WO1994022417A1

WO1994022417A1 - An oral hygiene pretreatment composition

Info

Publication number: WO1994022417A1
Application number: PCT/EP1994/000994
Authority: WO
Inventors: Paul Barnett; Kirsty Helen Burgon-Lyon; Emma Jane Cornwell; Carys Harbinson; Michael Ian Shaw
Original assignee: Smithkline Beecham Plc
Priority date: 1993-04-02
Filing date: 1994-03-29
Publication date: 1994-10-13
Also published as: AU6537594A

Abstract

Oral hygiene compositions comprising at least one polymer having pendant polyalkylene oxide groups are of use as a pretreatment step, prior to the use of an oral hygiene composition comprising an essentially water insoluble non-cationic anti-bacterial anti-plaque agent, to enhance the efficacy of the agent.

Description

AN ORAL HYGIENE PRETREATMENT COMPOSITION

This invention relates to a method of improving the efficacy of certain non- cationic anti-bacterial antiplaque agents by prior treatment of the oral cavity with a class of polymers having pendant polyalkylene oxide chains.

The advantages of providing an oral hygiene composition comprising an anti-bacterial agent for anti-plaque therapy are well recognised in the art. The cationic anti-bacterial agent chlorhexidine has been shown to be well adsorbed in the oral cavity and to have significant anti-plaque efficacy. It has not however been widely used as it tends to stain tooth surfaces. In addition, it is incompatible with many of the materials normally used to formulate a dentifrice. Accordingly, interest has focussed more recently on the incorporation of non-cationic anti-bacterial agents such as triclosan into oral hygiene compositions. It is however recognised that the efficacy of such agents is limited by their lack of oral substantivity. In addition, such agents are generally essentially water insoluble and so have a tendency to be preferentially solubilised by surfactant micelle phases and flavour oils, where present, and so be rendered unavailable for adsorption in the oral cavity. Various strategies have been suggested to alleviate this problem, including the addition of a pyrophosphate salt (EP 0 251 591, Beecham Group pic), the provision of a lamellar liquid crystal surfactant phase (EP 0 161 898, Unilever) and the addition of a synthetic anionic polycarboxylate polymer (US 4 894 220, Colgate-Palmolive).

Oral hygiene compositions comprising a class of polymers having carboxylic acid residues and pendant polyalkylene oxide chains are said to be effective as anti- adherence agents (EP 0 182 523-A). In addition, the incorporation of this class of polymers into oral hygiene compositions comprising a cationic anti-bacterial agent such as chlorhexidine is said to provide compositions with enhanced anti-adherence and anti-bacterial properties (GB 2 213 721 -A). In each instance, the compositions are said to be of use in anti-plaque therapy. The polymer may be used as a pre- treatment, prior to the use of the cationic anti-bacterial agent or a co-treatment. We have now surprisingly found that this class of polymers may also be used as a pre-treatment, prior to the use of a composition comprising a non-cationic anti¬ bacterial agent, to give enhanced anti-plaque efficacy.

Accordingly, the present invention provides for the use of at least one polymer which has one or more pendant polyalkylene oxide groups (hereinafter referred to as the polymer) in the manufacture of an oral hygiene composition to be used as a pre-treatment, prior to the use of an oral hygiene composition comprising an essentially water insoluble non-cationic anti-bacterial anti-plaque agent and an orally acceptable carrier or excipient.

In the alternative, the present invention provides a method of enhancing the antiplaque efficacy of an essentially water insoluble non-cationic anti-bacterial agent which method comprises initially using an effective amount of an orally acceptable composition comprising at least one polymer which has one or more pendant polyalkylene oxide groups and an orally acceptable carrier or excipient; followed by using an effective amount of an oral hygiene composition comprising an essentially water insoluble non-cationic anti-bacterial anti-plaque agent and an orally acceptable carrier or excipient.

Suitable polymers for use in oral hygiene compositions of the present invention are described in EP 0 182523-A (Imperial Chemical Industries pic), the disclosure of which is incorporated herein by way of reference.

Suitable polymers for use in the present invention may be acidic, amphoteric, basic or neutral. Preferred polymers are acidic, that is polymers which have at least one carboxylic acid group appended to the polymer backbone.

Preferably, in polymers for use in the present invention , the one or more pendant polyalkylene oxide groups appended to the polymers are ethylene oxide groups. At least a portion thereof may be alternative poly(lower)alkylene oxide groups such as polypropylene oxide.

Suitable polymers for use in oral hygiene compositions of the present invention comprise one or more repeating units of general structure A:

-{X(LCO₂H)_p}-

and one or more repeating units of general structure B:

-{Y[M-(ZO)_nR₃]_q}-

in which:

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 polymer;

Z is -CHRⁱCHR²- or -(CH₂)_m-;

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

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 unit-CHR^HR²©-, 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 an acyl group derived from a C^alkanoic acid ; m, where present, is a number of from 2 to 10; n is a number from 1 to 60; p is a number from 1 to 4; and q is a number from 1 to 4; each (CO2H) group is joined via an intermediary or intermediaries L to the hydrocaryl 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 (CO2H) 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 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 a (ZO)_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 -CO2H groups to the number of (ZO) groups, particularly where Z is -CH₂CH₂-, is within the range of 1:20 to 20:1.

Where Z is -CHRⁱCHR²-. R¹ and R² are both preferably hydrogen. Suitable values for R* or R², when present as a hydrocarbyl group, include lower alkyl, preferably methyl. Where Z is -(CH₂)_m-, m is preferably 4; this affords a ready preparation of -(ZO)_n- from tetrahydrofuran.

R3 is preferably a lower alkyl group, more preferably methyl.

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 corresponding salt anions CO2" (these being considered as CO2H group as far as the of ratio of carboxyl to -ZO- groups is concerned), the corresponding cations being, for example, those of ammonium (NH4⁺), alkaline earth metals or, preferably, alkali metals (e.g. Na⁺, K⁺).

In general structure A, each carboxyl group is joined to the hydrocarbyl residue X by means of an intermediary or intermediaries (i.e. by linking entity or entities), this or these being denoted by L, which is 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 cases where L represents more than one intermediary, to 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 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 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 aryl ring) and/or hetero atoms (particularly N and/or 0). Examples of possible linkages provided by L include a direct link or bond, -CH2-, -CH2CH2-, -CH2CI -NHCO-, CONHCH(CH3)- and -CONHCH(OH)-, where (apart from the direct link) the left- hand link is to X and the right-hand link(s) is to carboxyl. Preferably, L is one or more direct links, so 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).

In structure B, each (ZO)_n R^ 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 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 R^ group(s) with Y. In cases where q is 2 to 4, each (ZO)_n R^ group may be joined by M to the same or, in cases where M represents more than one intermediary, to the same or different carbon atoms in Y, although more than two (ZO)_n R^ 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 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.

Preferably, 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, such as benzyl ether and/or hetero atoms (particularly N and/or 0). Particularly preferred examples of chains provided by M are -C(O)O- and -CONH- where the left-hand link is to Y and the right-hand link is to (ZO)_n R^.

In the structure B, q is preferably 1 or 2, more preferably 1 (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 acid, fumaric acid, itaconic acid, N-methacryloylalanine (CH2=C(CH3)CONHCH(CH3)CO2*H), N- acryloylhydroxyglycine (CH₂=CHCONHCH(OH)CO2H) or, preferably, acrylic or methacrylic acid.

Preferably the structure B represents the repeat unit derived from the polymerisation (usually 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 formula HO (ZO)_n R^ (to form the ester) or an amine of formula H2N (ZO)_n R^ (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 derivative of methacrylic acid is used, to the following structures respectively for B:

O(ZO)_nR3 NH(ZO)_nR3

Preferred acidic polymers for use in oral hygiene compositions of the present invention have a ratio of acidic residues to pendant polyalkylene oxide residues of about 6:1 and in which each side chain comprises a polyethylenegylcol portion of molecular weight about 350.

In preferred polymers for use in compositions of the present, in the repeating units of general structure A:

X is -CH2C(CH3)-; L is a direct link; and p is 1; and in the repeating units of general structure B:

Y is -CH₂CH(CH3)-; M is -C(O)O; R³ is methyl; n is about 8; q is 1; R¹ and R² is each H; and the ratio of the repeating units of general structure A to the repeating units of general structure B is about 6:1.

Preferred polymers for use in compositions according to the present invention are obtainable by the copolymerisation of methacrylic acid and α-methoxy- co-methacryloyloxypolyethylene glycol in molar ratios of from about 10:1 to about 1:1, preferably about 6: 1. Preferably the α-methoxy-α>-methacryloyloxypolyethylene glycol is obtainable from a methoxy-ended polyethylene glycol in which the polyethylene glycol portion has a molecular weight in the range 100 to 2500, preferably 100 to 600, more preferably about 350. A particularly preferred polymer is obtainable by the copolymerisation of methacrylic acid and α-methoxy-ω- methacryloyloxypolyethylene glycol (in which the polyethylene glycol portion has a molecular weight of about 350) in molar ratio about 6:1. This may be represented by the general formula:

R¹{CH2C(CH3)(Cθ2H)}_x{CH2C(CH3)(Cθ2[CH₂CH2]nOCH3)}_yR"

In a suitable example, x is typically 6 or 7, y is 1 and n is from 2 to 15, average about 8 and the average molecular mass is about 60,000.

In oral hygiene compositions of the present invention, the polymer is typically present in a concentration of from about 0.50 to 30 weight % of the composition, preferably from about 0.1 to 5 weight %, more preferably 0.2 to 2 weight %.

Oral hygiene compositions of the present invention may comprise one or more polymers as hereinbefore defined, although normally only one will be present. Polymers for use in compositions of the present invention may be prepared according to the procedures previously described in EP 0 183 523- A, the disclosure of which is herein incorporated by way of reference.

Compositions comprising the aforementioned polymers are intended for use as a pre-treatment , prior to the use of an otherwise conventional composition comprising an essentially water insoluble noncationic anti¬ bacterial anti-plaque agent. Suitable such agents are well known in the art and include, for example, halogenated hydroxy diphenyl ethers and thioethers, halogenated hydroxy diphenylmethanes, phenolic compounds, including halogenated salicylanilides, benzoate esters including esters of 4- hydroxybenzoic acid, and carbanilides, in particular halogenated carbanilides. Examples of halogenated hydroxydiphenyl ethers include, for example, 3,3'-dibromo-5,5'-dichloro-2,2'-dihydroxydiphenyl ether and 2,4,4'-trichloro-2'-hydroxydiphenyl ether (triclosan); of which triclosan is particularly preferred. Examples of halogenated hydroxy diphenyl thioethers include bis-(2- hydroxy-3,5-dichlorophenyl)sulphide, and bw-(2-hydroxy-5-chlorophenyl)- sulphide.

Examples of halogenated hydroxy diphenylmethanes include 5,5'- dichloro-2,2'-dihydroxydiphenylmethane (dichlorophene), 2,2'-dihydroxy- 3,5,6,3',5',6'-hexachlorodiphenylmethane (hexachlorophene), 3,3 -dibromo- 5,5'-dichloro-2,2'-dihydroxydiphenylmethane (bromochlorophene), 5-chloro- 2-hydroxydiphenylmethane, 2,2'-methylene-bw-(3,4,6-trichlorophenol), 2,2'- methylene-bw-(4-chlorophenol), and 2,2'-methylene-b/s-(4-chloro-6- bromophenol). Examples of phenolic compounds, include, for example, 2-phenyl- phenol, 4-chlorophenol, 4-chloro-3-methylphenol, 4-chloro-3-methylphenol, 4-chloro-3,5-dimethylphenol, 2,4-dichloro-3,5-dimethylphenol, 5-methyl-2-pentylphenol, A-iso propyl-3-methylphenol, 4',5-dibromosalicylanilide, 3,4',5-tribromosalicylanilide,

2,3,3',5-tetrachlorosalicylanilide, 3,3',4,5'-tetrachlorosalicylanilide, 3,5- dibromo-3'-trifluoromethylsalicylanilide, and 5-/z-octanoyl-3'-trifluoro- methylsalicylanilide.

Examples of bw-phenolic compounds include, for example, 2,2'-methylene-bw-(3,4,6-trichlorophenol), 2,2'-methylene-W5-

(4-chlorophenol), and 2,2'-methylene-bw-(4-chloro-6-bromophenol).

Examples of benzoate esters include, for example, esters of hydroxybenzoic acid, especially the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, hexyl, heptyl and benzyl esters. Examples of carbanilides include, for example,

3,4,4'-trichlorocarbanilide, 3-trifluoromethyl-4,4'-dichlorocarbanilide, and 3,3',4-trichlorocarbanilide.

Preferably, the non-cationic anti-bacterial agent is triclosan. Typically, the water insoluble non cationic anti-bacterial agent will be present in the range 0.01 to 2%, preferably 0.1 to 1% by weight of the composition.

The oral hygiene compositions of the present invention comprise orally acceptable vehicles which are compatible with the polymer or non-cationic antibacterial agent incorporated therewith. Suitable conventional orally acceptable 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, wø-propanol, glycerol and sorbitol; thickening agents such as cellulose derivatives, for example, sodium carboxymethyl cellulose, hydroxypropyl and hydroxyethyl cellulose, hydroxypropyl methyl cellulose, ; certain gel stabilisers such as polyvinylpyrrolidone; sweeteners such as sodium saccharin; preservatives such as sodium benzoate and certain lower alkyl 4-hydroxy-benzoates; surfactants, including conventional anionic, cationic, amphoteric and non-ionic surfactants such as sodium lauryl sulphate, sodium cocomonoglyceride sulfonate, sodium lauryl sarcosinate, polyethoxylated sorbitol esters, polycondensates of ethylene oxide and propylene oxide (poloxamers); and certain colours and flavours, on the approved EC or FD & C lists. Where appropriate, suitable abrasives include those conventionally used in dentifrices, for instance, silica, alumina, aluminium hydroxide, calcium phosphates, including calcium pyrophoshate and dicalcium phoshate dihydrate, insoluble sodium metaphosphate and calcium carbonate. 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. Such ingredients, where included in the orally acceptable vehicle, will be included at levels conventionally used in oral hygiene compositions.

It will be readily appreciated by the skilled man that essentially water insoluble non-cationic antibacterial agent is solubilised in the orally acceptable vehicle. This may be achieved through conventional means such as incorporation of solubilising solvents; incorporation of solubilising surfactants; and adjusting the pH within orallly acceptable limits to encourage, where appropriate, anion formation.

Compositions of the present invention will have orally acceptable pH's, preferably in the range 5 to 10.5, more preferably 5 to 9.

In addition, compositions for use in the present invention may also comprise a fluoride ion source, to provide an anti-caries effect. Suitable such sources include for instance an alkali metal fluoride salt or an alkali monofluorphosphate, to provide between 100 and 2500, preferably from 300 to 1500 ppm of fluoride ions.

The oral hygiene compositions of the present invention may be in the form of any conventional pharmaceutically acceptable oral hygiene formulation that contains (and is compatible with) an effective amount of a polymer as hereinbefore defined. As examples of such formulations may the mentioned inter alia mouthwashes, rinses, irrigating solution, dentifrices, including abrasive and non- abrasive gel dentifrices, liquid dentifrices, denture cleaners, coated dental floss, coated or impregnated toothbrush bristle (natural or synthetic), inter-dental stimulator coatings, chewing gums, lozenges, breath freshners, forms and sprays. Such compositions will be formulated according to procedures well known in the art and using ingredients conventionally used for such formulations.

Suitably, the polymer and the noncationic antibacterial agent will be provided in oral hygiene compositions which are each mouthwashes.

In use, the consumer will use an orally effective amount of a first oral hygiene composition comprising the polymer, followed soon after by the use of a second oral hygiene composition comprising a noncationic antibacterial agent.

In a further aspect, the present invention provides an oral hygiene system comprising a first oral hygiene composition comprising an effective amount of an orally acceptable composition comprising at least one polymer which has one or more pendant polyalkylene oxide groups and an orally acceptable carrier or excipient; and a second composition comprising comprising an effective amount of an essentially water insoluble non-cationic anti-bacterial agent and an orally acceptable carrier or excipient.

The oral hygiene regime of the present invention will also be of benefit in reducing or preventing the formation of calculus, both directly as a consequence of the anticalculus activity of the polymer and indirectly as a consequence of the improved efficacy of the antiplaque agent. Plaque formation is recognised as a source of calculus. Accordingly, in a further aspect, the present invention provides a method of reducing or preventing the formation of calculus which method comprises initially using an effective amount of an orally acceptable composition comprising at least one polymer which has one or more pendant polyalkylene oxide groups and an orally acceptable carrier or excipient; followed by using an effective amount of an oral hygiene composition comprising an essentially water insoluble non-cationic anti- bacterial agent and an orally acceptable carrier or excipient.

Compositions for use in the present invention are prepared according to conventional processes, mixing the appropriate ingredients in the correct relative amounts and in any order that is suitable and thereafter and if necessary adjusting the pH to the desired final value. The present invention is now be illustrated by the following examples.

Examples

Preparation of polymer A

The following examples comprise the polymer made according to the following procedure, hereinafter referred to as polymer A:

Freshly distilled methacrylic acid (131.6g) and methoxypolyethyleneglycol 400 methacrylate (98.4g) were added to a 31, 4-necked round bottom flask. Industrial methylated spirirts (IMS) (BP grade, 1.841) was then added with stirring, the solution purged with nitrogen for 30min and then brought to gentle reflux. Initiator (4,4- azob/s(4-cyanovaleric acid, >75 water wet, Aldrich)(1.6g) in IMS (72ml) was then added dropwise over 30min at reflux. Stirring was continued at 78°C for a further 18h. Further initiator (1.32g) in IMS (56ml) was then added over 30min and stirring continued at 78°C for a further 24h. After cooling, solvent was removed under reduced pressure (rotary evaporator, water bath temperature less than 65°C). Water was then added and the polymer washed by agitation on the rotary evaporator for a further 30min. The water was decanted off and the polymer washed a second time with water (200ml). Polymer was dried under vacuum on a PTFE lined tray at 50° C/3mbar overnight, ground to a fine white powder in a coffee grinder and then dried at 50°C/3mbar for a further 24h. The yield of polymer was 200.8g (87%).

The polymer thus obtained contained methacrylic acid and α-methoxy-ω- methacryloyloxypolyethylene glycol (in which the polyethylene glycol portion has a molecular weight of about 350) in molar ratio about 6:1. This may be represented by the general formula:

R^,{CΗ₂C(CH3)(CO₂H)}_x{CH₂C(CH3)(Cθ2[CH₂CH2]_nOCΗ3)}_yR"

in which x is typically 6 or 7, y is 1 and n is between 2 and 15, average about 8. The average molecular mass was about 60,000 (measured by gel permeation chromatography).

Example 1: Mouthwash

Ethanol 5.00%

Sodium Carbonate 1.00

Flavour 0.50

Water qs

The mouthwash base can be used to provide compositions comprising either polymer A (at 0.1, 0.3, 0.5 or 1.0%) or triclosan (at 0.03, 0.05 or 0.1%).

Example 2: Mouthwash

Ethanol 15.00%

Propylene glycol 15.00

Glycerin 30.00

Flavour 1.00

Water qs

Example 3: Dentifrice

Glycerin 22.00 Hydroxypropyl methylcellulose 3.40

Titanium dioxide 1.00

Sodium saccharin 0.10

Poloxamer (Pluronic F108) 2.00

Flavour 1.00 Talin 0.02

Silica (RP93, Rhone-Poulenc)) 16.00

Deionised water qs

The dentifrice base may be used to provide a dentifrices comprising Polymer A (at 0.2, 0.5, 1, 1.5 or 2%).

Example 4: Dentifrice

Sorbitol soln (70%) 29.00% Calcium carbonate 35.00

Amorphous silica 2.00

Carrageenan 0.70

Carboxy methyl cellulose 0.60

Sodium lauryl sulphate 1.70 Sodium monofluorophosphate 0.80

Sodium hydroxide 0.102

Flavour 1.0

Sodium saccharin 0.38

Water qs

The dentifrice base may be used to provide a dentifrices comprising Polymer A (at 0.2, 0.5, 1, 1.5 or 2%) or triclosan (at 0.2 or 0.3%).

Example 5 - Effect of pre-treatment with polymer A on triclosan binding and retention.

Bovine incisors (n=l 12) were strung-up and soaked overnight in sterile, filtered, pooled human saliva at 37°C. The incisors were then rinsed in deionised water for 15s, divided into eight treatment groups and treated with either a solution of polymer A (10% soln in ethanol) or an ethanol solution. The bovine incisors were then rinsed twice in deionised water (lmin each rinse) before being placed in a triclosan solution (30% glycerin, 15%ethanol and 15%propylene glycol) for lmin. All solutions were pre-warmed to 37°C. The following solutions were tested:

Pretreatment Triclosan treatment polymer A (0.125%) in EtOH (10%) 0.15% polymer A (0.25%) in EtOH (10%) 0.15% polymer A (0.5%) in EtOH (10%) 0.15% polymer A ( 1.0%) in EtOH (10%) 0.15% polymer A (2.0%) in EtOH ( 10%) 0.15%

EtOH (10%) 0.15%

EtOH (10%) 0.10%

EtOH (10%) 0.05%

The bovine incisors of each treatment group were then rinsed in deionised water (three times, 60s, 25ml). Half the bovine incisors of each treatment group were then placed individually in methanol (3ml) for lmin, to extract any initially bound triclosan. Samples were then analysed by an HPLC assay for triclosan content. The data was analysed by Tukey statistical analysis (95% confidence level). The results are presented in table 1.

The other half of the bovine incisors were placed into separate sterilins and sterile, pooled human saliva (5ml) was pipetted onto each tooth. After a two hour incubation period (during which the bovine incisors were shaken at quarter speed on a Dently orbital shaker), the incisors were removed and rinsed twice (60s per rinse) in deionised water. The teeth were then placed into methanol (3 ml) for 1 min to extract any bound triclosan.

Samples were then analysed by an HPLC assay for triclosan content. The data was analysed by Tukey statistical analysis (95% confidence level). The results are presented in table 2.

Table 1 - initial triclosan binding

Treatment n value triclosan statistical av (μg/cm²) analysis triclosan only (0.15%) 8 1.779 * polymer A (0.125%) 8 2.065 * * polymer A (0.5%) 8 2.087 * * polymer A (0.25%) 9 2.420 * * polymer A (2.0%) 5 2.603 * * polymer A (1.0%) 9 2.613 *

Table 2 - triclosan retention

Treatment n value triclosan statistical av (μg/cm²) analysis triclosan only (0.15%) 8 0.139 * polymer A (0.25%) 9 0.264 * * polymer A (0.125%) 8 0.300 * * polymer A (2%) 5 0.364 * * polymer A (0.5%) 8 0.372 * * polymer A (1.0%) 9 0.47 *

It can be seen increasing concentrations of the polymer when used as a pre- tieatment result in an increase in both the level of initial binding of triclosan and the subsequent retention of triclosan to the saliva coated bovine enamel.

Example 6: Anti-calculus efficacy of polymer A

Potential anti-calculus agents may be screened in an acidimetric assay. In a test system, solutions of calcium (4mM) and phosphate (4mM) are mixed at physiological temperature and pH, resulting in the formation of a supersaturated solution of amorphous calcium phosphate. The degree of supersaturation reflects that likely to be found in plaque fluid. This amorphous calcium phosphate is then further transformed to hydroxyapatite. Each step is accompanied by the release of hydrogen ions, causing a fall in the pH of the solution which may be monitored with a pH meter. A potential anti-calculus agent which interfers with the conversion of amorphous calcium phosphate to crystalline hydroxyapatite may be expected to reduce this second release of hydrogen ions which will be reflected in an inhibition of the second drop in pH. Test solution (1% solution of polymer A in 50% aqueous ethanol, 1 ml) was added to phosphate stock solution (1ml of lOOmM Na₂PO4 in deionised water) in deionised water (22ml) at 37°C, with magnetic stirring. The pH of this solution was then adjusted to 7.4 with sodium hydroxide solution (0.1M) or hydrochloric acid (0.1M). Calcium stock solution (1ml of lOOmM CaCl2) was then added and the fall in pH monitored over a 30 minute period. The assay was then repeated using a control solution (either deionised water or 50% aqueous ethanol, 1ml) instead od the test solution. The results are shown in figure 1. Here it is shown that whilst the control solution gives both the expected first and second falls in pH, the test solution gives only the first fall. There is no sign of a second drop, suggesting that the test solution is effective in preventing the conversion of amorphous calcium phosphate to crystalline hydroxyapatite.

Claims

1. The use of at least one polymer which has one or more pendant polyalkylene oxide groups in the manufacture of an oral hygiene composition to be used as a pre- treatment, prior to the use of an oral hygiene composition comprising an essentially water insoluble non-cationic anti-bacterial anti-plaque agent, to enhance the efficacy of the agent

2. A use as claimed in claim 1 in which the polymers have at least one carboxylic acid group appended to the polymer backbone.

3. A use as claimed in claim 1 or 2 in which the one or more pendant polyalkylene oxide groups appended to the polymers are polyethylene oxide or polypropylene oxide groups.

4. A use as claimed in claim 1 in which the polymer comprises one or more repeating units of general structure A:

-{X(LCO₂H)_p}- and one or more repeating units of general structure B:

-{Y[M-(ZO)_nR₃]_q}-

in which:

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 polymer; Z is -CHR¹CHR²- or -(CH₂)_m-;

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 unit-CHR¹CHR²O-, 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 an acyl group derived from a (C1-.5) alkanoic acid ; m, where present, is a number from 2 to 10; n is a number from 1 to 60; p is a number from 1 to 4; and q is a number from 1 to 4; each (CO2H) group is joined via an intermediary or intermediaries L to the hydrocaryl residue X, and, in cases where p is 2 to 4, may be joined by L to die same or different carbon atoms of X;

L may be the same or different in die 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 (CO2H) groups cannot be directly linked to the same carbon atom in X; each ((ZO)_nR^)q group is joined via an intermediary or intermediaries M to die hydrocarbyl residue Y, and, in cases where q is 2 to 4, may be joined by M to die same or different carbon atoms of Y;

M may be the same or different in die 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 a (ZO)_n group with Y, except that more than two (ZO)_n groups cannot be direcdy linked to die same carbon atom in Y; the ratio of die number of -CO2H groups to the number of (ZO) groups, particularly where Z is -CH₂CH₂-, is within the range of 1:20 to 20:1.

5. A use as claimed in claim 4 in which, when Z is -CHR^lCHR²-. R¹ and R² are both hydrogen.

6. A use as claimed in claim 4 or 5 in which R-* is a lower alkyl group.

7. A use as claimed in any one of claims 4 to 6 in which L is a direct link or bond, -CH₂-, -CH₂CH₂-, -CH₂CH<, - HCO-, CONHCH(CH₃)- or - CONHCH(OH)-.

8. A use as claimed in claim7 in which L is one or more direct links.

9. A use as claimed in any one of claims 4 to 8 in which, in the structure A, p is l or 2.

10. A use as claimed in any one of claims 4 to 9 in which M is one or more groups of atoms, each group providing a linking chain of atoms.

11. A use as claimed in claim 10 in which M is -C(O)O- or -CONH-.

12. A use as claimed in any one of claims 4 to 11 in which q is 1 or 2.

13. A use as claimed in any one of claims 4 to 12 in which the structure A represents the repeat unit derivable by the addition polymerisation of a polymerisable olefinically unsaturated carboxylic acid.

14. A use as claimed in claim 13 in which die polymerisable olefinically unsaturated carboxylic acid is selected from maleic acid, fumaric acid, itaconic acid, N-methacryloylalanine (CH₂=C(OT₃)CONHCH(CH3)CC>2H), N- acryloylhydroxyglycine (CH2=CHCONHCH(OH)CO2H) acrylic or methacrylic acid.

15. A use as claimed in any one of claims 4 to 14 in which the structure B represents the repeat unit derived from the polymerisation 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) and a hydroxy compound of formula HO (ZO)_n R³ (to form the ester) or an amine of formula H2N (ZO)_n R³ (to form the amide).

16. A use as claimed in claim 15 in which structure B is derivable is acrylic or methacrylic acid.

17. A use as claimed in any one of claims 2 to 16 in which the acidic polymer have a ratio of acidic residues to pendant polyalkylene oxide residues of about 6: 1 and in which each side chain comprises a polyethylenegylcol portion of molecular weight about 350.

18. A use as claimed in any one of claims 4 to 17 in which in the repeating units of general structure A:

X is -CH2C(CH3)-; L is a direct link; and p is 1; and in die repeating units of general structure B:

Y is -CH2CH(CH₃)-; M is -C(O)O; R³ is methyl; n is about 8; q is 1; R¹ and R² is each H; and die ratio of the repeating units of general structure A to the repeating units of general structure B is about 6:1.

19. The use of an effective amount of at least one polymer in the manufacture of an oral hygiene composition for use as a pre-treatment, prior to the use of an oral hygiene composition comprising an essentially water insoluble non-cationic anti¬ bacterial anti-plaque agent, wherein the polymer is obtainable by the copolymerisation of methacrylic acid and α-methoxy-ω- methacryloyloxypolyethylene glycol in molar ratios of from about 10:1 to about 1:1.

20. A use as claimed in claim 19 in which the polymer is obtainable by the copolymerisation of methacrylic acid and α-methoxy-ω-methacryloyl- oxypolyethylene glycol (in which the polyethylene glycol portion has a molecular weight of about 350) in molar ratio about 6: 1.

21. A use as claimed in any of die preceding claims in which die the polymer is present in a concentration of from about 0.50 to 30 weight % of die composition.

22. An oral hygiene system comprising a first oral hygiene composition comprising an orally acceptable composition comprising at least one polymer as defined in any one of claims 1 to 21 and an orally acceptable carrier or excipient; and a second composition comprising comprising an essentially water insoluble non¬ cationic anti-bacterial agent and an orally acceptable carrier or excipient

23. An oral hygiene system as claimed in claim 22 in which die essentially water insoluble noncationic anti-bacterial agent is a halogenated hydroxy diphenyl edier or thioether, a halogenated hydroxydiphenylmetiiane, a phenolic compound, a benzoate ester or a carbanilide.

24. An oral hygiene system as claimed in claim 23 in which the essentially water insoluble noncationic anti-bacterial agent is triclosan.

25. An oral hygiene system as defined in any one of claims 22 to 24 for use in therapy.