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Publication numberUS3553314 A
Publication typeGrant
Publication dateJan 5, 1971
Filing dateDec 23, 1968
Priority dateDec 23, 1968
Publication numberUS 3553314 A, US 3553314A, US-A-3553314, US3553314 A, US3553314A
InventorsFrancis Marion D
Original AssigneeProcter & Gamble
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Oral compositions for calculus retardation
US 3553314 A
Abstract  available in
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Claims  available in
Description  (OCR text may contain errors)

United States Patent O 3,553,314 ORAL COMPOSITIONS FOR CALCULUS RETARDATION Marion D. Francis, Springfield Township, Hamilton County, Ohio, assignor to The Procter & Gamble Company, Cincinnati, Ohio, a corporation of Ohio No Drawing. Filed Dec. 23, 1968, Ser. No. 786,355

Int. Cl. A611 7/16 US. Cl. 42449 8 Claims ABSTRACT OF THE DISCLOSURE Oral compositions, such as toothpaste, mouthwash, and the like, containing certain methanecycloalkylhydroxydiphosphonic acids and their salts which retard dental calculus formation without damaging the 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 suificient 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 surface 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 endogenous and exogenous organisms.

A wide variety of chemical and biological agents have been suggested in the art to retard calculus formation or to remove calculus after it is formed. Mechanical removal of this material periodically by the dentist is, of course, routine dental ofiice 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 diglycolates as anticalculus agents; and US. Pat. 1,516,206 which discloses oral compositions containing various sugar lactones for this purpose.

Although certain of the art-disclosed chelators 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 3,553,314 Patented Jan. 5, 1971 by decalcification. Thus, the development of oral compositions which effectively retard calculus by calcium chelation has been impeded by safety considerations.

SUMMARY OF THE INVENTION It has now been discovered that certain methanecycloalkylhydroxydiphosphonic acids and pharmaceutically acceptable salts thereof (referred to collectively hereinafter as methanecycloalkylhydroxydiphosphonates which tennis intended to encompass both the free acid and salt forms) possess 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.

Unlike inorganic polyphosphonates such as pyrophosphates, the methanecycloalkylhydroxydiphosphonates 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 .01% to about 10% by weight of a methanecycloalkylhydroxydiphosphonate having the formula:

wherein n is an integer from 3 to 9, or a pharmaceutically acceptable salt 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), ammonium or low molecular weight substituted ammonium (e.g., mono-, diand triethanolammonium) salts; and (2) a carrier suitable for use in the oral cavity, the pH of said composition being in the range from about 5.0 to 11.0.

The methanecycloalkylhydroxydiphosphonates can be prepared by methods fully described in the US. patent application of John D. Curry, entitled Novel Methanecycloalkylhydroxydiphosphonic Acids and Salts Thereof, Ser. No. 786,358, filed Dec. 23, 1968, which is incorporated herein by reference.

S p e c i f i c methanecycloalkylhydroxydiphosphonates which are encompassed by the above general formula and which are useful in the present invention include the following:

I Methanecyclooctylhydroxydiphosphonic acid Methanecyclononylhydroxydiphosphonic acid Methanecyclodecylhydroxydiphosphonic acid Each of the sodium, potassium, calcium, magnesium, stannous, indium, ammonium, monoethanolammonium, diethanolammonium and triethanolammonium salts of the above recited methanecycloalkylhydroxydiphosphonic acids as well as any other pharmaceutically acceptable salt of these acids, can be used in the practice of the present invention.

Especially preferred methanecycloalkylhydroxydiphosphonates for the purpose of this invention are methanecyclopentylhydroxydisphosphonic acid, methanecycloheptylhydroxydiphosphonic acid and the pharmaceutically acceptable salts of these acids.

The concentration of methanecycloalkylhydroxydiphosphonate in the oral compositions of this invention can range from about .01% to about 10% by weight. Oral compositions which in the ordinary course of usage could he accidentally ingested should contain lower concentrations of methanecycloalkylhydroxydiphosphonate. Thus, a mouthwash in accordance with this invention preferably contains less than about 3% by weight of methanecycloalkylhydroxydiphosphonate. 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 methanecycloalkylhydroxydiphosphonate.

The pH of the composition of this invention can range from about 5.0 to about 11. Below about pH 5.0 damage to the dental enamel can occur in spite of the relative safety of the methanecycloalkylhydroxydiphosphonates. Above about pH 11.0 difficulty is encountered in formulating products having satisfactory flavor and mildness. A preferred pH range is from about 7.0 to about 10. The pH of the composition, of course, is determinative of the predominant salt form of the methanecycloalkylhydroxydiphosphonates present therein.

While it is not intended that this invention be limited by a particular theory of operation, it has been observed that the methanecycloalkyl hydroxydiphosphonates encompassed herein interfere with the progress of calculus formation by interfering with the conversion of amorphous calcium phosphate to crystalline calcium hydroxyl apatite. Amounts of methanecycloalkylhydroxydiphosphonates which are much too small to chelate any appreciable quantities of calcium have been found to retard the formation of calcium hydroxylapatite. This selective action on the formative calculus deposits without demineralizing action on the dental enamel is surprising.

The eflicacy of the compositions of this invention in calculus prophylaxis is demonstrated by the rat calculus and crystal growth inhibition tests which are conducted as follows:

RAT CALCULUS TEST Two groups of 20 to 21-day old Holtzman-Sprague- Dawley strain rats, each group comprising one male and one female member of each of 10 litters, were employed in this test, one group serving as the control and the other serving as the test group. The control group of animals was placed on a calculus inducing diet consisting of 50% cornstarch, 32% non-fat dry milk, 3% liver powder, celluflour, 1% cottonseed oil, 5% powdered sucrose, 1% CaCl -2H O, 2.7% NaH PO' -H O and 0.3% MgSO The test group of animals was placed on an identical diet except that 0.25% of methanecyclohexylhydroxydiphosphonate was added thereto.

Three 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 0-3 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.

The average of total calculus scores was 78.83 in the control group and 1.30 in the test group representing a 98.4% reduction in calculus.

CRYSTAL GROWTH INHIBITION DETERMINATION As hereinbefore stated, the methanecycloalkylhydroxydiphosphonates 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 effects of the methanecycloalkylhydroxydiphosphonates on the calcium phosphonate 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 methanecycloalkylhydroxydiphosphonate to be tested (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 sodium hydroxide. To this solution is added 1 ml. of a 0.1 M solution of CaCl -2H O preadjusted to pH 7.4 with sodium hydroxide. This mixture is held at a constant pH 7.4 throughout the reaction period.

After a sufiicient reaction time (as determined by the operator), generally within minutes, the solution is filtered through a 0.4511. millipore filter pad. The precipitate is air-dried and analyzed by X-ray diffraction. The solid calcium phosphate precipitated from the above-described solution without a methanecycloalkylhydroxydiphosphonate gives a typical hydroxylapatite pattern, while the calcium phosphate precipitated under the same conditions but in the presence of small amounts of the methanecycloalkylhydroxydiphosphonates of this invention is amorphous to X-rays.

Table 1 below shows the concentration of various polyphosphonates tested required to inhibit the formation of calcium hydroxylapatite under the conditions specified above.

TABLE 1 M concentration Compound: for inhibition Methanecyclopentylhydroxydiphosphonic acid, trisodium salt 5.00 l0 Methanecyclohexylhydroxydiphosphonic acid, trisodium salt 5.00 10 Methanecycloheptylhydroxydiphosphonic acid, monosodium salt 5.O0 10- The presence of the specified amounts of the methanecycloalkylhydroxydiphosphonates of Table 1 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 without methanecycloalkylhydroxydiphosphonate and the total formation of calcium orthorphosphate is greatly decreased. By way of comparison, ethylenediaminetetraacetic 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 1O- and 2.54 l0 respectively. At higher concentrations, these prior art compounds prevent precipitation of calcium phosphate in this test because of their powerful calcium sequestering properties.

A dentifrice, especially toothpaste, containing a methanecycloalkylhydroxydiphosphonate is preferred embodiment of this invention. Toothpaste compositions conventionally contain abrasive materials, sudsing agents, binders, humectants, flavoring and sweetening agents.

The abrasive materials and other adjuncts used in the practice of this invention are preferably not sources of much soluble calcium so that the crystal growth inhibiting capacity of methanecycloalkylhydroxydiphosphonate is not depleted to an extent that its anticalculus activity is impaired. Thus, conventional abrasives such as dicalcium orthophosphate and calcium carbonate are preferably not used. However, 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 2,3 to 20 Suitable sudsing agents are those which are reasonably stable and form suds throughout a wide pH range, preferably non-soap anionic organic synthetic detergents. Examples of such agents are water-soluble salts of alkyl sulfate having from 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 5% by 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 hydroxyethyl cellulose and water-soluble salts of cellulose ethers such as sodium carboxymethyl cellulose and sodium carboxymethyl hydroxyethyl cellulose. Natural gums such as gum karaya, gum arabic, and gum tragacanth can also be used. Colloidal magnesium aluminum silicate or finely divided silica can be used as part of the thickening agent to further improve texture. Thickening agents in an amount from 0.5% to 5.0% by weight of the total composition can be used.

It is also desirable to include some humectant material in a toothpaste to keep it from hardening. Suitable humectants include 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. Sv'veetening 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.

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

Sodium coconut monoglyceride sulfonate Sodium carboxymethyl cellulose 1.15

EXAMPLE I.-Continued Parts by weight Magnesium aluminum silicates 0.40 Flavoring 0.85 Trisodium salt of methanecyclohexylhydroxydiphosphonic acid pH, 5.90.

1 Prepared Nov. 26, 1963 This composition effectively retards calculus formation Without damaging dental enamel.

Toothpaste compositions substantially identical to the composition of Example I are prepared with methanecyclobutylhydroxydiphosphonic acid; methanecyclopentylhydroxydiphosphonic acid, methanecycloheptylhydroxydiphosphonic acid, methanecyclooctylhydroxydiphosphonic acid, methanecyclononylhydroxydiphosphonic acid, and methanecyclodecylhydroxydiphosphonic acid, respectively, rather than the trisodium salt of methanecyclohexylhydroxydiphosphonic acid, adjusting the pH to 5.9. These compositions substantially retard calculus formation and do not decalify dental enamel.

EXAMPLE II Yet another toothpaste is prepared having the following composition:

in accordance with U.S. Pat. 3,112,247 granted When employed in the customary manner, this toothpaste retards the formation of dental calculus and no decalcification of dental enamel is observed.

Several additional toothpastes are prepared having essentially the same composition as the toothpaste of Example II, but using the tripotassium salt of methanecyclopentylhydroxydiphosphonic acid; the monoammonium salt of methanecyclohexylhydroxydiphosphonic acid; the

'monocalcium salt of methanecyclooctylhydroxydiphosphonic acid; the dimagnesium salt of methanecyclodecylhydroxydiphosphonic acid; the distannous salt of methanecyclohexylhydroxydiphosphonic acid; and the monoindium salt of methanecyclopentyldroxydiphosphonic acid, respectively, rather than the monosodium salt of methanecycloheptylhydroxydiphosphonic acid. The pH of these compositions is adjusted to 7.0. These toothpaste formulations effectively retard calculus formation on dental enamel Without decalcifying same.

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

Example (parts by weight) III IV V VI 1 Polyoxyethylene (20 moles of ethylene oxide) sorbitan mono-oleate, a

Component Glycerine. ol

Tween Saccharin Sodium oyclamate vor Methanecycloalkylhydroxydiphosphonate nonionic emulsifier supplied by Atlas Powder Company.

2 Monosodium salt of methanecycloheptylhydroxydiphosphonic acid. 3 Trisodium salt of methanecyclohexylhydroxydiphosphonic acid.

4 Trisodium salt of methanecyclopentylhydroxydiphosphonic acid.

6 Trisodium salt; of methanecyclooctylhydroxydiphosphonic acid.

6 Adjusted to value indicated with sodium hydroxide.

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

EXAMPLE VII 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 Bis(triethanolammonium) salt of methanecyclohexylhydroxydiphosphonic acid pH, 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.

The prophylaxis paste set forth above is modified by replacing the bis(diethanolammonium) salt of methanecyclohexylhydroxydiphosphonic acid with the bis(diethanolarnmonium) salt of methanecyclopentylhydroxydiphosphonic acid, and the bis(monoethanolammonium) salt of methanecycloheptylhydroxydiphosphonic acid, respectively, with comparable results.

Toothpowders and the like can be prepared by conventional methods and containing, in addition to the usual ingredients, an amount of methanecycloalkylhydroxydiphosphonate within the ranges specified herein, to provide an effective means of retarding calculus formation Without damaging the tooth structure.

Those components other than methanecycloalkylhydroxydiphosphonates which were included in the foregoing examples and various mixtures of those components are illustrative of carriers suitable for use in the oral cavity.

In the reference to pH adjustments in the foregoing examples, it is to be understood that a base of a cation corresponding to the salt form of the methanecycloalkylhydroxydiphosphonate employed is used to adjust to higher pH values. In each case in which the methanecycloalkylhydroxydiphosphonate was added in its acid form to the example compositions, the pH was adjusted to the specified higher value with NaOH. Adjustments in pH to more acid levels is accomplished with HCl acid. It will be obvious to those skilled in the art that pH adjustments can be made with any acid or base suitable for use in the oral cavity.

What is claimed is:

1. An oral composition effective in inhibiting the formation of dental calculus without adversely affecting tooth structure, comprising (1) from about .01% to about 10% by weight of a methanecycloalkylhydroxydiphosphonate of the formula:

wherein n is an integer of from 3 to 9, or a pharmaceutically acceptable salt thereof; and (2) a carrier suitable for use in the oral cavity, the pH of the composition being within the range from about 5.0 to about 11.0.

2. The composition of claim 1 in which the methanecycloalkylhydroxydiphosphonate is methanecyclopentylhydroxydiphosphonic acid or a pharmaceutically acceptable salt thereof.

3. The composition of claim 1 in which the methanecycloalkylhydroxydiphosphonate is methanecyclohexylhydroxydiphosphonic acid or a pharmaceutically acceptable salt thereof.

4. The composition of claim 1 in which the methanecycloalkylhydroxydiphosphonate is methanecycloheptylhydroxydiphosphonic acid or a pharmaceutically acceptable salt thereof.

5. A toothpaste composition comprising (1) from about .01% to about 10% by weight of a methanecycloalkylhydroxydiphosphonate of the formula:

wherein n is an integer of from 3 to 9, or a pharmaceutically acceptable salt thereof; and (2) a carrier suitable for use in the oral cavity, the pH of the composition being within the range from about 5.0 to about 11.0.

6. The composition of claim 5 in which the methanecycloalkylhydroxydiphosphonate is methanecyclopentylhydroxydiphosphonic acid or a pharmaceutically acceptable salt thereof.

7. The composition of claim 5 in which the methanecycloalkylhydroxydiphosphonate is methanecyclohexylhydroxydiphosphonic acid or a pharmaceutically acceptable salt thereof.

8. The composition of claim 5 in which the methanecycloalkylhydroxydiphosphonate is methanecycloheptylhydroxydiphosphonic acid or a pharmaceutically acceptable salt thereof.

References Cited 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. 260502.4

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US4269828 *Jul 13, 1978May 26, 1981The Procter & Gamble CompanyIndole anti-inflammatory composition
US4275059 *Jul 31, 1978Jun 23, 1981The Procter & Gamble CompanySalicylate anti-inflammatory composition
US4282214 *Oct 22, 1979Aug 4, 1981The Procter & Gamble CompanyPhenylacetate anti-inflammatory composition
US4330530 *Dec 22, 1980May 18, 1982The Procter & Gamble CompanyAnti-arthritic compositions and method using gold salts and organophosphonates
US4634691 *Jan 19, 1983Jan 6, 1987The Procter & Gamble CompanyMethod for inhibiting tumor metastasis
US4868164 *Dec 19, 1986Sep 19, 1989Norwich Eaton Pharmaceuticals, Inc.Octahydro-pyridine diphosphonate compounds, pharmaceutical compositions, and methods for treating abnormal calcium and phosphate metabolism
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US4963681 *Jul 6, 1987Oct 16, 1990Norwich Eaton Pharmaceuticals, Inc.Process for synthesis of aminomethylene phosphonoalkylphosphinates
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US5662888 *May 3, 1996Sep 2, 1997Jeffrey Mitchell LaboratoriesToothpaste for smokers for solubilizing and removing tobacco tars
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Classifications
U.S. Classification424/49
International ClassificationA61K8/55, A61Q11/00, A61K8/30
Cooperative ClassificationA61K8/55, A61Q11/00
European ClassificationA61K8/55, A61Q11/00