Indian Patents. 272246:A COMPOSITION SUITABLE FOR ORAL USE,

Title of Invention	A COMPOSITION SUITABLE FOR ORAL USE,
Abstract	An oral composition having a pH in the range of from 3 to 8.5, comprising: (a) in the range of from 0.1 % to <10% w/w (based on the total weight of the oral composition) of a stock solution comprising a mixture of bioflavonoids and fruit acids or salts thereof; and (b) water; and, optionally, (c) a pharmaceutically acceptable carrier therefor.

Full Text	ORAL COMPOSITIONS. THEIR PREPARATION AND USE The present invention relates to flavonoid-containing compositions for use in the preparation of oral compositions, such as toothpastes, mouthwashes or dental rinses. In particular, it relates to oral compositions comprising an antibacterial bioflavonoid stock solution, their preparation and use. Certain compositions comprising flavonoids having antimicrobial, particularly antibacterial and especially anti- viral, activity are known. However, the term 'flavonoid' covers a large variety of differing compounds, which may be made available by extraction from various natural sources. Depending on both the source and the nature or method of extraction, the overall chemical composition of the resulting flavonoid mixture can itself vary widely. Individual flavonoids can vary greatly in their biological activity (or be inactive), both in terms of toxicity and effectiveness against microbes such as viruses and bacteria. Therefore, in combination, such flavonoids can also vary in their biological activity. It has been found that it is possible to synergise, enhance or facilitate the biological activity of certain combinations of flavonoids by the addition of other agents to the flavonoid composition. Much effort has therefore been directed to finding a suitable combination of flavonoids, with or without other agent(s), that will have a desired effectiveness against certain microbes but without accompanying toxic or other disadvantageous effects in use. An example of such a combination is to be found in a combination of orange extracts, known as bioflavonoids, and natural fruit acids such as vitamin C, which is used in the poultry industry to kill food-related microbes such as E coli and Salmonella. However, up until the present invention, it has not been proposed to use an orange- derived bioflavonoid/fruit acid combination in formulations for personal hygiene, such as oral, use. In particular, the known combination would be much too acidic for oral use. Furthermore, although it has been suggested that flavonoids be used in compositions such as toothpaste and mouthwash, these have either been unspecified as to their flavonoid components and/or limited to specific flavonoids. For example, patent specification no. WO 02/47615 discloses an oral composition comprising an organoleptically suitable carrier and a terpenoid and/or a flavonoid dispersed in the carrier; DE 19949575 discloses a combination of fluorides and flavonoids for treating dental disorders and preventing caries; and JP62051613 relates to a dentifrice composition containing 0.001-0.1 wt% flavonoid compound(s) selected from flavonol, chrysin, hesperetin and hesperidin. None of the prior art formulations disclose a combination of a bioflavonoid composition (itself comprising a particular combination of water-soluble flavonoid components) with one or more water-soluble fruit acid(s) in an amount and form suitable for oral administration as a solution, and having anti-bacterial activity. Accordingly, the present invention provides an oral composition having a pH in the range of from 3 to 8.5, preferably 3.5 to 8, preferably 4 to 7, more preferably 5 to 6.5, comprising: (a) in the range of from 0.1 % to (b) water; and, optionally, (c) a pharmaceutically acceptable carrier therefor, which may itself comprise (an)other pharmaceutically or pharmacologically acceptable ingredient(s) suitable for oral administration. Preferably, the oral composition comprises in the range of from 0.1 to 5% w/w of the stock solution, more preferably from 0.1 to 2% w/w, such as about 1%. Suitably, the oral composition comprises in the range of from 20 to 80% w/w water, towards the lower end of that range in the case of a toothpaste and towards the upper end for a liquid composition such as a mouthwash/rinse/spray. For example, a paste may comprise in the range of from 20 to 45% w/w water, such as 20 to 30% w/w, particularly if silica is included in component (c), and a liquid formulation may comprise in the range of from 60 to 80% w/w water (all w/w based on the total weight of the oral composition). Especially preferred is when the stock solution is preparable from water-soluble bioflavonoids in combination with a fruit acid, such as citric, malic and ascorbic acids. One or more of the acids are preferably neutralized with a suitable base, such as a quaternary ammonium base, for example a choline base, such as choline carbonate, bicarbonate or, preferably, hydroxide. More preferably, citric, malic and ascorbic acids are all used in the preparation of the composition, and especially preferred is when these are fully neutralized to provide citrate, malate and/or ascorbate salts. Especially preferred is choline ascorbate. Accordingly, it is preferred that the stock solution is substantially free from fruit acids, by which is meant that its pH is around neutral. Exemplary pH ranges for the stock solution are from 3 to 8.5, 3.5 to 8.5, 3.5 to 8, 4 to 8, 4 to 7.5, 4.5 to 7.5, 4.5 to 7, 5 to 7, 5 to 6.5, 5.5 to 6.5 and 5.5 to 6, the pH being for example about 5, about 5.5, about 6, about 6.5 or about 7. Not wishing to be bound by any particular theory, the present inventors believe that, as well as having a chelating effect on hard water, the fruit acids also synergise the biological activity of the active agents eg the bioflavonoids and choline ascorbate. Accordingly, a preferred stock solution comprises water-soluble bioflavonoids and choline ascorbate (present either as choline base (eg hydroxide) and ascorbic acid or as the salt per se). The stock solution preferably further comprises a non-toxic solvent, such as a water- miscible or hydrophilic solvent, and more preferably comprises water and a water- miscible co-solvent such as glycerine, a polyhydric alcohol or the like. Especially preferred is when the solvent comprises a water/glycerine mixture, preferably in the ratio of from 2:1 - 1:2 (water :co-solvent). More preferably, components (b) and (c) (the balance comprising water, co-solvent(s) and excipient(s) and or/or carriers)) are alcohol-, especially ethanol-, free. Accordingly, the stock solution preferably is preparable from: * Ascorbic acid and choline hydroxide (or other choline base) can be replaced by choline ascorbate, with amounts of glycerine and water (or alternative solvent(s)) increased appropriately. Preferred is when the solvent comprises approximately equal % of both glycerine and water, such as 5 to 25% each, such as 15% glycerine and 20% water (when choline is present as the hydroxide solution), or such as 25% glycerine and 25% water (when the choline and ascorbic acid are present as 5% choline ascorbate). Accordingly, the oral compositions of the present invention preferably are preparable from (based on the weight of the oral composition) : (a) (i) in the range of from 0.0002 - 1.5% w/w bioflavonoids [excluding biomass, which preferably contributes another 0.00024 - 1.83% w/w]; (ii) in the range of from 0.001 - 2.0% w/w citric acid; (iii) in the range of from 0.001 - 2.0% w/w malic acid; (iv) in the range of from 0.001 - 2.0% w/w ascorbic acid; (v) in the range of from 0.00045 - 2.03% w/w choline base; and (b) and (c) the balance comprising water, co-solvent(s) and excipient(s) and/or carrier(s). More preferably, the oral compositions of the present invention are preparable from (based on the weight of the oral composition): (a) (i) in the range of from 0.00045 - 0.9% w/w bioflavonoids [excluding biomass, which preferably contributes another 0.00055 - 1.1% w/w]; (ii) in the range of from 0.001 - 2.0% w/w citric acid; (iii) in the range of from 0.001 - 2.0% w/w malic acid; (iv) in the range of from 0.001 - 2.0% w/w ascorbic acid; (v) in the range of from 0.00045 - 2.03% w/w choline base; and (b) and (c) the balance comprising water, co-solvent(s) and excipient(s) and/or carrier(s). Since the stock solutions of the present invention therefore more preferably are preparable from the percentages given in the above-noted table, the oral compositions of the present invention more preferably are preparable from: (a) (i) in the range of from 0.000675 - 0.675% w/w bioflavonoids [excluding biomass]; (ii) in the range of from 0.015 - 1.5% w/w citric acid; (iii) in the range of from 0.015 - 1.5% w/w malic acid; (iv) in the range of from 0.005 - 0.5% w/w ascorbic acid; (v) in the range of from 0.015 - 0.9% w/w choline base; and (b) and (c) the balance comprising water, co-solvent(s) and excipient(s) and/or carrier(s). Since preferred oral compositions of the present invention comprise in the order of 1% w/w of the stock solution, in one embodiment, preferred oral compositions of the invention are preparable from: (a) (i) of the order of 0.0675% w/w bioflavonoids [excluding biomass]; (ii) of the order of 0.15% w/w citric acid; (iii) of the order of 0.15% w/w malic acid; (iv) of the order of 0.05% w/w ascorbic acid; (v) of the order of 0.09% w/w choline base; and (b) and (c) the balance comprising water, co-solvent(s) and excipient(s) and/or carrier(s). In another embodiment, most preferred oral compositions of the invention are preparable from: (a) (i) of the order of 0.01485% w/w bioflavonoids [excluding biomass]; (ii) of the order of 0.045% w/w citric acid; (iii) of the order of 0.045% w/w malic acid; (iv) of the order of 0.015% w/w ascorbic acid; and (b) and (c) the balance comprising water, co-solvent(s) and excipient(s) and/or carriers). hi another embodiment, most preferred oral compositions of the invention are preparable from: (a) (i) of the order of 0.01485% w/w bioflavonoids [excluding biomass]; (ii) of the order of 0.045% w/w citric acid; (iii) of the order of 0.045% w/w malic acid; (iv) of the order of 0.06% w/w choline ascorbate; and (b) and (c) the balance comprising water, co-solvent(s) and excipient(s) and/or carriers). The stock solution is prepared by processes known to those skilled in the art. Preferably, the co-solvents are mixed with the water at ambient temperature and then the acids involved in neutralization processes, such as ascorbic acid, are blended together with the solvent at an increased temperature, which is kept low enough to ensure no degradation of any of the ingredients. In the case of ascorbic acid, which thermally degrades above about 55 degC, the temperature is kept in the range of from about 25 to below 55 degC and is preferably in the region of 50 degC. Preferably, the neutralization involves addition of choline hydroxide to ascorbic acid in the blend (starting pH = 1.2; finishing pH = 5.5-6.0), or choline ascorbate (ie wherein the ascorbic is already neutralized) itself can be added. Then, the remaining acids (preferably, citric and malic) are added, followed by the bioflavonoids, resulting in a solution having a pH in the range of from about 2.0 to 6.5 but typically is from about 2.2 to 3.5, especially in the range of from 2.3 to 3.0. The remaining un-neutralised acids are also substantially neutralized, for example, by choline hydroxide, to result in a substantially neutral solution having a pH in the range of, for example, from 5 to 8.5, preferably 5.5 to 7, more preferably 5.5 to 6.5. The stated antimicrobial effect of prior art formulations comprising a bioflavonoid relies on the inhibition by the bioflavonoid of the uptake of essential amino acids in the cytoplasmic membrane of the microbe, such as by inhibiting the viral neuroamidase. However, the formulations of the present invention are believed to be effective because the combination of selected soluble bioflavonoids with choline ascorbate results in encapsulation of the microbe, breakdown of the flavonone and glucoside components into independent fragments, and subsequent deactivation of the microbe by the flavonone fragments and choline ascorbate. Preferably, the bioflavonoid mixture comprises water-soluble bioflavonoids in association with biomass resulting from the extraction process; accordingly, the bioflavonoid mixture may be associated with up to 40-60% w/w, preferably about 55% w/w, biomass (based on the weight of the bioflavonoid mixture). The bioflavonoids are preferably glucosides, especially those selected from isocriocirm, isonaringin, narangin, hesperidin, neohesperidin, neodiomin, naringenin, poncirin and rhiofolen, and more preferably each of these is present in the mixture. Especially preferred is when the major part of the bioflavonoid mixture comprises narangin and neohesperidin, such as when these comprise in excess of 75% of the bioflavonoid component (excluding biomass). Suitably, other bioflavonoids (such as flavonol, chrysin, hesperetin) are substantially absent from the bioflavonoid mixture and the bioflavonoid component therefore consists essentially of the water-soluble bioflavonoids listed hereinabove, although trace amounts of other bioflavonoids may be present. Especially preferred is when the water-soluble bioflavonoids comprise the following percentages (by weight of bioflavonoid in the total bioflavonoid component): A suitable source of such a water-soluble bioflavonoid mixture is herein referred to as 'HPLC 45', of which about 45% (of the total composition of HPLC 45) comprises such bioflavonoids, with the balance (about 55%) comprising biomass such as pectins, sugars and minor organic acids. As stated above, especially preferred is when the major part of the bioflavonoid mixture comprises narangin and neohesperidin, such as when these comprise in excess of 35% of the bioflavonoid component in a mixture with biomass such as HPLC 45. Accordingly, by weight of the total composition of HPLC 45, the following bioflavonoids are preferably present: The HPLC 45 is available from Exquim (the food arm of Grupo Ferrer) as Citrus Bioflavonoid Complex 45% HPLC. It is derived from a starting material comprised of the pith of immature, bitter (blood/red) oranges such as Seville oranges that are classed as 'inedible' and from which the pips, flesh and oily skin have been substantially removed or remain undeveloped. This starting material is crushed in a hydrophilic, ionic solvent such as water or water/alcohol mixtures, preferably water/ethanol in a ratio of about 1:10-20 (solvent: starting material). The resulting mixture is filtered to leave a water-soluble biomass, which is retained, and an insoluble biomass, which is discarded. The water- soluble biomass is then subject to fine filtration, after which it is flash-distilled to leave a brown, hygroscopic powder (HPLC 45). Preferably, the bioflavonoid mixture for use in the oral compositions of the present invention is distinguishable particularly by comprising water-soluble glucosides from the mixture obtained from grapefruit or other citrus fruits or other plant sources, which comprise water-insoluble flavonoids; and, more preferably, is distinguishable from the mixture obtained when substantial amounts of the seeds, pulp and/or flesh of such fruits are comprised in the starting material, which particularly comprise water-insoluble components. Furthermore, the more developed/mature starting material of the prior art is more likely to have been subjected to pesticides and/or synthetic fertilizing media, and are therefore less Organic' or pure in their origin than the bioflavonoid mixture of the solutions of the present invention. Preferably, the stock solution comprises 1-20%, preferably 2 to 15%, more preferably 3 to 15%, such as 3, 4, or 15, most preferred is 3.3% w/w of the HPLC45. Accordingly, the stock solution preferably comprises 0.45-9%, preferably 0.9 to 6.75%, more preferably 1.35 to 6.75%, such as 1.35, 1.8, or 6.75, most preferred is 1.485% of the bioflavonoid mixture. Preferably, the oral composition and, particularly in the absence of other ingredients except water, the stock solution has a pH of from about 3 to about 8.5, more preferably of from about 4 to 7.5, such as about 5 to 7 ; especially preferred is when the pH is about 5.5 to 6.5. Most preferably, therefore, the oral composition is substantially free of hydrogen ions, such as from fruit acids; the fruit acids used in the preparation of the stock solution and/or oral composition therefore having been substantially neutralised, preferably as described above by addition of a base to the stock solution. On the other hand, when the oral composition also comprises a buffering agent, then the pH of the stock solution can vary outside these ranges provided that the buffering agent is present in an amount effective to provide the oral composition with a pH within these ranges. Accordingly, component (c) of the oral compositions of this invention may comprise a buffering agent to regulate or adjust the pH of the final composition, such as an alkali metal hydroxide or ammonium hydroxide or a mono-, di- or tri-basic phosphate such as a tri(alkali metal) phosphate. Since the quantity of hydroxide is more difficult to measure than that of dibasic phosphate, it is preferred to use monobasic phosphates and dibasic phosphates. Another alternative is to use a combination of phosphoric acid with a dibasic or tribasic, such as tri(alkali metal), phosphate. The phosphates are preferably incorporated in the form of their sodium, potassium or ammonium salts; more preferably, sodium salts are employed. However, in cases where hypertensive effects of sodium ions are of concern, mono- and di-potassium phosphates may be used. When the buffering agent is disodium phosphate, for example, it may be present up to about 5% w/w of the oral composition, preferably in the range of from 0 to 0.5%, such as about 0.05% w/w. Another optional ingredient, component (c), may comprise a source of fluoride, such as sodium fluoride or sodium monofluorophosphate, up to about 0.5% w/w of the oral composition. The fluoride source is preferably in the range of from 0 to 0.15%, such as about 0.05% w/w in the case of liquid compositions but more in the case of toothpastes, where from 0 to 0.3%, such as around 0.24%, w/w or in the range of from 0 to 1500 ppm (as fluoride ions) is suitable. Other additives may be present in the oral compositions of the invention, such as flavouring, sweetening or colouring agents, or preservatives. Mint, such as from peppermint or spearmint, cinnamon, eucalyptus, citrus, cassia, anise and menthol are examples of suitable flavouring agents. Flavouring agents are preferably present in the oral compositions in an amount in the range of from 0 to 3%; preferably up to 2%, such as up to 0.5%, preferably around 0.2%, in the case of liquid compositions; but optionally more in the case of toothpaste, preferably 0.5 to 2%, more preferably around 1% w/w. Sweeteners include artificial or natural sweetening agents, such as sodium saccharin which may be present in an amount in the range of from 0 to 2%, preferably up to 1 % w/w, such as 0.05 to 0.3% w/w of the oral composition. Colouring agents are suitable natural or synthetic colours, such as titanium dioxide or CI 42090, or mixtures thereof. Colouring agents are preferably present in the oral compositions in an amount in the range of from 0 to 3%; preferably up to 0.1%, such as up to 0.05%, preferably around 0.005-0.0005%, in the case of liquid compositions; but optionally more in the case of toothpaste, preferably up to 1%, more preferably around 0.5% w/w. Of the usual preservatives, sodium benzoate is preferred in concentrations insufficient substantially to alter the pH of the oral composition, otherwise the amount of buffering agent may need to be adjusted to arrive at the desired pH. Other optional ingredients of component (c) may include other active agents such as anti- plaque agents and/or antimicrobial agents. Suitable agents include quaternary ammonium compounds such as domiphen bromide, cetyl pyridinium chloride (CPC), phenolic compounds, ethanol, and the preservatives mentioned above. Such active agents may be present in an amount in the range of from 0 to 4% w/w but may be as much as 70%, such as up to 30%, in the case of ethanol. For example, CPC or the like is preferably present up to 2%, such as about 0.05% w/w, especially in liquid oral compositions of the invention. Ethanol may comprise as much as 70%, preferably about 0 to 30%w/w in liquid compositions of the invention, such as about 15% w/w in a mouthspray, but preferred oral compositions of the invention are those wherein ethanol or any other alcohol is substantially absent. Other optional ingredients of component (c) may include humectants, surfactants (non- ionic, cationic or amphoteric), thickeners, gums and binding agents. Suitable humectants include glycerine, xylitol, glycerol and glycols such as propylene glycol, which may be present in an amount of up to 50% w/w each, but total humectant is preferably not more than about 60-80% w/w of the oral composition. For example, liquid oral compositions may comprise up to about 30% glycerine plus up to about 5%, preferably about 2% w/w xylitol. Surfactants are preferably not anionic and may include polysorbate 20 or cocoamidobetaine or the like in an amount up to about 6%, preferably about 1.5 to 3%, w/w of the oral composition. When the oral compositions of the invention are in the form of a mouthspray, it is preferred to include a film-forming agent up to about 3% w/w of the oral composition, such as in the range of from 0 to 0.1%, preferably about 0.001 to 0.01%, such as about 0.005% w/w of the oral composition. Suitable film-formers include sodium hyaluronate and those sold under the tradename Gantrez. When the oral compositions of the invention are in the form of toothpaste, it is preferred to include gums, binders and/or thickeners, such as colloidal silica, carrageenan and cellulose derivatives such as sodium carboxymethylceilulose. Such ingredients may be present in an amount up to about 3% w/w of the oral composition, such as up to about 2%, preferably about 0.5 to 1%, w/w of the oral composition. Toothpaste compositions of this invention may also comprise an abrasive agent, such as hydrated silica, dicalcium phosphate, or water-insoluble alkali metal metaphosphates, up to about 25% w/w and preferably in the range of from about 10 to about 15% w/w of the oral composition. The oral compositions of the present invention may be prepared by any method known in the art for the formulation of similar compositions, such as a toothpaste, mouthwash or rinse, mouthspray, or the like. AU methods comprise bringing the components (a) and (b) and, if present, (c) together in intimate physical admixture. Preferably, the compositions are packaged in suitable packaging such as a plastics or metallic tube, plastics or glass transparent, translucent or opaque bottle, jar or dispenser, with or without spray or other applicator means, together with instructions for use. Such packaging may itself be further packaged into a cardboard box or other suitable container and the same or further instructions for use may be inserted therein or inscribed thereon; suitably, such instructions may be inscribed on a pack insert or leaflet. The packaging preferably lists the active, main or all ingredients of the composition. The instructions may include those known to the person skilled in the art of oral compositions, particularly those for anti-bacterial use. Accordingly, they may recommend that a pea-sized amount of toothpaste be applied to the dentition at regular intervals, 2-3 times per day; that a mouthful of mouthwash or rinse be sluiced around the oral cavity at least once per day and preferably after meals; and the like. The oral compositions of the present invention may therefore be useful for treating, preventing or ameliorating the effects of a microbial, especially a bacterial, infection in the oral cavity or other periodontal disease; for cleaning, disinfecting or removing debris from the oral cavity; for refreshing, freshening, removing or improving the odour or taste in the oral cavity; and for generally attending to the hygiene, appearance and feel of the oral cavity. Accordingly, the present invention further provides a stock solution comprising a mixture of bioflavonoids and fruit acids (such as the mixture hereinbefore described) in the preparation of a medicament for the treatment of a microbial, especially a bacterial, infection in the oral cavity; in particular, wherein the medicament comprises in the range of from 0.1% to 10% w/w (based on the total weight of the oral composition) of the stock solution. Preferably, the present invention provides (a) a stock solution comprising a mixture of bioflavonoids and fruit acids together with (c) other pharmaceutically or pharmacologically acceptable ingredients suitable for oral administration (such as those described hereinbefore), in the preparation of a medicament for the treatment of a microbial, especially a bacterial, infection in the oral cavity; in particular, wherein the medicament comprises in the range of from 0.1% to 10% w/w (based on the total weight of the oral composition) of the stock solution. The oral compositions of the present invention are useful in the treatment or prevention of infections, disease or conditions arising from the following bacteria: Actinomyces odontolyticus, Actinomyces viscosus, Porphyromonas gingivalis, Prevotella intermedia, Prevote CLAIMS 1. An oral composition having a pH in the range of from 3 to 8.5, comprising: (a) in the range of from 0.1 % to (b) water; and, optionally, (c) a pharmaceutically acceptable carrier therefor. 2. An oral composition according to claim 1, wherein the bioflavonoid mixture is derived from the pith of immature bitter oranges. 3. An oral composition according to either claim 1 or claim 2, which comprises in the range of from 0.1 to 5% w/w of the stock solution, such as 0.5% or 1% w/w of the stock solution. 4. An oral composition according to any preceding claim, wherein the bioflavonoid mixture is water-soluble. 5. An oral composition according to any preceding claim, wherein the stock solution comprises a fruit acid salt selected from citrate, malate and ascorbate salts. 6. An oral composition according to any preceding claim, wherein the stock solution comprises a salt of fruit acid with a base, such as a quaternary ammonium base. 7. An oral composition according to claim 6, wherein the base is a choline base, such as choline ascorbate. 8. An oral composition according to any preceding claim, which is substantially free from fruit acids. 9. An oral composition according to any preceding claim, wherein the stock solution and/or the oral composition has a pH in the range of from 3.5 to 8. 10. An oral composition according to claim 9, wherein the stock solution and/or the oral composition has a pH in the range of from 4 to 7. 11. An oral composition according to claim 10, wherein the stock solution and/or the oral composition has a pH in the range of from 5 to 6.5. 12. An oral composition according to any preceding claim, wherein the bioflavonoid mixture is in association with biomass, such as in the range of from 40 to 60% w/w biomass, based on the weight of bioflavonoid mixture. 13. An oral composition according to any preceding claim, wherein the bioflavonoids are selected from isocriocirm, isonaringin, narangin, hesperidin, neohesperidin, neodiomin, aringenin, poncirin and rhiofolen, such as narangin and neohesperidin. 14. An oral composition according to any preceding claim, comprising in the range of from 20 to 80% w/w water, based on the weight of the oral composition, such as a toothpaste comprising 20-40% w/w water or a liquid composition comprising 60 to 80% w/w water. 15. An oral composition according to any preceding claim, comprising in the range of from 0 to 30% w/w alcohol, based on the weight of the oral composition. 16. An oral composition according to claim 15, wherein the alcohol is ethanol. 17. An oral composition according to any one of claims 1 to 15, which is substantially free of alcohol. 18. An oral composition according to claim 1 , having a pH in the range of from 5 to 6.5, comprising: (a) in the range of from 0.1 % to (b) 20 to 80% w/w water and from 0 to 30% w/w alcohol; and, optionally, (c) a pharmaceutically acceptable carrier therefor. 19. An oral composition according to any preceding claim, wherein the component (c) is selected from fluoridating agents, flavours, sweeteners, colours and preservatives; anti- plaque and antimicrobial agents; humectants, surfactants, thickeners, gums, binders and abrasive agents; and film-formers. 20. An oral composition according to any preceding claim, which is in the form of a paste, such as toothpaste. 21. An oral composition according to any one of claims 1 to 19, which is in the form of a liquid, such as a mouthspray, mouthrinse or mouthwash. 22. An oral composition according to any preceding claim suitable for treating, preventing or ameliorating the effects of a microbial, such as a bacterial, infection in the oral cavity or other periodontal disease; for cleaning, disinfecting or removing debris from the oral cavity; for refreshing, freshening, removing or improving the odour or taste in the oral cavity; or for attending to the hygiene, appearance and feel of the oral cavity. 23. Preparation of an oral composition as claimed in any preceding claim, comprising bringing components (a), (b) and/or (c) into intimate physical admixture. 24. Use of a stock solution comprising a mixture of bioflavonoids and fruit acids as defined in any one of claims 1 to 21 in the preparation of a medicament for the treatment of a microbial, especially a bacterial, infection in the oral cavity; such as, wherein the medicament comprises in the range of from 0.1% to 10% w/w (based on the total weight of the oral composition) of the stock solution. 25. Use according to claim 24, wherein the stock solution is in association with component (c), being other pharmaceutically or pharmacologically acceptable ingredients suitable for oral administration. 26. An oral composition or use as claimed in any one of claims 22, 24 and 25, wherein the microbial infection is selected from: Actinomyces odontolyticus, Actinomyces viscosus, Porphyromonas gingivalis, Prevotella intermedia, Prevotella buccae, Prevotella dentalis, Streptococcus gordonii, Streptococcus sanguinis, S oralis, Ssobrinus, Smutans, S intermedius, Lactobacillus acidophilus, Eubacterium nodatum, Actinomyces israelii, Actinomyces naeslundii, C albicans and C tropicalis.

Full Text

ORAL COMPOSITIONS. THEIR PREPARATION AND USE

The present invention relates to flavonoid-containing compositions for use in the preparation of oral compositions, such as toothpastes, mouthwashes or dental rinses. In particular, it relates to oral compositions comprising an antibacterial bioflavonoid stock solution, their preparation and use.

Certain compositions comprising flavonoids having antimicrobial, particularly antibacterial and especially anti- viral, activity are known. However, the term 'flavonoid' covers a large variety of differing compounds, which may be made available by extraction from various natural sources. Depending on both the source and the nature or method of extraction, the overall chemical composition of the resulting flavonoid mixture can itself vary widely. Individual flavonoids can vary greatly in their biological activity (or be inactive), both in terms of toxicity and effectiveness against microbes such as viruses and bacteria. Therefore, in combination, such flavonoids can also vary in their biological activity.

It has been found that it is possible to synergise, enhance or facilitate the biological activity of certain combinations of flavonoids by the addition of other agents to the flavonoid composition. Much effort has therefore been directed to finding a suitable combination of flavonoids, with or without other agent(s), that will have a desired effectiveness against certain microbes but without accompanying toxic or other disadvantageous effects in use. An example of such a combination is to be found in a combination of orange extracts, known as bioflavonoids, and natural fruit acids such as vitamin C, which is used in the poultry industry to kill food-related microbes such as E coli and Salmonella.

However, up until the present invention, it has not been proposed to use an orange- derived bioflavonoid/fruit acid combination in formulations for personal hygiene, such as oral, use. In particular, the known combination would be much too acidic for oral use.

Furthermore, although it has been suggested that flavonoids be used in compositions such as toothpaste and mouthwash, these have either been unspecified as to their flavonoid components and/or limited to specific flavonoids. For example, patent specification no. WO 02/47615 discloses an oral composition comprising an organoleptically suitable

carrier and a terpenoid and/or a flavonoid dispersed in the carrier; DE 19949575 discloses a combination of fluorides and flavonoids for treating dental disorders and preventing caries; and JP62051613 relates to a dentifrice composition containing 0.001-0.1 wt% flavonoid compound(s) selected from flavonol, chrysin, hesperetin and hesperidin. None of the prior art formulations disclose a combination of a bioflavonoid composition (itself comprising a particular combination of water-soluble flavonoid components) with one or more water-soluble fruit acid(s) in an amount and form suitable for oral administration as a solution, and having anti-bacterial activity.

Accordingly, the present invention provides an oral composition having a pH in the range of from 3 to 8.5, preferably 3.5 to 8, preferably 4 to 7, more preferably 5 to 6.5, comprising:

(a) in the range of from 0.1 % to
(b) water; and, optionally,

(c) a pharmaceutically acceptable carrier therefor, which may itself comprise (an)other pharmaceutically or pharmacologically acceptable ingredient(s) suitable for oral administration.

Preferably, the oral composition comprises in the range of from 0.1 to 5% w/w of the stock solution, more preferably from 0.1 to 2% w/w, such as about 1%. Suitably, the oral composition comprises in the range of from 20 to 80% w/w water, towards the lower end of that range in the case of a toothpaste and towards the upper end for a liquid composition such as a mouthwash/rinse/spray. For example, a paste may comprise in the range of from 20 to 45% w/w water, such as 20 to 30% w/w, particularly if silica is included in component (c), and a liquid formulation may comprise in the range of from 60 to 80% w/w water (all w/w based on the total weight of the oral composition).

Especially preferred is when the stock solution is preparable from water-soluble bioflavonoids in combination with a fruit acid, such as citric, malic and ascorbic acids. One or more of the acids are preferably neutralized with a suitable base, such as a quaternary ammonium base, for example a choline base, such as choline carbonate, bicarbonate or, preferably, hydroxide. More preferably, citric, malic and ascorbic acids

are all used in the preparation of the composition, and especially preferred is when these are fully neutralized to provide citrate, malate and/or ascorbate salts. Especially preferred is choline ascorbate. Accordingly, it is preferred that the stock solution is substantially free from fruit acids, by which is meant that its pH is around neutral. Exemplary pH ranges for the stock solution are from 3 to 8.5, 3.5 to 8.5, 3.5 to 8, 4 to 8, 4 to 7.5, 4.5 to 7.5, 4.5 to 7, 5 to 7, 5 to 6.5, 5.5 to 6.5 and 5.5 to 6, the pH being for example about 5, about 5.5, about 6, about 6.5 or about 7.

Not wishing to be bound by any particular theory, the present inventors believe that, as well as having a chelating effect on hard water, the fruit acids also synergise the biological activity of the active agents eg the bioflavonoids and choline ascorbate. Accordingly, a preferred stock solution comprises water-soluble bioflavonoids and choline ascorbate (present either as choline base (eg hydroxide) and ascorbic acid or as the salt per se).

The stock solution preferably further comprises a non-toxic solvent, such as a water- miscible or hydrophilic solvent, and more preferably comprises water and a water- miscible co-solvent such as glycerine, a polyhydric alcohol or the like. Especially preferred is when the solvent comprises a water/glycerine mixture, preferably in the ratio of from 2:1 - 1:2 (water :co-solvent). More preferably, components (b) and (c) (the balance comprising water, co-solvent(s) and excipient(s) and or/or carriers)) are alcohol-, especially ethanol-, free.

Accordingly, the stock solution preferably is preparable from:

* Ascorbic acid and choline hydroxide (or other choline base) can be replaced by choline ascorbate, with amounts of glycerine and water (or alternative solvent(s)) increased appropriately. Preferred is when the solvent comprises approximately equal % of both glycerine and water, such as 5 to 25% each, such as 15% glycerine and 20% water (when choline is present as the hydroxide solution), or such as 25% glycerine and 25% water (when the choline and ascorbic acid are present as 5% choline ascorbate).

Accordingly, the oral compositions of the present invention preferably are preparable from (based on the weight of the oral composition) :

(a) (i) in the range of from 0.0002 - 1.5% w/w bioflavonoids [excluding biomass, which preferably contributes another 0.00024 - 1.83% w/w];

(ii) in the range of from 0.001 - 2.0% w/w citric acid; (iii) in the range of from 0.001 - 2.0% w/w malic acid; (iv) in the range of from 0.001 - 2.0% w/w ascorbic acid;

(v) in the range of from 0.00045 - 2.03% w/w choline base; and

(b) and (c) the balance comprising water, co-solvent(s) and excipient(s) and/or carrier(s).

More preferably, the oral compositions of the present invention are preparable from (based on the weight of the oral composition):

(a) (i) in the range of from 0.00045 - 0.9% w/w bioflavonoids [excluding biomass, which preferably contributes another 0.00055 - 1.1% w/w];

(ii) in the range of from 0.001 - 2.0% w/w citric acid; (iii) in the range of from 0.001 - 2.0% w/w malic acid; (iv) in the range of from 0.001 - 2.0% w/w ascorbic acid;

(v) in the range of from 0.00045 - 2.03% w/w choline base; and

(b) and (c) the balance comprising water, co-solvent(s) and excipient(s) and/or carrier(s).

Since the stock solutions of the present invention therefore more preferably are preparable from the percentages given in the above-noted table, the oral compositions of the present invention more preferably are preparable from:

(a) (i) in the range of from 0.000675 - 0.675% w/w bioflavonoids [excluding biomass]; (ii) in the range of from 0.015 - 1.5% w/w citric acid;

(iii) in the range of from 0.015 - 1.5% w/w malic acid; (iv) in the range of from 0.005 - 0.5% w/w ascorbic acid; (v) in the range of from 0.015 - 0.9% w/w choline base; and

(b) and (c) the balance comprising water, co-solvent(s) and excipient(s) and/or carrier(s).

Since preferred oral compositions of the present invention comprise in the order of 1% w/w of the stock solution, in one embodiment, preferred oral compositions of the invention are preparable from:

(a) (i) of the order of 0.0675% w/w bioflavonoids [excluding biomass]; (ii) of the order of 0.15% w/w citric acid;

(iii) of the order of 0.15% w/w malic acid; (iv) of the order of 0.05% w/w ascorbic acid; (v) of the order of 0.09% w/w choline base; and

(b) and (c) the balance comprising water, co-solvent(s) and excipient(s) and/or carrier(s).

In another embodiment, most preferred oral compositions of the invention are preparable from:

(a) (i) of the order of 0.01485% w/w bioflavonoids [excluding biomass]; (ii) of the order of 0.045% w/w citric acid; (iii) of the order of 0.045% w/w malic acid;

(iv) of the order of 0.015% w/w ascorbic acid; and

(b) and (c) the balance comprising water, co-solvent(s) and excipient(s) and/or carriers).

hi another embodiment, most preferred oral compositions of the invention are preparable from:

(a) (i) of the order of 0.01485% w/w bioflavonoids [excluding biomass];

(ii) of the order of 0.045% w/w citric acid;

(iii) of the order of 0.045% w/w malic acid;

(iv) of the order of 0.06% w/w choline ascorbate; and

(b) and (c) the balance comprising water, co-solvent(s) and excipient(s) and/or carriers).

The stock solution is prepared by processes known to those skilled in the art. Preferably, the co-solvents are mixed with the water at ambient temperature and then the acids involved in neutralization processes, such as ascorbic acid, are blended together with the solvent at an increased temperature, which is kept low enough to ensure no degradation of any of the ingredients. In the case of ascorbic acid, which thermally degrades above about 55 degC, the temperature is kept in the range of from about 25 to below 55 degC and is preferably in the region of 50 degC. Preferably, the neutralization involves addition of choline hydroxide to ascorbic acid in the blend (starting pH = 1.2; finishing pH = 5.5-6.0), or choline ascorbate (ie wherein the ascorbic is already neutralized) itself can be added.

Then, the remaining acids (preferably, citric and malic) are added, followed by the bioflavonoids, resulting in a solution having a pH in the range of from about 2.0 to 6.5 but typically is from about 2.2 to 3.5, especially in the range of from 2.3 to 3.0. The remaining un-neutralised acids are also substantially neutralized, for example, by choline hydroxide, to result in a substantially neutral solution having a pH in the range of, for example, from 5 to 8.5, preferably 5.5 to 7, more preferably 5.5 to 6.5.

The stated antimicrobial effect of prior art formulations comprising a bioflavonoid relies on the inhibition by the bioflavonoid of the uptake of essential amino acids in the cytoplasmic membrane of the microbe, such as by inhibiting the viral neuroamidase. However, the formulations of the present invention are believed to be effective because the combination of selected soluble bioflavonoids with choline ascorbate results in encapsulation of the microbe, breakdown of the flavonone and glucoside components into independent fragments, and subsequent deactivation of the microbe by the flavonone fragments and choline ascorbate.

Preferably, the bioflavonoid mixture comprises water-soluble bioflavonoids in association with biomass resulting from the extraction process; accordingly, the bioflavonoid mixture may be associated with up to 40-60% w/w, preferably about 55% w/w, biomass (based on the weight of the bioflavonoid mixture). The bioflavonoids are preferably glucosides, especially those selected from isocriocirm, isonaringin, narangin, hesperidin,

neohesperidin, neodiomin, naringenin, poncirin and rhiofolen, and more preferably each of these is present in the mixture. Especially preferred is when the major part of the bioflavonoid mixture comprises narangin and neohesperidin, such as when these comprise in excess of 75% of the bioflavonoid component (excluding biomass). Suitably, other bioflavonoids (such as flavonol, chrysin, hesperetin) are substantially absent from the bioflavonoid mixture and the bioflavonoid component therefore consists essentially of the water-soluble bioflavonoids listed hereinabove, although trace amounts of other bioflavonoids may be present. Especially preferred is when the water-soluble bioflavonoids comprise the following percentages (by weight of bioflavonoid in the total bioflavonoid component):

A suitable source of such a water-soluble bioflavonoid mixture is herein referred to as 'HPLC 45', of which about 45% (of the total composition of HPLC 45) comprises such bioflavonoids, with the balance (about 55%) comprising biomass such as pectins, sugars and minor organic acids. As stated above, especially preferred is when the major part of the bioflavonoid mixture comprises narangin and neohesperidin, such as when these comprise in excess of 35% of the bioflavonoid component in a mixture with biomass such as HPLC 45. Accordingly, by weight of the total composition of HPLC 45, the following bioflavonoids are preferably present:

The HPLC 45 is available from Exquim (the food arm of Grupo Ferrer) as Citrus Bioflavonoid Complex 45% HPLC. It is derived from a starting material comprised of the pith of immature, bitter (blood/red) oranges such as Seville oranges that are classed as 'inedible' and from which the pips, flesh and oily skin have been substantially removed or remain undeveloped. This starting material is crushed in a hydrophilic, ionic solvent such as water or water/alcohol mixtures, preferably water/ethanol in a ratio of about 1:10-20 (solvent: starting material). The resulting mixture is filtered to leave a water-soluble biomass, which is retained, and an insoluble biomass, which is discarded. The water- soluble biomass is then subject to fine filtration, after which it is flash-distilled to leave a brown, hygroscopic powder (HPLC 45).

Preferably, the bioflavonoid mixture for use in the oral compositions of the present invention is distinguishable particularly by comprising water-soluble glucosides from the mixture obtained from grapefruit or other citrus fruits or other plant sources, which comprise water-insoluble flavonoids; and, more preferably, is distinguishable from the mixture obtained when substantial amounts of the seeds, pulp and/or flesh of such fruits are comprised in the starting material, which particularly comprise water-insoluble components. Furthermore, the more developed/mature starting material of the prior art is more likely to have been subjected to pesticides and/or synthetic fertilizing media, and are

therefore less Organic' or pure in their origin than the bioflavonoid mixture of the solutions of the present invention.

Preferably, the stock solution comprises 1-20%, preferably 2 to 15%, more preferably 3 to 15%, such as 3, 4, or 15, most preferred is 3.3% w/w of the HPLC45. Accordingly, the stock solution preferably comprises 0.45-9%, preferably 0.9 to 6.75%, more preferably 1.35 to 6.75%, such as 1.35, 1.8, or 6.75, most preferred is 1.485% of the bioflavonoid mixture.

Preferably, the oral composition and, particularly in the absence of other ingredients except water, the stock solution has a pH of from about 3 to about 8.5, more preferably of from about 4 to 7.5, such as about 5 to 7 ; especially preferred is when the pH is about 5.5 to 6.5. Most preferably, therefore, the oral composition is substantially free of hydrogen ions, such as from fruit acids; the fruit acids used in the preparation of the stock solution and/or oral composition therefore having been substantially neutralised, preferably as described above by addition of a base to the stock solution. On the other hand, when the oral composition also comprises a buffering agent, then the pH of the stock solution can vary outside these ranges provided that the buffering agent is present in an amount effective to provide the oral composition with a pH within these ranges.

Accordingly, component (c) of the oral compositions of this invention may comprise a buffering agent to regulate or adjust the pH of the final composition, such as an alkali metal hydroxide or ammonium hydroxide or a mono-, di- or tri-basic phosphate such as a tri(alkali metal) phosphate. Since the quantity of hydroxide is more difficult to measure than that of dibasic phosphate, it is preferred to use monobasic phosphates and dibasic phosphates. Another alternative is to use a combination of phosphoric acid with a dibasic or tribasic, such as tri(alkali metal), phosphate. The phosphates are preferably incorporated in the form of their sodium, potassium or ammonium salts; more preferably, sodium salts are employed. However, in cases where hypertensive effects of sodium ions are of concern, mono- and di-potassium phosphates may be used. When the buffering agent is disodium phosphate, for example, it may be present up to about 5% w/w of the oral composition, preferably in the range of from 0 to 0.5%, such as about 0.05% w/w.

Another optional ingredient, component (c), may comprise a source of fluoride, such as

sodium fluoride or sodium monofluorophosphate, up to about 0.5% w/w of the oral composition. The fluoride source is preferably in the range of from 0 to 0.15%, such as about 0.05% w/w in the case of liquid compositions but more in the case of toothpastes, where from 0 to 0.3%, such as around 0.24%, w/w or in the range of from 0 to 1500 ppm (as fluoride ions) is suitable.

Other additives may be present in the oral compositions of the invention, such as flavouring, sweetening or colouring agents, or preservatives. Mint, such as from peppermint or spearmint, cinnamon, eucalyptus, citrus, cassia, anise and menthol are examples of suitable flavouring agents. Flavouring agents are preferably present in the oral compositions in an amount in the range of from 0 to 3%; preferably up to 2%, such as up to 0.5%, preferably around 0.2%, in the case of liquid compositions; but optionally more in the case of toothpaste, preferably 0.5 to 2%, more preferably around 1% w/w. Sweeteners include artificial or natural sweetening agents, such as sodium saccharin which may be present in an amount in the range of from 0 to 2%, preferably up to 1 % w/w, such as 0.05 to 0.3% w/w of the oral composition. Colouring agents are suitable natural or synthetic colours, such as titanium dioxide or CI 42090, or mixtures thereof. Colouring agents are preferably present in the oral compositions in an amount in the range of from 0 to 3%; preferably up to 0.1%, such as up to 0.05%, preferably around 0.005-0.0005%, in the case of liquid compositions; but optionally more in the case of toothpaste, preferably up to 1%, more preferably around 0.5% w/w. Of the usual preservatives, sodium benzoate is preferred in concentrations insufficient substantially to alter the pH of the oral composition, otherwise the amount of buffering agent may need to be adjusted to arrive at the desired pH.

Other optional ingredients of component (c) may include other active agents such as anti- plaque agents and/or antimicrobial agents. Suitable agents include quaternary ammonium compounds such as domiphen bromide, cetyl pyridinium chloride (CPC), phenolic compounds, ethanol, and the preservatives mentioned above. Such active agents may be present in an amount in the range of from 0 to 4% w/w but may be as much as 70%, such as up to 30%, in the case of ethanol. For example, CPC or the like is preferably present up to 2%, such as about 0.05% w/w, especially in liquid oral compositions of the invention. Ethanol may comprise as much as 70%, preferably about 0 to 30%w/w in liquid compositions of the invention, such as about 15% w/w in a mouthspray, but

preferred oral compositions of the invention are those wherein ethanol or any other alcohol is substantially absent.

Other optional ingredients of component (c) may include humectants, surfactants (non- ionic, cationic or amphoteric), thickeners, gums and binding agents. Suitable humectants include glycerine, xylitol, glycerol and glycols such as propylene glycol, which may be present in an amount of up to 50% w/w each, but total humectant is preferably not more than about 60-80% w/w of the oral composition. For example, liquid oral compositions may comprise up to about 30% glycerine plus up to about 5%, preferably about 2% w/w xylitol. Surfactants are preferably not anionic and may include polysorbate 20 or cocoamidobetaine or the like in an amount up to about 6%, preferably about 1.5 to 3%, w/w of the oral composition.

When the oral compositions of the invention are in the form of a mouthspray, it is preferred to include a film-forming agent up to about 3% w/w of the oral composition, such as in the range of from 0 to 0.1%, preferably about 0.001 to 0.01%, such as about 0.005% w/w of the oral composition. Suitable film-formers include sodium hyaluronate and those sold under the tradename Gantrez.

When the oral compositions of the invention are in the form of toothpaste, it is preferred to include gums, binders and/or thickeners, such as colloidal silica, carrageenan and cellulose derivatives such as sodium carboxymethylceilulose. Such ingredients may be present in an amount up to about 3% w/w of the oral composition, such as up to about 2%, preferably about 0.5 to 1%, w/w of the oral composition.

Toothpaste compositions of this invention may also comprise an abrasive agent, such as hydrated silica, dicalcium phosphate, or water-insoluble alkali metal metaphosphates, up to about 25% w/w and preferably in the range of from about 10 to about 15% w/w of the oral composition.

The oral compositions of the present invention may be prepared by any method known in the art for the formulation of similar compositions, such as a toothpaste, mouthwash or rinse, mouthspray, or the like. AU methods comprise bringing the components (a) and (b) and, if present, (c) together in intimate physical admixture.

Preferably, the compositions are packaged in suitable packaging such as a plastics or metallic tube, plastics or glass transparent, translucent or opaque bottle, jar or dispenser, with or without spray or other applicator means, together with instructions for use. Such packaging may itself be further packaged into a cardboard box or other suitable container and the same or further instructions for use may be inserted therein or inscribed thereon; suitably, such instructions may be inscribed on a pack insert or leaflet. The packaging preferably lists the active, main or all ingredients of the composition. The instructions may include those known to the person skilled in the art of oral compositions, particularly those for anti-bacterial use. Accordingly, they may recommend that a pea-sized amount of toothpaste be applied to the dentition at regular intervals, 2-3 times per day; that a mouthful of mouthwash or rinse be sluiced around the oral cavity at least once per day and preferably after meals; and the like.

The oral compositions of the present invention may therefore be useful for treating, preventing or ameliorating the effects of a microbial, especially a bacterial, infection in the oral cavity or other periodontal disease; for cleaning, disinfecting or removing debris from the oral cavity; for refreshing, freshening, removing or improving the odour or taste in the oral cavity; and for generally attending to the hygiene, appearance and feel of the oral cavity. Accordingly, the present invention further provides a stock solution comprising a mixture of bioflavonoids and fruit acids (such as the mixture hereinbefore described) in the preparation of a medicament for the treatment of a microbial, especially a bacterial, infection in the oral cavity; in particular, wherein the medicament comprises in the range of from 0.1% to 10% w/w (based on the total weight of the oral composition) of the stock solution. Preferably, the present invention provides (a) a stock solution comprising a mixture of bioflavonoids and fruit acids together with (c) other pharmaceutically or pharmacologically acceptable ingredients suitable for oral administration (such as those described hereinbefore), in the preparation of a medicament for the treatment of a microbial, especially a bacterial, infection in the oral cavity; in particular, wherein the medicament comprises in the range of from 0.1% to 10% w/w (based on the total weight of the oral composition) of the stock solution.

The oral compositions of the present invention are useful in the treatment or prevention of infections, disease or conditions arising from the following bacteria: Actinomyces

odontolyticus, Actinomyces viscosus, Porphyromonas gingivalis, Prevotella intermedia, Prevote

CLAIMS

1. An oral composition having a pH in the range of from 3 to 8.5, comprising:

(a) in the range of from 0.1 % to
(b) water; and, optionally,

(c) a pharmaceutically acceptable carrier therefor.

2. An oral composition according to claim 1, wherein the bioflavonoid mixture is derived from the pith of immature bitter oranges.

3. An oral composition according to either claim 1 or claim 2, which comprises in the range of from 0.1 to 5% w/w of the stock solution, such as 0.5% or 1% w/w of the stock solution.

4. An oral composition according to any preceding claim, wherein the bioflavonoid mixture is water-soluble.

5. An oral composition according to any preceding claim, wherein the stock solution comprises a fruit acid salt selected from citrate, malate and ascorbate salts.

6. An oral composition according to any preceding claim, wherein the stock solution comprises a salt of fruit acid with a base, such as a quaternary ammonium base.

7. An oral composition according to claim 6, wherein the base is a choline base, such as choline ascorbate.

8. An oral composition according to any preceding claim, which is substantially free from fruit acids.

9. An oral composition according to any preceding claim, wherein the stock solution and/or the oral composition has a pH in the range of from 3.5 to 8.

10. An oral composition according to claim 9, wherein the stock solution and/or the oral composition has a pH in the range of from 4 to 7.

11. An oral composition according to claim 10, wherein the stock solution and/or the oral composition has a pH in the range of from 5 to 6.5.

12. An oral composition according to any preceding claim, wherein the bioflavonoid mixture is in association with biomass, such as in the range of from 40 to 60% w/w biomass, based on the weight of bioflavonoid mixture.

13. An oral composition according to any preceding claim, wherein the bioflavonoids are selected from isocriocirm, isonaringin, narangin, hesperidin, neohesperidin, neodiomin, aringenin, poncirin and rhiofolen, such as narangin and neohesperidin.

14. An oral composition according to any preceding claim, comprising in the range of from 20 to 80% w/w water, based on the weight of the oral composition, such as a toothpaste comprising 20-40% w/w water or a liquid composition comprising 60 to 80% w/w water.

15. An oral composition according to any preceding claim, comprising in the range of from 0 to 30% w/w alcohol, based on the weight of the oral composition.

16. An oral composition according to claim 15, wherein the alcohol is ethanol.

17. An oral composition according to any one of claims 1 to 15, which is substantially free of alcohol.

18. An oral composition according to claim 1 , having a pH in the range of from 5 to 6.5, comprising: (a) in the range of from 0.1 % to
(b) 20 to 80% w/w water and from 0 to 30% w/w alcohol; and, optionally,

(c) a pharmaceutically acceptable carrier therefor.

19. An oral composition according to any preceding claim, wherein the component (c) is selected from fluoridating agents, flavours, sweeteners, colours and preservatives; anti- plaque and antimicrobial agents; humectants, surfactants, thickeners, gums, binders and abrasive agents; and film-formers.

20. An oral composition according to any preceding claim, which is in the form of a paste, such as toothpaste.

21. An oral composition according to any one of claims 1 to 19, which is in the form of a liquid, such as a mouthspray, mouthrinse or mouthwash.

22. An oral composition according to any preceding claim suitable for treating, preventing or ameliorating the effects of a microbial, such as a bacterial, infection in the oral cavity or other periodontal disease; for cleaning, disinfecting or removing debris from the oral cavity; for refreshing, freshening, removing or improving the odour or taste in the oral cavity; or for attending to the hygiene, appearance and feel of the oral cavity.

23. Preparation of an oral composition as claimed in any preceding claim, comprising bringing components (a), (b) and/or (c) into intimate physical admixture.

24. Use of a stock solution comprising a mixture of bioflavonoids and fruit acids as defined in any one of claims 1 to 21 in the preparation of a medicament for the treatment of a microbial, especially a bacterial, infection in the oral cavity; such as, wherein the medicament comprises in the range of from 0.1% to 10% w/w (based on the total weight of the oral composition) of the stock solution.

25. Use according to claim 24, wherein the stock solution is in association with component (c), being other pharmaceutically or pharmacologically acceptable ingredients suitable for oral administration.

26. An oral composition or use as claimed in any one of claims 22, 24 and 25, wherein the microbial infection is selected from: Actinomyces odontolyticus, Actinomyces viscosus, Porphyromonas gingivalis, Prevotella intermedia, Prevotella buccae, Prevotella dentalis, Streptococcus gordonii, Streptococcus sanguinis, S oralis, Ssobrinus, Smutans, S intermedius, Lactobacillus acidophilus, Eubacterium nodatum, Actinomyces israelii, Actinomyces naeslundii, C albicans and C tropicalis.

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Patent Number

272246

Indian Patent Application Number

218/MUMNP/2009

PG Journal Number

14/2016

Publication Date

01-Apr-2016

Grant Date

23-Mar-2016

Date of Filing

29-Jan-2009

Name of Patentee

ORALDENT LIMITED

Applicant Address

Unit 11 Harvard Industrial Estate Kimbolton Cambridgeshire PE28 0NJ United Kingdom

Inventors:

#	Inventor's Name	Inventor's Address
1	Ian RIPLEY	Oraldent Ltd Unit 11 Harvard Industrial Estate Kimbolton Cambridgeshire PE28 0NJ United Kingdom
2	HOWARD THOMAS	Oraldent Ltd Unit 11 Harvard Industrial Estate Kimbolton Cambridgeshire PE28 0NJ United Kingdom

PCT International Classification Number

A61K 8/49

PCT International Application Number

PCT/GB2007/002758

PCT International Filing date

2007-07-20

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	0614353.1	2006-07-20	U.K.