NZ227596A - Oral hygiene composition comprising a cationic antibacterial agent and a polymer bearing pendant polyalkylene oxide side chains - Google Patents

Description

22 7 5 9 6 Priority Oate(s): £>.2>.

Comp'«t4" Specification Filed: Class; Publication Date: P.O. Journal, No: "JS'sEFmi" No.: Date.

NEW ZEALAND PATENTS ACT, 1953 COMPLETE SPECIFICATION ORAL HYGIENE COMPOSITION JflWe, IMPERIAL CHEMICAL INDUSTRIES PLC, a British company of, Imperial Chemical House, Millbank, London SW1P 3JF, ENGLAND "v hereby declare the invention for which )fc>/ we pray tha^a patent may be granted to r^O/us, and the method by which it is to b^^^rformed, to be particularly described in and by the following statement:- 1 - (followed by page 1A) 227596 IT/VM/3/87 oral hygiene composition This invention relates to oral hygiene compositions and to methods of using such compositions to prevent or 5 inhibit growth of bacteria on tooth surfaces.

The prevention of the adherent deposition of dental plaque on mammalian (particularly human) teeth is a highly desired result. Dental plaque results when cariogenic and other types of bacteria aggregate in 10 colonies on the surface of teeth and form a deposit which adheres tenaciously to the surface. It is believed that the deposition of plaque on the surface of a tooth is one of the first steps in the development of dental caries and periodontal disease.

Many attempts have been made to prevent the deposition of plaque on tooth surfaces and to effect removal of plaque from such surfaces. For example, brushing, dental flossing and the use of oral irrigators and interdental stimulators have been tried. Such 20 treatments are not, however, entirely successful and must often be supplemented with periodic treatment by dental professionals.

In our recently published European Patent Specification No 0,182,523A, we teach that certain 25 pharmaceutical compositions (as therein defined) are highly effective for preventing or significantly reducing (a) the colonisation of tooth surfaces or simulated tooth surfaces by cariogenic and other microorganisms commonly found in an oral environment, and (b) 30 the adherent deposition on tooth surfaces of dental plaque resulting from such microorganisms.

The preparation of polymers for use in the aforesaid certain pharmaceutical compositions is described in EP 0,182,523A, the disclosure in which is 35 incorporated herein by way of reference. 22 7 5 9 6 Chlorhexidine is a cationic antiseptic which has been widely used by the medical profession as a topical antibacterial agent for more than 20 years; the preparation thereof is described in UK 705,838. It has 5 been reported (Loe et al, Journal of Periodontal Research, 1970, Vol 5, pp79-83) that chlorhexidine can be used as an antiseptic in the oral environment and that in certain circumstances there is a tendency apparently for chlorhexidine to stain teeth. Such staining appears 10 to be a property which is common to cationic antiseptics. It has been shown (Addy et al, Journal of Periodontal Research, volume 9, pp 134-140) that such staining is the result of an interaction between the cationic antiseptic and dietary components, particularly those rich in 15 tannins, e.g. coffee, tea or red wine.

We have now found that where certain surfaces, e.g. tooth, or hydroxyapatite, are treated with a combination of both (a) a polymer, as hereinafter defined, which bears certain 20 pendant polyalkylene oxide chains, and (b) a cationic antibacterial agent, the resulting treated tooth surfaces surprisingly exhibit both enhanced antiadhesive and antibacterial properties to certain oral micro-organisms, i.e. the combination may effect control of so-called 25 "bio-fouling" of tooth surfaces.

Indeed, in the presence of the said polymer, equivalent antibacterial effects can be observed where the tooth surface is treated with a lower concentration of a solution of the antibacterial agent. Furthermore, we 30 have now found, surprisingly, (i) that the aforesaid tendency for staining with chlorhexidine is at least reduced, there is often no increase in staining even where more chlorhexidine is adsorbed on the tooth surface in the presence of the aforesaid polymer; (ii) the 35 antibacterial properties of certain cationic 22759G antibacterial agents, e.g. chlorhexidine and alexidine, are increased on simulated tooth surfaces if the surface is treated sequentially with or with a a combination of, an acidic polymer, e.g. Polymer 93W (as hereinafter 5 defined)and the aforesaid agent ; and (iii) where composite restorations, e.g. Occlusion (RTM), Opalux, Silux and Valux P50, etc, tend to be stained by cationic antiseptics such staining is at least alleviated in the presence of the aforesaid polymer. It will be 10 appreciated that reduction at least of such staining of anterior teeth is particularly desirable.

In accordance with the statements above the term "fouling" will be understood as a generic term referring to both the staining of teeth by cationic antiseptics, and the bio-fouling of tooth surfaces.

According to the present invention there is provided an oral hygiene composition comprising (i) an effective amount of a cationic antibacterial agent; and (ii) an effective amount of at least one polymer ,as hereinafter defined, which has one or more pendant polyalkylene oxide groups.

As examples of cationic antibacterial agents which may be used in the present invention may be mentioned inter alia benzalkonium chloride, bispyridinamines, e.g. octenidine, or preferably a poly-biguanide, e.g. alexidine, or more preferably a bis-biguanide, eg chlorhexidine.

By "polybiguanide" we mean a compound which has a plurality of in-chain biguanide residues of the general formula I NH NH M II -NH-C-NH-C-NH- I or tautomers thereof. Often there are two, three or four such in-chain residues in the antibacterial agent used in the present invention. However, we do not exclude the possibility that there may be sufficient to provide at least a major portion of the repeat units of a higher 22 7 5 9 6 molecular weight polymer, e.g of molecular weight up to about 10,000.

It will be appreciated that where a polybiguanide is used in the present invention it may be present as a 5 free base; preferably, however, it is present as a salt thereof, e.g. acetate or hydrochloride, or more preferably, particularly where the polybiguanide is a bis-biguanide which has the structure shown in general Formula II, as the di-gluconate, i.e. the di-gluconate 10 of l,6-di(4-chlorophenyl-diguanido)hexane, which is known in the art as chlorhexidine. nh nh ll II nh ci/ />nh-c-nh-c-nh(ch2) 6nh-c-nh-c-nh<. /> en II nh II We do not exclude the possibility that where a 20 polybiguanide, e.g. chlorhexidine, in the form of a free base is used in the present invention it may be in admixture (e.g. as a salt) on the tooth surface as a salt with an acidic polymer as hereinafter defined.

As possible explanations, without wishing to be 25 bound thereby, of the increased antibacterial effect of the oral hygiene composition of the present invention, we suggest: (i) an increase in the quantity of chlorhexidine adsorbed on the tooth surface; and/or 30 (ii) alteration in the strength of adsorption of chlorhexidine at the tooth surface such that it is more available to exert its antibacterial effect at the surface; and/or (iii) alteration in the orientation at the tooth surface 35 of adsorbed chlorhexidine such that the ? 2 7 5 9 6 antibacterial groups thereof are more accessible to bacteria approaching thereto; and/or (iv) ion-pairing between the cationic antibacterial 5 agent and the acid anions, where present, of the polymer.

In the composition according to the present invention, multiple hydrogen-bonds between the polymer, and the biguanide cations may contribute to the aforesaid 10 increase in quantity or alteration in strength of adsorption or orientation.

Polymers of which the oral hygiene composition according to the present invention are comprised are preferrably acidic, by which we mean that there is at 15 least one carboxylic acid group appended to the polymer backbone. However, we do not exclude the possibility that the polymer may be amphoteric, basic or neutral, although this not preferred.

The one or more pendant polyalkylene oxide groups 20 appended to the polymers of which oral hygiene compositions according to the present invention are comprised are preferably ethylene oxide groups.

However, we do not exclude the possibility that at least a portion thereof may be alternative poly(lower)-25 alkylene oxide groups, e.g. polypropylene.

As examples of polymers of which the oral hygiene composition according to the present invention are comprised may be mentioned inter alia polymers which comprise one or more repeating units of general structure 30 A 9 2 7 5 9 6 x and one or more repeating units of general structure B 10 Y wherein X, which in the repeating units of structure A may be the same or different, and Y, which in the repeating units of structure B may be the same or different, are hydrocarbyl, or substituted hydrocarbyl residues, providing a backbone for the 20 polymer; Z is -CHR1-CHRa-or-(CH2)m"; wherein, where Z is -CHR1-CHRS", R1, which in the same repeating unit of structure B (when n or q is 2 or more) or in different 25 repeating units of structure B may be the same or different, is hydrogen or a hydrocarbyl group; and R2, which in the same repeating unit of structure B (when n or q is 2 or more) or in different 30 repeating units of structure B may be the same or different, is, hydrogen or a hydrocarbyl group; except that R1 and R2 in a single ianit-CHR1-CHR2-0- cannot both be hydrocarbyl; 22 7 5 9 6 R3, which in the same repeating unit of structure B (when q is 2 or more) or in different repeating units of structure B may be the same or different, is hydrogen or a hydrocarbyl group or 5 an acyl group derived from an alkanoic acid having up to five carbon atoms; m, where present, is a number of from 2 to 10; n is a number of from 1 to 60; p is a number of from 1 to 4; and 10 q is a number of from 1 to 4; each (COjH) group is joined via an intermediary or intermediaries L to the hydrocarbyl residue X, and in cases where p is 2 to 4 may be joined by L to the same or different carbon atoms of X; L may be the same or different in the repeating units of structure A and is selected from one or more direct links and one or more groups of atoms each group providing a chain of one or more atoms for linking a (CO2H) group with X, except that more than two 20 (COaH) groups cannot be directly linked to the same carbon atom in X; each ((ZO)nR3)q group is joined via an intermediary or intermediaries M to the hydrocarbyl residue Y, and in cases where q is 2 to 4 may be joined by M 25 to the same or different carbon atoms of Y; M may be the same or different in the repeat units of structure B and is selected from one or more direct links and one or more groups of atoms each group providing a chain of one or more atoms for linking 30 a (Z0)n group with Y, except that more than two (ZO)n groups cannot be directly linked to the same carbon atom in Y; the ratio of the number of -C02H groups to the number of (ZO) groups, particularly where Z is -CH2CH2~, is 35 within the range of 1:20 to 20:1 22 75 9 Preferably both R1 and R2, where they are present, are hydrogen.

Where R1 or R2 is a hydrocarbyl group, it is preferably a lower alkyl group, more preferably methyl. 5 R3 is preferably a lower alkyl group, more preferably methyl.

Where Z is -(CHa)m-, m is preferably 4; this affords a ready preparation of-(ZO)n" from tetrahydrofuran.

It is to be understood that the definition of the polymer contained in the composition (as given above) is also intended to embrace a polymer in which at least some of the carboxyl groups in the repeat units of general structure A have been converted to the 15 corresponding salt anions C02- (these being considered as -COaH group as far as the ratio of carboxyl to -Z0-groups is concerned), the corresponding cations for example being those of ammonium (NH+4), or alkaline earth metals or preferably alkali metals (e.g. Na+, K+). We 20 do not exclude the possibility that the cation may be derived from the cationic antibacterial agent per se; indeed where the cationic antibacterial agent is present as a salt of the acid polymer such that there is substantially no free chlorhexidine in the mouth there is 25 a tendency for staining to be further reduced.

In general structure A, each carboxyl group is joined to the hydrocarbyl residue X by means of an intermediary or intermediaries (i.e. by a linking entity or entities), this or these being denoted by L, which is 30 selected from one or more direct links (i.e. one or more direct bonds) and one or more groups of atoms each group providing a chain of one or more atoms for linking a carboxyl group(s) with X. In cases where p is 2 to 4, each carboxyl group may be joined by L to the same or, in 35 cases where L represents more than one intermediary, to 22 75 9 6 the same or different carbon atoms in X, although more than 2 carboxyl groups cannot of course be directly linked to the same carbon atom of X (and also assuming that in such cases X has at least 2 carbon atoms, whereas 5 it should be appreciated that it is within the scope of the invention for X to have only 1 carbon atom). It will be noted that in principle L can represent up to 4 separate intermediaries in structure A (in cases where p is 4). L may be the same or different in the repeat 10 units of structure A.

In cases where L represents one or more groups of atoms each group providing a linking chain of atoms, the chain will normally comprise one or more carbon atoms (which could, for example, include carbon atoms in an 15 aryl ring) and/or hetero atoms (particularly N and/or 0). Examples of possible linkages provided by L are: l l l I l I CH2 CH2 CH2 NH CO CO I I I I I I CH2 CH CO NH NH I / \ I I I (direct CH(CH3) CH(OH) link or I bond) where (apart from the direct link) the top link is to X and the bottom link(s) is to carboxyl. It is preferred in the present invention, however, that L is one or more 30 direct links, such that each carboxyl group is joined directly to a carbon atom in the polymer backbone.

In the structure A, p is preferably 1 or 2, more preferably 1 (so that L can then represent one, or at most, two intermediaries). 22 7 5 9 In structure B, each (ZO)n R3 group is joined to the hydrocarbyl residue Y by means of an intermediary or intermediaries (i.e. by a linking entity or entities), this or these being denoted by M, which is selected from 5 one or more direct links (i.e. one or more direct bonds) and one or more groups of atoms each group providing a chain of one or more atoms for linking a (ZO)n R3 group(s) with Y. In cases where q is 2 to 4, each (ZO)n R3 group may be joined by M to the same or, in 10 cases where M represents more than one intermediary, to the same or different carbon atoms in Y, although more than two (ZO)n R3 groups cannot of course be directly linked to the same carbon atom of Y (and also assuming that in such cases Y has at least 2 carbon atoms, whereas 15 it should be appreciated that it is within the scope of the invention for Y to have only 1 carbon atom). M may be the same or different in the repeat units of structure B.

While M may represent one or more direct links, it 20 is preferred in the present invention that M is one or more groups of atoms each group providing a linking chain of atoms; such a chain will normally comprise one or more carbon atoms (which could, for example, include carbon atoms in an aryl ring, e.g. benzyl ether) and/or hetero 25 atoms (particularly N and/or 0). Particularly preferred examples of chains provided by M are: l l.

CO and CO I I 0 NH 1 I where the top link is to Y and the bottom link is 35 to (ZO)n R3. 22 75 9 6 - 11 " In structure B, q is preferably 1 or 2, more preferably l(so that M can then represent one, or at most two intermediaries).

Preferably the structure A represents the repeat unit derivable by the addition polymerisation (usually free-radical initiated) of a polymerisable olefinically unsaturated carboxylic acid. Examples of such acids are maleic (or fumaric) acid, itaconic acid, the acids of formulae C(CH,)=CH2 CH=CH 2 CO and CO I I NHCH(CH3)C02H NHCH(0H)C0jH N-methacryloyl alanine— N-acryloyl-hydroxy-glycine or preferably acrylic or methacrylic acid Preferably the structure B represents the repeat unit derived from the polymerisation (usually 20 free-radical initiated) of an addition polymerisable olefinically unsaturated ester or amide formed from the reaction of an unsaturated carboxylic acid (or an esterifiable or amidifiable derivative thereof such as an acid chloride or anhydride) and a hydroxy compound of 25 formula HO (Z0)n R3 (to form the ester) or an amine of formula HaN (Z0)n R3 (to form the amide).

Preferably the acid from which structure B is derivable is acrylic or methacrylic acid, particularly the latter, giving rise, where an ester or amide 30 derivative of methacrylic acid is used, to the following structures respectively for B: 22 75 9 -C(CH3)—CHa— -C(CHj) CH2 — I I CO and CO I . I 0 (ZO)n R3, NH (ZO)n R3 Preferably acidic polymers of which oral hygiene 10 compositions according to the present invention are comprised have a ratio of acidic residues to pendant polyalkylene oxide residues of about 6:1 (where each side chain is polyethylenegylcol of molecular weight about 350, i.e. so-called PEG 350).

Polymers for use in the present invention are more fully described in our aforesaid European Patent Specification No 0,182,523A the disclosure in which is incorporated herein by way of reference.

In oral hygiene compositions of the present 20 invention, the at least one polymer present therein is typically at least at a concentration of about 0.05 to 30 weight % of the composition, the preferred concentration range being from about 0.1 to 5 weight % and more preferably 0.2 to 2 weight %. 25 The concentration of the at least one antibacterial agent in oral hygiene compositions according to the present invention is about 0.001 to 10 weight % of the composition, the preferred concentration range being from about 0.001 to 1.0 weight % and more 30 preferably 0.01 to 0.1 weight %.

Preferably, the mass of the polymer is higher than the mass of the anti-bacterial agent in oral hygiene composition according to the present invention. However, we do not exclude the possibility that there may be more 35 anti-bacterial agent than polymer present. 22 7 5 9 6 The oral hygiene composition of the present invention typically comprises only one polymer as hereinbefore defined, although we do not exclude the possibility that two or more such polymers may be present 5 in the composition.

The skilled man by simple experiment will be able to formulate compositions according to the present invention in which the ratio of antibacterial agent to polymer is such that undesired reaction is avoided. 10 The oral hygiene composition of the present invention typically comprise a pharmaceutically acceptable vehicle which is compatible with the antibacterial efficacy of the cationic antibacterial agent, e.g. chlorhexidine. To maintain the efficacy of 15 chlorhexidine it may be necessary to adjust the concentration thereof in a particular vehicle, a suitable concentration may be determined by the skilled man by experiment.

Suitable conventional pharmaceutical^ acceptable 20 vehicles that can be employed in the oral hygiene compositions of the present invention include water, ethanol (wherein water, or a water/ethanol mixture will often be a major component of the vehicle); such humectants as propylene glycol, isopropanol, glycerol and 25 sorbitol; such gelling agents as cellulose derivatives, for example, hydroxypropyl and hydroxyethyl cellulose, polyoxypropylene/polyoxyethylene block copolymers, (so-called "Poloxamers"), for example Synperonic PE 39/70 and PEF 87; certain gel stabilisers such as 30 polyvinylpyrrolidone; sweeteners such as sodium saccharin; preservatives such as cetylpyridinium chloride, and certain lower alkyl parahydroxybenzoates; surfactants such as polyoxyethylene isohexadecyl ether (Arlasolve 200) and certain colours and flavours, on the 22 7 5 9 6 approved EEC or FD&C lists. It will be appreciated that the aforesaid vehicle is chosen such that it does not unduly inhibit the effectiveness of the oral hygiene composition according to the present invention; in 5 particular, an anionic material, eg an anionic cellulose derivative or an anionic Synperonic, is not preferred.

The oral hygiene compositions of the present invention may be in the form of any conventional 10 phamaceutically acceptable oral hygiene formulation that contains (and is compatible with) an effective amount of a polymer and antibacterial agent as hereinbefore defined. As examples of such formulations may be mentioned inter alia mouthwashes, rinses, irrigating 15 solutions, abrasive and non-abrasive gel dentifrices, denture cleansers, coated dental floss, coated or impregnated toothbrush bristle (natural or synthetic), inter-dental stimulator coatings, chewing gums, lozenges, breath fresheners, foams and sprays. 20 The present invention is now illustrated by the following Examples. The prefix "CT" to an Example number denotes a Comparative Test.

In most of the following Examples the oral bacterium Streptococus mutans NCTC 10449 was used as the 25 standard bacteria. It was grown in Brain Heart Infusion (BHI) (ex Oxoid) in a Bioflo Model C30 Fermenter. A 7 50 ml pot was used containing 350 ml of bacterial suspension. The bacteria were grown at 37°c with a dilution rate of 0.1h_l, an air flow of 0.24 litre/minute 30 and an agitation speed of 300 rpm. A sample (approximately 20 ml) of bacterial suspension was taken out of the fermenter for each experiment. The bacteria were centrifuged for 10 minutes at 4000 rpm, they were resuspended in modified Ringer's salts solution (0.54 35 grams/litre NaCl; 0.02 grams/litre KC1; 0.03 grams/litre 22 7 5 9 6 CaCl2; and 0.75 grams/litre sodium mercaptoacetate), recentrifuged, resuspended and diluted (10 x) in modified Ringer's salts solutions. The approximate bacterial concentration in the diluted salts solutions was 10® ml*1.

Streptococcus mitior NCTC 7 864 was grown in 100ml Brain Heat Infusion broth in batch culture for 24 hours. The culture was then centrifuged for 30 minutes at 3500rpm and washed twice by resuspending the pellet in saline and centrifuging. The bacterial suspension was then adjusted to approximately 107-10® cells per ml.

Whole saliva was used in further examples. Absorption surfaces Hydroxyapatite discs were made by compressing hydroxyapatite powder (calcium phosphate tribasic (Ca10 (OH)2 (P04)6 (ex Aldrich)) and sintering at 1100°C. The discs were re-used after heating in a furnace at 900°C for 2 hours between experiments.

Application of polymers Hydroxyapatite discs were treated for 2 minutes at room temperature with a solution (1% w/v) of a polymer, e.g. Polymer 93W, in a 1:1 (by volume) mixture of industrial methylated spirits/water. The discs were then washed by dipping and shaking 5 times in a container of flowing water at about 15°C.

Application of Anti-Bacterial Agent Aqueous solutions of chlorhexidine and IMS solutions of alexidine were separately adsorbed for certain periods of time onto the surfaces of hydroxyapatite discs which had been treated with polymer where appropriate (untreated discs were used in comparative tests). The discs were then washed by dipping and shaking 5 times into a container of flowing water. 22-75 9 6 Polymers The polymer herein referred to as "Polymer 93W" is an acidic polymer as described and prepared in Example 5 of our aforesaid EP.182523. (Other "acidic" polymers 5 hereinafter described were prepared by a similar process). Polymer 93W comprises methacrylic acid and PEG350MAt residues in molar ratio 6: 1.

By "PEG35 0MAt" we mean a polyethylene oxide of molecular weight about 350 which has been capped with 10 methoxy and methacryloyl groups, i.e.

CH2=C(CH3)COO(CH2CHsO)nCH3 where n is about 8.

PEG 150Mat, PEG1000 Mat and PEG 2000 Mat indicate similar polyethylene oxides of molecular weights 150, 15 1000 and 2000 respectively.

Polymer Mil was prepared under the conditions described in Example 15 of EP 182,523 except that a hydroxy ended PEG was used instead of an amino ended PEG. Loeffler's Methylene Blue 20 95% Ethyl alcohol (30 ml), methylene blue (0.3 g) and water (100 ml).

Examples 1-2 These Examples demonstrate that Polymer 93W retains its anti-adhesive properties in the presence of absorbed 25 chlorhexidine.

Hydroxyapatite discs were treated with a 1% w/w solution of Polymer 93W and then with certain antibacterial agents for set periods of time. The discs so treated were immersed in a bacterial suspension (30 30 mis) in a petri-dish for 2 hours. The discs were removed from the bacterial suspension and were washed by dipping and shaking 5 times in a container of flowing water. Bacteria adhering to the discs were stained using Loeffler's Methylene Blue. The reduction in bacterial 35 adhesion was determined by microscopic examination. 22 7 5 9 6 The results are shown in Table 1. table 1 Example No Antibacterial Agent Polymer % Anti-adhesion CT1 0 1%93 W 99 1 C 1%93 W 99 2 A 1%93 W 99 CT1: 1% 93W was used alone C: 1% chlorhexidine A : 1% alexidine From Table 1 it can be seen that chlorhexidine and alexidine do not reduce the anti- adhesive properties of Polymer 93W deposited on hydroxyapatite discs.

"%Anti-adhesion" ("% AA") is defined by the equation: (Area of neat surfacel-/Area of polymer-coated covered^with bact. / |surface covered with bact.j /Area of neat surface \ [covered with bacteriaj It will be appreciated that (a) where the polymer does not decrease the area of the surface which is coated with bacteria then: % AA = X-X x 100 = 0 X and (b) where the polymer prevents adhesion of bacteria to the surface then: % AA = X-0 x 100 = 100 22 7 5 Similar results were obtained when a specimen of material conventionally used in the preparation of a dental prosthetic device, as hereinafter described, was treated with polymer 93W and chlorhexidine was then 5 exposed to Streptococcus mitior NCTC 7864. examples 3-5 These Examples demonstrate that on hydroxyapatite the antibacterial effect of chlorhexidine at certain concentrations is increased where it is used in the 10 presence of Polymer 93W.

Solutions of chlorhexidine were absorbed onto sterile hydroxyapatite discs which had been treated with Polymer 93W. Cells of S^ mutans were taken from a fermenter and diluted 100 fold in BHI agar at 40°C. The 15 innoculated agar was overlayed onto HAP discs.

Agar coated discs were incubated at 37°C overnight. Bacterial growth throughout the agar was assessed on a scale of 0 (no growth) to 10 (control).

Since the surface of each hydroxyapatite disc was 20 brought into contact with the same number of bacteria in each case, anti-adhesion did not contribute to the observed result, i.e. antibacterial effect alone was being measured. The results in Table 2 reveal that the combination of Polymer 93W and chlorhexidine gave an 25 enhanced antibacterial effect compared to chlorhexidine per se at the same applied concentration of chlorhexidine.

In Comparative Tests CT's 2, 3, 4 and 5, the discs were not treated with Polymer 93W. Comparative Test 2 is 30 a blank; in Comparative Test 2A, the disc was treated with Polymer 93W only. 22 7 5 9 6 TABLE 2 Example Applied Treatment with Bacterial No Chlorhexidine concentration Polymer 93W growth CT2 0 NO CT2A 0 YES CT3 1 NO 8 CT4 0.1 NO CT5 0.01 NO 3 1 YES 0 4 0.1 YES 2 o o YES 4 EXAMPLES 6-9 These Examples demonstrate the combination of 20 anti-adhesive and antibacterial results which can be obtained from the use of a combination of a polymer and chlorhexidine and that such a combination provides an improvement over the discrete components per se.

Sterile hydroxyapatite discs were treated with a 1% 25 w/v solution of Polymer 93W and then with solutions of certain concentrations of chlorhexidine. The discs were incubated in freshly collected whole saliva for 1 hour at 37°C and washed by dipping and shaking 5 times into a container of flowing water. Excess water was removed 30 from the surface of each disc by touching the edge thereof with filter paper.

BHI agar containing 0.04% w/v Bromo Cresol Green (to render bacterial growth on the white hydroxy-apatite discs visible) was pipetted at 40°C onto the discs such 35 that a thin film of agar formed on the surface. 22 7 5 9 6 The discs were incubated at 37°C overnight. The results are shown in Table 3.

In Comparative Tests 6-10 the treatment with Polymer 93W was omitted. In Comparative Test 11, Polymer 93W was used, in the absence of chlorohexidine. 22 75 9 TABLE 3 Example Concentration of Presence of Bacterial No chlorhexidine (%) Polymer 9 3W qrowth CT6 1 NO No Growth 6 1 YES No growth CT7 0.1 NO Control level 4. 7 0.1 YES No Growth CT8 0.01 NO Control level 5. 8 O o YES A few colonies; greater than 99% reduction compared with control level 5 CT9 0.001 NO Control level 6. 9 0.001 YES 99% reduction compared with control level 6 CT10 0 NO Thick Growth: control level 7 CT11 0 YES 90% Reduction compared with CT7 control level 7 22 7 5 9 6 From Table 3 it can be seen that for certain concentrations of chlorhexidine, e.g. 0.01 and 0.001%, the presence of Polymer 93W increases the bactericidal and/or bacteriostatic effect thereof. CT11 demonstrates 5 the reduction in bacterial growth which arises from the anti-adhesion properties of the polymer per se.

EXAMPLES 10-20 These Examples reveal that treatment of hydroxyapatite discs with certain polymers 10 (a) increases the amount of chlorhexidine absorbed thereon and (b) improves the retention of the absorbed chlorhexidine through subsequent washing treatments.

Preparation of Polymers B3 and B18 Methacryloyl chloride (0.58 moles) was added over 2 hours to a mixture of toluene (600 ml), Jeff "360" or "2070" (0.5 moles) and 2,6-lutidine (0.56 moles) cooled in an ice-bath. A copious white precipitate formed. The 20 reaction mixture was allowed to stand for 3 hours, and the white precipitate was filtered off and washed with toluene. The filtrate was evaporated under reduced pressure and the residue was kept under vacuum to remove volatiles. Products (yield 80-90%) were characterised by 25 infra-red and proton magnetic resonance spectroscopy.

The amino-ended products from both reactions (with terminal butoxy or methoxy groups from "360" and "2070" respectively) were separately converted into the N-methacrylaloyl derivatives thereof and copolymerised 30 with methacrylic acid under the conditions described in Example 11 of EP 0.182,523A.

Hydroxyapatite discs were pre-equilibrated in double distilled water for 1 hour. The discs were removed from the water, blotted dry and kept at room 35 temperature for about 30 minutes. A UV reflectance scan 22 7 5 9 6 thereof was carried out. The Optical Density at 266 nm was typically about 0.9. Any disc which had an O.D. which was significantly different from this number was rejected.

The acceptable discs were immersed in 1% w/w (1:1/IMS: water) solution of polymer for 5 minutes. The discs were removed from the polymer solution; were washed by dipping and shaking 5 times in a container of flowing water; were blotted dry; left for 30 minutes and then scanned.

Each of the polymer-coated discs was immersed in aqueous (15 ml) chlorhexidine solution (0.02% w/v) for 1 hour. They were washed as described above, allowed to stand for 30 minutes and then scanned. They were then placed in a flow-through (250 ml/min) washing tank (1200 ml) for 1 hour; blotted dry; allowed to stand for 30 minutes and scanned. no • • TABLE 4 Example Polymer Applied Difference in % Chlorohexidine Number Chlorhexidine Optical Density retained after washing for Concentration at 266 nm 1 hour 17 hours % over blank H A disc CT12 73 0.02 0.01 nd nd CT13 B12 0.02 0.02 nd nd 62 0.02 0.12 80 49 11 86 0.02 0.15 93 58 12 93W 0.02 0.20 79 47 13 * 66 0.02 0.12 82 39 14 B9 0.02 0.22 82 50 58 0.02 0.14 86 68 16 B3 0.02 0.22 82 45 17 BIO 0.02 0.19 77 54 18 B18 0.02 0.30 85 57 19 B17 0.02 0.25 77 66 Mil 0.02 0.23 b b CT14 PMMA 0.02 0.02 nd nd CT15 None 0.02 0.01 nd nd CT16 None 0.2 0.06 nd nd CT17 None 2 0.18 23 nd PMMA: Polymethacrylic acid. n.d.: Not detected, i.e. below detection limit. b: Not determined* The meanings ascribed to the polymers listed in Table 4 are shown in Table 5. no /\o CJ1 CO O) 22 7 5 9 6 R TABLE 5 Polymer A Backbone Nature (Source) B Side Chain Mol wt Molar Ratios A: B CHR1CHR2 0 : COaH groups 7 3 Basic (DMAEM) PEG 350 3:1 B12 Amphoteric PEG 350 1.9:1.1:1 (MAA:DMAEM) 62 Acidic (MAA) PEG 150 3:1 1:1 86 Acidic (MAA) PEG 350 3.5:1 2.3:1 9 3W Acidic (MAA) PEG 350 6:1 1.3:1 66 Acidic (MAA) PEG 1000 3:1 7.7:1 B9 Acidic (MAA) PEG 1000 :1 0.9:1 58 Acidic (MAA) PEG 2000 :1 4.5:1 B3 Acidic (MAA) Jeff 360 6:1 1.1:1 B10 Acidic (MAA) Allyl- PEG 350 6:1 1.3:1 B18 Acidic (MAA) Jeff2070 34:1 1.2:1 B17 Acidic (MAA) PPG 1000 17:1 1:1 Mil Acidic (MAA) PEG 350 :1 0.9:1 DMAEMrN N-dimethyl-2-aminoethyl methacrylate.

MAA: Methacrylic acid.

MA: Maleic acid; PEG: Polyethylene glycol.

PPG: Polypropylene glycol; Jeff 360 : n-C4H9(OCHaCHa)40CHaCH(CH3)0CHaCH(CH3)NHa; Jeff 2070: CH30CH2CH20(CHaCHO)nCHaCH(CHS)NHa 22 7 5 96 wherein n is such that "2070" has an MW of about 2000 and R = H or CH3 in a ratio of about 7:3; Allyl-PEG 350: Ethoxylated allyl alcohol; Except for B10, the methacrylate or methacrylamido 5 derivatives of the indicated side chains were present as general structure B; B10: contains terminal hydroxy groups.

The aforesaid UV scanning was effected using a 10 Unican SP1750 Ultraviolet Spectrophotometer.

The "difference in Optical Density" results shown in Table 4 were determined therefrom.

From Tables 4 and 5, it can be seen that the acidic polymers significantly increased the amount of 15 chlorhexidine absorbed. Many of the hydroxyapatite surfaces coated with an acidic polymer absorbed more chlorhexidine from a 0.02% w/v solution than did the neat hydroxyapatite surface from a 2% w/v solution of chlorhexidine, i.e. a greater than a 100-fold 20 improvement was observed. The basic (Polymer 73) and amphoteric (Polymer B12) polymers gave no improvement in the amount of chlorhexidine adsorbed. Similarly, polymethacrylic acid yielded no increase in chlorhexidine adsorbed, indicating that it was the PEG (or PPG) chains, 25 and not the carboxyl groups, that were responsible for the observed effect.

The results of the washing experiments showed that after 1 hour about 23% of the initially adsorbed chlorhexidine was still adsorbed on bare hydroxyapatite 30 discs, whereas the amount for polymer treated discs was approximately 80%. After an overnight wash, the amount of adsorbed chlorhexidine, if any, remaining on the neat HAP discs was below the detection limit; and approximately 50-60% of the amount of chlorhexidine 227596 originally adsorbed on polymer-treated discs remained adsorbed. Thus, polymer-treated discs adsorbed more chlorhexidine than bare discs, and it was also less easily washed off the surface thereof.

EXAMPLES 21-29 These Examples, in combination with Examples 10-20 and 6-9, reveal an increase in anti-bacterial properties (at a certain chlorhexidine concentration) without the expected increase in staining.

General Procedure Hydroxyapatite discs were pre-equilibrated in double- distilled water for 1 hour. The pre-equilibrated discs were immersed in 1% w/v aqueous or IMS:water (1:1) solution of polymer for 5 minutes. They were removed 15 from the polymer solution and washed by dipping and shaking 5 times in a container of flowing water. The washed discs were then immersed in 15 ml of an aqueous chlorhexidine solution (of a concentration shown in Table 6) for 5 minutes. The discs were removed from the 20 chlorhexidine solution and immersed in 15 ml of a tea solution for 1 hour at room temperature. The discs were taken out of the tea solution and washed as described above. The steps of immersion in chlorhexidine and tea solution and washing were repeated 3 times, using fresh 25 chlorhexidine and tea solutions each time. After these three cycles the discs were immersed in tea solution overnight; they were then washed as described above, allowed to dry for 1 hour at room temperature and the amount of stain produced thereon was assessed. 30 The tea solution was prepared by adding 500 ml of boiling water to 2 tea bags. The tea bags were removed after 5 minutes, and the tea allowed to cool to room temperature. The tea was filtered using standard filter paper, and stored at 4°c prior to use. 22 7 5 96 The stained discs prepared in the General Procedure were scanned using UV/visible reflectance spectrophotometry as described in Examples 10-20 and compared with tea blanks (i.e. no chlorhexidine 5 adsorbed). Figure 1 shows typical UV- traces which were obtained. In Figure 1, a = bare hydroxyapatite disc; b = tea blank; and c,d,e, = tea/chlorhexidine treatments at 0.002%, 0.02% and 0.2% concentrations of chlorhexidine respectively.

The polymers listed in Table 6 (the chemical composition of which are given in Table 5) were evaluated for their effect on the stain formation of chlorhexidine in the presence of tea. The polymers were separately adsorbed from 1% w/v IMS/water (1:1) solutions. 0.2%, 15 0.2% and 0.002% w/v aqueous solutions of chlorhexidine were used. The discs were scanned using UV/visible reflectance spectrophotometry and the OD's at 266, 410 and 510 nm were measured. The OD's of tea blanks were also measured at these wavelengths, and these values were 20 subtracted from discs treated with chlorhexidine or polymer/ chlorhexidine combinations. Table 6 gives the results at 510 nm. They are expressed as ratios relative to the stain produced by a tea blank = 1.0. Similar results were obtained at 266 nm and 410 nm. In CT 18, 25 the polymer was omitted, i.e. chlorhexidine per se was used. 22 7 5 9 6 TABLE 6 Comparative Stain Development compared with "Natural" build-up from exposure to tea solutions.

O.D. Ratio (compared with natural tea stain) at 510 nm Example Polymer at applied Chlorhexidine No Concentrations of 0.2% 0.02% 0.002% CT18 - 4. 57 2.76 1.67 21 73 4.48 3.01 1.0 22 62 4.98 2. 65 1.0 23 86 4.48 3.26 1.0 24 93W 4.98 2.79 1.0 B9 4.75 3. 09 <1.0 26 B3 4. 39 3. 34 1.0 27 B10 4.76 3. 34 <1.0 28 B18 4.20 3.12 <1.0 29 B17 .03 2.95 <1.0 From Table 6 it can be seen that at the two higher 25 chlorhexidine concentrations (i.e. 0.2 and 0.02%) the presence or nature of the polymer had no substantial effect on the amount of stain produced on treatment of HAP discs. At the lowest concentration (i.e. 0.002%) of applied chlorhexidine, the majority of Examples show a 30 significant reduction in stain equal to or less than the minimal levels associated with exposure of HAP discs to the tea solutions. However, it will be appreciated from the results in Examples 10-20 and 6-9, that, for about the same stain as the control, the polymers had more 22 7 5 9 6 chlorhexidine absorbed thereon and exhibited an increased antibacterial effect.

EXAMPLES 30-31 These Examples illustrate the increase in the 5 quantity of chlorhexidine adsorbed onto a hydroxyapatite disc treated with a mixture of chlorhexidine and Polymer 93W compared to treatment of the HAP disc with a chlorhexidine solution per se.

An IMS solution (2% w/v) of Polymer 93W was mixed 10 with an appropriate (0.04% w/v) solution of chlorhexidine in water, at a solution ratio of 1:1 by volume. Hydroxyapatite discs were allowed to stand in the mixture for 1 hour and were then washed five times with water. The amount of chlorhexidine absorbed on the discs was 15 determined by UV reflectance spectrophotometry as described in Examples 10-20 (the Optical Density was measured at 266 nanometers).

In Comparative Tests 20 and 21, the discs were treated for 1 hour with 0.2 and 0.02 % solutions 20 respectively of chlorohexidine in a 1:1 by volume mixture of industrial methylated spirit and water.

The results are shown in Table 7. From Table 7 it can be seen that treatment of a HAP with the Polymer 93W/chlorhexidine mixture results in more chlorhexidine 25 being absorbed than from chlorhexidine solution per se. 22 7 5 9 6 TABLE 7 Example State of Concentration Increase in No addition of Optical of chlorhexidine Density at composition % w/v 266 nm Mixture 0.2 0.44 31 Mixture 0.02 0.12 CT19 Neat chlorhexidine solution 0.2 0.0 CT20 Neat 0.02 0.0 chlorhexidine solution EXAMPLES 32-33 These Examples illustrate the increased "kill" of a Polymer 93W/chlorhexidine mixture compared with that observed with neat chlorhexidine solution.

The discs prepared in Examples 30-31 were washed overnight in water and subjected to an S.mutans agar overlay experiment. They were placed in a petri-dish and covered with BHI agar (25 mis). S mutans (100 pi), grown in a fermenter (as described above) and diluted x 100 in Ringers salt solution, was pipetted onto the agar and evenly spread. The bacteria were grown overnight at 37°C; "lawns" of bacteria and "clear zones" free of bacteria were noted and measured. The results are shown in Table 8. The clear zones, i.e. zones where growth did not occur, are shown as a percentage of the area of the disc. 22 7 5 9 6 TABLE 8 It will be appreciated that where "% Area of disc where growth did not occur" is more than 100, this indicates that inhibition spread into the agar layer beyond the perimeter of the disc.

From Table 8, it can be seen that the mixture has 25 an increased antibacterial activity compared with chlorhexidine per se.

EXAMPLES 34-65 These Examples show that the combination of an anti-adhesive compound, Polymer 93W, and chlorhexidine 30 reduce the amount of staining, compared with chlorhexidine per se, generated on a variety of surfaces found in the oral environment. The surfaces comprised tooth, composite restorative materials, e.g. Occlusin and Opalux, and a methacrylate-based resin 35 conventionally used in.the preparation of dental Example Disc Concentration % Area of No Prepared of disc where in chlorhexidine growth did Example % w/v not occur No 32 0.2 225 33 31 0. 02 64 CT21 CT19 0.2 3 CT22 CT20 0. 02 0 22 7 5 9 6 prosthetic devices (hereinafter referred to for convenience as "PR"). specimens Residual flesh was removed with a scalpel from freshly extracted teeth, the teeth were then tumbled for 20 minutes in 50% sodium hypochlorite solutions and washed superficially with distilled water.

These and teeth containing restorative material were sonicated in alcohol for 10 minutes and then dried.

Samples of DR (25 mm x 10 mm x 3 mm) and discs of the aforementioned composite restoratives were washed in alcohol and dried. solutions a 1% and 0.5% solutions of Polymer 93W (lgm) in a mixture of industrial methylated spirit (50 ml) and water (50 ml). b Solutions (0.2%, 0.02%, and 0.002%) of chlorhexidine in water. c Appropriate mixtures of Polymer 93W and chlorhexidine were obtained by mixing equal volumes of solutions from a and b to afford the concentrations shown in the folowing Tables. d Human saliva was obtained by taking specimens (20 mis) from each of 6 volunteers, centrifuging for 20 minutes at 2,5000 rpm and pooling them. e Tea solution was prepared by boiling a sample (8g) of a commercial brand of tea in distilled water (80 ml) for 2 minutes, cooling the product to room temperature and filtering off the residual tea leaves. Evaluation Each surface was treated for 10 minutes with a sample of the saliva. Excess saliva was washed off.

In Examples 34-49, the surface was subjected to a first treatment for 10 minutes, superficially washed with distilled water, subjected to the second treatment for 10 minutes, rinsed and then immersed in the tea 22 7 5 96 solution for 1 hour; the procedure was repeated, the sample was left in the tea solution overnight and the whole procedure repeated every day for 5 days.

In examples 50-65 the above 5 day procedure was 5 repeated except that the first treatment was for 5 minutes and the second treatment was omitted, the samples were treated with appropriate mixtures of Polymer 93W and chlorhexidine.

The staining of the surfaces was compared visually 10 with the same surface treated only with water and scored on the following scale.

Scale 0 : No stain (ie Water-control taken as 0, although there was slight discolouration); 1 : Slight stain; 2 : Moderate stain; 3 : Heavy stain; and 4 : Very heavy stain.

In Tables 9, 10 and 17 OC = Occlusin OP = Opalux T = Tooth 25 PR = Prosthetic resin A =0.5% Polymer 93W AA = 1% Polymer 93W B = Water X =0.1% Chlorohexidine 30 XX = 0.2 Y = 0.01 YY = 0.02 Z = 0.001 ZZ = 0.002 W - 0.0001 22 75 9 TABLE 9 Example Surface Treatments Score No First or Second Single (10 mins) (10 mins) CT23 OC B 0 CT24 OP B 0 CT25 T B 0 CT26 PR B 0 CT27 OC X 3 CT28 OP X 3 CT29 T X 3 CT30 PR X 3 CT31 OC AA 0 CT32 OP AA 0 CT33 T AA 0 CT34 PR AA 0 34 OC AA XX 3 • 1 1 1 YY 1 36 1 1 1 1 ZZ 0 CT35 • 1 B XX 3 CT36 « • • • YY 2 CT37 1 1 • • ZZ 1 37 OP AA XX 4 38 t • 1 1 YY 2 39 I 1 • 1 ZZ 0 CT38 « « B XX 3 CT39 t 1 • 1 YY 2 22 7 5 9 6 TABLE 9 - Cont Example Surface Treatments Score No First or Second Single (10 mins) (10 mins) CT40 OP B ZZ 1 40 T AA XX 4 41 t t I 1 YY 2 42 1 1 1 I ZZ 0 CT41 t 1 B XX 3 CT42 1 1 1 1 YY 2 CT4 3 t 1 1 f ZZ 1 43 PR AA XX 4 44 f 1 1 1 YY 2 45 1 t 1 1 ZZ 0 CT44 1 i B XX 3 CT45 1 I 1 1 YY 2 CT46 1 1 1 1 ZZ 1 46 OC XX AA 0 47 OP • 1 1 • 0 48 T • t • I 0 49 PR t 1 1 1 0 22 7 5 9 6 TABLE 10 Example Surface Treatment Score No (mixture for 5 mins) CT47 OC B 0 CT48 OC X 4 CT49 OC Y 3 CT50 OC Z 1 CT51 OC W 1 CT52 OC A 0 50 OC A+Y 2 51 OC A+Y 0 52 OC A+Z 0 53 OC A+W 0 CT53 OP B 0 CT54 OP X 4 CT55 OP Y 3 CT56 OP Z 1 CT57 OP W 1 CT5 8 OP A 0 54 OP A+X 4 55 OP A+Y 3 56 OP A+Z 1 57 OP A+W 1 227598 ~ 38 ~ TABLE 11 Example Surface Treatment 1 Score No (mixture for 5 mins) CT59 T B 0 CT60 T X 4 CT61 T Y 3 CT62 T Z 1 CT63 T W 1 CT64 T A 0 58 T A+X 2 59 T A+Y 0 60 T A+Z 0 61 T A+W 0 CT65 PR B 0 CT66 PR X 4 CT67 PR Y 2 CT68 PR Z 1 CT69 PR W 1 CT70 PR A 0 62 PR X 2 63 PR Y 0 64 PR Z 0 65 PR A+W 0 From Table 9, it can be seen that at low concentration (eg 0.002%) of chlorhexidine staining of dental restorative, teeth or prosthetic resin is reduced if the surface thereof is first treated with a certain polymer. It can be seen further (Examples 46-49) that 35 where the surfaces are treated with a ?2 7 5 9 6 chlorhexidine solution and then with Polymer 93W the staining is reduced to control levels.

Table 10 reveals the results obtained on treating Occlusin and Opalux surfaces with mixtures of 5 chlorhexidine and Polymer 93W. There is a significant reduction in the staining of Occlusin, to control levels at chlorhexidine concentrations of 0.01% and less; a similar trend is apparent with Opalux.

Table 11 reveals the results obtained on treating 10 tooth surfaces and a prosthetic resin with a mixture of chlorhexidine and Polymer 93W. The trend in the reduction in staining is similar to that observed with Occlusin and Opalux.

Where a tooth with an Occlusin implant was 15 subjected to the above evaluation, the tooth and implant were slightly stained to the same extent such that the outline of the implant was further decreased. ) 2275 9 G

Claims (16)

WHAT WE CLAIM IS:

1. An oral hygiene composition-which comprises (i) at least one cationic anti-bacterial agent; and (ii) at least one polymer which bears pendant polyalkylene oxide side-chains; which components are present in amounts effective to control fouling (as hereinbefore defined) of tooth surfaces.

2. An oral hygiene composition as claimed in Claim 1 wherein the catonic anti-bacterial agent is a 10 polybiguanide or a salt thereof.

3. An oral hygiene composition as claimed in Claim 2 wherein the polybiguanide is a bis-biguanide.

4. An oral hygiene composition as claimed in Claim 3 wherein the bis-biguanide is chlorhexidine. 15 6. An oral hygiene composition as claimed in Claim 1 wherein the least one polymer comprises one or more repeating units of general Structure A. 20 25 (CO aH) and one or more repeating units of general structure B Y M ((ZO)nR3 Fq* wherein X, which in the repeating units of structure A may be the same or different, and Y, which in the 30 repeating units of structure B may be the same or different, are hydrocarbyl, or substituted hydrocarbyl residues, providing a backbone for / , the polymer; 227596 - 41 - Z is-CHRl-CHR»-or-(CH2)m-; wherein, where Z is -CHR1-CHR2 -

5 R1, which in the same repeating unit of structure B (when n or q is 2 or more) or in different repeating units of structure B may be the same or different, is hydrogen or a hydrocarbyl group; and 10 R2, which in the same repeating unit of structure B (when n or q is 2 or more) or in different repeating units of structure B may be the same or different, is, hydrogen or a hydrocarbyl group; except that R1 and R2 in a single 15 unit-CHRi-CHR2-©- cannot both be hydrocarbyl; R3 which in the same repeating unit of structure B (when q is 2 or more) or in different repeating units of structure B may be the same or different, is hydrogen or a hydrocarbyl group or 20 an acyl group derived from an alkanoic acid having up to five carbon atoms; m, where present, is a number of from 2 to 10; n is a number of from 1 to 60; p is a number of from 1 to 4; and 25 q is a number of from 1 to 4; each (COjH) group is joined via an intermediary or intermediaries L to the hydrocarbyl residue X, and in cases where p is 2 to 4 may be joined by L to the same or different carbon atoms of X; 30 L may be the same or different in the repeating units of structure A and is selected from one or more direct links and one or more groups of atoms each group providing a chain of one or more atoms for linking a (COaH) group with X, e$§eptL..t£iat more than two ?2 7596 - 42 - (COaH) groups cannot be directly linked to the same carbon atom in X; each (ZO)nR3)g group is joined via an intermediary or intermediaries M to the hydrocarbyl residue Y, 5 and in cases where q is 2 to 4 may be joined by M to the same or different carbon atoms of Y; M may be the same or different in the repeat units of structure B and is selected from one or more direct links and one or more groups of atoms each group 10 providing a chain of one or more atoms for linking a (Z0)n group with Y, except that more than two (Z0)n groups cannot be directly linked to the same carbon atom in Y; the ratio of the number of -C02H groups to the number of 15 (ZO) groups, particularly where Z is -CH2CH2-, is within the range of 1:20 to 20:1

6. An oral hygiene composition as claimed in claim 5 wherein,where Z is -CHR1-CHR2-, both R1 and R2 are hydrogen. 20

7. An oral hygiene composition as claimed in claim 5 where R3 is methyl.

8. An oral hygiene composition as claimed in claim 5 wherein, in structure A, L is a direct link, 25 -CHa—, -CHj-CHJ-, -CHj-CH =, -NH-C0-, - C0NHCH(CH3)- or -CONHCH(OH)-

9. An oral hygiene composition as claimed in Claim 5 wherein, in Structure A, p is 1 or 2. 30

10. An oral hygiene composition as claimed in Claim 5 wherein, in structure B, M is -COO-or CONH-

11. An oral hygiene composition as claimed in Claim 5 wherein, in structure B, q is 1 or 2.

12. An oral hygiene composition as claimed in Claim 5 35 wherein A or B represents the repeat unit derivable by 227596 - 43 - the addition-polymerisation of a polymerisable olefinically unsaturated carboxylic acid or an ester or amide derivative thereof respectively.

13. An oral hygiene composition as claimed in Claim 12 wherein the polymerisable olefinically unsaturated carboxylic acid is acrylic acid or methacrylic acid.

14. An oral hygiene composition as claimed in Claim 1 comprising a pharmaceutical^ acceptable vehicle which is water, ethanol, a humectant, gelling agent, gel stabiliser, sweetener, preservative, surfactant or an approved colour or flavour.

15. An oral hygiene composition as claimed in Claim 1 the form of mouthwash, rinse, irrigating solution, gel dentifrice, denture cleaner, coated dental floss, coated or impregnated tooth-brush bristle, inter-dental stimulator or coating, chewing gum, lozenge, breath freshener, foam or spray.

16. An oral hygiene composition as defined in claim 1 substantially as herein described with reference to any Example thereof or to the accompanying drawing. By Uis/Their authorised Agent A.J. PARK & SON