Oral care composition and method of use

Abstract

The present invention relates to oral care compositions comprising zinc oxide and zinc citrate and a hyaluronic acid or alkali metal hyaluronate polymer having a molecular weight greater than 100,000 Da (e.g., 300 kDa to 700 kDa), and methods of using and preparing these compositions.

Description

Technical Field

[0001] The present invention relates to oral care compositions comprising zinc oxide and zinc citrate and a high molecular weight hyaluronic acid or alkali metal hyaluronate polymer (> 100,000 Da) (e.g., 300 to 600 kDa) (e.g., about 480 kDa), and methods of using and preparing these compositions. Background Art

[0002] The oral cavity is subject to a variety of diseases, including periodontal diseases (including gingivitis and periodontitis), dental caries, tooth hypersensitivity, halitosis, and oral infections (e.g., fungal or bacterial infections of the oral mucosa).

[0003] Dental erosion involves demineralization and damage to tooth structure caused by acid erosion from non-bacterial sources. Erosion is initially found in enamel and, if left unchecked, may progress to underlying dentin. Generally, the pH of saliva is between 7.2 and 7.4. When the pH decreases and the hydrogen ion concentration becomes relatively high, tooth enamel can be micro-eroded, forming a porous, spongy, rough surface. If saliva remains acidic for a long time, remineralization may not occur, and the tooth will continue to lose minerals, resulting in weakening of the tooth and ultimately loss of structure.

[0004] Tooth hypersensitivity is acute, localized tooth pain in response to physical stimuli to the dentin surface (such as by thermal (hot or cold) stimuli, osmotic stimuli, tactile stimuli, combinations of thermal, osmotic, and tactile stimuli) to exposed dentin. Dentin exposure, often caused by gingival recession or enamel loss, frequently leads to hypersensitivity reactions.

[0005] Oral bacteria are the main cause of dental diseases, including dental caries, gingivitis, periodontitis, and halitosis. Bacteria associated with dental plaque convert sugars into glucan, an insoluble polysaccharide that provides the plaque with adhesive properties. Anaerobic bacteria in the plaque metabolize sugars to produce acids, which dissolve tooth minerals, damage enamel, and ultimately form dental caries.

[0006] Dental plaque is a sticky biofilm or mass of bacteria that is commonly present between teeth, along the gum line, and beneath the gum line margin. Dental plaque can cause dental caries and periodontal problems, such as gingivitis and periodontitis. Dental caries or tooth demineralization is caused by acids produced by the bacterial degradation of fermentable sugars.

[0007] Zinc is a well-known antimicrobial agent used in toothpaste compositions. Zinc is also a well-known mineral essential for human health and has been reported to help strengthen tooth enamel and promote cell repair. Unfortunately, at higher concentrations, zinc can impart a pronounced astringent taste to the composition. Therefore, there is a need for improved antibacterial toothpaste formulations that do not have the drawbacks of conventional compositions.

[0008] Hyaluronic acid (also known as hyaluron or hyaluronic acid) is an anionic, non-sulfated glycosaminoglycan (GAG) widely distributed throughout the connective tissues of vertebrates and is the most abundant higher molecular weight glycosaminoglycan in the extracellular matrix of soft periodontal tissues. Hyaluronic acid has been found to be effective in treating inflammatory processes in medical fields such as orthopedics, dermatology, and ophthalmology, and it has also been found to have anti-inflammatory and antibacterial effects in the treatment of gingivitis and periodontitis.

[0009] Although toothpaste and mouthwash are commonly used to deliver active ingredients (e.g., zinc ions), the effects may be transient because the active agent can be quickly rinsed out of the mouth by rinsing, eating, or drinking, and / or the effective concentration of the active agent can become ineffective by being rapidly diluted by saliva. Delivering toothpaste and mouthwash to the tight periodontal pocket located between the tooth root and the gum is particularly difficult.

[0010] Therefore, there is a need for improved preservatives for zinc-containing oral compositions. Summary of the Invention

[0011] It has been unexpectedly found that for an oral care composition comprising zinc oxide and / or zinc citrate selected in a certain concentration and amount, the inclusion of hyaluronic acid or an alkali metal hyaluronate polymer in a specific molecular weight (MW) range (e.g., MW > 100,000 Da, e.g., 300 kDa to 1 MDa) (e.g., 300 kDa to 600 kDa) (e.g., an average of 480 kDa) unexpectedly increases the uptake of zinc by enamel in the user's mouth. The formulation uses a comparable amount of zinc as present in current market formulations. However, although a comparable amount of zinc is used in the present invention (i.e., relative to various market formulations), it is believed that the amount of soluble zinc is actually increased relative to various market formulations. Without being bound by any theory, it is believed that the presence of hyaluronic acid of certain molecular weights (e.g., MW > 100,000 Da) (e.g., 300 kDa to 1 MDa) (e.g., 300 kDa to 600 kDa) (e.g., an average of 480 kDa) may contribute to increasing the amount of available soluble zinc, as well as delivering zinc ions to enamel, soft tissues, and oral mucosa, which helps to deliver and inhibit bacterial growth in the user's mouth. Without being bound by theory, hyaluronic acid of certain molecular weights (e.g., 300 kDa to 1 MDa) (e.g., 300 kDa to 600 kDa) (e.g., an average of 480 kDa) may result in improved mucosal adhesion properties, allowing the polymer to better interact with the natural mucin pellicle present on oral surfaces and providing improved effective delivery.

[0012] Additional studies have also shown that hyaluronic acid (e.g., MW > 100,000 Da) (e.g., 300 kDa to 1 MDa) (e.g., 300 kDa to 600 kDa) (e.g., average 480 kDa) can help reduce the amount of volatile sulfur compounds (VSCs) in vitro and improve the lubricity of toothpaste samples.

[0013] In one aspect, the present invention is an oral care composition (Composition 1.0), which comprises:

[0014] a. Zinc oxide and zinc citrate;

[0015] b. Hyaluronic acid (HA) or an alkali metal hyaluronate polymer having a molecular weight (MW) greater than 100,000 Da (e.g., a molecular weight of 300 kDa to 1 MDa) (e.g., a molecular weight of 300 kDa to 600 kDa) (e.g., a molecular weight of about 480 kDa).

[0016] For example, the present invention contemplates any of the following compositions (values are given as percentages by total weight of the composition unless otherwise stated).

[0017] 1.1 Composition 1.0, wherein the composition comprises a fluoride source.

[0018] 1.2 Composition 1.0 or 1.1, wherein the composition comprises a fluoride source selected from: stannous fluoride, sodium fluoride, potassium fluoride, sodium monofluorophosphate, sodium fluorosilicate, ammonium fluorosilicate, amine fluoride (e.g., N'-octadecyltrimethylenediamine-N,N,N'-tris(2-ethanol)-dihydrofluoride), ammonium fluoride, titanium fluoride, hexafluorosulfate, and combinations thereof.

[0019] 1.3 The composition of 1.2, wherein the fluoride source is stannous fluoride.

[0020] 1.4 Any of the foregoing compositions, wherein the fluoride source is a fluorophosphate.

[0021] 1.5 Any of the foregoing compositions, wherein the fluoride source is sodium monofluorophosphate.

[0022] 1.6 The composition of 1.2, wherein the fluoride source is sodium fluoride.

[0023] 1.7 Any of the foregoing compositions, wherein the fluoride source is a fluoride salt present in an amount of 0.1 wt% to 2 wt% (0.1 wt% to 0.6 wt%) of the total composition weight (e.g., sodium fluoride (e.g., about 0.32 wt%) or sodium monofluorophosphate).

[0024] 1.8 Any of the foregoing compositions, wherein the fluoride source is sodium fluoride in an amount of about 0.32% by weight based on the weight of the composition.

[0025] 1.9 Any of the foregoing compositions, wherein the fluoride source is a soluble fluoride salt that provides fluoride ions in an amount of 50 to 25,000 ppm (such as 750 to 2000 ppm, such as 1000 to 1500 ppm, such as about 1000 ppm, such as about 1450 ppm).

[0026] 1.10 Any of the foregoing compositions, wherein the fluoride source is sodium fluoride that provides fluoride in an amount of 750 to 2000 ppm (such as about 1450 ppm).

[0027] 1.11 Any of the foregoing compositions, wherein the fluoride source is selected from sodium fluoride and sodium monofluorophosphate and provides fluoride in an amount of 1000 ppm to 1500 ppm.

[0028] 1.12 Any of the foregoing compositions, wherein the fluoride source is sodium fluoride or sodium monofluorophosphate and provides fluoride in an amount of about 1450 ppm.

[0029] 1.13 Any of the foregoing compositions, wherein the pH is 7.5 to 10.5, such as 9.0 to 10.0, such as 9.4.

[0030] 1.14 Any of the foregoing compositions, which further comprises calcium carbonate.

[0031] 1.15 The foregoing composition, wherein the calcium carbonate is precipitated calcium carbonate high absorption (for example, 20% to 30% by weight of the composition) (for example, 25% of precipitated calcium carbonate high absorption).

[0032] 1.16 The foregoing composition, which further comprises precipitated calcium carbonate - light (for example, about 10% of precipitated calcium carbonate - light) (for example, about 10% of natural calcium carbonate).

[0033] 1.17 Any of the foregoing compositions, which further comprises an effective amount of one or more alkaline phosphates, such as sodium salts, potassium salts or calcium salts, such as those selected from alkali dibasic phosphates and alkali pyrophosphates, such as alkaline phosphates selected from the following: disodium hydrogen phosphate, dipotassium hydrogen phosphate, dicalcium phosphate dihydrate, calcium pyrophosphate, tetrasodium pyrophosphate, tetrapotassium pyrophosphate, sodium tripolyphosphate, disodium hydrogen orthophosphate, sodium dihydrogen phosphate, pentapotassium triphosphate, and mixtures of any two or more of these, for example, in an amount of 0.01% to 20% by weight of the composition, such as 0.1% to 8%, such as 0.1% to 5%, such as 0.3% to 2%, such as 0.3% to 1%, such as about 0.01%, about 0.1%, about 0.5%, about 1%, about 2%, about 5%, about 6%.

[0034] 1.18 Any of the foregoing compositions, which comprises tetrapotassium pyrophosphate, disodium hydrogen orthophosphate, sodium dihydrogen phosphate and pentapotassium triphosphate.

[0035] 1.19 Any of the foregoing compositions, which comprises polyphosphate.

[0036] 1.20 The foregoing composition, wherein the polyphosphate is tetrasodium pyrophosphate.

[0037] 1.21 The foregoing composition, wherein the tetrasodium pyrophosphate is 0.1 to 1.0% by weight (such as about 0.5% by weight).

[0038] 1.22 Any of the foregoing compositions, which further comprises an abrasive or particulate (such as silica).

[0039] 1.23 Any of the foregoing compositions, wherein the composition comprises 5% to 25% abrasive silica, such as 10% to 20% abrasive silica, such as 5% by weight, 10% by weight, 15% by weight, 20% by weight or 25% by weight of abrasive silica.

[0040] 1.24 Any of the foregoing compositions, wherein the silica is synthetic amorphous silica (such as 1% to 28% by weight) (such as 8% to 25% by weight).

[0041] 1.25 Any of the foregoing compositions, wherein the silica abrasive is silica gel or precipitated amorphous silica, such as silica having an average particle size of 2.5 to 12 microns.

[0042] 1.26 Any of the foregoing compositions, which further comprises small particle silica having a median particle size (d50) of 1 to 5 microns (such as 3 to 4 microns) (such as about 5% by weight of Sorbosil AC43 from PQ Corporation, Warrington, United Kingdom).

[0043] 1.27 Any of the foregoing compositions, wherein 20 to 30% by weight of the total silica in the composition is small particle silica (e.g., median particle size (d50) of 3 to 4 microns), and wherein the small particle silica is 1% to 8% (e.g., about 5% by weight) of the oral care composition.

[0044] 1.28 Any of the foregoing compositions, which comprises silica, wherein the silica is used as a thickening agent, such as particulate silica.

[0045] 1.29 Any of the foregoing compositions, which further comprises a nonionic surfactant, wherein the amount of the nonionic surfactant is 0.25% to 5%, such as 0.25% to 2% (e.g., about 0.5% by weight), selected from poloxamers (e.g., poloxamer 407), polysorbates (e.g., polysorbate 20), polyoxyethylene hydrogenated castor oil (e.g., polyoxyethylene 40 hydrogenated castor oil), and mixtures thereof.

[0046] 1.30 Any of the foregoing compositions, wherein the polypropylene oxide molecular weight (Mw) of the poloxamer nonionic surfactant is 3000 to 5000 g / mol, and the polyoxyethylene content is 60 mol% to 80 mol%, such as the poloxamer nonionic surfactant comprises poloxamer 407.

[0047] 1.31 Any of the foregoing compositions, which further comprises glycerol, wherein the total amount of glycerol is 25% to 40% (e.g., about 35%).

[0048] 1.32 The foregoing composition, wherein the amount of glycerol is about 35% by weight of the composition.

[0049] 1.33 The foregoing composition, wherein the amount of glycerol is about 26% by weight of the composition.

[0050] 1.34 Any of the foregoing compositions, which further comprises sorbitol, wherein the total amount of sorbitol is 10% to 40% (e.g., about 35%).

[0051] 1.35 Any of the foregoing compositions, which further comprises additional ingredients selected from the following: benzyl alcohol, methylisothiazolinone (“MIT”), sodium bicarbonate, lauryl alcohol, and polyphosphates.

[0052] 1.36 Any of the foregoing compositions, wherein benzyl alcohol is present in an amount of 0.1 to 0.8% by weight, or 0.2 to 0.7% by weight, or 0.3 to 0.6% by weight, or 0.4 to 0.5% by weight, such as about 0.1% by weight, about 0.2% by weight, about 0.3% by weight, about 0.4% by weight, about 0.5% by weight, about 0.6% by weight, about 0.7% by weight or about 0.8% by weight.

[0053] 1.37 Any of the foregoing compositions, wherein benzyl alcohol is about 0.4% by weight.

[0054] 1.38 Any of the foregoing compositions, which comprises a polymer film.

[0055] 1.39 Any of the foregoing compositions, which comprises a flavoring agent, a fragrance and / or a coloring agent.

[0056] 1.40 The foregoing composition, wherein the flavoring agent is sodium saccharin, sucralose, or a mixture thereof.

[0057] 1.41 Any of the foregoing compositions, wherein the composition comprises a thickening agent selected from: carboxyvinyl polymer, carrageenan, xanthan gum, hydroxyethyl cellulose, and water-soluble salts of cellulose ethers (such as sodium carboxymethyl cellulose and sodium carboxymethyl hydroxyethyl cellulose).

[0058] 1.42 Any of the foregoing compositions, wherein the composition comprises sodium carboxymethyl cellulose (for example, 0.5% to 1.5% by weight) (for example 0.8%).

[0059] 1.43 Any of the foregoing compositions, which comprises 5% to 40%, such as 10% to 35%, such as about 15%, about 25%, about 27%, about 30% and about 35% of water.

[0060] 1.44 Any of the foregoing compositions, which further comprises an antibacterial agent selected from the group consisting of: halogenated diphenyl ethers (such as triclosan), herbal extracts and essential oils (such as rosemary extract, tea extract, magnolia extract, thymol, menthol, cineole, geraniol, carvacrol, citral, honokiol, catechol, methyl salicylate, epigallocatechin gallate, epigallocatechin, gallic acid, miswak extract, seabuckthorn extract), biguanide preservatives (such as chlorhexidine, alexidine or octenidine), quaternary ammonium compounds (such as cetylpyridinium chloride (CPC), benzalkonium chloride, tetradecylpyridinium chloride (TPC), N-tetradecyl-4-ethylpyridinium chloride (TDEPC)), phenolic preservatives, hexetidine, octenidine, sanguinarine, povidone iodine, delmopinol, salifluor, metal ions (such as zinc salts, such as zinc chloride, zinc lactate, zinc sulfate, stannous salts, copper salts, iron salts), sanguinarine, propolis and oxygenating agents (such as hydrogen peroxide, buffered sodium perborate or sodium percarbonate), phthalic acid and its salts, monoperthalic acid and its salts and esters, ascorbyl stearate, oleoyl sarcosine, alkyl sulfates, dioctyl sulfosuccinate, salicylanilide, domiphen bromide, delmopinol, octapinol and other piperidyl derivatives, nicin preparations, chlorites; and mixtures of any of the foregoing substances.

[0061] 1.45 Any of the foregoing compositions, which comprises an antioxidant selected from the group consisting of coenzyme Q10, PQQ, vitamin C, vitamin E, vitamin A, BHT, anethole-dithiothione, and mixtures thereof.

[0062] 1.46 Any of the foregoing compositions, which comprises a whitening agent.

[0063] 1.47 Any of the foregoing compositions, which comprises a whitening agent selected from the group consisting of whitening active agents, the whitening active agents being selected from the group consisting of peroxides, metal chlorites, perborates, percarbonates, peroxyacids, hypochlorites, and combinations thereof.

[0064] 1.48 Any of the foregoing compositions, which further comprises hydrogen peroxide or a hydrogen peroxide source, such as urea peroxide or a peroxide salt or complex (e.g., such as peroxyphosphate, peroxycarbonate, perborate, peroxosilicate or persulfate; e.g., calcium peroxyphosphate, sodium perborate, sodium percarbonate, sodium peroxyphosphate and potassium persulfate), or a hydrogen peroxide polymer complex, such as a hydrogen peroxide - polyvinylpyrrolidone polymer complex.

[0065] 1.49 Any of the foregoing compositions, which further comprises an agent that interferes with or prevents bacterial attachment, such as ethyl lauroyl arginiate (ELA) or chitosan.

[0066] 1.50 Any of the foregoing compositions, which further comprises an amino acid.

[0067] 1.51 The foregoing composition, wherein the amino acid is a basic amino acid.

[0068] 1.52 The foregoing composition, wherein the basic amino acid has an L - configuration (e.g., L - arginine).

[0069] 1.53 Any of the foregoing compositions, wherein the basic amino acid is arginine or lysine in free form.

[0070] 1.54 Any of the foregoing compositions, wherein the basic amino acid is provided in the form of a dipeptide or tripeptide containing arginine or lysine or a salt thereof.

[0071] 1.55 Any of the foregoing compositions, wherein the basic amino acid is arginine, and wherein the arginine is present in an amount of 0.1% to 15% by weight of the total composition, such as 0.1% to 10% by weight, such as 0.1 to 5% by weight, such as 0.5% to 3% by weight, for example about 1%, 1.5%, 2%, 3%, 4%, 5% or 8%, wherein the weight of the basic amino acid is calculated in free form.

[0072] 1.56 Any of the foregoing compositions, wherein the amino acid is 0.1% to 6.0% by weight (e.g., about 1.5% by weight) of arginine.

[0073] 1.57 Any of the foregoing compositions, wherein the amino acid is about 1.5% by weight of arginine.

[0074] 1.58 Any of the foregoing compositions, wherein the amino acid is 4.5% to 8.5% by weight (e.g., 5.0%) of arginine.

[0075] 1.59 Any of the foregoing compositions, wherein the amino acid is about 5.0% by weight of arginine.

[0076] 1.60 Any of the foregoing compositions, wherein the amino acid is 3.5 wt% to 9 wt% arginine.

[0077] 1.61 Any of the foregoing compositions, wherein the amino acid is about 8.0 wt% arginine.

[0078] 1.62 Any of the foregoing compositions, wherein the amino acid is arginine in free form.

[0079] 1.63 Any of the foregoing compositions, wherein the ratio of the amount of zinc oxide (e.g., wt%) to the amount of zinc citrate (e.g., wt%) is from 1.5:1 to 4.5:1 (e.g., 2:1, 2.5:1, 3:1, 3.5:1, or 4:1).

[0080] 1.64 Any of the foregoing compositions, wherein based on the weight of the oral care composition, the amount of zinc citrate is from 0.25 to 1.0 wt% (e.g., 0.25 to 0.75 wt%, or 0.5 wt%), and zinc oxide may be present in an amount of from 0.75 to 1.25 wt% (e.g., 1.0 wt%).

[0081] 1.65 Any of the foregoing compositions, wherein the zinc citrate is about 0.5 wt%.

[0082] 1.66 Any of the foregoing compositions, wherein the zinc oxide is about 1.0 wt%.

[0083] 1.67 Any of the foregoing compositions, wherein the zinc citrate is about 0.5 wt% and the zinc oxide is about 1.0 wt%.

[0084] 1.68 Any of the foregoing compositions, wherein the average molecular weight of the hyaluronic acid or alkali metal hyaluronate polymer is from 200,000 to 1,500,000 Da, such as from 300,000 to 1,200,000 Da, or from 300,000 to 700,000 Da, or from 325,000 to 575,000 or from 700,000 to 1,100,000 Da, or from 300,000 to 450,000, or from 350,000 to 600,000 Da, or from 400,000 to 600,000, or from 900,000 to 1,100,000 Da, or about 370,000 Da, or about 480,000 Da, or about 550,000 Da, or about 1,000,000 Da.

[0085] 1.69 The foregoing composition, wherein the average molecular weight of the hyaluronic acid or alkali metal hyaluronate polymer is from 300,000 to 1,000,000 Da.

[0086] 1.70 The foregoing composition, wherein the average molecular weight of the hyaluronic acid or alkali metal hyaluronate polymer is from 300,000 to 700,000 Da (such as from 350 kDa to 575 kDa).

[0087] 1.71 The foregoing composition, wherein the average molecular weight of the hyaluronic acid or alkali metal hyaluronate polymer is from 400,000 to 600,000 Da.

[0088] 1.72 The oral care composition of 1.69, wherein the average molecular weight of the hyaluronic acid or alkali metal hyaluronate polymer is from 350 kDa to 575 kDa.

[0089] 1.73 The oral care composition of 1.71 or 1.72, wherein the average molecular weight of the hyaluronic acid or alkali metal hyaluronate polymer is about 480,000 Da.

[0090] 1.74 The oral care composition of 1.71 or 1.72, wherein the average molecular weight of the hyaluronic acid or alkali metal hyaluronate polymer is about 550,000 Da.

[0091] 1.75 The foregoing composition, wherein the hyaluronic acid or alkali metal hyaluronate polymer is a sodium hyaluronate polymer.

[0092] 1.76 Any of the foregoing compositions, wherein, based on the weight of the oral care composition, the composition comprises from 0.01 to 10 wt%, such as from 0.01 to 5 wt%, from 0.05 to 5 wt%, from 0.1 to 2 wt%, or from 0.1 to 1 wt%, or from 0.3 to 0.5 wt%, or about 0.4 wt% of the hyaluronic acid or alkali metal hyaluronate polymer.

[0093] 1.77 The foregoing composition, wherein, based on the weight of the oral care composition, the composition comprises from 0.05 to 5 wt% of the hyaluronic acid or alkali metal hyaluronate polymer.

[0094] 1.78 The foregoing composition, wherein, based on the weight of the oral care composition, the composition comprises from 0.025 to 2 wt% of the hyaluronic acid or alkali metal hyaluronate polymer.

[0095] 1.79 Any of the foregoing compositions, wherein, based on the weight of the oral care composition, the composition comprises about 0.05 wt% of the hyaluronic acid or alkali metal hyaluronate polymer.

[0096] 1.80 Any of the foregoing compositions, wherein, based on the weight of the oral care composition, the composition comprises about 0.1 wt% of the hyaluronic acid or alkali metal hyaluronate polymer.

[0097] 1.81 Any of the foregoing compositions, wherein the composition is free of ethanol.

[0098] 1.82 Any of the foregoing compositions, comprising:

[0099] a. 0.5% to 1.5% zinc oxide (e.g., 1 wt%);

[0100] b. 0.25% to 0.75% zinc citrate (e.g., 0.5 wt%);

[0101] c. 0.025 to 2 wt% hyaluronic acid (e.g., 0.05 wt%) (e.g., 0.1 wt%), wherein the molecular weight of hyaluronic acid is 300,000 to 700,000 Da (e.g., MW is about 480,000 Da).

[0102] 1.83 Any of the foregoing compositions, comprising:

[0103] a. 0.5% to 1.5% zinc oxide (e.g., 1 wt%);

[0104] b. 0.25% to 0.75% zinc citrate (e.g., 0.5 wt%);

[0105] c. 1.0% to 2.0% L-arginine (e.g., 1.5 wt%);

[0106] d. 0.025 to 2 wt% hyaluronic acid (e.g., 0.05 wt%) (e.g., 0.1 wt%), wherein the molecular weight of hyaluronic acid is 300,000 to 700,000 Da (e.g., MW is about 480,000 Da).

[0107] 1.84 Any of the foregoing compositions, comprising:

[0108] a. Approximately 1 wt% zinc oxide

[0109] b. Approximately 0.5% zinc citrate

[0110] c. Approximately 1.5% L-arginine

[0111] d. Approximately 0.05% hyaluronic acid, wherein the molecular weight of hyaluronic acid is 300,000 to 700,000 Da (e.g., MW is about 480,000 Da).

[0112] 1.85 Any of the foregoing compositions, comprising:

[0113] a. Approximately 1 wt% zinc oxide

[0114] b. Approximately 0.5% zinc citrate

[0115] c. Approximately 1.5% L-arginine

[0116] d. Approximately 0.1% hyaluronic acid, wherein the molecular weight of the hyaluronic acid is from 300,000 to 700,000 Da (e.g., MW is approximately 480,000 Da).

[0117] 1.86 Any of the foregoing compositions which, when administered to the oral cavity, e.g., by rinsing, optionally in combination with brushing, is effective in: (i) reducing or inhibiting the formation of dental caries, (ii) reducing, 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 tooth remineralization, (iv) alleviating tooth hypersensitivity, (v) alleviating or inhibiting gingivitis, (vi) promoting the healing of ulcers or wounds in the oral cavity, (vii) reducing the level of acid-producing bacteria, (viii) increasing the relative level of arginolytic bacteria, (ix) inhibiting the formation of microbial biofilms in the oral cavity, (x) raising and / or maintaining the plaque pH at a level of at least pH 5.5 after a sugar challenge, (xi) alleviating plaque accumulation, (xii) treating, alleviating or relieving dry mouth, (xiii) cleaning teeth and the oral cavity, (xiv) reducing erosion, (xv) preventing dental stains and / or whitening teeth, (xvi) immunizing teeth against cariogenic bacteria; and / or (xvii) promoting general health, including cardiovascular health, e.g., by reducing the likelihood of systemic infection via oral tissues.

[0118] 1.87 Any of the foregoing oral compositions, wherein the oral composition can be any of the following oral compositions selected from: toothpaste or dentifrice, mouth rinse or oral cleaner, topical oral gel, tablets, films, granules, gum and denture cleanser.

[0119] 1.88 A composition obtained by combining or obtainable by combining the ingredients listed in any of the foregoing compositions.

[0120] 1.89 Any of the foregoing compositions, wherein the amount of hyaluronic acid is an amount effective to provide a composition wherein the coefficient of friction measured by a tribometer (Bruker UMT) is 0.10 (e.g., approximately 0.08) or less, and the coefficient of friction is measured at 1 RPM.

[0121] 1.90 Any of the foregoing compositions which comprises an orally acceptable carrier.

[0122] 1.91 Any of the foregoing compositions, wherein the oral care composition is in a form selected from: toothpaste, transparent paste, gel, oral rinse, spray, and chewing gum.

[0123] A composition obtained by combining or obtainable by combining the ingredients listed in any of the foregoing compositions.

[0124] A composition used as described in any of the foregoing compositions.

[0125] In another embodiment, the present invention encompasses methods for improving oral health, the methods comprising administering an effective amount of an oral composition of any of the foregoing embodiments to the oral cavity of a subject in need thereof, e.g., methods for:

[0126] i. Reducing or inhibiting the formation of dental caries,

[0127] ii. Reducing, repairing, or inhibiting early enamel lesions, e.g., as detected by quantitative light-induced fluorescence (QLF) or electrical caries measurement (ECM),

[0128] iii. Reducing or inhibiting tooth demineralization and promoting tooth remineralization,

[0129] iv. Alleviating tooth hypersensitivity,

[0130] v. Alleviating or inhibiting gingivitis,

[0131] vi. Promoting the healing of ulcers or wounds in the oral cavity,

[0132] vii Reducing the level of acid-producing bacteria,

[0133] viii. Increasing the relative level of bacteria that break down arginine,

[0134] ix. Inhibiting the formation of microbial biofilms in the oral cavity,

[0135] x. Raising and / or maintaining the plaque pH at a level of at least pH 5.5 after a sugar attack,

[0136] xi. Alleviating plaque accumulation,

[0137] xii Treating dry mouth,

[0138] xiii. Enhancing systemic health, including cardiovascular health, e.g., by reducing the likelihood of systemic infection via oral tissues,

[0139] xiv. Whitening teeth

[0140] xv. Alleviating tooth erosion,

[0141] xvi. Providing immunity (or protection) to teeth against cariogenic bacteria and their effects, and / or

[0142] xvii. Cleaning teeth and oral cavity.

[0143] The present invention also includes the use of sodium bicarbonate, MIT (methylisothiazolinone), and benzyl alcohol and combinations thereof in the manufacture of the compositions of the present invention, for example, for the above methods of Composition 1.0 and any applicable cases described in the following etc. (et seq). Detailed Description

[0144] As used herein, "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 composition that is palatable and safe for topical administration to the oral cavity and provides benefits to teeth and / or the oral cavity. Thus, the term "oral care composition" specifically 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 is retained in the oral cavity for a time sufficient to achieve the intended use. 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.

[0145] Unless otherwise specified, the term "dentifrice" as used herein refers to a paste, gel, or liquid preparation. The dentifrice composition can be in any desired form, such as deep stripes, surface stripes, multi-layers, having a gel surrounding the paste, or any combination thereof. Alternatively, the oral composition is provided as a two-phase composition, where the separate compositions are combined when dispensed from separate compartment dispensers.

[0146] As used herein, "hyaluronic acid" is an anionic, non-sulfated glycosaminoglycan (GAG) that is widely distributed throughout the connective tissues of vertebrates and is the most abundant higher molecular weight glycosaminoglycan in the extracellular matrix of soft periodontal tissues. Hyaluronic acid can exist in its free acid form or in the form of a salt (e.g., an alkali metal salt). Hyaluronic acid has important hygroscopic, rheological, and viscoelastic properties, which fluctuate with changes in temperature, pH, ionic environment, and binding partners. However, these properties also highly depend on the chain length. The molecular weight of hyaluronic acid can reach over 10 7 Da, but also exists in a variety of smaller forms, the latter being referred to as low molecular weight hyaluronic acid or oligomeric hyaluronic acid.

[0147] Hyaluronic acid has been found to be effective in treating inflammatory processes in medical fields such as orthopedics, dermatology, and ophthalmology, and it has also been found to have anti-inflammatory and antibacterial effects in the treatment of gingivitis and periodontitis. Due to its tissue-healing properties, it has been proposed for use as an adjunct to mechanical treatment in the treatment of periodontitis. Hyaluronic acid affects endothelial cell proliferation and monolayer integrity and also has an effect on angiogenesis.

[0148] Amino acid

[0149] In certain aspects, Composition 1.0 and the like may contain basic amino acids. Basic amino acids that can be used in the compositions and methods of the present invention include not only naturally occurring basic amino acids such as arginine, lysine, and histidine, but also any basic amino acid that is water-soluble and provides an aqueous solution with a pH of 7 or higher and has a carboxyl group and an amino group in the molecule.

[0150] Accordingly, basic amino acids include, but are not limited to, arginine, lysine, serine, citrulline, ornithine, creatine, histidine, diaminobutyric acid, diaminopropionic acid, salts thereof, or combinations thereof. In one specific embodiment, the basic amino acid is selected from arginine, citrulline, and ornithine.

[0151] In certain embodiments, the basic amino acid is arginine, such as L-arginine, or a salt thereof.

[0152] In certain aspects, the compositions of the present invention (e.g., any of Composition 1.0 and the like) may contain neutral amino acids, which may include, but are not limited to, one or more neutral amino acids selected from the following: alanine, aminobutyric acid, asparagine, cysteine, cystine, glutamine, glycine, hydroxyproline, isoleucine, leucine, methionine, phenylalanine, proline, serine, taurine, threonine, tryptophan, tyrosine, valine, and combinations thereof.

[0153] The compositions of the present invention are intended for topical use in the oral cavity, and thus the salts used in the present invention should be safe for such use in the amounts and concentrations provided. Suitable salts include salts known in the art as pharmaceutically acceptable salts, which are generally considered to be physiologically acceptable in the amounts and concentrations provided. Physiologically acceptable salts include salts derived from pharmaceutically acceptable inorganic or organic acids or bases, such as acid addition salts formed by acids that form physiologically acceptable anions, such as hydrochloride or bromide salts, and base addition salts formed by bases that form physiologically acceptable cations, such as those derived from alkali metals (e.g., potassium and sodium) or alkaline earth metals (e.g., calcium and magnesium). Physiologically acceptable salts can be obtained using standard procedures known in the art, such as by reacting a sufficiently basic compound (e.g., an amine) with a suitable acid that provides a physiologically acceptable anion.

[0154] In certain embodiments, the basic amino acid is present in an amount corresponding to 0.1% to 15%, such as 0.1 wt% to 10 wt%, such as 0.1 wt% to 5 wt%, such as 0.5 wt% to 3 wt%, such as about 1%, 1.5%, 2%, 3%, 4%, 5% or 8% of the total weight of the composition, wherein the weight of the basic amino acid is calculated in free form.

[0155] Fluoride ion source

[0156] In certain aspects, the compositions of the present invention (e.g., any of Composition 1.0 and the like) may also comprise one or more fluoride ion sources, such as soluble fluoride salts. A wide variety of fluoride ion-generating materials can be used as the source of soluble fluoride in the compositions of the present invention. Some examples of suitable fluoride ion-generating materials are found in: U.S. Patent No. 3,535,421 to Briner et al.; U.S. Patent No. 4,885,155 to Parran, Jr. et al., and U.S. Patent No. 3,678,154 to Widder et al., each of which is incorporated herein by reference. Representative fluoride ion sources for use in the present invention (e.g., Composition 1.0 and the like) include, but are not limited to: stannous fluoride, sodium fluoride, potassium fluoride, sodium monofluorophosphate, sodium fluorosilicate, ammonium fluorosilicate, amine fluoride, ammonium fluoride, and combinations thereof. In certain embodiments, the fluoride ion source comprises stannous fluoride, sodium fluoride, sodium monofluorophosphate, and mixtures thereof. When the formulation contains a calcium salt, the fluoride salt is preferably a salt in which the fluoride is covalently bound to another atom, such as in sodium monofluorophosphate, rather than a salt that is only ionically bound, such as in sodium fluoride.

[0157] Surfactant

[0158] In some embodiments, the present invention may comprise an anionic surfactant (e.g., the composition in Composition 1.0 and the like), such as a water-soluble salt of a higher fatty acid monoglyceride monosulfate, such as the sodium salt of the monosulfated monoglyceride of hydrogenated coconut oil, sodium coco glyceride sulfate; higher alkyl sulfates, such as sodium lauryl sulfate; higher alkyl ether sulfates, such as the higher alkyl ether sulfate of the formula CH3(CH2) m CH2(OCH2CH2) n OSO3X, wherein m is from 6 to 16, such as 10, n is from 1 to 6, such as 2, 3 or 4, and X is Na, or, for example, sodium laureth-2sulfate (CH3(CH2) 10CH2(OCH2CH2)2OSO3Na); higher alkyl aryl sulfonates such as sodium dodecylbenzenesulfonate (sodium laurylbenzenesulfonate); higher alkyl sulfonatoacetates such as sodium lauryl sulfonatoacetate (sodium dodecyl sulfonatoacetate), higher fatty acid esters of 1,2-dihydroxypropane sulfonate, sulfocolaurate (N-2-ethyl potassium laurate sulfonatoacetamide), and sodium lauryl sarcosinate. "Higher alkyl" means, for example, C 6-30 alkyl. In some specific embodiments, the anionic surfactant (when present) is selected from sodium lauryl sulfate and ether lauryl sulfate. When present, the anionic surfactant is present in an effective amount, for example, > 0.001% by weight of the formulation, but not at a concentration that would irritate oral tissues (e.g., 1%), and the optimal concentration depends on the specific formulation and the specific surfactant. In one embodiment, the anionic surfactant is present at 0.03% to 5%, for example, 1.5% by weight.

[0159] In another embodiment, the cationic surfactants useful in the present invention can be broadly defined as derivatives of aliphatic quaternary ammonium compounds having a long alkyl chain containing 8 to 18 carbon atoms, such as lauryl trimethyl ammonium chloride, cetylpyridinium chloride, cetyl trimethyl ammonium bromide, diisobutylphenoxyethyl dimethyl benzyl ammonium chloride, cocoalkyl trimethyl ammonium nitrite, cetylpyridinium fluoride, and mixtures thereof. Illustrative cationic surfactants are the quaternary ammonium fluorides described in U.S. Patent No. 3,535,421 to Briner et al., which is incorporated herein by reference. Certain cationic surfactants can also act as bactericides in the composition.

[0160] Illustrative nonionic surfactants that can be used in the compositions of the present invention and the like can be broadly defined as compounds produced by the condensation of an alkylene oxide group (essentially hydrophilic) with an organic hydrophobic compound (which can essentially be aliphatic or alkyl aromatic). Examples of suitable nonionic surfactants include, but are not limited to: Pluronics, poly(ethylene oxide) condensates of alkylphenols, products derived by the condensation of the reaction products of ethylene oxide with propylene oxide and ethylenediamine, poly(ethylene oxide) condensates of aliphatic alcohols, long-chain tertiary amine oxides, long-chain tertiary phosphine oxides, long-chain dialkyl sulfoxides, and mixtures of these materials. In a specific embodiment, the composition of the present invention comprises a nonionic surfactant selected from poloxamers (e.g., poloxamer 407), polysorbates (e.g., polysorbate 20), polyoxyethylene hydrogenated castor oil (e.g., polyoxyethylene 40 hydrogenated castor oil), and mixtures thereof.

[0161] Exemplary zwitterionic surfactants that can be used in the compositions of the present invention, such as Composition 1.0 and the like, include betaines (such as cocoamidopropyl betaine); derivatives of aliphatic secondary and tertiary amines, where the aliphatic group can be straight or branched, and where one of the aliphatic substituents contains from about 8 to 18 carbon atoms and one contains an anionic hydrotropic group (such as carboxylate, sulfonate, sulfate, phosphate, or phosphonate); and mixtures of these substances.

[0162] Surfactants or mixtures of compatible surfactants can be present in the compositions of the present invention in an amount of from 0.1% to 5% by weight of the total composition, in another embodiment from 0.3% to 3% by weight, and in another embodiment from 0.5% to 2% by weight.

[0163] Flavoring agent

[0164] The oral care compositions of the present invention (such as any of Composition 1.0 and the like) can also contain flavoring agents. Flavoring agents used in the practice of the present invention include, but are not limited to, essential oils and various flavoring aldehydes, esters, alcohols, and the like, as well as sweetening agents such as sodium saccharin. Examples of essential oils include oils of spearmint, peppermint, wintergreen, sassafras, clove, sage, eucalyptus, marjoram, cinnamon, lemon, lime, grapefruit, and orange. Chemicals such as menthol, carvone, and anethole are also useful. Some embodiments employ oils of peppermint and spearmint.

[0165] The flavoring agent is incorporated into the oral composition at a concentration of from 0.01% to 2% by weight.

[0166] Chelating agent and anti-calculus agent

[0167] The oral care compositions of the present invention can also contain one or more chelating agents capable of complexing with calcium present in the bacterial cell wall. This binding of calcium weakens the bacterial cell wall and enhances bacterial lysis.

[0168] Another group of agents suitable for use as chelating agents or anti-tartar agents in the present invention are soluble pyrophosphates. The pyrophosphates used in the compositions of the present invention can be any alkali metal pyrophosphate. In certain embodiments, the salts include tetra-alkali metal pyrophosphates, di-alkali metal diacid pyrophosphates, tri-alkali metal monoacid pyrophosphates, and mixtures thereof, where the alkali metal is sodium or potassium. The salts are available both in their hydrated and anhydrous forms. The effective amount of pyrophosphate that can be used in the compositions of the present invention is generally sufficient to provide at least 0.1% by weight of pyrophosphate ions, such as from 0.1% to 3% by weight, such as from 0.1% to 2% by weight, such as from 0.1% to 1% by weight, such as from 0.2% to 0.5% by weight. Pyrophosphates also contribute to protecting the composition by reducing the water activity.

[0169] Polymer

[0170] The oral care composition of the present invention (e.g., any one of Composition 1.0 and the like) may also optionally contain one or more polymers, such as polyethylene glycol, poly(vinyl methyl ether / maleic acid) copolymer, polysaccharides (e.g., cellulose derivatives such as carboxymethyl cellulose, or polysaccharide gums such as xanthan gum or carrageenan). Acidic polymers (e.g., polyacrylate gels) may be provided in the form of their free acids or partially or fully neutralized water-soluble alkali metal (e.g., potassium and sodium) or ammonium salts. Certain embodiments include copolymers of maleic anhydride or acid with another polymerizable ethylenically unsaturated monomer (e.g., methyl vinyl ether (methoxyethylene)) having a molecular weight (M.W.) of from about 30,000 to about 1,000,000 (Mw) in a ratio of 1:4 to 4:1. These copolymers may be obtained, for example, as Gantrez AN 139 (M.W. 500,000), AN 119 (M.W. 250,000), and S-97 pharmaceutical grade (M.W. 70,000) (GAF Chemicals Corporation).

[0171] Other useful polymers include, for example, those of maleic anhydride with ethyl acrylate, 2-hydroxyethyl methacrylate, N-vinyl-2-pyrrolidone, or ethylene, the latter being obtainable, for example, as Monsanto EMA No. 1103 with M.W. 10,000 and EMA grade 61; and copolymers of acrylic acid with methyl methacrylate or 2-hydroxyethyl methacrylate, methyl acrylate or ethyl acrylate, isobutyl vinyl ether, or N-vinyl-2-pyrrolidone in a ratio of 1:1.

[0172] Generally suitable are polymerized ethylenically or ethylenically unsaturated carboxylic acids containing an active carbon-carbon ethylenic double bond and at least one carboxyl group, i.e., acids containing an ethylenic double bond which is readily operative during polymerization due to its presence in the α-β position relative to the carboxyl group or as part of a terminal methylene group in the monomer molecule. Illustrative such acids are acrylic acid, methacrylic acid, ethylacrylic acid, α-chloroacrylic acid, crotonic acid, β-acryloxypropionic acid, sorbic acid, α-chlorosorbic acid, cinnamic acid, β-styrylacrylic acid, muconic acid, itaconic acid, citraconic acid, mesaconic acid, glutaconic acid, aconitic acid, α-phenylacrylic acid, 2-benzylacrylic acid, 2-cyclohexylacrylic acid, angelic acid, umbellic acid, fumaric acid, maleic acid, and the anhydride. Other different ethylenic monomers copolymerizable with such carboxylic acid monomers include vinyl acetate, vinyl chloride, dimethyl maleate, and the like. The copolymer contains sufficient carboxylate groups for water solubility.

[0173] Another class of polymeric reagents includes compositions comprising homopolymers of substituted acrylamides and / or homopolymers of unsaturated sulfonic acids and their salts, particularly where the polymer is based on an unsaturated sulfonic acid selected from: acrylamidoalkanesulfonic acids, such as 2-acrylamido-2-methylpropane sulfonic acid, having a molecular weight of from about 1,000 to about 2,000,000, as described in U.S. Patent No. 4,842,847, issued to Zahid on June 27, 1989, which is incorporated herein by reference.

[0174] Another class of useful polymeric reagents includes polyamino acids, particularly those containing a proportion of anionic surfactant amino acids such as aspartic acid, glutamic acid, and phosphoserine, as disclosed in U.S. Patent No. 4,866,161 to Sikes et al., which is incorporated herein by reference.

[0175] In preparing oral care compositions, it is sometimes necessary to add some thickening materials to provide the desired consistency or to stabilize or enhance the performance of the formulation. In certain embodiments, the thickener is a carboxyvinyl polymer, carrageenan, xanthan gum, hydroxyethyl cellulose, and water-soluble salts of cellulose ethers, such as sodium carboxymethyl cellulose and sodium carboxymethyl hydroxyethyl cellulose. Natural gums, such as karaya gum, gum arabic, and tragacanth gum, can also be introduced. Silica can also be used as a thickener, such as synthetic amorphous silica. Colloidal magnesium aluminum silicate or finely divided silica can be used as a component of the thickening composition to further improve the texture of the composition. In certain embodiments, a thickener is used in an amount of from about 0.5% to about 5.0% by weight of the total composition. The thickener can be present in amounts of: 1 wt% to 15 wt%, 3 wt% to 10 wt%, 4 wt% to 9 wt%, 5 wt% to 8 wt%, such as 5 wt%, 6 wt%, 7 wt%, or 8 wt%.

[0176] Abrasive

[0177] In some aspects, the compositions of the present invention (e.g., any of Composition 1.0 and the like) may comprise an abrasive. Natural calcium carbonate is present in rocks such as chalk, limestone, marble, and travertine. It is also a major component of eggshells and mollusk shells. The natural calcium carbonate abrasive of the present invention is typically finely ground limestone, which may optionally be refined or partially refined to remove impurities. For use in the present invention, the average particle size of the material is less than 10 microns, e.g., 3 to 7 microns, e.g., about 5.5 microns. For example, the average particle size (D50) of small particle silica may be 2.5 to 4.5 microns. Since natural calcium carbonate can contain a high proportion of relatively large particles if not carefully controlled, which may unacceptably increase abrasiveness, preferably not more than 0.01% by weight, preferably not more than 0.004% of the particles cannot pass through a 325 mesh. The material has a strong crystal structure and is thus much harder and more abrasive than precipitated calcium carbonate. The tapped density of natural calcium carbonate is, for example, 1 to 1.5 g / cc, e.g., about 1.2, e.g., about 1.19 g / cc. Natural calcium carbonate has different polymorphs, such as calcite, aragonite, and vaterite, and calcite is preferred for the purposes of the present invention. Examples of commercially available products suitable for the present invention include 25-11 FG.

[0178] Precipitated calcium carbonate is typically prepared as follows: Limestone is calcined to produce calcium oxide (lime), which can then be converted back to calcium carbonate by reaction with carbon dioxide in water. Precipitated calcium carbonate has a different crystal structure from natural calcium carbonate. It is generally more brittle and porous and thus has lower abrasiveness and higher water absorption. For use in the present invention, the particles are small, e.g., the average particle size is 1 to 5 microns, and e.g., not more than 0.1% by weight, preferably not more than 0.05% of the particles cannot pass through a 325 mesh. The D50 of the particles can be, for example, 3 to 6 microns, e.g., 3.8 to 4.9, e.g., about 4.3; the D50 is 1 to 4 microns, e.g., 2.2 to 2.6 microns, e.g., about 2.4 microns, and the D10 is 1 to 2 microns, e.g., 1.2 to 1.4, e.g., about 1.3 microns. The particles have a relatively high water absorption, e.g., at least 25 g / 100 g, e.g., 30-70 g / 100 g. Examples of commercially available products suitable for the present invention include, for example, 15 Plus.

[0179] In certain embodiments, the present invention may comprise additional calcium-containing abrasives, such as calcium phosphate abrasives, such as tricalcium phosphate (Ca3(PO4)2), hydroxyapatite (Ca 10(PO4)6(OH)2), or dicalcium phosphate dihydrate (CaHPO4·2H2O, sometimes also referred to herein as DiCal), or calcium pyrophosphate, and / or silica abrasive, sodium metaphosphate, potassium metaphosphate, aluminum silicate, calcined alumina, bentonite or other siliceous materials, or combinations thereof.

[0180] In certain embodiments, the composition may comprise abrasive silica. Any silica suitable for oral care compositions can be used, such as particulate silica, precipitated silica or prophy silica.

[0181] For example, the silica can also be particulate silica (e.g., Sorbosil AC43 from PQ, Warrington, United Kingdom). The composition preferably comprises from 5 to 20 wt% particulate silica, or for example from 10 to 15 wt%, or for example 5 wt%, 10 wt%, 15 wt% or 20 wt% particulate silica.

[0182] In another embodiment, the abrasive can be high cleaning precipitated silica which has a pellicle cleaning ratio (PCR) greater than 85 when tested at a 20% loading, which is known in the art as high cleaning silica. Generally speaking, the average particle size d of high cleaning silica 50 is also from 5 to 15 μm and the oil absorption is from 40 to 120 cm 3 / 100 g of silica. The cleaning efficacy of precipitated silica is expressed by the pellicle cleaning ratio (PCR). This is typically measured at a 20% silica loading. High cleaning silica preferably has a PCR value greater than 85. The efficacy of precipitated silica can also be expressed with reference to its abrasive characteristics using radioactive dentin abrasion (RDA). Ideally, the RDA value of the oral composition should be below about 250 to protect the enamel / dentin. The methods for performing PCR and RDA are described, for example, in U.S. Patent Nos. 5,939,051 and 6,290,933 and “In Vitro Removal of Stain With Dentifrice”, G.K. Stookey et al., J. Dental Research, Vol. 61, pages 1236-9, November 1982. Generally speaking, the average particle size d of precipitated silica 50 is from 5 to 15 μm, and the oil absorption is from 40 to 120 cm 3 / 100 g of silica. The average particle size d 50 is from 5 to 15 μm and the oil absorption is from 40 to 120 cm3 Examples of precipitated silica per 100 g of silica include commercially available silicas such as 103 and 105 (Huber Silica Americas).

[0183] The composition preferably contains 5 to 20% by weight of highly purified precipitated silica, or for example 10 to 15% by weight, or for example 5% by weight, 10% by weight, 15% by weight or 20% by weight of highly purified precipitated silica.

[0184] The composition may also contain abrasive silica having an acidic pH in the composition. For example, polishing silica obtained from Grace under the name Sylodent TM may be used. The concentration of acidic silica abrasive contained in the dentifrice component is about 2% to about 35% by weight, about 3% to about 20% by weight, about 3% to about 15% by weight, about 10% to about 15% by weight. For example, the acidic silica abrasive may be present in an amount selected from: 2% by weight, 3% by weight, 4% by weight, 5% by weight, 6% by weight, 7% by weight, 8% by weight, 9% by weight, 10% by weight, 11% by weight, 12% by weight, 13% by weight, 14% by weight, 15% by weight, 16% by weight, 17% by weight, 18% by weight, 19% by weight, 20% by weight.

[0185] A commercially available acidic silica abrasive is Sylodent 783 available from W.R. Grace & Company, Baltimore, Md. When measured as a 5% by weight slurry in water, the pH of Sylodent 783 is 3.4 to 4.2. For use in the present invention, the average particle size of the silica material is less than 10 microns, for example 3 to 7 microns, for example about 5.5 microns.

[0186] Water

[0187] Water is present in the oral composition of the present invention (e.g., any one of Composition 1.0 and the like). The water used to prepare commercial oral compositions should be deionized and free of organic impurities. Water generally constitutes the balance of the composition and is 5% to 45% by weight of the oral composition, for example 10% to 20%, for example 25% to 35%. This amount of water includes the added free water plus the amount introduced with other materials (such as with sorbitol or silica or any component of the present invention). The Karl Fischer method is one measure for calculating free water.

[0188] Humectant

[0189] In some aspects, the compositions of the present invention (e.g., any of Composition 1.0 and the like) can incorporate humectants to reduce evaporation and also contribute to preservation by reducing water activity. Certain humectants can also impart a desired sweetness or flavor to the composition. Humectants are typically from 15% to 70% by weight of the composition in one embodiment, or from 30% to 65% in another embodiment, based on the pure humectant.

[0190] Suitable humectants include edible polyols such as glycerol, sorbitol, xylitol, propylene glycol, and other polyols and mixtures of these humectants. In certain embodiments, a mixture of glycerol and sorbitol can be used as the humectant component of the compositions herein.

[0191] pH regulator

[0192] In some aspects, the compositions of the present invention (e.g., any of Composition 1.0 and the like) can contain buffering agents. Examples of buffering agents include anhydrous carbonates (e.g., sodium carbonate), sesquicarbonates, bicarbonates (e.g., sodium bicarbonate), silicates, bisulfates, phosphates (e.g., monopotassium phosphate, monosodium phosphate, disodium phosphate, dipotassium phosphate, trisodium phosphate, sodium tripolyphosphate, potassium tripolyphosphate, phosphoric acid), citrates (e.g., citric acid, trisodium citrate dehydrate), pyrophosphates (sodium and potassium salts, e.g., potassium pyrophosphate), and combinations thereof. When the composition is dissolved in water, an oral rinse matrix, or a toothpaste matrix, the amount of buffering agent is sufficient to provide a pH of from about 5 to about 9, preferably from about 6 to about 8, more preferably about 7. The typical amount of buffering agent is from about 5% to about 35% by weight of the total composition, from about 10% to about 30% in one embodiment, and from about 15% to about 25% in another embodiment.

[0193] The present invention in its method aspects relates to the oral administration of a safe and effective amount of the compositions described herein.

[0194] The compositions and methods according to the present invention (e.g., Composition 1.0 and the like) can be incorporated into oral compositions for oral and dental care, such as toothpaste, clear pastes, gels, oral rinses, sprays, and chewing gums.

[0195] As used throughout, ranges are used as a 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 those of the cited references, the definitions in this disclosure shall control. It should be understood that when describing a formulation, it may be described in terms of its components, as is common in the art, although these components may react with each other during the preparation, storage, and use of the actual formulation, and such products are intended to be encompassed by the described formulation.

[0196] The following examples further describe and illustrate illustrative embodiments within the scope of the present invention. These examples are given for illustrative purposes only and should not be construed as limiting the present invention, as many variations can be made without departing from the spirit and scope of the present invention. Various modifications of the present invention will also be apparent to those skilled in the art and are intended to fall within the scope of the appended claims, in addition to those shown and described herein.

[0197] Example 1

[0198] Soluble Zinc Measurement

[0199] The ability of hyaluronic acid to increase the soluble zinc concentration was tested in a simple solution. The soluble zinc concentration was measured, and the results are detailed in Table 1 below. Procedure for measuring soluble zinc:

[0200] 1. Weigh 5 g of zinc-HA or zinc-chitosan solution into 50 mL centrifuge tubes separately. Repeat three times.

[0201] 2. Add 15 g of DI H2O. Vortex the solution to mix the entire solution completely.

[0202] 3. Centrifuge the samples at 12,500 rpm for 10 minutes. Take out 1 mL of the supernatant and place it in a 15 mL centrifuge tube.

[0203] 4. Add 0.5 mL of concentrated nitric acid and let the samples stand at room temperature for 30 minutes.

[0204] 5. Then add 3.5 mL of DI H2O and vortex.

[0205] The data obtained from the simple solutions analyzed by the above method are detailed in Table 1:

[0206] Table 1:

[0207]

[0208]

[0209] 1: Zinc oxide is present at 0.25 wt% in Samples A, C to E.

[0210] 2: The polymer contains 0.1% chitosan and 0.1% HA (1 MDa) and does not contain zinc.

[0211] 3: "HA" represents hyaluronic acid. HA is added at 0.1 wt%.

[0212] 4. Sample A contains 49.75 wt% deionized water. Sample B contains 49.80 wt% deionized water. Samples C to E contain 49.65% deionized water.

[0213] *p < 0.05, relative to all other samples (ANOVA + Tukey)

[0214] Example 2

[0215] Next, the ability of hyaluronic acid to enhance zinc uptake was measured in an in vitro test. Zinc uptake in the in vitro skin method was measured as follows:

[0216] Procedure for in vitro skin assay:

[0217] I. Preparation (Day 0)

[0218] A. Cut the in vitro skin from the donor sheet into 7 mm diameter discs using a punch.

[0219] B. Fill the hydration chamber with a 15% / 85% glycerol / deionized water solution (44 g glycerol, 256 g water). Hydrate approximately 30 in vitro skin discs overnight in the hydration chamber by placing them on a sieve rack.

[0220] II. Next day (Day 1)

[0221] A. Obtain 10 mL of parafilm-stimulated saliva that has been centrifuged at 8000 rpm for 10 minutes.

[0222] B. Remove the saliva supernatant and transfer it to a Max 10 speed mixing cup. Transfer the in vitro skin discs to the 10 mL saliva supernatant and incubate with rotation at 120 rpm at 37 °C for 2 hours on an orbital shaker to allow pellicle formation.

[0223] III. In vitro skin treatment (Day 1)

[0224] A. Place 5 mL of the zinc-HA or zinc-chitosan solution to be tested into separate Max 10 speed mixing cups.

[0225] B. Place 3 in vitro skin discs into each speed mixing cup, ensuring that the samples are completely immersed in the suspension.

[0226] C. Incubate the five cups on an orbital shaker (120 rpm) at 37 °C for 1 hour.

[0227] D. Remove the ex vivo skin discs from the solution and gently wash them 3 times by dipping the skin into deionized water (20 mL). Some substances may continue to adhere to the ex vivo skin, depending on how mucoadhesive they are to the ex vivo skin.

[0228] Replace the wash water with each new sample.

[0229] E. Place each ex vivo skin in a clean 15 mL conical tube and label it.

[0230] F. Add 0.5 mL of concentrated nitric acid to each 15 mL tube. Ensure that the ex vivo skin is completely immersed in the nitric acid (sometimes it tends to adhere to the side of the tube).

[0231] G. Leave the samples at room temperature overnight to digest the ex vivo skin with the acid.

[0232] IV. The Next Day (Day 2) A. Add 4.5 mL of deionized water to each 15 mL tube and vortex mix.

[0233] Table 2 details the zinc uptake in the ex vivo skin method:

[0234] Table 2:

[0235]

[0236] 1: Zinc oxide is present at 0.25 wt% in Samples A, C to E

[0237] 2: The polymer contains 0.1% chitosan and 0.1% HA (1 MDa)

[0238] 3: "HA" represents hyaluronic acid. HA is added at 0.1 wt%.

[0239] 4. Sample A contains 49.75 wt% deionized water. Sample B contains 49.80 wt% deionized water. Samples C to E contain 49.65% deionized water.

[0240] *p < 0.05, relative to zinc oxide control (ANOVA + Tukey)

[0241] p < 0.05, relative to Samples C and E

[0242] Thus, from the data presented in Tables 1 and 2 above, the sample with HA (average 480 kDa) unexpectedly improved the delivery of available zinc to the oral mucosa when measured relative to both higher and lower molecular weight hyaluronic acid samples. However, both the HA samples with 1 MDa and average 480 kDa hyaluronic acid were statistically different from the zinc control, confirming that the addition of HA improved zinc delivery. In addition, all hyaluronic acid-containing samples exhibited improved zinc solubility relative to the hyaluronic acid-free control samples (Table 1).

[0243] Example 3

[0244] Zinc Uptake by Hard Tissues In Vitro

[0245] Multiple formulations with zinc and hyaluronic acid were tested in an in vitro hard tissue model designed to demonstrate the ability to retain zinc on hydroxyapatite discs.

[0246] Dental Care Agent Formulations

[0247] (Amounts are listed as % by weight of the total composition)

[0248] Table 3

[0249]

[0250]

[0251] Dental Care Agent Formulations:

[0252] (Amounts are listed as % by weight of the total composition)

[0253] Table 4

[0254]

[0255]

[0256] The following Tables 5 and 6 show that formulations G, H, J, and K, all of which contain a certain amount of hyaluronic acid, can significantly improve zinc retention on HAP discs compared to equivalent formulations without HA. It should be noted that there is no statistically significant difference between the toothpastes with 0.05% and 0.1% HA:

[0257] Table 5

[0258] Formulation Zinc / μg / substrate Composition F 105.36 Composition G 125.03* Composition H 136.85*

[0259] * Statistically significant compared to Composition F

[0260] Table 6:

[0261] Formulation Zinc / μg / substrate Composition I 119.07 Composition J 181.40* Composition K 199.47*

[0262] *Statistically significant compared to Compound I

[0263] Example 4

[0264] Volatile sulfur compound (VSC) reduction efficacy

[0265] The following table shows the evaluation results of the volatile sulfur compound (VSC) reduction efficacy produced by bacteria in vitro in Composition G compared to Composition F. Generally speaking, methanethiol is a representative component of volatile sulfur compounds (VSCs), which can be used as a marker for quantitatively measuring oral odor by gas chromatography-flame photometric detector technology. Hydroxyapatite (HAP) was incubated with whole saliva to form a pellicle, and then treated with the test and control dentifrice slurries. After washing, the treated discs were transferred to headspace vials and incubated with a VSC solution to simulate oral odor (VSC) production. Methanethiol in the headspace was measured by gas chromatography-flame photometric detector, and the results were intended to determine the efficacy of the product in reducing oral odor.

[0266] Table 6 shows the methanethiol measurement results for evaluating VSC reduction efficacy by gas chromatography. As shown in Table 6, when measured relative to a similar toothpaste without hyaluronic acid (Composition F), Composition G (Table 3, 0.05% HA) showed a significant reduction in methanethiol reduction. Without being bound by theory, this unexpected improvement may be related to the increased availability of zinc ions in these formulations.

[0267] Table 7:

[0268] Formulation Log (Integrated hydrogen sulfide area) Composition F 6.53 Composition G 6.12*

[0269] Example 5

[0270] Antibacterial efficacy

[0271] In this example, the experimental method used was the Biofilm Growth Inhibition University of Manchester Model. The protocol of this model is as follows:

[0272] a.

[0273] a. (1) Dental plaque was collected from four healthy volunteers and pooled together as an inoculum. The optical density of the inoculum was matched to an absorbance of 0.3 at 610 nm.

[0274] b. (2) Sterile hydroxyapatite (HAP) discs were incubated with 1 mL of sterile artificial saliva (with 0.01 wt% sucrose) and 1 mL of pooled saliva in a 24-well microplate under anaerobic conditions at 37 °C for 24 hours.

[0275] c. (3) For each test dentifrice (and for each control), prepare a treatment solution of 1 part dentifrice: 2 parts sterile distilled water by weight. Add each freshly prepared treatment solution to three wells and allow it to contact the HAP discs therein for 10 minutes.

[0276] d. (4) Then remove the liquid phase from each well and replace it with 2 mL of sterile artificial saliva.

[0277] e. (5) Then maintain the discs under anaerobic conditions at 37 °C for 8 days.

[0278] f. (6) At 2-day, 4-day, and 8-day intervals, aseptically collect the discs and transfer them to half-strength pre-reduced thioglycollate medium (4.5 mL per disc).

[0279] g. (7) For each disc, plate 10 -4 、10 -5 and 10 -6 dilutions in duplicate on neomycin / vancomycin (NV) agar for total Gram-negative anaerobic bacteria.

[0280] h. (8) Use a sterile spreader to surface spread the plates and incubate them anaerobically at 37 °C for 72 hours, after which count the number of colonies on each plate.

[0281] Calculate the Log 10 CFU / ml for each test dentifrice or control (where CFU = colony-forming unit). A lower Log 10 CFU / ml indicates that the test dentifrice has greater efficacy in inhibiting biofilm growth.

[0282] The results obtained using the biofilm growth inhibition model method of The University of Manchester (above) are shown in Table 8, where the mean log 10 CFU / ml was obtained from discs incubated for 8 days in step 6 of the method. Table 8 lists the results for dentifrice formulations 1 to 7 that were evaluated.

[0283] Table 8

[0284]

[0285] * Means not sharing a letter are significantly different.

[0286] As shown in Table 8, compared to a similar-setting toothpaste without any hyaluronic acid (formulation 2), formulation 7 (which contains: 0.5% zinc citrate, 1.0% zinc oxide, 0.1% hyaluronic acid, 0.2% benzyl alcohol) showed significantly better antibacterial efficacy.

[0287] Example 6

[0288] Determine the lubricating effect of hyaluronic acid

[0289] To test the lubricating effect of hyaluronic acid, toothpaste with 1% zinc oxide and 0.5% zinc citrate was made into a slurry containing 0.05% or 0.1% hyaluronic acid (average MW 480 kDa). The protocol for this determination is as follows:

[0290] a. Prepare a slurry of 1 part TP and 1 part tap water.

[0291] b. Pour the slurry onto an in vitro skin substrate.

[0292] c. Measure the coefficient of friction as RPM increases from 0.1 to 20 with the probe 15 mm from the center and a normal force of 1 N.

[0293] d. After the slurry test, rinse the substrate with 10 mL of water and then measure the coefficient of friction in the same manner.

[0294] e. Repeat the test three times for all samples.

[0295] As the amount of hyaluronic acid increases, the coefficient of friction decreases (e.g., enhanced lubrication). After rinsing, the 0.1% hyaluronic acid sample showed higher lubricity compared to the control without any hyaluronic acid. However, among the rinsed samples, 0.05% hyaluronic acid had similar lubricity to the control sample. The average coefficient of friction (Coefficient of Friction, “COF”) of the rinsed samples at 1 RPM: The average COF for both the 0% HA and 0.05% HA samples was 0.12 (±0.02). The average coefficient of friction (“COF”) of the rinsed samples at 1 RPM with 0.1% HA was 0.08 (±0.02).

[0296] As used throughout, ranges are used as a shorthand description for each and every value within the range. Any value within the range can be selected as an 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 those of the cited references, the definitions in this disclosure shall control.

[0297] Unless otherwise indicated, all percentages and amounts expressed herein and elsewhere in the specification are to be understood as referring to weight percentages. The given amounts are based on the active weight of the materials.

[0298] Although the invention has been described with reference to some embodiments, those skilled in the art will understand that various modifications and changes can be made therein without departing from the scope of the invention as defined by the appended claims.

Claims

1. An oral care composition comprising: a. Zinc oxide present in an amount of 0.75 to 1.25% by weight and zinc citrate present in an amount of 0.25 to 1.0% by weight; and b. Hyaluronic acid having an average molecular weight of 300,000 to 700,000 Da present in an amount of 0.01 to 10% by weight, wherein the % by weight is based on the total weight of the composition.

2. The oral care composition according to claim 1, wherein the composition comprises a fluoride source.

3. The oral care composition according to claim 1 or 2, wherein the fluoride source comprises one selected from the group consisting of stannous fluoride, sodium fluoride, potassium fluoride, sodium monofluorophosphate, sodium fluorosilicate, ammonium fluorosilicate, amine fluoride, ammonium fluoride, titanium fluoride, hexafluorosulfate, and combinations thereof.

4. The oral care composition according to claim 1, wherein the oral care composition further comprises an amino acid.

5. The oral care composition according to claim 4, wherein the amino acid comprises a basic amino acid having an L-configuration.

6. The oral care composition according to claim 5, wherein the basic amino acid comprises arginine, and wherein the arginine is present in an amount corresponding to 0.1% to 15% by weight, where the weight of arginine is calculated in free form.

7. The oral care composition according to claim 6, wherein the arginine is present in an amount of 1% to 2% by weight.

8. The oral care composition according to claim 1, wherein the ratio of the % by weight of zinc oxide to the % by weight of zinc citrate is 1.5:1 to 4.5:

1.

9. The oral care composition according to claim 1, wherein the average molecular weight of the hyaluronic acid is 480,000 Da.

10. The oral care composition according to claim 1, wherein the average molecular weight of the hyaluronic acid is 550,000 Da.

11. The oral care composition according to claim 1, wherein the composition comprises the hyaluronic acid in an amount of 0.05 to 5% by weight.

12. The oral care composition according to claim 1, wherein the composition comprises the hyaluronic acid in an amount of 0.025 to 2% by weight.

13. The oral care composition according to claim 1, wherein the composition comprises the hyaluronic acid in an amount of 0.05% or 0.1% by weight.

14. The oral care composition according to claim 1, wherein the composition comprises: 0.25% to 0.75% by weight of the zinc citrate; and 0.025% to 2% by weight of the hyaluronic acid, wherein the average molecular weight of the hyaluronic acid is 300,000 to 600,000 Da.

15. The oral care composition according to claim 1, comprising: 0.25% to 0.75% by weight of the zinc citrate; 1.0% to 2.0% by weight of L-arginine; 0.025% to 2% by weight of the hyaluronic acid, wherein the average molecular weight of the hyaluronic acid is 300,000 to 700,000 Da.

16. The oral care composition according to claim 1, wherein the oral care composition is a dentifrice.

17. The oral care composition according to claim 1, wherein the average molecular weight of the hyaluronic acid is from 300,000 Da to 600,000 Da.

18. The oral care composition according to claim 1, wherein the average molecular weight of the hyaluronic acid is from 325,000 Da to 575,000 Da.

19. The oral care composition according to claim 5, wherein the basic amino acid is present in an amount of 0.5% to 3% by weight.

20. Use of the oral care composition according to claim 1 in the preparation of a product for improving oral health, wherein the use effectively: i. alleviates tooth hypersensitivity, ii. reduces plaque accumulation, and / or iii. cleans teeth and oral cavity.

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