Novel oral care formulations for the treatment of xerostomia - Patent Application 20070233633

Abstract

Formulations are provided for the treatment of xerostomia and relief of dry mouth symptoms.The formulations include a humectant (e.g., propylene glycol), a chelating agent (e.g., EDTA and its salts) and a transport enhancer (e.g., methylsulfonylmethane (MSM)).

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Application No. 63 / 329,355, filed April 8, 2022, entitled "Novel Oral Care Formulations for the Treatment of Xerostomia," the contents of which are incorporated herein by reference in their entirety.

[0002] FIELD OF THEINVENTION The present invention generally relates to the field of drugs that treat xerostomia and relieve the symptoms of dry mouth. In particular, the present invention relates to oral care formulations that include a humectant, a transport enhancer, and a chelating agent. In one exemplary embodiment, the present invention relates to oral care formulations that include MSM as a transport enhancer and a Generally Regarded as Safe ("GSRS") chelating agent. [Background technology]

[0003] Xerostomia is dry mouth caused by a reduction or absence of saliva flow. The condition can cause discomfort, interfere with speech and swallowing, make dentures difficult to wear, cause halitosis, and impair oral hygiene by causing a decrease in oral pH and increased bacterial growth. Long-term xerostomia can lead to severe tooth decay (caries) and oral candidiasis (chronic mucocutaneous candidiasis (CMC)). Xerostomia is a common condition in the elderly, affecting approximately 20% of the elderly population.

[0004] Dry mouth is a growing problem. As people get older, they take more medications. Approximately 2,000 drugs are known to cause dry mouth. 75% of prescription drugs and many over-the-counter (OTC) drugs have dry mouth as a side effect. The most common include anticholinergics, antiparkinsonians, antineoplastics (chemotherapy), antihypertensives, antianxiety drugs and antidepressants. As a result, approximately 70 million people have dry mouth, including one in three people over the age of 45.

[0005] Chemotherapy drugs can cause severe dryness and mouth sores while they are being taken, but these problems usually subside when treatment is stopped. Other common drug classes that cause xerostomia include antihypertensives, antianxiety medications, and antidepressants (selective serotonin reuptake inhibitors (SSRIs) are less severe than tricyclic antidepressants).

[0006] The increased use of illegal methamphetamine has led to an increased incidence of severe dental caries and periodontal inflammation in female mice caused by methamphetamine-induced xerostomia. The damage is exacerbated by drug-induced teeth grinding and clenching, along with increased intake of sugary beverages and poor oral hygiene under the influence of the drug. This combination causes rapid tooth destruction. Smoking also causes a decrease in saliva.

[0007] Some 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 trauma resulting in damage to the nerves of the salivary glands. Head and neck cancer, where radiation and chemotherapy are used, is another cause of dry mouth. Smoking usually causes a decrease in saliva. The increase in illegal methamphetamine use has led to an increase in the incidence of female mice, a severe form of tooth decay caused by methamphetamine-induced xerostomia. The damage is exacerbated by the grinding and clenching of teeth caused by the drug, and by the heat of the inhaled vapor.

[0008] With regard to the increasing elderly population and addictive use of drugs, the numerous negative side effects associated with salivary dysfunction will present medical, social and economic problems in the near future not only for the individuals themselves but also for society.

[0009] Problems caused by dry mouth include difficulty swallowing and eating, difficulty speaking due to dry vocal cords, dry throat, sore throat and mouth, cracked lips, dry tongue and dry mouth. In addition to these physical problems, dry mouth leads to increased risk of oral health problems such as cavities, gingivitis (inflammation of the gums), periodontitis (inflammation of the gums that can lead to tooth loss), stomatitis, fungal infections in the mouth and bad breath. Therefore, it is important to know 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 when the etiology is unclear and a possible systemic disorder is considered, further evaluation with a minor salivary gland biopsy (to detect Sjögren's syndrome, sarcoidosis, amyloidosis, TB, or cancer) and HIV testing should be performed. The lower lip is an appropriate site for biopsy. More information on xerostomia is available at www.merckmanuals.com / professional / dental-disorders / symptoms-of-dental-and-oral-disorders / xerostomia (accessed April 2, 2022).

[0011] The lack of moisture and lubrication typically provided by saliva has a variety of adverse effects on oral tissues (soft tissues), ranging from mild discomfort to extremely painful and infectious stomatitis. Persistent discomfort and dryness can also contribute to larger health problems by causing disruption of sleep, reduced ability to speak (which can affect sociability, mental health) and ability to eat (which can affect nutrition). Dry buccal tissue is a less effective barrier and more susceptible to penetration of physical irritants such as toxins and carcinogens in food, beverages and tobacco.

[0012] Saliva is also the mouth's primary defense against dental caries. Healthy saliva production helps prevent caries by physically removing bacteria from the oral cavity before they can attach to tooth and tissue surfaces and form a protective biofilm. Saliva production also helps dilute sugars and acids that are introduced with the ingestion of food and beverages. Its buffering capacity neutralizes acids and aids in the progression of digestion. The presence of calcium and phosphate provides a continuing opportunity for remineralization of tooth enamel, helping to reverse the progression of dental caries.

[0013] Many people with xerostomia use separate 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 formats and include viscous gels / pastes, sprays, rinses, mints and time-release tablets. They are applied multiple times a day or as needed for comfort. For hard tissue health, various treatments are used to directly address caries prevention (antiseptic rinses, fluoride products, calcium / phosphate treatments). Often, "dry mouth friendly" type products are recommended, such as toothpastes and mouth rinses. Dry mouth friendly products typically have a neutral pH and do not contain alcohol or other irritating ingredients (e.g., anionic surfactants or emulsifiers).

[0014] Various commonly available oral care compositions, such as toothpastes and mouth rinses, are primarily based on the cleaning ability of surfactants, soaps and / or detergents, along with mild abrasives. Some formulations add antibacterial agents, such as TRICLOSAN® or stannous fluoride, to enhance antiplaque action.

[0015] Formulations containing a transport enhancer (e.g., MSM) and a chelating agent (e.g., EDTA) have recently been shown to dramatically reduce plaque formation and be used for the prevention and treatment of adverse oral conditions and disorders (Bhushan et al., WO 2013 / 166459; Bhushan et al., WO 2014 / 100775; Bhushan et al., U.S. Pat. No. 9,616,008). A dental treatment product containing MSM and a chelating agent in accordance with the disclosures of the above patent applications is available commercially as LIVIONEX® Dental Gel.

[0016] Humectants are used in oral care products to prevent toothpaste from hardening when exposed to air, or in mouthwashes to improve moisture retention and mouthfeel and to increase the compatibility of poorly soluble ingredients such as flavor oils.

[0017] Propylene glycol is a small organic alcohol commonly used in toothpaste as a humectant. Propylene glycol is used in dental care products, such as toothpaste, to keep the product free of unwanted bacteria, yeast and mold (COLGATE®).

[0018] It would be desirable to design a single product that effectively and simply addresses the need for dry mouth relief (soft tissue comfort) and preventative oral hygiene benefits (cavity prevention). Summary of the Invention

[0019] It has been observed in accordance with the present invention that oral care products comprising a transport enhancer (e.g., MSM) and a chelating agent (e.g., EDTA), which show a dramatic reduction in plaque formation and are used for the prevention and treatment of adverse oral conditions and disorders (as described in Bhushan et al., WO 2013 / 166459; Bhushan et al., WO 2014 / 100775; Bhushan et al., U.S. Pat. No. 9,616,008), have shown the unexpected and surprising effect of a substantial and highly significant increase in unstimulated and stimulated saliva production, as well as a reduction in the sensation of dry mouth in subjects.

[0020] The invention provides formulations that include a humectant (e.g., the humectant is 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 U.S. Food and Drug Administration (FDA) GRAS (Generally Regarded as Safe) list, where the chelating agent is suitable for chronic intake; a penetration enhancer that is methylsulfonylmethane (MSM); one or more inert additives; and a liquid vehicle or carrier, wherein the chelating agent and penetration enhancer are present in a ratio effective to maintain improved iron ion levels in the body when taken in normal doses, and wherein the percentage of the wetting agent is about 0.5% to about 15.0% by weight, the percentage of the chelating agent is about 0.0001% to 15% by weight, and the percentage of the penetration enhancer is about 0.0001% to 0% by weight.

[0022] In one aspect of the present invention, the formulation can be administered in any suitable form, including paste, gel, solid and particulate solid, such as various toothpastes, gel dentifrices, dentifrices, chewing gums, tablets and lozenges.In addition, in certain embodiments, the formulation is completely composed of naturally occurring and / or GRAS ("Generally Regarded as Safe") components by the United States 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 present invention comprises a therapeutically effective amount of a wetting agent, a therapeutically effective amount of a chelating agent, and a composition comprising a compound represented by the following formula (I): [ka] (I) [In the formula, R 1 and R 2 are independently optionally substituted; C 2 ~C 6 Alkyl, C 1 ~C 6 Heteroalkyl, C 6 ~C 14 Aralkyl and C 2 ~C 12 heteroaralkyl, and Q is S or P. The method includes administering to a subject an effective amount of a formulation comprising an effective amount of a transport-enhancing agent having the formula:

[0025] Transport enhancers include, for example, methylsulfonylmethane (MSM; methylsulfone, dimethylsulfone, and DMSO 2 (also referred to as "non-linear").

[0026] The chelating agent may 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, pyrophosphates, metaphosphates, 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 preferred embodiments considered in conjunction with the following drawings, in which changes and modifications can be effected without departing from the spirit and scope of the novel concepts of the present disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0028] The terms used herein generally have their ordinary meaning in the art, within the context of the present invention and in the specific context in which each term is used. Certain terms used to describe the present invention are discussed below or elsewhere in this specification to provide further guidance to the practitioner regarding 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 does not affect the scope and meaning of the term, which is the same in the same context whether or not it is highlighted. It is understood that the same thing can be said in more than one way. Thus, alternative words and synonyms may be used for one or more of the terms discussed herein, and do not have any special meaning whether or not the term is detailed or discussed. Synonyms of certain terms are provided. The detailed description of one or more synonyms does not exclude the use of other synonyms. The use of examples anywhere in this specification, including examples of any term described herein, is merely illustrative and does not limit the scope and meaning of the present invention or any exemplified term in any way. Similarly, the present invention is not limited to the various embodiments provided herein.

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

[0030] When referring to a formulation component, the term used, e.g., "drug," is intended to encompass not only the specific molecular entity but also pharma- ceutically acceptable analogs thereof, including, but not limited to, salts, esters, amides, prodrugs, conjugates, active metabolites, and other such derivatives, analogs, and related compounds.

[0031] The terms "treat" and "treatment" as used herein refer to the administration of a drug or formulation to a clinically symptomatic human or animal suffering from an adverse condition, disorder or disease, to affect the reduction of the severity and / or frequency of symptoms, to eliminate the symptoms and / or their underlying causes, and / or to promote the amelioration or repair of damage. The terms "prevent" and "prevention" refer to the administration of a drug or composition to an individual without clinical symptoms who is predisposed to a particular adverse condition, disorder or disease, and thus relates to the prevention of the occurrence of the symptoms and / or their underlying causes. Unless otherwise stated, expressly or implicitly, in this specification, when the term "treatment" (or "treating") is used without reference to the possibility of prevention, it is intended to include prevention, such as "method of treating gingivitis" encompassing "method of preventing gingivitis".

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

[0033] "Pharmaceutically acceptable" means a substance that is not biologically or otherwise undesirable, e.g., the substance may be incorporated into the formulation of the present invention without causing undesirable biological effects or interacting in a deleterious manner with any of the other components of the dosage form formulation. However, when the term "pharmaceutically acceptable" is used to refer to a pharmaceutical excipient, it means that the excipient has met the necessary standards of toxicological and manufacturing testing and / or is included in the Inactive Ingredient Guide prepared by the U.S. Food and Drug Administration. As explained in more detail below, "pharmacologically active" (or simply "active"), as in the case of "pharmacologically active" derivatives or analogs, refers to derivatives or analogs that have the same type of pharmacological activity as the parent drug. As used herein, the terms "treat" and "treatment" refer to reducing the severity and / or frequency of symptoms, eliminating symptoms and / or underlying causes, preventing the occurrence of symptoms and / or their underlying causes, and improving or treating an undesirable condition or injury. Thus, for example, "treating" a subject includes the prevention of an adverse condition in a susceptible individual, as well as the treatment of an individual with a clinical condition by inhibiting or causing the regression of the condition. The term "chelating agent" (or "active agent") refers to a 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 pharma- ceutically acceptable derivatives of the active agents specifically described herein, including, but not limited to, salts, esters, amides, prodrugs, active metabolites, isomers, analogs, crystalline forms, hydrates, and the like. When the term "chelating agent" is used, or when a particular chelating agent is specifically identified, it should be understood that pharma-ceutically acceptable salts, esters, amides, prodrugs, active metabolites, isomers, analogs, and the like of the agent are intended, as well as the agent itself.

[0034] An "effective" amount or a "therapeutically effective" amount of an active agent refers to a non-toxic, but sufficient amount of the agent to provide a beneficial effect. The amount of an active agent that is "effective" will vary from subject to subject, depending on the age and general condition of the individual, the particular active agent, and the like. Unless otherwise indicated, a "therapeutically effective" amount as used herein is intended to include an amount effective to prevent an adverse condition and / or ameliorate an adverse condition, i.e., an amount effective to treat an adverse condition, as well as an amount effective to prevent an adverse condition and / or ameliorate an adverse condition.

[0035] As will be apparent to one of skill in the art upon reading this specification, each of the individual embodiments described and illustrated herein has distinct elements and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the invention. Any described method may be carried out in the order of events described or in any other order which is logically possible.

[0036] Unless otherwise indicated, the present invention is not limited to particular formulation components, modes of administration, chelating agents, or manufacturing processes, etc., as such may vary.

[0037] Unless otherwise defined, 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 pertains. In case of conflict, the present specification, including definitions, will control.

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

[0039] The lack of moisture and lubrication typically provided by saliva has a variety of adverse effects on oral tissues (soft tissues), ranging from mild discomfort to highly painful and infectious stomatitis. Persistent discomfort and dryness can also contribute to larger health problems by causing sleep disturbance, impaired ability to speak (which can affect sociability, mental health) and ability to eat (which can affect nutrition). Dry buccal tissue is a less effective barrier and more susceptible to penetration of physical irritants, such as toxins and carcinogens in food, beverages and tobacco. There remains a need for compositions that improve the relief of xerostomia.

[0040] Humectants are hygroscopic substances that attract and hold moisture from their surroundings by absorption and draw water vapor to their surface. Commonly used humectants include: Commonly used humectants include: Hyaluronic acid: This is a molecule found naturally in the body, but becomes less abundant in the body with age. Glycerin: Also called glycerin or glycerol, glycerin is a clear substance that occurs naturally in animal and plant tissues, including human tissue. Most glycerin in cosmetics is made from soy and sugar cane. Alpha hydroxy acids (AHAs): Alpha hydroxy acids, such as glycolic acid, lactic acid, and citric acid, are acids that are naturally derived from fruit and lactose. Along with drawing in water, glycolic acid comes from sugar cane, lactic acid from milk, and citric acid from citrus fruits.

[0041] The oral care formulation of the present invention comprises one or more humectants. Exemplary useful humectants may include, for example, glycerol, sorbitol, xylitol, maltitol, propylene glycol, hexylene glycol, butylene glycol, erythritol, isomalt, or combinations thereof. Humectants such as xylitol, erythritol, or combinations thereof may be particularly useful because they provide benefits and moisturizing properties to hard tissues of the oral cavity. In the disclosed formulation, one or more humectants may be present in an amount of 5% or more by total weight of the formulation, or 7% or more by total weight of the formulation. In the disclosed formulation, one or more humectants may be present in an amount of 15% or less by total weight of the formulation, or 12% or less by total weight of the formulation.

[0042] Humectants can improve the viscosity, mouthfeel and sweetness of the formulation, and can help protect the formulation from degradation or microbial contamination.Suitable humectants include edible polyhydric alcohols, such as glycerin, sorbitol, xylitol, propylene glycol, and other polyols, as well as mixtures of these humectants.Sorbitol can be provided as hydrogenated starch hydrolysates in the form of syrups, which in some cases contain mainly sorbitol (the product when starch is completely hydrolyzed to glucose and then hydrogenated), but due to incomplete hydrolysis and / or the presence of sugars other than glucose, it can also contain other sugar alcohols, such as mannitol, maltitol, and longer chain hydrogenated sugars, which in this case also function as humectants.

[0043] In some embodiments, the oral care composition for use according to the present disclosure comprises an orally acceptable humectant, including but not limited to polyhydric alcohols such as glycerin, sorbitol, xylitol or low molecular weight PEG. Some humectants also function as sweeteners. The one or more humectants are optionally present in an amount of 1% to 50% by weight based on the total weight of the composition. The one or more humectants are selected from glycerol, sorbitol, xylitol, maltitol, propylene glycol, hexylene glycol, butylene glycol, erythritol, isomalt, and combinations thereof.

[0044] Transport enhancers: The transport enhancer is selected to enhance the transport of the chelating agent through bodily tissues, extracellular matrices and / or cell membranes. An "effective amount" of a transport enhancer refers to an amount and concentration within a formulation of the invention sufficient to provide a measurable increase in the permeation of the chelating agent through one or more sites of the oral cavity or teeth in a subject compared to the absence of the transport enhancer in the formulation.

[0045] The concentration of the transport enhancer must be sufficient to carry the chelating agent across the cell membrane.The concentration or relative amount of the transport enhancer is therefore determined by the thickness of the cell membrane in the animal or human subject that ingests the formulation.In some embodiments, the concentration of MSM present in the formulation ranges from about 0.0001% to 30% by weight, or from about 0.01% to about 0.10, 1, 5, 10, 20, 30% by weight, preferably from about 0.01% to 1.0% by weight.

[0046] The transport enhancer generally has the formula (I): [ka] (I) [In the formula, R 1 and R 2 are independently optionally substituted; C 2 ~C 6 Alkyl, C 1 ~C 6Heteroalkyl, C 6 ~C 14 Aralkyl and C 2 ~C 12 heteroaralkyl, and Q is S or P. Q is S and R 1 and R 2 C 1 ~C 3 Compounds that are alkyl are preferred, with methylsulfonylmethane (MSM) being the transport enhancer of choice.

[0047] The phrases "having the formula" or "having the structure" are not intended to be limiting and are used in the same manner as the term "comprising" is commonly used. With respect to the above structures, the term "alkyl" refers to a saturated hydrocarbon group, straight, branched, or cyclic, containing 1-6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, cyclopentyl, cyclohexyl, and the like. Unless otherwise indicated, the term "alkyl" includes unsubstituted and substituted alkyl, where the substituents may be, for example, halo, hydroxyl, sulfhydryl, alkoxy, acyl, and the like. The term "alkoxy" contemplates an alkyl group attached through a single terminal ether bond; i.e., an "alkoxy" group may be represented as -O-alkyl, where 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 bonded, or indirectly bonded (such that different aromatic rings are bonded with 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 linked aromatic rings, such as phenyl, naphthyl, biphenyl, diphenylether, diphenylamine, benzophenone, and the like. "Aryl" includes unsubstituted and substituted aryl, where the substituents can be as described above for the optionally substituted "alkyl" groups. The term "aralkyl" refers to an alkyl group having an aryl substituent, where "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 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, and the like.The term "acyl" refers to a substituent having the formula -(CO)-alkyl, -(CO)-aryl, or -(CO)-aralkyl, where "alkyl", "aryl", and "aralkyl" are as defined above. The terms "heteroalkyl" and "heteroaralkyl" are used to refer to heteroatom-containing alkyl and heteroatom-containing aralkyl groups, respectively, i.e., alkyl and aralkyl groups in which one or more carbon atoms have been replaced with an atom 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 enhances the penetration of the formulation components through cell membranes, tissues and extracellular matrices. An "effective amount" of a transport enhancer refers to a concentration sufficient to provide a measurable increase in the penetration of one or more of the formulation components through membranes, tissues and extracellular matrices, as described immediately above. Suitable transport enhancers include, for example, methylsulfonylmethane (MSM; also referred to as methylsulfone), a combination of MSM and dimethylsulfoxide (DMSO), or a combination of MSM and, in a less preferred embodiment, DMSO, with MSM being particularly preferred. DMSO acts as a very strong solvent and therefore acts as a carrier for its solutes. In contrast, MSM acts in a completely different manner by forming hydrogen bonds with selected molecules and changing the charge characteristics of the target molecules, allowing them to pass through charged barriers such as biological membranes.

[0049] There is a difference in chemical structure between MSM and DMSO. Methylsulfonylmethane (MSM) has the formula (CH 3 ) 2 SO 2 It is an organosulfur compound with the formula: 2 It is known by several other names, including methyl sulfone, methyl sulfone, and dimethyl sulfone. This colorless solid is characterized by a sulfonyl functional group and is considered relatively chemically inert. MSM has the following structure: [ka] On the other hand, dimethyl sulfoxide (DMSO) is a compound with the formula (CH 3 ) 2 DMSO is an organosulfur compound with the molar ratio of 1:1. This colorless liquid is a widely used polar aprotic solvent that dissolves both polar and nonpolar compounds and is miscible in a wide range of organic solvents and water. DMSO has the following structure: [ka]

[0050] MSM is an odorless, extremely water-soluble (34% w / v at 79°F), white crystalline compound with a melting point of 108-110°C and a molecular weight of 94.1 g / mol. MSM functions as a multifunctional agent herein insofar as it not only increases cell membrane permeability but also functions as a "transport enhancer" (TFA) aiding in the transport of one or more formulation components to oral tissues. Additionally, MSM itself can provide medicinal benefits and function as an anti-inflammatory and analgesic agent. MSM is also a source of organic sulfur that acts to improve oxidative metabolism in living tissues and aids in scar reduction. MSM further possesses unique and beneficial solubilizing properties in that, although soluble in water as described above, it exhibits both hydrophilic and hydrophobic properties due to the presence of a polar S=O group and a non-polar methyl group. The molecular structure of MSM also allows for the formation of hydrogen bonds with other molecules, i.e., between the oxygen atom of each S=O group and the hydrogen atoms of other molecules, and van der Waals bonds, i.e., between the methyl groups and non-polar (e.g., hydrocarbon) portions of other molecules.

[0051] Chelating Agents: Chelation is the chemical bonding of a metal in a complex where the metal is part of a ring. The organic ligand is called a chelator or chelating agent, and the chelate is a metal complex. The more rings closed to 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. H 2 O and NH 3Monodentate ligands with one coordination atom such as are easily decomposed by other chemical processes, whereas multidentate chelators offering multiple bonds to the metal ion provide more stable complexes. Chlorophyll, the green plant pigment, is a chelate consisting of a central magnesium atom bound to four complex chelators (pyrrole rings). Heme is an iron chelate containing an iron(II) ion in a porphyrin center. Chelators provide a wide range of metal sequestrants for controlling metal ions in aqueous systems. By forming stable water-soluble complexes with polyvalent metal ions, chelators prevent undesirable interactions by blocking the normal reactivity of the metal ion. EDTA (ethylenediaminetetraacetic acid) is a good example of a common chelator with a nitrogen atom and a short-chain carboxyl group.

[0052] For the purpose of the present invention, being safe to consume is suitable for formulating a composition that can be consumed by subjects who need iron chelation.Examples of iron and calcium chelating agents include, but are not limited to, diethylenetriaminepentaacetic acid (DTPA), ethylenediaminetetraacetic acid (EDTA), nitrilotriacetic acid (NTA), 1,3-propylenediaminetetraacetic acid (PDTA), ethylenediaminedisuccinic acid (EDDS) and ethyleneglycoltetraacetic acid (EGTA).Any suitable chelating agent known in the art that is biologically safe and can chelate iron, calcium or other metals is suitable for the present invention.

[0053] The concentration of the chelating agent must be sufficient to transport the chelating agent across the cell membrane to access intracellular iron. Thus, the concentration of the chelating agent is determined by the thickness of the cell membrane in the animal or human subject ingesting the formulation. For example, in an exemplary evaluation, rats were administered drinking water containing 26 ppm (0.0026%) disodium EDTA (equivalent to 26 ppm (0.0026%) in humans) ad libitum. In some embodiments, the transport enhancer may be present in the formulation of the present invention in an amount ranging from about 0.0001% to about 15% by weight, typically ranging from about 0.001% to about 1% by weight, more typically ranging from about 0.10% to about 5% by weight.

[0054] Compounds useful as chelating agents herein include compounds that coordinate or complex with divalent or polyvalent metal cations and thus function as metal sequestering agents for such cations.Thus, the term "chelating agent" herein includes not only divalent and polyvalent ligands (typically referred to as "chelating agents"), but also monovalent ligands that can coordinate or complex with metal cations.

[0055] Suitable biocompatible chelating agents useful in connection 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, pharma- ceutically acceptable salts thereof, and any combination thereof.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, with representative acceptable EDTA salts typically selected from diammonium EDTA, disodium EDTA, dipotassium EDTA, triammonium EDTA, trisodium EDTA, tripotassium EDTA and calcium disodium EDTA.

[0057] EDTA is widely used as a substance for chelating metals in biological tissues and blood, and has been suggested for inclusion in various formulations. For example, U.S. Patent No. 6,348,508 to Denick Jr. et al. describes EDTA as a sequestering agent that binds metal ions. In addition to its use as a chelating agent, EDTA is also widely used as a preservative, replacing benzalkonium chloride, as described, for example, in U.S. Patent No. 6,211,238 to Castillo et al. U.S. Patent No. 6,265,444 to Bowman et al. discloses the use of EDTA as a preservative and stabilizer. However, EDTA is not generally applied topically in formulations of significant concentration due to its poor permeability through biological membranes.

[0058] Among the chelating / metal-entrapping substances that may be included in the composition may be 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, pharma- ceutical acceptable salts thereof, and any combination thereof.

[0059] Other exemplary chelating agents include phosphates, such as pyrophosphate, tripolyphosphate, and hexametaphosphate; chelating antibiotics, such as chloroquine and tetracycline; nitrogen-containing chelating agents that contain two or more chelating nitrogen atoms in an imino group or in an aromatic ring (e.g., diimines, 2,2'-bipyridine, etc.); and polyamines, such as cyclam (1,4,7,11-tetraazacyclotetradecane), N-(C 1 ~C 30 alkyl)-substituted cyclams (e.g., hexadecyclam, tetramethylhexadecylcyclam), 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) [5-[3-(5-aminopentyl-hydroxy-carbamoyl)propanoylamino]pentyl]-N-hydroxy-butanediamide; also known as desferrioxamine B, desferoxamine B, DFO-B, DFOA, DFB, desferal), deferiprone, pyridoxal isonicotinoyl hydrazone (PIH), salicylaldehyde isonicotinoyl hydrazone (SIH), ethane-1,2-bis(N-1-amino-3-ethylbutyl-3-thiol).

[0060] Suitable biocompatible chelating agents that may be useful in the practice of the present disclosure also include EDTA-4-aminoquinoline conjugates, e.g., Solomon et al., Med. Chem. 2: 133-138, 2006, ([2-(bis-ethoxycarbonylmethyl-amino)-ethyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-acetic acid ester, ([2-(bis-ethoxycarbonylmethyl-amino)-propyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-acetic acid ester, ([3-(bis-ethoxycarbonylmethyl-amino)-propyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-acetic acid ester, ([4-(bis-ethoxycarbonylmethyl-amino)-butyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-acetic acid ester, ([2-(bis-ethoxymethyl-amino)-ethyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-acetic acid ester, ([2-(bis-ethoxymethyl-amino)-propyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-acetic acid ester, ([3-(bis-ethoxymethyl-amino)-propyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-acetic acid ester, ([4-(bis-ethoxymethyl-amino)-butyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-acetic acid ester.

[0061] Natural chelating agents also include, but are not limited to, citric acid, phytic acid, lactic acid, acetic acid and their salts. Other natural 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 (BAYPURE® CX100; LANXESS GMBH (formerly Bayer Chemicals), Leverkusen, DE) or the salt of poly-aspartic acid (PASA - BAYPURE® DS100; LANXESS GMBH, Leverkusen, DE). In some embodiments, the chelating agent is the tetrasodium salt of L-glutamic acid N,N-diacetic acid (GLDA - DISSOLVINE®, AkzoNobel, Netherlands).

[0063] In some embodiments, the chelating agent incorporated in the formulation is a prochelating agent.Prochelating agent is a molecule that is converted to a chelating agent when exposed to appropriate chemical or physical conditions.For example, BSIH (sonicotinic acid [2-(4,4,5,5-tetramethyl-[1,3,2] dioxaborolan-2-yl)-benzylidene]-hydrazide) prochelating agent is converted by hydrogen peroxide into SIH (salicylaldehyde isonicotinoyl hydrazone) iron chelating agent, which inhibits iron-catalyzed hydroxyl radical generation.

[0064] Inactivated metal ion sequestration agents are sometimes referred to herein as "prochelators," although metal ion sequestration may involve encapsulation and complexation processes beyond the scope of chelation itself. The term "prochelator" is similar to the term "prodrug," insofar as a prodrug is a therapeutically inactive drug until activated in vivo, and a prochelator similarly cannot sequester a metal until activated in vivo.

[0065] formulation The compositions of the present invention can be formulated using various means. Techniques for formulation and administration can be found in "Remington: The Science and Practice of Pharmacy", Twenty Third Edition, Adeboye Adejare, editor-in-chief; Academic Press; 23rd edition (November 13, 2020). For administration to humans or animals, the preparation must meet sterility, pyrogenicity, general safety and purity standards comparable to those required by the FDA. Administration of pharmaceutical preparations can be carried out in various 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, tonicity agents, buffers and preservatives, provided that any such additives do not interact in a harmful manner with any of the other components of the formulation.It should also be noted that preservatives are generally not necessary in light of the fact that the selected chelating agent itself functions as a preservative.

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

[0068] The oral care compositions used in this disclosure contain significant levels of water. The water used in the manufacture of commercial oral compositions must be deionized and free of organic impurities. The amount of water in the composition includes the free water added and the amount of water introduced with other materials.

[0069] Mouthwash often contains a significant level of ethanol, which is often required to solubilize essential oils and prevent bacterial contamination.High levels of ethanol may be undesirable, because ethanol can worsen conditions such as xerostomia, in addition to the potential for abuse through ingestion.Therefore, in some embodiments, the oral care composition of the present invention is substantially free of ethanol, for example, contains 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 glycerin, sorbitol, propylene glycol, polyethylene glycol, xylitol, and mixtures thereof, e.g., at least 30% by weight, e.g., 40-50% by weight, of glycerin based on the weight of the composition.

[0071] In some embodiments, the formulation further comprises an emulsifier, the emulsifier being selected from the group consisting of gum arabic, modified starch, pectin, xanthan gum, gum ghatti, gum tragacanth, gum fenugreek, gum mesquite, mono- and diglycerides of long chain fatty acids, sucrose monoesters, sorbitan esters, polyethoxylated glycerol, stearic acid, palmitic acid, monoglycerides, diglycerides, propylene glycol esters, lecithin, emulsifying mono- and di-glycerides, propylene glycol monoesters, polyglycerol esters, mono- and di-glycerides. diacetylated tartaric acid esters, citrate esters of monoglycerides, stearoyl-2-lactate, polysorbates, succinylated monoglycerides, acetylated monoglycerides, ethoxylated monoglycerides, quillaja, 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 agent selected from the group consisting of vanilla, vanillin, ethyl vanillin, orange oil, peppermint oil, strawberry, raspberry, and mixtures thereof. The flavoring agent may also be other synthetic or natural flavors, or combinations thereof. EXAMPLES

[0073] The following examples are presented to provide those of ordinary skill in the art with a complete invention and description of how to make and use embodiments according to the invention, and are not intended to limit the scope of what the inventors regard as their discoveries. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation must be accounted for. Unless otherwise indicated, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric.

[0074] Measuring xerostomia The physical examination will focus on the oral cavity, specifically any apparent dryness (e.g., whether the mucosa is dry, sticky, or moist; whether the saliva is foamy, thick, stringy, or normal in appearance), the presence of 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 held against the buccal mucosa for 10 seconds. If the tongue depressor falls off immediately when released, saliva production is considered normal. The more difficult it is to remove the tongue depressor, the more severe the xerostomia. In women, the lipstick sign, where lipstick is stuck to the front teeth, can be a useful indicator of xerostomia.

[0076] If dryness is suspected, the submandibular, sublingual and parotid glands should be palpated while observing the duct openings for saliva secretion. The openings are at the anterior base of the tongue for the submandibular and sublingual glands and at the center of the inside of the cheek for the parotid gland. Drying the duct openings with gauze before palpation aids observation. If a graduated container is available, the patient may expectorate once to empty the mouth and then expectorate all the saliva into the container. Normal output is 0.3-0.4 mL / min. Significant xerostomia is 0.1 mL / min.

[0077] For patients in whom the presence of xerostomia is unknown, sialography can be performed by placing a collection device over the major duct orifice and then stimulating saliva production with citric acid or by chewing on paraffin. Normal parotid flow rates are 0.4 to 1.5 mL / min / gland. Flow observations can also help determine response to treatment.

[0078] Clinical Evaluation I: Effect of LivFresh Dental Gel Containing Propylene Glycol on Saliva Production in Individuals with Mild to Moderate Xerostomia (Dry Mouth) This study aimed to quantify the effects of a test dentifrice (LivFresh Dental Gel plus Propylene Glycol (Livionex, Los Gatos, CA, USA)) on non-stimulating and stimulated saliva production and oral comfort over a 2-week period in four individuals with mild to moderate xerostomia.

[0079] Summary: Baseline unstimulated saliva production for 5 min was measured followed by stimulated saliva production over 3 days. Subjects then switched from regular (non-Livionex) dentifrice to brushing their teeth for 2 min twice daily with LIVFRESH® Dental Gel plus Propylene Glycol (Livionex, Los Gatos, CA, USA). Unstimulated and stimulated saliva was collected for 5 min on days 1, 2, 3, 7 and 14 and subjects completed an open-ended questionnaire regarding the effect of the dental gel on dry mouth and overall oral comfort at each visit.

[0080] Materials and Methods: This study was conducted according to UCI-approved IRB protocol #2013-9778, and all clinical procedures were performed in accordance with the Declaration of Helsinki of 1975, updated in 2013. There were no major changes to the study design after study initiation. Ongoing recruitment through advertisements began in December 2021, and all study visits were completed by one investigator by the end of January 2022.

[0081] Subjects: Four patients were enrolled in this study. All patients met the following inclusion and exclusion criteria:

[0082] Inclusion Criteria:

[0083] 1. Men or non-pregnant women aged 18 or older.

[0084] 2. A minimum of 25 teeth are present.

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

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

[0087] 5. Telephone follow-up is available.

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

[0089] Exclusion criteria:

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

[0091] 2. Participation in any other clinical trial within the past 30 days prior to enrollment in this study.

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

[0093] 4. History of significant adverse effects after use of oral hygiene products, e.g. toothpaste and mouthrinse.

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

[0095] 6. Anti-inflammatory or immunosuppressant medications in the past 3 months.

[0096] 7. The presence of any condition, abnormality or situation at baseline that, in the opinion of the Investigator, may affect the patient's ability to comply with the study requirements.

[0097] Test Dentifrice: Test dentifrice used: LIVFRESH Dental Gel® - Latest Formulation (Livionex, Los Gatos, Calif., USA). [Table 1]

[0098] Test procedure

[0099] This single-center study was designed as a prospective study. Subjects underwent baseline unstimulated and then stimulated 5-min saliva collections for 3 days using standard techniques (see below), then replaced their usual oral hygiene regimen with brushing their teeth for 2 minutes twice daily for 14 days. In addition to the 3-day baseline, saliva was collected on days 1, 2, 3, 7, and 14. At each visit, subjects completed an open-ended questionnaire regarding perceived dryness of the mouth and overall sensation. Saliva was collected in standard sealed containers, labeled, and stored in sealed bags in the refrigerator. All samples were weighed on the same laboratory scale (Ohaus EX324N Explorer Analytical Balance) accurate to 0.0002 g at the end of the study.

[0100] Saliva collection was performed in accordance with the University of Southern California School of Dentistry guidelines for saliva collection (https: / / jada.ada.org / article / S0002-8177(14)63880-0 / pdf).

[0101] Collection of unstimulated whole saliva: Patients are instructed to refrain from consuming any food or beverages (except water) for 1 hour prior to the test session. Smoking, chewing gum, and coffee are prohibited during this time. Subjects are instructed to rinse their mouths several times with deionized water (distilled water) and then relax for 5 minutes.

[0102] Stimulated whole saliva collection - gum: Saliva collection was performed according to the following procedure:

[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 clear saliva from the mouth (start time).

[0106] 4. Instruct the subject to chew the inert gum base at a metronome pace (approximately 70 strokes / min).

[0107] 5. At 1 minute intervals, ask the subject to spit saliva into the tube without swallowing. Tell the subject "Spit it out and keep chewing" (after 1 minute), "Spit it out and keep chewing" (after 2 minutes), etc. Discard the first 2 minutes of collection. A plastic or paper cup can be used for this collection. Proceed with another 5 minute collection. If necessary, save this sample for analysis.

[0108] 6. Ask the patient to expectorate everything (i.e., both saliva and gum base) into the tube.

[0109] 7. After the gum base is removed from the tube, the tube and funnel containing the saliva are weighed.

[0110] Evaluation criteria: Saliva samples were weighed using a calibrated laboratory scale (Ohaus EX324N Explorer Analytical Balance) with an accuracy of 0.0002 g. Subjects' comments were recorded in a dedicated notebook.

[0111] Statistical analysis: Sample weights were reported with mean and standard deviation (SD). Changes over time in the digital continuous weighing scale were analyzed using a repeated measures analysis of variance (ANOVA) model.

[0112] Saliva collection: [Table 2]

[0113] Unstimulated (p=0.0045) and stimulated (p=0.00031) saliva collections increased significantly over the study period.

[0114] The mean unstimulated salivary flow rate (which correlates more closely with hyposalivation) was 0.16 ml / min at baseline and increased 7.9-fold to 1.25 ml / min by day 14 with brushing with the test dental gel. Unstimulated salivary flow rates of 0.10 to 0.25 ml / min are generally considered to be indicative of low or moderate hyposalivation.

[0115] The study showed substantial and significant increases in unstimulated and stimulated saliva production after brushing twice daily for two weeks with the test dental gel. These quantitative data were strongly supported by the subject comments, all of whom repeatedly stated that their mouths felt better and cleaner overall, and specifically that the sensation of dry mouth was reduced by brushing with the test dental gel.

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

[0117] Although the foregoing invention has been described in some detail by way of illustration and example, for purposes of clarity of understanding, it will be readily apparent to those skilled in the art in light of the teachings of this invention that certain changes and modifications can be made without departing from the spirit or scope of the appended claims.

Claims

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

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

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

4. 10. The formulation of claim 1, wherein the composition is selected from a toothpaste, a dentifrice gel, a dentifrice powder, a mouthrinse, a mouthwash, a tooth hardener, an anti-calculus composition, a gum, a lozenge, or a form suitable for applying the composition to an oral surface, teeth, or gums.

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

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

7. 2. 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. 13. 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. 2. The formulation of claim 1, wherein the chelating agent is selected from phosphate, pyrophosphate, tripolyphosphate and hexametaphosphate.

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

11. The chelating agent is cyclam (1,4,7,11-tetraazacyclotetradecane), N-(C 1 ~C 30 alkyl)-substituted cyclams (e.g., hexadecyclam, tetramethylhexadecylcyclam), 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]-N-hydroxysuccinamide] 2. The formulation of claim 1, wherein the polyamine is selected from the group consisting of N-[5-[3-(5-aminopentyl-hydroxy-carbamoyl)propanoylamino]pentyl]-N-hydroxy-butanediamide), desferrioxamine B, desferoxamine B, DFO-B, DFOA, DFB, desferal, deferiprone, pyridoxal isonicotinoyl hydrazone (PIH), salicylaldehyde isonicotinoyl hydrazone (SIH), and ethane-1,2-bis(N-1-amino-3-ethylbutyl-3-thiol).

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

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

14. 2. The formulation of claim 1, wherein the chelating agent is poly-aspartic acid or a salt thereof.

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

16. 2. 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 may further comprise an emulsifier, the emulsifier being selected from the group consisting of gum arabic, modified starch, pectin, xanthan gum, gum ghatti, gum tragacanth, gum fenugreek, gum mesquite, mono- and diglycerides of long chain fatty acids, sucrose monoesters, sorbitan esters, polyethoxylated glycerol, stearic acid, palmitic acid, monoglycerides, diglycerides, propylene glycol esters, lecithin, emulsified mono- and di-glycerides, propylene glycol monoesters, polyglycerol esters, diacetylated tartaric acid esters of mono- and di-glycerides.

10. The formulation of claim 1, wherein the cellulose is selected from the group consisting of: cellulose acetate, cellulose esters of monoglycerides, stearoyl-2-lactate, polysorbates, succinylated monoglycerides, acetylated monoglycerides, ethoxylated monoglycerides, quillaja, 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. 2. The formulation of claim 1, wherein the concentration of the chelating agent is from 0.002% w / v to 0.1% w / v.

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

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

21. 10. The formulation of claim 1, further comprising an isotonicity agent selected from sugars, buffers and sodium chloride.

22. 10. The formulation of claim 1, further comprising a buffering agent.

23. The formulation of claim 1, wherein the composition is capable of affecting hydration loss in areas contacted by the composition.

24. 10. The formulation of claim 1, wherein the composition is capable of increasing the lubricity or smoothness of an area contacted by the composition.

25. 25. A method of reducing hydration loss in oral tissues comprising contacting the oral tissue with a composition according to any one of claims 1 to 24.

26. 25. A method of increasing lubrication or smoothness in oral tissues comprising contacting the oral tissues with a composition according to any one of claims 1 to 24.

27. 25. A method of reducing the effects of xerostomia, dry mouth, or both, comprising contacting oral tissue with a composition according to any one of claims 1 to 24.

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