Oral compositions containing trifluoromethyl phenyl bis-biguanides as antiplaque agents

Oral compositions such as toothpastes, mouthwashes, and the like containing certain trifluoromethylphenyl bis-biguanides having excellent antiplaque performance and reduced tendency to stain the teeth.

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, 
prophylaxis pastes and topical solutions. 
The bis-biguanide antibacterial agents such as chlorhexidine, 1,6 
bis(N.sup.5 -p-chlorophenyl-N.sup.1 -biguanido) hexane, are known to be 
effective antiplaque agents, but it has been recognized that they have a 
tendency to produce severe staining of the teeth. Belgian Pat. No. 
801,703, issued Jan. 4, 1973, discloses the use of the insoluble salts of 
the bis-biguanides in oral compositions as a means of reducing the stain 
problem. Belgian Pat. No. 811,878, issued Sept. 4, 1974, U.S. patent 
application Ser. No. 495,951, filed Aug. 9, 1974, (and its 
continuation-in-part Ser. No. 584,304, filed June 6, 1975) and U.S. patent 
application Ser. No. 563,988, filed Apr. 1, 1975, (and its 
continuation-in-part Ser. No. 652,092, filed Jan. 27, 1976) disclose the 
use of metal ion chelator compounds, such as amino acids, 
aminopolycarboxylates and hydroxypyrones, with the bis-biguanides to 
reduce stain. My concurrently-filed copending application having Ser. No. 
670,518 (continuation-in-part of Ser. No. 589,232, filed June 23, 1975) 
discloses certain bisbiguanides, wherein the bridging alkylene group has 
from 1 to 4 carbon atoms instead of six, which have substantially lower 
staining tendencies then chlorhexidine. 
DESCRIPTION OF THE INVENTION 
It has now been discovered that certain novel bis-biguanide compounds 
wherein the bridging alkylene group is C.sub.1 to C.sub.4 alkylene, and 
wherein the terminal nitrogen atoms contain trifluormethylphenyl groups, 
have outstanding antiplaque activity and very low tendency to stain the 
teeth. 
The novel bis-biguanide compounds of this invention have the generic 
formula 
##STR1## 
wherein n is from 1 to 4 inclusive (preferably 2 to 4 inclusive); 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 and wherein R.sub.2 and R.sub.2 ' each represent either hydrogen or 
an alkyl radical of 1 to 2 carbon atoms. Preferred is the compound wherein 
z and z' are each 0, n is 2 and R, R', R.sub.2 and R.sub.2 ' are hydrogen. 
Preferably, the trifluoromethyl group is in the meta position; however, 
the corresponding ortho and para isomers are also suitable for use herein. 
The pharmaceutically acceptable salts of the foregoing compounds are 
especially desirable. The water soluble salts, especially the 
dihydrochloride, digluconate and diacetate salts, are the most desirable 
since they make possible the formation of clear solution compositions. In 
contrast with chlorhexidine, whose dihydrochloride salt is insoluble in 
water, the hydrochlorides of the compounds of the present invention are 
water-soluble. Typically, the hydrochloride salt is inherently formed in 
the preparation of chlorhexidine and of the compounds of the present 
invention. For purposes of this application, water-soluble salts are 
considered to be those having a solubility of greater than about 0.04% by 
weight in water at 25.degree. C. 
Examples of bis-biguanides falling within the scope of the present 
invention are the following: 
Bis(N.sup.5 -m-trifluoromethylphenyl-N.sup.1 -biguanido)methane 
1,2-bis(N.sup.5 -m-trifluoromethylphenyl-N.sup.1 -biguanido)ethane, 
1,4-bis(N.sup.5 -m-trifluoromethylphenyl-N.sup.1 -biguanido)butane, 
1,2-bis(N.sup.5 -m-trifluoromethylbenzyl-N.sup.1 -biguanido)ethane, 
1,2-bis(N.sup.5 -p-trifluoromethylphenyl-N.sup.1 -biguanido)ethane, 
1,2-bis(N.sup.5 -o-trifluoromethylphenyl-N.sup.1 -biguanido)ethane, 
1,2-bis(N.sup.5 -m-trifluoromethylphenyl-N.sup.5 -hexyl-N.sup.1 
-biguanido)ethane, 
1,2-bis(N.sup.5 -m-trifluoromethylphenyl-N.sup.5 -2-phenethyl-N.sup.1 
-biguanido)ethane, 
1,2-bis(N.sup.5 -m-trifluoromethylphenyl-N.sup.1 -ethyl-N.sup.1 
-biguanido)ethane, 
1,4-bis(N.sup.5 -m-trifluoromethylphenyl-N.sup.5 -ethyl-N.sup.1 
-methyl-N.sup.1 -biguanido)butane, 
1,2-bis(N.sup.5 -m-trifluormethyl-N.sup.5 -methyl-N.sup.1 -ethyl-N.sup.1 
-biguanido)-ethane, 
and their water soluble salts, for example, the digluconate, 
dihydrochloride and diacetate salts. The most preferred compounds are 
1,2-bis(N.sup.5 -m-trifluoromethylphenyl-N.sup.1 -biguanido)-ethane and 
its dihydrochloride, diacetate and digluconate salts. 
The compounds of the invention can be made by reacting ethylene or 
methylene diamine dihydrochloride (or an appropriately N,N' substituted 
ethylene or methylene diamine dihydrochloride) with sodium dicyanamide to 
give, for example, a bis(N.sup.3 -cyano-N.sup.1 -guanidino)ethane, which 
is then reacted with the hydrochloride of the desired m-trifluoromethyl 
phenylamine to give the desired bis-biguanide compound in the form of its 
hydrochloride salt. The general preparation procedure for bis-biguanides 
is well known in the art; see, for example, Warner et al. J. Pharm. Sci. 
62 No. 7, 1189-91 (1973) and Rose et al. J. Chem. Soc. 4422 (1956). 
The novel bis-biguanide antiplaque agents of the present invention are 
utilized in oral hygiene in the form of oral compositions which comprise 
from about 0.01% to about 2.5% (preferably from about 0.05% to about 1.2%, 
and most preferably from about 0.1% to about 0.8%) by weight of the 
bis-biguanide antiplaque agent and the balance, a carrier suitable for use 
in the oral cavity. All percentages herein are by weight, unless specified 
otherwise. Depending upon the composition, lesser or greater amounts may 
be used. In general, all that is required is to have an effective amount 
of the bis-biguanide compound in the mouth sufficient to give antiplaque 
and/or anticaries effectiveness. Generally, an amount of 0.001 grams or 
more per usage of the bis-biguanide can be considered as an effective 
amount for plaque control. 
The pH of the compositions of this invention is preferably maintained 
within the range of from about 4.5 to about 9.5. Below about 4.5, damage 
to dental enamel can occur. Above about 9.5, the alkalinity becomes 
cosmetically undesirable and may irritate soft tissue in the mouth. 
As previously stated, compositions of the present invention comprise the 
aforedescribed bis-biguanide antiplaque agents and a carrier suitable for 
use in the oral cavity. The carrier can be water or an organic solvent 
such as alcohol. Preferably, however, the carrier portion of the oral 
composition is a conventional toothpaste, mouthwash, chewing gum or the 
like. 
Dentifrices contain an abrasive polishing material and typically also 
contain sudsing agents, flavoring and sweetening agents. Toothpastes 
usually additionally contain humectants and binders and water. The 
dentifrices herein comprise from about 0.5% to about 95% abrasive in 
addition to the bis-biguanide antiplaque agent. 
Any abrasive polishing material which does not excessively abrade dentin 
can be used in these dentifrice compositions. 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-biguanide. These include, for 
example, condensation products of urea and formaldehyde such as disclosed 
by Cooley et al. in U.S. Pat. No. 3,070,510, granted Dec. 25, 1962, silica 
xerogels such as those disclosed in U.S. Pat. No. 3,538,230 to Pader et 
al., issued Nov. 3, 1970, hydrofluoric acid-treated amorphous silica 
abrasives such as those disclosed in U.S. Pat. No. 3,862,307 to DiGiulio, 
issued Jan. 21, 1975, and mineral abrasives coated with cationic polymers 
such as those disclosed in U.S. Ser. No. 471,941, Benedict, filed May 21, 
1974. The abrasives generally have a particle size of from about 0.1 to 
about 20 microns in diameter. 
The total amount of abrasive materials in the dentifrice embodiments of 
this invention can range from 0.5% to 95% by weight of the dentifrice. 
Preferably, toothpastes contain from about 6% to about 60%, and 
toothpowders contain from about 20% to about 95% abrasives. 
Dentifrices usually contain surface-active agents (also called sudsing 
agents). 
Suitable surface-active agents are those which are reasonably stable and 
form suds throughout a wide pH range, and which will not react with the 
bis-biguanide compound, i.e., nonsoap nonionic, cationic, zwitterionic and 
amphoteric organic synthetic detergents. 
The 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 organic hydrophobic compound which may be aliphatic or 
alkyl-aromatic in nature. The length of the hydrophilic or polyoxyalkylene 
radical which is condensed with any particular hydrophobic group can be 
readily adjusted to yield a water-soluble compound having the desired 
degree of balance between hydrophilic and hydrophobic elements. 
For example, a well-known class of nonionic synthetic detergents is made 
available on the market under the trade name of "Pluronic." These 
compounds are formed by condensing ethylene oxide with a hydrophobic base 
formed by the condensation of propylene oxide with propylene glycol. The 
hydrophobic portion of the molecule which, of course, exhibits water 
insolubility has a molecular weight of from about 1,500 to about 1,800. 
The addition of polyoxyethylene radicals to this hydrophobic portion 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 the 
condensation product. 
Other suitable nonionic synthetic detergents include: 
1. The polyethylene oxide condensates of alkyl phenols, e.g., the 
condensation products of alkyl phenols having an alkyl group containing 
from about 6 to 12 carbon atoms in either a straight chain or branched 
chain configuration, with ethylene oxide, the said ethylene oxide being 
present in amounts equal to 10 to 60 moles of ethylene oxide per mole of 
alkyl phenol. The alkyl substituent in such compounds may be derived from 
polymerized propylene, diisobutylene, octane, or nonane, for example. 
2. Those derived from the condensation of ethylene oxide with the product 
resulting from the reaction of propylene oxide and ethylene diamine -- 
products which may be varied in composition depending upon the balance 
between the hydrophobic and hydrophilic elements which is desired. For 
example, compounds containing from about 40% to about 80% polyoxyethylene 
by weight and having a molecular weight of from about 5,000 to about 
11,000 resulting from the reaction of ethylene oxide groups with a 
hydrophobic base constituted of the reaction product of ethylene diamine 
and excess propylene oxide, said base having a molecular weight of the 
order 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 corresponding to the following general 
formula, 
EQU R.sub.1 R.sub.2 R.sub.3 N.fwdarw.O, 
wherein R.sub.1 contains an alkyl, alkenyl or monohydroxy alkyl radical of 
from about 8 to about 18 carbon atoms from 0 to about 10 ethylene oxide 
moieties, and from 0 to 1 glyceryl moiety, and R.sub.2 and R.sub.3 contain 
from 1 to about 3 carbon atoms and from 0 to about 1 hydroxy group, e.g., 
methyl, ethyl, propyl, hydroxy ethyl, or hydroxy propyl radicals. The 
arrow in the formula is a conventional representation of a semi-polar 
bond. Examples of amine oxides suitable for use in this invention include 
dimethyldodecylamine oxide, oleyldi(2-hydroxyethyl)amine oxide, 
dimethyloctylamine oxide, dimethyldecylamine oxide, 
dimethyltetradecylamine oxide, 3,6,9-trioxaheptadecyldiethylamine oxide, 
di(2-hydroxyethyl)-tetradecylamine oxide, 2-dodecoxyethyldimethylamine 
oxide, 3-dodecoxy-2-hydroxypropyldi(3-hydroxypropyl)amine oxide, 
dimethylhexadecylamine oxide. 
5. Long chain tertiary phosphine oxides corresponding to the following 
general formula 
EQU RR'R"P.fwdarw.O 
wherein R contains an alkyl, alkenyl or monohydroxyalkyl radical ranging 
from 8 to 18 carbon atoms in chain length, from 0 to about 10 ethylene 
oxide moieties and from 0 to 1 glyceryl moiety and R' and R" are each 
alkyl or monohydroxyalkyl groups containing from 1 to 3 carbon atoms. The 
arrow in the formula is a conventional representation of a semipolar bond. 
Examples of suitable phosphine oxides are: 
dodecyldimethylphosphine oxide, 
tetradecyldimethylphosphine oxide, 
tetradecylmethylethylphosphine oxide, 
3,6,9-trioxaoctadecyldimethylphosphine oxide, 
cetyldimethylphosphine oxide, 
3-dodecoxy-2-hydroxypropyldi(2-hydroxyethyl)phosphine oxide, 
stearyldimethylphosphine oxide, 
cetylethylpropylphosphine 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. 
6. Long chain dialkyl sulfoxides containing one short chain alkyl or 
hydroxy alkyl radical of 1 to about 3 carbon atoms (usually methyl) and 
one long hydrophobic chain which contains alkyl, alkenyl, hydroxy alkyl, 
or keto alkyl radicals containing from about 8 to about 20 carbon atoms, 
from 0 to about 10 ethylene oxide moieties and from 0 to 1 glyceryl 
moiety. Examples include: 
octadecyl methyl sulfoxide, 2-ketotridecyl methyl sulfoxide, 
3,6,9-trioxaoctadecyl 2-hydroxyethyl sulfoxide, 
dodecyl methyl sulfoxide, 
oleyl 3-hydroxy propyl sulfoxide, 
tetradecyl methyl sulfoxide, 
3-methoxytridecyl methyl sulfoxide 3-hydroxytridecyl methyl sulfoxide, 
3-hydroxy-4-dodecoxybutyl methyl sulfoxide. 
The zwitterionic synthetic detergents useful in the oral compositions of 
the present invention can be broadly described as derivatives of aliphatic 
quaternary ammonium, phosphonium, and sulfonium compounds, in which the 
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., carboxy, 
sulfonate, sulfate, phosphate, or phosphonate. A general formula for these 
compounds is: 
##STR2## 
wherein R.sup.2 contains an alkyl, alkenyl, or hydroxy alkyl radical of 
from about 8 to about 18 carbon atoms, from 0 to about 10 ethylene oxide 
moieties and from 0 to 1 glyceryl moiety; Y is selected from the group 
consisting of nitrogen, phosphorus, and sulfur atoms; R.sup.3 is an alkyl 
or monohydroxyalkyl group containing 1 to about 3 carbon atoms; x is 1 
when Y is a sulfur atom and 2 when Y is a nitrogen or phosphorus atoms, 
R.sup.4 is an alkylene or hydroxyalkylene of from 1 to about 4 carbon 
atoms and Z is a radical selected from the group consisting of 
carboxylate, sulfonate, sulfate, phosphonate, and phosphate groups. 
Examples include: 
4-[N,N-di(2-hydroxyethyl)-N-octadecylammonio]-butane-1-carboxylate; 
5-[S-3-hydroxypropyl-S-hexadecylsulfonio]-3-hydroxypentane-1-sulfate; 
3-[P,P-diethyl-P-3,6,9-trioxatetradecoxylphosphonio]-2-hydroxypropane-1-pho 
sphate; 
3[N,N-dipropyl-N-3-dodecoxy-2-hydroxypropylammonio]-propane1-phosphonate; 
3-(N,N-dimethyl-N-hexadecylammonio)propane-1-sulfonate; 
3-(N,N-dimethyl-N-hexadecylammonio)-2-hydroxypropane-1-sulfonate; 
4-[N,N-di(2-hydroxyethyl)-N-(2-hydroxydodecyl)ammonio]-butane-1-carboxylate 
; 
3-[S-ethyl-S-(3-dodecoxy-2-hydroxypropyl)sulfonio]-propane-1-phosphate; 
3-[P,P-dimethyl-P-dodecylphosphonio]-propane-1-phosphonate; and 
5-[N,N-di(3-hydroxypropyl)-N-hexadecylammonio]2-hydroxypentane-1-sulfate. 
The cationic synthetic detergents useful in the oral compositions of the 
present invention can be broadly defined as quaternary ammonium compounds 
having one long alkyl chain containing from about 8 to about 18 carbon 
atoms such as lauryl trimethylammonium chloride; cetyl pyridinium 
chloride; cetyl trimethylammonium bromide; 
di-isobutylphenoxyethyldimethylbenzylammonium chloride; 
coconutalkyltrimethylammonium nitrite; cetyl pyridinium fluoride; etc. 
Especially preferred are the quaternary ammonium fluorides described in 
Briner et al, U.S. Pat. No. 3,535,421, issued Oct. 20, 1970, incorporated 
by reference, where said quaternary ammonium fluorides have detergent 
properties. 
The amphoteric synthetic detergents useful in the present invention can be 
broadly described as derivatives of aliphatic secondary and tertiary 
amines in which the aliphatic radical can be straight chain or branched 
and wherein one of the aliphatic substituents contains from about 8 to 
about 18 carbon atoms and one contains an anionic water solubilizing 
group, e.g., carboxylate, sulfonate, sulfate, phosphate, or phosphonate. 
Examples of compounds falling within this definition are sodium 
3-dodecylaminopropionate, sodium 3-dodecylaminopropane sulfonate, 
dodecyl-beta-alanine, N-alkyl-taurines such as the one prepared by 
reacting dodecylamine with sodium isethionate according to the teaching of 
Kosmin, U.S. Pat. No. 2,658,072, issued Nov. 3, 1973, N-higher alkyl 
aspartic acids such as those produced according to the teaching of Lynch, 
U.S. Pat. No. 2,438,091, issued Nov. 16, 1948, and the products sold under 
the trade name "Miranol" and described in Mannheimer, U.S. Pat. No. 
2,528,378 issued Oct. 31, 1950. 
Many additional nonionic, cationic, zwitterionic and amphoteric synthetic 
detergents are known to the art and can be used as sudsing agents in the 
compositions herein. Further examples can be found in McCutcheon's 
Detergents and Emulsifiers, 1972 Annual, published by Allure Publishing 
Corporation, which is incorporated herein by reference. 
The sudsing agent can be employed at levels ranging from about 0.5% to 
about 5.0% of the dentifrice composition. 
Dentifrices normally also contain flavoring agents. Suitable flavoring 
agents for use in the dentifrices herein include, for example, wintergreen 
oil (methyl salicylate), oil of peppermint, oil of sassafras (synthetic), 
and oil of anise. Flavoring agents are present at a level of from 0.01% to 
2.0%. 
Dentifrices normally also contain sweetening agents. Suitable sweetening 
agents for use in dentifrices include, for example, saccharin, dextrose 
and levulose. The sweetening agents are used at levels of from about 0.05% 
to about 2%. 
In toothpastes it is desirable to employ thickening agents such as 
hydroxyethylcellulose and water-soluble salts of cellulose ethers, 
including sodium carboxymethyl cellulose and sodium 
carboxymethylhydroxyethyl cellulose; or natural gums, including gum 
karaya, gum arabic and gum tragacanth. Also, colloidal magnesium aluminum 
silicate or finely divided silica can be used as part of the thickening 
agent to improve the texture of the product. Thickening agents are used at 
levels of from 0.1% to 5.0% of the toothpaste composition. 
It is also desirable to include a humectant material in toothpastes. 
Suitable materials for this purpose include glycerine, sorbitol, and other 
edible polyhydric alcohols or mixtures thereof. These materials can 
comprise from about 1% to about 50% of the toothpaste composition. In 
addition to the aforementioned typical components of a toothpaste, water 
usually comprises the balance of the toothpaste, and is usually present at 
levels up to about 50%. 
Mouthwashes generally comprise a water/ethyl alcohol solution and 
optionally other ingredients such as flavor, sweeteners, and humectants 
such as those mentioned above for dentifrices. The alcohol provides an 
antibacterial effect. Optionally, mouthwashes also contain sudsing agents 
such as those mentioned above for dentifrices. Humectants such as 
glycerine and sorbitol give a moist feel in the mouth and are desirably 
also present. Antibacterial agents are sometimes incorporated into 
mouthwashes (or dentifrices) at levels from about 0.01% to about 2.0%. 
Generally, mouthwashes suitable for use as carriers herein contain 5% to 
40% ethyl alcohol, 0% to 20% (preferably 5% to 20%) glycerine or other 
humectant, 0% to 2% (preferably 0.1% to 2%) 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. 
Chewing gum suitable for use as a carrier herein comprises a gum base and 
flavoring materials such as those mentioned above for dentrifrices. The 
flavoring materials are present at a level of 0.01% to about 2.0% of the 
final chewing gum composition. The gum base is a chewable plastic gum 
material such as natural rubber, chicle, polyvinyl acetate, ester gum, 
coumarone resin, and paraffin wax. The gum base is typically made from a 
mixture of two or more plastic gum materials to achieve a preferred degree 
of plasticity for chewing. Optionally, corn syrup is added as a softener 
and binder for the chewing gum and sugar is optionally added as a filler 
and sweetener. A typical chewing gum suitable as a carrier herein 
comprises 15% to 30% gum base, 15% to 20% corn syrup, 50% to 65% sugar, 
and 0.05% to 1.5% flavoring materials. 
Lozenges suitable as carriers herein comprise a hard sugar candy base and 
one or more flavoring materials. The flavoring materials are present at 
levels between 0.1% and 2.0%. Optionally, lozenges can contain various 
other materials. A typical lozenge suitable as a carrier in this invention 
is a hard candy comprised of a hard candy base containing 0.05% to 1.5% 
flavor. The hard candy base is a solidified solution of amorphous sugar 
which is generally formed from a sugar solution which has been cooked at 
high temperature so as to remove nearly all of the moisture. 
The flavoring materials and antiplaque agent are added before the moisture 
is removed. The flavoring materials mentioned hereinbefore for 
dentrifrices are also exemplary of those suitable for use in lozenges. 
When formulating the antiplaque agents of the present invention into an 
oral composition, the amount which is incorporated into the composition 
should be sufficient to provide at least 0.001 grams of antiplaque agent 
per usage of the composition. Thus, in dentifrices, where the amount of 
product used per usage is from about 1 to 4 grams, the amount of 
antiplaque agent in the dentrifrice should be at least about 0.03%, 
preferably from about 0.1% to about 2%, and most preferably from about 
0.5% to about 1.5%. In mouthwashes, typical usage is from about 10 to 20 
grams, and the amount of antiplaque agent in the mouthwash should be at 
least 0.01, preferably from about 0.5% to about 1.5%, and most preferably 
from about 0.1% to about 1.0%. 
Typical usage of chewing gum and lozenges is from about 1 to 4 grams and 
the amount of antiplague agent in the chewing gum or lozenge should be at 
least about 0.03%, preferably from about 0.1% to about 2%, and most 
preferably from about 0.5% to about 1.5%. 
Generally, oral compositions should contain from about 0.01% to about 2.5% 
of the antiplaque agent. 
The oral compositions of the present invention can also optionally contain 
additional therapeutic materials for use in the oral cavity such as 
anticaries agents, (e.g., water-soluble fluoride such as sodium fluoride 
and stannous fluoride) and anticalculus agents such as trisodium ethane 
1-hydroxy-1,1-diphosphonate. 
Although the novel bis-biguanide compounds of the present invention give 
considerably less staining of the teeth than chlorhexidine, they are not 
completely free of staining potential and it is, therefore, often 
desirable to include in the compositions of the invention certain 
chelating agents which are useful in combating the general tendency of 
bis-biguanide antiplaque agents to stain the teeth, as well as the 
tendency of the teeth to become stained from natural causes such as 
contact with certain foods and beverages. Such chelating agents are 
disclosed in Haefele, U.S. Pat. No. 3,937,807, issued Feb. 10, 1996; U.S. 
Ser. No. 584,304, Gieske and Juneja, filed June 6, 1975; and U.S. Ser. No. 
652,692, Gieske and Juneja, filed Jan. 27, 1976. Examples of chelating 
agents useful for this purpose are nitrilotriacetic acid, ethylenediamine 
diacetic acid, kojic acid, maltol, ethyl maltol, calcium dihydrogen 
ethylenediamine tetraacetate, di-N-substituted ethylene diamine diacetic 
acids wherein the substituents can be ethyl or 2-hydroxyethyl. The 
pharmaceutically acceptable water-soluble salts of these chelators are 
particularly useful, e.g., the sodium, potassium and ammonium salts. When 
a chelator is used, enough chelator should be present in the compositions 
such that some excess chelator is present in addition to that which reacts 
or would react with the bis-biguanide present. The concentration of such 
excess chelator generally ranges from about 0.01% to about 1.25% by weight 
of the composition. Generally, two moles of chelator react with one mole 
of bisbiguanide compound.

This invention will be further illustrated by the following examples: 
EXAMPLE I 
A toothpaste is prepared according to the following formula: 
______________________________________ 
Component Parts by weight 
______________________________________ 
Sorbitol (70% soln.) 20.00 
Sodium saccharin 0.21 
Veegum (colloidal magnesium aluminum 
silicate) 0.40 
Precipitated urea/formaldehyde 
condensate (abrasive) 30.00 
Flavor 1.00 
Sodium carboxymethylcellulose 
1.30 
Glycerine 10.00 
1,2-bis(N.sup.5 -m-bifluoromethylphenyl-N' 
biguanido)-ethane digluconate 
0.70 
Polyoxyethylene sorbitan (20) 
monoisostearate 1.50 
Distilled water balance to 100 
______________________________________ 
This toothpaste, when used in the normal manner, is effective in retarding 
the formation of dental plaque and produces an appreciably lower level of 
stain on the teeth than does chlorhexidine. 
EXAMPLE II 
A mouthwash in accordance with the present invention is formulated as 
follows: 
______________________________________ 
Component Parts by weight 
______________________________________ 
Ethyl alcohol (95% in water) 
12.00 
Cetyl pyridinium chloride 
0.10 
Polyoxyethylene (20) sorbitan monooleate 
0.12 
Sodium hydroxide (10% in water) 
0.02 
Sodium saccharin 0.055 
Flavoring 0.16 
1,2-bis(N.sup.5 -m-trifluoromethylphenyl-N'- 
biguanido)ethane dihydrochloride 
0.20 
Color 0.50 
Sorbitol (70% in water) 
12.00 
Distilled water balance to 100 
______________________________________ 
When used in the normal manner to rinse the mouth, this product is 
effective in retarding the formation of dental plaque and produces an 
appreciably lower level of stain on the teeth than does chlorhexidine. 
EXAMPLE III 
A chewing gum in accordance with the present invention is formulated as 
follows: 
______________________________________ 
Component Parts by weight 
______________________________________ 
Gum Base 21.30 
Ester Gum 6.40 
Coumarone resin 9.60 
Dry latex rubber 3.20 
Paraffin wax (M.P.180.degree. F.) 
2.10 
Sugar 58.45 
Corn Syrup (Baume 45) 18.20 
Flavoring 1.05 
1,2-bis(N.sup.5 -m-trifluoromethylphenyl-N'- 
biguanido)ethane diacetate 
1.00 
______________________________________ 
Chewing this gum in the normal manner retards the formulation of dental 
plaque and produces appreciably less staining of the teeth than does 
chlorhexidine. 
EXAMPLE IV 
When in the preceding examples the 1,2-bis(N.sup.5 
-m-trifluoromethylphenyl-N.sup.1 -biguanido)ethane salts are replaced by 
the digluconate or diacetate salts of the following compounds, similar 
results are obtained in that antiplaque performance is obtained with 
appreciably less staining to the teeth than is obtained if chlorhexidine 
is used: 
1,4-bis(N.sup.5 -m-trifluoromethylphenyl-N.sup.1 -biguanido)butane, 
1,2-bis(N.sup.5 -m-trifluoromethylbenzyl-N.sup.1 -biguanido)ethane, 
1,2bis(N.sup.5 -m-trifluoromethylphenyl-N.sup.5 -hexyl-N-.sup.1 
-biguanido)ethane, 
1,2-bis(N.sup.5 -m-trifluoromethylphenyl-N.sup.5 -2-phenethyl-N.sup.1 
-biguanido)ethane 
1,4-bis(N.sup.5 -m-trifluoromethylphenyl-N.sup.5 -ethyl-N.sup.1 
-methyl-N.sup.1 -biguanido)butane, 
1,2-bis(N.sup.5 -m-trifluoromethylbenzyl-N.sup.5 -methyl-N.sup.1 
-biguanido)ethane, 
1,2-bis(N.sup.5 -m-trifluoromethylphenyl-N.sup.5 -phenethyl-N.sup.1 
-biguanido)ethane, 
1,2-bis(N.sup.5 -p-trifluoromethylphenyl-N.sup.1 -biguanido)ethane, 
1,2-bis(N.sup.5 -o-trifluoromethylphenyl-N.sup.1 -biguanido)ethane, 
Bis-(N.sup.5 -m-trifluoromethylphenyl-N.sup.1 -biguanido)methane.