tartar-limiting action

CALLED PUBLICATIONS: - SUMMARY:

An oral composition such as a dentifrice, mouthwash, lozeng or chewing gum containing a polyphosphate as an anti-tooth surfactant such as tetra-alkali metal, pyrophosphate, and a compatible antibacterial anti-sealant. The anti-stick agent is a substantially water-soluble noncationic antibacterial agent such as 2,4,4'-trichloro-2¹ hydroxydifinyl ether (Triclosan). Anti-plaque efficiency is optimized by the presence of a bacterial effect enhancing agent which improves the delivery of the antibacterial agent to, and its retention on, oral surfaces.

The numbers in brackets indicate international identification code, iNID code. Letters in clamps indicate international document code.

513 702

US 4,627,977 (Gaffar et al) US 4,515,772 (Parran et al) and US 4,323,551 (Parran) describe oral compositions which include various polyphosphate compounds. In US 4,627,977, a linear molecularly dehydrated polyphosphate salt is used in conjunction with a fluoride ion emitting source and a synthetic linear polymeric polycarboxylate to inhibit tartar formation. In the patent application EP 89 200 710.5, the anti-tartar efficiency is optimized with a reduced amount of the linear molecularly dehydrated polyphosphate salt, in collaboration with the fluoride ion emitting source and an increased amount of the synthetic linear polymeric polycarboxylate.

In US 4,515,772 and US 4,323,551, water-soluble dialkali metal pyrophosphate is used alone or mixed with tetraalkali metal pyrophosphate.

Oral compositions which inhibit tartar formation on dental surfaces are highly desirable as tartar is one of the factors causing periodontal conditions. Thus, a reduction of tartar will favor oral hygiene.

Dental plaque is a precursor to tartar. Unlike tartar, however, plaque can be formed on any one

513 702 preferably part of the tooth surface, especially including the gingival rim. In addition to being less appealing visually, the plaque is included in the appearance of gingivitis.

Thus, it would be highly desirable to include antimicrobial agents known to reduce plaque in oral compositions containing anti-tartar agents. In fact, this has been described in US 4,022,550 (Vinson et al) wherein a compound which provides zinc ions as an anti-inflammatory agent is mixed with an antibacterial agent effective to retard the growth of plaque bacteria. A wide variety of antibacterial agents are disclosed with the zinc compounds, including cationic materials such as guanides and quaternary ammonium compounds, as well as noncationic compounds such as halogenated salicylanilides and halogenated hydroxydifinyl ethers.

Heretofore, the cationic antibacterial materials such as chlorhexydine, benzetonium chloride and cetylperydine chloride have been the subject of extensive study such as antibacterial anti-sticking agents. However, because they are used in conjunction with zinc as anti-tartar, they are ineffective when used with anionic materials such as polyphosphate as anti-tartar. This inefficiency is considered completely overwhelming because polyphosphates are chelating agents and the chelating effect has been previously known to increase the effectiveness of cationic antibacterial agents (see, e.g., Disinfection, Sterilization and Preservation, 2nd Ed., Black, 1977, p. 915 and Inhibition and Destruction of the Microbial Cell, Hugo, 1971, p. 215). Quaternary ammonium compound is actually present in the pyrophosphate containing plaque-limiting mouthwash of US 4,323,551 (Parran) and bisbiguanide as the antiplaque agent proposed in the oral pyrophosphate containing the antitanking composition of US 4,515,772 (Parran et al).

IN

513 702

Against the background of the surprising incompatibility of the cationic antibacterial agents with polyphosphates present as anti-dentifrice agents, it was quite unexpected that other antibacterial agents would be effective.

According to the invention, the composition contains an orally acceptable vehicle, an agent effective in improving the antibacterial effect of an antibacterial agent having an average molecular weight of about 1,000 to about 1,000,000 and containing at least one functional group which enhances the delivery of antibacterial agents. the action, the release of bacterial effect or the production of antibacterial effect, and at least one organic group, which improves retention of antibacterial effect or action.

An advantage of the present invention is that a composition is provided which is effective in reducing tartar formation and optimizing plaque reduction.

A further advantage of the present invention is that an oral anti-plaque, anti-toothstone composition is provided which is effective in reducing the onset of lingivitis.

Further advantages of the present invention will be apparent from a study of the following description.

513 702

Preferred embodiments of the composition are set forth in the claims dependent on claim 1.

Typical examples of antibacterial agents that are particularly desirable for anti-plaque effectiveness, safety and composition are:

Halogenated diphenyl ethers

2 ', 4,4'-trichloro-2-hydroxy-diphenyl ether (Triclosan) 2,2'-dihydroxy-5,5', dibromo-diphenyl ether

Halogenated salicylanilides

4 ', 5-dibromosalicylanilid

3,4 ', 5-trichlorosalicylanilide

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)

Benzoeestrar

Methyl - p-hydroxylbenzoic ester

Ethyl - p-hydroxybenzoic ester

Propyl - p-hydroxybenzoic ester

Butyl - p-hydroxybenzoic ester i

513 702

Halogenated carbanilides

3,4,4'-triklorocarbanilid

3-trifluoromethyl-4,4'diklorocarbanilid

3,3,4'-triklorocarbanilide

Phenolic compounds (including phenol and its homologs, mono- and poly-alkyl and aromatic halo- (e.g., F, Cl, Br, I.) -phenols, resorcinol and catechol and their derivatives and bisphenol compounds). These phenolic compounds include, inter alia:

Phenol and its homologs

<td>phenol</td><td>- phenol</td>

<td>2 methyl</td><td>- phenol</td>

<td>3 methyl</td><td>- phenol</td>

<td>4 methyl</td><td>- phenol</td>

<td>4 etel</td><td>- phenol</td>

<td>2,4-dimethyl</td><td>- phenol</td>

<td>2,5-dimethyl</td><td>- phenol</td>

<td>3,4-dimethyl</td><td>- phenol</td>

<td>2,6-dimethyl</td><td>- phenol</td>

<td>4-n-propyl</td><td>- phenol</td>

<td>4-n-butyl</td><td>- phenol</td>

<td>4-n-amyl</td><td>- phenol</td>

<td>4-tert-Amyl</td><td>- phenol</td>

<td>4-n-hexyl</td><td>- phenol</td>

<td>4-n-heptyl</td><td>- phenol</td>

<td>2-methoxy-4- (2-propenyl)</td><td>- phenol (Eugenol)</td>

<td>2-isopropyl-5-methyl</td><td>- phenol (thymol)</td>

Mono- and polyalkyl and aralkyl halophenols methyl - p-chlorophenol ethyl - p-chlorophenol n-propyl - p-chlorophenol n-butyl - p-chlorophenol n-amyl - p-chlorophenol

513 702 sec-amyl n-hexyl cyclohexyl n-heptyl n-octyl o-chlorophenol methyl ethyl n-propyl n-butyl n-amyl tert-amyl n-hexyl n-heptyl p-chlorophenol o-benzyl o-benzyl-m-methyl o-benzyl-m, m-dimethyl o-phenylethyl o-phenylethyl-m-methyl

3-methyl

3,5-dimethyl

6-ethyl-3-methyl

6-n-propyl-3-methyl

6-isopropyl-3-methyl

2-ethyl-3,5-dimethyl 6-sec. butyl 3-methyl 2-iso-propyl-3,5-dimethyl 6-diethylmethyl-3-methyl

6-isopropyl-2-ethyl-3-methyl

2-sec. amyl-3,5-dimethyl 2-diethylmethyl-3-5-dimethyl 6 sec. octyl-3-methyl 6-sec. octyl 3-3-methyl p-bromophenyl methyl

- p-chlorophenol

- p-chlorophenol

- p-chlorophenol

- p-chlorophenol

- p-chlorophenol

o-chlorophenol

o-chlorophenol

o-chlorophenol

o-chlorophenol

o-chlorophenol

o-chlorophenol

o-chlorophenol

o-chlorophenol

p-Chlorophenol

- p-chlorophenol

- p-chlorophenol

- p-chlorophenol

- p-chlorophenol

- p-chlorophenol

- p-chlorophenol

- p-chlorophenol

- p-chlorophenol

- p-chlorophenol

- p-chlorophenol

- p-chlorophenol

- p-chlorophenol

- p-chlorophenol

- p-chlorophenol

- p-chlorophenol

- p-chlorophenol

- p-chlorophenol

- p-chlorophenyl

- p-bromophenyl

513 702 ethyl n-propyl n-butyl n-amyl sec.-amyl n-hexyl cyclohyxel o-bromophenol

- p-bromophenol

- p-bromophenol

- p-bromophenol

- p-bromophenol

- p-bromophenol

- p-bromophenol

- p-bromophenol tert.-amyl n-hexyl n-propyl-m, m-dimethyl o-bromophenol o-bromophenol o-bromophenol

2-phenylphenol

4-chloro-2-methylphenol

4-chloro-3-methylphenol

4-chloro-3,5-methylphenol

2,4-dichloro-3,5-dimethylphenol

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

5- methyl-2-pentylphenol

4- isopropyl-3-methylphenol

5- chloro-2-hydroxydiphenylmethane

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 - resorcinol phenylethyl - resorcinol phenylpropyl - resorcinol

513 702 p-chlorobenzyl 5-chlorobenzyl 5-chloro 4 '-chloro 5-bromo 4'-bromo

- resorcinol

- resorcinol

- 2,4-dihydroxydiphenylmethane

- 2,4-dihydroxidifinylmethane

- 2,4-dihydroxydifinylmethane

- 2,4-dihydroxidifinylmethane

Bisphenol compounds bisphenol A

2,2'-methylene bis (4-chlorophenol)

2,2'-methylene bis (3,4,6-trichlorophenol = (hexchlorophenol))

2,2'-methylene bis (4-chloro-6-bromophenol) bis (2-hydroxy-3,5-dichlorophenyl) sulfide bis (2-hydroxy-5-chlorobenzyl) sulfide

Triclosan is disclosed in the aforementioned US 4,022,880 as an antibacterial agent in combination with an anti-tartaric agent which provides zinc ions and is disclosed in German patent specification DE 35 32 860 in combination with a copper compound. It is also disclosed as an antiplaque agent in a dentifrice formulated to contain a lamellar phase comprising liquid crystal with hytactite agent,

513 702 which has a slab spacing of less than 6.0 nm and which may optionally contain a zinc salt, in published patent application EP 0161898 (Lane et al) and in a dentifrice containing the zinc citrate trihydrate, in published patent application EP 0161899 (Saxton).

The linear molecularly dehydrated polyphosphate salts operative as anti-tartar agents herein are well known and are widely used in the form of their fully or partially neutralized water-soluble alkali metal (e.g., gallium and preferably sodium) or ammonium salts and any mixtures thereof.

Representative examples include sodium hexametaphosphate, sodium tripolyphosphate, disodium disura, trisodium monosura and tetrasodium pyrophosphates, the moss potassium salts and the like. Linear polyphosphates correspond to (NaPO3)_n, where n is about 2 to about 125. In the present invention, in the oral compositions in approximate amounts of weight ranging from 0.1 to 3%, typically 1 to 2.5% and more typically 1.5 to 2% are utilized. When n is at least 3 in (NaPO3)_n, the polyphosphates are glassy in nature.

Particularly desirable antitanking agents are tetra-alkali metal pyrophosphates, including mixtures thereof, such as tetrasodium pyrophosphate, tetracalcium pyrophosphate and mixtures thereof. Thus, the oral composition may contain a polyphosphate comprising antitanking agent which is substantially free of tetrasodium pyrophosphate or substantially free of the combination of tetrasodium pyrophosphate and tetrasodium pyrophosphate, the ratio of potassium to sodium pyrophosphate being greater than: An anti-tartaric agent comprising about 2% by weight of the oral compositions, of tetrasodium pyrophosphate, is particularly effective.

The antibacterial effect enhancing agent (AEA) which

513 702 improves the delivery of the antibacterial agent to and retention thereof on oral surfaces, utilized in amounts effective to achieve such improvement, in the range of the oral composition from about 0.05% to about 4%, preferably about 0.1 % to about 3%, more preferably about 0.5% to about 2.5% by weight.

This AEA may be a simple compound, preferably a polymerizable monomer, more preferably a polymer, the latter term being completely generic, including, for example, oligomers, homopolymers, copolymers of two or more monomers, ionomers, block copolymers, graft copolymers, crosslinked polymers and copolymers. . The AEA may be natural or synthetic and water insoluble or preferably water (saliva) soluble or swellable (hydrogenable, hydrogel forming). It has an average weight-based molecular weight of about 100 to about 1,000,000, preferably about 1,000 to about 1,000,000, more preferably about 2,000 or 2,500 to about 250,000 or 500,000.

The AEA usually contains at least one release enhancement group which is preferably acidic, such as a sulfone group, phosphine group or preferred phosphone or carboxyl group, or salt thereof, for example alkali metal or ammonium salt, and at least one organic retention enhancement the groups, which latter groups preferably have the formula - (X)_n-R wherein X is O, N, S, SO, SO2, P, PO or Si or the like, R is hydrophobic alkyl, alkenyl, acyl, aryl, alkaryl, aralkyl, heterocyclic or their inert substituted derivatives, and n is zero or 1 or more. The above-mentioned inert-substituted derivatives are intended to include substituents on R which are generally non-hydrophilic and do not significantly interfere with the desirable functions of AEA to improve the delivery of the antibacterial agent to, and retain therein, on oral surfaces such as halo, e.g. ,

Br, I and carbo and the like. Illustrations of such retention enhancement groups are given in the table below.

513 702

<td>n</td><td>X</td><td>~ (X)_nR</td>

<td> 0</td><td></td><td>methyl, ethyl, propyl, butyl, isobutyl, t-butyl, cyclohexyl allyl, benzyl, phenyl, chlorophenyl, xyxyl, pyridyl, furanyl, acetyl, benzoyl, butyryl, terephthaloyl etc.</td>

<td> 1</td><td> 0</td><td>ethoxy, benzyloxy, thioacetoxy, phenoxy, carboethoxy, carbobenzyloxy, etc.</td>

<td></td><td>N</td><td>ethylamino, diethylamino, propylamido, benzylamino, benzoylamido, phenylacetamido, etc.</td>

<td></td><td>S</td><td>thiobutyl, thioisobutyl, thioallyl, thiobenzyl, thiophenyl, thiopropionyl, phenylthioacetyl, thiobenzoyl, etc.</td>

<td></td><td>SE</td><td>butylsulfoxy, allylsulfoxy, benzylsulfoxy, phenylsulfoxy, etc.</td>

<td></td><td>sO₂</td><td>butylsulfonyl, allylsulfonyl, benzylsulfonyl, phenylsulfonyl, etc.</td>

<td></td><td>P</td><td>diethylphosphinyl, ethylvinylphosphinyl, ethylallylphosphinyl, ethylbenzylphosphinyl, ethylphenylphosphinyl, etc.</td>

<td></td><td>PO</td><td>diethylphosphinoxy, ethylvinylphosphinoxy, methylallylphosphinoxy, methylbenzylphosphinoxy, methylphenylphosphinoxy, etc.</td>

<td></td><td>Si</td><td>trimethylsilyl, dimethylbutylsilyl, dimethylbenzylsilyl, dimethyllyinylsilyl, dimenylallylsilyl etc.</td>

513 702

As used herein, the delivery enhancing group refers to one which adheres or substantially adhesively, cohesively or otherwise binds AEA (which carries this antibacterial agent) to oral surfaces (e.g., gums and gums) and thereby releases the antibacterial agent to these surfaces. The organic retention enhancing group, which is generally hydrophobic, otherwise adheres or binds the antibacterial agent to the AEA, thereby favoring retention of the antibacterial agent at this AEA and indirectly on the oral surfaces. In some cases, the attachment of the antibacterial agent by physical attachment thereof occurs with said AEA, especially when AEA is a cross-linked polymer, whose structure provides, by its nature, extended locations for such retention. The presence of a more hydrophobic higher molecular weight cross-linking group in the cross-linked polymer further promotes the physical retention of the antibacterial agent at or with the cross-linked AEA polymer.

Preferably, the AEA is an anionic polymer comprising a chain or back containing repetitive units each preferably containing at least one carbon atom and preferably at least one directly or indirectly dependent monovalent release enhancing group and at least one directly or indirectly pending monovalent retention-enhancing group or preferably otherwise bonded to atoms, preferably carbon in the chain. Less preferably, the polymer may contain delivery enhancing groups and / or retention enhancing groups and / or other divalent atoms or groups such as links in the polymer chain instead of or in addition to carbon atoms, or as crosslinking groups.

It should be understood that any examples or illustrations of AEA materials disclosed herein and which do not contain both delivery enhancement groups and retention enhancement groups can and should preferably be chemically modified in order to obtain the preferred AEA materials containing both of these groups and preferably a plurality of each of these groups. In the case of the preferred polymeric AEA materials, it is desirable, in order to maximize the antibacterial agent's substantivity and delivery to oral surfaces, that the repetitive units in the polymer chain or back containing the acid delivery enhancing groups comprise at least about 10%, preferably at least about 10%. about 50%, more preferably at least about 80% up to 95% or 100% by weight of the polymer.

According to a preferred embodiment of the present invention, the AEA material comprises a polymer containing repeating units in which one or more phosphonic acid including release enhancement groups are bonded to one or more carbon atoms in the polymer chain. An example of such an AEA material is poly (vinylphosphonic acid) containing units of the formula:

- (CH₂ - CH) E * O₃hrs₂ which does not, however, contain a retention enhancing group. However, a group of the latter type should be present in poly (1-phosphonopropene) having units of the formula:

II

<img file="SE513702C2_D0001.tif" />

A preferred phosphonic acid-containing AEA for use herein is poly (beta-styrene phosphonic acid) containing units of the formula:

III

- (CH -CH) // Ph PO₃hrs₂ wherein Ph is phenyl, the release-enhancing phosphon group and the retention-enhancing phenyl group are bonded to vicinal carbon atoms in the chain, or a copolymer of beta513 702 styrene phosphonic acid with vinylphosphonyl chloride having the units of formula III alternatively or in random units or in co-random units alpha-styrene phosphonic acid) containing units of the formula:

IV - (CH₂ -X .-----) Ph PO₃hrs₂ wherein the delivery and retention enhancement groups are geminally bound to the chain.

Its styrene phosphonic acid polymers and their copolymers with other inter-ethylenically unsaturated monomers generally have molecular weights in the range of about 2,000 to about 30,000, preferably about 2,500 to about 10,000. These inert monomers do not substantially interfere with the intended function of any copolymer utilized herein as an AEA.

Other phosphon group-containing polymers include, for example, phosphonated ethylene having units of the formula:

&lt;(CH₂)₁₄CHPO₃hrs₂l_nwherein, for example, may be a number or have a value giving the polymer a molecular weight of about 3,000; and sodium poly (butene-4,4-diphosphonate) having units of the formula:

WE

<img file="SE513702C2_D0002.tif" />

poly (allyl bis (phosphonoethylamine)) having units of the formula:

VII

<img file="SE513702C2_D0003.tif" />

Other phosphonated polymers, for example, poly (allyl phosphonoacetate), phosphonated polymethyl acrylate, etc., and the geminal diphosphonate polymers disclosed in EP-A-0321233 may be used herein as AEA materials, of course, provided they contain or are modified to

IN

513 702 contain the organic retention enhancement groups defined above.

In one aspect of the present invention, the oral composition comprises an orally acceptable vehicle or carrier, an agent effective to enhance the antibacterial effect of an antibacterial agent having an average molecular weight of about 1,000 to about 1,000,000, containing at least one functional group that enhances the delivery of antibacterial effect and at least one organic group that improves retention of antibacterial effects; wherein the agent containing these groups is free from or substantially free of water-soluble alkali metal or ammonium synthetic anionic linear polymer polycarboxylate salt having a molecular weight of about 1,000 to 1,000,000, and polyphosphate as anti-tartaric agent such as a mixture of potassium and sodium salts potassium to sodium in the composition is in the range up to less than about 3: 1, for example from about 0.37 to about 1.04: 1.

In another preferred embodiment, the AEA material comprises a synthetic anionic polymeric polycarboxylate which is also an inhibitor of alkaline phosphatase enzyme. Synthetic anionic polymeric polycarboxylates and their complexes with various cationic germicides, zinc and magnesium have been previously disclosed as antitanking agents themselves, in, for example, US 3,429,963 (Shedlovsky), US 4,152,420 (Gaffar), US 3,956,480 (Dichter et al), US 4,138,47 and US 4,183,914 (Gaffar et al). However, only in a disclosure substantially corresponding to US 4,627,977 (Gaffar et al) is disclosed the use of these polycarboxylates to inhibit the salivary hydrolysis effect of pyrophosphate comprising anti-tartaric agents in combination with a compound providing a source of fluoride ion. It should be understood that the synthetic anionic polymeric polycaboxylates so disclosed in these aforementioned patents

513 702 writings, when containing or modified to contain the above defined retention enhancement groups, are operative as AEA materials in the compositions and methods of the invention and these disclosures are hereby incorporated herein.

These synthetic anionic polymeric polycarboxylates are often utilized in the form of their free acids or preferably partially or more preferably fully neutralized water-soluble or water-swellable (hydrogenable, gel-forming) alkali metal (e.g., potassium and preferably sodium) or ammonium salts. Preferred are 1: 4 to 4: 1 copolymers of maleic anhydride or acid with another polymerizable ethylenically unsaturated monomer, preferably methyl vinyl ether / maleic anhydride having a molecular weight (Mw) of about 30,000 to about 1,000,000. These copolymers are available, for example, such as Gantrez, for example

AN 139 (MW 500,000), AN 119 (MW 250,000) and preferably S-97 Pharmaceutical Grade (MW 70,000) from

GAF Corporation.

Other polymeric polycarboxylates operating as AEA materials containing or modified to contain retention enhancing groups should include those disclosed in US 3,956,480 as mentioned above, such as the 1: 1 copolymers of maleic anhydride with ethyl acrylate, hydroxyethyl methacrylate, N-vinyl 2-nyl vinyl ethylene, the latter being available, for example, such as Monsanto EMA No. 1103, MW 10,000 and EMA Grade 61 and 1: 1 copolymers of acrylic acid with methyl and hydroxyethyl methacrylate, methyl or ethyl acrylate, isobutyl vinyl ether or N-vinyl-2-pyrollidone.

Further operative polymeric polycarboxylates disclosed in the aforementioned US 4,138,477 and US 4,183,914, and containing or modified to contain retention enhancing groups, include copolymers of

IN

513 702 maleic anhydride with styrene, isobutylene or ethyl vinyl ether, polyacrylic, polyidaconic and polymalainic acids and sulfoacrylic oligomers having MW as low as 1,000, available as

Uniroyal ND-2.

Generally suitable are polymerized retention-enhancing, group-containing, olefinically or ethylenically unsaturated carboxylic acids containing an activated carbon-to-carbon olefinic double bond and at least one carboxyl group, i.e., an acid containing an olefinic double bond, which acts as a primer in the process of polymerization upon polymerization. occupy the position with respect to the carboxyl group or as part of an ethylene grouping terminal. Illustrative of these acids are acrylic, methacrylic, ethacrylic, alpha-chloroacrylic, croton, beta-acryloxide propionic, sorbine, alpha-chlorosorbine, cinnamine, beta-styrylacrylic, mucon, itacon, citracone -, mesacone, glutacone, aconite, alpha-phenylacrylic, 2-benzylacrylic, 2-cyclohexylacrylic, angelic, umbelline, fumaric, maleic acids and anhydrides. Other various olefinic monomers that are copolymerizable with these carboxyl monomers include vinyl acetate, vinyl chloride, dimethyl, maleate and the like. Copolymers usually contain enough carboxylic salt groups for water solubility.

Also useful herein are so-called carboxy vinyl polymers disclosed as toothpaste components of US 3,980,767 (Chown et al), US 3,935,306 (Roberts et al), US 3,919,409 (Perla et al), US 3,911,904 (Harrison) and US 3,711,604 (Colod . They are commercially available, for example, under the trademarks Carbopol 934, 940 and 941 (BV) Goodrich), these products consist essentially of a colloidal water-soluble polymer of polyacrylic acid polymer crosslinked with from about 0.75 to about 2% polyallyl sucrose or polyallyl pentaerythritol as crosslinking agent, the crosslinked structures and linkages providing the desired retention enhancement and hydrocarbon enhancement through hydrochloride. or physical retention of the antibacterial agent or the like. Polycarbophil is somewhat similar and is a polyacrylic acid crosslinked with less than 0.2% divinyl glycol, with the lower proportion, molecular weight and / or hydrophobicity of this crosslinking agent tending to produce reduced or no retention enhancement. 2,5-dimethyl-1,5-hexadiene exemplifies a more effective retention-enhancing crosslinking agent.

The synthetic anionic polymeric polycarboxylate component is usually a hydrocarbon having freely selectable halogen and O-containing substituents and linkages as present in, for example, ester, ether and OH groups, and when present, are generally utilized in the present compositions in approximate weight amounts of up to about 4% (usually at least about 0.05%).

The AEA material may also include natural anionic polymeric polycarboxylates containing rate-enhancing groups. Carboxymethyl, cullulose and other binding agents, rubbers and film formers which are free from the above-defined delivery enhancement and / or retention enhancement groups are ineffective as AEA materials.

As illustrative of AEA materials containing phosphinic acid and / or sulfonic acid as release enhancing groups, mention may be made of polymers and copolymers containing units or groups derived from the polymerization of vinyl or allylphosphine and / or sulfonic acids substituted as needed on the 1 or 2 (or 3) carbon atom by an organic retention enhancing group having, for example, the formula defined above - (X)_n-R. Mixtures of these monomers can be utilized and copolymers thereof with one or more inter-polymerizable ethylenically unsaturated monomers such as those described above with respect to the operative

513 702 synthetic anionic polymeric carboxylates. As may be noted, in these and other herein operational polymeric AEA materials, usually only an acidic release enhancing group is attached to any given carbon atom or other atom in the polymer backbone or branch thereof. Polysiloxanes containing or modified to contain pendant release enhancement groups and retention enhancement groups may also be utilized as AEA materials herein. Also effective as AEA materials herein are ionomers containing or modified to contain delivery and retention enhancing groups. Economists are described on pages 546-573 of the Kirk-Othmer Encyclopedia of Chemical Technology, Third Edition, Supplement Volume, John Wiley and Sons, Inc. copyright 1984, and this description is hereby incorporated herein. Also effective as AEA materials herein, provided they contain or are modified to contain retention enhancing groups, are polyesters, polyurethanes and synthetic and natural polyamoids containing proteins and proteinaceous materials such as collagen, poly (arginine) and other polymerized amino acids. ____________ __________

When the oral preparation is prepared by initial dissolution of the polyphosphate and antibacterial agent in moisturizing and surfactant and addition thereto by the AEA, especially the polycarboxylate, in small increments, the solution becomes clear and can be characterized as a microemulsion. As the amount of polycarboxylate increases so that the finished oral preparation contains at least about 2.2% by weight thereof, the solution becomes milky and can be characterized as a macroemulsion. In these macroemulsion type compositions, the antibacterial agent's anti-plating action appears to be optimized.

A desirable weight ratio of the substantially water-soluble noncationic antibacterial agent to poly

513 The 702 phosphate antitanking agent is in excess of about 0.72: 1 to less than about 4: 1, for example from about 1: 1 to about 3.5: 1, especially from about 1: 6: 1 to about

2,7:1.

In order to optimize the anti-tartar effectiveness of the oral composition, inhibitors to enzymatic hydrolysis of the polyphosphate are advantageously present. These agents are an amount of a fluoride ion source sufficient to supply 25 ppm to 5,000 ppm fluoride ions, and up to 3% or more of the synthetic anionic polymeric carboxylate having a molecular weight of about 1,000 to about 1,000,000, preferably about 30,000. to about 500,000.

The sources of fluoride ions or fluorine-providing component, such as acid phosphatase and pyrophosphatase enzyme inhibitor component, are well known in the art as anticaries. These compounds may be slightly soluble in water or may be completely water soluble. They are characterized by their ability to release fluoride ions in water and by freedom from unwanted reaction with other components of the oral preparation. Among these materials are inorganic fluoride salts such as soluble alkali metal, alkaline earth metal salt, for example sodium fluoride, potassium fluoride, ammonium fluoride, calcium fluoride, a copper fluoride such kuprofluorid, zinc fluoride, barium fluoride, sodium fluorosilicate, ammonium fluorosilicate, natriumfluorzirkonat, ammoniumfluorzirkonat, sodium monofluorophosphate, aluminiummono- and difluorofosfat and fluorinated sodium calcium pyrophosphate . Alkali metals and tin fluorides such as sodium and stannous 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 a non-toxic amount, generally about 0.005 to about 3.0% in the preparation. In a tooth

513 702 care preparation, for example a dental gel, toothpaste (including cream), tooth powder or dental tablet, an amount of this compound which releases up to about 5,000 ppm Fion based on the weight of the preparation is considered to be satisfactory. any suitable minimum amount of this compound can be used, but it is preferred to utilize sufficient amount of compound to release about 300 to 2,000 ppm, more preferably about 800 to about 1,500 ppm of fluoride ion.

Typically, in the case of alkali metal fluorides, this component is present in an amount of up to about 2% by weight, based on the weight of the preparation, preferably in the range of about 0-05% to 1%. In the case of sodium monofluorophosphate, the compound may be present in an amount of about 0.1-3%, more typically about 0.76%.

In oral formulations such as mouthwashes, tablets and chewing gum, the fluorine-providing compound is typically present in an amount sufficient to release up to about 500 ppm, preferably about 25 to 300 ppm by weight of fluoride ion. Usually, about 0.005 to about 1.0% by weight of this compound is present.

In some highly preferred forms of the invention, the oral composition may be substantially liquid in nature, such as a mouthwash or mouthwash. In such a preparation, the vehicle is typically a water-alcohol mixture which suitably includes a humectant or humectant as described below. In general, the weight to water ratio of alcohol is in the range of about 1: 1 to about 20: 1, preferably about 3: 1 to 10: 1, and preferably 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

513 702% by weight of the preparation. The alcohol is typically ethanol or isopropanol. Ethanol is preferred.

The pH of this liquid and other formulations of the invention is generally in the range of from about 4.5 to about 9 and typically from about 5.5 to 8. The pH is preferably in the range of about 6 to about 8.0. It is noteworthy that the compositions of the invention can be applied orally at a pH below 5 without substantially scaling or otherwise damaging dental enamel. The pH can be controlled with an acid (e.g., citric or benzoic) or base (e.g., sodium hydroxide) or buffered (such as with sodium citrate, benzoate, carbonate or bicarbonate, disodium hydrogen phosphate, sodium dehydrogenphosphate, etc.).

In some other desirable form of the present invention, the oral composition may be substantially solid or paste-like in character, such as dental powder, a dental tablet or dentifrice, i.e., a toothpaste (toothpaste) or a gel-shaped dentifrice. The vehicle for these solid or paste-like oral preparations generally contains dentally acceptable polishing materials. Examples of polishing materials are water-insoluble sodium metaphosphate, potassium metaphosphate, tricalcium phosphate, dihydrated calcium phosphate, anhydrous dicalcium phosphate, calcium pyrophosphate, magnesium orthophosphate, trimagnesium phosphate, calcium carbonate, calcium carbonate, hydrated

Other suitable polishing materials include the particulate thermosetting plastics disclosed in US 3,070,510, issued December 15, 1962, such as melamine, phenol and urea formaldehyde and cross-linked polyepoxides and polyesters. Preferred polishing materials include crystalline silica with particle sizes of up to about 5 microns, an average particle size of up to about 1.1 microns, and a surface area of ​​up to about 50,000 cm 2 / g, silica gel or

513 702 collodial silica and complex amortic alkali metal aluminum silicate.

When visually clear gels are utilized, a collodial silica polishing agent such as those sold under the trademark SYLOID such as Syloid 72 and Syloid 74 or under the trademark SANTOCEL such as Santocel 100, alkali metal aluminum silicate complexes, is particularly useful as they have a refractive index near refractive index. liquid (including water and / or humectant) systems commonly used in dental care.

Many of the so-called water-insoluble polishing materials are anionic in nature and also include small amounts of soluble material. Thus, insoluble sodium metaphosphate can be formed in any suitable manner as illustrated by Thorpe's Dictionary of Applied Chemistry, Volume 9, 4th Edition, pages 510-511. The forms of insoluble sodium metaphosphate known as Madrell's salt and Kurrol's salt are further examples of suitable materials. These metaphosphate salts exhibit only a low solubility in water and are therefore usually referred to as insoluble metaphosphates (IMPs). There is in it a minor amount of soluble phosphate material such as impurities, usually a few percent such as up to 4% by weight. The amount of soluble phosphate material assumed to include a soluble sodium trimetaphosphate in the case of insoluble metaphosphate can be reduced or eliminated by water washing if desired. The insoluble alkali metal metaphosphate is typically used in powder form with a particle size such that no more than 1% of the material is greater than 37 microns.

The polishing material is usually present in the solid or paste-like compositions in weight concentrations of about 10% to about 99%. Preferably there is

513 702 it in amounts ranging from about 10% to about 75% in toothpaste and from about 70% to about 99% in tooth powder. In toothpastes, when the polishing material is siliceous in nature, it is generally present in an amount of about 10-30% by weight. Other polishing materials are typically in an amount of about 30-75% by weight.

In a toothpaste, the liquid carrier may comprise water and humectant, typically in an amount ranging from about 10% to about 80% by weight of the preparation. Glycerin, propylene glycol, sorbitol and polypropylene glycol provide examples of suitable humectants / carriers. Also advantageous are liquid mixtures of water and glycerine and sorbitol. In clear gels for which refractive index is an important aspect, about 2.5-30% by weight of water, 0 to about 70% by weight glycerine and about 20-80% by weight sorbitol are preferably used.

Toothpastes, creams and gels typically contain a natural or synthetic thickener or gelling agent in proportions of about 0.1 to about 10, preferably about 0.5 to about 5% by weight. A suitable thickener is synthetic hectorite, a synthetic collodial magnesium-alkali metal-silicate complex clay available, for example, such as Laponite (e.g. CP, SP 2002, D) marketed by Laporte Industries Limited. Laponite D has an analysis which by weight is approximately 58.00% SiO², 25.40% MgO, 3.05% Na₂O, 0.98% Li₂O and some water and trace metals. Its true specific density is 2.53 and it has an apparent bulk density (g / ml at 8% moisture) of 1.0.

Other suitable thickeners include Irish moss, iota carrageenan, tragacanth, starch polyvinylpyrrolidone, hydroxyethylpropyl cellulose, hydroxybutylmethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose

IN

513 702 (for example, available as Natrasol), sodium carboxymethyl cellulose, and colloidal silica such as finely ground Syloid (for example, 244). In some dentifrices prepared in accordance with the present invention, especially when more than 0.35% by weight of the water-insoluble antibacterial agent is used and a siliceous polish is present in an amount of less than 30% by weight, it may be desirable to include an agent which dissolves this antibacterial agents. These solubilizers include humectant polyols such as propylene glycol, dipropylene glycol and hexylene glycol, cellulose solvents such as methyl cellulose and ethyl cellulose solvents, vegetable oils and waxes containing at least about carbon atoms in a straight chain such as olive oil and ethyl acetate, castor oil and petroleum oil, castor oil and petroleum

It should be understood that, as is conventional, the oral preparations are intended to be sold or otherwise distributed in suitably labeled packages. Thus, a can of mouthwash will have a label which essentially describes it as a mouthwash or mouthwash and has instructions for its use; and a toothpaste, cream or gel will usually be in a compressible type, typically of aluminum, lined lead or plastic or some other squeezing dispenser, pump dispenser or pressurized dispenser for dispensing the contents, provided with a label which essentially describes the contents as a toothpaste, gel or toothpaste.

Organic surfactants are used in the compositions of the present invention to achieve increased prophylactic effect, to assist in the thorough and complete dispersion of the antitumor and antiplaque agent throughout the oral cavity, and to make the present compositions more acceptable in cosmetic terms. The

513 The 702 organic surfactant is preferably anionic, nonionic or anaphylactic in nature and it is preferred to use as a surfactant a detersive material which imparts detersive and foaming properties to the composition. Suitable examples of anionic surfactants are water-soluble salts of higher fatty acid monoglyceride monosulfates such as the sodium salt of the monosulfated monoglyceride of hydrogenated coconut oil fatty acids, higher alkyl sulfates such as sodium lauryl sulfate, alkylaryl sulfone sulfate, sodium sulfate sulfate, higher fatty acid esters of 1,2-dihydroxypropane sulfonate and the substantially saturated higher aliphatic acyl amides of lower aliphatic amino carboxylic acid compounds such as those having 12 to 16 carbon atoms in the fatty acid, alkyl or acyl radicals and the like. Examples of the latter amides are N-lauroyl sarcosine and sodium, potassium and ethanolamine salts of N-lauroyl, N-myristoyl or Npalmitoyl sarcosine which should be substantially free of soap or similar higher fatty acid materials. The use of these sarcosinate compounds in the oral compositions of the present invention is particularly advantageous as these materials exhibit an extended marked effect in the inhibition of acid formation in the oral cavity due to carbohydrate degradation, in addition to exerting some reduction in the solubility of tooth enamel in acidic solutions. Examples of water-soluble nonionic surfactants are ethylene oxide condensation products with various reactive hydrogen-containing compounds which are reactive therewith and have long hydrophobic chains (e.g., aliphatic chains having about 12 to 20 carbon atoms) which condensation products (ethoxamers) contain hydrophilic polyoxyethylene groups such as hydrophilic polyoxyethylene groups such as with fatty acids, polyhydric alcohols (e.g., sorbitan monostearate) and polypropylene oxide (e.g., Pluronic materials).

513 702

0.1-5% by weight, preferably about 1-2.5%. It is noteworthy that the surfactant can help dissolve the noncationic antibacterial agent and thereby reduce the necessary amount of solubilizing humectant.

Various other materials may be incorporated into the oral preparations of the present invention, such as whitening agents, preservatives, silicones, chlorophyll compounds and / or ammoniated materials such as urea, diamonium phosphate and mixtures thereof. If these adjuvants or adjuvants are present, they are incorporated into the formulations in amounts which have no significant adverse effect on the desired properties and characteristics. significant amounts of zinc, magnesium and other metal salts and materials, generally soluble, which would form complexes with the active components of the present invention are to be avoided.

Any suitable flavoring or sweetening material may also be utilized. Examples of suitable flavoring ingredients are flavoring oils, such as oil of spearmint, peppermint, wintergreen, sassafras, clover, sage, eucalyptus, marjoram, cinnamon, lemon and orange and methyl salocylate. Suitable sweeteners include sucrose, lactose, maltose, sorbitol, xylitol, sodium cyclamate, perillartin, AMP (aspartylphenylalanine, methyl ester), saccharin and the like. The flavoring and sweetening agents may conveniently each or together comprise from about 0.1% to 5% or more of the preparation. Furthermore, flavoring oils appear to contribute to the dissolution of the antibacterial agent.

In the preferred practice of the present invention, an oral preparation according to the invention is preferably applied, such as a mouthwash or dentifrice containing the composition of the present invention.

513 702 regularly on dental enamel, such as every day or every other or every three days or preferably from 1 to 3 times daily, at a pH of about 4.5 to about 9, generally about 5.5 to about 8, preferably about 6 to 8, for at least 2 weeks up to 8. weeks or more up to lifetime.

The compositions of the present invention may be incorporated into lozenges or chewing gum or other products, for example, by stirring in a hot rubber base, or coating the outer surface of a rubber base of which, by way of illustration, may be mentioned gelutone, rubber latex, vinylith resins, etc., preferably with conventional plasticizers or plasticizers. sugar or other sweeteners or the like, such as glucose, sorbitol and the like.

The following examples are further illustrative of the nature of the present invention, but it should be understood that the invention is not limited thereto. All quantities and proportions stated herein and in the appended claims are weight-based unless otherwise stated.

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

Example 1

The adsorption to and release from dental minerals with respect to agent antiplaques / antiviral efficacy is evaluated with the adsorption of antibacterial agent on

513 702 saliva-coated dental mineral disk of hydroxyapatite, in the presence of pyrophosphate and various amounts of polycarboxylate.

The recipes for the evaluated toothpastes are:

Parts by weight

<td></td><td>A</td><td>B</td>

<td>Glycerin</td><td> 10.000</td><td> 10.000</td>

<td>Iota-carrageenan</td><td> 0.750</td><td> 0.750</td>

<td>Sorbitol (70% solution)</td><td> 30.000</td><td> 30.000</td>

<td>Propylene glycol</td><td> 0.500</td><td> 0.500</td>

<td>Gantrez (13.02% solution)</td><td> 19.000</td><td> 15.500</td>

<td>Titanium dioxide</td><td> 0.500</td><td> 0.500</td>

<td>Water (deionized)</td><td> 9.957</td><td> 13.457</td>

<td>NaF</td><td> 0.243</td><td> 0.243</td>

<td>Sodium Saccharin</td><td> 0.300</td><td> 0.300</td>

<td>pyrophosphate</td><td> 2.000</td><td> 2.000</td>

<td>Sodium hydroxide (50%)</td><td> 1.000</td><td> 1.000</td>

<td>Kiseldioxidpolermedel</td><td></td><td></td>

<td>(Zeodent 113)</td><td> 20.000</td><td> 20.000</td>

<td>Riseldioxid thickener</td><td></td><td></td>

<td>(Sylodent 15)</td><td> 2.500</td><td> 2.500</td>

<td>Flavoring Oil</td><td> 0.950</td><td> 0.950</td>

<td>TCHE</td><td> 0.300</td><td> 0.300</td>

<td>SLS</td><td> 2.000</td><td> 2.000</td>

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

For testing the delivery of antibacterial agent to a saliva-coated hydroxyapatite disc, hydroxyapatite (HA) obtained from Monsanto Co. is washed. vigorously with distilled water, collected by vacuum filtration and allowed to dry overnight at 37 ° C. This dried HA is ground to a powder with a mortar and pestle. 150.00 mg of HA is placed in the cavity in a KBr pellet pad (Barnes Analytical,

513 702

Stanford, CT) and compressed for 6 minutes with 4,536 kilos in a Carver Laboratory press. The resulting 13 mm slices are sintered for 4 hours at 800 ° C in a Thermolyne oven. Parafilm-stimulated whole saliva is collected in an ice-cooled glass beaker. The saliva is cleared by centrifugation with 15,000 g for 15 minutes at 4 ° C. Sterilization of the clarified saliva is carried out at 4 ° C with stirring by irradiating the sample with UV light for 1.0 hour.

Each sintered disk is hydrated with sterile water in a polyethylene test tube. The water is then removed and replaced with 2.00 ml of saliva. A saliva membrane is formed by incubating the disc overnight at 37 ° C with continuous shaking in a water bath. After this treatment, the saliva is removed and the slices are treated with 1.00 ml of a solution containing antibacterial agent (the triclosan) in a liquid phase dentifrice solution, and incubated at 37 ° C with continuous shaking in the water bath. After 30 minutes the disc is transferred to a new tube and 5.00 ml of water is added, followed by gentle shaking of the disc with a Vortex. The disc is then transferred to a new tube and the washing procedure repeated twice. Finally, the disc is carefully transferred into a new tube to avoid co-transfer of any liquid along with the disc. Then 1.00 ml of methanol is added to the plate and shaken vigorously with a Vortex. The sample is left at room temperature for 30 minutes to extract the adsorbed triclosan in the methanol. The methanol is then extracted and cleared by centrifugation in a Beckman Microfuge 11 at 10,000 rpm for 5 minutes. After this treatment, the methanol is transferred into HPLC (high performance liquid chromatography) ampoules to determine the concentration of antibacterial agent. Triple samples were used in all experiments.

513 702

<td></td><td> 31</td>

<td>STATED bELOW</td><td>table summarizes the information: Chart Delivery of TCHE to saliva transfer</td>

<td>Toothpaste</td><td>drawn hydroxyapatite disc in micrograms</td>

<td>A</td><td> 130</td>

<td>B</td><td> 30</td>

The indicated data indicate that with increasing amount of Gantrez (toothpaste A) there is a very sharp increase in the delivery of TCHE to saliva-coated tooth minerals.

Example 2

The following toothpaste is effective as an antiplaque and

<td>anticalculus composition:</td><td>Parts by weight</td>

<td>Sorbitol (70%) Irish Moss</td><td> 22,00 1,00</td>

<td>Sodium hydroxide (50%) Gentrex (13.02% solution) Water (deionized) Sodium monofluorophosphate</td><td> 1,00 19,00 2,69 0,76</td>

<td>Sodium Saccharin</td><td> 0,30</td>

<td>pyrophosphate Hydrogenated alumina Flavoring Oil TCHE</td><td> 2,00 48,00 0,95 0,30</td>

<td>SLS</td><td> 2,00</td>

513 702

Example 3

<td>mouthwash</td><td>parts</td>

<td>Tetrasodium pyrophosphate</td><td> 2,00</td>

<td>Gantrez S-97</td><td> 2,50</td>

<td>Glycerin</td><td> 10.00</td>

<td>sodium fluoride</td><td> 0,05</td>

<td>Sodium lauryl</td><td> 0,20</td>

<td>TCHE</td><td> 0,06</td>

<td>Flavoring Oil</td><td> 0,40</td>

<td>Water QS to</td><td> 100,00</td>

Example 4

Tablet

75-80% sugar

1-20% corn syrup

0.1-1.0 Flavor oil

2% tetrasodium pyrophosphate

2.50% Gantrez S-97

0.01 to 0.05% NaF

0.01 to 0.1% TCHE to 5% magnesium stearate, lubricant

0.01 to 0.2% water

Example 5

Chewing gum

Gum base

Sorbitol (70%)

TCHE tetrasodium pyrophosphate

Gantrex S-97

parts

25,00

17,00

0.50 to 0.10

2,00

2,50

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

513 702

Example · 6

Chewing gum

Gum base

TCHE

Gantrez

NaF

Glycerin

Crystalline sorbitol

Tetrasodium pyrophosphate

Parts 30.00

0,50

2,00

0,05

0,50

53,00

2,00

Flavor oil and water QS to 100.00

In the previous examples, improved results are obtainable even when TCHE is replaced with each of phenol, 2,2'methylene bis (4-chloro-6-bromophenol), eugenol and thymol and / or when Gantrez is replaced with other AEA materials such as carbopolies (e.g., 934) or styrene phosphonic acid polymers having molecular weights in the range of about 3,000 to 10,000, such as poly (beta-styrene phosphonic acid), copolymers of vinyl phosphonic acid with beta-styrene phosphonic acid, and poly (alpha-styrene phosphonic acid), or sulfoacrylic oligomers, or a 1: 1 copolymer of maleic anhydride with ethyl acrylate.

Similarly, similar results are obtained when pyrophosphate (tetrasodium pyrophosphate) is replaced by tetrasodium pyrophosphate and tetrasodium pyrophosphate, the potassium to sodium weight ratio being a) 0.37: 1, b) 1.4: 1, c) 3: 1 and 3.5: 1.

This invention has been described with respect to certain preferred embodiments and it should be understood that modifications and variations thereof apparent to those skilled in the art will be included within the scope of the present application and the scope of the appended claims.

513 702