WO2020222095A1

WO2020222095A1 - Quaternary ammonium alkyl component containing oral care composition for treating caries

Info

Publication number: WO2020222095A1
Application number: PCT/IB2020/053871
Authority: WO
Inventors: Ingo Haeberlein; Brenda Schmid; Melanie Hauke; Ajmal SAFI
Original assignee: 3M Innovative Properties Company
Priority date: 2019-04-29
Filing date: 2020-04-23
Publication date: 2020-11-05
Also published as: EP3962444A1

Abstract

The invention relates to a composition for use in a method of treating caries by reducing the lactic acid release of lactic acid releasing bacteria in an oral biofilm in the mouth of a human being or animal, the composition comprising quaternary ammonium alkyl component(s) or mixtures thereof dissolved or dispersed in water in an amount of at least 0.005 wt.%. The invention also relates to a kit of parts for use in a method of treating caries by reducing the lactic acid release of lactic acid releasing bacteria in an oral biofilm in the mouth of a human being or animal, the kit of parts comprising Part A comprising certain quaternary ammonium alkyl component(s) or mixtures thereof or mixtures thereof, Part B comprising water, and optionally Part C comprising an application device.

Description

QUATERNARY AMMONIUM ALKYL COMPONENT CONTAINING ORAL CARE COMPOSITION FOR TREATING CARIES

Field of the Invention

The invention relates to a composition for use in a method of treating caries or reducing the risk of getting caries lesions by reducing the lactic acid release of lactic acid producing bacteria in an oral biofilm in the mouth of a living human or animal being.

The composition comprises certain quaternary ammonium alkyl component(s) dissolved or dispersed in water, optionally in combination with a carrier material.

Background

Dental plaque, which may include bacteria such as Streptococcus mutans, comprises a biofilm that forms on surfaces in the oral cavity. Dental plaque is at least partly responsible for dental caries, gingivitis, and periodontal diseases.

Bacteria in dental plaque metabolize carbohydrates (for example, simple sugars) in the mouth and produce organic acids that can etch tooth enamel, dentin, and cement. Dental plaque can serve as a substrate for the deposition of tartar or calculus. Build-up of dental plaque and calculus can lead to gingivitis and, ultimately, to periodontal disease.

A currently available method to remove dental plaque from teeth is mechanical removal with, for example, dental floss or a toothbrush. A toothbrush can aid in removing dental plaque from exposed surfaces of a tooth, and dental floss can aid in removing dental plaque from, for example, interproximal and subgingival surfaces. Proper and regular use of dental floss and a toothbrush can mechanically remove or reduce dental plaque, and can reduce the incidence of dental caries, gingivitis, and periodontal disease. Certain antimicrobial formulations are available (in the form of mouthwashes, rinses, and toothpastes, for example) to aid in the control and treatment of dental plaque, dental caries, gingivitis, and periodontal disease.

Prevention of caries often focuses on prevention of dental plaque formation and dental plaque removal from tooth surfaces. Thus, various attempts have been made to provide an oral composition which is suitable for cleaning teeth and/or reducing the amount of plague and oral biofilm.

Daily clinical experience, however, indicates that most of the dental plaque prevalent in patient’s mouth do not necessarily cause tooth demineralization, irrespective of the dietary behaviour of patients. Thus, recent clinical publications indicate, that the amount of plaque, which is permanently present in patient’s mouth, is almost little correlated with patient’s caries risk.

Meanwhile, it is also reported that dental caries results from an imbalance of the metabolic activity in the individual dental biofilm. This reflects the daily clinical experiences that only a small fraction of dental plaque might end up in tooth demineralization. Even more, certain studies with dental biofilm revealed that the bacterial composition of dental plaque does not necessarily indicate the prevailing metabolic (caries) activity of the individual dental plaque.

Attempts to influence the formation of biofilm and/or prevent the formation of plaque are described in various documents.

US 2001/0006622 A1 (Heckendorn et al.) describes a certain aminohydrofluoride component with an anti -bacterial and caries-prophylactic effect and its use in oral hygiene preparations. The aminohydrofluoride is said to inhibit the sugar degradation in acid- producing plaque bacteria and, owing to the formation of a hydrophobic film, increase the acid resistance of the hard tooth substance and thus have caries-prophylactic action. They also favour the remineralization of initial carious lesions.

WO 2014/094900 A1 (GABA International) relates to an oral care composition comprising an amine fluoride and an acidic polymer, wherein the amine fluoride and acidic polymer have first and second reactive groups which are arranged to react together to form a cross-linked copolymer of the amine fluoride and acidic polymer. The cross- linked polymer is said to provide significant protection against acidic attack of the tooth surface.

US 4,088,752 (Muhlemann et al) describes an oral care composition for plaque and inhibition containing a salt of an oxo-acid of phosphorous or mixed salt of an oxo-acid of phosphorous and hydrofluoric acid with an organic base. It is outlined that it is advantageous if basic groups are neutralized with hydrogen fluoride. The use of sodium fluoride and sodium trimetaphosphate are said to be effective and that the cariostatic effect was additive.

Geradu et al. (Eur J Oral Science (2007), 115, 148-152) refers to a study about plaque formation and lactic acid production after the use of amine fluoride / stannous fluoride mouth rinses. It is outlined that a daily use of AmF / SnF₂ rinse does not result in a reduction of plaque formation or in a reduction of sucrose metabolism in buccal and interproximal plaque.

Other attempts focus on the prevention of tooth demineralisation by applying fluoride products.

In this respect, typically highly concentrated fluoride gels are topically applied to a patient's teeth.

E.g., US 2013/0209375 A1 (Moy Argilagos et al.) suggests an oral care composition comprising a liquid phase containing water, dissolved tin, 200 to 2,000 ppm fluoride ions, 5-60 wt.% of a certain sugar alcohol and a certain organic acid salt.

However, sometimes a high exposure to fluoride is not always desirable as some of the fluoride may be absorbed into the body during the treatment.

Description of the Invention

None of the attempts suggested so far is completely satisfying.

As noted above, proper and regular use of dental floss and a toothbrush can reduce the amount of dental plaque.

However, clinical experience seems to indicate that irrespective of daily use of dental floss and/or a toothbrush, dental biofilm remains present on many tooth surfaces.

Moreover, a biofilm matrix such as dental plaque may contribute to the isolation of bacteria from the protective effect of antimicrobial compounds and, thus, may interfere with the function of antimicrobial formulations such as mouthwashes, rinses, and toothpastes. As a result, alternative methods and compositions to control or prevent the risk of caries are desirable.

In particular, it would be desirable to have a composition which is able to influence metabolic balances residing in oral biofilms which are left in a patient’s mouth. Such a composition should be easy in administering and simple in use.

Ideally, the composition should be easy to prepare and reasonable in price of manufacturing.

Further, the composition should not have undesired side effects like bad taste or being astringent.

There is also a desire for a product which does not require the application of high fluoride dosages to a patient. One or more of the above objects are addressed by the invention described in the present text.

In one embodiment the present invention features a composition, in particular an oral care composition, for use in a method of treating caries or reducing the risk of getting caries by reducing the lactic acid release of lactic acid producing bacteria in an oral biofilm in the mouth of a human being or animal, the composition comprising quaternary ammonium alkyl component(s) or mixtures thereof as described in the present text and claims dissolved or dispersed in water and being present in an amount of at least 0.005 wt.% with respect to the composition.

The invention is also related to a kit of parts as described in the present text and claims for use in a method of treating caries or reducing the risk of getting caries by reducing the lactic acid release of lactic acid producing bacteria in an oral biofilm in the mouth of a human being or animal, the kit of parts containing Part A comprising quaternary ammonium alkyl component(s) or mixtures thereof as described in the present text and claims, Part B comprising water, and optionally Part C comprising an application device.

Described is also a method of using the composition or kit of parts as described in the present text and claims, the method comprises the step of brining the composition in contact with oral biofilm and/or hard dental tissue in the mouth of a human being or animal. The invention is also directed to the use of certain quaternary ammonium alkyl component(s) or mixtures thereof as described in the present text and claims for producing a composition or a kit of parts as described in the present text and claims for use in a method of treating caries or reducing the risk of getting caries by reducing the lactic acid release of lactic acid producing bacteria in an oral biofilm in the mouth of a human being or animal.

It has been found that the treatment of caries is particular effective for patients (human beings and animals) which have or suffer from xerostomia.

Unless defined differently, for this description the following terms shall have the given meaning:

A "composition" is understood to be a mixture of two or more components.

A "dental or oral care composition" is a composition which is to be used in the dental field (including restorative and prosthodontic work) including the orthodontic area. In this respect the composition should be not detrimental to the patient's health and thus free of hazardous and toxic components being able to migrate out of the composition. Commercially available products have to fulfil certain requirements such as those given in DIN EN ISO 1942:2011-03.

As used herein, a "dental surface" or“dental hard tissue” refers to tooth structures (e. g., enamel, dentin, and cementum) and bone.

A“tooth structure” is any tooth structure, prepared or ready for preparation by the dentist. It can be a single tooth or two or more teeth. A tooth structure is also referred to as hard dental tissue in contrast to soft dental tissue (e.g. gingival).

“Caries” is understood as tooth decay, also known as dental caries which is a demineralization and/or breakdown of teeth due to acids made by bacteria.

“Dental plaque” is understood as is a biofilm or mass of bacteria that grows on surfaces within the mouth.

The term“biofilm” refers to a matrix containing bacteria. A biofilm in an oral cavity can include bacteria, epithelial cells, leukocytes, macrophages and further oral exudate. A“paste” is a substance that behaves as a solid until a sufficiently large load or stress is applied, at which point it flows like a fluid. Pastes typically consist of a suspension of granular material in a background fluid. The individual grains are jammed together like sand on a beach, forming a disordered, glassy or amorphous structure, and giving pastes their solid-like character. Pastes can be classified by their viscosity or their consistency comparable to dental impression material.

A“film forming component” is a substance which will cause a composition containing it to change from a liquid stage to a solid stage in such a manner as to form a film or coating on a surface. A definition of the term“film former” can also be found in DIN 55945 (1999-07-00). The term “film former” is often used in varnishes. The substance hydroxyethyl methacrylate (HEMA) cannot be regarded as a film former according to this definition.

A“film” is a thin sheet or strip of a preferably flexible material. A coating of a surface with a material typically results in a film.

A“toothpaste” (dentifrice) is a cleaning agent for the daily individual care. It is typically used as a prophylactic measure against caries, gingivitis or periodontitis. In contrast to this, a“prophylaxis paste” is a product which is used by a profession such as a dentist or a dental hygienist to remove adherent deposits such as stain, plaque or tartar which may stick to the surface of a natural tooth, artificial tooth crown or bridge or filling material. A prophylaxis paste is therefore typically used on slowly rotating paste carrier (sometimes also referred to as prophy cups). Most of the commercially available prophylaxis pastes have a different viscosity compared to toothpastes.

A“gel” is typically a colloidal system in which a porous matrix of interconnected particles spans the volume of a liquid medium. In general, gels are apparently solid, jelly- like materials. Both by weight and volume, gels are mostly liquid in composition and thus exhibit densities similar to liquids, however, have the structural coherence of a solid. An example of a common gel is edible gelatine. Many gels display thixotropy, that is, they become fluid when agitated, but re-solidify when resting. A“solvent” means a liquid which is able to at least partially disperse or dissolve a component at ambient conditions (e.g. 23°C). A solvent typically has a viscosity below 5 or below 1 or below 0.1 Pa*s at 23°C.

A“particle” means a substance being a solid having a shape which can be geometrically determined. Particles can typically be analysed with respect to e.g. grain size.

The mean particle size of a powder can be obtained from the cumulative curve of the grain size distribution and is defined as the arithmetic average of the measured grain sizes of a certain powder mixture. Respective measurements can be done using commercially available granulometers (e.g. CILAS Laser Diffraction Particle Size Analysis Instrument).

“Ambient conditions” mean the conditions which the inventive solution is usually subjected to during storage and handling. Ambient conditions may, for example, be a pressure of 900 to 1100 mbar, a temperature of 10 to 40 °C and a relative humidity of 10 to 100 %. In the laboratory ambient conditions are adjusted to 20 to 25 °C and 1,000 to 1,025 mbar.

A composition is“essentially or substantially free of’ a certain component, if the composition does not contain said component as an essential feature. Thus, said component is not wilfully added to the composition either as such or in combination with other components or ingredient of other components. A composition being essentially free of a certain component usually does not contain that component at all. However, sometimes the presence of a small amount of the said component is not avoidable e.g. due to impurities contained in the raw materials used.

As used herein, "a", "an", "the", "at least one" and "one or more" are used interchangeably. The terms "comprise" or“contain” and variations thereof do not have a limiting meaning where these terms appear in the description and claims. Also herein, the recitations of numerical ranges by endpoints include all numbers subsumed within that range (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.).

The terms "comprise" or“contain” and variations thereof do not have a limiting meaning where these terms appear in the description and claims.“Consisting essentially of’ means that specific further components can be present, namely those which do not materially affect the essential characteristic of the article or composition.“Consisting of’ means that no further components should be present. The term“comprise” shall include also the terms“consist essentially of’ and“consist of’.

“And/or” means one or both. E.g., the expression component A and/or component B refers to a component A alone, component B alone, or to both component A and component B.

Adding an“(s)” to a term means that the term should include the singular and plural form. E.g. the term“additive(s)” means one additive and more additives (e.g. 2, 3, 4, etc.).

Unless otherwise indicated, all numbers expressing quantities of ingredients, measurement of physical properties such as described below and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about".

Detailed Description

It has been found that by application of a composition comprising certain quaternary ammonium component(s) or mixtures thereof dissolved or dispersed in water as described in the present text, the lactic-acid release of lactic-acid releasing bacteria in the oral biofilm in the mouth of a living human or animal being can be significantly reduced.

As the lactic-acid release capacity is typically correlated with the caries activity of the oral biofilm, the composition described in the present text provides an effective means for reducing the risk of caries lesions.

Unexpectedly, this effect was observed even, if no further active components such as fluoride ions, hydroperoxides, hypochlorite, or heavy metal components etc. were present. This is in contrast to what is provided in the prior art.

As outlined in the examples described below, an in-vitro human saliva derived microcosm biofilm was used to apply the quaternary ammonium alky component described in the present text twice a day for at least 1 min each. In comparison to a control it was observed that an increasing concentration of the quaternary ammonium alkyl component lower lactic acid release of an oral microcosm biofilm substantially in presence of sucrose.

In comparison to a control it was also observed that increasing concentrations of the quaternary ammonium alkyl component lower the biofilm mass formation of an oral microcosm when continuously applied whereas a periodical application of the quaternary ammonium alkyl compound (e.g. twice a day) cause only little to moderate decline of biofilm mass formation.

Without wishing to be bound to a certain theory, this indicates that the quaternary ammonium alkyl component(s) can be used either as a biofilm metabolism control agent or as an agent for modifying the structure of the biofilm or as an agent functioning as a kind of cell membrane modifying agent. Independent of the mechanism, the quaternary ammonium alkyl component is effective for treating caries or reducing the risk of getting caries lesions.

The cell membrane modifying agent primarily refers to the cell membrane of the cells of the bacteria forming the biofilm and of the extra-cellular membranes constituting the biofilm.

The oral care composition described in the present text is designed to move from a plaque formation inhibition composition or dental plaque removal composition or biofilm reducing composition to a composition allowing the control of the metabolic balance on dental plaque.

The invention shows that certain quaternary ammonium alkyl component(s) are effective to accomplish caries activity control in a dental biofilm, i.e. being able to influence the metabolic balance of the dental biofilm.

Further, compared to previously used active components, the quaternary ammonium alky component(s) proposed in the present text are easily available at reasonable costs and essentially non-toxic to the patient.

In addition, as the quaternary ammonium component described in the present text does not comprise fluoride ions, the risk that this component has side-effects due to undesired interaction of fluoride ions with the human body is reduced or sometimes even eliminated.

The specific effect and mechanism which can be obtained by using the components and/or compositions described in the present text has not been reported or suggested in the prior art.

The oral care composition described in the present text for use in a method or therapy of treating caries by reducing the lactic acid release of lactic acid producing bacteria in an oral biofilm of a human or animal being comprises certain quaternary ammonium alkyl component(s) or mixtures thereof.

These quaternary ammonium alkyl component(s) can be characterized by the following formula:

R-N(CH₂CH₂OH)-CH₂CH₂CH₂-N(CH₂CH₂OH)₂ * 2HX

with R being selected from C_10-20 alkyl and X being selected from chloride, (hydrogen)carbonate, (hydrogen)sulphate, (hydrogen/di-hydrogen)phosphate, wherein chloride is typically preferred.

The formula refers to the quaternary ammonium (hydrogen)chloride, (hydrogen)carbonate, (hydrogen)sulphate or (hydrogen/di-hydrogen)phosphate salts of N'- Octadecyltrimethylenediamino-N,N,N'-tris(2-ethanol).

The carbon chain R is typically selected from decyl, dodecyl (lauryl), terradecyl (myristyl), hexadecyl (cetyl, palmityl), octadecyl (stearyl), eicosanyl, 9-cis-octadecen-1-yl (oleyl), 9-trans- octadecen-1-yl (elaidyl), cis,cis-9,1 2-octadecadien-1-yl (linolyl), cis,cis,cis-9,12,15- octadecatrien-1-yl (linolenyl) or 9-cis-eicosaen-1-yl (gadolyl).

The quaternary ammonium alkyl component comprises at least one of N,N,N'- tris(2-hydroxyethyl)-N'-octadecylpropane-1, 3-diamine dihydrochloride, N,N-bis(2- hydroxyethyl)oleylamine hydrochloride, and N,N-bis(2-hydroxyethyl)octadecylamine hydrochloride.

A preferred ammonium component which can be used is N'- Octadecyltrimethylendiamino-,N,N' - tris(2-ethanol)-dihydrochloride having the following structure:

The reduction of the lactic acid release can be determined as described in the example section.

The quaternary ammonium alky component(s) according to the present text are present in the composition in an amount of at least 0.005 wt.% with respect to the whole composition.

Other useful amounts for the quaternary ammonium alkyl component(s) include:

Lower limit: at least 0.005 or at least 0.05 or at least 0.1 wt.%;

Upper limit: utmost 5 or utmost 2 or utmost 1 wt.%;

Range: 0.005 to 5 or 0.05 to 2 or 0.1 to 1 wt.%;

wt.% with respect to the whole composition.

The oral care composition also comprises water.

Water is used for dissolving the quaternary ammonium alky component(s) contained in the composition, at least partially.

Water is typically present in an amount sufficient to fully dissolve the quaternary ammonium alky component(s) and other optional components being present in the composition.

It has been found that the desired effect of reducing the lactic-acid release can be achieved more effectively, if the quaternary ammonium component(s) are present in dissolved form in the composition.

The composition may comprise water in the following amounts:

Lower limit: at least 5 or at least 10 or at least 20 wt.%;

Upper limit: utmost 98 or utmost 95 or utmost 90 wt.%;

Range: 5 to 98 or 10 to 95 or 20 to 90 wt.%; wt.% with respect to the whole composition.

The following ratios were found to be particularly effective for achieving the desired result.

The ratio of quaternary ammonium alkyl component(s) to water is typically at least 0.005 / 100, or at least 0.05 / 100, or at least 0.1 / 100 with respect to weight.

The ratio of the quaternary ammonium component(s) to water can be in a range of 0.005 / 100 to 5 / 100, or in a range 0.05 / 100 to 2 / 100, or in a range of 0.1 / 100 to 1 / 100 with respect to weight.

The oral care composition may also comprise one or more carrier components. The nature and structure of the carrier component is not particularly limited, unless the desired result cannot be achieved.

Carrier components may help to adjust the rheological properties of the composition, to support the application and/or to trigger the release of active agent(s) contained in the composition.

If present, the carrier component is typically present in the following amount(s):

Lower limit: at least 1 or at least 2 or at least 5 wt.%;

Upper limit: utmost 90 or utmost 80 or utmost 70 wt.%;

Range: 1 to 90 or 2 to 80 or 5 to 70 wt.%;

wt.% with respect to the whole composition.

Different kinds of carrier components can be used, if desired.

Suitable carrier components are gel-forming components or paste-forming components.

Useful examples of gel-forming or paste-forming components include Irish moss, carboxymethyl cellulose, gum tragacanth, gum arabic, gum Karaya, sodium alginate, hydroxyethyl cellulose, methyl and ethyl cellulose, carrageenan, xanthan gum, polyvinyl pyrrolidone, and mixtures thereof.

These gel-forming or paste-forming components do not have abrasive properties with respect to the tooth surface. According to one embodiment, the carrier component is a film-forming agent.

Film-forming agents are suitable to improve adherence of the quaternary ammonium alkyl component(s) contained in the composition described in the present text to hard dental tissue, such as a tooth surface.

If film-forming agent(s) are present, the components contained in the composition described in the present text are typically dissolved or dispersed in the film forming component(s) and form together with the film forming component(s) a film or coating on the surface of hard dental tissue.

The molecular weight (Mw) of the film-forming agent can vary over a wide range (e.g. 2,000 to 1,200,000 g/mol). Typical ranges include 10,000 to 500,000 or 20,000 to 300,000 g/mol.

If desired, the molecular weight can be determined by GPC technology, using e.g. a polystyrene standard.

If the molecular weight of the film-forming agent is too low, the film forming component might not be able to form a sufficiently durable film or coating. Thus, the effect of a delayed release of the quaternary ammonium alkyl component might not be obtained. E.g., components like 2-hydroxy ethyl acrylate (HEMA), which are sometimes classified as film-forming agents, are not suitable as film forming component in the sense of the present text.

The film caused or produced by the film-forming agent typically has a thickness in a range of 0.5 mm to 100 mm or 10 mm to 50 mm.

Film formers or film-forming agents can be classified as natural film former, semi synthetic film formers, cellulose derivatives, poly(meth)acrylates and vinyl polymers.

Examples of natural film-forming agents include shellac, mastix, sandarac, tolubalsam, dammar resin, benzoe resin, keratin, maizin, gum Arabic and gelatines.

Examples of semi-synthetic film-forming agents include gelatines treated with formaldehyde and salol (acetaldehyde phenol condensate). Typical cellulose derivatives include cellulose acetate phthalate, hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose and hydroxypropylmethyl cellulose phthalate.

Examples of poly(meth)acrylates include copolymers of (meth)acrylic esters and amino functional (meth)acrylates, copolymers of (meth)acrylic acid and methyl methacrylate, polyacrylamide, polyacrylic acid and salts thereof, in particular partial salts thereof, including sodium salts.

Examples of vinyl polymers include polyvinyl pyrrolidon, polyvinyl acetate phthalate (e.g. hydroxypropyl- and hydroxypropyl-methylcellulose), homo- and copolymers of polyvinylacetate, homo- and copolymers of polyvinylpropionate, styrene acrylics, ethylene vinyl acetate, poly(hydroxyethyl methacrylate, poly(vinylethylene glycol acrylate, polyvinyl alcohol(s).

Particular examples for film-forming agent(s) include (e.g. fully or partially hydrolyzed) polyvinylalcohol, polymethylvinylether, polyvinylpyrrolidone, (e.g. aqueous) acrylic resin dispersions (e.g. Eudragit™, commercially available from Rohm), gelatine, polysaccharides (e.g. agarose), polyacrylamide, copolymers of vinylpyrrolidinone and acrylamide, hydrophilic cellulose derivatives (e.g. hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose), homo- and copolymers of polyvinylacetate, homo- and copolymers of polyvinylpropionate, styrene acrylics, ethylene vinyl acetate, polyurethanes, hydroxylated acrylates such as poly(hydroxyethyl methacrylate), poly(vinylethylene glycol acrylate), and combinations and mixtures thereof.

Examples of film-forming agents which are sometimes preferred include polyvinyl alcohol, gelatine, polyacrylic acid, partially neutralized polyacrylic acid and mixtures thereof.

If a film-forming agent is present, it is typically present in the following amounts:

Lower limit: at least 5 or at least 10 or at least 20 wt.%;

Upper limit: utmost 90 or utmost 80 or utmost 70 wt.%;

Range: 5 to 90 or 10 to 80 or 20 to 70 wt.%;

wt.% with respect to the whole composition. If desired, according to a further embodiment, the composition described in the present text may also comprise abrasive particles.

Examples of abrasive particles which may be present include perlite, bentonite, silica, alumina, aluminium hydroxide, ilmenite (FeTiO₃), zircon oxide, zircon silicate, calcium carbonate, sodium bicarbonate, titanium dioxide, precipitated lime, chalk, flour of pumice, zeolites, talcum, kaolin, kieselguhr, aluminium oxide, silicates and mixtures thereof.

The oral care composition described in the present text for use in a method or therapy of modifying the structure of an oral biofilm containing lactic acid producing bacteria of a living human or animal being may also comprise one or more amino acids.

There is no need for amino acids to be present, however, the presence of certain amino acids in combination with the quaternary ammonium alkyl component(s) may further help or even improve the efficacy or capacity of the oral care composition described in the present text.

The use of amino acids for reducing lactic acid release of lactic acid producing bacteria in an oral biofilm is described in European patent application number 18183601.6. The content of this application is herewith incorporated by reference. As described in EP 18183601.6, not all kinds of amino acids were found to be useful, but only a few.

By using a combination of the quaternary ammonium alkyl component(s) described in the present text in combination with certain amino acids has the following benefit.

On the one hand, the amino component(s) are used for modifying the structure of the oral biofilm and thus have an influence on the overall environment where the lactic acid producing bacteria are located.

On the other hand, the amino acid(s) have a direct impact on the metabolism of the lactic acid releasing bacteria.

The following amino acids were found to be useful for achieving the desired results: glycine, leucine, isoleucine, lysine, methionine, phenylalanine, serine, threonine, valine, tryptophan and mixtures thereof, with the following amino acids being sometimes preferred: glycine, phenylalanine, serine, isoleucine, leucine, methionine, with glycine and phenylalanine being sometimes being even more preferred.

The amino acids may be natural or synthetic.

The amino acids might be in D- or L-configuration, wherein the L-configuration is preferred.

In contrast, the following amino acids were found to be not effective for reducing the lactic-acid release of bacteria in a biofilm: proline, arginine, histidine, aspartic acid, glutamine, tyrosine and are therefore not suggested for this particular use.

According to one embodiment, the composition described in the present text does typically not contain these amino acids in an effective amount, e.g. more than 0.5 or more than 0.3 or more than 0.1 wt.%.

On the other hand, the amino acids selected from glycine, leucine, isoleucine, lysine, methionine, phenylalanine, serine, threonine, valine, tryptophan and mixtures thereof are present in an amount sufficient for achieving the desired result.

If present, the amino acids contained in the oral care composition are used in a therapeutically effective amount being sufficient to influence the lactic acid release metabolism of lactic acid releasing bacteria in an oral biofilm.

If present, the composition and the amino acids contained therein are used for a time period being sufficient to influence the lactic acid release metabolism of lactic acid releasing bacteria in an oral biofilm.

More precisely, the composition and the amino acids contained therein are typically present in an amount and applied for a time period effective to reduce the lactic acid release of lactic acid producing bacteria by more than 40% or more than 45% compared to the situation before the oral care composition described in the present text was used.

A suitable method for determining the effectiveness is described in the example section.

If present, the amino acid(s) are typically present in the following amounts: Lower limit: at least 0.1 or at least 1 or at least 2 wt.%;

Upper limit: utmost 15 or utmost 12 or utmost 10 wt.%;

Range: 0.1 to 15 or 1 to 12 or 2 to 10 wt.%;

wt.% with respect to the whole composition.

Depending on the amino acid used, certain concentrations might be even more effective than others.

If present, the following concentrations or amounts were found to be particular effective:

glycine in an amount of 0.1 to 10 wt.%; or

leucine in an amount of 0.1 to 5 wt.%; or

isoleucine in an amount of 0.1 to 5 wt.%; or

lysine in an amount of 0.1 to 10 wt.%; or

methionine in an amount of 0.1 to 10 wt.%; or

phenylalanine in an amount of 0.1 to 5 wt.%; or

serine in an amount of 0.1 to 10 wt.%; or

threonine in an amount of 0.1 tolO wt.%; or

valine in an amount of 0.1 to 8 wt.%; or

tryptophan in an amount of 0.1 to 2 wt.%;

wt.% with respect to the whole composition.

If present, the following concentrations or amounts were found to be effective, as well: glycine in an amount of 1 to 10 wt.%; or

leucine in an amount of 1 to 5 wt.%; or

isoleucine in an amount of 2 to 5 wt.%; or

lysine in an amount of 5 to 10 wt.%; or

methionine in an amount of 2 to 10 wt.%; or

phenylalanine in an amount of 1 to 5 wt.%; or

serine in an amount of 1 to 10 wt.%; or

threonine in an amount of 6 to 10 wt.%; or

valine in an amount of 3 to 8 wt.%; or

tryptophan in an amount of 0.5 to 2 wt.%;

wt.% with respect to the whole composition. The following ratios were found to be particularly effective for achieving the desired result.

If present, the ratio of amino acid(s) to water is typically at least 0.1 / 100, or at least 1.5 / 100, or at least 2 / 100 with respect to weight.

If present, the ratio of amino acid(s) to water can be in a range of 0.1 / 100 to 15 / 100, or in a range / 1.5 to 100 to 12 / 100, or in a range of 2 to 100 to 10 to 100 with respect to weight.

If amino acid(s) are present, the ratio of the quaternary ammonium alkyl component(s) to amino acid(s) is typically at least 1 / 0.5 or at least 1 / 1 or at least 1 / 2.

If present, the ratio of the quaternary ammonium alkyl component(s) to amino acid(s) can be in a range of 1 / 0.5 to 0.1 / 5, or in a range 1 / 1 to 1 / 5, or in a range of 1 / 2 to 1 / 5 with respect to weight.

The oral care composition described in the present text may also comprise additive(s). One or more additives can be present, if desired.

If present, additive(s) are typically present in the following amount(s):

Lower limit: at least 0.01 or at least 0.1 or at least 0.5 wt.%;

Upper limit: utmost 10 or utmost 8 or utmost 6 wt.%;

Range: 0.001 to 10 or 0.1 to 8 or 0.5 to 6 wt.%;

wt.% with respect to the whole composition.

Additive(s) which might be present include stabilizer(s), fluoride releasing agent(s), colourant(s), phosphate releasing agent(s), calcium releasing agent(s), anti microbial agent(s), buffer(s), surfactant(s), humectant(s), preservative agent(s), flavour additive(s) and mixtures thereof.

The composition might contain one or more stabilize^ s) as an additive.

If a stabilizer is present, the storage stability of the dental composition might be improved. That is, the individual components of the composition do not separate over time. A composition is defined as storage-stable, if the components do not separate from each other within 6 months or 12 months or 24 months or 36 months at ambient conditions. If a stabilizer is present, it is typically, present in a low amount.

Amounts, found to be useful, include 0.01 to 3 wt.% or 0.1 to 1 wt.% with respect to the weight of the whole composition.

Examples of stabilizer(s) include copolymers of 2,5-furandione with 1,9-decadiene and methoxyethene (e.g. Stabilize™, International Specialty Products (ISP) Comp.) and carboxy vinyl polymers (e.g. Carbopol™, Lubrizol Advanced Materials Comp.).

Stabilizers typically have a mean particle size below 500 mm or below 250 mm or below 100 mm.

In a further embodiment, the composition comprises one or more colourants. There is no need for a colourant to be present at all.

However, if it is present, it is typically present in an amount of at most 5 wt.% or of at most 3 wt.% or of at most 1 wt.% with respect to the whole composition. Typical ranges include 0.01 wt.% to 5 wt.% or 0.1 wt.% to 3 wt.% with respect to the whole composition.

The presence of a colourant may allow an easy detection in a patient's mouth

(especially compared to oral tissue and/or tooth substance) and control whether after the treatment all residues of the composition have been removed. E.g., a blue, green or violet colour may be suitable. Colouring of the dental composition can be achieved by incorporating colorants or pigments (organic and inorganic) into the composition.

Examples of colourants include red iron oxide 3395, Bayferrox™ 920 Z Yellow,

Neazopon™ Blue 807 (copper phthalocyanine-based dye) or Helio Fast Yellow ER and mixtures thereof.

In a further embodiment, the composition comprises one or more phosphate releasing agent(s) as an additive.

There is no need for a phosphate releasing agent to be present at all.

However, if it is present, it is typically present in an amount of at most 5 wt.% or of at most 3 wt.% or of at most 2 wt.% with respect to the whole composition. Typical ranges include 0.01 wt.% to 5 wt.% or 0.1 wt.% to 3 wt.% with respect to the whole composition. Examples of phosphate and/or calcium releasing agent(s) include calcium pyrophosphate, calcium carbonate, dicalcium phosphate dehydrate, amorphous calcium phosphate, casein phosphopeptide, calcium sodium phosphosilicate, trimetaphosphate, and mixtures thereof. In another embodiment, the composition comprises anti-microbial agent(s).

There is no need for an anti-microbial agent to be present at all.

However, if it is present, it is typically present in an amount of at most 2 wt.% or of at most 1 wt.% or of at most 0.5 wt.% with respect to the whole composition. Typical ranges include 0.01 wt.% to 2 wt.% or 0.1 wt.% to 1 wt.% with respect to the whole composition.

The presence of an anti-microbial agent might help reducing health risks for professionals in the dental offices and laboratories as well as for patients.

Useful anti-microbial agents include chlorhexidine or derivatives thereof and aldehydes (glutaraldyde, phthalaldehyde) and chlorhexidine or its derivatives and salts of phenolics or acids. It can also be preferred to use acid adducts of chlorhexidine or its derivatives like e.g., acetates, gluconates, chlorides, nitrates, sulphates or carbonates.

Chlorhexidine and its derivatives (hereinafter referred to as CHX) are commercially available in water-based solutions (e.g. a 20 % aqueous solution of CHX di gluconate, CAS 18472-51-0) or as a pure compound or as a salt. As additive the pure Chlorohexidine compound (CAS 55-56-1) and CHX salts like CHX diacetate monohydrate (CAS 56-95-1) or CHX dihydrochloride (CAS 3697-42-5) are preferred.

CHX also seems to be especially suited as an additive due in part to its well-known and proven anti-microbial action against Gram-positive and Gram-negative microorganisms including the oral Streptococci and Lactobacilli. CHX is bacteriostatic for Mycobaterium. CHX is also active against yeasts including Candida albicans and viruses including HIV, HBV, HCV, Influenza- and Herpes virus. A further advantage of CHX is its low toxicity.

Preferred anti-microbial agents include hexitidin, cetypyridiniumcloride (CPC), chlorhexidin (CHX), triclosan, stannous chloride, benzalkonium chloride, non-ionic or ionic surfactants (e.g. quaternary ammonium compounds), alcohols [monomeric, polymeric, mono-alcohols, poly-alcohols (e. g. xylitol, sorbitol), aromatic (e. g. phenol)], antimicrobial peptides (e. g. histatins), bactericins (e. g. nisin), antibiotics (e. g. tetracycline), aldehydes (e. g. glutaraldehyde) inorganic and organic acids (e. g. benzoic acid, salicylic acid, fatty acids) or there salts, derivative of such acids such as esters (e. g. p-hydroxy benzoate or other parabenes, laurizcidin), enzymes (e. g. lysozyme, oxidases), proteins (e. g. enamel matrix protein, proline rich proteins), fluoride, EDTA, essential oils (e. g. thymol). In another embodiment, the composition can comprise one or more buffer(s) as an additive. There is no need for a buffer to be present at all.

However, if it is present, it is typically present in an amount of at most 5 wt.% or of at most 3 wt.% or of at most 2 wt.% with respect to the whole composition. Typical ranges include 0.1 wt.% to 5 wt.% or 1 wt.% to 3 wt.% with respect to the whole composition.

Examples of buffers, which can be used, include acetic acid/acetate, tris(hydroxy- methyl)aminomethane (TRIS), N-(2-acetamido)-2-aminoethane sulfonic acid (ACES), N- (2-acetamido)imminodiacetate (ADA), N,N-bis(2-hydroxyethyl)-2-aminoethane sulfonic acid (BES), 2, 2-bis-(hydroxyethyl)-iminotris(hydroxylmethyl)m ethane (BIS-TRIS), 2- (cyclohexylamino)ethane sulfonic acid (CHES), 2-[4-(2-hy droxy ethyl- 1- piperazine)]ethane sulfonic acid (HEPES), 3-[4-(2-hydroxyethyl-1-piperazinyl)]propane sulfonic acid (HEPPS), 2-morpholinoethane sulfonic acid (MES), 3-morpholinopropane sulfonic acid (MOPS), piperazine-1, 4-bis(2-ethane sulfonic acid (PIPES), N- [tris(hydroxymethyl)-methyl]-2-aminoethane sulfonic acid (TES), N-[tris(hydroxy- methyl)-methyl]-glycine (TRICINE), and phosphate buffers, in particular hydrogen phosphate / dihydrogen phosphate buffers such as Na₂HPO₄, NaH₂PO₄, K₂HPO₄, KH₂PO₄.

In a further embodiment, the dental composition comprises one or more surfactant(s) as an additive. There is no need for a surfactant to be present at all.

However, if it is present, it is typically present in an amount of at most 5 wt.% or of at most 3 wt.% or of at most 2 wt.% with respect to the whole composition. Typical ranges include 0.01 wt.% to 5 wt.% or 0.1 wt.% to 3 wt.% with respect to the whole composition. Examples of surfactant(s) which can be used include water-soluble salts of alkyl sulphates and alkyl ether sulphates having 8 to 18 carbon atoms in the alkyl moiety, water-soluble salts of sulfonated monoglycerides of fatty acids having 8 to 18 carbon atoms in the alkyl radical and mixtures thereof. More specific examples include sodium lauryl sulphate and sodium coconut monoglyceride sulfonates. The composition might contain one or more humectant(s) as an additive. There is no need for a humectant to be present at all.

However, if it is present, it is typically present in an amount of at most 5 wt.% or of at most 3 wt.% or of at most 2 wt.% with respect to the whole composition. Typical ranges include 0.01 wt.% to 5 wt.% or 0.1 wt.% to 3 wt.% with respect to the whole composition.

Examples of humectant(s) which can be used include glycerine, sorbitol, mannitol, xylitol, propylene glycol, polyethylene glycol and mixtures thereof.

Examples of preservative agent(s) which can be present include sodium benzoate, citric acid and its salts, and combinations thereof.

Examples of flavour additive(s) which can be used include peppermint, spearmint, and combinations thereof.

According to one embodiment, the composition comprises, consists essentially of or consists of:

Component A (quaternary ammonium alkyl component) in an amount of 0.005 to 5 wt.%;

Component B (water) in an amount of 5 to 98 wt.%;

Component C (carrier component) in an amount of 0 to 90 wt.%;

Component D (amino acid) in an amount of 0 to 15 wt.%;

Component E (additive) in an amount of 0 to 10 wt.%;

wt.% with respect to the whole composition.

Component A (quaternary ammonium alkyl component) in an amount of 0.05 to 5 wt.%;

Component B (water) in an amount of 5 to 98 wt.%; Component C (carrier component) in an amount of 1 to 90 wt.%;

Component D (amino acid) in an amount of 0 to 15 wt.%;

Component E (additive) in an amount of 0 to 10 wt.%;

wt.% with respect to the whole composition.

Component A (quaternary ammonium alkyl component) in an amount of 0.1 to 2 wt.%;

Component B (water) in an amount of 5 to 98 wt.%;

Component C (carrier component) in an amount of 1 to 90 wt.%;

Component D (amino acid) in an amount of 0.1 to 15 wt.%;

Component E (additive) in an amount of 0.1 to 10 wt.%;

wt.% with respect to the whole composition.

The composition typically has a pH value in the range of 6 to 8. Thus, the composition is essentially neutral.

The composition can also be characterized by its viscosity. Depending on its chemical formulation, the viscosity may vary over a huge range.

If the composition is provided as liquid, the viscosity is typically in a range of 1 to 10 mPa*s or 1 to 1,000 mPa*s at 23°C.

If the composition is provided as gel or paste, the viscosity is typically in a range of 2,000 to 200,000 mPa*s at 23°C.

If desired, the viscosity of liquids can be measured using a Physica MCR 301 Rheometer (Anton Paar, Graz, Austria) with a cone/plate geometry CP25-1 under controlled shear rate at 23 °C (e.g. 100 s^-1). The diameter is 25 mm, the cone angle 1°, and the separation between the cone tip and the plate 49 mm.

If desired, the viscosity of pastes can be determined using a Physica MCR 301 Rheometer (Anton Paar, Graz, Austria) with a plate/plate geometry (PP15) at a constant shear rate of 1 s^-1 in rotation at 28 °C. The diameter of the plates is 10 mm and the gap between the plates is set to 2.0 mm. The composition described in the present text can typically be produced as follows:

The quaternary ammonium alkyl component(s) is provided and mixed with water, the optional carrier component(s), amino acid(s) and the optional additive(s).

Depending on the nature of the optional carrier component(s) and additive(s), the mixing is done by dissolving or dispersing the amino acid(s) in the carrier component(s) and additive(s), if desired, with the aid of a mixing device.

The mixing can be accomplished shortly before the use of the oral care composition or the oral care composition can already be provided in a mixed and storage stable form.

The present invention is also directed to a kit of parts for use in a method or therapy of reducing the caries activity by reducing the lactic acid release in an oral biofilm.

The kit of parts typically comprises

Part A comprising the quaternary ammonium alkyl component(s) described in the present text,

Part B comprising water for dissolving or dispersing the quaternary ammonium component(s), optionally in combination with a carrier component,

and optionally Part C comprising an application device.

The other components, such as amino acid(s), carrier component(s) or additive(s) as described in the present text can be present in Part A or Part B or Part A and Part B, as desired.

Providing the components of the composition in separated parts can be beneficial to improve the storage stability.

Before use, the practitioner will prepare the oral care composition by combining the respective components of the individual parts.

The application of the oral care composition can be done by various means and/or using various devices.

Possible application devices include cups, sponges, brushes, dental trays, syringes, mouth guards, and clear tray aligners. Clear tray aligners can straighten a dental patient’s teeth without the need for using wires and brackets of traditional braces. The aligners typically consist of a sequence of clear, removable trays that fit over the teeth to straighten them.

Using the composition or kit of parts described in the present text in combination with a dental tray, mouth guard or clear tray aligner can be advantageous, as these kinds of devices are typically worn for a longer period of time (e.g. 10 min to 12 hrs) and thus are well suited for applying the oral care composition described in the present text for a longer period of time, if desired.

For use of the composition described in the present text in combination with a dental tray, mouth guard or clear tray aligner, providing the composition in the form of a paste or gel was found to be advantageous.

During storage, the oral care composition described in the present text is typically packaged in a suitable packaging device.

The size and shape of the packaging device typically depends on the form how the composition is provided.

Suitable packaging devices include sealable bottles, tubes, vessels or foil bags (including glass or plastic bottles, e.g. equipped with a screw cap), blisters, syringes, etc.

The packaging device might be designed for single-use or repeated use.

As outlined above, the quaternary ammonium alkyl component is used for producing an oral care composition or a kit of parts for a particular use as described in the present text.

In particular, the quaternary ammonium alkyl component is used as an agent for treating caries or reducing the risk of getting carious lesions by modifying the structure of an oral biofilm containing lactic acid producing bacteria.

The composition described in the present text may be provided in different forms or shapes.

According to one embodiment, the composition is provided as liquid, e.g. in the form of an oral rinse or a mouth wash.

According to another embodiment, the composition is provided as gel. According to another embodiment, the composition is provided as paste, e.g. in the form of a toothpaste.

According to another embodiment, the composition is provided as gum, e.g. in the form of a chewing gum.

According to another embodiment, the composition is provided in a form which results in a coating after application.

For causing the desired effect, the composition has to be brought in contact with the oral biofilm or hard dental tissue. The oral biofilm is typically located on tooth surfaces, in particular hard dental tissue.

The bringing into contact can be achieved by different means, including rinsing, spraying, brushing, swabbing, coating or combinations thereof.

The bringing into contact is typically done for a time period being sufficient for causing the desired effect.

The bringing into contact is typically done for a duration of at least 1 min or of at least 2 min or at least 3 min or at least 4 min.

If desired, the step of bringing into contact can be repeated several times.

According to one embodiment, the oral care composition is applied in periodic application scheme.

Possible daily repeating schemes for a periodic application scheme are:

at least 2 times for at least 1 min within 24 hours;

at least 3 times for at least 1 min within 24 hours.

These kinds of repeating schemes are typically applied, if the oral care composition is provided in the form of a mouth wash or toothpaste.

According to one embodiment, the oral care composition is applied in a continuous application scheme.

Possible daily repeating schemes for a continuous application scheme are:

at least 1 hour within 24 hours;

at least 5 hours within 24 hours. These kinds of repeating schemes are typically applied, if the oral care composition is provided in the form of a gel or varnish to be applied either directly on the surface of the tooth structure or with the help of an application device.

Both application schemes can be repeated, if desired.

According to a further embodiment, the composition described in the present text is applied to form a coating or film which can persist on a tooth surface for at least 2 or 5 or 10 days up to 12 months or even longer.

Such a composition typically contains film-forming agent(s).

Suitable film-forming agents are described above.

All components used in the dental composition of the invention should be sufficiently biocompatible, that is, the composition should not produce a toxic, injurious, or immunological response in living tissue.

According to certain embodiments, the composition described in the present text does typically not comprise the following components alone or in combination:

oxidizing components in an amount of more than 0.5 wt.%;

heavy metal components comprising Zn, Sn or Cu in an amount of more than 0.1 wt.%;

fluoride anions in an amount of more than 0.1 wt.%;

wt.% with respect to the whole composition.

Certain embodiments of the composition described in the present text are essentially free of abrasive particles, in particular free of the abrasive particles described in the text above.

Essentially free means less than 1 or less than 0.5 or less than 0.1 wt.% or do not contain abrasive particles at all. Common to most of these substances is typically a comparable high hardness, e.g. above about Mohs 4 or above about 5.

Certain embodiments of the composition described in the present text are essentially free of oxidizing component(s) (e.g. less than 0.5 or less than 0.3 or less than 0.1 wt.%) or do not contain oxidizing components at all. Oxidizing component(s) which are typically not present are peroxide, hypochlorite, perborate, persulfate, peroxyphosphate, peroxycarbonate.

Sometimes oxidizing components have a negative effect in that they may react with the amino acids being present in the composition having the result that the reaction products are no longer suitable for acting as a metabolism modifying agent.

Certain embodiments of the composition described in the present text are essentially free of heavy metal component(s), in particular those comprising Zn, Sn or Cu (e.g. less than 0.1 or less than 0.05 or less than 0.01 wt.%) or do not contain heavy metal component(s) at all.

Similarly, sometimes heavy metal components may have a negative effect, too, in that they may react with the amino acids being present in the composition (e.g. by forming insoluble complexes) having the result that the reaction products are no longer suitable for acting as a metabolism modifying agent.

However, unavoidable traces of either of these components in the raw materials used for producing the composition may nevertheless be present.

Further embodiments of the invention are given below:

Embodiment 1

An oral care composition for use in a method of treating caries or reducing the risk of getting caries by reducing the lactic acid release of lactic acid producing bacteria in an oral biofilm in the mouth of a living human or animal, the composition comprising

quaternary ammonium alkyl component(s) in an amount of at least 0.05 wt.%, water,

the composition having a pH in the range of 6 to 8 and

having a viscosity of 1 to 1,000 mPa*s at 23°C,

the quaternary ammonium alkyl component being characterized by the following formula: R-N(CH₂CH₂OH)-CH₂CH₂CH₂-N(CH₂CH₂OH)₂ * 2HX, with R being selected from C_10-20 alkyl and X being selected from chloride, carbonate, sulphate, phosphate, wherein chloride is typically preferred. Embodiment 2

An oral care composition for use in a method of treating caries or reducing the risk of getting caries by reducing the lactic acid release of lactic acid producing bacteria in an oral biofilm in the mouth of a living human or animal being, the composition comprising quaternary ammonium alkyl component(s) in an amount of at least 0.05 wt.%, water,

gel-forming or paste-forming component(s),

the ratio of quaternary ammonium alkyl component to water being in a range of 0.05: 100 to 5: 100 with respect to weight,

the composition having a pH in the range of 6-8,

the quaternary ammonium alkyl component being N'-Octadecyltrimethylendiamino-N,N,N' -tris(2-ethanol)-dihydrochloride.

Embodiment 3

An oral care composition for use in a method of treating caries or reducing the risk of getting caries by reducing the lactic acid release of lactic acid producing bacteria in an oral biofilm in the mouth of a living human or animal being, the composition comprising quaternary ammonium alkyl component(s) in an amount of at least 0.1 wt.%, water,

gel-forming or paste-forming component(s),

the ratio of quaternary ammonium alkyl component to water being in a range of 0.1 : 100 to 5: 100 with respect to weight,

the composition having a pH in the range of 6-8 and

having a viscosity of 2,000 to 20,000 mPa*s at 23°C,

the quaternary ammonium alkyl component being characterized by the following formula: R-N(CH₂CH₂OH)-CH₂CH₂CH₂-N(CH₂CH₂OH)₂ * 2HX, with R being selected from C_10-20 alkyl and X being selected from chloride, carbonate, sulphate, phosphate, wherein chloride is typically preferred. Embodiment 4

amino acid(s) selected from glycine, leucine, isoleucine, lysine, methionine, phenylalanine, serine, threonine, valine, tryptophan and mixtures thereof,

the method of treating caries by reducing the lactic acid release comprising the step of applying the composition being applied to the oral biofilm and/or hard dental tissue for at least 1 min,

the quaternary ammonium alkyl component being characterized by the following formula: R-N(CH₂CH₂OH)-CH₂ CH₂CH₂-N(CH₂CH₂OH)₂ * 2HX, with R being selected from C_10- ₂₀ alkyl and X being selected from chloride, carbonate, sulphate, phosphate, wherein chloride is typically preferred.

Embodiment 5

quaternary ammonium alkyl component(s) in an amount of at least 0.05 wt.%, and water,

wt.% with respect to the weight of the whole composition,

the composition having a pH in the range of 6 to 8,

the method of treating caries by reducing the lactic acid release comprising the steps of applying the composition being applied to the oral biofilm and/or hard dental tissue according to either of the following application schemes:

at least 2 times for at least 1 min within 24 hours,

for at least 1 hour within 24 hours, or

for at least 2 days,

the quaternary ammonium alkyl component being characterized by the following formula: R-N(CH₂CH₂OH)-CH₂CH₂CH₂-N(CH₂CH₂OH)₂ * 2HX, with R being selected from C_10-20 alkyl and X being selected from chloride, carbonate, sulphate, phosphate, wherein chloride is typically preferred.

Embodiment 6

quaternary ammonium alkyl component(s) in an amount of at least 0.1 wt.%, and an amino acid selected from

glycine in an amount of 0.1 to 10 wt.%; or

leucine in an amount of 0.1 to 5 wt.%; or

isoleucine in an amount of 0.1 to 5 wt.%; or

lysine in an amount of 0.1 to 10 wt.%; or

methionine in an amount of 0.1 to 10 wt.%; or

phenylalanine in an amount of 0.1 to 5 wt.%; or

serine in an amount of 0.1 to 10 wt.%; or

threonine in an amount of 0.1 tolO wt.%; or

valine in an amount of 0.1 to 8 wt.%; or

tryptophan in an amount of 0.1 to 2 wt.%; or

mixtures thereof,

water,

wt.% with respect to the weight of the whole composition,

the composition having a pH in the range of 6 to 8,

the method of treating caries by reducing the lactic acid release comprising the steps of applying the composition to the oral biofilm and/or hard dental tissue with the aid of an application device selected from a dental tray, mouth guard or clear tray aligner the quaternary ammonium alkyl component being characterized by the following formula: R-N(CH₂CH₂OH)-CH₂CH₂CH₂-N(CH₂CH₂OH)₂ * 2HX, with R being selected from C_10-20 alkyl and X being selected from chloride, carbonate, sulphate, phosphate, wherein chloride is typically preferred. Embodiment 7

film-forming agent(s),

the ratio of quaternary ammonium alkyl component to water being in a range of 0.005: 100 to 5: 100 with respect to weight,

the composition being applied to the oral biofilm and/or hard dental tissue for at least 2 days,

All these compositions can be used in a method or therapy described in the present text.

The complete disclosures of the patents, patent documents, and publications cited herein are incorporated by reference in their entirety as if each were individually incorporated. Various modifications and alterations to this invention will become apparent to those skilled in the art without departing from the scope and spirit of this invention. The above specification, examples and data provide a description of the manufacture and use of the compositions and methods of the invention. The invention is not limited to the embodiments disclosed herein. One skilled in the art will appreciate that many alternative embodiments of the invention can be made without departing from the spirit and scope of thereof.

The following examples are given to illustrate, but not limit, the scope of this invention. Examples

Unless otherwise indicated, all parts and percentages are on a weight basis, all water is de-ionized water (DEI-water), and all molecular weights are weight average molecular weight. Moreover, unless otherwise indicated all experiments were conducted at ambient conditions (23°C; 1013 mbar).

Materials

Table 1

Preparation of Quaternary ammonium Alky Component

5.55 mg CaCl₂ was dissolved in 94.45 ml of deionized water. To this solution 14.925 ml of commercially available N'-Octadecyltrimethylendiamino-N,N,N'-tris(2- ethanol)-dihydrofluoride solution (Merck) was added. After rigorous shaking the solution was centrifuged for 10 min at 5000 rpm to remove precipitated CaF₂. The 5 w/w% N'- Octadecyltrimethylendiamino-N,N,N'-tris(2-ethanol)-dihyrdochloride solution was diluted in accordance to the described examples. Remaining fluoride ion concentration: about 4 ppm.

Preparation of Treatment Solution (for Exposure Procedure 1)

Different Treatment Solutions (TSx) used in Exposure Procedure 1 were prepared by dissolving the quaternary ammonium alkyl component in a liquid carrier medium in the amounts given below in Table 2.

The Treatment Solutions (TSx) had the following composition:

Table 2: Amounts are given in volume parts.

Preparation of MCM + Different Amounts of Quaternary Ammonium Alkyl Component (for Exposure Procedure 2)

Different MCM media containing different amounts of quaternary ammonium alkyl component were used in Exposure Procedure 2. General composition of MCM is listed above in Table 3.

The MCM media containing quaternary ammonium alkyl component had the following composition:

Table 3 Amounts are given in volume parts

Methods

Determination of Lactic Acid Release

To determine the metabolic activity of the biofilm sample, the accumulation of lactic acid in the supernatant (0.75 ml PBS-solution with 5% sucrose per each biofilm sample disc) was measured by using the Lactic acid dehydrogenase (LDH)- Nicotinamid- adenin-dinukleotid (NAD)- Phenazine Methosulphate (PMS) - Thiazolyl blue tetrazolium bromide(MTT) - enzyme assay.

To ensure that only freshly produced lactic acid is determined, the biofilm samples were washed (in three steps, each lasting 30 sec) in 1.5 ml PBS-solution.

After 30 min the accumulated amount of lactic acid in the supernatant was measured by analyzing 50 ml of the supernatant.

The lactic acid was quantified by the lactic acid specific enzyme assay described above. Known correlation between measured enzyme activity and amount of lactic acid was used to translate measured enzyme activity into the amount of lactic acid present in sample of the supernatant.

Determination of Mass of Biofilm

The mass of biofilm was determined as follows: Filter papers were put into 1.5 ml- reaction tubes and weighted. The biofilm, that was grown on the enamel disks was carefully wiped off with the pre-weighted filter papers. The filter papers containing the wet biofilms were placed back into the respective reaction tube and re-weighted. The wet biomass is calculated from the difference in weight. Exposure Procedure 1

Biofilm growth and periodic Exposure Procedure 1 (treatment):

Bovine sample disks are incubated in a 24 well plate containing 1.8 ml medium in an incubator at 37°C and 60 rpm circular movement. Medium and/ or treatment solutions were added by pipetting and removed by a suction pump.

Biofilms were grown in a MCM (mucine containing medium plus 1 % sucrose) human derived saliva biofilm system.

General procedure:

1. Four-hours inoculation of bovine sample disks with saliva-mcm media (MCM = mucine containing medium plus 1 % sucrose) at 37 °C.

2. 2 min treatment with quaternary ammonium alkyl component containing solution.

3. Fresh medium (MCM) for another 2-hour incubation.

4. 2 min treatment with quaternary ammonium alkyl component containing solution.

5. Fresh medium (MCM) for storage over night at 37 °C.

6. Day 2: 2 min treatment with quaternary ammonium alkyl component containing solution after 24 and 31 hours and fresh medium (MCM) after 22, 24, 26, and 31 hours.

7. Day 3: 2 min treatment with amine component containing solution after 48 hours and fresh medium (MCM) after 46 and 48 hours.

8. Samples were taken after 50 hours biofilm growth followed by lactic acid release and biomass evaluation.

Example 1

The biofilms were grown in continuous presence of sucrose and were treated as outlined in the General Procedure above.

The results are given in Table 4.

Table 4

It was observed that by using the quaternary ammonium alkyl component containing solution a significantly reduction of lactic acid release can be achieved in comparison to the control (DI-water treatment only).

After 50 hours biofilm growths and 4x treatments (concentration: 0.5 %), it was observed that the biofilm mass formation/reduction is not correlated to the reduction of lactic acid release.

After 50 hours biofilm growths and 4x treatments (concentration: 1.0 %), the inhibitory effect on biofilm metabolism was clearly measurable. A 90 % reduction of lactic acid production was observed.

After 50 hours biofilm growth and 4 x treatments the inhibitory effect of the quaternary alkyl component on biofilm mass growth increased with the amount of applied quaternary alkyl component.

Exposure Procedure 2

Bovine sample disks are incubated in a 24 well plate containing 1.8 ml medium in an incubator at 37°C and 60 rpm circular movement. Medium and/or treatment solutions were added by pipetting and removed by a suction pump.

General procedure:

1. Four-hours inoculation of bovine sample disks with saliva-mcm media (MCM = mucine containing medium plus 1 % sucrose) at 37 °C;

2. Fresh medium (MCM) containing quaternary ammonium alkyl component for 4 hours at 37°C;

3. Fresh medium (MCM) containing quaternary ammonium alkyl component for 14 hours at 37°C; 4. Fresh medium (MCM) containing quaternary ammonium alkyl component for 2 hours at 37°C;

5. Fresh medium (MCM) containing quaternary ammonium alkyl component for 2 hours at 37°C;

6. Samples were taken after 26 hours biofilm growth followed by lactic acid release and biomass evaluation.

Example 2: Human saliva derived biofilm model show reduction in lactic acid release by different concentrations ofN'-Octadecyltrimethylendiamino- N,N,N-tris(2-ethanol)- dihydrochloride

The biofilms were grown in continuous presence of sucrose and N'- Octadecyltrimethylendiamino-N,N,N'-tris(2-ethanol)-dihydrochloride at 0.005 %, 0.01 %, 0.025 %, 0.01 %, and at 0.1 % according to Exposure Procedure 2.

The results are given in Table 5.

Table 5: results of Exposure Procedure 2, continuous exposure

After 26-hours growth, and continuous presence of N'- Octadecyltrimethylendiamino-N,N,N'-tris(2-ethanol)-dihydrochloride in an amount of 0.005 wt.%, the biofilm showed a clear reduction in lactic acid release in comparison to the control (no N'-Octadecyltrimethylendiamino-N,N,N'-tris(2-ethanol)-dihydrochloride). In comparing the data about the influence of the N'-Octadecyltrimethylendiamino- N,N,N' -tris(2-ethanol)-dihydrochloride on biofilm mass growth, given in Tables 4 and 5, it becomes clear that the periodical application lowers only little biofilm mass accumulation, whereas continuous presence of N'-Octadecyltrimethylendiamino-N,N,N'-tris(2-ethanol)- dihydrochloride lowers strongly biofilm growth. In an agar diffusion test the antibacterial activity of N'-Octadecyltrimethylendiamino-N,N,N'-tris(2-ethanol)-dihydrochloride was investigated.

Agar Diffusion Test

The agar diffusion test is qualitative, easy to perform, and a simple method to determine the antimicrobial activity of diffusive test materials.

The methodology includes the inoculation of bacterial cells on nutrient agar Petri dishes and then paper disks containing a defined test substance concentration are placed on the lawn of bacteria. Afterward, the dishes are incubated for 24-48 h at 37°C. After incubation, the diameter of the zone of inhibited growth around the disk is measured (zone of inhibition). The size of the zone of inhibited growth is directly related to the susceptibility of the organism— the larger the zone, the more susceptible the organism is to the antibiotic

In this example a 1 : 10 dilution of human saliva with Brain-Heart-Infusion was used to grow on the agar plates. 100 ml of the dilution was applied to the agar plate and was spread equally over the agar surface with a sterile Drigalsky spatula.

The paper disks were placed on the agar plate (4 disks per plate). Then 15 ml of the test solutions (in different concentrations) was applied to the filter papers. A 1% H₂O₂ solution was used as a positive control. The Plates were incubated under anaerobic conditions for 48 h at 37°C. After incubation the zone of inhibition was measured in mm with a digital caliper. The test solutions (ATSx) had the following composition:

Table 6: Amounts are given in volume parts

The results are given in Table 7.

Table 7

The data of Table 7 show that N'-Octadecyltrimethylendiamino-N,N,N' -tris(2- ethanol)-dihydrochloride is at concentrations below 0.5 % not antibacterial active, although the biofilm mass declines in continuous presence of A Octadecyltrimethylendiamino-N,N,N'-tris(2-ethanol)-dihydrochloride which is accompanied by a decline in lactic acid formation by the biofilm (cf. Table 5). The significant decline of biofilm growth is not due to killing of the bacteria per se, which indicates that N'-Octadecyltrimethylendiamino-N,N,N' -tris(2-ethanol )- dihydrochloride change the metabolic balance of in the biofilm for lactic acid formation.

At concentration 0.0 % or 0.1 % a small antibacterial effect was observed in the agar diffusion test which might contribute to lower biofilm mass growth in addition.

It was observed that by using the quaternary ammonium alkyl component below a concentration of 0.05% no inhibitory effect on bacterial growth can be observed.

Claims

1. An oral care composition for use in a method of treating caries or reducing the risk of getting caries by reducing the lactic acid release of lactic acid producing bacteria in an oral biofilm in the mouth of a human being or animal,

the composition comprising a quaternary ammonium alkyl component or mixtures thereof dissolved or dispersed in water,

the quaternary ammonium alkyl component being present in the composition in an amount of at least 0.005 wt.%,

the quaternary ammonium alkyl component being characterized by the following formula:

R-N(CH₂CH₂OH)-CH₂CH₂CH₂-N(CH₂CH₂OH)₂ * 2HX

with R being selected from C_10-20 alkyl and X being selected from chloride, carbonate, sulphate or phosphate.

2. The oral care composition for use in a method according to any of the preceding claims, the quaternary ammonium alkyl component or mixtures thereof being applied for a time period effective to reduce the lactic acid release of lactic acid producing bacteria in an oral biofilm by more than 40%.

3. The oral care composition for use in a method according to any of the preceding claims comprising the quaternary ammonium alkyl component or mixtures thereof and water in a ratio of at least 0.005 / 100 with respect to weight.

4. The oral care composition for use in a method according to any of the preceding claims further comprising a carrier component not being water.

5. The oral care composition for use in a method according to the preceding claim, the carrier component being selected from gel-forming agent(s), paste-forming agent(s) and film-forming agent(s), preferably selected from Irish moss, carboxymethyl cellulose, gum tragacanth, gum arabic, gum Karaya, sodium alginate, hydroxyethyl cellulose, methyl and ethyl cellulose, carrageenan, xanthan gum, polyvinyl pyrrolidone, and mixtures thereof.

6. The oral care composition for use in a method according to any of the preceding claims further comprising at least one amino acid selected from glycine, leucine, isoleucine, lysine, methionine, phenylalanine, serine, threonine, valine, tryptophan and mixtures thereof.

7. The oral care composition for use in a method according to claim 6, the ratio of quaternary ammonium alkyl component or mixtures thereof to amino acid being at least 1 :0.5.

8. The oral care composition for use in a method according to any of the preceding claims, the composition being provided in the form of a liquid, gel, paste, gum or film.

9. The oral care composition for use in a method according to any of the preceding claims, the method of treating caries being achieved by a process comprising the step of bringing the oral care composition into contact with the oral biofilm or hard dental tissue, preferably for at least 1 min, or for at least 2 times within 24 hours or for at least 2 days.

10. The oral care composition for use in a method according to claim 9, the step of bringing the composition into contact with the oral biofilm or hard dental tissue being done by rinsing, spraying, brushing, swabbing, coating or combinations thereof.

11. The oral care composition for use in a method according to any of claims 9 to 10, the step of bringing the composition into contact with the oral biofilm or hard dental tissue being done with the aid of an application device, preferably with the aid of a dental tray, mouth guard or clear tray aligner.

12. The oral care composition for use in a method of treating caries or reducing the risk of getting caries by reducing the lactic acid release of lactic acid producing bacteria in an oral biofilm in the mouth of a human being or animal in particular according to any of the preceding claims, the composition comprising

a quaternary ammonium alkyl component or mixtures thereof in an amount of 0.005 to 5 wt.%,

R-N(CH₂CH₂OH)-CH₂CH₂-N(CH₂CH₂OH)₂ * 2HX

with R being selected from C_10-20 alkyl and X being selected from chloride, carbonate, sulphate or phosphate,

water,

the method of treating caries comprising the step of applying the composition to the oral biofilm or hard dental tissue according to either of the following application schemes:

at least 2 times for at least 1 min within 24 hours, or

for at least 1 hour within 24 hours, or

for at least for 2 days.

13. The oral care composition for use in a method according to any of the preceding claims, the human being or animal having or suffering from xerostomia.

14. A kit of parts for use in a method of treating caries or reducing the risk of getting caries by reducing the lactic acid release of lactic acid producing bacteria in an oral biofilm containing lactic acid producing bacteria in an oral biofilm in the mouth of a human being or animal, the kit of parts comprising Part A comprising the quaternary ammonium alkyl component or mixtures thereof as described in any of claims 1 to 13,

Part B comprising water, optionally in combination with a carrier component as described in any of claims 4 to 5, and

optionally Part C comprising an application device.

15. Use of the quaternary ammonium alkyl component or mixtures thereof as described in any of claims 1 to 13 for producing an oral care composition according to claims 1 to 13 or a kit of parts according to claim 14 for use in a method of treating caries or reducing the risk of getting caries by reducing the lactic acid release of lactic acid producing bacteria in an oral biofilm in the mouth of a human being or animal.