Methods for mediating an inflammatory response

Abstract

Described herein are methods of treating and / or alleviating a cytokine-mediated inflammatory disorder, such as gum disease, in a subject in need thereof, comprising applying an oral care composition to an oral cavity of the subject, the oral care composition comprising a stannous ion source; a nitrate ion source; and a water-soluble alkali metal polyphosphate source; and at least 10% water, by weight of the composition. Methods for treating and / or alleviating gum diseases are also described herein.

Description

METHODS FOR MEDIATING AN INFLAMMATORY RESPONSE CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of U.S. provisional application No.63 / 554,281, which was filed February 16, 2024, is titled Methods for Mediating an Inflammatory Response, and is incorporated herein by reference as if fully set forth. BACKGROUND

[0002] 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. LPS is a large, complex molecule that is a major component of the outer membrane of Gram-negative bacteria. LPS released from the Gram- negative cell wall functions as an endotoxin and stimulates immune responses that result in inflammation. LPS from different strains of Gram-negative bacteria differ but share a common structural pattern. The components of an LPS include a lipid A fraction, a core polysaccharide region composed of an inner core and an outer core, and an O-antigen. The differences among the structures of LPS result in their different virulence, i.e., levels of endotoxicity. Thus, some LPS are more harmful than others.

[0003] Toll-like receptors (TLRs) are present in the oral cavity and in the human body in many cell types, including on monocytes and alveolar macrophages that work as the first line of defense against pathogenic bacteria, inhaled foreign particles, and viruses. TLR4 is a receptor that recognizes LPS. The TLR4 pathway includes the cofactors myeloid differentiation factor 88 (MYD88), II-1 receptor associated kinase 2 (IRK2), and TNF receptor-activated factor 6 (TRAF6). When LPS binds to TLR4, the TRAF6 initiates activation of the nuclear factor kappa-light-chain- enhancer of activated B cells (NF-κB) pathway.

[0004] In the NF-κB pathway, bacterial LPS binds the TLR4 receptor, which then dimerizes and initiates a kinase cascade. The activated Toll-like receptor mediates the NF-κB signaling pathway, which induces the cell to release proinflammatory cytokines necessary to stimulate potent immune responses that lead to tissue destruction. Pro-inflammatory cytokines include, for example, interleukin 8 (IL-8), tumor necrosis factor alpha (TNFα), and prostaglandin E 2 (PGE 2). Higher levels of the cytokines correlate with higher levels of bacterial LPS and indicate more inflammation. Because periodontal diseases are associated with chronic inflammation due to oral bacteria, bacterial LPS-induced inflammation is a direct cause of periodontal disease.Porphyromonas gingivalis LPS stimulation of TLR4 results in an increase in IL-8 and TNFα, and this increase is linked to periodontal disease.

[0005] IL-8 is a chemokine involved in the recruitment and activation of certain white blood cells known as neutrophils to sites of inflammation or injury. IL-8 may be produced by a various cell types, including macrophages, epithelial cells, endothelial cells, and fibroblasts, in response to inflammatory stimuli such as a bacterial or viral infection, tissue injury, or exposure to pro- inflammatory cytokines. Dysregulation of IL-8, however, can contribute to the development and progression of several pathological conditions, such as autoimmune diseases, cancer, and chronic inflammatory disorders, including gingivitis and periodontitis, chronic obstructive pulmonary disorder (COPD), and rheumatoid arthritis.

[0006] Several factors may contribute to dysregulation of IL-8, including, for example, nicotine use. Cigarette smoke contains high levels of oxidants, which are known to stimulate immune cells to produce reactive oxygen species, including, for example, various cytokines and chemokines, including IL-8. Accordingly, nicotine users may have higher levels of circulating IL-8, resulting in increased susceptibility to various IL-8 mediated inflammatory diseases and conditions. Nicotine users face an increased risk of developing heart disease, stroke, lung diseases, diabetes, chronic obstructive pulmonary disease (COPD), tuberculosis, eye diseases, and problems of the immune system, including rheumatoid arthritis. Moreover, nicotine users are at an increased risk of developing problems in the oral cavity, such as gum disease and tooth loss.

[0007] Accordingly, novel compositions and treatments are needed for use by people at risk of developing IL-8 mediated inflammatory disorders, including, for example, for use by nicotine users, in order to reduce IL-8 concentration in affected tissues. BRIEF SUMMARY

[0008] This summary is intended merely to introduce a simplified summary of some aspects 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 key or critical 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.

[0009] Aspects disclosed herein are directed to methods for treating and / or alleviating an interleukin-8 (IL-8) mediated inflammatory disorder in a subject in need thereof, comprising applying an oral care composition to an oral cavity of the subject, the oral care composition comprising a stannous source, a nitrate ion source, and a pyrophosphate. In certain embodiments, the IL-8 mediated inflammatory disorder is selected from gum disease, chronic obstructive pulmonary disorder (COPD), pneumonia, bronchitis, Crohn’s disease, ulcerative colitis, or asthma, and in certain embodiments, the IL-8 mediated inflammatory disorder is gum disease, such as gingivitis, periodontitis, implantitis, or mucositis. In certain embodiments, the IL-8 mediated inflammatory disorder is gingivitis or periodontitis.

[0010] Also disclosed herein are methods for treating and / or alleviating symptoms of gum disease (such as gingivitis, periodontitis, implantitis, or mucositis) in a subject in need thereof, comprising applying an oral care composition to an oral cavity of the subject, the oral care composition comprising a stannous source, a nitrate ion source, and a pyrophosphate.

[0011] According to certain embodiments, the subject in need thereof is selected from nicotine users, patients with an inflammatory disease, patients with a bacterial or viral infection, obese people, or elderly people. In certain embodiments, the subject in need thereof is a nicotine user.

[0012] In certain embodiments disclosed herein, the method comprises applying the oral care composition to the oral cavity at least one a day, such as at least twice a day or at least 3 times a day, and in certain embodiments, the oral care composition is applied to the oral cavity for about 10 seconds to about 30 minutes, such as about 15 seconds to about 25 minutes, about 20 seconds to about 15 minutes, about 25 seconds to about 5 minutes, or about 30 seconds to about 2 minutes. According to certain embodiments of the disclosure, the oral care composition is applied to the oral cavity in an amount of about 0.1 to about 3 grams.

[0013] In certain embodiments, the stannous source is selected from stannous fluoride, stannous chloride, stannous pyrophosphate, stannous formate, stannous acetate, stannous gluconate, stannous lactate, stannous tartrate, stannous oxalate, stannous malonate, stannous citrate, stannous ethylene glyoxide, and combinations of two or more thereof, and in certain embodiments, the nitrate ion source is selected from lithium nitrate, sodium nitrate, potassium nitrate, magnesium nitrate, calcium nitrate, zinc nitrate, silver nitrate, ammonium nitrate, and a combination two or more thereof. According to certain embodiments of the methods disclosed herein, the oral care composition has a molar ratio of nitrate ions to stannous ions, both measured as free ions, of about0.5:1 to about 2:1. In certain embodiments, the phosphate ion source is selected from tetrasodium pyrophosphate, dicalcium orthophosphate dihydrate, dicalcium phosphate dihydrate, calcium hydrogen phosphate, calcium pyrophosphate, p-calcium pyrophosphate, tricalcium phosphate, calcium metaphosphate, potassium metaphosphate, sodium metaphosphate, and a combination of two or more thereof. In certain embodiments, the oral care composition comprises water in an amount ranging from about 5% to about 20%, such as from about 5% to about 7% or from about 12% to about 16%, by weight relative to the total weight of the oral care composition.

[0014] According to certain embodiments, the methods disclosed herein reduce an IL-8 concentration in a tissue of the subject, such as gum tissue of the subject. In certain embodiments, the IL-8 concentration is reduced by at least about 25%, such as at least 30%, at least 35%, at least 40%, at least 45%, or at least 50%. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Implementation of the present technology will now be described, by way of example only, with reference to the attached figures. 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 drawings in which:

[0016] FIG. 1 is a bar graph showing the optical density (OD) fold change at 640 nm for (1) untreated HEK-hTLR4 cells; (2) HEK-hTLR4 cells treated with 1 μg / mL of P. gingivalis LPS; (3) HEK-hTLR4 cells treated with 1 μg / mL of P. gingivalis LPS and Composition A; (4) HEK-hTLR4 cells treated with 1 μg / mL of P. gingivalis LPS and Composition B; and (5) HEK-hTLR4 cells treated with 1 μg / mL of P. gingivalis LPS and Composition C, as described in Example 2.

[0017] FIG.2 is a bar graph showing the fold change of IL-8 concentration for (1) untreated HEK- hTLR4 cells; (2) HEK-hTLR4 cells treated with 1 μg / mL of P. gingivalis LPS; (3) HEK-hTLR4 cells treated with 1 μg / mL of P. gingivalis LPS and Composition A; (4) HEK-hTLR4 cells treated with 1 μg / mL of P. gingivalis LPS and Composition B; and (5) HEK-hTLR4 cells treated with 1 μg / mL of P. gingivalis LPS and Composition C, as described in Example 2.

[0018] FIG.3 is a bar graph showing the average concentration of IL-8 (pg / mL) in (1) untreated HEK-hTLR4 cells, (2) HEK-hTLR4 cells treated with 1 μg / mL of P. gingivalis LPS; (3) HEK-hTLR4 cells treated with 1 μg / mL of P. gingivalis LPS and Composition D20; and (4) HEK-TLR4 cells treated with 1 μg / mL of P. gingivalis LPS and Composition E20, as described in Example 3.

[0019] FIG.4 is a bar graph showing the fold change of IL-8 concentration for (1) untreated HEK- hTLR4 cells, (2) HEK-hTLR4 cells treated with 1 μg / mL of P. gingivalis LPS; (3) HEK-hTLR4 cells treated with 1 μg / mL of P. gingivalis LPS and Composition D20; (4) HEK-hTLR4 cells treated with 1 μg / mL of P. gingivalis LPS and Composition D40; (5) HEK-hTLR4 cells treated with 1 μg / mL of P. gingivalis LPS and Composition E20; and (6) HEK-hTLR4 cells treated with 1 μg / mL of P. gingivalis LPS and Composition E40, as described in Example 3.

[0020] FIG. 5 illustrates assessment of SEAP activity was done by measuring the absorbance at OD 640 nm in HEK-hTLR2 cells with SNAPs solution treatment. The SEAP reporter gene is under the control of the IFN-β minimal promoter fused to five NF-kB and AP-1 binding site, thus, the activation of NF-kB will lead to expression of SEAP and activation of NF-kB can be detected by measuring SEAP activity (Note: Cell viability data are referred to the report of SNAPs-anti- inflammatory).

[0021] FIG. 6 illustrates assessment of SEAP activity was done by measuring the absorbance at OD 640 nm in HEK-hTLR4 cells with SNAPs solution treatment.The SEAP reporter gene is under the control of the IFN-β minimal promoter fused to five NF-kB and AP-1 binding site, thus, the activation of NF-kB will lead to expression of SEAP and activation of NF-kB can be detected by measuring SEAP activity (Note: Cell viability data are referred to the report of SNAPs-anti- inflammatory).

[0022] FIG.7 illustrates NF-kB deactivation effects of SNAPs solutions in HEK-hTLR2 cells in response to IL-1β stimulation.

[0023] FIG. 8 illustrates NF-kB deactivation effects of SNAP solutions in HEK-hTLR4 cells in response to LPS stimulation.

[0024] It should be understood that the various aspects are not limited to the compositions, arrangements, and instrumentality shown in the drawings. DETAILED DESCRIPTION

[0025] 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 recognizethat the same principles are equally applicable to, and can be employed in other compositions and methods. Before explaining the disclosed 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 particular embodiment disclosed herein. The terminology used herein is for the purpose of description and not of limitation.

[0026] 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”.

[0027] As used throughout, ranges are used as shorthand for describing each and every value that is within the 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.

[0028] 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.%.

[0029] All references cited herein are hereby incorporated by reference in their entireties. In the event of a conflict in a definition in the present disclosure and that of a cited reference, the present disclosure controls.

[0030] 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 “h”, “min”, “mL”, “nm”, and “µm” refer to hour, minute, milliliter, nanometer, and micrometer, respectively. The abbreviation “rpm” means revolutions per minute.

[0031] When referring to chemical structures and names, the symbols “C”, “H”, and “O” mean carbon, hydrogen, and oxygen, respectively. The symbols “-”, “=”, and “≡” mean single bond, double bond, and triple bond, 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, 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 polyoland a sweetener. If a particular oral care composition includes both a polyol and a sweetener, xylitol will serve only as either a polyol or a sweetener—not both.

[0036] For readability purposes, the chemical functional groups are in their adjective form; for each of the adjectives, the word “group” is assumed. For example, the adjective “alkyl” without a noun thereafter, should be read as “an alkyl group.”

[0037] As used herein, the term “oral fluid” refers to any fluid that originated in the oral cavity. Examples include, but are not limited to, saliva and gingival crevicular fluid (GCF). As used herein, the term “host cell” refers to any eukaryotic or prokaryotic cell (e.g., bacterial cells such as E. coli, yeast cells, mammalian cells, avian cells, amphibian cells, plant cells, fish cells, and insect cells), whether located in vitro or in vivo. For example, host cells may be located in a transgenic animal.

[0038] 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 or who has received treatment for a condition characterized by the presence of an IL-8 mediated inflammatory disorder, or in anticipation of possible susceptibility to an IL-8 mediated inflammatory disorder.

[0039] As used herein the term, “in vitro” refers to an artificial environment and to processes or reactions that occur within an artificial environment. In vitro environments include, but are not limited to, test tubes and cell cultures. The term “in vivo” refers to the natural environment (e.g., an animal or a cell) and to processes or reaction that occur within a natural environment.

[0040] As used herein, the term “pathogen” refers to a biological agent that causes a disease state (e.g., infection, cancer, etc.) in a host. “Pathogens” include, but are not limited to, viruses, bacteria, archaea, fungi, protozoans, mycoplasma, prions, and parasitic organisms.

[0041] As used herein, the term “microbe” refers to a microorganism and is intended to encompass both an individual organism, or a preparation comprising any number of the organisms.

[0042] As used herein, the term “microorganism” refers to any species or type of microorganism, including but not limited to, bacteria, archaea, fungi, protozoans, mycoplasma, and parasitic organisms.

[0043] The terms “bacteria” and “bacterium” refer to all prokaryotic organisms, including those within all of the phyla in the Kingdom Procaryotae. It is intended that the term encompass all microorganisms considered to be bacteria including Mycoplasma, Chlamydia, Actinomyces, Streptomyces, and Rickettsia. All forms of bacteria are included within this definition including cocci, bacilli, spirochetes, spheroplasts, protoplasts, etc. Also included within this term are prokaryotic organisms that are Gram-negative or Gram-positive. “Gram-negative” and “Gram- positive” refer to staining patterns with the Gram-staining process, which is well known in the art. (See e.g., Finegold and Martin, Diagnostic Microbiology, 6th Ed., CV Mosby St. Louis, pp.13-15 (1982)). “Gram-positive bacteria” are bacteria that retain the primary dye used in the Gram-stain, causing the stained cells to generally appear dark blue to purple under the microscope. “Gram- negative bacteria” do not retain the primary dye used in the Gram-stain, but are stained by the counterstain. Thus, Gram-negative bacteria generally appear red.

[0044] The term “non-pathogenic bacteria” or “non-pathogenic bacterium” includes all known and unknown non-pathogenic bacterium (Gram-positive or Gram-negative) and any pathogenic bacterium that has been mutated or converted to a non-pathogenic bacterium. Furthermore, a skilled artisan recognizes that some bacteria may be pathogenic to specific species and non- pathogenic to other species; thus, these bacteria can be utilized in the species in which it is non- pathogenic or mutated so that it is non-pathogenic.

[0045] As used herein, the term “cell culture” refers to any in vitro culture of cells, including, e.g., prokaryotic cells and eukaryotic cells. Included within this term are continuous cell lines (e.g., with an immortal phenotype), primary cell cultures, transformed cell lines, finite cell lines (e.g., non-transformed cells), bacterial cultures in or on solid or liquid media, and any other cell population maintained in vitro.

[0046] Disclosed herein are methods of treating and / or alleviating an IL-8 mediated inflammatory disorder in a subject in need thereof, wherein the method comprises applying to the oral cavity of the subject an oral care composition as disclosed herein.

[0047] As discussed above, dysregulation of IL-8 can contribute to the development and progression of several pathological conditions, including autoimmune diseases, cancer, and chronic inflammatory disorders (such as gingivitis, periodontitis, implantitis, or mucositis), chronic obstructive pulmonary disorder (COPD), and rheumatoid arthritis. Several factors are known to contribute to dysregulation of IL-8, and many patient populations may face an increasedrisk of IL-8 mediated inflammation. Namely, people at risk of IL-8 dysregulation and the consequent IL-8 mediated inflammation may include, for example, nicotine users; patients with inflammatory diseases (e.g., Crohn’s disease, ulcerative colitis), psoriasis, and asthma; patients with various infections, including bacterial and viral infections such as pneumonia, bronchitis, and urinary tract infections; obese people and people at risk of obesity-related complications, such as insulin resistance, type 2 diabetes, and cardiovascular disease; patients having chronic wounds, such as diabetic ulcers and pressure ulcers; and the elderly.

[0048] Nicotine can induce immune cells to produce reactive oxygen species, including IL-8. Accordingly, nicotine users may have higher levels of circulating IL-8, resulting in increased susceptibility to various IL-8 mediated inflammatory diseases and conditions. Nicotine is known as the primary addictive component in tobacco products and is known to weaken the body’s immune system. Users of tobacco products, including for example cigarettes, e-cigarettes, cigars, and dipping or chewing tobacco, are at increased risk of developing cancer, including leukemia, bladder cancer, cervical cancer, colon and rectal cancer, esophageal cancer, kidney cancer, liver cancer, lung cancer, mouth cancer, throat cancer, pancreatic cancer, and stomach cancer. In addition to cancer, tobacco users also face an increased risk of developing heart disease, stroke, lung diseases, diabetes, chronic obstructive pulmonary disease (COPD), tuberculosis, eye diseases, and problems of the immune system, including rheumatoid arthritis.

[0049] As used herein, a nicotine user includes a subject who uses a tobacco product, such as cigarettes, cigars, chewing tobacco, e-cigarettes, or other nicotine-containing device. In certain embodiments, the nicotine user may use the tobacco product at least one a week, such as at least twice a week, at least 3 times a week, or at least 4 times a week, at least 5 times a week, at least 6 times a week, or at least 7 times a week. In certain embodiments, the nicotine user may use the tobacco product at least once a day, such as at least twice a day, or at least 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times a day. In certain embodiments, the nicotine user is addicted to nicotine, and in certain embodiments, the nicotine use has been using at least one tobacco product for at least 3 months, such as at least 6 months, at least 9 months, at least a year, at least 2 years, or at least 3 years, such as at least 4, 5, 6, 7, 8, 9, or 10 years.

[0050] In addition to the health risks discussed above, nicotine users are also at an increased risk of developing problems in the oral cavity, such as gum disease (e.g., gingivitis and periodontitis) and tooth loss. Gingivitis is the earliest stage of gum disease, an inflammation of the gums causedby 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.

[0051] Periodontitis is more advanced gum disease. At this stage, the supporting bone and fibers that hold teeth in place are 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.

[0052] 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 results in open sores in the mouth, and is a known side effect of chemotherapy and radiotherapy.

[0053] Aspects the disclosure are directed to methods for reducing, alleviating, and / or treating IL- 8 mediated inflammatory disorders, such as COPD, pneumonia, bronchitis, Crohn’s disease, ulcerative colitis, asthma, and gum diseases, such as gingivitis, periodontitis, implantitis, or mucositis. It has been discovered that certain methods and compositions disclosed herein can provide significant reduction in the inflammatory response cytokine IL-8, which in turn may lead to a reduction, alleviation, and / or treatment of various IL-8 mediated inflammatory disorders in a subject in need thereof. The significant reduction in IL-8 was unexpected.

[0054] In certain embodiments, the methods disclosed herein reduce and / or inhibit the production of IL-8 in the oral cavity, such as in a periodontal tissue, and / or in the periodontal pocket. In some embodiments, the methods disclosed herein reduce the concentration of IL-8 by 5% or more, e.g., as compared to the concentration of IL-8 under similar conditions without the methods disclosed herein. In certain embodiments, the methods disclosed herein reduce the concentration of IL-8 by about 10% or more, about 15% or more, about 20% or more, about 25% or more, about 30% or more, about 35% or more, about 40% or more, about 45% or more, or about 50% or more, e.g., as compared to the concentration of IL-8 under similar conditions without the methods disclosed herein. For example, when the method includes applying an oral care composition in the form of a dentifrice by brushing, the method disclosed herein may reduce the concentration of IL-8 by oneof the foregoing amounts as compared to the concentration of IL-8 under similar conditions, such as brushing without the dentifrice disclosed herein. By way of another example, when the method includes applying an oral care composition in the form of a mouthwash by swishing, gargling, and / or rinsing, the method disclosed herein may reduce the concentration of IL-8 by one of the foregoing amounts as compared to the concentration of IL-8 under similar conditions without the application of the inventive mouthwash disclosed herein.

[0055] The method may achieve a reduction in the concentration of IL-8 in any period of time, such as after 2 hours to about 2 weeks, as measured in the oral cavity. The IL-8 concentration can be determined by any means known in the art, including, for example, by Enzyme Linked Immunosorbant Assay (ELISA) such as the commercially available Enzo IL-8 ELISA assay (Enzo Life Sciences, cat# ADI-900-156).

[0056] In accordance with another aspect, provided is a method for treating or alleviating gum disease, such as gingivitis, periodontitis, implantitis, or mucositis, the method comprising applying an oral care composition as disclosed herein to an oral cavity of a subject in need thereof, the oral care composition comprising a stannous source, a nitrate ion source, and a pyrophosphate. For instance, aspects of the disclosure, provide methods that reduce the amount of pathogenic bacteria, e.g., as compared to the growth rate of such pathogenic bacteria under similar conditions without the application of the methods disclosed herein. Periodontal pathogens participate in inflammation and disease progression and reducing them is important for maintaining health. Oral commensal bacteria actively participate with gingival tissue to maintain healthy neutrophil surveillance and normal tissue and bone turnover processes. Without being limited to any particular theory, it is believed that the methods disclosed herein may decrease the amount of pathogenic bacteria by mediating the IL-8 cytokine response.

[0057] 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 at least one a day, such as at least twice a day or at least three times a day. The methods disclosed herein may include administering the oral care composition to an oral cavity for about 10 seconds to about 30 minutes, e.g., about 15 seconds to about 25 minutes, about 20 seconds to about 15 minutes, about 25 seconds to about 5 minutes, or about 30 seconds to about 2 minutes. In some embodiments, the oral care compositions may be administered in a form that is maintained in the oral cavity overnight.

[0058] The methods disclosed herein may include administering about 0.1 gram to about 3 grams of the oral care composition, e.g., in the form of a dentifrice, to the oral cavity. For example, the oral care composition may be applied, e.g., in the form of a dentifrice, to the oral cavity in an amount of about 0.1 to about 3 grams, about 0.3 to about 3 grams, about 0.5 to about 3 grams, about 1 to about 3 grams, about 1.5 to about 3 grams, about 2 to about 3 grams, about 2.5 to about 3 grams; from about 0.1 to about 2.5 grams, about 0.3 to about 2.5 grams, about 0.5 to about 2.5 grams, about 1 to about 2.5 grams, about 1.5 to about 2.5 grams, about 2 to about 2.5 grams; from about 0.1 to about 2 grams, about 0.3 to about 2 grams, about 0.5 to about 2 grams, about 1 to about 2 grams, about 1.5 to about 2 grams; from about 0.1 to about 1.5 grams, about 0.3 to about 1.5 grams, about 0.5 to about 1.5 grams, about 1 to about 1.5 grams; from about 0.1 to about 1 gram, about 0.3 to about 1 gram, about 0.5 to about 1 gram; from about 0.1 to about 0.7 gram, about 0.3 to about 0.7 gram, about 0.5 to about 0.7 gram; from about 0.1 to about 0.4 gram, about 0.3 to about 0.4 gram, or any range or subrange thereof, based on the total weight of the oral care composition. In some embodiments, the oral care composition is in a form selected from a toothpaste; a gel; a mouthwash; a prophy; a spray; a lozenge; a tablet, a capsule; a strip; a patch; and a dissolvable film. The oral care compositions may also be in the form of a varnish or leave- on product (e.g., in the form of a gel, varnish, film etc.), and / or the like.

[0059] Suitable components, such as those listed below, may be included or excluded from the formulations 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.

[0060] The oral care compositions typically comprise a stannous ion source, preferably in an effective amount. The stannous ion source may be present in the oral care composition in an amount ranging from about 0.1 to about 5 wt.%, based on the total weight of the oral care composition. For example, the amount of stannous ion present in the oral care composition may be from about 0.1 to about 4 wt.%, about 0.1 to about 3 wt.%, about 0.1 to about 2 wt.%; from about 0.3 to about 5 wt.%, about 0.3 to about 4 wt.%, about 0.3 to about 3 wt.%, about 0.3 to about 2 wt.%; from about 0.6 to about 5 wt.%, about 0.6 to about 4 wt.%, about 0.6 to about 3 wt.%, about 0.6 to about 2 wt.%; from about 0.9 to about 5 wt.%, about 0.9 to about 4 wt.%, about 0.9to about 3 wt.%, about 0.9 to about 2 wt.%; from about 1.2 to about 5 wt.%, about 1.2 to about 4 wt.%, about 1.2 to about 3 wt.%, about 1.2 to about 2 wt.%; from about 1.5 to about 5 wt.%, about 1.5 to about 4 wt.%, about 1.5 to about 3 wt.%; from about 2 to about 5 wt.%, about 2 to about 4 wt.%, about 2 to about 3 wt.%; from about 3 to about 5 wt.%, about 4 to about 5 wt.%, or any range or subrange thereof, based on the total weight of the oral care composition. In at least one embodiment, oral care composition includes about 0.4 to about 0.5 wt.% of stannous ion source, such as about 0.45 wt.% of stannous ion source, based on the total weight of the oral care composition.

[0061] The stannous ion source may be selected from the group consisting of: stannous fluoride, stannous chloride, stannous pyrophosphate, stannous formate, stannous acetate, stannous gluconate, stannous lactate, stannous tartrate, stannous oxalate, stannous malonate, stannous citrate, stannous ethylene glyoxide, and combinations of two or more thereof. The stannous ion source may comprise stannous fluoride, stannous chloride, stannous acetate, and a combination of two or more thereof. In at least one embodiment, the stannous ion source comprises stannous fluoride, and at least one embodiment, the stannous ion source consists of stannous fluoride.

[0062] The oral care composition may include two or more, three or more, four or more, five or more, or six or more of stannous ion sources. For instance, oral care composition may comprise 2 to 7, 2 to 6, 2 to 5, 2 to 5, or 2 to 4; 3 to 7, 3 to 6, 2 to 5, or 3 to 5 stannous ion sources. In some embodiments, the oral care composition comprises stannous fluoride and stannous pyrophosphate. Additionally or alternatively, the oral care composition may comprise stannous fluoride and stannous chloride.

[0063] The oral care compositions typically comprise one or more nitrate ion sources, preferably present in an effective amount. The nitrate ion source(s) may be present in the oral care composition in an amount ranging from about 0.1 to about 5 wt.%, based on the total weight of the oral care composition. In some instances, the amount of nitrate ion present in the oral care composition may be from about 0.1 to about 4 wt.%, about 0.1 to about 3 wt.%, about 0.1 to about 2 wt.%; from about 0.3 to about 5 wt.%, about 0.3 to about 4 wt.%, about 0.3 to about 3 wt.%, about 0.3 to about 2 wt.%; from about 0.6 to about 5 wt.%, about 0.6 to about 4 wt.%, about 0.6 to about 3 wt.%, about 0.6 to about 2 wt.%; from about 0.9 to about 5 wt.%, about 0.9 to about 4 wt.%, about 0.9 to about 3 wt.%, about 0.9 to about 2 wt.%; from about 1.2 to about 5 wt.%, about 1.2 to about 4 wt.%, about 1.2 to about 3 wt.%, about 1.2 to about 2 wt.%; from about 1.5 to about5 wt.%, about 1.5 to about 4 wt.%, about 1.5 to about 3 wt.%; from about 2 to about 5 wt.%, about 2 to about 4 wt.%, about 2 to about 3 wt.%; from about 3 to about 5 wt.%, about 4 to about 5 wt.%, or any range or subrange thereof, based on the total weight of the oral care composition.

[0064] The one or more nitrate ion source may be in the form of a salt or an ion derived therefrom, including, e.g., nitrate salt selected from an alkali or alkaline earth metal nitrate. Examples of nitrate ion sources include lithium nitrate, sodium nitrate, potassium nitrate, magnesium nitrate, calcium nitrate, zinc nitrate, silver nitrate, ammonium nitrate, or a combination two or more thereof. In at least one embodiment, the nitrate ion source comprises potassium nitrate.

[0065] The oral care compositions may be formulated to have a molar ratio of nitrate ions to stannous ions, both measured as free ions, that is about 2:1 or less. For example, the oral care composition may have a molar ratio of nitrate ions to stannous ions, both measured as free ions, of from about 0.5:1 to about 2:1, about 0.5:1 to about 1.8:1, about 0.5:1 to about 1.6:1, about 0.5:1 to about 1.4:1, about 0.5:1 to about 1.2:1, about 0.5:1 to about 1:1; from about 0.7:1 to about 2:1, about 0.7:1 to about 1.8:1, about 0.7:1 to about 1.6:1, about 0.7:1 to about 1.4:1, about 0.7:1 to about 1.2:1, about 0.7:1 to about 1:1; from about 0.9:1 to about 2:1, about 0.9:1 to about 1.8:1, about 0.9:1 to about 1.6:1, about 0.9:1 to about 1.4:1, about 0.9:1 to about 1.2:1, about 0.9:1 to about 1:1, or any range or subrange thereof. In some embodiments, the oral care composition is formulated to have a molar ratio of nitrate ions to stannous ions, both measured as free ions, of about 1:1.

[0066] The oral care compositions typically comprise one or more phosphate ion source(s). The phosphate ion source(s) is preferably present in an effective amount. In some instances, the oral care composition may include one or more phosphate ion source(s) in an amount from about 0.1 to about 7 wt.%, based on the total weight of the oral care composition. For example, the one or more phosphate ion source(s) may be present in the oral care composition in an amount from about 0.1 to about 6 wt.%, about 0.1 to about 5 wt.%, about 0.1 to about 4 wt.%, about 0.1 to about 3 wt.%, about 0.1 to about 2 wt.%, about 0.1 to about 1 wt.%; from about 0.4 to about 7 wt.%, about 0.4 to about 6 wt.%, about 0.4 to about 5 wt.%, about 0.4 to about 4 wt.%, about 0.4 to about 3 wt.%, about 0.4 to about 2 wt.%, about 0.4 to about 1 wt.%; from about 0.8 to about 7 wt.%, about 0.8 to about 6 wt.%, about 0.8 to about 5 wt.%, about 0.8 to about 4 wt.%, about 0.8 to about 3 wt.%, about 0.8 to about 2 wt.%; from about 1.4 to about 7 wt.%, about 1.4 to about 6 wt.%, about 1.4 to about 5 wt.%, about 1.4 to about 4 wt.%, about 1.4 to about 3 wt.%; from about 2 to about7 wt.%, about 2 to about 6 wt.%, about 2 to about 5 wt.%, about 2 to about 4 wt.%, about 2 to about 3 wt.%; from about 3 to about 7 wt.%, about 3 to about 6 wt.%, about 3 to about 5 wt.%; from about 4 to about 7 wt.%, about 4 to about 6 wt.%, about 5 to about 7 wt.%, or any range or subrange thereof, based on the total weight of the oral care composition.

[0067] The phosphate source may preferably comprise a soluble phosphate compound, such as a phosphate salt. The phosphate source may be a phosphate ion source. Examples of phosphate ion sources include tetrasodium pyrophosphate, dicalcium orthophosphate dihydrate, dicalcium phosphate dihydrate, calcium hydrogen phosphate, calcium pyrophosphate, p-calcium pyrophosphate, tricalcium phosphate, calcium metaphosphate, potassium metaphosphate, sodium metaphosphate, or a combination thereof. The phosphate source may be a pyrophosphate salt, such as an alkali metal pyrophosphate salt. In certain embodiments, the alkali metal pyrophosphate is selected from a tetra alkali metal pyrophosphate, dialkali metal diacid pyrophosphate, trialkali metal monoacid pyrophosphate and mixtures thereof, wherein the alkali metals are sodium or potassium. For instance, the phosphate source may include tetrasodium pyrophosphate (TSPP), tetrapotassium pyrophosphate, sodium tripolyphosphate, tetrapolyphosphate, sodium trimetaphosphate, sodium hexametaphosphate or a combination of two or more thereof. The phosphate source may be chosen from orthophosphates, polymetaphosphates, pyrophosphates, and a combination of two or more thereof. In some instances, the phosphate source includes tetrasodium pyrophosphate (TSPP), sodium tripolyphosphate (STPP), or a combination thereof. In at least one embodiment, the phosphate source comprises tetrasodium pyrophosphate. The phosphate source, when in the form of a salt, maybe in their hydrated and / or unhydrated forms.

[0068] Additionally or alternatively, the oral care composition may include one or more anti- calculus agents. Examples of anti-calculus 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, phosphonoalkane carboxylic acids. Inorganic phosphate and polyphosphate salts that may be mentioned include monobasic, dibasic and tribasic sodium phosphates. Soluble pyrophosphates, such as those disclosed herein, may be useful anti-calculus agents. The pyrophosphate salts can be any of the alkali metal pyrophosphate salts.

[0069] The oral care composition may include the anti-calculus agents in an amount from about 0.1 to about 7 wt.%, based on the total weight of the oral care composition. For example, the anti- calculus agent(s) may be present in the oral care composition in an amount from about 0.1 to about 6 wt.%, about 0.1 to about 5 wt.%, about 0.1 to about 4 wt.%, about 0.1 to about 3 wt.%, about 0.1 to about 2 wt.%, about 0.1 to about 1 wt.%; from about 0.4 to about 7 wt.%, about 0.4 to about 6 wt.%, about 0.4 to about 5 wt.%, about 0.4 to about 4 wt.%, about 0.4 to about 3 wt.%, about 0.4 to about 2 wt.%, about 0.4 to about 1 wt.%; from about 0.8 to about 7 wt.%, about 0.8 to about 6 wt.%, about 0.8 to about 5 wt.%, about 0.8 to about 4 wt.%, about 0.8 to about 3 wt.%, about 0.8 to about 2 wt.%; from about 1.4 to about 7 wt.%, about 1.4 to about 6 wt.%, about 1.4 to about 5 wt.%, about 1.4 to about 4 wt.%, about 1.4 to about 3 wt.%; from about 2 to about 7 wt.%, about 2 to about 6 wt.%, about 2 to about 5 wt.%, about 2 to about 4 wt.%, about 2 to about 3 wt.%; from about 3 to about 7 wt.%, about 3 to about 6 wt.%, about 3 to about 5 wt.%; from about 4 to about 7 wt.%, about 4 to about 6 wt.%, about 5 to about 7 wt.%, or any range or subrange thereof, based on the total weight of the oral care composition.

[0070] In certain embodiments, the phosphate source may be an insoluble phosphate source, such as zinc phosphate. While zinc phosphate is considered insoluble (e.g., poorly soluble) in water, when placed in formulation, e.g., at acidic or basic pH, zinc phosphate can dissolve sufficiently upon use to provide an effective concentration of zinc ions to the enamel, thereby protecting against erosion, reducing bacterial colonization and biofilm development, and providing enhanced shine to the teeth. It has also been discovered that zinc phosphate in a formulation with a second phosphate source may enhance phosphate deposition, as explained in PCT Publication WO 2014 / 088573, the disclosure of which is hereby incorporated by reference in its entirety.

[0071] Any amount of zinc phosphate that is effective for protecting against enamel erosion and / or providing any of the other benefits described herein can be employed. Examples of suitable amounts of zinc phosphate can range from about 0.05 to about 5 wt.%, such as from about 0.1 to about 4 wt.%, or from about 0.5 to about 3 wt.%, or from about 0.5 to about 2 wt.%, or from about 0.8 to about 1.5 wt.%, or from about 0.9 to about 1.1 wt.%, or about 1 wt.%, relative to the total weight of the oral care composition.

[0072] In compositions comprising significant amounts of water, the zinc phosphate may act as a stabilizing agent for the stannous fluoride, so that the stannous fluoride remains in solution in the water. Stannous fluoride is generally considered unstable in water due to the hydrolytic andoxidative loss of stannous ions at typical pH ranges employed in oral care compositions. Consequently, stannous fluoride may be used herein in oral care compositions of the present disclosure containing no water or low water, or with a chelating agent. Alternatively, zinc phosphate and stannous fluoride can be combined together in a single phase formulation using standard mixing processes and typical pH ranges to form stable aqueous oral care compositions. The zinc phosphate remains essentially insoluble in the composition. However, the stannous fluoride has been shown to remain soluble and stable in solutions comprising relatively high amounts of water for extended periods of time, such as 3 months or longer at 40 °C.

[0073] As such, any desired amount of water can be employed in the oral care compositions disclosed herein. In compositions containing relatively high amounts of water, examples of suitable amounts of water range from about 10 wt.% or more, such as from about 12 wt.% or more, such as from about 14 wt.% to about 99 wt.% by weight. For example, the amount of water may be from about 15 wt.% to about 85 wt.%, or from about 20 wt.% to about 75 wt.%, or from about 25 wt.% to about 50 wt.%, or from about 30 wt.% to about 40 wt.%, for example, about 35 wt.%, by weight based on the total weight of the oral care composition. Amounts will 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.%, such as from about 10 wt.% to about 25 wt.%, from about 12 wt.% to about 20 wt.%, from about 14 wt.% to about 15 wt.% by weight, or about 14.5 wt.%, by weight relative to the total weight of the dentifrice composition.

[0074] In compositions containing relatively low or lower amounts of water, the water may be present in the oral care composition in an amount from about 1 to about 37 wt.%, such as from about 5 to about 35 wt.%, based on the total weight of the oral care composition. For example, the oral care composition may include water in an amount from about 5 to about 34 wt.%, about 5 to about 31 wt.%, about 5 to about 28 wt.%, about 5 to about 25 wt.%, about 5 to about 20 wt.%; about 5 to about 7 wt%, about 5.5 to about 6.5 wt%, about 6.3 wt%, from about 10 to about 37 wt.%, about 10 to about 34 wt.%, about 10 to about 31 wt.%, about 10 to about 28 wt.%, about 10 to about 25 wt.%; from about 15 to about 37 wt.%, about 15 to about 34 wt.%, about 15 to about 31 wt.%, about 15 to about 28 wt.%, about 15 to about 25 wt.%; from about 20 to about 37 wt.%, about 20 to about 34 wt.%, about 20 to about 31 wt.%, about 20 to about 28 wt.%; from about 25 to about 37 wt.%, about 25 to about 34 wt.%, about 25 to about 31 wt.%; from about 28 to about37 wt.%, about 28 to about 34 wt.%, about 28 to about 31 wt.%; from about 31 to about 37 wt.%; from about 37 to about 50 wt.%, about 37 to about 45 wt.%, or any range or subrange thereof, based on the total weight of the oral care composition.

[0075] In addition to or instead of zinc phosphate, the oral care composition may include an alternative zinc ion source. When present, the zinc ion source is preferably in an effective amount. The zinc ion source may be present in the oral care composition in an amount from about 0.1 to about 8 wt.%, based on the total weight of the oral care composition. For example, the amount of zinc ion source present in the oral care composition may be from about 0.1 to about 6 wt.%, about 0.1 to about 5 wt.%, about 0.1 to about 4 wt.%, about 0.1 to about 3 wt.%, about 0.1 to about 2 wt.%, about 0.1 to about 1 wt.%; from about 0.3 to about 8 wt.%, about 0.3 to about 6 wt.%, about 0.3 to about 5 wt.%, about 0.3 to about 4 wt.%, about 0.3 to about 3 wt.%, about 0.3 to about 2 wt.%; from about 0.6 to about 8 wt.%, about 0.6 to about 6 wt.%, about 0.6 to about 5 wt.%, about 0.6 to about 4 wt.%, about 0.6 to about 3 wt.%, about 0.6 to about 2 wt.%; from about 0.9 to about 8 wt.%, about 0.9 to about 6 wt.%, about 0.9 to about 5 wt.%, about 0.9 to about 4 wt.%, about 0.9 to about 3 wt.%, about 0.9 to about 2 wt.%; from about 1.2 to about 8 wt.%, about 1.2 to about 6 wt.%, about 1.2 to about 5 wt.%, about 1.2 to about 4 wt.%, about 1.2 to about 3 wt.%, about 1.2 to about 2 wt.%; from about 1.5 to about 8 wt.%, about 1.5 to about 6 wt.%, about 1.5 to about 5 wt.%, about 1.5 to about 4 wt.%, about 1.5 to about 3 wt.%; from about 2 to about 8 wt.%, about 2 to about 6 wt.%, about 2 to about 5 wt.%, about 2 to about 4 wt.%, about 2 to about 3 wt.%; from about 3 to about 8 wt.%, about 3 to about 6 wt.%, about 3 to about 5 wt.%; from about 4 to about 8 wt.%, about 4 to about 6 wt.%, about 4 to about 5 wt.%, or any range or subrange thereof, based on the total weight of the oral care composition.

[0076] The zinc ion source may be in the form of a salt. For example, the zinc ion source may comprise one or more zinc salt(s) chosen from zinc sulfate, zinc chloride, zinc acetate, zinc phenol sulfonate, zinc borate, zinc bromide, zinc nitrate, zinc glycerophosphate, zinc benzoate, zinc carbonate, zinc carnosine, zinc citrate, zinc hexafluorosilicate, zinc diacetate trihydrate, zinc oxide, zinc peroxide, zinc salicylate, zinc silicate, zinc stannate, zinc tannate, zinc titanate, zinc tetrafluoroborate, zinc gluconate, zinc lactate, zinc glycinate, zinc phosphate, and a combination of two or more thereof. In some embodiments, the zinc ion source is selected from zinc citrate, zinc oxide, zinc phosphate, zinc lactate, zinc sulfate, zinc silicate, zinc gluconate, and a combination of two or more thereof.

[0077] The oral care composition may include two or more, three or more, four or more, five or more, or six or more zinc ion sources. For instance, oral care composition may comprise 2 to 7, 2 to 6, 2 to 5, 2 to 5, or 2 to 4; 3 to 7, 3 to 6, 2 to 5, or 3 to 5 zinc ion sources. In some embodiments, the oral care composition comprises zinc oxide, zinc citrate, zinc phosphate, or a combination of two or more thereof. In at least one preferred embodiment, the oral care composition comprises zinc phosphate.

[0078] The oral care compositions may be formulated to have a weight ratio of the amount of zinc oxide to zinc citrate of from about 1.5:1 to about 4.5:1. For instance, the weight ratio of the amount of zinc oxide to zinc citrate may be from about 1.5:1 to about 4.5:1, about 1.5:1 to about 4:1, about 1.5:1 to about 3.5:1, about 1.5:1 to about 3:1, about 1.5:1 to about 2.5:1; from about 2:1 to about 4.5:1, about 2:1 to about 4:1, about 2:1 to about 3.5:1, about 2:1 to about 3:1; from about 2.5:1 to about 4.5:1, about 2.5:1 to about 4:1, about 2.5:1 to about 3.5:1; from about 3:1 to about 4.5:1, about 3:1 to about 4:1, or any range or subrange formed thereof. In some embodiments, the weight ratio of the amount of zinc oxide to zinc citrate is about 2:1, about 2.5:1, about 3:1, about 3.5:1, about 4:1, or a range formed thereof.

[0079] The oral care composition may include one or more surfactants, e.g., in an amount ranging from about 0.5 to about 8 wt.%, based on the total weight of the oral care composition. For example, the oral care composition may include one or more surfactant in an amount from about 0.5 to about 7 wt.%, about 0.5 to about 6 wt.%, about 0.5 to about 5 wt.%, about 0.5 to about 4 wt.%, about 0.5 to about 3 wt.%, about 0.5 to about 2 wt.%; from about 1 to about 9 wt.%, about 1 to about 8 wt.%, about 1 to about 7 wt.%, about 1 to about 6 wt.%, about 1 to about 5 wt.%, about 1 to about 4 wt.%, about 1 to about 3 wt.%, about 1 to about 2 wt.%; from about 2 to about 9 wt.%, about 2 to about 8 wt.%, about 2 to about 7 wt.%, about 2 to about 6 wt.%, about 2 to about 5 wt.%, about 2 to about 4 wt.%, about 2 to about 3 wt.%; from about 2.5 to about 9 wt.%, about 2.5 to about 8 wt.%, about 2.5 to about 7 wt.%, about 2.5 to about 6 wt.%, about 2.5 to about 5 wt.%, about 2.5 to about 4 wt.%, about 2.5 to about 3.5 wt.%; from about 3 to about 9 wt.%, about 3 to about 8 wt.%, about 3 to about 7 wt.%, about 3 to about 6 wt.%, about 3 to about 5 wt.%, about 3 to about 4 wt.%, about 3 to about 3.5 wt.%; from about 4 to about 9 wt.%, about 4 to about 8 wt.%, about 4 to about 7 wt.%, about 4 to about 6 wt.%, about 4 to about 5 wt.%; from about 5 to about 9 wt.%, about 5 to about 8 wt.%, about 5 to about 7 wt.%, about 5 to about 6 wt.%; from about 7 to about 9 wt.%, about 7 to about 8 wt.%, or any range or subrange thereof,based on the total weight of the oral care composition.

[0080] The oral care composition may comprise a surfactant system comprising of a plurality of surfactants. The surfactant system may comprise a plurality of 2 or more surfactants, e.g., 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, or 9 or more surfactants. In some instances, the oral care composition includes 2, 34, 5, 6, 7, 8, 9, 10 surfactants, or a range formed therefrom. For example, the oral care composition may comprise 2 to 4, 2 or 3, 3 or 4, 4 to 9, 4 to 8, 4 to 7, 4 to 6, 4 or 5; 5 to 9, 5 to 8, 5 to 7, 5 or 6; 6 to 9, 6 to 8, 6 or 7 surfactants.

[0081] The surfactant system may comprise one or more anionic surfactants, one or more cationic surfactants, one or more nonionic surfactants, one or more amphoteric surfactants, one or more zwitterionic surfactants, one or more bacterial surfactants, or combinations of two or more thereof. For example, the surfactant system comprises one or more non-sulfate based anionic surfactants, one or more amphoteric surfactants, one or more nonionic surfactants, and one or more amino acid surfactants. In some embodiments, the surfactant system comprises a single non-sulfate based anionic surfactant, a single amphoteric surfactant, a single nonionic surfactant, and a single amino acid surfactant. In at least one embodiment, the surfactant system comprises a single non-sulfate based anionic surfactant, a single amphoteric surfactant, a single nonionic surfactant, and a single amino acid surfactant. In further embodiments, the surfactant system consists of one or more anionic surfactant, one or more amphoteric surfactant, one or more nonionic surfactant, and one or more amino acid surfactant.

[0082] The oral care compositions disclosed herein may comprise one or more anionic surfactant(s). The one or more anionic surfactant(s) may be in an amount that ranges from about 0.1 to about 7 wt.%, based on the total weight of the oral care composition. In some instances, the one or more anionic surfactant(s) is present in the surfactant system in an amount from about 0.1 to about 6 wt.%, about 0.1 to about 5 wt.%, about 0.1 to about 4 wt.%, about 0.1 to about 3 wt.%, about 0.1 to about 2 wt.%, about 0.1 to about 1 wt.%; from about 0.4 to about 7 wt.%, about 0.4 to about 6 wt.%, about 0.4 to about 5 wt.%, about 0.4 to about 4 wt.%, about 0.4 to about 3 wt.%, about 0.4 to about 2 wt.%, about 0.4 to about 1 wt.%; from about 0.8 to about 7 wt.%, about 0.8 to about 6 wt.%, about 0.8 to about 5 wt.%, about 0.8 to about 4 wt.%, about 0.8 to about 3 wt.%, about 0.8 to about 2 wt.%; from about 1.4 to about 7 wt.%, about 1.4 to about 6 wt.%, about 1.4 to about 5 wt.%, about 1.4 to about 4 wt.%, about 1.4 to about 3 wt.%; from about 2 to about 7 wt.%, about 2 to about 6 wt.%, about 2 to about 5 wt.%, about 2 to about 4 wt.%, about 2 to about3 wt.%; from about 3 to about 7 wt.%, about 3 to about 6 wt.%, about 3 to about 5 wt.%; from about 4 to about 7 wt.%, about 4 to about 6 wt.%, about 5 to about 7 wt.%, or any range or subrange thereof, based on the total weight of the oral care composition.

[0083] The one or more anionic surfactant(s) may be selected be selected from sulfate based anionic surfactants and / or from non-sulfate based anionic surfactants, such as sulfonated monoglycerides of fatty acids, isethionates, sarcosinates, taurate, and a combination of two or more thereof. Examples of sulfate based anionic surfactants include ammonium lauryl sulfate, ammonium lauryl ether sulfate, sodium dodecyl sulfate, sodium coco-sulfate, ammonium coco- sulfate, and a combination of two or more thereof. In at least one embodiment, the oral care composition includes a sulfate based anionic surfactant, wherein the oral care composition is substantially free of or free of sodium lauryl sulfate and / or sodium lauryl ether sulfate.

[0084] The anionic surfactant(s) may have at least one acyl group, preferably, comprising a carbon chain of 8 to 21 carbons. In some instance, the alkyl group(s) of the anionic surfactant(s) comprise a carbon chain of 8 to 19 carbons, 8 to 17 carbons, 8 to 15 carbons, 8 to 13 carbons, 8 to 11 carbons; 9 to 21 carbons, 9 to 19 carbons, 9 to 17 carbons, 9 to 15 carbons, 9 to 13 carbons, 9 to 11 carbons; 11 to 21 carbons, 11 to 19 carbons, 11 to 17 carbons, 11 to 15 carbons, 11 to 13 carbons; 13 to 21 carbons, 13 to 19 carbons, 13 to 17 carbons, or any range or subrange thereof. The anionic surfactants disclosed herein may be incorporated in a salt form. The salt form of the anionic surfactants may have an alkali metal (e.g., sodium or potassium) and / or ammonium group.

[0085] Non-limiting examples of isethionates include sodium isethionate, sodium cocoyl isethionate, sodium lauroyl methyl isethionate, and sodium cocoyl methyl isethionate. Sulfonated monoglycerides of fatty acids include sodium coconut monoglyceride sulfonates and the like. Examples of acyl sarcosinates include potassium lauroyl sarcosinate, potassium cocoyl sarcosinate, sodium cocoyl sarcosinate, sodium lauroyl sarcosinate, sodium myristoyl sarcosinate, sodium oleoyl sarcosinate, sodium palmitoyl sarcosinate, ammonium lauroyl sarcosinate, and combinations of two or more thereof.

[0086] The anionic surfactant may be selected from taurates having a structure according to the following formula: wherein R1is a saturated orwith 6 to 18 carbon atoms,R2is H or methyl, and M+is H, sodium, or potassium (e.g., sodium methyl cocoyl taurate).

[0087] Additional examples of taurate surfactants include sodium cocoyl taurate, potassium cocoyl taurate, potassium methyl cocoyl taurate, sodium caproyl methyl taurate, sodium cocoyl taurate, sodium lauroyl taurate, sodium methyl cocoyl taurate (SMCT), sodium methyl lauroyl taurate, sodium methyl myristoyl taurate, sodium methyl oleoyl taurate, sodium methyl palmitoyl taurate, sodium methyl stearoyl taurate, and combinations of two or more thereof. In some embodiments, the oral care composition comprises sodium lauroyl methyl taurate (or sodium methyl lauroyl taurate), sodium methyl cocoyl taurate (SMCT), or a combination thereof. In at least one preferred embodiment, the surfactant system comprises sodium methyl cocoyl taurate.

[0088] The surfactant system may comprise one or more amphoteric surfactant(s), e.g., in an amount ranging from about 0.1 to about 5 wt.%, based on the total weight of the oral care composition. For example, the one or more amphoteric surfactant(s) may be present in the surfactant system in an amount ranging from about 0.1 to about 4 wt.%, about 0.1 to about 3 wt.%, about 0.1 to about 2 wt.%, about 0.1 to about 1 wt.%; from about 0.3 to about 5 wt.%, about 0.3 to about 4 wt.%, about 0.3 to about 3 wt.%, about 0.3 to about 2 wt.%, about 0.3 to about 1 wt.%; from about 0.6 to about 5 wt.%, about 0.6 to about 4 wt.%, about 0.6 to about 3 wt.%, about 0.6 to about 2 wt.%, about 0.6 to about 1 wt.%; from about 1 to about 5 wt.%, about 1 to about 4 wt.%, about 1 to about 3 wt.%, about 1 to about 2 wt.%; from about 1.5 to about 5 wt.%, about 1.5 to about 4 wt.%, about 1.5 to about 3 wt.%; from about 2 to about 5 wt.%, about 2 to about 4 wt.%, about 2 to about 3 wt.%; from about 3 to about 5 wt.%, about 3 to about 4 wt.%, about 4 to about 5 wt.%, including any range or subrange thereof, based on the total weight of the oral care composition.

[0089] Amphoteric surfactants are typically characterized by a combination of high surfactant activity, lather forming and mildness. The amphoteric surfactant may comprise a substituent containing 8 to 18 carbon atoms and a substituent containing one or more carboxylate, sulfonate, sulfate, phosphate, or phosphonate. For instance, the amphoteric surfactant may have an alkyl group comprising from 8 to 20 carbon atoms, 8 to 16 carbon atoms, 10 to 16 carbon atoms, or 10 to 13 carbon atoms. The amphoteric surfactant(s) may include, but are not limited to, derivatives of aliphatic secondary and tertiary amines in which the aliphatic radical can be straight chain or branched. In some cases, one of the aliphatic substituents of the amphoteric surfactant contains about 8 to about 18 carbon atoms and one of the aliphatic substituents contains an anionic watersolubilizing group, e.g., carboxy, sulfonate, sulfate, phosphate, or phosphonate. The amphoteric surfactants disclosed herein may be present in the oral care composition in a salt form.

[0090] The amphoteric surfactants may include alkyl amphopropionates, betaines, alkyl sultaines, alkyl amphoacetates, or a combination of two or more thereof. Preferably, the oral care composition includes an amphoteric surfactant selected from betaine surfactants (also referred to herein as betaines). Examples of betaine surfactants include, e.g., alkyl betaines, such as coco dimethyl carboxymethyl betaine, lauryl dimethyl carboxy-methyl betaine, lauryl dimethyl alpha- carboxyethyl betaine, cetyl dimethyl carboxymethyl betaine, lauryl bis-(2-hydroxyethyl)carboxy methyl betaine, stearyl bis-(2-hydroxypropyl)carboxymethyl betaine, oleyl dimethyl gamma- carboxypropyl betaine, lauryl bis-(2-hydroxypropyl)alpha-carboxyethyl betaine. In some instances, the betaine surfactant is selected from coca betaine, cocamidopropyl betaine, lauryl betaine, laurylhydroxy sulfobetaine, lauryldimethyl betaine, behenyl betaine, capryl / capramidopropyl betaine, lauryl hydroxysultaine, stearyl betaine, and a combination of two or more thereof. For instance, the betaine surfactant may be coco betaine, cocamidopropyl betaine, behenyl betaine, capryl / capramidopropyl betaine, lauryl betaine, or a combination of two or more thereof. In at least one embodiment, the oral care composition comprises coco betaine, cocamidopropyl betaine, or a combination thereof.

[0091] The surfactant system may comprise one or more nonionic surfactant(s). The one or more nonionic surfactant(s) may be present in an amount ranging from about 0.1 to about 7 wt.%, based on the total weight of the oral care composition. In some instances, the one or more nonionic surfactant(s) is present in the surfactant system in an amount ranging from about 0.1 to about 6 wt.%, about 0.1 to about 5 wt.%, about 0.1 to about 4 wt.%, about 0.1 to about 3 wt.%, about 0.1 to about 2 wt.%, about 0.1 to about 1 wt.%; from about 0.4 to about 7 wt.%, about 0.4 to about 6 wt.%, about 0.4 to about 5 wt.%, about 0.4 to about 4 wt.%, about 0.4 to about 3 wt.%, about 0.4 to about 2 wt.%, about 0.4 to about 1 wt.%; from about 0.8 to about 7 wt.%, about 0.8 to about 6 wt.%, about 0.8 to about 5 wt.%, about 0.8 to about 4 wt.%, about 0.8 to about 3 wt.%, about 0.8 to about 2 wt.%; from about 1.4 to about 7 wt.%, about 1.4 to about 6 wt.%, about 1.4 to about 5 wt.%, about 1.4 to about 4 wt.%, about 1.4 to about 3 wt.%; from about 2 to about 7 wt.%, about 2 to about 6 wt.%, about 2 to about 5 wt.%, about 2 to about 4 wt.%, about 2 to about 3 wt.%; from about 3 to about 7 wt.%, about 3 to about 6 wt.%, about 3 to about 5 wt.%; from about 4 to about 7 wt.%, about 4 to about 6 wt.%, about 5 to about 7 wt.%, or any range or subrange thereof, basedon the total weight of the oral care composition.

[0092] The one or more nonionic surfactant(s) may be selected from glucosides, compounds produced by the condensation of alkylene oxide groups (hydrophilic in nature) with an organic hydrophobic compound, which may be aliphatic or alkylaromatic in nature. Examples of glucoside surfactants include decyl glucoside, stearyl glucoside, lauryl glucoside, coco-glucoside, cetearyl glucoside, decyl lauryl glucoside, lauroyl ethyl glucoside, myristoyl ethyl glucoside, oleoyl ethyl glucoside, or a combination of two or more thereof. In some embodiments, the surfactant system includes one or more nonionic surfactant(s) chosen from lauryl glucoside, lauroyl ethyl glucoside, myristoyl ethyl glucoside, oleoyl ethyl glucoside, and a combination of two or more thereof. Additionally or alternatively, the glucoside surfactant may be chosen from polyglucosides, such as alkylpolyglucosides.

[0093] Further examples of nonionic surfactants include poloxamers, polyethylene oxide condensates of alkyl phenols, products derived from the condensation of ethylene oxide with the reaction product of propylene oxide and ethylene diamine, ethylene oxide condensates of aliphatic alcohols, acids, and esters, long chain tertiary amine oxides, long chain tertiary phosphine oxides, long chain dialkyl sulfoxides and mixtures of such materials. Additional examples of nonionic surfactants include polyoxyethylene, polyoxyethylene sorbitan esters, polyoxyl 40 hydrogenated castor oil, fatty alcohol ethoxylates, polyethylene oxide condensates of alkyl phenols, products derived from the condensation of ethylene oxide with the reaction product of propylene oxide and ethylene diamine, ethylene oxide condensates of aliphatic alcohols, long chain tertiary amine oxides, long chain tertiary phosphine oxides, long chain dialkyl sulfoxides, or a combination of two or more thereof. In some instances, the nonionic surfactant comprises amine oxides, fatty acid amides, ethoxylated fatty alcohols, block copolymers of polyethylene glycol and polypropylene glycol, glycerol alkyl esters, polyoxyethytene glycol octylphenol ethers, sorbitan alkyl esters, polyoxyethylene glycol sorbitan alkyl esters, or a combination of two or more thereof.

[0094] The surfactant system may comprise one or more the amino acid derived surfactant(s) in an amount that may vary, but may be present in an amount ranging from about 0.1 to about 7 wt.%, based on the total weight of the oral care composition. For example, the one or more amino acid derived surfactant(s) is present in the surfactant system in an amount ranging from about 0.1 to about 6 wt.%, about 0.1 to about 5 wt.%, about 0.1 to about 4 wt.%, about 0.1 to about 3 wt.%, about 0.1 to about 2 wt.%, about 0.1 to about 1 wt.%; from about 0.4 to about 7 wt.%, about 0.4to about 6 wt.%, about 0.4 to about 5 wt.%, about 0.4 to about 4 wt.%, about 0.4 to about 3 wt.%, about 0.4 to about 2 wt.%, about 0.4 to about 1 wt.%; from about 0.8 to about 7 wt.%, about 0.8 to about 6 wt.%, about 0.8 to about 5 wt.%, about 0.8 to about 4 wt.%, about 0.8 to about 3 wt.%, about 0.8 to about 2 wt.%; from about 1.4 to about 7 wt.%, about 1.4 to about 6 wt.%, about 1.4 to about 5 wt.%, about 1.4 to about 4 wt.%, about 1.4 to about 3 wt.%; from about 2 to about 7 wt.%, about 2 to about 6 wt.%, about 2 to about 5 wt.%, about 2 to about 4 wt.%, about 2 to about 3 wt.%; from about 3 to about 7 wt.%, about 3 to about 6 wt.%, about 3 to about 5 wt.%; from about 4 to about 7 wt.%, about 4 to about 6 wt.%, about 5 to about 7 wt.%, or any range or subrange thereof, based on the total weight of the oral care composition.

[0095] The amino acid derived surfactant may be anionic, non-ionic, amphoteric, or cationic. In some embodiments, the amino acid derived surfactant is an anionic surfactant. The amino acid derived surfactant may be based on alanine, arginine, aspartic acid, glutamic acid, glycine, isoleucine, leucine, lysine, phenylalanine, serine, tyrosine, valine, sarcosine, threonine, and taurine. The amino acid derived surfactants disclosed herein may be present in the oral care composition in a salt form. The most common cation associated with the acyl amino acid can be sodium or potassium. Alternatively, the cation can be an organic salt such as triethanolamine (TEA) or a metal salt.

[0096] The amino acid derived surfactant may be an acyl amino acid derived surfactant having an aliphatic carbon chain of 3 to 21 carbons. For instance, the amino acid derived surfactant may include an alkyl group comprised of a carbon chain of 3 to 21 carbons, 3 to 19 carbons, 3 to 17 carbons, 3 to 15 carbons, 3 to 13 carbons, 3 to 11 carbons, 3 to 9 carbons, 3 to 7 carbons; 4 to 21 carbons, 4 to 19 carbons, 4 to 17 carbons, 4 to 15 carbons, 4 to 13 carbons, 4 to 11 carbons, 4 to 9 carbons, 4 to 7 carbons; 6 to 21 carbons, 6 to 19 carbons, 6 to 17 carbons, 6 to 15 carbons, 6 to 13 carbons, 6 to 11 carbons, 6 to 9 carbons; 9 to 21 carbons, 9 to 19 carbons, 9 to 17 carbons, 9 to 15 carbons, 9 to 13 carbons, 9 to 11 carbons; 11 to 21 carbons, 11 to 19 carbons, 11 to 17 carbons, 11 to 15 carbons, 11 to 13 carbons; 13 to 21 carbons, 13 to 19 carbons, 13 to 17 carbons, or any range or subrange thereof.

[0097] The amino acid derived surfactant may be selected from a glutamic acid derived surfactant. The glutamic acid derived surfactant may be selected from an acyl glutamic acid derived surfactants having an alkyl group comprised of a carbon chain having 3 to 21 carbons or any of the ranges for the carbon chain described above with respect to the amino acid derived surfactant.For instance, the carbon chain of the acyl glutamic acid derived surfactant may be 4 to 19 carbons, optionally 6 to 17 carbons, or optionally 9 to 13 carbons. In some preferred embodiments, the amino acid derived surfactant comprises sodium cocoyl glutamate.

[0098] Additionally or alternatively, the oral care compositions may be formulated to have certain weight ratios of the amount of amino acid based surfactant(s) to the amount of nonionic surfactant(s). For example, the oral care composition may have a weight ratio of the total amount of amino acid based surfactant(s) to the total amount of nonionic surfactant(s) of from about 1:5 to about 5:1, about 1:4 to about 5:1, about 1:3 to about 5:1, about 1:2 to about 5:1, about 1:1 to about 5:1; from about 1:5 to about 4:1, about 1:4 to about 4:1, about 1:3 to about 4:1, about 1:2 to about 4:1, about 1:1 to about 4:1; from about 1:5 to about 3:1, about 1:4 to about 3:1, about 1:3 to about 3:1, about 1:2 to about 3:1, about 1:1 to about 3:1; from about 1:5 to about 2:1, about 1:4 to about 2:1, about 1:3 to about 2:1, about 1:2 to about 2:1, about 1:1 to about 2:1; from about 1:5 to about 1:1, about 1:4 to about 1:1, about 1:3 to about 1:1, about 1:2 to about 1:1, or about 1:1, including ranges or subranges formed thereof.

[0099] The oral care compositions may include a fluoride ion source. The fluoride ion source may be present in an effective amount. In some cases, the fluoride ion source is present in the oral care composition in an amount ranging from about 0.01 to about 5 wt.%, based on the total weight of the oral care composition. For example, the fluoride ion source may be present in an amount ranging from about 0.01 to about 5 wt.%, about 0.01 to about 4 wt.%, about 0.01 to about 3 wt.%, about 0.01 to about 2 wt.%, about 0.01 to about 1 wt.%; from about 0.05 to about 5 wt.%, about 0.05 to about 4 wt.%, about 0.05 to about 3 wt.%, about 0.05 to about 2 wt.%, about 0.05 to about 1 wt.%; from about 0.1 to about 5 wt.%, about 0.1 to about 4 wt.%, about 0.1 to about 3 wt.%, about 0.1 to about 2 wt.%; from about 0.3 to about 5 wt.%, about 0.3 to about 4 wt.%, about 0.3 to about 3 wt.%, about 0.3 to about 2 wt.%; from about 0.6 to about 5 wt.%, about 0.6 to about 4 wt.%, about 0.6 to about 3 wt.%, about 0.6 to about 2 wt.%; from about 0.9 to about 5 wt.%, about 0.9 to about 4 wt.%, about 0.9 to about 3 wt.%, about 0.9 to about 2 wt.%; from about 1.2 to about 5 wt.%, about 1.2 to about 4 wt.%, about 1.2 to about 3 wt.%, about 1.2 to about 2 wt.%; from about 1.5 to about 5 wt.%, about 1.5 to about 4 wt.%, about 1.5 to about 3 wt.%; from about 2 to about 5 wt.%, about 2 to about 4 wt.%, about 2 to about 3 wt.%; from about 3 to about 5 wt.%, about 4 to about 5 wt.%, or any range or subrange thereof, based on the total weight of the oral care composition.

[0100] The fluoride ion source may be selected from soluble fluoride ion salts. For example, the fluoride ion source may comprise sodium fluoride, potassium fluoride, calcium fluoride, zinc fluoride, zinc ammonium fluoride, lithium fluoride, ammonium fluoride, stannous fluoride, stannous fluorozirconate, sodium monofluorophosphate, potassium monofluorophosphate, laurylamine hydrofluoride, diethylaminoethyloctoylamide hydrofluoride, didecyldimethylammonium fluoride, cetylpyridinium fluoride, dilaurylmorpholinium fluoride, sarcosine stannous fluoride, glycine potassium fluoride, glycine hydrofluoride, amine fluorides or a combination of two or more thereof. In some embodiments, the fluoride ion source comprises sodium fluoride, sodium monofluorophosphate, or a combination thereof. Additional examples of fluoride ion source are disclosed in U.S. Patent No. 3,535,421, U.S. Patent No. 4,885,155, and U.S. Patent No.3,678,154, the disclosure of each of which is hereby incorporated by reference in their entirety.

[0101] In certain embodiments, the oral care composition of the disclosure may contain stannous fluoride and a source of fluoride ions or fluorine-providing agents in amounts sufficient to deliver, in total, from 25 ppm to 25,000 ppm (mass fraction) of fluoride ions, generally at least 500 ppm, e.g., from about 500 to about 2000 ppm, from about 800 to about 1800 ppm, from about 1000 to about 1600 ppm, from about 1200 to about 1550 ppm, or about 1450 ppm.

[0102] The oral care compositions may include one or more abrasive(s), e.g., in an amount ranging from about 5 to about 35 wt.%, based on the total weight of the oral care composition. In some embodiments, the one or more abrasive(s) is present in an amount ranging from about 5 to about 30 wt.%, about 5 to about 25 wt.%, about 5 to about 21 wt.%, about 5 to about 17 wt.%, about 5 to about 14 wt.%, about 5 to about 11 wt.%; from about 10 to about 35 wt.%, about 10 to about 30 wt.%, about 10 to about 25 wt.%, about 10 to about 21 wt.%, about 10 to about 17 wt.%, about 10 to about 14 wt.%; from about 15 to about 35 wt.%, about 15 to about 30 wt.%, about 15 to about 25 wt.%, about 15 to about 21 wt.%, about 15 to about 19 wt.%; from about 18 to about 35 wt.%, about 18 to about 30 wt.%, about 18 to about 25 wt.%, about 18 to about 21 wt.%; from about 21 to about 35 wt.%, about 21 to about 30 wt.%, about 21 to about 25 wt.%; from about 24 to about 35 wt.%, about 24 to about 30 wt.%; from about 27 to about 35 wt.%, about 27 to about 30 wt.%, or any range or subrange thereof, based on the total weight of the oral care composition.

[0103] The one or more abrasive(s) may include: silica, silicate, silicon, alumina (including calcined aluminum oxide), aluminosilicates, such as bentonite, zeolite, kaolin, and mica, siliceousor diatomaceous earth, pumice, calcium carbonate, cuttlebone, 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.

[0104] As used herein, “mica” refers to any of a group of hydrous aluminum silicate minerals with plate morphology and / or perfect basal (micaceous) cleavage. Mica can be, for example, sheet mica, scrap mica or flake mica, as exemplified by muscovite, biotite or phlogopite type micas. The abrasive may be selected from insoluble phosphates, such as orthophosphates, polymetaphosphates, pyrophosphates, and a combination thereof. Synthetic silicas include both silica gels and precipitated silicas that are prepared by the neutralization of aqueous silicate solutions with a strong mineral acid. Abrasives comprising silica may be useful in certain embodiments of the oral care composition. In certain embodiments, the oral compositions may comprise a particularly efficacious combination of silica abrasive particle species. For example, the abrasive(s) be selected from high cleaning silica, tetrasodium pyrophosphate (TSPP), sodium tripolyphosphate (STPP), and a combination of two or more thereof.

[0105] The oral care compositions may include an abrasive system comprising two or more abrasives. For example, an abrasive system comprise 2 to 7, 2 to 6, 2 to 5, 2 to 5, or 2 to 4; 3 to 7, 3 to 6, 2 to 5, or 3 to 5 abrasives. The abrasives may comprise one or more cleaning abrasive and / or one or more polishing abrasives. As appreciated by one of skill in the art, a single abrasive species typically performs at least some cleaning and polishing simultaneously. However, particles are generally categorized in the art by the predominant effect they have on a target oral surface. Typically, “polishing abrasives” are considered to be relatively small particles having high hardness, where abrasives with relatively large particle sizes and low hardness are considered to be “cleaning abrasives.” In certain embodiments, the oral care composition comprises two or more abrasives comprising silica. In some embodiments, the first abrasive is selected to be a harder and smaller abrasive, e.g., a higher cleaning and / or polishing abrasive, and the second abrasive is a typical cleaning abrasive. In some embodiments, the oral care composition includes at least one polishing abrasive and / or at least one cleaning abrasive. Further examples of abrasives are disclosed in U.S. Patent Publication No.2007 / 140986, which is incorporated herein in its entirety by reference for all purposes.

[0106] The oral care composition may include one or more thickening agent(s), e.g., in an amount ranging from about 0.5 to about 20 wt.%, based on the total weight of the oral care composition. For example, the amount of thickening agent(s) in the oral care composition may range from about 0.5 to about 17 wt.%, about 0.5 to about 14 wt.%, about 0.5 to about 11 wt.%, about 0.5 to about 9 wt.%, about 0.5 to about 7 wt.%, about 0.5 to about 5 wt.%, about 0.5 to about 4 wt.%, about 0.5 to about 3 wt.%; from about 1 to about 20 wt.%, about 1 to about 17 wt.%, about 1 to about 14 wt.%, about 1 to about 11 wt.%, about 1 to about 9 wt.%, about 1 to about 7 wt.%, about 1 to about 5 wt.%, about 1 to about 4 wt.%, about 1 to about 3 wt.%; from about 2 to about 20 wt.%, about 2 to about 17 wt.%, about 2 to about 14 wt.%, about 2 to about 11 wt.%, about 2 to about 9 wt.%, about 2 to about 7 wt.%, about 2 to about 5 wt.%, about 2 to about 4 wt.%, about 2 to about 3 wt.%; from about 4 to about 20 wt.%, about 4 to about 17 wt.%, about 4 to about 14 wt.%, about 4 to about 11 wt.%, about 4 to about 9 wt.%, about 4 to about 7 wt.%; from about 7 to about 20 wt.%, about 7 to about 17 wt.%, about 7 to about 14 wt.%, about 7 to about 11 wt.%; from about 10 to about 20 wt.%, about 10 to about 17 wt.%, about 10 to about 14 wt.%; from about 14 to about 20 wt.%, about 14 to about 17 wt.%, or any range or subrange thereof, based on the total weight of the oral care composition.

[0107] Thickening agents may be referred to as “thickeners” or “viscosity modifying agents.” Thickening agents are typically included to increase the viscosity of the oral care compositions. Nonetheless, in some instances, certain thickening agents provide additional, surprising benefits to the oral care compositions.

[0108] The one or more thickening agent(s) may be selected from a polysaccharide, a silica thickener, an acrylate, a polymer, and a combination of two or more thereof. Examples of polysaccharides include cellulose, carboxymethyl hydroxyethylcellulose, cellulose acetate propionate carboxylate, hydroxyethylcellulose, hydroxyethyl ethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, methyl hydroxyethylcellulose, microcrystalline cellulose, sodium cellulose sulfate, carrageenan, or a combination of two more thereof. Natural gums such as karaya, gum arabic, and gum tragacanth can also be incorporated. Colloidal magnesium aluminum silicate can also be used as a component of the thickening composition to further improve the composition's texture. Silica thickeners, which form polymeric structures or gels in aqueous media, may be present. Silica thickeners are typically physically andfunctionally distinct from the particulate silica abrasives as the silica thickeners are very finely divided and provide little or no abrasive action.

[0109] In some embodiments, the one or more thickening agent(s) comprises a polymer selected from polysaccharides, acrylates, polyvinyl pyrrolidone, polyitaconates, an acrylamides, and combinations thereof. Polyvinyl pyrrolidone generally refers to a polymer containing vinylpyrrolidone (e.g., N-vinylpyrrolidone, N-vinyl-2-pyrrolidione, and N-vinyl-2-pyrrolidinone) as a monomeric unit. The monomeric unit may include a polar imide group, four non-polar methylene groups, and a non-polar methane group. The polyvinyl pyrrolidone may have an average molecular weight in the range 5,000 to 100,000, preferably in the range 5,000 to 50,000. Polyvinyl pyrrolidones that have average molecular weights of 10,000, 30,000 and 40,000 may be commercially available from Sigma Chemjeal Co., GAF Corporation and Sigma Chemical Co. The polyvinyl pyrrolidone may form a hydrogen peroxide-polyvinyl pyrrolidone polymer complexes. Examples of polyvinyl pyrrolidone complexes include those disclosed in U.S. Pat. No. 5,122,370, the contents of which are incorporated herein by reference. In some embodiments, the polymer comprises crosslinked polyvinyl pyrrolidone (crosslinked PVP). In at least one embodiment, the polymer consists of polyvinyl pyrrolidone.

[0110] Examples of acrylates that may be included in the oral care composition include, e.g., isobutyl acrylate, tert-butyl acrylate, 2-ethylhexyl acrylate, lauryl acrylate, lauryl / tridecyl acrylate, cetyl acrylate, stearyl acrylate, cyclohexyl acrylate, benzyl acrylate, isobornyl acrylate, 2- methoxyethyl acrylate, 2-ethoxyethyl acrylate, 2-ethoxyethoxyethyl acrylate, 2-phenoxyethyl acrylate, tetrahydrofurfuryl acrylate, 2-hydroxyethyl acrylate, 2-hydroxypropyl acrylate, 4- hydroxybutyl acrylate, dimethylaminoethyl acrylate, 1,4-butanediol acrylate, or a combination of two or more thereof.

[0111] The acrylate may be chosen from diacrylates. In some embodiments, the oral care composition includes a diacrylate chosen from 1,4-butanediol, 1,6-hexanediol, tetraethylene glycol, tripropylene glycol, ethoxylated bisphenol-A, and a combination of two or more thereof. Triacrylate monomers include trimethylol propane, ethoxylated, glyceryl propoxy, and pentaerythritol.

[0112] Acrylates further include methacrylates, such as methyl methacrylate, ethyl methacrylate, n-butyl methacrylate, isobutyl methacrylate, tert-butyl methacrylate, 2-ethylhexyl methacrylate, lauryl methacrylate, alkyl methacrylate, tridecyl methacrylate, stearyl methacrylate, cyclohexylmethacrylate, benzyl methacrylate, isobornyl methacrylate, 2-hydroxyethyl methacrylate, 2- hydroxypropyl methacrylate, dimethylaminoethyl methacrylate, diethylaminoethyl methacrylate, glycidyl methacrylate, tetrahydrofurfuryl methacrylate, allyl methacrylate, ethylene glycol methacrylate, triethylene glycol methacrylate, tetraethylene glycol methacrylate, 1,3- butyleneglycol methacrylate, 1,6-hexanediol methacrylate, trimethylopropane methacrylate, ethoxyethyl methacrylate, trifluoroethyl methacrylate, or a combination of two or more thereof.

[0113] Examples of acrylamides include, but are not limited to, acrylamide, methacrylamide and di(C1-C30) alkyl-acrylamides and -methacrylamides such as those of methyl, ethyl, propyl, butyl, pentyl, hexyl and the like. N-substituted acrylamides that may be suitable include N- ethylacrylamide, N-tert-butylacrylamide, N-tert-octylacrylamide, N-octylacrylamide, N- decylacrylamide, N-dodecylacrylamide and the corresponding N-substituted methacrylamides. Other N-substituted acrylamides include N-hydroxymethyl acrylamide, N-isopropylacrylamide, N-methylacrylamide, N,N'-methylenebisacrylamide, N-isobutoxymethylacrylamide, N,N- dimethylacrylamide, and 2-acrylamido-2-methylpropanesulfonic acid.

[0114] The oral care compositions may include one or more polyol(s). The one or more polyol(s) may be present in the oral care composition in an amount ranging from about 1 to about 60 wt.%, based on the total weight of the oral care composition. For example, the oral care composition may include polyol(s) in an amount ranging from about 20 to about 55 wt.%, about 20 to about 50 wt.%, about 20 to about 45 wt.%, about 20 to about 40 wt.%, about 20 to about 37 wt.%, about 20 to about 34 wt.%, about 20 to about 31 wt.%, about 20 to about 28 wt.%; from about 25 to about 60 wt.%, about 25 to about 55 wt.%, about 25 to about 50 wt.%, about 25 to about 45 wt.%, about 25 to about 40 wt.%, about 25 to about 37 wt.%, about 25 to about 34 wt.%, about 25 to about 31 wt.%; from about 28 to about 60 wt.%, about 28 to about 55 wt.%, about 28 to about 50 wt.%, about 28 to about 45 wt.%, about 28 to about 40 wt.%, about 28 to about 37 wt.%, about 28 to about 34 wt.%, about 28 to about 31 wt.%; from about 31 to about 60 wt.%, about 31 to about 55 wt.%, about 31 to about 50 wt.%, about 31 to about 45 wt.%, about 31 to about 40 wt.%, about 31 to about 37 wt.%; from about 34 to about 50 wt.%, about 34 to about 45 wt.%, about 34 to about 40 wt.%; from about 37 to about 60 wt.%, about 37 to about 55 wt.%, about 37 to about 50 wt.%, about 37 to about 45 wt.%; from about 40 to about 60 wt.%, about 40 to about 55 wt.%, about 40 to about 50 wt.%, about 40 to about 45 wt.%, or any range or subrange thereof, based on the total weight of the oral care composition.

[0115] In other embodiments, the oral care composition may include polyol(s) in an amount ranging from about 0.5 to about 17 wt.%, about 0.5 to about 14 wt.%, about 0.5 to about 11 wt.%, about 0.5 to about 9 wt.%, about 0.5 to about 7 wt.%, about 0.5 to about 5 wt.%, about 0.5 to about 4 wt.%, about 0.5 to about 3 wt.%, about 0.5 to about 2 wt.%, about 0.5 to about 1 wt.%; from about 1 to about 20 wt.%, about 1 to about 17 wt.%, about 1 to about 14 wt.%, about 1 to about 11 wt.%, about 1 to about 9 wt.%, about 1 to about 7 wt.%, about 1 to about 5 wt.%, about 1 to about 4 wt.%, about 1 to about 3 wt.%, about 1 to about 2 wt.%; from about 2 to about 20 wt.%, about 2 to about 17 wt.%, about 2 to about 14 wt.%, about 2 to about 11 wt.%, about 2 to about 9 wt.%, about 2 to about 7 wt.%, about 2 to about 5 wt.%, about 2 to about 4 wt.%, about 2 to about 3 wt.%; from about 4 to about 20 wt.%, about 4 to about 17 wt.%, about 4 to about 14 wt.%, about 4 to about 11 wt.%, about 4 to about 9 wt.%, about 4 to about 7 wt.%; from about 7 to about 20 wt.%, about 7 to about 17 wt.%, about 7 to about 14 wt.%, about 7 to about 11 wt.%; from about 10 to about 20 wt.%, about 10 to about 17 wt.%, about 10 to about 14 wt.%; from about 14 to about 20 wt.%, about 14 to about 17 wt.%, or any range or subrange thereof, based on the total weight of the oral care composition.

[0116] The polyol(s) may be chosen from glycols or compounds with numerous hydroxyl groups. The one or more polyols may be liquid at ambient temperature (25 °C). The polyol may be a humectant. In some embodiments, the polyol(s) comprises glycerin, glycol, inositol, maltitol, mannitol, sorbitol, xylitol, propylene glycol, polypropylene glycol (PPG), polyethylene glycol (PEG), a block copolymer of PPG and PEG, a saccharide (e.g., fructose, glucose, sucrose and mixtures of saccharides, such as honey), or a combination of two or more thereof. For instance, the oral care composition comprises maltitol, mannitol, sorbitol, xylitol, a polypropylene glycol (PPG), a polyethylene glycol (PEG), a block copolymer of PPG and PEG, or a combination or two or more thereof.

[0117] In some embodiments, the oral care composition includes one or more polyol selected from the group consisting of C2-C32 polyols. The one or more polyols may have from 2 to 32 carbon atoms, from 3 to 16 carbon atoms, or from 3 to 12 carbon atoms. For example, the oral care composition may comprise ethylene glycol, propylene glycol, butylene glycol, hexylene glycol, glycerin, diglycerin, diethylene glycol, and dipropylene glycol, or a combination of two or more thereof. Additional, non-limiting examples of polyols that may, optionally, be included in the oral care include and / or may be chosen from alkanediols such as glycerin, 1,2,6-hexanetriol,trimethylolpropane, ethylene glycol, propylene glycol, butylene glycol, pentylene glycol, hexylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, pentaethylene glycol, dipropylene glycol, 2-butene-1,4-diol, 2-ethyl-1,3-hexanediol, 2-methyl-2,4-pentanediol, caprylyl glycol, 1,2-hexanediol, 1,2-pentanediol, and 4-methyl-1,2-pentanediol; glycol ethers such as ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, ethylene glycol monomethyl ether acetate, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol mono-n-propyl ether, ethylene glycol mono-iso-propyl ether, diethylene glycol mono-iso-propyl ether, ethylene glycol mono-n-butyl ether, ethylene glycol mono-t-butyl ether, diethylene glycol mono-t-butyl ether, 1-methyl-1-methoxybutanol, propylene glycol monomethyl ether, propylene glycol monoethyl ether, propylene glycol mono-t- butyl ether, propylene glycol mono-n-propyl ether, propylene glycol mono-iso-propyl ether, dipropylene glycol monomethyl ether, dipropylene glycol monoethyl ether, dipropylene glycol mono-n-propyl ether, dipropylene glycol mono-iso-propyl ether, sorbitol, sorbitan, triacetin, and a mixture thereof.

[0118] Additionally or alternatively, the oral care composition may include polyol(s) having a molecular weight of from about 100 to 5000 g / mol. For instance, the polyol may comprise a polyethylene glycol, a polypropylene glycol, a block polymer of polyethylene glycol and polypropylene glycol, or a combination of two or more thereof. In some embodiments, the polyol comprises a polypropylene glycol, a polypropylene glycol, and / or a block polymer of polyethylene glycol and polypropylene glycol having a molecular weight of about 100 to about 900, about 200 to about 800, about 400, about 1500 to about 2500, about 2000 to about 4500 or any range or subrange thereof. In some embodiments, the polyol is a polyethylene glycol, such as polyethylene glycol 600 (CAS-25322-68-3). In some embodiments, the compositions of the disclosure comprise one or more polyethylene glycols, for example, polyethylene glycols in a molecular weight range from 200 to 800. For example, the compositions may comprise one or more of polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol, 600 or polyethylene glycol 800.

[0119] The oral care compositions may, in some embodiments, comprise one or more amino acid(s) in an effective amount. In some embodiments, the one or more amino acid(s) may be present in the oral care composition in an amount ranging from about 0.1 to about 10 wt.%, about 0.1 to about 8 wt.%, about 0.1 to about 6 wt.%, about 0.1 to about 4 wt.%, about 0.1 to about 2wt.%, about 0.1 to about 1 wt.%, about 0.1 to about 0.5 wt.%; from about 0.5 to about 10 wt.%, about 0.5 to about 8 wt.%, about 0.5 to about 6 wt.%, about 0.5 to about 4 wt.%, about 0.5 to about 2 wt.%, about 0.5 to about 1 wt.%; from about 1 to about 10 wt.%, about 1 to about 8 wt.%, about 1 to about 6 wt.%, about 1 to about 4 wt.%, about 1 to about 2 wt.%; from about 2 to about 10 wt.%, about 2 to about 8 wt.%, about 2 to about 6 wt.%, about 2 to about 4 wt.%; from about 3 to about 10 wt.%, about 3 to about 8 wt.%, about 3 to about 6 wt.%, about 3 to about 4 wt.%; from about 4 to about 10 wt.%, about 4 to about 8 wt.%, about 4 to about 6 wt.%; from about 6 to about 10 wt.%, about 6 to about 8 wt.%; from about 8 to about 10 wt.%, including any range or subrange thereof, based on the total weight of the oral care composition.

[0120] The one or more amino acids may be selected from basic amino acids, neutral amino acids, and combinations thereof. The basic amino acids may be selected from naturally occurring basic amino acids, such as arginine, lysine, and histidine, and non-naturally occurring basic amino acids having a carboxyl group and an amino group in the molecule, which are water-soluble and provide an aqueous solution with a pH of 7 or greater. Examples of basic amino acids include arginine, lysine, serine, citrulline, ornithine, creatine, histidine, diaminobutanoic acid, diaminoproprionic acid, salts thereof or combinations thereof. In some embodiments, the basic amino acids are selected from arginine, citrulline, and ornithine. In certain embodiments, the basic amino acid is arginine, e.g., L-arginine, or a salt thereof. Additionally or alternatively, the one or more amino acid can be chosen from neutral amino acids, which can include, but are not limited to, one or more neutral amino acids selected from the group consisting of alanine, aminobutyrate, asparagine, cysteine, cystine, glutamine, glycine, hydroxyproline, isoleucine, leucine, methionine, phenylalanine, proline, serine, taurine, threonine, tryptophan, tyrosine, valine, and combinations thereof.

[0121] In some embodiments, the oral care compositions may include one or more sweeteners. The oral care composition may include caloric sweeteners and / or non-caloric sweeteners. Examples of non-caloric sweeteners include saccharin, for example, sodium saccharin, acesulfame, neotame, cyclamate or sucralose; natural high-intensity sweeteners, such as thaumatin, stevioside or glycyrrhizin; or sugar alcohols, such as sorbitol, xylitol, maltitol and mannitol. Examples of caloric sweeteners include sugars, such as fructose, glucose, sucrose, and high fructose syrups.

[0122] The one or more sweetener(s) may be present in the oral care composition in an amount ranging from about 0.1 to about 50 wt.%, based on the total weight of the oral care composition. For example, the oral care composition may have a total amount of sweetener(s) ranging from about 0.1 to about 40 wt.%, about 0.1 to about 30 wt.%, about 0.1 to about 20 wt.%, about 0.1 to about 10 wt.%, about 0.1 to about 5 wt.%, about 0.1 to about 3 wt.%; from about 1 to about 50 wt.%, about 1 to about 40 wt.%, about 1 to about 30 wt.%, about 1 to about 20 wt.%, about 1 to about 10 wt.%, about 1 to about 5 wt.%, about 1 to about 3 wt.%; from about 5 to about 50 wt.%, about 5 to about 40 wt.%, about 5 to about 30 wt.%, about 5 to about 20 wt.%, about 5 to about 10 wt.%; from about 10 to about 50 wt.%, about 10 to about 45 wt.%, about 10 to about 40 wt.%, about 10 to about 35 wt.%, about 10 to about 30 wt.%, about 10 to about 25 wt.%; from about 15 to about 50 wt.%, about 15 to about 45 wt.%, about 15 to about 40 wt.%, about 15 to about 37 wt.%, about 15 to about 34 wt.%, about 15 to about 31 wt.%, about 15 to about 28 wt.%, about 15 to about 25 wt.%; from about 20 to about 50 wt.%, about 20 to about 45 wt.%, about 20 to about 40 wt.%, about 20 to about 37 wt.%, about 20 to about 34 wt.%, about 20 to about 31 wt.%, about 20 to about 28 wt.%; from about 25 to about 50 wt.%, about 25 to about 45 wt.%, about 25 to about 40 wt.%, about 25 to about 37 wt.%, about 25 to about 34 wt.%, about 25 to about 31 wt.%; from about 28 to about 50 wt.%, about 28 to about 45 wt.%, about 28 to about 40 wt.%, about 28 to about 37 wt.%, about 28 to about 34 wt.%, about 28 to about 31 wt.%; from about 31 to about 50 wt.%, about 31 to about 45 wt.%, about 31 to about 40 wt.%, about 31 to about 37 wt.%; from about 34 to about 50 wt.%, about 34 to about 45 wt.%, about 34 to about 40 wt.%; from about 37 to about 50 wt.%, about 37 to about 45 wt.%, or any range or subrange thereof, based on the total weight of the oral care composition.

[0123] In some embodiments, the oral care composition is substantially free or free of caloric sweeteners. For example, the oral care compositions may have about 4 wt.% or less, about 3 wt.% or less, about 2 wt.% or less, about 1 wt.% or less, about 0.5 wt.% or less, or about 0.1 wt.% or less, based on the weight of the oral care composition. In at least one embodiment, the oral care composition contains about 0 wt.% or 0 wt.% of caloric sweeteners, based on the weight of the oral care composition.

[0124] The oral care compositions of the present disclosure may include a flavoring agent. The flavoring agent is typically incorporated in the oral care composition at a concentration of about 0.01 to about 3 wt.% by weight of the oral care composition. For example, the amount of flavoringagent(s) present in the oral care composition may range from about 0.01 to about 2 wt.%, about 0.01 to about 1 wt.%, about 0.01 to about 0.5 wt.%, about 0.01 to about 0.1 wt.%; from about 0.1 to about 3 wt.%, about 0.1 to about 2 wt.%, about 0.1 to about 1 wt.%, about 0.1 to about 0.5 wt.%; from about 0.5 to about 3 wt.%, about 0.5 to about 2 wt.%, about 0.5 to about 1 wt.%; from about 1 to about 3 wt.%, about 1 to about 2 wt.%; from about 2 to about 3 wt.%, including any range or subrange thereof, based on the total weight of the oral care composition.

[0125] Suitable flavoring agents include, but are not limited to, 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.

[0126] The oral care compositions may include one or more colorants. Exemplary colorants can include natural or uncertified colors from natural sources or certified colors for the effect of color. In some embodiments, the colorant can include dyes, certified aluminum lakes or colors derived from a natural source. The colorant may be water-based, oil-based or dry. The colorants can be primary colors, blends of colors or discrete mixtures of colors, such as confetti. The concentrations of the colorant in the oral care composition may be from trace amount to about 0.6 wt.%, from about 0.1 to about 0.5 wt.%, about 0.2 to about 0.4 wt.%, or about 0.15 to about 0.35 wt.%, based on the total weight of the oral care composition.

[0127] The oral care composition may include 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.

[0128] 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 to about 20 wt.%, based on the total weight of the oral care composition. In some instances, the total amount of pH adjuster is from about 0.05 to about 15 wt.%, about 0.1 to about 10 wt.%, or about 0.12 to about 5 wt.%, including ranges and sub-ranges therebetween, based on the total weight of the oral care composition.

[0129] 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.

[0130] The oral care compositions disclosed herein may be made according to methods and procedures known to those skilled in the art.

[0131] In some aspects, embodiments are provided for a method of treating and / or alleviating an interleukin-8 (IL-8) mediated inflammatory disorder in a subject in need thereof, wherein the subject is a nicotine user. The method comprises applying an oral care composition to an oral cavity of the subject, the oral care composition comprising a stannous source, a nitrate ion source, and a pyrophosphate. In some embodiments, the oral care composition may be any described herein. In some embodiments, the IL-8 mediated inflammatory disorder is selected from gum disease, chronic obstructive pulmonary disorder (COPD), pneumonia, bronchitis, Crohn’s disease, ulcerative colitis, or asthma. In some embodiments, the gum disease is selected from gingivitis, periodontitis, implantitis, or mucositis. In some embodiments, the oral care composition is one set forth below. In some embodiments, the IL-8 mediated inflammatory disorder is selected from gum disease, chronic obstructive pulmonary disorder (COPD), pneumonia, bronchitis, Crohn’s disease, ulcerative colitis, or asthma. In some embodiments, the gum disease is selected from gingivitis, periodontitis, implantitis, or mucositis. In some embodiments, the subject in need thereof is additionally selected from patients with an inflammatory disease, patients with a bacterial or viral infection, obese people, or elderly people. In some embodiments, the method comprises applying the oral care composition to the oral cavity at least one a day, such as at least twice a day or at least 3 times a day. In some embodiments, the oral care composition is applied to the oral cavity for about 10 seconds to about 30 minutes, such as about 15 seconds to about 25 minutes, about 20seconds to about 15 minutes, about 25 seconds to about 5 minutes, or about 30 seconds to about 2 minutes. In some embodiments, the oral care composition is applied to the oral cavity in an amount of about 0.1 to about 3 grams. In some embodiments, the stannous source is selected from stannous fluoride, stannous chloride, stannous pyrophosphate, stannous formate, stannous acetate, stannous gluconate, stannous lactate, stannous tartrate, stannous oxalate, stannous malonate, stannous citrate, stannous ethylene glyoxide, and combinations of two or more thereof. In some embodiments, the stannous source comprises stannous fluoride. In some embodiments, the nitrate ion source is selected from lithium nitrate, sodium nitrate, potassium nitrate, magnesium nitrate, calcium nitrate, zinc nitrate, silver nitrate, ammonium nitrate, and a combination two or more thereof. In some embodiments, the nitrate ion source comprises potassium nitrate. In some embodiments, the oral care composition has a molar ratio of nitrate ions to stannous ions, both measured as free ions, of about 0.5:1 to about 2:1. In some embodiments, the phosphate ion source is selected from tetrasodium pyrophosphate, dicalcium orthophosphate dihydrate, dicalcium phosphate dihydrate, calcium hydrogen phosphate, calcium pyrophosphate, p-calcium pyrophosphate, tricalcium phosphate, calcium metaphosphate, potassium metaphosphate, sodium metaphosphate, and a combination of two or more thereof. In some embodiments, the oral care composition comprises water in an amount ranging from about 5% to about 20%, such as from about 5% to about 7% or from about 12% to about 16%, by weight relative to the total weight of the oral care composition. In some embodiments, the method reduces an IL-8 concentration in a tissue of the subject, such as gum tissue of the subject. In some embodiments, the IL-8 concentration is reduced by at least about 25%, such as at least 30%, at least 35%, at least 40%, at least 45%, or at least 50%.

[0132] In some aspects, embodiments are provided for a method of treating and / or alleviating symptoms of gum disease in a subject in need thereof, comprising applying an oral care composition to an oral cavity of the subject, the oral care composition comprising a stannous source, a nitrate ion source, and a pyrophosphate, wherein the subject in need thereof is a nicotine user. In some embodiments, the oral care composition may be any described herein. In some embodiments, the gum disease is selected from gingivitis, periodontitis, implantitis, or mucositis. In some embodiments, the method comprises applying the oral care composition to the oral cavity at least one a day, such as at least twice a day or at least 3 times a day. In some embodiments, the amount of oral care composition applied to the oral cavity is about 0.1 gram to about 3 grams. Insome embodiments, the stannous source comprises stannous fluoride. In some embodiments, the nitrate ion source is selected from lithium nitrate, sodium nitrate, potassium nitrate, magnesium nitrate, calcium nitrate, zinc nitrate, silver nitrate, ammonium nitrate, and a combination two or more thereof. In some embodiments, the nitrate ion source comprises potassium nitrate. In some embodiments, the oral care compositions have a molar ratio of nitrate ions to stannous ions, both measured as free ions, of about 0.5:1 to about 2:1. In some embodiments, the phosphate ion source is selected from tetrasodium pyrophosphate, dicalcium orthophosphate dihydrate, dicalcium phosphate dihydrate, calcium hydrogen phosphate, calcium pyrophosphate, p-calcium pyrophosphate, tricalcium phosphate, calcium metaphosphate, potassium metaphosphate, sodium metaphosphate, and a combination of two or more thereof.

[0133] List of Embodiments

[0134] The following list of embodiments represents some embodiments herein and is not limiting to other embodiments found elsewhere herein.

[0135] 1. In some embodiments, the disclosure relates to a method of treating and / or alleviating an interleukin-8 (IL-8) mediated inflammatory disorder in a subject in need thereof, comprising applying an oral care composition to an oral cavity of the subject, the oral care composition comprising: a stannous ion source; a nitrate ion source; a water-soluble alkali metal polyphosphate; and at least 10% water, by weight of the composition.

[0136] 2. The method according to embodiment 1, wherein the stannous ion source is selected from: stannous fluoride; stannous chloride; stannous pyrophosphate; stannous formate; stannous acetate; stannous gluconate; stannous lactate; stannous tartrate; stannous oxalate; stannous malonate; stannous citrate; stannous ethylene glyoxide; and a combination of two or more thereof.

[0137] 3. The method according to embodiment 1 or embodiment 2, wherein the nitrate ion source is selected from an alkali or alkaline earth metal nitrate, or zinc nitrate, silver nitrate, or ammonium nitrate.

[0138] 4. The method according to any foregoing embodiment, wherein the nitrate ion source is selected from: lithium nitrate, sodium nitrate, potassium nitrate, magnesium nitrate, calcium nitrate, zinc nitrate, silver nitrate, ammonium nitrate, and a combination two or more thereof.

[0139] 5. The method according to any foregoing embodiment, wherein the nitrate ion source comprises potassium nitrate.

[0140] 6. The method according to any foregoing embodiment, wherein the water-soluble alkali metal polyphosphate is selected from: a pyrophosphate; a tripolyphosphate; a tetraphosphate; a hexametaphosphate; and combination of two or more thereof.

[0141] 7. The method according to any foregoing embodiment, wherein the water-soluble alkali metal polyphosphate is selected from: sodium pyrophosphate; potassium pyrophosphate; sodium tripolyphosphate; potassium tripolyphosphate; and a combination of two or more thereof.

[0142] 8. The method according to any foregoing embodiment, wherein the nitrate ion source comprises potassium nitrate and the water-soluble alkali metal polyphosphate salt comprises tetrasodium pyrophosphate.

[0143] 9. The method according to any foregoing embodiment, wherein the IL-8 mediated inflammatory disorder is selected from: gum disease; chronic obstructive pulmonary disorder (COPD); pneumonia; bronchitis; Crohn’s disease; ulcerative colitis; and asthma.

[0144] 10. The method according to embodiment 9, wherein the gum disease is selected from: gingivitis; periodontitis; implantitis; and mucositis.

[0145] 11. The method according to any foregoing embodiment, wherein the subject in need thereof is selected from: a nicotine user; a patient with an inflammatory disease; a patient with a bacterial or viral infection, an obese person, or an elderly person.

[0146] 12. The method according to any foregoing embodiment, wherein the subject in need thereof is a nicotine user.

[0147] 13. The method according to any foregoing embodiment, comprising applying the oral care composition to the oral cavity at least once a day, optionally at least twice a day or at least 3 times a day.

[0148] 14. The method according to any foregoing embodiment, wherein the oral care composition is applied to the oral cavity for about 10 seconds to about 30 minutes, such as about 15 seconds to about 25 minutes, about 20 seconds to about 15 minutes, about 25 seconds to about 5 minutes, or about 30 seconds to about 2 minutes.

[0149] 15. The method according to any foregoing embodiment, wherein the oral care composition is applied to the oral cavity in an amount of about 0.1 to about 3 grams.

[0150] 16. The method according to any foregoing embodiment, wherein the stannous ion source comprises stannous fluoride.

[0151] 17. The method according to any foregoing embodiment, wherein the oral care composition has a molar ratio of nitrate ions to stannous ions, both measured as free ions, of about 0.5:1 to about 2:1.

[0152] 18. The method according to any foregoing embodiment, wherein the oral care composition comprises water in an amount ranging from about 10% to about 30%, such as from about 12% to about 25% or from about 15% to about 20%, by weight relative to the total weight of the oral care composition.

[0153] 19. The method according to any foregoing embodiment, wherein the method reduces an IL-8 concentration in a tissue of the subject, such as gum tissue of the subject.

[0154] 20. The method according to embodiment 19, wherein the IL-8 concentration is reduced by at least about 25%, such as at least 30%, at least 35%, at least 40%, at least 45%, or at least 50%.

[0155] 21. In some embodiments, the disclosure relates to a method of treating and / or alleviating symptoms of gum disease in a subject in need thereof, comprising applying an oral care composition to an oral cavity of the subject, the oral care composition comprising: a stannous ion source; a nitrate ion source; a water-soluble alkali metal polyphosphate; and at least 10% water, by weight of the composition.

[0156] 22. The method according to embodiment 21, wherein the gum disease is selected from: gingivitis; periodontitis; implantitis; and mucositis.

[0157] 23. The method according to embodiment 21 or embodiment 22, wherein the subject in need thereof is a nicotine user.

[0158] 24. The method according to any one of embodiments 21 to 23, comprising applying the oral care composition to the oral cavity at least one a day, optionally at least twice a day or at least 3 times a day.

[0159] 25. The method according to any one of embodiments 21 to 24, wherein the amount of oral care composition applied to the oral cavity is about 0.1 gram to about 3 grams.

[0160] 26. The method according to any one of embodiments 21 to 25, wherein the stannous ion source is selected from: stannous fluoride; stannous chloride; stannous pyrophosphate; stannous formate; stannous acetate; stannous gluconate; stannous lactate; stannous tartrate; stannous oxalate; stannous malonate; stannous citrate; stannous ethylene glyoxide; and a combination of two or more thereof.

[0161] 27. The method according to any one of embodiments 21 to 26, wherein the nitrate ion source is selected from lithium nitrate, sodium nitrate, potassium nitrate, magnesium nitrate, calcium nitrate, zinc nitrate, silver nitrate, ammonium nitrate, and a combination two or more thereof.

[0162] 28. The method according to embodiment 27, wherein the nitrate ion source comprises potassium nitrate.

[0163] 29. The method according to any one of embodiments 21 to 28, wherein the oral care composition has a molar ratio of nitrate ions to stannous ions, both measured as free ions, of about 0.5:1 to about 2:1.

[0164] 30. The method according to any one of embodiments 21 to 29, wherein the water- soluble alkali metal polyphosphate is selected from: a pyrophosphate; a tripolyphosphate; a tetraphosphate; a hexametaphosphate; and a combination of two or more thereof.

[0165] 31. The method according to any one of embodiments 21 to 30, wherein the water- soluble alkali metal polyphosphate is selected from: tetrasodium pyrophosphate; potassium pyrophosphate; sodium tripolyphosphate; potassium tripolyphosphate; and a combination of two or more thereof.

[0166] 32. The method according to any one of embodiments 21 to 31, wherein the nitrate ion source comprises potassium nitrate and the water-soluble alkali metal polyphosphate salt comprises tetrasodium pyrophosphate.

[0167] 33. In some embodiments, the disclosure relates to a method of treating and / or alleviating an interleukin-8 (IL-8) mediated inflammatory disorder in a subject in need thereof, comprising applying an oral care composition to an oral cavity of the subject, the oral care composition comprising: a stannous ion source; a nitrate ion source; and a water-soluble alkali metal polyphosphate source; and at least 10% water, by weight of the composition, wherein the subject in need thereof is a nicotine user.

[0168] 34. The method according to embodiment 33, wherein the IL-8 mediated inflammatory disorder is selected from: gum disease; chronic obstructive pulmonary disorder (COPD); pneumonia; bronchitis; Crohn’s disease; ulcerative colitis; and asthma.

[0169] 35. The method according to embodiment 34, wherein the gum disease is selected from: gingivitis; periodontitis; implantitis; and mucositis.

[0170] 36. The method according to any one of embodiments 33 to 35, wherein the subject in need thereof is selected from: a nicotine user; a patient with an inflammatory disease; a patient with a bacterial or viral infection, an obese person, or an elderly person.

[0171] 37. The method according to any one of embodiments 33 to 36, comprising applying the oral care composition to the oral cavity at least one a day, optionally at least twice a day or at least 3 times a day.

[0172] 38. The method according to any one of embodiments 33 to 37, wherein the oral care composition is applied to the oral cavity for about 10 seconds to about 30 minutes, such as about 15 seconds to about 25 minutes, about 20 seconds to about 15 minutes, about 25 seconds to about 5 minutes, or about 30 seconds to about 2 minutes.

[0173] 39. The method according to any one of embodiments 33 to 38, wherein the oral care composition is applied to the oral cavity in an amount of about 0.1 to about 3 grams.

[0174] 40. The method according to any one of embodiments 33 to 39, wherein the stannous ion source is selected from: stannous fluoride; stannous chloride; stannous pyrophosphate; stannous formate; stannous acetate; stannous gluconate; stannous lactate; stannous tartrate; stannous oxalate; stannous malonate; stannous citrate; stannous ethylene glyoxide; and a combination of two or more thereof.

[0175] 41. The method according to embodiment 40, wherein the stannous ion source comprises stannous fluoride.

[0176] 42. The method according to any one of embodiments 33 to 41, wherein the nitrate ion source is selected from lithium nitrate, sodium nitrate, potassium nitrate, magnesium nitrate, calcium nitrate, zinc nitrate, silver nitrate, ammonium nitrate, and a combination two or more thereof.

[0177] 43. The method according to embodiment 42, wherein the nitrate ion source comprises potassium nitrate.

[0178] 44. The method according to any one of embodiments 33 to 43, wherein the oral care composition has a molar ratio of nitrate ions to stannous ions, both measured as free ions, of about 0.5:1 to about 2:1.

[0179] 45. The method according to any one of embodiments 33 to 44, wherein the water- soluble alkali metal polyphosphate is selected from a pyrophosphate; a tripolyphosphate; a tetraphosphate; a hexametaphosphate; and a combination of two or more thereof.

[0180] 46. The method according to any one of embodiments 33 to 45, wherein the water- soluble alkali metal polyphosphate is selected from: tetrasodium pyrophosphate; potassium pyrophosphate; sodium tripolyphosphate; potassium tripolyphosphate; and a combination of two or more thereof.

[0181] 47. The method according to any one of embodiments 33 to 46, wherein the nitrate ion source comprises potassium nitrate and the water-soluble alkali metal polyphosphate salt comprises tetrasodium pyrophosphate.

[0182] 48. The method according to any one of embodiments 33 to 47, wherein the oral care composition comprises water in an amount ranging from about 10% to about 30%, such as from about 12% to about 25% or from about 15% to about 20%, by weight relative to the total weight of the oral care composition.

[0183] 49. The method according to any one of embodiments 33 to 48, wherein the method reduces an IL-8 concentration in a tissue of the subject, such as gum tissue of the subject.

[0184] 50. The method according to embodiment 49, wherein the IL-8 concentration is reduced by at least about 25%, such as at least 30%, at least 35%, at least 40%, at least 45%, or at least 50%.

[0185] 51. In some embodiments, the disclosure relates to a method of treating and / or alleviating symptoms of gum disease in a subject in need thereof, comprising applying an oral care composition to an oral cavity of the subject, the oral care composition comprising: a stannous ion source; a nitrate ion source; and a water-soluble alkali metal polyphosphate source; and at least 10% water, by weight of the composition, wherein the subject in need thereof is a nicotine user.

[0186] 52. The method according to embodiment 51, wherein the gum disease is selected from: gingivitis; periodontitis; implantitis; and mucositis.

[0187] 53. The method according to embodiment 51 or embodiment 52, comprising applying the oral care composition to the oral cavity at least once a day, optionally at least twice a day or at least 3 times a day.

[0188] 54. The method according to any one of embodiments 51 to 53, wherein the amount of oral care composition applied to the oral cavity is about 0.1 gram to about 3 grams.

[0189] 55. The method according to any one of embodiments 51 to 54, wherein the stannous ion source comprises stannous fluoride.

[0190] 56. The method according to any one of embodiments 51 to 55, wherein the nitrate ion source is selected from: lithium nitrate; sodium nitrate; potassium nitrate; magnesium nitrate; calcium nitrate; zinc nitrate; silver nitrate; ammonium nitrate; and a combination two or more thereof.

[0191] 57. The method according to any one of embodiments 51 to 56, wherein the nitrate ion source comprises potassium nitrate.

[0192] 58. The method according to any one of embodiments 51 to 57, wherein the oral care composition has a molar ratio of nitrate ions to stannous ions, both measured as free ions, of about 0.5:1 to about 2:1.

[0193] 59. The method according to any one of embodiments 51 to 58, wherein the water- soluble alkali metal polyphosphate is selected from: a pyrophosphate; a tripolyphosphate; a tetraphosphate; a hexametaphosphate; and a combination of two or more thereof.

[0194] 60. The method according to any one of embodiments 51 to 59, wherein the water- soluble alkali metal polyphosphate is selected from: tetrasodium pyrophosphate; potassium pyrophosphate; sodium tripolyphosphate; potassium tripolyphosphate; and a combination of two or more thereof.

[0195] 61. The method according to any one of embodiments 51 to 60, wherein the nitrate ion source comprises potassium nitrate and the water-soluble alkali metal polyphosphate salt comprises tetrasodium pyrophosphate. EXAMPLES Example 1

[0196] Example Composition A and Example Composition 1 were prepared in accordance with aspects of the disclosure. Both compositions contained 0.454 wt.% of stannous fluoride, 0.5 wt.% of potassium nitrate, and 1.2 wt.% of tetrasodium pyrophosphate, as shown in Table 1 below. Although Example Composition X was not prepared, its preparation is contemplated and is within the scope of the present disclosure. Table 1 Weight %Water 6.3 14.5 22.7 Flavorants, sweeteners, 2.1 10.1 10.1 Example 2

[0197] The efficacy of stannous fluoride toothpastes in deactivating the NF-κB pathway and in reducing inflammatory markers activated by the P. gingivitis endotoxin LPS were studied.

[0198] Supernatants of toothpaste were prepared by mixing 1:4 of Composition A (described above in Example 1) in sterile water and centrifuging for 10 minutes at 4,000 g. Additionally, two samples of commercially available toothpastes containing stannous fluoride stabilized with gluconate (rather than KNO3 and TSPP) were similarly prepared by mixing 1:4 of each toothpaste in sterile water and centrifuging for 10 minutes at 4,000 g to create Comparative Composition B and Comparative Composition C. The supernatants were collected as toothpaste test material and further diluted in the tissue culture media before treating the cells.

[0199] HEK-hTLR4 cells (Invivogen, hkb-htlr4) were co-incubated with the toothpaste supernatants of Composition A, Composition B, and Composition C overnight at 37oC with 5% CO2in the presence of 1 μg / mL ultrapure P. gingivalis lipopolysaccharide (LPS) (Invivogen, tlrl- ppglps).

[0200] NF-κB analysis was performed using HEK-blue detection media per Invivogen’s protocol (Invivogen, hb-det). The quantification of the IL-8 analysis was performed on the cell supernatants using the Enzo IL-8 ELISA kit (Enzo, ADI-900-156). The cell viability analysis was performed using PrestoBlue cell viability reagent per the Invitrogen protocol (Invitrogen, A13262). The concentration of the IL-8 was normalized using the cells treated with only culture medium. A T- test was conducted to calculate the p-values with 95% confidence.

[0201] The results of the NF-κB analysis are shown below in Table 2, and the results of the IL-8 quantification are shown in Table 3 below. Table 2 – Average Optical Density at 640 nm Sample Average Std Dev Average OD OD (normalized toa e o a e - Sample Average Std Dev (pg / mL) 7 32

[0202] The results demonstrate that the stannous fluoride stabilized with nitrate and phosphate (Composition A) was significantly better at reducing ultrapure P. gingivalis LPS-induced NF-κB activation than Composition B, the stannous fluoride toothpastes stabilized with gluconate (p<0.05). As shown in FIG.1, the fold change of the optical density (OD) reads at 640 nm were significantly reduced for HEK-TLR4 cells in the presence of both 1 μg / mL LPS and Composition A, as compared to untreated HEK-TLR4 cells and 1 μg / mL LPS and Composition B. A high OD reading indicates more activation of NF-κB. Additionally, the Composition A exhibited significantly stronger potency in the reduction of inflammatory markers IL-8 induced by the P. gingivalis LPS compared to both Compositions B and C (p<0.05). As shown in FIG. 2, Composition A showed a 47.9% inhibition of IL-8 concentration in the culture media (p<0.0001), while Composition B showed a 0.502% inhibition of IL-8 concentration (p>0.05) and Composition C showed a -8.1% inhibition of IL-8 concentration (p>0.05).

[0203] Accordingly, Composition A exhibited stronger in vitro efficacy in deactivating NF-κB and inhibiting inflammatory markers than either of the gluconate-stabilized stannous fluoridecommercial toothpastes of Composition B or Composition C. Example 3

[0204] The efficacy of stannous fluoride compositions in deactivating NF-κB and in reducing the inflammatory markers activated by the P .gingivalis endotoxin LPS were studied.

[0205] Composition D20 was prepared by mixing 1:20 of Composition A (described above in Example 1) in sterile water and centrifuging for 10 minutes at 4,000 g, and Composition D40 was prepared by mixing 1:40 of Composition A in sterile water and centrifuging for 10 minutes at 4,000 g.

[0206] Composition E20 was prepared by mixing 1:20 of Composition 1 (described above in Example 1) in sterile water and centrifuging for 10 minutes at 4,000 g to create Composition E20. Likewise, Composition E40 was prepared by mixing 1:40 of Composition 1 in sterile water and centrifuging for 10 minutes at 4,000 g to create Composition E40. The supernatants were collected as toothpaste test material and further diluted in the tissue culture media before treating the cells.

[0207] HEK-hTLR4 cells (Invivogen, hkb-htlr4) were co-incubated with the toothpaste supernatants overnight at 37oC with 5% CO2 in the presence of 1 μg / mL ultrapure P. gingivalis lipopolysaccharide (LPS) (Invivogen, tlrl-ppglps).

[0208] The quantification of IL-8 was performed as described above in Example 2, and the results are shown in Table 4 below and in FIG.3. Table 4 – pg / mL of IL-8 with P. gingivalis LPS pg / mL IL-8 R li t R li t R li t R li t A e

[0209] The results demonstrate that both the stannous fluoride stabilized with nitrate and phosphate at a 20x dilution (Composition D20) and the stannous fluoride stabilized with zincphosphate at a 20x dilution (Composition E20) significantly reduced ultrapure P. gingivalis LPS- induced NF-κB activation (p<0.001). As shown in FIG. 3, the pg / mL of IL-8 were significantly reduced for HEK-hTLR4 cells in the presence of both 1 μg / mL LPS and Composition D20, as compared to untreated HEK-hTLR4 cells. Likewise, the pg / mL of IL-8 were significantly reduced for HEK-hTLR4 cells in the presence of both 1 μg / mL LPS and Composition E20, as compared to untreated HEK-hTLR4 cells.

[0210] Cell viability: Cell viability was measured for each of the untreated HEK-TLR4 cells, and the cells treated with LPS, as well as LPS plus Compositions D20, D40, E20, and E40 as described above. To prepare a mirror plate, a 96-well plate was arranged to have Compositions D20, D40, E20, and E40 in each of columns 2-5, respectively, for 6 rows, as well as a row in each column for untreated cells and a row for cells treated with LPS.130 μL of full medium (DMEM + FBS + p / s + Normocin + selection) was added in columns, and 130 μL was transferred from the second to the third column and mixed well by pipetting up and down a few times. Then 130 μL was transferred from the third to the fourth column and mixed well, and 130 μL was transferred from the fourth to the fifth column and mixed well. Dilutions were done as described for each treatment. In the untreated wells and in the LPS wells, 130 μL of full medium was added. On the plate with HEK-hTLR4 cells, 100 μL was transferred from the mirror plate to the LPS cell plate across the plate. 100 μL of LPS (2 ng / mL in full medium) was added to each well of the HEK-hTLR4 cell plate, except for the untreated wells. Then 100 μL of full medium was added to the untreated wells. The plate was mixed and incubated overnight at 37oC and 5% CO2 before cell viability was measured.

[0211] The results demonstrated that each of the prepared compositions had adequate cell viability. Specifically, as shown in FIG.4, percent cell viability was as follows for Compositions D20, D40, E20, and E40, respectively: 112.4%, 92.3%, 99.6%, and 98.2%. The cell viability for the LPS-treated well was 97.2%, wherein all values are relative to the untreated cells at 100% cell viability. Example 4

[0212] This examples was undertaken to investigate the NF-kB deactivation effects between SNAP solutions with different component combinations, and to determine which component(s) played key roles in NF-kB deactivation.Summary

[0213] All the SNAP solutions, listed below in the Testing Samples section, exhibited strong effects on NF-kB deactivation, but not Sol 4 (KNO3) and Sol 5 (TSPP), in both HEK-hTLR2 and HEK-hTLR4 cell line in response to IL-1β or LPS stimulation respectively, suggesting the Sn(II) and Sn(IV) play the key role in decreasing NF-kB activation activity in SNAP solutions. Specifically, in HEK-hTLR2 cells, Sol 3b and 7 showed the best performance on decreasing NF- kB activation (~92% inhibition) in contrast to cells treated with IL-1β only, followed by Sol 1, 3a and 6 (~90% inhibition) and Sol 2 (~85% inhibition). In HEK-hTLR4 cells, Sol 3a and 6 possessed ~88% decrease in NF-kB activation in contrast to LPS only treated group, followed by Sol 1 (~87%), Sol 3b and 7 (~85%), and Sol 2 (~68%). Note that Sol 5 here has slightly inhibition effects (~35%).

[0214] In summary, the NF-kB deactivation effect of SNAP solutions in HEK-hTLR2 cells with IL-1β stimulation is : Sol 3b and 7 > Sol1, 3a and 6 > Sol 2 > Sol 5 > Sol 4, while in HEK-hTLR4 cells with LPS stimulation, the effect is : Sol 3a and 6> Sol 1 > Sol 3b and 7 > Sol 2 >Sol 5 > Sol 4. Statistical analysis showed that differences between each group’s comparison are significant (Student’s test, p value < 0.05). Procedure

[0215] HEK-Blue detection medium was prepared by reconstituting HEK-Blue detection powder (InvivoGen cat# hb-det2) into endotoxin free H20 and warmed up at 37 degree water bath until ready to use. Cell suspension was prepared by detaching cells and resuspending in PBS, counted and then added into the prepared HEK-Blue detection medium. Cells were plated into 96 well F bottom plates with 180ul medium per well. Next, 20ul total volume of the mixture of IL-1β (Final: 1ng / mL) or LPS (Final :1ug / mL) with final 100x diluted SNAPs solutions were prepared and added into plates per well. Treated cells were incubated overnight at 37 °C and 5% CO2 cell culture incubator. Next day secreted embryonic alkaline phosphatase (SEAP) activity was detected by reading plates at OD 640 nm with a microplate reader.The SEAP reporter gene is under the control of the IFN-β minimal promoter fused to five NF-kB and AP-1 binding site in HEK-hTLR2 and 4 cells, thus, the activation of NF-kB will lead to expression of SEAP and activation of NF-kB can be detected by measuring SEAP activity.Testing Samples Sol 1 (full Sn(II) + KNO3+ TSPP) (Sn Level: 4.54%) Sol 2 (Sn(II) + KNO3) (Sn Level: 4.54%) Sol 3a (100% Sn(II) + TSPP) (Sn Level: 4.54%) Sol 3b (100% Sn(IV)+TSPP) (Sn Level: 4.54%) Sol 4 KNO3 (Sn level: 0%) Sol 5 TSPP (Sn level: 0%) Sol 6 (50 % Sn(II), 50% Sn(IV) + KNO3 + TSPP) (Sn Level: 4.54%) Sol 7 (0 % Sn(II), 100% Sn(IV) + KNO3 + TSPP) (Sn Level: 4.54%) Results

[0216] Referring to FIG.5, assessment of SEAP activity was done by measuring the absorbance at OD 640 nm in HEK-hTLR2 cells with SNAPs solution treatment. The SEAP reporter gene is under the control of the IFN-β minimal promoter fused to five NF-kB and AP-1 binding site, thus, the activation of NF-kB will lead to expression of SEAP and activation of NF-kB can be detected by measuring SEAP activity (Note: Cell viability data are referred to the report of SNAPs-anti- inflammatory).

[0217] Referring to FIG.6, assessment of SEAP activity was done by measuring the absorbance at OD 640 nm in HEK-hTLR4 cells with SNAPs solution treatment.The SEAP reporter gene is under the control of the IFN-β minimal promoter fused to five NF-kB and AP-1 binding site, thus, the activation of NF-kB will lead to expression of SEAP and activation of NF-kB can be detected by measuring SEAP activity (Note: Cell viability data are referred to the report of SNAPs-anti- inflammatory).

[0218] Referring to FIG.7, NF-kB deactivation effects of SNAPs solutions in HEK-hTLR2 cells in response to IL-1β stimulation.

[0219] Referring to FIG. 8, NF-kB deactivation effects of SNAP solutions in HEK-hTLR4 cells in response to LPS stimulation. Discussion

[0220] As shown in FIGS.5 and 6, SEAP activity was monitored by culturing HEK-hTLR2 and HEK-hTLR4 cells in HEK-blue detection medium with or without SNAPs treatment. SEAP activity is an indicator for NF-kB activation, therefore in FIGS.7 and 8, the % decrease of NF-kB activation was analyzed under different SNAPs treatment in these two cell lines compared withcells treated with stimulation reagents only.

[0221] In FIG.7, in HEK-hTLR2 cells, Sol 3b and 7 have the highest inhibition effect on NF-kB activation (~92%). Sol 1, 3a and 6 showed similar deactivation effects (~90% inhibition). Sol 2 gave ~ 85% inhibition effects. Sol 5 (12%) and Sol 4 (5%) barely have effects on NF-kB deactivation. Student’s t test results indicated that % inhibition of Sol 3b and 7 is significantly greater than Sol 1, 3a and 6 ( p value < 0.05), whereas Sol 2 showed significantly lower inactivation effects than Sol 1, 3a and 6 (p value < 0.05). There is no significant difference between Sol 3b and 7 or Sol 1, 3a and 6. Due to the presence of 100% Sn(IV) in both Sol 3b and 7, it indicated that Sn (IV) seems to have better performance in deactivation of NF-kB than Sn (II) in HEK-hTLR2 cells. When in the absence of TSPP in Sol 2, the inhibition effect of SNAPs is significantly lower than Sol 1, suggesting the importance of TSPP in the SNAPs containing Sn(II). Furthermore, KNO3 seems not that important for Sn(II) due to the non-significant between Sol 1 and 3a. In conclusion, the inhibition effects on NF-kB activation are Sol 3b and 7 (~92%) > Sol1, 3a and 6 (~90%) > Sol 2 (~85%) > Sol 5 (~12%) > Sol 4 (~5%).

[0222] In FIG.8, in HEK-hTLR4 cells, Sol 3a and 6 possessed ~88% decrease in NF-kB activation in contrast to LPS only treated group, followed by Sol 1 (~87%), Sol 3b and 7 (~85%), and Sol 2 (~68%). Sol 5 here has slightly inhibition effects (~35%). Student’s t test results indicated that % inhibition between group Sol 3a and 6 versas Sol 1 is significant. Moreover, the effects of Sol 3b and 7 are greater than Sol 2, but significantly lower than Sol 1 ( p value < 0.05). Due to the quite close inhibition effects between Sol 1, 3a, 3b, 6, and 7, it indicates that Sn(II) and Sn(IV) exhibited similar performance on NF-kB deactivation in HEK-hTLR4 cells. The much lower effect of Sol 2 indicated the importance of TSPP for Sn(II) in SNAPs, whereas the close effect between Sol 3b and 7 suggested KNO3 seems not important for Sn (IV). In conclusion, the inhibition effects on NF-kB activation are Sol 3a and 6 (~88%)> Sol1 (~87%)> Sol 3b and 7 (~85%) >Sol 2 (~68%) > Sol 5 (~35%) > Sol 4 (~-5%).

[0223] Although the NF-kB deactivation results seems different from what we observed with regard to the inhibition effect of SNAPs on IL-8 level in response to stimulation, where the effects in HEK-hTLR2 cells is : Sol1 (~85% inhibition) > Sol3b (~74%) > Sol3a and 6 ( ~64%) > Sol 2 and 7 (~47%); in HEK-hTLR4 cells is: Sol3b and 7 (~97%) > Sol1 and 6 (~84%) > Sol3a (~66%)> Sol 2 (~40%) ( Refer to the report of anti-inflammatory effects of SNAPs, date: 12-02-21), it seems that these two experiments all indicated the importance of TSPP on Sn(II) effects on anti-inflammatory, whereas for Sn(IV), KNO3 seems not that important.

[0224] Furthermore, in HEK-hTLR2 cells with regard to IL-8 level decreasing, Sol 1 with presence of Sn (II) showed the best performance, whereas Sol 7 with Sn (IV) showed the lowest. However, in NF-kB deactivation, Sol1 and 7 showed quite similar results. In HEK-hTLR4 cells, Sol 3b and 7 with presence of Sn (IV) seem to exhibit the greatest effect on decreased IL-8 level, whereas in terms of NF-kB deactivation, Sn(II) and Sn(IV) showed similar performance. All these results suggest that it might be important to use more than one assay to evaluate the anti-inflammatory performance of Sn (II) and Sn(IV) in SNAPs solutions. Overall, SNAPs exhibit great anti- inflammatory effects. Example 5

[0225] In this Example, chewing tobacco, tobacco extract, or nicotine will be used to stimulate TLR4 and IL-8 production. HEK-hTLR4 cells will be grown to at least 80% confluency in 96-well plates at 37oC and 5% CO2. Culture media should contain DMEM, 10% FBS, 1% penicillin- streptomycin, Normocin, and HEK-Blue selection. If basic media does not already contain L- glutamine, 1% L-glutamine will be added.

[0226] Sample compositions will be mixed at desired concentrations in sterile cell culture water, and samples centrifuged. Supernatant will be collected as test material, and supernatant further diluted in prepared media to twice the desired final concentration.

[0227] Cells will be treated with chewing tobacco, tobacco extract, or nicotine for a period of time (e.g., 3-24 hours), washed, and incubated. In addition, for the detection of intracellular levels of TLR4, cells may be permeabilized with permeabilization buffer (eBioscience) and stained with anti-human TLR4 Ab or relevant isotype. TLR4 expression may be assessed on a FACScan flow cytometer (BD Biosciences). The relative TLR4 surface or intracellular levels will be quantified by subtracting the mean fluorescent intensity (MFI) from the MFI values of isotype matched control for each sample.

[0228] Either LPS or Ultrapure LPS will be diluted to 2 ng / mL in prepared media. Old media will be aspirated from confluent cells.100 µL of prepared chewing tobacco, tobacco extract, or nicotine supernatant and 100 µL of LPS will be added to the cells. The final concentrations will be half of what is applied, as the LPS and treatment dilute each other. The cells will be incubated overnight. After collecting cell culture media, prepared PrestoBlue cell viability reagent will be added (1:10 dilution in media), and incubated with the cells for 10-30 minutes. Fluorescence will be read at560 / 590 ex / em to determine post-treatment viability. Supernatant of HEK-hTLR4 cells will be submitted to IL-8 ELISA to quantify levels of IL-8 in the presence or absence of LPS and chewing tobacco, tobacco extract, or nicotine.

Claims

CLAIMS What Is Claimed Is:

1. A method of treating and / or alleviating an interleukin-8 (IL-8) mediated inflammatory disorder in a subject in need thereof, comprising applying an oral care composition to an oral cavity of the subject, the oral care composition comprising: a stannous ion source; a nitrate ion source; a water-soluble alkali metal polyphosphate; and at least 10% water, by weight of the composition.

2. The method according to claim 1, wherein the stannous ion source is selected from: stannous fluoride; stannous chloride; stannous pyrophosphate; stannous formate; stannous acetate; stannous gluconate; stannous lactate; stannous tartrate; stannous oxalate; stannous malonate; stannous citrate; stannous ethylene glyoxide; and a combination of two or more thereof.

3. The method according to claim 1 or claim 2, wherein the nitrate ion source is selected from an alkali or alkaline earth metal nitrate, or zinc nitrate, silver nitrate, or ammonium nitrate.

4. The method according to any foregoing claim, wherein the nitrate ion source is selected from: lithium nitrate, sodium nitrate, potassium nitrate, magnesium nitrate, calcium nitrate, zinc nitrate, silver nitrate, ammonium nitrate, and a combination two or more thereof.

5. The method according to any foregoing claim, wherein the nitrate ion source comprises potassium nitrate.

6. The method according to any foregoing claim, wherein the water-soluble alkali metal polyphosphate is selected from: a pyrophosphate; a tripolyphosphate; a tetraphosphate; a hexametaphosphate; and combination of two or more thereof.

7. The method according to any foregoing claim, wherein the water-soluble alkali metal polyphosphate is selected from: sodium pyrophosphate; potassium pyrophosphate; sodium tripolyphosphate; potassium tripolyphosphate; and a combination of two or more thereof.

8. The method according to any foregoing claim, wherein the nitrate ion source comprises potassium nitrate and the water-soluble alkali metal polyphosphate salt comprises tetrasodium pyrophosphate.

9. The method according to any foregoing claim, wherein the IL-8 mediated inflammatory disorder is selected from: gum disease; chronic obstructive pulmonary disorder (COPD); pneumonia; bronchitis; Crohn’s disease; ulcerative colitis; and asthma.

10. The method according to claim 9, wherein the gum disease is selected from: gingivitis; periodontitis; implantitis; and mucositis.

11. The method according to any foregoing claim, wherein the subject in need thereof is selected from: a nicotine user; a patient with an inflammatory disease; a patient with a bacterial or viral infection, an obese person, or an elderly person.

12. The method according to any foregoing claim, wherein the subject in need thereof is a nicotine user.

13. The method according to any foregoing claim, comprising applying the oral care composition to the oral cavity at least once a day, optionally at least twice a day or at least 3 times a day.

14. The method according to any foregoing claim, wherein the oral care composition is applied to the oral cavity for about 10 seconds to about 30 minutes, such as about 15 seconds to about 25 minutes, about 20 seconds to about 15 minutes, about 25 seconds to about 5 minutes, or about 30 seconds to about 2 minutes.

15. The method according to any foregoing claim, wherein the oral care composition is applied to the oral cavity in an amount of about 0.1 to about 3 grams.

16. The method according to any foregoing claim, wherein the stannous ion source comprises stannous fluoride.

17. The method according to any foregoing claim, wherein the oral care composition has a molar ratio of nitrate ions to stannous ions, both measured as free ions, of about 0.5:1 to about 2:

1.

18. The method according to any foregoing claim, wherein the oral care composition comprises water in an amount ranging from about 10% to about 30%, such as from about 12% to about 25% or from about 15% to about 20%, by weight relative to the total weight of the oral care composition.

19. The method according to any foregoing claim, wherein the method reduces an IL-8 concentration in a tissue of the subject, such as gum tissue of the subject.

20. The method according to claim 19, wherein the IL-8 concentration is reduced by at least about 25%, such as at least 30%, at least 35%, at least 40%, at least 45%, or at least 50%.

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