Abstract:
An oral hygiene compositions possessing antiplaque and antigingivitis properties containing stannous fluoride stabilized with stannous gluconate in an orally acceptable carrier at pH of from about 3.0% about 4.79 and said composition is substantially free of a calcium ion source.

Description:
This is a continuation of application Ser. No. 097,010, filed on Sept. 14, 1987, now abandoned. 
    
    
     TECHNICAL FIELD 
     The present invention relates to oral compositions such as liquid dentifrices, toothpastes and mouthwashes, which provide antiplaque and antigingivitis benefits. 
     BACKGROUND OF THE INVENTION 
     Plaque is recognized as a precursor of such oral diseases as caries and gingivitis. The gums of the mouth of humans and lower animals may be harmed by deposits of dental plaque, a combination of minerals and bacteria found in the mouth. The bacteria associated with plaque can secrete enzymes and endotoxins which can irritate the gums and cause an inflammatory gingivitis. As the gums become increasingly irritated by this process they have a tendency to bleed, lose their toughness and resiliency, and separate from the teeth, leaving periodontal pockets in which debris, secretions, more bacteria and toxins further accumulate. It is also possible for food to accumulate in these pockets, thereby providing nourishment for increased growth of bacteria and production of endotoxins and destructive enzymes. This can result in destruction of bone and gum tissue. 
     With such problems being possible from plaque/gingivitis it is not surprising that extensive efforts have been expended in trying to find effective treatment compositions. Many of these efforts have used quaternary ammonium compounds or bis-biquanides such as chlorhexidine which is used in Peridex® sold by The Procter &amp; Gamble Company. 
     Another material which has been considered is stannous ion. Such a material is disclosed in Svatun B., &#34;Plaque Inhibiting Effect of Dentifrices Containing Stannous Fluoride&#34;, Acta Odontol. Scand., 36, 205-210 (1978); and Bay l., and Rolla, G., &#34;Plaque Inhibition and Improved Gingival Condition By Use of a Stannous Fluoride Toothpaste&#34;, Scand. J. Dent. Res., 88, 313-315 (1980). 
     In spite of the many disclosures in the antiplaque/antigingivitis area, the need for improved products still exists. The present invention is directed to the recognition that stannous fluoride when used in combination with stannous gluconate provides improved efficacy. The gluconate salt provides an optimal stannous reservoir since stannous ions are lost during manufacture and storage. 
     It is an object of the present invention therefore to provide compositions which deliver an improved antiplaque/antigingivitis benefit. 
     It is a further object of the present invention to provide improved products utilizing stannous fluoride and stannous gluconate. 
     It is still a further object of the present invention to provide an effective method for treating plaque/gingivitis with the above described compositions. 
     These and other objects will become clearer from the detailed description which follows. 
     All percentages and ratios used herein are by weight of the total composition unless otherwise specified. Additionally, all measurements are made at 25° C. in the composition or in an aqueous solution/dispersion unless otherwise specified. 
     SUMMARY OF THE INVENTION 
     The present invention embraces an oral composition comprising: 
     (a) a safe and effective amount of stannous fluoride; and 
     (b) a safe and effective amount of stannous gluconate; 
     (c) a pharmaceutically acceptable carrier 
     wherein said composition has a pH of from about 3.0 to about 5.0 and is substantially free of calcium ion sources. By &#34;substantially free&#34; is meant less than about 2%. 
     The present invention also encompasses a method for retarding the development of plaque/gingivitis using these compositions. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The compositions of the present invention comprise stannous fluoride and stannous gluconate and a pharmaceutically acceptable carrier. 
     By &#34;oral composition&#34; as used herein means a product which in the ordinary course of usage is not intentionally swallowed for purposes of systemic administration of particular therapeutic agents, but is rather retained in the oral cavity for a time sufficient to contact substantially all of the dental surfaces and/or oral tissues for purposes of oral activity. 
     By &#34;safe and effective amount&#34; as used herein means sufficient amount of material to provide the desired benefit while being safe to the hard and soft tissues of the oral cavity. 
     By the term &#34;comprising&#34;, as used herein, is meant that various additional components can be conjointly employed in the compositions of this invention as long as the listed materials perform their intended functions. 
     By the term &#34;carrier&#34;, as used herein, is meant a suitable vehicle which is pharmaceutically acceptable and can be used to apply the present compositions in the oral cavity. 
     Stannous Fluoride 
     Stannous fluoride is the first essential component of the present compositions. This material is a staple item of commerce and is present in the present composition at a level of from about 0.05% to about 1.1%, preferably from about 0.4% to about 0.95%. It should be recognized that separate soluble stannous and fluoride salts may be used to form stannous fluoride in-situ as well as adding the salt directly. Suitable salts include stannous chloride and sodium fluoride among many others. 
     Stannous Gluconate 
     Stannous gluconate is the second of the essential components of the present compositions. This material is a known stannous chelate and may be provided to the present compositions as the chelate or as separate soluble stannous and gluconate salts and the chelate formed in-situ such as with stannous fluoride. Such salts include stannous chloride and sodium gluconate. Stannous gluconate is present in the present compositions at a level of from about 0.1% to about 11%, preferably from about 2% to about 4%. 
     Pharmaceutically Acceptable Carrier 
     The carrier for the stannous components can be any vehicle suitable for use in the oral cavity. Such carriers include the usual components of mouthwashes, toothpastes, tooth powders, prophylaxis pastes, lozenges, gums and the like and are more fully described hereinafter. Dentifrices and mouthwashes are the preferred systems. 
     The abrasive polishing material contemplated for use in the present invention can be any material which does not excessively abrade dentin and do not provide calcium ions which may precipitate with, for example, the fluoride ions provided from stannous fluoride. These include, for example, silicas including gels and precipitates, insoluble sodium polymetaphosphate, β-phase calcium pyrophosphate, hydrated alumina, and resinous abrasive materials such as particulate condensation products of urea and formaldehyde, and others such as disclosed by Cooley et al. in U.S. Pat. No. 3,070,510, Dec. 25, 1962, incorporated herein by reference. Mixtures of abrasives may also be used. Abrasives such as calcium carbonate, calcium phosphate and regular calcium pyrophosphate are not preferred for use in the present compositions since they provide calcium ions which can complex F - . 
     Silica dental abrasives, of various types, can provide the unique benefits of exceptional dental cleaning and polishing performance without unduly abrading tooth enamel or dentin. Silica abrasive materials are also exceptionally compatible with sources of soluble fluoride. For these reasons they are preferred for use herein. 
     The silica abrasive polishing materials useful herein, as well as the other abrasives, generally have an average particle size ranging between about 0.1 and 30 microns, preferably 5 and 15 microns. The silica abrasive can be precipitated silica or silica gels such as the silica xerogels described in Pader et al., U.S. Pat. No. 3,538,230, issued Mar. 2, 1970 and DiGiulio, U.S. Pat. No. 3,862,307, Jun. 21, 1975, both incorporated herein by reference. Preferred are the silica xerogels marketed under the tradename &#34;Syloid&#34; by the W. R. Grace &amp; Company, Davison Chemical Division. Preferred precipitated silica materials include those marketed by the J. M. Huber Corporation under the tradename, &#34;Zeodent&#34;, particularly the silica carrying the designation &#34;Zeodent 119&#34;. These silica abrasives are described in U.S. Pat. No. 4,340,583, Jul. 29, 1982, incorporated herein by reference. 
     The abrasive in the compositions described herein is present at a level of from about 6% to about 70%, preferably from about 15% to about 25% when the dentifrice is a toothpaste. Higher levels, as high as 95%, may be used if the composition is a toothpowder. 
     Flavoring agents can also be added to dentifrice compositions. Suitable flavoring agents include oil of wintergreen, oil of peppermint, oil of spearmint, oil of sassafras, and oil of clove. Sweetening agents which can be used include aspartame, acesulfame, saccharin, dextrose, levulose and sodium cyclamate. Flavoring and sweetening agents are generally used in dentifrices at levels of from about 0.005% to about 2% by weight. 
     Dentifrice compositions can also contain emulsifying agents. Suitable emulsifying agents are those which are reasonably stable and foam throughout a wide pH range, including non-soap anionic, nonionic, cationic, zwitterionic and amphoteric organic synthetic detergents. Many of these suitable surfactants are disclosed by Gieske et al. in U.S. Pat. No. 4,051,234, Sept. 27, 1977, incorporated herein by reference. 
     It is common to have an additional water-soluble fluoride compound present in dentifrices and other oral compositions in an amount sufficient to give a fluoride ion concentration in the composition at 25° C. and/or when it is used of from about 0.0025% to about 5.0% by weight, preferably from about 0.005% to about 2.0% by weight, to provide additional anticaries effectiveness. Preferred fluorides are sodium fluoride, indium fluoride, and sodium monofluorophosphate. Norris et al., U.S. Pat. No. 2,946,725, issued Jul. 26, 1960 and Widder et al., U.S. Pat. No. 3,678,154, issued Jul. 18, 1972 disclose such salts as well as others. 
     Water is also present in the toothpastes of this invention. Water employed in the preparation of commercially suitable toothpastes should preferably be deionized and free of organic impurities. Water generally comprises from about 10% to 50%, preferably from about 20% to 40%, by weight of the toothpaste compositions herein. These amounts of water include the free water which is added plus that which is introduced with other materials such as with sorbitol. 
     In preparing toothpastes, it is necessary to add some thickening material to provide a desirable consistency. Preferred thickening agents are carboxyvinyl polymers, carrageenan, hydroxyethyl cellulose and water soluble salts of cellulose ethers such as sodium carboxymethyl cellulose and sodium carboxymethyl hydroxyethyl cellulose. Natural gums such as gum karaya, gum arabic, and gum tragacanth can also be used. Colloidal magnesium aluminum silicate or finely divided silica can be used as part of the thickening agent to further improve texture. Thickening agents in an amount from 0.5% to 5.0% by weight of the total composition can be used. 
     It is also desirable to include some humectant material in a toothpaste to keep it from hardening. Suitable humectants include glycerin, sorbitol, and other edible polyhydric alcohols at a total level of from about 15% to about 70%. 
     Also desirable for inclusion in the toothpastes of the present invention are other stannous salts such as stannous pyrophosphate and antimicrobials such as quaternary ammonium salts, bis-biquanide salts, nonionic antimicrobial salts and flavor oils. Such agents are disclosed in U.S. Pat. No. 2,946,725, Jul. 26, 1960, to Norris et al. and U.S. Pat. No. 4,051,234, Sept. 27, 1977 to Gieske et al., incorporated herein by reference. These agents, if present, are included at levels of from about 0.01% to about 1.5%. 
     Another preferred embodiment of the present invention is a mouthwash composition. Conventional mouthwash composition components can comprise the carrier for the antimicrobial of the present invention. Mouthwashes generally comprise from about 20:1 to about 2:1 of a water/ethyl alcohol solution and preferably other ingredients such as flavor, sweeteners, humectants and sudsing agents such as those mentioned above for dentifrices. The humectants, such as glycerin and sorbitol give a moist feel to the mouth. Generally, on a weight basis the mouthwashes of the invention comprise 5% to 60% (preferably 18% to 25%) ethyl alcohol, 0% to 20% (preferably 5% to 20%) of a humectant, 0% to 2% (preferably 0.01% to 0.15%) emulsifying agent, 0% to 0.5% (preferably 0.005% to 0.06%) sweetening agent such as saccharin, 0% to 0.3% (preferably 0.03% to 0.3%) flavoring agent, and the balance water. The amount of additional antimicrobial agent in mouthwashes is typically from about 0.01% to about 1.5% by weight. 
     Suitable lozenge and chewing gum components are disclosed in U.S. Pat. No. 4,083,955, Apr. 11, 1978 to Grabenstetter et al., incorporated herein by reference. 
     The pH of the present compositions and/or its pH in the mouth can be any pH which is safe for the mouth&#39;s hard and soft tissues and will provide optimal effect of the stannous gluconate. Such pH&#39;s are from about 3.0 to about 5.0, preferably from about 4.0 to about 5.0, most preferably about 4.5. 
     METHOD OF MANUFACTURE 
     The carrier compositions of the present invention can be made using methods which are common in the oral products area. A specific method of manufacture is set forth in the Examples. 
     COMPOSITION USE 
     The present invention in its method aspect involves applying to the oral cavity safe and effective amounts of the compositions described herein. These amounts (e.g. from about 0.3 to about 15 g), if it is a toothpaste or mouthwash, are kept in the mouth for from about 15 to about 60 seconds. 
     The following examples further describe and demonstrate preferred embodiments within the scope of the present invention. The examples are given solely for illustration and are not to be construed as limitations of this invention as many variations thereof are possible without department from the spirit and scope thereof. 
     EXAMPLES I-IV 
     The following dentifrice compositions are representative of the present invention. 
     
         ______________________________________      Weight %Component    I       II        III   IV______________________________________Water        12.500  12.500    12.500                                12.500Sorbitol     47.891  45.727    43.437                                41.328(70% Solution)Glycerin     10.198  10.198    10.198                                10.000PEG-12       --      --        --    --Titanium Dioxide        0.525   0.525     0.525 0.525Silica       20.000  20.000    20.000                                20.000Na Carboxymethyl        1.050   1.050     1.050 1.000CelluloseNa Carrageenan        --      --        --    0.350Magnesium Alumina        0.408   0.408     0.408 --SilicateHydroxyethyl --      --        --    --CelluloseNa Alkyl Sulfate        4.000   4.000     4.000 4.000(27.9% Solution)Na Gluconate 0.632   2.395     4.790 5.514Stannous Fluoride        0.454   0.454     0.454 0.454Stannous Chloride        --      1.141     1.141 2.198DihydrateStannous     1.040   --        --    --PyrophosphateNa Saccharin 0.200   0.200     0.200 0.230Flavor       0.851   0.851     0.851 1.000FD&amp;C Blue #1 0.051   0.051     0.051 0.051(1% Solution)Na Hydroxide 0.200   0.500     0.395 0.850(50% Solution)pH           4.5     4.5       4.5   4.5______________________________________ 
    
     EXAMPLES V-VIII 
     The following dentifrice compositions are representative of the present invention. 
     
         ______________________________________      Weight %Component    V       VI        VII   VIII______________________________________Water        12.500  16.500    12.500                                12.500Sorbitol     45.712  42.255    45.754                                45.908(70% Solution)Glycerin     10.000  10.000    10.000                                10.000PEG-12       --      3.000     --    --Titanium Dioxide        0.525   0.525     0.525 0.525Silica       20.000  20.000    20.000                                20.000Na Carboxymethyl        1.000   --        1.000 0.900CelluloseNa Carrageenan        0.350   0.450     0.350 0.350Magnesium Alumina        --      --        --    --SilicateHydroxyethyl --      0.400     --    --CelluloseNa Alkyl Sulfate        4.000   4.000     4.000 4.000(27.9% Solution)Na Gluconate 2.082   2.395     2.395 2.082Stannous Fluoride        0.454   0.454     0.454 0.908Stannous Chlorife        1.500   1.141     1.141 0.846DihydrateStannous     --      --        --    --PyrophosphateNa Saccharin 0.230   0.230     0.230 0.230Flavor       1.000   1.000     1.000 1.000FD&amp;C Blue #1 0.051   0.050     0.051 0.051(1% Solution)Na Hydroxide 0.600   0.600     0.600 0.700(50% Solution)pH           4.5     4.5       4.5   4.5______________________________________ 
    
     Procedure for Making Dentifrice 
     In preparing the dentifrice formulations, sorbitol and one half of the water are added to the mix tank and heating to 77° C. initiated. Saccharin, titanium dioxide, and silica may be added to the mixture during this heating period. Sufficient agitation is maintained to prevent the settling of the insoluble components. The glycerin is added to a separate vessel and is also heated to 77° C. When both the solutions have attained the required temperature, the carboxymethyl cellulose (CMC) and carrageenan are blended together and slowly added to the glycerin under vigorous agitation. When the CMC and carrageenan are sufficiently dispersed in the glycerin, this mixture is added to the sorbitol/water mixture. The resulting mixture is then blended for a period of time sufficient to allow complete hydration of the binders (about 15 minutes). When the paste is of acceptable texture, the flavor, sodium alkyl sulfate, and color are added. One half of the remaining water is then added to a separate mix tank and allowed to heat to 77° C. After the water attains the necessary temperature, the sodium gluconate is added under medium agitation and allowed to dissolve completely. The stannous chloride dihydrate is then added to the gluconate solution and also allowed to dissolve. This mixture is added to the main mix. The stannous fluoride is added to the remaining water (also at 77° C.) and the resulting solution is added to the main mix and allowed to blend thoroughly before final pH adjustment with sodium hydroxide. The completed paste is agitated for approximately 20 minutes before being milled and deaerated. 
     EXAMPLES IX-XII 
     The following are mouthrinse compositions representative of the present invention. 
     
         ______________________________________         Weight %Component       IX      X       XI    XII______________________________________Stannous Fluoride           0.100   0.100   0.100 0.100Stannous Chloride           0.375   0.375   0.550 0.285DihydrateSodium Gluconate           0.521   1.041   0.690 0.425Glycerin        8.000   10.000  --    --Sorbitol (70%   --      --      10.000                                 12.000aqueous solution)Ethanol         10.000  10.000  10.000                                 10.000Polysorbate 80  0.300   0.300   --    --Sorbitan Diisostearate           --      --      0.200 0.200Sodium Saccharin           0.050   0.050   0.050 0.050Flavor          0.150   0.150   0.150 0.150Sodium Hydroxide (50%)           0.020   0.020   0.020 0.020Benzoic Acid    0.050   0.050   0.050 0.050FD&amp;C Blue #1    0.020   0.020   0.020 0.020(1% solution)Water           80.414  77.894  78.170                                 76.700pH              4.5     4.5     4.5   4.5______________________________________ 
    
     EXAMPLE XIII 
     The following is a toothpowder representative of the present invention. 
     
         ______________________________________Component           Weight %______________________________________Stannous Fluoride   0.454Stannous Chloride Dihydrate               1.500Sodium Gluconate    2.082Silica              74.964Sodium Sulfate      20.000Sodium Lauryl Sulfate               1.000Flavor              1.000Sodium Saccharin    0.200______________________________________ 
    
     EXAMPLE XIV-XVI 
     The following are topical gels representative of the present invention. 
     
         ______________________________________Component       XIV        XV      XVI______________________________________Stannous Fluoride           0.454      0.454   0.454Stannous Chloride           1.141      1.500   2.200DihydrateSodium Gluconate           1.750      2.082   2.500Glycerin        92.855     70.000  50.000Sorbitol (70% Solution)           --         21.964  42.146Sodium Carboxymethyl           0.600      0.800   --CelluloseHydroxyethyl Cellulose           --         --      0.500Flavor          1.000      1.000   1.000Sodium Saccharin           0.200      0.200   0.200Sodium Alkyl Sulfate           2.000      2.000   1.000(27.9%)______________________________________ 
    
     EXAMPLE XVII-XX 
     The following are mouthrinse tablets representative of the present invention. 
     
         ______________________________________Component     XVII    XVIII     XIX   XX______________________________________Stannous Fluoride         0.100 g 0.100 g   0.100 g                                 0.100 gStannous Chloride         0.375 g 0.375 g   0.550 g                                 0.375 gDihydrateSodium Gluconate         0.500 g 1.000 g   0.700 g                                 0.700 gFlavor        0.150 g 0.150 g   0.150 g                                 0.150 gSodium Saccharin         0.050 g 0.050 g   0.050 g                                 0.200 gMannitol      1.000 g --        --    --Sodium Carboxymethyl         0.050 g --        --    --CelluloseGum Arabic    --      --        2.000 gCorn Starch   --      2.000 g   0.500 g                                 --Sodium Benzoate         0.030 g 0.030 g   0.030 g                                 0.025 gCitric Acid   --      --        --    0.200 gSodium Carbonate         --      --        --    0.100 gSodium Bicarbonate         --      --        --    0.200 gGlycine       --      --        --    0.050 g______________________________________