CA1090257A - Alkylenedioxybis (alkyl-propanedioic) compounds as dental calculus inhibitor - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

The invention provides oral compositions which are effective to inhibit formation of dental calculus. The composition comprises an alklenedioxybis (alkyl-propanedioic acid) compound selected from the group consisting of acids having the formula:

Description

43_4 379 A

;257 INHIBITION OF DENTAL CALCIJLUS

BACK~ROUND OF T~3:E INVEN~ION
The field of this invention is "oral compositions"
which term herein means products intended for lntroduction into the oral cavity in such a manner as to contact exposed dental surfaces therein. Examples of such products are animal foods and beverages, chewing gums and oral hygiene products including mouth washes, prophylaxis pastes, topical solutions and dentifrices such as toothpastes, tooth powders, dental creams and the like.

Dental calculus, or tartar as it is sometimes called, is a deposit which forms on the surfaces of teeth predominantly at or near the gingival margin. Supragingival calculus appears most heavily in areas near the orifices of the salivary ducts.
Mature calculus contains an inorganic portion which is largely calcium phosphate arranged in a hydroxyapatite crystal lattice structure similar to that occurring in bone, enamel or dentine.
An organic portion is typically also present consisting of desquamated epithelial cells, salivary sediment, food debris, various types of microorganisms, etc.

As calculus develops, it becomes visibly white or yellowish unless stained or discolored by some e~traneous sub-stance. In addition to being undesirable from an esthetic standpoint, mature calculus deposits are sources of irritation of the gingiva and thereby a contributing factor to gingivitis and other diseases of the supporting structures of' the teethg the irritation decreasing the resistance of tissues to endo-genous and exogenous organisms.
Periodic mechanical removal of this material by a 3 dentist or dental technician is routine dental office procedure.

5~

There have also been proposed a number of che~lical agents for calculus removal. For example, alkali metal and ammonium diglycolates and diglycolates of organic bases such as urea, guanidine or ethanolamine are suggested for that use in U.K.

Patent 995,330 issued 16 June 1965 to R. A. Oetker. In French Patent 2,108,827 published 26 May 1972 it is said that the calcium ion-sequestering capability of sodium gluconate can be used for removal of tartar from the teeth. In U.S. Patent 1,516,206 issued 18 November 1924 to C. Pfanstiehl it is said that a tartar solvent effect is provided by use of an aqueous solution of a lactone or anhydride of a weak organic hydroxy acid, e.g., galactonic acid, together wi~h a weak organic acid such as maleic or citric acid, and it is taught in U.S. Patent 3,429,963 issued 25 February 1969 to L. Shedlovsky that dental calculus can be removed by use of dental preparations containing a hydrolyzed copolymer of ethylene and maleic anhydride having an average molecular weight of at least about 1500.
In some instances, chemical agents have been said to be capable of retarding calculus formation. For example, in the aforementioned U.S. 3,429,963 it is disclosed that a reduction in calculus formation was observed in rats when the drinking water given to the rats contained 1 percent of a hydrolyzed co~
polymer of ethylene and maleic anhydride. In the aforementioned U.K. Patent 995,330 it is said that a reduction in tartar forma-tion was produced by the use of toothpastes containing the aforementioned diglycolates. Another polymer, i.e., a poly-ester of a polycarboxylic acid having three or more carboxyl groups and a polyalkylene ether having at least two hydroxyl groups, is described as a calculus retarding agent in U.S.
Patent 3,542,917 issued 24 November 1970 to A. M. Schwartz et al.
In U.S. Patent 3,920,837 issued 18 November 1975 to M. Schmidt-~ ~0 ~ 5 7 Dunker et al it is said that tartar formation can be reduced by cyclohexanehexacarboxylic acid or its water-soluble salts, and in U.K. Patents 1,373,001 and -003 issued 6 November 1974 to R. Hoyles et al, it is said that calculus can be reduced by use of a denti~rice containin~ a sparingly water-soluble zinc salt, e.g,, zinc citrate. ~arious phosphorous compounds such as, eOg., ethane-1-hydroxyl~ diphosphonic acid (hereinafter EHDP) have also been proposed for such use in U.S. Patent 3,488,419 issued 6 ~anuary 1970 to H. W. McCune et al.
Some chemical agents heretofore proposed for calculus removal or retardation contain functional groups of uncertain effect on animals in terms of toxicity, side effects, etc.
Certain other kinds of compounds containing only carbon, hydro-gen, oxygen and possibly physiologically acceptable cations are believed essentially free from such uncertainty and there-fore preferable for use in oral compositions. Also desirable for present purposes are compounds of relatively simple struc-ture and low molecular weight, as well as compounds which can be prepared without resort to a polymerization process. Accord-ingly~ oral compositions containing compounds which meet those criteria and substantially inhibit dental calculus formation are highly desirable, and it is an ob~ect of this invention to provide such compositions. Another object is a method for inhibiting dental calculus formation by use of such compositions.
Other obJects will be apparent from the following disclosure in which percentages are by weight except where other~ise noted.

SU~MARY OF THE IN~EN~ION
This invention provides an oral composition effective in inhibiting formation of dental calculus, said composition comprising ~1) a propanedioic acid compound selected from the group consisting of acids having the structural formula:

5~
COOH COOH
X -- C -- O -- Y -- O -- C -- Z
. COOH COOH
wherein Y is Rl or R3 R5 ~ R7~ ~ R9 - C _ ---C - -' C ''''--t OC ~ C
R2 R4 R6 ~ R8~ ~ RlO~
m n and X and ~ are each independently Rll if' Y is R

Rl3 R2 and 14 R3 R5 ~ R7~ ~ R9 R15' C - C ~R87L~ Rl,o7 ~ n wherein Rl through R 5 are each independently hydrogen or lower alkyl; m is O or l; n is the sum of m and 0, l, 2 or ~; and the sum of 2m and n is 0, 1, 2 or 3, and physiologically acceptable salts of said acids and (2) a carrier suitable for use in the : oral cavity, said compound being present in said composition in amount and concentration sufficient to substantially inhibit formation of dental calculus.
The preferred aspect of the present invention comprises compounds selected from the group consisting of acids adding the structural formula:

CIOOH IOOH

R C -C - O ~ CR - O - C - CR

COOH COOH
wherein R is hydrogen or lower alkyl and each R can be the same as or different from any other R in the formula.

DESCRIPTION OF PREFERRED EMBODIMENTS
In the foregoing structural formula, it is understood that the R substituents in the general formulae representing d Z (i Rll R12 R13 R14 R15) -can be the same or different for each o X and Z. Also, as used herein "]ower alkyl means Cl-C4 alkyl which can be branched (e.g., isopropyl, isobutyl or tert-butyl) or cyclic (cyclopropyl or cyclobutyl) but which are preferably straight-chain (methyl, ethyl, n-propyl ' -5a- .

_ 3~
or n-butyl).
In some preferred embodiments of the invention ~ and Z
are each independently represented by the formula COOH
'15 These compounds are herein designated bis(carboxyalkoxypro-panedioic acid) compounds. In some of those embodiments it is preferred, particularly if m is 1, that Rl and R15 in each of X and Z each independently be hydrogen or normal alkyl; and in some of those embodiments it is even more desirable that the sum of the carbon atoms in R1`4 and R15 is not greater than 4 for both X and Z. In many of those embodiments the average number of carbon atoms in the Rls in X, Y and Z is preferably not greater than 2 and even more desirably not greater than 1. It , is especially preferred in those embodiments that all R's be hydrogen.
In other preferred embodiments of the invention Y is Rl Rll - C - and X and Z are each independently - C - R12. These R2 , R13 compounds are herein designated alkylenedioxybis(alkyl-propanedioic acid) compounds. In those embodiments it is pre-ferred that the R's in X, Y and Z are each independently hydrogen or normal alkyl and even more preferred that they are each independently hydrogen, methyl or ethyl. In some other of those embodiments it is preferred that one of Rl and R2 is hydrogen and even more preferred that both are hydrogen. In still other of those embodiments it is preferred that at least two R's in each - C _ R-2 radical is hydrogen, and also preferred R13 Rll that the total number of carbon atoms in each of these - C - R12 radicals is not greater than 7. In a particularly preferred embodiment each R in X, Y and Z is hydrogen.
The above described embodiments are generally pre-ferred on the basis of relatively low molecular weight.
The compound represented by the foregoing formula GOOH
when X and Z are - O - C - H2, m and n are each 1, and all R's in Y are hydrogen is `designated 2,2'-bis(carboxymethoxy)-

2,2'-~oxydiethylenedioxy)-bis(propanedioic acid) and is here-inafter for convenience called BCOBPDA. That acid and varia-kions thereof can be prepared by the following procedure,additional details of which are set forth in U.S. Patent

3,950,3~8 issued to Kent P. Lannert April 13, 1976.
To prepare said compounds, a diol (dihydric alcohol) ; having the form~la R R5 ~ R7 ~ ~ R9 ~
HO - C C. - - OC ~l - C - OH

R4 R6 ~ R8 Jm ~ R10/ n in which R3-R10, m and n have the aforesaid significance is reacted with a base strong enough to deprotonate the hydroxy groups of the diol (e.g., metallic sodium or potassium or sodium or potassium hydride, tert-butoxide or amide) and form a conjugate base in which the deprotonated oxygen atoms of the diol are associated with cations furnished by that base (e.g., sodium or potassium ions). It will be apparent from the fore-; going that diols preferred for this use include diethylene glycol, ethylene glycol and other straight-chain alkane diols having both of their hydroxyl groups terminally situated, i.e., 1,3-propanediol, 1,4-butanediol and 1,5-pentanediol, but khat 25'7 many other diols, e.g.~ 1,3-butanediol, 3,7-decanediol, 3-methyl-2,6-heptanediol, 3-ethyl-5-propyl-2,6-oct~anediol~
etc., can likewise be used.
The conversion of alcohols to their conjugate base forms is known in the art. The reaction is conveniently carried out between 0 and 115C. in any solvent for the alcohol not adversely reactive with the strong base. Examples of suitable solvents include tetrahydrofuran, dimethylsulfoxide, dimethyl-formamideg ethylether, 1,2-dimethoxyethane, bis (2-methoxyethyl~-10 ether and the like. In those instances where the reactant diolis a liquid, an excess of such diol may be employed as the sol-vent. Mixed solvents can be used, if desired. More detailed discussion of the conversion of alcohols to con~ugate bases is found in such references as Morrison and Boyd, 'Organic Chemistry, 3rd edition, Allyn and Bacon, Inc. (1973) pp. 526, 527; Feuer and Hooz, The~ Chemistry of' the' Ethe_nkage, edited by Patai, Interscience Publishers (1967 ), Chapter 10, p. 447; and Schmidt and Bayer, Methoden Der Organischen Chemie (Houben-Weyl ) Band VI/2, Georg Theime Verlag, (1963) Saurstoff Vergindunger 1, 20 Teil 2 and bibliographies provided in the foregoing references.
The conjugate base ~orm of the diol is then reacted with a ketomalonate ester COOA
C = O
COOA
which will convert the deprotanated oxygen atoms of the diol to COOA
-0~,0 COOA

substituents. In the ester formula above, A is any organic moiety which will not interfere, e.gO, by virtue of chemical 2~i'7 reactivity or steric hindrance, to prevent the desired ester-base reaction. The reaction will normally proceed in all cases when A is methyl or ethyl, and the use of diethylketomalonate is typically preferred. ~he reaction is usually carried out between -~0 and 50Co (preferably between -20 and 30C~) and ad~antageously in the solvent used in preparation of the con-jugate base. The quantity of the ketomalonate ester present and the severity of reaction conditions should be controlled to bring about reaction of one molecule of the ester ~or each deprotonated oxygen atom in the conjugate base of the diol.
The product of the ester-base reaction is then re-acted with a bromo- or iodocarboxylate having the structural formula DCCOOA in which ~ is bromine or iodine and R14, R15 and A have the aforesaid significance, to convert the -0' radicals of the conjugate base to -OCC00A substituents and thereby yield the ester forms of the acids and/or salts employed in the present invention. The bromo- or iodocarboxylate may be added as such or produced in situ, e.g., by using a mixture of sodium iodide or bromide and an appropriate chlorocarboxylate such as, for example, ethylchloroacetate, methyl-2-chloropropionate, ethyl-2-chlorobutyrate, methyl-2-chloroisobutyrate or the like. A reaction temperature between -20 and 100C. is usually satisfactory, and an elevated or atmospheric pressure can be usedO
Reaction of the resulting hexacarboxylic acid esters with an alkali metal (e.g., sodium or potassium~ hydroxide yields the alkali metal salts useful in this invention. Any of S~

those salts can be converted to the corresponding acid (e.g., BCOBPDA) by treatment with a strong acid, e.g. HCl, H2SO4 or a strongly acidic ion exchange resin. The corresponding ammonium, mono- or di(Cl-C3 alkyl)ammonium or mono- or di(~l- C3 alkanol) ammonium salts can be prepared by reacting such acids with ammonia~ an appropriate alkylamine or alkanolamine or hydroxide thereof in accordance with procedures well known in the art.
Alternatively in the foregoing procedure for prepara-tion of the bis(carboxyal~oxy-propanedioic acld) compounds (e.g., BCOBPDA) used in this invention, the diol can be mi~ed first with the ketomalonate ester and the mixture then reacted with a strong base of the kind described hereinbefore. In another alternative to said procedure, especially useful when there may be steric hindrance by one or both of the R's in the - CCOOA

radicals to be included in such compounds, a monoalcohol form of that radical (i.e., HOCCOOA) is reacted with a strong base to form the conjugate base of that alcohol, the conjugate base is reacted with the ketomalonate ester, and two molecules of the product of that ester-base reaction are reacted with each mole-cule of a dihalide counterpart of the aforementioned diol, e.g., ~, ~ ~ ' ~
a dibromide having the formula Br - C - C - \

in which R3- Rl0, m and n have the aforesaid significance.

The compound represented by the foregoing formula when Y is -CH2~ and both X and Z are -CH3 is herein designated 2,2'-dimeth~1-2,2'-(methylenedioxy)-bis~propanedioic acid) (hereinafter for convenience called DMBPDA). The tetrasodium salt of that acid can be prepared by contacting an appropriate diester of methyl tartronic acid, e.g., a di(lower alkyl)ester such as diethyl methyl tartronate, with a base strong enough to deprotonate the hydroxy group of that diester (e.g., metallic sodium or potassium or sodium or potassium hydride, tert-butoxide or am~de) and form a conjugate base in ~hich the deprotonated oxygen atom of the diester is associated with a cation furnished by that base (e.gO, a sodium or potassium ion), then reacting that conjugate base with a dihalomethane (e.g., dibromomethane) in a two-to-one molar ratio to form the tetra-ester o~ DMBPDA, and then saponifying that tetraester with sodium hydroxide.
Sodium salts of acids represented by the foregoing Rll formula when X and Z are - C - R12 and at least one of R
Rl3 R12, and Rl3 is lower alkyl can be made by procedure analogous to that just described but in which the methyl tartronate di~
ester is at least partly replaced with a tartronic acid diester having on its hydroxylated carbon atom an alkyl substituent that is appropriately larger than methyl, e.g.~ ethyl, n-propyl, n-butyl, isopropyl, isobutyl~ tert-butyl, etc. Sodium salts . ~ Rl ~ of acids represented by that formula when Y is - C - and at least one of Rl and ~2 is lower alkyl can be made by procedure analogous to that ~ust described but in which the dihalomethane is replaced with a dihaloalkane having two halogen atoms directly attached to the same carbon atom of an alkylene radical that is appropriately larger than methylene, e.g., a dihaloalkane such as l,l-diiodoethane, l~l-dibronlopropane~ 2,2-dibromopro-pane, 2,2-dibromobutane, 2-methyl-3,3-dibromopentane, 2,2-dimethyl-3,3-dibromo-5-methylhexane, etc.
The conversion of hydroxylated compounds to their conjugate base forms is known in the art and described herein-before Reactions of such con~ugate bases with haloalkanes to form ether linkage containing compounds are also known in the art. In the hereinbefore described procedure to produce alkylenedioxybis(alkyl-propanedioic acid) compounds (e.g., DMBPDA), it is usually desirable to use a diiodoalkane or, generally even more preferably, a dibromoalkane. Either may be added to the alkyl tartronate diester as such or produced in situ, e.g., by using a mixture of sodium iodide or bromide and an appropriate dichloroalkane such as, for example, dichloromethane, l,l-dichloroethane, l,l-dichloro-n-propane, 2,2-dlchloropropane, 2,2-dichloro-n-butane or the like. A
reaction temperature between -20 and 100C. is usually satisfactory and an elevated or atmospheric pressure can be used.
Any of the aforementioned alkylenedioxybis(alkyl-propanedioic acid) salts can be converted to the corresponding acid (e.g., DMBPDA) by treatment with a strong acid, e.g., HCl, H2SO4 or a strongly acidic ion exchange resin. Other metal salts of the resulting acids can be prepared by neutralization with the appropriate metal hydroxide~ e.g., an alkali metal hydroxide such as potassium hydroxide. The corresponding ammonium, mono- or di(Cl-C3 alkyl)ammonium or mono- or di(Cl-C3 3 alkanol)ammonium salts can be prepared by treating such acids with ammonia, an appropriate alkylamine or alkanolamine or hydroxide thereof in accordance with procedures well known in the art.
In the oral compositions of this invention, the pro-portions in which the propanedioic acid compounds are present as acids and/or partially-substituted or fully-substituted salts thereof are dependent on the pH of the compositionO That pH is normally between about 4 and about 11~ although in some instances ; it may be higher or lower than that range. Below about pH 4 there is a greater danger of damage to dental enamel despite the relative safety of the aforementioned acid or its saltsO
Above about pH llg greater difficulty is encountered in formu-lating products having satisfactory ~lavor and mildness. A
preferred pH range is from about 6 to about 10. In many embodi-; ments, the physlologically acceptable salts employed are pre-ferably water-soluble salts such as e.g., sodium, potassium or ammonium salts, to facilitate their dissolution in saliva.
As aforesaid, some embodiments of this invention are oral hygiene products such as dentifrices, mouth washes, prophy-laxis pastes and topical solutions. A dentifrice, especially toothpaste, containing a calculus-inhibiting amount of an acid represented by the foregoing formula and/or a physiologically acceptable salt thereof is a preferred embodiment of this inven-tion. A mouth wash containing such an acid and/or salt is another preferred embodiment. Except for inclusion of a propanedioic acid compound as aforesaid, many formulations of such products are well known in the artO For example, typical formulations of toothpastes and mouth washes compatible with calculus-inhibiting compounds of the kind employed in accor-3 dance with this invention are described in U.S. ~atents 3,639,569 ` - ~

issued 1 February 1972 to R. F. Medcalf, Jr.~ 3,54~,678 issued 1 December 1970 to W. J. Griebstein, 3,678,154 issued 18 July 1972 to J. S. Widder et al and 3,959,458 issued 25 May 1976 to F. O. Agricola et al Under conditions of normal use, the oral compositions of this invention are physiologically acceptable, iOeO, capable of introduction into the oral cavity without significant adverse effect on tooth structure o~ other in~ury to health. Subject to the limits of such acceptability, the calculus-inhibiting amounts and concentrations of the propanedioic acid compounds can be varied widely in the oral compositions of this invention.
Such amounts and concentrations are also readily definable for each kind of oral composition by formulators skilled in the art. Generally, concentrations from 0.01% to about 10% are preferred. Oral compositions which in ordinary usage may be accidentally or intentionally ingested can contain relatively low but still highly effective concentrations. Of course, any such ingested composition should be phy;siologically (i.e., digestively) acceptable. Thus~ a mouth wash in accordance with this invention typically contains between about Ool and about 3% of the aforementioned calculus-inhibiting compound. Denti-frice compositions, topical solutions and prophylaxis pastes, the last normally administered professionally, may desirably contain up to about 10% or even more thereof but usually con-tain between about Ool and about 5% and even more typically between about 1 and about 2~ thereof.
Ilhile it is not intended that this invention be limited to any particular theory of operation, it appears that 3~ the propanedioic acid compounds inhibit calculus formation by B

~1[3~257 interfering with the conversion o~ dissolved calcium phosphate in saliva to crystalline deposits in the nature of calcium hydroxyapatite. Hence, the compositions of this invention preferably do not contain soluble polyvalent cations in an amount likely to deplete the crystal growth inhibiting capacity of those compounds to the extent that their calculus formation inhibiting activity would be essentially neutralized.
The following specific examples are illustrative only and do not imply any limitations on the scope of the invention.
EXAMPLES_I - V
A. Evaluations of Calculus Inhi~ition Evaluations of the effectiveness of compounds employed in accordance with this invention to inhibit calculus formation were carried out fundamentally as described in "A Method and Apparatus for Studying In Vitro Calculus" by S. ~ankelowitz et al of the Colgate-Palmolive Co., Journal of Dental Research 44 (No. 4), 648-53 (1965). In accordance with that method, now well known in the art, simulated oral calculus deposits are caused to be formed on glass slides by mechanically rotating the slides edgewlse and vertically at 0O5 rpm in such a way that each slide passes alternately through a small sample of whole human saliva containing 001% of added monocalcium phosphate and then through a forced draft of air which at least partially dries each slide before it passes again through that saliva sample. As stated in the journal article just mentioned, the resulting calculus deposits have been found similar to oral calculus deposits in both composition and ~-ray diffraction pattern.
In the present evaluations, 150 mls of stimulated saliva were collected over a three-day period (50 ml/day) from a donor whose saliva had been previously found to have a sub-s~antial tendency toward calculus forma~ionO The collected saliva was also of a type in which, under the conditions of this test, calculus formation is inhibited by EHDP substantially more than by water substituted for the EHDP in a comparative test run. Each 50 ml portion of the saliva was kept frozen until ready for useO At that time the combined 150 ml sample was neutralized to pH 7_ .05 after addition of the 001% of mono-calcium phosphate, thoroughly stirred and then divided into 25 ml aliquots. To one aliquot was added l ml of a O.l M
solution of the tetrasodium salt of DMBPDA or the hexasodium salt of BCOBPDA, and to a second aliquot was added l ml of a 0.1 M solution of the prior art anti-calculus compound EHDP, each of those solutions having been previously neutralized with NaOH or H2S04. To a third aliquot was added l ml of distilled water.
For comparative test purposes, the three aliquots were then placed in identical side-by~side trough-like containers in an oven equipped with apparatus adapted to rotate a separate set of three 22 x 40 mm glass slides (spaced about 120 apart in relation to khe rotating shaft on which they were mounted) through each of the saliva containers and to maintain a steady horizontal flow o~ air against the slides and perpendicular to the axis of their rotation. All slides used were essentially identical and mounted on the shaft such that the same portion (24 mm) of the length of each slide passed through the appro-priate saliva sample~
In the oven just described, the calculus formation test was continued for 20 consecutive hours with the interior of the oven ~aintained at 37- 1C. and a relative humidity 5~

between 76 and 78%. The saliva samples were then removed from the oven, after which rotation o~ the slides in the flow of air was con~inued for an additional hour before removal of the slides from the oven. The weight of each slide and any deposit remaining thereon was then compared with the weight of the slide prior to its use in this test, and visual appraisals of the deposits were made using photographs taken o~ each slide under identical conditions to further eliminate variables ~rom those appraisals. Results were recorded separately for each of the three slides in each set and then averaged. In the test of the hexasodium salt of BCOBPDA the entire procedure was repeated using saliva from the same donorO The entire procedure was repeated using saliva from a di~ferent donor for both the hexa-sodium salt o~ BCOBPDA and the tetrasodium salt of DMBPDA. The results of the various runs were averaged in each case to pro-vide the results reported hereinafterO
1. DMBPDA
In the tests of the tetrasodium salt of DMBPDA, it was - found that the weights of simulated calculus on the slides that had been exposed to the salivas containing that salt averaged 0.32 mg, those on the slides used in the comparative runs with EHDP averaged 0.30 mg, and those on the slides used in the comparative runs with water averaged 0.67 mgO Thus, in the runs using the DMBPDA salt, formation of the simulated calculus averaged 52% less than in the comparative runs using water, while in the runs using EHDP it averaged 55~O less than in the comparative runs using waterO In the visual appraisals, the amounts of opaque material deposited on the slides that had been exposed to the salivas containing the DMBPDA salt were judged to be, on average, about the same as those on the slides used .. . . .... . . . .

in the comparative runs with EHDP and much less than half as great as those on the slides used in the comparative runs with waterO

In the tests of the hexasodium sa~t of BCOBPDA it was found that the weights of simulated calculus on the slides that had been exposed to the salivas containing that salt averaged 0O26 mg, those on the slides used in the comparative runs with EHDP averaged 0.26 mg, and those on the slides used in the comparative runs with water averaged 0.78 mg. Thus, in the runs using the hexasodium salt of BCOBPDA, formation of the simulated calculus averaged 67% less than in the comparative runs using water, while in the comparative runs using EHDP it likewise averaged 67% less than in the comparative runs using waterO In the visual appraisal, the amounts of opaque material deposited on the slides that had been exposed to the salivas containing the sodium salt of BCOBPDA were judged to be, on average, essentially the same as those on the slides used in . . .
the comparative runs with E~DP and much less than half as great as those on the slides used in the comparati.ve runs with water.

B. Pre~aration of Oral Com~ositions ,, , The compounds tested in Part A o~ these examples, the corresponding acids and other physiologically acceptahle salts of those acids are useful ~or inhibition o~ dental calculus for-mation when incorporated in compatible carriers or vehicles of any of the usual types. The following are examples of mouth wash compositions comprising at least one of such compounds.

EXAMPLES
Comp ent _ I II III `I~
-Glycerine 10.0 10.0 10.0 10O0 Ethyl alcohol 16.5 16O5 16.5 16.5 Water 670172 67.17267.172 70.192 Tween 801* .12 .12 .12 o12 Saccharin .45 045 45 .02 Sodium Cyclamate 0.75 0.75 0.75 Oo4 Flavor o088 .o88.o88 o088 Salt of DMBPDA or BCOBPDA 23.o 34 42.o 5108 pH 7O0 7O0 805 lOoO

.
Polyoxyethylene (20 moles of ethylene oxide) sorbitan monooleate - a nonionic emulsifier supplied by Atlas Powder CoO
2Tetraammonium salt of DMBPDA or hexaammonium salt of BCOBPDA.
3Tetra(triethanolammonium~ salt of DMBPDA or hexa(tri-ethanol ammonium) salt of BCOBPDAo 4Tetrasodium salt of DMPDA or hexasodium salt of BCOBPDAo 5Tetrapotassium salt of DMPDA or hexapotassium salt - of BCOBPDA~
Adjus~ed to value indicated with NaOH or H2SO4.

The following is an example of a toothpaste composi-tion comprising at least one of such comp~oundsO

* Trademark EXAMPLE V
COMPONENT Parts by Weight Water 31.58 Sorbitol 6 25 Saccharin 0.12 Calcium pyrophosphatel 39.00 Glycerine 18.00 Sodium alkyl (coconut) sulfate 0.40 Sodium coconut monoglyceride sulfonate 0.75 10 Sodium carboxymethyl cellulose 1.15 Magnesium aluminum silicates 0.40 : ~lavoring 0.85 DM~PDA or BCOBPDA 1.00 pH 5.90 _ Prepared in accordance with U.S. Patent 3,112,247 granted November 26, 1963.
Adjusted to indicated pH with sodium hydroxide.

Other examples of toothpaste compositions comprising at least one of said propanedioic acid compounds are substan-tially identical to the toothpaste composition above exceptfor substitution of the corresponding potassium or ammonium salt of DMBPDA or BCOBPDA, or the sodium, potassium or ammonium salt of 2,2'-diethyl-2,2'-(methylenedioxy)-bis(propanedioic acid), 2,2'-diisopropyl-2,2'-(methylenedioxy)-bis(propanedioic acid), or a 2,2'-bis(carboxymethoxy)-2,2'-(C2-C5 polymethylene-dioxy)-bis(propanedioic acid), e.g., 2,2'-bis(carboxymethoxy)-2,2' (ethylenedioxy)-bis(propanedioic acid)O
Additional examples of oral compositions comprising 43_4379A

25~7 at least one of such compounds include other mouth washes and toothpastes, tooth powders, dental creams and prophylaxis pastes for use by a dentist or dental technician in polishing of teeth after removal of calculus deposits. Examples of such compositions~ except for inclusion of a calculus-inhibiting compound of the kind used in accordance with the present inven-tion, are described in the aforementioned UOSo Patents 3,544,678, 3,639,569, 3,678,154 and 3,959,4580 Typically, toothpastes are aqueous compositions containing a po~ishing agent, a surfactant~
a binder, a humectant, a preservative, flavoring and sweetening agents and optionally therapeutic agentsO Mouth washes typi-cally contain water, ethanol, flavoring, sweetening and coloring agents and optionally a surfactantO Other examples of oral compositions comprising at least one of the compounds used in accordance with this invention include human foods and beverages such as soft drinks, candies, pastries, etc., foods for pets or livestock, chewing gums, etc. Such beverages, as distin-guished from mere drinking water, typically contain a flavoring agent, a nutrient or sweetening agent, and optionally thera-peutic agents. Chewing gums typically contain base materials,plasticizers or softeners, sugar or other suitable carbohydrates such as glucose, sorbitol, etc. Sugarless gums may contain other sweetening agents such as saccharin or sodium cyclamate.
The ingredients of each of the foregoing oral compositions, other than said propanedioic acid compounds, as well as various mixtures of such ingredients are illustrative o~ carriers suit-able for use in the oral cavity in accordance with the present inventionO

Claims (13)

The embodiments of the invention in which an exclu-sive property or privilege is claimed are defined as follows:

1. An oral composition effective in inhibiting forma-tion of dental calculus, said composition comprising (1) an alkylenedioxybis (alkyl-propanedioic acid) compound selected from the group consisting of acids having the structural formula:

wherein R is hydrogen or lower alkyl and each R can be the same as or different from other R in said formula, and pharmaceutically acceptable salts of said acids and (2) a carrier suitable for use in the oral cavity, said compound being present in said composition in amount and concentration sufficient to substantially inhibit formation of dental calculus.

2. A composition according to claim 1 wherein said carrier comprises a dental polishing agent, flavoring agent, chewing gum base material, or human or animal food.

3. A composition according to claim 2 wherein at least one R in the -CR2- radical is hydrogen and the number of carbon atoms in each of the two -CR3 groups is not greater than 7.

4. A composition according to claim 3 selected from the group consisting of oral hygiene products and chewing gums.

5. A composition according to claim 3 wherein R is hydrogen, methyl or ethyl.

6. A composition according to claim 3 wherein each R in the -CR2- radical is hydrogen.

7. A composition according to claim 3 wherein at least two R's in each of the two -CR3 groups in said formula are hydrogen.

8. A composition according to claim 2 wherein each R
in said formula is hydrogen.

9. A composition according to claim 8 selected from the group consisting of oral hygiene products.

10. A composition according to claim 8, said compound being selected from the group consisting of alkali metal and ammonium salts of said acids.

11. A composition according to claim 10 selected from the group consisting of foods and beverages to be ingested by humans or lower animals.

12. A composition according to claim 10 selected from the group consisting of mouth washes having a pH between about 4 and about 11, said concentration being between about 0.1% and about 3% by weight of said composition wherein said carrier comprises a flavoring agent.

13. A composition according to claim 10 selected from the group consisting of toothpastes having a pH between about 4 and about 11, said concentration being between about 0.1%
and about 5% by weight of said composition wherein said carrier comprises a dental polishing agent or a flavouring agent.