CA1136991A - Stannous fluoride and a phytic acid compound in oral composition - Google Patents
Stannous fluoride and a phytic acid compound in oral compositionInfo
- Publication number
- CA1136991A CA1136991A CA000357308A CA357308A CA1136991A CA 1136991 A CA1136991 A CA 1136991A CA 000357308 A CA000357308 A CA 000357308A CA 357308 A CA357308 A CA 357308A CA 1136991 A CA1136991 A CA 1136991A
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- Prior art keywords
- stannous
- phytate
- phytic acid
- composition
- compound
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
- A61K8/20—Halogens; Compounds thereof
- A61K8/21—Fluorides; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
- A61K8/24—Phosphorous; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/55—Phosphorus compounds
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- Life Sciences & Earth Sciences (AREA)
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- General Health & Medical Sciences (AREA)
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- Epidemiology (AREA)
- Chemical & Material Sciences (AREA)
- Inorganic Chemistry (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Cosmetics (AREA)
Abstract
Abstract of the Disclosure An oral, tooth-treating composition which comprises 0.04 to 10% by weight of stannous fluoride and not less than 0.1% by weight of a phytic acid compound, the molar ratio of the phytic acid compound to stannous fluoride being in the range of from 0.01 : 1 to 4 : 1 and the composition being aci-dic, is effective in inhibiting dental caries and shows a prolonged effect after application. When a difficultly soluble stannous compound such as stannous pyrophosphate is further blended preferably so that a portion of the difficultly soluble stannous compound is in a precipitate form, the composition is good in storage stability. The oral composition may be used as dentifrices, mouthwashes, oral bands, topical solutions, cavity sealers, prophylactic pastes, dental flosses and the like.
Description
~3~9~
This invention relates to oral, tooth-treating com-positions for use as dentifrices, topical solutions or pastes, disintegratable tablets, oral bands, cavity sealers, gels for ultrasonic treatment, gels for iontophoresis, prophylactic pastes, dental flosses, desensitizers of teeth, mouthwashes in the form of liquids, tablets, powders or gels, chewing gum and the like. More particularly, this invention relates to oral compositions containing stannous fluoride and a phytic acid compound such as phytic acid, its alkali metal or alkaline eaxth metal salts and phytin which are effective dental caries inhibitors capable of increasing the acid resistance of the tooth enamel upon application.
It is well known that stannous compounds can provide tooth enamel and dentin with an improved acid resistance due to the action of stannous ions. It is also known that when teeth are treated with oral compositions containing both stannous ions and fluorine ions, for example, oral compositions containing stannous fluoride SnF2 or stannous chloride fluo-ride SnClF, not only the acid resistance of the tooth sub-stance is improved by stannous ions, but fluorine is alsotaken up by the tooth substance, with outstanding results of caries inhibition, caries control, desensitization of hyper-sensitive ~Qntill (see J. C. Muhler et al, J.A.D.A., 51, 665 (1955)).
For the above reason, it was a common practice to apply stannous compound to teeth or to blend stannous com-pounds into oral compositions such as dentifrices.
However, their efficacy is not found to be very high.
. ~
~113~i9~1 Further, the increased acid resistance of the tooth enamel is kept for only a limited period of time after treatment because the effect relatively easily disappears as a result of the self-cleansing action of saliva, or as a result of brushing, masti~
cation and the like. Moreover, stannous compound solutions are not stable during storage and active dissolved stannous ions are likely to dcactivate.
Aqueous solutions of stannous fluori(le are most widely used, but readily show a reduced efficacy in caries prophylaxis because, as a result of hydrolysis or atmospheric oxidation, stannous ions tend to be converted into inert tin compounds ~in-soluble tin hydroxide, tin oxide, tin oxyfluoride, stannic tin compounds, etc.) which cannot produce the above-mentioned effect, and consequently the quantity of active dissolved stannous ions is considerably reduced. The lower the concentration of stannous fluoride is and the higher the storage temperature is, the more outstanding this tendency is.
In the case of stannous fluoride-containing dentifrices, the stannous fluoride tends to react with other ingredients to form insoluble tin hydroxide, tin phosphate and the like, as well as soluble, but highly stable, complexes, resulting in a reduced quantity of active free stannous ions. This tendency is out-standing at pH 6.0 or higher. Furthermore, hydrolysis or dissolved oxygen causes Sn2 in dentifrices to be oxidized into Sn4 . This causes a further reduction of the quantity of active dissolved stannous ions. Accordingly, the desired effect of blending stan-nous fluoride into dentirices is not fully attained.
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A variety of attempts have been made to prevent this reduction in the quantity of active dissolved stannous ions during storage. For instance, United States Pat. No.
This invention relates to oral, tooth-treating com-positions for use as dentifrices, topical solutions or pastes, disintegratable tablets, oral bands, cavity sealers, gels for ultrasonic treatment, gels for iontophoresis, prophylactic pastes, dental flosses, desensitizers of teeth, mouthwashes in the form of liquids, tablets, powders or gels, chewing gum and the like. More particularly, this invention relates to oral compositions containing stannous fluoride and a phytic acid compound such as phytic acid, its alkali metal or alkaline eaxth metal salts and phytin which are effective dental caries inhibitors capable of increasing the acid resistance of the tooth enamel upon application.
It is well known that stannous compounds can provide tooth enamel and dentin with an improved acid resistance due to the action of stannous ions. It is also known that when teeth are treated with oral compositions containing both stannous ions and fluorine ions, for example, oral compositions containing stannous fluoride SnF2 or stannous chloride fluo-ride SnClF, not only the acid resistance of the tooth sub-stance is improved by stannous ions, but fluorine is alsotaken up by the tooth substance, with outstanding results of caries inhibition, caries control, desensitization of hyper-sensitive ~Qntill (see J. C. Muhler et al, J.A.D.A., 51, 665 (1955)).
For the above reason, it was a common practice to apply stannous compound to teeth or to blend stannous com-pounds into oral compositions such as dentifrices.
However, their efficacy is not found to be very high.
. ~
~113~i9~1 Further, the increased acid resistance of the tooth enamel is kept for only a limited period of time after treatment because the effect relatively easily disappears as a result of the self-cleansing action of saliva, or as a result of brushing, masti~
cation and the like. Moreover, stannous compound solutions are not stable during storage and active dissolved stannous ions are likely to dcactivate.
Aqueous solutions of stannous fluori(le are most widely used, but readily show a reduced efficacy in caries prophylaxis because, as a result of hydrolysis or atmospheric oxidation, stannous ions tend to be converted into inert tin compounds ~in-soluble tin hydroxide, tin oxide, tin oxyfluoride, stannic tin compounds, etc.) which cannot produce the above-mentioned effect, and consequently the quantity of active dissolved stannous ions is considerably reduced. The lower the concentration of stannous fluoride is and the higher the storage temperature is, the more outstanding this tendency is.
In the case of stannous fluoride-containing dentifrices, the stannous fluoride tends to react with other ingredients to form insoluble tin hydroxide, tin phosphate and the like, as well as soluble, but highly stable, complexes, resulting in a reduced quantity of active free stannous ions. This tendency is out-standing at pH 6.0 or higher. Furthermore, hydrolysis or dissolved oxygen causes Sn2 in dentifrices to be oxidized into Sn4 . This causes a further reduction of the quantity of active dissolved stannous ions. Accordingly, the desired effect of blending stan-nous fluoride into dentirices is not fully attained.
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A variety of attempts have been made to prevent this reduction in the quantity of active dissolved stannous ions during storage. For instance, United States Pat. No.
2,946,725 and British Pat. Nos. 804,486 and 845,611 disclose a dentifrice containing a stannous compound, said stannous compound being difficultly soluble but capable of dissolving to supply at lcast 10 but not more than 1000 parts per million ot stannous ions when in association with water, and being present in said dcntifrice in an amount suffic;ent to provide said stannous compound in undissolved and undissociated form.
These difficultly soluble stannous compounds such as stannous pyrophosphate, stannous metaphosphate and stannous tartrate are blended as a "reservoir" into dentifrices together with soluble stannous compounds such as stannous fluoride. The difficultly soluble stannous compound serves to supply a small quantity of stannous ions for a prolonged period of time to maintain the concentration of stannous ions constant. Another approach is to stabilize stannous ions by adding a certain type of organic chelating or complexing agents. Examples of such agents for increasing the storage stability of stannous ions are carboxylic acids such as malic acid, citric acid and their salts as disclosed in United States Pat. No. 3,282,792; hydroxyethyl nitrilodiacetic acid and its salts as disclosed in Unitcd States Pat. No.
These difficultly soluble stannous compounds such as stannous pyrophosphate, stannous metaphosphate and stannous tartrate are blended as a "reservoir" into dentifrices together with soluble stannous compounds such as stannous fluoride. The difficultly soluble stannous compound serves to supply a small quantity of stannous ions for a prolonged period of time to maintain the concentration of stannous ions constant. Another approach is to stabilize stannous ions by adding a certain type of organic chelating or complexing agents. Examples of such agents for increasing the storage stability of stannous ions are carboxylic acids such as malic acid, citric acid and their salts as disclosed in United States Pat. No. 3,282,792; hydroxyethyl nitrilodiacetic acid and its salts as disclosed in Unitcd States Pat. No.
3,544,678; aldonic acid and its derivatives as disclosed in United States Pat. No. 3,105,798; and methane diphosphon;c acid, ethane-l-hydroxy-l,l-diphosphonic acid and their derivatives as disclosed in United States Pat. No. 3,549,677 and British Pat.
No. 1,160,640.
~. ~
~13~i9~1 Ilowever, when difficultly soluble stannous compounds are blended as a "reservoir", particularly into relatively vis-cous systems such as dentifrices, gels and prophylactic pastes, such compounds do always have sufficient capacity for supplying dissolved stannous ions, resulting in a considerable reduction of active dissolved stannous ions with time. Furthermore, the acid resistance of tooth enamel is not fully improved as shown in the experiments described below.
In the technique for stabilizing stannous ions by add-ing a chelating or complexing agent, care must be taken such that stannous ions are not stabilized to an excessive extent because the reactivity of the stannous ions with the tooth substance is otherwise inhibited and one does not obtain the desired effect.
In addition to stannous compounds and fluorine com-pounds, investigations have been made on a variety of compounds having caries inhibitory effect. For example, an attempt has heen made to use sodium and potassium phytates to reduce the solu-bility of hydroxyapatite in acid. However, the effect of these phytates has not been generally recognized. Other examples using phytic acid are British Pat. No. 1,384,375 which discloses an oral hygiene composition comprising a divalent metal salt of phytic acid such as calcium phytate mixed with a monofluoro-phosphate, and British Patent No. 1,408,922 which discloses an oral composition comprising two separa~e phases, one phase containing a water-soluble calcium compound and the other phase containing a water-soluble organic or inorganic phosphoric acid compound such as phytic acid and optionally, a water-soluble ~13~99~
fluorine compound. ~lowever~ the evaluation of these compositions has not been widely established.
There has now been found an oral composition which is an effective dental caries inhibitor capable of highly increasing the acid resistance of the tooth enamel. The invention of the present application consists in an oral, tooth-treating composi-tion comprising stannous fluoride and a phytic acid compound, the content of stannous fluoride being 0.04 to 10% by weight of thc total amount of tho composition, the content of the phytic acid compound being not less than 0.1% by weight of the total amount of the composition, the molar ratio of the phytic acid compound to stannous fluoride being in the range of from 0.01 : 1 to 4 : 1, the composition being acidic, all components of the composition be-ing orally acceptable and substantially non-toxic.
Preferably the phytic acid compound content is 0.3 - 20%
of the total amount of the composition. It is also preferred that the molar ratio range of the phytic acid compound to the stannous fluoride is from 0.02 : 1 to 3 : 1, and that the pH be from 2 to 6.
It is to be noted that percents are by weight hereinafter. By the term "non-toxic" is meant that the component should not be one which gives rise to toxic effects in the subject whose teeth are being treated, under the conditions of use.
The present composition renders the tooth enamel highly resistive to acid upon application and hence is very effective for preventing dental caries as compared with the cases where stannous fluoride or a phytic acid compound is applied alone, or where a phytic acid compound is applied in combination with sodium ~3~99~
fluorlde or sodium monofluorophosphate. Particularly, an oral composition in which the contents of stannous fluoride and the phytic acid compound are 0.1 to 4% (especially 0.3 to 4%) by weight and 0.5 to 10% by weight of the total composition, respec-tively, the molar ratio of the phytic acid compound to stannous fluoridc is in the range of from 0.025 : 1 to 2.5 : 1, and the pH
of the composition is 2 to 6, gives an unexpcctedly high acid resistallce to the tooth enamel. It is further preferred that the pl-l of such a composition be from 2 to 5.5.
Moreover, it h~s been found that one can prevent a sub-stantial reduction of the efficacy of the compositions with time and permit the stannous ion to exert its effect efficiently as well as improving the acid resistance of the tooth substancs, by incorporating a phytic acid compound such as sodium phytate into an oral composition containing both a relatively highly soluble stannous compound such as stannous fluoride and a relatively difficultly soluble stannous compound such as stannous pyrophos-phate.
Measurements of the amount of stannous ions in a con-ventional system containing a highly soluble stannous compound and a difficultly soluble stannous compound, before and after a long term storage in an oxidizing atmosphere, revealed that the quantities of dissolved stannous ions were both very low. This system was found to be not particularly effective in improving the acid resistance of tooth enamel treated therewith. An attempt to add a variety of chelating and complexing agents to such systems containing both highly soluble and difficultly soluble stannous i9~L
compounds failed to produce increased powers of solubilizing and stabilizing stannous ions or increased effect of improving the acid resistance of tooth enamel. A slight increase of the solubilizing power was observed only when citric acid, oxalic acid, EDTA or tannic acid was added. However, these acids were insufficient to improve the acid resistance of tooth enamel or to supply and maintai.n active dissolved stannous ions.
It has, howevcr, becn found tllat addition of a phytic acid compound to a system containing both highly soluble and difficultly soluble stannous compounds can minimize or elimi.nate reduction of the quantity of active dissolved stannous ions on ageing of the system, even for a long term in an oxidizing atmosphere, and that the acid resistance of tooth enamel treat-ed with such a phytic acid containing composition is remarkably improved over tooth enamel treated with simple aqueous stannous fluoride solutions. The effect due to the addition of a phytic acid compound is fully exerted over a wide pH range, especially over the pH range of 2 to 7, even in dentifrices. Particularly, when a phytic acid compound is added to a system containing a highly soluble stannous compound and a difficultly soluble stannous compound which is partially in undissociated form or as a precipitate, the phytic acid compound promotes the dissociation of the difficultly soluble stannous compound precipitate (reservoir), that is, ensures constant supply of stannous ions by permitting the difficultly soluble stannous compound to become gradually soluble at a proper level over a prolonged period of time, and increases the storage stability of the stannous ion 1~3~9g~
without adversely affecting the reactivity of the stannous ion, but rather enhancing the effectiveness of the stannous ion. In summary~ the phytic acid compound not only ensures constant supply of active dissolved stannous ions and improved maintenance of the activity of stannous ion, but also coacts with stannous ion syncrgistically to further improve the acid resistance of tooth enamel over that obtained when stannous ion is uscd alone. The use of thc phytic acid compound in com-bination with the partially precipitated, difficultly soluble stannous compound cnsures the storage stability and high reac-tivity with the tooth substance of stannous ion in the pH range of 3 to 6 usually employed for dentifrices, without causing any problem in the preparation of dentifrices, gels or prophylaxis pastes.
The phytic acid compounds which can be used in the present invention in combination with stannous fluoride include phytic acid itself and salts of phytic acid in which all or some , .
of the hydrogen atoms in the phosphate groups at the 1- to 6-positions of phytic acid are replaced by metal or ammonium sub-Stituents, for example, alkali metal salts of phytic acid such as s-odium phytate, potassium phytate and lithium phytate, ammonium phytate, divalent metal salts of phytic acid such as magnesium phytate, zinc phytate and calcium phytate, trivalent metal salts such as aluminum phytate and phytin, and double salts thereof.
In the present invention, myo-inositolpentaphosphoric acid es-pecially having a hydroxy group at the 2-position and metal and ammonium salts thereof in ad-ition to phytic acid (myo-inositol-.~, ~36~
hexaphosphoric acid) and metal and ammonium salts thereof fall under the category of the phytic acid compound of the present in-vention. Mixtures of any of these salts are also included. Parti-cularly preferred are those soluble in water. More preferably, the phytic acid compound is selected from the group consisting of phytic acid, sodium phytate, potassium phytate, lithium phytate, ammonium phytate and mixtures thereof.
T}le phytic acid compound should be prescnt in an amount of 0. l~o or more of thc total composition and the molar ratio of the phytic acid compound to stannous fluoride in the range of from 0.01 : 1 to 4 : 1. Within this range, the properties of imparting a high acid resistance to the tooth enamel and of stabilizing the stannous in the composition, are especially well attained. With-out any phytic acid compound, or when the phytic acid compound is added in amounts outside the above-prescribed content and molar ratio ranges, the resulting compositions are less effective. Con-tents of the phytic acid compound of more than 20% adversely affect the efficacy of the composition and are thus not generally desir-able.
The upper limit of stannous fluoride content is 10%.
Stannous fluoride may be added in amounts exceeding its saturation level of solubility. At certain proportions of stannous fluoride to phytic acid compound, particularly when the amount o~ the phytic acid compound is relatively smaller than that of the stannous fluoride, there often occurs precipitation, which however causes no problem. An improved acid resistance can be imparted to the tooth enamel either in the presence or in the absence of a precipitate 1~3~
insofar as the contents and the relative molar ratio of the phytic acid compound and stannous fluoride fall within the above-prescribed ranges.
The difficultly soluble stannous compounds include not only stannous pyrophosphate, but also stannous metaphosphate, stannous oxide, stannous oxal-ate, stannous phosphate, etc., and mixtures thereof. The amount of the diffi-cultly soluble stannous compound varies with the amounts of stannous fluoride and the phytic acid compound iand is generally ;n tlle range of 0.05 to 10% by weight of the composit;on as stannolls tin. The preferred blending range is 0.1 to 3% for stannous pyrophosphate, 0.1 to 2% for stannous metaphosphate, and 0.1 to 2% for stannous oxalate. As stated above, the difficultly soluble stannous compound is preferably blended in amounts such that a portion of the compound is a precipitate or in an undissociated form. The precipitate of this difficultly soluble stannous compound acts as a "reservoir" of stannous ions, enabling the quantity of active dissolved stannous ions to be maintained at a substantially constant level over a prolonged period of time. By including the phytic acid compound in the composition containing stannous fluoride (a highly soluble stannous compound) and the difficultly soluble stannous compound, elution of stannous ions from the difficultly soluble stannous compound is promoted, the storage stability of stannous ions is increased, and stannous ions are maintained active. Blending of the phytic acid compound permits stannous iOIl to exert its effect and as a result of the synergistic effect with stannous ion, contributes to improving the A
113~
acid resistance of tooth enamel. In this case, the amount of the phytic acid compound is preferably from 0.1 to 20%, more preferably 0.4 to 15%, especially 0.5 to 5% by weight of the composition, more particularly 0.5 to 3%.
In the compositions of the invention, including those in which a difficultly soluble stannous compound is present, stannous fluoride may be replaced by other highly soluble stan-nous compounds such as stannous chloridc, stannous chloride fluoride, stannous acetate, sodium stannous fluoride, potassium stannous fluoride, stannous hexaflurozirconate, stannous sulfate, stannous tartrate, stannous gluconate and the like. lVhen a difficultly soluble stannous compound is present, the amount of highly soluble stannous compound should generally be within the range of 0.03 to 5%, preferably O.Q8 to 3%, of the composition, as stannous tin still more preferred is 0.1 to 3%.
In the oral composition according to this invention, a further fluorine compound may be used. The coexistence of fluorine ion is very effective for caries prophylaxis. The fluorine com-pounds which can be used include sodium fluoride, potassium fluoride, lithium fluoride, ammonium fluoride, sodium monofluoro-phosphate, sodium hydrogen monofluorophosphate, potassium mono-fluorophosphate, ammonium monofluorophosphate, potassium hexa-fluorozirconate, potassium hexafluorotitanate, and mixtures thereof.
Also useful are cesium fluoride, nickel fluoride, zirconium fluoride, silver fluoride, hexylamine hydrofluoride, laurylamine hydrofluoride, cetylamine hydrofluoride, glycine hydrofluoride, lysine hydro-~3~g~1 fluoride, alanine hydrofluoride and the like. The fluorine compound is included in the oral composition so as to give a total concentration of fluorine of preferably 50 - 10,000 ppm, more preEerably 00 - 10,000 ppm. In preparing dentifrices, the total amount of fluorine is preferably not more than 1000 ppm.
Ihe oral composition according to this invention may further includc additional well-known ingredients clepend-ing on the type and form of a particular oral composition. Any desired known ingredients may be mixed with stannous fluoride and the phytic acid compound, and optionally the difficultly soluble stannous compound and the further fluorine compound, in water to produce an oral composition. The application forms of the oral composition according to this invention include denti-frices, topical solutions or pastes, disintegratable tablets, oral bands, cavity sealers, gels for ultrasonic treatment, gels ~13~g~1 for iontophoresis, prophylactic pastes, dental flosses, desen-sitizers of teeth, mouthwashes in the form of liquids, tablets, powders and gels, chewing gum and the like.
Liquid mouthwashes and topical solutions, for example, may be prepared by adding stannous fluoride and the phytic acid compound, and optionally the difficultly soluble stannous com-pound and the fluorine compound, to a suitable solvent such as distilled or deionized water and ethanol. Sweetening agents such as saccharine, etc., and flavoring agents such as peppermint oil, spearmint oil, anise oil, etc. may also be added in a small amount, if desired. Gel-type mouthwashes and topical pastes may be prepared by adding to the above-prepared solution a humectant such as glycerin, sorbitol, pro-pylene glycol, polyethylene glycol and the like in an amount of 5 - 70 wt%, a binder such as xanthan gum, guar gum, car-rageenan, hydroxyethyl cellulose, sodium carboxymethyl cel-lulose and the like in an amount of 0.3 - 10 wt%, and an anti-septic agent such as ethyl parahydroxybenzoate, and butyl parahydroxybenzoate and the like in a minor amount. Further, tablets and powders may be prepared in a usual manner using well-known tablet or powder-forming agents, for example, a vehicle such as lactose and mannitol, a disintegrator and a binder such as corn starch and carboxymethyl cellulose.
Oral bands may be prepared by dissolving or dis-persing in water stannous fluoride and the phytic acid com-pound together with necessary components, for example, a tacky high-molecular substance soluble in water or changing into a gel in water such as sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, sodium polyacrylate, sodium alginate, dextran, gelatin, carrageenen and the like in a usual blending amount of 20 - 99 wt%; a poly-hydric alcohol such as polyethylene glycol, propylene glycol, sorbitol, glycerin and the like in a usual blending amount of 1 - 50 wt%; and a surface-active agent such as an anion active agent and a nonion active agent (e.g. polyoxyethylene stearate or polyoxyethylene sorbitan monooleate) in a usual blending amount of 0 - 30 wt%. The resulting solution or dispersion is freeze dried to remove water and form a film which is cut into a desired shape.
Dentifrices may include an abrasive such as calcium pyrophosphate, insoluble alkali metal metaphosphates (e.g.
insoluble sodium metaphosphate), titanium dioxide, resins, aluminum hydroxide, silicic anhydride, aluminosilicate and the like in a usual blending amount of 20 - 60 wt~; a binder such as xanthan gum, guar gum, carrageenan, hydroxyethyl cellulose, propylene glycol alginate, sodium carboxymethyl cellulose and the like in a usual blending amount of 0.5 -5 wt%; a humectant such as glycerin, sorbitol and other polyhydric alcohols in a usual blending amount of 15 - 40 wt~;
a foaming agent such as water-soluble salts of the higher alkyl sulfates having 8 to 18 carbon atoms in the alkyl group (e.g. sodium lauryl sulfate), water-soluble salts of sulfonated monoglycerides of higher fatty acids having 10 to 18 carbon atoms in the fatty acid group (e.g. sodium coconut monoglyceride sulfonate), salts of amides of higher fatty ~ - 14 -113~g~
acid having 12 to 16 carbon atoms in the fatty acid group with lower aliphatic amino acids (e.g. sodium-N-methyl-N-palmitoyl tauride or sodium N-lauroyl sarcosinate), sucrose fatty acid ester having 12 to 18 carbon atoms in the fatty acid group ~e.g. sucrose monolaurate), condensates of sorbi-tan monostearate with approximately 60 moles of ethylene oxide, condensates of ethylene oxide with propylene oxide conden-sates of propylene glycol and the like in a usual blending amount of 0.5 - 3 wt%; a sweetening agent; a flavoring agent;
an antiseptic agent; an anticariogenic agent such as chloro-hexidine; and any other ingredients. In dentifrices, insoluble alkalimetal metaphosphates and silicic anhydride may prefer-ably be used as an abrasive, and nonionic water-soluble high molecular compounds such as hydroxyethyl cellulose, propylene glycol alginate, xanthan gum and guar gum may preferably be used as a binder.
The oral composition of this invention is acidic.
The pH of the composition may fall within the range of 2 - 7, more preferably 2 - 6, especially 2 - 5.5 in order to derive the best results from the composition. The pH of dentifrices containing the difficultly soluble stannous compound may be pref~rably 3 - 6. The acidity may be adjusted by phytic acid or its salt. Alternatively, the acidity may be adjusted to a desired level by adding an organic acid such as citric acid, tartaric acid, lactic acid, malonic acid, malic acid, L-ascorbic acid, acetic acid, and succinic acid or alkali metal salts thereof, an inorganic acid such as hydrochloric acid and phosphoric acid, or an alkali such as sodium hydroxide.
113~g~1 The oral composition of this invention may be used in an ordinary manner depending upon its type and form. For example, mouthwashes in the form of liquids may be applied with or without dilution with water while those in the form of tablets, powders or gels may be applied after they are dis-solved or dispersed in water. Oral bands may be attached to teeth. Then the high-molecular substance which is the main component of the band is gelated and becomes tacky upon con-tact with sali~a. With the tacky band firmly adhered to the teeth, the active ingredients (stannous fluoride and the phytic acid compound) in the band act on the teeth. A topical solu-tion or gel may be directly applied to a tooth surface.
As described above, the oral composition of this invention is applied to teeth directly or after it is prepared into a form suitable for oral application by diluting with, dissolving in or dispersing in water. Upon application to a tooth surface, stannous fluoride and the phytic acid compound contained at the above-prescribed contents and relative molar ratio in the composition exhibit a synergistic effect on the tooth enamel, thereby substantially enhancing the acid resis-tance of the tooth enamel. The oral composition of this in-vention can be applied at room temperature or approximately 30C without a reduction in the acid resistance improvement.
Further, the efficacy after application is retained for an extended period of time. It was found that the acid resistance of the tooth enamel treated with the present composition re-mains high even after the tooth is washed with running tap water for 24 hours. It was also found that stannous ions are 9~1 stable in the composition for a long period of storage. This means that the present composition is an effective dental caries inhibitor which can be stored for an extended period of time and shows a prolonged activity after ap~lication.
The following examples are illustrative of the present inven-tion, but it is to be unclerstood that the invention is not limited thereto. ~11 percentages ill the examplos are percent.lges by weight Ull-less otherwise spoci~:ied.
Example 1 Stannous fluoride and pentasodium phytate of the formula:
~ 0 OH ) ~ O \ O~l ) 5 were added to water in given amounts. Hydrochloric acid or aqueous sodium hydroxide solution was added to adjust the pH, yielding a number of test solutions varying in stannous fluoride content, pentasodium phytate content, pentasodium phytate/stannous fluoride molar ratio, and pH.
An enamel block made of a bovine enamel (incisor) was immers-ed for 3 minutes in each of the test solutions at 30C. Each block was brushed twenty times, that is, ten times in each of the longitudinal and transverse directions with a toothbrush. For the purpose of deter-mining the retention of the activity, the treated enamels were allowed to stand in tap water a'c 37C for 20 hours. Thereafter, the thus treated enamels were subjected to decalcification in an acidic solution ~L~L369~
(buffered solution of 0.1 M acetate at pH 4.5) at 20C for 2 hours. After decalcification, the surface hardness (~ickers hardness number : VHN) was measured on the enamel surface of each enamel block to evaluate the effect of the test solution on the acid resistance of the enamel.
After the test solutions prepared as above were stored for 1 month at 40C, the above test procedure was repeated to determine the acid resistance for evaluation of the stability of the solutions under storage.
For comparison, enamel blocks were treated with aqueous solutions containing varying amounts of stannous fluoride at pH 3.0 and aqueous solutions containing varying amounts of pentasodium phytate at pH 3.0, respectively. After the blocks were subjected to decalcification, the Vickers hardness was measured in the same manner as above.
The results are shown in Tables 1 and 2. Each hardness value in the Tables is an average of 15 measurements.
It should be noted that the acid-resistance evalua-tion for the tooth enamel subjected to decalcification under the above-described conditions followed by hardness measure-ment is a very severe one because the samples treated with 8% SnF2 in water were decalcified to a considerable extent in the above-mentioned decalcifying solution. Accordingly, hardnesses above 150, particularly above 200 indicate a consider-able improvement in acid resistance. Oral compositions result-ing in such high hardnesses are very effective in inhibiting dental caries.
Symbols in the "Stability" column in the Tables have - lS -1~3~g~1 the following meanings. The stability of the test solutions under storage was evaluated by comparing the effect on the increment of the acid-resistance by a test solution stored at 40C for 1 month with that by an initial test solution.
O : Retention of efficacy of a stored test solution is 80% or more.
: Retention of efficacy is 65~ or more.
X : Retention of efficacy is less than 65~o.
Other abbreviations in the Tablcs, are as follows:
P*-5Na is pentasodium phytatc, VHN is Vickers Hardness number, "u.m." is "unmeasurable" which means that hardness measurement is impossible because of destruction of a tooth surface by decalcification (Vickers hardness is less than 50) under the above-described severe test conditions.
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Table 2 . P -5Na/SnF2Content Content of SnF2 of p -5Na pH VHN
(molar ratio)(~) (%) ~ ___ L
¦ Z.D 0.4 4.0 4 226 , ~13~;~g~
Exam~le 2 Test solutions were prepared by adding 1.2% by weight of stannous fluoride and a given amount of pentapotassium phytate, pentamagnesium phytate or pentacalcium phytate to water. Hydrochloric acid or aqueous sodium hydroxide solution was added to the test solutions to adjust the pH.
The test procedure described in Example 1 was re-peated to evaluate the acid resistance of enamel blocks treated with the test solutions.
The results are shown in Table 3.
Table 3 Vickers hardness at Phytate (-I soluti on pS.0 phytate 5 305 230 183 phytate 1 240 160 120 ll 5 250 164 132 Pentacalcium 1 166 121 70 As shown in Tables 1 - 3, a specific combination of stannous fluoride with the phytic acid compound, where the contents of stannous fluoride and the phytic acid compound are 0.04 to 10~ and not less than 0.1% by weight, respectively, - 2~ -1~3~i~91 and the molar ratio of the phytic acid compound to stannousfluoride is in the range of from 0.01 : l to 4 : 1, provides a significant improvement in the acid resistance of tooth enamel as compared with the use of a single component, stan-nous fluoride or the phytic acid compound, or a combination of sodium fluoride and the phytic acid compound or other prior art oral compositions. More particularly, when the content of the phytic acid compound is 0.3 to 20~, specifically 0.5 to 10% by weight and the molar ratio of the phytic acid com-pound to stannous fluoride is in the range of from 0.02 : lto 3 : l, specifically from 0.025 : l to 2.5 : l, the acid resistance of tooth enamel is remarkably improved. Even after the treated enamel is washed with running tap water for 20 hours, the acid resistance provided by the composition of this invention is kept high. This means that the effect is retain-ed for an extended period of time.
Example 3 A number of test solutions having the following composition were prepared using the chelating and complexing agents listed in Table 4. The pH of these solutions was adjusted to S.0 by adding sodium hydroxide or hydrochloric acid.
Stannous fluoride 0.4 %
Stannous pyrophosphate 1.0 ~
Chelating or complexing agent as shown in Table 4 Water balance 100. 0 %
For each test solution, both immediately after pre--~3~3~i~9~
paration and after the solution had been stored for 10 days at 20C in an oxygen desiccator at l atmospheric pressure, the quantity of dissolved stan-nous ions was measured by the following method and the Vickers hardness of an enamel block treated with the test solution was measured as described in Example 1, except that the rinsing conditions of the enamel block in tap water are at 20~C for 10 - 20 minutes. The results are shown in Table 4.
Measurement of the quantity of stannous ions Quantitave analysis of stannous ions was conducted by the iodometric titration on a supernatant liquid obtained by removing a precipitate from each solution in a centrifugal separator (lO,000 - 12,000 r.p.m.). The quantity of stannous ions dissolved in the supernatant liquid was determined using a O.OSN iodine solution.
~, -26-. ~~
~13~
Table 4 Chelating and Amount* Initial ~ After 10 days complexing I storage agents (%) Sn2+(%) ~lN Sn2+(%) ¦ VHN
~phytate 1.0 0.49 228 0.33 160 tion Sodium citra~ 0.38 0.45 150 0.21 1 103 Ctoivmepara-Malonic acid 0.13 0.25 120 0.15 96 ..
acid 0.25 _ 130 _ 110 -Oxalic acid 0.16 0.39 1430.23 96 ..
Lactic acid 0.12 0.28 1200.18 80 -Tartaric acid 0.20 0.32 148 0.13 86 -Benzoic acid 0.16 0.31 133 0.18 93 ..
L-glutamic 0.19 0.24 1220.12 84 ..
Malic acid 0.17 0.27 1080.14 92 ..
Maleic acid 0.15 0.22 1200.12 81 .-Fumaric acid 0.15 0.21 110 0.12 85 ..
Adipic acid 0.19 0.25 1300.17 96 ..
Glutaric acid 0.17 0.23 103 0.14 93 ..
L-aspartic acid 0.17 0.23 1050.13 89 ..
Succinicacid 0.08 0.22 120 0.15 99 ..
Cinnamic ac.id 0.19 0.21 118 0.10 75 ..
EDTA 0.48 0.49 1350.30 81 ..
Tannic acid 0.44 0.33 1250.24 96 ..
None _ 0.20 1030.14 93 ..
* Each of the chelating and complexing agents was blended in an equal molar amount to 1.0% pentasodium phytate.
~3~
The results in Table 4 show that the use of a phytate not only contributes to the solubilization of tin in the ini-tial solution, but also permits the quantity of stannous ions to be maintained at a sufficiently high level after a long term storage in an oxidizing atmosphere, improving the storage stability of the solution. The phytate is highly effective to retain the activity of stannous ion and to improve the acid resistance of the enamel.
The procedure of Example 3 was repeated except that pentasodium phytate was replaced by phytic acid and pentapotas-sium phytate. Similar results were obtained.
Example 4 Stannous fluoride 0.4 %
Stannous pyrophosphate as shown in Tables 5 - 7 Pentasodium phytate "
Water balance 100.O %
A number of test solutions having the above composition were prepared (the pH of the solutions was adjusted with sodium hydroxide or hydrochloric acid to 4.0 - 6.0). As described in Example 3, for each test solution, the quantity of dis-solved stannous ions and the degree of improvement of enamel acid resistance (represented by the Vickers hardness number after decalcification of an enamel block treated with each test solution) were measured both immediately after prepara-tion and after the solution had been stored for 7 days at 20C in an oxygen desiccator at 1 atmospheric pressure. The results are shown in Tables 5, 6 and 7.
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Table 7 Vickers hardness after enamel decalcification ! Pentadosium phytate (%) ¦ o 1.0 ~t~AU~ ~,r~ t~ O 1.0 O 1.0 2.0
No. 1,160,640.
~. ~
~13~i9~1 Ilowever, when difficultly soluble stannous compounds are blended as a "reservoir", particularly into relatively vis-cous systems such as dentifrices, gels and prophylactic pastes, such compounds do always have sufficient capacity for supplying dissolved stannous ions, resulting in a considerable reduction of active dissolved stannous ions with time. Furthermore, the acid resistance of tooth enamel is not fully improved as shown in the experiments described below.
In the technique for stabilizing stannous ions by add-ing a chelating or complexing agent, care must be taken such that stannous ions are not stabilized to an excessive extent because the reactivity of the stannous ions with the tooth substance is otherwise inhibited and one does not obtain the desired effect.
In addition to stannous compounds and fluorine com-pounds, investigations have been made on a variety of compounds having caries inhibitory effect. For example, an attempt has heen made to use sodium and potassium phytates to reduce the solu-bility of hydroxyapatite in acid. However, the effect of these phytates has not been generally recognized. Other examples using phytic acid are British Pat. No. 1,384,375 which discloses an oral hygiene composition comprising a divalent metal salt of phytic acid such as calcium phytate mixed with a monofluoro-phosphate, and British Patent No. 1,408,922 which discloses an oral composition comprising two separa~e phases, one phase containing a water-soluble calcium compound and the other phase containing a water-soluble organic or inorganic phosphoric acid compound such as phytic acid and optionally, a water-soluble ~13~99~
fluorine compound. ~lowever~ the evaluation of these compositions has not been widely established.
There has now been found an oral composition which is an effective dental caries inhibitor capable of highly increasing the acid resistance of the tooth enamel. The invention of the present application consists in an oral, tooth-treating composi-tion comprising stannous fluoride and a phytic acid compound, the content of stannous fluoride being 0.04 to 10% by weight of thc total amount of tho composition, the content of the phytic acid compound being not less than 0.1% by weight of the total amount of the composition, the molar ratio of the phytic acid compound to stannous fluoride being in the range of from 0.01 : 1 to 4 : 1, the composition being acidic, all components of the composition be-ing orally acceptable and substantially non-toxic.
Preferably the phytic acid compound content is 0.3 - 20%
of the total amount of the composition. It is also preferred that the molar ratio range of the phytic acid compound to the stannous fluoride is from 0.02 : 1 to 3 : 1, and that the pH be from 2 to 6.
It is to be noted that percents are by weight hereinafter. By the term "non-toxic" is meant that the component should not be one which gives rise to toxic effects in the subject whose teeth are being treated, under the conditions of use.
The present composition renders the tooth enamel highly resistive to acid upon application and hence is very effective for preventing dental caries as compared with the cases where stannous fluoride or a phytic acid compound is applied alone, or where a phytic acid compound is applied in combination with sodium ~3~99~
fluorlde or sodium monofluorophosphate. Particularly, an oral composition in which the contents of stannous fluoride and the phytic acid compound are 0.1 to 4% (especially 0.3 to 4%) by weight and 0.5 to 10% by weight of the total composition, respec-tively, the molar ratio of the phytic acid compound to stannous fluoridc is in the range of from 0.025 : 1 to 2.5 : 1, and the pH
of the composition is 2 to 6, gives an unexpcctedly high acid resistallce to the tooth enamel. It is further preferred that the pl-l of such a composition be from 2 to 5.5.
Moreover, it h~s been found that one can prevent a sub-stantial reduction of the efficacy of the compositions with time and permit the stannous ion to exert its effect efficiently as well as improving the acid resistance of the tooth substancs, by incorporating a phytic acid compound such as sodium phytate into an oral composition containing both a relatively highly soluble stannous compound such as stannous fluoride and a relatively difficultly soluble stannous compound such as stannous pyrophos-phate.
Measurements of the amount of stannous ions in a con-ventional system containing a highly soluble stannous compound and a difficultly soluble stannous compound, before and after a long term storage in an oxidizing atmosphere, revealed that the quantities of dissolved stannous ions were both very low. This system was found to be not particularly effective in improving the acid resistance of tooth enamel treated therewith. An attempt to add a variety of chelating and complexing agents to such systems containing both highly soluble and difficultly soluble stannous i9~L
compounds failed to produce increased powers of solubilizing and stabilizing stannous ions or increased effect of improving the acid resistance of tooth enamel. A slight increase of the solubilizing power was observed only when citric acid, oxalic acid, EDTA or tannic acid was added. However, these acids were insufficient to improve the acid resistance of tooth enamel or to supply and maintai.n active dissolved stannous ions.
It has, howevcr, becn found tllat addition of a phytic acid compound to a system containing both highly soluble and difficultly soluble stannous compounds can minimize or elimi.nate reduction of the quantity of active dissolved stannous ions on ageing of the system, even for a long term in an oxidizing atmosphere, and that the acid resistance of tooth enamel treat-ed with such a phytic acid containing composition is remarkably improved over tooth enamel treated with simple aqueous stannous fluoride solutions. The effect due to the addition of a phytic acid compound is fully exerted over a wide pH range, especially over the pH range of 2 to 7, even in dentifrices. Particularly, when a phytic acid compound is added to a system containing a highly soluble stannous compound and a difficultly soluble stannous compound which is partially in undissociated form or as a precipitate, the phytic acid compound promotes the dissociation of the difficultly soluble stannous compound precipitate (reservoir), that is, ensures constant supply of stannous ions by permitting the difficultly soluble stannous compound to become gradually soluble at a proper level over a prolonged period of time, and increases the storage stability of the stannous ion 1~3~9g~
without adversely affecting the reactivity of the stannous ion, but rather enhancing the effectiveness of the stannous ion. In summary~ the phytic acid compound not only ensures constant supply of active dissolved stannous ions and improved maintenance of the activity of stannous ion, but also coacts with stannous ion syncrgistically to further improve the acid resistance of tooth enamel over that obtained when stannous ion is uscd alone. The use of thc phytic acid compound in com-bination with the partially precipitated, difficultly soluble stannous compound cnsures the storage stability and high reac-tivity with the tooth substance of stannous ion in the pH range of 3 to 6 usually employed for dentifrices, without causing any problem in the preparation of dentifrices, gels or prophylaxis pastes.
The phytic acid compounds which can be used in the present invention in combination with stannous fluoride include phytic acid itself and salts of phytic acid in which all or some , .
of the hydrogen atoms in the phosphate groups at the 1- to 6-positions of phytic acid are replaced by metal or ammonium sub-Stituents, for example, alkali metal salts of phytic acid such as s-odium phytate, potassium phytate and lithium phytate, ammonium phytate, divalent metal salts of phytic acid such as magnesium phytate, zinc phytate and calcium phytate, trivalent metal salts such as aluminum phytate and phytin, and double salts thereof.
In the present invention, myo-inositolpentaphosphoric acid es-pecially having a hydroxy group at the 2-position and metal and ammonium salts thereof in ad-ition to phytic acid (myo-inositol-.~, ~36~
hexaphosphoric acid) and metal and ammonium salts thereof fall under the category of the phytic acid compound of the present in-vention. Mixtures of any of these salts are also included. Parti-cularly preferred are those soluble in water. More preferably, the phytic acid compound is selected from the group consisting of phytic acid, sodium phytate, potassium phytate, lithium phytate, ammonium phytate and mixtures thereof.
T}le phytic acid compound should be prescnt in an amount of 0. l~o or more of thc total composition and the molar ratio of the phytic acid compound to stannous fluoride in the range of from 0.01 : 1 to 4 : 1. Within this range, the properties of imparting a high acid resistance to the tooth enamel and of stabilizing the stannous in the composition, are especially well attained. With-out any phytic acid compound, or when the phytic acid compound is added in amounts outside the above-prescribed content and molar ratio ranges, the resulting compositions are less effective. Con-tents of the phytic acid compound of more than 20% adversely affect the efficacy of the composition and are thus not generally desir-able.
The upper limit of stannous fluoride content is 10%.
Stannous fluoride may be added in amounts exceeding its saturation level of solubility. At certain proportions of stannous fluoride to phytic acid compound, particularly when the amount o~ the phytic acid compound is relatively smaller than that of the stannous fluoride, there often occurs precipitation, which however causes no problem. An improved acid resistance can be imparted to the tooth enamel either in the presence or in the absence of a precipitate 1~3~
insofar as the contents and the relative molar ratio of the phytic acid compound and stannous fluoride fall within the above-prescribed ranges.
The difficultly soluble stannous compounds include not only stannous pyrophosphate, but also stannous metaphosphate, stannous oxide, stannous oxal-ate, stannous phosphate, etc., and mixtures thereof. The amount of the diffi-cultly soluble stannous compound varies with the amounts of stannous fluoride and the phytic acid compound iand is generally ;n tlle range of 0.05 to 10% by weight of the composit;on as stannolls tin. The preferred blending range is 0.1 to 3% for stannous pyrophosphate, 0.1 to 2% for stannous metaphosphate, and 0.1 to 2% for stannous oxalate. As stated above, the difficultly soluble stannous compound is preferably blended in amounts such that a portion of the compound is a precipitate or in an undissociated form. The precipitate of this difficultly soluble stannous compound acts as a "reservoir" of stannous ions, enabling the quantity of active dissolved stannous ions to be maintained at a substantially constant level over a prolonged period of time. By including the phytic acid compound in the composition containing stannous fluoride (a highly soluble stannous compound) and the difficultly soluble stannous compound, elution of stannous ions from the difficultly soluble stannous compound is promoted, the storage stability of stannous ions is increased, and stannous ions are maintained active. Blending of the phytic acid compound permits stannous iOIl to exert its effect and as a result of the synergistic effect with stannous ion, contributes to improving the A
113~
acid resistance of tooth enamel. In this case, the amount of the phytic acid compound is preferably from 0.1 to 20%, more preferably 0.4 to 15%, especially 0.5 to 5% by weight of the composition, more particularly 0.5 to 3%.
In the compositions of the invention, including those in which a difficultly soluble stannous compound is present, stannous fluoride may be replaced by other highly soluble stan-nous compounds such as stannous chloridc, stannous chloride fluoride, stannous acetate, sodium stannous fluoride, potassium stannous fluoride, stannous hexaflurozirconate, stannous sulfate, stannous tartrate, stannous gluconate and the like. lVhen a difficultly soluble stannous compound is present, the amount of highly soluble stannous compound should generally be within the range of 0.03 to 5%, preferably O.Q8 to 3%, of the composition, as stannous tin still more preferred is 0.1 to 3%.
In the oral composition according to this invention, a further fluorine compound may be used. The coexistence of fluorine ion is very effective for caries prophylaxis. The fluorine com-pounds which can be used include sodium fluoride, potassium fluoride, lithium fluoride, ammonium fluoride, sodium monofluoro-phosphate, sodium hydrogen monofluorophosphate, potassium mono-fluorophosphate, ammonium monofluorophosphate, potassium hexa-fluorozirconate, potassium hexafluorotitanate, and mixtures thereof.
Also useful are cesium fluoride, nickel fluoride, zirconium fluoride, silver fluoride, hexylamine hydrofluoride, laurylamine hydrofluoride, cetylamine hydrofluoride, glycine hydrofluoride, lysine hydro-~3~g~1 fluoride, alanine hydrofluoride and the like. The fluorine compound is included in the oral composition so as to give a total concentration of fluorine of preferably 50 - 10,000 ppm, more preEerably 00 - 10,000 ppm. In preparing dentifrices, the total amount of fluorine is preferably not more than 1000 ppm.
Ihe oral composition according to this invention may further includc additional well-known ingredients clepend-ing on the type and form of a particular oral composition. Any desired known ingredients may be mixed with stannous fluoride and the phytic acid compound, and optionally the difficultly soluble stannous compound and the further fluorine compound, in water to produce an oral composition. The application forms of the oral composition according to this invention include denti-frices, topical solutions or pastes, disintegratable tablets, oral bands, cavity sealers, gels for ultrasonic treatment, gels ~13~g~1 for iontophoresis, prophylactic pastes, dental flosses, desen-sitizers of teeth, mouthwashes in the form of liquids, tablets, powders and gels, chewing gum and the like.
Liquid mouthwashes and topical solutions, for example, may be prepared by adding stannous fluoride and the phytic acid compound, and optionally the difficultly soluble stannous com-pound and the fluorine compound, to a suitable solvent such as distilled or deionized water and ethanol. Sweetening agents such as saccharine, etc., and flavoring agents such as peppermint oil, spearmint oil, anise oil, etc. may also be added in a small amount, if desired. Gel-type mouthwashes and topical pastes may be prepared by adding to the above-prepared solution a humectant such as glycerin, sorbitol, pro-pylene glycol, polyethylene glycol and the like in an amount of 5 - 70 wt%, a binder such as xanthan gum, guar gum, car-rageenan, hydroxyethyl cellulose, sodium carboxymethyl cel-lulose and the like in an amount of 0.3 - 10 wt%, and an anti-septic agent such as ethyl parahydroxybenzoate, and butyl parahydroxybenzoate and the like in a minor amount. Further, tablets and powders may be prepared in a usual manner using well-known tablet or powder-forming agents, for example, a vehicle such as lactose and mannitol, a disintegrator and a binder such as corn starch and carboxymethyl cellulose.
Oral bands may be prepared by dissolving or dis-persing in water stannous fluoride and the phytic acid com-pound together with necessary components, for example, a tacky high-molecular substance soluble in water or changing into a gel in water such as sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, sodium polyacrylate, sodium alginate, dextran, gelatin, carrageenen and the like in a usual blending amount of 20 - 99 wt%; a poly-hydric alcohol such as polyethylene glycol, propylene glycol, sorbitol, glycerin and the like in a usual blending amount of 1 - 50 wt%; and a surface-active agent such as an anion active agent and a nonion active agent (e.g. polyoxyethylene stearate or polyoxyethylene sorbitan monooleate) in a usual blending amount of 0 - 30 wt%. The resulting solution or dispersion is freeze dried to remove water and form a film which is cut into a desired shape.
Dentifrices may include an abrasive such as calcium pyrophosphate, insoluble alkali metal metaphosphates (e.g.
insoluble sodium metaphosphate), titanium dioxide, resins, aluminum hydroxide, silicic anhydride, aluminosilicate and the like in a usual blending amount of 20 - 60 wt~; a binder such as xanthan gum, guar gum, carrageenan, hydroxyethyl cellulose, propylene glycol alginate, sodium carboxymethyl cellulose and the like in a usual blending amount of 0.5 -5 wt%; a humectant such as glycerin, sorbitol and other polyhydric alcohols in a usual blending amount of 15 - 40 wt~;
a foaming agent such as water-soluble salts of the higher alkyl sulfates having 8 to 18 carbon atoms in the alkyl group (e.g. sodium lauryl sulfate), water-soluble salts of sulfonated monoglycerides of higher fatty acids having 10 to 18 carbon atoms in the fatty acid group (e.g. sodium coconut monoglyceride sulfonate), salts of amides of higher fatty ~ - 14 -113~g~
acid having 12 to 16 carbon atoms in the fatty acid group with lower aliphatic amino acids (e.g. sodium-N-methyl-N-palmitoyl tauride or sodium N-lauroyl sarcosinate), sucrose fatty acid ester having 12 to 18 carbon atoms in the fatty acid group ~e.g. sucrose monolaurate), condensates of sorbi-tan monostearate with approximately 60 moles of ethylene oxide, condensates of ethylene oxide with propylene oxide conden-sates of propylene glycol and the like in a usual blending amount of 0.5 - 3 wt%; a sweetening agent; a flavoring agent;
an antiseptic agent; an anticariogenic agent such as chloro-hexidine; and any other ingredients. In dentifrices, insoluble alkalimetal metaphosphates and silicic anhydride may prefer-ably be used as an abrasive, and nonionic water-soluble high molecular compounds such as hydroxyethyl cellulose, propylene glycol alginate, xanthan gum and guar gum may preferably be used as a binder.
The oral composition of this invention is acidic.
The pH of the composition may fall within the range of 2 - 7, more preferably 2 - 6, especially 2 - 5.5 in order to derive the best results from the composition. The pH of dentifrices containing the difficultly soluble stannous compound may be pref~rably 3 - 6. The acidity may be adjusted by phytic acid or its salt. Alternatively, the acidity may be adjusted to a desired level by adding an organic acid such as citric acid, tartaric acid, lactic acid, malonic acid, malic acid, L-ascorbic acid, acetic acid, and succinic acid or alkali metal salts thereof, an inorganic acid such as hydrochloric acid and phosphoric acid, or an alkali such as sodium hydroxide.
113~g~1 The oral composition of this invention may be used in an ordinary manner depending upon its type and form. For example, mouthwashes in the form of liquids may be applied with or without dilution with water while those in the form of tablets, powders or gels may be applied after they are dis-solved or dispersed in water. Oral bands may be attached to teeth. Then the high-molecular substance which is the main component of the band is gelated and becomes tacky upon con-tact with sali~a. With the tacky band firmly adhered to the teeth, the active ingredients (stannous fluoride and the phytic acid compound) in the band act on the teeth. A topical solu-tion or gel may be directly applied to a tooth surface.
As described above, the oral composition of this invention is applied to teeth directly or after it is prepared into a form suitable for oral application by diluting with, dissolving in or dispersing in water. Upon application to a tooth surface, stannous fluoride and the phytic acid compound contained at the above-prescribed contents and relative molar ratio in the composition exhibit a synergistic effect on the tooth enamel, thereby substantially enhancing the acid resis-tance of the tooth enamel. The oral composition of this in-vention can be applied at room temperature or approximately 30C without a reduction in the acid resistance improvement.
Further, the efficacy after application is retained for an extended period of time. It was found that the acid resistance of the tooth enamel treated with the present composition re-mains high even after the tooth is washed with running tap water for 24 hours. It was also found that stannous ions are 9~1 stable in the composition for a long period of storage. This means that the present composition is an effective dental caries inhibitor which can be stored for an extended period of time and shows a prolonged activity after ap~lication.
The following examples are illustrative of the present inven-tion, but it is to be unclerstood that the invention is not limited thereto. ~11 percentages ill the examplos are percent.lges by weight Ull-less otherwise spoci~:ied.
Example 1 Stannous fluoride and pentasodium phytate of the formula:
~ 0 OH ) ~ O \ O~l ) 5 were added to water in given amounts. Hydrochloric acid or aqueous sodium hydroxide solution was added to adjust the pH, yielding a number of test solutions varying in stannous fluoride content, pentasodium phytate content, pentasodium phytate/stannous fluoride molar ratio, and pH.
An enamel block made of a bovine enamel (incisor) was immers-ed for 3 minutes in each of the test solutions at 30C. Each block was brushed twenty times, that is, ten times in each of the longitudinal and transverse directions with a toothbrush. For the purpose of deter-mining the retention of the activity, the treated enamels were allowed to stand in tap water a'c 37C for 20 hours. Thereafter, the thus treated enamels were subjected to decalcification in an acidic solution ~L~L369~
(buffered solution of 0.1 M acetate at pH 4.5) at 20C for 2 hours. After decalcification, the surface hardness (~ickers hardness number : VHN) was measured on the enamel surface of each enamel block to evaluate the effect of the test solution on the acid resistance of the enamel.
After the test solutions prepared as above were stored for 1 month at 40C, the above test procedure was repeated to determine the acid resistance for evaluation of the stability of the solutions under storage.
For comparison, enamel blocks were treated with aqueous solutions containing varying amounts of stannous fluoride at pH 3.0 and aqueous solutions containing varying amounts of pentasodium phytate at pH 3.0, respectively. After the blocks were subjected to decalcification, the Vickers hardness was measured in the same manner as above.
The results are shown in Tables 1 and 2. Each hardness value in the Tables is an average of 15 measurements.
It should be noted that the acid-resistance evalua-tion for the tooth enamel subjected to decalcification under the above-described conditions followed by hardness measure-ment is a very severe one because the samples treated with 8% SnF2 in water were decalcified to a considerable extent in the above-mentioned decalcifying solution. Accordingly, hardnesses above 150, particularly above 200 indicate a consider-able improvement in acid resistance. Oral compositions result-ing in such high hardnesses are very effective in inhibiting dental caries.
Symbols in the "Stability" column in the Tables have - lS -1~3~g~1 the following meanings. The stability of the test solutions under storage was evaluated by comparing the effect on the increment of the acid-resistance by a test solution stored at 40C for 1 month with that by an initial test solution.
O : Retention of efficacy of a stored test solution is 80% or more.
: Retention of efficacy is 65~ or more.
X : Retention of efficacy is less than 65~o.
Other abbreviations in the Tablcs, are as follows:
P*-5Na is pentasodium phytatc, VHN is Vickers Hardness number, "u.m." is "unmeasurable" which means that hardness measurement is impossible because of destruction of a tooth surface by decalcification (Vickers hardness is less than 50) under the above-described severe test conditions.
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Table 2 . P -5Na/SnF2Content Content of SnF2 of p -5Na pH VHN
(molar ratio)(~) (%) ~ ___ L
¦ Z.D 0.4 4.0 4 226 , ~13~;~g~
Exam~le 2 Test solutions were prepared by adding 1.2% by weight of stannous fluoride and a given amount of pentapotassium phytate, pentamagnesium phytate or pentacalcium phytate to water. Hydrochloric acid or aqueous sodium hydroxide solution was added to the test solutions to adjust the pH.
The test procedure described in Example 1 was re-peated to evaluate the acid resistance of enamel blocks treated with the test solutions.
The results are shown in Table 3.
Table 3 Vickers hardness at Phytate (-I soluti on pS.0 phytate 5 305 230 183 phytate 1 240 160 120 ll 5 250 164 132 Pentacalcium 1 166 121 70 As shown in Tables 1 - 3, a specific combination of stannous fluoride with the phytic acid compound, where the contents of stannous fluoride and the phytic acid compound are 0.04 to 10~ and not less than 0.1% by weight, respectively, - 2~ -1~3~i~91 and the molar ratio of the phytic acid compound to stannousfluoride is in the range of from 0.01 : l to 4 : 1, provides a significant improvement in the acid resistance of tooth enamel as compared with the use of a single component, stan-nous fluoride or the phytic acid compound, or a combination of sodium fluoride and the phytic acid compound or other prior art oral compositions. More particularly, when the content of the phytic acid compound is 0.3 to 20~, specifically 0.5 to 10% by weight and the molar ratio of the phytic acid com-pound to stannous fluoride is in the range of from 0.02 : lto 3 : l, specifically from 0.025 : l to 2.5 : l, the acid resistance of tooth enamel is remarkably improved. Even after the treated enamel is washed with running tap water for 20 hours, the acid resistance provided by the composition of this invention is kept high. This means that the effect is retain-ed for an extended period of time.
Example 3 A number of test solutions having the following composition were prepared using the chelating and complexing agents listed in Table 4. The pH of these solutions was adjusted to S.0 by adding sodium hydroxide or hydrochloric acid.
Stannous fluoride 0.4 %
Stannous pyrophosphate 1.0 ~
Chelating or complexing agent as shown in Table 4 Water balance 100. 0 %
For each test solution, both immediately after pre--~3~3~i~9~
paration and after the solution had been stored for 10 days at 20C in an oxygen desiccator at l atmospheric pressure, the quantity of dissolved stan-nous ions was measured by the following method and the Vickers hardness of an enamel block treated with the test solution was measured as described in Example 1, except that the rinsing conditions of the enamel block in tap water are at 20~C for 10 - 20 minutes. The results are shown in Table 4.
Measurement of the quantity of stannous ions Quantitave analysis of stannous ions was conducted by the iodometric titration on a supernatant liquid obtained by removing a precipitate from each solution in a centrifugal separator (lO,000 - 12,000 r.p.m.). The quantity of stannous ions dissolved in the supernatant liquid was determined using a O.OSN iodine solution.
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Table 4 Chelating and Amount* Initial ~ After 10 days complexing I storage agents (%) Sn2+(%) ~lN Sn2+(%) ¦ VHN
~phytate 1.0 0.49 228 0.33 160 tion Sodium citra~ 0.38 0.45 150 0.21 1 103 Ctoivmepara-Malonic acid 0.13 0.25 120 0.15 96 ..
acid 0.25 _ 130 _ 110 -Oxalic acid 0.16 0.39 1430.23 96 ..
Lactic acid 0.12 0.28 1200.18 80 -Tartaric acid 0.20 0.32 148 0.13 86 -Benzoic acid 0.16 0.31 133 0.18 93 ..
L-glutamic 0.19 0.24 1220.12 84 ..
Malic acid 0.17 0.27 1080.14 92 ..
Maleic acid 0.15 0.22 1200.12 81 .-Fumaric acid 0.15 0.21 110 0.12 85 ..
Adipic acid 0.19 0.25 1300.17 96 ..
Glutaric acid 0.17 0.23 103 0.14 93 ..
L-aspartic acid 0.17 0.23 1050.13 89 ..
Succinicacid 0.08 0.22 120 0.15 99 ..
Cinnamic ac.id 0.19 0.21 118 0.10 75 ..
EDTA 0.48 0.49 1350.30 81 ..
Tannic acid 0.44 0.33 1250.24 96 ..
None _ 0.20 1030.14 93 ..
* Each of the chelating and complexing agents was blended in an equal molar amount to 1.0% pentasodium phytate.
~3~
The results in Table 4 show that the use of a phytate not only contributes to the solubilization of tin in the ini-tial solution, but also permits the quantity of stannous ions to be maintained at a sufficiently high level after a long term storage in an oxidizing atmosphere, improving the storage stability of the solution. The phytate is highly effective to retain the activity of stannous ion and to improve the acid resistance of the enamel.
The procedure of Example 3 was repeated except that pentasodium phytate was replaced by phytic acid and pentapotas-sium phytate. Similar results were obtained.
Example 4 Stannous fluoride 0.4 %
Stannous pyrophosphate as shown in Tables 5 - 7 Pentasodium phytate "
Water balance 100.O %
A number of test solutions having the above composition were prepared (the pH of the solutions was adjusted with sodium hydroxide or hydrochloric acid to 4.0 - 6.0). As described in Example 3, for each test solution, the quantity of dis-solved stannous ions and the degree of improvement of enamel acid resistance (represented by the Vickers hardness number after decalcification of an enamel block treated with each test solution) were measured both immediately after prepara-tion and after the solution had been stored for 7 days at 20C in an oxygen desiccator at 1 atmospheric pressure. The results are shown in Tables 5, 6 and 7.
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Table 7 Vickers hardness after enamel decalcification ! Pentadosium phytate (%) ¦ o 1.0 ~t~AU~ ~,r~ t~ O 1.0 O 1.0 2.0
4.0 Initial 123 108 208 230 218 tion 7 days 93 84 153 178 172 pH 5.0 Initial 108 98 209 228 209 _ 7 days 63 70 - 139 162 170 6.0 Initial 83 92 108* 147 143 7 days 80 82 78* 122 126 * Tin is completely dissolved in a solution and hence, no precipitate is present. (Tables 5- 9) Example 5 The following toothpastes were prepared by mixing the ingredients with water.
Carboxymethyl cellulose 1.3~
Ethyl parahydroxybenzoate 0.006%
Stannous fluoride 0.4~
Pentasodium phytate as shown in Tables 8 & 9 Sodium saccharin 0.2%
Flavor 1.0%
Aluminosilicate 25.0%
Stannous pyrophosphate 1.0%
Sodium lauryl sulfate 2.0%
Glycerin 25.0%
Water Balance 100. 0 3~99~
Hydrochloric acid was used for pH adjustment.
For each toothpaste, the quantity of dissolved stannous ions and the degree of improvement of enamel acid resistance were measured both immediately after preparation and also after the solution had been stored for 30 days at 20C in an oxygen desiccator at 1 atmospheric pressure. The degree of improvement of enamel acid resistance was evaluated by thoroughly mixing equal weights of a toothpaste composition and water. A block of bovine enamel was immersed in the re-sulting slurry at 30C for 3 minutes. Following the proceduredescribed in Example 1, the Vickers hardness of the enamel block at the surface was measured after decalcification.
The quantity of dissolved stannous ions was measured by adding two parts by weight of water to one part of a tooth-paste and stirring the mixture for 2 hours. The quantity of stannous ions dissolved as a result of this 2 hour stirring ; was measured by the iodometric titration as described in Example 3. The measured value was converted into the cor-responding solubility in the original toothpaste. It should be noted that the total quantity of stannous ions is calcu-lated to be 0.87% provided that all stannous fluoride and stannous pyrophosphate are entirely solubilized in the tooth-paste.
The results are shown in Tables 8 and 9.
. - 31 -113~
Table 8 Vickers hardness after enamel decalcification Toothpaste 1~ Pentasodium phytate ¦ pH ¦ 0% ¦ 0.5% 1.0~ 2.0% 2.5%
! I I
Fresh paste ¦ ¦ 112 133 164 180 189 Aftex 30 days ¦ 84 116 133 162 158 aging _ . .__ Fresh paste 5.0 96 139 148 214 177*
~fter 30 days 80 119 121 169 159*
aglng I ... __ Table 9 Quantity of dissolved Sn2+ (%) .._ ____ Toothpaste Penta ~ n pb~tate pH 0% 0.5% 1.0% 2.0~ 2.5%
.
Fresh paste 4.00.38 0.43 0.46 0.52 0.60 After 30 days 0.36 0.43 0.47 0.53 0.58 aging - ... _ Fresh paste 5.00.53 0.53 0.59 0.76 0.82*
After 30 days 0.48 ¦ 0.53 0.60 0.75 0.81*
aglng I .
Note: Only the toothpaste containing 0% pentasodium phytate was aged for 10 days in an oxygen desic-cator.
As seen from the results in Tables 5 - 9, by adding a phytate to a system containing highly soluble stannous fluoride and difficultly soluble stannous pyrophosphate, the quantity of dissolved stannous ions is increased in the initial solution and maintained after aging in an oxidizing atmosphere, allowing stannous ion to fully exert its effect. The addi-tion of the phytate can also enhance the acid resistance of tooth enamel. The effect produced by the addition of the phytate was also observed in toothpastes at relatively high pH levels.
Example 6: Dentifrice Insoluble sodium metaphosphate 40.0 ~
Silicic anhydride 3.0 %
Propylene glycol 3.0 %
Glycerin 10.0 ~
Sorbitol 10.0 %
Xanthan gum 0.5 %
Carboxymethyl cellulose0.6 %
Sodium lauryl sulfate 2.0 %
Flavor 0.5 %
Saccharin 0.1 %
Butyl parahydroxybenzoate0.01%
Stannous fluoride 0,4 ~
Pentasodium phytate 2.5 %
Water Balance 100.0 %
Stannous fluoride and pentasodium phytate were dis-solved in some of the water. In order to prepare a dentifrice, this solution was mixed with the paste obtained by blending the other ingredients with the remaining water.
Example 7_ Dentifrice Stannous fluoride 0.41 %
Phytic acid 2.5 ~
Malonic acid 0.31%
Insoluble sodium metaphosphate 40.0 %
Propylene glycol 3,0 %
Glycerin 10.0 ~
Sorbitol 5,0 %
Hydroxyethyl cellulose 1.5 %
Sodium lauryl sulfate 2.0 %
Flavor 0~5 %
Saccharin 0.1 %
Butyl parahydroxybenzoate0.01%
Water Balance 100.0 %
Tnedentifrice was prepared as in Example 6.
Example 8: Dentifrice Calcium pyrophosphate 40.0 %
Propylene glycol 3.0 %
Glycerin 10.0 %
Sorbitol 5.0 %
Guar gum 0.5 %
Carrageenan 0.5 %
Sodium lauryl sulfate 1.0 %
Saccharose monolaurate 1.5 %
Flavor 0 5 %
113~g~
Saccharin 0.1 %
Butyl parahydroxybenzoate0.01%
Stannous fluoride 0.2 %
Sodium fluoride 0.11%
Pentasodium phytate 1.0 ~
Water Balance 100.O %
Tllcdentifrice was prepared as in Example 6.
Example 9: Dentifrice Silicic anhydride 25.0 %
Propylene glycol 3.0 %
Glycerin 8.0 %
Sorbitol 12.0 %
Hydroxyethyl cellulose 3.0 %
Sodium lauryl sulfate 1.5 %
Flavor 0.5 %
Saccharin 0.2 %
Butyl parahydroxybenzoate0.01%
Stannous fluoride 0.4 ~
Pentapotassium phytate 2.5 %
Water Balance 100.0 %
T~e dentifrice was prepared as in Example 6.
Example 10: Dentifrice Insoluble sodium metaphosphate 40.0 %
Propylene glycol 3.0 %
Glycerin 4.0 %
Sorbitol 12.0 %
113~g9~
Xanthan gum 1.2 %
Sodium lauryl sulfate 2.0 %
Flavor 0.5 %
Saccharin 0.1 %
Butyl parahydroxybenzoate 0.01%
Stannous fluoride 0.4 ~
Trimagnesium phytate 3.5 %
Water Balance 100.0 %
Tlle dentifrice was prepared as in Example 6.
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Stannous fluoride and phytatewere dissolved in 50 parts of water. To prepare a topical paste, this solution was mixed with the composi-tion obtained by blending the remaining ingredients in 50 parts of water.
Example 18: Topical solution for dental use Stannous fluoride 1.2 %
Pentasodium phytate 6.3 %
l~lavor 0.5 %
Saccharin 0.2 %
Ethanol 10 . O %
Water Balance 100.0 %
The topical solution for dental use was prepared by adding the above ingredi.ents to water.
Example 19: Topical solution for dental use Stannous fluoride 1.2 %
Pentasodium phytate 4.5 %
Trisodium citrate dihydrate0.5 %
Flavor 0.5 %
Saccharin 0.2 %
Ethanol 10.0 %
Water Balance 100.0 %
The topical solution was prepared as in Example 18.
Example 20: Desensitizer (liquid) Stannous fluoride 0.4 %
Pentasodium phytate 3.0 %
Flavor 0-5 %
~l3~9~
Saccharin 0.1 %
Ethanol 10.0 %
Water Balance 100. 0 %
~ilc solution was prepared as in Example 18.
Example 21- Cavity sealer (liquid) Stannous fluoride 1.2 %
Pentasodium phytate 6.0 %
Flavor 0.25%
Saccharin 0.05%
Ethanol 10.0 %
Water Balance 100 . O %
Th~ solution was prepared as in Example 18.
Example 22: Prophylactic paste Stannous fluoride 1.2 %
Pentasodium phytate 6.0 %
Propylene glycol 3.0 %
Glycerin 10.0 %
Sorbitol 10.0 %
Guar gum 2.0 %
Zirconium silicate 50.0 %
Sodium lauryl sulfate 1.0 %
Flavor 0.5 %
Saccharin 0.1 %
Butyl parahydroxybenzoate0.01%
Water Balance 100. 0 %
3~
The paste was prepared as in Example 11.
Example 23: Disintegratable tablet Stannous fluoride 4.0 mg Phytic acid 20.0 mg Flavor 10.0 mg Saccharin 1.0 mg Corn starch 1.0 g The above ingredients were mixed and tableted by conventional means.
E,xample 24: Oral band Stannous f]uoride 300.0 mg Pentasodium phytate 1.5 g Sodium carboxymethyl cellulose 0.5 g Polyvinyl alcohol 0.5 g Hydroxypropyl cellulose 9.0 g Polyethylene glycol 4000 1.0 g Flavor 0.05g The above ingredients were dissolved in water to yield a solution weighing 100 g. The solution was freeze dried to remove the water and formed into a film ready for use as an oral band. When applied to teeth, the band becomes tacky due to absorption of water in saliva and firmly adheres to the tooth surface.
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Example 35: Mouthwash (tablet) Stannous fluoride 0.2 g Pentapotassium phytate 1.0 g Flavor 0.2 g Saccharin o.osg Mannitol 2.0 g Sodium carboxymethyl cellulose 0.05g Water small amount 'I'hc above ingrcdients were mixed and tablcted by conventional means. For use, the tablet is dissolved in 100 ml of water and the mouth is washed therewith for 30 - 60 seconds.
Example 36: Mouthwash (tablet) Stannous fluoride 0.08g Phytic acid 0.4 g Flavor 0.2 g Saccharin o.osg Gum arabic 2.0 g Corn starch 0.5 g Water small amount The above ingredients were mixed and tableted by conventional means. For use, the tablet is dissolved in 100 ml of water and the mouth is washed therewith for 30 - 60 seconds.
Examp_es 37 - 39: Dentifrices Example 37 Example 38 Example 39 Stannous fluoride 0.4 % 0.4 % 0.4 %
Stannous oxalate - 1.0 1.0 - ~ 3~
Stannous pyrophosphate 1.0 - -Pentasodium phytate 2.5 2.0 1.0 Insoluble sodium meta-phosphate 40.0 - 40.0 Aluminosilicate - 25.0 Hydroxyethyl cellulose 1.5 - 1.0 Sodium carboxymethyl cellulose - 1.3 0.5 Glycerin 25.0 15.0 15.0 Sodium lauryl sulfate 2.0 2.0 2.0 Saccharin 0.2 0.2 0.2 Flavor 1.0 1.0 1.0 Ethyl parahydroxybenzoate 0.006 0.006 0.006 Water Balance Balance Balance 100 . O % 100 . O % 100 . O
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tn z; 1 ~ o ~ u s~ _1 ~1 H ~ U ,,U~ ~ o .~ o ~ ~ ~ O ~ U (d a) 1 1~; 1~ U ~ U
a) ~ o X u~ 1 3 E~
li:l ..... _ .__ . _ .. _ ._ - ~3~91 Mouthwashes were prepared by blending the ingredients with water.
Example 46: Mouthwash (tablet) Stannous fluoride 0.2 g Stannous pyrophosphate 0.5 g Pentasodium phytate 0.5 g Flavor 0.2 g Saccharin 0.05g Mannitol 2.0 g Carboxymothyl cellulose 0.05g Water some pH 5.0 The above ingredients were mixed and tableted by conventional means. For use, the tablet is dissolved in 100 ml of water and the mouth is washed therewith for 30 - 60 seconds.
Examples 47 - 49: Topical solutions Example 47 Example 48 Example 49 Stannous fluoride 1.2 % 1.2 % 0.6 %
Stannous pyrophosphate 2.0 2.0 2.0 Pentasodium phytate 6.3 4.5 6.0 29 Sodium monofluorophosphate - - 1.14 Trisodium citrate dihydrate - 0.5 Flavor 0.5 0.5 0.5 Saccharin 0.2 0.2 0.2 Ethanol 10.0 10.0 10.0 Water Balance Balance Balance Total100.0 100.0 100.0 pH 3.0 3.0 3.0 Topical solutions were prepared by adding the ingredi-ents to water.
;4~
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0\ ,1 ~ ~
,1 ~r o o o o o ou~ ~ oIn ~ O O
u~ o ~ o ~r _ . ___ 0\o ~, ~ 0\o O N O O O O OIS~ N O 11') ~ O O
U~ I ~ .
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m ~
_ _ ~ _.
U~
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~ ~ o~ ,~
r~ ~~ ~ o o ~ o ~r ~ U U
Lr) ~ ~o ~o o Z ~ ~ ~ o u~
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U~ O O Ul ~ 1 ~X ~15 h ~ X
~1 ~ >t aU) Q ~O~ ~ g .C ~., O~
a ~ ~: ~ o ~ (a u ~ ~1 IJ a) o ~1~1 o~ ~ O f~ O
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_ 3f~
Topical pastes were prepared by mixing 50 parts of water containing stannous compounds, sodium phytate and optionally fluo-rine compound with 50 parts of water containing the remaining in-gredients.
Carboxymethyl cellulose 1.3~
Ethyl parahydroxybenzoate 0.006%
Stannous fluoride 0.4~
Pentasodium phytate as shown in Tables 8 & 9 Sodium saccharin 0.2%
Flavor 1.0%
Aluminosilicate 25.0%
Stannous pyrophosphate 1.0%
Sodium lauryl sulfate 2.0%
Glycerin 25.0%
Water Balance 100. 0 3~99~
Hydrochloric acid was used for pH adjustment.
For each toothpaste, the quantity of dissolved stannous ions and the degree of improvement of enamel acid resistance were measured both immediately after preparation and also after the solution had been stored for 30 days at 20C in an oxygen desiccator at 1 atmospheric pressure. The degree of improvement of enamel acid resistance was evaluated by thoroughly mixing equal weights of a toothpaste composition and water. A block of bovine enamel was immersed in the re-sulting slurry at 30C for 3 minutes. Following the proceduredescribed in Example 1, the Vickers hardness of the enamel block at the surface was measured after decalcification.
The quantity of dissolved stannous ions was measured by adding two parts by weight of water to one part of a tooth-paste and stirring the mixture for 2 hours. The quantity of stannous ions dissolved as a result of this 2 hour stirring ; was measured by the iodometric titration as described in Example 3. The measured value was converted into the cor-responding solubility in the original toothpaste. It should be noted that the total quantity of stannous ions is calcu-lated to be 0.87% provided that all stannous fluoride and stannous pyrophosphate are entirely solubilized in the tooth-paste.
The results are shown in Tables 8 and 9.
. - 31 -113~
Table 8 Vickers hardness after enamel decalcification Toothpaste 1~ Pentasodium phytate ¦ pH ¦ 0% ¦ 0.5% 1.0~ 2.0% 2.5%
! I I
Fresh paste ¦ ¦ 112 133 164 180 189 Aftex 30 days ¦ 84 116 133 162 158 aging _ . .__ Fresh paste 5.0 96 139 148 214 177*
~fter 30 days 80 119 121 169 159*
aglng I ... __ Table 9 Quantity of dissolved Sn2+ (%) .._ ____ Toothpaste Penta ~ n pb~tate pH 0% 0.5% 1.0% 2.0~ 2.5%
.
Fresh paste 4.00.38 0.43 0.46 0.52 0.60 After 30 days 0.36 0.43 0.47 0.53 0.58 aging - ... _ Fresh paste 5.00.53 0.53 0.59 0.76 0.82*
After 30 days 0.48 ¦ 0.53 0.60 0.75 0.81*
aglng I .
Note: Only the toothpaste containing 0% pentasodium phytate was aged for 10 days in an oxygen desic-cator.
As seen from the results in Tables 5 - 9, by adding a phytate to a system containing highly soluble stannous fluoride and difficultly soluble stannous pyrophosphate, the quantity of dissolved stannous ions is increased in the initial solution and maintained after aging in an oxidizing atmosphere, allowing stannous ion to fully exert its effect. The addi-tion of the phytate can also enhance the acid resistance of tooth enamel. The effect produced by the addition of the phytate was also observed in toothpastes at relatively high pH levels.
Example 6: Dentifrice Insoluble sodium metaphosphate 40.0 ~
Silicic anhydride 3.0 %
Propylene glycol 3.0 %
Glycerin 10.0 ~
Sorbitol 10.0 %
Xanthan gum 0.5 %
Carboxymethyl cellulose0.6 %
Sodium lauryl sulfate 2.0 %
Flavor 0.5 %
Saccharin 0.1 %
Butyl parahydroxybenzoate0.01%
Stannous fluoride 0,4 ~
Pentasodium phytate 2.5 %
Water Balance 100.0 %
Stannous fluoride and pentasodium phytate were dis-solved in some of the water. In order to prepare a dentifrice, this solution was mixed with the paste obtained by blending the other ingredients with the remaining water.
Example 7_ Dentifrice Stannous fluoride 0.41 %
Phytic acid 2.5 ~
Malonic acid 0.31%
Insoluble sodium metaphosphate 40.0 %
Propylene glycol 3,0 %
Glycerin 10.0 ~
Sorbitol 5,0 %
Hydroxyethyl cellulose 1.5 %
Sodium lauryl sulfate 2.0 %
Flavor 0~5 %
Saccharin 0.1 %
Butyl parahydroxybenzoate0.01%
Water Balance 100.0 %
Tnedentifrice was prepared as in Example 6.
Example 8: Dentifrice Calcium pyrophosphate 40.0 %
Propylene glycol 3.0 %
Glycerin 10.0 %
Sorbitol 5.0 %
Guar gum 0.5 %
Carrageenan 0.5 %
Sodium lauryl sulfate 1.0 %
Saccharose monolaurate 1.5 %
Flavor 0 5 %
113~g~
Saccharin 0.1 %
Butyl parahydroxybenzoate0.01%
Stannous fluoride 0.2 %
Sodium fluoride 0.11%
Pentasodium phytate 1.0 ~
Water Balance 100.O %
Tllcdentifrice was prepared as in Example 6.
Example 9: Dentifrice Silicic anhydride 25.0 %
Propylene glycol 3.0 %
Glycerin 8.0 %
Sorbitol 12.0 %
Hydroxyethyl cellulose 3.0 %
Sodium lauryl sulfate 1.5 %
Flavor 0.5 %
Saccharin 0.2 %
Butyl parahydroxybenzoate0.01%
Stannous fluoride 0.4 ~
Pentapotassium phytate 2.5 %
Water Balance 100.0 %
T~e dentifrice was prepared as in Example 6.
Example 10: Dentifrice Insoluble sodium metaphosphate 40.0 %
Propylene glycol 3.0 %
Glycerin 4.0 %
Sorbitol 12.0 %
113~g9~
Xanthan gum 1.2 %
Sodium lauryl sulfate 2.0 %
Flavor 0.5 %
Saccharin 0.1 %
Butyl parahydroxybenzoate 0.01%
Stannous fluoride 0.4 ~
Trimagnesium phytate 3.5 %
Water Balance 100.0 %
Tlle dentifrice was prepared as in Example 6.
9~
._, ~o o o ". ,,, U~ o o U~ ~ ~ o ~o ~ o ~ o ' ~i o o o ~ oo ._ . ~ ~
~S~ ~`J O OO O 11~ Ll') Ll~ O In N ~ D
----~ o o o o o D
~3 0 00 1-) 0 1$~ O Ul ~ 1: D
~n ,i I 1` 1 1 u~ O I O ~ o I I o o o o ..... ........ _.... .. __._.. _____.____ ,1 ~r oo o o o o u~ o Ln ~ ~ o o ~ i O O OO ~d o _ ~ .
O O O O `O O U~ O U~ ~ O
~1 ~ ) O ~O O OO Id ~ool o\ ,~ O _ ~I er O O OO O 11') 0 U~ O
~1 o t~ 1 o I I O O O ~d o o\ ,_~ ~ ~1 $ ~1 ~ o O O O U> O U~~ ~ O
_, ~ O ~ O O O O O
~ ~a) 1~1 Z ~ u~ ~ N ~rl ~ Ql ~-~ IJ ~ 1::
O H al ~
E l ~ ~ Q~
r-l ~ 0 ~ C,) O
l ~ ~
~1 u~
r-l Z~ O O O ~1 0 >~
Ul H ~ )S l ~\ O ~ O ~ 0 ~1 0 ~1 ~ )-1 l h~1 ~ O ~ O O td td X ~ m ~ 3 ~3~
Stannous fluoride and phytatewere dissolved in 50 parts of water. To prepare a topical paste, this solution was mixed with the composi-tion obtained by blending the remaining ingredients in 50 parts of water.
Example 18: Topical solution for dental use Stannous fluoride 1.2 %
Pentasodium phytate 6.3 %
l~lavor 0.5 %
Saccharin 0.2 %
Ethanol 10 . O %
Water Balance 100.0 %
The topical solution for dental use was prepared by adding the above ingredi.ents to water.
Example 19: Topical solution for dental use Stannous fluoride 1.2 %
Pentasodium phytate 4.5 %
Trisodium citrate dihydrate0.5 %
Flavor 0.5 %
Saccharin 0.2 %
Ethanol 10.0 %
Water Balance 100.0 %
The topical solution was prepared as in Example 18.
Example 20: Desensitizer (liquid) Stannous fluoride 0.4 %
Pentasodium phytate 3.0 %
Flavor 0-5 %
~l3~9~
Saccharin 0.1 %
Ethanol 10.0 %
Water Balance 100. 0 %
~ilc solution was prepared as in Example 18.
Example 21- Cavity sealer (liquid) Stannous fluoride 1.2 %
Pentasodium phytate 6.0 %
Flavor 0.25%
Saccharin 0.05%
Ethanol 10.0 %
Water Balance 100 . O %
Th~ solution was prepared as in Example 18.
Example 22: Prophylactic paste Stannous fluoride 1.2 %
Pentasodium phytate 6.0 %
Propylene glycol 3.0 %
Glycerin 10.0 %
Sorbitol 10.0 %
Guar gum 2.0 %
Zirconium silicate 50.0 %
Sodium lauryl sulfate 1.0 %
Flavor 0.5 %
Saccharin 0.1 %
Butyl parahydroxybenzoate0.01%
Water Balance 100. 0 %
3~
The paste was prepared as in Example 11.
Example 23: Disintegratable tablet Stannous fluoride 4.0 mg Phytic acid 20.0 mg Flavor 10.0 mg Saccharin 1.0 mg Corn starch 1.0 g The above ingredients were mixed and tableted by conventional means.
E,xample 24: Oral band Stannous f]uoride 300.0 mg Pentasodium phytate 1.5 g Sodium carboxymethyl cellulose 0.5 g Polyvinyl alcohol 0.5 g Hydroxypropyl cellulose 9.0 g Polyethylene glycol 4000 1.0 g Flavor 0.05g The above ingredients were dissolved in water to yield a solution weighing 100 g. The solution was freeze dried to remove the water and formed into a film ready for use as an oral band. When applied to teeth, the band becomes tacky due to absorption of water in saliva and firmly adheres to the tooth surface.
1~3~9~
. ~ o . , , . ,. . . . C .
o ~o o o o o ._ __ __ ,~
~r o oO u~ ~ o o . , . , . , . . . .
o ~ o o o o o ___ ,,_ ,~ o_ N N ~ ~ . . : O
_.~ O C~l OO -I
r~ e~ O ~ l O O S~' _._, O ~ O O O O O ~
U~~ O r-l N O O O .,~ .
~1 OS~ ooIIIIooo o _ 3 . ,~ .~_ 3 a~ .4 O ~r CO N O O O
~C N O O O OO O O
X __ ~ NIt ) oo If) ~-1 0 ~-1 N O O O OO O O .4 ~_1 ~1 N O NU') _I O O
N O_i I I OO O O r~
.~ . ri .~ ~ ~r o I I I I In ~ o o ~ O
N O N OO O O r~
~ ~-I ' ~
N O~r I I IO ~ O ~
~ m O ~
.. ~ _ ... __ a ~ ~ ~ '~ E~ O ~ ~ ~ O
l ~ ,~
N ~! r~ i U~ ~ ~ O O O U ~1 _I r r H ~ I J ~ r1 h ~ O
1~ ~ a~ O ~ d X _ ... ____ ~ -~3~9~
Example 35: Mouthwash (tablet) Stannous fluoride 0.2 g Pentapotassium phytate 1.0 g Flavor 0.2 g Saccharin o.osg Mannitol 2.0 g Sodium carboxymethyl cellulose 0.05g Water small amount 'I'hc above ingrcdients were mixed and tablcted by conventional means. For use, the tablet is dissolved in 100 ml of water and the mouth is washed therewith for 30 - 60 seconds.
Example 36: Mouthwash (tablet) Stannous fluoride 0.08g Phytic acid 0.4 g Flavor 0.2 g Saccharin o.osg Gum arabic 2.0 g Corn starch 0.5 g Water small amount The above ingredients were mixed and tableted by conventional means. For use, the tablet is dissolved in 100 ml of water and the mouth is washed therewith for 30 - 60 seconds.
Examp_es 37 - 39: Dentifrices Example 37 Example 38 Example 39 Stannous fluoride 0.4 % 0.4 % 0.4 %
Stannous oxalate - 1.0 1.0 - ~ 3~
Stannous pyrophosphate 1.0 - -Pentasodium phytate 2.5 2.0 1.0 Insoluble sodium meta-phosphate 40.0 - 40.0 Aluminosilicate - 25.0 Hydroxyethyl cellulose 1.5 - 1.0 Sodium carboxymethyl cellulose - 1.3 0.5 Glycerin 25.0 15.0 15.0 Sodium lauryl sulfate 2.0 2.0 2.0 Saccharin 0.2 0.2 0.2 Flavor 1.0 1.0 1.0 Ethyl parahydroxybenzoate 0.006 0.006 0.006 Water Balance Balance Balance 100 . O % 100 . O % 100 . O
, ~
1~3~9~1 , .. . .~ _.
In,1 ~ ~ ~ O O ~ O O
~r . . . II I I . ~ . .
o o o o o o ~ o U~
~ m 0\ U~
~r,1 ~ ~ ~ ~ o o ~: o o ~r o o o I o I I o o o ~ o L~
o _.. _.. _ .. _ ... __ . .... _ . __ ___. _ ___ OP
~n .~ ~ u~ O u~ In ~ O ~ O O
~r . . . I I I . . . . ~ . .
O O ~J O O O ~ ~1 O In m ~ _ ___ . _ _ _ ~ dP Q) X ~ ~ Ln o In In ~ O O O O
~r . .. I I. I . . ~ ~ . .
U~
~ ~ ~0 _ .__ ~1 ~ o o u~u~ ~ O S:: O o ~r o ~i ~ I o I I o o o ~ o u~
~ ~ m .,1 _.~
~I ~
_ o ~ O O u~ o o o O ~ ~ O O O O ~0 ~
~ _ _ m __ _ o ~ ~ ~
u~ Z; .
l ~~ O ~ ~ U
o ~ ~ ~ ~ nU~ U ~ 'u ~r ~ u~ q ~ u 'R U~ ~ ~
tn z; 1 ~ o ~ u s~ _1 ~1 H ~ U ,,U~ ~ o .~ o ~ ~ ~ O ~ U (d a) 1 1~; 1~ U ~ U
a) ~ o X u~ 1 3 E~
li:l ..... _ .__ . _ .. _ ._ - ~3~91 Mouthwashes were prepared by blending the ingredients with water.
Example 46: Mouthwash (tablet) Stannous fluoride 0.2 g Stannous pyrophosphate 0.5 g Pentasodium phytate 0.5 g Flavor 0.2 g Saccharin 0.05g Mannitol 2.0 g Carboxymothyl cellulose 0.05g Water some pH 5.0 The above ingredients were mixed and tableted by conventional means. For use, the tablet is dissolved in 100 ml of water and the mouth is washed therewith for 30 - 60 seconds.
Examples 47 - 49: Topical solutions Example 47 Example 48 Example 49 Stannous fluoride 1.2 % 1.2 % 0.6 %
Stannous pyrophosphate 2.0 2.0 2.0 Pentasodium phytate 6.3 4.5 6.0 29 Sodium monofluorophosphate - - 1.14 Trisodium citrate dihydrate - 0.5 Flavor 0.5 0.5 0.5 Saccharin 0.2 0.2 0.2 Ethanol 10.0 10.0 10.0 Water Balance Balance Balance Total100.0 100.0 100.0 pH 3.0 3.0 3.0 Topical solutions were prepared by adding the ingredi-ents to water.
;4~
._ _ .~ _ ~ ~D O O~r o o oIn ~`3 0 ~ o o U~ . . . . . . I . I . . . . ~ .
o ~ ~ n o ~ o o o o ~1 o m~ O
_ __ ___ O,o ~ a) O~o U~ ~ O U~ ~ o o . . . I . . . . . . . . . 0 .
O ~ m ~
U~ ._. ~ _ ~0 ~I ~ 0\o P~ N N O ~ O OO O Ou') N Oll~ ~ O O
11~ . . . I .. . . . . . . . ~ .
~ ~IN ~D ~ o ~I ,1 o o o o,~ O ~
"C ~1 ~ o ~ _ _ _ .
0\ ,1 ~ ~
,1 ~r o o o o o ou~ ~ oIn ~ O O
u~ o ~ o ~r _ . ___ 0\o ~, ~ 0\o O N O O O O OIS~ N O 11') ~ O O
U~ I ~ .
O~ O O O O ~1 O
m ~
_ _ ~ _.
U~
E~
Z a ~ ~ U~ U~ N ~rl O H ~ .~3 ~ Q
~ ~ o~ ,~
r~ ~~ ~ o o ~ o ~r ~ U U
Lr) ~ ~o ~o o Z ~ ~ ~ o u~
H ~ ~ O a) ~1 O
U~ O O Ul ~ 1 ~X ~15 h ~ X
~1 ~ >t aU) Q ~O~ ~ g .C ~., O~
a ~ ~: ~ o ~ (a u ~ ~1 IJ a) o ~1~1 o~ ~ O f~ O
x u~ X E4 u~ m P~
_ 3f~
Topical pastes were prepared by mixing 50 parts of water containing stannous compounds, sodium phytate and optionally fluo-rine compound with 50 parts of water containing the remaining in-gredients.
Claims (11)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. An oral, tooth-treating composition comprising stannous fluoride and a phytic acid compound, the content of stannous flouride being 0.04 to 10% by weight of the total amount of the composition, the content of the phytic acid compound being not less than 0.1% by weight of the total amount of the composition, the molar ratio of the phytic acid com-pound to stannous fluoride being in the range of from 0.01:
1 to 4 : 1, the composition being acidic, all components of the composition being orally acceptable and substantially non-toxic.
1 to 4 : 1, the composition being acidic, all components of the composition being orally acceptable and substantially non-toxic.
2. An oral composition according to Claim 1, wherein the content of stannous fluoride is 0.1 to 4% by weight of the total amount of the composition, the content of the phytic acid compound is 0.3 to 20% by weight of the total amount of the composition, the molar ratio of the phytic acid compound to stannous fluoride is in the range of from 0.02 :
1 to 3 : 1, and the composition has a pH of 2 to 6.
1 to 3 : 1, and the composition has a pH of 2 to 6.
3. An oral composition according to Claim 2, wherein the contents of stannous fluoride and the phytic acid compound are 0.3 to 4% and 0.5 to 10% by weight of the total amount of the composition, respectively, the molar ratio of the phytic acid compound to stannous fluoride is in the range of from 0.025 : 1 to 2.5 : 1, and the pH of the composition is 2 to 5.5.
4. An oral composition according to Claim 1, 2 or 3, wherein the phytic acid compound is at least one member selected from the group consisting of phytic acid, sodium phytate, potassium phytate, lithium phytate, ammonium phytate, magnesium phytate, zinc phytate, calcium phytate, aluminium phytate, phytin and double salts thereof.
5. An oral composition according to Claim 1, where-in a difficultly soluble stannous compound is further added in an amount of 0.05 to 10% by weight of the total amount of the composition as stannous tin.
6. An oral composition according to Claim 5, where-in a portion of the difficultly soluble stannous compound is in a precipitate form.
7. An oral composition according to Claim 5 or 6, wherein the difficultly soluble stannous compound is at least one member selected from the group consisting of stannous pyro-phosphate, stannous metaphosphate, stannous oxide, stannous oxalate and stannous phosphate.
8. An oral composition according to Claim 5 or 6, wherein stannous fluoride is present in an amount of 0.08 to 3% by weight of the composition, stannous pyrophosphate is present in an amount of 0.1 to 3% by weight of the composition, and the phytic acid compound is present in an amount of 0.5 to 5% by weight of the composition.
9. An oral composition according to Claim 5 or 6, wherein the phytic acid compound is at least one member selected from the group consisting of phytic acid, sodium phytate, potassium phytate, lithium phytate, ammonium phytate, magnesium phytate, zinc phytate, calcium phytate, aluminum phytate, phytin and double salts thereof.
10. An oral composition according to Claim 5 or 6, wherein the com-position has a pH of 2 to 7.
11. An oral composition according to Claim 5 or 6, wherein the phytic acid compound is at least one member selected from the group consisting of phytic acid, sodium phytate, potassium phytate, lithium phytate, ammonium phytate, magnesium phytate, zinc phytate, calcium phytate, aluminum phytate, phytin and double salts thereof and wherein the composition has a pH of 3 to 6.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP54-97627 | 1979-07-31 | ||
| JP54097627A JPS5835965B2 (en) | 1979-07-31 | 1979-07-31 | Oral composition |
| JP54-121194 | 1979-09-20 | ||
| JP54121194A JPS5846483B2 (en) | 1979-09-20 | 1979-09-20 | Oral composition |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1136991A true CA1136991A (en) | 1982-12-07 |
Family
ID=26438794
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000357308A Expired CA1136991A (en) | 1979-07-31 | 1980-07-30 | Stannous fluoride and a phytic acid compound in oral composition |
Country Status (3)
| Country | Link |
|---|---|
| CA (1) | CA1136991A (en) |
| FR (1) | FR2462160A1 (en) |
| SE (1) | SE8005321L (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10555883B2 (en) | 2015-07-01 | 2020-02-11 | Colgate-Palmolive Company | Oral care compositions and methods of use |
| US10588840B2 (en) | 2016-06-24 | 2020-03-17 | Colgate-Palmolive Company | Oral care compositions and methods of use |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8920796D0 (en) * | 1989-09-14 | 1989-11-01 | Rolla Gunnar | Dentifrice compositions |
| ITMI991453A1 (en) * | 1999-07-01 | 2001-01-01 | Farmila Farma Milano | OPHTHALMIC COMPOSITIONS IN THE FORM OF AQUEOUS GEL |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE638645A (en) * | 1961-07-10 | 1900-01-01 | ||
| IE33101B1 (en) * | 1968-08-05 | 1974-03-20 | Schneider R & Co Kg | Dental preparations |
| GB1384375A (en) * | 1971-04-29 | 1975-02-19 | Beecham Group Ltd | Oral hygiene compositions |
| GB1573727A (en) * | 1978-05-19 | 1980-08-28 | Colgate Palmolive Co | Dentifrices |
-
1980
- 1980-07-23 SE SE8005321A patent/SE8005321L/en not_active Application Discontinuation
- 1980-07-30 FR FR8016864A patent/FR2462160A1/en active Granted
- 1980-07-30 CA CA000357308A patent/CA1136991A/en not_active Expired
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10555883B2 (en) | 2015-07-01 | 2020-02-11 | Colgate-Palmolive Company | Oral care compositions and methods of use |
| US10588840B2 (en) | 2016-06-24 | 2020-03-17 | Colgate-Palmolive Company | Oral care compositions and methods of use |
| US10617620B2 (en) | 2016-06-24 | 2020-04-14 | Colgate-Palmolive Company | Oral care compositions and methods of use |
| US11207254B2 (en) | 2016-06-24 | 2021-12-28 | Colgate-Palmolive Company | Oral care compositions and methods of use |
| US11234915B2 (en) | 2016-06-24 | 2022-02-01 | Colgate-Palmolive Company | Oral care compositions and methods of use |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2462160A1 (en) | 1981-02-13 |
| SE8005321L (en) | 1981-02-01 |
| FR2462160B1 (en) | 1984-10-12 |
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