US3584116A - Oral compositions for calculus retardation - Google Patents

Abstract

ORAL COMPOSITIONS, SUCH AS TOOTHPASTE, MOUTHWASH, AND THE LIKE, CONTAINING CERTAIN PERFLUORO-1,2-DIPHOSPHONOCYCLOALK-1,2-ENES AND SALTS THEREOF, WHICH RETARD DENTAL CALCULUS FORMATION WITHOUT DAMAGING TOOTH STRUCTURE.

Description

U S a e Pate s "w 16 claims No Drawing. Filed Dec. 11, 1967, Ser."- Int. Cl. A61k 7/16 U.S. 01.424-52 ABSTRACT OF THE DISCLOSURE j Oral compositions,'such as,toothpaste, mouthwash, and the like, containing certain perfluoro-1,2-dipliosphonocycloalk-1,2-enes and salts thereof, which retard dental calculus formation without damaging tooth structure.

BACKGROUND OF THE INVENTION 3,584,116 Patented June 8, 1971 calcification. Thus, the development of oral .compositions which effectively retard calculus calcium chelation has been impeded by safety considerations. Safe and effective anticalculus agents have been developed (see. for example US. application Ser. No. 668,702, filed Sept. '18, ,1967, by Homer W :McCune .and Nathaniel .B. Tucker), now abandoned, however, researcherscontinueto seek alternative anticalculus agents for use in oral compositions.

SUMMARY OF THE INVENTION It has now been discovered that certain perfluoro-L2} diphosphonocycloalk-l,2-enes and salts thereof (some- 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 may consist 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 caused by deposits of calculus 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 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, forexample, British Pat. 490,384, granted Feb. 15, 1937, which discloses oral compositions containing ethylenediaminetetraacetic acid, and related polycarboxylic acids as anticalculus agents; German Auslegeschrift 1,149,138, published May 22, 1963, which discloses certain watersoluble diglycolates as anticalculus agents; and U.S. Pat 1,516,206 which discloses oral compositions containing various sugar lactones for this purpose.

Although certain of the art-disclosed chelators are pur- I times referredv to collectively hereinafter ,as PFDC) possess the surprising capacityto 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 Although PFDC possess only nominal calcium sequestering capacities in the pH range characteristic or oral compositions, they effectively 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 irorganic polyphosphates such as pyrophosphates, the PFDC resist hydrolysis in aqueous products and therefore remain in an active form throughout the normal shelf-like 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 improvide 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 from about 0.01% to about 10% by weight of at least one anticalculus agent selected from the group consisting of those of the structural formula:

CPO3M2 2)n --CPO Mz wherein n is an integer from 2 to 4 and M is hydrogen or a pharmaceutically acceptable salt forming cation such as alkali metal (e.g., sodium and potassium), alkaline earth metal (e.g., calcium and magnesium), stannous, indium, ammonium, or low molecular weight substituted ammonium e.g., mono-, di-, and triethanol-ammonium); the pH of the composition being within the range from about 5.0 to about 11.0.

PFDC can be prepared by any suitable method, however, an especially preferred method involves reacting trialkyl phosphites with 1,2-dichloroperfluorocycloalkenes in accordance with the procedures fully described by Frank in J. Org. Chem., 30, 3663 (1965), and hydrolyzing the resulting esters.

. The concentration of PFDC in the oral compositions of this invention can range from about 0.01% to about 10% by weight. Oral compositions which in the ordinary course of usage are likely to be accident-ally ingested in substantial volumes should contain lower concentrations of PFDC. Thus, a mouthwash in accordance with this invention preferably contains less than about 3% by weight of PFDC. Dentifrice compositions and topical solutions, 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 PFDC.

The pH of the compositions 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 relatives safety of the PFDC. Above about pH 11.0 difficulty is encountered in formulating products having satisfactory flavor, mildness, and safety. A preferred pH range is from about 6.5 to about 10. The pH of the composition, of course, is determinative of the predominant salt form of the PFDC present therein.

While it is not intended that this invention be limited by a particular theory of operation, it has been observed that PFDC interfere with the progress of calculus formation by interfering with the conversion of amorphous calcium phosphate to crystalline calcium hydroxylapatite. Amounts of PFDC 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 was demonstrated by the Crystal Growth Inhibition test which was conducted as follows:

CRYSTAL GROWTH INHIBITION DETERMINATION As hereinbefore stated, the PFDC 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 PFDC on the calcium phosphate formed on addition of calcium ion to orthophosphate ion at constant pH. The procedure is as follows using a representative PFDC compound as an example:

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 disodium 3,4,5-hexafiuor-1,2-diphosph0nocyclopent-1,2-ene (HFDC) 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 sufficient reaction time as determined by the operator, generally within 90 minutes, the solution is filtered through a 0.45p. millipore filter pad, dried, and analyzed by X-ray dilfration. The solid calcium phosphate precipitated from the above-described solution without HFDC gives a typical hydroxylapatite pattern, while the calcium phosphate precipitated under the same conditions but in the presence of small amounts of HFDC 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 1.5 X 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 have little or no effect in this test do not reduce calculus in rats.

The concentration of HFDC required to inhibit the formation of calcium hydroxylapatite under the conditions specified above was found to be 1.82 10- M. The presence of this concentration of a representative PFDC in the test solutions of the Crystal Inhibition Test results in the precipitation of an amorphous calcium phosphate rather than crystalline calcium hydroxylapatite as occurs without HFDC. 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 of hydroxylapatite at molar concentrations of 2.45 X 10- and 2.54 10* respectively. At higher concentrations, these prior art compounds prevent precipitation of calcium phosphate in this test because of their removal of calcium ion from solution by their se- 4 questering properties, not by their crystal inhibition properties.

The safety of PFDC 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 PFDC in accordance with this inventin at pH 7.0 and pH 10.0. Every four hours the teeth are examined for decalcification. Under visible light, enamel decalcification can be detected by a loss of inter, while opaque spots or slight surface roughtening. 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;

A dentifrice, especially toothpaste, containing PFDC is a preferred embodiment of this invention. Toothpaste compositions conventionally contain abrasive materials, sudsiug 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 PFDC 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 fl-phase calcium pyrophosphate prepared for example in accordance with the teachings of Schweizer, US. Pat. 3,112,247, granted Nov. 26, 1963, while 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, ureaformaldehyde, 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 by weight of the dentifrice. Preferably, toothpastes contain from 20% to 60% by weight of abrasive. Abrasive particle size preferably ranges from 2p to 20,11.

Suitable sudsing agents are those which are reasonably stable and form suds throughout a wide pH range, preferably nonsoap 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 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 hydroxyethylcellulose 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.

Melamine/urea/tormaldehyde resin 1 Urea/formaldehyde resin L Sodium metaphosphate Alumina Z Sodium carboxymethyl cellulose Hydroxyethylcellulose Magnesium aluminum silicate Sodium lauryl sulfate Sodium coconut monoglyceride sulfonate Saccharin Several mouthwash compositions are prepared in accordance with this invention as follows:

It is also desirable to include some humectant mate- Parts by weight rial in a toothpaste to keep it from hardening. Suitable 5 Example X XI 'ifi humectants include glycerine, sorbitol, and other edible polyhydric alcohols. The humectant can comprise up to 5 1M 10.0 1M m about 3% by weight of the toothpaste composition. yl alco ol 16. 16. 5 16.3 16.15 Suitable flavoring agents include oil of Wintergreen, g ;gggfi i i 3,1; oil of peppermint, oil of Spearmint, oil of sassafras, and Sodium cyclamate- .075 .075 .075 oil of clove. Sweetening agents which can be used include 5533?, 4'??? a??? saccharin, dextrose, levulose and sodium cyclamate. g g 0 10 0 Several representative oral compositions illustrating this invention are set forth in the following examples. Polvoxyethylene moles oiethylcne oxide) sorbitan monooleatea 15 ith ifl fit fi itislfiiiii lliiffififi EXAMPLE I l I 1 giammonium salt of 3,4,5-hexafluor0-lIZ-diphosphonocyclopent- A toothPaste of the following composmon 18 prepared ,4 Tripotassium salt of 3,4,5-hexafluoro-1,2-diphosphonocyclopentby conventional methods. 1,2-ene.

Parts by Weight 5 Tr1 sod1um salt of 3,4,fi-hexafluoro-l,2-d1phosphonocyclopent-l, 2 ene. W t 31 5 8 th Adflustefi to value indicated with the base solution corresponding to a 61 2O esa use Srb1t01 When used in the same manner as conventional mouthsaccllarln wash, at least once daily, each of the above compositions Calcwrp Pyrophosphate 39-00 materially reduces accumulation of calculus on the sur- Glyflerlne 18-00 faces of teeth. No decalcification is observed after seven g gf alkyl (t l sulgite Ki 25 days exposure of dental enamel to these compositions. 0 mm coconu monog yceri e su ona e 7 Sodium carboxymethyl cellulose 1-15 EXAMPLE XIV Mangeisium alllmlmlm slllcates Q40 A prophylaxis paste for use by the dentist for removal f j g of stains and polishing the teeth after mechanical removal 1315051111111 sallt 2 3,4,5'heXafiurliz'dlphosphom" 1 50 of calculus deposits is formulated as follows:

c co ent- -ene p 530 Parts bywt.

n N va' Prepared in accordance with US. Pat. 3,112,247 granted 2 10 pumlce 1 Nov. 26, 1963. 2 5

c r ThlS composition effectively retards calculus formation y 6 me I 7 a Hydroxyethylcellulose .22 on dental enamel and when tested in the Continuous Im- Saccharin 33 2 ;;i gg g g sti gzi g no decalclficatlon 18 noted Disodium salt of 3,4,5-hexafiuoro-l,Z-diphosphonoy P cycl0pent-1,2-ene 4.0 Toothpaste compos1t1on substantially identical to the Trisodium Salt of 3 4 5 h H 12 h composition of Example I are prepared with the dipotas- 40 home do In 12 exa uoro' 1p 4 0 sium salt of 3,4 tetrafluoro-l,Z-diphosphonocyclobut-1,2- f y pe ene, the monocalcium salt of 3,4,5,6 octafiuoro-l,2-dip phosphonocyclohex-l,Z-ene; 3,4 tetrafluoto-LZ-diphos- When applied to the teeth with a prophylactic rubber phonocyclobut-1,2-ene; 3,4,5,6 octafiuoro 1,2-diphoscup in the conventional manner, this composition helps phonocyclohex-l,2-ene; and the di(triethanolammonium) retard the development of new calculus deposits. salt of 3,4,5-hexafluoro-l,Z-diphosphonocyclopent-1,2-ene Toothpowders and the like can be prepared by convenraltherhthan tlie disodium2 salt ofd3,4,5-hex:fluoro-1,Z-ditiOnal1 methods and containing, in addition to the usual p osp onocyc opent l, -ene, a justing t e pH to 5.9. ingre ients, an amount of PFDC within the ranges speci- These compositions substantially retard calculus formafied herein, to provide an effective means of retarding no; atrlild do no; defiatlcifty1 detntal enamtelw d calTc Elus formation ttivithcilut dimagglfgDtlg tolgtli1 structure. or er examp es 0 0o pas e composl ions in accor ose componen s ot er t an w 1c were inance with the invention are set forth in Table 1 below. cluded in the foregoing examples and various mixtures of TABLE 1 Parts by weight Example II III IV V VI VII VIII IX Component:

Flavoring Diammonlum salt of 3,4,5-hexafiuoro-l,2-diphosphonocyclopent-1,Z-ene. Monocalclum salt of 3,4-tetrafiuoro-l,2-diphosphonocyclobut-l,2-ene- Distannous salt of 3,e-tetrafluoro-l,2-diphosphonocyclobut-1,2-ene Indium salt of 3,4-tetrafluoro-1,2-diphosphonocyclobut-l,2-ene Triammonium salt of 3,4-tetrafiuoro-1,2-diphosphonocyclobut-l,2'ene Trisodium salt of 3,4,5,fi-octafluoro l,2-diphosphonocyclohex-1,2-ene Distannous salt of 3,4,5,6-octafiuoro-l,2-diphosphonocyclohex-1,2-ene a lege (diethanolammonium) salt of 3,4,5,6-octafluoro-l,2-diphosphonocyclohex-1,2-ene a er Adjust pH to 5. 5

As described in U.S. Pat. 3,070,510. 9 Prepared in accordance with U.S. Pat. 3,003,919.

Balance 6. 5 7. 0

those components are illustrative of carriers suitable for use in the oral cavity.

In 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 PFDC employed is used. In each case in which the PFDC was added in its acid form to the example compositions, the pH was adjusted to the specified value with NaOH. Adjustments in pH to more acid levels when adding the PFDC in the salt forms is accomplished with HCI. 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. A method for inhibiting the formation of dental calculus without adversely afiecting tooth structure, comprising the application to dental surfaces of a composition comprising from about 0.1% to about 5.0% by weight of an anticalculus agent selected from the group consisting of those of the formula:

wherein n is an integer from 2 to 4 and the pharmaceutically acceptable salts thereof, and 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 method of claim 1 wherein the anticalculus agent is 3,4,5-hexafluoro-1,2-diphosphonocyclopent-1,2- ene or an alkali metal, alkaline earth metal, stannous, indium, ammonium, or low molecular weight substituted ammonium salt thereof.

3. In a dentifrice composition containing from about 5% to about 95% by weight of a dentifrice abrasive and having a pH within the range from about 5.0 to about 11.0, the improvement comprising the incorporation therein of from about 0.1% to about 5.0% by weight of an anticalculus agent selected from the group consisting of those of the formula:

-CPO3Hz wherein n is an integer from 2 to 4 and the pharmaceutically acceptable salts thereof.

4. The. composition of claim 3 wherein the anticalculus agent is 3,4,5-hexafiuoro-1,Z-diphosphonocyclopent-1,2- ene, or an alkali metal, alkaline earth metal, stannous, indium, ammonium or loW molecular weight substituted ammonium salt thereof.

5.1 In a mouth ash composition containing a flavoring agent and having a pH within the range from about 5 .0 to about 11.0, the improvement comprising the incorporation therein of from about 0.1% to about 5.0% by weight of an anticalculus agent selected from the group consisting of those of the formula:

|-'--CP 03H: 2)n ll 1 fif wherein n is an integer from 2 to 4 and the pharmacew tically acceptable salts thereof. p

6. The composition of claim 5 wherein the anticalculus agent is 3,4,5 hexafluoro-l,2-diphosphonocyclopent 1,2- ene or an alkali metal, alkaline earth metal, stannous, indium, ammonium, or low molecular weight substituted ammonium salt thereof;

' References Cited Frank, Journal of Organic Chemistry, vol. 31, pp. 1521 1524, May 1966. Copy in POSL. 1 Hoffman et al., Journal of Periodontology, vol. 34,.p. 44, July 1963. M V v RICHARD LI'HUFF, Primary Examiner