Mouthwash compositions and methods

Abstract

The present application relates to novel antibacterial mouthwash compositions comprising hyaluronic acid, cetylpyridinium chloride # imgabs0 # and taurine salt surfactants having unexpected stability, and their use in the treatment of plaque, gingivitis, halitosis, implant infections, tooth decay, inflammation and tooth coloration, and in favor of moisturizing and protecting teeth and gums.

Description

Technical Field

[0001] The present application relates to a new antibacterial mouthwash composition comprising hyaluronic acid, cetylpyridinium chloride and a taurine surfactant, having unexpected stability, and its use in the treatment of dental plaque, gingivitis, halitosis, implant infections and dental caries, as well as in contributing to moisturizing and protecting teeth and gums. Background Art

[0002] Xerostomia or dry mouth is an acute or chronic condition mainly caused by a lack of saliva. It may be caused by underlying diseases such as Sjogren's syndrome, dehydration, salivary gland trauma, alcohol intake or drug side effects. It is considered to be an increasing condition in the general population. Approximately 15% to 20% of young adults complain of dry mouth, and 30% to 40% of people aged 60 to 80 complain of dry mouth. Patients with xerostomia may also suffer from extensive dental caries such as dental caries, including areas that are usually not prone to decay, such as the lower incisors and tooth roots. One possible explanation is that the pellicle present with saliva provides a protective barrier between acid and the tooth surface, and such a barrier weakens in the absence of saliva.

[0003] Oral surgeries, including tooth extraction and dental implantation, may also disrupt the oral environment. Dental implants may become infected, leading to inflammation in soft tissues and bone loss around the implant. In fact, a high percentage of implants fail within the first year due to bacterial infection.

[0004] The most widely used antibacterial agent in mouthwashes in the United States, cetylpyridinium chloride (CPC) presents challenges in formulation. Since cetylpyridinium is strongly cationic, it can form salts or complexes with anionic compounds in the formulation. For example, hyaluronic acid (HA) is a natural ingredient that provides moisturizing, anti-inflammatory and barrier protection benefits to oral soft tissues, making it a desirable ingredient for use in mouthwashes, but it is an acid and thus has the potential to interact with CPC. Developing a stable mouthwash formulation containing HA and CPC has proven challenging. Anionic surfactants such as sodium lauryl sulfate (SLS) are widely used in dentifrice formulations. SLS has such benefits as being neutral in terms of product taste, for example, and in mouthwashes, it can help dissolve flavoring agents. However, recently consumers have shown interest in developing various oral care products that do not contain SLS. Many mouthwashes also contain ethanol, which is antibacterial and helps dissolve ingredients that are poorly soluble in water, but ethanol may exacerbate dry mouth and is not liked by many consumers.

[0005] There is a need for a mouthwash with such improvements: it kills the unwanted bacteria that cause dental plaque, gingivitis, bad breath, implant infections, and tooth decay and it also helps to moisturize and protect the teeth and gums. Summary of the Invention

[0006] Due to the formation of cetylpyridinium hyaluronate precipitates, various antimicrobial mouthwash formulations tested by adding 0.10% HA to a commercial mouthwash body containing 0.075% cetylpyridinium chloride (CPC) and 0.28% zinc lactate (ZnLac) did not pass stability tests, such as freeze-thaw cycles.

[0007] Although anionic surfactants may form stable micelles with positively charged CPC, thereby preventing interaction with HA, such surfactants may impede the delivery of CPC to the teeth. Various surfactants were screened for their ability to inhibit the formation of CPC-HA complexes. The effectiveness of CPC was tested by measuring CPC uptake and antibacterial activity in a short interval kill test (SIKT).

[0008] Some surfactants were completely ineffective at inhibiting the formation of CPC-HA complexes. Polyethylene glycol 40 hydrogenated castor oil, used as a surfactant in several mouthwash formulations containing HA, inhibited the formation of CPC-HA complexes but also impeded CPC uptake. However, unexpectedly, sodium methyl cocoyl taurate was effective at both inhibiting the formation of CPC-HA complexes and enhancing CPC uptake.

[0009] Accordingly, the present disclosure provides an antimicrobial mouthwash composition comprising hyaluronic acid, cetylpyridinium chloride and a taurate surfactant and the use of such a composition for treating and inhibiting dental plaque, gingivitis, bad breath, implant infections, and tooth decay and for helping to moisturize and protect the teeth and gums.

[0010] Other applicable fields of the present invention will become apparent from the detailed description provided below. It should be understood that the detailed description and specific examples, while indicating preferred embodiments of the invention, are intended for purposes of illustration only and are not intended to limit the scope of the invention. Detailed Description

[0011] The following description of the preferred embodiments is exemplary in nature and is in no way intended to limit the invention, its application, or uses.

[0012] As used throughout, ranges are used as shorthand for describing each and every value within the range. Any value within the range can be selected as the endpoint of the range. Additionally, all references cited herein are hereby incorporated by reference in their entirety. In the event of a conflict between the definitions in this disclosure and the definitions of the cited references, the definitions in this disclosure shall control.

[0013] Unless otherwise indicated, all percentages and amounts expressed herein and elsewhere in the specification are to be understood as being weight percentages relative to the total composition. The amounts given are based on the active weight of the materials.

[0014] As is customary in the art, the compositions described herein are sometimes described in terms of their components, although the components may dissociate, associate, or react in the formulation. For example, ions are typically provided to the formulation in the form of salts that can dissolve and dissociate in aqueous solution. It is understood that the present invention encompasses both the mixtures of the described components and the products obtained therefrom.

[0015] It is understood that all components in the compositions described herein are safe and palatable at the relevant concentrations for oral administration as a mouthwash.

[0016] In a first aspect, the present disclosure provides an antibacterial mouthwash composition (Composition 1) comprising: hyaluronic acid (HA); cetylpyridinium chloride (CPC); an effective amount of a taurate surfactant represented by formula (1):

[0017]

[0018] wherein R1 is a saturated or unsaturated, straight-chain or branched C 7-17 alkyl group, R2 is H or methyl, and M + is H, sodium, or potassium (e.g., wherein the taurate surfactant is sodium methyl cocoyl taurate); and at least 70% water by weight of the composition. For example, the present disclosure provides the following embodiments of Composition 1:

[0019] 1.1 Composition 1, wherein the taurate surfactant is sodium methyl cocoyl taurate.

[0020] 1.2 Any of the foregoing compositions, wherein the taurate surfactant is sodium methyl cocoyl taurate in an amount of 0.3 wt% to 0.8 wt%.

[0021] 1.3 Any of the foregoing compositions, wherein the taurate surfactant is sodium methyl cocoyl taurate in an amount of 0.4 wt% to 0.5 wt%.

[0022] 1.4 Any of the foregoing compositions, wherein the amount of CPC is from 0.05% to 0.1% by weight.

[0023] 1.5 Any of the foregoing compositions, wherein the amount of CPC is about 0.075% by weight

[0024] 1.6 Any of the foregoing compositions, wherein the HA is provided in the form of sodium hyaluronate.

[0025] 1.7 Any of the foregoing compositions, wherein the amount of HA is equivalent to 0.05% to 0.5% by weight of sodium hyaluronate.

[0026] 1.8 Any of the foregoing compositions, wherein the amount of HA is equivalent to 0.1% to 0.4% by weight of sodium hyaluronate.

[0027] 1.9 Any of the foregoing compositions, wherein the amount of HA is equivalent to 0.05% to 0.15% by weight of sodium hyaluronate.

[0028] 1.10 Any of the foregoing compositions, wherein the amount of HA is equivalent to about 0.1% by weight of sodium hyaluronate.

[0029] 1.11 Any of the foregoing compositions, wherein the average molecular weight of the HA is at least 5 kDa.

[0030] 1.12 Any of the foregoing compositions, wherein the average molecular weight of the HA is at least 100 kDa.

[0031] 1.13 Any of the foregoing compositions, wherein the average molecular weight of the HA is at least 300 kDa.

[0032] 1.14 Any of the foregoing compositions, wherein the average molecular weight of the HA is from 5 kDa to 1 MDa.

[0033] 1.15 Any of the foregoing compositions, wherein the average molecular weight of the HA is from 300 kDa to 1 MDa.

[0034] 1.16 Any of the foregoing compositions, wherein the HA is in the form of sodium hyaluronate having an average MW > 100,000 Da, such as from 300 kDa to 1 MDa.

[0035] 1.17 Any of the foregoing compositions further comprises a zinc ion source.

[0036] 1.18 The foregoing composition, wherein the zinc ion source is an orally acceptable soluble zinc salt, such as an orally acceptable soluble zinc salt selected from zinc lactate, zinc citrate, and combinations thereof.

[0037] 1.19 Any of the foregoing compositions further comprises a zinc salt, wherein the zinc salt is zinc lactate.

[0038] 1.20 Any of the aforementioned compositions further comprises a zinc salt, wherein the zinc salt is zinc lactate in an amount of 0.1% to 0.5% by weight, for example 0.2% to 0.4% by weight.

[0039] 1.21 Any of the aforementioned compositions further comprises a zinc salt, wherein the zinc salt is zinc lactate corresponding to zinc lactate dihydrate in an amount of about 0.28% by weight.

[0040] 1.22 Any of the aforementioned compositions further comprises a zinc salt, wherein the zinc salt is zinc lactate in an amount of 0.2% to 0.4% by weight, and further comprises lactic acid in an amount of 0.4% to 0.6% by weight.

[0041] 1.23 Any of the aforementioned compositions further comprises a fluoride ion source, such as sodium fluoride.

[0042] 1.24 Any of the aforementioned compositions further comprises a fluoride ion source, and the fluoride ion source is sodium fluoride in an amount of 0.04% to 0.06% by weight.

[0043] 1.25 Any of the aforementioned compositions further comprises a nonionic surfactant.

[0044] 1.26 Any of the aforementioned compositions further comprises a nonionic surfactant, wherein the nonionic surfactant is poloxamer.

[0045] 1.27 Any of the aforementioned compositions further comprises a nonionic surfactant, wherein the nonionic surfactant is poloxamer 407 in an amount of 0.3% to 0.5% by weight.

[0046] 1.28 Any of the aforementioned compositions further comprises a humectant, such as a humectant selected from propylene glycol, glycerol, sorbitol, and combinations thereof.

[0047] 1.29 Any of the aforementioned compositions further comprises a humectant, wherein the humectant comprises a total of 10% to 25% by weight of propylene glycol, glycerol, and sorbitol.

[0048] 1.30 Any of the aforementioned compositions further comprises a flavoring agent and a sweetening agent, such as a sweetening agent selected from saccharin, sucralose, and combinations thereof.

[0049] 1.31 Any of the aforementioned compositions further comprises a flavoring agent and a sweetening agent, wherein the sweetening agent comprises a combination of saccharin and sucralose.

[0050] 1.32 Any of the aforementioned compositions further comprises a flavoring agent and a sweetening agent, wherein the sweetening agent comprises a combination of sodium saccharin in an amount of 0.01% to 0.03% by weight and sucralose in an amount of 0.001% to 0.003% by weight.

[0051] 1.33 Any of the foregoing compositions further comprises a preservative.

[0052] 1.34 Any of the foregoing compositions further comprises a preservative, wherein the preservative comprises potassium sorbate in an amount of 0.04% to 0.06% by weight.

[0053] 1.35 Any of the foregoing compositions further comprises a preservative, wherein the preservative comprises sodium benzoate in an amount of 0.01% to 0.15% by weight, such as about 0.05% or about 0.1% by weight.

[0054] 1.36 Any of the foregoing compositions comprises a food coloring, such as one or more orally acceptable water-soluble dyes, such as one or more FD&C water-soluble dyes.

[0055] 1.37 Any of the foregoing compositions, wherein all ingredients are safe and palatable at relevant concentrations when administered orally as a mouthwash.

[0056] 1.38 Any of the foregoing compositions, wherein the pH is from pH 4 to pH 5.

[0057] 1.39 Any of the foregoing compositions, wherein the delivery of CPC to the teeth is enhanced relative to a formulation in which the taurate surfactant, such as sodium methyl cocoyl taurate, is replaced with PEG-40 hydrogenated castor oil.

[0058] 1.40 Any of the foregoing compositions, wherein the antibacterial activity measured in a short-interval kill test (SIKT) is superior to a formulation in which the taurate surfactant, such as sodium methyl cocoyl taurate, is replaced with PEG-40 hydrogenated castor oil.

[0059] 1.41 Any of the foregoing compositions, which does not form cetylpyridinium hyaluronate precipitate in freeze-thaw cycle tests, such as freezing to -30 °C and then thawing to 30 °C.

[0060] 1.42 Any of the foregoing compositions, which does not form cetylpyridinium hyaluronate precipitate after aging for four weeks at 40 °C.

[0061] 1.43 Any of the foregoing compositions, which does not form cetylpyridinium hyaluronate precipitate after aging for four weeks at -10 °C.

[0062] 1.44 Any of the foregoing compositions does not contain ethanol.

[0063] 1.45 Any of the foregoing compositions does not contain PEG-40 hydrogenated castor oil.

[0064] 1.46 Any of the foregoing compositions that do not contain betaine surfactants.

[0065] 1.47 Any of the foregoing compositions that do not contain cocamidopropyl betaine.

[0066] 1.48 Any of the foregoing compositions that do not contain sodium cocoyl glutamate.

[0067] 1.49 Any of the foregoing compositions that do not contain decyl glucoside.

[0068] 1.50 Any of the foregoing compositions that do not contain sodium lauryl sulfate.

[0069] 1.51 Any of the foregoing compositions that do not contain ionic surfactants other than taurate surfactants.

[0070] 1.52 Any of the foregoing compositions that do not contain ionic surfactants other than sodium methyl cocoyl taurate.

[0071] 1.53 Any of the foregoing compositions is formed by combining the following components:

[0072] 0.05% to 0.15% of sodium hyaluronate,

[0073] 0.05% to 0.1% of cetylpyridinium chloride

[0074] 0.3% to 0.8% of sodium methyl cocoyl taurate, and

[0075] 75% to 85% by weight of water,

[0076] and optionally further comprising one or more of the following: a zinc ion source, a humectant, a nonionic surfactant, a fluoride ion source, a humectant, a preservative, a sweetener, a flavoring agent, and / or a dye,

[0077] wherein all percentages are by weight of the composition.

[0078] 1.54 Any of the foregoing compositions is formed by combining the following components:

[0079] 0.05% to 0.15% of sodium hyaluronate,

[0080] 0.07% to 0.08% of cetylpyridinium chloride

[0081] 0.4% to 0.5% of sodium methyl cocoyl taurate,

[0082] 0.2% to 0.4% of zinc L-lactate dihydrate, and

[0083] 75% to 85% water,

[0084] wherein all percentages are by weight of the composition.

[0085] 1.55 Any of the foregoing compositions, formed by combining ingredients comprising:

[0086] 0.05% to 0.15% sodium hyaluronate,

[0087] 0.07% to 0.08% cetylpyridinium chloride

[0088] 0.4% to 0.5% sodium methyl cocoyl taurate,

[0089] 0.2% to 0.4% zinc L-lactate dihydrate,

[0090] 15% to 20% humectant, said humectant comprising glycerol, propylene glycol and sorbitol, 0.3% to 0.5% poloxamer 407,

[0091] 0.04% to 0.06% L-lactic acid,

[0092] 0.04% to 0.06% sodium fluoride,

[0093] 0.02% to 0.03% sweetener, said sweetener comprising sucralose and sodium saccharin,

[0094] 0.05% to 0.2% flavoring agent, said flavoring agent comprising one or more cooling agents,

[0095] 0.01% to 0.15% preservative, said preservative selected from potassium sorbate, sodium benzoate and combinations thereof,

[0096] 0.00005% to 0.0005% water-soluble dye, and

[0097] 75% to 85% water,

[0098] wherein all percentages are by weight of the composition.

[0099] 1.56 Any of the foregoing compositions, used as an antibacterial agent in the oral cavity.

[0100] 1.57 Any of the foregoing compositions, for the treatment of dry mouth.

[0101] 1.58 Any of the foregoing compositions, for the treatment and inhibition of dental plaque.

[0102] 1.59 Any of the foregoing compositions, for the treatment and inhibition of gingivitis.

[0103] 1.60 Any of the foregoing compositions, for treating and inhibiting halitosis.

[0104] 1.61 Any of the foregoing compositions, for treating and inhibiting implant infections.

[0105] 1.62 Any of the foregoing compositions, for treating and inhibiting dental caries.

[0106] 1.63 Any of the foregoing compositions, for treating and inhibiting dental caries.

[0107] 1.64 Any of the foregoing compositions, for moisturizing and protecting teeth and gums.

[0108] 1.65 Any of the foregoing compositions, for reducing inflammation in the oral cavity.

[0109] 1.66 Any of the foregoing compositions, for reducing tooth discoloration.

[0110] 1.67 Any of the foregoing compositions that do not form visible precipitates after freeze-thaw cycles (30 °C to -30 °C to 30 °C).

[0111] 1.68 Any of the foregoing compositions, which are stable in terms of appearance, CPC level, pH level, and HA level under the following storage conditions: 4 weeks at -10 °C, 4 weeks at 40 °C, and 4 weeks at 49 °C.

[0112] 1.69 Any of the foregoing compositions that exhibit antibacterial activity, such as providing at least 25% killing in a short-time kill assay, for example, in a short-time kill assay substantially as described in Example 1.

[0113] 1.70 Any of the foregoing compositions that exhibit anti-inflammatory activity, such as reducing the release of IL-8 caused by treatment with a pro-inflammatory stimulant (using IL-1α), for example, in an assay substantially as described in Example 2.

[0114] 1.71 Any of the foregoing compositions that exhibit anti-discoloration activity, such as reducing tooth discoloration due to coffee, tea, and wine, for example, as demonstrated in an assay substantially as described in Example 3.

[0115] 1.72 Any of the foregoing compositions containing zinc, wherein HA enhances zinc uptake relative to the same formulation except that HA is replaced with an equal amount of water.

[0116] In another aspect, the present disclosure also provides for inhibiting the formation of cetylpyridinium in a mouthwash containing cetylpyridinium chloride Method for hyaluronate precipitate, including adding taurate surfactant, e.g., to form a mouthwash composition according to any one of Composition 1 and the like and so on.

[0117] In another aspect, the present disclosure provides the use of taurate surfactant in the manufacture of a mouthwash containing cetylpyridinium chloride and hyaluronic acid for inhibiting the formation of cetylpyridinium hyaluronate precipitate, e.g., wherein the mouthwash is a mouthwash composition according to any one of Composition 1 and the like and so on.

[0118] In another aspect, the present disclosure provides a method for treating or preventing one or more of dry mouth, dental plaque, gingivitis, halitosis, dental implant infection, tooth decay, and / or dental caries, including administering to the oral cavity of a subject in need thereof a composition according to any one of Composition 1 and the like and so on, e.g., once or more times a day.

[0119] In another aspect, the present disclosure provides a method for reducing inflammation in the oral cavity, including administering to the oral cavity of a subject in need thereof a composition according to any one of Composition 1 and the like and so on, e.g., once or more times a day.

[0120] In another aspect, the present disclosure provides a method for reducing tooth staining, including applying to the teeth of a subject in need thereof a composition according to any one of Composition 1 and the like and so on, e.g., once or more times a day.

[0121] In another aspect, the present disclosure provides a method for delivering zinc to the tooth pellicle, including administering to the oral cavity of a subject in need thereof a composition according to any one of Composition 1 and the like and so on, wherein the composition contains a zinc ion source; e.g., administering once or more times a day.

[0122] The foregoing methods including administering to the oral cavity or teeth of a subject a composition according to any one of Composition 1 and the like and so on include applying any one of the compositions as described herein to the teeth or oral cavity, e.g., by gargling or rinsing, or otherwise administering the composition to the oral cavity of a subject in need thereof. The composition can be administered regularly, e.g., once or more times a day (e.g., twice a day).

[0123] In various embodiments, administering the compositions of the present disclosure to teeth can provide one or more of the following specific benefits: (i) reducing or inhibiting the formation of dental caries, (ii) alleviating, repairing, or inhibiting pre-carious lesions of tooth enamel, e.g., as detected by quantitative light-induced fluorescence (QLF) or electrical caries measurement (ECM), (iii) reducing or inhibiting tooth demineralization and promoting remineralization, (iv) alleviating tooth hypersensitivity, (v) reducing or inhibiting gingivitis, (vi) promoting the healing of ulcers or wounds in the oral cavity, (vii) reducing the levels of acid-producing and / or malodor-producing bacteria, (viii) treating, alleviating, or reducing dry mouth, (ix) cleaning teeth and the oral cavity, (x) whitening teeth, (xi) reducing tartar accumulation, (xii) reducing or preventing oral malodor, (xiii) reducing staining, (xiv) reducing inflammation, and / or (xv) promoting systemic health, including cardiovascular health, e.g., by reducing the likelihood of systemic infections caused via oral tissues.

[0124] In another aspect, the present disclosure provides the use of a taurate surfactant in the manufacture of a mouthwash comprising cetylpyridinium chloride and hyaluronic acid for the treatment or prevention of one or more of dry mouth, dental plaque, gingivitis, bad breath, dental implant infection, tooth decay, and / or dental caries, such as in any one of Composition 1 and the like.

[0125] As used herein, an "oral care composition" refers to a composition whose intended use includes oral care, oral hygiene, and / or oral appearance, or whose intended method of use includes administration to the oral cavity, and refers to a palatable and safe composition for topical administration to the oral cavity and for providing benefits to teeth and / or the oral cavity. Thus, the term "oral care composition" expressly excludes compositions that are highly toxic, unpalatable, or otherwise unsuitable for administration to the oral cavity. In some embodiments, the oral care composition is not intended to be swallowed, but rather is retained in the oral cavity for a time sufficient to affect the intended utility. The oral care compositions disclosed herein can be used in non-human mammals such as companion animals (e.g., dogs and cats), as well as by humans. In some embodiments, the oral care compositions disclosed herein are used by humans. Oral care compositions include, for example, dentifrices and mouthwashes. In some embodiments, the present disclosure provides mouthwash formulations.

[0126] Unless otherwise specified, weight percentages as used herein are based on the weight of the composition.

[0127] As used herein, "orally acceptable" refers to a substance that is safe and palatable at relevant concentrations for use in oral care formulations such as mouthwashes.

[0128] As used herein, "nonionic surfactant" generally refers to a compound produced by the condensation of an oxyalkylene group (inherently hydrophilic) with an organic hydrophobic compound which can be aliphatic or alkylaromatic in nature. Examples of suitable nonionic surfactants include poloxamers (sold under the trade name ), polyoxyethylene, polyoxyethylene sorbitan esters (sold under the trade name ), polyoxyethylene 40 hydrogenated castor oil, fatty alcohol ethoxylates, poly(ethylene oxide) condensates of alkylphenols, products condensed from the reaction products of ethylene oxide with propylene oxide and ethylenediamine, ethylene oxide condensates of aliphatic alcohols, alkyl polyglycosides (e.g., fatty alcohol ethers of polyglucosides such as fatty alcohol ethers of polyglucosides, such as decyl ethers, lauryl ethers, decyl ethers, octyl ethers, myristyl ethers, stearyl ethers and other ethers of glucose and polyglucoside polymers, including, for example, mixed ethers of decyl / octyl (C8-10) glucoside, cocoalkyl (C8-16) glucoside and lauryl (C12-16) glucoside), long-chain tertiary amine oxides, long-chain tertiary phosphine oxides, long-chain dialkyl sulfoxides, and mixtures of such substances.

[0129] In some embodiments, the nonionic surfactant includes amine oxides, fatty acid amides, ethoxylated fatty alcohols, block copolymers of polyethylene glycol and polypropylene glycol, glycerol alkyl esters, polyethylene glycol octylphenol ethers, sorbitan alkyl esters, polyethylene glycol sorbitan alkyl esters, and mixtures thereof. Examples of amine oxides include, but are not limited to, lauramidopropyl dimethylamine oxide, myristamidopropyl dimethylamine oxide, and mixtures thereof. Examples of fatty acid amides include, but are not limited to, coco monoethanolamide, lauramide monoethanolamide, coco diethanolamide, and mixtures thereof. In certain embodiments, the nonionic surfactant is a combination of an amine oxide and a fatty acid amide. In certain embodiments, the amine oxide is a mixture of lauramidopropyl dimethylamine oxide and myristamidopropyl dimethylamine oxide. In certain embodiments, the nonionic surfactant is a combination of lauryl / myristylamidopropyl dimethylamine oxide and coco monoethanolamide. In certain embodiments, the nonionic surfactant is present in an amount of 0.01% to 5.0%, 0.1% to 2.0%, 0.1% to 0.6%, 0.2% to 0.4%, about 0.2%, or about 0.5%.

[0130] Mouthwashes typically contain significant levels of ethanol, which is often required to dissolve essential oils and prevent bacterial contamination. High levels of ethanol may be undesirable because, in addition to the possibility of abuse by ingestion, ethanol can also exacerbate conditions such as dry mouth. Thus, in some embodiments, the oral care compositions of the present invention are substantially free of ethanol, e.g., contain less than 1% ethanol.

[0131] Humectants can increase the viscosity, mouthfeel, and sweetness of a product and can also help protect the product from degradation or microbial contamination. Suitable humectants include edible polyols such as glycerol, sorbitol, xylitol, propylene glycol, and other polyols and mixtures of these humectants. Sorbitol can be provided in some cases as a hydrogenated starch hydrolysate in the form of a syrup, which mainly contains sorbitol (the product when starch is completely hydrolyzed to glucose and then hydrogenated), but may also contain other sugar alcohols such as mannitol, maltitol, and long-chain hydrogenated saccharides due to incomplete hydrolysis and / or the presence of sugars other than glucose, and in such cases these other sugar alcohols can also be used as humectants. In some embodiments, the humectant is present at a level of 5% to 25% by weight, such as 15% to 20%.

[0132] Flavoring agents useful in the present invention can include: extracts or oils from aromatic plants such as mint, spearmint, cinnamon, wintergreen, and combinations thereof; cooling agents such as menthol, methyl salicylate, and commercially available products such as those from Symrise The sweetening agents (other than polyols that also act as humectants) useful in the present invention are preferably non-saccharide sweetening agents such as non-saccharide sweetening agents selected from saccharin, acesulfame-K, aspartame, neotame, stevia, and sucralose.

[0133] Other ingredients that can optionally be included in the compositions according to the present invention include green tea, ginger, sea salt, coconut oil, turmeric, white turmeric (curcumin), grape seed oil, ginseng, monk fruit, vitamin E, basil, chamomile, pomegranate, aloe vera, and charcoal. Any one of such ingredients can be present in an amount of 0.01% to 2% by weight of the composition, such as 0.01% to 1%, or 0.01% to 0.5%, or 0.01% to 0.1%.

[0134] Examples

[0135] Example 1 - Formulation Screening

[0136] A mouthwash formulation containing SMCT, CPC, and HA was prepared as follows:

[0137] Table 1

[0138]

[0139] Except for sodium methyl cocoyl taurate and the test surfactants, the ingredients and amounts in the formulations are the same. Considering the different amounts of surfactants, the amount of water is adjusted by weight / weight. The test surfactants are as follows:

[0140] A. 0.3% PEG-40 hydrogenated castor oil

[0141] B. Sodium cocoyl glutamate 0.45%

[0142] C. Sodium cocoyl glutamate 0.7%

[0143] D. Decyl glucoside 0.45%

[0144] E. Decyl glucoside 0.7%

[0145] F. Cocamidopropyl betaine 0.45%

[0146] G. Cocamidopropyl betaine 0.7%

[0147] Formulations containing PEG - 40 hydrogenated castor oil or sodium methyl cocoyl taurate passed the freeze - thaw cycle (30 °C to - 30 °C to 30 °C). Precipitates were seen immediately after thawing the PEG 40 formulation; however, the precipitates redissolved within 24 hours. CPC uptake tests were performed on HAP discs to test the availability of CPC. Two formulations containing sodium methyl cocoyl taurate delivered significantly higher CPC uptake than the formulations with PEG40 hydrogenated castor oil, and due to the formation of cetylpyridinium hyaluronate precipitates, little CPC delivery was seen in the case of other surfactants.

[0148] Table 2

[0149]

[0150] For comparison, two commercial mouthwash formulations containing CPC were tested as positive controls. One showed a CPC uptake of 0.014 ppm on HAP discs; the other showed a CPC uptake of 0.009 ppm on HAP discs. Thus, the formulation containing hyaluronic acid, CPC, and sodium methyl cocoyl taurate delivered CPC better than the same formulations with different surfactants and also better than the commercial formulations tested.

[0151] Then, in a short - term kill assay, the antibacterial activity of the formulation with 0.45% sodium methyl cocoyl taurate was tested relative to the formulation with 0.30% PEG 40 hydrogenated castor oil. The kill percentage of the 0.45% sodium methyl cocoyl taurate formulation was 28.47%, compared to 22.79% kill for 0.30% PEG40 hydrogenated castor oil, indicating (as expected) that enhanced CPC delivery is associated with enhanced antibacterial activity.

[0152] The above sodium methyl cocoyl taurate formulations were further evaluated with additional preservatives at different levels (0.05 wt% and 0.1 wt% sodium benzoate) and were shown to be stable in freeze - thaw cycle assays and under different storage conditions (4 weeks at - 10 °C, 4 weeks at 40 °C, and 4 weeks at 49 °C) in terms of appearance, CPC level, NaF level, pH level, and HA (as detected by ELISA).

[0153] Table 3A: 0.10% HA / 0.45% SMCT / 0.05% sodium benzoate

[0154]

[0155] Table 3B: 0.10% HA / 0.7% SMCT / 0.05% sodium benzoate

[0156]

[0157] Table 3C: 0.10% HA / 0.45% SMCT / 0.1% sodium benzoate (freeze - thaw assay only)

[0158]

[0159] Example 2: Anti-inflammatory Effect Measured in the IL-8 Release Assay

[0160] Hyaluronic acid is a muco - adhesive polymer that occurs naturally in soft periodontal tissues. Literature and external clinical studies have shown that hyaluronic acid (HA) can provide anti - inflammatory and healing benefits to oral soft tissues. Hyaluronic acid (550 kDa Biomost, Bloomage Bioactive) was incorporated at 0.10% into the CPC / Zn mouthwash base. The anti - inflammatory test evaluated the potential modulation of interleukin due to anti - inflammatory compounds after treatment with a pro - inflammatory stimulant (IL - 1α), screening for the read - out marker interleukin 8 (IL - 8).

[0161] Mouthwash formulations containing SMCT, zinc lactate, and CPC with and without HA were prepared as in Example 1. The specific formulations were the same except for the presence or absence of HA; the amount of water was adjusted to make up to 100%.

[0162] Table 2

[0163]

[0164] Human skin from an abdominoplasty was used (donor: female, born in 1981). Skin samples were cut into pieces approximately 8 mm × 3 mm thick and cultured. Organ cultures of in vitro human skin were used as a substrate to evaluate the regulatory activity of skin samples on interleukin 8 levels in the presence of IL-1α. The interleukin 8 readout was measured using an ELISA test. On day 1, the skin samples were acclimated to the culture medium. On day 2, the test samples were applied before and during incubation in the presence of IL-1α. Each time before applying the test sample, the skin samples were gently cleaned, the test sample was applied and covered with a 6 mm delivery membrane. On day 3, the organ cultures were removed from the wells and analyzed for IL-8.

[0165] IL-8 was measured by absorbance from 450 nm to 570 nm, and a standard curve was prepared to enable the measurement of IL-8, in pg / ml. The concentration of IL-8 was measured in the presence of two test formulations and expressed as the absolute concentration / weight of the tissue sample (abs / weight). In the presence of test formulation A without HA, the average IL-8 release was 41.2 abs / weight. In the presence of test formulation B with HA, the average IL-8 release was 21.4 abs / weight. Statistical analysis using the Tukey ANOVA test confirmed the significance of this difference:

[0166] ANOVA:

[0167]

[0168] Grouping information using the Tukey method and 95% confidence

[0169]

[0170] Means that do not share letters are significantly different.

[0171] These results demonstrate that the addition of 0.10% hyaluronic acid to the CPC / Zn mouthwash formulation significantly contributes to reducing the release of IL-8 due to treatment with a pro-inflammatory stimulant (using IL-1α). Compared to the placebo mouthwash, the test formulation containing 0.10% hyaluronic acid contributes to reducing the regulation of IL-8 by 48%, 21.4 versus 41.2 respectively. This highlights the benefit of hyaluronic acid in reducing inflammation on soft tissues after exposure to inflammatory stimulants.

[0172] Example 3 - Prevention of Staining Using Different Molecular Weights and Amounts of HA

[0173] The effect of hyaluronic acid on whitening and stain prevention was evaluated using different molecular weights of HA in a mouthwash containing SMCT, CPC, and HA.

[0174] Table 3

[0175]

[0176] Three variants of the above preparations were tested:

[0177] a) Low molecular weight HA (0.1% sodium hyaluronate, <5 kDa)

[0178] b) Medium molecular weight HA (sodium hyaluronate, 300 kDa)

[0179] (c) High molecular weight HA (sodium hyaluronate, 1 MDa)

[0180] L, A, B, and WIO baseline measurements of bovine teeth were taken using a spectroshade microII (Medical High Technologies) and divided into treatment groups consisting of 6 teeth per group. After baseline measurements, each cell was placed in a separate test product (detailed below) for 60 seconds, after which the cells were exposed to a staining broth composed of coffee, tea, and wine for 5 minutes. Subsequently, artificial saliva was placed in the cells for an additional 5 minutes. This product / stain / artificial saliva cycle was repeated 14 times; the product / stain / saliva was renewed each cycle. Measurements were taken every two cycles. The teeth were blotted dry before measuring the L, A, B, and W values. Tukey ANOVA tests were used to determine statistical significance. The following table describes the ΔW values for the anti-staining efficacy of mouthwashes containing hyaluronic acid on bovine teeth. Letters (A, B) indicate values that are statistically different from each other. The smaller the number, the better, indicating less staining.

[0181]

[0182] There is a directional benefit of hyaluronic acid molecular weight on anti-staining. Relative to water alone, medium and high molecular weight HA provide anti-staining benefits after 14 cycles. This may be attributed to improved film-forming ability of the higher molecular weight hyaluronate, resulting in an enhanced efficacy staining barrier.

[0183] The preparations used were as described above, except that the amount of water was adjusted to compensate for the amount of HA, and further staining experiments were conducted with medium molecular weight HA at 0.05% HA, 0.1% HA, and 0.4% HA. The results are as follows:

[0184]

[0185] Example 4: Effect of HA on Zinc Deposition

[0186] Adding hyaluronic acid to a zinc-containing oral care preparation is associated with increased zinc deposition on the oral surface covered by an in vitro pellicle. Using a Vitroskin model covered with a pellicle, in which the Vitroskin discs were pre-incubated with artificial saliva to form a pellicle mimicking the tooth pellicle, the use of 0.1% hyaluronic acid in a CPC-Zn mouthwash preparation showed increased zinc deposition.

[0187] In mouthwashes containing zinc and CPC with and without 0.1% HA, HA actually slightly decreased the level of soluble zinc, but significantly increased zinc deposition on the Vitroskin in vitro model of the oral mucosa covered with a pellicle:

[0188]

[0189] Formulations that do not share letters are statistically different (Tukey, 95% CI).

[0190] Although the present disclosure has been described with respect to specific examples, including the presently preferred modes of carrying out the present disclosure, those skilled in the art will recognize that there are many variations and permutations of the systems and techniques described above. It is understood that other embodiments may be utilized and structural and functional modifications may be made without departing from the scope of the present disclosure.

Claims

1. An antibacterial mouthwash composition comprising hyaluronic acid (HA); cetylpyridinium chloride (CPC); an effective amount of a taurine surfactant represented by formula (1): wherein R1 is a saturated or unsaturated, straight-chain or branched C 7-17 alkyl group, R2 is H or methyl, and M + is H, sodium or potassium (for example, wherein the taurate surfactant is sodium methyl cocoyl taurate); and at least 70% water by weight of the composition.

2. The composition according to claim 1, wherein the taurate surfactant is sodium methyl cocoyl taurate.

3. The composition according to any one of the preceding claims, wherein the amount of the taurate surfactant is sodium methyl cocoyl taurate in an amount of 0.3% to 0.8% by weight.

4. The composition according to any one of the preceding claims, wherein the amount of CPC is 0.05% to 0.1% by weight.

5. The composition according to any one of the preceding claims, wherein the amount of HA is equivalent to 0.05% to 0.5% by weight of sodium hyaluronate.

6. The composition according to any one of the preceding claims, wherein the average molecular weight of the HA is 300 kD to 1 MDa.

7. The composition according to any one of the preceding claims, further comprising a zinc salt, such as a zinc salt selected from zinc lactate, zinc citrate, and combinations thereof.

8. The composition according to any one of the preceding claims, further comprising a zinc salt, wherein the zinc salt is zinc lactate in an amount of 0.1% to 0.5% by weight.

9. The composition according to any one of the preceding claims, further comprising a fluoride ion source, such as sodium fluoride.

10. The composition according to any one of the preceding claims, further comprising a nonionic surfactant, such as poloxamer.

11. The composition according to any one of the preceding claims, further comprising a nonionic surfactant, wherein the nonionic surfactant is poloxamer 407 in an amount of 0.3% to 0.5% by weight.

12. The composition according to any one of the preceding claims, further comprising a humectant, such as a humectant selected from propylene glycol, glycerol, sorbitol, and combinations thereof.

13. The composition according to any one of the preceding claims, wherein the pH is pH 4 to pH 5.

14. The composition according to any one of the preceding claims, wherein, relative to a formulation in which the taurate surfactant, such as sodium methyl cocoyl taurate, is replaced with PEG-40 hydrogenated castor oil, the delivery of CPC to the teeth is enhanced, and / or wherein the antibacterial activity measured in a short-term killing test (SIKT) is superior to a formulation in which the taurate surfactant, such as sodium methyl cocoyl taurate, is replaced with PEG-40 hydrogenated castor oil.

15. The composition according to any one of the preceding claims, wherein the composition does not form cetylpyridinium hyaluronate precipitate during freeze-thaw cycle testing, such as freezing to -30 °C and then thawing to 30 °C, or after aging at 40 °C for four weeks, or after aging at -10 °C for four weeks.

16. Any of the preceding compositions, the composition being free of ethanol, PEG-40 hydrogenated castor oil, betaine surfactant, sodium lauryl sulfate, and / or any ionic surfactant other than sodium methyl cocoyl taurate.

17. Any of the preceding compositions, the composition being formed by combining the following components: a. 0.05% to 0.15% of sodium hyaluronate, b. Cetylpyridinium chloride at 0.05% to 0.1% c. 0.3% to 0.8% of sodium methyl cocoyl taurate, and d. 75% to 85% of water, and optionally further comprising one or more of a zinc ion source, a humectant, a nonionic surfactant, a fluoride ion source, a humectant, a preservative, a sweetener, a flavoring agent, and / or a dye, wherein all percentages are by weight of the composition.

18. Any of the preceding compositions, the composition being formed by combining the following components: a. 0.05% to 0.15% of sodium hyaluronate, b. Cetylpyridinium chloride from 0.07% to 0.08% c. 0.4% to 0.5% sodium methyl cocoyl taurate, d. 0.2% to 0.4% zinc L-lactate dihydrate, and e. 75% to 85% water, wherein all percentages are by weight of the composition.

19. Any of the foregoing compositions, the composition being formed by combining components comprising: a. 0.05% to 0.15% sodium hyaluronate, b. Cetylpyridinium chloride from 0.07% to 0.08% c. 0.4% to 0.5% sodium methyl cocoyl taurate, d. 0.2% to 0.4% zinc L-lactate dihydrate, e. 15% to 20% humectant, the humectant comprising glycerol, propylene glycol and sorbitol, f. 0.3% to 0.5% poloxamer 407, g. 0.04% to 0.06% L-lactic acid, h. 0.04% to 0.06% sodium fluoride, i. 0.02% to 0.03% sweetener, the sweetener comprising sucralose and sodium saccharin, j. 0.05% to 0.2% flavoring agent, the flavoring agent comprising one or more cooling agents, k. 0.01% to 0.15% preservative, the preservative selected from potassium sorbate, sodium benzoate and combinations thereof, l. 0.00005% to 0.0005% water-soluble dye, and m. 75% to 85% water, wherein all percentages are by weight of the composition.

20. A method for inhibiting the formation of cetylpyridinium hyaluronate precipitates in a mouthwash containing cetylpyridinium chloride and hyaluronic acid, comprising adding a taurate surfactant, such as to form a mouthwash composition according to any one of the preceding claims. ​ 21. A method of treating or preventing one or more of xerostomia, dental plaque, gingivitis, halitosis, dental implant infection, dental caries and / or tooth decay, comprising administering to the oral cavity of a subject in need thereof a composition according to any one of claims 1 to 19.

22. A method of reducing inflammation in the oral cavity, comprising administering to the oral cavity of a subject in need thereof a composition according to any one of claims 1 to 19.

23. A method of reducing tooth staining, comprising administering to the teeth of a subject in need thereof a composition according to any one of claims 1 to 19.

24. A method of delivering zinc to the dental pellicle, comprising administering to the oral cavity of a subject in need thereof a composition according to claim 7 or 8.

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