IE43411B1 - Oral compostions containing trifluoromethyl phenyl bis-biguanides as antiplaque agents - Google Patents

Abstract

A composition for oral and/or dental care, e.g. in the form of a tooth cleaning agent or mouthwash or chewing gum, contains a vehicle for use in the oral cavity and antiplaque agent of the formula (1) in which n is a number from 1 up to and including 4, X and X' are each an alkylene radical which contains 1-3 C atoms, z and z' are zero or one, R and R' are each hydrogen atoms, alkyl radicals with 1-12 C atoms or aralkyl radicals with 7-12 C atoms, and R2 and R2' are each hydrogen atoms or alkyl radicals with 1-2 C atoms, or a pharmacologically acceptable salt of a compound of the formula (1).

Description

This invention relates to oral compositions such as toot hpastes and mouthwashes containing « I'i'Lain trifluororaethylphenyl bis-biguanides having excellent antiplaque performance and reduceJ tendency to stain the teeth. to The field of this invention is oral compositions whieh term is used herein to designate products whieh in the ordinary eourse of usage are retained in tiie oral cavity for a time .ind in a manner sufficient, to contact essentially all of tin· dental surfaces, but are not intentionally ingested. Such products include, for example, dentifrices, mouthwashes, prophylaxis pastes and topical solutions. lhe bis-biguanide and antibacterial agents hexidine, 1,6 bis (N ^-p-chloropheny 1-N 1-b iguan i do ) lies.me •inch as chlora r i? known to be effective antiplaque agents, but it has been recognised that they have a tendency to produce severe staining of the teeth. Belgian Patent 8()1,705 di scloses the use of the insoluble salts of the bis-biguanides in oral compositions as a means of reducing the stain problem. Belgian Patent 811,378 and British Patent Specification No. 1,507,846 disclose Lhe use of metal ion chelator compounds, such as amino acids, aminopolycarboxyI ates and hydroxypyrones, with the bis-biguanides to reduce stain. DIOS (German Published Specification) No. 2,627,?43 discloses certain bis-biguanides, 3 4 1 Λ wherein Lhe bridging alkylene group has from 1 to 4 carbon alons instead of six, which have substantially lower staining tendencies than chlorhexidine.

Description of the Invention Tt has now been discovered that certain novel bis-biguanide compounds wherein the bridging alkylene group is Cj to alkylene, and wherein the terminal nitrogen atoms contain trifluorraethylphenyl 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 wherein n is from 1 l.o 4 inclusive (preferably 2 lo 4 inclusive); wherein X and X’ each represent an alkylene rad15 ical containing from 1 to 3 carbon atoms, wherein z and z’ each can be either () or 1; wherein R and R’, each represent either hydrogen, an alkyl radical containing from 1 to 12 carbon atoms, or an aralkyl radical containing from 7 to 12 carbon atoms and wherein Rg and Rg · each represent either hydrogen or an alkyl radical of 1 to 2 carbon atoms. Preferred is the compound Wfherein z. and z* are each 0, n is 2 and R, R’, Rg and Rg1 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 , , Pspec [«ill y t h< i' dihydrochloride, d i gl neonate and dine ctalc s.i i 1 s , are the most desirable since I hey iiiuk. puss i 1,1 c 1 he 1 ι > rut, 11 i * ii < > 1 ( Ic. ι r solution < ι χήρο s i 1 i mi·.. In ;i) contrast w i t h chi <>rhe x. i <1 i n<', whose d i hydro» 111 or i de salt is insoluble in water, the hydrochlorides of the compounds of the present invention are water-soluble. Typically, the 3 11 t - 4 hydrin-hloritie sail, is inherently formed in lhe preparation of < h lorhe x i d i lie and of I he compounds of t.he present invention. for purposes of l.h i s application, water-soluble salts are considered to be I.hose having a solubil i I.y of r, greater than about 0.04% by weight in water at 25°!'.

Exarapl.es of bis-biguanidines falling within the scope of the present invention are the following: flis( N 5_ni- tr i f luor ome thyl phenyl-N '-bi guan idi no (methane, 1,2-b i s (N 5-m-t.ri fluoromethyl pheny1-N * -bi guan idino)ethane, 1,4-bis(N^-ja-trifluoromethylpheny1-N *-biguanido(butane , 1,2-b is (N '’-rn-tr if luorome thy Ibenzyi-N '-biguanido (ethane , 1.2- b is(N 5-p-lrifluoromethylpheny1~N *-bi guan ido(ethane , I ,2-bis(N^-o-trifcaorome thylpheny1-N *-biguan ido )e thane , I ,2-bis(S '’-m-tr ifluoromethylpheny1-N^_bexyf_N1_bi guanido) IS e thane , t , 2-b i s (N 5-m-l.i· i f 1 uorome Ihy! pheny I -N 2-phene t hy I -N '-b iguail i do )e I hane , I t 2-b i s I N ^-jn-1 r i 1' I uorome thy I pheny I -N ' -e I hy I -N * -l> i guan i do ) e thane , I,4-bi s(N -m- tr i fluoromet hy1pheny 1 -ethy1-N*-me thyl-N'biguan ido(butane, 1.2- bis(N ’’-rn.-tr i f Iuoromethyl -N ^-me thyl-N'-ethyl-N'-biguanido(ethane , and their water soluble salts, for example, the digluconat.c, 2.S dihydrochloride and diaeetate salts. the most, preferred compounds are l,2-bis(N '^-m-t. r i fl uorome I hy 1 pheny 1 -N '-biguanido) ethane and its di hydrochloride , diaeetate and digluconate salts, Hie compounds ot the invention can be made by reading .50 ethylene or methylene di,imine <1 i hydroc h I o r i de (or an appropriately N,N' substituted ethylene or melhylenc diamine dihydro e.hLoride) or a homologue thereof with sodium dicyanamide to Λ j give, for example, a bis (\ -cyano-N -guanidino )et hane , which - 5 is then reacted wi III t.he hydrochloridc of the desired in-I.rifiuoromethyl pheny I ami ne or other isomer to give fhe 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 0.01% Lo 2.5% (preferably from 0.05% to 1.2%, and most preferably from 0.1% to 0.8%) by weight of t.he bis-biguanide antiplaque agent and I he balance, a carrier suitable for use in the oral cavity. All percentages herein are by weight, unless specified otherwise. Depending upon Lhe composition, lesser or greater amounts may be used. In general, all that is required is to have an effective amount of t.he bis-biguanide compound in the mouth sufficient l.o give.· antiplaque and/or ant.icaries 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 4.5 to 9-5- Below 4.5, damage to dental enamel can occur. Above 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, I lie carrier portion of lhe oral ( oinposi ι ion is a lunvcnl ional preparal ion such as a toothpaste, mouthwash ur «hewing gum. 434 1 1 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 0.5% to 95% abrasive in addition to the bisbiguanide anti plaque agent.

Any abrasive |x>lishing material which tines not excessively abrade dentin can be used in these dentifrice compositions. These include, for example, calcium carbonate, ilicalcium orthophosphate dihydrate, calcium pyrophosphate, calcium polymetaphosphate and insoluble sodium polyroethaphosphate. Preferably, however, the abrasive is one which has a high degree of cumpatibi lity with the bis-biguanide. These include, for example, condensation products of urea and formaldehyde such as disclosed by Cooley et al. in U.S. Patent 3,070,510, granted December 25, 1962, silica xerogels such as those disclosed in I'.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, and mineral abrasives coated with cationic polymers such as those disclosed in Or i ! ; sh Patent 8|«·<1 1 ieal.iun No. 1,506,(145 . The abrasives generally have .< particle size of from 0.1 to 20 microns in d iamutcr. lhe total amount oi abrasive material.-, in the dent.i frice embodiments ol this invention can range from 0.5% to 95% by weight of the dentifrice. Preferably, toothpastes contain from 6% to 60%, and 1001 hpowder s contain from 20% to '15% abrasives.

Dentifrices usually contain surface-active agents (also called sudsing agents). 3 4 11 - Ί 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 Lhe present, invention may be broadly defined a.s 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 gr-'up can be readily adjusted to yield a water-soluble compound having the desired degree of balance between hydrophilic and hydrophobic elements.

IS for example, a well-known class of nonionic syntheticdetergents i.s made available on the market under the trade name of PluiOiiit. These compounds are formed by condensing ethylene oxide with a hydrophobic base formed by the condensation of propy I ene oxide with propylene glycol. I'he hydroYu pliobit port ion of I lie miilciule whirl), of ·. ours;·, exhibits wafer insolubility lots a molecular weight of from I , >01) tn 1,.SOU. The addition of polyoxyethylene radicals to this hydrophobic portion tends to increase the water· solubility of the molecule as a whole and tbe liquid character of the products is retained up to the point where polyoxyethylene content is about 5θί of the total weight of the condensation produc t .

Other suitable, nonionic synthetic detergents include: 1. lhe polyethylene oxide condensates of alkyl phenols, .30 e.g., the condensation products of alkyl phenols having an alkyl group containing from 0 to 12 < arbon atoms in either a straight, (bain or branched rliain configuration, with ethyl4 3 -J 1 1 - 8 <·(!·· oxide, I lie s.ijil e I Iiy I rm· oxide bein··. | >«·«·.*«· ι»I in .imuiinls eipi.il In III l.o (ill moles of ethylene oxide pee mole of alkyl plienoL. The alkyl substituent in such imnpounds may be derived from polymerized propylene, d i i sobutylene-, octane, or nonane, for example. 2. Those derived from the condensid iim of ethylene oxidewith the product resulting from the re.nfion of propylene oxide and ethylene diamine - products which may be varied in composition depending upon Lhe balance between the hydro3 phobic and hydrophilic elements which is desired. For example, compounds containing from 40^ to 80% polyoxyethylene by weight and having a molecular· weight of from 5,000 to 11,000 resulting from the reaction of ethylene oxide groups with a hydrophobic base const ituled of (he react ion product of ethylene diamine and excess propylene oxide, said base having a molecular wright ni' tin* iii’ilir ot 2,5Ot > ta» \ , ι if >11, arr sa ι ι s f ai lory. a. the condensation product, oi' aliphatic alcohols having from Ί to IS (.irbon at,oms, in either straight, chain or branched chain configuration, with ethylene oxide, e.g. a inronut alii cohol ethy lent' oxide ι ninlrnsat e having from 10 to 50 moles of ethylene oxide per mole of coconut alcohol , the coconut alcohol fraction having from It) to 14 carbon atoms. 4. Long chain tertiary amine oxictis corresponding tea the following general formula: R KOR whi rein contains an alkyl, alkenyl or- rnnnohydroxy alkyl radical of from S to carbon atoms from 0 to 10 ethylene oxi dr moiet ies, and from 0 to 1 glycer yl moiet y, and RQ and R, contain from 1 to 5 carbon atoms arid from 0 to 1 hydroxy t) group, e.g. methyl, ethyl, propyl, hydroxy ethyl, or hydroxy propyl radicals. Ihe arrow in the' formula is a conventional representation of a semi-po 1 ar bond. Examples of amine- oxide's 434 1 suitable for use in this invention include dimethyldodecylamine oxide, oleyldi(2-hydroxyethyl)amine oxide, dimethyloctyl amine oxide, dimethyldecylamine oxide, dimethyltetradecylamine oxide, 3,6,9-trioxahepLadecyldicthylamine oxide, di(2-hydro5 xyethyl )tetradeeylamine oxide, 2-dndeeoxyethyldimethylaminc ox ith·, 3-dotle.coxy-2-hydroxypropyldi (3-hydroxypropyl )amine oxide, and dimethyl hcxadecylamine oxide.

. Long chain tertiary phosphine oxides corresponding to the following general formula RR’ R P-> 0 wherein R contains an al'yl, alkenyl or monohydroxyalkyl radical ranging from 3 to l8 carbon atoms in chain length, from 0 to 10 ethylene oxide moieties and from 0 to 1 glyceryl moiety anti R* and Rn are each alkyl or monohydroxyalkyl groups containing from 1 to 3 carbon atoms. Ihe arrow in the formula is a conventional representation of a semi-polar bond. Examples of suitable phosphine oxides are: dodecyld ime thylphosphine oxide, tetradecyId imethylphosphine oxide, I.e trade» y 1 me thy 1 e I by I phosph ine oxide, 3,0,9-tr i oxaot I adet y I tl i me ( hy I phosph i ne oxide, cc l.yl d i methyl phosph i ne ox i tie , 3-dodecoxy-2-hydroxypropyIdi(2-hydroxye thyl)phosph ine oxide , sLeary1dimethylphosphine oxide, ce Lyle thy1 propyl phosphine oxide , oleyldiethylphosphine oxide, dodecyl diethylphosphine oxi de, tetrade.cyldiethylphosphine oxide , dodecyl di propyl phosphine oxide, dodecyldi(hydroxyme thyl )phosphine oxide , dodecyldi(2-hydroxyethyl)phosphine oxide , tetradecylmet hy1-2-hydroxypropylphosphine oxide , oleyldimethylphosphirie oxide, and 3-111 - 10 2-hydro My ib > 6. Long cli.'iin dialkyl sulfoxides containing one short chain alkyl or hydroxy alkyl radical of 1 Lo 3 carbon atoms (usually methyl) and one long hydrophobic chain which contains alkyl, alkenyl, hydroxy alkyl, or keto alkyl radicals containing from 8 to 20 carbon atoms, from 0 to 10 ethylene oxide moieties and from 0 to 1 glyceryl moiety. Examples include: octadccyl methyl sulfoxide, 2- ketotrideeyl methyl sulfoxide, 3,6,9-trioxaoctadecyl 2-hydroxyethyl sulfoxide, dodecyl methyl sulfoxide, oleyl 3-hydroxy p.opyl sulfoxide, tetradecyl methyl sulfoxide, 3— me I lutxy t.c i ilecy I me thy 1 sulfoxide, 3-hydroxy 1.1· i de< y 1 melhyl sulfoxide and 3—hydroxy-4-«lode coxy bitty 1 me thyl so 1 fox i lie .

Tlie zwit.terionic synthetic detergents useful in the oral compositions of the present invention can be broadly described as dcriyativi-s of aliphatic quaternary ammonium, phosphonium, and sulfonium compounds, in which the aliphatic radicals can be straight chain or hranched, and wherein one of the aliphatic substituents contains from 8 to lS 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: wherein R“ contains an alkyl, alkenyl, or hydroxy alkyl radical of from S to 18 carbon atoms, from 0 to 10 ethylene oxide moieties anil from 0 to 1 glyceryl moiety; Y is selected from the group consisting of nitrogen, phosphorus, anil sulfur (κΊ)χ R2 _ j(+)-CH7-R4 -Z(_) 3 11 1 -113 atoms; R is an alkyl or monohydroxyalkyl group containing 1 to 3 carbon atoms; x is 1 when Y is a sulfur atom and 2 when Y is a nitrogen or phosphorus atom, is an alkylene or hydroxyalkylene of from 1 to 4 carbon atoms and Z is a radical selected from the group consisting of carboxyiate, sulfonate, sulfate, phosphonate, and phosphate groups.

Examples include: - [N,N - di(2 - hydroxyethyl) - N - octadccylammonioJbutane - 1 - carboxyiate; IO 5 - (S - 3 - hydroxypropyl- S - hexadecylsulfonioj - 3 hydroxypenLane - I - sulfate; - [P,P - diethyl - P - 3,6,9 - trioxatetradecoxylphosphonioj - 2 - hydroxypropane - 1 - phosphate; - [N,N - dipropyl — N — 3 — dodecoxy - 2 - hydroxy15 propylaramonioJ - propane - 1 - phosphonate; - (N,N - dimethyl - N - hexadecylammonio)propane - 1 sulfonate; - (N,N - dimethyl - N - hexadecylammonio) - 2 - hydroxypropane - 1 - sulfonate; 4 - [N,N - di(2 - hydroxyethyl) - N - (2 - hydroxydodecyl) ammonio] - butane - 1 - carboxyiate - [S - ethyl - S - (3 - dodecoxy - 2 - hydroxypropyl]sulfonioj - propane - 1 - phosphate; - [P,P - dimethyl - P - dodecylphosphonioJ - propane 25 1 - phosphonate; and - [N,N - di(3 - hydroxypropy1) - N - hexadecylammonioJ2 - hydroxypentane - 1 - sulfate.

The cationic synthetic detergents useful in the oral compositions of the present invention can be broadly defined a.s quaternary ammonium compounds having one long alkyl chain containing from 3 to l8 carbon atoms such as lauryl triinethylanunon i urn chloride; cetyl pyridinium chloride; cetyl I r Line' thyl amnion i nm bromi de; eli-isobutyl phenoxye t hy ldime thy 1 30 3 4 11 - 12 Inn zy I ammo 11 i om chloride; i o< onu La 1 ky I I ι· i me tliyl amnion ium nitrile; and cetyl pyridinium fluoride. Especially preferred are the quaternary ammonium fluorides described in Biiner et al, U.S. Patent 3,535,421, issued October 20, 1970, 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 ali10 phatic radical can be straight chain or branched and wherein our of tho aliphatic substituents contains from 8 to l8 carbon atoms and one coni.tins an anionic water solubilizing group, e.g., carboxylate, sulfonate, sulfate, phosphate, or phosphonatc. Examples of rnmpounds falling within Lhis definition are sodium 3-dodecyl.uninopropionate , sodium 3-dodecylami nopropane sulfonate, dodecyl-beta-alanine, N-alkyl-taurincs such as t.he one prepared b, reacting dodeeylamine with sodium isethionate according to tin- leaching of Ko-anin, U.S. Patent. No. 2 , <> 58,072 , issued November 3, 197’, N-liighcr alkyl aspart ir 211 ac ι its sue 11 as I Iio.m· produced according to I lie I < ai h i ng ο I Lynch, U.S. Patent No. 2,433,()01, j smiiiI November 1 (>, 1943, and the products sold under the trade name Miratwl and described in Haimheimer, U.S. Patent No. 2,528,378 issued October 31, 1950.

Many additional nonionie, catiimii , zwitlerioiiic and amphoteric synthetic detergents arc known to the act and can be used as sudsing agents in tiie compositions herein. Further examples can be found in McCutcheon 1s Pet crgents and Emulsi fiei~s, 19 y 2 Annual , published by Allure Publishing Corporation.

Fhe sudsing agent can be employed at levels ranging from 0.5 to 5.0/' of the dciili frier composition. 3 4 11 Dentifrices normally also contain flavouring agents. Suitable flavouring agents for use in the dentifrices herein include, for example, winter-green oil (methyl salicylate), oil of peppermint, oil of sassafras (synthetic), and oil of anise. Flavouring 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 .05% to 2%. tn toothpastes it is desirable to employ thickening agents such as hydroxyethyl-cellulose and water-soluble salts of cellulose ethers, including sodium carboxymethyl cellulose and sodium carboxymethylhydroxyethyl cellulose; or natural IS gums, including gum karaya, gum arabic and gum tragacanth. Also, colloidial magnesium aluminium 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 as levels of from 0.1% to 5.0% of the toothpaste compos20 i t ion .

It is also desirable Lo 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 1% to 50% of the toothpaste composition. In addition Lo the aforementioned typical components of a toothpaste, water usually comprises the balance of the toothpaste, and is usually present at levels up to 50%.

Mouthwashes generally comprise a water/ethyl alcohol solution and optionally other ingredients such as flavour, sweeteners, and humectants such as those mentioned above for dentifrices. The alcohol provides an antibacterial effect. /13 4 11 Η 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 .01% to 2.0%.

Generally, mouthwashes suitable for use as carriers herein contain 5% to 40% ethyl alcohol, 0% to 20% (preferably 5% to 20%) glye criiif or other humectants, 11% to 2% (pee fe rah I y 0.1% t.o 2%) sudsing agent, <>%. 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%) flavouring agent, and the balance, water.

Chewing gum suitable for use as a carrier herein comprises a gum base and flavouring materials such as those mentioned above for dentifrices. The flavouring materials are present at a level of 0.01% tt, 2.0% of the final ch< wing 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 i.s 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 3θ% gum base, 15% to 20% corn syrup, 50% to 65% sugar, and 0.05 to 1.5% flavouring mat.er i a 1 s . l.ozcnges suitable as carriers herein (omprise a hard sugar candy base and one or more flavouring materials. 1 he flavouring materials are present, at levels between (». 01 % and 2.0%.

Optionally, lozenges can contain various other mater4 3 4 11 - 15 Lals. 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% flavour. 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 flavouring materials and antiplaque agent are added before the moisture is removed. The flavouring materials mentioned hereinbefore for dentifrices are also exemplary of those IO suitable for use in lozenges.

Wlu-n fot'inu I a t i ng the ant i piaquc agents ni thi* present invent inn into an oral composition, the amount which is iucorporaled into tin.· composition should be sufficient lo 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 1 to 4 grams, the amount of antiplaque agent in the dentifrice should be at least 0.03%, preferably from 0.1% to 2%, and most preferably from 0.5% to 1.5%· Γη 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 0.5% to 1.5 %, and most preferably from 0.1% to 1.0%.

Typical usage of (hewing gum and lozenges is from about 1 to 4 grams and the amount of ani iplaque agent in I he chewing gum or lozenge should be at. least 0.03%, preferably from 0.1% to 2%, and most preferably from 0.5% to 1.5%.

Generally, oral compositions should contain from 0.01% t.o 2.5% of · be ani iplaque agent , rile Di al ( iiiiiposil ions of the prcscnl invention c an also opt ionally iiinlain additional Iherapeul ic materials for use in I be oral cavity auch as anticarics agents, (e.g., watersoluble fluoride smb as sodium fluoride and stannous fluoride) and anticalculus agents such as trisodiiun ethane 1-hydroxy-1,14 3 41 1 - ιό il ί ι>1 n is |>1 ιι ιι ι a 1.1 ·.

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 bisbiguanide 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. Patent 3,937,807, issued February 10, 197b; and in British Patent Specification No. 1,507,846. Examples of chelating agents useful for this purpose are uitri1o-lriacetic acid, ethyIenediaminc diacetic acid, ko.jic acid, mal Lol , ethyl mal tol, calcium dihydrogen ethylenediamine tetraacetate, and di-N-substituted ethylene diamine diacetic acids wherein the substituents can be ethyl or 2-hydroxyethyl. The pharmaceutically acceptable watersoluble salts of llirsc chelators .111· par I i cu I ar 1 y useful e.g., ( hr sodium, potassium anil ammonium salt s. When a chelator is used, enough chelator should he present, in the compositions such that some excess chelator is present in addition to that which reacts or would react with Lhe bis-biguanide present.

The concentration of such excess chelator generally ranges from 0.01:? to 1.25? by weight of the composition. Generally, two moles of chelator react with one mole of bis-biguanide compound.

This invention will be further illustrated by the following examples: EXAMPLE Γ A l uiil lipasl 1· 1 pr, · pa red ,11 Kirill il” to the following 1'0 rmu I .1 >7 3 111 ίο 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 Flavour 1.00 Sodium carboxymethylcellulose 1.30 Glycerine 10.00 1,2 — bi.s(N^ - m - hi f I noromet.hy I pheny I - Ν' biguanido) - clhaiic digluconate 0.70 Polyoxyethylene sorbitan (20) monoisost.caral.e 1 . 50 Distilled water balance to 100 This toothpaste, when used in the normal manner, i.s 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 weigh t Ethyl alcohol (95% in wafer) 12.00 Cetyl pyridinium chloride 0. 10 Polyoxyethylene (20) sorbitan monoolenfe 0.12 Sodium hydroxide ( 10% in water) (J.02 Sodium saccharin ().() 5 5 F1 avour i ng 0. I (, 1,2 - bis(N^ - ra - trifluoromethylphenyl -N’biguanido)e1hane dihydrochloride 0.20 Colour 0.50 Sorbitol (7(). in water) 12.00 Distilled water balance to 100 3 4 11 - 18 When used in Lhe normal manner Lo rinse the mouth, this product is effective in retarding tho formation of dental plaque and produces an appreciably lower level of stain on the teeth than does chlorhexidine.

EXAMPLE III A chewing gum in arrortlancR with the present in ven tion Is formulated as follows: Component Parl> i by we i gh t Gum base 21.30 10 Ester Gum 6.40 Coumarone resin 9.60 Dry latex rubber 3.20 Paraffin wax (M.P. l3O°E)2.1O Sugar 58.45 15 Corn Syrup (Baume 45) IS. 20 flavouring 1.05 1,2 - bis (N5 - m - trifluoromethylphenyl _N ' - biguanido)etbane diacetate 1.00 Chewing gum in the normal manner retards the formulation of dental plaque and produces appreciably less staining of the l.eeth than does rh 1 nrlic x i d i ne .

EXAMPLE 1V When in the preceding examples the 1,2 - bis (ν’ - m trifluoromethylphenyl - S'1 - bi guan l do )e thane salts are replaced by the digluconate or diacetate salts of the following compounds, similar results are obtained in that antiplaque perl oiin.nice is obtained with appreciably less staining to the teeth than ls obtained if chlorhexidine is used: 1,4 - b i s t \ m—1 r i fl uoroinet hy 1 pheny I -N 1 -b i guan i do )but ane , 1,2 -b i s ( \ ’-in-1 r i 1' Iuorome t hylbenzy1-N1-biguan i do)e t hane , 1,2 -b i si\ '-m-tri I luoromelhy i pheny1 - N ’-hexy1-N’-b i guan i do ) .bane 434 1 J - 19 1.2- bis(N5-m-trlfluoromethylphenyl-N^-2-phenethyl-N^bIguanido)ethane, l,<|-bis(N 5_m_ tri f 1 uorone thy 1 phenyl-N ^-e thy 1 -N1 -me thyl N -biguanido)butane, 1.2- bi s(N5-m-tri fluoronethylbenzyl-N ^-me thy1-N1biguanido)ethane, 1, 2-bis(N5-Il^-tΓifluorolIιethylphenyl-N5-phenethyl-N^biguan ido)e thane , 1.2- bis(N^-p—trtfluoromethylphenyl-N^-biguanido)ethane, 1.2- bis(N^-o-trifluoromethylphenyl-N^-biguanido)ethane, and Bis-(N$-m-trifluoromethylphenyl -N^-biguanido)methane.

Claims (12)

1. I. Λ his-biguanide compound having the generic formula: wherein n i.s from 1 to 4 inclusive; X and X· each represent 5 an alkylene radical containing from 1 fo 3 carbon atoms: z and z* are each 0 or 1; R and R’ are each hydrogen, an alkyl radical containing from 1 to 12 carbon atoms or an aralkyl radical cont aining from 7 to 12 carbon atoms; and and R,' are each hydrogen or an alkyl radical of 1 to 2 carbon atomsj Ιθ and the pharmaceutically acceptable salts thereof.
2. 2. A compound according to claim 1 wherein the salt is a water-soluble salt.
3. 3. A eompmind according to claim 1 or 2 wherein t.he salt is d i hydroch I or-i de diaeetate* or digluconafe salt. 15
4. 4. Λ compound according to any one of claims i to j wherein n equals 2, z and z' are each 0 and R, R', R^ anc l R 2 ' ai-e each hydrogen.
5. 5. Λ compound according to any one of claims 1 to 4 wherein the trif1uoromethy1 groups are in the meta position. (j. Λ bi s-b i guan ide compound or a pharmaceutically acceptable salt (hereof substantially as hereLnbcfore described in the Examples.
6. 6. 7. An oral composition comprising a carrier suitable for use in the oral cavity and from 0.01% t.o 2.5% by weight of 25 composition of an antiplaque agent consisting of a bis-biguanide compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof according to any one of claims 1 Lo 6.
7. 7. 8. A composition according to claim 7 wherein the amount of antiplaque agent in the composition is from 0.05% to 1.2% by 5 weight of the composition.
8. 8. 9. A composition according to claim 7 wherein the amount of antiplaque agent in the composition is from 0.1% to 2.0% by weight of the composition and the composition contains as an additional ingredient from 0.5% to 95% by weight of the
9. 9. 10 composition of an abrasive.
10. 10. A composition according to claim 7 in the form of a mouthwash wherein I.In; antiplaque agent is present al a level o f f rom 0.5% the compos it to ion 1.5% by weight of tin; composition and contains as additional components: 15 A. f rom 5% to 40% ethyl alcohol; B. f rom 0% to 20% humectant; C. from 0% to 2% sudsing agent; D. f rom 0% to 0.5% sweetening agent; E. from 0.05% to 0.3% flavouring agent; and 20 F. water .
11. ll. A composition according to any one of claims 7 to 10 which additionally contains from 0.01% to 1.25% by weight of the composition of a chelator in excess of the amount of chelator which will react with the bis-biguanide compound, 25 said chelator being n i tr i iotr i ace t i <· ac i <1, ethylenediamine diacetic acid, kojic acid, mall.ol, ethyl maltol , calcium dihydrogen ethylenediamine tetraacetate, a di-N-substituled ethylene diamine diacetic acid wherein the substituents are ethyl or- 2-hydroxyet.hyl, and thi; pharmaceutically acceptable wat.er30 soluble salts of said chelators. - 22
12. 12. A composition according to claim 7 substantially hereinbefore described in the Examples. as