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Publication numberUS3639569 A
Publication typeGrant
Publication dateFeb 1, 1972
Filing dateFeb 19, 1968
Priority dateFeb 19, 1968
Also published asDE1908067A1, DE1908067B2
Publication numberUS 3639569 A, US 3639569A, US-A-3639569, US3639569 A, US3639569A
InventorsMedcalf Ralph F Jr
Original AssigneeProcter & Gamble
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Oral compositions for calculus retardation
US 3639569 A
Abstract  available in
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Claims  available in
Description  (OCR text may contain errors)

United States Patent 3,639,569 ORAL COMPOSITIONS FOR CALCULUS RETARDATION Ralph F. Medcalf, IL, Cincinnati, Ohio, assignor to The Procter & Gamble Company, Cincinnati, Ohio N0 Drawing. Filed Feb. 19, 1968, Ser. No. 706,685 Int. Cl. A61k 7/16, 27/00 US. Cl. 42448 8 Claims ABSTRACT OF THE DISCLOSURE Oral compositions, such as toothpaste, mouthwash, and the like, containing certain tris(phosphonoalkyl)amines and their salts which retard dental calculus formation without damaging tooth structure.

BACKGROUND OF THE INVENTION The field of this invention is oral compositions which term is used herein to designate products which in the ordinary course of usage are retained in the oral cavity for a time sufficient to contact substantially all of the dental surfaces, but are not intentionally ingested. Such products include, for example, dentifrices, mouthwashes, prophylaxis pastes and topical solutions.

Dental calculus, or tartar as it is sometimes called, is a deposit which forms on the surfaces of the teeth at the gingival margin. Supragingival calculus appears principally in the areas near the orifices of the salivary ducts; e.g., on the lingual surfaces of the lower anterior teeth and on the buccal surfaces of the upper first and second molars, and on the distal surfaces of the posterior molars.

Mature calculus consists of an inorganic portion which is largely calcium phosphate arranged in a hydroxylapatite crystal lattice structure similar to bone, enamel and dentine. An organic portion is also present and consists of desquamated epithelial cells, leukocytes, salivary sediment, food debris and various types of microorganisms.

As the mature calculus develops, it becomes visibly white or yellowish in color unless stained or discolored by some extraneous agency. In addition to being unsightly and undesirable from an aesthetic standpoint, the mature calculus deposits are constant sources of irritation of the gingiva and thereby are a contributing factor to gingivitis and other diseases of the supporting structures of the teeth, the irritation decreasing the resistance of tissues to endogeneous and exogenous organisms.

A wide variety of chemical and biological agents have een suggested in the art to retard calculus formation or to remove calculus after it is formed. Mechanical removal of this material periodically by the dentists is, of course, routine dental office procedure.

The chemical approach to calculus inhibition generally involves chelation of calcium ion which prevents the calculus from forming and/or breaks down mature calculus by removing calcium. A number of chelating agents have been employed for this purpose. See, for example, British Pat. 490,384, granted Feb. 15, 1937, which discloses oral compositions containing ethylenediaminetetraacetic acid, nitrilotriacetic acid and related compounds as anticalculus agents; German Auslegeschrift 1,149,138, published May 22, 1963, which discloses certain Water-soluble digylcolates as anticalculus agents; and US. Patent 1,516,206 which discloses oral compositions containing various sugar lactones for this purpose.

Although certain of the art-disclosed chelaters are purportedly safe for use on dental enamel, the chemical similarity of calculus to the tooth structure limits the usefulness of the chelation approach since the more effective chelators can seriously damage the tooth structure by decalcification. Thus, the development of oral compositions which effectively retard calculus by calcium chelation has been impeded by safety considerations. Safe and effective anticalculus compositions are disclosed in the copending application of Homer W. McCune and Nathaniel B. Tucker, Serial No. 689,265, filed December 11, 1967; however, researchers continue to search for alternative compositions.

SUMMARY OF THE INVENTION It has now been discovered that certain tris(phosphonoalkyl) amines and salts thereof posses the surprising capacity to retard the development of dental calculus without removing calcium from dental enamel or otherwise damaging the tooth structure when employed in oral compositions maintained within defined pH limits. The term tris(phosphonalkyl)amines as used hereinafter is intended to encompass both the free acid and salt forms.

The compositions of this invention retard calculus formation by a mechanism that is believed to involve the inhibition of hydroxylapatite crystal growth as will be discussed more fully hereinafter.

Unlike inorganic polyphosphates such a pyrophosphates, the tris(phosphonalkyl)amines employed in the compositions of this invention resist hydrolysis in aqueous products and therefore remain in an active form throughout the normal shelf-life of such products.

It is therefore an object of this invention to provide novel oral compositions which retard the formation of calculus without otherwise affecting the tooth structure.

It is another object of this invention to provide an improved method for retarding the development of dental calculus.

Other objects will become apparent from the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION This invention is an oral composition effective in inhibiting the formation of dental calculus without adversely affecting the tooth structure comprising 1) from about .0l% to about 10% by weight of at least one tris(phosphonoalkyl)amine selected from the group consisting of those having the formula:

wherein R R R R R and R are each hydrogen or lower alkyl (1-4 carbon atoms), and pharmaceutically acceptable salts thereof, such as alkali metal (e.g., sodium and potassium), alkaline earth metal (e.g., calcium and magnesium), non-toxic heavy metal (e.g., stannous and indium), and ammonium or low molecular weight substituted ammonium (e.g., mono-, di-, and triethanolammoniurn) salts; and (2) a carrier suitable for use in the oral cavity, the pH of the composition being within the range from about 4.0 to about 11.0.

The preferred tris(phosphonoalkyl)amines for the purpose of this invention are tris(phosphonomethyl)amine; tris(l phosphonoethyl)amine; tris(2-phosphono-2-propyl)amine; and their pharmaceutically acceptable salts. T ris(phosphonomethyl)amine is especially preferred. The following additional compounds are exemplary of those which can be used herein:

(a) bis(phosphonomethyl)-1-phosphonoethyl amine;

(b) bis (phosphonomethyl)-2.-phosphono-2-propyl amine;

(c) bis(l-phosphonoethyl)phosphonornethyl amine;

(d) bis(2-phosphono-2-propyl)phosphonomethyl amine;

(e) tris( l-phosphono-l-pentyl) amine;

(f) bis (phosphonomethyl -2-phosphono-2-hexyl amine; and

(g) the pharmaceutically acceptable salts of acids (a) through (f), e.g., the sodium, potassium, calcium, magnesium, ammonium, triethanolammonium, diethanolammonium, and monoethanolammonium salts.

Mixtures of any of the foregoing tris (phosphonoalkyl)- amines can be used in the compositions of this invention.

The concentration of tris (phosphonoalkyl) amines in the oral compositions of this invention can range from about .0l% to about 10% by weight. Oral compositions which in the ordinary course of usage could be accidentally ingested should contain lower concentrations. Thus, a mouthwash in accordance with this invention preferably contains less than about 3% by weight of tris(phosphonoalkyl)amine. Dentifrice compositions, topical solutions and prophylaxis pastes, the latter to be administered professionally, can contain up to about 10% by weight, preferably from about 0.1% to about 5.0% by weight of tris (phosphono alkyl) amine.

The pH of the compositions of this invention can range from about 4.0 to about 11. Below about pH 4.0 damage to the dental enamel can occur in spite of the relative safety of the tris(phosphonoalkyl)amines. Above about pH 11.0 difficulty is encountered in formulating products having satisfactory flavor and mildness. A preferred pH range is from about 6.0 to about 8.0. The pH of the composition, of course, is determinative of the predominant salt form of the tris(phosphonoalkyl)- amines present therein. For example, at pH 7.0 using sodium hydroxide tris(phosphonomethyl)amine is predominantly in the tetrasodium form.

While it is not intended that this invention be limited by a particular theory of operation, it has been observed that the tris(phosphonoalkyl)amines encompassed herein interfere with the progress of calculus formation by interfering with the conversion of X-ray amorphous calcium phosphate to crystalline calcium hydroxylapatite. Amounts of tris(phosphonoalkyl)amine which are much too small to chelate any appreciable quantities of calcium have been found to retard the formation of calcium hydroxylapatite. The selective action on the formative calculus deposits without demineralizing action on the dental enamel is surprising. The eflioacy of the compositions of this invention in calculus prophylaxis was demonstrated by the Crystal Growth Inhibition Test which was conducted as follows:

Two weeks after the commencement of the test, the animals were sacrificed and their molars were graded for severity of calculus by assessing the area and depth of accumulation on each of the 44 dental surfaces examined in each animal. Grading was made on a -3 scale for each surface, 0 being no detectable calcified deposits, 3 being coverage of 50100% of the surface with a thick deposit and intermediate values representing gradations between these extremes. The total calculus score for each animal was determined by adding the grades for each of the 44 surfaces.

Compared to the control group, the test group of animals revealed a 44% reduction in calculus. From a study of related structures it is believed that the tris(phosphonoalkyl)amines are not appreciably absorbed in the digestive tract, thus any anticalculus effect observed in this test is due to topical exposure of the dental surfaces to the tris(phosphonoalkyl)amine during ingestion rather than any systemic effect.

Crystal growth inhibition determination As hereinbefore stated, the tris(phosphonoalkyl) amines inhibit the growth of calcium hydroxylapatite crystals and in this way interfere with the normal formation of calcium hydroxylapatite from solution. This test is to determine the effect of the tris(phosphonoalkyl)- amines on the calcium phosphate formed on addition of calcium ion to orthophosphate ion at constant pH. The procedure is as follows:

1 ml. of a 0.1 M stock solution of NaH PO -H O is diluted with 22 ml. of distilled water. 1 ml. of an aqueous solution of the disodium salt of tris(phosphonomethyl)- amine at a concentration sufficient to provide the desired ultimate concentration in the reaction mixture is added to the diluted NaH PO solution and the solution is adjusted to pH 7.4 with NaOH. To this solution is added 1 ml. of a 0.1 M solution of CaCl -2H O preadjusted to pH 7.4 with NaOH. This mixture is held at a constant pH of 7.4 throughout the reaction period.

After a sufficient reaction time as determined by the operator, generally within minutes, the solution is filtered through a 0.45 Millipore filter pad, dried, and analyzed by X-ray diffraction. The solid calcium phosphate precipitated from the above-described solution without a tris(phosphonoalkyl)amine gives a typical hydroxylapatite pattern, while the calcium phosphate precipitated under the same conditions but in the presence of small amounts of the tris(phosphonoalkyl)amines of this invention is amorphous to X-rays.

Those compounds which are effective in inhibiting the growth of hydroxylapatite crystals at concentrations of less than l.5 10 M under the conditions of this test are effective in reducing calculus formation in rats, while several compounds outside the scope of this invention that had little or no effect in this test did not reduce calculus in rats.

When tested in the Crystal Growth Inhibition Determination the tetrasodium salt of tris(phosphonomethyl) amine was found to inhibit crystal growth at a concentration of 2.0 10- M. Thus, the presence of that amount of a tris(phosphonoalkyl)amine in the test solutions of the Crystal Growth Inhibition test results in the precipitation of an amorphous calcium phosphate rather than crystalline calcium hydroxylapatite as occurs in the absence of these compounds. By way of comparison, ethylenediami'netetraacetic acid and nitrilotriacetic acid which have been suggested for use as anticalculus agents in the art fail to inhibit crystal growth at molar concentrations of 2.45 10 and 2.54 10 respectively. At higher concentrations, these prior art compounds prevent precipitation of calcium phosphate in this test because of their powerful calcium sequestering properties.

The safety of tris(phosphonoalkyl)amines for use in contact with dental surfaces is determined by the Continuous Immersion Test conducted as follows: Mature human teeth are immersed in aqueous solutions or dispersions of oral compositions containing a tris (phosphonoalkyl)amine in accordance with this invention at pH 7.0 and pH 10. Every four hours the teeth are examined for decalcification. Under visible light, enamel decalcification can be detected by a loss of luster, white opaque spots or slight surface roughening. The teeth are examined macroscopically and microscopically at the end of seven days. If no decalcification is observed through this period, the compositions cause no damage to dental enamel, and are considered safe in this respect for use in the oral cavity.

predominantly B-phase calcium pyrophosphate prepared.

in accordance with the teachings of Schweizer, US. Pat.

3,112,247, granted Nov. 26, 1963, which contains relatively little soluble calcium can be used. An especially preferred class of abrasives for use herein are the particulate thermosetting polymerized resins as described by Cooley et al. in US. Pat. 3,070,510, granted Dec. 25, 1962. Suitable resins include, for example, melamines, phenolics, ureas, melamine-ureas, melamine-formaldehydes, urea formaldehydes, melamine urea-formaldehydes, cross-linked epoxides, and cross-linked polyesters.

Other suitable abrasives include alumina and the insoluble non-calcium metaphosphates such as sodium metaphosphate. Mixtures of abrasives can also be used. In any case, the total amount of abrasive in the dentifrice embodiments of this invention can range from 0.5 to 95% by weight of the dentifrice. Preferably, toothpastes contain from 20% to 60% by weight of abrasive. Abrasive particle size preferably ranges from 2, to 20 Suitable sudsing agents are those which are reasonably stable and form suds throughout a wide pH range, pref.- erably non-soap anionic organic synthetic detergents. Examples of such agents are water-soluble salts of alkyl sulfate having from 10 to 18 carbon atoms in the alkyl radical, such as sodium lauryl sulfate, water-soluble salts of sulfonated monoglycerides of fatty acids having from 10 to 18 carbon atoms, such as sodium monoglyceride sulfonates; salts of C -C fatty acid amides of taurine, such as sodium N-methyl-N-palmitoyl tauride; salts of C -C fatty acid esters of isethionic acid; and substantially saturated aliphatic acyl amides of saturated monoaminocarboxylic acids having 2 to 6 carbon atoms and in which the acyl radical contains 12 to 16 carbon atoms, such as sodium N-lauroyl sarcoside. Mixtures of two or more sudsing agents can be used.

The sudsing agent can be present in the dentifrice compositions of this invention in an amount from 0.5 to weight of the total compositions.

In preparing toothpastes, it is necessary to add some thickening material to provide a desirable consistency. Preferred thickening agents are hydrovyethylcellulose and water-soluble salts of cellulose ethers such as sodium carboxymethylcellulose and sodium carboxymethylhydroxyethylcellulose. Natural gums such as gum karaya, gum arabic, and gum tragacanth can also be used. Colloidal magnesium aluminum silicate or finely divided silica can be used as part of the thickening agent to further improve texture. Thickening agents in an amount from 0.5% to 5.0% by weight of the total composition can be used.

It is also desirable to include some humectantmaterial in a toothpaste to keep it from hardening. Suitable humectants include glycerine, sorbitol, and other edible polyhydric alcohols. The humectant can comprise up to about 36% by weight of the toothpaste composition.

Suitable flavoring agents include oil of Wintergreen, oil of peppermint, oil of spearmint, oil of sassafras, and oil of clove. Sweetening agents which can be used include saccharin, dextrose, levulose and sodium cyclamate.

Several representative oral compositions illustrating this invention are set forth in the following examples.

6 EXAMPLE I A toothpaste of the following composition is prepared by conventional methods.

Parts by weight Water 31.58 Sorbitol 6.25 Saccharin 0.12 Calcium pyrophosphate 1 39.00 Glycerine 18.00 Sodium alkyl (coconut) sulfide 0.40 Sodium coconut monoglyceride sulfonate 0.75 Sodium carboxymethyl cellulose 1.15 Magnesium aluminum silicates 0.40 Flavoring 0.85 Disodium salt of tris(phosphonomethyl)amine 1.50 pH 2 5.90

1 Prepared in accordance with 11.8. Pat. 3,112, 24? granted Nov. 26. 1963.

Adjusted to indicated pH with sodium hydroxide.

This composition effectively retards calculus formation on dental enamel and when tested in the Continuous Immersion Test described herein no decalcification was noted after seven days exposure.

Toothpaste compositions substantially identical to the composition of Example I are prepared with the dipotassium salt of tris(phosphonomethyl)amine; the diammonium salt of tris(phosphonomethyl)amine; the monocalcium salt of tris (phosphonomethyDamine; and the monomagnesium salt of tris(phosphonomethyl)amine, respectively, rather than the disodium salt of tris(phosphonomethyl)amine, adjusting the pH to 5.9. These compositions substantially retard calculus formation and do not decalcify dental enamel.

Several mouthwash compositions are prepared in accordance with this invention as follows:

Parts by weight oi Component I II III IV Glycerine 10. 0 10. 0 10. 0 l0. 0 Ethyl alcohol... 16. 5 16.5 16. 5 16. 5

ater 67. 172 67. 172 67. 172 70. 192 Tween 8O .12 .12 .12 .12 Saccharin 045 045 045 02 Sodium cyclamate 0. 75 0. 75 0. 75 04 Flavor 088 088 088 088 Tris (phosphonoalkyl) amin 2 3.0 3 4. 0 4 2.0 5 1. 8 pH 0 7.0 8. 5 10. 0 10. 0

1 Polyoxyethylene (20 moles of ethylene oxide) sorbitan monooleatea nonionic emulsifier supplied by Atlas Powder Company.

2 Diamanonium salt of tris (l-phosphono-l-pontyl) amine. aD2111?i(triethanolammonium) salt of his (phospunonomethyl)-2-hexyl 4 Pentascdium salt of tris (phosphonornethyl) amine.

B Tris (phosphonomethyl) amine.

6 Ad usted to value indicated with sodium hydroxide.

When used in the same manner as conventional mouthwash, at least once daily, each of the above compositions materially reduces the accumulation of calculus on the surfaces of teeth. No decalcification is observed after seven days exposure of dental enamel to these compositions.

EXAMPLE V A prophylaxis paste for use by the dentist for removal of stains and polishing the teeth after mechanical removal of calculus deposits is formulated as follows:

Parts by weight Navajo pumice 77.10 T10 4.00 Glycerine 17.75 Hydroxyethylcellulose .22 Saccharin .33

Diindium salt of bis(phosphonomethyl)-1-phosphono-l-butyl amine 8.0

When applied to the teeth with a prophylactic rubber cup in the conventional manner, this composition retards the development of new calculus deposits.

Toothpowders and the like can be prepared by conventional methods and containing, in addition to the usual ingredients, an amolmt of tris(phosphonoa1kyl)amine Within the ranges specified herein, to provide an effective means of retarding calculus formation without damaging the tooth structure.

Those components other than tri(phosphonoalkyl)- amine which were included in the foregoing examples and various mixtures of those components are illustrative of carriers suitable for use in the oral cavity.

What is claimed is:

1. In a dentifrice composition containing from about 5% to about 95% by weight of a dentifrice abrasive selected from the group consisting of fi-phase calcium pyrophosphate, particulate thermosetting polymerized resin, alumina, sodium metaphosphate and mixtures thereof, and having a pH within the range from about 4.0 to about 11.0, the improvement comprising the incorporation therein of from about 0.1% to about 5.0% by weight of a tris(phosphonoalkyl)amine selected from the group consisting of those of the formula:

wherein R R R R R and R are each hydrogen or lower alkyl, and the pharmaceutically acceptable salts thereof.

2. The composition of claim 1 wherein the tris(phosphonoalkyl)amine is tris(phosphonomethyl)amine or a pharmaceutically acceptable salt thereof.

3. In a mouthwash composition consisting of a flavoring agent, glycerine, ethanol, sweetener, emulsifier and water, the improvement comprising the incorporation therein of from 0.1% to about 5.0% by weight of a tris(phsphonoalkyl)amine selected from the group consisting of those of the formula:

wherein R R R R R and R are each hydrogen or lower alkyl and the pharmaceutically acceptable salts thereof.

4. The composition of claim 3 wherein the tris(phosphonoalkyl)amine is tris(phosphonomethyl)amine or a pharmaceutically acceptable salt thereof.

5. In a chewing gum composition containing a chewing gum base and having a pH within the range from about 4.0 to about 11.0, the improvement comprising the incorporation therein of from about 0.1% to about 5.0%

by weight of a tris(phosphonoalkyl)ami.ne selected from the group consisting of those of the formula:

R1CR B5 H303? R Ra POaHg wherein R R R R R and R are each hydrogen or lower alkyl, and the pharmaceutically acceptable salts thereof.

6. The composition of claim 5 wherein the tris(phosphonoalkyl)amine is tris(phosphonomethyl)amine or a pharmaceutically acceptable salt thereof.

7. In a dental prophylaxis paste composition containing a dental abrasive and having a pH within the range from about 4.0 to about 11.0, the improvement which comprises the incorporation therein of from about 0.1% to about 5.0% by weight of a tris (phosphonoalkyDamine selected from the group consisting of those of the formula:

POgHz wherein R R R R R and R are each hydrogen or lower alkyl, and the pharmaceutically acceptable salts thereof.

8. The composition of claim 7 wherein the tris(phosphonoalkyl)amine is tris(phosphonomethyl)amine or a pharmaceutically acceptable salt thereof.

References Cited UNITED STATES PATENTS 3,234,140 2/1966 Irani 260-5025 3,288,846 11/1966 Irani et al 260502.5

3,429,914 2/ 1969 Crutchfield et a1. 260502.5

3,442,604 5/1969 Smith et a1. 42457 FOREIGN PATENTS 1,225,818 9/1966 Germany 424-204 OTHER REFERENCES Dental Abstracts, vol. 12, No. 9, pp. 539-544, September 1967.

Draus et al., Dental Progress, vol. 3, No. 2, pp. 79-81, January 1963.

Grossman, J. Oral Surg., Oral Med., and Oral Path, vol. 7, pp. 484-487, May 1954.

RICHARD L. HUFF, Primary Examiner U.S. Cl. X.R. 42454, 204

Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US3864472 *Nov 6, 1972Feb 4, 1975Colgate Palmolive CoClear lemon-flavored mouthwash
US3947570 *Nov 22, 1974Mar 30, 1976Colgate-Palmolive CompanyOral product
US4143128 *Jun 10, 1977Mar 6, 1979Colgate Palmolive CompanyOral compositions for calculus retardation
US4144324 *Aug 7, 1978Mar 13, 1979Colgate Palmolive CompanyOral compositions for calculus retardation
US4233288 *Mar 12, 1979Nov 11, 1980Cornell John AGum emulsified liquid package for delivering and preserving liquid content in the mouth
US5000940 *May 30, 1989Mar 19, 1991Nabisco Brands, Inc.Devices, compositions and the like having or containing an inorganic pyrophosphate
US5000943 *May 30, 1989Mar 19, 1991Nabisco Brands, Inc.Canine biscuits containing an inorganic pyrophosphate
US5000973 *May 30, 1989Mar 19, 1991Nabisco Brands, Inc.Nutritionally-balanced canine biscuits containing an inorganic pyrophosphate
US5011679 *May 30, 1989Apr 30, 1991Nabisco Brands, Inc.Raw hide having a coating containing an inorganic pyrophosphate
US5015485 *May 30, 1989May 14, 1991Nabisco Brands, Inc.Dog biscuits having a coating containing an inorganic pyrophosphate
US5047231 *May 30, 1989Sep 10, 1991Nabisco Brands, Inc.Raw hide containing an inorganic pyrophosphate
US5094870 *Feb 11, 1991Mar 10, 1992Nabisco Brands, Inc.Canine biscuits containing an inorganic pyrophosphate
US5114704 *Feb 20, 1991May 19, 1992Nabisco Brands, Inc.Raw hide having a coating containing an inorganic pyrophosphate
US6455080Mar 16, 2000Sep 24, 2002Wm. Wrigley Jr., CompanyChewing gum containing controlled release acyclic carboxamide and method of making
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EP2478777A1Dec 21, 2006Jul 25, 2012Kraft Foods Global Brands LLCComposition providing a cooling sensation substantially similar to that provided by menthol
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Classifications
U.S. Classification424/48, 514/102, 424/54
International ClassificationA61Q11/00, A61K8/55, A61K8/30
Cooperative ClassificationA61K8/55, A61Q11/00
European ClassificationA61Q11/00, A61K8/55