Oral care compositions, methods, and kits

Abstract

The aqueous oral care composition comprises calcium, fluoride, citrate, and water. The composition comprises at least 2 moles of citrate for every 3 moles of calcium, and at least 1 mole of fluoride for every mole of calcium. The water is present in the composition in an amount of at least 50% by weight, based on the total weight of the composition. The composition is a solution.

Description

[Background technology]

[0001] Oral care compositions having fluoride and calcium ions are described, for example, in US Pat. Nos. 10,064,802 and 10,682,300. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0002] Fluoride has been a staple ingredient in monograph mouthrinses, toothpastes, varnishes, etc. for decades. In recent years, attempts have been made to incorporate additional calcium and phosphate ions to aid in tooth remineralization and the formation of hydroxyapatite and fluoroapatite in tooth structures. Traditional materials have a number of limitations. First, when calcium and fluoride ions are placed in the same aqueous solution, highly insoluble calcium fluoride is formed, which has a solubility in water of only 8-10 ppm and typically precipitates out of solution. This limits the available calcium and fluoride that can be placed in aqueous compositions to achieve a therapeutic effect. Second, various formulations have attempted in the past to add compounds such as calcium phosphate or even particles of hydroxyapatite, but the problem surrounding these types of materials is that the same physiological pH required to dissolve hydroxyapatite in tooth structures is required to release the calcium or phosphate in the material, which is counterproductive. Third, the addition of other desirable ions, such as zinc or strontium, also results in insoluble fluorides with minimal ionic bioavailability. As a result, formulations containing fluoride and calcium and / or other beneficial cations in a single solution with additional bioavailable ions are desirable, as such compositions would benefit the uptake of those ions in the tooth structure, providing additional benefits (e.g., antimicrobial activity, tooth matrix reinforcement, etc.).

[0003] The term "metastable" refers to a quasi-equilibrium state of a material in which the amount of free energy is greater than the amount of free energy contained in the equilibrium state.

[0004] The term "supersaturated" refers to a composition (eg, an aqueous solution) that contains more solute (eg, calcium citrate or hydrates thereof) than is dissolved at equilibrium.

[0005] The term "chemical complex" refers to a molecular entity formed by loose bonds containing two or more constituent molecular entities (ionic or uncharged) or corresponding chemical species. The bonds between the components of the complex are usually weaker than covalent bonds. Thus, the term "chemical complex" can be considered as any combination of components where the molecules of each component are mixed and weakly bonded to each other. The term "chemical complex" does not necessarily require ionic or other bonds between the components. A chemical complex also does not include covalent bonds between the components of the complex.

[0006] The term "solution" refers to a homogeneous mixture of two or more substances (a solvent and one or more solutes) in relative amounts that can be continuously varied up to the solubility limit of any one of the solutes in the solvent (under standard temperature and pressure conditions). As used herein, a "solution" does not have an amount of solute visible to the naked human eye (e.g., in the form of a precipitate), but may contain nanoparticles that are not visible to the naked human eye (e.g., particles having an average longest dimension of less than 50 nanometers, less than 20 nanometers, or less than 10 nanometers).

[0007] The term "aqueous solution" refers to a solution in which water is the solvent.

[0008] The term "free fluoride" refers to isolated fluoride in solution (e.g., the amount of fluoride in solution that has not formed an insoluble complex or particle), the concentration of which in solution can be determined by a meter with a fluoride-selective electrode (fluoride probe).

[0009] The terms "comprising" and variations thereof do not have a limiting meaning when these terms appear in the specification and claims. It will be understood that such terms mean the inclusion of the recited step or element or group of steps or elements, but not the exclusion of any other step or element or group of steps or elements. "Consisting of" means including and limited to what follows the phrase "consisting of". Thus, the phrase "consisting of" indicates that the recited elements are necessary or mandatory, and that no other elements may be present. "Consisting essentially of" means including any elements recited after this phrase, and is limited to other elements that do not interfere with or contribute to the activity or action of the recited elements as specified in this disclosure. Thus, the phrase "consisting essentially of" indicates that the recited elements are necessary or mandatory, but that other elements are optional and may be present or absent depending on whether they materially affect the activity or action of the recited elements.

[0010] In this application, terms such as "a," "an," and "the" are not intended to refer only to a singular entity, but include a general class of which a particular example may be used for illustration. The terms "a," "an," and "the" are used interchangeably with the phrases "at least one" and "one or more." The phrases "at least one of" and "including at least one of," followed by a list, refer to any one of the items in the list, and any combination of two or more items in the list.

[0011] The term "or" is generally used in its ordinary sense including "and / or" unless the content clearly dictates otherwise.

[0012] The term "and / or" means one or all of the listed elements or a combination of any two or more of the listed elements.

[0013] Also, all numbers herein are intended to be modified by the term "about." When used herein in connection with a measured quantity, the term "about" refers to the variation in the measured quantity that would be expected by a person of ordinary skill in the art making the measurement and exercising a level of care commensurate with the purpose of the measurement and the precision of the measuring device used. As used herein, a number "up to" (e.g., up to 50) is inclusive of that number (e.g., 50).

[0014] Also herein, the recitations of numerical ranges by endpoints include all numbers subsumed within that range as well as the endpoints (eg, 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.).

[0015] Throughout this specification, references to "one embodiment," "an embodiment," "particular embodiment," "some embodiments," or the like mean that the particular features, configurations, compositions, or characteristics described in connection with the embodiment are included in at least one embodiment of the disclosure. Thus, the appearances of such phrases in various places throughout this specification do not necessarily refer to the same embodiment of the disclosure. Furthermore, the particular features, configurations, compositions, or characteristics may be combined in any suitable manner in one or more embodiments.

[0016] The above summary of the present disclosure is not intended to describe each embodiment or every implementation disclosed in the present disclosure. The following description more particularly illustrates exemplary embodiments. In several places throughout the application, guidance is provided through lists of examples, which examples can be used in various combinations. In each instance, the recited list serves only as a representative group and should not be interpreted as an exclusive list.

[0017] In some embodiments, the present disclosure relates to a method for stabilizing calcium and other ions useful in oral care solutions in the presence of fluoride. The method offers the possibility of delivering ions for remineralization, antimicrobial effects, and other potential uses in dental and / or orthodontic compositions. In general, the method of the present disclosure utilizes a specific order and timing of combination of ingredients and the chelating effect of citric acid (a trifunctional carboxylic acid) or, in some embodiments, etidronic acid (a bisphosphonic acid structure). Surprisingly, it has been discovered that the order and timing of addition of certain components is important to obtain a stable solution in a pH range acceptable for oral use.

[0018] In some embodiments, the method may include reacting (in an aqueous solution) a calcium source with a chelating agent (e.g., etidronic acid or citric acid) to form a metastable (e.g., supersaturated metastable) aqueous solution of calcium citrate, calcium etidronate, or hydrates thereof. The method may then include adding a water-soluble fluoride salt or salt solution to the metastable solution immediately after formation of the metastable solution. Specifically, in some embodiments, the water-soluble fluoride salt or salt solution may be added to the metastable supersaturated solution before calcium citrate or hydrates thereof precipitate. In some embodiments, the water-soluble fluoride salt or salt solution may be added to the metastable supersaturated solution within 0.5 minutes, 1.0 minutes, 1.5 minutes, 2.0 minutes, 3.0 minutes, or 5.0 minutes of formation of the supersaturated metastable solution. Surprisingly, it has been discovered that when the fluoride salt solution is added within this time frame, an aqueous solution containing a complex of citrate, calcium, and a monovalent ion may be formed. Such aqueous solutions have been observed to be clear, with no visible precipitate, and with measurable free fluoride in solution up to thousands (1000's) ppm. However, if the fluoride salt solution is not added within this time frame, a precipitate of insoluble calcium citrate will form and no complex will form (i.e., fluoride must be added before the supersaturated calcium citrate or its hydrate precipitates).

[0019] In some embodiments, the metastable solution (eg, a metastable supersaturated solution) can include water and the reaction product of a calcium source and a chelating agent.

[0020] In some embodiments, suitable calcium sources for the metastable solution can include salts such as hydrates of calcium hydroxide, calcium acetate, calcium carbonate, calcium bicarbonate, or calcium nitrate, hi some embodiments, suitable calcium sources can include calcium hydroxide or calcium acetate.

[0021] In some embodiments, the chelating agent may include citric acid or etidronic acid. Citric acid has been found to be more stable at higher concentrations than its etidronate counterpart. As a result, in some embodiments, the chelating agent may include citric acid. In some embodiments, citric acid may be included as a mixture of carboxylic or phosphonic acids and citric acid. It has been found that calcium ions in an aqueous solution require at least two moles of chelating acid groups per mole of calcium ion to form a stable solution, and as a result, three moles of chelating functional groups (carboxylic acid or carboxylate) of citric acid are sufficient. Additional chelating groups may be utilized (e.g., in a mixture of citric acid and additional acid, or by adding additional citric acid) without affecting stability, but not exclusively.

[0022] In some embodiments, the calcium source may be present in the metastable solution (e.g., a metastable supersaturated solution) in an amount of at least 0.0005% by weight (or 5 parts per million by weight (ppm)), at least 0.005% by weight (or 50 ppm), at least 0.05% by weight (or 500 ppm), at least 0.5% by weight, or at least 5.0% by weight, based on the total weight of the solution, and the chelating agent may be present in the metastable solution in an amount such that the molar ratio of calcium ions to chelating functional acid groups is at least 1 to 2 and the molar ratio of calcium ions to citric acid is 1.5:1 or less.

[0023] In some embodiments, water may be present in a metastable solution (e.g., a metastable supersaturated solution) in an amount of at least 50% by weight, at least 70% by weight, at least 80% by weight, at least 90% by weight, or at least 99% by weight, based on the total weight of the solution.

[0024] In some embodiments, the aqueous fluoride solution may include a fluoride salt and water. Suitable fluoride salts may include sodium fluoride, potassium fluoride, amine fluoride, silver diamine fluoride, or ammonium fluoride. In some embodiments, the fluoride salt may include sodium fluoride or ammonium fluoride. It has been discovered that sodium fluoride and ammonium fluoride can provide higher concentrations of free fluoride and greater stability than potassium fluoride.

[0025] In some embodiments, the fluoride salt may be present in the aqueous fluoride solution in a concentration of at least 0.00024 wt.% (or 2.4 ppm), at least 0.0024 wt.% (or 24 ppm), at least 0.024 wt.% (or 240 ppm), at least 0.24 wt.% (or 2400 ppm), at least 2.4 wt.%, or at least 5 wt.%, based on the total weight of the aqueous fluoride solution, and water may be present in the aqueous fluoride solution in an amount of at least 50 wt.%, at least 70 wt.%, at least 80 wt.%, at least 90 wt.%, or at least 99 wt.%, based on the total weight of the aqueous fluoride solution.

[0026] As previously described, the method of the present disclosure may produce an aqueous solution that includes calcium, fluoride, and citrate. In some embodiments, the aqueous solution may include free fluoride, complexes that include any or all of calcium and citrate, fluoride, and stable calcium fluoride (CaF2) nanoparticles dispersed in the solution. Such a solution may be considered a one-part composition. The CaF2 nanoparticles may be stable; that is, they remain suspended or dissolved in the solution such that the nanoparticles do not grow or precipitate (or do not substantially grow or precipitate) from the solution.

[0027] In some embodiments, the free fluoride may be present in the aqueous solution in an amount of at least 0.0002% (or 2.0 ppm), at least 0.00024% (or 2.4 ppm), at least 0.001% (or 10 ppm), at least 0.002% (or 20 ppm), at least 0.01% (or 100 ppm), at least 0.05%, or at least 0.50% by weight, based on the total weight of the aqueous solution. In some embodiments, the free fluoride may be present in an amount of up to 1.0%, up to 2.0%, up to 5.0%, or up to 10% by weight, based on the total weight of the aqueous solution.

[0028] In some embodiments, calcium may be present in an amount of at least 0.0005% (or 5 ppm), at least 0.002% (or 20 ppm), at least 0.02% (or 200 ppm), at least 0.2% (or 2,000 ppm), or at least 0.5% by weight based on the total weight of the aqueous solution. In some embodiments, calcium may be present in an amount of up to 1.0%, up to 2.0%, up to 5.0%, or up to 10% by weight based on the total weight of the aqueous solution.

[0029] In some embodiments, the molar ratio of citrate to calcium in the aqueous solution may be such that at least 2 moles of citrate are present for every 3 moles of calcium. It has been found that precipitation occurs when the molar ratio of citrate to calcium ions in the aqueous solution is less than this.

[0030] In some embodiments, the molar ratio of fluoride to calcium in the aqueous solution may be such that at least one mole of fluoride is present for every mole of calcium. It has been found that precipitation occurs when the molar ratio of fluoride to calcium is less than this.

[0031] In some embodiments, the aqueous solution may include water as a solvent to form a clear solution. In some embodiments, water may be present in the aqueous solution in an amount such that it accounts for 100%, at least 90%, at least 80%, or at least 70% by weight of the aqueous solution not accounted for by calcium, fluoride, and citrate.

[0032] In some embodiments, the aqueous solution may include calcium fluoride nanoparticles dispersed in the aqueous solution. The nanoparticles may have an average longest dimension of less than 50 nanometers (nm), less than 20 nm, less than 10 nm, or less than 5 nm. In some embodiments, the calcium fluoride nanoparticles may be present in the aqueous solution at a concentration and size such that the nanoparticles are not visible (to the naked human eye) in the aqueous solution.

[0033] In some embodiments, after the aqueous solution is prepared to form a stable aqueous solution, additional fluoride may be added to increase the concentration of free fluoride in the solution. In this regard, the additional fluoride may be provided such that there is at least an additional 0.1%, an additional 0.5%, an additional 1.0%, an additional 2.0%, or an additional 5% by weight of fluoride, based on the total weight of the stable aqueous solution upon formation, up to the solubility limit of the fluoride salt.

[0034] As previously mentioned, in some embodiments, the oral care one-part composition (e.g., solution) of the present disclosure is an aqueous composition (e.g., solution), but may contain a small amount of one or more organic solvents. Exemplary organic solvents are selected from ethanol, isopropanol, dimethyl sulfoxide (DMSO), isoprene sulfone (IS), butadiene sulfone (BS), piperylene sulfone (PS), ethyl acetate, methyl acetate, isopropyl acetate, acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), and combinations thereof.

[0035] In some embodiments, the aqueous oral care one-part composition (e.g., solution) does not include an organic solvent that functions as a liquid carrier (as opposed to an organic solvent used as a carrier / solvent for a flavoring or sweetening agent). For example, certain additives may be provided as a solution or dispersion in an organic solvent as a liquid carrier. If any organic solvent (functioning as a liquid carrier) is present in the aqueous oral care one-part composition (e.g., solution) of the present disclosure, the organic solvent is present in an amount of less than 5% by weight, based on the total weight of the aqueous composition (e.g., solution).

[0036] In some embodiments, the aqueous oral care composition of the present disclosure is a shelf stable solution without precipitation (detectable by the naked human eye) for at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months when stored in a sealed container at room temperature and atmospheric pressure. Thus, the aqueous oral care solution of the present disclosure can remain transparent (i.e., clear or translucent without any haze) upon storage for at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months.

[0037] As mentioned above, the aqueous oral care compositions of the present disclosure can exhibit the above stability while also having a pH that is acceptable for oral use. In this regard, the aqueous oral care compositions can have a pH of 2-11, or 3-10.

[0038] In some embodiments, the aqueous oral care one-part compositions (e.g., solutions) of the present disclosure may include a pharma- ceutically acceptable buffering agent. The type and amount of such buffering agent may be selected to provide the oral care composition (e.g., solution) with a pH of at least 3.0, at least 3.5, at least 4.0, at least 4.5, at least 5.0, at least 5.5, at least 6.0, or at least 6.5. In certain embodiments, the type and amount of such buffering agent may be selected to provide the oral care composition (e.g., solution) with a pH of at most 10, at most 9, at most 8.5, at most 7.5, or at most 7. In certain embodiments, the type and amount of such buffering agent may be selected to provide the oral care composition (e.g., solution) with a pH of 6.5-7.5, or a pH of 7.0. A wide variety of suitable pharma-ceutically acceptable buffering agents may be included. Examples include acetates (e.g., sodium acetate), sodium carbonate, citrates (e.g., sodium citrate), tartrates, glycylglycine, histidine, glycine, lysine, arginine, glycine, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, tris(hydroxymethyl)-aminomethane, potassium phosphate, potassium hydrogen phosphate, potassium dihydrogen phosphate, or mixtures thereof.

[0039] The aqueous oral care one-part compositions (e.g., solutions) of the present disclosure may also further include one or more active agents in addition to a fluoride source. If included, the one or more additional active agents will usually, but not always, include one or more active agents that are active in the oral cavity against disorders, diseases, or conditions of the teeth, gums, cheeks, tongue, palate, etc.

[0040] In some embodiments, the solutions of the present disclosure may further comprise a phosphate, which may be present in the form of a water-soluble phosphate salt, such as ammonium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, tris(hydroxymethyl)-aminomethane, potassium phosphate, potassium hydrogen phosphate, potassium dihydrogen phosphate, or a mixture thereof.

[0041] In order to form fluoroapatite, in addition to calcium and fluoride, phosphate must be present. Although low levels of phosphate may be present in saliva, it is desirable to have an additional source of phosphate. It has been discovered that phosphate can be added to the composition of the present disclosure without destroying the stabilization benefits described above.

[0042] Examples of additional active agents that can be used include one or more of whitening agents, anti-tartar agents, remineralizing agents, stannous sources, antibacterial agents, antioxidants, saliva stimulants, breath fresheners, antiplaque agents, anti-inflammatory agents, H2 blockers, desensitizing agents, nutrients, and proteins.Optionally, various combinations of such additional active agents can be used.When used, one or more additional active agents are typically used in an amount sufficient to obtain the intended effect.

[0043] When utilized, antibacterial agents can include a wide variety of orally acceptable antibacterial agents, including, for example, triclosan, 8-hydroxyquinoline, zinc ions, stannous ions, cupric compounds, phthalic acid and its salts, quaternary ammonium compounds, sanguinarine, salicylanilide, salicylic acid, thymol, eugenol, neomycin, kanamycin, clindamycin, amoxicillin, tetracycline, doxycycline, minocycline, metronidazole, chlorhexidine, and the like.

[0044] If utilized, the antioxidant can be a wide variety of orally acceptable antioxidants, examples of which include butylated hydroxyanisone, butylated hydroxytoluene, vitamin A, carotenoids, vitamin E, flavonoids, polyphenols, ascorbic acid or its salts, chlorophyll, melatonin, and the like.

[0045] If utilized, the saliva stimulant can be a wide variety of orally acceptable saliva stimulants, examples of which include lactic acid, succinic acid, ascorbic acid, adipic acid, fumaric acid, and tartaric acid.

[0046] If utilized, the breath freshener can be a wide variety of orally acceptable breath fresheners, examples include zinc salts such as zinc salts of gluconate, citrate, chlorite, alpha-ionone, and the like.

[0047] When utilized, the antiplaque agent can be a wide variety of orally acceptable antiplaque agents. Examples include stannous salts, copper, magnesium or strontium salts, dimethicone copolyols, such as cetyl dimethicone copolyol, papain, glucamylase, glucose oxidase, urea, calcium lactate, calcium glycerophosphate, strontium polyacrylate, and the like. Further examples of antiplaque agents include biofilm inhibitors, particularly those described in U.S. Patent No. 8,968,709 (Yang et al.).

[0048] When utilized, the anti-inflammatory agent can be a wide variety of orally acceptable anti-inflammatory agents, including steroids such as fluocinolone and hydrocortisone, non-steroidal anti-inflammatory drugs such as ketorolac, flurbiprofen, ibuprofen, naproxen, indomethacin, diclofenac, etodolac, indomethacin, sulindac, tolmetin, ketoprofen, fenoprofen, piroxicam, nabumetone, acetylsalicylic acid, salicylic acid, diflunisal, meclofenamate, mefenamic acid, oxyphenbutazone, phenylbutazone, and the like.

[0049] If utilized, the H2 blocker can be a wide variety of orally acceptable H2 blockers, including, for example, cimetidine, ethinidine, ranitidine, tiotidine, rupitidine, denetidine, famotidine, roxatidine, pifatidine, ramutidine, zarutidine, nizatidine, mifentidine, lamixotidine, roxydine, visfentidine, sfotidine, ebrotidine, impromudin, and the like.

[0050] If utilized, the desensitizing agent can be a wide variety of orally acceptable desensitizing agents, examples of which include potassium citrate, potassium chloride, potassium tartrate, potassium bicarbonate, potassium oxalate, potassium nitrate, strontium salts, arginine, acetylsalicylic acid or its salts, salicylic acid or its salts, codeine, acetaminophen, and the like.

[0051] In some embodiments, any number of additional conventional orally acceptable remineralizing agents may be utilized.

[0052] When utilized, nutrients can be a wide variety of orally acceptable nutrients, including vitamins such as vitamin C, D, thiamine, riboflavin, folic acid, nicotinamide, niacin, pyridoxine, bioflavonoids, and the like, supplements such as amino acids, lipotropics, fish oils, polyunsaturated fatty acids, eicosapentaenoic acid, docosahexanic acid, coenzyme Q10, ubiquinone, minerals such as potassium, and the like.

[0053] If utilized, the protein can include a wide variety of orally acceptable proteins, including milk proteins, peroxide generating enzymes, amylase, papain, glucoamylase, glucose oxidase, and the like.

[0054] In certain embodiments, the aqueous oral care one-part composition (e.g., solution) of the present disclosure may optionally include a thickening agent to provide the composition (e.g., solution) with a suitable viscosity that allows for the desired application method. For example, a sufficient amount of a suitable thickening agent can be used to obtain a composition (e.g., solution) viscosity that is suitable for maintaining the composition (e.g., solution) in an inverted mouthpiece tray applicator for up to 4 minutes (a typical time for a professionally applied fluoride treatment) and yet is sufficiently fluid to have acceptable handling characteristics for a dental practitioner (e.g., when dispensing into a dental tray applicator). Alternatively, a suitable thickening agent can be used in a sufficient amount to obtain a suitable viscosity for application to a tooth surface. Alternatively, a suitable thickening agent can be used in a sufficient amount to obtain a suitable viscosity for application to a tooth surface as a thick gel / gum / strip.

[0055] In certain embodiments, the type and amount of thickener may be selected to provide the oral care composition (e.g., solution) with a viscosity of at least 0.05 Pascal-second at a shear rate of 1.0 / second. In certain embodiments, the type and amount of thickener may be selected to provide the oral care composition (e.g., solution) with a viscosity of up to 0.5 Pascal-second at a shear rate of 1.0 / second. In certain embodiments, the type and amount of thickener may be selected to provide the oral care composition (e.g., solution) with a viscosity of up to 500 Pascal-second or up to 5000 Pascal-second at a shear rate of 1.0 / second.

[0056] In certain embodiments, the thickener may be present in the oral care one-part composition (e.g., solution) in an amount of 0.1% to 10% by weight or 0.1% to 5% by weight. In certain embodiments, the thickener is present in the oral care one-part composition (e.g., solution) in an amount of less than 2.5% by weight, based on the total weight of the aqueous composition (e.g., solution). In certain embodiments, the thickener is present in an amount of at least 0.5% by weight, based on the total weight of the aqueous composition (e.g., solution).

[0057] Suitable thickening agents are typically those that are generally safe for human consumption (FDA approved for internal use), do not bind fluoride ions, and do not significantly affect the bioavailability of fluoride ions.

[0058] In certain embodiments, the thickening agent is selected from natural gums, water soluble cellulose derivatives (such as hydroxyethyl cellulose, carboxymethyl cellulose, and the like), inorganic fillers (e.g., colloidal silica, fumed silica, alumina, titania, and zinc oxide), alkylene oxide polymers (e.g., polyethylene glycol, polypropylene glycol, and copolymers of polyethylene glycol and polypropylene glycol), modified water soluble starches, crosslinker polyacrylic acids, and combinations thereof.

[0059] In certain embodiments, the aqueous oral care composition (e.g., solution) of the present disclosure may include one or more optional additives, including flavoring agents (i.e., flavorings) and sweeteners. Other optional additives include surfactants. Various combinations of such additives can be used, if desired. Other optional additives include preservatives.

[0060] In certain embodiments, the aqueous oral care compositions (e.g., solutions) of the present disclosure may include a surfactant. Typically, such surfactants are anionic surfactants, examples of which include polysorbates, glycerol, polyglycerol-based surfactants, or combinations thereof. When present, the surfactant can be used in any suitable amount, most often an amount sufficient to impart wetting properties. A suitable amount is typically 0.1% to 5.0% by weight based on the total weight of the aqueous composition (e.g., solution).

[0061] In certain embodiments, the aqueous oral care compositions (e.g., solutions) of the present disclosure may include preservatives such as potassium sorbate, CPC, CHG, methylparaben, ethylparaben, propylparaben, any other paraben-based preservatives, and mixtures. Suitable amounts are typically 0.001% to 5.0% by weight based on the total weight of the aqueous composition (e.g., solution).

[0062] In certain embodiments, the aqueous oral care composition (e.g., solution) of the present disclosure is included in a kit. Typically, such a kit includes an applicator (e.g., toothbrush, cotton swab) for the oral care composition (e.g., solution). Such an applicator may be incorporated into a container that contains the oral care composition (e.g., solution).

[0063] In certain embodiments, the oral care compositions (e.g., solutions) are provided in individual sealed unit dose containers. At the time of use, the seal of such individual sealed unit dose container is broken, the composition (e.g., solution) is taken with an applicator, and the composition (e.g., solution) is applied to the tooth surface.

[0064] In certain embodiments, the oral care composition (e.g., solution) is provided in a multi-dose container. During use, a drop of the composition (e.g., solution) can be dispensed onto a tray, piece of plastic, piece of paper, dish, well, pan, etc., the composition (e.g., solution) can be taken up with an applicator, and the composition (e.g., solution) can be applied to the tooth surface.

[0065] In certain embodiments, the kit may further comprise one or more of a dental restorative, tray, dish, well, or pan. Examples of dental restoratives include, but are not limited to, adhesives, primers, cements, liners, sealants, amalgams, resins, resin composites, glass ionomers, resin-modified glass ionomers, glass ceramics, ceramics, metals, plastics, or combinations thereof.

[0066] The aqueous oral care compositions (e.g., solutions) of the present disclosure can be made using any technique known to those of skill in the art. In certain embodiments, the ingredients can be added together and dissolved as described above.

[0067] In certain embodiments, the aqueous oral care composition (e.g., solution) of the present disclosure is used in a method of providing fluoride to a patient's dental surfaces. The method includes applying an aqueous oral care composition (e.g., solution) described herein to a patient's dental surfaces. The aqueous oral care composition may be applied alone, or the aqueous oral care composition may be incorporated into another composition (e.g., toothpaste, mouthrinse, varnish) before being applied.

[0068] The present disclosure also provides methods, such as, for example, providing fluoride and calcium to a patient's dental surfaces and reducing the incidence of dental caries, which involve applying to the patient's dental surfaces an aqueous oral care one-part composition described herein.

[0069] In certain embodiments, applying the aqueous oral care one-part composition (eg, solution) comprises painting the oral care one-part composition (eg, solution) onto the patient's dental surfaces.

[0070] In certain embodiments, applying the aqueous oral care one-part composition (e.g., solution) comprises dispensing the oral care one-part composition (e.g., solution) into a dental tray and attaching the tray containing the oral care one-part composition (e.g., solution) to the patient's dental surfaces. In certain embodiments, the dental tray includes an orthodontic aligner treatment tray.

[0071] In certain embodiments, the aqueous oral care compositions (e.g., solutions) of the present disclosure are used in a method for reducing the incidence of dental caries (e.g., by preventing or arresting dental caries) in a patient in need of treatment, the method comprising applying an aqueous oral care composition (e.g., solution) described herein to the patient's dental surfaces.

[0072] In certain embodiments, the aqueous oral care compositions (e.g., solutions) of the present disclosure are used in a method of reducing dentin hypersensitivity and / or root hypersensitivity (e.g., during caries treatment and / or of exposed tooth roots) in a patient in need of treatment. The method comprises applying an aqueous oral care composition (e.g., solution) described herein to the patient's tooth surfaces.

[0073] In certain embodiments, the aqueous oral care compositions (e.g., solutions) of the present disclosure are used in a method of treating a patient's dental surface, the method comprising applying an aqueous oral care one-part composition (e.g., solution) disclosed herein to a patient's dental surface to form a treated dental surface, and optionally applying a dental restorative to the treated dental surface.

[0074] In certain embodiments, the patient's dental surface treated with the methods described herein includes enamel, dentin, cementum, root, or a combination thereof.

[0075] In certain embodiments of the above methods, the applying comprises applying the oral care composition (e.g., a solution) to the patient's dental surfaces. In certain embodiments of the above methods, the applying comprises dispensing the oral care composition (e.g., a solution) into a dental tray (e.g., an orthodontic aligner treatment tray) and attaching the tray containing the oral care composition (e.g., a solution) to the patient's dental surfaces.

[0076] In certain embodiments of the above methods, the oral care composition (eg, a solution) is applied to the tooth surface and then subsequently dried (eg, using flowing air).

[0077] In certain embodiments of the above methods, the oral care composition (e.g., solution) is applied to the tooth surface and then subsequently wiped with cotton, paper, and any other wiping material to remove excess oral care composition (e.g., solution) from the tooth surface.

[0078] In certain embodiments of the above methods, the method further comprises placing a dental restorative on the surface of the tooth to which the oral care composition has been applied. In certain embodiments of the above methods, the method further comprises combining the oral care composition and the dental restorative to form a dental restorative composition, and then applying the dental restorative composition to the tooth. Examples of dental restorative materials include, but are not limited to, adhesives (such as 3M SCOTCHBOND Universal Adhesive, available from 3M Company, St. Paul, MN, USA), primers, cements (such as 3M RelyX UNICEM 2 AUTOMIX Self-Adhesive Resin Cement, available from 3M Company, St. Paul, MN, USA), liners (such as 3M ESPE VITREBOND Plus Light Cure Glass Ionomer Liner / Base), sealants, amalgams, resins, resin composites (such as 3M FILTEK Z250 Universal Restorative), glass ionomers (such as 3M KETAC Universal APLICAP Glass Ionomer Restorative), resin-modified glass ionomers (such as RelyX Luting Plus RMGI Cement), glass ceramics, ceramics, metals, plastics, or combinations thereof.

[0079] In certain embodiments of the above methods, after drying the oral care composition on the teeth, the method may further comprise coating the dried oral care composition with a moisture permeable polymer layer to allow moisture penetration for treatment of, for example, incipient caries, white spots, and the like. EXAMPLES

[0080] [Table 1]

[0081] Example Preparation Procedure The general procedure for preparing the examples was to combine the ingredients, measured according to the tables and descriptions below, in the following order: First, the calcium compound was dissolved in water, followed by the addition of citric acid (or other chelating agent, e.g., etidronic acid) and mixing the mixture well to form a solution. The fluoride-containing compound was then added and mixed well. In some examples, an alternative but equivalent procedure was used. Aqueous solutions of the calcium compound and citric acid (or alternative chelating agent) were prepared separately and then mixed with a second aqueous solution of the fluoride-containing compound to obtain the desired concentration of the ingredients. The critical order of addition is to first prepare a metastable aqueous solution containing calcium citrate or its hydrate (or a suitable chelating agent) and then add the fluoride-containing compound, typically within 5 minutes. The solutions of the examples were observed for at least 24 hours to ensure that they remained in solution and no precipitate formed. The inventive examples were stable and did not form precipitates. The comparative examples were not stable solutions in that a visible precipitate formed, sometimes immediately after preparation or within at least 24 hours.

[0082] [Table 2] A "YES" indicates that the example was a stable solution and no precipitate was observed. A "NO" indicates that a precipitate was observed and therefore the comparative example was not a stable solution. * CEx.A had a content equivalent to EX-1E. However, CEx.A was a comparative example because the proper order of addition was not followed and the ingredients were all combined at approximately the same time. A precipitate formed because a metastable aqueous solution containing calcium citrate was not first formed prior to the addition of the fluoride-containing compound.

[0083] [Table 3]

[0084] [Table 4]

[0085] [Table 5]

[0086] [Table 6]

[0087] Measurement of free fluoride in the examples Free fluoride in various examples was measured with a Mettler Toledo meter equipped with a Cole Parmer fluoride ion-selective electrode. Prior to measuring the free fluoride content of the examples, the fluoride ion-selective electrode was first calibrated with parts per million (ppm) fluoride standards using TISAB II (Total Ionic Strength Adjustment Buffer II, available from Sigma-Aldrich). The ppm concentration of fluoride in these solutions was measured with the fluoride electrode by mixing the example solutions with 5 ml of TISAB II solution, inserting the electrode into each example solution, and recording the parts per million (ppm) of free fluoride ions in the solution after stabilizing for 2 minutes.

[0088] [Table 7]

[0089] Addition of various levels of phosphate to the stabilized calcium examples Table 7 shows that the addition of various levels of phosphate to Example EX-1F does not result in the formation of precipitates in the presence of stabilizing complexes containing calcium, citrate, and fluoride.

[0090] [Table 8]

[0091] Addition of potassium nitrate (a tooth desensitizing agent) Table 8 shows that the addition of potassium nitrate (KNO3), a desensitizing agent, to various examples (Examples EX-1F, EX-1H, and EX-1I) does not result in the formation of a precipitate in the presence of a stabilizing complex containing calcium, citrate, and fluoride. A quantity of 0.25 grams of KNO3 was added to 5 grams of each of these examples. The nitrate dissolved and the solution remained clear and free of precipitate.

[0092] [Table 9]

[0093] Long-term stability of examples containing stabilized calcium complexes + additives Table 9 shows the long-term stability of several examples including the stabilized calcium complex of Example EX-1A in combination with various additional ingredients useful in dental compositions. In all examples, no precipitation was observed even after several months (mo.) at room temperature (RT).

[0094] [Table 10]

[0095] Toothpaste Example Table 10 shows exemplary toothpaste composition Examples EX-1F-TP and EX-1J-TP prepared using stabilized calcium, citrate, fluoride complex Examples EX-1F and EX-1J as stock solutions.

[0096] [Table 11]

[0097] Mouthwash Example Table 11 shows an exemplary mouthwash formulation EX-1F-MW prepared using the stabilized calcium, citrate, fluoride complex Example EX-1F as a stock solution.

[0098] [Table 12]

[0099] Stock solutions for dental compositions Table 12 shows exemplary stock solutions for subsequent dental compositions prepared using Examples EX-1A, EX-1B, and EX-1M as stock solutions.

[0100] [Table 13]

[0101] "Paste B" preparation for resin-modified glass ionomer (RMGI) dental compositions Resin-modified glass ionomer (RMGI) cements are two-parts that set (harden) when combined. The following RMGI examples were prepared as paste-paste (Paste "A" and Paste "B") two-part reaction systems. The calcium-stabilized complex examples (EX-1A, EX-1B, and EX-1M) above were used in the stock solutions set forth in Table 12. The stock solutions set forth in Table 12 were then used in the preparation of the Paste "B" examples shown in Table 13 below.

[0102] [Table 14]

[0103] Preparation of resin-modified glass ionomer (RMGI) cement To prepare RMGI using the prepared Paste "B" examples shown in Table 13, a suitable Paste "A" was required to react with Paste "B". The Paste "A" source was obtained by taking / using only the white paste (base paste) from one of the two syringe barrels in the commercial product RelyX™ Luting Plus Automix Resin-Modified Glass Ionomer Cement from 3M. Alternatively, the white paste "A" (base paste) can also be obtained from the commercial 3M product RelyX™ Luting Plus Cement Clicker™ Dispenser Refill. Paste "A" and Paste "B" were hand mixed on a mixing pad for 20 seconds in a 5:4 part ratio (A:B) respectively using a dental spatula. The mixed examples were then placed in a 37°C oven to cure and harden (set). The mixture was tapped with a spatula to ensure it was set, and the time was recorded.

[0104] The set times of these RMGI examples were compared to a control sample prepared in the same manner, except that it used commercially available RelyX™ Luting Plus Automix Resin-Modified Glass Ionomer Cement, which already came in a double-barrel syringe system containing Paste "A" and Paste "B." Table 14 shows the set times (min:sec) for resin-modified glass ionomer Examples EX-RMGI-1, EX-RMGI-2, and EX-RMGI-3, which contained Examples EX-1A, EX-1B, and EX-1M, respectively, as raw materials.

[0105] [Table 15]

[0106] Long-term stability study of resin-modified glass ionomer (RMGI) cement A commercially available 3M product RelyX™ Luting Plus Cement Clicker™ dispenser was used to provide a product simulant storage container for an experiment evaluating the long-term stability at high temperatures of RMGI cement examples made using Examples EX-1A, EX-1B, and EX-1M. A yellow catalyst material (commercially available paste "B") was removed from each syringe cylinder of the RelyX™ Luting Plus Cement Clicker™ dispenser product. The emptied syringe cylinders were then filled with Examples EX-Paste-B1, EX-Paste-B2, and EX-Paste-B3. In each dispenser, the original commercially available paste "A" was left in the adjacent syringe cylinder. These simulant products containing Examples EX-Paste-B1, EX-Paste-B2, and EX-Paste-B3 were stored in a temperature-controlled oven at 45° C. for several weeks. Table 15 shows the set times (min:sec) for experimental resin-modified glass ionomer Examples EX-RMGI-1, EX-RMGI-2, and EX-RMGI-3 (prepared using EX-1A, EX-1B, and EX-1M, respectively) after extended storage in the product container at 45° C. for 4 weeks, 6 weeks, and 10 weeks.

[0107] [Table 16]

[0108] Examples Including Hardenable Monomers and Copolymers for Dental Compositions Example EX-5A Example EX-5A was prepared in the following manner: A 0.5 gram quantity of Example EX-1B (1.5:1 molar ratio of citrate:calcium and 2:1 molar ratio of fluoride:calcium) shown in Table 2 was mixed with 0.5 g of 10% VBCP aqueous solution. A 1.5 g quantity of HEMA was added to the mixture. The HEMA was initiated with 0.22% CPQ, 1.0% EDMAB, 0.3% DPIHFP, and 0.1% 9,10-EDMOA. Then, a 0.5 g quantity of CDMA / GDMA oligomer blend was added to the mixture. The CDMA / GDMA oligomer blend was initiated with 0.22% CPQ, 1.0% EDMAB, 0.3% DPIHFP, and 0.1% 9,10-EDMOA. Finally, a 0.1 g quantity of SR454 was added to the mixture. SR454 was started with CPQ 0.22%, EDMAB 1.0%, DPIHFP 0.3%, and 9,10-EDMOA 0.1%. This mixture formed a clear solution that appeared stable and free of precipitation.

[0109] Additional comparative examples: CEx.G~CEx.K Comparative example CEx.G A 0.1 M aqueous solution of calcium nitrate was mixed with another 0.2 M aqueous solution of ammonium fluoride. When these two solutions were mixed, an insoluble calcium fluoride salt precipitate was formed (no chelating agent (e.g., citrate) was present).

[0110] Comparative example CEx.H A 0.32 gram quantity of calcium succinate was added to 9.68 g of DI water (3.2% w / w). At this concentration, calcium succinate was found to be only slightly soluble. A 10 gram quantity of 0.4 M NaF solution was added to the calcium succinate mixture. The new mixture did not form a clear solution (did not dissolve completely). Instead, a cloudy slurry (precipitate) was formed (there was no suitable chelating agent (e.g., citrate) present).

[0111] Comparative example CEx.I A 0.31 g quantity of calcium fumarate was added to 9.72 g of DI water (3.1% w / w). At this concentration, calcium fumarate was found to be only slightly soluble. A 10 gram quantity of 0.4 M NaF solution was added to the calcium fumarate mixture. The new mixture did not form a clear solution (did not dissolve completely). Instead, a cloudy slurry (precipitate) formed (there was no suitable chelating agent (e.g., citrate) present).

[0112] Comparative example CEx.J A solution of Ca(OH)2 and citric acid was prepared with a molar ratio of 0.1 mole hydroxide to 0.15 mole citrate. A clear solution was formed initially. However, after waiting a few minutes (about 30 minutes), a precipitate formed, presumably calcium citrate or its hydrate. Thus, the mixture was not able to effectively react with the fluoride salt at this point. This is a comparative example because the proper addition order was not followed in that the fluoride-containing compound was not added within 5 minutes of the formation of the metastable aqueous solution containing calcium citrate (i.e., before calcium citrate or its hydrate precipitated).

[0113] Comparative example CEx.K: A quantity of 2.282 grams of calcium citrate tetrahydrate was stirred in 18.20 grams of DI water (11.1% w / w). Calcium citrate tetrahydrate was essentially insoluble at this concentration. A quantity of 20.07 grams of 0.4 M ammonium fluoride solution was added to the calcium citrate tetrahydrate mixture. No visible change in the mixture was observed and calcium citrate tetrahydrate remained undissolved and did not go into solution.

Claims

1. Aqueous oral care composition, calcium, Fluorides, and Citrate, A complex containing, and Contains water, The aqueous oral care composition contains at least 2 moles of citrate for every 3 moles of calcium, The aqueous oral care composition contains at least 1 mole of fluoride for every 1 mole of calcium, Water is present in an amount of at least 50% by weight based on the total weight of the aqueous oral care composition. The aqueous oral care composition is an aqueous oral care composition that does not contain precipitate.

2. The aqueous oral care composition according to claim 1, characterized in that the pH is 2 to 11.

3. The aqueous oral care composition according to claim 1, further comprising one or more of free fluoride, calcium citrate complex, and calcium fluoride nanoparticles.

4. The aqueous oral care composition according to claim 1, wherein calcium is present in an amount of at least 20 ppm based on the total weight of the aqueous oral care composition.

5. The aqueous oral care composition according to claim 1, wherein fluoride is present in an amount of at least 20 ppm based on the total weight of the aqueous oral care composition.

6. The aqueous oral care composition according to claim 1, further comprising free fluoride present in an amount of at least 50 ppm based on the total weight of the aqueous oral care composition.

7. The aqueous oral care composition according to claim 1, further comprising a water-soluble phosphate.

8. A method for preparing an aqueous oral care composition according to any one of claims 1 to 7, Reacting a calcium source with a citrate source in an aqueous solution to form a metastable aqueous solution containing calcium citrate or its hydrate, and A method comprising adding a water-soluble fluoride salt solution to the metastable aqueous solution before the calcium citrate or its hydrate precipitates.

9. The calcium source includes calcium hydroxide, calcium acetate, calcium carbonate, or calcium bicarbonate. The citrate source contains citric acid, and The aforementioned water-soluble fluoride salt solution contains sodium fluoride, potassium fluoride, silver fluoride diamine, or ammonium fluoride. The method according to claim 8, characterized by one or more of the following.

10. The calcium source is present in the metastable aqueous solution in an amount of at least 5 ppm based on the total weight of the metastable aqueous solution, and The water-soluble fluoride salt solution further contains a water-soluble fluoride salt present in an amount of at least 20 ppm based on the total weight of the water-soluble fluoride salt solution. The method according to claim 8, characterized by one or more of the following.

11. An aqueous oral care composition according to any one of claims 1 to 7, for use in the manufacture of a drug for supplying fluoride to the surface of a patient's teeth.

12. A toothpaste composition, A toothpaste composition comprising the aqueous oral care composition according to any one of claims 1 to 7.