LU87430A1 - COMPOSITION FOR ORAL HYGIENE - Google Patents

Description

Composition for oral hygiene

The present invention relates to oral hygiene compositions and methods of using these compositions to prevent or inhibit the growth of bacteria on dental surfaces.

The prevention of the member deposit of. dental plaque on the teeth of mammals (especially humans) is a highly desired result.

Dental plaque is formed when cariogenic bacteria and other types collect in colonies on the surface of the teeth and form a deposit that adheres tenaciously to the surface. · The deposit of plaque on the surface of a tooth is believed to be -on, one of the first stages of the development of dental caries and periodontitis.

Many attempts have been made to prevent the deposition of plaque on dental surfaces and to effect the removal of plaque from these surfaces. For example, the use of brush and dental floss and the use of oral irrigators and interdental stimulators have been tried. However, these treatments are not perfectly satisfactory and often have to be supplemented by periodic treatment at the dentist.

In its recently published European patent no. 0.182.523A, the Applicant indicates that certain pharmaceutical compositions (as defined therein) are highly effective in preventing or significantly weakening (a) colonization of dental surfaces or dental surfaces simulated by micro cariogenic and other organisms frequently found in the oral environment and (b) the adherent deposit, on dental surfaces, of dental plaque produced by these microorganisms.

The preparation of polymers for use in the abovementioned pharmaceutical compositions is described in document EP 0.182.523A, the content of which is incorporated herein by reference.

Chlorhexidine is a cationic antiseptic that has been widely used in the medical profession as a topical antibacterial agent for over 20 years; and its preparation is described in document UK 705.838. It has been reported (Loe et al, Journal of Periodontal Research, 1970, Vol 5, pages 79-83) that chlorhexidine can be used as an antiseptic in the oral environment and that under certain circumstances chlorhexidine, apparently tends to alter the staining of teeth. This discoloration turns out to be a property common to cationic antiseptics. He demonstrated (Addy et al, Journal of Periodontal Research, volume 9, pages 134-140) that this discoloration is the result of an interaction between the cationic antiseptic and the components of the diet, in particular those rich in tannin, for example coffee, tea or red wine.

We have now discovered that when certain surfaces, for example teeth or hydroxyapatite, are treated with a combination of (a) a polymer, as defined below, which carries certain poly chains (alkylene oxide) while (b) from a cationic antibacterial agent, the resulting treated dental surfaces surprisingly exhibit both improved anti-adhesive and anti-bacterial properties with respect to certain microorganisms in the mouth, ie that is to say, this combination can effectively control the so-called "biological" staining of dental surfaces. In fact, in the presence of this polymer, equivalent antibacterial effects can be observed when the dental surface is treated with a solution of the antibacterial agent at a lower concentration. In addition, the Applicant has discovered with surprise (i) that the aforementioned tendency to color alteration with chlorhexidine is at least attenuated and that there is often no increase in the color alteration: the same when a greater amount of chlorhexidine is adsorbed on the dental surfaces in the presence of the abovementioned polymer; (ii) that the antibacterial properties of certain cationic antibacterial agents, for example chlorhexidine and alexidine, are accentuated on simulated dental surfaces if the surface is treated successively, or by means of a combination, of a polymer acid, for example the polymer 93W (as defined below) and the abovementioned agent; and (iii) that when composite restorations, for example with Occlusion (product brand), Opalux, Silux and Valux P50, etc. tend to undergo a coloration alteration by cationic antiseptics, this alteration coloring is at least attenuated in the presence of the aforementioned polymer. It should be noted that reducing at least this alteration in coloring of the anterior teeth is particularly desirable.

The subject of the present invention is a composition for oral hygiene which comprises: (i) an effective amount of a cationic antibacterial agent; and (ii) an effective amount of at least one polymer, as defined below, which comprises one or more pendant poly (alkylene oxide) radicals.

As examples of cationic antibacterial agents which can be used according to the present invention, there may be mentioned, inter alia, benzalkonium chloride, bispyridinamines, for example octenidine, or preferably a poly-biguanide, for exampleexidine, or more advantageously a bis-biguanide, for example chlorhexidine.

By "polybiguanide" is meant a compound which comprises several biguanide chain residues of the general formula I

or their tautomers. There are often two, three or four of these chain residues in the antibacterial agent used in the present invention. However, the Applicant does not exclude the possibility that there may be enough of them to provide at least the major part of the repeating units of a polymer of higher molecular weight, for example a molecular weight up to approximately 10,000.

It should be noted that when a polybiguanide is used in the present invention, it may be present in the free base state, but it is preferably present in the salt state, for example acetate or hydrochloride, or more advantageously, in particular when the polybiguanide is a bis-biguanide which has the structure indicated in general formula II, in the state of digluconate, namely the digluconate of 1,6-di- (4-chlorophenyl- diguanido) hexane, which is known in the art under the name of chlorhexidine.

The Applicant does not exclude the possibility that when a polybiguanide, for example chlorhexidine, in the form of a free base is used in the present invention, it may be in a mixture (for example in the state of salt) on dental surfaces in the state of salt with an acidic polymer as defined below.

As possible explanations for the increased antibacterial effect of the composition for oral hygiene of the present invention, the Applicant suggests, but without wishing to be bound by the hypothesis: (i) an increase in the amount of chlorhexidine adsorbed on the surface dental; and / or (ii) a modification of the adsorption force of chlorhexidine on the dental surface such that it is more available to exert its antibacterial effect on the surface; and / or (iii) a modification of the orientation of the chlorhexidine adsorbed on the dental surface such that the antibacterial radicals are more accessible for the bacteria which approach it; and / or (iv) an ion pairing between the cationic antibacterial agent and the acid anions, if any, of the polymer.

In the composition according to the present invention, multiple hydrogen bonds between the polymer and the biguanide cations can contribute to the abovementioned increase in the quantity or in the modification of the adsorption force or of the orientation.

The polymers from which the compositions for oral hygiene in accordance with the present invention are formed are preferably acidic, the term by which is meant that there is at least one carboxylic acid radical pendant on the polymer backbone. However, the Applicant does not exclude the possibility that the polymer may be amphoteric, basic or neutral, although this is not preferred.

The pendant poly (alkylene oxide) radical (s) carried by the polymers from which the compositions for oral hygiene in accordance with the present invention are preferably formed by ethylene oxide radicals. However, the Applicant does not exclude the possibility that at least some of them may alternatively be poly (lower alkylene oxide) radicals, for example poly (propylene oxide).

As examples of polymers from which the compositions for oral hygiene in accordance with the present invention are formed, mention may be made, among others, of polymers which comprise one or more recurring units of general structure A

and one or more recurrent units of 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 the same or different, are substituted hydrocarbyl or hydrocarbyl residues, constituting a skeleton for the polymer; 1 2 Z represents -CHR -CHR - or - (CH «) -, where, when 1? ù m Z represents -CHR -CHR -, r \ which, in the same recurring unit of structure B (when n or q represents 2 or more) or in different recurring units of structure B, may be the same or different, is a hydrogen atom or a hydrocarbyl radical; and 2 R, which in the same repeating unit of structure B (when n or q represents 2 or more) or in repeating units, different of structure B, may be the same or different, is a hydrogen atom or a radical hydrocarbyl; 12 12 except that R and R in a single unit -CHR -CHR -0- cannot both be hydrocarbyl radicals; 3 R, which in the same repeating unit of structure B (when q represents 2 or more) or in different repeating units of structure B, may be the same or different, is a hydrogen atom or a hydrocarbyl radical or else a acyl radical derived from an alkanoic acid having up to five carbon atoms; m, when 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 radical (CO ^ H) is united by one or more intermediates L to the hydrocarbyl residue X and in the case where p represents 2 to 4, can be united by L to the same carbon atom or to carbon atoms different from X; L can be identical or different in the recurring units of structure A and is chosen from one or more direct bonds and one or more groups of atoms, each group bringing a chain of one or more atoms to unite a radical (CC> 2H ) to X, except that more than two radicals (CC ^ H) cannot be directly linked to the same carbon atom in X; 3 each radical ((ZO) R) is united by one or more intermediate interiors M to the hydrocarbyl residue Y and in the cases where q represents 2 to 4, can be united by M to the same carbon atom or to atoms carbon other than Y; M can be the same or different in the repeating units of structure B and is chosen from one or more direct bonds and one or more groups of atoms, each group providing a chain of one or more atoms to unite a radical (ZO) ^ with Y, except that more than two radicals (ZO) n cannot be united directly with the same carbon atom in Y; the ratio of the number of radicals -CC ^ H to the number of radicals (ZO), in particular when Z is in the range from 1:20 to 20: 1.

1 2

Preferably, R and R, when present, are both hydrogen atoms.

1 2

When R or R is a hydrocarbyl radical, this is preferably a lower alkyl radical and more advantageously methyl.

3

Preferably, R is a lower alkyl radical and more advantageously methyl.

When Z is -, m is Pr® ^ ®rence 4; this allows easy preparation of - (ZO) ^ - from tetrahydrofuran.

It should be observed that the definition of the polymer contained in the composition (as given above) also aims to designate a polymer in which at least some of the carboxyl radicals in the recurring units of general structure A have been converted into the corresponding salified anions CC ^ (these being considered as -CC ^ H radicals insofar as it is the ratio of carboxyl radicals to radicals -Z0-), the corresponding cations being, for example, ammonium cations (NH ^), or cations of alkaline earth metals or, preferably, of alkali metals (for example Na +, K +). The Applicant does not exclude the possibility that the cation may originate from the cationic antibacterial agent itself; in fact, when the cationic antibacterial agent is present in the salt of the acid polymer so that there is substantially no free chlorhexidine in the mouth, the appearance of spots tends to be further reduced.

In general structure A, each carboxyl radical is united to the hydrocarbyl residue X by one or more intermediates (that is to say one or more linking entities), the latter or these being indicated by L which is chosen among one or more direct bonds (that is to say one or more direct valences) and one or more groups of atoms, each group providing a chain of one or more atoms to join one or more carboxyl radicals to x.

In cases where p is 2 to 4, each carboxyl radical can be united by L to the same carbon atom or, in cases where L represents more than one intermediate, to the same carbon atom or to different carbon atoms of X, although more than 2 carboxyl radicals obviously cannot be united directly to the same carbon atom of X (and also assuming that in such cases X contains at least 2 carbon atoms, although it should be observed that 'It is within the scope of the invention that X contains only one carbon atom). It should be noted that in principle L can represent up to four distinct intermediaries in structure A (in cases where p is 4). L can be the same or different in the recurring units of structure A.

In cases where L represents one or more groups of atoms, each group providing a chain of linking atoms, the chain normally includes one or more carbon atoms (which could, for example, include carbon atoms in a ring aryl) and / or heteroatom (in particular N and / or 0). Examples of possible linking systems provided by L are:

where (except in the case of the direct bond) the upper bond goes to X and the lower bond (s) go to carboxyl. In the present invention, it is however preferred that L is one or more direct bonds, so that each carboxyl radical is directly linked to a carbon atom of the polymer backbone.

In structure A, p is preferably 1 or 2 and more advantageously 1 (so that L can represent one or, at most, two intermediates).

3

In structure B, each radical (ZO) nR is joined to the hydrocarbyl residue Y by one or more intermediates (that is to say one or more linking entities), the latter or these being indicated by M which is chosen from one or more direct bonds (that is to say one or more direct valences) and one or more groups of atoms, each group providing a chain of one or more atoms for the bond of one or more radicals (ZO) RJ with Y. In n 1 3

the cases where q is worth 2 to 4, each radical (ZO) nR

may be united by M to the same carbon atom or in cases where M represents more than one intermediate, to the same carbon atom or to carbon atoms different from Y, although more than two radicals (ZO) nR obviously cannot be united directly to the same carbon atom of Y (and also assuming that · in such cases Y includes at least 2 carbon atoms, although it should be observed that it falls within the framework of the invention that Y contains only one carbon atom). M can be the same or different in the recurring units of structure B.

Although M can represent one or more direct bonds, it is preferred, in the present invention, that M represents one or more groups of atoms, each group providing a chain of linking atoms; such a chain normally comprises one or more carbon atoms (which could, for example, include carbon atoms in an aryl ring, for example benzyl ether) and / or heteroatom (in particular N and / or O). Particularly preferred examples of chains represented by M are:

where the upper bond goes to Y and the lower bond goes to (ZO) R.

η

In structure B, q is preferably 1 or 2 and more advantageously 1 (so that M can represent one or, at most, two intermediaries).

Preferably, structure A represents the repeating unit which can be obtained by addition polymerization (usually initiated by free radicals) of a polymerizable olefinically unsaturated carboxylic acid. Examples of such acids are maleic (or fumaric) acid, itaconic acid, the acids of the formulas

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

Preferably, structure B represents the repeating unit resulting from the polymerization (usually initiated by free radicals) of a polymerizable olefinically unsaturated ester or amide formed by the reaction of an unsaturated carboxylic acid (or of an esterifiable or amidifiable derivative of the latter such as an acid chloride or anhydride) and of a hydroxylated compound of formula HO (ZO) nR (for the formation of the ester) or of an amine of formula (for the formation amide).

Preferably, the acid from which the structure B can be derived is acrylic or methacrylic acid, in particular the latter, which gives rise, when an ester or amide derived from methacrylic acid is used, to the respective structures below. for B:

Preferably, the acid polymers from which the compositions for oral hygiene in accordance with the invention are formed have a ratio of the acid residues to the pendant poly (alkylene oxide) residues of approximately 6: 1 (where each side chain is a polyethylene glycol chain with a molecular weight of approximately 350, i.e. PEG 350).

The polymers to be used in the present invention are described in more detail in the aforementioned European patent No. 0.182.523A of the Applicant mentioned here by reference.

In the oral hygiene compositions of the present invention, the at least single polymer contained therein is typically at a concentration of about 0.05 to 30% by weight of the composition, the preferred concentration being about 0.1 to 5% by weight and more advantageously 0.2 to 2% by weight.

The concentration of the at least unique antibacterial agent in the oral hygiene compositions according to the present invention is approximately 0.001 to 10% by weight of the composition, the preferred concentration being approximately 0.001 to 1.0% by weight and more advantageously from 0.01 to 0.1% by weight.

Preferably, the mass of the polymer is greater than the mass of the antibacterial agent in the composition for oral hygiene according to the present invention. However, the Applicant does not exclude the possibility that there is more antibacterial agent than polymer.

The composition for oral hygiene of the present invention typically comprises a single polymer as defined above, although the Applicant does not exclude the possibility that two or more of these polymers are present in the composition.

Those skilled in the art are able, by simple experience, to formulate compositions in accordance with the present invention in which the ratio of the antibacterial agent to the polymer is such that this unwanted reaction is avoided.

The oral hygiene composition of the present invention typically comprises a pharmaceutically acceptable excipient which is compatible with the antibacterial efficacy of the cationic antibacterial agent, for example chlorhexidine. To maintain the effectiveness of chlorhexidine, it may be necessary to adjust the concentration of it in a particular excipient, an appropriate concentration which can be determined experimentally by a person skilled in the art.

Suitable conventional pharmaceutically acceptable excipients which can be used in the oral hygiene compositions of the present invention include water, ethanol (where water or a water / ethanol mixture is often a major component of excipient); humectants such as propylene glycol, isopropanol, glycerol and sorbitol; gelling agents such as cellulose derivatives, for example 1 * hydroxypropyl- or hydroxyethylcellulose, polyoxypropylene / polyoxyethylene block copolymers (called "Poloxamers"), for example Synperonic PE 39/70 or PEF 87; certain gel stabilizers such as 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 colorants and flavorings from the lists having EEC or FD&C approval. It should be observed that the aforementioned excipient is chosen so that it does not inhibit, in a disturbing manner, the effectiveness of the composition for oral hygiene in accordance with the present invention; in particular, an anionic agent, for example 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 pharmaceutically acceptable oral hygiene composition which contains (and is compatible with) an effective amount of a polymer and an antibacterial agent such as defined above. As examples of such compositions, mention may be made, inter alia, of mouthwashes, toothpastes, irrigation solutions, abrasive or non-abrasive gelled toothpastes, products for cleaning teeth, coated dental floss, coated or impregnated toothbrush bristles (natural or synthetic), interdental coatings or stimulators, chewing gum, lozenges, breath fresheners, foams and sprays.

The invention is illustrated by the examples below. The prefix "TC" in an example number indicates a comparison test.

In most of the examples below, the oral bacterium Streptococcus mutans NCTC 10449 is used as the reference bacterium. It is cultivated in brain and heart infusion (BHI) (company Oxoid) in a Bioflo model C30 fermenter.

A 750 ml jar containing 350 ml of the bacteria suspension is used. The bacteria are cultured at 37 ° C. at a dilution rate of 0.1 hr. An air flow rate of 0.24 liters / minute and a stirring speed of 300 revolutions / minute. A sample (about 20 ml) of the bacteria suspension from the fermenter is taken for each experiment. The bacteria are centrifuged for 10 minutes at 4000 rpm, they are resuspended in modified Ringer's saline (NaCl 0.54 g / liter; KC1 0.02 g / liter; CaC ^ 0.03 g / liter and sodium mercaptoacetate 0.75 g / liter), they are centrifuged again, they are resuspended and diluted (10 ×) in modified Ringer's saline. The approximate concentration of bacteria in diluted salt solutions g is 10 / ml.

Streptococcus mitior

NCTC 7864 is cultured in 100 ml of broth and heart infusion broth for 24 hours in a batch fashion. The culture is then centrifuged for 30 minutes at 3500 rpm, then the pellet is washed twice by resuspending it in physiological saline and centrifuging it. The suspension of bacteria is then adjusted to approximately 10-10 cells per ml.

In the other examples, total saliva is used.

Absorption surfaces

Hydroxyapatite disks are made by pressing hydroxyapatite powder (tribasic calcium phosphate Ca ^ iOH ^ iPO ^ g (Aldrich)) which is sintered at 1100 ° C. The discs are reused after heating in the oven at 900 ° C. for 2 hours between the experiments.

Application of polymers

The hydroxyapatite disks are treated for 2 minutes at room temperature using a solution (1% w / v) of a polymer, for example polymer 93W, in a 1: 1 mixture (by volume). industrial denatured alcohol and water. The discs are then washed by immersion and "stirring 5 times in a container under running water at about 15 ° C.

Application of the antibacterial agent

Aqueous solutions of chlorhexidine and solutions of alexidine in industrial denatured alcohol are adsorbed separately on various surfaces of hydroxyapatite discs which have been treated with the polymer when necessary (untreated discs being used in comparison tests). The discs are then washed and stirred 5 times in a container under running water.

Polymers

The polymer called here "polymer 93W" is an acidic polymer as described and prepared in Example 5 of the document EP.182.523 cited above. (Other "acid" polymers described below are prepared according to an analogous process). Polymer 93W includes residues of methacrylic acid and PEG350M.at in a molar ratio of 6: 1.

By "PEG350Mat" is meant a poly (ethylene oxide) with a molecular weight of approximately 350 which has been blocked at the ends by methoxy and methacryloyl radicals, namely

where n is approximately 8.

PEG150Mat, PEGlOOOMat and PEG2000Mat denote varieties of poly (ethylene oxides) having molecular weights of 150, 1000 and 2000 respectively.

The Mil polymer is prepared under the conditions described in Example 15 of document EP 182. 523, except that a PEG with terminal hydroxyl radicals is used rather than a PEG with terminal amino radicals.

Loeffler methylene blue

95% ethanol (30 ml), methylene blue (0.3 g) and water (100 ml).

EXAMPLES 1-2

The present examples demonstrate that the 93W polymer retains its non-stick properties in the presence of absorbed chlorhexidine.

Hydroxyapatite discs are treated with a 1% w / w solution of the 93W polymer, then with certain antibacterial agents for fixed times. The discs thus treated are then immersed in a suspension of bacteria (30 ml) in a Petri dish for 2 hours. The discs are removed from the bacteria suspensions and washed by immersion and stirring 5 times in a container under running water. The bacteria adhering to the discs are stained with Loeffler's methylene blue. By microscopic examination, the decrease in adhesion of the bacteria is determined.

The results are given in Table 1.

TABLE 1

It can be deduced from Table 1 that chlorhexidine and alexidine do not weaken the non-stick properties of the 93W polymer deposited on the hydroxyapatite discs.

The "anti-adhesion" ("AA")% is defined by the following relation:

It should be observed: (a) that when the polymer does not reduce the extent of the surface which is covered with bacteria, we have:

and (b) that when the polymer prevents the adhesion of bacteria to the surface, there is:

Similar results are obtained by subjecting a sample of a material of traditional use for the preparation of a dental prosthesis apparatus, as described below, to treatment with the polymer 93W and chlorhexidine, and then in exhibitor at Streptococcus mitior NCTC 7864.

EXAMPLES 3-5

The present examples demonstrate that on hydroxyapatite, the antibacterial effect of chlorhexidine at certain concentrations is increased when it is used in the presence of the polymer 93W.

Chlorhexidine solutions are absorbed on sterile hydroxyapatite disks which have been treated with polymer 93W. We take cells from S_. mutans in a fermenter and diluted 100 times in BHI agar at 40 ° C. The inoculated agar is poured onto the hydroxyapatite (PAH) discs.

The agar plates are incubated at 37 ° C overnight. The growth of bacteria is evaluated through the agar on a scale of 0 (no growth) to 10 (control).

Because the surface of each hydroxyapatite disc is in contact with the same number of bacteria in each case, the anti-adhesion effect does not contribute to the observed result, i.e. only the antibacterial effect is measured. The results collated in Table 2 reveal that the combination of the polymer 93W and chlorhexidine exerts an increased antibacterial effect in comparison with chlorhexidine taken alone, for the same chlorhexidine concentration.

In the TC 2, 3, 4 and 5 comparison tests, the discs are not treated with the 93W polymer. Comparison test 2 is a blank control and in comparison test 2A, the disc is treated only with the polymer 93W.

TABLE 2

EXAMPLES 6-9

The present examples illustrate the combination of anti-adhesive and antibacterial results which can be obtained by using a combination of a chlorhexidine polymer and demonstrate that such a combination offers an advantage over the use of the separate constituents taken in isolation.

Sterile hydroxyapatite discs are treated with a 1% w / v solution of the 93W polymer, then with chlorhexidine solutions in various concentrations. The discs are incubated at 37 ° C for 1 hour in freshly collected total saliva, then washed by immersion and stirring 5 times in a container under running water. Excess water is removed from the surface of each disc by touching the edge of the disc with filter paper.

Pipette of brain and heart agar containing 0.04% w / v bromocresol green (to make the growth of bacteria visible on white hydroxyapatite discs) at 40 ° C on the discs so as to form a thin layer of agar on the surface.

Discs are incubated at 37 ° C overnight.

The results are presented in Table 3.

In comparison tests 6 to 10, the treatment with the polymer 93W is omitted. In comparison test 11, the polymer 93W is used in the absence of chlorhexidine.

It can be deduced from Table 3 that for certain concentrations of chlorhexidine, for example 0.01 and 0.001%, the presence of the polymer 93W increases the bactericidal and / or bacteriostatic effect of chlorhexidine. Comparison test 11 demonstrates the reduction in bacterial growth which results from the non-stick properties of the polymer alone. EXAMPLES 10 - 20

The present examples demonstrate that the treatment of hydroxyapatite disks with certain polymers (a) increases the amount of chlorhexidine absorbed on the disks, and (b) improves the retention of the chlorhexidine absorbed throughout subsequent washing treatments.

Preparation of polymers B3 and B18

Methacryloyl chloride (0.58 mole) is added over 2 hours to a mixture of toluene (600 ml), Jeff "360" or "2070" (0.5 mole) and 2,6-lutidine (0, 56 mole) cooled in an ice bath. An abundant white precipitate is formed.

The reaction mixture is left to stand for 3 hours and the white precipitate is filtered off and washed with toluene. The filtrate is evaporated under reduced pressure and the residue is maintained under vacuum to remove the volatile constituents. The products are characterized (yield of 80-90%) by infrared spectroscopy and proton magnetic resonance.

The products with terminal amino radicals of the two reactions are converted (with butoxy or methoxy radicals provided by "360" and "2070" respectively) separately into their N-methacryloyl derivatives and they are copolymerized with methacrylic acid under the conditions described in Example 11 of document EP 0.182.523a.

Hydroxyapatite disks are brought to pre-equilibrium in double distilled water for 1 hour. The discs are removed from the water, dried by wiping and stored at room temperature for about 30 minutes. A scan of their reflectance in the UV is carried out. Their optical density at 266 nm is typically around 0.9. Any disc having an optical density significantly different from this value is rejected.

The acceptable discs are immersed for 5 minutes in a solution (l: l / industrial denatured alcohol / water) at 1% w / w of the polymer. The discs are removed from the polymer solution, washed by immersion and stirring 5 times in a container under running water, dried by wiping, allowed to stand for 30 minutes and subjected to scanning examination .

Each of the polymer-coated discs is immersed in an aqueous solution (15 ml) of chlorhexidine (0.02% w / v) for 1 hour. They are washed as described above, allowed to stand for 30 minutes and subjected to scanning examination.

They are then placed in a flow-through wash basin (1200 ml) (250 ml / minute) for 1 hour, then dried by wiping, allowed to stand for 30 minutes and subjected to scanning examination.

Notes to Table 5 MDMAE: N, N-dimethyl-2-aminoethyl methacrylate ΑΜΑ: methacrylic acid AM: maleic acid PEG: polyethylene glycol PPG: polypropylene glycol

where n is such that "2070" has a PM of about 2000 and R = H or CH ^, in a ratio of about 7: 3;

Allyl-PEG 350: ethoxylated allyl alcohol; except for B10, the methacrylic and methacrylamid derivatives of the side chains indicated are present in the form of the general structure B; B10: contains terminal hydroxyl radicals.

Scanning is carried out in the UV indicated above using a Unican SP1750 ultraviolet spectrophotometer.

We deduce the "difference in optical density" whose results are given in Table 4.

It can be deduced from Tables 4 and 5 that the acid polymers significantly increase the amount of chlorhexidine absorbed. Many of the hydroxyapatite surfaces coated with an acidic polymer absorb more chlorhexidine from a 0.02% w / v solution than does the surface of untreated hydroxyapatite from a chlorhexidine solution. 2% w / v, that is to say an improvement of more than 100 times. The basic polymer (polymer 73) and the amphoteric polymer (polymer B12) bring no improvement in the amount of chlorhexidine adsorbed. Similarly, poly (methacrylic acid) does not increase the amount of chlorhexidine adsorbed, which indicates that it is the PEG (or PPG) chains and not the carbo-xyl radicals which are at the origin of the observed effect. .

The results of the washing experiments show that after 1 hour, the chlorhexidine initially adsorbed is still adsorbed for about 23% on the bare hydroxyapatite discs, while the amount on the discs treated with the polymer is about 80%. . After washing overnight, the amount of chlorhexidine adsorbed, if any, remaining on untreated hydroxyapatite discs is below the detection limit; and the chlorhexidine originally adsorbed on the discs treated with the polymer remains adsorbed for about 50 to 60%. Thus, the discs treated with the polymer adsorb more chlorhexidine than bare discs and chlorhexidine is also less easily removed by washing their surface.

EXAMPLES 21 - 29

The present examples, in combination with Examples 10-20 and 6-9, reveal an increase in the antibacterial properties (at a certain concentration of chlorhexidine), without the expected increase in the color change.

General procedure

Hydroxyapatite disks are brought to the equilibrium beforehand for 1 hour in double-distilled water. The discs which have reached their equilibrium are immersed for 5 minutes in a solution of the polymer at 1% w / v in water or in industrial denatured alcohol; water (1: 1). They are removed from the polymer solution and washed by immersion and stirring 5 times in a container under running water. The washed discs are then immersed in 15 ml of an aqueous solution of chlorhexidine (at a concentration indicated in Table 6) for 5 minutes. The disks are removed from the chlorhexidine solution and immersed in 15 ml of tea solution for 1 hour at room temperature. The discs are then removed from the tea solution and washed as described above. The operations of immersion in the chlorhexidine and tea solutions and washing are repeated 3 times, each time taking fresh solutions of chlorhexidine and tea. After these three cycles, the discs are immersed in a tea solution overnight, then washed as described above, dried for 1 hour at room temperature and the extent of the alteration is determined. of staining that has occurred.

The tea solution is prepared by pouring 500 ml of boiling water over 2 tea bags. The tea bags are removed after 5 minutes, then the tea is allowed to cool to room temperature. The tea is filtered with ordinary filter paper and stored at 4 ° C until ready to use.

The altered discs prepared according to the general procedure are subjected to a scan using a UV / visible reflectance spectrophotometer, as described in examples 10 to 20, and the results are compared with white tea controls (this is i.e. without adsorbed chlorhexidine). Fig. 1 indicates the typical UV readings that are obtained. In Fig. 1, a = naked hydroxyapatite disc; b = white tea control; and c, d, and e = tea / chlorhexidine treatments at respective chlorhexidine concentrations of 0.002%, 0.02% and 0.2%.

The effect exerted by the polymers listed in Table 6 (the chemical composition of which is given in Table 5) is evaluated on the alteration of the coloring by chlorhexidine in the presence of tea. The polymers are adsorbed separately from a 1% w / v solution in industrial denatured alcohol / water (1: 1). 0.2%, 0.02% and 0.002% aqueous chlorhexidine solutions are used. The discs are subjected to scanning examination using a spec-trophotometer with UV / visible reflectance and the optical densities are measured at 266, 410 and 510 nm. The optical density of the white tea controls is also measured at these wavelengths and these values are subtracted from those recorded on the discs treated with chlorhexidine or a polymer / chlor-hexidine combination. Table 6 gives the results obtained at 510 nm. They are expressed in the form of the report, the change in color produced by the white tea control being taken equal to 1.0. Similar results are determined at 266 nm and 410 nm. In the TC 18 test, the polymer is omitted, that is to say that chlorhexidine is used alone.

TABLE 6

Appearance of the change in color compared to the "natural" deposit during exposure in a tea solution

It can be deduced from Table 6 that at the two higher concentrations of chlorhexidine (namely 0.2 and 0.02%), the presence and the nature of the polymer have no appreciable effect on the extent of the alteration coloring produced by treatment of hydroxyapatite discs. At the lower concentration (i.e. 0.002%) of chlorhexidine, in most examples a significant decrease in the color change is observed up to or below the minimum values associated with the exposure of the hydroxyapatite disks to tea solutions. Nevertheless, it can be deduced from the results of Examples 10-20 and 6-9 that for roughly the same color change as the control, the polymers carry more absorbed chlorhexidine and exert an increased antibacterial effect. EXAMPLES 30-31

The present examples illustrate the increase in the amount of chlorhexidine adsorbed on a hydroxyapatite disc treated with a mixture of chlorhexidine and the polymer '93W, the comparison being made with the treatment of the hydroxyapatite disc with a solution of chlorhexidine alone.

A solution of the polymer 93W (2% w / v) in industrial denatured alcohol is mixed with a suitable solution (0.04% w / v) of chlorhexidine in water, in a ratio 1: 1 by volume between solutions. The hydroxyapatite discs are allowed to stand in the mixture for 1 hour, then washed 5 times with water. The amount of chlorhexidine absorbed on the discs is determined by UV reflectance spectrophotometry as described in Examples 10-20 (the optical density being measured at 266 nanometers).

In comparison tests 20 and 21, the disks are treated for 1 hour in 0.2% and 0.02% solutions of chlorhexidine respectively in a 1: 1 mixture by volume of industrial denatured alcohol and water.

The results are given in Table 7.

/

It can be deduced from Table 7 that the treatment of a hydroxyapatite disc with the 93W / chlorhexidine polymer mixture causes more chlorhexidine to be absorbed than from the chlorhexidine solution alone.

TABLE 7

EXAMPLES 32-33

The present examples illustrate the increase in the "lethal power" of a 93W / chlor-hexidine polymer mixture, in comparison with the lethal power of a chlorhexidine solution alone.

The disks prepared in Examples 30-31 are washed overnight in water and subjected to the experience of applying an agar layer containing S. mutans. They are placed in a petri dish and covered with agar for infusion of the brain and heart (25 ml), then a pipette is applied to the agar, on which it is spread evenly. .mutans (100yxl) grown in a fermenter (as described above)> diluted 100 X in Ringer's saline. The bacteria are cultivated overnight at 37 ° C. and the "lawns" of bacteria and the "clear areas" free of bacteria are observed and measured. The results are collated in Table 8. The light areas, that is to say the areas where growth has not occurred, are explained as a percentage of the surface of the disc.

TABLE 8

It should be observed that when the "surface area of the growthless disc, in%" is greater than 100, this indicates that the inhibition has spread in the agar layer beyond the perimeter of the disc.

It can be deduced from Table 8 that the mixture has a higher antibacterial activity than that of chlorhexidine alone.

EXAMPLES 34 - 65

The present examples show that the combination of a non-stick compound, namely the polymer 93W, and chlorhexidine reduces the extent of the color alteration, in comparison with the chlorhexidine taken alone, as manifested. on various surfaces found in the oral environment. The surfaces are in particular those of the teeth, of composite restorative materials, for example of Occlusin and of Opalux, and of a methacrylic base resin of current use for the manufacture of dental prosthesis devices (noted here -after for convenience "PR").

Test tubes

By means of a scalpel, the residual flesh of freshly extracted teeth is removed, then the teeth are stirred for 20 minutes in 50% sodium hypochlorite solutions and washed superficially with distilled water. These teeth and others containing restorative materials are exposed to ultrasound in alcohol for 10 minutes and then dried.

Wash with alcohol and dry samples of PR (25 mm X 10 mm X 3 mm) and discs of these composite restorative materials.

Solutions a 1% and 0.5% solutions of the 93W polymer (1 g) in a mixture of industrial denatured alcohol (50 ml) and water (50 ml).

b Solutions (0.2%, 0.02% and 0.002%) of chlorhexidine in water.

c Appropriate mixtures of 93W polymer and chlorhexidine are prepared by mixing equal volumes of solutions a and b to arrive at the concentrations indicated in the tables below, d Human saliva is collected by collecting samples (20 ml ) in each of 6 volunteers, by centrifuging them for 20 minutes at 2,500 rpm and then collecting them, e A tea solution is prepared by heating to boiling for 2 minutes in distilled water (80 ml) a sample (8 g) of a marketed tea, allowing the product to cool to room temperature, and by filtering off the residual tea leaves.

Evaluation

Each surface is treated for 10 minutes using a saliva sample. Excess saliva is removed by rinsing.

In Examples 34-49, the surface is subjected to a first treatment for 10 minutes, it is washed superficially with distilled water, it is subjected to a second treatment for 10 minutes, it is rinsed and then immersed in the tea solution for 1 hour; the operation is repeated, the surface is left in contact with the tea solution overnight and the complete procedure is repeated each day for 5 days.

In Examples 50-65, the 5-day procedure described above is repeated, except that the first treatment is carried out for 5 minutes and the second treatment is omitted, the test pieces being treated using suitable mixtures. 93W polymer and chlorhexidine.

The alteration in color of the surfaces is visually compared with that of the same surface treated only with water, the evaluation being made on the following scale.

Scale 0: No alteration (that is to say that the water control is taken equal to 0, although there is a slight alteration of coloring) 1: Light coloring 2: Moderate coloring 3: Coloring intense 4: Very intense coloring

In Tables 9, 10 and 11 OC = Occlusin OP = Opalux D = Tooth PR = Prosthesis resin A = 0.5% of polymer 93W AA = 1% of polymer 93W B = water X = 0.1% of chlorexidine XX = 0.2% chlorhexidine Y = 0.01% chlorhexidine YY = 0.02% chlorhexidine Z = 0.001% chlorhexidine ZZ = 0.002% chlorhexidine W = 0.0001% chlorhexidine TABLE 9

TABLE 9 (continued)

TABLE 10

TABLE 11

It can be deduced from Table 9 that at a low concentration (for example 0.002%) the color alteration induced by chlorhexidine on a dental restoration, the teeth or a prosthesis resin is weakened if the surface of the latter is of first treated with a certain polymer.

We can also observe (examples 46-49) that when the surfaces are treated with a chlorhexidine solution, then with the polymer-93W, the color change is weakened to the control values .

Table 10 shows the results obtained when surfaces of Occlusin and Opalux are treated with mixtures of chlorhexidine and 93W polymer. There is a significant reduction in the color change on the Occlusin up to the control values for chlorhexidine concentrations of 0.01% if not less and a similar trend is apparent with Opalux.

Table 11 shows the results obtained when the dental surfaces and a prosthesis resin are treated with a mixture of chlorhexidine and 93W polymer. The tendency to reduce color is similar to that observed on Occlusin and Opalux.

When a tooth with an Occlusin obturation is subjected to the above examination, the tooth and the obturation are faintly colored to the same degree, so that the contour of the obturation is more masked.

Claims (15)

1. Composition for oral hygiene, characterized in that it comprises (i) an effective amount of at least one cationic antibacterial agent, and (ii) an effective amount of at least one polymer which carries side chains of poly (alkylene oxide) pendant. 2. Composition for oral hygiene according to claim 1, characterized in that the cationic antibacterial agent is a polybiguanide or a salt thereof. 3. Composition for oral hygiene according to claim 2, characterized in that the polybiguanide is a bis-biguanide. 4. Composition for oral hygiene according to claim 3, characterized in that the bis-biguanide is chlorhexidine. 5. Composition for oral hygiene according to any one of the preceding claims, characterized in that the at least single polymer comprises one or more recurring units of general structure A

and one or more recurrent units of 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 the same or different, are substituted hydrocarbyl or hydro-carbyl residues, constituting a backbone for the polymer;

R1, which in the same repeating unit of structure B (when n or q represents 2 or more) or in different repeating units of structure B, may be the same or different, is a hydrogen atom or a hydrocarbyl radical; and R 'which, in the same repeating unit of structure B (when n or q represents 2 or more) or in different repeating units of structure B, may be the same or different, is a hydrogen atom or a hydrocarbyl radical; except that R and R in a single unit -CHR -CHR -0- cannot be. both of the hydrocarbyl radicals; R, which in the same repeating unit of structure B (when q represents 2 or more) or in different repeating units of structure B, may be the same or different, is a hydrogen atom or a hydrocarbyl radical or else a radical acyl from an alkanoic acid having up to five carbon atoms; m, when 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 g is a number from 1 to 4; each radical (CC ^ H) is united by one or more intermediates L to the hydrocarbyl residue X and in the case where p represents 2 to 4, can be united by L to the same carbon atom or to carbon atoms different from X; L can be identical or different in the recurring units of structure A and is chosen from one or more direct bonds and one or more groups of atoms, each group bringing a chain of one or more atoms to unite a radical (C02h) to X, except that more than two radicals (CO2H) cannot be directly linked to the same carbon atom in X; each radical ((ZO) nR ^) g is united by one or more intermediates M to the hydrocarbyl residue Y and in the cases where q represents 2 to 4, can be united by M to the same carbon atom or to different carbon atoms of Y; M can be the same or different in the repeating units of structure B and is chosen from one or more direct bonds and one or more groups of atoms, each group providing a chain of one or more atoms to unite a radical (ZO) n with Y, except that more than two radicals (ZO) ^ cannot be directly linked to the same carbon atom in Y; the ratio of the number of radicals -CC ^ H to ηθΓη £> Γ6 of the radicals (ZO), in particular when Z is -Ct ^ CE ^ -is in the range from 1:20 to 20: 1. 6. Composition for oral hygiene according to claim 5, characterized in that when λ? λ? Z is -CHR -CHR -, R and R are both hydrogen atoms. 7. Composition for oral hygiene according to any one of claims 5 and 6, charac- terized in that R is a methyl radical. 8. Composition for oral hygiene according to any one of claims 5 to 7, characterized in that in structure A, L is a direct bond,

9. Composition for oral hygiene according to any one of claims 5 to 8, characterized in that in structure A, p is 1 or 2. 10. Composition for oral hygiene according to any one of claims 5 to 9, characterized in that in structure B, M is -COO- or C0NH-. 11. Composition for oral hygiene according to any one of claims 5 to 10, characterized in that in structure B, q is worth 1 or 2. 12. Composition for oral hygiene according to any one of claims 5 to 11, characterized in that A or B represents the repeating unit which can be obtained by addition polymerization of an olefinically unsaturated polymerizable carboxylic acid or d 'an ester or amide derived therefrom, respectively. 13. Composition for oral hygiene according to claim 12, characterized in that the polymerizable olefinically unsaturated carboxylic acid is acrylic or methacrylic acid. 14. Composition for oral hygiene according to any one of the preceding claims, characterized in that it comprises a pharmaceutically acceptable excipient which is water, ethanol, a humectant, a gelling agent, a stabilizer for gel, sweetener, preservative, surfactant * or approved color or flavor. 15. Composition for oral hygiene according to any one of the preceding claims, characterized in that it is presented in the form of mouthwash, toothpaste water, irrigation solution, gelled toothpaste, product for cleaning teeth, coated dental floss, coated or impregnated toothbrush bristles, interdental coating or stimulator, chewing gum, lozenge, breath freshener, foam or spray .