Oral care compositions and methods

Abstract

Disclosed herein are oral care compositions comprising docosahexaenoic acid (DHA) and at least one of (i) a stannous ion source, such as stannous fluoride, or (ii) tetradecyl aminobutyroylvalylaminobutyric urea trifluoroacetate, optionally further comprising arginine or a salt thereof, and methods of using the oral care compositions to treat inflammation in the oral cavity.

Description

ORAL CARE COMPOSITIONS AND METHODSCROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of priority from U.S. Provisional Patent Application No. 63 / 670,369, filed 12 July 2024, the contents of which are hereby incorporated herein by reference in their entirety.BACKGROUND

[0002] Dental plaque is a soft deposit that forms on teeth and comprises an accumulation of bacteria and bacterial by-products. Besides being unsightly, plaque is implicated in the occurrence of gingivitis and other forms of periodontal disease. Pathogenic bacteria, including bacteria found in plaque, produce a virulent endotoxin, lipopolysaccharide (LPS), that causes the chronic inflammation of the gum line which can progress to affect the bone that surrounds and supports teeth.

[0003] Macrophages are tissue resident cells of the innate immune system and play an important role in regulating inflammation within the gingival tissues. Monocytes from circulation are recruited to tissue and become macrophages within the tissue. Macrophage polarization refers to the process by which macrophages produce distinct functional phenotypes as a reaction to their environment. The macrophages can be polarized to develop a pro-inflammatory (Ml) phenotype or an anti-inflammatory (M2) phenotype. The M2 phenotype not only resolves inflammation, but can also advantageously promote tissue regeneration and repair.

[0004] It would therefore be beneficial to include bio-active compounds in an oral care composition that influence macrophage polarization and thereby treat inflammatory conditions in the oral cavity through macrophage-mediated inflammation suppression.BRIEF SUMMARY

[0005] This summary is intended merely to introduce a simplified summary of some embodiments of one or more implementations of the present disclosure. Further areas of applicability of the present disclosure will become apparent from the detailed description provided hereinafter. This summary is not an extensive overview, nor is it intended to identify all elements of the present teachings, nor to delineate the scope of the disclosure. Rather, its purpose is merely to present one or more concepts in simplified form as a prelude to the detailed description below.

[0006] In certain embodiments, there is provided an oral care composition, which comprises: docosahexaenoic acid (DHA); and at least one of (i) a stannous ion source or (ii) tctradccyl aminobutyroylvalylaminobutyric urea trifluoroacetate.

[0007] DHA may be present in the oral care composition in an amount ranging from, for example, about 0.005 wt% to about 10 wt%, such as from about 0.01 wt% to about 5 wt%, or such as from about 0.1 wt% to about 3 wt%, based on the total weight of the oral care composition.

[0008] In certain embodiments, the oral care composition comprises DHA and (i) a stannous ion source. The stannous ion source may be present in the oral care composition in an amount ranging from, for example, about 0.0001 wt% to about 10 wt%, such as from about 0.005 wt% to about 2.5 wt%, or such as from about 0.01 wt% to about 1 wt%, based on the total weight of the oral care composition.

[0009] In certain embodiments, the stannous ion source is selected from the group consisting of stannous fluoride, stannous chloride, stannous acetate, stannous tartrate, stannous oxalate, sodium stannous citrate, stannous gluconate, stannous phosphate, stannous pyrophosphate, stannous sulfate, and combinations thereof. In some embodiments, the stannous ion source is stannous fluoride.

[0010] In certain embodiments, the oral care composition comprises DHA and (ii) tetradecyl aminobutyroylvalylaminobutyric urea trifluoroacetate. The tetradecyl aminobutyroylvalylaminobutyric urea trifluoroacetate may be present in the oral care composition in an amount ranging from, for example, about 0.001 wt% to about 5 wt%, such as from about 0.01 wt% to about 2 wt%, or such as from about 0.05 wt% to about 1 wt%, based on the total weight of the oral care composition.

[0011] In additional embodiments, the oral care composition comprises DHA and both (i) a stannous ion source, such as stannous fluoride, and (ii) tetradecyl aminobutyroylvalylaminobutyric urea trifluoroacetate. The oral care composition of the disclosure may also further comprise, for example, one or more fluoride ion sources other than, or in addition to, any stannous fluoride present, such as sodium fluoride. The oral care composition of the disclosure may also further comprise one or more metal ion sources other than, or in addition to, any stannous ion source present, such as a zinc ion source.

[0012] In certain embodiments, the oral care composition further comprises arginine or a salt thereof, such as L-arginine or a salt thereof. The composition may comprise free arginine, or asalt of arginine selected from the group consisting of arginine hydrochloride, arginine carbonate, arginine bicarbonate, arginine phosphate, arginine hydroxide, and combinations thereof. In some embodiments, the arginine or salt thereof is present in the oral care composition in an amount ranging from about 0.5 wt% to about 3 wt%, such as from about 1 wt% to about 2 wt%, or such as from about 1.3 wt% to about 1.7 wt%, based on the total weight of the oral care composition.

[0013] In further embodiments, the oral care composition of the disclosure is in the form of a mouthwash, a mouth rinse, a toothpaste or a solid film. In certain embodiments, the oral care compositions is in the form of a solid film that is dissolvable or disintegrable.

[0014] In certain embodiments, there is provided a method of treating oral inflammation in a subject in need thereof, which comprises applying the oral care composition of the disclosure to the site of inflammation in the oral cavity of the subject. The site of inflammation may be on the gum, lip or cheek of the subject, for example.

[0015] In some embodiments of the method of the disclosure, the subject suffers from periodontitis, gingivitis, implantitis or mucositis. The method may comprise, for example, applying the oral care composition to the site of inflammation in the oral cavity of the subject for about 5 seconds to about 30 minutes, such as for about 10 seconds to about 20 minutes, or such as for about 30 seconds to about 2 minutes. The method may also comprise, for example, applying the oral care composition to the site of inflammation in the oral cavity of the subject at least once a day, such as at least twice a day, or such as at least three times a day.

[0016] In certain embodiments, the method of the disclosure increases expression of one or more of ARG1, GPR18 or GPR32 in a tissue of the oral cavity of the subject. For example, the method may increase expression of one or more of ARG1, GPR18 or GPR32 in a tissue of the oral cavity of the subject compared to applying a corresponding oral care composition that comprises DHA but does not comprise (i) a stannous ion source and does not comprise (ii) tetradecyl aminobutyroylvalylaminobutyric urea trifluoroacetate. The method may comprise, for example, increasing the expression of one or more of ARG1, GPR18 or GPR32 in a tissue of the oral cavity of the subject, such as the gum, by at least 10%, such as by at least 25%, such as by at least 50%, or such as by at least 100%.

[0017] A further embodiment provides a method of treating oral inflammation in a subject in need thereof, which comprises sequentially applying to the site of inflammation in the oral cavity of the subject an oral care composition comprising DHA and another oral care composition comprisingat least one of (i) a stannous ion source, such as stannous fluoride or (ii) tetradecyl aminobutyroylvalylaminobutyric urea trifluoro acetate. In certain embodiments, at least one of the compositions further comprises arginine or a salt thereof.BRIEF DESCRIPTION OF THE DRAWINGS

[0018] The features and advantages of the disclosure will be apparent from the following more detailed description of certain embodiments and as illustrated in the accompanying Figures in which:

[0019] FIG. 1A is a bar graph illustrating the effect of stannous fluoride and DHA oil, individually, on the CD 163 surface marker for pro-resolution macrophages compared to a control.

[0020] FIG. IB is a bar graph illustrating the effect of stannous fluoride and DHA oil, individually, on the CD40 surface marker for pro-inflammatory macrophages compared to a control.

[0021] FIG. 1C is a bar graph illustrating the effect of stannous fluoride and DHA oil, combined, on the CD 163 surface marker for pro-resolution macrophages compared to a control.

[0022] FIG. ID is a bar graph illustrating the effect of stannous fluoride and DHA oil, combined, on the CD40 surface marker for pro-inflammatory macrophages compared to a control.

[0023] FIG. 2A is a bar graph illustrating the effects of DHA oil, and DHA oil in combination with other components, on the gene expression of ARG1.

[0024] FIG. 2B is a bar graph illustrating the effects of DHA oil, and DHA oil in combination with other components, on the gene expression of GPRI 8.

[0025] FIG. 2C is a bar graph illustrating the effects of DHA oil, and DHA oil in combination with other components, on the gene expression of GPR32.

[0026] It should be understood that the disclosure is not limited to the particular compositions and results shown in the Figures.DETAILED DESCRIPTION

[0027] For illustrative purposes, the principles of the present disclosure are described by referencing various exemplary embodiments thereof. Although certain embodiments of the disclosure are specifically described herein, one of ordinary skill in the art will readily recognize that the same principles are equally applicable to, and can be employed in, other compositions and methods. Before explaining various embodiments of the present disclosure in detail, it is to be understood that the disclosure is not limited in its application to the details of any particularembodiments disclosed herein. The terminology used herein is for the purpose of description and not of limitation.

[0028] As used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural references unless the context dictates otherwise. The singular form of any class of the ingredients refers not only to one chemical species within that class, but also to a mixture of those chemical species. The terms “a” (or “an”), “one or more” and “at least one” may be used interchangeably herein. The terms “comprising”, “including”, and “having” may be used interchangeably. The term “include” should be interpreted as “include, but are not limited to”. The term “including” should be interpreted as “including, but are not limited to”.

[0029] As used throughout, ranges are used as shorthand for describing each and every value that is within the range. It should be appreciated and understood that the description in a range format is merely for convenience and brevity, and should not be construed as an inflexible limitation on the scope of any embodiments or implementations disclosed herein. Accordingly, the disclosed range should be construed to have specifically disclosed all the possible subranges as well as individual numerical values within that range. Any value within the range can be selected as the terminus of the range. Thus, a range from 1-5, includes specifically 1, 2, 3, 4 and 5, as well as subranges such as 2-5, 3-5, 2-3, 2-4, 1-4, etc.

[0030] The term “about” when referring to a number means any number within a range of 10% of the number. For example, the phrase “about 2 wt%” refers to a number between and including 1.8 wt% and 2.2 wt%.

[0031] The abbreviations and symbols as used herein, unless indicated otherwise, take their ordinary meaning. The abbreviation “wt%” means percent by weight with respect to the oral care composition. The symbol “°” refers to a degree, such as a temperature degree or a degree of an angle. The symbols “hr”, “min”, “mL”, “pL”, “nM”, “pM”, “mM”, “pg”, and “ng” refer to hour, minute, milliliter, microliter, nano mole, micro mole, milli mole, micro gram and nano gram, respectively.

[0032] Any member in a list of species that are used to exemplify or define a genus may be mutually different from, or overlapping with, or a subset of, or equivalent to, or nearly the same as, or identical to, any other member of the list of species. Further, unless explicitly stated, such as when reciting a Markush group, the list of species that define or exemplify the genus is open,and it is given that other species may exist that define or exemplify the genus just as well as, or better than, any other species listed.

[0033] The phrases, “a mixture thereof,” “a combination thereof,” or a combination of two or more thereof’ do not require that the mixture include all of A, B, C, D, E, and F (although all of A, B,C, D, E, and F may be included). Rather, it indicates that a mixture of any two or more of A, B, C,D, E, and F can be included. In other words, it is equivalent to the phrase “one or more elements selected from the group consisting of A, B, C, D, E, F, and a mixture of any two or more of A, B, C, D, E, and F.” Likewise, the term “a salt thereof” also relates to “salts thereof.” Thus, where the disclosure refers to “an element selected from the group consisting of A, B, C, D, E, F, a salt thereof, and a mixture thereof,” it indicates that that one or more of A, B, C, D, E and F may be included, one or more of a salt of A, a salt of B, a salt of C, a salt of D, a salt of E, and a salt of F may be included, or a mixture of any two of A, B, C, D, E, F, a salt of A, a salt of B, a salt of C, a salt of D, a salt of E, and a salt of F may be included.

[0034] All components and elements positively set forth in this disclosure can be negatively excluded from the claims. In other words, the oral care compositions of the instant disclosure can be free or essentially free of all components and elements positively recited throughout the instant disclosure. In some instances, the oral care compositions of the present disclosure may be substantially free of non-incidental amounts of the ingredient(s) or compound(s) described herein. A non-incidental amount of an ingredient or compound is the amount of that ingredient or compound that is added into the oral care composition by itself. For example, an oral care composition may be substantially free of a non-incidental amount of an ingredient or compound, although such ingredient(s) or compound(s) may be present as part of a raw material that is included as a blend of two or more compounds.

[0035] Some of the various categories of components identified may overlap. In such cases where overlap may exist and the oral care composition includes both components (or the composition includes more than two components that overlap), an overlapping compound does not represent more than one component. For example, certain compounds may be characterized as both a humectant and a sweetener. If a particular oral care composition includes both a humectant and a sweetener (e.g., xylitol), the compound will serve only as either a humectant or a sweetener — not both.

[0036] Embodiments of the disclosure include an oral care composition, which comprises:docosahexaenoic acid (DHA); and at least one of (i) a stannous ion source or (ii) tctradccyl aminobutyroylvalylaminobutyric urea trifluoroacetate.

[0037] As used herein, the term “oral care composition” means a composition that is delivered to the oral surfaces. In certain embodiments, the oral care composition is further defined as a product which, during the normal course of usage, is not for the purposes of systemic administration of particular therapeutic agents, and not intentionally swallowed but rather is retained in the oral cavity for a time sufficient to contact oral tissues.

[0038] Various biomarkers have been implicated in the inflammatory pathways associated with oral tissues. Three genes that may be upregulated in inflamed tissues in the oral cavity and that are known to have a pro-resolution effect on inflammation include arginase 1 (ARG1), G protein- coupled receptor 18 (GPR18), and G protein-coupled receptor 32 (GPR32). ARG1 may be identified by NCBI Ref. Seq. NM_000045 or Ensembl Protein ID ENSG00000118520. The structures of human arginase 1 cDNA and its encoded protein have been extensively studied. See Iyer et al., “Mouse Model for Human Arginase Deficiency,” Molecular and Cellular Biology, vol. 22, pp. 4491-4498 (2002). GPR18 may be identified by NCBI Ref. Seq. NM_001098200.2 or Ensembl Protein ID ENSG00000125245. The structure of GPR18 and its role in the resolution stage of the inflammatory response is documented, for example, in Honkisz-Orzechowska et al., “Uncovering the Power of GPR18 Signalling: How RvD2 and Other Ligands Could Have the Potential to Modulate and Resolve Inflammation in Various Health Disorders,” Molecules, vol. 29, pp. 1258, 27 pages (2024). GPR32 may be identified by NCBI Ref. Seq. NM_001506.2 or Ensembl Protein ID ENSG00000142511. Like GPR18, GPR32 is a G protein-coupled receptor known for its pro-inflammatory resolution response. See, e.g., Serhan, C. N. et al., “Lipid Mediators in the Resolution of Inflammation,” Cold Spring Harbor Perspectives in Biology, pp. 1-21 (2015).

[0039] As shown in FIG. 2A, FIG. 2B and FIG. 2C, DHA oil combined with either stannous fluoride or tetradecyl aminobutyroylvalylaminobutyric urea trifluoro acetate (e.g., Syn®-Hycan) surprisingly induces the gene expression of ARG1, GPR18 and GPR32, compared to a control and compared to DHA oil alone. The results illustrate an unexpected synergistic effect of compositions of the disclosure on macrophages. More particularly, stannous ion sources, such as stannous fluoride, and DHA are potent macrophage gene regulators that, in combination, unexpectedlysynergi stically upregulate the pro-resolution arginine metabolism gene ARG1 and genes of omega- 3 fatty acid metabolite receptors (GPR18, GPR32). These genes arc associated with the M2 macrophage phenotype that promotes inflammation resolution. Tetradecyl aminobutyroylvalylaminobutyric urea trifluoro acetate and DHA in combination also unexpectedly synergistically upregulate pro-resolution arginine metabolism (ARG1) and genes of omega-3 fatty acid metabolite receptors (GPR18, GPR32). Without being bound to any particular theory, expression of these receptors indicates that a stannous ion source, such as stannous fluoride, and tetradecyl aminobutyroylvalylaminobutyric urea trifluoroacetate unexpectedly potentiate the proresolving effect of DHA.

[0040] Oral care compositions of the disclosure that comprise DHA in combination with either (i) a stannous ion source, such as stannous fluoride, (ii) tetradecyl aminobutyroylvalylaminobutyric urea trifluoroacetate (e.g., Syn®-Hycan), or both, can therefore influence macrophage polarization and treat inflammatory conditions in the oral cavity through macrophage-mediated inflammation suppression.

[0041] Docosahexaenoic acid, frequently referred to herein as “DHA,” is an omega-3 fatty acid. DHA can be found naturally in marine sources including cold-water, fatty fish, such as tuna and salmon and also in seaweed. DHA is also a frequent component of fish oil supplements. Apart from natural sources, DHA can be synthesized from alpha-linolenic acid. Oils comprising DHA are commercially available.

[0042] Stannous ion sources include, for example, stannous fluoride, stannous chloride, stannous acetate, stannous tartrate, stannous oxalate, sodium stannous citrate, stannous gluconate, stannous phosphate, stannous pyrophosphate, stannous sulfate, and combinations thereof. Stannous fluoride is a chemical compound of formula SnFo. Stannous fluoride can be synthesized, for example, by reacting mossy tin and anhydrous HF, or dissolving stannous oxide in aqueous HF. Stannous fluoride of at least 99% purity is also commercially available. Tetradecyl aminobutyroylvalylaminobutyric urea trifluoroacetate is a synthetic tripeptide, commercially available as Syn®-Hycan.

[0043] In some embodiments of the disclosure, the oral care composition comprises DHA and (i) a stannous ion source. Further embodiments comprise DHA and (ii) tetradecyl aminobutyroylvalylaminobutyric urea trifluoroacetate. Additional embodiments comprise DHAand both (i) a stannous ion source and (ii) tetradecyl aminobutyroylvalylaminobutyric urea trifluoroacctatc.

[0044] The oral care composition of the disclosure can comprise DHA, a stannous ion source and tetradecyl aminobutyroylvalylaminobutyric urea trifluoroacetate components in any appropriate amounts. For example, the oral care composition may comprise DHA in an amount ranging from about 0.005 wt% to about 10 wt%, such as from about 0.01 wt% to about 5 wt%, or such as from about 0.1 wt% to about 3 wt%, based on the total weight of the oral care composition. The oral care composition may comprise a stannous ion source in an amount ranging from about 0.0001 wt% to about 10 wt%, such as from about 0.005 wt% to about 2.5 wt%, or such as from about 0.01 wt% to about 1 wt%, based on the total weight of the oral care composition, or from about 5 pM to about 500 pM, such as from about 10 pM to about 200 pM. The oral care composition may comprise tetradecyl aminobutyroylvalylaminobutyric urea trifluoroacetate in an amount ranging from about 0.001 wt% to about 5 wt%, such as from about 0.01 wt% to about 2 wt%, such as from about 0.05 wt% to about 1 wt%, such as from about 0.05 wt% to about 0.2 wt%, based on the total weight of the oral care composition.

[0045] The oral care compositions of the disclosure may further comprise arginine or a salt thereof, such as L-arginine or a salt thereof. For instance, the oral care compositions may comprise free arginine, or a salt of arginine, such as a salt selected from the group consisting of arginine hydrochloride, arginine carbonate, arginine bicarbonate, arginine phosphate, arginine hydroxide, and combinations thereof. The arginine or salt thereof may be present in the oral care composition in an amount ranging from, for example, about 0.5 wt% to about 3 wt%, such as from about 1 wt% to about 2 wt%, or such as from about 1.3 wt% to about 1.7 wt%, based on the total weight of the oral care composition.

[0046] As discussed herein and illustrated in the Examples, the combination of DHA and a stannous ion source has been shown to synergistically increase ARGi expression, an enzyme in the arginine metabolism pathway that is associated with anti-inflammatory and tissue repair processes. Without being bound by any theory, by adding arginine or a salt thereof, the availability of substrate for ARGI is increased, further enhancing the production of anti-inflammatory metabolites such as ornithine and poly amines. These metabolites support tissue repair and resolution of inflammation. Additionally, increased ARGI activity can reduce the availability of arginine for nitric oxide synthase, thereby decreasing the production of pro-inflammatory nitricoxide. This shift in arginine metabolism promotes a more pronounced anti-inflammatory environment. Therefore, the combination of DHA, arginine or a salt thereof, and at least one of (i) a stannous ion source or (ii) tetradecyl aminobutyroylvalylaminobutyric urea trifluoroacetate, is believed to synergistically enhance the resolution of inflammation by modulating macrophage phenotypes and optimizing arginine metabolism towards anti-inflammatory and tissue repair pathways.

[0047] The oral care composition of the disclosure may be in any appropriate form. Exemplary forms of the composition include, but are not limited to, a toothpaste or a dentifrice, a mouthwash or a mouth rinse, lozenge, mint, cream, patch, strip or gum (e.g., chewing gum) a topical oral gel, a denture cleanser, sprays, and the like. In some embodiments, the oral care composition is in the form of a mouthwash, a mouth rinse, a toothpaste or a solid film. In some embodiments, the oral care composition is not in solid form; for example, in some embodiments the oral care composition is not in the form of a pill, tablet, capsule or powder. In some embodiments, the oral care composition is not intended for swallowing, e.g., as a supplement or other nutritional composition.

[0048] As used herein, the term “dentifrice” means paste, gel, or liquid formulations, unless otherwise specified. In some embodiments, a dentifrice composition can be a combination of pastes, gels, or paste and gel. The dentifrice composition can be in any desired form such as deep striped, surface striped, multi-layered, having the gel surrounding the paste, or any combination thereof. Alternatively, the oral care composition may be dual phase and dispensed from separated compartment dispenser(s). In certain embodiments, the oral care composition is a mouthwash or a mouth rinse.

[0049] In some embodiments, the oral care compositions further comprise additional ingredients as known in the art and as disclosed below. These additional ingredients may include, but are not limited to, one or more other fluoride ion sources in addition to any stannous fluoride present, one or more other metal ion sources in addition to any stannous ion sources present, humectants, emulsifiers, flavoring agents, sweeteners, anti-calculus agents, abrasives, surfactants, surfactants, anti-bacterial agents, thickening agents, whitening agents, colorants, pH adjusters, clean feel agents, foam modulators, viscosity modifiers, anti-sensitivity agents, antioxidants, calcium phosphates, water, and combinations thereof. Such ingredients would be known to those skilled in the art of oral care. However, non-limiting examples of these ingredients are provided herein. Suitable components, such as those listed herein, may be included or excluded from theformulations for the oral care compositions depending on the specific combination of other ingredients and the form of the oral care compositions. Additionally or alternatively, the oral care compositions may in some embodiments have a single phase, which contains the components and / or ingredients of the oral care composition. In other embodiments, the oral care composition may include two or more phases, such as two, three, four, or five phases. In other embodiments, the oral care composition of the disclosure does not comprise one or more of the recited additional ingredients.

[0050] The ingredients for use in the compositions described herein should be orally acceptable. As used herein, “orally acceptable” may refer to any ingredient that is present in a composition as described in an amount and form which does not render the composition unsafe for use in the oral cavity.

[0051] In some embodiments, in addition to any stannous fluoride present, the oral care compositions further comprise one or more other fluoride ion sources. The other fluoride ion source may be useful, for example, as an anti-caries agent. The other fluoride ion sources may be selected from any fluoride ion source known in the art, including, for example, sodium fluoride, potassium fluoride, sodium fluorosilicate, ammonium fluorosilicate, potassium monofluorophosphate, sodium monofluorophosphate, ammonium monofluorophosphate, indium fluoride, amine fluoride such as N'-octadecyltrimethylendiamine-N,N,N'-tris(2-ethanol)- dihydrofluoride (i.e., olafhir) or N-octadeca-9-enylamine hydrofluoride (i.e., dectaflur), ammonium fluoride, titanium fluoride, hexafluorosulfate, and combinations thereof.

[0052] The one or more other fluoride ion sources may be present in an amount providing a clinically efficacious amount of total soluble fluoride ion to the oral care composition. In some embodiments, the one or more other fluoride ion sources may be present in the oral care composition in an amount ranging from about 0.005 wt% to about 5 wt%, based on the total weight of the oral care composition. In certain embodiments, the total fluoride content of the oral care composition, including that contributed by any stannous fluoride present, ranges from about 25 ppm to about 25,000 ppm.

[0053] In some embodiments, in addition to any stannous ions present, the oral care compositions further comprise one or more other metal ion sources, such as a zinc ion source or a copper ion source. For example, in certain embodiments, the oral care composition comprises a zinc ionsource selected from zinc oxide, zinc citrate, zinc lactate, zinc phosphate, and combinations thereof.

[0054] In some embodiments, the oral care compositions further comprise one or more humectants. A humectant keeps oral care compositions from hardening upon exposure to air by reducing evaporation and / or contributing to preservation by lowering water activity. Certain humectants can also impart desirable sweetness or flavor to oral care compositions. In certain exemplary embodiments, the one or more humectants are selected from glycerin, sorbitol, xylitol, propylene glycol, as well as other polyols and combinations thereof. The one or more humectants may be present in the oral care composition in a combined total amount of, for example, from about 10 wt% to about 40 wt%, based on the total weight of the oral care composition.

[0055] In some embodiments, the oral care compositions further comprise one or more emulsifiers. Any emulsifier known in the art for oral care use may be incorporated, including for example, polyglyceryl-4 caprate, polyethylene glycol (PEG), PEG-40 hydrogenated castor oil, alkyl polyglucosides, polysorbates, and combinations thereof. In certain embodiments, the emulsifier may be chosen from poloxamers (e.g., PLURONICS®) and other non-ionic emulsifiers. In certain embodiments, the emulsifier is polyglyceryl-4 caprate (TEGOSOFT® PC). The one or more emulsifiers may be present in the oral care composition in a combined total amount of, for example, from about 0.01 wt% to about 2 wt%, based on the total weight of the oral care composition.

[0056] In some embodiments, the oral care compositions further comprise one or more flavoring agents. Suitable flavoring agents include essential oils and various flavoring aldehydes, esters, alcohols, and similar materials. Examples of the essential oils include oils of spearmint, peppermint, wintergreen, sassafras, clove, sage, eucalyptus, marjoram, cinnamon, lemon, lime, grapefruit, and orange. Also useful are such chemicals as menthol, carvone, and anethole. Additional flavoring agents may include, but are not limited to menthol, artificial vanilla, cinnamon derivatives, and various fruit flavors, spearmint oil, peppermint oil, cinnamon oil, oil of wintergreen (methylsalicylate), clove oil, bay oil, anise oil, eucalyptus oil, thyme oil, cedar leaf oil, oil of nutmeg, oil of sage, oil of bitter almonds, cassia oil, and a combination of two or more thereof. The one or more flavoring agents may be present in the oral care composition in a combined total amount of, for example, from about 0.01 wt% to about 5 wt%, based on the total weight of the oral care composition.

[0057] In some embodiments, the oral care compositions further comprise one or more sweeteners useful, for example, to enhance taste of the composition. Sweeteners may include, but arc not limited to, sucralose, maltodextrin, dextrose, polydextrose, sucrose, maltose, dextrin, dried invert sugar, mannose, xylose, ribose, fructose, levulose, galactose, sugar alcohols, such as sorbitol, mannitol, xylitol, maltitol, and isomalt, aspartame, neotame, saccharin and salts thereof (e.g., sodium saccharin), gum arabic, dipeptide-based intense sweeteners, cyclamates, dihydrochalcones, or the like, or combinations thereof. The one or more sweeteners may be present in the oral care composition in a combined total amount of, for example, from about 0.1 wt% to about 5 wt%, based on the total weight of the oral care composition.

[0058] In some embodiments, the oral care compositions further comprise one or more anticalculus agents. Illustrative anticalculus agents include, but are not limited to, phosphates and polyphosphates, polyaminopropane sulfonic acid (AM PS), polyolefin sulfonates, polyolefin phosphates, diphosphonates such as azacycloalkane-2, 2-diphosphonates (e.g., azacycloheptane- 2,2-diphosphonic acid), N-methyl azacyclopentane-2,3-diphosphonic acid, ethane- 1 -hydroxy- 1,1- diphosphonic acid (EHDP) and ethane- 1 -amino- 1,1 -diphosphonate, and phosphonoalkane carboxylic acids. Useful inorganic phosphate and polyphosphate salts include monobasic, dibasic and tribasic sodium phosphates. Soluble pyrophosphates may be useful anti-calculus agents. The pyrophosphate salts can be any of the alkali metal pyrophosphate salts. In certain embodiments, salts include tetra alkali metal pyrophosphate, dialkali metal diacid pyrophosphate, trialkali metal monoacid pyrophosphate and mixtures thereof, wherein the alkali metals are sodium or potassium. The pyrophosphates may also contribute to preservation of the compositions by lowering water activity. Exemplary pyrophosphates may include tetrasodium pyrophosphate (TSPP), tetrapotassium pyrophosphate, sodium tripolyphosphate, tetrapolyphosphate, sodium trimetaphosphate, sodium hexametaphosphate and mixtures thereof. The salts may be useful in both their hydrated and / or unhydrated forms. An effective amount of pyrophosphate salt that may be included in the oral care compositions disclosed herein is generally enough to provide least about 0.1 wt% pyrophosphate ions, e.g., from about 0.1 wt% to about 3 wt%, based on the total weight of the oral care composition.

[0059] In some embodiments, the oral care compositions further comprise one or more abrasives that remove debris and surface stains on teeth, and which are also commonly referred to as polishing agents. Illustrative abrasives include, but are not limited to, silica, silicate, silicon,alumina (including calcined aluminum oxide), aluminosilicates, such as bentonite, zeolite, kaolin, and mica, siliceous or diatomaceous earth, pumice, calcium carbonate, cuttlcbonc, insoluble phosphates, composite resins, such as melamine resin, phenolic resin, and urea-formaldehyde resin, polycarbonate, silicon carbide, boron carbide, microcrystalline wax, microcrystalline cellulose, including combinations of colloidal microcrystalline cellulose and carboxymethylcellulose, and combinations and derivatives thereof. The one or more abrasives may be present in the oral care composition in a combined total amount of, for example, from about 5 wt% to about 35 wt%, based on the total weight of the oral care composition.

[0060] In some embodiments, the oral care compositions further comprise one or more surfactants. Exemplary surfactants include, but are not limited to, anionic, cationic, zwitterionic, and nonionic surfactants, and combinations thereof. The one or more surfactants may be present in the oral care compositions in a combined total amount of, for example, from about 0.01 wt% to about 10 wt% based on the total weight of the oral care composition.

[0061] Non-ionic surfactants arc known in the ail and generally include surfactants that are not electrically charged. An exemplary nonionic surfactant may be poly(oxyethylene)- poly(oxypropylene) block copolymers. Such copolymers are known commercially by the nonproprietary name of poloxamers. The name poloxamer is often used in conjunction with a numeric suffix to designate the individual identification of each copolymer. Poloxamers may have varying contents of ethylene oxide and propylene oxide which results in poloxamers that have a wide range of chemical structures and molecular weights. One poloxamer that may be mentioned is Poloxamer 407, sold under the trade name PLURONIC® F127 by BASF, Inc. (Parsippany, N.J.). In certain embodiments, the oral care compositions disclosed herein may comprise poloxamer as the at least one surfactant.

[0062] Anionic surfactants that may be used in the oral care compositions disclosed herein include, for example: (i) water-soluble salts of higher fatty acid monoglyceride monosulfates, such as the sodium salt of the monosulfated monoglyceride of hydrogenated coconut oil fatty acids such as sodium N-methyl N-cocoyl taurate, sodium cocomonoglyceride sulfate; (ii) higher alkyl sulfates, such as sodium lauryl sulfate; (iii) higher alkyl-ether sulfates, such as those of formula CH3(CH2)mCH2(OCH2CH2)nOSO3X, wherein m is 6-16, e.g., 10, n is 1-6, e.g., 2, 3 or 4, and X is Na or K, for example sodium laureth-2 sulfate (CH3(CH2)IOCH2 (OCFECFDOSChNa); (iv) higher alkyl aryl sulfonates such as sodium dodecyl benzene sulfonate (sodium lauryl benzene sulfonate);and (v) higher alkyl sulfoacetates, such as sodium lauryl sulfoacetate (dodecyl sodium sulfoacctatc), higher fatty acid esters of 1,2 dihydroxy propane sulfonate, sulfocolauratc (N-2-cthyl laurate potassium sulfoacetamide) and sodium lauryl sarcosinate.

[0063] In some embodiments, the oral care compositions disclosed herein may comprise an anionic surfactant. In some embodiments, the anionic surfactant is the water soluble salt of alkyl sulfates having from 10 to 21 carbon atoms in the alkyl radical and water soluble salts of sulfonated monoglycerides of fatty acids having from 10 to 18 carbon atoms. Sodium lauryl sulfate, sodium lauryl sarcosinate, and sodium coconut monoglyceride sulfonates are examples of anionic surfactants of that type.

[0064] In some embodiments, the oral care compositions further comprise one or more antimicrobial agents and / or one or more preservatives, such as methylisothiazolinone (MIT), sodium benzoate, potassium sorbate, benzyl alcohol, and combinations thereof. In another example, the oral care composition may comprise one or more antibacterial agents selected from halogenated diphenyl ether (e.g. triclosan), herbal extracts and essential oils (e.g., rosemary extract, tea extract, magnolia extract, thymol, menthol, eucalyptol, geraniol, carvacrol, citral, hinokitol, catechol, methyl salicylate, epigallocatechin gallate, epigallocatechin, gallic acid, miswak extract, sea-buckthorn extract), bisguanide antiseptics (e.g., chlorhexidine, alexidine or octenidine), quaternary ammonium compounds (e.g., cetylpyridinium chloride (CPC), benzalkonium chloride, tetradecylpyridinium chloride (TPC), N-tetradecyl-4-ethylpyridinium chloride (TDEPC)), phenolic antiseptics, hexetidine, octenidine, sanguinarine, povidone iodine, delmopinol, salifluor, other metal ions (e.g., stannous salts, copper salts, iron salts), sanguinarine, propolis and oxygenating agents (e.g., hydrogen peroxide, buffered sodium peroxyborate or peroxycarbonate), phthalic acid and its salts, monoperthalic acid and its salts and esters, ascorbyl stearate, oleoyl sarcosine, alkyl sulfate, dioctyl sulfosuccinate, salicylanilide, domiphen bromide, delmopinol, octapinol, and other piperidino derivatives, nicin preparations, chlorite salts; and combinations of any of the foregoing.

[0065] The one or more antibacterial or preservative agents may optionally be present in the oral care composition in a combined total amount of, for example, from about 0.01 wt% to about 0.5 wt%, based on the total weight of the oral care composition.

[0066] In some embodiments, the oral care compositions further comprise at least one thickening agent. A thickening agent may provide a desirable consistency and / or stabilize and / or enhanceperformance (e.g., provide desirable active release characteristics upon use) of the oral care compositions disclosed herein. Exemplary thickening agents include, for example, carboxy vinyl polymers, carrageenan (also known as carrageenan gum), xanthan, hydroxyethyl cellulose (HEC), natural and synthetic clays (e.g., VEEGUM® and laponite), water soluble salts of cellulose ethers (e.g., sodium carboxymethylcellulose (CMC) and sodium carboxymethyl hydroxyethyl cellulose), natural gums (e.g., gum karaya, xanthan gum, gum arable, and gum tragacanth), colloidal magnesium aluminum silicate, silica (e.g., finely divided silica), polyvinyl pyrrolidone, carbowaxes, fatty acids and salts thereof, and mixtures thereof. In some embodiments, a mixture of thickening silica and carrageenan gum may be used as the thickener in the oral care compositions disclosed herein. The one or more thickening agents may be present in the oral care composition in a combined total amount of, for example, from about 0.5 wt% to about 20 wt%, based on the total weight of the oral care composition.

[0067] In some embodiments, the oral care compositions further comprise one or more whitening agents. The one or more whitening agents can include materials or substances that are effective to, capable of, or configured to provide whitening of a tooth surface to which it is applied and can include, for example, peroxides, metal chlorites, perborates, percarbonates, peroxyacids, hypochlorites, hydroxyapatite, and combinations thereof.

[0068] Additional whitening agents include hydrogen peroxide or a hydrogen peroxide source, e.g., urea peroxide or a peroxide salt or complex (e.g., such as peroxyphosphate, peroxycarbonate, perborate, peroxy silicate, or persulphate salts); for example, calcium peroxyphosphate, sodium perborate, sodium carbonate peroxide, sodium peroxyphosphate, and potassium persulfate or hydrogen peroxide polymer complexes such as hydrogen peroxide-poly vinyl pyrrolidone polymer complexes.

[0069] In some embodiments, the oral care compositions further comprise one or more colorants. Colorants herein include pigments, dyes, lakes and agents imparting a particular luster or reflectivity such as pearling agents. In various embodiments, colorants are operable to provide a white or light-colored coating on a dental surface, to act as an indicator of locations on a dental surface that have been effectively contacted by the composition, and / or to modify appearance, in particular color and / or opacity, of the composition to enhance attractiveness to the consumer. Any orally acceptable colorant can be used, including FD&C dyes and pigments, talc, mica, magnesium carbonate, calcium carbonate, magnesium silicate, magnesium aluminum silicate, silica, titaniumdioxide, zinc oxide, red, yellow, brown and black iron oxides, ferric ammonium ferrocyanide, manganese violet, ultramarine, titaniatcd mica, bismuth oxychloride, and mixtures thereof. The one or more colorants may be present in the oral care composition in a combined total amount of, for example, from about 0.001 wt% to about 20 wt%, based on the total weight of the oral care composition.

[0070] In some embodiments, the oral care composition comprises one or more pH adjusters to increase or decrease the overall pH of the oral care composition. For example, one or more acids may be included to decrease the pH of the oral care composition. Examples of suitable acids for decreasing the pH of the oral care composition include, but are not limited to, citric acid, acetic acid, and the like. The oral care composition may include one or more bases, such as sodium hydroxide, potassium hydroxide and the like, to increase the pH of the oral care composition. Additional or alternative acids and bases that are suitable for adjusting the pH of the oral care composition are readily known to one of ordinary skill in the art.

[0071] The amount of the pH adjuster in the oral care composition may be based on the desired pH of the final oral care composition and / or product. For example, the total amount of the pH adjuster may range from about 0.05 wt% to about 20 wt%, based on the total weight of the oral care composition.

[0072] The oral care compositions may have a pH from 4.5 to about 10, 4.5 to about 9, 4.5 to about 8, 4.5 to about 7, 4.5 to about 6; from about 5 to about 10, about 5 to about 9, about 5 to about 8, about 5 to about 7, about 5 to about 6; from about 6 to about 10, about 6 to about 9, about 6 to about 8, or about 6 to about 7; from about 7 to about 10, about 7 to about 9, or about 7 to about 8, including any ranges and subranges therebetween.

[0073] In some embodiments, the oral care compositions further comprise one or more bicarbonate salts useful for example to impart a “clean feel” to teeth and gums due to effervescence and release of carbon dioxide. Any orally acceptable bicarbonate can be used, including without limitation alkali metal bicarbonates such as sodium and potassium bicarbonates, ammonium bicarbonate, and the like. The one or more bicarbonate salts may be present in the oral care composition in a combined total amount of, for example, from about 0.1 wt% to about 50 wt%, based on the total weight of the oral care composition.

[0074] In some embodiments, the oral care compositions further comprise at least one foam modulator, useful for example to increase amount, thickness or stability of foam generated by thecomposition upon agitation. Any orally acceptable foam modulator can be used, including without limitation polyethylene glycols (PEGs), also known as polyoxyethylenes. High molecular weight PEGs are suitable, including those having an average molecular weight of 200,000 to 7,000,000, for example 500,000 to 5,000,000, or 1,000,000 to 2,500,000. One or more PEGs may be present in the oral care composition in a combined total amount of, for example, from about 0.1 wt% to about 10 wt%, based on the total weight of the oral care composition.

[0075] In some embodiments, the oral care compositions further comprise at least one viscosity modifier, useful for example to help inhibit settling or separation of ingredients or to promote redispersibility upon agitation of a liquid oral care composition. Any orally acceptable viscosity modifier can be used, including without limitation, mineral oil, petrolatum, clays and organo- modified clays, silicas and the like. The one or more viscosity modifiers may be present in the oral care composition in a combined total amount of, for example, from about 0.01 wt% to about 10 wt%, based on the total weight of the oral care composition.

[0076] In some embodiments, the oral care compositions further comprise one or more antisensitivity agents, e.g., potassium salts such as potassium nitrate, potassium bicarbonate, potassium chloride, potassium citrate, and potassium oxalate; capsaicin; eugenol; strontium salts; chloride salts and combinations thereof. The one or more antisensitivity agents may be present in the oral care composition in a combined total amount of, for example, from about 1 wt% to about 20 wt%, based on the total weight of the oral care composition.

[0077] In some embodiments, the oral care compositions further comprise one or more antioxidants. Any orally acceptable antioxidant can be used, including butylated hydroxy anisole (BHA), butylated hydroxytoluene (BHT), vitamin A, carotenoids, co-enzyme Q10, PQQ, Vitamin A, Vitamin C, Vitamin E, anethole-dithiothione, flavonoids, polyphenols, ascorbic acid, herbal antioxidants, chlorophyll, melatonin, and mixtures thereof.

[0078] In some embodiments, the oral care compositions further comprise a source of calcium and phosphate selected from (i) calcium-glass complexes, e.g., calcium sodium phosphosilicates, and (ii) calcium-protein complexes, e.g., casein phosphopeptide-amorphous calcium phosphate, a soluble calcium salt, e.g., selected from calcium sulfate, calcium chloride, calcium nitrate, calcium acetate, calcium lactate, and combinations thereof.

[0079] In some embodiments, the oral care compositions further comprise water. The amount of water may depend on the form of the oral care composition, e.g., as a mouthwash, a dentifrice, afilm, a gel, a paste, etc. Water employed in the preparation of commercial oral compositions should be deionized and free of organic impurities. Water commonly makes up the balance of the compositions and includes about 5 wt% to about 99 wt%, such as from about 10 wt% to about 90 wt%, from about 65 wt% to about 85 wt%, or about 70 wt% to about 80 wt%, or any range or subrange thereof, by weight based on the total weight of the oral care composition. This amount of water includes the free water that is added plus any amount of water that may be introduced with other materials, such as with sorbitol or silica or any components of the oral care composition disclosed herein. The Karl Fischer method is a one measure of calculating free water.

[0080] The amount of water can vary depending on the type of oral care composition. In an embodiment where the composition is a dentifrice, such as toothpaste, the amount of water can range, for example, from about 5 wt% to about 50 wt%, based the total weight of the dentifrice composition.

[0081] In some embodiments, the oral care composition is based on a dentifrice formulation comprising ingredients as set forth in Table A below, wherein ingredients are listed by weight of the composition.

[0082] Table A - Exemplary base dentifrice composition

[0083] In some embodiments, the oral care composition is based on a dentifrice formulation comprising ingredients as set forth in Table B below, wherein ingredients are listed by weight of the composition.

[0084] Table B - Exemplary base dentifrice composition

[0085] In some embodiments, the oral care composition is based on a dentifrice formulation comprising ingredients as set forth in any of the compositions in Table C below, wherein ingredients are listed by weight of the composition.

[0086] Table C - Exemplary base dentifrice compositions

[0087] In certain embodiments of the disclosure, the oral care composition disclosed herein comprises, as a dentifrice base, stannous fluoride or stannous chloride; a water soluble nitrate salt, such as potassium nitrate; a water-soluble alkali metal polyphosphate, such as tetrasodium pyrophosphate; and more than 10% water, by weight of the composition. In certain embodiments, the weight of the potassium nitrate and tetrasodium pyrophosphate is effective to stabilize the stannous fluoride or stannous chloride.

[0088] In some embodiments, the oral care composition is a solid film, such as a ribbon strip or tape. The solid film may be dissolvable and / or disintegrable. As used herein, the term or expression “dissolvable” may refer to the ability to disperse into a liquid. For example, a dissolvable solid film may disperse into a liquid, such as saliva or water. As used herein, the term or expression “disintegrable” may refer to the ability to decompose into constituent elements, parts, and / or small particles. It should be appreciated that the ability of the solid film to be dissolvable and / or disintegrable may be provided by one or more components of the oral care composition. For example, an orally acceptable vehicle and / or water-soluble polymer incorporated into the oral care composition may at least partially contribute to the dissolvable and / or disintegrable properties of the oral care composition. In at least one implementation, the solid film may be dissolvable and / or disintegrable in water, saliva, or a combination thereof. For example, the oral care composition may be applied to soft tissue surface of the oral cavity, such as the gum, lip or check, and added water and / or saliva acts to dissolve or disintegrate the film to release the components of the composition.

[0089] The solid film may be dissolvable and / or disintegrable in a predetermined amount of time and / or rate. For example, the solid film may be completely dissolvable and / or disintegrable in about 30 seconds or less, about 1 min or less, about 2 min or less, about 3 min or less, about 5 min or less, about 10 min or less. It should be appreciated that conventional oral care compositions in the form of a solid film are often not dissolvable or disintegrable; and thus, need to be physically removed (e.g., peeling, abrading, etc.) after a predetermined period of time.

[0090] Further embodiments include methods of using the oral care compositions of the disclosure. An embodiment of the disclosure includes a method of treating oral inflammation in a subject in need thereof, which comprises applying the oral care composition of the disclosure to the site of inflammation in the oral cavity of the subject.

[0091] As used herein, the term “subject” refers to individuals (e.g., human) to be treated by the methods or compositions of the present invention. Subjects include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and most preferably includes humans. In the context of the disclosure, the term “subject” generally refers to an individual who will receive treatment for a condition characterized by inflammation.

[0092] In certain embodiments, the subject may be an individual who exhibits oral inflammation, e.g., gingivitis, periodontitis, implantitis, mucositis, and the like. In certain embodiments, the subject may be an individual who is at risk of developing oral inflammation, e.g., gingivitis, periodontitis, implantitis, mucositis, and the like. Subjects that may experience oral inflammation or subjects at risk of developing oral inflammation may include, for example, subjects of an increased age (e.g., adults or the elderly), cancer patients, subjects with preexisting oral disease (e.g., gingivitis, periodontitis), subject with dental implants, subjects taking certain medications, diabetics, subjects with poor dental hygiene habits, subjects with poor dietary habits, smokers, and / or subjects with tooth decay, tooth erosion and / or fractured teeth. According to certain embodiments, the subject may suffer from a down-regulation or other deficiency of ARG1, GPR18, or GPR32. For example, the subject may suffer from hyperargininemia or hyperammonemia as a result of ARG 1 deficiency. Embodiments of the disclosure include applying an oral care composition to the oral cavity of a subject at risk of developing oral inflammation, thereby reducing their risk of developing oral inflammation.

[0093] The oral inflammation may be any soft tissue-related inflammation in the oral cavity. The site of inflammation can be, for example, on the gum, lip or cheek of the subject. In some embodiments, the subject suffers from gingivitis, periodontitis, implantitis or mucositis.

[0094] Gingivitis is the earliest stage of gum disease, an inflammation of the gums caused by plaque buildup at the gumline. If daily brushing and flossing do not remove the plaque, it produces toxins (poisons) that can irritate the gum tissue, causing gingivitis. Symptoms may include bleeding during brushing and flossing. At this early stage in gum disease, damage can be reversed, since the bone and connective tissue that hold the teeth in place are not yet affected.

[0095] Periodontitis is a more advanced gum disease. At this stage, the supporting bone and fibers that hold teeth in place arc irreversibly damaged. Gums may begin to form a pocket below the gumline, which traps food and plaque. Proper dental treatment and improved home care can usually help prevent further damage. In advanced periodontitis, the fibers and bone supporting the teeth are destroyed, which can cause teeth to shift or loosen. This can affect bite and, if aggressive treatment is ineffective or unavailable, the teeth may need to be removed.

[0096] Implantitis, including peri-implantitis, is an inflammatory reaction wherein there may be loss of supporting bone in the tissues surrounding an implant. Mucositis is an inflammation of the mucosa, the mucous membranes that line the mouth and the gastrointestinal tract. Mucositis may result in open sores in the mouth, and is a known side effect of chemotherapy and radiotherapy.

[0097] According to certain embodiments of the methods disclosed herein, the oral care composition may be applied to the oral cavity of the subject in need thereof for about 5 seconds to about 30 minutes, such as for about 10 seconds to about 20 minutes, or such as for about 30 seconds to about 2 minutes. The methods may include, for example, applying the oral care composition to the subject at least once a day, such as at least twice a day, or such as at least three times a day.

[0098] As demonstrated in the Examples below, oral care compositions of the disclosure unexpectedly synergistically upregulate pro-resolution arginine metabolism (ARG1) and genes of omega-3 fatty acid metabolite receptors (GPR18, GPR32). Exemplary methods of the disclosure include increasing expression of ARG1, GPR18 or GPR32 in a tissue of the oral cavity of the subject. For instance, embodiments include increasing expression of one or more of ARG1, GPR18 or GPR32 in a tissue of the oral cavity of the subject compared to applying a corresponding oral care composition that comprises DHA but does not comprise (i) a stannous ion source, such as stannous fluoride, and does not comprise (ii) tetradecyl aminobutyroylvalylaminobutyric urea trifluoroacetate. A “corresponding oral care composition” is one that comprises the same ingredients as the composition of the disclosure, with the exception that it does not comprise (i) a stannous ion source, such as stannous fluoride, and does not comprise (ii) tetradecyl aminobutyroylvalylaminobutyric urea trifluoroacetate. Such methods can include, for example, increasing the expression of one or more of ARG1, GPR18 or GPR32 in a tissue of the oral cavity of the subject, such as the gum, by at least 10%, such as by at least 25%, such as by at least 50%, or such as by at least 100%, compared to a corresponding oral care composition that comprises DHA without a stannous ion source or tetradecyl aminobutyroylvalylaminobutyric ureatri fluoroacetate.

[0099] Additional embodiments of the disclosure include methods of treating oral inflammation in a subject in need thereof, which comprises sequentially applying to the site of inflammation in the oral cavity of the subject an oral care composition comprising DHA and another oral care composition comprising at least one of (i) a stannous ion source, such as sodium fluoride, and (ii) tetradecyl aminobutyroylvalylaminobutyric urea trifluoroacetate.

[0100] At least one of the compositions in such an embodiment may further comprise, for example, arginine or a salt thereof. Each composition may also further comprise additional ingredients mentioned previously herein, including but not limited to one or more other fluoride ion sources in addition to any stannous fluoride present, one or more other metal ion sources in addition to any stannous ion sources present, humectants, emulsifiers, flavoring agents, sweeteners, anti-calculus agents, abrasives, surfactants, surfactants, anti-bacterial agents, thickening agents, whitening agents, colorants, pH adjusters, clean feel agents, foam modulators, viscosity modifiers, anti- sensitivity agents, antioxidants, calcium phosphates, water, and combinations thereof.

[0101] “Sequentially applying” the two oral care compositions as used herein means that the subject first applies one composition to the oral cavity, then separately applies the other composition to the oral cavity. In some embodiments, the method may comprise applying one composition that comprises DHA, then applying a second composition that comprises at least one of (i) a stannous ion source, such as stannous fluoride or (ii) tetradecyl aminobutyroylvalylaminobutyric urea trifluoroacetate. As an alternative, the method may comprise applying one composition that comprises at least one of (i) a stannous ions source, such as stannous fluoride, or (ii) tetradecyl aminobutyroylvalylaminobutyric urea trifluoroacetate, then applying a second composition that comprises DHA.

[0102] The two compositions may be in the same form or a different form and each may be in the form of, for example, a mouthwash, a mouth rinse, a toothpaste or a solid film. In some embodiments, one composition is in the form of a toothpaste and the other composition is in the form of a mouth rinse or mouthwash. In further embodiments, the first composition applied to the oral cavity is in the form of a toothpaste and the second composition applied to the oral cavity is in the form of a mouth rinse or mouthwash.

[0103] In some embodiments, the compositions are sequentially applied such that the secondcomposition is applied within 5 minutes, such as within 3 minutes, or such as within 1 minute of initially applying the first composition to the oral cavity.

[0104] The oral care compositions disclosed herein may be made according to methods and procedures known to those skilled in the art. In certain embodiments, the compositions can be made by incorporating DHA (such as in the form of DHA oil) and a stannous ion source, such as stannous fluoride, and / or tetradecyl aminobutyroylvalylaminobutyric urea trifluoroacetate (e.g., Syn®-Hycan) into a pre-formulated mouthwash, mouth rinse or toothpaste, or including those components in a formulation that is then processed into a solid film.

[0105] The examples and other embodiments described herein are exemplary and not intended to be limiting in describing the full scope of compositions and methods of this disclosure. Equivalent changes, modifications and variations of specific embodiments, materials, compositions and methods may be made within the scope of the present disclosure, with substantially similar results.EXAMPLES

[0106] Experiments were conducted to evaluate the influence of DHA oil in combination with other components such as stannous fluoride and Syn®-Hycan on surface markers of macrophages or on macrophage gene regulation. The experiments tested the ability of the combinations to alter macrophage polarization in vitro. THP-1 monocytes were differentiated into macrophages and treated with Ml inducing factors LPS and interferon gamma (INF-y), in the presence or absence of the tested combinations. Macrophage polarization was determined based on surface expression of specific Ml and M2 markers by flow cytometry, and Ml and M2 transcript expression was tested by qPCR.

[0107] Macrophage polarization

[0108] THP-1 monocytic cells were cultured at 2 x 105- l x 106cells / mL in RPMI-1640 supplemented with 10% FBS, 2-mercaptoethanol (50 pM), and penn-strep (50 I.U. / mL penicillin and 50 pg / mL streptomycin). For macrophage differentiation, 0.8 x 106THP-1 cells were treated with phorbol 12-myristate 13-acetate (PMA) (100 nM) in 6-well plates for 24 hrs, followed by 24 hrs in a normal growth medium. Ml polarization was accomplished by a further stimulation with INFy (PeproTech, Catalog# 300-02) at a final concentration of 20ng / mL, and LPS (Sigma, L4391) at a final concentration of 100 ng / mL for 24 hrs. As a positive control for M2 macrophage markers, PMA treated THP-1 cells were stimulated with IL-4 (PeproTech, Catalog# 200-04) at a finalconcentration of 20 ng / mL and IL-13 (PeproTech, Catalog# 300-13) at a final concentration of 20 ng / mL for 48 hrs.

[0109] The bioactive effects of DHA oil (Algal oil, 40% DHA), stannous fluoride and Syn®-Hycan (peptide in a glycerin / water suspension) were tested, including the effect of a combination of DHA oil with either stannous fluoride or Syn®-Hycan on Ml polarization. DHA oil in combination with Vitamins B3, B5, B6, C and E (B-PLEX®), Vitamin C (SC50), Vitamin B3 (VitB) and Zigerone (ZGB) were also tested for comparison. 20 mM stock solutions were prepared for BPLEX, SC50, VitB, stannous fluoride and ZGB, which were further diluted directly into cell culture media at the desired final concentration. All compounds were dissolved in sterile water, with the exception of ZGB, which was dissolved in DMSO. DHA oil (Algal oil - 40% DHA w / w) and Syn®-Hycan (0.1% peptide w / v) stocks were diluted directly into cell culture medium. The bioactive compounds and combinations were tested at a range of concentrations as indicated in Table 1, for the duration of the INFy / LPS Ml polarization treatment to determine toxicity and macrophage polarization. For flow cytometric analysis, cells were rinsed with PBS and incubated for 5 min at 37°C with 5 mM EDTA, scraped and collected in FACS tubes.Table 1: Compounds and combinations tested

[0110] Flow cytometry

[0111] Cells were labeled with the live cell marker, eFluor506 (eBiosciences), according to the manufacturer’s instructions, washed and labeled with fluorescent tagged antibodies in a 50 pl volume, for 30 minutes on ice, and washed with FACS buffer (Hanks7-, 1% BSA, 0.5 mM EDTA). Cells were fixed with 1.6% paraformaldehyde for 15 minutes on ice and resuspended in 250 pl of FACS buffer. All antibodies were from Biolegend, as follows: CD40-AF647 (2 pL), CD 14- PacBlue (1 pL), CD206-PE (1 pL), CD163-BV421 (2 pL). Flow cytometry was performed on a SA3800 spectral flow cytometer (Sony), and 20,000 gated events were captured. Debris was excluded using SSC-Area (SSC-A) by FSC-Area (FSC-A), and doublet cells were excluded using FSC-width (FSC-W) by FSC-height (FSC-H). Dead macrophages were excluded by gating on by eFlour 5061ow. The geometric mean fluorescence intensity (gMFI) of the CD markers is reported. Ml and M2 macrophages, without any compound stimulation, were used as a control. Data analysis was performed using FlowJo software (vl0.8; Tree Star). ANOVA was performed with a Bonferroni test for multiple comparisons.

[0112] RNA extraction

[0113] Macrophages were collected and washed, and RNA was extracted using RNeasy Mini kit (Qiagen, Germany) following the manufacturer’s instructions. The RNA was quantified using NanoDrop 1000 (Thermo Scientific).

[0114] Quantitative Polymerase gene expression (qPCR) and relative gene expression

[0115] Complementary DNA was synthesized using iScript cDNA Synthesis Kit (Bio-Rad). A 2- pL volume of the cDNA was used as a template in subsequent gene expression assays. SsoAdvanced Universal SYBR Green Supermix (Bio-Rad) was used for qPCR with PrimePCR PreAmp SYBR Green Assays (Bio-Rad) following the manufacturer’s instructions as shown in Table 2. The gene expression was normalized to Actin and GAPDH, and the treated Ml macrophages’ gene expression profiles were compared to non-treated Ml cells.Table 2: qPCR assays carried out

[0116] Effect ofDHA and stannous fluoride, individually and combined, on macrophages

[0117] CD 163 is a surface marker of pro-resolution macrophages. CD40 is a surface marker of pro-inflammation macrophages. FIG. 1A is a bar graph illustrating the effect of stannous fluoride and DHA oil, individually, on the CD 163 surface marker for pro-resolution macrophages compared to a control. FIG. IB is a bar graph illustrating the effect of stannous fluoride and DHA oil, individually, on the CD40 surface marker for pro-inflammation macrophages compared to a control. Stannous fluoride suppresses pro-inflammation macrophages as seen by the reduction in CD40 in FIG. IB. DHA oil selectively promotes pro-resolution macrophages as seen by the increase in CD163, with essentially no effect on CD40.

[0118] FIG. 1C is a bar graph illustrating the effect of stannous fluoride and DHA oil, combined, on the CD 163 surface marker for pro-resolution macrophages compared to a control. FIG. ID is a bar graph illustrating the effect of stannous fluoride and DHA oil, combined, on the CD40 surface marker for pro-inflammatory macrophages compared to a control. When treatment with a stannous ion source such as stannous fluoride was combined with DHA oil, they surprisingly worked synergistically to promote pro-resolution macrophages and suppress pro-inflammatory macrophages. This unexpected synergistic effect indicates that these bioactive compounds target different aspects of the inflammation onset and inflammation resolution biological processes and can translate to more potent clinical effects.

[0119] Induced gene expression by DHA and either stannous fluoride or Syn®-Hycan, combined

[0120] As discussed above, the experiments tested changes in the gene expression profile of macrophages during the polarization assay in the presence of combined molecules. FIG. 2A is a bar graph illustrating the effects of DHA oil, and DHA oil in combination with other components, on the gene expression of ARG1. FIG. 2B is a bar graph illustrating the effects of DHA oil, and DHA oil in combination with other components, on the gene expression of GPR18. FIG. 2C is abar graph illustrating the effects of DHA oil, and DHA oil in combination with other components, on the gene expression of GPR32.

[0121] The data in FIG. 2A, FIG. 2B and FIG. 2C shows that DHA oil combined with either a stannous ion source, such as stannous fluoride, or Syn®-Hycan surprisingly induced the gene expression of ARG1, GPR18 and GPR32, compared to a control (untreated Ml pro-inflammatory phenotype) and compared to treatment with DHA oil alone. The data illustrate an unexpected synergistic upregulating effect between these molecules on macrophages. On the other hand, combination of DHA oil with either B-PLEX®, SC50, VitB3 or ZGB, down-regulated the gene expression of ARG1, GPR18, and GPR32 compared to DHA oil alone.

[0122] The data establish that a stannous ion source, such as stannous fluoride, and DHA are potent macrophage gene regulators that, in combination, unexpectedly synergistically upregulate pro-resolution arginine metabolism (ARG1) and genes of omega-3 fatty acid metabolite receptors (GPR18, GPR32). These genes are associated with the M2 macrophage phenotype that promotes inflammation resolution. Syn®-Hycan and DHA in combination also unexpectedly synergistically upregulate pro-resolution arginine metabolism (ARG1) and genes of omega-3 fatty acid metabolite receptors (GPR18, GPR32). Without being bound to any particular theory, expression of these receptors indicates that a stannous ion source, such as stannous fluoride, and Syn®-Hycan unexpectedly potentiate a pro-resolving effect of DHA.

[0123] In view of these experiments, DHA may be combined with either a stannous ion source, such as stannous fluoride, or Syn®-Hycan, or both, in an oral care composition to influence macrophage polarization and thereby treat inflammatory conditions in the oral cavity through macrophage-mediated inflammation suppression.

[0124] The present disclosure has been described with reference to exemplary implementations. Although a limited number of implementations have been shown and described, it will be appreciated by those skilled in the art that changes may be made in these implementations without departing from the principles and spirit of the preceding detailed description. It is intended that the present disclosure be construed as including all such modifications and alterations insofar as they come within the scope of the appended claims or the equivalents thereof.

Claims

CLAIMSWhat Is Claimed Is:

1. An oral care composition, which comprises: docosahexaenoic acid (DHA); and at least one of (i) a stannous ion source or (ii) tetradecyl aminobutyroylvalylaminobutyric urea trifluoroacetate.

2. The oral care composition of claim 1, wherein DHA is present in the oral care composition in an amount ranging from about 0.005 wt% to about 10 wt%, such as from about 0.01 wt% to about 5 wt%, or such as from about 0.1 wt% to about 3 wt%, based on the total weight of the oral care composition.

3. The oral care composition of any one of the preceding claims, which comprises DHA and (i) a stannous ion source.

4. The oral care composition of any one of the preceding claims, wherein the (i) stannous ion source is present in the oral care composition in an amount ranging from about 0.0001 wt% to about 10 wt%, such as from about 0.005 wt% to about 2.5 wt%, or such as from about 0.01 wt% to about 1 wt%, based on the total weight of the oral care composition.

5. The oral care composition of any one of the preceding claims, wherein the stannous ion source is selected from the group consisting of stannous fluoride, stannous chloride, stannous acetate, stannous tartrate, stannous oxalate, sodium stannous citrate, stannous gluconate, stannous phosphate, stannous pyrophosphate, stannous sulfate, and combinations thereof.

6. The oral care composition of any one of the preceding claims, wherein the stannous ion source is stannous fluoride.

7. The oral care composition of any one of the preceding claims, which comprises DHA and (ii) tetradecyl aminobutyroylvalylaminobutyric urea trifluoroacetate.

8. The oral care composition of any one of the preceding claims, wherein the (ii) tetradecyl aminobutyroylvalylaminobutyric urea trifluoroacetate is present in the oral care composition in an amount ranging from about 0.001 wt% to about 5 wt%, such as from about0.01 wt% to about 2 wt%, or such as from about 0.05 wt% to about 1 wt%, based on the total weight of the oral care composition.

9. The oral care composition of any one of the preceding claims, which comprises DHA, (i) a stannous ion source and (ii) tetradecyl aminobutyroylvalylaminobutyric urea trifluoroacetate.

10. The oral care composition of claim 9, wherein the stannous ion source is stannous fluoride.

11. The oral care composition of any one of the preceding claims, which further comprises arginine or a salt thereof.

12. The oral care composition of claim 11, wherein the arginine comprises L-arginine or a salt thereof.

13. The oral care composition of any one of claims 11-12, wherein the arginine comprises free arginine.

14. The oral care composition of any one of claims 11-12, wherein the arginine comprises a salt of arginine selected from the group consisting of arginine hydrochloride, arginine carbonate, arginine bicarbonate, arginine phosphate, arginine hydroxide, and combinations thereof.

15. The oral care composition of any one of claims 11-14, wherein the arginine or salt thereof is present in the oral care composition in an amount ranging from about 0.5 wt% to about 3 wt%, such as from about 1 wt% to about 2 wt%, or such as from about 1.3 wt% to about 1.7 wt%, based on the total weight of the oral care composition.

16. The oral care composition of any one of the preceding claims, wherein the oral care composition is in the form of a mouthwash, a mouth rinse, a toothpaste or a solid film.

17. A method of treating oral inflammation in a subject in need thereof, which comprises applying the oral care composition of any one of the preceding claims to the site of inflammation in the oral cavity of the subject.

18. The method of claim 17, wherein the site of inflammation is on the gum, lip or cheek of the subject.

19. The method of any one of claims 17-18, wherein the subject suffers from at least one of periodontitis, gingivitis, implantitis or mucositis.

20. The method of any one of claims 17-19, which comprises applying the oral care composition to the site of inflammation in the oral cavity of the subject for about 5 seconds to about 30 minutes, such as for about 10 seconds to about 20 minutes, or such as for about 30 seconds to about 2 minutes.

21. The method of any one of claims 17-20, which comprises applying the oral care composition to the site of inflammation in the oral cavity of the subject at least once a day, such as at least twice a day, or such as at least three times a day.

22. The method of any one of claims 17-21, wherein the method increases expression of one or more of ARG1, GPR18 or GPR32 in a tissue of the oral cavity of the subject.

23. The method of claim 22, wherein the method increases expression of one or more of ARG1 , GPR 18 or GPR32 in a tissue of the oral cavity of the subject compared to applying a corresponding oral care composition that comprises DHA but does not comprise (i) a stannous ion source and does not comprise (ii) tetradecyl aminobutyroylvalylaminobutyric urea trifluoroacetate.

24. The method of any one of claims 22-23, which comprises increasing the expression of one or more of ARG1, GPR18 or GPR32 in a tissue of the oral cavity of the subject, such as the gum, by at least 10%, such as by at least 25%, such as by at least 50%, or such as by at least 100%.

25. The method of any one of claims 17-24, wherein the oral care composition comprises:DHA in an amount ranging from about 0.005 wt% to about 10 wt%, such as from about 0.01 wt% to about 5 wt%, or such as from about 0.1 wt% to about 3 wt%, based on the total weight of the oral care composition; anda stannous ion source in an amount ranging from about 0.0001 wt% to about 10 wt%, such as from about 0.005 wt% to about 2.5 wt%, or such as from about 0.01 wt% to about 1 wt%, based on the total weight of the oral care composition.

26. The method of any one of claims 17-24, wherein the oral care composition comprises:DHA in an amount ranging from about 0.005 wt% to about 10 wt%, such as from about 0.01 wt% to about 5 wt%, or such as from about 0.1 wt% to about 3 wt%, based on the total weight of the oral care composition; and tetradecyl aminobutyroylvalylaminobutyric urea trifluoroacetate in an amount ranging from about 0.001 wt% to about 5 wt%, such as from about 0.01 wt% to about 2 wt%, or such as from about 0.05 wt% to about 1 wt%, based on the total weight of the oral care composition.

27. The method of any one of claims 25-26, wherein the oral care composition further comprises arginine or a salt thereof in an amount ranging from about 0.5 wt% to about 3 wt%, such as from about 1 wt% to about 2 wt%, or such as from about 1.3 wt% to about 1.7 wt%, based on the total weight of the oral care composition.

28. A method of upregulating ARG1, GPR18, GPR32, or a combination thereof, in a subject in need thereof, which comprises locally applying the oral care composition of any one of claims 1-16 to the oral cavity of the subject.

29. The method of claim 28, wherein the oral care composition comprises:DHA in an amount ranging from about 0.005 wt% to about 10 wt%, such as from about 0.01 wt% to about 5 wt%, or such as from about 0.1 wt% to about 3 wt%, based on the total weight of the oral care composition; and a stannous ion source in an amount ranging from about 0.0001 wt% to about 10 wt%, such as from about 0.005 wt% to about 2.5 wt%, or such as from about 0.01 wt% to about 1 wt%, based on the total weight of the oral care composition.

30. The method of claim 28, wherein the oral care composition comprises:DHA in an amount ranging from about 0.005 wt% to about 10 wt%, such as from about 0.01 wt% to about 5 wt%, or such as from about 0.1 wt% to about 3 wt%, based on the total weight of the oral care composition; and tetradecyl aminobutyroylvalylaminobutyric urea trifluoroacetate in an amount ranging from about 0.001 wt% to about 5 wt%, such as from about 0.01 wt% to about 2 wt%, or such as from about 0.05 wt% to about 1 wt%, based on the total weight of the oral care composition.

31. The method of any one of claims 28-30, wherein the oral care composition further comprises arginine or a salt thereof in an amount ranging from about 0.5 wt% to about 3 wt%, such as from about 1 wt% to about 2 wt%, or such as from about 1.3 wt% to about 1.7 wt%, based on the total weight of the oral care composition.

32. The method of any one of claims 28-31, wherein the subject suffers from oral inflammation.

33. The method of claim 32, wherein the subject suffers from at least one of periodontitis, gingivitis, implantitis or mucositis.

34. The method of any one of claims 28-31, wherein the subject is at risk for developing oral inflammation.

35. The method of claim 34, wherein the subject is at risk for developing at least one of periodontitis, gingivitis, implantitis or mucositis.

36. The method of any one of claims 28-35, wherein the method increases expression of one or more of ARG1, GPR18 or GPR32 in a tissue of the oral cavity of the subject compared to applying a corresponding oral care composition that comprises DHA but does not comprise (i) a stannous ion source and does not comprise (ii) tetradecyl aminobutyroylvalylaminobutyric urea trifluoroacetate.

37. The method of any one of claims 28-36, which comprises increasing the expression of one or more of ARG1, GPR18 or GPR32 in a tissue of the oral cavity of the subject, such as the gum, by at least about 10%, at least about 25%, at least about 50%, or at least about 100%.

38. A method of treating oral inflammation in a subject in need thereof, which comprises sequentially applying to the site of inflammation in the oral cavity of the subject a first oral care composition comprising DHA and a second oral care composition comprising at least one of (i) a stannous ion source or (ii) tetradecyl aminobutyroylvalylaminobutyric urea trifluoroacetate.

39. The method of claim 38, wherein at least one of the first oral care composition or the second oral care composition further comprises arginine or a salt thereof.

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