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1. WO1991007163 - COMPOSITION DE SOINS BUCCAUX EN FLUORURE STANNEUX STABILISE

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[ EN ]

STABILIZED STANNOUS FLUORIDE COMPOSITIONS FOR ORAL CARE
This invention relates to aqueous stannous fluoride compositions for oral care with increased stannous ion stability. In particular, this invention is directed to compositions comprising stannous fluoride stabilized with a copolymer of maleic anhydride or acid and a lower alkyl vinyl ether. The compositions of the invention are particularly useful in the form of aqueous gel compositions, aqueous mouthwash compositions and aqueous toothpaste compositions.
Stannous fluoride has been used in oral care products since the early 1950's, and stannous fluoride has been reported to be an effective agent for treating various oral conditions and diseases including plaque, gingivitis, sensitivity, enamel decalcification, and periodontitis, among others. Product stability is an outstanding problem because stannous fluoride is
unstable in water and forms stannous oxy-fluoride and stannic compounds, both of which reduce or inhibit enamel fluoridation, that is, formation of stannous fluorophosphate and fluorapatite. This instability has required formulation of home treatment gels as anhydrous gels. Despite highly specialized precautionary measures during formulation of oral care products, significant variations are found in stannous ion concentrations of commercial dentifrice gel products among different manufacturers as well as among batches of the same brand of dentifrice because of stannous ion instability.
The original aqueous stannous fluoride
formulations have been reformulated as stannous ion-free compositions because of the instability of the stannous ion in water. Numerous stannous fluoride formulations with "stabilizing agents" have been proposed.
U.S. Patent 3,445,567 claims that aqueous stannous fluoride compositions can be stabilized with sorbitol or a mixture of sorbitol and glycerine.
However, this composition lacks the shelf-life stability required for commercial use.
U.S. Patents 3,711,604, 3,919,409, 3,935,306 and 3,980,767 disclose toothpaste and dentifrice
formulations including soluble fluoride compounds, including stannous fluoride. The toothpaste
formulations use a variety of standard ingredients and gelling agents including carboxyvinyl polymers sold under the tradename Carbopol- and insoluble abrasives such as silica and silicates. The stannous fluoride containing embodiments disclosed in these patents lack the stability found in the compositions of this
invention.
U.S. Patent 4,418,057 describes another approach. Stannous fluoride is formulated as a non-aqueous gel mixture including anhydrous glycerin and hydroxyethyl cellulose gelling agent. Total exclusion of moisture from the moisture is required to protect the stannous ion.
U.S. Patent 4,259,316, while noting the instability of stannous fluoride, proposes a
compositions containing phytic acid for inhibiting dental caries. Both dry dentrifices and aqueous gel and mouthwash formulations are described. If protected from moisture, the dentrifices would appear to retain the stannous ion in efficacious form. The stannous ion would rapidly convert to the ineffective oxy-stannous or stannate forms upon exposure to moisture in solution or in the oral cavity. Apparently, excess amounts of stannous fluoride are added in an effort to offset the loss of stannous ion. However, this requires the exposure of the user to excessive, unsafe levels of stannous ion.
EPO application 88308337.0 (Publication No. 0 311 260 A3) published April 12, 1989 describes
compositions containing stannous fluoride, and as a stannous reservoir to replace stannous ion lost through degradation, stannous gluconate. Mouthwashes are described. Listed as suitable abrasive polishing agents are silicas, including gels and precipitates, insoluble sodium polymetaphosphate; β-phase calcium pyrophosphate; alumina and resinous abrasive materials which do not contribute soluble calcium ions which form complexes with the fluoride ion. Calcium carbonate, calcium phosphate and regular calcium pyrophosphate are
excluded.
U.S. Patent 4,254,101 describes compositions containing a humectant, silica abrasive, a carboxyvinyl polymer, water and fluoride compounds as optional ingredients. The only carboxyvinyl polymers disclosed are colloidally water-soluble polymers of acrylic acid crosslinked with polyallyl sucrose or polyallyl
pentaerythritol . A variety of fluoride compounds including sodium fluoride are described as suitable optional ingredients. Stannous fluoride is included in the list of suitable fluoride compounds although no suggestion is made about its instability or that it could be used as an effective source of stannous ion. It is presented as equivalent to sodium fluoride as source of fluoride ion. Phosphorus-containing anticalculus agents are also listed as optional ingredients.
U.S. Patent 4,515,772 describes oral
compositions including dentrifices and aqueous
compositions including toothpastes and mouthwashes containing certain pyrophosphate salts as anticalculus formulations. In the prior art description, it lists a number of chelating agents proposed as anticalculus agents, including EDT (ethylenedia inetetraacetic acid) , nitrilotriacetic acid, polyphosphonates and fluoride, and carbonyl diphosphonates. The patent lists as suitable abrasives silica, calcium pyrophosphate, β-' phase pyrophosphate, alumina and other materials. A comprehensive list of fluoride ion sources are listed. Stannous fluoride is included in the list although no suggestion is made about its instability or that it could be used as an effective source of stannous ion. A variety of flavoring agents are disclosed. Included in a list of binders are gums and carboxyvinyl polymers.
U.S. Patent 3,956,479 describes use of
quaternary anticalculus compounds in dental creams, tables or powders containing polishing agents such as water-insoluble phosphates, binders, detergents, gelling agents, flavoring agents, and fluoride-containing compounds such as sodium fluoride, stannous fluoride and sodium monofluorophosphate. Mouthwashes are also described.
U.S. Patent 4,627,977 describes oral paste and gel dentifrice compositions containing a calculus-inhibiting amount of a linear molecularly dehydrated polyphosphate salt, and to inhibit hydrolysis of the polyphosphate salt in the saliva, a combination of a fluoride ion-providing source and a synthetic linear polymeric polycarboxylate. Included in the list of suitable polycarboxylates are copolymers of maleic anhydride or acid and ethylenically unsaturated monomers including alkyl vinyl ethers available as Grantrez AN 139, AN 119, and S97. An extensive list of fluoride ion sources are provided, including sodium and stannous fluorides and sodium monofluorophosphate. An extensive list of polishing agents are provided including water-insoluble phosphates, silicates and silicas, bentonites and inorganic polishing agents. Silicas are listed as preferred.
A. Gaffar et al in Compend.Contin.Educ. Dent, Suppl. No. 8, 242-250 (1987) and Thomas G. Schiff in Compend.Contin.Educ. Dent, Suppl. No. 8, 275-277 (1987) describe evaluations of pyrophosphate toothpaste
compositions containing sodium fluoride and a copolymer of methoxyethylene and maleic anhydride known as
"GANTREZ" as anticalculus dentifrices. The oral cavity contains enzymes which attack and degrade the
pyrophosphates, rapidly removing their anticalculus activity. The enzymes require soluble magnesium ion for activity. The copolymer is provided to complex
magnesium ions, making them unavailable to the enzymes and thus inhibiting their activity. Its purpose is to protect the pyrophosphates and maintain their
anticalculus activity.
The present invention provides an aqueous stannous fluoride composition for oral care, containing stannous fluoride and a lower alkyl vinyl ether and maleic anhydride or maleic acid copolymer in an amount sufficient to effectively stabilize the stannous
fluoride concentration, the composition being
substantially free from soluble pyrophosphate and aldehyde containing flavoring agents.
An embodiment of the invention resides in the stannous fluoride being in combination with a stannous ion chelating copolymer of an alkyl vinyl ether and maleic anhydride in an amount to effectively stabilize the stannous ion.
In an embodiment of the invention, the
composition is an aqueous non-abrasive home treatment gel composition. In this embodiment, the composition may contain from 10 to 30 weight percent water, from 0.05 to 5 and preferably from 0.5 to 5 weight percent of the chelating copolymer and from 0.05 to 5 and
preferably from 0.3 to 0.5 weight percent stannous fluoride. The weight ratio of stannous fluoride to copolymer is preferably between 0.01 to 1.0. The composition is substantially free from all abrasives and aldehyde group containing flavoring agents.
In another embodiment of the invention, the composition is an aqueous mouthwash. In this
embodiment, the composition may contain from 80 to 98 weight percent water, from 0.05 to 5 and preferably from 0.5 to 5 weight percent of the chelating copolymer and from 0.05 to 5 and preferably from 0.05 to 0.5 weight percent stannous fluoride. The weight ratio of stannous fluoride to copolymer is preferably between 0.01 to l.o. The composition is substantially free from soluble phosphates such as pyrophosphate and aldehyde group containing flavoring agents.
In still another embodiment of the invention, the composition is an aqueous toothpaste. In this embodiment, the composition may contain from 10 to 30 weight percent water, from 0.05 to 5 and preferably from 0.5 to 5 weight percent of the chelating copolymer and from 0.05 to 5 and preferably from 0.3 to 0.5 weight percent stannous fluoride and an insoluble abrasive agent. The weight ratio of stannous fluoride to
copolymer is preferably between 0.01 to 1.0. The composition is substantially free from silica, soluble phosphates such as soluble pyrophosphates (i.e.,
tetrasodium pyrophosphate, tetrapotassium phosphates, etc. ) , and aldehyde group containing compounds.
The method of this invention for formulating a stabilized aqueous composition for oral care comprises the step of dispersing the stannous fluoride in an aqueous solution of an alkyl vinyl ether and maleic anhydride copolymer, the amount of said copolymer being sufficient to stabilize the stannous fluoride
concentration during formulation.
This invention is directed to a stannous fluoride formulation which is "effectively stabilized".

that is, the stannous fluoride concentration in the product after three months at forty-five degrees
centigrade remains at an acceptable therapeutic level. Product stability after three months as forty-five degrees centigrade is comparable to product stability after three years at room temperature.
The essential ingredients of the compositions of this invention are stannous fluoride and the stannous ion chelating copolymer in an effectively stabilizing amount.
The term "effectively stabilized" and
"effectively stabilizing amount" is defined to mean that the stannous ion concentration, expressed as stannous fluoride, after three months storage under the
conditions described in Example 3 is equivalent to about 70 percent or more of the original concentration of stannous ion at the time of formulation.
The stannous ion stabilizing copolymer is a copolymer of maleic anhydride or acid and a
polymerizable ethylenically unsaturated monomer, preferably a lower alkyl vinyl ether such as
methoxyethylene, having a molecular weight of from about 30,000 to 1,000,000. The mole ratios of the maleic anhydride or acid to the ethylenically unsaturated monomer is preferably from 1:4 to 4:1. Suitable
polymers are available from GAF under the tradename "GANTREZ" and are disclosed in U.S. Patent 4,627,977. These copolymers have the unique ability to form
chelates with the stannous ion which are sufficiently strong to provide oxidation protection to the stannous ion while being sufficiently weak to not remove calcium from the tooth structure. EDTA and other strong
chelating agents are undesirable because they deplete calcium from the tooth enamel.
The term "lower alkyl" is defined to be a straight or branch-chained hydrocarbon group having from 1 to 6 carbons and preferably from 1 to 4 carbons and including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl groups.
The compositions of this invention may contain other conventional components such as anti-foaming agents, gelling agents, humectants, flavoring agents, anticariogenic agents, soluble fluoride compounds, surfactants, coloring or whitening agents, antibacterial agents, preservatives, chlorophyll compounds, and additional ammoniated materials which do not interfere with the stability of the stannous ion by reacting therewith or with the stannous ion chelating polymer. Suitable materials are described in U.S. Patents
4,418,057, 4,254,101 and 4,627,977.
The present compositions which are non-abrasive home treatment gels may also contain
conventional aqueous gelling agents.
The compositions which are toothpaste
compounds may contain one or more abrasive agents (other than silica or silicates) and can contain other
conventional ingredients to impart the desired
consistency, texture, resistance to hardening, flavor and the like.
Suitable abrasive agents include insoluble phosphates such as calcium pyrophosphate, β-phase pyrophosphate, and alkali metal etaphosphates. We have discovered that the stabilizing function of the stannous ion chelating polymer is not effective in the presence of silica and silicates.
Any conventional humectant can be used.
Suitable humectants include sorbitol, glycerin, or other polyhydric alcohols, the natural or synthetic gums conventionally used as hardening control agents and binders.
Suitable gelling agents for use in the non-abrasive gel composition of this invention include from 0.1 to 10 and preferably from 0.5 to 5 weight percent gelling agent. Gelling agents should be silica and silicate free compounds such as Irish moss, gum
tragacanth, starch, polyvinlypyrolidone, hydroxyethyl propylcellulose, hydroxybutyl methyl cellulose,
hydroxypropyl methyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, and the like.
The compositions can also contain flavoring agents which do not have an aldehyde group. We have discovered that aldehyde-containing flavoring agents such as cinnaldehyde, while not reacting directly with the stannous ion, interact with the stannous ion
chelating polymer, allowing stannous oxidation to occur.
The non-abrasive gels may have a pH within the range of from 2 to 11 and preferably from 2.5 to 5.0. The mouthwash compositions of the invention may have a pH within the range of from 2.5 to 1 and preferably from 3 to 7. The toothpaste compositions of the invention may have a pH within the range of from 2 to 11 and preferably from 3 to 7.
The formulations of this invention are
manufactured using procedures which protect the stannous ion from oxidation. The stannous fluoride is initially dissolved in an aqueous solution containing the stannous chelating copolymer. This solution may be mixed with other components by conventional procedures to form the compositions of the invention. In a preferred
procedure, a premix solution is prepared by dispersing from 0.5 to 26 weight percent stannous fluoride in water containing from 5.0 to 26 weight percent stannous ion stabilizing copolymer, the weight ratios of the stannous fluoride to copolymer being from 0.01 to 1.0 in the premix solution. This solution can be then mixed with other components by conventional procedures to form the formulations of this invention. Additional protection from oxidation can be provided during manufacture by carrying out the procedures in an inert atmosphere.
For additional protection against the
oxidation, the product should be stored in oxygen impermeable containers. Preferred containers are laminated tube such as "GLAMINATE" tubes (American Can Company) . Suitable tubes are laminates of a flexible plastic such as a polyolefin (i.e., low density
polyethylene, etc.) and an oxygen barrier layer such as an oxygen impermeable metal foil (i.e., aluminum foil). The laminates include other conventional layers such as adhesives (i.e., ethylene copolymers) , paper or other non-woven fibrous materials, and the like. For
toothpaste, the layer exposed to the stannous fluoride toothpaste should be essentially free from toxic substances and materials which would be released into the toothpaste during manufacture, storage or use and impair the stability of the toothpaste composition.
A preferred gel formulation can have the formulation shown in Table A-l.

TABLE A-l
Ingredients Weiσht Percent
Purified Water USP 10 - 20
Sorbitol Solution (70%) USP 50 - 80
Stannous chelating copolymer 0.5 - 5.0
Stannous Fluoride USP 0.3 - 0.5
Glycerin 96% USP 5 - 20
Sodium Carboxymethylcellulose 0.5 - 5.0
Flavor 0.3 - 1.0
Preservative 0.1 - 1.0

For additional protection against the
oxidation, the mouthwash product should be stored in containers which have low oxygen permeability and which preferably do not expose the contents to silica, silicates, oxygen, any other materials which would reduce the stability of the stannous ion, or introduce physiologically unacceptable substances into the contents. Preferred containers are bottles made of an oxygen impermeable organic polymer such as polyethylene phthalate.
A preferred mouthwash formulation can have the composition shown in Table A-2.
This invention is further described by the following specific but non-limiting examples.
Percentages are weight percents unless otherwise
indicated.

TABLE A-2
Ingredients Weight Percent

Purified Water USP 80 - 98
Stannous Chelating Copolymer 0.1 - 5.0

Stannous Fluoride 0.05 - 0.5

Tween-80a 0.1 - 2.0 Pluoronic F127b 0.1 2.0
Flavor 0.5 - 2
Glycerin 1 - 10
Sorbitol 1 - 10
Denatured Ethanol 1 - 10
Sodium Benzoate 0.01 - .2

PEG 40c 0.1 - 1.0

Tween-80a is polyoxyethylenesorbitan monooleate.
Pluronic F127*b is a condensate of ethylene oxide with propylene oxide condensates of propylene glycol. PEG 40c is sorbitan diisostearate available from Emery
Industries.
Preferred toothpaste formulations have the compositions shown in Table A-3.

TABLE A-3
Ingredients Weight Percent
Purified Water USP 10 - 30
Carbopola 0.05 - 1.0
Sodium CMCb 0.1 - 2.0
Glycerin 96% USP 5.0 - 30
Xanthan Gum (KELTROL) 0.1 - 1.5
Methylparaben NF 0.1 - 5.0
Propylparaben NF 0.01 - .10
Polyethylene Glycol 400c 0.1 - 4.0
Stannous Chelating Copolymer 0.5 - 5.0
Stannous Fluoride 0.3 - 0.5
Sorbitol 70% USP 10 - 35
Sodium Saccharin USP Crystal 0.05 - 0.5
Calcium Pyrophosphate 30 - 45
Zinc Citrate 0.1 - 2.0
Insoluble Sodium Metaphosphate 30 - 45
Sodium Lauryl Sulfate Needles 0.05 - 3.0
Sodium Hydroxide NF (10% sol'n) 0.5 - 5.0
Flavor 0.5 - 1.5

Carbopol is a carboxyvinyl polymer available from B.F. Goodrich Company.
Sodium CMC-*--* is carboxymethyl cellulose.
Polyethylene Glycol 400c is polyethylene glycol having a molecular weight of about 400, available from Union Carbide.
EXAMPLE 1
An aqueous solution containing methyl vinyl ether-maleic anhydride copolymer and percent stannous fluoride is mixed with the other ingredients listed below to form a non-abrasive home treatment gel product having the following composition:

Ingredients
Purified Water USP
Sorbitol Solution (70%) USP
Copolymera
Stannous Fluoride USP
Glycerin 96% USP
Sodium Carboxymethylcellulose
Blue FD&C #1 (1% solution)
Yellow FD&C #10 (1% solution)

Flavor - Felton Spearmint HF
Triple Distilled A-1895 0.50
Copolymer3 is the free acid of a methyl vinyl ether and maleic anhydride copolymer having a molecular
weight of about 30,000 to about 1,000,000.
EXAMPLE 2
The procedure of Example 1 was repeated to form another non-abrasive home treatment gel including the following ingredients:
Ingredients
Purified Water USP
Sorbitol Solution (70%) USP
Copolymera
Stannous Fluoride USP
Glycerin 96 USP
Sodium Carboxymethylcellulose
Grape Flavor #11540
Tartaric Acid

Copolymer3 is the free acid of a methyl vinyl ether and maleic anhydride copolymer having a molecular
weight of about 30,000 to about 1,000,000.
EXAMPLE 3
The non-abrasive home treatment gel of Example 1 was analyzed to determine the initial concentrations of stannous and fluoride ions achieved at formulation and to determine the initial ion concentrations after l, 2, and 3 months storage at 45*C. in sealed oxygen impermeable tubes.

The following results were obtained,
concentrations being reported as weight percents.
S as S F F__as_Snf2 EH
0.432 3.6
0.421 3.8
0.417 3.8

0.405 3.8"
EXAMPLE 4
The non-abrasive home treatment gel of Example 2 was analyzed to determine the initial concentrations of stannous and fluoride ions achieved at formulation and to determine the initial ion concentrations after 1, 2, and 3 months storage at 45'C. in sealed oxygen impermeable tubes.
The following results were obtained,
concentrations being reported as weight percents.
Time Sn as SnF2 F as Snf2 pH
Initial 0.461 0.433 3.5 one month 0.423 0.418 3.6 two months 0.423 0.413 3.6 three months 0.413 0.409 3.7
EXAMPLE 5
The following Example illustrates the
stabilizing effect of the alkyl vinyl ether/maleic anhydride copolymers on stannous fluoride in an aqueous environment such as encountered during formulation of stannous fluoride containing oral care products. Two sample solutions of 0.455 percent by weight stannous fluoride in deionized water were prepared. In the first sample solution, the stannous fluoride was added to the deionized water. In a second sample solution, the stannous fluoride was added to a solution of 1 percent by weight of methyl vinyl ether-maleic anhydride
copolymer in deionized water. In the first sample solution a precipitate of stannous oxides appeared almost immediately and the intensity of the precipitate increased with time. Analyses of the supernatant and sediment portions of centrifuged samples revealed that the concentration of stannous fluoride in the
supernatant and sediment portions were 0.371 percent by weight and 0.099 percent by weight respectively. The second sample solution was clear and there was no evidence of precipitation. These results were confirmed by comparative sample analyses using a turbidity meter. Analyses of the supernatant and sediment portions of centrifuged samples revealed that the concentration of stannous fluoride in the supernatant was 0.456 percent by weight and no stannous fluoride was detected in the sediment portion.
EXAMPLE 6
An aqueous solution containing methyl vinyl ether-maleic anhydride copolymer and percent stannous fluoride is prepared to form a stabilized stannous fluoride solution. This solution is mixed with the other ingredients listed in Table A-4. The amounts of the ingredients are selected- to yield a final mouthwash composition having the following composition:

TABLE A-4
Ingredients
Purified Water
Glycerin 96% USP
Stannous Fluoride
Copolymer3
Sodium phosphate, dibasic USP
FD2C Blue #1 (1% solution)
FD2C Yellow #10 (1% solution)
Ethyl Alcohol 95% USP
Methyl Paraben
Propyl Paraben
PEG 40b
Spice Mint flavor (Noville # 30712)

Copolymer3 is the free acid of a methyl vinyl ether and maleic anhydride copolymer having a molecular
weight of about 70,000, benzene-free, and sold
under the tradename GANTREZ S-97BF by GAF
Corporation. It is purchased in a liquid form
containing 10 wt.% copolymer.
PEG 40 is sorbitan diisostearate available from Emery
Industries.
EXAMPLE 7
An aqueous solution containing methyl vinyl ether-maleic anhydride copolymer and percent stannous fluoride is prepared to form a stabilized stannous fluoride solution. This solution is mixed with the other ingredients listed in Table B below. The amounts of the ingredients are selected to yield a final
toothpaste composition having the following composition:

TABLE B
Ingredients Weight Percent
Purified Water 29.00
Polyethylene Glycol 400 0.40
Glycerin 96% USP 5.00
Methylparaben NF 0.15
Propylparaben NF 0.05
Copolymer3 1.00
Stannous Fluoride 0.455
Sodium Hydroxide (10% solution) 4.50
Sorbitol 70% USP 16.275
Sodium Saccharin USP Crystal 0.20
Calcium Pyrophosphate 40.00
Zinc Citrate 0.40
Glycerine 96% USP 5.00
Natural Mint Flavor A-1159 FELTON 1.00
Sodium Lauryl Sulfate Needles 1.00

Copolymer3 is the free acid of a methyl vinyl ether and maleic anhydride copolymer having a molecular
weight of about 70,000, benzene-free, and sold under the tradename GANTREZ S-97BF by GAF
Corporation.
EXAMPLE 8
Dentifrice compositions prepared as described in Example 7 and having the formulations shown in Table C were analyzed to determine the initial concentrations of stannous and fluoride ions achieved at formulation and to determine the initial ion concentrations after 1, 2, and 3 months storage at 45*C. in sealed oxygen impermeable tubes.


Copolymer3 is the free acid of a methyl vinyl ether and maleic anhydride copolymer having a molecular
weight of about 70,000, benzene-free, and sold under the tradename GANTREZ S-97BF by GAF
Corporation.
The following results were obtained,
concentrations being reported as weight percents.
Formulation A


Formulation D
Xiffie Sn as SnFo F as SnF2 pH
Initial 0.447 0.429 5.7 one month 0.443 0.440 5.6 two months 0.455 0.420 5.8 three months 0.458 0.441 5.8
EXAMPLE 9
Dentifrice compositions prepared as described in Example 7 and having the formulations shown in Table D were analyzed to determine the initial concentrations of stannous and fluoride ions achieved at formulation and to determine the initial ion concentrations after 1, 2, and 3 months storage at 45°C. in sealed oxygen
impermeable tubes.


Sodium Saccharin USP
Crystal 0.20 0.20 0.20 0.20 0.2-Θ

Calcium


Copolymer3 is the free acid of a methyl vinyl ether and maieic anhydride copolymer having a molecular
weight of about 70,000, benzene-free, and sold
under the tradename GANTREZ S-97BF by GAF
Corporation.
Tween-80b is polyoxyethylenesorbitan monooleate.
Pluronic F127c is a condensate of ethylene oxide with propylene oxide condensates of propylene glycol.

The following results were obtained, concentrations being reported as weight percents.
Formulation E