FI93691C - Oral hygiene composition - Google Patents

Description

93691

This invention relates to oral hygiene compositions that can be used to inhibit or inhibit the growth of bacteria on tooth surfaces.

Prevention of the formation of a sticky deposit of tooth plaque on the surface of mammalian (especially human) teeth is highly desirable. Dental plaque is formed when tooth decay and other types of bacteria aggre-10 colonize the surface of the teeth and form a precipitate that adheres firmly to the surface. Plaque deposition on the tooth surface is believed to be one of the first steps in the development of tooth decay and dental disease.

Numerous attempts have been made to prevent plaque from depositing on the surfaces of the 15 teeth and to remove plaque from these surfaces. For example, brushing, the use of dental floss, the use of flushing solutions and interdental stimulants have been tried. However, these treatments are not entirely satisfactory and in addition to them, intermittent treatment by ham-20 massage professionals is often required.

In recently published EP Patent Application Publication No. 0 182 523A, we disclose that certain pharmaceutical compositions (as defined therein) are highly effective in preventing or significantly reducing (a) the formation of plaque-forming and other microorganism colonies on the tooth surfaces that are common in the oral environment; to treated tooth surfaces, and (b) the sticky deposition of tooth plaque on tooth surfaces caused by these microorganisms.

A polymeric preparation for use in the above-mentioned certain pharmaceutical compositions is described in EP 0 182 523A, which is incorporated herein by reference.

Chlorhexidine is a cationic antiseptic that has been widely used in medicine as a topical antibacterial agent for more than 20 years; its preparation is described in UK Patent 705,838. It has been reported [Löe et al., Journal of Periodontal Research 5 (1970) 79-83] that chlorhexidine can be used as an antiseptic in the oral environment and that under certain conditions chlorhexidine clearly appears to tend to stain teeth. This staining appears to be a common property of cationic antiseptics. It has been shown (Addy et al., Journal of Periodontal Research 9 10 pp. 134-140) that this staining is due to the interaction between a cationic antiseptic and food ingredients, especially tannin-rich foods such as coffee, tea or red wine. .

We have now found that when certain surfaces, for example a tooth or hydroxyapatite surface, are treated with a combination comprising both (a) a polymer with certain open (pendant) polyalkylene oxide chains as defined herein and (b) a cationic antibacterial agent, the resulting treated Surprisingly, the surfaces of the 20 teeth have both increased adhesion and anti-bacterial properties against certain oral microorganisms, which means that the combination may control the so-called "biological staining" of the tooth surfaces. Indeed, in the presence of said polymer 25, the same inhibitory effects on bacterial growth can be observed as when the tooth surface is treated with a low concentration solution of an antibacterial agent. In addition, we have now surprisingly found that (i) the aforementioned tendency to stain with chlorhexidine is at least reduced, often staining is not increased, although more chlorhexidine is adsorbed on the tooth surface in the presence of the aforementioned polymer; (ii) the antibacterial properties of certain cationic antibacterial agents, e.g., chlorhexidine and Alek-35, are increased on treated tooth surfaces if the surface is sequentially treated with an acidic polymer, e.g., Polymer 93W (as defined below). , or a combination of an acidic polymer and the above substance; and (iii) when composite restorations, e.g., Occlusion (RTM), Opalux, Silux, and Valux P50, etc., tend to stain by cationic antiseptics, this stain is at least reduced in the presence of the above polymer. It should be understood that a reduction in discoloration of at least the front-10 teeth is particularly desirable.

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 defined hereinbefore having one or more open polyalkyleneoxy groups. The composition according to the invention is characterized by what is stated in claim 1.

Cationic antibacterial agents that can be used in this invention are benzalkonium chloride, bispyridinamines, e.g. octenidine, or preferably a poly-biguanide, e.g. alexidine, or more preferably a bis-biguanide, e.g. chlorhexidine.

By "polybiguanide" we mean a compound in which 25 have several intrachain biguanide residues of the general formula

NH NH

-NH-C-NH-C-NH I

30 or its tautomers. Often used in this invention: The antibacterial agent contains two, three or four such intrachain residues. However, we do not rule out the possibility that there may be so many 35 that at least most of the repeating units have a higher molecular weight, e.g., a molecular weight of up to about 10,000.

It is to be understood that when polybiguanide is used in this invention, it may exist as the free base; preferably, however, it exists as a salt, e.g. acetate or hydrochloride, or more preferably, especially when the polybiguanide is a bis-biguanide having the general structure of formula II, as digluconate, this means: 1,6-di (4-chlorophenyldiguanido ) hexane di-gluconate, known in the art as chlorhexidine.

ÖNH N11 / —λ nh-c-nh-c-nh (ch2) 6nh-c-nh-c-nh <\ ne l n

NH NH

15

We do not rule out the possibility that when a polybiguanide, e.g. chlorhexidine, is used in this invention as the free base, it may be in admixture (e.g. as a salt) on the tooth surface as a salt with the hap-20 polymer defined later herein.

As possible explanations, without wishing to be bound by them, for the increased antibacterial effect of the oral hygiene composition of this invention, we propose the following: i) an increase in the amount of chlorhexidine adsorbed on the tooth surface; and / or ii) changing the intensity of adsorption of chlorhexidine on the tooth surface so that it is more available to use its antibacterial effect on the surface; and / or iii) the orientation of the adsorbed chlorhexidine: a change in the surface of the tooth so that its antibacterial groups have easier access to bacteria approaching the tooth; and / or iv 5,93691 iv) ion pairing between the cationic antibacterial agent and the acidic anions of the polymer, if present.

In the composition of the present invention, the many hydrogen bonds between the polymer and the biguanide cations may contribute to an increase in the above amount or to a change in the intensity or orientation of the adsorption.

The polymers contained in the oral hygiene composition of this invention are acidic, meaning that at least one carboxylic acid group is attached to the polymer backbone.

The one or more open polyalkylene oxide groups associated with the polymers contained in the oral hygiene compositions of this invention are preferably an ethylene oxide group. However, we do not rule out the possibility that at least part of it may be an alternative poly (lower) alkylene oxide group, e.g. polypropylene.

The oral hygiene compositions of this invention contain polymers containing one or more repeating units having the general structure A

-X -: - ---- '

L

25 --v r (coaH) p \ and one or more repeating units having the general structure B 1 ·> -C— Y —--

M

^ ((zoJ nR ^ TjN 35 6 93691 wherein X, which may be the same or different in the repeating units of structure A, and Y, which may be the same or different in the repeating units of structure B, are hydrocarbon or substituted hydrocarbon residues and form the backbone of polymer 5. Z is -CHR 1 CHR 2 - or - (CH 2) b -, wherein when Z is CHR 1 CHR 2 -, R 1 in a similar repeating unit of structure B (when n or g is 2 or greater) or in a repeating unit of structure B 10 the units may be the same or different, is hydrogen or a hydrocarbon group, and R 2, which in a similar repeating unit of structure B (when n or g is 2 or greater) or in repeating units of structure B may be the same or different, is hydrogen or a hydrocarbon group except that R1 and R2 in one unit -CHRI-CHR2-O- may not both be hydrocarbon groups, R3 which in the repeating unit of structure B (when g is 2 or greater) or in different repeating units of structure B may be the same or different, o n is hydrogen or a hydrocarbon group or an acyl group derived from an alkanoic acid having up to five carbon atoms; m, when present, is 2-10; n is a number from 1 to 60; 25 p is a number from 1 to 4; and g is a number from 1 to 4; each (CO 2 H) group is attached to the hydrocarbon residue X via an intermediary group or groups L and, in cases where p is 2 to 4, may be attached by L to the same or a different carbon atom of X; L may be the same or different in the repeating units of structure A and may be one or more direct linking groups or one or more atomic groups, each group forming a chain of one or more atoms for attaching a (CO 2 H) -35 group to X, except that no more than two (CO 2 H) groups may be directly attached to the same atom in X;

II

7 93691 each ((ZO) nR3) q group is attached to the hydrocarbon residue Y by an intermediary group or groups M and, in cases where q is 2 to 4, may be attached by M to the same or a different carbon atom of Y; 5 M may be the same or different in the repeating units of structure B and may be one or more straight-chain groups or one or more atomic groups, each group forming a chain of one or more atoms to attach the (Z0) n-group to Y, except that more than 10 two (ZO) n groups may be directly attached to the same carbon atom in Y.

The ratio of the number of -CO 2 H groups to the number of (ZO) groups, especially when Z is -CH 2 CH 2 -, is in the range of 1:20 to 20: 1.

Preferably, both R 1 and R 2, when present, are hydrogen.

When R1 or R2 is a hydrocarbon group, it is preferably a lower alkyl group, more preferably methyl.

R3 is preferably a lower alkyl group, more preferably methyl for 20 min.

When Z is - (CH 2) b, m is preferably 4; this allows the (Z0) n group to be prepared directly from tetrahydrofuran.

It is to be understood that the definition of polymer in the composition (as given above) is intended to include a polymer in which at least some of the carboxyl groups in the repeating units of general structure A have been converted to the corresponding salt anions CO 2 - (these are considered -CO 2 H groups in the definition of carboxyl group). the corresponding cations are, for example, ammonium (NH4 ') or alkaline earth metals or, preferably, alkali metals (e.g. Na *, K *). We do not rule out the possibility that the cation may be derived from a cationic antibacterial agent; indeed, when the cationic antibacterial agent is present as a salt of the acidic poly-35 polymer with substantially no free chlorhexidine in the mouth, the tendency to stain is further reduced.

____. l 93691 8

In the general structure A, each carboxyl group is attached to the hydrocarbon residue X by an intermediary group or groups (e.g., a linker group or groups) denoted by L, which may be one or more 5 direct linker groups (i.e., one or more direct bonds) or one or more atomic groups, each group forming a chain of one or more atoms for attachment of the carboxyl group (s) to X. In cases where p is 2 to 4, each carboxyl group may be attached by L 10 to the same or, in cases where L is more than one intermediary group, to the same or a different carbon atom in X, although of course more than 2 carboxyl groups cannot be directly attached to the same X (and also assuming that in such cases X has at least two carbon atoms, while it should be understood that it is within the scope of the invention that X has only one carbon atom). It should be noted that in principle L can have up to 4 distinct groups of intermediaries in structure A (in cases where p is 4). L may be the same or different in the repeating units 20 of structure A.

In cases where L is one or more atomic groups, each group forming a linking atomic chain, the chain usually contains one or more carbon atoms (which could be, for example, carbon atoms of the aryl ring) and / or heteroatoms (especially N and / or O).

Examples of possible joints formed by L are:

I I I I I I

CH2 ch2 ch2 NH CO CO

30 | | i I I

CH0 CH CO NH NH

«

ί / \ I I I

straight 'CH (CH-) CH (OH)

joint I

35 or bond 9 93691 wherein (except in direct coupling) the upper bond is to X and the lowest bond (s) is to the carboxyl. However, in the present invention, it is preferred that L is one or more direct bonds, so that each carboxyl group is directly attached to the carbon atom of the polymer backbone.

In structure A p is preferably 1 or 2, more preferably 1 (wherein L may then be one or at most two intermediary groups).

In structure B, each (Z0) nR3 group is attached to the hydrocarbon residue Y by an intermediary group or groups (i.e., a linker group or groups) denoted by M, which may be one or more direct linking groups (this means one or more direct si-15 dos) or one or more atomic groups, each group forming a chain of one or more atoms for attaching the (Z0) nR3 group (s) to Y. In cases where g is 2 to 4, each (Z0) nR3 group may be attached by M to the same or, in cases where M is more than one intermediary group, to the same or different carbon atoms in Y, although not more than two (Z0) Of course, the nR3 group can be directly attached to the same carbon atom of Y (and also assuming that in such cases Y has at least two carbon atoms, while it should be understood that it is within the scope of the invention that there is only one carbon atom in Y). M may be the same or different in the repeating units of structure B.

Although M may be one or more direct linker groups, in the present invention it is preferred that M is one or more atomic groups each forming a linking atom-30 chain; such a chain usually contains one or more carbon atoms (which could, for example, be carbon atoms of a ** 'aryl ring, e.g. benzyl ether) and / or heteroatoms (especially N and / or O). Particularly preferred examples of chains formed by M are: 35 10 93691

I I

CO and CO

I I

5 0 NH

I I

wherein the upper bond is to Y and the lowest bond is to the (Z0) nR3 group.

In structure B, q is preferably 1 or 2, more preferably min 1 (so then M may be one or at most two mediator groups).

Preferably, structure A is a repeating unit obtained by addition polymerization (usually starting with free radicals) of a polymerizable, olefinically unsaturated carboxylic acid. Examples of these acids are maleic (or fumaric) acid, ita-cononic acid, acids of the formulas 20 c (ch3) = ch2 ch = ch2

CO and CO

I I

25 NHCH (CH3) CO2H NHCH (OH) CO2H

N-methacryloylalanine-N-acryloylhydroxyglycine or preferably acrylic or methacrylic acid.

Preferably, structure B is a repeating unit obtained by polymerizing (usually starting with free radicals) an addition polymerizable, olefinically unsaturated ester or amide formed with an unsaturated carboxylic acid (or an esterifiable or amidable derivative thereof, such as an acid chloride or anhydride). 4 11 93691 by reaction with a hydroxy compound of formula HO (ZO) „R3 (to form an ester) or an amine of formula H2N (ZO) nR3 (to form an amide).

Preferably, the acid from which structure B can be obtained is an acrylic or methacrylic acid, in particular the latter, whereby the use of an ester or amide derivative of methacrylic acid, the following structures are obtained for B.

io -c (ch3) - ch2-- -c (ch3) - ch2—

I I

CO and CO

1 3 1 3

0 (Z0) nRJ NH (Z0) nR

15

Preferably, in the acidic polymers contained in the oral hygiene compositions of the invention, the ratio of acidic residues to open polyalkylene oxide residues is about 6: 1 (wherein each side chain is polyethylene glycol having a molecular weight of about 350, i.e.: so-called PEG 350).

The polymers used in this invention are described in more detail in the above-mentioned EP patent application publication 0 182 523, which is incorporated herein by reference.

In the oral hygiene compositions of this invention, the at least one polymer therein is typically present in a concentration of about 0.05 to 30% by weight of the composition, with a preferred concentration range of about 0.1 to 5% by weight and more preferably 0.2 to 2% by weight.

The content of the at least one antibacterial agent in the oral hygiene compositions of this invention is about 0.001 to 10% by weight of the composition, the preferred concentration range is about 0.001 to 1.0% by weight, and more preferably 0.01 to 0.1% by weight.

Preferably, the weight of the polymer is greater than the weight of the anti-bacterial agent in the oral hygiene composition of this invention. However, we do not rule out the possibility that there may be more antibacterial agent than polymer.

The oral hygiene compositions of this invention typically contain only one polymer as previously defined herein, although we do not rule out the possibility that the composition may contain two or more such polymers.

One skilled in the art can, by a simple experiment, formulate the compositions of this invention in which the ratio of antibacterial agent to polymer is such that an undesired reaction can be avoided.

The oral hygiene composition of this invention typically contains a pharmaceutically acceptable vehicle suitable for the antibacterial efficacy of a cationic antibacterial agent, e.g., chlorhexidine. In order to maintain the efficacy of chlorhexidine, it may be necessary to adjust its concentration in a particular vehicle; one skilled in the art can determine the appropriate concentration experimentally.

Suitable conventional pharmaceutically acceptable vehicles that can be used in the oral hygiene compositions of this invention include water, ethanol (wherein water or a water / ethanol mixture is often the major component of the vehicle); a humectant such as propylene glycol, isopropanol, glycerol and sorbitol; gelling agents such as cellulose derivatives, for example hydroxypropyl and hydroxyethylcellulose, polyoxypropylene-30 / polyoxyethylene copolymers (so-called "Poloxamers" polymers), for example Synperonic PE 39/70 and PEF 87; certain gel stabilizers such as polyvinylpyrrolidone; sweetening agents such as sodium saccharin; preservatives such as cetylpyridinium chloride and certain lower alkyl parahydroxybenzoates; surfactants 1

«I

13,93691 agents such as polyoxyethylene isohexadecyl ether (Ar-lasolve 200); and certain colors and flavors from EEC or FD&C lists. It is to be understood that the above-mentioned vehicle-11 is selected so as not to unduly inhibit the efficacy of the oral hygiene composition of this invention; in particular an anionic material, e.g. anionic cellulose derivatives or an anionic Synperonic compound are not preferred.

The oral hygiene compositions 10 of this invention may be in any conventional pharmaceutically acceptable oral hygiene formulation containing (and suitably) an effective amount of a polymer and antibacterial agent as previously defined herein. Examples of such formulations include mouthwashes, washing solutions, rinsing solutions, abrasive and non-abrasive gel toothpastes, denture cleaners, coated dental floss, coated or impregnated toothpaste, toothpaste, toothbrush, natural tooth, , foams and sprays.

The present invention will now be illustrated by the following examples. The prefix "CT" in the example number indicates a reference number.

25 In most of the following examples, oral bacteria

Streptococcus mutans NCTC 10,449 was used as a standard bacterium. It was grown in Brain Heart Infusion (BHI) medium (Oxoid) in a Bioflo Model C30 fermentor. A 750 ml vessel containing 350 ml of bacterial suspension was used. Bacteria were grown at 37 ° C with a dilution rate of 0.1 h -1, an air flow of 0.24 liters / minute »· -: and a stirring speed of 300 rpm. A sample of the bacterial suspension (approximately 20 ml) was taken from the fermentor for each experiment. The bacteria were centrifuged for 10 minutes at 4,000 rpm, suspended in modified Ringer's 14,93691 saline (0.54 g / l NaCl, 0.02 g / l KCl, 0.03 / 1 CaCl2 and 0.75 g / l sodium mercaptoacetate). ), centrifuged again, resuspended and diluted (10x) in modified Ringer's saline. The bacterial concentration in dilute saline was about 10® ml'1.

Streptococcus mitior strain NCTC 7864 was grown in 100 ml of Brain Heart Infusion broth in batch culture for 24 hours. The culture was then centrifuged for 30 minutes at 3,500 rpm and washed twice by suspending the button in physiological saline and centrifuging. The bacterial suspension was then adjusted to a concentration of about 107 to 10® ml'1.

In some examples, whole saliva was used.

15 Absorption surfaces

Hydroxyapatite wafers were prepared by pressing hydroxyapatite powder (calcium phosphate, tribasic, Ca10 (OH) 2 (PO4) 6, Aldrich) and sintering at 1,100 ° C. The discs were reused after heating in an oven at 900 ° C for two hours between experiments.

Addition of polymers

The hydroxyapatite wafers were treated for two minutes at room temperature with a polymer solution, e.g. Polymer 93W, (1%, w / v), in a 1: 1 (v / v) mixture of industrial methylated alcohols and water. The discs were then washed by dipping and shaking five times in a vessel containing running water at about 15 ° C.

Addition of antibacterial agent

Aqueous solutions of chlorhexidine and IMS solutions of Alexei-30 didine were adsorbed separately on the surface of hydroxylapatite wafers, which had been treated with a polymer, where appropriate (untreated wafers were used in comparative experiments). The discs were then washed by dipping and shaking five times in a vessel containing 35 running water.

* · 15 93691

Polymers The polymer referred to herein as "Polymer 93W" is an acidic polymer described and prepared in our aforementioned EP 182 523 Example 5 5. (The other "acidic" polymers described hereinafter were prepared by a similar method). Polymer 93W polymer contains methacrylic acid and PEG350MAt residues in a molar ratio of 6: 1.

By "PEG350MAt" we mean polyethylene-10 oxide having a molecular weight of about 350 and having methoxy and methacryloyl groups at the ends, that is: CH2 = C (CH3) C00 (CH2CH2O) nCH3, where n is about 8.

PEG 150Mat, PEG1000 Mat, and PEG 2,000 Mat are similar polyethylene oxides having molecular weights of 150, 1,000, and 2,000, respectively.

The Polymer Mil polymer was prepared under the conditions described in the example of EP 182 523 except that hydroxy-terminated PEG was used instead of amino-terminated PEG.

Loeffler's methylene blue 95% ethyl alcohol (30 mL), methylene blue 25 (0.3 g) and water (100 mL).

Examples 1-2 These examples show that Polymer 93W polymer retains its anti-adhesive properties in the presence of adsorbed chlorhexidine.

30 Hydroxyapatite wafers were treated with 1% (w / w)

Polymer 93W solution and then with certain antibacterial agents for certain periods of time. The discs thus treated were immersed in a bacterial suspension (30 ml) in a petri dish for two hours. The discs were removed from the bacterial suspension 35 and washed by dipping and shaking five times in a vessel containing running water. Bacteria adhering to the discs were stained using Loeffler methylene blue. The reduction in bacterial adhesion was determined by microscopic examination.

5

Table I

Example Antibacterial Polymer Anti-adhesion% No._substance_ CT1 0 1% 93 W 99 10 1 C 1% 93 W 99 2 A 1% 93 W 99 CT1: 1% 93 W was used alone C: 1% chlorhexidine A: 1% alexidine 15 It can be seen from Table 1 that chlorhexidine and alexin do not reduce the anti-adhesive properties of the Polymer 93W polymer blended on hydroxyapatite wafers.

"% Adhesion" ("% AA") is defined by the equation: 20 ^ / Bacterial-covered ^ - f Bacterial-covered \ [bare surface j (polymer-coated) V surface area J Vsurface area /% AA 1_ / 25 / Bacterial covered \ f bare surface surface)

Vala J

It is to be understood that (a) when the polymer does not reduce the surface area covered by the bacteria, it is:

X - X

% AA = - k 100 = 0

X

And (b) when the polymer prevents bacteria from adhering to the surface i ’is

- O

% AA * - x 100 = 100

40 X

17 93691

Similar results were obtained when the material commonly used in the manufacture of dentures was treated with Polymer 93W polymer and chlorhexidine and then exposed to Streptococcus mitior NCTC 7864.

Examples 3-5 These examples show that on the hydroxyapatite surface the antibacterial effect of chlorhexidine at certain concentrations is increased when used in the presence of Poly-10 mer 5 93W polymer.

Chlorhexidine solutions were absorbed onto sterile hydroxyapatite discs treated with Polymer 93W polymer. S. mutans cells were taken from the fermentor and diluted 100-fold in BHI agar at 40 ° C.

15 Inoculated agar was placed on top of HAP discs.

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

Since the surface of each hydroxyapatite disc was brought into contact with an equal number of bacteria in each case, the anti-adhesion did not affect the observed result, that is, only the antibacterial effect was measured. The results in Table 2 show that the combination of Polymer 93W polymer and chlorhexidine increased the antibacterial effect compared to chlorhexidine alone at the same chlorhexidine concentration used.

In comparative experiments, CT 2, 3, 4, and 5 wafers were not treated with Polymer 93W polymer. Comparative Experiment 2 is a blank test; In Comparative Experiment 30A, the wafer was treated with Polymer 93W polymer only.

«·« 18 93691

Table 2

Example Chlorine Treatment Polymer Bacterial No._hexidine Content with 93W Polymer Rich Growth 5 CT2 0 No 10 CT2A 0 Yes 10 CT3 1 No 8 CT4 0.1 No 10 CT5 0.01 No 10 10 3 1 Yes 0 4 0.1 Yes 2 5 0.01 Yes 4

Examples 6-9 These examples demonstrate results that combine anti-adhesive and anti-bacterial growth effects and can be obtained using a combination of polymer and chlorhexidine, and that such a combination enhances the effect of the individual components alone.

Sterile hydroxyapatite wafers were treated with 1% (w / v) Polymer 93W polymer solution and then with solutions containing specified concentrations of chlorhexidine. The discs were incubated in freshly collected coconut for one hour at 37 ° C and washed by immersion and shaking five times in a vessel containing running water. Excess water was removed from the surface of each disc by touching its edge with filter paper.

BHI agar containing 0.04% (w / v) bromocresol-30 green (to visualize bacterial growth on white hydroxyapatite discs) was pipetted onto the discs at 40 ° C to form a thin agar film on the surface.

The discs were incubated at 37 eC overnight. The results are shown in Table 3.

In Comparative Experiments 6-10, treatment with Polymer 93W was omitted. In Comparative Experiment 11, Polymer 93W polymer was used without chlorhexidine.

19 93691

Table 3

Pre- Chlorohexylene- Polymer 93W- Bacterial marker dine polymer growth 5 No. concentration (%) present% _ CT6 1 No No growth 6 1 Yes No growth 10 CT7 0.1 No Control level 4 7 0.1 Yes No growth 15 CT8 0.01 No Control level 5 8 0.01 Yes A few colonies; more than 99% reduction compared to control level 5 CT9 0.001 No Control level 6 9 0.001 Yes 99% reduction 25 compared to control level 6 CT10 0 No Thick growth:

Control level 7 30 CT11 0 Yes 90% reduction compared to control level 35 of CT7

It can be seen from Table 3 that at certain chlorhexidine concentrations, e.g. 0.01 and 0.001%, the presence of Polymer 93W increases its bactericidal and / or antibacterial activity. CT11 shows a reduction in 40 bacterial growth due to the anti-adhesion properties of the polymer alone.

Examples 10-20 These examples reveal that treatment of hydroxyapatite wafers with certain polymers 45 a) increases the amount of chlorhexidine absorbed therein and 20 93691 b) improves the retention of absorbed chlorhexidine during subsequent washing treatments.

Preparation of polymers B3 1a B18

Methacryloyl chloride (0.58 moles) was added over 2 hours to a mixture of toluene (600 mL), Jeff "360" or "2,070" (0.5 moles) and 2,6-lutidine (0, 56 moles), and bath cooling. A copious white precipitate formed. The reaction mixture was allowed to stand for three 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. The products (yield 80-90%) were characterized using infrared and proton magnetic resonance / spectroscopy.

The amino-terminal products obtained from both reactions (having terminal butoxy or methoxy groups from "360" and "2070", respectively) were separately converted to their N-methacrylooyl derivatives and co-polymerized with methacrylic acid in EP 0 182 20 523A as an example. conditions.

The hydroxyapatite wafers were pre-equilibrated in doubly distilled water for one hour. The discs were removed from the water, wiped dry and kept at room temperature for 30 minutes. UV-reflectance Sean was performed.

The optical density at 266 nm was typically about 0.9. The disc by O.D. differed significantly from this figure, was rejected.

Acceptable discs were immersed in 1% (w / w, IMS: water 1: 1) polymer solution for five minutes. The discs were removed from the polymer solution, washed by dipping and shaking five times in a vessel containing running water, wiped dry, left to stand for 30 minutes and measured.

35 21 93691

Each polymer-coated disc was immersed in aqueous chlorhexidine solution (0.02%, w / v, 15 mL) for one 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) wash tank, (1,200 ml) for one hour, wiped dry, allowed to stand for 30 minutes and measured. 1 22 9 3 6 91 Π3

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Table 5

Polymer A B Molar ratios

Body Side Chain - Nature Mol. weight A; B CHR1 CHR2 0:> (Source) CO, Η groups 73 Alkaline (DMAEM) PEG 350 3: 1 10 B12 Amphoteric PEG 350 1.9: 1.1: (EARTH: DMAEM) 62 Acidic (EARTH) PEG 150 3: 1 1: 1 86 Hapan (MAA) PEG 350 3.5: 1 2,3: 1 93W Hapan (MAA) PEG 350 6: 1 1,3: 1 15 66 Hapan (MAA) PEG 1000 3: 1 7 , 7: 1 B9 Hapan (MAA) PEG 1000 25: 1 0.9: 1 58 Hapan (MAA) PEG 2000 10: 1 4.5: 1 B3 Hapan (MAA) Jeff 360 6: 1 1.1: 1 20 BIO Acid (MAA) Allyl PEG 350 6: 1 1.3: 1 B18 Acid (MAA) Jeff2070 34: 1 1.2: 1 B17 Acid (MAA) PPG 1000 17: 1 1: 1 MH Acid (MAA) PEG 350 5: 1 0.9: 1 25 ---- 1 DMAEM: N, N-dimethyl-2-aminoethyl methacrylate.

COUNTRY: Methacrylic acid MA: Maleic acid PEG: Polyethylene glycol 3 ^ PPG: Polypropylene glycol;

Jeff 360: n-C4H9 (OCH2CH2) 4OCH2CH (CH3) OCH2CH (CH3) NH2;

Jeff 2070: CHo0CH „CH-O (CH„ CH0) CH.CH (CH,) NH0 ill l n 2 il

35 R

24 93691 where n is a number such that "2070" has a molecular weight of about 2,000 and R = H or CH3 in a ratio of about 7: 3; allyl-PEG 350: ethoxylated allyl alcohol. With the exception of B10, methacrylate or methacrylamide derivatives in which side chains shown were in the form of general structure B. BIO: contains terminal hydroxy groups.

The above UV scanning measurement was performed using a Unica SP1750 ultraviolet spectrophotometer.

It determined the “differences in op-10 density” shown in Table 4.

It can be seen from Tables 4 and 5 that the acidic polymers would significantly increase the amount of chlorhexidine adsorbed. Many acid polymer coated hydroxyapatite surfaces absorb more chlorhexidine from a 0.02% (w / v) solution than a bare hydroxyapatite surface from a 2% (w / v) chlorhexidine solution, i.e., more than a 100-fold improvement was observed. Alkaline (Polymer 73) or amphoteric (Polymer B12) polymers did not increase the amount of chlorhexidine absorbed. 20 Polymethacrylic acid also did not increase the amount of chlorhexidine absorbed, indicating that the PEG (or PPG) chains, not the carboxyl groups, correspond to the observed effect.

The results of the washing experiments showed that after one hour 25, about 23% of the initially adsorbed chlorhexidine was still adsorbed on the bare hydroxyapatite wafers, while the polymer-treated wafers had about 80%. After washing overnight on bare HAP wafers, the amount of adsorbed chlorhexidine remaining, if any, was below the detection limit and about 50-60% of the amount of chlorhexidine originally adsorbed on the polymer-treated wafers remained adsorbed. Thus, polymer-treated wafers adsorbed more chlorhexidine than bare wafers, and chlorhex-35 didine was also more difficult to rinse off their surface.

25 93691

Examples 21-29 These examples, together with Examples 10-20 and 6-9, show an increase in antibacterial properties (at a certain chlorhexidine content) without increasing the expected staining.

General method

The hydroxyapatite wafers were pre-equilibrated in doubly distilled water for one hour. The pre-equilibrated wafers were immersed in a 1% (w / v) solution of polymer ve-10 or IMS: water (1: 1) for five minutes. They were removed from the polymer solution and washed by dipping and shaking five times in a vessel containing running water. The washed discs were then immersed in 15 ml of an aqueous solution of chlorhexidine (the pi-15 concentrations are shown in Table 6) for five minutes. The discs were removed from the chlorhexidine solution and immersed in 15 ml of tea solution for one hour at room temperature. The discs were removed from the road solution and washed as described above. The steps were immersed in chlorhexidine and tea solutions and the washing was repeated three times using fresh chlorhexidine and tea solutions each time. After these three cycles, the discs were immersed in the road solution overnight, after which they were washed as described above, allowed to dry at room temperature for one hour, and the amount of color formed on the disc was determined.

The tea solution was prepared by adding 500 ml of boiling water to two tea bags. The tea bags were removed after five minutes and the tea was allowed to cool to room temperature. The tea was filtered through normal filter paper and kept at 4 ° C before use.

Stained wafers prepared by the general method were measured using a UV / visible light-reflectance photometer, as in Examples 10-20, and compared to teenol experiments (i.e., no adsorbed chlorhexidine). Figure 1 shows the typical 26 93691 UV spectra obtained. In Figure 1: a = bare hydroxyapatite disc? b = teenoll test jac, d and e * tea / chlorhexidine treatments with chlorhexidine contents of 0.002%, 0.02% and 0.2%, respectively.

5 The polymers listed in Table 6 (the chemical composition of which is given in Table 5) were evaluated for their effect on chlorhexidine-induced discoloration in the presence of tea. The polymers were separately adsorbed from 1% (w / v) IMS / water (1: 1) solutions. 0.2%, 0.02% and 0.002% aqueous chlorhexidine solutions were used. The discs were measured using a UV / visible light-reflectance spectrophotometer and the O.D. at 266, 410 and 510 nm were measured. The O.D.s of the bovine experiments were also measured at these wavelengths and these values were subtracted from disks treated with chlorhexidine or polymer / chlorhexidine combinations. Table 6 gives the results at 510 nm.

They are expressed as ratios relative to the color formed by the teen zero test - 1.0. Similar results were obtained at wavelengths of 266 nm and 410 nm. In CT18, the polymer was omitted, that is: chlorhexidine alone was used.

II

27 93691

Table 6

Comparative development of discoloration compared to "natural" ^ formation when exposed to road solutions.

Example Polymer O.D. ratio compared to "natural" No. of staining at 510 nm with chlorhexidine contents used 10 ___ 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 15 23 86 4.48 3.26 1.0 24 93W 4.98 2.79 1.0 25 B9 4.75 3.09 <1.0 26 B3 4.39 3.34 1.0 27 BIO 4.76 3.34 <1.0 20 28 B18 4.20 3.12 <1.0 29 B17 5.03 2.95 <1.0 _________l

It can be seen from Table 6 that at two higher-25-chlorhexidine concentrations (i.e., 0.2 and 0.02%), the presence or nature of the polymer did not substantially affect the amount of color formed during HAP wafer treatment. The lowest chlorhexidine content used (this is: 0.002%) in most examples has a clear reduction in discoloration equal to or less than the minimum levels associated with the road solutions when exposed to HAP wafers. However, it should be understood from the results of Examples 10-20 and 6-9 that in order to obtain approximately the same staining as in the controls, the polymers had more chlorhexidine absorbed on their surface and had an increased antibacterial effect.

Examples 30-31 These examples illustrate the increase in the amount of chlorhexidine adsorbed on the surface of a hydroxyapatite disc treated with a mixture of chlorhexidine and a Po-5 lymer 93W polymer compared to the treatment of a HAP wafer with chlorhexidine alone.

An IMS solution (2%, w / v) of Polymer 93W was mixed with a suitable solution of chlorhexidine in water (0.04%, w / v) in a solution ratio of 1: 1 by volume. The hydroxyapatite disks were allowed to stand in the mixture for one hour, after which they were washed five times with water. The amount of chlorhexidine absorbed on the discs was determined by UV-ref-15 lecture spectrometry as described in Examples 10 to 20 (optical density was measured at 266 nanometers).

In Comparative Experiments 20 and 21, the wafers were treated for one hour with 0.2 and 0.02% chlorhexidine solutions, 20 with a 1: 1 mixture of industrial methylated alcohol and water, respectively.

The results are shown in Table 7. It can be seen from Table 7 that treatment of HAP with the Polymer 93W polymer / chlorhexidine blend results in more chlorhexidine being absorbed compared to the chlorhexidine solution alone.

Table 7

Pre- Added Chlorohex- Addition optical- sign composition in dine-containing density no_world% w / v at 266 nm * 30 Mixture 0.2 0.44 31 Mixture 0.02 0.12 CT19 Chlorine 0.2 0 35 hexidine solution CT20 Chlorine alone 0.02 0.0 hexidine solution • · «29 93691

Examples 32-33 These examples illustrate the increased "lethality" of the Polymer 93W polymer / chlorhexidine blend compared to the chlorhexidine solution alone.

The wafers prepared in Examples 30 to 31 were washed overnight in water and subjected to a S. mutans agar coating test. They were placed in a petri dish and covered with BHI agar (25 ml). A suspension of S. mutans (100 μΐ) grown in a fermentor (as described above) diluted 100-fold in Ringer's saline was pipetted onto agar and spread evenly. Bacteria were grown overnight at 37 ° C, bacterial "fields" and bacterial-free "bright zones" were observed and measured. The results are shown in Table 15 8. Bright zones, this means: areas where no growth occurred are expressed as a percentage of the disc area.

Table 8 20

Pre- Disc, finished- Chlorhex-% disc area-labeled with exemplin content with no growth in cat No._of%% w / v_nothed 32 30 0.2 225 25 33 31 0.02 64 CT21 CT19 0.2 3 CT22 CT20 0.02 0

It is to be understood that when the “% of the area of the disc at which no growth occurred” is greater than 100, this indicates that the inhibition spread to the agar layer outside the circumference * of the disc.

It can be seen from Table 8 that the antibacterial activity of the mixture was increased compared to chlorhexidine alone.

9 · • · 30 93691

Examples 34-65 These examples show that the combination of an anti-adhesive compound, Polymer 93W polymer, and chlorhexidine reduces the amount of staining compared to chlorhexidine alone on many different surfaces present in the oral environment. The surfaces were a tooth, filler materials, e.g., Occlus and Opalux, and a methacrylate-based resin commonly used in the manufacture of dentures (hereinafter referred to as "PR" for convenience).

Samples The remaining meat was removed with scalpel from the newly removed teeth, after which the teeth were tumbled for 20 minutes in 50% sodium hypochlorite-15 solutions and washed from the surface with distilled water. These teeth, as well as the patch-containing teeth, were sonicated in alcohol for 10 minutes, after which they were dried.

DR samples (25 mm x 10 mm x 3 mm) and discs made from the above spot fill materials were washed in alcohol and dried.

Solutions: a) 1% and 0.5% Polymer 93W polymer solution (1 g) in a mixture of industrial methylated alcohol (50 ml) and water (50 ml).

B) chlorhexidine solutions (0.2%, 0.02% and 0.002%) in water.

c) Appropriate blends of Polymer 93W polymer and chlorhexidine were obtained by mixing equal volumes of the solutions of (a) and (b) to obtain the concentrations mentioned in the following tables.

.. d) Human saliva was obtained by sampling • (20 ml) from each of the six volunteers, centrifuging the saliva for 20 minutes at 25,000 rpm and combining the saliva.

35 1

II

«•« 31 93691 e) A tea solution was prepared by boiling a commercial tea grade sample (8 g) in distilled water (80 ml) for two minutes, cooling the product to room temperature and filtering the remaining tea leaves.

5 Evaluation

Each surface was treated with a saliva sample for 10 minutes. Excess saliva was washed away.

In Examples 34-49, the surface was first treated for 10 minutes, washed with distilled water, treated 10 times for 10 minutes, rinsed and then immersed in the tea solution for one hour, the process repeated, the sample left in the tea solution overnight and the whole process repeated every day for five days.

In Examples 50-65, the above five-day procedure was repeated, except that the first treatment lasted five minutes and the second treatment was omitted, the samples were treated with appropriate blends of Polymer 93W polymer and chlorhexidine.

The discoloration of the surfaces was visually compared to 20 of the same surface treated with water only and evaluated on the following scale.

Scale 0: no color (this means: the water control is considered zero even if it showed a slight darkening); 25 1: faint color; : 2: reasonable color; 3: strong color; and 4: very intense color.

In Tables 9, 10, and 17, 30 OC 1 occlusin

OP - opalux T tooth PR - prosthetic resin A 0.5% polymer 93W 35 AA - 1% polymer 93W

• · 93691

-----— I

32 B = water X = 0.1 chlorhexidine XX = 0.2% chlorhexidine Y = 0.01% chlorhexidine 5 YY = 0.02% chlorhexidine Z = 0.001% chlorhexidine ZZ = 0.002% chlorhexidine W = 0.0001% chlorhexidine> · • · 33 9 3 6 91

Table 9 --r ---

Example Surface Treatments Stage No. ** First Second or single (10 min) (10 min) CT23 OC B 0 10 CT24 OP B 0 CT2 5 TB 0 CT26 PR B 0 CT27 OC X 3 CT28 OP X 3 15 CT29 TX 3 CT30 PR X 3 CT31 OC AA 0 CT32 OP AA 0 CT33 T AA 0.

20 CT34 PR AA 0 34 OC AA XX 3 35 '' '* YY 1 36' '' 'ZZ 0.: 25 CT35 *' B XX 3 CT36 '' '' YY 2 CT37 '' "ZZ 1 37 OP AA XX 4 30 38 "'' YY 2 • · 39 '*' 'ZZ 0 CT38' 'B XX 3 CT39"' 'YY 2 _ T7 34 9 3 6 91

Table 9 (continued) I-1-1-1-i

Example Surface j Treatments Scale No. \ ^ First or Second j single (10 min) j (10 min) CT40 OP B ZZ 1 10______ 40 T AA XX 4 41 '' * 'YY 2 42' 1 ”ZZ 0 CT41” B XX 3 15 CT42 * ' '' YY 2 CT43 '' '' ZZ 1 43 PR AA XX 4 44 '' '' YY 2 20 45 ·· '· ZZ 0 CT44' 'B XX 3 CT4 5' '' 'YY 2 CT4 6' '' 1 ZZ 1: 25 46 oc XX AA 0 47 OP '·' '0 48 T ·' '· 0 49 PR' '*' 0 • · ««

Table 10 35 93691

Example Surface Treatment Scale No. (mixture for 5 min) 5______ CT47 OC B 0 CT48 OC X 4 CT49 OC Y 3 CT50 OC Z 1 10 CT51 OC W 1 CT52 OC A 0 50 OC A + Y 2 51 OC A + Y 0 52 OC A + Z 0 15 53 OC A + W 0 CT53 OP B 0 CT54 OP X 4 CT55 OP Y 3 20 CT56 OP Z 1 CT57 OP W 1 CT58 OP A 0 54 OP A + X 4 55 OP A + Y 3! , ... 25 56 OP A + Z 1 57 OP A + W 1

Table 11 36 ^ 3691

Example Surface Treatment Scale 5 (mixture for 5 min)

i ------ I

CT59 TB 0 CT60 TX 4 CT61 TY 3 10 CT62 TZ 1 CT63 TW 1 CT64 TA 0 58 T A + X 2 59 T A + Y 0 15 60 T A + Z 0 61 T A + W 0 CT65 PR B 0 CT66 PR X 4 20 CT67 PR Y 2 CT68 PR Z 1 CT69 PR W 1 CT70 PR A 0 62 PR X 2 25 63 PR Y 0 64 PR Z 0 65 PR A + W 0 | It can be seen from Table 9 that at a low chlorhexidine content (e.g. 0.002%) the discoloration of the patch material, tooth or prosthetic resin is reduced if their surface is first treated with a particular polymer. It can further be seen (Examples 46-49) that when surfaces are treated with chlorhexidine solution and then

II

93691 37 ten Polymer with 93W polymer, the staining decreases to the control level.

Table 10 shows the results obtained when treating Occlusin and Opalux surfaces with mixtures of chlorhexidine-5 and Polymer 93W polymer. Occlusin surface discoloration is significantly reduced to control levels with a chlorhexidine content of 0.01% or less; a similar direction is seen on the Opalux surface.

Table 11 shows the results obtained by filling the tooth surfaces and prosthetic resin with a mixture of chlorhexidine and Polymer 93W polymer. The direction of reduction of discoloration is similar to that of Occlusin and Opalux surfaces.

When a tooth with an Occlusin site was evaluated as described above, the tooth and site stained slightly, but to the same extent, so that the site boundary further weakened. 1 * <

Claims (12)

An oral hygiene composition, characterized in that it contains (i) an effective amount of at least one cationic antibacterial agent, which is benzalkonium chloride, bispyridinamine or polybiguanide; and (ii) an effective amount of at least one polymer having open polyalkylene oxide side chains and containing one or more repeating units of the general structure A - L 15 f (CO 2 hT 2) and one or more repeating units of the general structure B where 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 equal or various, are hydrocarbons, or substituted hydrocarbon groups and form the backbone of the polymer; Z is -CHR 3 CHR 2 - or - (CH 2) B-, where Z is -CHR 1 -CHR 2 - R1, which is in the same repeating unit in structure B (di n or g is 2 or more) or in different repeats units in structure B may be the same or different, are hydrogen or a hydrocarbon group; and «43 9 3691 R2, which in the same repeating unit in structure B (dd n or q is 2 or more) or in different repeating units in structure B, may be the same or different, is hydrogen or a hydrocarbon group; except that R1 and R2 in a single unit -CHRx-CHR2-0- cannot both be hydrocarbon groups; R3, which in the same repeating unit in structure B (dl n or g is 2 or more) or in different repeating units in structure B, may be the same or different, is hydrogen or a hydrocarbon group or an acyl group derived from an alkanoic acid having to five carbon atoms; m, where present, is a tai 2 - 10; n is a tai 1-60; p is a tai 1-4; and q is a tai 1-4; each (CO 2 H) group is joined via an intermediate group or groups L to the hydrocarbon group X, and in those cases where p is 2 to 4 may be joined by L to the same or different carbon atom in X; 20. may be the same or different in the repeating units of structure A and may be one or more direct bonding groups or one or more atomic groups, each group constituting a chain of one or more atoms, for coupling one (CO 2 H) - group to X, except that more than two. (CO 2 H) groups cannot be directly linked to the same carbon atom in X; each (ZO ^R ^ group is joined via an intermediate group or groups M to the hydrocarbon group Y, and in cases where q is 2 to 4, may be joined by M to the same or different carbon atoms in Y; M may be equal or different in the repeating units of structure B and may be one or more direct bonding groups or one or more atomic groups, each group constituting a chain of one or more atoms, to copy one (Z0) n group to Y, except that more than two (Z0) 2 - <44 93691 groups cannot be directly linked to the pure carbon atom 1 Y; the ratio of the number of -CO 2 H groups to the number (ZO) groups, especially where Z is -CH 2 CH 2 -, is in the range of 1:20 - 20: 1. An oral hygiene composition according to claim 1, characterized in that the cationic antibacterial agent is polybiguanide or a salt thereof. 3. Oral hygiene composition according to claim 2, characterized in that the polybiguanide is bisbiguanide. An oral hygiene composition according to claim 3, characterized in that the bisbiguanide is chlorhexidine. 5. An oral hygiene composition according to claim 1, characterized in that Z is -CHR 2 CHR 2 - and both R 1 and R 2 are hydrogen. 6. An oral hygiene composition according to claim 1, characterized in that R 3 is methyl. An oral hygiene composition according to claim 1, characterized in that L, in structure A, is a direct bond -CH2-, -CH2-CH2-, -CH2-CH =, -NH-CO-, -CONHCH ( CH3) - or -CONHCH (OH) - An oral hygiene composition according to claim 1, characterized in that p, in structure A, is 1 or 2. An oral hygiene composition according to claim 1, characterized in that M, in structure B, is -C00-30 or CONH-. :. An oral hygiene composition according to claim 1, characterized in that q, in structure B, is 1 or 2. Oral hygiene composition according to claim 1, characterized in that A or B is a recurring unit obtainable by the addition polymerization of a polymerizable olefinically unsaturated carboxylic acid or an ester and an amide derivative thereof. Oral hygiene composition according to claim 1, characterized in that the polymerizable, olefinically unsaturated carboxylic acid is acrylic acid or methacrylic acid. ··