Oral composition containing a receptor regulator

Abstract

The present disclosure provides a composition configured for oral use, the composition comprising at least one active ingredient, an ion channel modulator that binds to one or more receptors selected from at least one of TRPA1, TRPV1, TRPV3, TRPM8, NAV1.7, and combinations thereof, and at least one filler.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 355,201, filed on June 24, 2022, which is hereby incorporated by reference in its entirety for all purposes.

[0002] The present disclosure relates to compositions intended for human use. The compositions are adapted for oral use and are adapted to deliver substances such as nicotine, flavor, and / or active ingredients during use. Such compositions may include tobacco, or products derived from tobacco, or may be tobacco - free alternatives.

Background Art

[0003] There are many categories of products intended for oral use and enjoyment. For example, oral tobacco products containing nicotine. Nicotine is known to have both stimulant and anxiolytic properties and has been available for many years. Conventional forms of so-called smokeless tobacco products include moist snuff, snus, and chewing tobacco, which are typically formed almost entirely of particulate, granular, or shredded tobacco and which are either portioned by the user or provided to the user in individual portions such as disposable pouches or sachets. See, for example, the types, components, and processing methods of smokeless tobacco formulations described in U.S. Patent Nos. 6,668,839 to Williams; 6,834,654 to Williams; 6,953,040 to Atchley et al.; 7,032,601 to Atchley et al.; 7,694,686 to Atchley et al.; 7,810,507 to Dube et al.; 7,819,124 to Strickland et al.; 7,861,728 to Holton, Jr. et al.; 7,901,512 to Quinter et al.; 8,627,828 to Strickland et al.; and 11,246,334 to Atchley, each of which is incorporated herein by reference.

[0004] In addition, conventional tobacco and non-tobacco materials are combined with other ingredients to form product forms that are distinct from conventional smokeless products, examples of which include lozenges, pastilles, gels, etc. For example, see U.S. Patent Application Publication Nos. 2008 / 0196730 to Engstrom et al.; 2008 / 0305216 to Crawford et al.; 2009 / 0293889 to Kumar et al.; 2010 / 0291245 to Gao et al.; 2011 / 0139164 to Mua et al.; 2012 / 0037175 to Cantrell et al.; 2012 / 0055494 to Hunt et al.; 2012 / 0138073 to Cantrell et al.; 2012 / 0138074 to Cantrell et al.; 2013 / 0074855 to Holton, Jr.; 2013 / 0074856 to Holton, Jr.; 2013 / 0152953 to Mua et al.; 2013 / 0274296 to Jackson et al.; 2015 / 0068545 to Moldoveanu et al.; 2015 / 0101627 to Marshall et al.; and 2015 / 0230515 to Lampe et al., each of which is incorporated herein by reference for the types of products described therein.

[0005] There is a continuing interest in the development of new types of oral products that deliver beneficial sensory or biological activities. Such products typically contain flavoring agents and / or active ingredients such as nicotine, caffeine, botanicals or cannabidiol. The forms of such products can be diverse and include pouch products containing powdered or granular compositions, lozenges, pastilles, liquids, gels, emulsions, meltable compositions, and the like. See, for example, U.S. Patent Application Publication Nos. 2022 / 0160675 to Gerardi et al.; 2022 / 0071984 to Poole et al.; 2021 / 0378948 to Gerardi et al.; 2021 / 0330590 to Hutchens et al.; 2021 / 0186081 to Gerardi et al.; 2021 / 0177754 to Keller et al.; 2021 / 0177043 to Gerardi et al.; 2021 / 0177038 to Gerardi et al.; 2021 / 0169867 to Holton, Jr. et al.; 2021 / 0169792 to Holton, Jr. et al.; 2021 / 0169132 to Holton, Jr. et al.; 2021 / 0169121 to St. Charles and 2021 / 0169122 to St. Charles, each of which is incorporated herein by reference for the types of products described therein.

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

Patent Document 6

Problems to be Solved by the Invention

[0007] (Summary of the Invention) Oral products, such as those containing nicotine with a matrix, are used by sandwiching the product between the cheek and the gum. Active ingredients in the oral product, such as nicotine, are then released from the product, absorbed through the oral mucosa, thereby entering the bloodstream and circulating systemically. Desirable sensory attributes are an important factor for oral products that consumers will accept. Some consumers may prefer oral products that "imitate" exactly the oral and throat sensations brought about by tobacco-containing products, or oral products that result in a reduction in the oral and throat sensations brought about by tobacco-containing products or provide an alternative to such oral and throat sensations. For example, it may be desirable to provide oral products having a variety of sensory attributes, such as flavor, intensity / quality, impact, stimulation, smoothness, and benefit. It has been found by the present disclosure that including in the oral product a regulator of certain ion channels, such as those associated with feeling heat, cold, itching, or pain, can favorably affect the experience of users of the oral product, for example, by reducing the tingling or "intensely stimulating" sensations sometimes associated with nicotine-containing oral products.

Means for Solving the Problems

[0008] Accordingly, in one aspect, provided is a composition configured for oral use, the composition comprising at least one filler; at least one active ingredient selected from the group consisting of botanical materials, stimulants, amino acids, vitamins, antioxidants, dietary supplements, cannabinoids, cannabinimimetics, terpenes, pharmaceuticals, and combinations thereof; and an ion channel regulator selected from the group consisting of a TRPA1 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, a TRPV1 agonist, a TRPV3 agonist, a TRPM8 agonist, a NaV1.7 antagonist, a P2X3 antagonist, and combinations thereof.

[0009] In some embodiments, the ion channel modulator is selected from the group consisting of a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, and combinations thereof. In some embodiments, the ion channel modulator is (i) a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, or a combination thereof; and (ii) a TRPA1 antagonist or a TRPA1 channel blocker.

[0010] In some embodiments, the ion channel modulator is: (i) a TRPM8 agonist or a TRPV1 agonist; and (ii) a TRPA1 antagonist or a TRPA1 inhibitor. In some embodiments, the ion channel modulator is a TRPA1 antagonist or a TRPA1 channel blocker.

[0011] In some embodiments, the ion channel modulator is selected from the group consisting of caryophyllene oxide, alpha-ionone, phenethyl phenylacetate, gamma-dodecalactone, beta-caryophyllene, 2-hexenal, eucalyptol, L-menthol, 3-phenylpropyl homovanillate, benzyl cinnamate, beta-bulbonene, cinnamyl cinnamate, citronellyl acetate, hydroxy-alpha-sanshool, liquiritin, methyl-alpha-ionone, phytol, spathulenol, and combinations thereof.

[0012] In some embodiments, the ion channel modulator is a combination of benzyl cinnamate, caryophyllene oxide, and nootkatone. In some embodiments, the ion channel modulator is a combination of benzyl cinnamate, caryophyllene oxide, and alpha-ionone. In some embodiments, the ion channel modulator is a combination of benzyl cinnamate and caryophyllene oxide.

[0013] In some embodiments, the active ingredient comprises a basic amine functionality. In some embodiments, the active ingredient comprising a basic amine functionality is nicotine. In some embodiments, the composition comprises nicotine in an amount of about 0.001 to about 10% by weight, calculated as the free base, based on the total weight of the composition.

[0014] In some embodiments, at least one filler comprises a cellulose material. In some embodiments, the cellulose material comprises microcrystalline cellulose. In some embodiments, at least one filler further comprises a cellulose derivative in an amount of about 1% to about 3% by weight, based on the total weight of the composition. In some embodiments, the cellulose derivative is hydroxypropyl cellulose.

[0015] In some embodiments, the composition further comprises an organic acid, an alkali metal salt of the organic acid, or a combination thereof. In some embodiments, the alkali metal is sodium or potassium. In some embodiments, the composition comprises an organic acid and a sodium salt of the organic acid. In some embodiments, the ratio of the organic acid to the sodium salt of the organic acid is about 0.1 to about 10.

[0016] In some embodiments, the composition comprises about 0.05, about 0.1, about 1, about 1.5, about 2, or about 5 to about 10, about 15, or about 20 molar equivalents of an organic acid, an alkali metal salt thereof, or a combination thereof, relative to the active ingredient comprising a basic amine functionality, calculated as the amine free base. In some embodiments, the composition comprises about 2 to about 10 molar equivalents of an organic acid, an alkali metal salt thereof, or a combination thereof, relative to the active ingredient comprising a basic amine functionality, calculated as the amine free base.

[0017] In some embodiments, the organic acid has a logP value of about 1 to about 12. In some embodiments, the organic acid has a logP value of about 3 to about 12. In some embodiments, the organic acid has a logP value of about 3 to about 10. In some embodiments, the organic acid has a logP value of about 3 to about 8.

[0018] In some embodiments, the organic acid is an alkyl carboxylic acid, an aryl carboxylic acid, an alkyl sulfonic acid, an aryl sulfonic acid, or any combination thereof.

[0019] In some embodiments, the organic acid includes methyl, or a tocopherol monoester of a dicarboxylic acid, or a combination thereof. In some embodiments, the dicarboxylic acid is malonic acid, succinic acid, glutaric acid, adipic acid, fumaric acid, maleic acid, or a combination thereof. In some embodiments, the organic acid includes succinic acid tocopherol, succinic acid monomethyl, fumaric acid monomethyl, glutaric acid monomethyl, or a combination thereof.

[0020] In some embodiments, the organic acid includes octanoic acid, decanoic acid, benzoic acid, heptanesulfonic acid, or a combination thereof. In some embodiments, the organic acid includes lactic acid. In some embodiments, the organic acid includes benzoic acid. In some embodiments, the organic acid is benzoic acid, sodium benzoate, or a combination thereof.

[0021] In some embodiments, at least a portion of the active ingredient containing basic amine functionality associates with at least a portion of the organic acid or its alkali metal salt, and the association is in the form of a basic amine-organic acid salt, an ion pair between the basic amine and the conjugate base of the organic acid, or both forms.

[0022] In some embodiments, the pH of the composition is from about 4.0 to about 9.0. In some embodiments, the pH of the composition is from about 4.5 to about 7. In some embodiments, the pH of the composition is from about 5.5 to about 7. In some embodiments, here, the pH of the composition is from about 4.0 to about 5.5. In some embodiments, the pH of the composition is from about 7.0 to about 9.0.

[0023] In some embodiments, the composition further comprises a solubility enhancer. In some embodiments, the solubility promoter is glycerol, propylene glycol, or another wetting agent described herein.

[0024] In some embodiments, the composition comprises from about 10 to about 50 weight percent of at least one filler and from about 5 to about 60 weight percent of water, based on the total weight of the composition.

[0025] In some embodiments, the composition further comprises one or more flavoring agents, one or more salts, one or more sweeteners, one or more binders, one or more wetting agents, one or more gums, tobacco materials, or combinations thereof.

[0026] In some embodiments, the composition comprises less than about 10 weight percent of tobacco material, excluding the nicotine component present, based on the total weight of the composition. In some embodiments, the composition does not contain tobacco material.

[0027] In some embodiments, the composition is a composition encapsulated in a pouch to form a pouch product, optionally in granular form.

[0028] In some embodiments, the composition is in the form of a gel, pastille, gum, chewable, melt, tablet, lozenge, granular material, or powder.

[0029] The present disclosure includes, without limitation, the following embodiments.

[0030] Embodiment 1: A composition configured for oral use, comprising at least one active ingredient selected from the group consisting of botanical materials, stimulants, amino acids, vitamins, antioxidants, dietary supplements, cannabinoids, cannabinimimetics, terpenes, pharmaceuticals, and combinations thereof; an ion channel regulator selected from the group consisting of a TRPA1 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, a TRPV1 agonist, a TRPV3 agonist, a TRPM8 agonist, a NaV1.7 antagonist, a P2X3 antagonist, and combinations thereof; and at least one filler.

[0031] Embodiment 2: The composition according to Embodiment 1, wherein the ion channel regulator is selected from the group consisting of a TRPA1 agonist, a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, and combinations thereof.

[0032] Embodiment 3: The ion channel regulator is (i) a TRPM8 agonist, a TRPV1 agonist, a TRPV3 agonist, or a combination thereof, and (ii) a TRPA1 antagonist or a TRPA1 channel blocker and is the composition according to Embodiment 1.

[0033] Embodiment 4: The ion channel regulator is (i) a TRPM8 agonist or a TRPV1 agonist; and (ii) a TRPA1 antagonist or a TRPA1 channel blocker and is the composition according to Embodiment 1.

[0034] Embodiment 5: The composition according to Embodiment 1, wherein the ion channel regulator is a TRPA1 antagonist or a TRPA1 channel blocker.

[0035] Embodiment 6: The composition according to any one of Embodiments 1 to 5, wherein the active ingredient contains nicotine.

[0036] Embodiment 7: The composition according to embodiment 6, wherein nicotine is calculated as the free base and is present in an amount of about 0.001 to about 10% by weight based on the total weight of the composition.

[0037] Embodiment 8: The composition according to any one of embodiments 1 to 7, wherein at least one filler comprises a cellulose material.

[0038] Embodiment 9: The composition according to embodiment 8, wherein the cellulose material comprises microcrystalline cellulose.

[0039] Embodiment 10: The composition according to embodiment 8 or 9, wherein at least one filler further comprises a cellulose derivative in an amount of about 1% to about 3% by weight based on the total weight of the composition.

[0040] Embodiment 11: The composition according to embodiment 10, wherein the cellulose derivative is hydroxypropyl cellulose.

[0041] Embodiment 12: The composition according to any one of embodiments 1 to 11, further comprising one or more flavoring agents, one or more salts, one or more sweeteners, one or more binders, one or more wetting agents, one or more gums, tobacco materials, or combinations thereof.

[0042] Embodiment 13: The composition according to any one of embodiments 1 to 12, comprising about 10% by weight or less of tobacco material, excluding the nicotine component present, based on the total weight of the composition.

[0043] Embodiment 14: The composition according to any one of embodiments 1 to 12, which does not contain tobacco material.

[0044] Embodiment 15: The composition according to any one of embodiments 1 to 14, which is enclosed in a pouch to form a pouch product, and the composition is optionally in a granular form.

[0045] Embodiment 16: A composition according to any one of Embodiments 1 to 14, in the form of a gel, pastille, gum, chewable, meltable, tablet, lozenge, granular material or powder.

[0046] These and other features, aspects and advantages of the present disclosure will become apparent from a reading of the following "Detailed Description" in conjunction with the accompanying drawings, which are briefly described below. The present invention includes any two, three, four or more of the above embodiments, in any combination, as well as any combination of any two, three, four or more features or elements described in the present disclosure, whether or not such features or elements are explicitly combined in the description of a particular embodiment herein. Since the present disclosure is intended to be read as a whole, any separable feature or element of the present disclosure is intended to be combinable in any of its various aspects and embodiments, unless the context clearly dictates otherwise.

[0047] The aspects of the present disclosure have been described in such general terms above, and reference is now made to the accompanying drawings, which are not necessarily drawn to scale. These drawings are for illustrative purposes only and should not be construed as limiting the present disclosure.

Brief Description of the Drawings

[0048]

Figure 1

Detailed Description

[0049] The present disclosure will now be described more fully hereinafter with reference to these example embodiments thereof as described herein. These example embodiments are described so that this disclosure will be thorough and complete and will fully convey the scope thereof to those skilled in the art. In fact, the disclosure may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements.

[0050] As used herein and in the claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise.

[0051] References to “percent dry weight” or “dry weight basis” refer to weight based on the dry components (i.e., all components excluding water). References to “wet weight” refer to the weight of the mixture including water. Unless otherwise indicated, references to “percent weight” of a mixture reflect the total wet weight of the mixture (i.e., including water).

[0052] The present disclosure provides a composition configured for oral use that includes at least one active ingredient and one or more regulators of one or more of certain receptors associated with sensations such as hot, cold, pain, heat, salty, sweet, sour, bitter, and umami. According to the present disclosure, modulating one or more ion channel receptors including, but not limited to, TRPA1, TRPV1, TRPM8, P2X3, and NaV1.7 can improve the sensory properties experienced during the use of an oral product containing certain active ingredients such as nicotine, for example, by reducing sensations such as intense or tingling sensations that are often associated with such products.

[0053] Accordingly, provided herein is a composition configured for oral use, the composition comprising at least one active ingredient selected from the group consisting of botanical materials, stimulants, amino acids, vitamins, antioxidants, dietary supplements, cannabinoids, cannabinimimetics, terpenes, pharmaceuticals, and combinations thereof; an ion channel regulator selected from the group consisting of a TRPA1 agonist, a TRPA1 antagonist, a TRPA1 channel blocker, a TRPV1 agonist, a TRPV3 agonist, a TRPM8 agonist, a NaV1.7 antagonist, a P2X3 antagonist, and combinations thereof; and at least one filler. The relative amounts of the various components within the composition may vary and are typically selected to impart the desired sensory and performance characteristics to the composition. Exemplary individual components of the composition are further described hereinbelow.

[0054] Active ingredient The compositions disclosed herein include an active ingredient. As used herein, "active ingredient" refers to one or more substances belonging to any of the following categories: API (active pharmaceutical ingredient), food additives, natural pharmaceuticals, and naturally occurring substances that can have an effect on humans. Exemplary active ingredients include any component known to affect one or more biological functions in the body, such as a component that provides a pharmacological activity or other direct effect in the diagnosis, cure, alleviation, treatment or prevention of disease, or a component that affects the structure or any function of the human body (e.g., a component that imparts a stimulating effect on the central nervous system, has a tonic effect, an antipyretic or analgesic effect, or other useful effects on the body). In some embodiments, the active ingredient may be of the type commonly referred to as a dietary supplement, dietary food, "phytochemical" or "functional food". These types of additives are substances generally available from natural sources that, in the art, are not classified or regulated as drugs but provide one or more beneficial biological effects (e.g., health promotion, disease prevention, or other pharmaceutically active ingredients).

[0055] Non-limiting examples of active ingredients include those that fall into the categories of nicotine, botanical ingredients, stimulants, amino acids, and / or pharmaceutical, nutritional, and health-beneficial ingredients (e.g., vitamins such as B6, B12, and C, and / or cannabinoids such as tetrahydrocannabinol (THC) and cannabidiol (CBD)). Each of these categories is further described herein below. The specific selection of the active ingredient will vary depending on the desired flavor, texture, and desired properties of the particular product.

[0056] The specific percentage of the active ingredients present will vary depending on the desired properties of the particular product. Typically, the active ingredient or combination thereof is present at a total concentration of at least about 0.001% by weight of the composition, such as in the range of about 0.001% to about 30% by weight. In some embodiments, the active ingredient or combination of active ingredients is present at a concentration of about 0.1% w / w to about 10%, about 20%, or about 30% by weight, such as, for example, about 0.5% w / w to about 30% by weight, about 0.5% w / w to about 20% by weight, about 0.5% w / w to about 10% by weight, about 1% to about 10% by weight, or about 1% to about 5% by weight, based on the total weight of the composition. In some embodiments, the active ingredient or combination of active ingredients is present at a concentration of about 0.001%, about 0.01%, about 0.1%, or about 1% by weight, up to a maximum of about 20% by weight, such as, for example, about 0.001%, about 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.009%, about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, or about 0.9% to about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20% by weight, based on the total weight of the composition. Further suitable ranges for specific active ingredients are provided hereinbelow.

[0057] Active ingredients containing basic amine functionality In some embodiments, the compositions disclosed herein include, as an active ingredient, a substance containing a basic amine functionality. By "basic amine" is meant a molecule containing at least one basic amine functional group. Examples of basic amines include, but are not limited to, alkaloids. By "basic amine functionality" or "basic amine functional group" is meant a group containing a nitrogen atom having a lone pair of electrons. The basic amine functional group is bonded or incorporated into the molecule through one or more covalent bonds to the nitrogen atom. The basic amine may be a primary, secondary or tertiary amine, which means that the nitrogen holds one, two or three covalent bonds to carbon atoms. Because of the lone pair of electrons on the nitrogen atom, such amines are named "basic", which means that the lone pair of electrons is available for hydrogen bonding. The basicity of the basic amine (i.e., the electron density on the nitrogen atom and, as a result, the availability and strength of hydrogen bonding to the nitrogen atom) can be affected by the nature of neighboring atoms, the steric volume of the molecule, etc.

[0058] In some embodiments, the active ingredient containing a basic amine functionality is nicotine or a nicotine component. By "nicotine component" is meant any suitable form of nicotine (e.g., free base, salt or ion pair) for effecting oral absorption of at least a portion of the nicotine present. Nicotine is released from the composition and absorbed through the oral mucosa, thereby entering the bloodstream where it is circulated systemically.

[0059] When present in the composition, the source of nicotine may be diverse and may be natural or synthetic. Nicotine may be tobacco-derived (e.g., tobacco extract) or non-tobacco-derived (e.g., synthetic or obtained by other means). Most preferably, nicotine is present in nature and is obtained as an extract from Nicotiana species (e.g., tobacco). Nicotine may have the enantiomeric form of S(−)-nicotine, R(+)-nicotine, or a mixture of S(−)-nicotine and R(+)-nicotine. Most preferably, nicotine is in the form of S(−)-nicotine (e.g., in a form that is substantially all S(−)-nicotine) or a racemic mixture consisting mainly or predominantly of S(−)-nicotine (e.g., a mixture consisting of about 95 parts by weight of S(−)-nicotine and about 5 parts by weight of R(+)-nicotine). Most preferably, nicotine is utilized in a substantially pure form or an essentially pure form. A highly preferred nicotine utilized has a purity of greater than about 95 percent, more preferably greater than about 98 percent, and most preferably greater than about 99 percent on a weight basis.

[0060] Typically, the nicotine component is selected from the group consisting of nicotine free base, nicotine as an ion pair, and nicotine salts. In some embodiments, at least a portion of the nicotine is in its free base form. In some embodiments, at least a portion of the nicotine is present as a nicotine salt, as described hereinbelow, or at least a portion of the nicotine is present as an ion pair with at least a portion of an organic acid or its conjugate base.

[0061] Typically, the nicotine component (calculated as the free base) is present at a concentration of at least about 0.001% by weight of the composition, for example in the range of about 0.001% to about 10%. In some embodiments, the nicotine component, calculated as the free base, is present at a concentration of about 0.1% w / w to about 10% by weight, based on the total weight of the composition, for example, about 0.1% w / w, about 0.2% by weight, about 0.3% by weight, about 0.4% by weight, about 0.5% by weight, about 0.6% by weight, about 0.7% by weight, about 0.8% by weight, or about 0.9% by weight to about 1% by weight, about 2% by weight, about 3% by weight, about 4% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, or about 10% by weight. In some embodiments, the nicotine component, calculated as the free base, is present at a concentration of about 0.1% w / w to about 3% by weight, based on the total weight of the composition, for example, about 0.1% w / w to about 2.5% by weight, about 0.1% by weight to about 2.0% by weight, about 0.1% by weight to about 1.5% by weight, or about 0.1% by weight to about 1% by weight.

[0062] Botanical In some embodiments, the active ingredient includes a botanical component. As used herein, the term "botanical component" or "botanical" refers to any plant material or material derived from fungi, plant materials in their natural form, and plant materials derived from natural plant materials, such as extracts or isolates from plant materials, or processed plant materials (e.g., plant materials that have been subjected to heat treatment, fermentation, decolorization, or other processing processes that can alter the physical and / or chemical properties of the material). For the purposes of the present disclosure, "botanical" includes, but is not limited to, "herbaceous materials" (e.g., tea or tisane tea) that do not develop recalcitrant woody tissues and are often valued for their beneficial or sensory properties in the body. References to botanical materials as "non-tobacco" are intended to exclude tobacco materials (i.e., do not include any species of the genus Nicotiana).

[0063] When present, botanicals are typically present at a concentration of about 0.01% w / w to about 10% by weight, such as about 0.01% w / w, about 0.05% by weight, about 0.1% by weight, or about 0.5% to about 1% by weight, about 2% by weight, about 3% by weight, about 4% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, or about 10% by weight, about 11% by weight, about 12% by weight, about 13% by weight, about 14% by weight, or about 15% by weight, based on the total weight of the composition.

[0064] Botanical materials useful in the present disclosure may include, but are not limited to, any of the compounds and sources recited herein, including mixtures thereof. Certain botanical materials of this type are sometimes referred to as nutraceuticals, dietary supplements, "phytochemicals" or "functional foods". Certain botanicals as plant materials or their extracts have found use in traditional herbal medicine and are further described herein.

[0065] Non-limiting examples of non-tobacco botanical materials include acai berry (Euterpe oleracea martius), acerola (Malpighia glabra), alfalfa, allspice, angelica root, anise (e.g., star anise), annatto seeds, apple (Malus domestica), apricot oil, ashwagandha, Bacopa monniera, baobab, basil (Ocimum basilicum), bay, beavermint, beet root, bergamot, blackberry (Morus nigra), black cohosh, black pepper, black tea, blueberry, boldo (Peumus boldus), borage, chervil, chive, chlorophyll, chocolate, coriander, cinnamon (Cinnamomum cassia), citronella (Cymbopogon citratus), citrus fruits, clary sage, clove, coconut (Cocos nucifera), coffee, comfrey leaves and roots, coriander seeds, cranberry, cumin, curcumin, damiana, dandelion, Dorstenia arifolia, Dorstenia odorata, Echinacea, elderberry, elderflower, endive (Anethum graveolens), evening primrose, eucalyptus, fennel, feverfew, flax, Galphimia glaucaglauca), garlic, ginger (Zingiber officinale), ginkgo biloba, ginseng, goji berries, hydrastis, grape seeds, grapefruit, grapefruit rose (Citrus paradisi), soursop (Annona muricata), green tea, guarana, gotu kola (gutu kola), Japanese quince, hazel, asa, hibiscus flower (Hibiscus sabdariffa), honeybush, hops, amchazul, jambu (Spilanthes oleraceae), jasmine (Jasminum officinale), juniper berries (Juniperus communis), Kaempferia parviflora (Thai ginseng), kava, laurel, lavender, lemon (Citrus limon), lemon balm, lemongrass, licorice, lilac, shiitake mushroom, lutein, maca (Lepidium meyenii), mace, marjoram, matcha, milk thistle, mint (menthe), mulberry, Nardostachys chinensis, nutmeg, olive, oolong tea, orange (Citrus sinensis), oregano, papaya, paprika, mugwort, peppermint (Mentha piperita), pimento, potato peel, primrose, quercetin, quince, purple perilla, resveratrol, Rhizoma gastrodiae, Rhodiola, rooibos (red or green), rose hip (Rosa canina), rosemary, saffron, sage, St. John's wort, frankincense, salvia (Salvia officinalisofficinalis), celery, saw palmetto, Sceletium tortuosum, Schisandra, Silybum marianum, Skullcap, spearmint, Spikenard, Spirulina, slippery elm bark, high tannin sorghum bran, high tannin sorghum grain, Mentha spicata, Spirulina, star anise, birch bark, tarragon, thyme, chizhan, turmeric, Turnera aphrodisiaca, Prunus jamasakura, valerian, vanilla, Viola odorata, wild yam root, wintergreen, Withania somnifera, yacon root, yellow dock, yerba mate and yerba santa are mentioned without limitation.

[0066] Stimulant In some embodiments, the active ingredient comprises one or more stimulants. As used herein, the term "stimulant" refers to a substance that enhances the activity of the central nervous system and / or the body, for example, enhancing concentration, cognition, vitality, mood, wakefulness, etc. Non-limiting examples of stimulants include caffeine, theacrine, theobromine, and theophylline. Theacrine (1,3,7,9-tetramethyluric acid) is a purine alkaloid structurally related to caffeine and has stimulant, analgesic, and anti-inflammatory effects. The stimulants present may be natural, naturally derived, or fully synthetic. For example, certain botanical materials (guarana, tea, coffee, cocoa, etc.) may have stimulant effects due to the presence of, for example, caffeine or related alkaloids and are thus "natural" stimulants. "Naturally derived" means that the stimulant (e.g., caffeine, theacrine) is in a purified form outside of its natural (e.g., botanical) matrix. For example, caffeine can be obtained by extraction and purification from a botanical source (e.g., tea). "Fully synthetic" means that the stimulant is obtained from chemical synthesis. In some embodiments, the active ingredient comprises caffeine. In some embodiments, the active ingredient is caffeine. In some embodiments, caffeine is present in an encapsulated form. One example of encapsulated caffeine is Vitashure® available from Balchem Corp., 52 Sunrise Park Road, New Hampton, NY, 10958.

[0067] When present, the stimulant or combination of stimulants (e.g., caffeine, theacrine, and combinations thereof) is typically at a concentration of about 0.1% w / w to about 15% by weight, such as about 0.1% w / w, about 0.2% by weight, about 0.3% by weight, about 0.4% by weight, about 0.5%, about 0.6% by weight, about 0.7%, about 0.8% by weight, or about 0.9% by weight to about 1% by weight, about 2% by weight, about 3% by weight, about 4% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, about 10% by weight, about 11% by weight, about 12% by weight, about 13% by weight, about 14% by weight, or about 15% by weight, based on the total weight of the composition.

[0068] Amino acid In some embodiments, the active ingredient includes an amino acid. As used herein, the term "amino acid" refers to an organic compound containing each functional group of an amine (-NH2) and a carboxyl (-COOH) or a sulfonic acid (SO3H) along a side chain (R group) specific to each amino acid. The amino acid may be proteinogenic or non-proteinogenic. "Proteinogenic" means that the amino acid is one of the 20 naturally occurring amino acids found in proteins. Examples of proteinogenic amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. "Non-proteinogenic" means either that the amino acid is not naturally found in proteins or that it is not directly produced by cellular machinery (e.g., it is a product of post-translational modification). Non-limiting examples of non-proteinogenic amino acids include gamma-aminobutyric acid (GABA), taurine (2-aminoethanesulfonic acid), theanine (L-γ-glutamylethylamide), hydroxyproline, and beta-alanine.

[0069] When present, the amino acid or combination of amino acids (e.g., taurine, theanine, and combinations thereof) is typically in a concentration of about 0.1% w / w to about 15% by weight, such as about 0.1% w / w, about 0.2% by weight, about 0.3% by weight, about 0.4% by weight, about 0.5% by weight, about 0.6% by weight, about 0.7% by weight, about 0.8% by weight, or about 0.9% by weight to about 1% by weight, about 2% by weight, about 3% by weight, about 4% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, about 10% by weight, about 11% by weight, about 12% by weight, about 13% by weight, about 14% by weight, or about 15% by weight, based on the total weight of the composition.

[0070] Vitamins and Minerals In some embodiments, the active ingredient comprises a vitamin or combination of vitamins. As used herein, the term "vitamin" refers to an organic molecule (or set of related molecules) that is an essential micronutrient required for the proper functioning of metabolism in mammals. There are 13 vitamins required for human metabolism, which are vitamin A (as all-trans-retinol, all-trans-retinyl-ester, and all-trans-beta-carotene, and other provitamin A carotenoids), vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3 (niacin), vitamin B5 (pantothenic acid), vitamin B6 (pyridoxine), vitamin B7 (biotin), vitamin B9 (folic acid or folate), vitamin B12 (cobalamin), vitamin C (ascorbic acid), vitamin D (calciferol), vitamin E (tocopherols and tocotrienols), and vitamin K (quinone). In some embodiments, the active ingredient comprises vitamin C. In some embodiments, the active ingredient is a combination of vitamin C, caffeine, and taurine. In some embodiments, the active ingredient comprises one or more of vitamin B6 and B12. In some embodiments, the active ingredient comprises theanine and one or more of vitamin B6 and B12.

[0071] When present, the vitamin or combination of vitamins (e.g., vitamin B6, vitamin B12, vitamin E, vitamin C, or combinations thereof) is typically in a concentration of about 0.01% w / w to about 6% by weight, such as about 0.01% by weight, about 0.02% by weight, about 0.03% by weight, about 0.04% by weight, about 0.05% by weight, about 0.06% by weight, about 0.07% by weight, about 0.08% by weight, about 0.09% by weight, or about 0.1% w / w to about 0.2% by weight, about 0.3% by weight, about 0.4% by weight, about 0.5% by weight, about 0.6% by weight, about 0.7% by weight, about 0.8% by weight, about 0.9% by weight, or about 1% by weight, based on the total weight of the composition.

[0072] In some embodiments, the active ingredient includes vitamin A. In some embodiments, vitamin A is encapsulated. In some embodiments, the vitamin is vitamin B6, vitamin B12, vitamin E, vitamin C, or a combination thereof.

[0073] In some embodiments, the active ingredient includes a mineral. As used herein, the term "mineral" refers to an inorganic molecule (or set of related molecules) that is an essential micronutrient required for the proper functioning of multiple systems in mammals. Non-limiting examples of minerals include iron, zinc, copper, selenium, chromium, cobalt, manganese, calcium, phosphorus, sulfur, magnesium, and the like. In some embodiments, the active ingredient includes iron. Suitable sources of iron include, but are not limited to, ferrous salts such as ferrous sulfate and ferrous gluconate. In some embodiments, the iron is encapsulated.

[0074] In some embodiments, the active ingredient comprises calcium, magnesium, or a combination thereof. In some embodiments, calcium, magnesium, or a combination thereof are present as soluble salts of calcium and / or magnesium such that calcium ions and / or magnesium ions are present in the composition during use and are available in the user's oral cavity. Examples of salts include acetates, citrates, gluconates, lactates, nitrates, glycerophosphates, threonates, and the like. Other divalent metal cations, and salts thereof, may also be used, for example those containing copper or zinc.

[0075] In some embodiments, the presence of calcium ions and / or magnesium ions can enhance or reduce the activation of certain receptors (e.g., TRPA1). For example, see Zhao et al., Nature September 2020;585(7823):141-145, which suggests that TRPA1 exhibits a bimodal response to Ca ions with sensitization at low calcium ion concentrations and desensitization at high Ca ion concentrations. As an example, and without limitation, isirin (AG-3-5; 1-(2-hydroxyphenyl)-4-(3-nitrophenyl)-3,6-dihydropyrimidin-2-one), a synthetic super-agonist of TRPM8, induces a [Ca2+]-dependent response in a standard physiological solution at pH 7.3. However, raising the extracellular [H+] from pH 7.3 to approximately pH 6 abolished the response to isirin (Andersson et al., Journal of Neuroscience June 9, 2004, 24(23)5364-5369). The desired concentration of calcium ions or magnesium ions can vary depending on the desired effect. The desired concentration and resulting effect at a particular receptor can also affect, or be affected by, the pH and logP of the composition.

[0076] Cannabinoid In some embodiments, the active ingredient comprises one or more cannabinoids. As used herein, the term "cannabinoid" refers to a class of diverse natural or synthetic chemical compounds that act on cannabinoid receptors (i.e., CB1 and CB2) in cells that modify neurotransmitter release in the brain. Cannabinoids are cyclic molecules that exhibit certain properties such as the ability to easily cross the blood-brain barrier. Cannabinoids can be naturally occurring from plants (phytocannabinoids), such as cannabis, naturally occurring from animals (endocannabinoids), or artificially manufactured (synthetic cannabinoids). Cannabis species express at least 85 different phytocannabinoids, which can be divided into subclasses and include cannabigerol, cannabinchromene, cannabidiol, tetrahydrocannabinol, cannabinol and cannabinodiol, and other cannabinoids such as cannabigerol (CBG), cannabinchromene (CBC), cannabidiol (CBD), tetrahydrocannabinol (THC), cannabinol (CBN) and cannabinodiol (CBDL), cannabinocyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidiovalerate (CBDV), cannabinchromevarin (CBCV), cannabigerovalerate (CBGV), cannabigerol monomethyl ether (CBGM), cannabinolic acid, cannabidiolic acid (CBDA), cannabinol propyl variant (CBNV), cannabinotriol (CBO), tetrahydrocannabinolic acid (THCA) and tetrahydrocannabivarinic acid (THCV A).

[0077] In some embodiments, the cannabinoid is selected from the group consisting of cannabigerol (CBG), cannabinchromene (CBC), cannabidiol (CBD), tetrahydrocannabinol (THC), cannabinol (CBN) and cannabidiolic acid (CBDL), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabinchromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), cannabinerolic acid, cannabidiolic acid (CBDA), cannabinol propyl variant (CBNV), cannabinotriol (CBO), tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarinic acid (THCV A), and mixtures thereof. In some embodiments, the cannabinoid comprises at least tetrahydrocannabinol (THC). In some embodiments, the cannabinoid is tetrahydrocannabinol (THC). In some embodiments, the cannabinoid comprises at least cannabidiol (CBD). In some embodiments, the cannabinoid is cannabidiol (CBD). In some embodiments, the CBD is synthetic CBD.

[0078] In some embodiments, the cannabinoid (e.g., CBD) is added to the composition in the form of an isolate. The isolate is an extract from a plant such as cannabis, where the active material of interest (in this case a cannabinoid such as CBD) is present at a high purity, e.g., greater than 95%, greater than 96%, greater than 97%, greater than 98%, or approximately 99% purity.

[0079] In some embodiments, the cannabinoid is an isolate of CBD at high purity, and the amount of any other cannabinoid in the composition is about 1 wt% or less of the composition, e.g., about 0.5 wt% or less of the composition, e.g., about 0.1 wt% or less of the composition, e.g., about 0.01 wt% or less of the composition.

[0080] The selection of cannabinoids that may be present within the disclosed compositions and their specific percentages may vary depending on the desired flavor, texture, and other properties of the composition.

[0081] In some embodiments, the cannabinoid (e.g., CBD) is present in the composition at a concentration in the range of at least about 0.001% by weight of the composition, such as from about 0.001% to about 2% by weight of the composition. In some embodiments, the cannabinoid (e.g., CBD) is present in the composition at a concentration of about 0.1% to about 1.5% by weight, based on the total weight of the composition. In some embodiments, the cannabinoid (e.g., CBD) is present in the oral composition at a concentration of about 0.4% to about 1.5% by weight, based on the total weight of the oral composition.

[0082] As an alternative to or in addition to cannabinoids, the active ingredient may include cannabinimetics, which are a class of compounds derived from plants other than cannabis and have biological effects on the endocannabinoid system similar to cannabinoids. Examples include yangonin, alpha - amyrin or beta - amyrin (also classified as terpenes), cyanidin, curcumin (turmeric), catechin, quercetin, salvianolic acid A, N - acyl ethanolamine, and N - alkylamide lipids. Such compounds can be used in the same amounts and ranges as specifically noted herein for cannabinoids.

[0083] Terpenes Active ingredients suitable for use in the present disclosure may also be classified as terpenes, many of which are associated with biological effects, such as a sedative effect. Terpenes have the general formula (C5H8) nIt is understood to have and contain monoterpenes, sesquiterpenes and diterpenes. Terpenes can be acyclic, monocyclic or bicyclic in structure. Some terpenes confer potentiating effects when used in combination with cannabinoids or cannabinimimetics. Examples include beta-caryophyllene, linalool, limonene, beta-citronellol, linalyl acetate, (alpha or beta) pinene, geraniol, carvone, eucalyptol, menthone, iso-menthone, piperitone, myrcene, beta-bulbonene and germacrene, which may be used alone or in combination.

[0084] In some embodiments, the terpene can be a terpene derived from a phytocannabinoid-producing plant such as a plant from the cannabis sativa species line such as hemp. Suitable terpenes in this regard include so-called "C10" terpenes, which are terpenes containing 10 carbon atoms, and so-called "C15", which are terpenes containing 15 carbon atoms. In some embodiments, the active ingredient contains more than one terpene. For example, the active ingredient can contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more terpenes as defined herein. In some embodiments, the terpene is selected from pinene (alpha and beta), geraniol, linalool, limonene, carvone, eucalyptol, menthone, iso-menthone, piperitone, myrcene, beta-bulbonene, germacrene, and mixtures thereof.

[0085] Antioxidant In some embodiments, the active ingredient comprises one or more antioxidants. As used herein, the term "antioxidant" refers to a substance that prevents or inhibits oxidation by terminating free radical reactions, and a substance that can retard or prevent some types of cell damage. Antioxidants may be naturally occurring or synthetic. Naturally occurring antioxidants include those found in foods and botanical materials. Non-limiting examples of antioxidants include certain botanical materials, vitamins, polyphenols, and derivatives of phenol.

[0086] Examples of botanical materials with antioxidant properties include, but are not limited to, acai berry, purple udo palm, allspice, annatto seed, apricot oil, basil, bee balm, yerba mate, black pepper, blueberry, blackcurrant seed oil, chervil, cinnamon, dark chocolate, potato peel, grape seed, carrot, ginkgo, St. John's wort, saw palmetto, green tea, black tea, black cohosh, cayenne, chamomile, clove, cocoa powder, cranberry, dandelion, grapefruit, honeybush, purple aster, garlic, knotweed, white lettuce, ginger, golden seal, Japanese quince, hibiscus flower, amacha, kava, lavender, licorice, marjoram, thistle, mint, oolong tea, beetroot, orange, oregano, papaya, pennyroyal, peppermint, red clover, rooibos (red or green), rose hip, rosemary, sage, clary sage, celery, spearmint, spirulina, nettle tea, high-tannin sorghum bran, high-tannin sorghum grain, urushi bran, the leaves and roots of hirahariso, the fruit of kukko, gotu kola, thyme, turmeric, Japanese lacquer tree, St. John's wort, wild yam root, wintergreen, the root of yacon, nagabagishigishi, yerba mate, yerba santa, Bacopa monniera, Withania somnifera, Japanese butterbur, and Silybum marianum. Such botanical materials can be provided in raw or dried form, as essential oils, or in the form of extracts. Botanical materials (and their extracts) often contain compounds from a variety of classes known to confer antioxidant effects, such as minerals, vitamins, isoflavones, phytosterols, allyl sulfides, dithiolthiones, isothiocyanates, indoles, lignans, flavonoids, polyphenols, and carotenoids.Examples of compounds found in botanical extracts or oils include ascorbic acid, peanut hull, resveratrol, sulforaphane, beta-carotene, lycopene, lutein, coenzyme Q, carnitine, quercetin, kemperol, etc. For example, see Santhosh et al., Phytomedicine, 12(2005)216 - 220, which is incorporated herein by reference.

[0087] Non-limiting examples of other suitable antioxidants include citric acid, vitamin E or its derivatives, tocopherol, epicatechol, epigallocatechol, epigallocatechin gallate, erythorbic acid, sodium erythorbate, 4-hexylresorcinol, theaflavin, theaflavin A or B monogallate, theaflavin digallate, phenolic acid, glycoside, quercitrin, isoquercitrin, hyperoside, polyphenol, catechol, resveratrol, oleuropein, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tertiary butylhydroquinone (TBHQ), and combinations thereof.

[0088] When present, the antioxidant is typically in a concentration of about 0.001% w / w to about 10% by weight, such as about 0.001% by weight, about 0.005% by weight, about 0.01% w / w, about 0.05% by weight, about 0.1% by weight, or about 0.5% by weight to about 1% by weight, about 2% by weight, about 3% by weight, about 4% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, or about 10% by weight, based on the total weight of the composition.

[0089] Pharmaceutical ingredient In some embodiments, the active ingredient comprises a pharmaceutical active ingredient (API). The API can be any known agent adapted for therapeutic, prophylactic, or diagnostic use. These include, for example, synthetic organic compounds, proteins and peptides, polysaccharides and other sugars, lipids, phospholipids, inorganic compounds (e.g., magnesium, selenium, zinc, nitrates), neurotransmitters or their precursors (e.g., serotonin, 5-hydroxytryptophan, oxitriptan, acetylcholine, dopamine, methionine), and nucleic acid sequences having therapeutic, prophylactic, or diagnostic activity. Non-limiting examples of APIs include analgesics and antipyretics (e.g., acetylsalicylic acid, acetaminophen, 3-(4-isobutylphenyl)propanoic acid), phosphatidylserine, myo-inositol, docosahexaenoic acid (DHA, omega-3), arachidonic acid (AA, omega-6), S-adenosylmethionine (SAM), beta-hydroxy-beta-methylbutyrate (HMB), cytidine (cytidine-5'-diphosphate-choline), and cotinine.

[0090] When present, the amount of the API can vary. For example, when present, the API is typically at a concentration of about 0.001% w / w to about 10% by weight, such as about 0.01% by weight, about 0.02%, about 0.03% by weight, about 0.04% by weight, about 0.05% by weight, about 0.06% by weight, about 0.07% by weight, about 0.08% by weight, about 0.09% by weight, about 0.1% w / w, about 0.2% by weight, about 0.3% by weight, about 0.4% by weight, about 0.5% by weight, about 0.6% by weight, about 0.7% by weight, about 0.8% by weight, about 0.9% by weight, or about 1% by weight to about 2% by weight, about 3% by weight, about 4% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, or about 10% by weight, based on the total weight of the composition.

[0091] Encapsulation and Stabilization of the Active Ingredient In some embodiments, the active ingredients described herein may be sensitive to degradation (e.g., oxidative, photolytic, thermal, evaporative) during the processing or storage of the composition. In such embodiments, the active ingredients (e.g., caffeine, vitamin A, and iron (Fe)) may be encapsulated or, alternatively, the composition may be modified with suitable ingredients (e.g., fillers, binders, etc.) to provide enhanced stability to the active ingredient. For example, binders such as functional celluloses (e.g., cellulose ethers such as, but not limited to, hydroxypropyl cellulose), or alginate-based materials (e.g., cross-linked alginate) may be utilized to enhance the stability of such actives against degradation or to impart extended and / or separate delivery of the active ingredient. Additionally, encapsulated actives may need to be paired with excipients in the composition to increase their solubility and / or bioavailability. Non-limiting examples of suitable excipients include beta-carotene, lycopene, vitamin D, vitamin E, coenzyme Q10, vitamin K, and curcumin.

[0092] In other embodiments, the initial amount of the active ingredient may be increased to compensate for progressive degradation losses in order to provide the desired concentration of the active ingredient by weight. Thus, initial amounts greater than those disclosed herein are contemplated by this disclosure.

[0093] Ion channel modulator The compositions described herein include one or more ion channel modulators. As used herein, the term "modulator" means a substance that activates, enhances or inhibits (i.e., blocks) a particular ion channel, and is also referred to herein as a receptor. The ion channels (i.e., receptors) modulated by the modulator are generally ion channels that confer sensations such as hot, cold, pain, tingling, salty, sweet, sour, bitter and umami. In some embodiments, the ion channels to be modulated are those that confer hot, cold, pain or tingling sensations. Non-limiting examples of such classes of ion channels are transient receptor potential channels (TRP). TRP is a family of non-selective cationic channels consisting of 28 mammalian members, which are divided into the following six subfamilies: canonical (TRPC), vanilloid (TRPV), ankyrin (TRPA), melastatin (TRPM), polycystin (TRPP) and mucolipin (TRPML) types. A subset of TRP channels from the M and V subfamilies and essentially TRPA1 can be classified as thermosensitive channels, covering together a wide range of sensitivities to temperatures from noxiously cold to warm. Upon activation of the TRP channel, Ca 2+Ions enter the cell through channels, causing cell depolarization and leading to the transmission of sensory signals. TRP channels are particularly sensitive to potentially stimulatory components contained in plants and herbs and influence the detection of potentially harmful environmental stimuli. A subset of thermosensitive TRP channels is also expressed by the sensory nerves of the trigeminal nerve in the oral cavity among other tissues, where they are involved in sensations related to irritation, pain, warmth, cold, tingling or numbness, such as those found in herbs and spices caused by certain substances. Many or even all of the modulators disclosed herein may also be referred to as "sensates", which are compounds that chemically induce somatosensation through the stimulation of the fifth cranial nerve (trigeminal nerve) in addition to or instead of olfactory or gustatory nerves. Sensates include agents that, by interacting with (e.g., stimulating) the trigeminal nerve, produce a warming / hotting effect, a cooling effect, a tingling effect and a numbing effect.

[0094] In some embodiments, the modulator is selected from any suitable compound that confers the necessary modulating activity on the relevant receptor. To modulate the activity of one or more of TRPV1, TRPV3, TRPM8, and TRPA1, the modulator can bind to any suitable binding site of the receptor necessary to modulate the activity. In some embodiments, the modulator is a single compound that modulates a single receptor. In some embodiments, the modulator is a single compound that modulates two or more receptors. For example, hydroxy-alpha-sanshool ((2E,6Z,8E,10E)-N-(2-hydroxy-2-methylpropyl)dodeca-2,6,8,10-tetraenamide), a molecule found in plants of the genus Zanthoxylum and believed to underlie the numbing and tingling sensations caused by Sichuan peppercorns, is an agonist at TRPV1 and TRPA1, although evidence suggests that the KCNK3, KCNK9, and KCNK18 potassium channels primarily underlie the effects of sanshool. See, for example, Bautista et al., Nat. Neurosci. 2008, 11(7):772-9. One of ordinary skill in the art will recognize that modulation of more than one receptor type by any given compound can occur, and such combinations are contemplated herein.

[0095] In some embodiments, the regulator is selected from the following: 3-phenylpropionic acid; acetic acid; benzaldehyde; benzoic acid; benzyl alcohol; 1-butanol; butyric acid; 4-isopropylbenzaldehyde; 2-methoxy-4-vinylphenol; octanoic acid; octanal; guaiacol; lactic acid; 3,4-dihydrocoumarin; ethanol; glycerol; 1-octanol; phenylacetaldehyde; phenylacetic acid; propylene glycol; propionic acid; pyruvic acid; dimethyl sulfide; 4-methyl-5-thiazoleethanol; vanillin; menthol; camphor; eucalyptol; decanoic acid; eugenol; hexylresorcinol; lauric acid; triacetin; 2-phenylethanol; hexanal; 1-pentanol; bornyl acetate; ethyl methylphenylglycidate; triethyl citrate; linalool; isobutanol; isobutyraldehyde; isobutyric acid; 4-(2,5,6,6-tetramethylcyclohex-2-en-1-yl)-but-3-en-2-one; alpha-pinene; cyclotene; 3-methylindole; methyl 2-(methylamino)benzoate; (1R,9S)-4,11,11-trimethyl-8-methylidenebicyclo[7.2.0]undec-4-ene; p-menthan-3-one; piperitone; thymol; 2-ethylphenol; 2,6-dimethoxyphenol; 6-methylquinoline; methylisoeugenol; 2-methoxy-4-methylphenol; methyl benzoate; ethyl benzoate; 2-methylbutyraldehyde; gamma-butyrolactone; 2-methylvaleric acid; ethyl isobutyrate; ethyl lactate; furfuryl mercaptan; acetophenone; carveol; carvone; gamma-terpinene; 4'-methoxyacetophenone; methyl phenylacetate; diphenyl ether; ethyl phenylacetate; isoamyl phenylacetate; phenethyl phenylacetate; 3-phenyl-2-propenoic acid, phenylmethyl ester; phenethyl acetate; phenethyl isobutyrate; 4-methoxybenzyl acetate; gamma-octalactone; benzyl formate; gamma-nonalactone; gamma-undecalactone; 4-methylbenzaldehyde; 1-methoxy-4-methylbenzene; 4-methoxybenzyl alcohol; gamma-heptalactone; ethyl propionate; 3-methylvaleric acid;Diethyl malonate; Ethyl butyrate; Acetal; Propyl butyrate; Isoamyl propionate; (-)-Citronellol; Citronellal; Isoamyl butyrate; Ethyl heptanoate; Ethyl octanoate; Ethyl dodecanoate; Methyl hexanoate; Hydroxycitronellal; 2-Pentanone; Gamma-valerolactone; 2,6-Dimethylpyridine; 2,6-Dimethylpyrazine; Ethyl isovalerate; 4-Methylpyridine; 3-Methylpyridine; 2-Methylpyrazine; Butyl isovalerate; Butyl butyrate; Valeric acid; Propyl acetate; Ethyl formate; Isobutyl acetate; Isopropyl myristate; Ethyl decanoate; Diethyl sebacate; 2-Heptanone; Pentanal; Heptanoic acid; 1-Hexanol; 1-Heptanol; Nonenoic acid, methyl ester; Nonanoic acid; 2-Undecanone; Octyl acetate; Decanal; 1-Dodecanol; Dodecanal; Linaryl acetate; 2-Methylbutyric acid; Maltol; Veratraldehyde; Piperonal; Ethylvanillin; Methyl 4-methoxybenzoate; 4'-Methylacetophenone; Methyl anthranilate; 2-Methyl-1-butanol; Benzyl acetate; Phenethyl isovalerate; p-Tolyl acetate; Citronellol; Ethyl acetate; Ethyl acetoacetate; Hexanoic acid; Hexyl acetate; 1,4-Dimethoxybenzene; Citronellyl acetate; (7R,11R)-3,7,11,15-Tetramethylhexadec-2-en-1-ol; 1,3-Dimethoxybenzene; 6-Methyl-5-hepten-2-one; (1S,4S)-(-)-Camphor; 1,4-Cineole; 3-Methyl-2-(2Z)-2-pentenyl-2-cyclopenten-1-one; 2,4,5-Trimethylphenol; Carvacrol; Isovaleric acid; Gluconic acid; 2,4,6-Trimethylphenol; 4-Ethylpyridine; 3-Ethylpyridine; Ethyl valerate; Ethyl levulinate; Isobutyl butyrate; Pentyl hexanoate; Pentyl butyrate; Terpinene-4-ol; Terpinolene; Isobutyl isovalerate; 3-Methylbutanal; Alpha-angelica lactone; Methyl 2-furoate; 5-Methylfurfural; 3-Ethylphenol; Methyl butyrate; Ethyl 2-butenoate; 4-Propylphenol; Isoamyl isovalerate; Gamma-caprolactone; 2,3,5-Trimethylphenol; Delta-octalactone; Delta-decalactone;Gamma-decalactone; Delta-dodecalactone; 2-nonanone; Delta-hexalactone; Methyl 2-methylbutyrate; 2-acetylpyrrole; Hexyl octanoate; 4-acetylpyridine; 2-acetylpyridine; 2,3,5,6-tetramethylpyrazine; 2-acetyl-5-methylfuran; Beta-pinene; 1-hexen-3-one; Fenchol; Hex-3-enyl acetate; 3-methylbutyl octanoate; 3-methylbutyl hexanoate; l-menthol; d-carboxylic; Gamma-dodecalactone; Alpha-terpineol; Hexyl butyrate; 2-methoxy-4-propylphenol; 2-methoxy-3-methylpyrazine; 2-pentenoic acid, 2-methyl-; 2-methyltetrahydrofuran-3-one; 3-(methylthio)propionaldehyde; Delta-nonalactone; Beta-ocimene; Sabinene; 1-octen-3-ol; Neomenthol; Furaneol; Dimethyl trisulfide; 2,3-hexanedione; Hex-3-enoic acid; Benzeneacetaldehyde, alpha-ethylidene-; Ethyl maltol; 4-(4-hydroxyphenyl)-2-butanone; 2,3-dimethylpyrazine; Linalyl oxide; Hexyl hexanoate; Alpha-caryophyllene; Ethyl 2-methylbutyrate; Butyryl lactic acid butyl; Hexyl 2-methylbutanoate; Butanoic acid, 1,1-dimethyl-2-phenylethyl ester; 3-ethyl-2,5-dimethylpyrazine; 4,11,11-trimethyl-8-methylene-(1S,4E,9R)-bicyclo[7.2.0]undeca-4-ene; 2-ethyl-3,5-dimethylpyrazine; Menthone; 2,3,5-trimethylpyrazine; 2-ethyl-3-methylpyrazine; 2,3-diethylpyrazine; Menthyl acetate; Propylidenephthalide; Acetylpyrazine; Alpha-amylcinnamaldehyde; 2-propenoic acid, 3-phenyl-, 3-phenyl-2-propenyl ester; 3-phenyl-1-propanol; 4-ethylphenol; 4-methoxybenzaldehyde; 4-heptanone; Ethyl nonanoate; 2,5-dimethylpyrazine; Isoamyl alcohol; Ethyl hexanoate; Allyl hexanoate; Butyl acetate; Isoamyl acetate; Ethyl tetradecanoate; Nonanal; Linalyl benzoate; Beta-damascone;5-Methyl-6,7-dihydro-5H-cyclopenta[b]pyrazine; 2-Isobutyl-3-methoxypyrazine; 2-Ethyl-4-hydroxy-5-methyl-3(2H)-furanone; 2,6-Nonadien-1-ol; Hex-3-enyl formate; 5,6,7,8-Tetrahydroquinoxaline; cis-3-Hexenyl 3-methylbutanoate; Massoia lactone; (+)-Isomenthol; Isobutyl phenylacetate; Benzyl phenylacetate; 4-(4-Methoxyphenyl)-2-butanone; 2,6-Dimethyl-5-heptenal; 1-Penten-3-one, (1E)-1-[(1R)-2,6,6-Trimethyl-2-cyclohexen-1-yl]-furfuryl propionate; Hexyl formate; 5-Ethyl-3-hydroxy-4-methylfuran-2(5H)-one; 2-Hydroxy-4-methylbenzaldehyde; 6-Hexyltetrahydro-2H-pyran-2-one; 3-Methylcyclopentane-1,2-dione; D-Piperitone; 3-Hexenyl 2-methylbutyrate; Ethyl 3-(methylthio)propionate; 3,4-Dimethyl-1,2-cyclopentanedione; 3,5-Dimethyl-1,2-cyclopentanedione; Methyl 3-(methylthio)propionate; 5-Methyl-2-thiophenecarboxaldehyde; 5-Methylquinoxaline; 2-Isopropyl-4-methylthiazole; Butyl 2-methylbutyrate; 2,4-Dimethylbenzaldehyde; Theaspirane; p-Mentha-8-thiol-3-one; p-Cresyl isovalerate; Orange oil; Linalyl butyrate; 1-Phenylethyl acetate; 2,6,6-Trimethyl-2-cyclohexene-1,4-dione; S-Methyl butanethioate; 4-Ethyl-2-methoxyphenol; (-)-Beta-bulbonene; Ethyl 3-hydroxybutyrate; 3-Ethyl-2-hydroxy-2-cyclopenten-1-one; 3-Hydroxy-4,5-dimethylfuran-2(5H)-one; Whiskey lactone; N-Ethyl-p-methane-3-carboxamide; Borneol; 3-(Methylthio)-1-hexanol; (+)-Linalool; 2-Methoxybenzyl alcohol; 3-Propylphenol; (+)-Isomentone; 3-Methylbutyl pentanoate; 2-Methoxy-6-methylphenol; Ethyl (methylthio)acetate; Rhodinyl acetate;(+)-alpha-Pinene; Isoamyl lactate; Nicotine; 2-Mercaptopinane; 1,6-Cyclodecadiene, 1-methyl-5-methylene-8-(1-methylethyl)-; (+)-Camphene; Spathulenol; (-)-Bornyl acetate; 5-Ethyl-4-hydroxy-2-methylfuran-3(2H)-one; 3,5,5-Trimethylcyclohexane-1,2-dione; 1-Oxacycloheptadec-10-en-2-one; (3R)-3,7-Dimethylocta-6-en-1-ol; 6-Methyl-2-(oxiran-2-yl)hepta-5-en-2-ol; Isobutyl 2-methylbutyrate; Methyl dihydrojasmonate; Ambrox; 2-Cyclohexen-1-one, 4-(2-butenylidene)-3,5,5-trimethyl-; l-Lactic acid; Alpha-terpinyl acetate; 3-Ethylcyclopentane-1,2-dione; 5-Nonen-2-one; Isobutyl decanoate; 2-Ethoxy-3-methylpyrazine; Tiglic acid; 3,7,11,15-Tetramethylhexadeca-2-en-1-ol; 3-Methyl-2-buten-1-thiol; (+)-Nicotine; d-Camphor; (+)-Menthol; 2-Ethyl-6-methoxyphenol; l-Menthyl acetate; Guaiol; Oxacyclohexadecan-2-one; Beta-bulbonene; Ethyl crotonate; (+)-Neomenthol; (1R,2S,4R)-Borneol; exo-1,7,7-Trimethyl-bicyclo[2.2.1]heptan-2-ol; (-)-Carvone; D-Limonene; (-)-Camphene; (-)-Beta-pinene; (-)-Alpha-pinene; (1S,2R,4S)-(-)-Bornyl acetate; (-)-Linalool; (+)-Menthone; (-)-Alpha-terpineol; (-)-Camphor; l-(+)-Tartaric acid; Cinnamic acid; Liquiritin; Hexyl lactate; 2-sec-Butyl-3-methoxypyrazine; 2-Acetylthiazole; Beta-spathulenol; Isobutyl acetoacetate; 1-Methyl-2-oxopropyl butyrate; 3-Methylnonane-2,4-dione; N-(2-Methylpropyl)-(2E,6Z,8E)-2,6,8-decatrienamide; 3-Mercaptohexyl hexanoate; 3,7-Dimethylocta-7-en-1-ol; 2-Methyl-1-[1-(2-methylbutoxy)ethoxy]butane;Menthy lisovalerate; 4-Methyl-2-phenyl-1,3-dioxolane; Cinnamaldehyde; Methyl cinnamate; Isoborneol acetate; Anethole; Geraniol; Ethyl cinnamate; Methyl isoeugenol; Citral; Beta-ionone; Sorbic acid; trans-2,cis-6-Nonadienal; Neral; Nerol; Sumatra; Camphor; Isoeugenol; (-)-Borneol; Nootkatone; Jasmon; (E)-Jasmon; Nerol acetate; Geranyl acetate; Geranyl acetone; Cinnamic acid, cinnamyl ester; Cinnamyl cinnamate; (Z)-1-(2,6,6-Trimethyl-1-cyclohexen-1-yl)-2-buten-1-one; Amyl cinnamaldehyde; 2-Benzylidene heptanal; (-)-Neo-isomenthol; Caryophyllene oxide; trans-2-Hexenyl acetate; 5-Ethyl-2-methoxyphenol; 3-Methylcyclohexane-1,2-dione; (7E)-1-Oxacycloheptadec-7-en-2-one; 4-Hydroxy-5-methylfuran-3(2H)-one; Vanillyl butyl ether; Isopentyl cinnamate; Benzyl cinnamate; Phytol; cis-3-Hexen-1-ol; 2-Hexenal; Beta-caryophyllene; Humulene; 4-(2,5,6,6-Tetramethyl-2-cyclohexen-1-yl)-3-buten-2-one; Isocaryophyllene; (E)-Beta-ocimene; Alpha-ionone; Geranyl formate; Cinnamyl acetate; trans-2-Hexenoic acid; 3-Hexanoic acid; trans-3-Hexen-1-ol; Nerolidol; Cinnamyl alcohol; 2-Hexen-1-ol; (1Z,4E,8E)-2,6,6,9-Tetramethylcycloundeca-1,4,8-triene; (2E,6E)-Nona-2,6-dien-1-ol; (Z)-3,7,11,15-Tetramethylhexadec-2-en-1-ol; (4Z)-4,11,11-Trimethyl-8-methylidene bicyclo[7.2.Undeca-4-ene; cis-3-hexenyl butyrate; cis-3-hexenyl hexanoate; trans-3-hexenyl acetate; spirantol; ethyl (2Z)-but-2-enoate; vanitrope; trans-caryophyllene; cis-3-hexenoic acid; oxacycloheptadeca-10-en-2-one; geranyl butyrate; methyl 2-nonenoate; 5-methyl-2-hepten-4-one; cis-4-decenal; ethyl 3-hexanoate; cis-6-nonenal; (Z)-non-6-en-1-ol; cis-4-heptenal; (2E,6Z)-non-2,6-dien-1-ol; cis-3-hexenyl acetate; ethyl 2-octenoate; cis-3-hexenyl 2-methylbutanoate; cis-3-hexenyl formate; 2-octen-4-one; 2-methyl-2-pentenoic acid; damascenone; 3,7,11,15-tetramethyl-2-hexadecen-1-ol; methyl 2-nonenoate; 6-methyl-3,5-heptadien-2-one; (2Z)-2-phenyl-2-butenal; alpha-ionone; 3-propylidenephthalide; 1-methyl-5-methylene-8-(1-methylethyl)-1,6-cyclodecadiene; trans-4-decen-1-al; ethyl 2-chloro-2-(phenylhydrazono)acetate; 3-hexenyl 2-methylbutanoate; propylidenephthalide; 3-hexen-1-ol, formate; (E)-2-epi-beta-caryophyllene; 2-phenyl-2-butenal; isomentone; 2-methyl-(2Z)-2-pentenoic acid; megastigmatrienone a; (1E,4E,8E)-2,6,6,9-tetramethylcycloundeca-1,4,8-triene; (7Z)-oxacycloheptadeca-7-en-2-one; (+)-borneol; (-)-neomenthol; exo-1,7,7-trimethylbicyclo[2.2.1] hepta-2-yl acetate; (+)-isoborneol; (+)-camphor; (2E,6Z,8E,10E)-N-(2-hydroxy-2-methylpropyl)dodeca-2,6,8,10-tetraenamide; hydroxy-beta-sanshool; (+)-beta-pinene; ambroxan; cubebol; (2E,6E,8E)-N-(2-methylpropyl)-2,6,8-decatrienamide; (E)-oxacycloheptadeca-10-en-2-one; picrotoxin; (1S)-6,6-dimethyl-2-methylenebicyclo[3.1.1]heptane; (1R)-(-)-menthyl acetate; (2R,5R)-5-methyl-2-(propan-2-yl)cyclohexyl acetate; spathulenol; benzyl alcohol, cinnamate; (2E,6E,8Z)-N-(2-methylpropyl)deca-2,6,8-trieneamide; (S)-alpha-methylionone; methyl-alpha-ionone; (1S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol; 4-(but-2-en-1-ylidene)-3,5,5-trimethylcyclohex-2-enone; ethyl 3-(methylthio)butyrate; bicyclo[3.1.1]heptane, 6,6-dimethyl-2-methylene-, (1S,5S)-; (2Z,6E)-2,6-dimethyl-10-methylidenedodeca-2,6,11-trienaal; (2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol; hydroxy-alpha-sanshool; N-(2-hydroxy-2-methylpropyl)dodeca-2,6,8,10-tetraenamide; ascorbic acid; (S)-(1Z,6Z)-8-isopropyl-1-methyl-5-methylenecyclodeca-1,6-diene; jasmine oil; alpha-caryophyllene; 3-phenylpropyl homovanillate; (1E,4E,8E)-2,6,6,9-tetramethyl-1,4,8-cycloundecatriene; (1E,8E)-2,6,6,9-tetramethylcycloundeca-1,4,8-triene; (1R,2S,6S,7R,8S)-1-methyl-5-methylidene-8-propan-2-yltricyclo[5.3.0.02,6]decane; (8E,10E)-N-(2-hydroxy-2-methylpropyl)dodeca-2,6,8,10-tetraenamide; and mixtures thereof.

[0096] In some embodiments, the regulator is selected from the group consisting of caryophyllene oxide, alpha-ionone, phenethyl phenylacetate, gamma-dodecalactone, beta-caryophyllene, 2-hexenal, eucalyptol, L-menthol, 3-phenylpropyl homovanillate, benzyl cinnamate, beta-bulbonene, cinnamyl cinnamate, citronellyl acetate, hydroxy-alpha-sanshool, glycyrrhizin, methyl-alpha-ionone, phytol, spathulenol, and combinations thereof.

[0097] In some embodiments, the regulator comprises a combination of benzyl cinnamate, caryophyllene oxide and notkatone. In some embodiments, the regulator comprises a combination of benzyl cinnamate, caryophyllene oxide and alpha-ionone. In some embodiments, the regulator comprises a combination of benzyl cinnamate and caryophyllene oxide.

[0098] In some embodiments, the composition includes an agent or sensate that provides a cooling effect to a user of such a composition. Suitable cooling agents include menthane, menthone, menthone ketal, menthone glycerol ketal, substituted p-menthane, acyclic carboxamides, monomethyl glutarate, substituted cyclohexane amides, substituted cyclohexane carboxamides, substituted ureas and sulfonamides, substituted methanol, hydroxymethyl and hydroxymethyl derivatives of p-menthane, 2-mercapto-cyclo-decanone, hydroxycarboxylic acids having 2 to 6 carbon atoms, cyclohexane amides, menthyl acetate, menthyl salicylate, N,2,3-trimethyl-2-isopropylbutanamide (WS-23), N-ethyl-2,2-diisopropylbutanamide, N-ethyl-p-menthane-3-carboxamide (WS-3), the ethyl ester of N-[[5-methyl-2-(1-methylethyl)cyclohexyl]carbonyl]glycine (WS5), and the substantially pure ethyl ester of N-[[5-methyl-2-(1-methylethyl)cyclohexyl]carbonyl]glycine disclosed in U.S. Patent No. 7,189,760 to Erman et al., which is incorporated herein by reference in its entirety, isopulegol, menthyloxypropanediol, 3-(1-menthoxy)propane-1,2-diol, 3-(1-menthoxy)-2-methylpropane-1,2-diol, p-menthane-2,3-diol, p-menthane-3,8-diol, 6-isopropyl-9-methyl-1,4-dioxaspiro[4,5]decan-2-methanol, menthyl succinate and its alkaline earth metal salts, trimethylcyclohexanol, N-ethyl-2-isopropyl-5-methylcyclohexanecarboxamide, peppermint oil, peppermint oil, 3-(1-menthoxy)ethan-1-ol, 3-(1-menthoxy)propan-1-ol, 3-(1-menthoxy)butan-1-ol, N-ethylamide of 1-menthyl acetate, 1-menthyl-4-hydroxypentanoate, 1-menthyl-3-hydroxybutyrate, N,2,3-trimethyl-2-(1-methylethyl)-butanamide, N-ethyl-trans-2-cis-6-nonadienamide, N,N-dimethylmenthyl succinamide, substituted p-menthane, substituted p-menthane-carboxamide, 2-isopropyl-5-methylcyclohexanol, menthone glycerol ketal, 3-1-menthoxypropane-1,2-diol, menthyl lactate, WS-30, WS-14, eucalyptus extract (p-menthane-3,8-diol), menthol (including natural and synthetic and derivatives thereof), menthol 2-propylene glycol carbonate, menthol ethylene glycol carbonate, menthol glyceryl ether, N-tert-butyl-p-menthane-3-carboxamide, p-menthane-3-carboxylic acid glycerol ester, methyl-2-isopropyl-bicyclo(2.2.1)-heptane-2-carboxamide (WS3), menthol methyl ether, menthyl pyrrolidone carboxylate, 2,5-dimethyl-4-(1-pyrrolidinyl)-3(2H)-furanone, cyclic a-ketoenamine and cycloten derivatives, such as cyclopentene, including but not limited to 3-methyl-2-(1-pyrrolidinyl)-2-cyclopentene-1-one and 5-methyl-2-(1-pyrrolidinyl)-2-cyclopentene-1-one. Other compounds include the alpha-ketoenamines disclosed in U.S. Patent No. 6,592,884 to Hofmann et al., which are incorporated herein by reference in their entirety. These and other suitable cooling agents are further described in the following U.S. Patents, which are incorporated herein by reference in their entirety: U.S. Patent No. 4,230,688; No. 4,032,661; No. 4,459,425; No. 4,178,459; No. 4,296,255; No. 4,136,163; No. 5,009,893; No. 5,266,592; No. 5,698,181; No. 6,277,385; No. 6,627,233; No. 7,030,No. 273. Other suitable cooling agents are further described in the following U.S. patent applications, which are hereby incorporated by reference in their entireties: U.S. Patent Application Publication No. 2005 / 0222256; No. 2005 / 0265930. In some embodiments, the cooling agent includes menthol, eucalyptus, mint, menthol, menthyl esters, eucalyptol, WS-3, WS-23, WS-5, Evercool™ 180 ((1R,2S,5R)-N-(4-(cyanomethyl)phenyl)menthyl carboxamide), Evercool™ 190 ((1R,2S,5R)-N-(2-(pyridin-2-yl)ethyl)menthyl carboxamide), or combinations thereof.,

[0099] In some embodiments, the composition includes a modifier or sensate that provides a warming effect to a user of such a composition. Effective warming agents include, but are not limited to, vanillyl alcohol n-butyl ether, vanillyl alcohol n-propyl ether, vanillyl alcohol isopropyl ether, vanillyl alcohol isobutyl ether, vanillyl alcohol n-amino ether, vanillyl alcohol isoamyl ether, vanillyl alcohol n-hexyl ether, vanillyl alcohol methyl ether, vanillyl alcohol ethyl ether, gingerol, shogaol, paradol, gingerone, capsaicin, dihydrocapsaicin, nordihydrocapsaicin, homocapsaicin, homodihydrocapsaicin, ethanol, isopropyl alcohol, iso-amyl alcohol, benzyl alcohol, glycerin, and combinations thereof. In some embodiments, the warming agent includes vanillyl ethyl ether, capsaicin, or combinations thereof.

[0100] In some embodiments, the composition includes a modulator or sensate that provides a tingling effect, a prickling effect, or a numbing effect to a user of such a composition. Agents that provide a tingling effect include, but are not limited to, Jambu Oleoresin or Dutch Cress (Spilanthes sp.), where the active ingredients are spilanthol; Sichuan pepper extract (Zanthoxylum peperitum), including sanshool-I, sanshool-II, and sanshool amide; perillartine; 4-(1-mentoxy methyl)-2-phenyl-1,3-dioxolane; black pepper extract (components known as Piper nigrum), including the active ingredients chavicine and piperine; purple coneflower (Echinacea) extract; northern dandelion extract; trans-perillartine, and red pepper oleoresin. In some embodiments, alkylamides extracted from materials such as jambu or sanshool may be included. Further examples of "tingling" type sensates include those disclosed in U.S. Patent Nos. 6,780,443, 6,159,509, 5,545,424, and 5,407,665, each of which is incorporated herein by reference in its entirety.

[0101] In some embodiments, the composition includes a modulator of the P2X3 receptor. The P2X3 receptor is an adenosine triphosphate (ATP)-activated ion channel expressed in peripheral sensory neurons and is recognized to play a role in the development of pathological pain, such as neurovascular orofacial pain. The P2X3 receptor is expressed, for example, in the tongue mucosa and can at least partially influence glossodynia.

[0102] In some embodiments, the modulator binds to a TRP receptor (e.g., TRPA1, TRPV1, TRPV3, TRPM8, or combinations thereof), a voltage-gated sodium channel receptor subtype (e.g., Nav1.7), a purinergic (e.g., P2X3) receptor, or combinations thereof. Suitable modulators bind to the relevant receptor via some of the electrostatic molecular interactions (e.g., van der Waals, electrostatic, hydrogen bonding, hydrophobic, and others) between the receptor and the modulator, and physical-chemical complementarity. In some embodiments, the modulator exhibits selective binding to one receptor over other receptors (e.g., the modulator exhibits a relatively large binding energy to the protein of a particular receptor relative to that of one or more other receptor proteins).

[0103] It will be appreciated by those skilled in the art that each of the modulators disclosed herein can bind to a suitable receptor or receptors and modulate its activity (i.e., act as an agonist, antagonist or inhibitor). When a voltage modulator interacts with a receptor, the interaction has a given binding energy. The binding energy can be determined based on the following equation:

[0104]

Equation

[0105] In some embodiments, the modulator activates (operates) or inhibits (antagonizes) the receptor following binding to the associated receptor. In some embodiments, the modulator inhibits the receptor by channel blockade (channel blocker) of the receptor, which acts by binding to a portion of the pore of the ion channel to inhibit the passage of ions through the channel, a mechanism that is different from and distinguishable from that of conventional antagonists that act by blocking channel opening. Thus, in some embodiments, the modulator is an agonist, antagonist, or channel blocker of one or more ion channels (e.g., TRPA1, TRPV1, TRPV3, TRPM8, Nav1.7, P2X3, or combinations thereof). In some embodiments, the modulator is an agonist, antagonist, or channel blocker of one or more of TRPA1, TRPV1, TRPV3, TRPM8, Nav1.7, and P2X3. It will be appreciated by those skilled in the art that a given compound may be a modulator of one or more of TRPA1, TRPV1, TRPV3, TRPM8, Nav1.7, and P2X3. In some embodiments, the modulator utilized is a single compound. In some embodiments, the respective modulators of one or more of TRPA1, TRPV1, TRPV3, TRPM8, Nav1.7, and P2X3 are separate compounds.

[0106] In some embodiments, the modulator is an agonist, antagonist, or inhibitor (i.e., channel blocker) of one or more of TRPA1, TRPV1, TRPV3, and TRPM8. To modulate the respective activities of TRPM1, TRPV3, TRPM8, and TRPA1, the modulator can bind to any suitable binding site (e.g., orthosteric, allosteric, or within the channel pore) necessary to modulate the activity.

[0107] In some embodiments, the regulated ion channel is transient receptor potential cation channel, subfamily A, member 1, also known as transient receptor potential ankyrin 1 (TRPA1), and sometimes referred to as the wasabi receptor. TRPA1 is best known as a sensor for pain, cold, and itch in humans and other mammals, and as a sensor for environmental irritants that cause other protective responses (tearing, airway resistance, and coughing). A TRPA1 modulator can bind to any suitable binding site (i.e., within the TRPA1 protein) necessary to regulate its activity. In some embodiments, the modulator binds to the TRPA1 receptor. In some embodiments, the modulator is a TRPA1 agonist, a TRPA1 antagonist, or a TRPA1 channel blocker. In some embodiments, the modulator is a TRPA1 antagonist. In some embodiments, the modulator is a TRPA1 channel blocker.

[0108] In some embodiments, the modulator is a TRPA1 antagonist that binds to one or more sites selected from Arg852, Gln979, His983, Ile858, Leu982, Met978, Trp711, Val861, Val967, Ala836, Gln940, Ile837, Leu847, Leu848, Leu863, Leu867, Leu871, Met844, Phe841, Phe884, Phe947, Ser887, Tyr840, and combinations thereof. In some embodiments, the TRPA1 antagonist binds to one or more sites selected from Arg852, Gln979, His983, Ile858, Leu982, Met978, Trp711, Val861, Val967, and combinations thereof. In some embodiments, the TRPA1 agonist binds to one or more sites selected from Ala836, Gln940, Ile837, Leu847, Leu848, Leu863, Leu867, Leu871, Met844, Phe841, Phe884, Phe947, Ser887, Tyr840, and combinations thereof.

[0109] In some embodiments, the TRPA1 antagonist is selected from cinnamic acid, cinnamyl esters; hexylresorcinol; l-menthol; 2-ethyl-6-methoxyphenol, linalyl oxide, 2-methoxy-6-methylphenol, methyl 2-(methylamino)benzoate, eucalyptol, and mixtures thereof. In some embodiments, the TRPA1 antagonist is selected from cinnamyl cinnamate, liquiritin, 3-phenylpropyl homovanillate, benzyl cinnamate, caryophyllene (beta-), phenethyl phenylacetate, hydroxy-alpha-sanshool, phytol, bulbonene (beta), and mixtures thereof.

[0110] In some embodiments, the modulator is a TRPA1 inhibitor. In some embodiments, the TRPA1 inhibitor binds to one or more sites selected from Leu867, Leu870, Leu871, Ile946, Ser873, Thr873, Thr874, Phe944, Val948, Phe877, Ile878, Leu880, Leu881, Met912, Phe909, Thr908, Ile906, Ile905, Ile950, Leu956, Val942, Met953, Leu952, Phe884; and combinations thereof.

[0111] In some embodiments, the TRPA1 inhibitor is selected from 3-phenylpropyl homovanillate; benzyl alcohol, cinnamate; benzyl phenylacetate; alpha-amyl cinnamaldehyde; linalyl benzoate; phenethyl isovalerate; carvacrol; thymol; 5-ethyl-2-methoxyphenol; vanitrope; and mixtures thereof. In some embodiments, the TRPA1 inhibitor is selected from cinnamyl cinnamate, citronellyl acetate, eucalyptol, 2-hexenal, dodecalactone (gamma-), menthol (l-), spathulenol, bulbonene (beta), benzyl cinnamate, caryophyllene oxide, caryophyllene (beta-), alpha-ionone, phenethyl phenylacetate, methyl-alpha-ionone, phytol, and mixtures thereof. In some embodiments, the TRPA1 inhibitor is a channel blocker such as 2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-[4-(1-methylpropyl)phenyl]acetamide.

[0112] In some embodiments, the ion channel is transient receptor potential melastatin 8 (TRPM8), which is also known as the cool and menthol receptor 1 (CMR1). When activated, TRPM8 confers a cool sensation. TRPM8 is activated by certain "cooling agents" such as menthol, borneol, and linalool, or when the ambient temperature drops below about 26°C. In some embodiments, the modulator binds to the TRPM8 receptor.

[0113] In some embodiments, the modulator is a TRPM8 agonist. In some embodiments, the TRPM8 agonist binds to one or more sites selected from Arg1007, Arg841, Asn741, Asp781, Ile845, Leu1000, Phe738, Tyr1004, Tyr745, Val848; and combinations thereof.

[0114] In some embodiments, the TRPM8 agonist is selected from (1Z,4E,8E)-2,6,6,9-tetramethylcycloundeca-1,4,8-triene; beta-caryophyllene; liquiritin; (E)-2-epi-beta-caryophyllene; bicyclo[7.2.0]undec-4-ene, 4,11,11-trimethyl-8-methylene-, (1R,4E,9S)-; (4Z)-4,11,11-trimethyl-8-methylidenebicyclo[7.2.0]undec-4-ene; bicyclo[7.2.0]undec-4-ene, 4,11,11-trimethyl-8-methylene-, (1S,4E,9R)-; isocaryophyllene; ambroxan; spathulenol; caryophyllene oxide; (-)-beta-bulbonene; oxacycloheptadeca-10-en-2-one, (E)-; cubebol; trans-caryophyllene; gamma-dodecalactone; hydroxy-alpha-sanshool; citronellyl acetate; (2E,6Z,8E,10E)-N-(2-hydroxy-2-methylpropyl)dodeca-2,6,8,10-tetraenamide; (8E,10E)-N-(2-hydroxy-2-methylpropyl)dodeca-2,6,8,10-tetraenamide; N-(2-hydroxy-2-methylpropyl)dodeca-2,6,8,10-tetraenamide; hydroxy-beta-sanshool; 2-hexenal; and mixtures thereof.

[0115] In some embodiments, the ion channel is transient receptor potential cation channel, subfamily V member 1 (TRPV1), which is also known as the capsaicin receptor and vanilloid receptor 1. When activated by an agonist such as capsaicin or resiniferatoxin, TRPV1 confers the sensation of burning heat and pain. In some embodiments, the modulator binds to the TRPV1 receptor. In some embodiments, the modulator comprises a TRPV1 agonist.

[0116] In some embodiments, the TRPV1 agonist binds to one or more sites selected from Ala548, Ala568, Ala667, Asn553, Glu572, Ile571, Ile663, Leu517, Leu555, Leu664, Leu671, Met549, Phe518, Phe545, Phe593, Ser514, Thr552, Tyr513, Tyr556, and combinations thereof.

[0117] In some embodiments, the TRPV1 agonist is selected from phenylacetic acid phenethyl; 2-propenoic acid, 3-phenyl-, 3-phenyl-2-propenyl ester; theaspirane; (7R,11R)-3,7,11,15-tetramethylhexadec-2-en-1-ol; 4-(2,5,6,6-tetramethylcyclohex-2-en-1-yl)but-3-en-2-one; cinnamic acid cinnamyl; alpha-ionone; beta-spathulenol; spathulenol; phytol; 1-penten-3-one, 1-[(1R)-2,6,6-trimethyl-2-cyclohexen-1-yl]-, (1E)-; (S)-alpha-methylionone; guaiol; 3,7,11,15-tetramethylhexadec-2-en-1-ol; 3,7,11,15-tetramethyl-2-hexadecen-1-ol; (Z)-3,7,11,15-tetramethylhexadec-2-en-1-ol; vanillyl butyl ether; 4-ethyl-2-methoxyphenol; 6-methyl-2-(oxiran-2-yl)hepta-5-en-2-ol; 2-methoxy-4-methylphenol; 2-methoxy-4-vinylphenol; benzyl cinnamate; 2-propenoic acid; 3-phenyl-, phenylmethyl ester; and mixtures thereof.

[0118] In some embodiments, the ion channel is a transient receptor potential cation channel, subfamily V member 3 (TRPV3), which functions as a sensor for innocuous warm temperature. When activated by an agonist such as carbachol, thymol or eugenol, TRPV3 confers a sense of warmth. In some embodiments, the modulator binds to the TRPV3 receptor. In some embodiments, the modulator comprises a TRPV3 agonist.

[0119] In some embodiments, the TRPV3 agonist binds to one or more sites selected from Arg693, His430, His426, His417, Leu420, Leu694, Leu429, Trp433, Thr421, and combinations thereof.

[0120] In some embodiments, the TRPV3 agonist is selected from ethyl vanillin; 2,6-dimethoxyphenol; vanillin; and mixtures thereof.

[0121] In some embodiments, the ion channel is a NaV1.7 sodium ion channel. Nav1.7 is present at the terminals of pain-sensing nerves and is normally highly expressed in two types of neurons; nociceptive (pain) neurons in the dorsal root ganglion (DRG), which is part of the autonomic nervous system, and trigeminal ganglion neurons and sympathetic ganglion neurons. Nav1.7 has been associated with pain signals, and certain analgesics (e.g., the local anesthetic lidocaine) mediate their effects by electrically blocking voltage-dependent sodium channels that include Nav1.7. In some embodiments, the modulator binds to the NaV1.7 channel. In some embodiments, the modulator comprises a NaV1.7 antagonist.

[0122] In some embodiments, the ion channel modulator is selected from the group consisting of a TRPA1 agonist, a TRPA1 antagonist, a TRPA1 inhibitor, a TRPV1 agonist, a TRPV3 agonist, a TRPM8 agonist, a NaV1.7 antagonist, and combinations thereof.

[0123] In some embodiments, the modulator comprises at least (i) a TRPM8 agonist and a TRPV1 agonist; and (ii) a TRPA1 antagonist or a TRPA1 inhibitor. In some embodiments, the modulator comprises at least (i) a TRPM8 agonist or a TRPV1 agonist; and (ii) a TRPA1 antagonist or a TRPA1 inhibitor. In some embodiments, the modulator comprises at least (i) a TRPM8 agonist and a TRPV3 agonist; and (ii) a TRPA1 antagonist or a TRPA1 inhibitor. In some embodiments, the modulator comprises at least (i) a TRPM8 agonist or a TRPV3 agonist; and (ii) a TRPA1 antagonist or a TRPA1 inhibitor. In some embodiments, the modulator comprises (i) a TRPM1 agonist, a TRPV3 agonist and a TRPV8 agonist; and (ii) a TRPA1 antagonist or a TRPA1 inhibitor. In some embodiments, the modulator comprises at least (i) a TRPV3 agonist or a TRPV1 agonist; and (ii) a TRPA1 antagonist or a TRPA1 inhibitor.

[0124] In some embodiments, the TRPA1 antagonist or inhibitor has a binding affinity for the TRPA1 receptor that is stronger than the binding affinity of one or more of a TRPM8 agonist, a TRPV1 agonist, and a TRPV3 agonist for their respective receptors. In some embodiments, the TRPA1 antagonist or inhibitor has a binding affinity for the TRPA1 receptor that is stronger than the binding affinity of a TRPM8 agonist for the TRPM8 receptor. In some embodiments, the TRPA1 antagonist or inhibitor has a binding affinity for the TRPA1 receptor that is stronger than the binding affinity of a TRPV1 agonist for the TRPV1 receptor. In some embodiments, the TRPA1 antagonist or inhibitor has a binding affinity for the TRPA1 receptor that is stronger than the binding affinity of a TRPV3 agonist for the TRPV3 receptor. In some embodiments, the TRPA1 antagonist or inhibitor has a binding affinity for the TRPA1 receptor that is stronger than the binding affinity of a TRPV1 agonist for the TRPV1 receptor, stronger than the binding affinity of a TRPV3 agonist for the TRPV3 receptor, and stronger than the binding affinity of a TRPM8 agonist for the TRPM8 receptor. In some embodiments, the TRPA1 antagonist or inhibitor has a binding affinity for the TRPA1 receptor that is stronger than the binding affinity of one or more of a TRPM8 agonist, a TRPV1 agonist, and a TRPV3 agonist for their respective receptors.

[0125] The amount of ion channel modulator present in the composition can vary. The amount of a single ion channel modulator present can vary based on the activity, titer, selectivity, and desired effect of the modulator. For example, in some embodiments, any single ion channel modulator can be present in the composition in an amount in the range of about 0.005 wt% to about 2 wt% based on the total weight of the composition. One or more modulators can be present in the composition, each capable of modulating the same receptor or different receptors.

[0126] Filler The compositions described herein include at least one filler. The filler can satisfy multiple functions such as enhancing certain sensory acceptabilities, e.g., texture and mouthfeel, and enhancing the tackiness or compressibility of the product, etc.

[0127] Generally, the filler is a porous particulate material and is cellulose-based. For example, suitable fillers are any non-tobacco plant materials or their derivatives including cellulose materials derived from such sources. Examples of cellulose non-tobacco plant materials include cereal grains (e.g., corn, barley, wheat, rye, buckwheat, etc.), sugar beets (e.g., FIBREX® brand filler available from International Fiber Corporation), rice bran fiber, and mixtures thereof. Non-limiting examples of derivatives of non-tobacco plant materials include starches (e.g., from potatoes, wheat, rice, corn), natural cellulose, and modified cellulose materials.

[0128] "Starch", as used herein, can refer to pure starch, modified starch, or starch derivatives from any source. Starch is present in almost all green plants and typically in granular form in many types of plant tissues and organs (e.g., seeds, leaves, rhizomes, roots, tubers, sprouts, fruits, grains, and stems). Starch can vary in composition and in the shape and size of the granules. Often, starches from different sources have different chemical and physical properties. A particular starch can be selected for inclusion in a mixture based on its ability to impart a particular sensory acceptability to the starch material. Starches from a variety of sources can be used. For example, the main sources of starch include cereal grains (e.g., rice, wheat, and corn) and root vegetables (e.g., potato and cassava). Other examples of starch sources include acorn, kudzu, aracacha, banana, barley, beans (e.g., broad bean, lentil, pea, chickpea, fava bean), breadnut, buckwheat, arrowroot, chestnut, taro, kudzu, yam, millet, oat, okra, dasheen, sago, sorghum, sweet potato, quinoa, rye, tapioca, taro, tobacco, arrowroot, and yam. Some starches are modified starches. Modified starches have undergone one or more structural modifications and are often designed to change their thermal properties. Some starches have been developed by genetic modification and are considered "modified" starches. Other starches are modified after they are obtained. For example, modified starches can be starches that have been subjected to chemical reactions such as esterification, etherification, oxidation, depolymerization (thinning), etc., which can be by acid catalysis or oxidation, decolorization, sugar transfer, and depolymerization (e.g., dextrinization in the presence of a catalyst), crosslinking, enzyme treatment, acetylation, hydroxypropylation, and / or partial hydrolysis in the presence of a base. Other starches are processed by heat treatment such as alphaization, dextrinization, and / or cold water swelling methods.Examples of certain modified starches include monophosphate starch, distarch glycerol, diphosphate starch esterified with sodium trimetaphosphate, phosphate diphosphate starch, acetylated diphosphate starch, acetate starch esterified with acetic anhydride, acetate starch esterified with vinyl acetate, acetylated adipic acid distarch, acetylated distarch glycerol, hydroxypropyl starch, hydroxypropyl distarch glycerol, sodium octenyl succinate starch.

[0129] Further examples of potential fillers include maltodextrin, dextrose, calcium carbonate, calcium phosphate, lactose, and sugar alcohols. Combinations of fillers may also be used. In some embodiments, the filler comprises a mixture of glucose and a starch-derived polysaccharide. One such suitable mixture of glucose and a starch-derived polysaccharide is EMDEX® available from JRS PHARMA LP, USA, 2981 Route22, Patterson, NY 12563-2359.

[0130] In some embodiments, the particulate filler is a cellulose material or a cellulose derivative. One particularly preferred particulate filler for use in the compositions described herein is microcrystalline cellulose (“mcc”). The MCC may be synthetic, semi-synthetic, or it may be obtained entirely from natural cellulose. The MCC may be selected from the group consisting of AVICEL® grades PH-100, PH-102, PH-103, PH-105, PH-112, PH-113, PH-200, PH-300, PH-302, VIVACEL® grades 101, 102, 12, 20, and EMOCEL® grades 50M and 90M, etc., and mixtures thereof. In one embodiment, the composition comprises MCC as a particulate filler. The amount of mcc present may vary depending on the desired properties.

[0131] The amount of filler can vary, but is typically up to about 75 weight percent of the total weight of the composition. Typical ranges of filler (e.g., MCC) within the composition can be, depending on the total mass of the composition, from about 10 to about 75 percent, such as about 10, about 15, about 20, about 25, or about 30 to about 35, about 40, about 45, or about 50 weight percent (e.g., about 20 to about 50 weight percent, or about 25 to about 45 weight percent). In certain embodiments, the amount of filler is at least about 10 weight percent, such as at least about 20 percent, or at least about 25 percent, or at least about 30 percent, or at least about 35 percent, or at least about 40 percent, based on the total weight of the composition.

[0132] In one embodiment, the filler further comprises a cellulose derivative, or a combination of such derivatives. In some embodiments, the composition comprises from about 1 to about 10 weight % cellulose derivative, based on the total weight of the composition, and certain embodiments comprise from about 1 to about 5 weight % cellulose derivative. In certain embodiments, the cellulose derivative is a cellulose ether (including carboxyalkyl ethers), which means that a cellulose polymer having hydrogen of one or more hydroxyl groups in the cellulose structure is replaced with each group of alkyl, hydroxyalkyl or aryl. Non-limiting examples of such cellulose derivatives include methylcellulose, hydroxypropyl cellulose ("HPC"), hydroxypropyl methylcellulose ("HPMC"), hydroxyethyl cellulose and carboxymethyl cellulose ("CMC"). In one embodiment, the cellulose derivative is one or more of methylcellulose, HPC, HPMC, hydroxyethyl cellulose and CMC. In one embodiment, the cellulose derivative is HPC. In some embodiments, the composition comprises from about 1 to about 3 weight % HPC, based on the total weight of the composition.

[0133] Water Before use of the composition by a consumer, the water content of the composition may vary depending on the desired properties. Typically, the composition has less than about 60 weight percent water, generally from about 1 to about 60 weight % water, for example, from about 5 to about 55, from about 10 to about 50, from about 20 to about 45, or from about 25 to about 40 weight percent water, including amounts of water of at least about 5 weight %, at least about 10 weight %, at least about 15 weight %, and at least about 20 weight %. In some embodiments, the composition has less than about 10 weight percent water, for example, about 9 weight percent or less, about 7 weight percent or less, about 5 weight percent or less, about 4 weight percent or less, about 3 weight percent or less, or about 2 weight percent or less. In some embodiments, the water content of the composition is in the range of from about 0.1 weight percent to about 10 weight percent, based on the total weight of the composition.

[0134] Organic acid In some embodiments, the compositions disclosed herein include one or more organic acids. As used herein, the term "organic acid" refers to an organic (i.e., carbon-based) compound characterized by acidic properties. Typically, organic acids are relatively weak acids (i.e., they do not dissociate completely in the presence of water), such as carboxylic acids (-CO2H) or sulfonic acids (-SO2OH). As used herein, reference to an organic acid means an organic acid that is intentionally added. In this regard, an organic acid can be intentionally added as a specific composition component, as opposed to being merely inherently present as a component of another composition component (e.g., a small amount of organic acid that may be inherently present in a composition component, such as a tobacco material).

[0135] Suitable organic acids typically have a lipophilic range (i.e., a polarity that confers an appropriate balance of water and organic solubility). Typically, the lipophilicity of suitable organic acids, as indicated by logP, varies from about 1 to about 12 (more soluble in octanol than in water). In some embodiments, the organic acid has a logP value of from about 1 to about 12, such as about 1.0, about 1.5, about 2.0, about 2.5, about 3.0, about 3.5, about 4.0, about 4.5, about 5.0, about 5.5, about 6.0, about 6.5, about 7.0, about 7.5, or about 8.0 to about 8.5, about 9.0, about 9.5, about 10.0, about 10.5, about 11.0, about 11.5, or about 12.0.

[0136] Without wishing to be bound by theory, moderately lipophilic (e.g., logP of about 1.4 to about 4.5) organic acids result in ion pairs with nicotine, which are of a polarity that confers good octanol-water partitioning of the ion pair, and thus nicotine is believed to partition into octanol versus water. As discussed above, such partitioning into octanol is predicted to be a favorable oral bioavailability.

[0137] In certain embodiments, the organic acid has a logP value of from about 3.0 to about 8.0, about 10.0, or even 12.0. In some embodiments, the presence of certain solvents or solubilizers (e.g., inclusion of glycerin or propylene glycol in the composition) can be beneficial for solubilizing organic acids having basic amines, the organic acids and corresponding salts or their ion pairs, for highly lipophilic (e.g., greater than about 4.5) organic acids.

[0138] In some embodiments, the organic acid is a carboxylic acid or a sulfonic acid. The carboxylic acid or sulfonic acid functional group can be attached to each group of any alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl having, for example, 1 to 20 carbon atoms (C1 - C 20 ). In some embodiments, the organic acid is an alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl carboxylic acid or sulfonic acid.

[0139] As used herein, "alkyl" refers to any straight-chain or branched-chain hydrocarbon. An alkyl group may be saturated (i.e., having all sp 3 carbon atoms) or unsaturated (i.e., having at least one unsaturated site). As used herein, the term "unsaturated" refers to the presence of a carbon-carbon sp 2 double bond at one or more positions within the alkyl group. An unsaturated alkyl group may be monounsaturated or polyunsaturated. Representative straight-chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl. Branched-chain alkyl groups include, but are not limited to, isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and 2-methylbutyl. Representative unsaturated alkyl groups include, but are not limited to, ethylene or vinyl, allyl, 1-butenyl, 2-butenyl, isobutenylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, and the like. An alkyl group may be either unsaturated or saturated.

[0140] As used herein, "cycloalkyl" refers to a carbocyclic group, which may be monocyclic or bicyclic. A cycloalkyl group includes a ring having 3 to 7 carbon atoms as a monocyclic ring, or a ring having 7 to 12 carbon atoms as a bicyclic ring. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. A cycloalkyl group may be either unsaturated or saturated and may contain one or more sites of unsaturation (e.g., cyclopentynyl or cyclohexenyl).

[0141] As used herein, the term "aryl" refers to a carbocyclic aromatic group. Examples of aryl groups include, but are not limited to, phenyl and naphthyl. An aryl group may be either unsaturated or saturated.

[0142] As used herein, "heteroaryl" and "heterocycloalkyl" each refer to an aromatic or non-aromatic ring system, where one or more of the ring atoms are heteroatoms, such as nitrogen, oxygen, and sulfur. A heteroaryl group or a heterocycloalkyl group contains up to 20 carbon atoms and 1 to 3 heteroatoms selected from N, O, and S. Heteroaryl or heterocycloalkyl may be a monocyclic ring having 3 to 7 ring members (e.g., 2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, and S), or a bicyclic ring having 7 to 10 ring members (e.g., 4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, and S), such as a bicyclo[4,5], [5,5], [5,6], or [6,6] system. Examples of heteroaryl groups include, without limitation by way of example, pyridyl, thiazolyl, tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phthalazinyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, benzotriazolyl, benzisoxazolyl, and isatinoyl. Examples of heterocycloalkyl include, without limitation by way of example, dihydroipyridyl, tetrahydropyridyl (piperidyl), tetrahydrothiophenyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidinone, tetrahydrofuranyl, tetrahydropyranyl, bis-tetrahydropyranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, piperazinyl, quinuclidinyl, and morpholinyl.The heteroaryl group and the heterocycloalkyl group may be unsaturated or saturated.

[0143] As used herein and applied to any of the above alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, "substituted" means that one or more hydrogen atoms are each independently replaced by a substituent. Typical substituents include, but are not limited to, -Cl, Br, F, alkyl, -OH, -OCH3, NH2, -NHCH3, -N(CH3)2, -CN, -NC(=O)CH3, -C(=O)-, -C(=O)NH2 and -C(=O)N(CH3)2. Wherever it is described as "optionally substituted", the group may be substituted with one or more of the above substituents independently selected for each case. In some embodiments, the substituent may be one or more methyl groups or one or more hydroxyl groups.

[0144] In some embodiments, the organic acid is an alkylcarboxylic acid. Non-limiting examples of alkylcarboxylic acids include formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, undecanoic acid, dodecanoic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, and the like.

[0145] In some embodiments, the organic acid is an alkylsulfonic acid. Non-limiting examples of alkylsulfonic acids include propanesulfonic acid, heptanesulfonic acid, and octanesulfonic acid.

[0146] In some embodiments, the alkylcarboxylic acid or sulfonic acid is substituted with one or more hydroxyl groups. Non-limiting examples include glycolic acid, 4-hydroxybutyric acid, and lactic acid.

[0147] In some embodiments, the organic acid may include more than one carboxylic acid group or more than one sulfonic acid group (e.g., two, three, or more carboxylic acid groups). Non-limiting examples include oxalic acid, fumaric acid, maleic acid, and glutaric acid. In an organic acid containing multiple carboxylic acids (e.g., 2 to 4 carboxylic acid groups), one or more of the carboxylic acid groups may be esterified. Non-limiting examples include monomethyl succinate, monomethyl fumarate, monomethyl citrate, or dimethyl citrate, etc.

[0148] In some embodiments, the organic acid may include one or more carboxylic acid groups and one or more hydroxyl groups. Non-limiting examples of such acids include tartaric acid, citric acid, etc.

[0149] In some embodiments, the organic acid is an arylcarboxylic acid or an arylsulfonic acid. Non-limiting examples of arylcarboxylic acids and sulfonic acids include benzoic acid, toluic acid, salicylic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

[0150] Further non-limiting examples of organic acids that may be useful in certain embodiments include 2-(4-isobutylphenyl)propanoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, adipic acid, ascorbic acid (L), aspartic acid (L), alpha-methylbutyric acid, camphoric acid (+), camphor-10-sulfonic acid (+), cinnamic acid, cyclamic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, flufenamic acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, isovaleric acid, lactobionic acid, lauric acid, levulinic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, oleic acid, palmitic acid, pamoic acid, phenylacetic acid, pyroglutamic acid, pyruvic acid, sebacic acid, stearic acid, and undecylenic acid.

[0151] Examples of suitable acids include, but are not limited to, the list of organic acids in Table 1.

[0152]

Table 1

[0153] The selection of the organic acid may further depend on additional properties in addition to consideration of the logP value. For example, the organic acid should be recognized as safe for human consumption and should be recognized as having acceptable flavor, odor, volatility, stability, etc. The determination of a suitable organic acid is within the purview of one of ordinary skill in the art.

[0154] In some embodiments, the organic acid is a monoester of a dicarboxylic acid or a polycarboxylic acid. In some embodiments, the dicarboxylic acid is malonic acid, succinic acid, glutaric acid, adipic acid, fumaric acid, maleic acid, or a combination thereof. In some embodiments, the dicarboxylic acid is succinic acid, glutaric acid, fumaric acid, maleic acid, or a combination thereof. In some embodiments, the dicarboxylic acid is succinic acid, glutaric acid, or a combination thereof.

[0155] In some embodiments, the alcohol that forms the monoester of the dicarboxylic acid is a lipophilic alcohol. Examples of suitable lipophilic alcohols include, but are not limited to, octanol, menthol, and tocopherol. In some embodiments, the organic acid is an octyl monoester of a dicarboxylic acid, such as monooctyl succinate, monooctyl fumarate, and the like. In some embodiments, the organic acid is a monomethyl ester of a dicarboxylic acid. Certain menthyl esters may be desirable in the oral compositions described herein for the cooling sensation they can impart upon use of the products containing the composition. In some embodiments, the organic acid is monomethyl succinate, monomethyl fumarate, monomethyl glutarate, or a combination thereof. In some embodiments, the organic acid is a monotocopheryl ester of a dicarboxylic acid. Certain tocopheryl esters may be desirable in the oral compositions described herein for the antioxidant effect they can impart. In some embodiments, the organic acid is tocopheryl succinate, tocopheryl fumarate, tocopheryl glutarate, or a combination thereof.

[0156] In some embodiments, the organic acid is a carotenoid derivative having one or more carboxylic acids. Carotenoids are tetraterpenes, which means that they are produced from eight isoprene molecules and contain 40 carbon atoms. Thus, they are usually lipophilic due to the presence of unsaturated aliphatic long chains and are generally yellow, orange or red in color. Certain carotenoid derivatives can be advantageous in oral compositions to impart both ion pairing in the composition and act as a colorant. In some embodiments, the organic acid is (2E,4E,6E,8E,10E,12E,14E,16Z,18E)-20-methoxy-4,8,13,17-tetramethyl-20-oxoicos-2,4,6,8,10,12,14,16,18-nonaenoic acid (bixin) or an isomer thereof. Bixin is an apocarotenoid found in annatto seeds from Bixa orellana and is a naturally occurring pigment that gives annatto its reddish orange color. Bixin is soluble in fats and alcohols but insoluble in water and is chemically unstable when isolated and, via isomerization, converts to an isomer of the double bond having the structure:

[0157] [Chemical formula] to trans-bixin (β-bixin). In some embodiments, the organic acid is the structure:

[0158] [Chemical formula] (2E,4E,6E,8E,10E,12E,14E,16E,18E)-4,8,13,17-tetramethylicos-2,4,6,8,10,12,14,16,18-nonaenedioic acid (nor-bixin), a water-soluble hydrolysis product of bixin, having the structure:

[0159] In some embodiments, more than one type of organic acid may be present. For example, the composition may include two or three or four or more organic acids. Thus, references herein to "organic acid" contemplate mixtures of two or more organic acids. The relative amounts of the plurality of organic acids may vary. For example, the composition may include equal amounts of two or three or more organic acids, or may include different relative amounts. In such a manner, when combined with other organic acids, it is possible to impart a desired average logP range for the combination, including certain organic acids (such as citric acid or myristic acid) having logP values outside the desired range. In some embodiments, it may be desirable to include an organic acid in a composition having a logP value outside the desired range for purposes such as, but not limited to, providing a desired sensory acceptability, stability, for example as a flavor component. Further, certain lipophilic organic acids have undesirable flavor and / or aroma characteristics, which may preclude their presence as the sole organic acid (e.g., in equimolar or greater amounts relative to nicotine). Without wishing to be bound by theory, it is believed that combinations of different organic acids may result in a desired ion pairing, while the concentration of any single organic acid in the composition remains below a threshold, which may be found to be undesirable from a sensory acceptability perspective.

[0160] In some embodiments, the composition includes an organic acid that is a monoester of a dicarboxylic acid, or the composition is a carotenoid derivative having one or more carboxylic acids as described above herein and further includes an additional organic acid or a salt thereof. In some embodiments, the additional organic acid is benzoic acid, an alkali metal salt thereof, or a combination thereof.

[0161] In some embodiments, the composition comprises an alkali metal salt of an organic acid. For example, at least a portion of the organic acid may be present in the composition in the form of an alkali metal salt. Suitable alkali metals include lithium, sodium, and potassium. In some embodiments, the alkali metal is sodium or potassium. In some embodiments, the alkali metal is sodium. In some embodiments, the composition comprises an organic acid and a sodium salt of the organic acid.

[0162] In some embodiments, the weight ratio of the organic acid to its sodium salt (or other alkali metal) of the organic acid is from about 0.1 to about 10, such as about 0.1, about 0.25, about 0.3, about 0.5, about 0.75, or about 1 to about 2, about 5, or about 10. For example, in some embodiments, both the organic acid and its sodium salt are added to other components of the composition, where the organic acid is added in an equimolar amount with the sodium salt, or as a minor amount of the sodium salt, or in an excess amount of the sodium salt. One of ordinary skill in the art will recognize that the relative amounts are determined by the desired pH and ionic strength of the composition. For example, the organic acid may be added in an amount that provides the desired pH level of the composition, while the alkali metal (e.g., sodium) salt is added in an amount that provides the desired degree of ion pairing. As will be understood by one of ordinary skill in the art, the amount of the organic acid (i.e., the protonated form) present in the composition relative to the alkali metal salt or conjugate base form present in the composition will vary depending on the pH of the composition, the pKa of the organic acid, as well as the actual relative amounts initially added to the composition.

[0163] The amount of the organic acid or its alkali metal salt present in the composition relative to a basic amine (e.g., nicotine) can vary. Generally, as the concentration of the organic acid (or its conjugate base) increases, the percentage of the basic amine (e.g., nicotine), which is an ion neutralized by the organic acid, increases. This is typically due to the logP (log of the partition coefficient) of the basic amine (e.g., nicotine) in the form of an ion pair 10) increases the octanol / water partition measured thereby. In some embodiments, the composition is calculated as the free base of the basic amine and contains from about 0.05, about 0.1, about 1, about 1.5, about 2, or about 5 to about 10, about 15, or about 20 molar equivalents of an organic acid, an alkali metal salt thereof, or a combination thereof relative to the basic amine (e.g., nicotine).

[0164] In some embodiments, the composition contains from about 2 to about 10, or from about 2 to about 5 molar equivalents of an organic acid, an alkali metal salt thereof, or a combination thereof relative to the basic amine (e.g., nicotine) based on the free base basis. In some embodiments, the organic acid, an alkali metal salt thereof, or a combination thereof is present at a molar ratio to the basic amine (e.g., nicotine) of about 2, about 3, about 4, or about 5 to about 6, about 7, about 8, about 9, or about 10. In embodiments where more than one organic acid, an alkali metal salt thereof, or both are present, it will be understood that such molar ratios reflect the total amount of organic acid present.

[0165] In certain embodiments, the inclusion of the organic acid is sufficient to impart to the composition a pH of from about 4.0 to about 9.0, such as from about 4.5 to about 7.0, or from about 5.5 to about 7.0, from about 4.0 to about 5.5, or from about 7.0 to about 9.0. In some embodiments, the inclusion of the organic acid is sufficient to impart to the composition a pH of from about 4.5 to about 6.5, such as about 4.5, about 5.0, or from about 5.5 to about 6.0, or about 6.5. In some embodiments, the organic acid is provided in an amount sufficient to impart to the composition a pH of from about 5.5 to about 6.5, such as about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, or from about 6.0 to about 6.1, about 6.2, about 6.3, about 6.4, or about 6.5. In other embodiments, a mineral acid (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, etc.) is added to adjust the pH of the composition to a desired value.

[0166] In some embodiments, the organic acid is added to other composition components either as the free acid, neat (i.e., in its native solid or liquid form), or, for example, as a solution in water. In some embodiments, the alkali metal salt of the organic acid is added to other composition components either neat or, for example, as a solution in water. In some embodiments, the organic acid and a basic amine (e.g., nicotine) are combined either before addition to the composition or such that a salt is formed within the composition and exists as such in the composition. In other embodiments, the organic acid and a basic amine (e.g., nicotine) exist as individual components within the composition and form an ion pair upon contact with moisture (e.g., saliva in the consumer's mouth).

[0167] In some embodiments, the organic acid is added to other composition components either as the free acid, neat (i.e., in its native solid or liquid form), or, for example, as a solution in water. In some embodiments, the alkali metal salt of the organic acid is added to other composition components either neat or, for example, as a solution in water. In some embodiments, the organic acid and the basic amine-containing active ingredient (e.g., nicotine) are combined prior to addition to the composition to form a salt or such that a salt is formed within the composition and exists in the composition as such.

[0168] Ion pairing In some embodiments, at least a portion of the active ingredient (e.g., nicotine) containing basic amine functionality is associated with at least a portion of the organic acid or its alkali metal salt present in the composition. Depending on a plurality of variables (such as the concentration of the organic acid, pH, nature, etc.), the active ingredient containing basic amine functionality present in the composition can exist in solution (i.e., fully solvated) as a free base, as a cation, as a salt, or in any combination thereof, in a plurality of forms including counter-ionized ions. In some embodiments, the association between the active ingredient containing basic amine functionality and at least a portion of the organic acid or its alkali metal salt is in the form of an ion pair between the active ingredient containing basic amine functionality and the conjugate base of the organic acid. In other embodiments, the organic acid and the basic amine-containing active ingredient (e.g., nicotine) are present as individual components in the composition and form an ion pair upon contact with moisture (e.g., saliva in the consumer's mouth). In some embodiments, the oral composition contains nicotine benzoate and sodium benzoate, where at least a portion of the nicotine ions and benzoate ions present are in an ion-paired form.

[0169] Ion pairing describes the partial association of oppositely charged ions in a relatively concentrated solution to form a distinct chemical species called an ion pair. The strength of the association (i.e., ion pairing) depends on the electrostatic force of attraction between the positive and negative ions (i.e., protonated basic amines such as nicotine and the conjugate bases of organic acids). By "conjugate base" is meant the base resulting from the deprotonation of the corresponding acid (e.g., benzoate is the conjugate base of benzoic acid). On average, a certain population of these ion pairs exists at any given time, but the formation and dissociation of ion pairs is continuous. In the compositions disclosed herein and / or upon oral use of said compositions (e.g., upon contact with saliva), active ingredients containing a basic amine functionality such as nicotine and the conjugate bases of organic acids are present at least partially in the form of ion pairs. Without wishing to be bound by theory, it is believed that such ion pairing may minimize the chemical degradation of active ingredients containing a basic amine functionality and / or enhance the oral availability of active ingredients containing a basic amine functionality (e.g., nicotine). At alkaline pH values (e.g., from about 7.5 to about 9), certain basic amine-containing active ingredients such as nicotine are mostly present in the free base form, which has relatively low water solubility and low stability in terms of evaporation and oxidative degradation, but high mucosal availability. Conversely, at acidic pH values (e.g., from about 6.5 to about 4), certain active ingredients such as nicotine are mostly present in the protonated form, which has relatively high water solubility and higher stability in terms of evaporation and oxidative degradation, but low mucosal availability.

[0170] One of ordinary skill in the art will recognize that the degree of ion pairing in the disclosed compositions can vary both before and during consumer use, based on, for example, pH, the nature of the organic acid, the concentration of the active ingredient including basic amine functionality, the concentration of the organic acid or the conjugate base of the organic acid present in the composition, the water content of the composition, the ionic strength of the composition, and the like. One of ordinary skill in the art will also recognize that ion pairing is an equilibrium process that is affected by the aforementioned variables. Accordingly, quantification of the degree of ion pairing is difficult or impossible by calculation or direct observation. However, the presence of ion pairing can be demonstrated through alternative means, for example, through the partitioning of the active ingredient including basic amine functionality between octanol and water, or by performing membrane permeation studies of aqueous solutions of the active ingredient including basic amine functionality plus organic acid and / or their conjugate bases.

[0171] As described above, the active ingredient including basic amine functionality can be nicotine or a nicotine component. However, other active ingredients including basic amine functionality are contemplated herein. One of ordinary skill in the art will recognize that many of the active ingredients described herein below can be composed of molecules that can be categorized as basic amines. Accordingly, ion pairing of such basic amine-containing active ingredients with the organic acids described herein is contemplated.

[0172] Flavoring agent In some embodiments, the compositions described herein include a flavoring agent. As used herein, "flavoring agent" or "flavor substance" is any flavorful or aromatic substance that can modify the sensory properties associated with an oral product. Examples of sensory properties that can be modified by a flavoring agent include taste, mouthfeel, moistness, and / or aroma / odor. To avoid doubt, such flavoring agents are distinct and distinguishable from the modifiers (e.g., sensates) disclosed herein. The flavoring agent may be natural or synthetic, and the flavor characteristics imparted thereby can be described as, but are not limited to, fresh, sweet, herbal, confectionary, floral, fruity or spicy.

[0173] A flavoring agent may be an imitation, synthetic or natural ingredient, or a blend thereof. Flavoring agents include naturally occurring flavor materials, botanicals, botanical extracts, synthetically obtained materials, or combinations thereof (e.g., tobacco, cannabis, licorice, hydrangea, phyllostachys pubescens leaves, chamomile, fenugreek, maple, matcha, peppermint, anise seed (anis), turmeric, Indian spices, Asian spices, herbs, wintergreen, cherry, berry, redberry, cranberry, peach, apple, orange, mango, clementine, lemon, lime, tropical fruit, papaya, rhubarb, grape, durian, dragon fruit, cucumber, blueberry, mulberry, citrus, damson, bourbon, scotch, whiskey, gin, tequila, rum, spearmint, peppermint, lavender, aloe vera, cardamom, celery, cascarilla, nutmeg, sandalwood, bergamot, geranium, cart, nasturtium, kinnow, shisha, pine, honey essence, rose oil, vanilla, lemon oil, orange oil, orange blossom, cherry blossom, cassia, caraway, cognac, jasmine, ylang-ylang, sage, fennel, pimento, ginger, coriander, coffee, asa, mint oil from any species of the genus Mentha, star anise, cocoa, lemongrass, rooibos, flax, ginkgo biloba, hazel, hibiscus, laurel, mate, orange peel, rose, green tea or black tea such as tea, thyme, English ivy, elderflower, basil, bay leaf, cumin, oregano, paprika, rosemary, saffron, lemon peel, mint, perilla, curcuma, cilantro, gingergrass, blackcurrant, English plantain, pimento, mace, damiana, marjoram, olive, lemon balm, lemon basil, chive, caraway, verbena, tarragon, limonene), and other additives such as charcoal, chlorophyll, minerals, botanicals or agents that provide a refreshing effect may be mentioned.

[0174] The flavoring agent may be in any suitable form, such as a liquid like oil, a solid like powder, or a gas. In some examples, the flavoring agent can be imparted in a spray-dried form or a liquid form. In some embodiments, the liquid flavoring substance is disposed on (i.e., adsorbed or absorbed in or on) a porous particulate carrier, such as microcrystalline cellulose, which is then combined with other composition components.

[0175] The amount of flavoring agent utilized in the composition may vary, but is typically at most about 10% by weight, and certain embodiments are characterized by a flavoring agent content of at least about 0.1% by weight, such as about 0.5% to about 10% by weight, about 1% to about 5% by weight, or about 2% to about 4% by weight, based on the total weight of the composition.

[0176] Taste modifying agent To improve the sensory acceptability of the compositions disclosed herein, the compositions may include one or more taste modifying agents ( "taste modifier") that can act to mask, alter, block, or improve, for example, the flavor of the compositions described herein. In some embodiments, the taste modifying agent modifies one or more of a bitter, sweet, salty, or sour taste. In some embodiments, the composition includes an active ingredient having a bitter taste and a taste modifying agent that masks or blocks the perception of the bitter taste. Suitable taste modifying agents include, but are not limited to, gamma-aminobutyric acid (GABA), adenosine monophosphate (AMP), lactitol, or combinations thereof.

[0177] When present, representative amounts of the taste modifying agent are about 0.01% by weight or more, about 0.1% by weight or more, or about 1.0% by weight or more, but typically less than about 10% by weight of the total weight of the composition (e.g., about 0.01% by weight, about 0.05% by weight, about 0.1% by weight, or about 0.5% to about 1%, about 5% by weight, or about 10% by weight of the total weight of the composition).

[0178] Salt In some embodiments, the composition may further comprise a salt (e.g., an alkali metal salt) typically utilized in an amount sufficient to impart the desired sensory attributes to the composition. Non-limiting examples of suitable salts include sodium chloride, potassium chloride, ammonium chloride, table salt, and the like.

[0179] When present, representative amounts of the salt are about 0.5 weight percent or more, about 1.0 weight percent or more, or about 1.5 weight percent or more, but typically occupy about 10 weight percent or less, or about 7.5 weight percent or less, or about 5 weight percent or less (e.g., about 0.5 to about 5 weight percent) of the total weight of the composition.

[0180] Sweetener To improve the sensory properties of the composition according to the present disclosure, one or more sweeteners may be added. The sweetener can be any sweetener, or combination of sweeteners, in natural or artificial form, or as a combination of natural and artificial sweeteners. Examples of natural sweeteners include fructose, sucrose, glucose, maltose, mannose, galactose, lactose, stevia, honey, and the like. Examples of artificial sweeteners include sucralose, isomaltulose, maltodextrin, saccharin, aspartame, acesulfame K, neotame, and the like. In some embodiments, the sweetener comprises one or more sugar alcohols. A sugar alcohol is a polyol derived from a monosaccharide or disaccharide having a partially or fully hydrogenated form. The sugar alcohol has, for example, about 4 to about 20 carbon atoms and includes erythritol, arabinitol, ribitol, isomalt, maltitol, dulcitol, iditol, mannitol, xylitol, lactitol, sorbitol, and combinations thereof (e.g., hydrogenated starch hydrolysates). In some embodiments, the sweetener is sucralose, acesulfame K, or a combination thereof.

[0181] When present, the sweetener, or combination of sweeteners, may occupy from about 0.01 to about 20 weight percent or more of the composition, based on the total weight of the composition, such as from about 0.01 to about 0.1 weight percent, from about 0.1 to about 1 weight percent, from about 1 to about 5 weight percent, from about 5 to about 10 weight percent, or from about 10 to about 20 weight percent. In some embodiments, the combination of sweeteners is present at a concentration of from about 0.01 weight percent to about 0.1% of the composition, such as at a concentration of about 0.01, about 0.02, about 0.03, about 0.04, about 0.05, about 0.06, about 0.07, about 0.08, about 0.09, or about 0.1 weight percent of the composition. In some embodiments, the combination of sweeteners is present at a concentration of from about 0.1 weight percent to about 0.5 weight percent of the composition, such as at a concentration of about 0.1, about 0.2, about 0.3, about 0.4, or about 0.5 weight percent. In some embodiments, the combination of sweeteners is present at a concentration of from about 1 weight percent to about 3 weight percent of the composition.

[0182] Binder of the composition In certain embodiments, the composition may include a binder, or combination of binders, to impart desired physical properties and physical strength to the composition, such as a thickener or gelling agent. Typical binders can be organic or inorganic, or combinations thereof. Representative binders include, but are not limited to, povidone, sodium alginate, starch-based binders, pectin, carrageenan, pullulan, zein, and combinations thereof. The binder can be utilized in an amount sufficient to impart the desired physical properties and physical strength to the composition. The amount of binder utilized in the composition can vary, but is typically up to about 30 weight percent, and certain embodiments are characterized by a binder content of at least about 0.1 weight percent, such as from about 1 to about 30 weight percent, or from about 5 to about 10 weight percent, based on the total weight of the composition.

[0183] Other suitable binders include gums, such as natural gums. As used herein, natural gums refer to polysaccharide materials of natural origin having binding properties, which are also useful as thickeners or gelling agents. Representative natural gums derived from plants, which are typically water-soluble to some extent, include xanthan gum, guar gum, gum arabic, ghatti gum, tragacanth gum, karaya gum, locust bean gum, gellan gum, and combinations thereof. When present, the natural gum binder material is typically present in an amount of up to about 5% by weight, such as about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, or about 1% to about 2, about 3, about 4, or about 5% by weight, based on the total weight of the composition.

[0184] Humectant In certain embodiments, one or more humectants may be utilized in the composition. Examples of humectants include, but are not limited to, polyols such as glycerin, propylene glycol, and the like. When included, the humectant is typically provided in an amount sufficient to impart the desired moisture characteristics to the composition. Further, in some instances, the humectant may impart the desired flow characteristics to the composition for deposition in the mold.

[0185] When present, the humectant typically occupies about 5% or less (e.g., about 0.5 to about 5% by weight) of the weight of the composition. When present, representative amounts of the humectant are about 0.1% to about 1% by weight, or about 1% to about 5% by weight, based on the total weight of the composition.

[0186] Buffer In certain embodiments, the compositions of the present disclosure may include a pH adjuster or a buffer. Examples of pH adjusters and buffers that may be used include metal hydroxides (e.g., alkali metal hydroxides such as sodium hydroxide and potassium hydroxide), and other alkali metal buffering materials such as metal carbonates (e.g., potassium carbonate or sodium carbonate), or metal bicarbonates such as sodium bicarbonate, but are not limited thereto. Non-limiting examples of suitable buffers include alkali metal acetates, glycine salts, phosphates, glycerophosphates, citrates, carbonates, bicarbonates, borates, or mixtures thereof.

[0187] When present, the buffer is typically present in an amount of less than about 5 percent, based on the weight of the composition, e.g., from about 0.5 wt% to about 5 wt%, such as from about 0.75 wt% to about 4 wt%, from about 0.75 wt% to about 3 wt%, or from about 1 wt% to about 2 wt%, based on the total weight of the composition.

[0188] Colorant The colorant may be utilized in an amount sufficient to impart the desired physical properties to the composition. Natural or synthetic colorants such as natural or synthetic dyes, food-grade colorants, and pharmaceutical-grade colorants may be used. Examples of colorants include a variety of dyes and pigments such as caramel colorants, and titanium dioxide. Natural colorants such as curcumin, beet juice extract, spirulina; also a variety of synthetic pigments may also be used. The amount of colorant utilized in the composition may vary, but when present, is typically up to about 3 wt%, such as about 0.1 wt%, about 0.5 wt%, or from about 1 wt% to about 3 wt%, based on the total weight of the composition.

[0189] Oral care additive In some embodiments, the composition includes an oral care component (or a mixture of such components). The oral care component imparts the ability to inhibit tooth decay or tooth loss, the ability to inhibit periodontal disease, the ability to relieve mouth pain, the ability to whiten teeth, or otherwise inhibit tooth staining, the ability to stimulate saliva, the ability to inhibit bad breath, the ability to freshen breath, etc. For example, an effective amount of components such as thyme oil, eucalyptus oil, and zinc (e.g., components of a formulation commercially available as ZYTEX® from Discus Dental) can be incorporated into the composition. Other examples of components that can be incorporated in the desired effective amounts within the present composition can include those incorporated within the types of oral care compositions described below: Takahashi et al., Oral Microbiology and Immunology, 19(1), 61-64 (2004); Thistle U.S. Patent No. 6,083,527; and Jakubowski U.S. Patent Application Publication No. 2006 / 0210488, and Cummins et al. U.S. Patent Application Publication No. 2006 / 02228308. Other exemplary components of tobacco-containing formulations can include those contained in formulations commercially available as MALTISORB® by Roquette, and formulations commercially available as DENTIZYME® by NatraRx. When present, representative amounts of oral care additives are at least about 1%, often at least about 3%, frequently at least about 5% of the total dry weight of the foaming composition. The amount of oral care additive within the foaming composition typically does not exceed about 30%, often does not exceed about 25%, frequently does not exceed about 20% of the total dry weight of the foaming composition.

[0190] Processing aid If necessary for downstream processes of the composition such as granulation, mixing or molding, a flow aid can also be added to the composition to enhance its fluidity. In some embodiments, the composition (e.g., in the form of a melt and a chewable) may be surface-treated with an anti-sticking agent such as oil, silicone, etc. Exemplary flow aids include microcrystalline cellulose, silica, polyethylene glycol, stearic acid, calcium stearate, magnesium stearate, zinc stearate, sodium stearyl fumarate, carnauba wax, and combinations thereof. In some embodiments, the flow aid is sodium stearyl fumarate.

[0191] When present, a representative amount of the flow aid can account for at least about 0.5 percent, or at least about 1 percent, of the total dry weight of the composition. Preferably, the amount of the flow aid in the composition does not exceed about 5 percent of the total dry weight of the composition, and frequently does not exceed about 3 percent.

[0192] Other additives Other additives can be included in the disclosed compositions. For example, the composition can be treated, blended, formulated, combined and / or mixed with other materials or components. The additives can be artificial, or can be obtained from herbs or biological sources, or can be derived from biological sources. Examples of further types of additives include thickening or gelling agents (e.g., fish gelatin), emulsifiers, preservatives (e.g., potassium sorbate, etc.), disintegrating aids or combinations thereof. See, for example, U.S. Patent No. 9,237,769 to Mua et al., U.S. Patent No. 7,861,728 to Holton, Jr. et al., U.S. Patent Application Publication No. 2010 / 0291245 to Gao et al., and U.S. Patent Application Publication No. 2007 / 0062549 to Holton, Jr. et al., which are each incorporated herein by reference, for representative components, combinations of components, relative amounts of these components, and the manner and method of using these components.

[0193] The typical inclusion ranges of such additional additives can vary depending on the nature and function of the additive and the intended effect on the final composition. By way of example, the range can be up to about 10% by weight (e.g., about 0.1% to about 5% by weight) based on the total weight of the composition.

[0194] The additives described above can be utilized together (e.g., as an additive formulation) or separately (e.g., individual additive components can be added at different stages involved in the preparation of the final mixture). Further, additives of the types described above may be encapsulated so as to be imparted in the final product or in the composition. Encapsulated additives by way of example are described, for example, in Atchley's WO2010 / 132444, which is hereby incorporated by reference.

[0195] Particulates In some embodiments, any one or more of the filler, tobacco material, other composition components, and the overall composition described herein can be described as particulate material. As used herein, the term "particulate" refers to a material in the form of a plurality of individual particles, some of which can be in the form of aggregates of a plurality of particles, and the particles have an average length:width ratio of less than 2:1, e.g., less than 1.5:1, e.g., about 1:1. In various embodiments, the particles of the particulate material can be described as being substantially spherical or granular.

[0196] The particle size of the particulate material can be measured by sieve analysis. As will be immediately recognized by those skilled in the art, sieve analysis (otherwise known as a gradation test) is a method used to measure the particle size distribution of a particulate material. Typically, sieve analysis involves a nest of columns with sieves equipped with screens, preferably in the form of wire mesh cloth. A pre-weighed sample can be introduced into the top or uppermost sieve in the column that has the largest screen opening or mesh size (i.e., the largest pore diameter of the sieve). Each lower sieve in the column has a screen opening or mesh size that is progressively smaller than the sieve above it. Typically, the base of the column of sieves is a receiving portion that collects any particles having a particle size smaller than the bottom or lowest screen opening size or mesh size in the column (having the smallest screen opening or mesh size).

[0197] In some embodiments, the column sieve can be placed on or in a mechanical stirrer. The stirrer causes each vibration of the sieve in the column. The mechanical stirrer can be activated for a given time to ensure that all particles are collected in the correct sieve. In some embodiments, the column sieve is stirred for a time between 0.5 minutes and 10 minutes, such as between 1 minute and 10 minutes, such as between 1 minute and 5 minutes, such as approximately 3 minutes. Once the stirring of the sieve in the column is complete, the material collected in each sieve is weighed. Then, the weight of each sample in each sieve can be divided by the total weight to obtain the percentage of the mass retained in each sieve. As will be readily appreciated by those skilled in the art, the screen opening or mesh size for each sieve in the column used for sieve analysis can be selected based on the particle size, or based on the known maximum / minimum particle size of the sample to be analyzed. In some embodiments, the column sieve can be used for sieve analysis, where the column includes 2 to 20 sieves, such as 5 to 15 sieves. In some embodiments, the column sieve can be used for sieve analysis, where the column includes 10 sieves. In some embodiments, the maximum screen opening or mesh size of the sieve used for sieve analysis can be 1000 μm, such as 500 μm, such as 400 μm, such as 300 μm.

[0198] In some embodiments, any particulate material (e.g., filler, tobacco material, and overall composition) referred to herein can be characterized by having at least 50 wt% of the particles with a particle size measured by sieve analysis of about 1000 μm or less, such as about 500 μm or less, such as about 400 μm or less, such as about 350 μm or less, such as about 300 μm or less. In some embodiments, at least 60 wt% of the particles of any particulate material referred to herein, when measured by sieve analysis, have a particle size of about 1000 μm or less, such as about 500 μm or less, such as about 400 μm or less, such as about 350 μm or less, such as about 300 μm or less. In some embodiments, at least 70 wt% of the particles of any particulate material referred to herein, when measured by sieve analysis, have a particle size of about 1000 μm or less, such as about 500 μm or less, such as about 400 μm or less, such as about 350 μm or less, such as about 300 μm or less. In some embodiments, at least 80 wt% of the particles of any particulate material referred to herein, when measured by sieve analysis, have a particle size of about 1000 μm or less, such as 500 μm or less, such as about 400 μm or less, such as about 350 μm or less, such as about 300 μm or less. In some embodiments, at least 90 wt% of the particles of any particulate material referred to herein, when measured by sieve analysis, have a particle size of about 1000 μm or less, such as about 500 μm or less, such as about 400 μm or less, such as about 350 μm or less, such as about 300 μm or less. In some embodiments, at least 95 wt% of the particles of any particulate material referred to herein, when measured by sieve analysis, have a particle size of about 1000 μm or less, such as about 500 μm or less, such as about 400 μm or less, such as about 350 μm or less, such as about 300 μm or less. In some embodiments, at least 99 wt% of the particles of any particulate material referred to herein, when measured by sieve analysis, have a particle size of about 1000 μm or less, such as about 500 μm or less, such as about 400 μm or less, such as about 350 μm or less, such as about 300 μm or less.In some embodiments, about 100 weight percent of the particles of any particulate material referred to herein have a particle size measured by sieve analysis of about 1000 μm or less, such as about 500 μm or less, such as about 400 μm or less, such as about 350 μm or less, such as about 350 μm or less.

[0199] In some embodiments, at least 50 weight percent, such as at least 60 weight percent, such as at least 70 weight percent, such as at least 80 weight percent, such as at least 90 weight percent, such as at least 95 weight percent, such as at least 99 weight percent of the particles of any particulate material referred to herein have a particle size measured by sieve analysis of from about 0.01 μm to about 1000 μm, such as from about 0.05 μm to about 750 μm, such as from about 0.1 μm to about 500 μm, such as from about 0.25 μm to about 500 μm. In some embodiments, at least 50 weight percent, such as at least 60 weight percent, such as at least 70 weight percent, such as at least 80 weight percent, such as at least 90 weight percent, such as at least 95 weight percent, such as at least 99 weight percent of the particles of any particulate material referred to herein have a particle size measured by sieve analysis of from about 10 μm to about 400 μm, such as from about 50 μm to about 350 μm, such as from about 100 μm to 350 μm, such as from about 200 μm to about 300 μm.

[0200] Preparation of the Composition The manner in which the various components of the mixture are combined can be diverse. As such, for example, a total mixture of multiple components having powder mixture components can be relatively homogeneous per se. The components noted above, which can be in liquid form or dry solid form, can be added and mixed in a pretreatment step before being mixed with any remaining components of the mixture, or simply mixed together with all other liquid or dry components. The various components of the mixture may be contacted, combined, or mixed together using any mixing technique or equipment known in the art. Any mixing method that brings the mixture components into intimate contact, for example, a mixer characterized by an impeller or other structure capable of intense agitation, can be used. Examples of mixing equipment include casting drums, conditioning cylinders or drums, liquid spraying equipment, conical type blenders, ribbon blenders, mixers available as FKM130, FKM600, FKM1200, FKM2000, and FKM3000 from Littleford Day, Inc., Plough Share type mixer cylinders, Hobart mixers, and the like. See, for example, the methodologies of the type described in U.S. Patent Nos. 4,148,325 to Solomon et al., 6,510,855 to Korte et al., and 6,834,654 to Williams, each of which is incorporated herein by reference. The manner and method of compounding the mixture will be apparent to those skilled in the art. See, for example, the methodologies of the type described in U.S. Patent Nos. 4,148,325 to Solomon et al., 6,510,855 to Korte et al., 6,834,654 to Williams, 4,725,440 to Ridgway et al., and 6,077,524 to Bolder et al., each of which is incorporated herein by reference.

[0201] In some embodiments, the composition can be prepared such that the mixture of the composition can be used in a non-starch molding process or a starch-based molding process. Examples of types of molds that can be used in the production process include, for example, starch molds, non-starch molds, pectin molds, plastic tray molds, silicone tray molds, metal tray molds, neoprene tray molds, and the like.

[0202] Configuration for Oral Use Provided herein is a composition configured for oral use. The term "configured for oral use", as used herein, means that during use, the saliva in the user's mouth causes the composition to be provided in a form such that one or more of the components of the composition (e.g., basic amines, flavoring agents, and / or active ingredients) pass into the user's mouth. In certain embodiments, the composition is adapted to deliver components to the user through the mucosa in the user's mouth, the user's digestive system, or both, and in some examples, such components can be absorbed through the mucosa in the mouth or through the digestive tract when the product is used, and are nicotine components, or active ingredients (e.g., but not limited to, nicotine, stimulants, vitamins, amino acids, botanicals, or combinations thereof).

[0203] The compositions configured for oral use described herein can take a variety of forms including gels, pastilles, gums, chewables, melts, tablets, lozenges, granules, powders, and pouches. The gels can be soft or hard. Certain compositions of the present disclosure are in solid form. Certain compositions can exhibit, for example, one or more of the following characteristics: crispy, granular, chewable, syrupy, pasty, fluffy, smooth, and / or creamy. In certain embodiments, the desired texture properties can be selected from the group consisting of adhesiveness, compactness, density, dryness, fracturability, granularity, gumminess, hardness, heaviness, water absorbency, water release, mouth coating, coarseness, slipperiness, smoothness, viscosity, wetness, and combinations thereof.

[0204] The compositions of the present disclosure may be soluble. As used herein, the terms "soluble," "dissolve," and "dissolvable" refer to compositions having water-soluble components that interact with the moisture in the mouth and enter into solution, thereby causing the gradual consumption of the composition. According to one aspect, a soluble composition can persist in the user's mouth for a given period of time until it completely dissolves. The dissolution rate can vary widely from about 1 minute or less to about 60 minutes. For example, an immediate-release composition typically dissolves and / or releases a desired component (e.g., an active ingredient, a flavor, etc.) in about 2 minutes or less, often in about 1 minute or less (e.g., about 50 seconds or less, about 40 seconds or less, about 30 seconds or less, or about 20 seconds or less). Dissolution can occur by any means, such as melting, forceful fragmentation (e.g., chewing), enzymatic or other chemical disintegration, or disruption of the interaction between the components of the composition. In other embodiments, the product does not dissolve while it remains in the user's mouth.

[0205] The compositions disclosed herein can be formed into a variety of shapes including pills, tablets, spheres, strips, films, sheets, coins, cubes, beads, ovoids, obloids, cylinders, bean-shaped, sticks or rods. The cross-sectional shape of the composition can be diverse and exemplary cross-sectional shapes include circular, square, elliptical, rectangular, etc. Such shapes can be formed by a variety of methods using equipment such as moving belts, nip, extruders, granulating devices, compression devices, etc.

[0206] A composition configured for oral use is in the form of a pastille. As used herein, the term "pastille" refers to a soluble oral composition made by solidifying a liquid composition or a gel composition such that the final composition is a somewhat hardened solid gel. The rigidity of the gel can vary widely. The pastille product can alternatively be referred to as a soft lozenge. In certain embodiments, the pastille products of the present disclosure are characterized by an adhesion sufficient to withstand light chewing motions in the mouth without rapid disintegration. The pastille products of the present disclosure typically do not exhibit the very deformable chewing quality found in conventional chewing gums.

[0207] In some embodiments, the products disclosed herein may be in the form of soluble lozenge products configured for oral use. Exemplary lozenge-type products of the invention have the form of lozenges, tablets, microtabs, or other tablet-type products. For example, the types of nicotine-containing lozenges, lozenge formulations, lozenge forms and configurations, lozenge properties, and techniques for formulating or manufacturing lozenges are described below: U.S. Patent No. 4,967,773 to Shaw; No. 5,110,605 to Acharya; No. 5,733,574 to Dam; No. 6,280,761 to Santus; No. 6,676,959 to Andersson et al.; No. 6,248,760 to Wilhelmsen; and No. 7,374,779 to Wilhelmsen; U.S. Patent Application Publication No. 2001 / 0016593 to Wilhelmsen; No. 2004 / 0101543 to Liu et al.; No. 2006 / 0120974 to Mcneight; No. 2008 / 0020050 to Chau et al.; No. 2009 / 0081291 to Gin et al.; and No. 2010 / 0004294 to Axelsson et al., which are incorporated herein by reference.

[0208] Lozenge products are generally described as "hard" and are thus distinguished from soft lozenges (i.e., pastilles). Hard lozenges are a mixture of sugars and / or carbohydrates in an amorphous state. Although they are made from an aqueous syrup, the initially present water evaporates as the syrup boils during processing, and the water content in the finished product is very low, for example, 0.5 wt% to 1.5 wt%. To obtain a hard and non-sticky lozenge, the melting temperature generally has to reach a hard crack stage, for example, a temperature in the range of 149 °C to 154 °C.

[0209] In some embodiments, the composition can be chewable, which means that the composition has a gentle resilience or "springiness" and the desired degree of malleability when chewed. The composition in chewable form may dissolve completely or may be in the form of a non-soluble gum where only certain components (e.g., active ingredients, flavors, sweeteners) dissolve and leave a non-dissolved matrix behind. Chewable embodiments generally include a binder, such as a natural gum or pectin. In some embodiments, the composition in chewable form includes pectin and an organic acid together with one or more sugar alcohols in an amount of at least 50 wt% based on the total weight of the composition. Generally, pectin is present in an amount of about 1 to about 3 wt% based on the total weight of the composition.

[0210] In some embodiments, the composition can be meltable, as discussed, for example, in Cantrell et al., U.S. Patent Application Publication No. 2012 / 0037175, which is incorporated herein by reference in its entirety. As used herein, "melt," "melting," and "meltability" refer to the ability of a composition to change from a solid state to a liquid state. That is, melting occurs when a substance (e.g., the compositions disclosed herein) typically changes from a solid to a liquid upon application of heat. Application of heat in the context of the compositions disclosed herein is effected by the internal temperature of the user's mouth. Thus, the term "meltability" refers to a composition that can liquefy in the user's mouth, as it is intended to distinguish compositions that change phase from solid to liquid and simply disintegrate through loss of adhesion within the composition in the oral cavity from compositions that simply dissolve in the oral cavity as water-soluble components of the composition that interact with moisture. Generally, meltable compositions include the lipids described above herein. In some embodiments, the composition in meltable form includes lipids in an amount of about 35 to about 50 weight percent, based on the total weight of the composition, and sugar alcohols in an amount of about 35 to about 55 weight percent, based on the total weight of the composition. In some embodiments, the sugar alcohol is isomalt, erythritol, sorbitol, arabinitol, ribitol, maltitol, dulcitol, iditol, mannitol, xylitol, lactitol, or a combination thereof. In some embodiments, the sugar alcohol is isomalt.

[0211] In certain embodiments, the composition is in the form of compressed or molded pellets. Exemplary pellets are in the range of about 250 mg to about 1500 mg, such as about 250 mg to about 700 mg, or about 700 mg to about 1500 mg in weight. The pellets can have any of a variety of forms, including the form of conventional pills or tablets. Generally, the composition in tablet form comprises a blend of glucose-polysaccharide and a sugar alcohol. In some embodiments, the blend of glucose-polysaccharide is present in an amount of about 35 to about 50 wt% based on the total weight of the composition; the sugar alcohol is present in an amount of about 30 to about 45 wt% based on the total weight of the composition. In some embodiments, the sugar alcohol is isomalt, erythritol, sorbitol, arabinitol, ribitol, maltitol, dulcitol, iditol, mannitol, xylitol, lactitol, or a combination thereof. In some embodiments, the sugar alcohol is isomalt.

[0212] In one embodiment, the composition of the present disclosure is disposed within a moisture-permeable container (e.g., a water-permeable pouch). The composition enclosed in the pouch can be in any desired form. In certain embodiments, the composition is in granular form. Such a composition in the form of a water-permeable pouch is typically used by placing one pouch containing the composition in the mouth of a human subject / user. Generally, the pouch is placed anywhere within the user's oral cavity, for example, under the lip in the same manner as a moist snuff product is commonly used. The pouch is preferably not chewed or swallowed unless the pouch composition or material is ingestible (e.g., soluble or dispersible) as described hereinbelow. Then, exposure to saliva causes some of the components of the composition therein (e.g., flavoring agent and / or nicotine) to pass through, for example, the water-permeable pouch, imparting flavor and satisfaction to the user, and the user is not required to spit out any portion of the mixture. After about 10 minutes to about 60 minutes of use / enjoyment, typically after about 15 minutes to about 45 minutes, a substantial amount of the mixture is ingested by the human subject, and the pouch can be removed from the mouth of the human subject for disposal.

[0213] In some embodiments, the oral products provided herein may be in the form of a center-filled pastille or lozenge, for example, such that the interior (or at least a portion) of the product has one or more different sensory acceptabilities (e.g., texture, mouthfeel, taste, etc.) from its outer surface (or other portion thereof). Such center-filled pastille or lozenge formulations may include a foamy center fill surrounded by a harder outer shell that is liquid and / or gel and / or meltable and / or chewable and / or gummy, and / or may be associated with the pastille-type or lozenge products described herein. In such embodiments, the center fill may be described as having a lower stiffness and / or increased softness compared to the outer shell. In some embodiments, the center fill may or may not contain an active ingredient therein. For example, in some embodiments, both the outer shell and the center fill formulation may contain an active ingredient such that they provide a sustained release of the active ingredient therefrom. In some embodiments, at least the outer shell formulation includes the pastille formulation described above herein. In other embodiments, both the outer shell formulation and the center fill formulation may include the pastille formulations described herein that have similar or different sensory acceptabilities.

[0214] Thus, in certain embodiments, the compositions disclosed herein and any of the other ingredients noted above are combined within a moisture permeable packet or pouch that serves as a container for use of the composition to provide a pouch product configured for oral use. Certain embodiments of the present disclosure are described with reference to the accompanying drawings, and these described embodiments pertain to sniff tobacco products having an outer pouch that contains the mixtures described herein. As will be described in more detail below, such embodiments are given by way of example only, and the pouch products of the present disclosure may include compositions in other forms. The mixture / structure of such a packet or pouch, e.g., the container pouch 102 in the embodiments illustrated in the drawings, may vary. Referring to the drawings, a first embodiment of a pouch product 100 is shown. The pouch product 100 includes a moisture permeable container in the form of a pouch 102 that contains a material 104 that includes the composition described herein.

[0215] Suitable packets, pouches or containers of the type used for the manufacture of smokeless tobacco products are available under the trade names CatchDry, Ettan, General, Granit, Goteborgs Rape, Grovsnus White, Metropol Kaktus, Mocca Anis, Mocca Mint, Mocca Wintergreen, Kicks, Probe, Prince, Skruf and TreAnkrare. The mixture may be contained within a pouch and packaged in a manner and using ingredients of the type used for the manufacture of conventional sniff tobacco type products. The pouch provides a liquid permeable container of a type that may be considered to be similar in properties to the mesh-like type of material used for the structure of a tea bag. The components of the mixture are immediately diffused through the pouch into the user's mouth.

[0216] Non-limiting examples of suitable types of pouches are, for example, those described below: U.S. Patent No. 5,167,244 to Kjerstad, and U.S. Patent No. 8,931,493 to Sebastian et al., each of which is incorporated herein by reference; as well as U.S. Patent Application Publication Nos. 2016 / 0000140, 2016 / 0073689, 2016 / 0157515, and 2016 / 0192703 to Sebastian et al. The pouches may be provided as individual pouches, or multiple pouches (e.g., 2, 4, 5, 10, 12, 15, 20, 25, or 30 pouches) may be joined (e.g., in an end-to-end manner) or linked together such that individual pouches or aliquots can be readily removed for use from a single pouch or a matrix of pouches.

[0217] Example pouches may be made from materials and in such a way that the pouch undergoes controlled dispersion or dissolution during use by the user. Such pouch materials may have forms such as mesh, screen, perforated paper, permeable fabric, etc. For example, a pouch material made from a rice paper mesh-like form or perforated rice paper can dissolve in the user's mouth. As a result, the pouch and each mixture can undergo complete dispersion within the user's mouth under normal use conditions, and thus both the pouch and the mixture can be ingested by the user. Other examples of pouch materials can be made using water-dispersible films that form materials (e.g., binders such as alginate, carboxymethylcellulose, xanthan gum, pullulan, etc.) in combination with materials such as ground cellulose plastics (e.g., wood pulp with a fine particle size). Preferred pouch materials can be designed and manufactured to be water-dispersible or water-soluble while allowing a sufficient amount of the mixture content to permeate through the pouch material before the pouch undergoes loss of its physical strength under normal use conditions. If desired, flavoring components, disintegration aids, and other desired components can be incorporated or applied within the pouch material.

[0218] The amount of material contained within each product unit, e.g., within a pouch, may vary. In some embodiments, the weight of the composition within each pouch is at least about 50 mg, such as from about 50 mg to about 1 gram, from about 100 to about 800 mg, or from about 200 to about 700 mg. In some smaller embodiments, the weight of the composition within each pouch may be from about 100 to about 300 mg. For larger embodiments, the weight of the composition within each pouch may be from about 300 mg to about 700 mg. If desired, other components may be contained within each pouch. For example, at least one flavored strip, strip, piece or sheet of a flavored water-soluble or water-soluble material (e.g., a breath-freshening edible film type material) may be placed within each pouch, with or without at least one capsule. Such a strip or sheet may be folded or crumpled so as to be immediately incorporated within the pouch. See, for example, the types and techniques of materials described in U.S. Patent Nos. 6,887,307 to Scott et al. and 6,923,981 to Leung et al., which are incorporated herein by reference, and EFSA Journal (2004) 85, 1-32.

[0219] The pouch products described herein can be packaged within any suitable inner packaging material and / or outer container. For example, see also the various types of containers for smokeless type products described below: U.S. Patent No. 7,014,039 to Henson et al.; U.S. Patent No. 7,537,110 to Kutsch et al.; U.S. Patent No. 7,584,843 to Kutsch et al.; U.S. Patent No. 8,397,945 to Gelardi et al., U.S. Design Patent No. D592,956 to Thiellier, U.S. Design Patent No. D594,154 to Patel et al.; and U.S. Design Patent No. D625,178 to Bailey et al.; U.S. Patent Application Publication No. 2008 / 0173317 to Robinson et al.; U.S. Patent Application Publication No. 2009 / 0014343 to Clark et al.; U.S. Patent Application Publication No. 2009 / 0014450 to Bjorkholm; U.S. Patent Application Publication No. 2009 / 0250360 to Bellamah et al.; U.S. Patent Application Publication No. 2009 / 0266837 to Gelardi et al.; U.S. Patent Application Publication No. 2009 / 0223989 to Gelardi; U.S. Patent Application Publication No. 2009 / 0230003 to Thiellier; U.S. Patent Application Publication No. 2010 / 0084424 to Gelardi; and U.S. Patent Application Publication No. 2010 / 0133140 to Bailey et al.; U.S. Patent Application Publication No. 2010 / 0264157 to Bailey et al.; and U.S. Patent Application Publication No. 2011 / 0168712 to Bailey et al.

[0220] Many modifications and other embodiments of the invention having the benefits of the teachings presented above will come to the mind of those skilled in the art to which the invention pertains. Accordingly, it is to be understood that the invention is not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended "claims". Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

Examples

[0221] Aspects of the invention are more fully illustrated by the following examples, which are set forth to illustrate certain aspects of the invention and are not to be construed as limitations thereof.

[0222] Example 1. Pouch product containing nicotine and ion channel regulator An oral pouch product containing nicotine and an ion channel modulator is prepared. A filler and a nicotine source (e.g., nicotine benzoate solution) are combined with an ion channel modulator, sodium chloride, a sweetener, deionized water, and optionally sodium benzoate to impart a composition. The composition is transferred to a pouch filler, and the pouch filler contents are added into a non-woven fleece and the fleece is heat-sealed to fabricate an oral pouch product. Water is added to the pouch to impart a desired moisture content. The nicotine content of each pouch in the form of nicotine benzoate is about 6.0 mg based on free base nicotine.

Claims

1. A composition formulated for oral use, At least one active ingredient selected from the group consisting of botanical materials, stimulants, amino acids, vitamins, antioxidants, nutritional supplements, cannabinoids, cannabimimates, terpenes, pharmaceuticals, and combinations thereof. Ion channel modifiers selected from the group consisting of TRPA1 agonists, TRPA1 antagonists, TRPA1 channel blockers, TRPV1 agonists, TRPV3 agonists, TRPM8 agonists, NaV1.7 antagonists, and combinations thereof, and at least one type of filler A composition containing the following:

2. The composition according to claim 1, wherein the ion channel regulator is selected from the group consisting of TRPA1 agonists, TRPM8 agonists, TRPV1 agonists, TRPV3 agonists, and combinations thereof.

3. The composition according to claim 1, wherein the ion channel regulator is a TRPA1 antagonist or a TRPA1 channel blocker.

4. The composition according to claim 1, wherein the active ingredient comprises nicotine.

5. The composition according to claim 4, wherein nicotine is calculated as a free base and is present in an amount of 0.001 to 10% by weight of the composition based on the total weight of the composition.

6. The composition according to claim 1, wherein at least one filler comprises a cellulose material.

7. The composition according to claim 6, wherein the cellulose material includes microcrystalline cellulose.

8. The composition according to claim 6, wherein at least one filler further comprises a cellulose derivative in an amount of 1% to 3% by weight, based on the total weight of the composition.

9. The composition according to claim 8, wherein the cellulose derivative is hydroxypropylcellulose.

10. The composition according to claim 1, further comprising one or more flavoring agents, one or more salts, one or more sweeteners, one or more binders, one or more wetting agents, one or more gums, tobacco materials, or a combination thereof.

11. The composition according to claim 1, comprising 10% by weight or less of tobacco material, excluding any nicotine components present, based on the total weight of the composition.

12. The composition according to claim 1, which does not contain tobacco material.

13. A composition according to any one of claims 1 to 12, which is enclosed in a pouch to form a pouch product, wherein the composition is optionally in the form of granules.

14. The composition according to any one of claims 1 to 12, which is in the form of a gel, pastille, gum, chewable material, melt, tablet, lozenge, granular material, or powder.

15. The composition according to claim 1, wherein the ion channel regulator is benzyl cinnamate, dodecalactone, or a combination thereof.

16. The composition according to claim 1, wherein the ion channel regulator is liquiritin, phytol, or a combination thereof.

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