IE43411L - Anti-plaque agents - Google Patents

Description

4 J '» 1 v This invention relates to oral lompositions such a.s toothpastes and mouthwashes containing crrtain trifluoro-raethylphenyl bis-biguanides having excellent antiplaque performance and reduce-1 tendency to stain the teeth.

The field of thi.s 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 suf f i ■ »;n t t,o contact essentially all of ttie dental surfaces, but are not intentionally invested. Such |() products include, for example, dentifrices, mouthwashes, prophylaxis pastes ami topical solutions.

The bis-biguanide and antibacteria I agents such as chlor-hcxidine, 1,0 bis (N^-p-4^ discloses certain bis-biguanides, 4 3 4 1 \ wherein I,he bridging alkylene group has from 1 to 4 carbon atoms instead of six, which have substantially lower staining tendencies than chlorhexidine.

Description of the Invention Tt has now been discovered that certain novel bis-big- uanide 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 where i u n is from 1 to 4 inclusive (preferably 2 lo 4 inclusive); wherein X and X' each represent an alkylene rad- teal containing from 1 to 3 carbon atoms, wherein z and z' each can be either O 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 R^ and ' each represent either 20 hydrogen or an alkyl radical of 1 to 2 carbon atoms. Preferred is the compound wherein /. and z1 are each 0, n is 2 and R, R', R2 and R^1 are hydrogen. Preferably, the tri-fluoromethyl group is in the meta position; however, the corresponding ortho and para-isomers arc also suitable for 25 use herein. The pharmareutica 11y acceptable salts of the foregoing compounds are especially desirable. The water soluble salts, especially the cl i hydrochl or i de , d i gl neonate and d i ace ta t e sails, are the most, desirable since I hey make pi >ss i b I e I 11 (• I o rut. 11 i < ji o I ' I 1 m r sol u( j on roinposi I i oils. 111 contrast- with < h I orlie \ i d i ne , whose d i hydrochloride salt is insoluble in water, the hydrochlorides of the compounds ol' the present invention are water-soluble. Typically, the 4 3 1* I hydrochloride sail, i .s i nhcrcntly formed in the preparation ol" < h lorhc x i d i lie arid of I.hi* compounds of the present invention. For purposes of l,h i s ap(> I i < a I. i on , water-soluble salts are considered l.o be I.host* having a solubility of 'i greater than about 0.04'X by weight in water at 25°f".

ExampLes of bis-biguanidines falling within the scope of the present invention are the following: nis(N"*-m- tr if1uoromethylphenyl-N'-biguanidino)methane, 1 , 2-b i s (N -*-rn-tri f 1 uorome thyl pheny 1 - N ' -biguan idino)ethane, 1 ,4-bis (N tr i f 1 uorome thyl pheny I -N ' -biguanido ) butane , 1 ,2-bis(N ^-in-tr i f 1 uorome thylbenzy1-N '-b iguan ido (ethane, 1 , 2-b is (N "*-p-t r i f 1 uorome thyl pheny I -N ' -b i guan ido )e thane , I,2-bis(N ^-o-trifiuoromethy1pheny1-N'-b iguan ido )e thane, I,2-bis(N^-m-trifluoromet hylphenyl-N^-hexy1-N'-bi guan ido ) e thane, I , 2-1) i s ( N ^-ni-1 L fl uorome I hy! pheny 1 -N ^-2-phent* t hy I -N *-b Ljlc-uani do )cthanc , I , 2-b i s ( N ''-jn- I r i f I uoi'iiw: thy I pheny I -N ' —e t hy I -N ' -b i guan i The ((impounds of the invention ran be made by reacting .10 ethylene or methylene diamine dihydroch1 oride (or an appropriately N,N' substituted ethylene or methylene diamine dihydro-chlori.de) or a homologue thereof with sodium dicyanamide to give, for example, a bis (N -cyano-N' -yuan i d i no )e thane, which IS 4 3 4 1 * is then react.ed with I.lie liyiiroi li I or i tit- ill' the desired m-(,ri-1' I uorome t.l\y 1 pheny I ami rn> or other isonx'r to give the desired bi.s-biguanide compound in the form of its hydrochloride salt. The general preparation procedure for bis-biguanides is well 5 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 10 compositions which comprise from 0.01',& to 2.5% (preferably from 0.05% to i.2%, and most preferably from 0. to 0.8/R) by weight of the- bis-biguanide ant i plaque agent and t ho balance, a carrier .suitable for use in the oral cavity. All percentages herein are by weight, unless specified otherwi.se. 15 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 U> give antiplaque and/or anlicaries effectiveness. Generally, an amount of 0.001 grams or more per usage of t.he 20 bis-biguanide can be considered as an effective amount for plaque control.

The pli 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 alk-25 alinity 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 30 cavity. The carrier can be water or an organic: solvent such as alcohol. Preferably, however, I lie carrier port ion of the oral < ompo.s i i ion is a convenl ionaI preparal ion such as a t oo t lip.'is te , mouthwash or chewing :411m. 434 11 - 6 Dentifrices contain an abrasive polishing material and typically also contain sudsing agents, flavoring and sweetening agents. Toothpastes usually additionally contain hwncctants and binders and water. The dentifrices herein ■J comprise from 0.5% to 95^ abrasive in addition to the bis- biguanide antlplatjue agent.

Any abrasive |>olishing material which dues 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 polyraethaphos-phate. Preferably, however, the abrasive is one which has a high degree of compatibiIity with the bis-biguanide. These include, for example, condensation products of urea and formaldehyde such as disclosed by Cooley e (. al. in U.S. Talent 3,070,510, granted December 25, 1962, silica xerogels such as those disclosed in I1 .S. Patent 3)53^,2.10, to Pader et al., issued Vovember 3, 1970, hydrofluoric acid-treated amorphous silica abrasives such as those disclosed in U.S. Patent 3)862,307, to Di'iiulio, issued January 21, 1975, arid mineral abrasives coated with cationic polymers such as those disclosed in British Patent S[n-ci 1 ical.ion No. 1 ,506,045 * 1'he abrasives generally have a particle size of from O.I to 20 microns in d iamoter.

'Ihe 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 b% to 00rJ, and toothpowders contain from 2b% to l>5^ abrasives.

Dentifrices usually contain surface-active agents (also ,10 called sudsing agents). 434 1 1 Suitable surface-activk agents are those which are reasonably stable anil form suds throughout a wide pH range, and which will not react with the bis-biguanide compound, i.e., nonsuap nonionic, cationic, zwitterionic and amphoteric organic synthetic detergents.

The nonionic synthetic detergents which can be used with the or.il compositions of the present invention may be broadly defined as compounds produced by the condensation of alkylene oxide groups (hydrophilic in nat.ure) with an organic hydrophobic compound which may be aliphatic or alkyl-aromatic in 10 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.

I 5 For example, a well-known class of nonionic synthetic detergents is made available on the market under the trade name of "Pluronic ". These compounds arc formed by condensing ethylene oxide with a hydrophobic base formed by I he c ondeiis-,it ion (if propylene oxide wilh propylene glycol . I'lie hydro— 211 pliol> i < por I i on of I lie ino I ei ii I e which, of course, e * !i i !> i ! s water insolubility has a molecular weight of from 1, >00 to I,SOU. The addition of polyoxyethylone radicals to this hydrophobic: portion tends to increase t he water solubility of the molecule as a whole and the liquid character of the 2S products is retained up to the point where polyoxye t-hylene content is about 50,? of the total weight of the condensation product.

Other suitable nonionic: synthetic detergents include: 1. Ihe polyethylene oxide condensates of alkyl phenols, ,30 e.g., the condensation products of alkyl phenols having an alkyl group containing from (> to 12 carbon atoms in either a straight, chain or branched chain configuration, with ethyl- 4 3 J 1 1 <-iii' oxide, tlii' said ethylene oxide beiii", pre.sen I in anioiui I s <(|ii.il In ID to tit) moles i»l' i'l-liy I I'm* 'ix i tli - |iit iinili- t>| alkyl phenol. The alkyl subst i I uen I. in .such compounds may be derived from polymerized propylene, <1 i isobuty lene, octane, or S nonanC) for example. 2. Those derived from the eonden.sal ion 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 hydro-10 phobic and hydrophilic elements which is desired. For example, compounds containing from 40% to 8056 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 Ij.'iM' toilet it.tiled i>l' Ihe reac t inn proeluc I of ethylene 15 cl i .im i lie and rxi e->s propyI ene i» x i de , ».i i 11 base li.i v i i ili. . i ill < ► I — i'i n I a i" we i ^li I cil- t lie order «it 2 , 5< >0 to \ , t H H11 are ^iil i>l'in i urv , t. the condensation product of aliphat ic alcohols having from ^ to 1 H carbon atoms, in either straight chain or branched chain configuration, with ethylene oxide, e.g. a coconut al— 20 cdIioI ethylene- oxide condensate having 10 Lo 30 moles of ethylene oxide per mole of coconut alcohol , the? coconut alcohol frac tion having from 10 to 14 carbon atoms. 4. Long chain tertiary amine oxides corresponding to the following general formula: K K0I< S-^0 wherein contains au alkyl, alkcnyl or inoiiohyilroxy alkyl radical of from S to 1^ carbon atoms from 0 to 10 ethylene oxide moiet.ie.s, aiul from 0 to 1 glyceryl moiety, and R7 and R, contain from I to 5 carbon atoms and from 0 to 1 hydroxy .50 group, e.^. methyl, ethyl, propyl, hydroxy ethyl, or hydroxy propyl radicals. Ihe arrow in the- formula is a conventional rcpresentalion of a semi-polar bond. fxamples of amine oxides 4 3 4 11 9 suitable for use in this invention include dimethyldodecyl-amine oxide, oleyldi(2-hydroxyethyl)amine oxide, dimethyloctyl-amine oxide, dimethyldecylamine oxide, dimethyltetradecylamine oxide, 3,6,9-trioxaheptadecyldiethylamine oxide, di(2-hydro-5 xyethyl ) te l.radecy lamine oxide, 2-doderoxyethyldimethylamine ox i.«l«» , 3-dodec-oxy-2-hydroxypropy Idi (3-hydroxypropyl )araino oxide, and dimethyl hexadecylamine oxide.

. Long chiiii) tertiary phosphine oxides corresponding to the following general formula RR' R**P-»0 wherein R contains an al'-'yl, alkenyl or monohydroxy3lkyl radical ranging from S to l8 carbon atoms in chain length, from 0 to 10 ethylene oxide moieties and from 0 to 1 glyceryl moiety and R' and K" are each alkyl or monohydroxyalkyl IS groups containing from 1 to .1 carbon atoms. The arrow in the formula is a conventional representation of a semi-polar bond. Examples of suitable phosphine oxides art-: 2<> 2 5 dodeey1dimethylphosphine oxide, te tradecyIdime(hy1phosphine ox i de, l.e tradet y 1 mc thy 1 e I by I phosph ine o * i de , .1, (> , 9-' r i oxaoe I ndeey I d i me ( hy I pliospli i ne ox i de, ee l.y 1 d i me thy 1 phosph i ne oxide, 3—dodeeoxy-2—hydroxypropyIdi(2-hydroxye thyl)phosph ine ox ide, s teary 1 d ime thyl phosph ine ox i de , cetylethylpropylphosphine oxide, oleyldiethylphosphine oxide, dodecyldiethylphosphine oxide, tetradecyldiethylphosphine oxide, dodecyldi propylphosphine oxide, dodecyldi(hydroxymethyl)phosphine oxide, dodecyldi ( 2-hydroxye t.hyl )phosphine oxide , tetradecylmet hy1-2-hydroxypropy1phosphine oxide, oleyldime t.hyl phosph i ne oxide, and 4 3 i 1 1 2-hydroxydode< y 1 cl i me thy I pho.sph i rie midc, 6. Long chain dlalkyl sulfoxides containing one short chain alkyl or hydroxy alkyl radical of 1 to 3 carbon atoms (usually methyl) and one long hydrophobic chain which contains 5 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: 1—hydroxy-4 -dodecoxy buty 1 mc t.hy 1 mi 1 l ox i de.

The zwitterionic synthetic detergent* useful in the oral rumpus i t i ons of the present invention can be broadly described as derivatives of aliphatic quaternary ammoniun, phosphonium, 2() and sulfonium compounds, in which the aliphatic radicals can be straight chain or branched, and wherein one of the aliphatic substituents contains from S to lS carbon atoms and one contains an anionic water solubilizing group, e.g., carboxy, sulfonate, sulfate, phosphate, or phosphonate. A general 2 5 formula for these compounds is: wherein R~ contains an alkyl, alkenyl, or hydroxy alkyl radical of from S to lS carbon atoms, from 0 to 10 ethylene oxide moieties and from 0 to 1 glyceryl moiety; Y is selected 30 from the group eonsisting of nitrogen, phosphorus, and sulfur octadccyl methyl sulfoxide, 2-ketotridecyl methyl sulfoxide, 3>6,9-trioxaoctadecyl 2—hydroxyethy1 sulfoxide, dodecyl methyl sulfoxide, oleyl 3-hydroxy p.opyl sulfoxide, tetradecyl ine thyl sulfoxide, 3-me I hoxy t.e i decy I methyl sulfoxide, 3—hydroxytrideeyI methyl sulfoxide and (K'^x R2 - -CH,-R4 ) 4 3 11 1 3 atoms; R is an alkyl or monohyclroxyalkyl group containing 1 to 3 carbon atoms; x i.s 1 when Y is a sulfur atom and 2 when Y is a nitrogen or phosphorus atom, R^ is an alkylene or hydroxyalkylene of from 1 to 4 carbon atoms and Z is a 5 radical selected from the group consisting of carboxylate, sulfonate, sulfate, phosphonate, and phosphate groups.

Examples include: 4 - [N,N - di(2 - hydroxyethyl ) - N - octadecyl amnion ioJ-buLane - 1 - carboxylate; l<) S - [S - 3 - hyclroxypropy I- S - hexadecylsulfonio j - 3 - hydroxypentane - 1 - sulfate; 3 - - diethyl - P - 3,6,9 - trioxatetradecoxyl- phosphonio] - 2 - hydroxypropane - 1 - phosphate; 3 - - dipropyl - M - 3 - dodecoxy - 2 - hydroxy- propylammonioJ - propane - 1 - phosphonate; 3 - (N,N - dimethyl - N - hexadecylammonio)propane - 1 -sulfonate; 3 - (N,N - dimethyl - N - hexadecylammonio) - 2 - hydro-xypropane - 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 - - dimethyl - P - dodecylpho.sphonioJ - propane - 2 5 1 - phosphonate; and - [N,N - di(3 - hyclroxypropy 1 ) - N - hexadecylammon ioj- 2 - hydroxypentane - 1 - .sulfate.

The- cationic synthetic detergent.s useful in the oral compositions of the present invention can be broadly defined 30 as quaternary ammonium compounds having one long alkyl chain containing from S to 18 carbon atoms such as lauryl tri-inethylanimon i um chloride; cc-tyl pyridinium chloride; cetyl I r ime t hy1 amnion i um bromi de; d i-isobutylphenoxyet hyldime thy1- 4 3 4 11 ben /. y I ammo 11 i i im chloride; e oi otui La I k y 1 I r i me t.liy I amnion j ■ i >>t n i 1.1- i l.e ; and cet.yl (>y r i d i n i um fluoride. Especially preferred are the quaternary ammonium fluorides described in Briner et al, U.S. Patent 3,535,421, issued October 20, 1970, 5 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 ali-10 phatic radical can be straight chain or branched and wherein one of the aliphatic substituents contains from 8 to 18 carbon atoms and one contains an anionic: water soltibi 1 i z ing group, e.g. , caiboxyI a Ie, sulfonate, sulfate, phosphate, or phosphon-at.e. Examples of compounds falling within this definition IS are sodium 3-dodecylaminopropionate, sodium 3-dodecylamino-propanc sulfonate, dodee-y I-be ta-alan i ne , N-alkyl-taurines such as the one prepared b, reacting dodeey1 amine with sodium isothionate according to the- leaching of Kosmin, U.S. Patent So. 2 ,<»5N ,072 , issued November 3, 19 7 3 , N-li i gher alkyl asparl i e 2n -"ids such as I host • produced according In I lie I 1,tilling ol Lynch, U.S. Patent No. 2,438,091, issued November 1 (), 1948, .ttid the product.s sold under tin? trade name "Miranol" and described in Maiuiheimer, U.S. Patent No. 2,528,378 issued October 31, 19 SO.

Many additional nonionic, cat.ionic , /m i t t e r i 0111 c and am photeric synthet it detergents arc known to the art and can he used as sudsing agents in the compositions herein. Further examples can be.- found in McCu tcheon ' s De t er gen t s and Emul si f-iers , 19 7 - Annual , published by Allure- Publishing Corporation. 'he sudsing agent can be employed at levels ranging from 0. 5 to 5 . 0/" of the den t. i !'r i ce compos it ion. 4 3 4 1 1 Don I. i f r i ces normally aLso contain flavouring agents. Suitable f I avour i ng agents for use in the dentifrices herein i tie I iiilc , for <'xaiii|tl «•, w i ul e-rgre Dentifrices normally also contain sweetening agents. Suitable sweetening agents for use in dentifrices include, for example, saccharin, dextrose and levulose. The 10 sweetening agents are used at levels of from ,05/t to 2%.

In 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 carboxyme thylhydroxyethyl cellulose-; or natural IS gums, including gum karaya, gum arabic and gum t.ragacanth. 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 compos-20 it ion. it is also desirable to include a humectant material in toothpastes. Suitable materials for thi.s purpose include glycerine, sorbitol, and other edible- polyhydric alcohols or mixtures thereof. These materials can comprise from 1% to 25 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 5055.

Mouthwashes generally comprise a water/ethyl alcohol 30 se»lutie)ti and opticjnally other ingredients such as flavour, sweeteners, and humt.-c tan t.s such as those mentioned above for elent i f r i ces. The alcohol provide:s an antibacterial effect. 4 3 4 11 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 5 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%) glyc crinc or other hurarctants, 11% t.o 2% (prefer-ah I y IO (). I % t.o 2%) sudsing agent, ()% to 0.5% (preferably 0.05% to 0.5%) sweetening agent such as saccharin and ()% 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 flavour-ing materials such as those mentioned above- lor dentifrices. The flavouring materials are present at a level of 0.()1% to 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 Of 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 I 5% to 30% gum base, 15% to 20% corn syrup, 50? to 65% sugar, and 0.05 to 1.5% flavouring mater i a 1s.

I.o/.enges suitable as carriers herein comprise a hard sugar' candy base and one or more flavouring materials. The flavouring materials are present, at levels between o . I) 1and 2. (•/.'. 3() Optionally, lo/enges can contain various other mater- 4 3 4 11 Lais. A typical lozenge suitable as a carrier in this invention is «i hard candy comprised of a hard candy base containing 0.0556 to 1 . 556 flavour. The hard candy base is a solidified solution of amorphous sugar which is generally 5 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 lO suitable for use in lozenges.

When formulating the antiplaque agents ol' the present invention into an oral composition, the amount which Is in— cofpiiialL-d into the compos i Lion should be sufficient, to provide at least. 0.001 grams of antiplaque agent per usage of 15 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)6 to 2%, and most, preferably from 0.5$ to 1.5^- In mouthwashes, typical usage is from about 10 to 20 20 grams, and the amount of antiplaque agent, in the mouthwash should be at least 0.01, preferably from 0.556 to 1.5 %, and most preferably from 0. 1% to 1.0%.

Typical usage of < hewing gum and lozenges i s from about. 1 to 4 grams and Lhe amount of antiplaque agent in the chewing 25 gum or lozenge should be at. least 0.03!?, preferably from 0.156 to 2%, and most preferably from 0.5^ to 1 . 5& Generally, oral compositions should contain from 0.01;? to 2 . of the ant iplaque agent, I'he oral compositions of the present invention can also 30 opt ionally contain additional I hrrapeut ic materials for use in the oral cavity audi as anl i caries agents, (e.g., water-soluble fluoride such as sodium fluoride and stannous fluoride) and ant. icali ulus agents sm h as trisodium ethane 1-hydroxy-1 , 1 - 4341 1 (I i |)I|I|S|)||I)II.|I <' .

Al though the novel b is-b L^uan i de < umpounds of Ihe present. invention give considerably less staining of the Leeth than chlorhexidine, they are not completely free of staining 5 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 10 such as contact with certain foods and beverages. Such chelating agents are disclosed in Haefele, U.S. Patent 3,937>807, issued February 10, 197t>; and in British Patent Specification No. 1,507,846. Examples of chelating agents useful for this purpose are nitri1o-lriairtic acid, ethyIenedLaminc diacetic IS acid, kojic acid, malLol, ethyl maltol, calcium dihydrogen ethylenediamine tetraacetate, and di-N-substituted ethylene diamine diacet ic acids wherein the subst.i luents can be ethyl or 2-hydroxye t.hyl . The pharmaceutical ly acceptable water-soluble salts of these chelators are particularly useful e.g., 2<> I he sodium, potassium and ammonium salt . 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 25 from 0.01:? to 1.25" by weight of the composition. Generally, two moles of chelator react, with one mole of bis-biguanide compound. 1'his invention will be further illustrated by the following examples: I. \ AMPLE r A I .nit hpasl e i s prepared a< < ord i ng Id the lol lowing formula 4 3 111 Component. Parts by we i gh t Sorbitol {70% soin. ) 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 — bis(N^ - m — l> i 1' I uorome l.hy I pheny 1 - N' — 1» i guan ido ) - el hum- di gluconate O.70 Polyoxyethylene sorb it.."in (20) mono isostcara l.e 1.50 Distilled water balance to 100 Thi.s 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 t.he teeth than does chlorhexidino.

EXAMPLE II A mouthwash in accordance with the present invention is formulated as follows: Component Parts by weigh t Ethyl alcohol (95# in water) 12.00 Cetyl pyridinium chloride 0.10 Polyoxyethy 1 ene (2(>) sorbitan monoolcate 0. 12 Sodium hydroxide ( I!)'/, in water) 0.()2 Sodium saccharin 0.055 .10 Flavouring 0. 16 1,2 - bis(N^ - n - tr i f 1 uorome t.hyl pheny 1 - N' - b i :;uan i do )e 1 hane d i hydrochloride 0.20 Col our 0.50 Sorbitol (7()- i n water) 12.00 Distilled naler balance to 100 4 3 4 11 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 yum in accordance with the present invention I.s formulated a.s follows: Component Parts by weight Gum ba se 21.30 Ester Gum 6.40 Coumarone resin 9.60 Dry latex rubber 3-20 Paraffin wax (M.P. l30°F.)2.10 Sugar 5$. 4 5 '5 Corn Syrup (Baume 4S) lS.20 Flavouring 1.OS 1,2 — bis (N"* - in - tr if 1 uorome thy L pheny 1 -N 1 - biguanido)ethane diacetate 1.00 Chewing gum in the normal manner retards the formulation of dental plaque and produces appreciably less staining of the teeth than does eh Inrhexidine.

EXAMPLE I V When in the preceding examples the 1,2 - bis (N^ - m -trif1uoromethylphenyl - N1 - 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 ls obtained if chlorhe \ idine is used: 1,4 - b i s I \ '-m- t r i I'l uo come t hyl pheny I - N * -b i guan ido )bu t ane , 1,2 -b i s ( \ —in— t r i 1' 1 uorome t hyl benzy 1 -N ' -b i guan i do )e t hane , 1 ,2 -b i I S ""-m-fcr i I I nor oi:n; t I ly I phen y I - N 5-hexy 1 -N ' - b i gtinn i do ) e thane 4 3 4 t I 1 , 2-bis(N^-m-tr ifluororaethylphenyl-N"'-2-phenethyl-N*-b1guanido)ethane, 1,^-bis(N^-m-trif1uoromethylphenyl-N^-ethy1-N1-methyl-N -biguanidojbutane, 1,2-bis(N^-m-trifluoromethylbenzyl-N^-methyl-N1- biguanido)ethane, 1,2-bis(N^-m-trifluoromethylphenyl-N^-phenethyl-N biguan ido)c thane, 1,2-bis(N^-p—trifluoromethylphenyl-N*-biguanido)ethane, 1, 2-bis(N~*-o-trif 1uoromethylphenyl-N^-biguanido )ethane, and Bis-(N~-m-trifluoromethylphenyl -N*-biguanido)methane.

Claims (4)

1.3 4 11 - 20 CI.A IMS I . A l> i s-b i yuan i do compound having I.he generic formula: R Nil Nil K K ' Nil NH K' //~\ I I * I 1 > "I. ff\ / V^xj^-N - C -Nil - C - N-(CH2)n-N - C -Nll-C -N-( X' ) CK3 wherein n i.s from 1 to 4 inclusive; X and X' each represent 5 an alkylene radical containing from 1 to 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 containing from 7 to 12 carbon atoms; and and R2 ' are each hydrogen or an alkyl radical of 1 to 2 carbon atoms■ and the pharmaceutically acceptable salts thereof.

2. A compound according to claim 1 wherein the salt is a water-soluble salt.

3. A compound according to claim 1 or 2 wherein the salt is d i hydroch I in-i do diacetate or digluconate salt.

4.- A compound according to any one of claims 1 to 3 wherein n equals hydrogen. n equals 2, z and z1 are each 0 and R, R', R^ and R ' arc each S. A compound according to any one of claims 1 t.o 4 wherein the trif1uoromethyl groups are in the meta position. 2" 0. A bis-biguanide compound or a pharmaceutically acceptable sail thereof substantially as herembeforc described in the Kxamples. 7. An oral composition comprising a carrier suitable for use in the oral cavity and from 0.0l;t to 2.5$ by weight of 25 composition of an antiplaque agent consisting of a bis-b>-guanide compound according to any one of claims 1 to 6 or a - 21 - pharmaceut i cnl Ly acceptable salt thereof according to any one of claims 1 to 6. 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. 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 10 composition of an abrasive. 10. A composition aoc^'d i ng to claim 7 in the form of a mouthwash wherein the an t i pi aque agent i.s present al a level o t' f roin 0. 5% I .o I.5% by weight of the composition and wherein the composition contains as additional components: 15 A. from 5% to 40# ethyl alcohol; B. from 0# to 20$ humectant; C. from 0% to 2% sudsing agent; D. from 0% to 0.5# sweetening agent; E. from 0.05# to 0.3# flavouring agent; and 2() F. water. 11. 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, 2 5 said chelator being n i tr i lotr i ace t ic acid, e thy I cried i am i no diacetic acid, ko.jic acid, mall-ol, ethyl maltoI, calcium di-hydrogen e thylened iamine tetraacetate, a d i-N-.subs t i tut ed ethylene diamine diacetic acid wherein the substituents are ethyl or 2-hydroxyot.hyl , and the pharmaceutically acceptable water-3(> soluble salts of said chelators. 4341 I - 22 - 12. A composition according to claim 7 substantially as hereinbefore described in the Examples. F. R. KELLY & CO. AGENTS FOR THE APPLICANTS.