CA1042806A - Oral compositions for plaque, caries and calculus retardation with reducted staining tendencies - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
Oral compositions such as toothpastes, mouth-washes and the like containing a particular substantive bis-biguanide compound which inhibits the formation of plaque and caries, and specific chelating compounds which inhibit the tendency of the bis-biguanide compound to produce a stain on oral surfaces, and also maintain the bis-biguanide as a water-soluble salt.

Description

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 and in a manner sufficient to contact essentially all of the dental surfaces, but are not intentionally ingested. Such products include, for example, dentifrices, mouthwashes, propylaxis pastes and topical solutions.
The bis-biguanide compounds of this invention are known, having been disclosed in U.S. Patent 2,684,924, Rose et al., patented July 27, 1954; U.S. Patent 2,990,425, Senior et al., patented June 27, 1961; U.S. Patent 2,830,006, ~:~

... ~,: . . .................... . . .

. .: . . . - . . . . . . .,. . . :' .. . . . .. . . . . . . .

10428~6 surtwell et al, patented April 8, 1958; and U. S. Patent

2,863,919, Burtwell et al., patented December 9, 1958, and Kemanord British Patent 1,381,361, published January 22, 1975.
The antipla~ue activity of the bis-biguanides is also known.
The combining of the bis-biguanide compounds with certain amino carboxylate compounds to reduce the tendency of the bis-biguanide compounds to stain teeth is described in U. S.
Patent 3,937,807 of John W. Haefele, issued February 10, 1976.
These compounds, however, form insoluble salts with the bis-biguanide compounds. Our U. S. Patent 4,051,234, dated September 27, 1977 discloses that ethylenediamine diacetate and its salts are effective in reducing staining by the bis-biguanides, without the formation of insoluble salts.
SUMMARY OF THE INVENTION
It has now been discovered that if the specific bis-biguanide compounds disclosed herein and~the specific chelating compounds disclosed herein are used together in the oral cavity in the concentrations set forth herein, with the ~ -chelating compound in a molar excess as set forth herein after, and the compounds either being used together or sequentially, the stain that is normally caused by continuous use of the bis-biguanide compounds alone is effectively reduced. It is preferred that the chelating compound and the bis-biguanide compound be used together. ~

- ::, - ., ~~.

A~

1~4Z8Q6 .
DETAILED DESCRIPTION OF THE I.~IVENTION
. 5he bis-biguanide compounds of this invention have the generic formula: -_ . , .. ;.,.- . - ., . . . . , - .
. , . , : : . . ~ .
, . . : ... - ~ .,, - - - .. ,. , :

.. , , .. .; , . . . . .: . . .. ., - . . .. , , - , . .

.- . -.~ .- . . . . ! . . , . ~ .

- ` 10428~6 ~x)~ R~ c~2~n Na ~ x)z ~ ~

. . .. . .. ;.. I`.. . . . . . .. .: . .. - . -.. .. . .. . .. . ... ~ . . . . . . . . . ~. . .

.... ~ ~ .. - ,,. .... .. ; .. ~ . ;. . - ,, .-. . -.. . ......... - . . ... ~. ;; i.-.; . . - . . .-. . `

104Z~Q6 wherein A and A' each represent either (1) a phenyl radical which optionally is substituted by an alkyl or alkoxy group containing from 1 to about 4 carbon atoms, a nitro aroup, or a halogen atom; (2) an alkyl group containing from 1 to about 12 carbon atoms; or (3) alicyclic groups containing from 4 to about 12 carbon atoms, wherein X and X' each represent an alkylene radical containing from 1 to 3 carbon atoms; wherein z and z' each can be either 0 or 1; wherein R and R' each represent either hydrogen, an alkyl radical containing from 1 to about 12 carbon atoms, or an aralkyl radical containing from 7 to about 12 carbon atoms; wherein n is an integer from 2 to 12 inclusive; and wherein the polymethylene chain (CH2)n may optionally be interrupted by oxygen or sulfur atoms, aromatic nuclei, etc. The salts of the above compounds are especially desirable. The water-soluble salts are the most desirable since it is then possible to form clear solution compositions. Suitable water-soluble salts include the acetate, -~
the hydrochloride, and especially the gluconate salt of the above compounds. Water-insoluble salts are disclosed in U.S.
Patent No. 4,025,616 of John W. Haefele, dated May 24, 1977t -and in Haefele's U.S. Patent No. 3,934,002 issued January 20, 1976. Water-insoluble salts for the purpose of this application are those having a solubility in 25C. water of less than about 0.04%. Specific examples of these bis-biguanide compoNnds are dislcosed hereinafter.

. ~
.. .. , . --:. -. . . .

~ he above compounds aré effective antiplaque agents which demonstrate anticaries activity. Rowever, when compo-~itions containing these co~pounds are used continuously~in a program of oral hygiene, a rather offensive brown stain S ~orms on the oral surfaces which is resistant to removal by ordinary brushing with conventional dentifrices. This stain pro~lem prevents compositions containing these bis-biguanide compounds from being accepted ~y the consumer. The bis-bi-guanide compounas are normally used in amounts of from about 0.01% to about 2.~% by weight of the composition, preferably from about 0.05% to about 1.2%, ana most preferably from about 0.1% to about 0.8%. Depending upon the composition, lesser or greater a~ounts may be used. In general, all that i~ re~uired is to have an effective amount of the bis-b;guani2e salt in the mouth sufficient to give antiplaque and/or anti-caries effectiveness.
The specific chelator compounds which have now been found to be effective in inhibiting stain, but which do not precipitate the bis-biguanide compounds are kojic acid, maltol, ethyl maltol, calcium dihydrogen ethylenediamine tetraacetate, ethylene diaminediacetic acid (EDDA) and di-N-substituted ethylene diaminediacetic acids wherein the substitu-ents can be methyl, ethyl or 2-hydroxyethyl. The di-N- -~
substituted ethylenediamine diacetic acids can be symmetrical or unsymmetrical (i.e., one substituent group and one acetic acid group on each nitrogen or two substituent groups on one nitrogen and two acetic acid groups on the other nitrogen);

~Ir . . .. .
-6- ~

.. . .. .
- : . - -:

104Z~3~6 however, the symmetrical structures, i.e., N,N'-dimethylethylene-diamine-N,N'diacetic acid, N,N'-diethylethylenediamine-N,N'-diacetic acid and N,N'-di-(2-hydroxyethyl)ethylenediamine-N,N'-diacetic acid, are preferred. The pharmaceutically acceptable, water-soluble salts (i.e., salts being soluble to the extent of greater than 0.04~ by weight in 25C. water) of the chelator compounds can also be used. Examples of pharm-aceutically acceptable water-soluble salts , , s - 6a -104Z8~6 are sodium, potassium, indium, stannous, ammonium and low molecular weight substituted ammonium salts such as the mono-, di- and tri-Cl and C3 alkyl and alkano~ammonium salts, e.g., diethylammonium, monoethanolammonium and triethanolammonium salts. Mixtures of these chelator com?ounds can also be used.- The preferred chelator compounds~are ethylënediaminè-diacetic acid, kojic acid, maltol and calcium dihydrogen ethylenediamine tetraacetate and their pharmaceutically ~ acceptable water-soluble salts. The chelator compounds of the present invention have relatively low chelating potential for calcium and are therefore safer for use in the mouth than the amino carboxylate compounds disclosed in the aforementioned U. S. Patent No. 3,937,807.
Some chelators such as ethylenediaminetetraacetic ~;-acid and iminodiacetic acidj precipitate the bis-biguanide compound and are also ~ery damaging to tooth enamel. Both of ~
these undesirable effects are avoided by use of the chelators ~;
of the present invention.
The concentration of the cheiator compound in the ;~
oral compositions of this invention can range from about 0.10 to about 1.25% (preferably from about 0.1% to about 1.0%) by weight in excess of the amount which will react-with the bis-biguanide cor.pound present. h'ithin the pH range of the oral ~
compositions of the present invention, it is to be understood ~ -,: :
25 that the chelator com~ounds react with the bis-biguanide -compounds in the ratio of two moles of chelator to one mole -~ ~ -of bis-biguanidc compound.
,: "
' ' ' : `-'-, :, .
., I ~ . -, ~ I -7- ;~

A,~ ` ~ .
.~ .
.

.

~ . . ~
1()428~6 :- , s ~ o~ic acid, which ~s 5-hydroxy-2-(hydro~methyl)-4-pyrone, ~s a known metal ion chelator, the preparation of whi~h has been described in British patent 826,244, Dece~ber 31, 1959, to Pfizer. `
S Maltol, which is 3-hydroxy-2-methyl-4-pyrone, is a known metal ion chelator which can be pr~pared by alkaline hyarolysis of streptomycin salts as described ~y Schenck et al., J P~. Chem. Soc. 67, 2276 (1945). `
Calcium dihydrogen ethylenediamine tetraacetate --10 -~s a k~own material ha~ing the structure -.

.- . . ~ . ~ . , : ... .:. , : . ~ .

: ~428~6 ' o .1 C - o\ ~o - I . o CE~2~ ,Ca~ ~C~2 i2/C~ 12 COO~ COOE~

~04Z8Q6 The calcium disodium salt can be prepared by treating an a~ueous solution of ethylenediamine tetraacetate with powdered calcium carbonate, ~iltering off the unreacted c~onate, and then adding methanol to ~he filtered solution S to cause precipitation of ~he calcium disodium e~hylenedi-amine tetraacetate. The disodium salt can be converted to the dihydrosen acid form by acidification in a~ueous ~olution. See Astakhov et al. Zhur. Obscher. Rhim, i780-85 ~1950), also C.A. 45 2409~1951).
Ethyl maltol, also called 2-ethylpyromeconic acid ~s a known compound, the preparation of which is described in - British Patent 1,057,446, published February 1, 1967.
N,N'-di-(2-hydroxyethyl)ethylenediamine-N,N'-diacetic ~cid is a kno~m compound, the preparation of which has been describëd in British Patent 727,483, published March 13, 1952.
N,N'-dialkylethylenediamine-N,~'diacetic acids are known compounds, the preparation of which has been described in British Patent 727,465, published April 6, 1955.
The pH of the compositions of this invention is preferably maintained within the range of from about 4.5 to about 9.0, more preferably the pH is from about 5.0 to about 7.5 when the chelator is ko3ic acid or a salt thereof, from about 6.5 to about 7.5 when the chelator is maltol, ethyl maltol, ethylenediaminediacetic acid, the disubstituted ethylenediamine diacetic acids, or salts thereof, and from about 5.5 to about 7.5 when the chelator is calcium chelate _g_ l ..... ., . . . . , . :

10428~6 . ~- ~
of ethylenediamine tetraacetate or a salt thereof. Below about 4.5, damage to dental enamel can occur. Above about 9.0, the alkalinity becomes cosmetically undesirable and may irritate soft tissue in the mouth. The pH of the compositions of the in~ention can be adjusted if necessary, ~y commonly--used acidifying agents such as acetic acid, gluconic acid, etc., or alkalizing agents such as sodium hydroxide, potas- ;
sium hydroxide, etc. -~n adaition to the es~ential components of the oral compositions of this invention as described in the foregoing, such compositions can 21so contain carriers sui~able for use in the oral cavity. Such carriers include the usual components of toothpaste, toothpowder, mouthwash, prophylaxis pastes - and the like as more fully described hereinafter.

In addition to the bis-biguanides and chelating com-ounds of this invention, it is possible to include a phos-phorus-containing anticalculus agent as disclosed i~ Haefele, ` U. S. Patent No. 3,934,002, issued January 20, 1976. How- ~- -ever, if a ~olution is desired containing water-soluble bis-biguanide salt, then the phosphorus-containing anti-calculus agent should not be used since it will form an .
~ insoluble salt with the bis-biguanide compound.

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' . , `25 ,~, . . . . ..
.~ . . . :
,. .. .;

$~ -. '',~' ' ' ,' -10- ' ~

A dentifrice, especially toothpaste, is a preferred enbodiment of this invention. Dentifrices contain an abrasive polishing material and typically also contain sudsing agents, flavoring agents and sw`eetening agents. Toothpaste composi- -S tions additionally contain binders, humectants ana water.
The abrasive, which generally comprises from about 0.5% to about 95% by weight of a dentifrice, generally has a particle size of from about 0.1 to about 20 microns in dial^,eter and can be any abrasive polishing material which does not 10 excessively abrade tooth dentin. These include, for example, calcium carbonate, dicalcium orthophosphate dihydrate, calcium pyrophosphate, calcium polymetaphosphate and insoluble sodium polymetaphosphate. Preferably, however, the abrasive is one which has a high degree of compatibility with the bis-15 biguanides. These include, for example, silica xerogels suchas those described in U.S. Patent 3,538,230 to Pader et al., issued November 3, 1970; hydrofluoric acid-treated amorphous silica abrasives such as those disclosed in U.S. Patent

3,862,307 to DiGiulio, issued January 21, 1975; mineral -` 20 abrasives coated with cationic polymers such as those disclosed i by J. J. Benedict in Canadian Application No. 225,264, `~ filed April 23, 1975; and condensation products of urea and formaldehyde such as those disclosed by Cooley et al., in U. S. Patent 3,070,510, issued December 25, 1972.
The total amount of abrasive materials in the aenti-frice embodiments of this invention can range from about 0.5%
to about 95% by weight of the dentifrice. Preferably tooth-pastes contain from about 6% to about 60% and toothpowders contain from about 20% to about 95%. -~

-lOa-, , ",.'' ~' ~.

.... ~ . . . . . .. .

1~:)4Z806 Suitable sudsing agents are.those which are rea-sonabl~ stable and form suds throughout a wide p~ range, and which will not react Witl the bis-biguanide compoun.d, i e., non-soap nonionic, cationic, zwitterionic and amphoteric .organic synthetic detergents. .
~ he nonionic synthetic detergents which can be used with the oral compositions of the present invention may be broadly defined as compounds produced by the condensation of alkylene oxide groups (hydrophilic in nature) with an org2nic hydrophobic compound which may be aliphatic or a~kyl-aromatic in nature. The length of the hydrophilic or polyoxyaIkylene radical which is condensed with any particular hyarophobic group can be readily adjusted to yield a water-soluble compound having ~he desired degree of balance between hydrophilic and hydrophobic elements.
For example, a weli-known class of nonionic syn-thetic detergents is made available on the market under the trademark of ~Pluronicn. These co~pounds are for~ed by condensing ethylene oxide with a hydropho~ic base formed by the condensation of propylene oxi2e with propylene glycol.
The hydrophobic portion of the molecule which, of course, exhibits water-insolubility has a molecular weiaht of from about 1,500 to about 1,800. The addition of polyoxyethylene radicals to this hydrophobic ~ortion tends to increase the water-solubility of the molecule as a whole and the liquid character of the products is retained up to the point where polyoxyethylene content is about 50% of the total weight of - 20 the condensation product.
Other suitable nonionic synthetic detergents include: -1. The polyethylene oxi~e condensates of alkyl phenols, e.g., the condensation products of alkyl phenols having an al~yl group containing from about 6 to 12 carbon .
atoms in cither a straight chain or branchca chain configura-tion, ~ith ethylcne oxide, the said ethylcne oxide be-ng prcsent in amounts equal to 10 to 60 moles of ethylcne oxiae ,, . , . ,,, . .. . . , . .. , , , , ~. . ..

per mole of alkyl pheno~. The alkyl subst~tuent in such compounds may be derived from poly~erized oropylene, diiso-butylene, octane, or nonane, for example.
2. Those derived fro~ the condensation of ethylene oxide with the product resulting from the react;on of pro-pylene oxide with ethylene ai2mine -- products which may be ~aried in composition depending upon the balance between the hydrophobic and hydrophilic elements which is desired. For example, compounas containing from about 40% to about 80%
-po-lyoxyethylene by weight and having a molecular weight of from about 5,000 to about 11,000 resulting from the reaction of ~thylene oxide groups with a hydrophobic base constituted of the reaction product of ethylene diamine and excess pro-pylene oxide, said base having a molecular weisht of the order ~5 of 2,500 to 3,000, are satisfactory.
3. The condensation product of aliphatic alcohols having from 8 to 18 carbon atoms, in either straight chain or branched chain configuration, with ethylene oxide, e.g., a coconut alcohol ethylene oxide condensate having from 10 to 30 moles of ethylene oxide per mole of coconut alcohol, the coconut alcohol fraction having from 10 to 14 carbon atoms.

4. Long chain tertiary amine oxides cor_esponding to the following general formula:

o , .
104Z80~; . - , -.

RlR2R3N , ~ O, . . ~;
; ,.
, wherein Rl contains an alkyl, al~enyl or monohydroxy alkyl radical of from about 8 to about 18 car~on atoms, fro~ O to about 10 ethylene oxide moieties, and from O to 1 glyceryl -iety, and R2 and R3 contain from l to about 3 carbon atoms S and frcm O to about l hydroxy group, e.g., methyl, ethyl, propyl, hydroxy ethyl, or hydroxy propyl radicals. The arrow ~n the formula is a conventional representation of a semi-polar ~ond. Examples of amine oxides suitable for use in this in~ention include dimethyldodecylamine oxide, oleyldi-t2-hydroxyethyl)amine oxide, dimethyloctylamine oxide, di-met~yldecylamine oxide, dimethyltetradecylamine oxide, 3,6,9-trioxaheptadecyldiethylamine oxide, di(2-hydroxyethyl)-tetradecylamine oxide, 2-doaecoxyeth-~ldimethylamine oxide, 3-dodecoxy-2-hydroxypropyldi(3-hydroxypropyl)amine oxide, lS dimethylhexadecylamine oxide.

5. Long chain tertiary phosphine oxides corres-h~ f~ t~ina aeneral formula:

- ... , , ::, , ; . . . . ....................... .. .

: .. , . ~ . . .

:.. :. .. . . . - ,: , , . . - ... .. .. ... . ~ . .

~ .
104Z806 i - ~'R P ~ v .. . . .

t;, ' ' , " . ` ` ' `'.,: '.:~ ' ., ^ ., "' 1042806- , wherein R contains an alkyl, alkenyl or monohydroxyalkyl .
rzdical ranging fro~ 8 to 18 car~on atoms in chain length, - from 0 to about 10 ethylene oxide moieties and from 0 to 1 glyceryl ~oiety and R' and R~ are each alkyl or mono-hydroxyalkyl groups containing from 1 to 3 carbon atoms.
T~e arrow in,~he for~ula is a conventional representation of a se~i-polar bond. Exa~ples of sui.2ble phosphine oxides are:
do~ecyldimethylphosphine Oxiae ~

.. . ...
tetradecyldimethylphosphine oxide, tetradecylmethyle~hylphosphine oxide, 3,6,9-trioxaoctadecyldimethylphosphine oxide, cetyldimethylphosphine oxiae, 3-dodecoxy-2-hydroxypropyldi(2-hyaroxyethyl)phosphine oxide, :, . :
stearyldi~ethylphosphine oxide, -:-c~tylethylpropylphosphine oxide,oleyldiethylphosphine oxide, dodecyldiethylphosphine oxide, tetradecyldiethylphosphine oxide, dodecyldipropylphosphine oxide, ! 20 dodecylai(hydroxy~ethyl)phosphine oxide, dodecyldi(2-h~droxyethyl)pXosphine oxide, -tetradecylmethyl-2-hydro~ypropylphosphine oxide, oleyldimethylphosphine oxide, ; 2-hydroxydodecyldimethylphosphine oxide.

6. Long chain dialkyl sulfoxides containing one short chain a~:yl or hydroxy al~yl rzdical of 1 to about 3 carbon atoms (usually mcthyl) and one long hydrophobic chain ' ., . ._ ~.

1042~6 whicb contains alkyl, alkenyl, hydrox~ alkyl, or keto aIkyl radicals containing from about 8 to abQut 20 car~on atoms, from 0 to about 10 ethylene oxide moieties and from 0 to l glyceryl moiety. Examples include:
S octadecyl methyl sulfoxide, 2-ketotridecyl methyl sulfoxide, 3,6,9-trioxaoctadecyl 2-hy~roxyethyl s~lfoxide, ~odecyl methyl sulfoxid~, -oleyl 3-hydroxy propyl sulfoxiae, tetradecyl methyl sulfoxide, 3-methoxytridecyl methyl sulfoxide, 3-hydroxytridecyl methyl sulfoxide, 3-hydroxy-4-aodecoxybutyl methyl sulfoxide.
The zwitterionic synthetic detergents useful in the oral compositions of the present in~ention can ~e broadly described as derivati~es of aliphatic quaternary ~mmonium, phosphonium, ana sulfonium compounds, in which th2 aliphatic radicals can be straight chain or branched, and wherein one of the aliphatic substituents contains from about 8 to 18 carbon atoms and one contains an anionic water-solubilizing group, e.g., car~oxy, sulfonate, sulfate, phosphate, or phosphonate. A general formula for these compounds is:

- ~ : . : ,. .. .,, ~ . . . .. ... - -, . - . , .. .... - .. . - .. , - . , .

: . ' ~ .
, ' i042806 ~- ' ,t ., , , I X, ~12 _ y (~ 2 -- R - 2 .

- . - 1 04Z806 ..
wherein ~ contains an al~.yl, alkenyl, or hydroxy alkyl radical of from zbout 8 to about 18 carbon a~o~s, from 0 to about 10 ethylene oxide ~oieties an~ from .0 to 1 glyceryl moiety; Y is sçlected from ~he group consisting of nitrogen, 5 phosp~orus, znd sulfur ato~s; R is an alkvl.or monohydroxy-. ..
~ alkyl group containing 1 to zbout 3 carbon atoms; x is 1 .
.
when Y is a sulfur atom and 2 when Y is a nitrogen or phos~
phorus atom; R is an alkylene or hydroxyalkylene group of from 1 to about 4 carbon atoms; and Z is a radical selected from 10 the group consisting of carboxylate, sulfonate, sulfate, :-phosphonate, and phosphate groups.
Examples include:

4-[N,N-di(2-hydroxyethyl)-N-octaaecylz~.onio]-butane-l-carboxyla.te; --; 15 5-15-3-hyaroxypropyl-S-hexadecylsulfonio~-3-hydroxypentane-' .,~
sulfate; . . .:~

3-~P,P-diethyl-P-3,6,9-trioxatetraaecoxylphosphonio]-2- :
hydrox~-propane-l-phosphzte; ; :.
3-[N,~l-dipropyl-N-3-dodecoxy-2-hydroxypropylalr~onio]-propane-l-phosphonate;

3-(N,N-dimethyl-N-hexadecylammonio)propane-l-sulfonate; ~ ;:

3-~N,~-di~ethyl-N-hexadecylammonio)-2-hydroxypropane-1- :~
sulfonate; . :

4-lN,N-di(2-hydroxyethyl)-~-(2-hydroxydodecyl)a~onio]- .i; ~:~
butane-l-carboxylate;

3-[S-ethyl-S-(3-dodecoxy-2-hydroxypropyl)sulfonio~-propane-l-phosphate; ~-3-1P,P-dimethyl-P-dodecylphosphonio]-propane-l-phosphonate; '.

and . .

5-~ -di(3-hydroxypropyl)-~-hexadccylam~onio~-2-hyaroxy-pentane-l-sulfate.
.:. , .
' 104Z~06 The cationic synthetic aetergents useful in the oral co~positions of the present invention can he broadly defined as quaternary ammonium compounds having 1 long alkyl chain containi~g fro~ about 8 to 2bout 18 carbon atoms such 5 ~ as lauryl tri~ethylammonium chloride; cetyl pyridinium chloride;
- cetyl trim~thyl2m~0nium bro~ide; di-isobutylphenoxyethoxyethyl-- diD~thylbenzylamL~onium chloride; coconutalkyltrimethylammonium nitrite; cetyl pyridinium fluoride; etc. Especially pre~
ferred are the ~uaternary ammonium fluorides described in U.S. Patent-3,535,421, Briner et al., issued October 20, 1970, where said quaternary am~.onium fluorides have aetergent properties.
The amphoteric synthetic detergents useful in the present in~cntion can be broadly described as derivatives of aliphatic secondary and tertiary am~nes in which the zli-phatic radical can be straight chain or branched and wllerein one of the aliphatic substituents contair.s from about 8 to about 18 carbon ato~.s and one contains an anionic water-solubilizing group, e.g., carboxylate, sulfonate, sulfate, phosphate, or phosphonate. Examples of compounds falling within this ~efinition are sodium 3-dodecylaminopropionate, sodium 3-dodccylaminopropane sulfonate, dodecyl-beta-alanine, N-alkyl-taurines such as the one prepared by react;ng dodecyl-amine with sodium isethionate according to the teaching of ~;
U.S. Patent 2,65~072, Xosmin,.No~e~er 3, 1953, N-higher al~yl aspartic acids such as those produced according to the teaching of U.S. ratent 2,~38,091, Lynch, ~arch 16, 1948, and " ~
~ -20-.

., . - ~ , . . ~ .

the products sold under the trademark "Miranol" and described in U. S. Patent 2,528,738, Mannheiner, October 31, 1950.
The sudsing agent~can be present in the dentrifrice compositions of this invention in an amount from 0.5% to 5%
by weight of the total compositions.
It is preferable to have a water-soluble fluoride compound present in an amount to give a fluoride concentration of from about 0.0025% to about 5.0%, preferably from about 0.005% to about 2.0%, to provide additional anticaries effectiveness. Suitable fluoride sources are disclosed in the examples given hereinafter. Preferred fluorides are sodium fluoride, stannous fluoride, indium fluoride, and sodium monofluorophosphate. Reference is made to Norris et al, U. S. Patent 2,946,725 issued July 26, 1960; British Patent 1,421,064; and Widder et al, U. S. Patent 3,678,154, -issued July 18, 1972, which disclose dentrifrice compositions containing fluoride sources.
All parts, percentages and ratios herein are by weight unless otherwise indicated.
ln 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 flnely divided silica can be used as -'~ -. 104Z~3Q6 .
'~rt of the thickening agent to fur~her i~rove texture.
$hickeni~g agents in an amount from 0.5% to 5.C~ by weight of the total composition can be used.
It is also desirable to include so~ humectant aterial in a toothpaste to keep it from hardening. Suit-able humectants include glycerine, sorbitol, and other edible polyhydr~c alcohols. The humRctant can ~o~prise up to about - 36S by weight of ~he toothpaste composition.
Suitable flavoring agents include oil of winter- -10~ green, 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.
Flavoring agents are generally used in dentifrices at levels of from about 0.01% to 2% and sweetening agents at levels of from about 0.05% to about 2%. Typically, the dentifrices of the invention contain from about 0.1% to about 2.0% of the bis-biguanides of the invention.
A mouthwash composition is another preferred carrier for the bis-biguanides and the specific chelating compounds of the present invention. Mouthwashes generally comprise a water/
ethyl alcohol solution and preferably other ingredients such as flavor, sweeteners, humectants and sudsing agents such as those mentioned above for dentifrices. The humectants, such as glycerine and sorbitol give a moist feel to the-mouth.
Generally, the mouthwashes of the invention comprise 5% to 60% (preferably 10% to 25%) ethyl alcohol, 0% to 20% (pref-erably 5% to 20%) glycerine or other humectant, 0% to 2%
(preferably 0.1% to 1.5%) sudsing agent, 0% to 0.5% (preferably 0.05% to 0.5%) sweetening agent such as saccharin and 0% to 0.3% -(preferably 0.05% to 0.3%) flavoring agent, and the balance water.
The amount of bis-biguanide antibacterial agent in mouthwashes is typically from about 0.01% to about 1.2%.
~ -22-In its method aspect, the present invention com-prises a method of reducing dental pla~ue and/or caries by applying to the oral cavity an effective zmount of a compo-sition of the invention. Any amount which is sufficien' to achieve the desired reZuction is an effective amount.
Generally, a~ amount which supplies at least about .001 g.
per usage of the bis-biguani2e co~pound is effective.
Several representative oral compositions illus-tra~ing this invention are set forth in ~he following examples.
EXA~LE I
An aqueous solution is prepared containing O.2%
chlorhexidine 11,6-di-(N -p-chlorophenyl-N -diguanido)hexane]
digluconate and 1.0~ kojic acid, and is adjusted to pEI 6.S with 2.5N sodium hydroxide. No precipitate ~orms. The resulting ~ 042806 clear composition, when used in the mouth, inhibits the formation of plaque, calculus, caries and gingivitis, ~ut - with continued use, does not form the large amount of stain that would-result if the kojic acid were not present. Sub-~tant~ally sLmilar results are obtained when the 1% ko~ic - ~cid is replaced by an equal amount o~ maltol, ethyl maltol, ethylenediaminediacetic acid, disodium N,N'-di~2-hydroxy-ethyl)ethylenediamine-N,N'-diacetate, disodium N,N'-dimethyl-ethylenediamine-N,N'diacetate, disodium N,N'-diethylethylene-diamine-N,N'diacetate or calcium disodium ethylenediamine tetraacetate.
EXAMPLE II
0.025 gram sodium fluoride was added to 100 grams of the solution of Example I. This solution inhibits the formation of plaque and calculus, and in addition, has greater anticaries effectiveness.
EXAMPLE III
An aqueous solution is prepared containing 0.2%
chlorhexidine digluconate; 1.0% kojic acid, 1% poly-oxyethylene (20~ sorbitan monolaurate, and the pH is adjusted to 6.0 with 2.5N sodium hydroxide. ~his solution, when used in the mouth on a regular basis, inhibits the formation of plague, calculus and caries without e~cessive stain formation.
The solution is clear.
; 25 Several mouthwash compositions illustratin~ this invention are set forth in the following examples: -..
. ..
. ~
-23- ~

.. . . _ - 104Z806 . -~
. o u~ In O ~D . , o I .'' . -..
~ OtD O O . I
., ~ o o ~, ~

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. ~ . . .
. 3 8 ~ O ~ o ~ Q S: .
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~110 ~D O O ''.--l .
,... J~ ~ o ' .a. .. . ..
O . , I , ...
O L' o U~ U~ ~ ~ . , ., , .
~ o o U~ o o .
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~ . o O I . ' . ,.
, 0 ~ .',:,., ~ X d ~ . ' ' ,.:.
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~J ~ O . ,~ ., .
~: X' O ~ q~ O . ~, ,.
o ~ ~ ~ .~
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~- c ~ e ~ ~ . l~ :
O ~ .C C: O ~ h O :
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0C ~ X O E~ S h ~1 ~ ~ ~ :
O 0 ~1 0 ~ h O O O ,1 ~ ~ h u f~ ~ ~ 0--~ O
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O ~I J~ O O S ~ O ~ ~ h- 0 ~5 ~ . .
t~~ Ci~ C~ tJ h X X 1~ E~ U~ 3 ~o U~ :

._. .

o ~ o . ~! ' .
.. .

EXA*~E IX
. A tooth2o~der which constitutes yet another embodiment of this invention has the following formulation:
- ' '; , . ' ' ' '.
Component . Percent bv Wei~ht S Calcium pyrophos~ha~e . . g2.30 Polyoxyethylene t20) - 2.30 sor~itan monol2urate Soaium saccharin 0.25 Flavoring 1.45 .
Chlorhexidine diacetate 0.70 Calcium diammonium ethylene- .
diamine tetraacetate 3.00 When diluted with water an~ brushed upon the teeth in the con~entional manner, this composition has a . p~ of approximately 7Ø The composition retards the for~lat~on of pla~ue, calculus,. and caries without exces-. .
sive stainins~

:;:, , ~,;: . ~ . . .. -, . ... - .. .. . . .. . . . . . . . . . .

104Z8()6..
.. :
EXAMPLE X

A prophy~axis paste for use in the dental office-for remo~al of stains and polishing the tooth surface after ~echanical remo~al of calculus is formulated as follows:

S Component ercent bY Weight ComPosition A: -Navajo pumice 67.1 T~O2 4.0 Glycerine . .lS.352 ' ' .
i0 ~ydroxyethylcellulose .222 Sodium saccharin . , .326 . . .
61ycine fluoride . 1.0 ~altol : - 12.0 , Composition B: ....
............. .
Chlorhexidine digluconate . 2.7 Water 97-30 ~ ~ `

Immediately prior to use, S.S qm. of Composition ~
are mixed with 5.5 gm. of Composition B to attain the de- ;
sired texture and adjusted to pll 7Ø' ~he paste is then applied to the tooth surfaces with a rubber prophylactic cup in the conventional manner. This composition inhibits ~.
the formation of plaque, calculus, and caries without ad-verse effects of stain formation.

.

.

- 104Z806 .
~XAMP~E X~
A too~hpaste preparea in accoraance with this ~nvention has the following composition: ;

Component Percent by Weicht S Preeipitated urea/formaldehyde . 31.00 condensate ~abrasive) . ..
Sorbitol (70~ aqueous solution) 6.25 Glycerine 18.00 Polyoxye'hylene sorbi~an . - l.S0 ~20) monoisostearate .
~ydroxyethylcellul~se l.lS .
~agnesium aluminum sil~cate O.40 Sodium saccharin .. 0.04 Fla~oring 0;95 Disodium ethane-l-hydroxy- . O.S~ ..
. ~ l~l-diphosphonate . .
Calcium aipotassium e'hylene-diamine tetraacetate 4.0 sOaium monofluorophosphate 3.00 Soaium fluoride 0.03 Chlorhexidine dislucona.e . Q.~0 Water balance : .:
Mol~ ratio polyphosphonate/fluoride about 2.4.
pEI adjusted to 7.5 with 5~NaOH. ~-. _ . .. .
This composition is ~ffective in retarding the formation of d~ntal calculus when used in a conventional manncr. This composition also inhibits plaque and caries. .~;

p~- - . .
... , . , , . .... , ~ .. . .. . . . .. .. ....

104Z8~6-o - ,;
EXAMP~E XI~ .
. ~ mouthwash of the present inventio~ is prepa:ed according to.the foll~wing formula: . .. .
, - Component Per~ent bY Wei~ht . . -5 Chlorhexidine digluconate . 0.20 - Calcium disodium ethylene- .
diz~ine tetraacetate 0.9 .~ Polyoxye~hylene sorbitan (20~ 1.0 ~. monoisostearate . .
Etha~oi 12.0 ;~ Sodium saccharin 0,045 Glycerol . . 6.0 Flavor _0.08 Water balance . pH adjustea to 7.0 with 2N sodium hydroxide .. . : .

_......... ..... . .

.,, . ~.,. ... . ;y . .,. ,. ,, .. -, , .. ... , : .~. , . . ~ . . .:

1(~42806 EXAMPLE XIII
Oral surfaces are treated sequentially with a 0.2%
aqueous solution of chlorhexidine digluconate and then a 1%
aqueous solution of calcium disodium ethylenediamine tetraacetate containing 0.25~ sodium fluoride. The amount of stain which is observed after daily use of this sequential treatment for 14 days -is much lower than when only chlorhexidine digluconate is used.
Substitution of kojic acid or maltol for the calcium disodium -ethylenediamine tetraacetate gives substantially similar results.
Substantially similar results are obtained when the chelators in Examples III to XIII are replaced by an equal amount of ethylenediaminediacetic acid. ;;
When in the above examples the following water-soluble fluoride agents are substituted, either wholly or in part, for the sodium fluoride, substantially equivalent results are obtained in that the formulas provide additional anticaries ac~ivity: Sodium monofluorophosphate, stannous fluoride, potassium fluoride, lithium fluoride, cesium fluoride, ammonium fluoride, indium fluoride, stannous fluorizirconate, lead fluoride, palladium fl~uoride, zinc fluoride, zirconium fluoride, hexylamine hydrofluoride, laurylamine hydrofluoride, myristylamine hydrofluoride, decanolamine hydrofluoride, octadecenylamine hydrofluoride, myristoxyamine hydrofluoride, diethylam-~noethyloctoylamide hydrofluoride, diethanolamino-ethyloleylamide hydrofluoride, diethanolaminopropyl-N'-octadecenyl-amine dihydrofluoride, l-ethanol-2-hexadecylimidazGline dihydro-fluoride, octoylethanolamine hydrofluoride, octyltrimethyl-ammonium fluoride, dodecylethyldimethylammonium ,~ :

- 29 - ~
.. , ..:
:
' ' ':.:

1t)4Z8Q~; , flusriae, tetraethylammonium fluoride, dilauryldimethyl-ammonium fluori~e, ~ octadecenyIbenzyldimethyla~monium fluoride, dioctyldiet.~ylammonium fluoride, cyclohexyl-cetyldimethylammoniu~ fluoride, furfuryllauryldimethyl-ammonium fluoride, phenoxyethylcetyldimethylammonium fluorice, ~ N'-tetrame~hyl-N:N'-dilaurylethylene-diammonium difluoride, N-cetylpyridinium fluoride, N:n-dilauryl-mor-pholinium fluoride, N-myristyl-N-ethylmorpholinium fluoride, N-~octylaminocarbonylethyl)-N-be~zyl-dimethylammonium fl~oride, S N-~ -hydroxydodecyl)trimethylammonium fluoride, N-phenyl-N-hexade~yldiethylammonium fluoride, N-cyclohcxyl-N-octadecyl-dimethylammo~ium fluoride, N-~2-carbomethoxyethyl)-N-benzyl-dimethylammonium fluoride, N-(2-carbocyclohexoxyethyl)-N-myristyldimethylammonium fluoride, N-(2-carbobenzyloxye~hyl)-N-dodecyldimethylammonium fluoride, N-t2-(N:N'-dimethylamino-carbonyl)-ethyl]-N-dodecylaiethylammonium fluoride, N-carboxy-methyl-N-eicosyldimethylammonium fluoride, betaine hydro-fluoride, sarcosine stannous fluoride, alanine stannous fluoride, glycine potassi~m fluoride, sarcosine potassium fluoride, glycine hydrofluoride, lysine hydrofluoride, ala-nine hydrofluoride, betaine zirconium fluoride, and mixtures thereof in, e.g., 1:1 proportions. The glycine fluorides ~ -are preferred.
When in the above examples the followin,~ surface-acti~e agents are inserted in an amount of from about 1 to 2% as an additional ingredient, substantially equivalent results are obtained, except that the compositions have enhanced dctergency effects: Polypropylene glycol (M.W.
1700) polyoxycthylene (M.W. 1500); polyoxypropylene (70) 2~ ethylenediamine polyoxyethylene (100); coconut alcohol poly-oxye~hylene (20); dimethyldodecylamine oxide; oleyldi(2-hydroxyethyl)aminc oxide; dimcthyloctylamine oxidc; dimethyl-~ .

.

lQ9~Z8(~6 decylamine oxide; dimethyltetradecylamine oxide; 3,6,9-trioxaheptadecyldiethylaminP oxide; di(2-hydroxyethyl)-tetradecylamine oxide; 2-dodecoxyethyldimethylamine oxide;
3-dodecoxy-2-hydroxypropyldi(3-hydroxypropyl)amine oxide; ~.:
dimethylhexadecylamine oxide; dodecyldimethylphosphine oxide; ~:
tetradecyldimethylphosphine oxide; tetradecylmethylethylphosphine , -oxide; 3,6,9-trioxaoctadecyldimethylphosphine oxide; cetyldi- ~ `
methylphosphine oxide; 3-dodecoxy-2-hydroxypropyldi(2-hydroxy- -~
ethyl)phosphine oxide; stearyldimethylphosphine oxide; cetyl-ethylpropylphosphine oxide; oleyldiethylphosphine oxide; ~ .
dodecyldiethylphosphine oxide; tetradecyldiethylphosphine oxide; .~ -:
dodecyldipropylphosphine oxide; dodecyldi(hydroxymethyl)phosphine ;
oxide; dodecyldi(2-hydroxyethyl)phosphine oxide; tetradecylmethyl- `
2-hydroxypropylphosphine oxide; oleyldimethylphosphine oxide;
2-hydroxydodecyldimethylphosphine oxide; octadecyl methyl : ::
sulfoxide; 2-ketotridecyl methyl sulfoxide; 3,6,9-trioxaoctadecyl : :~
2-hydroxyethyl sulfoxide; dodecyl methyl sulfoxide; oleyl 3-hydroxypropyl sulfoxide; tetradecyl methyl sulfoxide; 3-methoxytridecyl methyl sulfoxide; 3-hydroxytridecyl methyl sulfoxide; 3-hydroxy-4-dodecoxybutyl methyl sulfoxide; 4-[N,N-di(2-hydroxyethyl)-N-octadecylammonio]-butane-l-carboxylate;
5-[S-3-hydroxypropyl-S-hexadecylsulfonio]-3-hydroxypentane-1-sulfate; 3-[P,P-diethyl-P-3,6,9-trioxatetradecoxylphosphonio]-2-hydroxypropane-1-phosphate; 3,[N,N-dipropyl-N-3-dodecoxy-2-hydroxypropylammonio]-propane-l-phosphonate; 3-(N,N-dimethyl-N-hexadecylammonio]propane-l-sulfonate; 3-(N,N-dimethyl-N-hexa-decylammonio)-2-hydroxypropane-1-sulfonate; 4-[N,N-di(2-hydroxy-ethyl)-N-(2-hydroxydodecyl)ammonio]-butane-1-carboxylate;
3-[S-ethyl-S-(3-dodecoxy-2-hydroxypropyl)sulfonio]-propane-1- :
phosphate; 3-[P,P-dimethyl-P-dod ~ylphosphonio]-propane-l-phosphonate; 5-[N,N-di(3-hydroxypropyl)-N-hexadecylammonio]-2- ~-hydroxypentane-l-sulfate; dodecyltrimethylammonium chloride;

nonylbenzylethyldimethylammonium nitrate; tetradecylpyridinium ; .
-...... . . . . . : :. . . . :

bromide; octadecylbutylpropylmethylphosphonium ni.trite; decyl-dimethylsulfonium chloride; (hexylphenyl)dimethylben~ylammonium fluoride; eicosyldimethylbenzylphosphonium chloride; coconut-alkylmethylmorpholinium nitrate; octadecylmethylbenzylsul- :~
fonium sulfate; laurylpyridinium chloride; laurylpyridinium bromide; laurylpyridinium bisulfate; laurylpyridinium-5-chloro- :
2-mercaptobenzothiazole; laurylpicolinium-p-toluenesulfonate;
tetradecylpyridinium bromide; cetylpyridinium chloride; cetyl-pyridinium bromide; laurylisoquinolinium bromlde; lauryliso-quinolinium saccharinate; alkylisoquinolinium bromide; N-cetyl-N-ethyl-morpholinium ethosulfate; benzalkonium chloride; mono-quaternaries R4N X (one R group is fatty); octadecyltrimethyl-ammonium chloride; coconut alkyl trimethylammonium chloride; . .
dodecylbenzyltri(octyldecyl)ammonium chloride; monoquaternaries -R4N+X (two R groups are fatty); dihexadecyldimethylammonium ; -chloride; di-coconut alkyl dimethylammonium chloride; monoquater- - .
naries R4N X ~(three R groups are fatty); tri(hydrogenated ::
tallow) methylammonium chloride; distilled tallow amine acetate;
diamine acetates; N-oleyl propylene diamine monoacetate; con-densation product of octyl phenol with 15 moles of ethylene .:
oxide per mole of octyl phenol; dimethyldodecylamine oxide;
dodecyldimethylphosphine oxide; tetradecyl methyl suIfoxide;
3-(N,N-dimethyl-N-hexadecylammonio)propane-l-sulfonate; 3- :
dodecylaminopropionate; and dodecyl-beta-alanine.
When in the above examples, the following bis- : :
biguanide compounds are substituted, either wholly or in part (50%) for the preferred chlorhexidine digluconate, substantially . .~:
equivalent results are obtained in that plaque, calculus, : -caries and gingivitis are inhibited with reduced staining as :;.
compared to the use of the bis-biguanide compounds alone:
1,6-bis-(3-ethylhexylbiguanidohexane)dihydrochloride; 1,6-di-(N5-phenyl-Nl-diguanido)hexane tetrahydrochloride; 1,6-di- ;

-, ... .. ,, , . ~ , . . ~ ., . . ... . - . . - . . . -104Z8Q6 ~: ~
(N5-phenyl-N5-methyl-Nl-diguanido)hexane dihydrochloride; 1,6-di-(N -_-chlorophenyl-N -diguanido~hexane dihydrochloride; 1,6-di-(N5-2,6-dichlorophenyl-Nl-diguanido)-hexane dihydrochloride;
1,6-di-(N5-p-methoxyphenyl-Nl-diguanido)hexane dihydrochloride;
1,6-di-(N5-_-nitrophenyl-Nl-diguanido)hexane dihydrochloride;
~,~'-di-(N5-phenyl-Nl-diguanido)-di-n-propylether dihydrochloride;
, ~-di-(N5-p-chlorophenyl-Nl-diguanido)-di-n-propylether tetrahydrochloride; l,6-di-(N5-2,4-dichlorophenyl-Nl-diguanido) hexane tetrahydrochloride; 1,6-di-(N5-p-methylphenyl-Nl-diguanido) hexane dihydrochloride; 1,6-di-(N -2,4,5-trichlorophenyl-Nl-diguanido)hexane tetrahydrochloride; 1,6-di-[N5-alpha-(p-chloro-phenyl)ethyl-Nl-diguanido] hexane dihydrochloride; ~,~'-di- -(N5-p-chlorophenyl-Nl-diguanido)m-xylene dihydrochloride; 1,12-di-(N5-~-chlorophenyl-Nl-diguanido) dodecane dihydrochloride;
1,10-di-(N5-phenyl-Nl-diguanido) decane tetrahydrochloride; 1,12- `
di-(N5-phenyl-Nl-diguanido) dodecane tetrahydrochloride; 1,6-di-(N5-p-chlorophenyl-N~-diguanido)hexane tetrahydrochloride;
ethylene bis(l-tolyl biguanide); ethylene bis(p-tolyl biguanide);
ethylene bis(3,5-dimethylphenyl biguanide); ethylene bis(3,5-dimethylphenyl biguanide); ethylene bis~p-tert-amylphenyl biguanide); ethylene bis(nonylphenyl biguanide); ethylene bis (phenyl ~iguanide); ethylene bis(N-butylphenyl biguanide);
ethylene bis(2,5-diethoxyphenyl biguanide); ethylene bis(2,4-dimethylphenyl biguanide); ethylene bis(o-diphenyl biguanide);
ethylene bis(mixed amyl naphthyl biguanide); N-butyl ethylene bis(phenyl biguanide); trimethylene bis(o-tolyl biguanide);
N-butyl trimethylene bis(phenyl biguanide); tetramethylene bis(l-tolyl biguanide); the specific compaunds disclosed in U.S. Patent 2,863,919, Burtwell et al., (December 9, 1958), the specific compounds disclosed in U.S. Patent 3,468,~98, Cutler et al., (September 23, 1969); and the corresponding pharmaceutically acGeptable salts of all of the abo~e such as ,.

10428Q6 : ~ -the acetates; gluconates; hydrochlorides; hydrobromides; citrates, ~
bisulfites, fluorides; polymaleates; N-coconut alkyl sarcosinates; ~ .
phosphites; hypophosphites; perfluorooctanoates; silicates;
sorbates; salicylates; maleates; tartrates; fumarates; ethylene-diaminetetraacetates; iminodiacetates; cinnamates; thiocyanates;
arginates; pyromellitates; tetracarboxybutyrates; benzoates;
glutarates; monofluorophosphates; perfluoropropionates; and the salts prepared by reacting the following salts with the bis-biguanide compounds: Disodium ethane-l-hydroxy-l,l-diphosphonate; :i disodium salt of ethane-1,2-dicarboxy-1,2-diphosphonic acid;
dipotassium salt of ethane-1,2-dicarboxy-1,2-dihydroxy-1,2-diphosphonic acid; the monocalcium salt of ethene-1,2-dicarboxy-l-phosphonic acid; the monomagnesium salt of ethane-1,2-dicarboxy-l-hydroxy-l,l-diphosphonic acid; the di(triethanolammonium) salt of ethane-1,2-dicarboxy-1,2-diphosphonic acid; the disodium salt of ethane-1,2-dicarboxy-1,2-diphosphonic acid; diammonium salt of ethane-1,2-dicarboxy-1,2-diphosphonic acid; monocalcium ~ : .
salt of ethane-1,2-dicarboxy-1,2-dihydroxy-1,2-diphosphonic acid; distannous salt of ethane-1,2-dicarboxy-1-hydroxy-1,2-diphosph:onic acid; indium salt of ethene-1,2-dicarboxy-1-phosphonic acid; triammonium salt of ethane-1,2-dicarboxy-1,2- ::
dihydroxy-1,2-diphosphonic acid; trisodium salt of ethene-1,2- .~:.
dicarboxy-l-phosphonic acid; distannous salt of ethane-1,2- ~.
dicarboxy-1,2-diphosphonic acid; hexasodium salt of cyclic .
tetraphosphonic acid; trisodium salt of methanecyclohexylhydroxy-diphosphonic acid; diammonium salt of methanecyclobutylhydroxy-diphosphonic acid; monocalcium salt of methanecyclopentylhydroxy- ~
diphosphonic acid; distannous salt of methanecycloheptylhydroxy- . ~ :
diphosphonic acid; indium salt of methanecyclooctylhydroxydi-phosphonic acid; triammonium salt of methanecyclononylhydroxy- :
diphosphonic acid; trisodium salt of methanecyclodecylhydroxy-diphosphonic acid; distannous salt of methanecyclohexylhydroxy .
'. ~;"' - 35 - ~

1~4Z806 ~ ~
.. .
diphosphonic acid; methanecycloalkylhydroxydiphosphonic acid;
tris(l-phosphonoethyl)amine; tetrasodium salt of tris(2-phos-phono-2-propyl)amine; dipotassium salt of bis(phosphonomethyl)-l-phosphonoethyl amine; monocalcium salt of bis(phosphonomethyl)-2-phosphono-2-propyl amine; monomagnesium salt of bis(l- :
phosphonoethyl)phosphonomethyl amine; distannous salt of ~.
bis(2-phosphono-2-propyl)phosphonomethyl amine; "Victamide"* :
and mixtures thereof, e.g., 1:1 and 1:1:1 ratios. ~ ~ .

*Trademark for the ammonium salt of an amido polyphosphate, in very finely divided form; it is used as a sequestering agent for metallic ions.

Claims (18)

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

1. An oral composition effective in inhibiting the formation of plaque, caries and calculus comprising:
(A) from about 0.01% to about 2.5% by weight of a bis-biguanide compound having the generic formula:

wherein A and A' each represent either (1) a phenyl radical which can contain as substituents up to two alkyl or alkoxy groups containing from 1 to about 4 carbon atoms, a nitro group, or a halogen atom; (2) an alkyl group containing from 1 to about 12 carbon atoms; or (3) alicyclic groups containing from 4 to about 12 carbon atoms; wherein X and X' each represent an alkylene radical containing from 1 to 3 carbon atoms; wherein z and z' each can be either 0 or 1; wherein R and R' each represent either hydrogen, an alkyl radical containing from 1 to about 12 carbon atoms, or an aralkyl radical containing from 7 to about 12 carbon atoms; wherein n is an integer from 2 to 12 inclusive; and wherein the polymethylene chain (CH2)n can be interrupted by up to 5 ether, thioether, phenyl, or naphthyl moieties; or the pharmaceutically acceptable salts thereof; and (B) from about 0.10% to about 1.25% by weight, in excess of the amount which will react with the bis-biguanide compounds, of a chelator compound selected from the group consisting of kojic acid, maltol, ethyl maltol, calcium dihydrogen ethylenediamine tetraacetate, ethylenediamine diacetic acid, and the di-N-substituted ethylenediamine diacetic acids wherein the substituents are selected from the group consisting of methyl, ethyl and 2-hydroxyethyl, and the water-soluble pharmaceutically acceptable salts of said chelators, said composition having a pH of from about 4.5 to about 9Ø

2. The composition of Claim 1 wherein the ethylenediaminediacetic acid or di-N-substituted ethylene-diamine diacetic acids are symmetrical.

3. The composition of Claim 2 wherein the bis-biguanide compound is a water-soluble salt.

4. The composition of Claim 3 wherein the pH is from about 5.0 to about 7.5 when the chelator compound is kojic acid or a water-soluble pharmaceutically acceptable salt thereof, from about 6.5 to about 7.5 when the chelator compound is maltol, ethyl maltol, ethylenediaminediacetic acids or the symmetrical di-N-substituted ethylenediamine diacetic acids or the water soluble pharmaceutically acceptable salts thereof and from about 5.5 to about 7.5 when the chelator compound is calcium dihydrogen ethylenediamine tetraacetate or water-soluble pharmaceutically acceptable salt thereof.

5. The composition of Claim 3 wherein the chelators are selected from the group consisting of kojic acid, maltol, calcium dihydrogen ethylenediamine tetraacetate, ethylene-diaminediacetic acid and the pharmaceutically acceptable water-soluble salts of said chelators.

6. The composition of Claim 5 wherein the pH is from about 5.0 to about 7.5 when the chelator compound is kojic acid or a water-soluble pharmaceutically acceptable salt thereof, from about 6.5 to about 7.5 when the chelator compound is maltol, ethylenediaminediacetic acid or a water-soluble pharmaceutically acceptable salt thereof and from about 5.5 to about 7.5 when the chelator compound is calcium dihydrogen ethylenediamine tetraacetate or a water-soluble pharmaceutically acceptable salt thereof.

7. The composition of Claim 6 wherein the bis-biguanide compound is a water-soluble salt of 1,6-di-(N5-p-chlorophenyl-N1-diguanido)hexane.

8. The composition of Claim 7 wherein the salt of 1,6-di-(N5-p-chlorophenyl-N1-diguanido)hexane is selected from the group consisting of the hydrochloride, acetate and gluconate salt.

9. The composition of Claim 3 containing a water-soluble source of fluoride in a quantity sufficient to provide fluoride in an amount of from about 0.0025% to about 5.0% as F-.

10. The composition of Claim 3 containing from about 0.05% to about 1.2% by weight of the bis-biguanide compound and from about 0.1% to about 1% by weight of the chelator compound in excess of that which will react with the bis-biguanide compound.

11. The composition of Claim 3 wherein the bis-biguanide compound is [1,6-di-(N5-p-chlorophenyl-N1-di-guanido)hexane digluconate.

12. The composition of Claim 3 wherein the bis-biguanide compound is present as a pharmaceutically accept-able salt selected from the group consisting of the hydro-chloride, acetate, and gluconate salts.

13. The composition of Claim 3 wherein A - (X)z an ethylhexyl group and n is 6.

14. The composition of Claim 3 wherein A and A' are each p-chlorophenyl groups, z and z' are 0, and n is 6.

15. The composition of Claim 3 in the form of a dentifrice comprising as an additional ingredient from about 0.5% to about 95% of an abrasive polishing agent.

16. The composition of Claim 15 wherein the abrasive is selected from the group consisting of silica xerogels, hydrofluoric acid-treated amorphous silica, mineral abrasives coated with cationic polymers and condensation products of urea and formaldehyde.

17. The composition of Claim 16 wherein the bis-biguanide is [1,6-di-(N5-p-chlorophenyl-N'-diguanido)hexane].

18. The composition of Claim 3 in the form of a mouthwash comprising as additional ingredients (A) from about 5% to about 60% ethanol;
(B) from about 5% to about 20% glycerine;
(C) from about 0.1% to about 1.5% of a nonsoap, nonionic, cationic, zwitterionic or amphoteric sudsing agent;
(D) from about 0.05% to about 0.5% sweetening agent;
(E) from about 0.05% to about 0.3% flavoring agent; and (F) water.