AQUEOUS POLYPHENOL AND METABISULFITE SALT COMPOSITIONS

FIELD OF THE INVENTION

The present invention relates to aqueous compositions, in particular aqueous oral care compositions such as mouthwashes, oral rinses or mouth sprays comprising at least one polyphenol, in particular epigallocatechin gallate (EGCG) and an effective amount of a metabisulfite salt as stabilizing agent. Surprisingly it has been found that the stability of polyphenols in aqueous compositions can be effectively improved by the addition of an amount of between about 0.01 wt% and 0.099 wt% of a metabisulfite salt based on the total weight of the composition.

BACKGROUND OF THE INVENTION

Oral malodor, commonly referred to as bad breath is generally caused by digestive system problems, oral bacteria, diet, or a combination of any of these factors. Oral bacteria lead to the formation of plaque, which is the origin of dental caries, gingivitis, and dental calculus, as well as bad breath. In order to prevent and treat oral malodor products especially designed for the topical administration in the oral cavity may be used to deliver oral health benefits and to provide breath freshness. Products for oral hygiene such as mouthwashes, oral rinses or mouth sprays usually contain active ingredients such as chelating agents, anti-microbial agents or antioxidants in order to suppress bad breath, remove oral debris, diminish bacteria in the mouth and/ or refresh the mouth with a pleasant taste.

Polyphenols are generally characterized by a very strong oxidizing effect. In addition, they often have an antimicrobial activity and also act as a deodorant against various unpleasant odors. This combination of activities makes them generally interesting for an application in dental and oral care, for example for the treatment of caries, gingivitis, periodontosis and halitosis. The antibacterial activity acts as a protection against caries and gingivitis (plaque formation), while the antioxidizing effect prevents inflammatory processes or mitigates their progress. The deodorizing properties reduce bad breath by binding malodorous components and the antimicrobial activity prevents the development of halitosis by controlling the sulphur- generating bacteria in the oral cavity.

The use of polyphenols, in particular epigallocatechin gallate in oral care compositions is e.g. disclosed in WO 01/17494, WO 2005/ 025527, EP 0 067 476 and GB 2372209.

The use of polyphenols, in particular epigallocatechin gallate in aqueous compositions is, however, limited because polyphenols rapidly decompose in aqueous media which results in the formation of degradation products which tend to stain compositions to a darker color such as brown upon storage. Even though only a small portion of the polyphenols is normally decomposed, this is usually sufficient to stain compositions containing a significant portion of water. Especially in water based oral care products and products for the treatment of the oral cavity, such as mouthwashes, oral rinses and mouth sprays, discoloration is unacceptable and leads to rejection of the product by the consumer.

Several methods to circumvent the stability issue of polyphenols and in particular EGCG in oral compositions or in aqueous media have been reported. WO2005/025527, for example, discloses oral effective agents in the form of a toothpaste, a mouthwash, or a mouthwash concentrate comprising less than 7.5% of water. WO2005/087224 discloses a composition for stabilizing EGCG in water phase comprising 0.1-25.0% by wt. of epigallocatechin gallate, 0.1-5.0% by wt. of a cationic polymer, an anionic polymer or a mixture thereof and 0.1-10.0 wt.-% of an antioxidant. However, WO 2005/087224 discloses that if the antioxidant such as sodium metabisulfite is less than 0.1 % by weight, the effect of stabilization of EGCG is not sufficient.

So far, no simple, cost effective and generally applicable solution for the stabilization of polyphenols, in particular of EGCG in aqueous compositions, in particular aqueous oral care compositions such as mouthwashes, oral rinses or mouth sprays is available. For these reasons, polyphenols have practically not been used in such aqueous oral care compositions.

SUMMARY OF THE INVENTION One embodiment of the present invention is an aqueous composition containing a polyphenol and about 0.01 wt% to about 0.094 wt% a metabisulfite salt based on the total weight of the composition.

Another embodiment of the present invention is an aqueous composition containing a polyphenol, more than 90 wt% of free water, and at least 0.01 wt% of metabisulfite salt, based on the total weight of the composition.

An additional embodiment of the present invention is a method for prevention and/or treatment of caries, gingivitis, halitosis and/or inflammatory processes in the oral cavity. This method includes contacting the oral cavity surface with a composition containing a polyphenol and about 0.01 wt% to about 0.094 wt% of a metabisulfite salt based on the total weight of the composition.

A further embodiment of the present invention is a method for freshening the breath of a human or an animal. This method includes contacting the oral cavity surface of a human or animal with a composition containing a polyphenol and about 0.01 wt% to about 0.094 wt% of a metabisulfite salt based on the total weight of the composition.

Another embodiment of the present invention is a method of stabilizing a polyphenol in an aqueous composition. This method includes admixing from about 0.01 wt% to about 0.094 wt% of a metabisulfite salt, based on the total weight of the composition, into a composition containing a polyphenol.

An additional embodiment of the present invention is a method for reducing the discoloration of a polyphenol in an aqueous composition. This method includes admixing from about 0.01 wt% to about 0.094 wt% of a metabisulfite salt, based on the total weight of the composition, into a composition containing a polyphenol.

A further embodiment of the present invention is a method of making an aqueous oral care composition. This method includes combining from about 0.01 w% to about 0.094 wt% of a metabisulfite salt, based on the total weight of the composition, with a polyphenol.

A further embodiment of the present invention is a method of making a functional water beverage. This method includes combining from about 0.01 w% to about 0.094 wt% of a metabisulfite salt, based on the total weight of the composition, with a polyphenol.

DETAILED DESCRIPTION OF THE INVENTION

One object of the present invention is to provide novel aqueous compositions comprising polyphenols which do not discolor upon storage.

Furthermore, the invention is concerned with aqueous oral care compositions comprising at least one polyphenol, which, preferably, are capable of treating the entire spectrum of diseases and disorders occurring in teeth and oral cavity. Such compositions are capable to both act against caries and gingivitis and reliably control halitosis or prevent the development thereof, which are active against inflammation of the oral cavity and especially peridontosis, and which may also be used to treat oxidative stress conditions in biological tissues of the oral cavity. Additionally, the compositions should have an attractive appearance to make them marketable as mouthwashes, oral rinses or mouth sprays and keep this appearance even after storage at room temperature. At a minimum, the compositions of the present invention at least undergo less of a change than products of the prior art.

Surprising, it has been found that the stability of polyphenols in aqueous media can be significantly enhanced by the addition of an amount of less than 0.099 wt% of a metabisulfite salt. Thereby, a brown discoloration of the compositions upon storage can be significantly reduced and the full activity of the active ingredient is maintained. Furthermore, due to the small amount of stabilizing agent needed any unwanted side effects resulting from the stabilizing agent, such as for example, an unpleasant off-odor, a discoloration or other adverse effects can be minimized.

Thus, in one embodiment the invention relates to aqueous compositions comprising at least one polyphenol, in particular epigallocatechin gallate and an amount of 0.01 wt% to 0.094 wt% of a metabisulfite salt, preferably an amount of 0.03 wt% to 0.07 wt% based on the total weight of the composition.

In another embodiment the invention relates to aqueous oral care compositions comprising at least one polyphenol, in particular epigallocatechin gallate and an amount of 0.01 wt% to 0.094 wt% of a metabisulfite salt, preferably an amount of 0.03 wt% to 0.07 wt% based on the total weight of the composition.

As used herein, the term "aqueous composition" means that the referenced composition comprises at least 10% by weight of free water which is added to the composition or already

present in the composition. Preferably, the aqueous compositions according to the invention comprise 30 wt% to 99.99 wt%, even more preferably 50 wt% to 95 wt% of free (added) water based on the total weight of the composition.

If the aqueous composition is a mouthwash or an oral rinse, the water content is preferably from about 50% to about 90%, more preferably from about 70% to about 85% by weight of the total composition.

The water content of a composition according to the invention can be determined by known methods in the art, such as for example, those disclosed in 'Karl Fischer Titration: Determination of Water, Chemical Laboratory practice/ Anleitungen fur die chemische Laboratoriumspraxis, Vol. 20, Eugene Scholz, Springer Verlag, 1984'.

Non-limiting examples of such aqueous compositions include beverages, such as, tea or juices, as well as oral care compositions, such as mouthwashes, mouth sprays, and oral rinses.

The water, used in compositions of the present invention should preferably be deionized, distilled, free of organic impurities and bacteria, and substantially free of metal ions.

In the present invention, the term "metabisulfite salt" refers to metabilsulfite salts such as sodium, potassium, calcium or ammonium metabisulfite and the like. Preferably sodium or potassium metabisulfite, in particular sodium metabisulfite (CAS 7681-57-4) are used according to the invention whereas "pyrosulfite", "metabisulphite" and "pyrosulphite" are interchangable with metabisulfite. Any metabisulfite grades can be used. Preferably, the metabisulfite salt used according to the invention has a purity of 95%, more preferably of 97% (e.g., determinable by the test method of the American National Standard Institute (ANSI) PH 4.276-1980).

The polyphenols are preferably selected from the group consisting of polyphenols present in green tea extracts like catechins, polyphenols present in extracts of red grape skin like resveratrol, polyphenols present in olives, olive waste water etc. like hydroxytyrosol and oleuropein, and their mixtures.

When the polyphenols are optically active substances, a reference to such a substance is a reference to every single stereoisomer, especially each of the optically active enantiomers (preferably to the optically active enantiomer found in nature) and to any mixtures thereof, especially racemates.

In all embodiments of the invention, catechins obtainable from green tea extracts such as epicatechin gallate (ECG), epigallocatechin (EGC), gallocatechin gallate (ECG) and epigallocatechin gallate (EGCG) are preferred, in particular epigallocatechin gallate.

The term "epigallocatechin gallate" (EGCG; with the chemical name (2R,3R)-2-(3,4,5- Trihydroxy-phenyl)-3,4-dihydro-1 (2H)-benzopyran-3,5,7-triol-3-(3,4,5-trihydroxybenzonate)) encompasses, besides (-)-epigallocatechin-3-gallate, also green tea extracts containing (-)- EGCG, as well as, (-)-EGCG derivatives, such as, pharmaceutically acceptable salts, esters, glycosides or sulphates thereof. Mixtures of such components are also possible.

In a preferred embodiment, the EGCG has a purity of at least 80%, preferably of at least 85%, more preferably of at least 90%, even more preferably at least 92% and most preferably of at least 90%.

In all embodiments of the invention the EGCG is preferably in the form of a green tea extract containing at least 85% of EGCG. Such extracts are, for example, commercially available from DSM Nutritional Products Ltd, Kaiseraugst, Switzerland as Teavigo™ (green tea extract containing > 90 % of EGCG), as well as Teavigo TG (Tablet Grade) (a green tea extract containing ca. 88% of EGCG admixed with ca. 3% of pectin), the latter having a very good flowability. Both have a good water-solubility. Most preferably in all embodiments of the invention a green tea extract containing ≥ 90 % of EGCG, such as, Teavigo is used.

EGCG can be obtained by any of the processes described in, e.g., US 6,383,392, EP 1 103 550, US 10/246,112 and EP 1 077 211.

In another preferred embodiment, the EGCG used according to the invention is provided as a component of a mixture of green tea catechins and in such a mixture EGCG is usually present in an amount of up to 50% of the total green tea catechins, preferable in an amount from about 10 to about 50% and more preferable in an amount of about 20 to about 50% and most preferable in an amount of about 30 to about 50%. Other catechins present in green tea are such as Epigallocatechin (EGC), Epicatechingallate (ECG), Epicatechin (EC) and

Gallocatechingallate (GCG). Therefore, in another preferred embodiment of the present invention, the EGCG is provided as a component of a mixture of green tea catechins and in such a mixture EGCG is usually the main component and the total amount of other polyphenols and/or catechins is low, preferably about 5 % by weight or less, more preferably about 3 % by weight or less based on the total weight of the mixture.

A preferred embodiment for (-)-epigallocatechin gallate is a green tea fraction comprising at least 85.0 wt% of (-)-epigallocatechin gallate (EGCG) and at most 2.0 wt% of caffeine. Another preferred embodiment is a green tea fraction comprising at least about 90.0 wt% of (-)-epigallocatechin gallate (EGCG) and at most about 1.6 wt% of caffeine, whereas this green tea fraction preferably comprises at most 4.0 wt% of epicatechin (EC), and/or at most 4.0 wt% of catechin, and/or at most 2.0 wt% of gallocatechin gallate (GCG), and/or at most 5.0 wt% of epicatechin gallate (ECG).

A further preferred embodiment for (-)-epigallocatechin gallate is a green tea extract comprising at least about 91.7 wt% of (-)-epigallocatechin gallate (EGCG) and at most about 1.43 wt% of caffeine, especially a green tea extract comprising from about 91.7 to about 97.13 wt% of EGCG, from 0 to about 3.15 wt% of epicatechin (EC), from 0 to about 3.1 wt% of catechin, from about 0.2 to 1.52 wt% of gallocatechin gallate (GCG), from about 0.38 to about 4.62 wt% of epicatechin gallate (ECG) and from 0 to 1.43 wt% of caffeine, based on the total weight of the green tea extract.

As used herein, the term "green tea extract" also encompasses green tea that was brewed and spray-dried afterwards.

Resveratrol can be used in its essentially pure form derived from natural sources or from chemical synthesis, in a product form containing resveratrol and further additives, e.g. as a directly compressible form or as an extract.

The extracts of red grape skin are especially those containing resveratrol in an amount of at least about 30 weight%, preferably in an amount in the range of from about 30 wt% to 100 wt%, more preferably in an amount of at least about 50 wt%, most preferably in an amount in the range of from about 50 wt% to about 99 wt%, based on the total amount of the red wine extract.

The term "resveratrol" as used herein comprises a derivative, metabolite or analogue thereof. The carbon-carbon double bond may be trans or cis and includes cis/trans mixtures. Etherified or esterified hydroxy groups may be derived from non-substituted or substituted, straight or branched chain alkyl groups having 1 to 26 carbon atoms or from non-substituted or substituted, straight or branched chain aliphatic, araliphatic or aromatic carboxylic acids having 1 to 26 carbon atoms. Etherified hydroxy groups may further be glycoside groups and esterified hydroxy groups may further be glucuronide or sulfate groups. Of primary interest for the purposes of the invention is (trans)-resveratrol.

Hydroxytyrosol and/or oleuropein can be used in its/their essentially pure form derived from natural sources or from chemical synthesis, in a product form containing it/them and further additives, e.g. as a directly compressible form or as an extract, i.e. hydroxytyrosol may be of synthetic origin or it may be obtained together with other water-soluble polyphenols such as tyrosol and oleuropein from extraction of olive leaves, olive fruits and vegetation water of olive oil production.

In all embodiments of the present invention mixtures of hydroxytyrosol with oleuropein, preferably in a weight ratio in the range of from about 1 :1 to about 200:1 , more preferably in a weight ratio in the range of from about 5:1 to 200:1 , most preferably in a weight ratio in the range of from about 10:1 to about 100:1 , may be used.

In other embodiments of the present invention mixtures of hydroxytyrosol with tyrosol, preferably in a weight ratio in the range of from 1 : 1 to 50 : 1 , more preferably in a weight ratio in the range of from 3 : 1 to 50 : 1 , most preferably in a weight ratio in the range of from 5 : 1 to 30 : 1 , may be used.

Examples of references that disclose the extraction of oleuropein and/or hydroxytyrosol from olive leaves are WO 02/18310, US 2002/0198415, WO 2004/005228, US 6,416,808 and US 2002/0058078, which disclose a method for acidic hydrolysis of olive vegetation water for 2 to 12 months until at least 90% of the present oleuropein has been converted. A method of extraction of phenolic compounds from olives, olive pulps, olive oil and oil mill waste water is described by Usana Inc. patents US 6,361 ,803 and WO 01/45514 and in US 2002/0004077. EP-A 1 582 512 describes an extraction of hydroxytyrosol from olive leaves. A method for obtaining hydroxytyrosol and/or oleuropein from the vegetation water of de-pitted olives is disclosed in US 2004/0039066 A1 in paragraphs [0080]-[0091].

Derivatives of hydroxytyrosol may be esters as well as physiologically/pharmaceutically acceptable salts. Preferred examples are the mono-, di- and triesters of hydroxytyrosol with (un)saturated carbonic acids R-COOH, whereby R is an alkyl or alkenyl chain having 2 to 22 carbon atoms.

Commercially available hydroxytyrosol containing olive extracts which may be used according to the invention include e.g. extracts from olive fruits such as Polyphen-Oil™ from Life Extension, OleaSelect™ from Indena, Hytolive® from Genosa, Prolivols from Seppic, OLIVE LEAF or OLIVE Water Extract of Olea europea from Lalilab, Hitofulvic from Ebiser, hydrolysed olive leaf extract, such as described in EP1582512, olive leaf extract, rich in oleuropein, such as available from Furfural and HIDROX® from CreAgri.

Preferably HIDROX® commercially available from CreAgri such as HIDROX® 2% spray dried powder, HIDROX® Gold freeze dried powder (9%) and HIDROX® 6% freeze dried powder organic olive juice extract are used.

The amount of polyphenol(s) in the aqueous compositions according to the invention is not particularly limited. As a rule, the content of the polyphenols may be in the range of about 0.01 wt% to about 10 wt%, preferably in the range of about 0.05 wt% to about 8 wt%, e.g., in the range of about 0.1 wt% to about 5 wt% based on the total weight of the composition.

As acidic liquids may be detrimental to the teeth of the user, the aqueous compositions according to the invention, in particular the aqueous oral care compositions, preferably have a pH in excess of 5, in particular in the range of 5 to 8, more in particular in the range of 5.5 to 6.5.

Preferably, the aqueous compositions according to the invention are aqueous oral care compositions. As used herein, the term "aqueous oral composition" comprises products suitable for topical administration in the oral cavity of a mammal, particularly a human, used for oral hygiene such as oral rinses, mouth rinses, mouth washes, mouth wash concentrates, mouth sprays and breath fresheners without being limited thereto.

The aqueous oral compositions according to the invention are products, which in the ordinary course of usage, are not intentionally swallowed for purposes of systemic administration of

particular therapeutic agents, but are rather retained in the oral cavity for a time sufficient to contact substantially all of the dental surfaces and/or oral tissues for purposes of oral activity.

The aqueous oral care compositions of the present invention are of course intended for human use, but they can equally advantageously be used for animals, such as household pets.

The aqueous oral care compositions of the invention encompass cosmetic compositions as well as therapeutic compositions or a combination of the two. Cosmetic compositions include commercial over-the-counter products that help remove oral debris before or after brushing, temporarily suppress bad breath, diminish bacteria in the mouth and refresh the mouth with a pleasant taste and/or odor. Therapeutic compositions have the benefits of their cosmetic counterparts, but also contain an added active ingredient that helps protect against some oral diseases. Exemplary aqueous oral care compositions are antiseptic and anti-plaque mouth rinses, anti-cavity mouth rinse comprising fluoride to protect against tooth decay, anti gingivitis rinses, breath freshening mouth rinses, topical antibiotic rinses, enzyme rinses, artificial saliva rinses, rinses that control tartar as well as mouth rinses that are intended to kill the germs that cause plaque, gingivitis, and bad breath.

The amount of the at least one polyphenol in the aqueous oral care composition according to the invention is preferably in the range of about 0.01 wt% to about 5 wt%, more preferably in the range of about 0.01 wt% to about 3 wt%, most preferably in the range of about 0.01 wt% to about 2 wt%.

The aqueous oral care compositions of the invention may contain the components and additives known to the skilled person in the art and described in the pertinent literature such as 'Formulierungstechnik' (formulation techniques), H. Mollet, A. Grubenmann Wiley VCH 2000. Such ingredients include, but are not limited to: active ingredients such as antibacterial, antimicrobial or anti-caries agents, coloring agents; sweeteners, buffering systems, flavors, flavor boosters, cooling agents, surfactants, humectants, emulsifiers, preservatives, and combinations thereof. The incorporation of these agents into the composition is not critical and where a benefit is seen, their incorporation is recommended.

Anti caries agents include phosphates, pyrophosphates, phosphonates and mixtures thereof.

Quaternary ammonium antimicrobial agents may also be present in the aqueous oral care compositions of the invention. Quaternary ammonium compounds are among the most common of the cationic antimicrobial agents. In oral compositions, they are highly effective in promoting oral hygiene by inhibiting or reducing the number of plaque forming bacteria. Quaternary ammonium antibacterial agents which may be included in compositions according to the invention include those in which one or two of the substitutes on the quaternary nitrogen has a carbon chain length (typically alkyl group) from about 8 to about 20, typically from about 10 to about 18 carbon atoms while the remaining substitutes (typically alkyl or benzyl group) have a lower number of carbon atoms, such as from about 1 to about 7 carbon atoms, typically methyl or ethyl groups. Dodecyl trimethyl ammonium bromide, tetradecylpyridinium chloride, domiphen bromide, N-tetradecyl-4-ethyl pyridinium chloride, dodecyl dimethyl (2-phenoxyethyl) ammonium bromide, benzyl dimethylstearyl ammonium chloride, cetyl pyridinium chloride, quaternized 5-amino- 1 ,3-bis(2-ethyl-hexyl)-5- methyl hexa hydropyrimidine, benzalkonium chloride, benzethonium chloride and methyl benzethonium chloride are exemplary of typical quaternary ammonium antibacterial agents. Quaternary ammonium antimicrobial agents are included in the present invention at levels of about 0.01 wt% to about 0.5 wt%, preferably from about 0.01 wt% to below about 0.2 wt%, more preferably from about 0.01 wt% to about 0.15 wt%.

Further non-limiting examples of ingredients which may be added to the aqueous oral care compositions according to the invention comprise, thymol, canola oil, eucalyptol, methyl salicylate, menthol, chlorhexidine gluconate, benzalkonium chloride, cetylpyridinium chloride, hydrogen peroxide, fluoride, enzymes, calcium, zinc chloride, tin chloride and mixtures thereof. Preferred according to the invention is the addition of an additional amount of zinc chloride and/ or tin chloride in an amount of about 0.05 wt% to about 5 wt%, preferably of about 0.2 wt% to about 1 wt% based on the total weight of the composition.

In another preferred embodiment the aqueous compositions according to the invention are water based beverages such as tea, milk or juices. The term beverages also includes carbonated and non-carbonated beverages, e.g. mineral waters or so-called functional water beverages. The term functional water beverages relates to beverages e.g. known as "near water", "fortified water", "aquaceutical" as well as "infused water" and relates to water-based beverages which have an additional benefit, e.g. a special flavor and/or contain further (functional) ingredients. One simple example for a functional water beverage is a mixture of water with very little juice, another exampe is carbonated or non-carbonated water enriched e.g. with vitamins or other nutrients. Particular preferred aqueous composition according to

the invention are functional water beverages. The functional water beverages may optionally contain other nutrients, minerals and vitamins, for example, calcium, iron, zinc, copper, manganese, iodine, magnesium, vitamin A, vitamin C ₁ vitamin E, niacin, thiamin, vitamin B6, vitamin B2, vitamin B 12, folic acid, selenium, and pantathonic acid and mixtures of these as well as flavoring ingredients.

The amount of the at least one polyphenol, in particular epigallocatechin gallate (EGCG) in the water-based beverages is preferably in the range of about 0.01 wt% to about 5 wt%, more preferably in the range of about 0.01 wt% to about 1 wt%, most preferably in the range of about 0.01 wt% to about 0.2 wt%.

Sodium benzoate is widely used as a preservative in pharmaceuticals and food products. An effective concentration range for sodium benzoate in the compositions of the present invention is generally from about 0.05 wt% to about 0.2 wt% by weight of the total composition.

Examples of suitable weak carboxylic acids that may be used in the present compositions include citric acid, tartaric acid (D, L, DL, or a mixture thereof), acetic acid, and benzoic acid. The most preferred carboxylic acid is citric acid. The carboxylic acid primarily serves as an acidulant but contributes to the antibacterial activity of the composition in a synergistic manner. Preferably, this carboxylic acid should be present in the composition at a concentration of from about 0.01% to about 1.0wt%of the total composition with the most desired level being about 0.1 wt%.

Buffering agents adjust the pH of the final formulation. Generally, the buffering agent should be capable of bringing the pH to a physiologically acceptable level of an excess of 5.0, preferably between 5 and 7, even more preferably between 5.5 to 6.5. Exemplary buffering agents for use in the present compositions are an alkali metal or alkaline earth metal salt, and an amine (e.g., ammonium) salt of the weak carboxylic acid. The preferred buffering agents are sodium citrate, potassium citrate, sodium bicarbonate, potassium bicarbonate and sodium acetate. Preferably, the buffering agent should be present in the composition according to the invention at a concentration of from about 2.0 wt% to about 5.0 wt% by weight of the total composition.

Sweetening agents may be included in the compositions according to the invention to sweeten the taste of the composition. While sodium saccharin is the preferred sweetening agent, any food-use approved natural or artificial sweeteners are contemplated within the scope of the present invention. These sweeteners are, for example, sorbitol, xylitol, asparatame, sucralose and sucrose. Preferably, sodium saccharin is present in the composition at a concentration of from 0% to about 0.20% by weight of the total with the most desired level being about 0.15 wt%. When employing a sweetening agent other than sodium saccharin, any amount required to produce an equivalent level of sweetening to the 0 wt% to about 0.2 wt% sodium saccharin will suffice. Additionally, any mixture of sweetening agents having an equivalent sweetening effect and that is compatible to the formulation is contemplated within the term of sweetening agents.

A flavoring agent or a mixture of compatible flavoring agents represent still another optional ingredient of compositions of the present invention. Such flavoring agents are well known in the art. Suitable flavoring agents include, for example, anise, cassia, clove, dihydroanethole, estragole, menthol, peppermint, oxanone, phenyl ethyl alcohol, sweet birch, thymol, eugenol, eucalyptol, wintergreen, spearmint oil (both natural and synthetic analog), cinnamic aldehyde, cinnamon, menthone, alpha-ionone, ethyl vanillin, limonene, isoamylacetate, benzaldehyde, ethylbutyrate and many others. Mixtures of such flavoring agents are also contemplated. In the herein described compositions, the flavoring agents comprise from about 0.01 wt% to about 5.0 wt%, preferably from about 0.05 wt% to about 2.0 wt% and most preferably from about 0.1 wt% to about 1.0 wt% of the present composition. Surfactants may be included in the composition according to the invention to keep the composition clear and to prevent it from becoming turbid. The surfactants are known to solubilize flavoring agents and other ingredients, e.g., in a mouthwash formulation. Any food grade surfactants can be employed and are ascertainable to one skilled in the art. A particularly suitable surfactant is an alkyl sulfate anionic surfactant. Examples of the alkyl sulfate surfactants are sodium lauryl sulfate (i.e., sodium dodecyl sulfate), and sodium tetradecyl sulfate. Other salts (e.g., potassium, magnesium, and ammonium) of the foregoing alkyl sulfates can also be used. Mixtures of such surfactants are also contemplated. Preferably, a surfactant is present in the composition at a concentration of from about 0.25 wt% to about 1.5 wt% by weight of the total composition.

Preferred surfactant used in compositions of the invention are ethoxylated castor oils such as PEG 50 hydrogenated castor oil and PEG 60 hydrogenated castor oil as well as copolymers

of ethylene oxide and propylene oxide (Poloxamer block polymers) such as Pluracare F 68 NF [INCI Poloxamer 188, CAS 9003-11-6] or Pluracare F127 and F 127NF [INCI Poloxamer 407, CAS 9003-11-6] as well as mixtures thereof in an amount of 1 to 5 wt.-% based on the weight of the total composition.

Another optional ingredient in the composition according to the invention is a humectant. Humectants are well known in the art. The humectant may be a single agent or a mixture of compatible humectants. In the present invention, suitable humectants include xylitol, glycerin and sorbitol as well as other polyhydroxy alcohols such as propylene glycol, butylene glycol, polyethylene glycol, hexylene glycol, and mixtures thereof. These polyhydroxy alcohols are soluble in water, alcohols, ethers and lower aliphatic hydrocarbons and also act to solubilize the flavoring agents of the present invention. The humectant may comprise from about 5 wt% to about 20 wt% of the inventive compositions, preferably from about 10 wt% to about 15 wt%. The preferred humectants include glycerin and/or sorbitol.

Compositions of the present invention may optionally include a water-soluble fluoride compound present in the composition in an amount sufficient to give a fluoride ion concentration in the composition at 25°C. of from about 0.0025% to about 5.0% by weight, preferably from about 0.005% to about 2.0% by weight when it is used to provide additional anticaries effectiveness. A wide variety of fluoride ion-yielding materials can be employed as sources of soluble fluoride in the present compositions. Examples of suitable fluoride ion- yielding materials are found in U.S. Pat. No. 3,535,421 and U.S. Pat. No. 3,678,154. Representative fluoride ion sources include: stannous fluoride, sodium fluoride, potassium fluoride, sodium monofluorophosphate and many others. Stannous fluoride and sodium fluoride are particularly preferred, as well as mixtures thereof.

In a preferred embodiment, the invention relates to aqueous oral care compositions according to the invention comprising an additional fluoride ion source in an amount of 0.15 wt% to 2.5 wt%.

Also desirable for inclusion in the compositions of the present invention are other stannous salts which will not inhibit the activity of the quaternary ammonium compound such as stannous pyrophosphate and stannous gluconate and other antimicrobials such as bis- biquanide salts, copper bisglycinate and nonionic antimicrobial salts. Also useful are

enzymes, including endoglycosidase, papain, dextranase, mutanase and mixtures thereof. Such agents are disclosed in U.S. Pat. No. 2,946,725 and U.S. Pat. No. 4,051 ,234.

Another preferred, nonessential component of compositions of the present invention is a cooling agent or a combination of cooling agents. Suitable cooling agents are those described in U.S. Pat. No. 4,136,163, U.S. Pat. No. 4,230,688, and U.S. Pat. No. 4,032,661.

Particularly preferred cooling agents are N-ethyl-p-menthane-3-carboxamide (WS-3 supplied by Sterling Organics),disclosed in U.S. Pat. No. 4,136,163 and N-2,3-trimethyl-2- isopropylbutanamide which is commercially available as WS-23 from Wilkinson Sword Limited and disclosed in U.S. Pat. No. 4,230,688. Another particularly preferred cooling agent is 3-1-menthoxypropane 1 ,2-diol (TK-10 supplied by Takasago Perfumery Co., Ltd.,

Tokyo, Japan). This material is disclosed in U.S. Pat. No. 4,459,425.

An additional amount of antioxidants may be useful in compositions of the present invention and may be included herein. The additional antioxidants may further enhance the stability of the polyphenol(s) and/ or may act synergistically with the metabisulfite salt. Antioxidants are disclosed in texts such as Cadenas and Packer, The Handbook of Antioxidants, 2001 (Enrique Cadenas and Lester Packer) by Marcel Dekker, Inc. Antioxidants that may be included in the compositions of the present invention include, but are not limited to, Vitamin E, ascorbic acid (vitamin C), Uric acid, carotenoids, Vitamin A, flavonoids, melatonin, aminoindoles, lipoic acids, and mixtures thereof, preferably Vitamin E and Vitamin C as well as derivatives thereof. Vitamin E may be included in the present compositions at levels of from about 0.01 wt% to about 0.10 wt%, preferably from about 0.01 wt% to about 0.05 wt%.

Another optional component of the compositions of the present invention is ethyl alcohol. Ethyl alcohol provides several functions when combined in the compositions of the present invention. Its inclusion can be, but is not limited to use as an additional antibacterial or as an astringent. Furthermore, ethyl alcohol is normally included mouthwashes in order to impart bite and freshness to the mouthwash. The ethyl alcohol may, in some instances, act to enhance the solubilization of certain flavor oils, and may enhance the cleansing efficacy. Ethyl alcohol can be incorporated in the present invention at a level of less than about 40 wt%, preferably less than about 10 wt% and most preferably at a level of less than 2 wt%.

However, it has been found that more than adequate antibacterial activity can be achieved and the formulation can remain water-clear without the inclusion of the alcohol in the

composition. Thus, in a preferred embodiment, the compositions of the present invention contain no alcohol.

While the manner of mixing the ingredients is not critical, it is preferred to add all the ingredients into water at ambient temperature or at a slightly elevated temperature under constant mixing. Filtration may be employed, after complete mixing, to enhance the clarity of the resulting solution. If the pH is outside the range of 5-8.0, it is adjusted by adding more of the carboxylic acid or the buffering agent.

The present invention also includes aqueous oral care compositions comprising at least one polyphenol with the definitions and preferences as given above, more than about 90 wt% of free water and at least about 0.01 wt% preferably from about 0.01 wt% to about 5 wt%, more preferably from about 0.02 wt% to about 1 wt% of a metabisulfite salt to the composition, based on the total amount of the composition.

Surprisingly, it has additionally been found that ascorbic acid or a derivative thereof is capable to stabilize a polyphenol in an aqueous composition if used in a very specific concentration range. Thus, in a further embodiment the invention relates to aqueous compositions comprising a polyphenol with the definitions and preferences as given above and an amount of ascorbic acid or a derivative thereof in the range of about 0.001 to about 0.01 wt%, based on the total weight of the composition.

The ascorbic acid and/ or derivatives thereof for use in accordance with the present invention may be ascorbic acid and/ or any non-toxic, non skin-irritating water-soluble or oil-soluble ascorbic acid derivative. The term ascorbic acid and/ or derivatives thereof encompasses ascorbic acid as well as esters of ascorbic acid, and ester salts of ascorbic acid such as ascorbyl phosphates as well as ascorbic acid derivatives such as ascorbyl palmitate, ascorbyl tetraisopalmitate (for example available from DSM), ascorbyl dipalmitate (for example, NIKKOL CP available from Nikko Chemical), ascorbyl linoleate, ascorbyl octanoate, 2-O-D-glucopyranosyl-L-ascorbic acid, which is an ester of ascorbic acid and glucose and usually referred to as L-ascorbic acid 2-glucoside or ascorbyl glucoside, and its metal salts.

The term "ascorbyl phosphate" as used herein denotes metal salts of mono- and poly- phosphoric acid esters of ascorbic acid wherein the phosphorylated hydroxy group of the

ascorbic acid molecule features one or more phosphoric acid (phosphate) units, and metal cations, e.g. sodium and/or magnesium or calcium ions, are also present. The term "poly" generally denotes 2 - 10, preferably 2 - 4, phosphate units. The ascorbyl phosphates may also be referred to in general as "ascorbyl (poly)phosphates" to embrace both mono- and polyphosphates. Typical ascorbyl phosphates for use in the present invention are L-ascorbic acid phosphate ester salts such as sodium ascorbyl phosphate, potassium ascorbyl phosphate, magnesium ascorbyl phosphate, calcium ascorbyl phosphate and sodium magnesium L-ascorbyl-2-monophosphate. Commercially available ascorbyl phosphates comprise trisodium L-ascorbyl-2-monophosphate which is available as STAY-C ^® 50 form DSM Nutritional Products AG, (4303 Kaiseraugst, Switzerland) and magnesium L-ascorbyl phosphate available from Showa Denko) and sodium magnesium L-ascorbyl-2- monophosphate. The preferred ascorbyl phosphate for the purposes of the present invention is trisodium L-ascorbyl-2-monophosphate.

In all above embodiments preferably water soluble ascorbic acid and/ or derivatives thereof such as an ascorbyl phosphate is used. Preferably ascorbic acid, sodium or sodium magnesium or sodium calcium ascorbyl phosphate or mixtures thereof, most preferably ascorbic acid and/ or trisodium-L-ascorbyl-2-monophosphate are incorporated into the aqueous compositions according to the invention.

Further embodiments of the invention include the use of the aqueous oral care compositions according to the invention for the prevention and/or treatment of caries, gingivitis, halitosis and/ or inflammatory processes in the oral cavity, in particular pariodontosis, as well as, the use of aqueous oral care compositions according to the invention for freshening the breath of a mammal, e.g., a human or an animal, said use comprising contacting the oral cavity surface with the oral care compositions of the invention.

The present invention additionally relates to a method for the prevention and/or treatment of caries, gingivitis, halitosis and/or inflammatory processes in the oral cavity, as well as, for providing breath freshness to a mammal, e.g., a human or to an animal. The method of treatment herein comprises contacting the dental enamel, tongue, and other surfaces of the oral cavity in the mouth of a mammal, e.g., a human or an animal with an oral care composition according to the present invention.

In another embodiment, the invention relates to a method of stabilizing as well as to a method of reducing the discoloration of a polyphenol with the definitions and preferences as

given above in an aqueous composition. The method includes the addition of an amount of about 0.01 wt% to about 0.094 wt%, preferably an amount of about 0.03 wt% to about 0.07 wt% of a metabisulfite salt to the composition based on the total amount of the composition. Preferably, the methods are applied at ambient temperature. The term ambient temperature refers to temperatures of about 15 to 45 ⁰ C, preferably of 18 to 30 °C, most preferably of 20 to 28 °C.

Additionally, the invention relates to a method of stabilizing as well as to a method of reducing the discoloration of a polyphenol with the definitions and preferences as given above in an aqueous composition containing more than about 90 wt% of water. The methods comprise the addition of at least about 0.01 wt% preferably from about 0.01 wt% to about 5 wt%, more preferably from about 0.02 wt% to about 1 wt% of a metabisulfite salt to the composition based on the total amount of the composition. Preferably, the methods are applied at ambient temperature. The term ambient temperature refers to temperatures of about 15 to 45 ⁰ C, preferably of 18 to 30 ⁰ C, most preferably of 20 to 28 ⁰ C.

Furthermore the invention relates to method of stabilizing as well as to a method of reducing the discoloration of a polyphenol with the definitions and preferences as given above in an aqueous composition. The methods includes the addition of an amount of about 0.001 wt% to about 0.01 wt% of ascorbic acid or a derivative thereof to the composition, based on the total amount of the composition. Preferably, the methods are applied at ambient temperature. The term ambient temperature refers to temperatures of about 15 to 45 °C, preferably of 18 to 30 ⁰ C, most preferably of 20 to 28 ⁰ C.

A further embodiment of the present invention is a method of making an aqueous oral care composition. This method includes combining from about 0.01 w% to about 0.094 wt% of a metabisulfite salt, based on the total weight of the composition, with a polyphenol. An additional embodiment of the present invention is an aqueous oral care composition made by this process.

The following examples are provided to further illustrate the compositions and methods of the present invention. These examples are illustrative only and are not intended to limit the scope of the invention in any way.

EXAMPLES

Example 1 : Stabilization of epigallocatechin gallate with sodium metabisulfite (SMBS) The compositions are prepared by dissolving 0.25 wt% of Teavigo™ (green tea extract comprising > 90% of EGCG) and an amount of sodium metabisulfite as indicated below in distilled water. The color is evaluated by colorimetry using a Minolta Spectrometer CM- 360Od, immediately after preparation and after storage at RT (at about 22 ⁰ C) for 2 and 6 weeks. The colorimetric evaluation is carried out in accordance with a CIE 1976 Lxaxb Colorspace evaluation as described in 'Colour Physics for Industry' by Roderick McDonald, Society of Dyers & Colorists, March 1997. In accordance with δE = [(L-L ₀ ) ² + (a-a ₀ ) ² + (fa- bo) ² ] ¹ ' ² the value δE results from a so called colour space, wherein L represents brightness, positive values for 'a' mean red colours, negative values for 'a' mean green colours, positive values for 'b' mean yellow colours, negative values for 'b' mean green blue colours.

Table 1 Stabilization of EGCG with SMBS

The result of the experiment clearly indicates that an aqueous composition comprising EGCG and less than 0.1 wt-% of sodium metabisulfite effectively protects the composition against discoloration. An addition of more than 0.1 wt.-% of EGCG does not lead to a better color stabilization. The non stabilized sample was so discolored after 6 weeks of storage at RT that it would not be suitable for commercial purposes. In contrast the compositions according to the invention comprising less than 0.1 wt%, preferably between 0.01 to 0.094 wt% of sodium metabisulfite showed only a slight to almost no discoloration which, in a product such as a mouthwash or an oral rinse would not interfere with a commercial exploitation.

Example 2: Comparative example

In order to show the superior effect of sodium metabisulfite to stabilize EGCG in the concentration range according to the invention a comparative experiment was performed according to the conditions outlined in experiment 1 using ascorbic acid as stabilizing agent.

Table 2 Comparative Results

As can be seen from table 2, the aqueous compositions comprising SMBS in the indicated amounts discolor equally or to a much smaller degree than composition comprising ascorbic acid as stabilizer.

Example 3: Stabilization of epigallocatechin qallate with ascorbic acid (Vit. C)

In order to show the optimal level for stabilizing EGCG with ascorbic acid the same experiment as outlined in example 1 was repeated using different concentrations of ascorbic acid as indicated in table 3. The results are summarized in table 3.

Table 3 Stabilization of EGCG with ascorbic acid

As can be seen from table 3 the optimal concentration range of ascorbic acid in order to stabilize EGCG in an aqueous composition is from about 0.001 to about 0.01 wt%, based on the total weight of the composition.

Example 4: Mouthwash formulations

The mouthwashes whose formulas are shown below are prepared by intimately mixing the different components in the appropriate quantities, by means of conventional techniques.

Example 5: Near clear water with EGCG:

Ingredients Weight (g)

Sucrose, fine crystalline 7.20

Citric Acid 50% w/w 2.00

Sodium benzoate 0.20

Flavour Ginger Ale Givaudan 60131-76 0.10

Flavour Lemon Givaudan 78444-76 0.20

Dry Vitamin E 15% CC 0.16

Sodium metabisulfite 0.10

EGCG (TEAVIGO™) 0.11

Water ad 1000

Preparation

• Dissolve Sodium benzoate & sodium metabisulfite in a small quantity of water (50 to 100 ml).

• Add Citric Acid solution, Dry Vitamin E 15% CC and TEAVIGO.

• Stir until TEAVIGO has dissolved. • Add Sugar, stirr again and add water to 1 litre.

Example 6: Functional water beverage:

A functional water beverage is prepared dissolving 90 mg of EGCG and 24 mg of sodium metabisulfite in a suitable beverage application (240 ml serving size).

Example 7: Functional water beverage:

A functional water beverage is prepared dissolving 300 mg of EGCG and 120 mg of sodium metabisulfite in a suitable beverage application (240 ml serving size).

All documents, including U.S. patents and patent publications are incorporated by reference as if recited in full herein.

The scope of the present invention is not limited by the description, examples, and suggested uses herein and modifications can be made without departing from the spirit of the invention. Thus, it is intended that the present invention cover modifications and variations of this invention provided that they come within the scope of the appended claims and their equivalents.