WO2006005211A1

WO2006005211A1 - Oral hygiene agents containing a chitosan derivative

Info

Publication number: WO2006005211A1
Application number: PCT/CH2005/000389
Authority: WO
Inventors: Christine Garbers; Dally Moya-Argilagos; Riccardo A. A. Muzzarelli
Original assignee: Gaba International Ag
Priority date: 2004-07-12
Filing date: 2005-07-07
Publication date: 2006-01-19

Abstract

The invention relates to oral hygiene agents, which contain a polymer with repetitive units of formula (I), in which R represents -NH2, -NHCOCH3 or R', whereby methyl pyrrolidone groups constitute at least 90 mole % of R'. It has been found that said polymer prevents the adhesion of Streptococcus mutans to the surface of the tooth. Said oral hygiene agents containing the polymer are thus effective against caries.

Description

Oral care containing chitosan derivative

The present invention relates to a Mundpflegemit¬ tel comprising a chitosan derivative and its use for the prevention or treatment of caries.

Caries is mainly caused by acids that are produced by oral bacteria. These acids demineralize the hydroxyapatite that forms the enamel. An important bacterial species responsible for caries is Streptococcus mutans, which can accumulate in large numbers on the teeth and which is regarded as the bacterial agent chiefly responsible for the disintegration of the tooth enamel. The reduction of this microorganism on the Zahnoberflä¬ che is therefore of vital importance in the prevention and treatment of dental caries.

Chitosan is obtained by chitin (a polymer of ß ~ (l, 4) - glycosidically bound repetitive units of N-acetyl-D-glucosamine) by deacetylation in an alkaline medium ge. The degree of deacetylation increases with increasingly severe deacetylation conditions, but with harsh deacetylation conditions, cleavage of the polymer backbone is also observed. Commercially available types of chitosan are therefore only partially deacetylated, with degrees of deacetylation typically ranging from 0.70 to 0.90.

Chitosan itself has been used in oral care products. Chitosan, which is actually present in the formulation of the oral hygiene product and also in the oral cavity, is a cationic polymer because its deacetylated amino groups are protonated at physiological pHs. This is considered essential because the unprotonated chitosan is almost insoluble in aqueous media. It is also believed that this cationic chitosan either attaches to the negatively charged tooth surface, thereby preventing the deposition of oral bacteria, or it attaches to the membranes of the oral bacteria, thereby preventing their attachment to the tooth surface (See, for example, Sano, H. et al., Bull. Tokyo dent. Coli., Vol. 42, No. 4, pp. 243-249, 2001). It is further known that chitosan can be degraded to low molecular weight fragments by lysozyme present in saliva, and this low molecular weight chitosan has also been found to be active against oral bacteria (see, eg, Sano, H. , et al., Bull. Tokyo dent. Coli., Vol. 42, No. 4, pp. 243-249, 2001).

Some derivatives of chitosan have also been considered as agents for preventing the attachment of oral bacteria to the tooth surface. These are, for example, imidazolyl chitosan (eg Tarsi, R., et al., J. Dent. Res. 76 (2), pp. 665-672, 1997), N-carboxymethyl chitosan (eg Muzzarelli, R. et al., J. Chem Cosmetol 20, pp. 201-208, 2002), ethylene glycol chitin (Sano, H., et al., Bull. Tokyo dent. Coli., Vol. 32, No. 1, pp. 9-17, 1991) and sulfated and phosphorylated chitosan (Sano, H., et al., Bull. Tokyo dent. Coli., Vol. 42, No. 4, pp. 243-249, 2001).

A major disadvantage of most prior art studies on chitosan derivatives as agents. Tooth decay is that they do not take into account that the oral bacteria are not found in a planktonic state, but are embedded in a biofilm that covers the tooth surface and also contains polysaccharides that are secreted by many of these bacteria. To a certain extent, this biofilm prevents active agents from coming into contact with the bacteria; it can enable individual active agents to pass through the biofilm and enter into contact with the bacteria more easily than other agents, and can thus lead to apparent activities Agen¬ zien lead, which differ significantly from those observed in planktonic bacterial cultures wer¬ the. Prior art studies that do not take into account the influence of biofilm are thus believed not to provide reliable predictions of in vivo activities.

Recently, an in vitro model for testing active agents in bacteria stored in a biofilm has been developed (Guggenheim, B., et al., Caries Research 36, pages 93-100, 2002). In this study, biofilms with a selection of oral bacteria, but which did not include Streptococcus mutans, were cultured in vitro on hydroxyapatite discs in mixtures of saliva and nutrient medium. The effectiveness of chlorhexidine and triclosan-containing formulations on the biofilms so formed was investigated.

The nature of a microbial biofilm and its behavior against active agents depend on the history of its development. Therefore, even in vitro studies that take into account the biofilm effect and use the same microorganisms, depending on how the Bioflim is grown was different results for the same active agent.

A chitosan derivative in which at least 30% of all amino groups are different from -NH ₂ and -NHCOCH ₃ and in which at least 90% of the said amino groups different from -NH ₂ and -NHCOCH _{3 have been} converted into methylpyrrolidone groups in US-A-5,378,472, as disclosed for wound healing, by stimulating an immune response involving macrophages and providing amino sugar for incorporation into connective tissue.

It is an object of the present invention to provide an improved oral care product.

Accordingly, the present invention provides an oral hygiene composition comprising a polymer having repeating units of the following formula (I):

in which repetitive unit (I) R is -NH ₂ , -NHCOCH ₃ or R ¹ , where at least 90 mol% of the R 'methylpyrrolidone groups of the following formula (II):

: N:

are.

The above polymer having repeating units (I) is hereinafter referred to as "methylpyrrolidone chitosan".

It has surprisingly been found that the above polymer reduces the number of colony-forming units (CFU's) of Streptococcus mutans m biofilms containing this bacterium, among other oral bacteria, and that it is therefore effective against caries. On the one hand, the reduction in the CFUs of Streptococcus mutans could be due to the fact that methylpyrrolidone chitosan prevents the adhesion of Streptococcus mutans to the tooth surface or that it has an antivital effect on Streptococcus mutans. It has also surprisingly been found that the methylpyrrolidone chitosan, which has a lower proportion of protomernary amino groups than chitosan, which served as starting material for its preparation, in the aqueous media of oral hygiene products at physiological pH (ie at pH values from about 4 to about 7.5, preferably from about 6 to about 7.5) is nevertheless better soluble than the latter, and that methylpyrrolidone chitosan by the other additives present in these media, in particular those in most Mund¬ care agents present gel-forming or moisturizing Po¬ polymers or abrasives, which are common in toothpastes are not like or absorbed.

The requirement that "at least 90 mol%" of R 'should be methylpyrrolidone should be understood to make this percentage as close as technically possible to 100 mol%.

The methylpyrrolidone chitosan used in the oral hygiene composition of the present invention may typically comprise at least about 0.5 mol% of repeating units in which R is methylpyrrolidone of the above formula (II). In a more preferred embodiment of the oral hygiene product, the methylpyrrolidone chitosan comprises about 0.5 to about 60 mol%, more preferably about 0.5 to about 20 mol%, and particularly preferably about 4 to about 20 mol% or on the other hand about 0.5 to about 10 mol% of such repetitive units. Also preferably, the methylpyrrolidone chitosan comprises from about 80 mole% to about 20 mole%, more preferably from about 80 mole% to about 60 mole% of repeat units in which R is -NH ₂ . Can thylpyrrolidonchitosan Me¬ in the relative proportions of _-NH2 - and -NHCOCH ₃ groups by ¹ H-NMR in D ₂ O / DCl solutions are determined at 7O ⁰ C (see Lavertu, M. et al, Journal. of

Pharmaceutical and Biomedical Analysis, 32, pp. 1149-1158, 2003). Using the same method, the relative proportions of -NHCOCH ₃ and methylpyrrolidone groups can be determined (with their methyl signals being taken as the measured variable, for example).

In a preferred embodiment, the oral hygiene products according to the invention are water-containing, the water content preferably being in a range from 10 to 90% by weight, more preferably in the range from 50 to 90% by weight. Percent, based on the oral care product, may be.

However, the aqueous mouth-care preparations according to the invention are not solutions of 16 g of methylpyrrolidone chitosan per liter. The oral hygiene compositions according to the invention are also not solutions of 4% by weight in distilled water or in acetate buffer pH 5.0.

In another preferred embodiment, the oral hygiene product according to the invention is a dry preparation which, in addition to the methylpyrrolidone chitosan, optionally contains further solid additives customary for an oral hygiene product and which is directly wetted or dissolved before use with water or with saliva. However, the oral care compositions according to the invention in the form of a dry preparation are not freeze-dried methylpyrrolidone chitosan.

The oral mucosa is able to absorb certain therapeutically or prophylactically active agents, whereby the permeation into the oral mucosa is favored with increasing lipophilicity of the agent. In a literature reference known to the Applicant (Eur. Journal of Pharm. Sciences 21, pp. 351-359, February 2004), attempts were made to increase the permeability of the poorly permeable antiviral acyclovir into the oral mucosa by means of methylpyrrolidone chitosan. However, increasing the penetration of substances with poor permeability into the oral mucosa by means of the methylpyrrolidone chitosan is not the goal of the oral hygiene products of the present invention. For the oral hygiene products according to the invention it is therefore initially preferred that they do not contain acyclovir. Rather preferably, they do not contain any poor permeability into the oral mucosa. even more preferably, they do not contain antivirals which are poorly permeable to the oral mucosa, and more preferably do not contain any agents which are poorly permeable to the oral mucosa and therapeutically or prophylactically active. For the purposes of the present application, a "therapeutically or prophylactically active agent" is considered to be "poorly permeable to the oral mucosa" if the log of its partition coefficient between n-octanol and water at room temperature is in the range from -3 to -0.5 the measurement of the partition coefficient after equilibration can be carried out between 50 ml of 1% (w / v) solution of the agent in water and 50 ml of n-octanol. The partition coefficient of a compound between n-octanol and aqueous solutions is used in the art as an approximate guide to the penetration capacity of a compound into biological membranes.

In a preferred embodiment of the oral hygiene preparation, the methylpyrrolidone chitosan has an average molecular weight in the range from 10,000 to 1,000,000 daltons, more preferably from 100,000 to 400,000 daltons, particularly preferably from 100,000 to 200,000 daltons.

The synthesis of the methylpyrrolidone chitosan which can be used in the present invention is based on chitosan derived from the shells of crustaceans of the sea (eg crabs, shrimps, krill, lobsters, crawfish, duck mutton, steer crabs) Insects, fungi, such as Aspergillus or Agaricus, or molluscs, such as octopus, derived chitin. The chitosan is reacted with levulinic acid, wherein the -NH ₂ ~ groups in chitosan react with keto groups of levulinate and are converted to imine groups. These imine groups are reduced to secondary amine groups, and the amine groups cyclize to methylpyrrolidone groups of the above formula (II).

The reduction of the imine groups to amine groups can be carried out, for example, by means of catalytic hydrogenation, by means of sodium borohydride, sodium cyanoborohydride or by means of formic acid. The cyclization of the amine groups to methylpyrrolidone groups may even occur spontaneously after the reduction of the imine groups.

Such a process for the preparation of crude crude chitosan methylpyrrolidone chitosan using free levulinic acid is disclosed in US-A-5,378,472, which patent publication is incorporated herein by reference. Under the one-pot conditions of US Pat. No. 5,378,472, a methylpyrrolidone chitosan is obtained in which typically about from about 30 to about 45 mol% of the repeat units R are present as methylpyrrolidone (see also entries 3 and 4 in Table 1) 1 and Table 3 in Rinaudo, M., et al., Carbohydrate Polymers 46, pp. 339-348, 2001).

Instead of free levulinic acid, an ester of levulinic acid, such as the methyl ester, may be used for imine formation.

The chitosan can be previously adjusted in its molecular weight by means of partial hydrolysis (see, for example, Muzzarelli et al., International Journal of Biological Macromolecules). cules 16/4, pages 177-180, 1994). The chitosan can be fractionated into fractions on a preparative scale, whether partially hydrolysed or not, by dissolving the chitosan in acid and then gradually increasing the pH, whereby the gradual precipitation of fractions with sin¬ kendem molecular weight is effected. The precipitated chitosan fractions obtained can be reduced to their average molecular weight and their molecular weight distribution in known manner by gel permeation chromatography using, for example, N-acetylglucosamine oligomer or pullulan as retention time standards, or by using a Multi Angle Laser Light Scattering "- (MALLS) detector are examined.

Purification of the methylpyrrolidone chitosan is primarily intended to remove excess, unreacted lavulanic acid as well as salts and other chemical compounds formed during the reduction step. If these compounds were not removed, they would react with themselves to form black pigments. Since the chemical species to be removed are of low molecular weight, separation is readily accomplished by dialysis against desalted water or by anion exchange or by desalting on suitable chromatographic supports or by precipitation of the polymer at constant pH with ethanol containing the low molecular weight compounds in Lo ¬ sung, achieved.

The oral hygiene compositions according to the invention include methylpyrrolidone chitosan in preferably 0.01 to 2 percent by weight, more preferably in 0.1 to 1 percent by weight, based on the oral hygiene product. The oral hygiene products according to the invention can be prepared in a known manner using customary additives and / or auxiliaries, as are well known to the person skilled in the art. A useful starting point for an oral hygiene product according to the invention may be a previously known oral care composition comprising chitosan, wherein instead of the chitosan an equal amount of methylpyrrolidone chitosan is used. The oral hygiene products according to the invention can be, for example, in the form of a chewable tablet, a toothpaste, a toothpowder, a mouthwash solution, a dental gel, a formulation for bad breath, a chewing gum, a saliva replacement fluid or a touch solution. They are preferably in the form of chewable tablets, toothpastes, toothpowder, mouthwashes, formulations against halitosis, chewing gum, saliva substitute fluids or coating solutions.

In order to achieve a physiologically acceptable pH of from about 4 to about 7.5, a pharmaceutically acceptable acid such as hydrochloric acid, hydrofluoric acid, phosphoric acid or lactic acid can be added. This also helps to protonate the -NHa groups of methylpyrrolidone chitosan, thereby increasing its solubility. Preference is given to using hydrofluoric acid, since the fluoride itself also acts as an anti-caries agent.

Examples of suitable abrasives are alkaline earth metal phosphates (eg dicalcium phosphate dihydrate, anhydrous dicalcium phosphate, tricalcium phosphate), insoluble alkali metal metaphosphates, finely ground or colloidal silica gels, aluminum hydroxide hydrates, aluminum silicates, aluminum magnesium silicates and alkaline earth metal carbonates. Suitable plastics, for example polyethylenes, can also be used. These scouring agents can typically be used in amounts of from 10 to 60 percent by weight. Binders or thickeners for tooth pastes are gel-forming agents of natural or synthetic origin. Examples of these are water-insoluble alginates, carrageenates, guar gum, tragacanth, water-soluble cellulose ethers (for example methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose), aerosils and bentonites. In general, the content of binding agent is 0.5 to 10% by weight. Examples of plasticizers and humectants for toothpastes according to the invention are polyhydroxylic alcohols, such as glycerol, propylene glycol, glucose syrup, polyethylene glycols, sorbitol, polypropylene glycols and polyvinylpyrrolidone. They can typically be used in amounts of 10 to 40 percent by weight.

Mouthwash solutions according to the invention are preferably aqueous, alcoholic or mixed aqueous / alcoholic solutions. Additives and auxiliaries for winding solutions are examples of emulsifiers, humectants as exemplified above for toothpastes, sweeteners such as sorbitol, xylitol and various drug extracts.

Dental gels according to the invention may contain as carrier material a swollen mixture of natural or synthetic hydrocolloids. Examples thereof are methylcellulose, hydroxyalkylcelluloses, carboxymethylcellulose, water-soluble and swellable salts of polyacrylic acids, algmates,

Carraghenate and guar gum. The above-mentioned humectants and, if desired, pigments can also be mixed in small amounts into the respective gelase. Salivary replacement fluids according to the invention may comprise, as thixotropic agent, hydroxyalkylcelluloses, such as hydroxyethylcellulose, hydroxypropylcellulose or low-substituted hydroxypropylcellulose. The inventive salivary replacement fluids may further comprise inorganic salts typical of human saliva, such as NaCl, MgCl ₂ , CaCl ₂ and KCl; and they can be buffered by means of, for example, a dihydrogen phosphate / hydrogen phosphate or carbonate / bicarbonate buffer to a pH and a buffering capacity, as are typical of human saliva. The salivary fluids of the invention may further comprise humectants as described above for toothpastes.

Further examples of oral care products according to the invention are touch preparations, chewable tablets, tooth powders and formulations for bad breath. In Touchierlosungen and Formu¬ lierungen against halitosis can be used as additives the same sub stances as in Spullosungen. Additives for chewable tablets may be binders and sugars such as sucrose, glucose, lactose or preferably non-cariogenic sugars such as xylitol, mannitol or sorbitol.

According to the invention, the oral hygiene products according to the invention can preferably be improved by adding flavorings customary in oral care products and aromatic substances to the taste. Examples of these are saccharin, quaternary ammonium saccharinates, cyclamates, coumarin, vanillin, peppermint, cerous minzol, anisole, menthol, anethole, citrusol or other essences such as apple, eucalyptus or mint essence. In a preferred embodiment, the oral hygiene compositions according to the invention may also comprise an additional fluoride source customary for oral care products, such as NaF, KF, NaHFPO ₃ , SnF ₂ or TiF ₄ . These fluoride sources are known. Further examples of a known fluoride source that can be used in the oral hygiene compositions of the present invention are amine fluorides. Examples of amine fluorides are disclosed in WO-A-98/22727, WO-A-01/39737 and DE-PS-1198493, incorporated herein by reference. Among the amine fluorides, N, N-bis (2-hydroxyethyl) aminopropyl-N '- (2-hydroxyethyl) octadecylamine dihydrofluoride is preferred.

In another preferred embodiment, the oral hygiene products may further comprise an antibacterial agent common in oral hygiene products. The preferred antibacterial agent is chlorhexidine or chlorhexidine digluconate. The amount of antibacterial agent, if used, may preferably be in the range of 0.05 to 0.20 weight percent based on the oral care product. In another preferred embodiment, the weight ratio of methylpyrrolidone chitosan to antibacterial agent (in particular chlorhexidine or chlorhexidine digluconate) can be in the range from 5: 1 to 1: 1, and more preferably it is about 2: 1 In most preferred embodiments, the amounts of methylpyrrolidone chitosan and chlorhexidine (or chlorhexidine digluconate) are 0.2% by weight or 0.1% by weight, based on the oral hygiene product.

The invention will now be further illustrated by reference to the following non-limiting examples.

Example 1: Toothpaste Additional weight percent

Methylpyrrolidone chitosan 0.5

Amine fluoride, F ^~ = 1.4 10

(Olaflur, GABA) Sorbitol 25

(Sorbidex NC 16203, Cerestar) Hydroxyethyl Cellulose 2

(Tylose H 10'0OO P, Clariant)

Titanium dioxide 1, 5 (Kemira AFDC, Kemira)

Saccharin 0.2

(Saccharin 550X, Oskar Berg) Hydrated silica gel 20

(Tixosil 63, Rhodia) Water Q.S.

In a steel mixing machine equipped with a stirrer and a homogenizer (rotor / stator system) and / or a dissolver, all the above additives are combined and the formulation is first homogenized at a low level until the viscosity increases , This is done under vacuum (about 0.6 bar) to avoid foam formation and air entrapment during mixing. As soon as the mass is free of lumps and the viscosity has increased, the homogenizing force is increased. Finally, as soon as the mass is free of lumps and is smooth and soft, the residual pressure of the vacuum is lowered to 0.1-0.2 bar to remove the remaining air. The temperature must be kept below 30 ° C.

Example 2: Toothpaste Addition% by weight Methylpyrrolidone chitosan 1,2

Sodium fluoride 0.3095

Sorbitol 25

(Neosorb, Roquette)

Aroma free

(Peppermint oil, spearmint oil or menthol)

Hydroxyethylcellulose 1.9

(Tylose H 10'0OO P, Clariant)

Titanium dioxide 1.2

(Kemira AFDC, Kemira)

Sodium saccharin 0.15

(JMC)

Methylparaben 0.02

(Nipagin M)

Propylparaben 0.18

(Nipasol M)

PEG-40 hydrogenated castor oil on the flavor

(Cremophor RH 410, BASF) (max

Hydrated silica gel 20

(Tixosil 63, Rhodia)

Cocoamidopropyl betaine 1.5

(Tego Betain F 50)

Water O.S.

The formulation is prepared as described in Example 1.

Example 3 Mouthwash Solution Addition Weight Percent

Methylpyrrolidone chitosan 0.5 sodium fluoride 0.0555 (= 250 ppm F ^" ) saccharin 0, 07

(Saccharin 550X, Moolsan)

Aroma 0, 2 (peppermint or menthol)

PEG-40 hydrogenated castor oil 0.6

(Cremophor RH 410, BASF) propylene glycol 2.0

(USP, Dow Chemical) Polyaminopropyl biguanide 0.05

(Cosmocil CQ, Avecia) Hydroxyethyl cellulose 0.05

(Tylose H 10'000 P, Clariant) Demineralized Water Q.S.

The water is added to the mixing kettle. The propylene glycol, the hydrogenated castor oil and the peppermint oil are mixed in the process and this mixture is added to the water under inert conditions. Finally, the remaining additives are added with stirring.

Example 4: Saliva replacement fluid

Additional weight percent

Methylpyrrolidone chitosan 3.00

Hydroxyethylcellulose 1.00

Sodium chloride 0.042 potassium chloride 0.060

MgCO ₃ .6H ₂ O 0.026

CaCl ₂ .2H ₂ O 0.007

K ₂ HPO ₄ 0.017

Sorbitol 20.00 water QS The preparation involves the dispersion of the hydroxy ethylcellυlose in water at 7O ⁰ C by using a homo-mixer for 15 minutes. Thereafter, the anorgani¬'s salts are dissolved in the formulation. The salts are added to adapt the formulation to the physicochemical and organoleptic properties of human saliva. Finally, the Methylpyrrolidonchitosan is dissolved at 40 ⁰ C. The packaging of the formulation is carried out in a sterile environment. It is intended for single dose use.

Example 5: Dental Gel

Additional weight percent

Methylpyrrolidone chitosan 2.00

Hydroxyethyl cellulose 2.00 xylitol 10.00

Maltite 10.00

Polysorbate-20 0.35

Carvacrol (flavor) 0.15

Chlorhexidine digluconate 0.50 Water Q.S.

The gel is made by using a homo-mixer her¬ by the hydroxyethyl cellulose is dispersed at 65 ⁰ C for 15 minutes in water, is then cooled to 4O ⁰ C and the reduced sugar xylitol and maltitol are added, thereby obtaining a clear solution becomes. Previously mixed polysorbate-20 and flavor are then added. The methylpyrrolidone chitosan, previously dissolved in a minimum amount of water, is added, followed by the chlorhexidine digluconate. Example 6: In vitro test of methylpyrrolidone chitosan against oral bacteria embedded in a biofilm

The test method is based on that of Guggenheim et al. 80 (1), pp. 363-370 (2001); Shapiro, S., et al., Caries Res. 36, pp. 93-100 (2001); Guggenheim, B., et al., J. Dent. 2002)).

The biofilms were cultured using Streptococcus mutans OMZ 918, Streptococcus oralis OMZ 607, Veilonella dispar OMZ 493, Actinomyces naeslundii OMZ 745 and Fusobacterium nucleatum OMZ as bacteria and further using Candida albicans OMZ 110. These microorganisms were obtained from the culture collection of the Institute of Oral Microbiology and General Immunology of the University of Zurich.

The pre-cultures of the microorganisms were determined by In¬ incubation at 37 ^C C on Columbia blood agar plates, then incubated at 37 ° C on liquid Universal Medium ( "FUM"; Guggenheim, B., et al, Infect Immun 42, pages 459-470... , 1983) with Sörensen buffer pH 7.2 containing 0.3 glucose (for Veilonella dispar also 1% sodium lactate was added).

Methylpyrrolidone chitosan was prepared as described in US-A-5,378,472.

9 mm diameter sintered hydroxyapatite discs were used to grow the biofilms. The discs were previously coated with a salivary membrane by incubation in saliva for 4 hours. The membrane-coated hydroxyapatite disks were coated with a mixed culture of microorganisms inoculated by mixing equal volumes of each of the pre-cultured microorganisms, which in turn had previously been adjusted to OD ₅₅₀ = 1.0. Incubation of the seeded slices was at 37 ^° C. for 45 minutes in a culture medium consisting of a mixture of saliva and FUM. After a certain growth period in saliva, the incubation was repeated at intervals in fresh culture medium. The discs containing the growing biofilms were exposed at intervals to test solutions of methylpyrrolidone chitosan. A control panel of slices was exposed at intervals to pure water. The biofilms were harvested after 64.5 hours.

Their composition was analyzed by culture techniques using either Columbia blood agar plates (for the total number determination) or using suitable nutrient media for selective cultivation of the individual strains, and counting the CFU's under a stereomicroscope. Table 1 shows the CFUs of the microorganisms used in the harvested biofilms.

Table 1. CFU's of microorganisms (mean / standard deviation, of three tests) in biofilms after treatment with test solutions of methylpyrrolidone chitosan

Tested Compounds Total A. naes V. dispar F. nuc S. mutans S. oralis C. albi dung lundii leatum cans

Methylpyrrolidon¬ 1, 6xlO ⁸ / * 6, 2xlO ^fa / ** 3, 3x10 '/ * chitosan 8, 9xlO ⁷ 2, OxIO ⁶ 2, 3xlO ⁷

Comparison (Was¬ 8, 3xlO ^a / 6,7xlO ^ö / 8, lxlθ ^b / 1, 0xl0 ^d / 1, 6xlO ^ö / 2, 5xlO ⁴ /

I ser) 9, IxIO ⁷ 8, IxIO ⁷ 6, 2xlO ⁶ 3, 6xlO ⁷ 1, OxIO ⁸ 1, 7xlO ⁴

Below the detection limit

** Did not grow significantly in the biofilms

It can be seen that methylpyrrolidone chitosan interferes with Streptococcus mutans.

9 9 -

The total number of live / dead microorganisms wur¬ the determined by fluorescent staining using the solution of the "LIVE / DEAD BacLight ™ Bacterial Viability Kit ^®" (Molecu- lar Probes BV, Leiden, Netherlands). Table 2 lists the results obtained.

Antiviral activity with methylpyrrolidone-chitosan according to analysis by means of fluorescence staining, which indicates the percentage of living bacteria in the biofilms after the treatment

Claims

claims

1. Oral care product, characterized in that it contains a polymer with repetitive units of the following formula (D:

(D

in which repeat unit (I) R is -HH ₂ , -NHCOCH ₃ or R ', where at least 90 mol% of the R' methylpyrrolidone groups of the following formula (II):

: N:

are.

2. Oral care product according to claim 1, characterized gekenn¬ characterized in that in 0.5 to 60 mol%, preferably in 0.5 to 20 mol% of the repetitive units R methylpyrrolidone groups of the above formula (II). - 2 A -

3. Oral care product according to claim 1 or 2, characterized in that the average molecular weight of the poly mer is 10,000 to 1,000,000 daltons, preferably 100,000 to 400,000 daltons and more preferably 100,000 to 200,000 daltons.

4. Oral care product according to one of claims 1 to 3, characterized in that it comprises 0.01 to 2 percent by weight, preferably 0.1 to 1 percent by weight of polymer, based on the oral hygiene product.

5. Oral care product according to one of claims 1 to 4, characterized in that it comprises an additional fluoride source, in particular an amine fluoride.

6. Oral care product according to claim 5, characterized gekenn¬ characterized in that the amine fluoride is N, N-bis (2-hydroxyethyl) aminopropyl-N '- (2-hydroxyethyl) octadecylamine-di-hydrofluoride.

7. Oral care product according to one of claims 1 to 6, characterized in that it comprises an antibacterial agent.

8. Oral care product according to claim 7, characterized gekenn¬ characterized in that the antibacterial agent is chlorhexidine or chlorhexidine digluconate.

9. oral hygiene product according to claim 7 or 8, characterized in that it comprises the antibacterial agent in an amount of 0.05 to 0.2 percent by weight, based on the oral hygiene product.

10. Mnd care agent according to claim 7 or 8, characterized in that the weight ratio of methylpyrrolidone chitosan to antibacterial agent in the range of 5: 1 to 1: 1 and is preferably about 2: 1.

11. Oral care product according to one of claims 1 to 10, in the form of a chewable tablet, a toothpaste, a Zahn¬ powder, a mouthwash, a dental gel, a Formu¬ lation against halitosis, a chewing gum, a saliva liquid or a Touchierlösung.

12. Use of the polymer as defined in claim 1 defi niert for the preparation of an oral hygiene product for the prevention or treatment of caries.