Novel oral care formulations for treating xerostomia

Abstract

A formulation for treating and alleviating xerostomia is provided. Formulations comprising a humectant (e.g., propylene glycol), a chelating agent (e.g., EDTA and salts thereof), and a transport promoter (e.g., methylsulfonylmethane (MSM)) are provided.

Description

Inventors: Rajeev Bhushan and Amit Goswami CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application Serial No. 63 / 329,355, filed on April 8, 2022, entitled “NOVEL ORAL CARE FORMULATIONS FOR TREATMENT OF XEROSTOMIA,” the contents of which are incorporated herein by reference in their entirety. Technical Field

[0002] The present invention generally relates to the field of agents for treating xerostomia and relieving dry mouth symptoms. In particular, the present invention relates to oral care formulations containing humectants, transport enhancers and chelating agents. In an exemplary embodiment, it relates to an oral care composition containing MSM (as a transport enhancer) and a chelating agent that is generally accepted as safe ("GRAS"). Background Art

[0003] Xerostomia is dry mouth caused by reduced or absent saliva flow. This condition may cause discomfort, affect speech and swallowing, make it difficult to wear dentures, cause halitosis (bad breath), and impair oral hygiene by lowering oral pH and increasing bacterial growth. Long-term xerostomia may lead to severe tooth decay (dental caries) and oral candidiasis (chronic mucocutaneous candidiasis (CMC)). Xerostomia is a common condition in the elderly, affecting approximately 20% of the elderly.

[0004] Dry mouth is a growing problem. As people age, the number of medications they take increases. About 2,000 medications are known to cause dry mouth. 75% of prescription drugs and many over-the-counter (OTC) medications have dry mouth as a side effect. The most common include: anticholinergics, anti-Parkinson's drugs, anti-neoplastic drugs (chemotherapy), anti-hypertensive drugs, antianxiety drugs, and antidepressants. As a result, about 70 million people suffer from dry mouth, and 1 in 3 people over the age of 45 have dry mouth.

[0005] Chemotherapy drugs can cause severe dryness and stomatitis when they are taken; these problems usually go away when treatment stops. Other common drug classes that cause xerostomia include antihypertensives, antianxiety drugs, and antidepressants (selective serotonin reuptake inhibitors (SSRIs) cause less severe xerostomia than tricyclics).

[0006] The increase in illegal methamphetamine use has led to rising rates of meth mouth, which is severe tooth decay and periodontitis caused by methamphetamine-induced xerostomia. The damage is exacerbated by drug-induced teeth grinding and clenching, as well as the intake of large amounts of sugary drinks while under the influence of the drug and poor oral hygiene. This combination can lead to rapid destruction of teeth. Smoking can also lead to a decrease in saliva.

[0007] Several systemic disorders, such as Sjögren's syndrome, diabetes, rheumatoid arthritis, and systemic lupus erythematosus, are also known to cause dry mouth. Other causes include head and neck injuries that damage the nerves to the salivary glands. Head and neck cancers treated with radiation and chemotherapy are another cause of dry mouth. Smoking often results in decreased saliva. The increase in illegal methamphetamine use has led to an increasing incidence of meth mouth, which is severe tooth decay caused by methamphetamine-induced xerostomia. The damage is exacerbated by drug-induced grinding and clenching of the teeth, as well as the heat from inhaling the steam. This combination can lead to rapid destruction of teeth.

[0008] With the aging population and its dependent use of medications, the numerous negative side effects associated with salivary dysfunction will pose medical socioeconomic problems not only to individuals but also to society in the near future.

[0009] Problems with dry mouth include difficulty swallowing and eating, difficulty speaking due to dry vocal cords, a feeling of thirst, sore throat and mouth, chapped lips, dry tongue, and dry mouth. In addition to these physical problems, dry mouth can also lead to oral health problems such as an increased risk of cavities, gingivitis (inflammation of the gums), periodontitis (inflammation of the gums that leads to tooth loss), mouth ulcers, fungal infections in the mouth, and bad breath. Therefore, it is important to understand the extent of dry mouth so that preventive measures can be taken to prevent oral health problems.

[0010] The cause of xerostomia is often obvious, but if the cause is unclear and a systemic disorder is thought to be possible, further evaluation should be done with a minor salivary gland biopsy (to test for Sjögren's syndrome, sarcoidosis, amyloidosis, TB, or cancer) and HIV testing. The lower lip is a convenient site for a biopsy. More information about xerostomia is available at www(dot)merckmanuals(dot)com / professional / dental-disorders / symptoms-of-dental-and-oral-disorders / xerostomia (accessed April 2, 2022).

[0011] The lack of moisture and lubrication that saliva typically provides can have a range of negative effects on the oral tissues (soft tissues), from mild discomfort to extremely painful and infected mouth ulcers. Persistent discomfort and dryness can also cause disrupted sleep and impair the ability to speak (impairing social skills and potentially affecting psychological health) and eat (potentially affecting nutrition), leading to more serious health problems. Dry cheek tissue is a less effective barrier and is more easily penetrated by physical irritants such as toxins and carcinogens in food, beverages, and tobacco.

[0012] Saliva is also the mouth’s primary defense against tooth decay. A healthy flow of saliva helps prevent cavities by physically removing bacteria from the mouth before they can attach to tooth and tissue surfaces and form a protective biofilm. Saliva flow also helps dilute sugars and acids from food and beverage intake. The buffering capacity neutralizes acids and aids in the digestive process. The presence of calcium and phosphates provides a continuous opportunity for remineralization of tooth enamel, helping to reverse the tooth decay process.

[0013] Many people with xerostomia use different products to address hard tissue health and soft tissue comfort. For soft tissue comfort, saliva substitute products are typically designed to provide lubrication and moisture. These products come in a variety of forms, including viscous gels / pastes, sprays, mouthwashes, mints, and sustained-release tablets. They can be used multiple times a day or as needed for comfort. For hard tissue health, different treatments (antibacterial rinses, fluoride products, calcium / phosphate treatments) are used to directly address the problem of cavity prevention. "Dry mouth-friendly" versions of products, such as toothpastes and mouthwashes, are often recommended. Dry mouth-friendly products typically have a neutral pH and do not contain alcohol or other irritating components (e.g., anionic surfactants or emulsifiers).

[0014] The various oral care compositions commonly available (e.g., toothpastes and mouthwashes) are primarily based on the cleaning power of surfactants, soaps and or detergents and mild abrasives. Some formulations have added antimicrobial agents, e.g. or stannous fluoride to enhance the anti-plaque effect.

[0015] Recently, it has been demonstrated that formulations containing transport enhancers (e.g., MSM) and chelating agents (e.g., EDTA) can significantly reduce the formation of dental plaque and have been used to prevent and treat adverse oral conditions and disorders (WO 2013 / 166459 of Bhushan et al.; WO 2014 / 100775 of Bhushan et al.; U.S. Pat. No. 9,616,008 of Bhushan et al.). According to the disclosure of the above patent applications, dental treatment products containing MSM and chelating agents are It is available in the market in the form of dental gel.

[0016] Humectants have been used in oral care products to prevent toothpaste from hardening upon exposure to air, or to provide improved moisturization and mouthfeel in mouthwashes, and to enhance the miscibility of poorly soluble ingredients such as flavoring oils.

[0017] Propylene glycol is a small molecule organic alcohol that is commonly used in toothpaste as a humectant. Propylene glycol has been used in dental care products such as toothpaste to ensure that the product is free of unwanted bacteria, yeast and mold.

[0018] It was desirable to design a single product that effectively and easily met the needs of both dry mouth symptom relief (soft tissue comfort) and oral health prevention benefits (cavity protection). Summary of the invention

[0019] It has now been observed that oral care products comprising a transport enhancer (e.g., MSM) and a chelating agent (e.g., EDTA) (disclosed in WO 2013 / 166459 to Bhushan et al.; WO 2014 / 100775 to Bhushan et al.; U.S. Pat. No. 9,616,008 to Bhushan et al.) can significantly reduce plaque formation and are used to prevent and treat adverse oral conditions and disorders, exhibiting unexpected and surprising effects of substantially and highly significantly increasing unstimulated and stimulated saliva production and alleviating the sensation of dry mouth in the subject.

[0020] The present invention provides a formulation comprising a humectant (e.g., a humectant selected from glycerol, sorbitol, xylitol, maltitol, propylene glycol, hexylene glycol, butylene glycol, erythritol, isomalt, and combinations thereof), a transport enhancer (e.g., MSM), and a chelating agent (e.g., EDTA).

[0021] The present invention provides a formulation comprising: a wetting agent on the GRAS (Generally Recognized As Safe) list of the United States Food and Drug Administration (FDA), wherein the chelating agent is suitable for long-term administration; a penetration enhancer, which is methylsulfonylmethane (MSM); one or more inert excipients; and a liquid vehicle or carrier; wherein the chelating agent and the penetration enhancer are present in a ratio effective to maintain iron homeostasis in the body when used at conventional doses, and wherein the percentage of the wetting agent is about 0.5% to about 15.0%, the percentage of the chelating agent is about 0.0001% to 15%, and the percentage of the penetration enhancer in the composition is about 0.0001% to 0% by weight.

[0022] In one aspect of the invention, the formulation can be administered in any suitable form, including pastes, gels, solids and granular solid compositions, such as various toothpastes, gel dentifrices, tooth powders, chewing gums, tablets and lozenges. In addition, in particular embodiments, the formulation consists entirely of naturally occurring and / or GRAS ("generally recognized as safe") components classified by the U.S. Food and Drug Administration. However, the present invention also contemplates non-GRAS components in the formulation.

[0023] In certain embodiments, the humectant is propylene glycol.

[0024] The method involves administering to a subject an effective amount of a formulation consisting of a therapeutically effective amount of a wetting agent, a therapeutically effective amount of a chelating agent, and an effective transport-enhancing amount of a transport enhancer having formula (I), Where R 1 and R 2 Each independently selected from C2-C6 alkyl, C1-C6 heteroalkyl, C6-C 14 Arylalkyl and C2-C 12 heteroarylalkyl, any of which may be substituted, and Q is S or P.

[0025] The transport enhancer can be, for example, methylsulfonylmethane (MSM; also known as dimethyl sulfone, dimethyl sulfone, and DMSO2).

[0026] The chelating agent can be selected from ethylenediaminetetraacetic acid (EDTA), ethylene glycol tetraacetic acid (EGTA), cyclohexanediaminetetraacetic acid (CDTA), hydroxyethylethylenediaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA), dimercaptopropanesulfonic acid (DMPS), dimercaptosuccinic acid (DMSA), aminotrimethylenephosphonic acid (ArPA), citric acid, acetic acid, phosphoric acid, pyrophosphate, metaphosphate, malic acid polymers, and the like, and acceptable salts thereof and any combination thereof.

[0027] These and other aspects will become apparent from the following description of the preferred embodiments taken in conjunction with the following drawings, but changes and modifications may be made thereto without departing from the spirit and scope of the novel concepts of the present disclosure. DETAILED DESCRIPTION

[0028] In the context of the present invention and in the specific context in which each term is used, the terms used in this specification generally have their ordinary meaning in the art. Certain terms used to describe the present invention are discussed below or in other parts of this specification, so as to provide practitioners with additional guidance on the description of the present invention. For convenience, certain terms may be highlighted, for example, using italics and / or quotation marks. The use of highlighting has no effect on the scope and meaning of the terms; whether or not it is highlighted, the scope and meaning of the terms are the same in the same context. It should be understood that the same thing can be described in more than one way. Therefore, alternative language and synonyms can be used for any one or more of the terms discussed herein, regardless of whether the terms are described or discussed in detail herein, and no special meaning is given to the terms. Synonyms for certain terms are provided. The detailed description of one or more synonyms does not exclude the use of other synonyms. The examples used anywhere in this specification (including examples of any terms discussed herein) are only illustrative and do not limit the scope and meaning of the present invention or any exemplary terms in any way. Similarly, the present invention is not limited to the different embodiments given in this specification.

[0029] Where a range of values ​​is provided, it is understood that each intermediate value between the upper and lower limits of the range (to one tenth of the lower limit, unless the context clearly indicates otherwise) and any other stated or intermediate values ​​within the stated range are encompassed within the present invention. The upper and lower limits of these smaller ranges may be independently included within these smaller ranges and are also encompassed within the present invention, subject to any specifically excluded limits in the stated ranges. Where a stated range includes one or two limits, ranges excluding either or both of those included limits are also encompassed within the present invention.

[0030] When referring to formulation components, the terms used (e.g., "agent") are intended to encompass not only the specific molecular entity, but also pharmaceutically acceptable analogs thereof, including, but not limited to, salts, esters, amides, prodrugs, conjugates, active metabolites, and other such derivatives, analogs, and related compounds.

[0031] As used herein, the terms "treating and treatment" refer to the administration of a medicament or formulation to a clinically symptomatic individual human or animal suffering from an adverse condition, disorder or disease to reduce the severity and / or frequency of symptoms, eliminate symptoms and / or their potential causes, and / or promote improvement or remedy of damage. The terms "preventing and prevention" refer to the administration of a medicament or composition to an individual without clinical symptoms suffering from a specific adverse condition, disorder or disease, and therefore involve the prevention of the occurrence of symptoms and / or their potential causes. Unless otherwise expressly or impliedly stated herein, if the term "treatment or treating" is used without mentioning possible prevention, it is intended to also cover prevention, so "a method for treating gingivitis" will be interpreted as covering "a method for preventing gingivitis".

[0032] "Optional" or "optionally present" (as in "optional substituent" or "optionally present additive") means that the subsequently described component (e.g., substituent or additive) may or may not be present, and thus the description includes instances where the component is present and instances where the component is not present.

[0033] "Pharmaceutically acceptable" means that it is not a biologically or otherwise undesirable material, for example, the material can be incorporated into the formulation of the present invention without causing any undesirable biological effect, or does not interact with any other component of the dosage form formulation in a harmful manner. However, when the term "pharmaceutically acceptable" is used to refer to a pharmaceutical excipient, it is implied that the excipient meets the required standards for toxicology and manufacturing testing, and / or the excipient is included in the Inactive Ingredient Guide formulated by the U.S. Food and Drug Administration. As further explained in detail below, "pharmacologically active" as in a "pharmacologically active" (or simply "active") derivative or analog refers to a derivative or analog having the same type of pharmacological activity as the parent agent. As used herein, the term "treatment" refers to reducing the severity and / or frequency of symptoms, eliminating symptoms and / or potential causes, preventing the occurrence of symptoms and / or their potential causes, and improving or remedying undesirable conditions or damage. Thus, for example, "treating" a subject involves preventing an adverse condition in an individual susceptible to infection, as well as treating an individual with clinical symptoms by inhibiting the condition or causing regression of the condition. The term "chelator" (or "active agent") refers to any chemical compound, complex or composition that exhibits a desired effect in a biological context (i.e., when administered to a subject or introduced into a cell or tissue in vitro). The term includes pharmaceutically acceptable derivatives of those active agents specifically mentioned herein, including but not limited to salts, esters, amides, prodrugs, active metabolites, isomers, analogs, crystalline forms, hydrates, and the like. When the term "chelator" is used, or when a particular chelator is specifically identified, it is understood that the pharmaceutically acceptable salts, esters, amides, prodrugs, active metabolites, isomers, analogs, etc. of the agent are intended to represent the agent itself.

[0034] An "effective" amount or "therapeutically effective" amount of an active agent means an amount of the agent that is non-toxic but sufficient to provide a beneficial effect. An "effective" amount of an active agent varies from subject to subject, depending on the age and general condition of the individual, the specific active agent or agents, etc. Unless otherwise indicated, the term "therapeutically effective" amount as used herein (i.e., in addition to an amount effective to treat an adverse condition) is intended to encompass an amount effective to prevent an adverse condition and / or to ameliorate an adverse condition.

[0035] As will be apparent to those skilled in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features that can be readily separated or combined with the features of any of the other several embodiments without departing from the scope or spirit of the invention. Any recited method may be performed in the order of events recited or in any other order that is logically possible.

[0036] Unless otherwise stated, the present invention is not limited to specific formulation components, modes of administration, chelating agents, manufacturing processes, etc., as these may vary.

[0037] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the event of a conflict, the present document, including definitions, will control. Wetting agent:

[0038] Xerostomia, or dry mouth, is a common condition caused by insufficient saliva production. It is increasingly common in the aging population and is a side effect of many medications and cancer treatments. Severe cases of xerostomia are often associated with salivary gland dysfunction, a condition called Sjögren's syndrome.

[0039] The lack of moisture and lubrication that saliva typically provides can have a range of negative effects on oral tissues (soft tissues), from mild discomfort to extremely painful and infected mouth ulcers. Continued discomfort and dryness can also cause sleep disruptions and impair the ability to speak (impairing social skills, which can affect mental health) and eat (which can affect nutrition), leading to more serious health problems. Dry cheek tissue is a less effective barrier and is more easily penetrated by physical irritants such as toxins and carcinogens in food, beverages, and tobacco. There remains a need for compositions that can improve xerostomia relief.

[0040] A humectant is a hygroscopic substance that attracts and retains surrounding water by absorbing it, drawing water vapor onto a surface. Common humectants include: Commonly used. The most commonly used include: Hyaluronic acid: This is a molecule that occurs naturally in the body, but as we age, our bodies produce less and less of this molecule. Glycerin: Also known as glycerine or glycerol, this is a clear substance that occurs naturally in animal and plant tissues, including human tissue. Much of the glycerin in cosmetics is made from soy and sugar cane. Alpha-hydroxy acids (AHA): Alpha-hydroxy acids (such as glycolic, lactic, and citric acids) are acids that are naturally derived from fruit and lactose. In addition to absorbing water, glycolic acid comes from sugar cane, lactic acid comes from milk, and citric acid comes from citrus fruits.

[0041] Oral care formulations of the present invention include one or more wetting agents. Exemplary useful wetting agents can include, for example, glycerol, sorbitol, xylitol, maltitol, propylene glycol, hexylene glycol, butylene glycol, erythritol, isomalt or its combination. Wetting agents (for example xylitol, erythritol or its combination) may be particularly useful because they can not only provide benefits for the hard tissues of the oral cavity, but also can provide moisture retention properties. In disclosed goods, one or more wetting agents can exist in an amount of not less than 5% or not less than 7% based on the gross weight of the goods. In disclosed goods, one or more wetting agents can exist in an amount of not more than 15% or not more than 12% based on the gross weight of the goods.

[0042] Wetting agent can enhance the viscosity, mouthfeel and sweet taste of product, and can also help to protect product from degradation or microbial contamination.Suitable wetting agent comprises edible polyol, for example the mixture of glycerine, sorbitol, xylitol, propylene glycol and other polyols and these wetting agents.Sorbitol can provide with the hydrogenated starch hydrolysate in the form of syrup in some cases, mainly comprises sorbitol (starch is fully hydrolyzed into glucose, then the product after hydrogenation), but due to incomplete hydrolysis and / or the sugar that has glucose, can also comprise other sugar alcohols, for example mannitol, maltitol and long-chain hydrogenated sugar, and these other sugar alcohols also play the effect of wetting agent in this case.

[0043] In certain embodiments, the oral care composition used for use according to this disclosure comprises an acceptable wetting agent in the oral cavity, including but not limited to polyols, such as glycerol, sorbitol, xylitol or low molecular weight PEG etc. Several wetting agents also play the effect of sweeteners. One or more wetting agents optionally exist in a total amount of 1 % by weight to 50 % by weight by the total weight of the composition. One or more wetting agents are selected from glycerol, sorbitol, xylitol, maltitol, propylene glycol, hexylene glycol, butylene glycol, erythritol, isomalt and combinations thereof. Transport enhancers:

[0044] The transport enhancer is selected to facilitate transport of the chelating agent through the body's tissues, extracellular matrix, and / or cell membranes. An "effective amount" of a transport enhancer means an amount and concentration in a formulation of the invention sufficient to significantly increase the permeation of the chelating agent through one or more sites of the oral cavity or teeth of a subject as compared to the absence of the transport enhancer in the formulation.

[0045] The concentration of the transport facilitator must be sufficient to transfer the chelating agent across the cell membrane. Therefore, the concentration or relative amount of the transport facilitator will be determined by the thickness of the cell membrane of the animal or human subject that ingests the formulation. In some embodiments, the concentration of MSM in the formulation of the present invention is from about 0.0001 wt.% to 30 wt.%, or from about 0.01 wt.% to about 0.10 wt.%, 1 wt.%, 5 wt.%, 10 wt.%, 20 wt.%, 30 wt.%, and preferably in the range of about 0.01 wt.% to 1.0 wt.%.

[0046] Transport enhancers generally have the formula (I) Where R 1 and R 2 Each independently selected from C2-C6 alkyl, C1-C6 heteroalkyl, C6-C 14 Arylalkyl and C2-C 12 heteroarylalkyl, any of which may be substituted, and Q is S or P. Where Q is S and R 1 and R 2 Compounds that are C1-C3 alkyl are preferred, with methylsulfonylmethane (MSM) being the best transport enhancer.

[0047] The phrase "having the formula" or "having the structure" is not intended to be limiting and is used in the same manner as the commonly used term "comprising". With respect to the above structure, the term "alkyl" refers to a linear, branched or cyclic saturated hydrocarbon group containing 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, etc. If not otherwise specified, the term "alkyl" includes unsubstituted and substituted alkyl groups, wherein the substituents may be, for example, halo, hydroxyl, mercapto, alkoxy, acyl, etc. The term "alkoxy" refers to an alkyl group bound by a single terminal ether bond; that is, an "alkoxy" group may be represented as -O-alkyl, wherein alkyl is as defined above. The term "aryl" refers to an aromatic substituent containing a single aromatic ring or multiple aromatic rings fused together, directly connected or indirectly connected (such that different aromatic rings are bound to a common group such as a methylene or ethylene moiety). Preferred aryl groups contain 5 to 14 carbon atoms. Exemplary aryl groups contain one aromatic ring or two fused or connected aromatic rings, for example, phenyl, naphthyl, biphenyl, diphenyl ether, diphenylamine, benzophenone, etc. "Aryl" includes unsubstituted and substituted aryl, wherein the substituent can be as described above about the "alkyl" group optionally substituted. The term "aralkyl" refers to an alkyl group with an aryl substituent, wherein "aryl" and "alkyl" are as defined above. Preferred aralkyl groups contain 6 to 14 carbon atoms, and particularly preferred aralkyl groups contain 6 to 8 carbon atoms. Examples of aralkyl groups include, but are not limited to: benzyl, 2-phenyl-ethyl, 3-phenyl-propyl, 4-phenyl-butyl, 5-phenyl-pentyl, 4-phenylcyclohexyl, 4-benzylcyclohexyl, 4-phenylcyclohexylmethyl, 4-benzylcyclohexylmethyl, etc. The term "acyl" refers to a substituent having the formula -(CO)-alkyl, -(CO)-aryl, or -(CO)-aralkyl, wherein "alkyl," "aryl," and "aralkyl" are as defined above. The terms "heteroalkyl" and "heteroaralkyl" are used to refer to heteroatom-containing alkyl and aralkyl groups, respectively, i.e., alkyl and aralkyl groups in which one or more carbon atoms are replaced by atoms other than carbon, such as nitrogen, oxygen, sulfur, phosphorus, or silicon, typically nitrogen, oxygen, or sulfur.

[0048] The formulation also includes an effective amount of a transport enhancer that promotes the penetration of formulation components through cell membranes, tissues, and extracellular matrices. An "effective amount" of a transport enhancer means a concentration sufficient to significantly increase the penetration of one or more formulation components through membranes, tissues, and extracellular matrices, as just described. Suitable transport enhancers include, for example, methylsulfonylmethane (MSM; also known as dimethyl sulfone), a combination of MSM and dimethyl sulfoxide (DMSO), or a combination of MSM and DMSO (a less preferred embodiment), with MSM being particularly preferred. DMSO is a transport enhancer, but is essentially a solvent and is not particularly suitable for formulations according to the present invention. DMSO is an efficient solvent and is therefore a carrier for its solutes. In contrast, MSM works in a completely different way, by forming hydrogen bonds with selected molecules and changing the charge characteristics of the target molecule, thereby enabling the target molecule to pass through charged barriers such as biological membranes.

[0049] There is a difference between the chemical structures of MSM and DMSO. Methylsulfonylmethane (MSM) is an organosulfur compound with the formula (CH3)2SO2. It is also known by several other names, including DMSO2, dimethyl sulfone, and dimethyl sulfone. This colorless solid has a sulfonyl functional group and is considered to be relatively chemically inert. MSM has the structure: On the other hand, dimethyl sulfoxide (DMSO) is an organic sulfur compound having the formula (CH3)2SO. This colorless liquid is a widely used polar aprotic solvent that can dissolve both polar and nonpolar compounds and is miscible with a wide range of organic solvents and water. DMSO has the structure:

[0050] MSM is an odorless, highly water-soluble (34% w / v at 79°F), white crystalline compound with a melting point of 108°C-110°C and a molecular weight of 94.1 g / mol. MSM is used herein as a multifunctional agent that not only increases the permeability of cell membranes, but also acts as a "transport enhancer" (TFA) to help transport one or more formulation components to oral tissues. In addition, MSM itself provides a pharmaceutical effect and can be used as an anti-inflammatory and analgesic agent. MSM can also improve oxidative metabolism in biological tissues and is a source of organic sulfur, which helps reduce scars. In addition, MSM also has unique and beneficial solubilizing properties because it is soluble in water (as described above), but due to the presence of polar S=O groups and non-polar methyl groups, MSM exhibits both hydrophilicity and hydrophobicity. The molecular structure of MSM also allows the formation of hydrogen bonds with other molecules, i.e., the oxygen atom of each S═O group forms hydrogen bonds with hydrogen atoms of other molecules, and allows the formation of van der Waals associations, i.e., the methyl groups form van der Waals associations with non-polar (e.g., hydrocarbon) fragments of other molecules. Chelating agents:

[0051] Chelation is the formation of a chemical bond with a metal in a complex where the metal is part of a ring. Organic ligands are called chelators or chelating agents, and chelates are metal complexes. The greater the number of ring closures on the metal atom, the more stable the compound. The stability of the chelate is also related to the number of atoms in the chelate ring. Monodentate ligands with one coordinating atom (such as H2O or NH3) are easily broken down by other chemical processes, while polydentate chelators can make multiple bonds with metal ions, providing a more stable complex. Chlorophyll (a green plant pigment) is a chelate composed of a central magnesium atom connected to four complexing chelators (pyrrole rings). Heme is an iron chelate containing an iron (II) ion in the center of the porphyrin. Chelating agents offer a variety of multivalent sequestering agents to control metal ions in aqueous systems. Chelating agents prevent undesirable interactions by forming stable, water-soluble complexes with multivalent metal ions, blocking the normal reactivity of the metal ions. EDTA (ethylenediaminetetraacetic acid) is a good example of a common chelating agent, having a nitrogen atom and a short chain carboxyl group.

[0052] For the purposes of the present invention, a chelating agent that is safe to ingest is suitable for preparing a composition that can be consumed by a subject who needs iron chelation. Examples of chelating agents for iron and calcium include, but are not limited to, diethylenetriaminepentaacetic acid (DTPA), ethylenediaminetetraacetic acid (EDTA), nitrilotriacetic acid (NTA), 1,3-propylenediaminetetraacetic acid (PDTA), ethylenediaminedisuccinic acid (EDDS), and ethylene glycoltetraacetic acid (EGTA). Any suitable chelating agent known in the art, as long as it is biosafe and can chelate iron, calcium or other metals, is suitable for use in the present invention.

[0053] The concentration of the chelator must be sufficient to allow the chelator to transfer across the cell membrane to access the intracellular iron. Therefore, the concentration of the chelator will be determined by the thickness of the cell membrane of the animal or human subject that ingests the formulation. For example, in an exemplary evaluation, rats were given free access to water containing 26 ppm (0.0026%) disodium EDTA, which is equivalent to 260 ppm (0.026%) after adjustment for human dosage. In some embodiments, the amount of transport enhancer present in the formulation of the present invention can be in the range of about 0.0001 wt.% to about 15 wt.%, typically in the range of about 0.001 wt.% to about 1 wt.%, and more typically in the range of about 0.10 wt.% to about 5 wt.%.

[0054] Compounds used as chelating agents herein include any compound that coordinates or forms a complex with a divalent or multivalent metal cation, thereby acting as a multivalent sequestering agent for such cations. Thus, the term "chelating agent" herein includes not only divalent and multivalent ligands (typically referred to as "chelators"), but also monovalent ligands that are capable of coordinating or forming a complex with a metal cation.

[0055] Suitable biocompatible chelating agents that can be used in conjunction with the present invention include, but are not limited to, monomeric polyacids such as EDTA, cyclohexanediaminetetraacetic acid (CDTA), N-(2-hydroxyethyl)ethylenediaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA), dimercaptopropanesulfonic acid (DMPS), dimercaptosuccinic acid (DMSA), aminotrimethylenephosphonic acid (ATPA), citric acid, pharmaceutically acceptable salts thereof, and combinations of any of the above. Other exemplary chelating agents include: phosphates such as pyrophosphates, tripolyphosphates, and hexametaphosphates, malic acid polymers, and the like.

[0056] EDTA and acceptable EDTA salts are particularly preferred, wherein representative acceptable EDTA salts are typically selected from diammonium EDTA, disodium EDTA, dipotassium EDTA, triammonium EDTA, trisodium EDTA, tripotassium EDTA and calcium disodium EDTA.

[0057] EDTA has been widely used as a metal chelator in biological tissues and blood, and has been suggested to be included in a variety of formulations. For example, U.S. Patent No. 6,348,508 to Denick Jr. et al. describes EDTA as a multivalent chelating agent to bind metal ions. In addition to being used as a chelating agent, EDTA is also widely used as a preservative to replace benzalkonium chloride, as described in, for example, U.S. Patent No. 6,211,238 to Castillo et al. Bowman et al. U.S. Patent No. 6,265,444 discloses the use of EDTA as a preservative and stabilizer. However, due to the poor permeability of EDTA to biological membranes, it is not usually used in any significant concentration formulation for topical application.

[0058] Among the chelating materials / sequestering materials that may be included in the composition, mention may be made of biocompatible chelating agents, including, but not limited to, monomeric polyacids such as EDTA, cyclohexanediaminetetraacetic acid (CDTA), N-(2-hydroxyethyl)ethylenediaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA), dimercaptopropanesulfonic acid (DMPS), dimercaptosuccinic acid (DMSA), aminotrimethylenephosphonic acid (ATPA), citric acid, pharmaceutically acceptable salts thereof, and combinations of any of the foregoing.

[0059] Other exemplary chelating agents include: phosphates such as pyrophosphate, tripolyphosphate, and hexametaphosphate. Other exemplary chelating agents include: phosphates such as pyrophosphate, tripolyphosphate, and hexametaphosphate; chelated antibiotics such as chloroquine and tetracycline; nitrogen-containing chelators containing two or more chelating nitrogen atoms within the imino group or in the aromatic ring (e.g., diimine, 2,2'-bipyridine, etc.); and polyamines such as cyclopentadiene (1,4,7,11-tetraazacyclotetradecane), N-(C1-C 30alkyl) substituted cyclamines (e.g., hexadecyclam, tetramethylhexadecylcyclamine), diethylenetriamine (DETA), spermine, diethylnorspermine (DENSPM), diethylhomospermine (DEHOP), deferoxamine (N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutanoyl}amino)pentyl]-N-hydroxysuccinamide, or N'-[5-(acetyl(hydroxy)amino]pentyl}- Desferrioxamine B, desferoxamine B, DFO-B, DFOA, DFB or desferal, deferiprone, pyridoxal isonicotinoyl hydrazone (PIH), salicylaldehyde isonicotinoyl hydrazone (SIH), ethane-1,2-bis(N-1-amino-3-ethylbutyl-3-thiol).

[0060] In addition, suitable biocompatible chelators useful in practicing the present disclosure include EDTA-4-aminoquinoline conjugates, such as ([2-(bis-ethoxycarbonylmethyl-amino)-ethyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-acetic acid ethyl ester, ([2-(bis-ethoxycarbonylmethyl-amino)-propyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-acetic acid ethyl ester, ([3-(bis-ethoxycarbonylmethyl-amino)-propyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-acetic acid ethyl ester, ([4-(bis-ethoxycarbonylmethyl-amino)-butyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-acetic acid ethyl ester. ethyl ester, ([2-(bis-ethoxymethyl-amino)-ethyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-ethyl acetate, ([2-(bis-ethoxymethyl-amino)-propyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-ethyl acetate, ([3-(bis-ethoxymethyl-amino)-propyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-ethyl acetate, ([4-(bis-ethoxymethyl-amino)-butyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-ethyl acetate as described in Solomon et al., Med. Chem. [Medicinal Chemistry] 2: 133-138, 2006.

[0061] In addition, natural chelating agents include but are not limited to citric acid, phytic acid, lactic acid, acetic acid and their salts. Other natural chelating agents and weak chelating agents include but are not limited to curcumin (turmeric), ascorbic acid, succinic acid and the like.

[0062] In some embodiments, the chelating agent is selected from the tetrasodium salt of iminodisuccinic acid ( CX100; LANXESS GMBH (formerly Bayer Chemicals), Leverkusen, Germany) or salts of polyaspartic acid (PASA- DS100; LANXESS, Leverkusen, Germany). In some embodiments, the chelating agent is tetrasodium L-glutamic acid N,N-diacetoacetate (GLDA- AkzoNobel (Netherlands).

[0063] In some embodiments, the chelating agent incorporated into the formulation is a pro-chelating agent. A pro-chelating agent is any molecule that can be converted to a chelating agent under appropriate chemical or physical conditions. For example, BSIH (isonicotinic acid [2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzylidene]-hydrazide) pro-chelating agent is converted by hydrogen peroxide to SIH (salicylic aldehyde isonicotinoyl hydrazone) iron chelating agent, which inhibits the generation of hydroxyl radicals catalyzed by iron.

[0064] Inactivated metal ion sequestrants are sometimes referred to herein as "prochelators," although chelation of metal ions may involve sequestration and complexation processes beyond sequestration itself. The term "prochelator" is similar to the term "prodrug" in that a prodrug is a therapeutically inactive agent prior to in vivo activation, and a prochelator must be activated in vivo to sequester metal ions. Preparations

[0065] A variety of methods can be used to prepare the compositions of the present invention. Techniques for preparation and administration can be found in: "Remington: The Science and Practice of Pharmacy" 23rd edition, edited by Adeboye Adejare; Academic Press; 23rd edition (November 13, 2020). For human or animal administration, the preparation should meet sterility, pyrogenicity, general safety and purity standards comparable to FDA requirements. Administration of pharmaceutical formulations can be carried out in a variety of ways, some of which are described herein.

[0066] Other possible additives for incorporation into at least partially aqueous formulations include, but are not limited to, thickeners, isotonicity agents, buffers, and preservatives, provided that any such excipients do not adversely interact with any other components of the formulation. It should also be noted that preservatives are generally not necessarily necessary, given that the selected chelating agent itself acts as a preservative.

[0067] The chelating agent and the penetrant are dissolved in a solvent selected from the following non-limiting list of solvents that can be used: water, ethanol, acetone, DMSO, isopropanol, glycerol, propylene glycol, polyethylene glycol, propylene carbonate, and ethyl acetate.

[0068] The oral care compositions used in the present disclosure contain significant levels of water. Water used to prepare commercial oral compositions should be deionized water and free of organic impurities. The amount of water in the composition includes the free water added plus the amount introduced with other materials.

[0069] Mouthwashes typically contain significant levels of ethanol, which is often needed to dissolve essential oils and prevent bacterial contamination. High levels of ethanol may be undesirable because, in addition to the potential for abuse through ingestion, ethanol may also aggravate conditions such as xerostomia. Thus, in some embodiments, the oral care compositions of the present invention are substantially free of ethanol, e.g., contain less than 1% ethanol or less than 0.1% ethanol.

[0070] In some embodiments, the oral care composition is a dentifrice comprising a humectant, e.g. selected from glycerol, sorbitol, propylene glycol, polyethylene glycol, xylitol and mixtures thereof, e.g. comprising at least 30%, e.g. 40%-50% glycerol by weight of the composition.

[0071] In some embodiments, the formulation further comprises an emulsifier, wherein the emulsifier is selected from the group consisting of gum arabic, modified starch, pectin, xanthan gum, gum ghatti, ghatti), tragacanth gum, fenugreek gum, sweet bean gum, mono- and diglycerides of long chain fatty acids, sucrose monoesters, sorbitan esters, polyethoxylated glycerol, stearic acid, palmitic acid, monoglycerides, diglycerides, propylene glycol esters, lecithin, lactated mono- and diglycerides, propylene glycol monoesters, polyglycerol esters, diacetylated tartaric acid monoglycerides and diglycerides, citric acid monoglycerides, stearoyl-2-lactate, polysorbates, succinic acid monoglycerides, acetylated monoglycerides, ethoxylated monoglycerides, quince bark, whey protein isolate, casein, soy protein, vegetable protein, pullulan, sodium alginate, guar gum, locust bean gum, tragacanth gum, tamarind gum, carrageenan, furcellaran, gellan gum, psyllium, curdlan, konjac mannan, agar, and cellulose derivatives, or combinations thereof.

[0072] In some embodiments, the beverage formulation further comprises a flavoring selected from the group consisting of vanilla, vanillin, ethyl vanillin, orange oil, peppermint oil, strawberry, raspberry, and mixtures thereof. The flavoring may also be other synthetic or natural flavors, or a combination thereof. Examples

[0073] The following examples are presented to provide a complete invention to those skilled in the art and to describe how to make and use the embodiments according to the invention, and are not intended to limit the scope of the inventor's discovery. Although every effort has been made to ensure the accuracy of the numbers used (e.g., amounts, temperatures, etc.), some experimental errors and deviations should still be considered. Unless otherwise stated, parts are parts by weight, molecular weight is weight average molecular weight, temperature is degrees Celsius, and pressure is or is close to atmospheric pressure. Measurement of xerostomia.

[0074] The physical examination focuses on the oral cavity, particularly any significant dryness (eg, whether the mucosa is dry, sticky, or moist; whether the saliva is foamy, thick, stringy, or normal in appearance), the presence of any lesions caused by Candida albicans, and the condition of the teeth.

[0075] The presence and severity of xerostomia can be assessed in several ways. For example, a tongue depressor can be placed against the buccal mucosa for 10 seconds. If the tongue depressor falls off immediately after release, salivary flow is considered normal. The more difficult it is to remove the tongue depressor, the more severe the xerostomia. In women, lipstick marks (i.e., lipstick adhered to the front teeth) may be a useful indicator of xerostomia.

[0076] If dryness is present, the submandibular, sublingual, and parotid glands should be palpated while observing the flow of saliva from the duct openings. The submandibular and sublingual openings are located in front of the base of the tongue, and the parotid opening is located in the middle of the inner cheek. It is helpful to wipe the duct openings dry with a square of gauze before palpation. If a graduated container is available, the patient can cough once to empty the mouth and then cough all the saliva into the container. Normal production is 0.3 to 0.4 mL / min. Significant xerostomia is 0.1 mL / min.

[0077] For patients in whom it is unclear whether xerostomia is present, sialometry can be performed by placing a collection device over the main duct opening and then stimulating saliva production with citric acid or by chewing paraffin. Normal parotid flow is 0.4 to 1.5 mL / min / gland. Flow monitoring can also help determine response to therapy. Clinical Evaluation I: Effects of LivFresh Dental Gel with Propylene Glycol on Saliva Production in Individuals with Mild to Moderate Xerostomia (Dry Mouth)

[0078] The aim of this study was to quantify the effects of a test dentifrice (LivFresh Dental Gel plus propylene glycol (Livionex, Los Gatos, CA, USA) on unstimulated and stimulated saliva production and oral comfort in four individuals with mild to moderate xerostomia over a 2-week period.

[0079] Overview: Baseline unstimulated and stimulated saliva production was measured over a 5-minute period over the next 3 days. Subjects then switched from their regular (non-Livionex) dentifrice to Dental gel plus propylene glycol (Livionex, Los Gatos, CA, USA) was applied twice daily for 2 minutes. Unstimulated and stimulated saliva were collected over 5 minutes on days 1, 2, 3, 7, and 14, and subjects completed an open-ended questionnaire at each visit regarding the effect of the dental gel on their dry mouth and overall oral comfort.

[0080] Materials and Methods: This study was conducted under UCI-approved IRB protocol #2013-9778, and all clinical procedures were performed in accordance with the Helsinki Declaration of 1975 (updated in 2013). No major changes were made to the study design after the start of the study. Rolling recruitment by advertisement was initiated in December 2021, and all study visits were completed by a single reviewer by the end of January 2022.

[0081] Subjects: Four patients were included in this study. They all met the following inclusion and exclusion criteria:

[0082] Inclusion criteria:

[0083] 1. Male or non-pregnant female, aged 18 years and above.

[0084] 2. Have at least 25 teeth.

[0085] 3. Willing and able to provide written informed consent.

[0086] 4. Willing and able to comply with study visits as described in the protocol.

[0087] 5. Follow-up can be done by telephone.

[0088] 6. Mild to moderate xerostomia diagnosed by a dentist

[0089] Exclusion criteria:

[0090] 1. Unable or unwilling to sign the informed consent form.

[0091] 2. Participated in any other clinical research within 30 days before inclusion in this study.

[0092] 3. Subjects who must undergo dental treatment during the study period.

[0093] 4. History of significant adverse reactions after using oral hygiene products such as toothpaste and mouthwash.

[0094] 5. Allergy to personal care / consumer products or their ingredients.

[0095] 6. Taking anti-inflammatory drugs or immunosuppressants in the past 3 months.

[0096] 7. The presence of any condition, abnormality, or circumstance at baseline that the principal investigator believes may affect the patient's ability to comply with study requirements.

[0097] Study Dentifrice: Test Dentifrice Used: LIVFRESH Dental -Update formulation (Livionex Inc., Los Gatos, CA, USA). Table 1: List of components and related functions of the tested dentifrices

[0098] Test plan

[0099] This single-center study was designed as a prospective study. Subjects performed baseline unstimulated and stimulated 5-minute saliva collections using standard techniques (see below) over the next 3 days, and then their regular oral hygiene regimen was changed to brushing twice a day with the test dentifrice for 2 minutes over a 14-day period. In addition to the 3 baseline days, saliva was collected on days 1, 2, 3, 7, and 14. At each visit, subjects completed an open-ended questionnaire about their oral dryness and overall feeling. Saliva was collected in a standard sealed container, labeled, and stored in a sealed bag in a refrigerator. At the end of the study, all samples were weighed using the same laboratory balance (Ohaus EX324N Explorer analytical balance) with an accuracy of 0.0002g.

[0100] Saliva collection was performed according to the University of Southern California School of Dentistry's saliva collection guidelines (https: / / jada(dot)ada(dot)org / article / S0002-8177(14)63880-0 / pdf).

[0101] Unstimulated whole saliva collection: Patients are advised to avoid any food or drink (except water) for one hour before the test session. Smoking, chewing gum, and coffee intake are also prohibited during this hour. Subjects are advised to rinse their mouths several times with deionized (distilled) water and then relax for five minutes.

[0102] Stimulated Whole Saliva-Gum Collection: Saliva collection was performed according to the following protocol:

[0103] 1. Instruct the subject to sit still.

[0104] 2. Instruct the subject to tilt his head forward over the funnel.

[0105] 3. Instruct the subject to swallow to empty the mouth of saliva (start time).

[0106] 4. Instruct the subject to chew the inert gum base to the rhythm of a metronome (approximately 70 times per minute).

[0107] 5. Every minute, ask the subject to spit saliva into the tube without swallowing. Tell the subject: "Spit it out, keep chewing" (after the first minute), "Spit it out, keep chewing" (after the second minute), etc. Discard the first two minutes of collection. Plastic or paper cups can be used for collection. Continue to collect for another 5 minutes. Save this sample for further analysis if necessary.

[0108] 6. Ask the patient to spit everything (ie, saliva and gum base) into the tube.

[0109] 7. Remove the gum base from the funnel and weigh the tube and funnel containing the saliva.

[0110] Evaluation criteria: Saliva samples were weighed using a calibrated laboratory balance (Ohaus EX324N Explorer analytical balance) with an accuracy of 0.0002 g. The subject's comments were recorded in a dedicated notebook.

[0111] Statistical Analysis: Sample weights were described using mean and standard deviation (SD). A repeated measures analysis of variance (ANOVA) model was used to analyze changes in the digital continuous weighing balance over time.

[0112] Saliva Collection: Table 2: Average saliva collected within 5 minutes

[0113] During the study period, both unstimulated (p=0.0045) and stimulated (p=0.00031) saliva collection increased significantly.

[0114] The mean unstimulated salivary flow rate (more closely associated with hyposalivation) was 0.16 ml / min at baseline and increased 7.9-fold to 1.25 ml / min after brushing with the test dental gel at day 14. An unstimulated salivary flow rate between 0.10 and 0.25 ml / min is generally considered a low salivary flow rate or moderate hyposalivation.

[0115] This study demonstrated that brushing twice daily with the test dental gel resulted in a large and highly significant increase in both unstimulated and stimulated saliva production after 2 weeks. These quantitative data were strongly supported by the comments of the subjects, who repeatedly stated that their mouths felt better and cleaner overall, and that brushing with the test dental gel, in particular, relieved their sensation of dry mouth.

[0116] All publications and patent applications cited in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[0117] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, those skilled in the art may readily make certain changes and modifications based on the teachings of the invention without departing from the spirit or scope of the appended claims.

Claims

1. A preparation comprising: Wetting agent; a penetration enhancer, the penetration enhancer being methylsulfonylmethane (MSM); one or more inert excipients; and a liquid vehicle or carrier; wherein the humectant and the penetration enhancer are present in a ratio effective to treat one or more symptoms of xerostomia and / or relieve dry mouth, and The percentage of the chelating agent is about 0.05% to 15%, and the percentage of the penetration enhancer in the composition is about 0.0001% to 30% by weight.

2. The formulation of claim 1, wherein the xerostomia is associated with a condition or disorder selected from the group consisting of Sjögren's syndrome, diabetes, rheumatoid arthritis, systemic lupus erythematosus, head and neck injuries resulting in salivary gland nerve damage, radiation and chemotherapy to the head and neck, smoking, and methamphetamine use.

3. The formulation of claim 1, wherein the xerostomia is a side effect associated with the use of a drug.

4. The formulation of claim 1, wherein the composition is selected from toothpaste, gel dentifrice, tooth powder, mouthwash, mouth rinse, tooth hardener, anticalculus composition, chewing gum, lozenge or a form suitable for applying the composition to oral surfaces, teeth or gums.

5. The formulation of claim 1, wherein the humectant is selected from one or more of glycerin, sorbitol, xylitol, maltitol, propylene glycol, hexylene glycol, butylene glycol, erythritol, isomalt, and combinations thereof.

6. The formulation of claim 4, wherein the humectant is propylene glycol.

7. The formulation of claim 1, wherein the chelating agent is selected from ethylenediaminetetraacetic acid (EDTA), ethylene glycol tetraacetic acid (EGTA), cyclohexanediaminetetraacetic acid (CDTA), hydroxyethylethylenediaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA), dimercaptopropanesulfonic acid (DMPS), dimercaptosuccinic acid (DMSA), aminotrimethylenephosphonic acid (ArPA), citric acid, acetic acid, and acceptable salts thereof, and any combination thereof.

8. The formulation of claim 12, wherein the EDTA salt is selected from diammonium EDTA, disodium EDTA, dipotassium EDTA, triammonium EDTA, trisodium EDTA, tripotassium EDTA, tetrasodium EDTA, tetrapotassium EDTA, calcium disodium EDTA, and combinations thereof.

9. The formulation of claim 1, wherein the chelating agent is selected from the group consisting of phosphates, pyrophosphates, tripolyphosphates and hexametaphosphates.

10. The formulation of claim 1, wherein the chelator is a nitrogen-containing chelator containing two or more chelating nitrogen atoms within an imino group or in an aromatic ring, a diimine, or a 2,2'-bipyridine.

11. The formulation of claim 1, wherein the chelating agent is a polyamine selected from the group consisting of cyclopentadienyl (1,4,7,11-tetraazacyclotetradecane), N-(C1-C 30 alkyl)-substituted cyclopentylamine (e.g., hexacyclopentylamine, tetramethylhexadecylcyclopentylamine), diethylenetriamine (DETA), spermine, diethylnorspermine (DENSPM), diethylhomospermine (DEHOP), deferrin (N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutanoyl}amino)pentyl]-N-hydroxysuccinamide, or N '-[5-(acetyl-hydroxy-amino)pentyl]-N-[5-[3-(5-aminopentyl-hydroxy-carbamoyl)propionylamino]pentyl]-N-hydroxy-succinamide), deferoxamine B, deferoxamine B, DFO-B, DFOA, DFB, desferrioxamine, deferiprone, pyridoxal isonicotinoyl hydrazone (PIH), salicylaldehyde isonicotinoyl hydrazone (SIH), ethane-1,2-bis(N-1-amino-3-ethylbutyl-3-thiol).

12. The formulation of claim 1, wherein the chelating agent is an EDTA-4-aminoquinoline conjugate selected from the group consisting of ([2-(bis-ethoxycarbonylmethyl-amino)-ethyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-ethyl acetate, ([2-(bis-ethoxycarbonylmethyl-amino)-propyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-ethyl acetate, ([3-(bis-ethoxycarbonylmethyl-amino)-propyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-ethyl acetate, ([4-(bis-ethoxycarbonylmethyl-amino)-butyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-ethyl acetate Ethyl ([2-(bis-ethoxymethyl-amino)-ethyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-ethyl acetate, ([2-(bis-ethoxymethyl-amino)-propyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-ethyl acetate, ([3-(bis-ethoxymethyl-amino)-propyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-ethyl acetate, ([4-(bis-ethoxymethyl-amino)-butyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-ethyl acetate.

13. The formulation of claim 1, wherein the chelating agent is the tetrasodium salt of iminodisuccinic acid.

14. The formulation of claim 1, wherein the chelating agent is polyaspartic acid or a salt thereof.

15. The formulation of claim 1, wherein the chelating agent is the tetrasodium salt of L-glutamic acid N,N-diacetoacetate.

16. The formulation of claim 1, wherein the chelating agent is a natural chelating agent selected from citric acid, phytic acid, lactic acid, acetic acid and salts thereof, and curcumin.

17. The formulation of claim 1, wherein the formulation further comprises an emulsifier, wherein the emulsifier is selected from the group consisting of gum arabic, modified starch, pectin, xanthan gum, gum ghatti, gum tragacanth, fenugreek gum, sweet bean gum, mono- and di-glycerides of long chain fatty acids, sucrose monoesters, sorbitan esters, polyethoxylated glycerol, stearic acid, palmitic acid, mono- and di-glycerides, propylene glycol esters, lecithin, lactated mono- and di-glycerides, propylene glycol monoesters, polyglycerol esters , diacetylated tartaric acid mono- and diglycerides, monoglyceride of citric acid, stearoyl-2-lactate, polysorbate, monoglyceride of succinate, acetylated monoglycerides, ethoxylated monoglycerides, quince bark, whey protein isolate, casein, soy protein, vegetable protein, pullulan, sodium alginate, guar gum, locust bean gum, tragacanth gum, tamarind gum, carrageenan, furcellaran, gellan gum, psyllium, curdlan, konjac mannan, agar, and cellulose derivatives, or combinations thereof.

18. The formulation of claim 1, wherein the concentration of the chelating agent is 0.002% to 0.1% w / v.

19. The formulation of claim 1, wherein the concentration of MSM is 0.005% to 3% w / v.

20. The formulation of claim 1, wherein the concentration of the wetting agent is 0.05% to 15% w / v.

21. The formulation of claim 1, further comprising an isotonic agent selected from the group consisting of a sugar, a buffer and sodium chloride.

22. The formulation of claim 1, further comprising a buffer.

23. The formulation of claim 1, wherein the composition can affect hydration loss in an area contacted by the composition.

24. The formulation of claim 1, wherein the composition increases the lubricity or lubricity of an area contacted by the composition.

25. A method of reducing hydration loss in oral tissue, the method comprising: The oral tissue is contacted with a composition according to any one of claims 1-24.

26. A method of increasing lubricity or lubricity in oral tissue, the method comprising: The oral tissue is contacted with a composition according to any one of claims 1-24.

27. A method of alleviating the effects of xerostomia, dry mouth, or both, the method comprising: The oral tissue is contacted with a composition according to any one of claims 1-24.

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