Methods for mediating inflammatory responses

Abstract

This article describes a method for treating and / or alleviating cytokine-mediated inflammatory conditions such as gingival disease in a subject in need, the method comprising applying an oral care composition to the 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. This article also describes methods for treating and / or alleviating gingival disease.

Description

[0001] Cross-reference of related applications This application claims the benefit of U.S. Provisional Application No. 63 / 554,281, filed February 16, 2024, entitled "Methods for Mediating an Inflammatory Response," which is incorporated herein by reference as fully set forth herein. Background Technology

[0002] Pathogenic bacteria (including those found in plaques) produce lipopolysaccharide (LPS), a toxic endotoxin that causes chronic inflammation of the gingival line, which can develop to affect the bone surrounding and supporting the teeth. LPS is a large complex molecule and a major component of the outer membrane of Gram-negative bacteria. Released from the Gram-negative cell wall, LPS acts as an endotoxin and stimulates an inflammatory immune response. LPS from different strains of Gram-negative bacteria differ but share a common structural pattern. The components of LPS include a lipid A fraction, a core polysaccharide region consisting of an inner and outer nucleus, and an O antigen. Differences in LPS structure result in varying virulence, i.e., endotoxicity levels. Therefore, some LPS are more harmful than others.

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

[0004] In the NF-κB pathway, bacterial LPS binds to the TLR4 receptor, which then dimers and initiates a kinase cascade. Activated Toll-like receptors mediate the NF-κB signaling pathway, which induces the release of pro-inflammatory cytokines essential for a potent immune response leading to tissue destruction. Pro-inflammatory cytokines include, for example, interleukin-8 (IL-8), tumor necrosis factor-α (TNFα), and prostaglandin E2 (PGE2). Higher levels of cytokines are associated with higher levels of bacterial LPS and indicate more inflammation. Because periodontal disease is associated with chronic inflammation caused by oral bacteria, bacterial LPS-induced inflammation is a direct cause of periodontal disease. *Porphyromonas gingivalis* (… Porphyromonas gingivalis LPS stimulation of TLR4 leads to an increase in IL-8 and TNFα, and this increase is associated with periodontal disease.

[0005] IL-8 is a chemokine involved in recruiting and activating certain white blood cells, called neutrophils, to sites of inflammation or damage. IL-8 can be produced by a variety of cell types, including macrophages, epithelial cells, endothelial cells, and fibroblasts, in response to inflammatory stimuli such as bacterial or viral infections, tissue damage, or exposure to pro-inflammatory cytokines. However, dysregulation of IL-8 can contribute to the development and progression of several pathological conditions, such as autoimmune diseases, cancer, and chronic inflammatory conditions, including gingivitis and periodontitis, chronic obstructive pulmonary disease (COPD), and rheumatoid arthritis.

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

[0007] Therefore, there is a need for novel compositions and treatments for use by people at risk of developing IL-8-mediated inflammatory conditions, including, for example, for nicotine users, in order to reduce IL-8 concentrations in affected tissues. Summary of the Invention

[0008] This summary is intended only to provide a simplified overview of some aspects of one or more embodiments of the present disclosure. Further areas of applicability will become apparent from the detailed description provided below. This summary is not an exhaustive overview, nor is it intended to identify key or essential elements of the teachings, nor is it intended to define the scope of the disclosure. Rather, the purpose of this summary is merely to present one or more concepts in a simplified form as a prelude to the detailed description that follows.

[0009] The aspects disclosed herein relate to methods for treating and / or alleviating interleukin-8 (IL-8)-mediated inflammatory conditions in subjects of need, the methods comprising applying an oral care composition to the oral cavity of the subject, the oral care composition comprising a stannous source, a nitrate ion source, and pyrophosphate. In some embodiments, the IL-8-mediated inflammatory condition is selected from gingival diseases, chronic obstructive pulmonary disease (COPD), pneumonia, bronchitis, Crohn's disease, ulcerative colitis, or asthma, and in some embodiments, the IL-8-mediated inflammatory condition is a gingival disease such as gingivitis, periodontitis, implantitis, or mucositis. In some embodiments, the IL-8-mediated inflammatory condition is gingivitis or periodontitis.

[0010] This article also discloses a method for treating and / or alleviating symptoms of gingival diseases (such as gingivitis, periodontitis, implantitis, or mucositis) in subjects in need, the method comprising applying an oral care composition to the oral cavity of the subject, the oral care composition comprising a stannous source, a nitrate ion source, and pyrophosphate.

[0011] In some embodiments, the subjects in need are selected from nicotine users, patients with inflammatory diseases, patients with bacterial or viral infections, obese individuals, or elderly individuals. In some embodiments, the subjects in need are nicotine users.

[0012] In some embodiments disclosed herein, the method comprises applying the oral care composition to the oral cavity at least once daily, such as at least twice daily or at least three times daily, and in some embodiments, applying the oral care composition 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 some embodiments of this disclosure, the oral care composition is applied to the oral cavity in an amount of about 0.1 grams to about 3 grams.

[0013] 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 nitrate ion source is selected from lithium nitrate, sodium nitrate, potassium nitrate, magnesium nitrate, calcium nitrate, zinc nitrate, silver nitrate, ammonium nitrate, and combinations of two or more thereof. According to certain embodiments of the methods disclosed herein, the molar ratio of nitrate ions to stannous ions in the oral care composition is from about 0.5:1 to about 2:1, and both the nitrate ions and the stannous ions are measured in the form of free ions. 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 combinations of two or more thereof. In some embodiments, the oral care composition comprises water in an amount ranging from about 5% to about 20% by weight, such as from about 5% to about 7% by weight 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 the concentration of IL-8 in the subject's tissues, such as the subject's gingival tissue. 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%. Attached Figure Description

[0015] Embodiments of the invention will now be described by way of example only with reference to the accompanying drawings. Features and advantages of this disclosure will become apparent from the following more detailed description of certain embodiments and as illustrated in the accompanying drawings, in which: Figure 1 The following are bar graphs showing the changes in optical density (OD) at 640 nm: (1) untreated HEK-hTLR4 cells; (2) HEK-hTLR4 cells treated with 1 µg / mL Porphyromonas gingivalis LPS; (3) HEK-hTLR4 cells treated with 1 µg / mL Porphyromonas gingivalis LPS and composition A; (4) HEK-hTLR4 cells treated with 1 µg / mL Porphyromonas gingivalis LPS and composition B; and (5) HEK-hTLR4 cells treated with 1 µg / mL Porphyromonas gingivalis LPS and composition C, as described in Example 2.

[0016] Figure 2The bar graph shows the fold change in IL-8 concentration for the following: (1) untreated HEK-hTLR4 cells; (2) HEK-hTLR4 cells treated with 1 µg / mL Porphyromonas gingivalis LPS; (3) HEK-hTLR4 cells treated with 1 µg / mL Porphyromonas gingivalis LPS and composition A; (4) HEK-hTLR4 cells treated with 1 µg / mL Porphyromonas gingivalis LPS and composition B; and (5) HEK-hTLR4 cells treated with 1 µg / mL Porphyromonas gingivalis LPS and composition C, as described in Example 2.

[0017] Figure 3 The bar graph shows the average concentration (pg / mL) of IL-8 in the following: (1) untreated HEK-hTLR4 cells; (2) HEK-hTLR4 cells treated with 1 µg / mL of Porphyromonas gingivalis LPS; (3) HEK-hTLR4 cells treated with 1 µg / mL of Porphyromonas gingivalis LPS and composition D20; and (4) HEK-TLR4 cells treated with 1 µg / mL of Porphyromonas gingivalis LPS and composition E20, as described in Example 3.

[0018] Figure 4 The bar graph shows the fold change in IL-8 concentration for the following: (1) untreated HEK-hTLR4 cells; (2) HEK-hTLR4 cells treated with 1 µg / mL *Porphyromonas gingivalis* LPS; (3) HEK-hTLR4 cells treated with 1 µg / mL *Porphyromonas gingivalis* LPS and composition D20; (4) HEK-hTLR4 cells treated with 1 µg / mL *Porphyromonas gingivalis* LPS and composition D40; (5) HEK-hTLR4 cells treated with 1 µg / mL *Porphyromonas gingivalis* LPS and composition E20; and (6) HEK-hTLR4 cells treated with 1 µg / mL *Porphyromonas gingivalis* LPS and composition E40, as described in Example 3.

[0019] Figure 5 This study demonstrates the assessment of SEAP activity in HEK-hTLR2 cells treated with SNAP solution at OD 640 nm. The SEAP reporter gene is controlled by an IFN-β minimal promoter fused to five NF-κB and AP-1 binding sites; therefore, NF-κB activation induces SEAP expression, and NF-κB activation can be detected by measuring SEAP activity (Note: cell viability data are available in the SNAP anti-inflammatory report).

[0020] Figure 6This study demonstrates the assessment of SEAP activity by measuring absorbance at OD 640 nm in HEK-hTLR4 cells treated with SNAP solution. The SEAP reporter gene is controlled by an IFN-β minimal promoter fused to five NF-κB and AP-1 binding sites; therefore, NF-κB activation induces SEAP expression, and NF-κB activation can be detected by measuring SEAP activity (Note: cell viability data are available in the SNAP anti-inflammatory report).

[0021] Figure 7 This study demonstrated the NF-κB inactivation effect of SNAP solution in response to IL-1β stimulation in HEK-hTLR2 cells.

[0022] Figure 8 This study demonstrates the NF-κB inactivation effect of SNAP solution in response to LPS stimulation in HEK-hTLR4 cells.

[0023] It should be understood that the aspects are not limited to the composition, arrangement and means shown in the accompanying drawings. Detailed Implementation

[0024] For illustrative purposes, the principles of this disclosure are described with reference to its various exemplary embodiments. While certain embodiments of this disclosure have been specifically described herein, those skilled in the art will readily recognize that the same principles are equally applicable and can be used in other compositions and methods. Before explaining the disclosed embodiments in detail, it should be understood that this disclosure is not limited in its application to the details of any particular embodiment disclosed herein. The terminology used herein is for descriptive purposes only and is not intended to be limiting.

[0025] As used herein and in the appended claims, unless the context otherwise requires, the singular forms “a or an” and “the” include plural references. The singular form of any class of ingredients refers not only to a single chemical species within that class but also to mixtures of such chemical species. The terms “a / an,” “one or more,” and “at least one” are used interchangeably herein. The terms “comprising,” “including,” and “having” are used interchangeably. The term “include” should be construed as “including, but not limited to.”

[0026] As used throughout, "range" is used as a shorthand to describe each value within the range. Any value within the range can be chosen as an endpoint of the range. Therefore, the range 1-5 specifically includes 1, 2, 3, 4, and 5, as well as subranges such as 2-5, 3-5, 2-3, 2-4, 1-4, etc.

[0027] The term “about” when referring to a number means any number within the range of 10% of said number. For example, the phrase “about 2 wt.%” refers to a number between and including 1.8 wt.% and 2.2 wt.%.

[0028] All references cited herein are hereby incorporated herein by reference in their entirety. In the event of any conflict between the definitions in this disclosure and those in the cited references, this disclosure shall prevail.

[0029] Unless otherwise specified, abbreviations and symbols used herein have their ordinary meanings. The abbreviation "wt.%" refers to a weight percentage relative to the oral care composition. The symbol "°" refers to a degree, such as a temperature degree or an angle degree. The symbols "h", "min", "mL", "nm" and "µm" refer to hours, minutes, milliliters, nanometers, and micrometers, respectively. The abbreviation "rpm" indicates revolutions per minute.

[0030] When referring to chemical structures and names, the symbols "C", "H", and "O" represent carbon, hydrogen, and oxygen, respectively. The symbols "-", "=", and "≡" represent single, double, and triple bonds, respectively.

[0031] Any member in the list of species used to exemplify or define a genus may be different from, overlap with, be a subset of, be equivalent to, or be nearly identical to, any other member in the list of species. Furthermore, unless explicitly stated otherwise, as when referring to the Markush group, the list of species defining or exemplifying a genus is open, and it is assumed that other species defining or exemplifying a genus may exist, as well as or better than any other species listed.

[0032] The phrase "mixtures thereof," "combinations thereof," or "combinations of two or more thereof" does 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 means that it may include any two or more of A, B, C, D, E, and F. 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 any two or more of A, B, C, D, E, and F." The term "one of its salts" also refers to "a plurality of its salts". Therefore, when this disclosure refers to "elements selected from the group consisting of: A, B, C, D, E, F, their salts and mixtures thereof", it means that it may include one or more of A, B, C, D, E and F, may include one or more of salts of A, B, C, D, E and F, or may include a mixture of any two of salts of A, B, C, D, E, F, salts of A, B, C, D, E and F.

[0033] All components and elements affirmatively set forth in this disclosure may be negatively excluded from the claims. In other words, the oral care compositions of this disclosure may be free of or substantially free of all components and elements affirmatively set forth throughout this disclosure. In some cases, the oral care compositions of this disclosure may be substantially free of non-accidental amounts of the ingredients or compounds described herein. A non-accidental amount of an ingredient or compound is the amount of said ingredient or compound added alone to the oral care composition. For example, the oral care composition may be substantially free of non-accidental amounts of an ingredient or compound, but such an ingredient or compound may be present as part of a raw material included as a blend of two or more compounds.

[0034] Some of the categories of the identified components may overlap. Where overlap is possible and the oral care composition comprises two components (or more than two overlapping components), an overlapping compound does not represent more than one component. For example, some compounds can be characterized as both a polyol and a sweetener. If a particular oral care composition comprises both a polyol and a sweetener, xylitol will be used only as either a polyol or a sweetener, not both.

[0035] For readability purposes, chemical functional groups are presented in their adjective forms; for each adjective, the word "group" is assumed. For example, the adjective "alkyl" without a noun should be read as "alkylgroup".

[0036] As used herein, the term "oral fluid" refers to any fluid originating 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 Escherichia coli). E. coli (These include) 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 can be located in transgenic animals.

[0037] As used herein, the term "subject" refers to an individual (e.g., a human) who will be treated by the methods or compositions of the present invention. Subjects include, but are not limited to, mammals (e.g., rats, monkeys, equines, bovines, pigs, canines, felines, etc.), and most preferably include humans. In the context of this disclosure, the term "subject" generally refers to an individual who will receive or has received treatment for symptoms characterized by the presence of IL-8-mediated inflammation, or who is expected to have a potential susceptibility to IL-8-mediated inflammation.

[0038] As used herein, the term "in vitro" refers to an artificial environment and the processes or reactions that occur within that environment. In vitro environments include, but are not limited to, test tubes and cell cultures. The term "in vivo" refers to a natural environment (e.g., an animal or cell) and the processes or reactions that occur within that environment.

[0039] 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, protozoa, mycoplasma, prions, and parasites.

[0040] As used herein, the term “microorganism” refers to a microbial organism and is intended to encompass both a single organism and a preparation containing any number of organisms.

[0041] As used herein, the term “microorganism” means any kind or type of microorganism, including but not limited to bacteria, archaea, fungi, protozoa, mycoplasma, and parasites.

[0042] The terms “bacteria” and “bacterium” refer to all prokaryotes, including prokaryotes within all phyla of the Kingdom Procaryotae. The term is intended to encompass all microorganisms considered to be bacteria, including mycoplasma, chlamydia, actinomycetes, streptomyces, and rickettsiae. This definition includes all forms of bacteria, including cocci, bacilli, spirochetes, spheroids, protoplasts, etc. The term also includes Gram-negative or Gram-positive prokaryotes. “Gram-negative” and “Gram-positive” refer to the staining patterns of the Gram staining process, which are well known in the art. (See, for example, Finegold and Martin, Diagnostic Microbiology, 6th ed., CV Mosby St. Louis, pp. 13-15 (1982)). Gram-positive bacteria retain the primary dye used in Gram staining, causing the stained cells to typically appear deep blue to purple under a microscope. Gram-negative bacteria do not retain the primary dye used in Gram staining but are stained with counterstain. Therefore, Gram-negative bacteria typically appear red.

[0043] The term "non-pathogenic bacteria" or "non-pathogenic bacterium" includes all known and unknown non-pathogenic bacteria (Gram-positive or Gram-negative) as well as any pathogenic bacteria that have been mutated or transformed into non-pathogenic bacteria. Furthermore, those skilled in the art will recognize that some bacteria may be pathogenic to a particular species but non-pathogenic to others; therefore, these bacteria can be used in species in which they are non-pathogenic or mutated to make them non-pathogenic.

[0044] As used herein, the term "cell culture" refers to any in vitro culture of cells, including, for example, prokaryotic and eukaryotic cells. This term includes continuous cell lines (e.g., continuous cell lines with an immortalized phenotype), primary cell cultures, transformed cell lines, limited cell lines (e.g., untransformed cells), bacterial cultures in or on solid or liquid media, and any other cell populations maintained in vitro.

[0045] This document discloses a method for treating and / or alleviating IL-8-mediated inflammatory conditions in subjects in need, wherein the method comprises applying an oral care composition as disclosed herein to the oral cavity of the subject.

[0046] As discussed above, IL-8 dysregulation can contribute to the development and progression of several pathological conditions, including autoimmune diseases, cancer, and chronic inflammatory conditions such as gingivitis, periodontitis, implantitis, or mucositis, chronic obstructive pulmonary disease (COPD), and rheumatoid arthritis. Several factors are known to contribute to IL-8 dysregulation, and many patient populations may face an increased risk of IL-8-mediated inflammation. Specifically, individuals at risk of developing IL-8 dysregulation and consequently 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 (e.g., pneumonia, bronchitis, and urinary tract infections); obese individuals and those at risk of obesity-related complications (e.g., insulin resistance, type 2 diabetes, and cardiovascular disease); patients with chronic wounds (e.g., diabetic ulcers and pressure ulcers); and older adults.

[0047] Nicotine can induce immune cells to produce reactive oxygen species, including IL-8. Therefore, nicotine users may have higher levels of circulating IL-8, thus increasing their susceptibility to various IL-8-mediated inflammatory diseases and symptoms. Nicotine is known as the main addictive component of tobacco products and is known to weaken the body's immune system. Users of tobacco products (including, for example, cigarettes, e-cigarettes, cigars, and dipped or chewed tobacco) have an increased risk of developing cancers, including leukemia, bladder cancer, cervical cancer, colorectal cancer, esophageal cancer, kidney cancer, liver cancer, lung cancer, oral cancer, laryngeal cancer, pancreatic cancer, and stomach cancer. In addition to cancer, tobacco users also face an increased risk of heart disease, stroke, lung disease, diabetes, chronic obstructive pulmonary disease (COPD), tuberculosis, eye diseases, and immune system problems, including rheumatoid arthritis.

[0048] As used herein, nicotine users include subjects who use tobacco products such as cigarettes, cigars, chewing tobacco, electronic cigarettes, or other nicotine-containing devices. In some embodiments, nicotine users may use tobacco products at least once a week, such as at least twice a week, at least three times a week, or at least four times a week, at least five times a week, at least six times a week, or at least seven times a week. In some embodiments, nicotine users may use tobacco products at least once a day, such as at least twice a day, or at least three, four, five, six, seven, eight, nine, ten, eleven, or twelve times a day. In some embodiments, nicotine users are addicted to nicotine, and in some embodiments, nicotine use has been with at least one tobacco product for at least three months, such as at least six months, at least nine months, at least one year, at least two years, or at least three years, such as at least four, five, six, seven, eight, nine, or ten years.

[0049] In addition to the health risks discussed above, nicotine users also have an increased risk of oral problems 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 caused by plaque buildup at the gum line. If daily brushing and flossing fail to remove plaque, it produces toxins (toxic substances) that can irritate gum tissue, leading to gingivitis. Symptoms may include bleeding during brushing and flossing. In this early stage of gum disease, the damage is reversible because the bone and connective tissue that hold teeth in place are not yet affected.

[0050] Periodontitis is a more advanced stage of gum disease. At this stage, the supporting bone and fibers that hold teeth in place suffer irreversible damage. Periodontal pockets may begin to form below the gum line, trapping 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 occlusion, and if aggressive treatment is ineffective or unavailable, tooth extraction may be necessary.

[0051] Implantitis (including peri-implantitis) is an inflammatory reaction in which loss of supporting bone may occur in the tissue surrounding the implant. Mucositis is an inflammation of the mucous membranes, the lining of the oral cavity and gastrointestinal tract. Mucositis can cause open ulcers in the mouth and is a known side effect of chemotherapy and radiation therapy.

[0052] This disclosure relates to methods for reducing, alleviating, and / or treating IL-8-mediated inflammatory conditions such as COPD, pneumonia, bronchitis, Crohn's disease, ulcerative colitis, asthma, and gingival diseases such as gingivitis, periodontitis, implantitis, or mucositis. It has been found that certain methods and compositions disclosed herein can provide a significant reduction in the inflammatory response cytokine IL-8, which may consequently lead to a reduction, alleviation, and / or treatment of various IL-8-mediated inflammatory conditions in subjects of need. The significant reduction in IL-8 is unexpected.

[0053] In some embodiments, the methods disclosed herein reduce and / or inhibit the production of IL-8 in the oral cavity (such as in periodontal tissues and / or periodontal pockets). In some embodiments, the methods disclosed herein reduce IL-8 concentration by 5% or more, for example, compared to IL-8 concentration under similar conditions without the methods disclosed herein. In some embodiments, the methods disclosed herein reduce IL-8 concentration 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, for example, compared to IL-8 concentration under similar conditions without the methods disclosed herein. For example, when the method includes applying an oral care composition in the form of a dental flosser by brushing teeth, the methods disclosed herein can reduce the IL-8 concentration by one of the aforementioned amounts compared to IL-8 concentration under similar conditions (such as brushing teeth without the dental flosser disclosed herein). By way of another example, when the method includes applying an oral care composition in the form of a mouthwash by rinsing, gargling and / or rinsing, the method disclosed herein can reduce the IL-8 concentration by one of the aforementioned amounts compared to the IL-8 concentration under similar conditions without the application of the innovative mouthwash disclosed herein.

[0054] If measured in the oral cavity, the method can achieve a reduction in IL-8 concentration at any time period, such as from 2 hours to about 2 weeks. IL-8 concentration can be determined by any means known in the art, including, for example, by enzyme-linked immunosorbent assay (ELISA), such as the commercially available Enzo IL-8 ELISA assay (Enzo LifeSciences, catalog number ADI-900-156).

[0055] According to another aspect, a method for treating or alleviating gingival diseases such as gingivitis, periodontitis, implantitis, or mucositis is provided, the method comprising applying an oral care composition as disclosed herein to the oral cavity of a subject in need, the oral care composition comprising a stannous source, a nitrate ion source, and pyrophosphate. For example, aspects of this disclosure provide methods for reducing the amount of pathogenic bacteria, for example, compared to the growth rate of such pathogenic bacteria under similar conditions without the application of the methods disclosed herein. Periodontal pathogens are involved in inflammation and disease progression, and reducing them is important for maintaining health. Oral commensal bacteria actively participate in gingival tissue to maintain healthy neutrophil surveillance and normal tissue and bone turnover processes. Without being limited by any particular theory, it is believed that the methods disclosed herein can reduce the amount of pathogenic bacteria by mediating an IL-8 cytokine response.

[0056] According to certain embodiments of the methods disclosed herein, the oral care composition may be applied to the oral cavity of a subject in need at least once daily, such as at least twice daily or at least three times daily. The methods disclosed herein may include applying the oral care composition to the oral cavity for about 10 seconds to about 30 minutes, for example, 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 composition may be applied in a form that remains in the oral cavity overnight.

[0057] The methods disclosed herein may include applying an oral care composition of about 0.1 g to about 3 g to the oral cavity, for example, in the form of a dental flosser. For example, based on the total weight of the oral care composition, the oral care composition may be applied to the oral cavity, for example, in the form of a dental flosser, in the following amounts: about 0.1 g to about 3 g, about 0.3 g to about 3 g, about 0.5 g to about 3 g, about 1 g to about 3 g, about 1.5 g to about 3 g, about 2 g to about 3 g, about 2.5 g to about 3 g; about 0.1 g to about 2.5 g, about 0.3 g to about 2.5 g, about 0.5 g to about 2.5 g, about 1 g to about 2.5 g, about 1.5 g to about 2.5 g, about 2 g to about 2.5 g; about 0.1 g to about 2 grams, about 0.3 grams to about 2 grams, about 0.5 grams to about 2 grams, about 1 gram to about 2 grams, about 1.5 grams to about 2 grams; about 0.1 grams to about 1.5 grams, about 0.3 grams to about 1.5 grams, about 0.5 grams to about 1.5 grams, about 1 gram to about 1.5 grams; about 0.1 grams to about 1 gram, about 0.3 grams to about 1 gram, about 0.5 grams to about 1 gram; about 0.1 grams to about 0.7 grams, about 0.3 grams to about 0.7 grams, about 0.5 grams to about 0.7 grams; about 0.1 grams to about 0.4 grams, about 0.3 grams to about 0.4 grams, or any range or subrange thereof. In some embodiments, the oral care composition is in the form of toothpaste; gel; mouthwash; prophy; spray; lozenge; tablet; capsule; strip; patch; and soluble film. The oral care composition may also be in the form of varnish or no-rinse products (e.g., in the form of gel, varnish, film, etc.).

[0058] Depending on the specific combination of other ingredients and the form of the oral care composition, the formulation of the oral care composition may or may not include suitable components, such as those listed below. Alternatively, in some embodiments, the oral care composition may have a single phase containing components and / or ingredients of the oral care composition. In other embodiments, the oral care composition may include two or more phases, such as biphasic, triphasic, tetraphasic, or pentaphasic phases.

[0059] Oral care compositions typically contain a preferably effective amount of a stannous ion source. Based on the total weight of the oral care composition, the stannous ion source may be present in the oral care composition in an amount ranging from about 0.1 wt.% to about 5 wt.%. For example, based on the total weight of the oral care composition, the amount of stannous ions present in the oral care composition may be about 0.1 wt.% to about 4 wt.%, about 0.1 wt.% to about 3 wt.%, about 0.1 wt.% to about 2 wt.%; about 0.3 wt.% to about 5 wt.%, about 0.3 wt.% to about 4 wt.%, about 0.3 wt.% to about 3 wt.%, about 0.3 wt.% to about 2 wt.%; about 0.6 wt.% to about 5 wt.%, about 0.6 wt.% to about 4 wt.%, about 0.6 wt.% to about 3 wt.%, about 0.6 wt.% to about 2 wt.%; about 0.9 wt.% to about 5 wt.%, about 0.9 wt.% to about 4 wt.%, about 0.9 wt.% to about 3 wt.%, about 0.9 wt.% to about 2 wt.%; about 1.2 wt.% to about 5 wt.%, about 1.2 wt.% to about 5 wt.%. wt.% to about 4 wt.%, about 1.2 wt.% to about 3 wt.%, about 1.2 wt.% to about 2 wt.%; about 1.5 wt.% to about 5 wt.%, about 1.5 wt.% to about 4 wt.%, about 1.5 wt.% to about 3 wt.%; about 2 wt.% to about 5 wt.%, about 2 wt.% to about 4 wt.%, about 2 wt.% to about 3 wt.%; about 3 wt.% to about 5 wt.%, about 4 wt.% to about 5 wt.%, or any range or subrange thereof. In at least one embodiment, based on the total weight of the oral care composition, the oral care composition includes about 0.4 wt.% to about 0.5 wt.% of a stannous ion source, such as about 0.45 wt.% of a stannous ion source.

[0060] 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 glycolate, and combinations of two or more thereof. The stannous ion source may comprise stannous fluoride, stannous chloride, stannous acetate, and combinations of two or more thereof. In at least one embodiment, the stannous ion source comprises stannous fluoride, and in at least one embodiment, the stannous ion source is composed of stannous fluoride.

[0061] Oral care compositions may include two or more, three or more, four or more, five or more, or six or more stannous ion sources. For example, an oral care composition may contain 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. Alternatively or alternatively, the oral care composition may comprise stannous fluoride and stannous chloride.

[0062] Oral care compositions typically contain one or more nitrate ion sources, preferably present in an effective amount. Based on the total weight of the oral care composition, the nitrate ion source may be present in the oral care composition in an amount ranging from about 0.1 wt.% to about 5 wt.%. In some cases, based on the total weight of the oral care composition, the amount of nitrate ions present in the oral care composition may be about 0.1 wt.% to about 4 wt.%, about 0.1 wt.% to about 3 wt.%, about 0.1 wt.% to about 2 wt.%; about 0.3 wt.% to about 5 wt.%, about 0.3 wt.% to about 4 wt.%, about 0.3 wt.% to about 3 wt.%, about 0.3 wt.% to about 2 wt.%; about 0.6 wt.% to about 5 wt.%, about 0.6 wt.% to about 4 wt.%, about 0.6 wt.% to about 3 wt.%, about 0.6 wt.% to about 2 wt.%; about 0.9 wt.% to about 5 wt.%, about 0.9 wt.% to about 4 wt.%, about 0.9 wt.% to about 3 wt.%, about 0.9 wt.% to about 2 wt.%; about 1.2 wt.% to about 5 wt.%; wt.%, about 1.2 wt.% to about 4 wt.%, about 1.2 wt.% to about 3 wt.%, about 1.2 wt.% to about 2 wt.%; about 1.5 wt.% to about 5 wt.%, about 1.5 wt.% to about 4 wt.%, about 1.5 wt.% to about 3 wt.%; about 2 wt.% to about 5 wt.%, about 2 wt.% to about 4 wt.%, about 2 wt.% to about 3 wt.%; about 3 wt.% to about 5 wt.%, about 4 wt.% to about 5 wt.% or any range or subrange thereof.

[0063] One or more nitrate ion sources may be in the form of salts or ions derived therefrom, including nitrates, for example, selected from alkali metal or alkaline earth metal nitrates. Examples of nitrate ion sources include lithium nitrate, sodium nitrate, potassium nitrate, magnesium nitrate, calcium nitrate, zinc nitrate, silver nitrate, ammonium nitrate, or combinations of two or more of these. In at least one embodiment, the nitrate ion source comprises potassium nitrate.

[0064] Oral care compositions can be formulated to have a molar ratio of nitrate ions to stannous ions of about 2:1 or less, both of which are measured as free ions. For example, oral care compositions can have the following molar ratios of nitrate ions to stannous ions, both of which are measured as free ions: 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; about 0.7:1 to about 2:1, about 0. The ratios are approximately 7:1 to 1.8:1, about 0.7:1 to 1.6:1, about 0.7:1 to 1.4:1, about 0.7:1 to 1.2:1, about 0.7:1 to 1:1; about 0.9:1 to 2:1, about 0.9:1 to 1.8:1, about 0.9:1 to 1.6:1, about 0.9:1 to 1.4:1, about 0.9:1 to 1.2:1, about 0.9:1 to 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 of about 1:1, both of which are measured as free ions.

[0065] Oral care compositions typically contain one or more phosphate ion sources. The phosphate ion source is preferably present in an effective amount. In some cases, based on the total weight of the oral care composition, the composition may include one or more phosphate ion sources in amounts from about 0.1 wt.% to about 7 wt.%. For example, based on the total weight of the oral care composition, one or more phosphate ion sources may be present in the oral care composition in the following amounts: about 0.1 wt.% to about 6 wt.%, about 0.1 wt.% to about 5 wt.%, about 0.1 wt.% to about 4 wt.%, about 0.1 wt.% to about 3 wt.%, about 0.1 wt.% to about 2 wt.%, about 0.1 wt.% to about 1 wt.%; about 0.4 wt.% to about 7 wt.%, about 0.4 wt.% to about 6 wt.%, about 0.4 wt.% to about 5 wt.%, about 0.4 wt.% to about 4 wt.%, about 0.4 wt.% to about 3 wt.%, about 0.4 wt.% to about 2 wt.%, about 0.4 wt.% to about 1 wt.%; about 0.8 wt.% to about 7 wt.%, about 0.8 wt.% to about 6 wt.%, about 0.8 wt.% to about 5 wt.%; wt.%, about 0.8 wt.% to about 4 wt.%, about 0.8 wt.% to about 3 wt.%, about 0.8 wt.% to about 2 wt.%; about 1.4 wt.% to about 7 wt.%, about 1.4 wt.% to about 6 wt.%, about 1.4 wt.% to about 5 wt.%, about 1.4 wt.% to about 4 wt.%, about 1.4 wt.% to about 3 wt.%; about 2 wt.% to about 7 wt.%, about 2 wt.% to about 6 wt.%, about 2 wt.% to about 5 wt.%, about 2 wt.% to about 4 wt.%, about 2 wt.% to about 3 wt.%; about 3 wt.% to about 7 wt.%, about 3 wt.% to about 6 wt.%, about 3 wt.% to about 5 wt.%; about 4 wt.% to about 7 wt.%, about 4 wt.% to about 6 wt.%, about 5 wt.% to about 7 wt.% wt.% or any range or subrange thereof.

[0066] The phosphate source may preferably comprise a soluble phosphate compound, such as a phosphate. 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 combinations thereof. The phosphate source may be a pyrophosphate, such as an alkali metal pyrophosphate. In some embodiments, the alkali metal pyrophosphate is selected from tetraalkali metal pyrophosphates, dialkali metal dihydrogen pyrophosphates, trialkali metal monohydrogen pyrophosphates, and mixtures thereof, wherein the alkali metal is sodium or potassium. For example, the phosphate source may include tetrasodium pyrophosphate (TSPP), tetrapotassium pyrophosphate, sodium tripolyphosphate, tetrapolyphosphate, sodium trimetaphosphate, sodium hexametaphosphate, or combinations of two or more thereof. The phosphate source may be selected from orthophosphates, polymetaphosphates, pyrophosphates, and combinations of two or more thereof. In some cases, 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. When in salt form, the phosphate source may be in its hydrated and / or unhydrated form.

[0067] Alternatively or concurrently, oral care compositions may include one or more anti-tartar agents. Examples of anti-tartar agents include, but are not limited to: phosphates and polyphosphates, polyaminopropane sulfonic acid (AMPS), polyolefin sulfonates, polyolefin phosphates, diphosphates such as aziridine-2,2-diphosphates (e.g., aziridine-heptane-2,2-diphosphate), N-methylaziridine-pentane-2,3-diphosphate, ethane-1-hydroxy-1,1-diphosphate (EHDP), and ethane-1-amino-1,1-diphosphate, and phosphoryl alkane carboxylic acids. Inorganic phosphates and polyphosphates that may be mentioned include monobasic, dibasic, and ternary sodium phosphates. Soluble pyrophosphates, such as those disclosed herein, may be useful anti-tartar agents. Pyrophosphates may be any alkali metal pyrophosphate.

[0068] Based on the total weight of the oral care composition, the oral care composition may include an amount of anti-tartar agent of about 0.1 wt.% to about 7 wt.%. For example, based on the total weight of the oral care composition, the anti-tartar agent may be present in the oral care composition in the following amounts: about 0.1 wt.% to about 6 wt.%, about 0.1 wt.% to about 5 wt.%, about 0.1 wt.% to about 4 wt.%, about 0.1 wt.% to about 3 wt.%, about 0.1 wt.% to about 2 wt.%, about 0.1 wt.% to about 1 wt.%; about 0.4 wt.% to about 7 wt.%, about 0.4 wt.% to about 6 wt.%, about 0.4 wt.% to about 5 wt.%, about 0.4 wt.% to about 4 wt.%, about 0.4 wt.% to about 3 wt.%, about 0.4 wt.% to about 2 wt.%, about 0.4 wt.% to about 1 wt.%; about 0.8 wt.% to about 7 wt.%, about 0.8 wt.% to about 6 wt.%, about 0.8 wt.% to about 5 wt.% wt.%, about 0.8 wt.% to about 4 wt.%, about 0.8 wt.% to about 3 wt.%, about 0.8 wt.% to about 2 wt.%; about 1.4 wt.% to about 7 wt.%, about 1.4 wt.% to about 6 wt.%, about 1.4 wt.% to about 5 wt.%, about 1.4 wt.% to about 4 wt.%, about 1.4 wt.% to about 3 wt.%; about 2 wt.% to about 7 wt.%, about 2 wt.% to about 6 wt.%, about 2 wt.% to about 5 wt.%, about 2 wt.% to about 4 wt.%, about 2 wt.% to about 3 wt.%; about 3 wt.% to about 7 wt.%, about 3 wt.% to about 6 wt.%, about 3 wt.% to about 5 wt.%; about 4 wt.% to about 7 wt.%, about 4 wt.% to about 6 wt.%, about 5 wt.% to about 7 wt.% wt.% or any range or subrange thereof.

[0069] In some embodiments, the phosphate source may be an insoluble phosphate source, such as zinc phosphate. Although zinc phosphate is considered insoluble in water (e.g., poorly water-soluble), when placed in formulations, for example at acidic or alkaline pH, zinc phosphate can dissolve sufficiently upon use to provide an effective concentration of zinc ions to the enamel, thereby preventing erosion, reducing bacterial colonization and biofilm development, and providing enhanced luster to the teeth. It has also been found that zinc phosphate in formulations having a second phosphate source can enhance phosphate deposition, as explained in PCT Publication WO 2014 / 088573, the disclosure of which is hereby incorporated herein by reference in its entirety.

[0070] Zinc phosphate can be used in any amount to effectively prevent enamel erosion and / or provide any other benefits described herein. Examples of suitable amounts of zinc phosphate relative to the total weight of the oral care composition can range from about 0.05 wt.% to about 5 wt.%, such as about 0.1 wt.% to about 4 wt.%, or about 0.5 wt.% to about 3 wt.%, or about 0.5 wt.% to about 2 wt.%, or about 0.8 wt.% to about 1.5 wt.%, or about 0.9 wt.% to about 1.1 wt.% or about 1 wt.%.

[0071] In compositions containing a large amount of water, zinc phosphate can be used as a stabilizer for stannous fluoride, allowing the stannous fluoride to remain in the aqueous solution. Stannous fluoride is generally considered unstable in water because stannous ions are hydrolyzed and oxidized and lost within the typical pH range used in oral care compositions. Therefore, stannous fluoride can be used herein in oral care compositions of this disclosure that are anhydrous or contain small amounts of water or have chelating agents. Alternatively, zinc phosphate and stannous fluoride can be combined together using standard mixing methods and typical pH ranges to form a single-phase formulation to create a stable aqueous oral care composition. Zinc phosphate remains substantially insoluble in the composition. However, stannous fluoride has been shown to remain soluble and stable in solutions containing a relatively large amount of water for extended periods (e.g., 3 months or longer) at 40°C.

[0072] Therefore, any desired amount of water can be used in the oral care compositions disclosed herein. In compositions containing relatively high amounts of water, examples of suitable water amounts range from about 10 wt.% or more, such as about 12 wt.% or more, such as about 14 wt.% to about 99 wt.%. For example, based on the total weight of the oral care composition, the water amount can be about 15 wt.% to about 85 wt.%, or about 20 wt.% to about 75 wt.%, or about 25 wt.% to about 50 wt.%, or about 30 wt.% to about 40 wt.%, for example, about 35 wt.%. The amount will vary depending on the type of oral care composition. In embodiments where the composition is a dental cleaning agent such as toothpaste, the amount of water relative to the total weight of the dental cleaning agent composition may 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.%, or about 14.5 wt.%.

[0073] In compositions containing relatively little or less water, water may be present in the oral care composition in an amount of about 1 wt.% to about 37 wt.%, such as about 5 wt.% to about 35 wt.%, based on the total weight of the oral care composition. For example, based on the total weight of the oral care composition, the oral care composition may include the following amounts of water: about 5 wt.% to about 34 wt.%, about 5 wt.% to about 31 wt.%, about 5 wt.% to about 28 wt.%, about 5 wt.% to about 25 wt.%, about 5 wt.% to about 20 wt.%; about 5 wt.% to about 7 wt.%, about 5.5 wt.% to about 6.5 wt.%, about 6.3 wt.%, about 10 wt.% to about 37 wt.%, about 10 wt.% to about 34 wt.%, about 10 wt.% to about 31 wt.%, about 10 wt.% to about 28 wt.%, about 10 wt.% to about 25 wt.%; about 15 wt.% to about 37 wt.%, about 15 wt.% to about 34 wt.%, about 15 wt.% to about 31 wt.%, about 15 wt.% to about 28 wt.%, about 15 wt.% to about 25 wt.%; about 15 wt.% to about 37 wt.%, about 15 wt.% to about 34 wt.%, about 15 wt.% to about 31 wt.%, about 15 wt.% to about 28 wt.%, about 15 wt.% to about 28 wt.%. wt.% to about 25 wt.%; about 20 wt.% to about 37 wt.%, about 20 wt.% to about 34 wt.%, about 20 wt.% to about 31 wt.%, about 20 wt.% to about 28 wt.%; about 25 wt.% to about 37 wt.%, about 25 wt.% to about 34 wt.%, about 25 wt.% to about 31 wt.%; about 28 wt.% to about 37 wt.%, about 28 wt.% to about 34 wt.%, about 28 wt.% to about 31 wt.%; about 31 wt.% to about 37 wt.%; about 37 wt.% to about 50 wt.%, about 37 wt.% to about 45 wt.% or any range or subrange thereof.

[0074] In addition to or in place of zinc phosphate, oral care compositions may include alternative zinc ion sources. When present, the zinc ion source is preferably in an effective amount. Based on the total weight of the oral care composition, the zinc ion source may be present in the oral care composition in an amount of about 0.1 wt.% to about 8 wt.%. For example, based on the total weight of the oral care composition, the amount of zinc ion source present in the oral care composition may be about 0.1 wt.% to about 6 wt.%, about 0.1 wt.% to about 5 wt.%, about 0.1 wt.% to about 4 wt.%, about 0.1 wt.% to about 3 wt.%, about 0.1 wt.% to about 2 wt.%, about 0.1 wt.% to about 1 wt.%; about 0.3 wt.% to about 8 wt.%, about 0.3 wt.% to about 6 wt.%, about 0.3 wt.% to about 5 wt.%, about 0.3 wt.% to about 4 wt.%, about 0.3 wt.% to about 3 wt.%, about 0.3 wt.% to about 2 wt.%; about 0.6 wt.% to about 8 wt.%, about 0.6 wt.% to about 6 wt.%, about 0.6 wt.% to about 5 wt.%, about 0.6 wt.% to about 4 wt.%, about 0.6 wt.% to about 4 wt.%. wt.% to about 3 wt.%, about 0.6 wt.% to about 2 wt.%; about 0.9 wt.% to about 8 wt.%, about 0.9 wt.% to about 6 wt.%, about 0.9 wt.% to about 5 wt.%, about 0.9 wt.% to about 4 wt.%, about 0.9 wt.% to about 3 wt.%, about 0.9 wt.% to about 2 wt.%; about 1.2 wt.% to about 8 wt.%, about 1.2 wt.% to about 6 wt.%, about 1.2 wt.% to about 5 wt.%, about 1.2 wt.% to about 4 wt.%, about 1.2 wt.% to about 3 wt.%, about 1.2 wt.% to about 2 wt.%; about 1.5 wt.% to about 8 wt.%, about 1.5 wt.% to about 6 wt.%, about 1.5 wt.% to about 5 wt.%, about 1.5 wt.% to about 4 wt.% wt.%, about 1.5 wt.% to about 3 wt.%; about 2 wt.% to about 8 wt.%, about 2 wt.% to about 6 wt.%, about 2 wt.% to about 5 wt.%, about 2 wt.% to about 4 wt.%, about 2 wt.% to about 3 wt.%; about 3 wt.% to about 8 wt.%, about 3 wt.% to about 6 wt.%, about 3 wt.% to about 5 wt.%; about 4 wt.% to about 8 wt.%, about 4 wt.% to about 6 wt.%, about 4 wt.% to about 5 wt.% or any range or subrange thereof.

[0075] The zinc ion source can be in the form of a salt. For example, the zinc ion source can comprise one or more zinc salts selected from: zinc sulfate, zinc chloride, zinc acetate, zinc phenolsulfonate, 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 combinations 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 combinations of two or more thereof.

[0076] Oral care compositions may include two or more, three or more, four or more, five or more, or six or more zinc ion sources. For example, an oral care composition may contain 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 of these. In at least one preferred embodiment, the oral care composition comprises zinc phosphate.

[0077] Oral care compositions can be formulated to have a weight ratio of zinc oxide to zinc citrate of about 1.5:1 to about 4.5:1. For example, the weight ratio of zinc oxide to zinc citrate can be 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; 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; 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; about 3:1 to about 4.5:1, about 3:1 to about 4:1, or any range or subrange thereof. In some embodiments, the weight ratio 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 thereof.

[0078] Based on the total weight of the oral care composition, the oral care composition may include, for example, one or more surfactants in amounts ranging from about 0.5 wt.% to about 8 wt.%. For example, based on the total weight of the oral care composition, the oral care composition may include one or more surfactants in the following amounts: about 0.5 wt.% to about 7 wt.%, about 0.5 wt.% to about 6 wt.%, about 0.5 wt.% to about 5 wt.%, about 0.5 wt.% to about 4 wt.%, about 0.5 wt.% to about 3 wt.%, about 0.5 wt.% to about 2 wt.%; about 1 wt.% to about 9 wt.%, about 1 wt.% to about 8 wt.%, about 1 wt.% to about 7 wt.%, about 1 wt.% to about 6 wt.%, about 1 wt.% to about 5 wt.%, about 1 wt.% to about 4 wt.%, about 1 wt.% to about 3 wt.%, about 1 wt.% to about 2 wt.%; about 2 wt.% to about 9 wt.%, about 2 wt.% to about 8 wt.%, about 2 wt.% to about 7 wt.%, about 2 wt.% to about 6 ... wt.% to about 5 wt.%, about 2 wt.% to about 4 wt.%, about 2 wt.% to about 3 wt.%; about 2.5 wt.% to about 9 wt.%, about 2.5 wt.% to about 8 wt.%, about 2.5 wt.% to about 7 wt.%, about 2.5 wt.% to about 6 wt.%, about 2.5 wt.% to about 5 wt.%, about 2.5 wt.% to about 4 wt.%, about 2.5 wt.% to about 3.5 wt.%; about 3 wt.% to about 9 wt.%, about 3 wt.% to about 8 wt.%, about 3 wt.% to about 7 wt.%, about 3 wt.% to about 6 wt.%, about 3 wt.% to about 5 wt.%, about 3 wt.% to about 4 wt.%, about 3 wt.% to about 3.5 wt.%; about 4 wt.% to about 9 wt.%, about 4 wt.% to about 8 wt.%, about 4 wt.% to about 7 wt.%, about 4 wt.% to about 6 wt.%, about 4 wt.% to about 5 wt.%; about 5 wt.% to about 9 wt.%, about 5 wt.% to about 8 wt.%, about 5 wt.% to about 7 wt.%, about 5 wt.% to about 6 wt.%; about 7 wt.% to about 9 wt.%, about 7 wt.% to about 8 wt.% or any range or subrange thereof.

[0079] Oral care compositions may comprise a surfactant system comprising a variety of surfactants. The surfactant system may comprise two or more surfactants, for example, three or more, four or more, five or more, six or more, seven or more, eight or more, or nine or more surfactants. In some cases, oral care compositions comprise two, three, four, five, six, seven, eight, nine, or ten surfactants, or ranges thereof. For example, oral care compositions may comprise 2 to four, two or three, three or four, four to nine, four to eight, four to seven, four to six, four or five; five to nine, five to eight, five to seven, five or six; six to nine, six to eight, six or seven surfactants.

[0080] 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 amphoteric surfactants, one or more bacterial surfactants, or combinations of two or more of these. For example, the surfactant system may comprise one or more nonsulfate-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 nonsulfate-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 nonsulfate-based anionic surfactant, a single amphoteric surfactant, a single nonionic surfactant, and a single amino acid surfactant. In other embodiments, the surfactant system comprises one or more anionic surfactants, one or more amphoteric surfactants, one or more nonionic surfactants, and one or more amino acid surfactants.

[0081] The oral care compositions disclosed herein may contain one or more anionic surfactants. Based on the total weight of the oral care composition, the amount of one or more anionic surfactants may range from about 0.1 wt.% to about 7 wt.%. In some cases, based on the total weight of the oral care composition, one or more anionic surfactants are present in the surfactant system in the following amounts: about 0.1 wt.% to about 6 wt.%, about 0.1 wt.% to about 5 wt.%, about 0.1 wt.% to about 4 wt.%, about 0.1 wt.% to about 3 wt.%, about 0.1 wt.% to about 2 wt.%, about 0.1 wt.% to about 1 wt.%; about 0.4 wt.% to about 7 wt.%, about 0.4 wt.% to about 6 wt.%, about 0.4 wt.% to about 5 wt.%, about 0.4 wt.% to about 4 wt.%, about 0.4 wt.% to about 3 wt.%, about 0.4 wt.% to about 2 wt.%, about 0.4 wt.% to about 1 wt.%; about 0.8 wt.% to about 7 wt.%, about 0.8 wt.% to about 6 wt.%, about 0.8 wt.% to about 5 wt.% wt.%, about 0.8 wt.% to about 4 wt.%, about 0.8 wt.% to about 3 wt.%, about 0.8 wt.% to about 2 wt.%; about 1.4 wt.% to about 7 wt.%, about 1.4 wt.% to about 6 wt.%, about 1.4 wt.% to about 5 wt.%, about 1.4 wt.% to about 4 wt.%, about 1.4 wt.% to about 3 wt.%; about 2 wt.% to about 7 wt.%, about 2 wt.% to about 6 wt.%, about 2 wt.% to about 5 wt.%, about 2 wt.% to about 4 wt.%, about 2 wt.% to about 3 wt.%; about 3 wt.% to about 7 wt.%, about 3 wt.% to about 6 wt.%, about 3 wt.% to about 5 wt.%; about 4 wt.% to about 7 wt.%, about 4 wt.% to about 6 wt.%, about 5 wt.% to about 7 wt.% wt.% or any range or subrange thereof.

[0082] One or more anionic surfactants may be selected from sulfate-based anionic surfactants and / or non-sulfate-based anionic surfactants, such as sulfonated monoglycerides of fatty acids, hydroxyethanesulfonates, sarcosinates, taurines, and combinations of two or more thereof. Examples of sulfate-based anionic surfactants include ammonium lauryl sulfate, ammonium lauryl ether sulfate, sodium lauryl sulfate, sodium cocoyl sulfate, ammonium cocoyl sulfate, and combinations of two or more thereof. In at least one embodiment, the oral care composition comprises a sulfate-based anionic surfactant, wherein the oral care composition is substantially free of or does not contain sodium lauryl sulfate and / or sodium lauryl ether sulfate.

[0083] Anionic surfactants may have at least one acyl group, preferably comprising a carbon chain having 8 to 21 carbons. In some cases, the alkyl group of the anionic surfactant comprises a carbon chain having 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 salt form. The salt form of the anionic surfactant may have alkali metal (e.g., sodium or potassium) and / or ammonium groups.

[0084] Non-limiting examples of hydroxyethyl sulfonates include sodium hydroxyethyl sulfonate, sodium cocoyl hydroxyethyl sulfonate, sodium lauroyl methyl hydroxyethyl sulfonate, and sodium cocoyl methyl hydroxyethyl sulfonate. Sulfonated monoglycerides of fatty acids include sodium cocoyl monoglyceride sulfonate, etc. Examples of acyl sarcosine salts include potassium lauroyl sarcosine, potassium cocoyl sarcosine, sodium cocoyl sarcosine, sodium lauroyl sarcosine, sodium myristoyl sarcosine, sodium oleoyl sarcosine, sodium palmitoyl sarcosine, ammonium lauroyl sarcosine, and combinations of two or more of these.

[0085] Anionic surfactants can be selected from taurine salts having a structure according to the following formula: Where R1 is a saturated or unsaturated, straight or branched alkyl chain having 6 to 18 carbon atoms, R2 is H or methyl, and M + It is H, sodium, or potassium (e.g., sodium methylcocoyl taurate).

[0086] Other examples of taurine surfactants include sodium cocoyl taurate, potassium cocoyl taurate, potassium methyl cocoyl taurate, sodium hexanoyl 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 stearyl 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 combinations thereof. In at least one preferred embodiment, the surfactant system comprises sodium methyl cocoyl taurate.

[0087] Based on the total weight of the oral care composition, the surfactant system may contain, for example, one or more amphoteric surfactants in amounts ranging from about 0.1 wt.% to about 5 wt.%. For example, based on the total weight of the oral care composition, one or more amphoteric surfactants may be present in the surfactant system in amounts ranging from: about 0.1 wt.% to about 4 wt.%, about 0.1 wt.% to about 3 wt.%, about 0.1 wt.% to about 2 wt.%, about 0.1 wt.% to about 1 wt.%; about 0.3 wt.% to about 5 wt.%, about 0.3 wt.% to about 4 wt.%, about 0.3 wt.% to about 3 wt.%, about 0.3 wt.% to about 2 wt.%, about 0.3 wt.% to about 1 wt.%; about 0.6 wt.% to about 5 wt.%, about 0.6 wt.% to about 4 wt.%, about 0.6 wt.% to about 3 wt.%, about 0.6 wt.% to about 2 wt.%, about 0.6 wt.% to about 1 wt.%; about 1 wt.% to about 5 wt.%, about 1 wt.% to about 4 wt.%, about 1 wt.% to about 3 wt.%, about 1 wt.% to about 2 wt.%; about 1.5 wt.% to about 5 wt.%, about 1.5 wt.% to about 4 wt.%, about 1.5 wt.% to about 3 wt.%; about 2 wt.% to about 5 wt.%, about 2 wt.% to about 4 wt.%, about 2 wt.% to about 3 wt.%; about 3 wt.% to about 5 wt.%, about 3 wt.% to about 4 wt.%, about 4 wt.% to about 5 wt.%, including any range or subrange thereof.

[0088] Amphoteric surfactants are typically characterized by a combination of high surfactant activity, foam formation, and mildness. Amphoteric surfactants may contain substituents having 8 to 18 carbon atoms and substituents containing one or more carboxylates, sulfonates, sulfates, phosphates, or phosphonates. For example, amphoteric surfactants may have alkyl groups containing 8 to 20 carbon atoms, 8 to 16 carbon atoms, 10 to 16 carbon atoms, or 10 to 13 carbon atoms. Amphoteric surfactants may include, but are not limited to, derivatives of aliphatic secondary and tertiary amines, wherein the aliphatic group may be linear 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 anionic water-solubilizing groups, such as carboxyl groups, sulfonates, sulfates, phosphates, or phosphonates. The amphoteric surfactants disclosed herein may be present in oral care compositions in the form of salts.

[0089] Amphoteric surfactants may include alkyl amphoteric propionates, betaines, alkyl sulfobetaines, alkyl amphoteric acetates, or combinations of two or more thereof. Preferably, the oral care composition includes an amphoteric surfactant selected from betaine surfactants (also referred to herein as betaine). Examples of betaine surfactants include, for example, alkyl betaines such as cocoyl dimethyl carboxymethyl betaine, lauryl dimethyl carboxymethyl betaine, lauryl dimethyl α-carboxyethyl betaine, cetyl dimethyl carboxymethyl betaine, lauryl bis-(2-hydroxyethyl) carboxymethyl betaine, stearyl bis-(2-hydroxypropyl) carboxymethyl betaine, oleyl dimethyl γ-carboxypropyl betaine, and lauryl bis-(2-hydroxypropyl) α-carboxyethyl betaine. In some cases, the betaine surfactant is selected from cobetaine, cocamidopropyl betaine, lauryl betaine, lauryl hydroxysulfonyl betaine, lauryl dimethyl betaine, behenyl betaine, capryloyl / decanoyl betaine, lauryl hydroxysulfonyl betaine, stearyl betaine, and combinations of two or more thereof. For example, the betaine surfactant may be cobetaine, cocamidopropyl betaine, behenyl betaine, capryloyl / decanoyl betaine, lauryl betaine, or combinations of two or more thereof. In at least one embodiment, the oral care composition comprises cobetaine, cocamidopropyl betaine, or combinations thereof.

[0090] The surfactant system may contain one or more nonionic surfactants. Based on the total weight of the oral care composition, one or more nonionic surfactants may be present in an amount ranging from about 0.1 wt.% to about 7 wt.%. In some cases, based on the total weight of the oral care composition, one or more nonionic surfactants are present in the surfactant system in amounts ranging from: about 0.1 wt.% to about 6 wt.%, about 0.1 wt.% to about 5 wt.%, about 0.1 wt.% to about 4 wt.%, about 0.1 wt.% to about 3 wt.%, about 0.1 wt.% to about 2 wt.%, about 0.1 wt.% to about 1 wt.%; about 0.4 wt.% to about 7 wt.%, about 0.4 wt.% to about 6 wt.%, about 0.4 wt.% to about 5 wt.%, about 0.4 wt.% to about 4 wt.%, about 0.4 wt.% to about 3 wt.%, about 0.4 wt.% to about 2 wt.%, about 0.4 wt.% to about 1 wt.%; about 0.8 wt.% to about 7 wt.%, about 0.8 wt.% to about 6 wt.%, about 0.8 wt.% to about 5 wt.%; wt.%, about 0.8 wt.% to about 4 wt.%, about 0.8 wt.% to about 3 wt.%, about 0.8 wt.% to about 2 wt.%; about 1.4 wt.% to about 7 wt.%, about 1.4 wt.% to about 6 wt.%, about 1.4 wt.% to about 5 wt.%, about 1.4 wt.% to about 4 wt.%, about 1.4 wt.% to about 3 wt.%; about 2 wt.% to about 7 wt.%, about 2 wt.% to about 6 wt.%, about 2 wt.% to about 5 wt.%, about 2 wt.% to about 4 wt.%, about 2 wt.% to about 3 wt.%; about 3 wt.% to about 7 wt.%, about 3 wt.% to about 6 wt.%, about 3 wt.% to about 5 wt.%; about 4 wt.% to about 7 wt.%, about 4 wt.% to about 6 wt.%, about 5 wt.% to about 7 wt.% wt.% or any range or subrange thereof.

[0091] One or more nonionic surfactants may be selected from glucosides, compounds formed by the condensation of an olefinic group (which is inherently hydrophilic) with an organic hydrophobic compound, said organic hydrophobic compound being inherently aliphatic or alkyl aromatic. Examples of glucoside surfactants include decyl glucoside, stearyl glucoside, lauryl glucoside, cocoyl glucoside, cetearyl glucoside, decyl lauryl glucoside, lauroyl ethyl glucoside, myristoyl ethyl glucoside, oleoyl ethyl glucoside, or combinations of two or more thereof. In some embodiments, the surfactant system comprises one or more nonionic surfactants selected from lauryl glucoside, lauroyl ethyl glucoside, myristoyl ethyl glucoside, oleoyl ethyl glucoside, and combinations of two or more thereof. Alternatively or additionally, glucoside surfactants may be selected from polyglucosides, such as alkyl polyglucosides.

[0092] Other examples of nonionic surfactants include poloxamer, alkylphenol polyoxyethylene condensates, products derived from the condensation of ethylene oxide with propylene oxide and ethylenediamine, aliphatic alcohols, acids and esters, long-chain tertiary amine oxides, long-chain tertiary phosphine oxides, long-chain dialkyl sulfoxides, and mixtures of such materials. Further examples of nonionic surfactants include polyoxyethylene, polyoxyethylene dehydrated sorbitol esters, polyoxyethylene 40 hydrogenated castor oil, fatty alcohol ethoxylates, alkylphenol polyoxyethylene condensates, products derived from the condensation of ethylene oxide with propylene oxide and ethylenediamine, aliphatic alcohol ethylene oxide condensates, long-chain tertiary amine oxides, long-chain tertiary phosphine oxides, long-chain dialkyl sulfoxides, or combinations of two or more of these. In some cases, nonionic surfactants comprise amine oxides, fatty acid amides, ethoxylated fatty alcohols, block copolymers of polyethylene glycol and polypropylene glycol, glyceryl alkyl esters, polyoxyethylene glycol octylphenol ether, sorbitol alkyl esters, polyoxyethylene glycol sorbitol alkyl esters, or combinations of two or more of these.

[0093] Based on the total weight of the oral care composition, the surfactant system may contain varying amounts of one or more amino acid-derived surfactants, but may be present in amounts ranging from about 0.1 wt.% to about 7 wt.%. For example, based on the total weight of the oral care composition, one or more amino acid-derived surfactants are present in the surfactant system in amounts ranging from: about 0.1 wt.% to about 6 wt.%, about 0.1 wt.% to about 5 wt.%, about 0.1 wt.% to about 4 wt.%, about 0.1 wt.% to about 3 wt.%, about 0.1 wt.% to about 2 wt.%, about 0.1 wt.% to about 1 wt.%; about 0.4 wt.% to about 7 wt.%, about 0.4 wt.% to about 6 wt.%, about 0.4 wt.% to about 5 wt.%, about 0.4 wt.% to about 4 wt.%, about 0.4 wt.% to about 3 wt.%, about 0.4 wt.% to about 2 wt.%, about 0.4 wt.% to about 1 wt.%; about 0.8 wt.% to about 7 wt.%, about 0.8 wt.% to about 6 wt.%, about 0.8 wt.% to about 5 wt.% wt.%, about 0.8 wt.% to about 4 wt.%, about 0.8 wt.% to about 3 wt.%, about 0.8 wt.% to about 2 wt.%; about 1.4 wt.% to about 7 wt.%, about 1.4 wt.% to about 6 wt.%, about 1.4 wt.% to about 5 wt.%, about 1.4 wt.% to about 4 wt.%, about 1.4 wt.% to about 3 wt.%; about 2 wt.% to about 7 wt.%, about 2 wt.% to about 6 wt.%, about 2 wt.% to about 5 wt.%, about 2 wt.% to about 4 wt.%, about 2 wt.% to about 3 wt.%; about 3 wt.% to about 7 wt.%, about 3 wt.% to about 6 wt.%, about 3 wt.% to about 5 wt.%; about 4 wt.% to about 7 wt.%, about 4 wt.% to about 6 wt.%, about 5 wt.% to about 7 wt.% wt.% or any range or subrange thereof.

[0094] Amino acid-derived surfactants can be anionic, nonionic, amphoteric, or cationic. In some embodiments, the amino acid-derived surfactant is anionic. Amino acid-derived surfactants can 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 can be present in oral care compositions in the form of salts. The most common cations associated with acyl amino acids can be sodium or potassium. Alternatively, the cation can be an organic salt, such as triethanolamine (TEA), or a metal salt.

[0095] Amino acid-derived surfactants can be acyl amino acid-derived surfactants with aliphatic carbon chains of 3 to 21 carbons. For example, amino acid-derived surfactants may include alkyl groups comprising carbon chains having carbons of 3 to 21, 3 to 19, 3 to 17, 3 to 15, 3 to 13, 3 to 11, 3 to 9, or 3 to 7; carbons of 4 to 21, 4 to 19, 4 to 17, 4 to 15, 4 to 13, 4 to 11, 4 to 9, or 4 to 7; carbons of 6 to 21, 6 to 19, 6 to 17, 6 to 15, 6 to 13, 6 to 11, or 6 to 9; carbons of 9 to 21, 9 to 19, 9 to 17, 9 to 15, 9 to 13, or 9 to 11; carbons of 11 to 21, 11 to 19, 11 to 17, 11 to 15, or 11 to 13; carbons of 13 to 21, 13 to 19, or 13 to 17, or any range or subrange thereof.

[0096] Amino acid-derived surfactants may be selected from glutamate-derived surfactants. Glutamate-derived surfactants may be selected from acylglutamate-derived surfactants having an alkyl group, wherein the alkyl group comprises a carbon chain having 3 to 21 carbons or any range of carbon chains described above with respect to amino acid-derived surfactants. For example, the carbon chain of an acylglutamate-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.

[0097] Alternatively, the oral care composition may be formulated to have a certain weight ratio of amino acid-based surfactant to nonionic surfactant. For example, the oral care composition may have the following weight ratios of total amino acid-based surfactant to total nonionic surfactant: 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; 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; 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; 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; 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 the ranges or subranges formed therefrom.

[0098] 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 wt.% to about 5 wt.% based on the total weight of the oral care composition. For example, based on the total weight of the oral care composition, the fluoride ion source may be present in amounts ranging from: about 0.01 wt.% to about 5 wt.%, about 0.01 wt.% to about 4 wt.%, about 0.01 wt.% to about 3 wt.%, about 0.01 wt.% to about 2 wt.%, about 0.01 wt.% to about 1 wt.%; about 0.05 wt.% to about 5 wt.%, about 0.05 wt.% to about 4 wt.%, about 0.05 wt.% to about 3 wt.%, about 0.05 wt.% to about 2 wt.%, about 0.05 wt.% to about 1 wt.%; about 0.1 wt.% to about 5 wt.%, about 0.1 wt.% to about 4 wt.%, about 0.1 wt.% to about 3 wt.%, about 0.1 wt.% to about 2 wt.%; about 0.3 wt.% to about 5 wt.%, about 0.3 wt.% to about 2 wt.%; about 0.3 wt.% to about 5 wt.%. wt.% to about 4 wt.%, about 0.3 wt.% to about 3 wt.%, about 0.3 wt.% to about 2 wt.%; about 0.6 wt.% to about 5 wt.%, about 0.6 wt.% to about 4 wt.%, about 0.6 wt.% to about 3 wt.%, about 0.6 wt.% to about 2 wt.%; about 0.9 wt.% to about 5 wt.%, about 0.9 wt.% to about 4 wt.%, about 0.9 wt.% to about 3 wt.%, about 0.9 wt.% to about 2 wt.%; about 1.2 wt.% to about 5 wt.%, about 1.2 wt.% to about 4 wt.%, about 1.2 wt.% to about 3 wt.%, about 1.2 wt.% to about 2 wt.%; about 1.5 wt.% to about 5 wt.%, about 1.5 wt.% to about 4 wt.%, about 1.5 wt.% to about 3 wt.%; about 2 wt.% to about 5 wt.%, about 2 wt.% to about 4 wt.%, about 2 wt.% to about 3 wt.%; about 3 wt.% to about 5 wt.%, about 4 wt.% to about 5 wt.% or any range or subrange thereof.

[0099] The fluoride ion source may be selected from soluble fluoride 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, diethylaminoethyloctylamide hydrofluoride, dialcyldimethylammonium fluoride, hexadecylpyridinium fluoride cation, dilaurylmorpholine fluoride cation, stannous sarcosinate fluoride, potassium glycine fluoride, glycine hydrofluoride, fluorinated amine, or combinations of two or more thereof. In some embodiments, the fluoride ion source comprises sodium fluoride, sodium monofluorophosphate, or combinations thereof. Further examples of fluoride ion sources are disclosed in U.S. Patent Nos. 3,535,421, 4,885,155, and 3,678,154, the disclosure of each of which is hereby incorporated by reference in its entirety.

[0100] In some embodiments, the oral care compositions of this disclosure may contain stannous fluoride and a fluoride ion source or fluoride provider in an amount sufficient to deliver a total of 25 ppm to 25,000 ppm (mass fraction), typically at least 500 ppm, for example, about 500 ppm to about 2,000 ppm, about 800 ppm to about 1,800 ppm, about 1,000 ppm to about 1,600 ppm, about 1,200 ppm to about 1,550 ppm, or about 1,450 ppm of fluoride ions.

[0101] Based on the total weight of the oral care composition, the oral care composition may include, for example, one or more abrasives in an amount ranging from about 5 wt.% to about 35 wt.%. In some embodiments, based on the total weight of the oral care composition, one or more abrasives are present in amounts ranging from: about 5 wt.% to about 30 wt.%, about 5 wt.% to about 25 wt.%, about 5 wt.% to about 21 wt.%, about 5 wt.% to about 17 wt.%, about 5 wt.% to about 14 wt.%, about 5 wt.% to about 11 wt.%; about 10 wt.% to about 35 wt.%, about 10 wt.% to about 30 wt.%, about 10 wt.% to about 25 wt.%, about 10 wt.% to about 21 wt.%, about 10 wt.% to about 17 wt.%, about 10 wt.% to about 14 wt.%; about 15 wt.% to about 35 wt.%, about 15 wt.% to about 30 wt.%, about 15 wt.% to about 25 wt.%, about 15 wt.% to about 21 wt.%, about 15 wt.% to about 35 wt.%, about 15 wt.% to about 20 wt.%, about 15 wt.% to about 21 wt.%, about 15 wt.% to about 35 wt.%, about 15 wt.% to about 30 wt.%, about 15 wt.% to about 25 wt.%, about 15 wt.% to about 21 wt.%, about 15 wt.% to about 35 wt.%, about 15 wt.% to about 35 wt.%, about 15 wt.% to about 35 wt.%, about 15 wt.% to about 25 wt.%, about 15 wt.% to about 21 wt.%, about 15 wt.% to about wt.% to about 19 wt.%; about 18 wt.% to about 35 wt.%, about 18 wt.% to about 30 wt.%, about 18 wt.% to about 25 wt.%, about 18 wt.% to about 21 wt.%; about 21 wt.% to about 35 wt.%, about 21 wt.% to about 30 wt.%, about 21 wt.% to about 25 wt.%; about 24 wt.% to about 35 wt.%, about 24 wt.% to about 30 wt.%; about 27 wt.% to about 35 wt.%, about 27 wt.% to about 30 wt.% or any range or subrange thereof.

[0102] One or more abrasives may include: silica, silicates, silicon, alumina (including calcined alumina), aluminosilicates such as bentonite, zeolite, kaolin and mica, siliceous clay or 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 carboxymethyl cellulose) and combinations and derivatives thereof.

[0103] As used herein, “mica” refers to any of a group of hydrated aluminum silicate minerals having a platy morphology and / or perfect matrix (mica-like) cleavage. Mica can be, for example, platy mica, fragmented mica, or scaly mica, as exemplified by muscovite, biotite, or phlogopite-type mica. Abrasives can be selected from insoluble phosphates, such as orthophosphates, polymetaphosphates, pyrophosphates, and combinations thereof. Synthetic silica includes both silica gel and precipitated silica prepared by neutralizing an aqueous silicate solution with a strong inorganic acid. Abrasives containing silica can be used in certain embodiments of oral care compositions. In some embodiments, the oral composition can contain a particularly effective combination of silica abrasive particles. For example, the abrasive can be selected from high-cleanliness silica, tetrasodium pyrophosphate (TSPP), sodium tripolyphosphate (STPP), and combinations of two or more of these.

[0104] Oral care compositions may include an abrasive system comprising two or more abrasives. For example, the abrasive system 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 abrasives. The abrasives may comprise one or more cleaning abrasives and / or one or more polishing abrasives. As understood by those skilled in the art, a single abrasive material typically performs at least some cleaning and polishing simultaneously. However, particles are generally classified in the art according to their primary function on the target oral surface. Generally, "polishing abrasive" is considered to be relatively small particles with high hardness, while abrasives with relatively large particle size and low hardness are considered "cleaning abrasives." In some embodiments, the oral care composition comprises two or more abrasives comprising silica. In some embodiments, the first abrasive is selected as a harder and smaller abrasive, such as a higher cleaning and / or polishing abrasive, and the second abrasive is a typical cleaning abrasive. In some embodiments, the oral care composition comprises 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 by reference in its entirety for all purposes.

[0105] Based on the total weight of the oral care composition, the oral care composition may include one or more thickeners in an amount ranging from about 0.5 wt.% to about 20 wt.%. For example, based on the total weight of the oral care composition, the amount of thickener in the oral care composition can range from about 0.5 wt.% to about 17 wt.%, about 0.5 wt.% to about 14 wt.%, about 0.5 wt.% to about 11 wt.%, about 0.5 wt.% to about 9 wt.%, about 0.5 wt.% to about 7 wt.%, about 0.5 wt.% to about 5 wt.%, about 0.5 wt.% to about 4 wt.%, about 0.5 wt.% to about 3 wt.%; about 1 wt.% to about 20 wt.%, about 1 wt.% to about 17 wt.%, about 1 wt.% to about 14 wt.%, about 1 wt.% to about 11 wt.%, about 1 wt.% to about 9 wt.%, about 1 wt.% to about 7 wt.%, about 1 wt.% to about 5 wt.%, about 1 wt.% to about 4 wt.%, about 1 wt.% to about 3 wt.% wt.%; about 2 wt.% to about 20 wt.%, about 2 wt.% to about 17 wt.%, about 2 wt.% to about 14 wt.%, about 2 wt.% to about 11 wt.%, about 2 wt.% to about 9 wt.%, about 2 wt.% to about 7 wt.%, about 2 wt.% to about 5 wt.%, about 2 wt.% to about 4 wt.%, about 2 wt.% to about 3 wt.%; about 4 wt.% to about 20 wt.%, about 4 wt.% to about 17 wt.%, about 4 wt.% to about 14 wt.%, about 4 wt.% to about 11 wt.%, about 4 wt.% to about 9 wt.%, about 4 wt.% to about 7 wt.%; about 7 wt.% to about 20 wt.%, about 7 wt.% to about 17 wt.%, about 7 wt.% to about 14 wt.%, about 7 wt.% to about 11 wt.%; about 10 wt.% to about 20 wt.%, about 10 wt.% to about 17 wt.%, about 10 wt.% to about 14 wt.%; about 14 wt.% to about 20 wt.%, about 14 wt.% to about 17 wt.% or any range or subrange thereof.

[0106] Thickeners can be referred to as "thickeners" or "viscosity modifiers." They are typically included to increase the viscosity of oral care compositions. However, in some cases, certain thickeners provide additional, surprising benefits to oral care compositions.

[0107] One or more thickeners may be selected from polysaccharides, silica thickeners, acrylates, polymers, and combinations of two or more thereof. Examples of polysaccharides include cellulose, carboxymethyl hydroxyethyl cellulose, cellulose acetate propionate carboxylate, hydroxyethyl cellulose, hydroxyethyl ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl hydroxyethyl cellulose, microcrystalline cellulose, sodium cellulose sulfate, carrageenan, or combinations of two or more thereof. Natural gums, such as gum arabic, gum arabic, and astragalus gum, may also be incorporated. Colloidal magnesium aluminum silicate may also be used as a component of the thickening composition to further improve the texture of the composition. Silica thickeners may be present in aqueous media to form polymeric structures or gels. Silica thickeners are generally physically and functionally different from particulate silica abrasives because silica thickeners are very finely dispersed and provide minimal or no abrasive action.

[0108] In some embodiments, one or more thickeners comprise polymers selected from polysaccharides, acrylates, polyvinylpyrrolidone, polyitacrylates, acrylamide, and combinations thereof. Polyvinylpyrrolidone generally refers to a polymer containing vinylpyrrolidone (e.g., N-vinylpyrrolidone, N-vinyl-2-pyrrolidone, and N-vinyl-2-pyrrolidone) as a monomer unit. The monomer unit may include a polar imide group, four nonpolar methylene groups, and a nonpolar methane group. The average molecular weight of polyvinylpyrrolidone can range from 5,000 to 100,000, preferably from 5,000 to 50,000. Polyvinylpyrrolidones with average molecular weights of 10,000, 30,000, and 40,000 are commercially available from Sigma Chemjeal Co., GAF Corporation, and Sigma Chemical Co. Polyvinylpyrrolidone (PVP) can form hydrogen peroxide-PVP polymer complexes. Examples of PPVP complexes include those disclosed in U.S. Patent No. 5,122,370, the contents of which are incorporated herein by reference. In some embodiments, the polymer comprises cross-linked PPVP. In at least one embodiment, the polymer consists of PPVP.

[0109] Examples of acrylates that may be included in oral care compositions include, for example, 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 combinations of two or more of these.

[0110] The acrylate may be selected from diacrylates. In some embodiments, the oral care composition includes a diacrylate selected from 1,4-butanediol, 1,6-hexanediol, tetraethylene glycol, tripropylene glycol, ethoxylated bisphenol-A, and combinations of two or more thereof. The triacrylate monomer includes trimethylolpropane, ethoxylated glycerylpropoxy, and pentaerythritol.

[0111] Acrylic esters also 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, cyclohexyl methacrylate, 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-butanediol methacrylate, 1,6-hexanediol methacrylate, trimethylolpropane methacrylate, ethoxyethyl methacrylate, trifluoroethyl methacrylate, or combinations of two or more of these.

[0112] Examples of acrylamide include, but are not limited to, acrylamide, methacrylamide, and bis(C1-C1)acrylamide. 30Alkyl-acrylamides and methyl-acrylamides, such as those with methyl, ethyl, propyl, butyl, pentyl, hexyl, etc. Possibly suitable N-substituted acrylamides include N-ethylacrylamide, N-tert-butylacrylamide, N-tert-octylacrylamide, N-octylacrylamide, N-decylacrylamide, N-dodecylacrylamide, and their corresponding N-substituted methylacrylamides. Other N-substituted acrylamides include N-hydroxymethylacrylamide, N-isopropylacrylamide, N-methylacrylamide, N,N'-methylenebisacrylamide, N-isobutoxymethylacrylamide, N,N-dimethylacrylamide, and 2-acrylamido-2-methylpropanesulfonic acid.

[0113] Oral care compositions may include one or more polyols. Based on the total weight of the oral care composition, one or more polyols may be present in the oral care composition in an amount ranging from about 1 wt.% to about 60 wt.%. For example, based on the total weight of the oral care composition, the oral care composition may include polyols in the following amounts: about 20 wt.% to about 55 wt.%, about 20 wt.% to about 50 wt.%, about 20 wt.% to about 45 wt.%, about 20 wt.% to about 40 wt.%, about 20 wt.% to about 37 wt.%, about 20 wt.% to about 34 wt.%, about 20 wt.% to about 31 wt.%, about 20 wt.% to about 28 wt.%; about 25 wt.% to about 60 wt.%, about 25 wt.% to about 55 wt.%, about 25 wt.% to about 50 wt.%, about 25 wt.% to about 45 wt.%, about 25 wt.% to about 40 wt.%, about 25 wt.% to about 37 wt.%, about 25 wt.% to about 34 wt.%, about 25 wt.% to about 31 wt.%; about 28 ...37 wt.%, about 25 wt.% to about 34 wt.%, about 25 wt.% to about 31 wt.%; about 28 wt.% to about 37 wt.%, about 2 wt.% to about 60 wt.%, about 28 wt.% to about 55 wt.%, about 28 wt.% to about 50 wt.%, about 28 wt.% to about 45 wt.%, about 28 wt.% to about 40 wt.%, about 28 wt.% to about 37 wt.%, about 28 wt.% to about 34 wt.%, about 28 wt.% to about 31 wt.%; about 31 wt.% to about 60 wt.%, about 31 wt.% to about 55 wt.%, about 31 wt.% to about 50 wt.%, about 31 wt.% to about 45 wt.%, about 31 wt.% to about 40 wt.%, about 31 wt.% to about 37 wt.%; about 34 wt.% to about 50 wt.%, about 34 wt.% to about 45 wt.%, about 34 wt.% to about 40 wt.%; about 37 wt.% to about 60 wt.% wt.%, about 37 wt.% to about 55 wt.%, about 37 wt.% to about 50 wt.%, about 37 wt.% to about 45 wt.%; about 40 wt.% to about 60 wt.%, about 40 wt.% to about 55 wt.%, about 40 wt.% to about 50 wt.%, about 40 wt.% to about 45 wt.% or any range or subrange thereof.

[0114] In other embodiments, based on the total weight of the oral care composition, the oral care composition may include polyols in the following amounts: about 0.5 wt.% to about 17 wt.%, about 0.5 wt.% to about 14 wt.%, about 0.5 wt.% to about 11 wt.%, about 0.5 wt.% to about 9 wt.%, about 0.5 wt.% to about 7 wt.%, about 0.5 wt.% to about 5 wt.%, about 0.5 wt.% to about 4 wt.%, about 0.5 wt.% to about 3 wt.%, about 0.5 wt.% to about 2 wt.%, about 0.5 wt.% to about 1 wt.%; about 1 wt.% to about 20 wt.%, about 1 wt.% to about 17 wt.%, about 1 wt.% to about 14 wt.%, about 1 wt.% to about 11 wt.%, about 1 wt.% to about 9 wt.%, about 1 wt.% to about 7 wt.%, about 1 wt.% to about 5 wt.%, about 1 wt.% to about 4 wt.%, about 1 wt.% to about 3 wt.%, about 1 wt.% to about 2 wt.%; about 2 wt.% to about 20 wt.%, about 2 wt.% to about 17 wt.%, about 2 wt.% to about 14 wt.%, about 2 wt.% to about 11 wt.%, about 2 wt.% to about 9 wt.%, about 2 wt.% to about 7 wt.%, about 2 wt.% to about 5 wt.%, about 2 wt.% to about 4 wt.%, about 2 wt.% to about 3 wt.%; about 4 wt.% to about 20 wt.%, about 4 wt.% to about 17 wt.%, about 4 wt.% to about 14 wt.%, about 4 wt.% to about 11 wt.%, about 4 wt.% to about 9 wt.%, about 4 wt.% to about 7 wt.%; about 7 wt.% to about 20 wt.% wt.%, about 7 wt.% to about 17 wt.%, about 7 wt.% to about 14 wt.%, about 7 wt.% to about 11 wt.%; about 10 wt.% to about 20 wt.%, about 10 wt.% to about 17 wt.%, about 10 wt.% to about 14 wt.%; about 14 wt.% to about 20 wt.%, about 14 wt.% to about 17 wt.% or any range or subrange thereof.

[0115] Polyols may be selected from glycols or compounds having a number of hydroxyl groups. One or more polyols may be liquid at ambient temperature (25°C). Polyols may be humectants. In some embodiments, polyols comprise glycerol, ethylene glycol, inositol, maltitol, mannitol, sorbitol, xylitol, propylene glycol, polypropylene glycol (PPG), polyethylene glycol (PEG), block copolymers of PPG and PEG, sugars (e.g., fructose, glucose, sucrose, and mixtures of sugars such as honey), or combinations of two or more thereof. For example, oral care compositions comprise maltitol, mannitol, sorbitol, xylitol, polypropylene glycol (PPG), polyethylene glycol (PEG), block copolymers of PPG and PEG, or combinations of two or more thereof.

[0116] In some embodiments, the oral care composition includes a component selected from C2-C 32 One or more polyols comprising the group consisting of polyols. One or more polyols may have 2 to 32 carbon atoms, 3 to 16 carbon atoms, or 3 to 12 carbon atoms. For example, an oral care composition may comprise ethylene glycol, propylene glycol, butylene glycol, hexanediol, glycerin, diglycerin, diethylene glycol, and dipropylene glycol, or a combination of two or more of these. Other non-limiting examples of polyols that may optionally be included in oral care include and / or may be selected from alkyl glycols such as glycerol, 1,2,6-hexanetriol, trimethylolpropane, ethylene glycol, propylene glycol, butanediol, pentanediol, hexanediol, diethylene glycol, triethylene glycol, tetraethylene glycol, pentaethylene glycol, dipropylene glycol, 2-buten-1,4-diol, 2-ethyl-1,3-hexanediol, 2-methyl-2,4-pentanediol, octanediol, 1,2-hexanediol, 1,2-pentanediol, and 4-methyl-1,2-pentanediol; glycol ethers such as ethylene glycol monomethyl ether and 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 monoisopropyl ether, diethylene glycol monoisopropyl ether, ethylene glycol mono-n-butyl ether, ethylene glycol mono-tert-butyl ether, diethylene glycol mono-tert-butyl ether, 1-methyl-1-methoxybutanol, propylene glycol monomethyl ether, propylene glycol monoethyl ether, propylene glycol mono-tert-butyl ether, propylene glycol mono-n-propyl ether, propylene glycol monoisopropyl ether, dipropylene glycol monomethyl ether, dipropylene glycol monoethyl ether, dipropylene glycol mono-n-propyl ether, dipropylene glycol monoisopropyl ether, sorbitol, dehydrated sorbitol, triacetin, and mixtures thereof.

[0117] Alternatively or concurrently, oral care compositions may include polyols having a molecular weight of about 100 g / mol to 5000 g / mol. For example, the polyol may comprise polyethylene glycol, polypropylene glycol, block polymers of polyethylene glycol and polypropylene glycol, or combinations of two or more of these. In some embodiments, the polyol comprises polypropylene glycol, polypropylene glycol, and / or block polymers 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 polyethylene glycol, such as polyethylene glycol 600 (CAS-25322-68-3). In some embodiments, the compositions disclosed herein comprise one or more polyethylene glycols, such as polyethylene glycols with a molecular weight range of 200 to 800. For example, the composition may contain one or more of the following: polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600 or polyethylene glycol 800.

[0118] In some embodiments, the oral care composition may contain an effective amount of one or more amino acids. In some embodiments, based on the total weight of the oral care composition, one or more amino acids may be present in the oral care composition in amounts ranging from: about 0.1 wt.% to about 10 wt.%, about 0.1 wt.% to about 8 wt.%, about 0.1 wt.% to about 6 wt.%, about 0.1 wt.% to about 4 wt.%, about 0.1 wt.% to about 2 wt.%, about 0.1 wt.% to about 1 wt.%, about 0.1 wt.% to about 0.5 wt.%; about 0.5 wt.% to about 10 wt.%, about 0.5 wt.% to about 8 wt.%, about 0.5 wt.% to about 6 wt.%, about 0.5 wt.% to about 4 wt.%, about 0.5 wt.% to about 2 wt.%, about 0.5 wt.% to about 1 wt.%; about 1 wt.% to about 10 wt.%, about 1 wt.% to about 8 wt.%, about 1 wt.% to about 6 wt.%, about 1 wt.% to about 4 wt.%, about 1 wt.% to about 2 wt.%; about 2 wt.% to about 10 wt.%, about 2 wt.% to about 8 wt.%, about 2 wt.% to about 6 wt.%, about 2 wt.% to about 4 wt.%; about 3 wt.% to about 10 wt.%, about 3 wt.% to about 8 wt.%, about 3 wt.% to about 6 wt.%, about 3 wt.% to about 4 wt.%; about 4 wt.% to about 10 wt.%, about 4 wt.% to about 8 wt.%, about 4 wt.% to about 6 wt.%; about 6 wt.% to about 10 wt.%, about 6 wt.% to about 8 wt.%; about 8 wt.% to about 10 wt.%, including any range or subrange thereof.

[0119] One or more amino acids may be selected from basic amino acids, neutral amino acids, and combinations thereof. Basic amino acids may be selected from naturally occurring basic amino acids such as arginine, lysine, and histidine, as well as non-naturally occurring basic amino acids having a carboxyl and amino group in their molecule, which are water-soluble and provide an aqueous solution with a pH of 7 or higher. Examples of basic amino acids include, but are not limited to, arginine, lysine, serine, citrulline, ornithine, sarcosine, histidine, diaminobutyric acid, diaminopropionic acid, their salts, or combinations thereof. In some embodiments, the basic amino acid is selected from arginine, citrulline, and ornithine. In some embodiments, the basic amino acid is arginine, such as L-arginine, or a salt thereof. Additionally or alternatively, one or more amino acids may be selected from neutral amino acids, which may include, but are not limited to, one or more neutral amino acids selected from the group consisting of: alanine, gamma-aminobutyric acid, asparagine, cysteine, cystine, glutamine, glycine, hydroxyproline, isoleucine, leucine, methionine, phenylalanine, proline, serine, taurine, threonine, tryptophan, tyrosine, valine, and combinations thereof.

[0120] In some embodiments, the oral care composition may include one or more sweeteners. The oral care composition may include caloric sweeteners and / or calorie-free sweeteners. Examples of calorie-free sweeteners include saccharin, such as sodium saccharin, acesulfame potassium, neotame, cyclamate, or sucralose; natural high-intensity sweeteners, such as sematrandezine, steviol, 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 corn syrup.

[0121] Based on the total weight of the oral care composition, one or more sweeteners may be present in the oral care composition in an amount ranging from about 0.1 wt.% to about 50 wt.%. For example, based on the total weight of the oral care composition, the oral care composition may have a total amount of sweetener ranging from: about 0.1 wt.% to about 40 wt.%, about 0.1 wt.% to about 30 wt.%, about 0.1 wt.% to about 20 wt.%, about 0.1 wt.% to about 10 wt.%, about 0.1 wt.% to about 5 wt.%, about 0.1 wt.% to about 3 wt.%; about 1 wt.% to about 50 wt.%, about 1 wt.% to about 40 wt.%, about 1 wt.% to about 30 wt.%, about 1 wt.% to about 20 wt.%, about 1 wt.% to about 10 wt.%, about 1 wt.% to about 5 wt.%, about 1 wt.% to about 3 wt.%; about 5 wt.% to about 50 wt.%, about 5 wt.% to about 40 wt.%, about 5 wt.% to about 30 wt.%, about 5 wt.% to about 20 wt.%, about 5 wt.% to about 10 wt.%; about 10 wt.% to about 50 wt.%, about 10 wt.% to about 45 wt.%, about 10 wt.% to about 40 wt.%, about 10 wt.% to about 35 wt.%, about 10 wt.% to about 30 wt.%, about 10 wt.% to about 25 wt.%; about 15 wt.% to about 50 wt.%, about 15 wt.% to about 45 wt.%, about 15 wt.% to about 40 wt.%, about 15 wt.% to about 37 wt.%, about 15 wt.% to about 34 wt.%, about 15 wt.% to about 31 wt.%, about 15 wt.% to about 28 wt.%, about 15 wt.% to about 25 wt.%; about 20 wt.% to about 50 wt.%, about 20 wt.% to about 45 wt.% wt.%, about 20 wt.% to about 40 wt.%, about 20 wt.% to about 37 wt.%, about 20 wt.% to about 34 wt.%, about 20 wt.% to about 31 wt.%, about 20 wt.% to about 28 wt.%; about 25 wt.% to about 50 wt.%, about 25 wt.% to about 45 wt.%, about 25 wt.% to about 40 wt.%, about 25 wt.% to about 37 wt.%, about 25 wt.% to about 34 wt.%, about 25 wt.% to about 31 wt.%; about 28 wt.% to about 50 wt.%, about 28 wt.% to about 45 wt.%, about 28 wt.% to about 40 wt.%, about 28 wt.% to about 37 wt.%, about 28 wt.% to about 34 wt.%, about 28 wt.% to about 31 wt.%.%; about 31 wt.% to about 50 wt.%, about 31 wt.% to about 45 wt.%, about 31 wt.% to about 40 wt.%, about 31 wt.% to about 37 wt.%; about 34 wt.% to about 50 wt.%, about 34 wt.% to about 45 wt.%, about 34 wt.% to about 40 wt.%; about 37 wt.% to about 50 wt.%, about 37 wt.% to about 45 wt.% or any range or subrange thereof.

[0122] In some embodiments, the oral care composition is substantially free of or contains no caloric sweeteners. For example, based on the weight of the oral care composition, the composition may contain 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. In at least one embodiment, the composition contains about 0 wt.% or 0 wt.% of a caloric sweetener based on the weight of the composition.

[0123] The oral care compositions disclosed herein may include flavoring agents. Flavoring agents are typically incorporated into the oral care compositions at a concentration of about 0.01 wt.% to about 3 wt.% based on the weight of the oral care composition. For example, based on the total weight of the oral care composition, the amount of flavoring present in the oral care composition may range from about 0.01 wt.% to about 2 wt.%, about 0.01 wt.% to about 1 wt.%, about 0.01 wt.% to about 0.5 wt.%, about 0.01 wt.% to about 0.1 wt.%; about 0.1 wt.% to about 3 wt.%, about 0.1 wt.% to about 2 wt.%, about 0.1 wt.% to about 1 wt.%, about 0.1 wt.% to about 0.5 wt.%; about 0.5 wt.% to about 3 wt.%, about 0.5 wt.% to about 2 wt.%, about 0.5 wt.% to about 1 wt.%; about 1 wt.% to about 3 wt.%, about 1 wt.% to about 2 wt.%; about 2 wt.% to about 3 wt.%, including any range or subrange thereof.

[0124] Suitable flavoring agents include, but are not limited to, essential oils and various flavoring aldehydes, esters, alcohols, and similar materials. Examples of essential oils include spearmint, peppermint, wintergreen, sassafras, clove, sage, eucalyptus, marjoram, cinnamon, lemon, lime, grapefruit, and orange oils. Such chemicals as menthol, carvone, and anethole are also useful. Other flavoring agents may include, but are not limited to, menthol, artificial vanilla, cinnamon derivatives, and various fruit spices, spearmint oil, peppermint oil, cinnamon oil, wintergreen oil (methyl salicylate), clove oil, laurel oil, anise oil, eucalyptus oil, thyme oil, cedarwood oil, nutmeg oil, sage oil, bitter almond oil, cinnamon oil, and combinations of two or more of these.

[0125] Oral care compositions may include one or more colorants. Exemplary colorants may include natural or uncertified colors from natural sources or certified colors for color effects. In some embodiments, colorants may include dyes, certified aluminum lakes, or colors derived from natural sources. Colorants may be water-based, oil-based, or dry. Colorants may be primary colors, color blends, or discrete mixtures of colors, such as confetti. Based on the total weight of the oral care composition, the concentration of colorants in the oral care composition may be trace to about 0.6 wt.%, about 0.1 wt.% to about 0.5 wt.%, about 0.2 wt.% to about 0.4 wt.%, or about 0.15 wt.% to about 0.35 wt.%.

[0126] Oral care compositions 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 acids suitable for decreasing the pH of an oral care composition include, but are not limited to, citric acid, acetic acid, etc. Oral care compositions may include one or more bases, such as sodium hydroxide, potassium hydroxide, etc., to increase the pH of the oral care composition. Other or alternative acids and bases suitable for adjusting the pH of an oral care composition are readily known to those skilled in the art.

[0127] The amount of pH adjuster in an oral care composition can be based on the desired pH of the final oral care composition and / or product. For example, the total amount of pH adjuster can range from about 0.05 wt.% to about 20 wt.% based on the total weight of the oral care composition. In some cases, the total amount of pH adjuster is about 0.05 wt.% to about 15 wt.%, about 0.1 wt.% to about 10 wt.%, or about 0.12 wt.% to about 5 wt.%, including ranges and subranges therein, based on the total weight of the oral care composition.

[0128] The pH of the oral care composition may be 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; 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; about 6 to about 10, about 6 to about 9, about 6 to about 8 or about 6 to about 7; about 7 to about 10, about 7 to about 9 or about 7 to about 8, including any range and subrange therein.

[0129] The oral care compositions disclosed herein can be prepared according to methods and procedures known to those skilled in the art.

[0130] In some aspects, an embodiment of a method for treating and / or alleviating interleukin-8 (IL-8)-mediated inflammatory conditions in a subject in need is provided, wherein the subject is a nicotine user. The method comprises applying an oral care composition to the oral cavity of the subject, the oral care composition comprising a stannous source, a nitrate ion source, and pyrophosphate. In some embodiments, the oral care composition may be any oral care composition described herein. In some embodiments, the IL-8-mediated inflammatory condition is selected from gingival disease, chronic obstructive pulmonary disease (COPD), pneumonia, bronchitis, Crohn's disease, ulcerative colitis, or asthma. In some embodiments, the gingival disease is selected from gingivitis, periodontitis, implantitis, or mucositis. In some embodiments, the oral care composition is the oral care composition described below. In some embodiments, the IL-8-mediated inflammatory condition is selected from gingival disease, chronic obstructive pulmonary disease (COPD), pneumonia, bronchitis, Crohn's disease, ulcerative colitis, or asthma. In some embodiments, the gingival disease is selected from gingivitis, periodontitis, implantitis, or mucositis. In some embodiments, the subjects in need are additionally selected from patients with inflammatory diseases, patients with bacterial or viral infections, obese individuals, or elderly individuals. In some embodiments, the method comprises applying an oral care composition to the oral cavity at least once daily, such as at least twice daily or at least three times daily. 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 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 composition is applied to the oral cavity in an amount of about 0.1 g to about 3 g. 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 glycol, 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 combinations of two or more thereof. In some embodiments, the nitrate ion source comprises potassium nitrate. In some embodiments, the molar ratio of nitrate ions to stannous ions in the oral care composition is from about 0.5:1 to about 2:1, wherein both nitrate ions and stannous ions are measured in the form of free ions. 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 combinations of two or more thereof.In some embodiments, the oral care composition comprises water in an amount ranging from about 5% to about 20% by weight, such as from about 5% to about 7% by weight 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 the concentration of IL-8 in the tissues of a subject, such as the gingival tissue of a 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%.

[0131] In some aspects, embodiments of methods for treating and / or alleviating symptoms of gingival disease in a subject in need are provided, the methods comprising applying an oral care composition to the oral cavity of the subject, the oral care composition comprising a stannous source, a nitrate ion source, and pyrophosphate, wherein the subject in need is a nicotine user. In some embodiments, the oral care composition may be any oral care composition described herein. In some embodiments, gingival 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 once daily, such as at least twice daily or at least three times daily. In some embodiments, the amount of the oral care composition applied to the oral cavity is from about 0.1 g to about 3 g. 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 combinations of two or more thereof. In some embodiments, the nitrate ion source comprises potassium nitrate. In some embodiments, the molar ratio of nitrate ions to stannous ions in the oral care composition is from about 0.5:1 to about 2:1, wherein both nitrate ions and stannous ions are measured in the form of free ions. 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 combinations of two or more thereof.

[0132] List of Implementation Examples The following list of embodiments illustrates some of the embodiments described herein, but is not limited to other embodiments found elsewhere in this document.

[0133] 1. In some embodiments, this disclosure relates to a method of treating and / or alleviating interleukin-8 (IL-8)-mediated inflammatory conditions in a subject of need, the method comprising applying an oral care composition to the 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.

[0134] 2. The method according to Example 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 glycol; and combinations of two or more thereof.

[0135] 3. The method according to Example 1 or Example 2, wherein the nitrate ion source is selected from alkali metal or alkaline earth metal nitrates, or zinc nitrate, silver nitrate or ammonium nitrate.

[0136] 4. The method according to any one of the foregoing embodiments, 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 combinations of two or more thereof.

[0137] 5. The method according to any one of the foregoing embodiments, wherein the nitrate ion source comprises potassium nitrate.

[0138] 6. The method according to any one of the foregoing embodiments, wherein the water-soluble alkali metal polyphosphate is selected from: pyrophosphate; tripolyphosphate; tetraphosphate; hexametaphosphate; and combinations of two or more thereof.

[0139] 7. The method according to any one of the foregoing embodiments, wherein the water-soluble alkali metal polyphosphate is selected from: sodium pyrophosphate; potassium pyrophosphate; sodium tripolyphosphate; potassium tripolyphosphate; and combinations of two or more thereof.

[0140] 8. The method according to any one of the foregoing embodiments, wherein the nitrate ion source comprises potassium nitrate, and the water-soluble alkali metal polyphosphate comprises tetrasodium pyrophosphate.

[0141] 9. The method according to any one of the foregoing embodiments, wherein the IL-8-mediated inflammatory condition is selected from: gingival disease; chronic obstructive pulmonary disease (COPD); pneumonia; bronchitis; Crohn's disease; ulcerative colitis; and asthma.

[0142] 10. The method according to Example 9, wherein the gingival disease is selected from: gingivitis; periodontitis; implantitis; and mucositis.

[0143] 11. The method according to any one of the foregoing embodiments, wherein the subject in need is selected from: nicotine users; patients with inflammatory diseases; patients with bacterial or viral infections; obese individuals; or elderly individuals.

[0144] 12. The method according to any one of the foregoing embodiments, wherein the subject in need is a nicotine user.

[0145] 13. The method according to any one of the foregoing embodiments, comprising applying the oral care composition to the oral cavity at least once a day, optionally at least twice a day, or at least three times a day.

[0146] 14. The method according to any one of the foregoing embodiments, 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.

[0147] 15. The method according to any one of the foregoing embodiments, wherein the oral care composition is applied to the oral cavity in an amount of about 0.1 g to about 3 g.

[0148] 16. The method according to any one of the foregoing embodiments, wherein the tin subion source comprises tin subfluoride.

[0149] 17. The method according to any one of the foregoing embodiments, wherein the molar ratio of nitrate ions to stannous ions in the oral care composition is from about 0.5:1 to about 2:1, and both the nitrate ions and the stannous ions are measured in the form of free ions.

[0150] 18. The method according to any one of the foregoing embodiments, wherein the oral care composition comprises water in an amount ranging from about 10% to about 30% by weight, such as from about 12% to about 25% by weight or from about 15% to about 20% by weight, relative to the total weight of the oral care composition.

[0151] 19. The method according to any one of the foregoing embodiments, wherein the method reduces the concentration of IL-8 in the subject's tissue, such as the subject's gingival tissue.

[0152] 20. The method according to Example 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%.

[0153] 21. In some embodiments, this disclosure relates to a method of treating and / or alleviating symptoms of gingival disease in a subject in need, the method comprising applying an oral care composition to the 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.

[0154] 22. The method according to Example 21, wherein the gingival disease is selected from: gingivitis; periodontitis; implantitis; and mucositis.

[0155] 23. The method according to Example 21 or Example 22, wherein the subject in need is a nicotine user.

[0156] 24. The method according to any one of Examples 21 to 23, comprising applying the oral care composition to the oral cavity at least once a day, optionally at least twice a day, or at least three times a day.

[0157] 25. The method according to any one of Examples 21 to 24, wherein the amount of the oral care composition applied to the oral cavity is from about 0.1 g to about 3 g.

[0158] 26. The method according to any one of Examples 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 glycol; and combinations of two or more thereof.

[0159] 27. The method according to any one of Examples 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 combinations of two or more thereof.

[0160] 28. The method according to Example 27, wherein the nitrate ion source comprises potassium nitrate.

[0161] 29. The method according to any one of Examples 21 to 28, wherein the molar ratio of nitrate ions to stannous ions in the oral care composition is from about 0.5:1 to about 2:1, and both the nitrate ions and the stannous ions are measured in the form of free ions.

[0162] 30. The method according to any one of Examples 21 to 29, wherein the water-soluble alkali metal polyphosphate is selected from: pyrophosphate; tripolyphosphate; tetraphosphate; hexametaphosphate; and combinations of two or more thereof.

[0163] 31. The method according to any one of Examples 21 to 30, wherein the water-soluble alkali metal polyphosphate is selected from: tetrasodium pyrophosphate; potassium pyrophosphate; sodium tripolyphosphate; potassium tripolyphosphate; and combinations of two or more thereof.

[0164] 32. The method according to any one of Examples 21 to 31, wherein the nitrate ion source comprises potassium nitrate and the water-soluble alkali metal polyphosphate comprises tetrasodium pyrophosphate.

[0165] 33. In some embodiments, this disclosure relates to a method of treating and / or alleviating interleukin-8 (IL-8)-mediated inflammation in a subject of need, the method comprising applying an oral care composition to the 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 of need is a nicotine user.

[0166] 34. The method according to Example 33, wherein the IL-8-mediated inflammatory condition is selected from: gingival disease; chronic obstructive pulmonary disease (COPD); pneumonia; bronchitis; Crohn's disease; ulcerative colitis; and asthma.

[0167] 35. The method according to Example 34, wherein the gingival disease is selected from: gingivitis; periodontitis; implantitis; and mucositis.

[0168] 36. The method according to any one of Examples 33 to 35, wherein the subject in need is selected from: nicotine users; patients with inflammatory diseases; patients with bacterial or viral infections; obese individuals; or elderly individuals.

[0169] 37. The method according to any one of Examples 33 to 36, comprising applying the oral care composition to the oral cavity at least once a day, optionally at least twice a day, or at least three times a day.

[0170] 38. The method according to any one of Examples 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.

[0171] 39. The method according to any one of Examples 33 to 38, wherein the oral care composition is applied to the oral cavity in an amount of about 0.1 g to about 3 g.

[0172] 40. The method according to any one of Examples 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 glycol; and combinations of two or more thereof.

[0173] 41. The method according to Example 40, wherein the tin subion source comprises tin subfluoride.

[0174] 42. The method according to any one of Examples 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 combinations of two or more thereof.

[0175] 43. The method according to Example 42, wherein the nitrate ion source comprises potassium nitrate.

[0176] 44. The method according to any one of Examples 33 to 43, wherein the molar ratio of nitrate ions to stannous ions in the oral care composition is from about 0.5:1 to about 2:1, and both the nitrate ions and the stannous ions are measured in the form of free ions.

[0177] 45. The method according to any one of Examples 33 to 44, wherein the water-soluble alkali metal polyphosphate is selected from pyrophosphate; tripolyphosphate; tetraphosphate; hexametaphosphate; and combinations of two or more thereof.

[0178] 46. ​​The method according to any one of Examples 33 to 45, wherein the water-soluble alkali metal polyphosphate is selected from: tetrasodium pyrophosphate; potassium pyrophosphate; sodium tripolyphosphate; potassium tripolyphosphate; and combinations of two or more thereof.

[0179] 47. The method according to any one of Examples 33 to 46, wherein the nitrate ion source comprises potassium nitrate and the water-soluble alkali metal polyphosphate comprises tetrasodium pyrophosphate.

[0180] 48. The method according to any one of Examples 33 to 47, wherein the oral care composition comprises water in an amount ranging from about 10% to about 30% by weight, such as from about 12% to about 25% by weight or from about 15% to about 20% by weight, relative to the total weight of the oral care composition.

[0181] 49. The method according to any one of Examples 33 to 48, wherein the method reduces the concentration of IL-8 in the subject's tissue, such as the subject's gingival tissue.

[0182] 50. The method according to Example 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%.

[0183] 51. In some embodiments, this disclosure relates to a method of treating and / or alleviating symptoms of gingival disease in a subject in need, the method comprising applying an oral care composition to the 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 is a nicotine user.

[0184] 52. The method according to Example 51, wherein the gingival disease is selected from: gingivitis; periodontitis; implantitis; and mucositis.

[0185] 53. The method according to Example 51 or Example 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 three times a day.

[0186] 54. The method according to any one of Examples 51 to 53, wherein the amount of the oral care composition applied to the oral cavity is from about 0.1 g to about 3 g.

[0187] 55. The method according to any one of Examples 51 to 54, wherein the tin subion source comprises tin subfluoride.

[0188] 56. The method according to any one of Examples 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 combinations of two or more thereof.

[0189] 57. The method according to any one of Examples 51 to 56, wherein the nitrate ion source comprises potassium nitrate.

[0190] 58. The method according to any one of Examples 51 to 57, wherein the molar ratio of nitrate ions to stannous ions in the oral care composition is from about 0.5:1 to about 2:1, and both the nitrate ions and the stannous ions are measured in the form of free ions.

[0191] 59. The method according to any one of Examples 51 to 58, wherein the water-soluble alkali metal polyphosphate is selected from: pyrophosphate; tripolyphosphate; tetraphosphate; hexametaphosphate; and combinations of two or more thereof.

[0192] 60. The method according to any one of Examples 51 to 59, wherein the water-soluble alkali metal polyphosphate is selected from: tetrasodium pyrophosphate; potassium pyrophosphate; sodium tripolyphosphate; potassium tripolyphosphate; and combinations of two or more thereof.

[0193] 61. The method according to any one of Examples 51 to 60, wherein the nitrate ion source comprises potassium nitrate, and the water-soluble alkali metal polyphosphate comprises tetrasodium pyrophosphate.

[0194] Example Example 1 Example composition A and example composition 1 were prepared according to various aspects of this disclosure. Both compositions contain 0.454 wt.% stannous fluoride, 0.5 wt.% potassium nitrate, and 1.2 wt.% tetrasodium pyrophosphate, as shown in Table 1 below. Although example composition X was not prepared, its preparation is contemplated and within the scope of this disclosure.

[0195] Table 1 Example 2 The efficacy of stannous fluoride toothpaste in inactivating the NF-κB pathway and reducing inflammatory markers activated by Porphyromonas gingivalis endotoxin LPS was investigated.

[0196] Toothpaste supernatant was prepared by mixing composition A (described above in Example 1) in sterile water at a 1:4 ratio and centrifuging at 4,000 g for 10 minutes. Additionally, two samples of commercially available toothpaste containing stannous fluoride stabilized with gluconate (instead of KNO3 and TSPP) were similarly prepared by mixing each toothpaste in sterile water at a 1:4 ratio and centrifuging at 4,000 g for 10 minutes to produce comparative composition B and comparative composition C. The supernatant was collected as toothpaste test material and further diluted in tissue culture medium before cell treatment.

[0197] HEK-hTLR4 cells (Invivogen, hkb-htlr4) were incubated overnight at 37°C and 5% CO2 with toothpaste supernatants of compositions A, B and C in the presence of 1 µg / mL ultrapure Porphyromonas gingivalis lipopolysaccharide (LPS) (Invivogen, tlrl-ppglps).

[0198] NF-κB analysis was performed using HEK-blue assay medium according to the Invivogen protocol (Invivogen, hb-det). IL-8 levels in cell supernatant were quantified using the Enzo IL-8 ELISA kit (Enzo, ADI-900-156). Cell viability was analyzed using the PrestoBlue cell viability assay according to the Invitrogen protocol (Invitrogen, A13262). IL-8 concentrations were normalized using cells treated with culture medium only. A T-test was performed to calculate p-values ​​with 95% confidence.

[0199] The results of NF-κB analysis are shown in Table 2 below, and the results of IL-8 quantification are shown in Table 3 below.

[0200] Table 2 – Average optical density at 640 nm Table 3 – Normalized IL-8 The results showed that nitrate- and phosphate-stannous fluoride (composition A) was significantly superior to gluconate-stannous fluoride toothpaste composition B in reducing LPS-induced NF-κB activation in ultrapure *Porphyromonas gingivalis* (p < 0.05). Figure 1 As shown, compared with untreated HEK-TLR4 cells and 1 µg / mL LPS and composition B, the fold change in optical density (OD) readings of HEK-TLR4 cells at 640 nm was significantly reduced in the presence of 1 µg / mL LPS and composition A. The high OD readings indicate a higher degree of NF-κB activation. Furthermore, composition A showed significantly greater potency in reducing the inflammatory marker IL-8 induced by *Porphyromonas gingivalis* LPS compared to both compositions B and C (p < 0.05). Figure 2 As shown, composition A exhibited 47.9% inhibition of IL-8 concentration in the culture medium (p < 0.0001), composition B exhibited 0.502% inhibition of IL-8 concentration (p > 0.05), and composition C exhibited -8.1% inhibition of IL-8 concentration (p > 0.05).

[0201] Therefore, compared to either Composition B or Composition C, which are gluconate-stannous fluoride commercial toothpastes, Composition A exhibits stronger in vitro efficacy in inactivating NF-κB and inhibiting inflammatory markers.

[0202] Example 3 The efficacy of stannous fluoride compositions in inactivating NF-κB and reducing inflammatory markers activated by Porphyromonas gingivalis endotoxin LPS was investigated.

[0203] Composition D20 was prepared by mixing composition A (described above in Example 1) in sterile water at a ratio of 1:20 and centrifuging at 4,000 g for 10 minutes, and composition D40 was prepared by mixing composition A in sterile water at a ratio of 1:40 and centrifuging at 4,000 g for 10 minutes.

[0204] Composition E20 was prepared by mixing composition 1 (described above in Example 1) at a ratio of 1:20 in sterile water and centrifuging at 4,000 g for 10 minutes. Similarly, composition E40 was prepared by mixing composition 1 at a ratio of 1:40 in sterile water and centrifuging at 4,000 g for 10 minutes. The supernatant was collected as toothpaste test material and further diluted in tissue culture medium before cell treatment.

[0205] HEK-hTLR4 cells (Invivogen, hkb-htlr4) and toothpaste supernatant were incubated overnight at 37°C and 5% CO2 in the presence of 1 µg / mL ultrapure Porphyromonas gingivalis lipopolysaccharide (LPS) (Invivogen, tlrl-ppglps).

[0206] As described in Example 2 above, IL-8 quantification was performed, and Table 4 below and Figure 3 The results are shown in the figure.

[0207] Table 4 – IL-8 pg / mL in the presence of Porphyromonas gingivalis LPS The results showed that both 20-fold dilutions of stannous fluoride stabilized with nitrate and phosphate (composition D20) and 20-fold dilutions of stannous fluoride stabilized with zinc phosphate (composition E20) significantly reduced LPS-induced NF-κB extinguishing in ultrapure *Porphyromonas gingivalis* (p < 0.001). Figure 3 As shown, compared with untreated HEK-hTLR4 cells, the IL-8 pg / mL of HEK-hTLR4 cells was significantly reduced in the presence of both 1 µg / mL LPS and composition D20. Similarly, compared with untreated HEK-hTLR4 cells, the IL-8 pg / mL of HEK-hTLR4 cells was significantly reduced in the presence of both 1 µg / mL LPS and composition E20.

[0208] Cell viability: As described above, cell viability was measured for each of the following: untreated HEK-TLR4 cells and cells treated with LPS, as well as LPS plus compositions D20, D40, E20, and E40. To prepare the mirror plates, 96-well plates were arranged with six rows of compositions D20, D40, E20, and E40 in each of columns 2-5, and rows of untreated cells and LPS-treated cells in each column. 130 µL of total culture medium (DMEM + FBS + p / s + Normocin + selection agent) was added to each column, and 130 µL was transferred from column 2 to column 3, mixing thoroughly several times by pipetting. Then, 130 µL was transferred from column 3 to column 4 and mixed thoroughly, and then transferred from column 4 to column 5 and mixed thoroughly. Dilutes were performed as described for each treatment. 130 µL of total culture medium was added to the untreated wells and the LPS wells. On a plate containing HEK-hTLR4 cells, 100 µL of LPS was transferred across the plate from the mirror plate to an LPS cell plate. 100 µL of LPS (2 ng / mL in total culture medium) was added to each well of the HEK-hTLR4 cell plate, except for the untreated wells. Then, 100 µL of total culture medium was added to the untreated wells. The plates were mixed and incubated overnight at 37°C and 5% CO2 before measuring cell viability.

[0209] The results showed that each of the prepared compositions possessed sufficient cell viability. Specifically, such as Figure 4 As shown, the cell viability percentages of compositions D20, D40, E20, and E40 are 112.4%, 92.3%, 99.6%, and 98.2%, respectively. The cell viability of the LPS-treated wells is 97.2%, and all values ​​are relative to untreated cells with 100% cell viability.

[0210] Example 4 This case study was conducted to investigate the NF-κB inactivation between SNAP solutions with different combinations of components and to identify which components play a key role in NF-κB inactivation.

[0211] Summarize All SNAP solutions listed below in the Test Samples section (except for Sol 4 (KNO3) and Sol 5 (TSPP)) exhibited strong NF-κB inactivation in both the HEK-hTLR2 and HEK-hTLR4 cell lines in response to IL-1β or LPS stimulation, indicating that Sn(II) and Sn(IV) play a key role in reducing NF-κB activation activity in SNAP solutions. Specifically, in HEK-hTLR2 cells, Sol 3b and 7 showed the best performance in reducing NF-κB activation (approximately 92% inhibition) compared to cells treated with IL-1β alone, followed by Sol 1, 3a, and 6 (approximately 90% inhibition) and Sol 2 (approximately 85% inhibition). In HEK-hTLR4 cells, NF-κB activation was reduced by approximately 88% with Sol 3a and 6 compared to the LPS-only treatment group, followed by Sol 1 (approximately 87%), Sol 3b and 7 (approximately 85%), and Sol 2 (approximately 68%). It should be noted that Sol 5 showed a slight inhibitory effect (approximately 35%).

[0212] In summary, under IL-1β stimulation, the NF-κB inactivation effect of SNAP solution in HEK-hTLR2 cells was: Sol3b and 7 > Sol1, 3a and 6 > Sol2 > Sol5 > Sol4, while under LPS stimulation in HEK-hTLR4 cells, the effect was: Sol3a and 6 > Sol1 > Sol3b and 7 > Sol2 > Sol5 > Sol4. Statistical analysis showed that the differences between the groups were significant (Student's t-test, p < 0.05).

[0213] program HEK-Blue assay medium was prepared by reconstituted HEK-Blue assay powder (InvivoGen catalog # hb-det2) into endotoxin-free H2O and heated in a 37°C water bath until ready for use. Cell suspensions were prepared by isolating and resuspending cells in PBS, counting them, and then adding them to the prepared HEK-Blue assay medium. Cells were plated into 96-well F-type plates, with 180 µl of medium per well. Next, a mixture of 20 µl of IL-1β (final: 1 ng / mL) or LPS (final: 1 μg / mL) with a final 100-fold dilution of SNAP solution was prepared and added to each well. The treated cells were incubated overnight at 37°C in a 5% CO2 cell incubator. The next day, secreted embryonic alkaline phosphatase (SEAP) activity was detected by reading the plate at OD 640 nm using a microplate reader. The SEAP reporter gene is controlled by an IFN-β minimal promoter fused to five NF-κB and AP-1 binding sites in HEK-hTLR2 and 4 cells. Therefore, activation of NF-κB will induce SEAP expression, and NF-κB activation can be detected by measuring SEAP activity.

[0214] Test sample Sol 1 (total 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%) result refer to Figure 5SEAP activity was assessed by measuring absorbance at OD 640 nm in HEK-hTLR2 cells treated with SNAP solution. The SEAP reporter gene is controlled by an IFN-β minimal promoter fused to five NF-κB and AP-1 binding sites; therefore, NF-κB activation induces SEAP expression, and NF-κB activation can be detected by measuring SEAP activity (Note: cell viability data are available in the SNAP anti-inflammatory report).

[0215] refer to Figure 6 SEAP activity was assessed by measuring the absorbance at OD 640 nm in HEK-hTLR4 cells treated with SNAP solution. The SEAP reporter gene is controlled by an IFN-β minimal promoter fused to five NF-κB and AP-1 binding sites; therefore, NF-κB activation induces SEAP expression, and NF-κB activation can be detected by measuring SEAP activity (Note: cell viability data are available in the SNAP anti-inflammatory report).

[0216] refer to Figure 7 SNAP solution responded to IL-1β stimulation in the inactivation of NF-κB in HEK-hTLR2 cells.

[0217] refer to Figure 8 SNAP solution responded to LPS stimulation in the inactivation of NF-κB in HEK-hTLR4 cells.

[0218] discuss like Figure 5 and 6 As shown, SEAP activity was monitored by culturing HEK-hTLR2 and HEK-hTLR4 cells in HEK-blue assay medium with or without SNAP treatment. SEAP activity is an indicator of NF-κB activation, therefore... Figure 7 and 8 In this study, the reduction in NF-κB activation under different SNAP treatments was analyzed in both cell lines compared to cells treated with only the stimulating agent.

[0219] exist Figure 7In HEK-hTLR2 cells, Sol 3b and 7 showed the highest inhibitory effect on NF-κB activation (approximately 92%). Sol 1, 3a, and 6 showed similar inactivation effects (approximately 90% inhibition). Sol 2 produced approximately 85% inhibition. Sol 5 (12%) and Sol 4 (5%) had little effect on NF-κB inactivation. Studen's t-test results indicated that the inhibition percentages of Sol 3b and 7 were significantly greater than those of Sol 1, 3a, and 6 (p < 0.05), while the inactivation effect of Sol 2 was significantly lower than that of Sol 1, 3a, and 6 (p < 0.05). There were no significant differences between Sol 3b and 7 or between Sol 1, 3a, and 6. Given the presence of 100% Sn(IV) in both Sol 3b and 7, this suggests that Sn(IV) appears to have better performance than Sn(II) in inactivating NF-κB in HEK-hTLR2 cells. When TSPP was absent in Sol 2, the inhibitory effect of SNAP was significantly lower than that in Sol 1, indicating the importance of TSPP in SNAP containing Sn(II). Furthermore, due to the non-significant difference between Sol 1 and 3a, KNO3 appears to be less important for Sn(II). In summary, the inhibitory effect on NF-κB activation was: Sol 3b and 7 (approximately 92%) > Sol 1, 3a and 6 (approximately 90%) > Sol 2 (approximately 85%) > Sol 5 (approximately 12%) > Sol 4 (approximately 5%).

[0220] exist Figure 8 In HEK-hTLR4 cells, compared with the LPS-only treatment group, Sol 3a and 6 reduced NF-κB activation by approximately 88%, followed by Sol 1 (approximately 87%), Sol 3b and 7 (approximately 85%), and Sol 2 (approximately 68%). Sol 5 showed a slight inhibitory effect (approximately 35%). Studen's t-test results showed that the inhibition percentage between Sol 3a and 6 and Sol 1 was significant. Furthermore, the effects of Sol 3b and 7 were greater than those of Sol 2, but significantly less than those of Sol 1 (p < 0.05). Since the inhibitory effects among Sol 1, 3a, 3b, 6, and 7 were very similar, this suggests that Sn(II) and Sn(IV) exhibit similar performance in NF-κB inactivation in HEK-hTLR4 cells. The much lower effect of Sol 2 suggests the importance of TSPP for Sn(II) in SNAP, while the close effect between Sol 3b and 7 suggests that KNO3 appears to be unimportant for Sn(IV). In summary, the inhibitory effects on NF-κB activation are: Sol 3a and 6 (approximately 88%) > Sol 1 (approximately 87%) > Sol 3b and 7 (approximately 85%) > Sol 2 (approximately 68%) > Sol 5 (approximately 35%) > Sol 4 (approximately -5%).

[0221] Although the NF-κB inactivation results appear to differ from our observations regarding the inhibitory effect of SNAP on IL-8 levels in response to stimulation, with the effect in HEK-hTLR2 cells being: Sol 1 (approximately 85% inhibition) > Sol 3b (approximately 74%) > Sol 3a and 6 (approximately 64%) > Sol 2 and 7 (approximately 47%); and in HEK-hTLR4 cells being: Sol 3b and 7 (approximately 97%) > Sol 1 and 6 (approximately 84%) > Sol 3a (approximately 66%) > Sol 2 (approximately 40%) (see the report on the anti-inflammatory effects of SNAP, dated 12-02-21), it seems that both experiments demonstrate the importance of TSPP for the anti-inflammatory effect of Sn(II), while KNO3 appears to be less important for Sn(IV).

[0222] Furthermore, regarding the reduction of IL-8 levels in HEK-hTLR2 cells, Sol 1 showed the best performance in the presence of Sn(II), while Sol 7 with Sn(IV) showed the lowest performance. However, in terms of NF-κB inactivation, Sol 1 and 7 showed fairly similar results. In HEK-hTLR4 cells, Sol 3b and 7 appeared to have the greatest effect on the reduction of IL-8 levels in the presence of Sn(IV), while Sn(II) and Sn(IV) showed similar performance in NF-κB inactivation. All these results suggest that it may be important to use more than one assay to evaluate the anti-inflammatory properties of Sn(II) and Sn(IV) in SNAP solution. Overall, SNAP exhibits good anti-inflammatory activity.

[0223] Example 5 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 in 96-well plates at 37°C and 5% CO2 until at least 80% confluence. The culture medium should contain DMEM, 10% FBS, 1% penicillin-streptomycin, Normocin, and HEK-Blue selector. If the basal medium is already free of L-glutamine, 1% L-glutamine will be added.

[0224] The sample composition was mixed at the desired concentration in sterile cell culture water and the sample was centrifuged. The supernatant was collected as the test material and further diluted to twice the desired final concentration in the prepared culture medium.

[0225] Cells were treated with chewed tobacco, tobacco extract, or nicotine for a period of time (e.g., 3–24 hours), washed, and incubated. Alternatively, to detect intracellular TLR4 levels, cells were permeabilized with permeation buffer (eBioscience) and stained with anti-human TLR4 Ab or a relevant isotype. TLR4 expression could be assessed on a FACScan flow cytometer (BD Biosciences). Relative TLR4 surface or intracellular levels were quantified by subtracting the mean fluorescence intensity (MFI) value from the isotype-matched control for each sample.

[0226] Dilute LPS or ultrapure LPS to 2 ng / mL in the prepared culture medium. Aspirate the old culture medium from the confluent cells. Add 100 µL of the prepared chewed tobacco, tobacco extract, or nicotine supernatant and 100 µL of LPS to the cells. Since the LPS and treatment are diluted with each other, the final concentration will be half of the applied concentration. Incubate the cells overnight. After collecting the cell culture medium, add the prepared PrestoBlue cell viability reagent (1:10 diluted in the culture medium) and incubate with the cells for 10–30 minutes. Read the fluorescence at 560 / 590 ex / em to determine post-treatment viability. Perform an IL-8 ELISA on the supernatant of HEK-hTLR4 cells to quantify IL-8 levels in the presence or absence of LPS and chewed tobacco, tobacco extract, or nicotine.

Claims

1. A method for treating and / or alleviating interleukin-8 (IL-8)-mediated inflammation in a subject of need, the method comprising applying an oral care composition to the oral cavity of the subject, the oral care composition comprising: Tin ion source; Nitrate ion source; Water-soluble alkali metal polyphosphates; and The composition contains at least 10% water by weight.

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 combinations of two or more thereof.

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

4. The method according to any one of the preceding claims, 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 combinations of two or more thereof.

5. The method according to any one of the preceding claims, wherein the nitrate ion source comprises potassium nitrate.

6. The method according to any one of the preceding claims, wherein the water-soluble alkali metal polyphosphate is selected from: pyrophosphate; tripolyphosphate; tetraphosphate; hexametaphosphate; and combinations of two or more thereof.

7. The method according to any one of the preceding claims, wherein the water-soluble alkali metal polyphosphate is selected from: sodium pyrophosphate; potassium pyrophosphate; sodium tripolyphosphate; potassium tripolyphosphate; and combinations of two or more thereof.

8. The method according to any one of the preceding claims, wherein the nitrate ion source comprises potassium nitrate, and the water-soluble alkali metal polyphosphate comprises tetrasodium pyrophosphate.

9. The method according to any one of the preceding claims, wherein the IL-8-mediated inflammatory condition is selected from: gingival disease; chronic obstructive pulmonary disease (COPD); pneumonia; bronchitis; Crohn's disease; ulcerative colitis; and asthma.

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

11. The method according to any one of the preceding claims, wherein the desired subject is selected from: nicotine users; patients with inflammatory diseases; patients with bacterial or viral infections; obese individuals; or elderly individuals.

12. The method according to any one of the preceding claims, wherein the subject in need is a nicotine user.

13. The method according to any one of the preceding claims, comprising applying the oral care composition to the oral cavity at least once a day, optionally at least twice a day, or at least three times a day.

14. The method according to any one of the preceding claims, 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 one of the preceding claims, wherein the oral care composition is applied to the oral cavity in an amount of about 0.1 g to about 3 g.

16. The method according to any one of the preceding claims, wherein the tin subion source comprises tin subfluoride.

17. The method according to any one of the preceding claims, wherein the molar ratio of nitrate ions to stannous ions in the oral care composition is from about 0.5:1 to about 2:1, and both the nitrate ions and the stannous ions are measured in the form of free ions.

18. The method according to any one of the preceding claims, wherein the oral care composition comprises water in an amount ranging from about 10% to about 30% by weight, such as from about 12% to about 25% by weight 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 one of the preceding claims, wherein the method reduces the concentration of IL-8 in the subject's tissue, such as the subject's gingival tissue.

20. The method of 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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