Oral products containing a basic amine and an ionizing agent

Abstract

The present disclosure provides compositions adapted for oral use, the compositions comprising at least one filler, water, a basic amine, and an organic acid, an alkali metal salt of an organic acid, or a combination thereof, wherein the organic acid has a logP value of about 1.4 to about 8.0. At least a portion of the basic amine is associated with at least a portion of the organic acid or its alkali metal salt. The association is in the form of an ion pair between the basic amine and the organic acid salt, an ion pair between the basic amine and the conjugate base of the organic acid, or a combination of both. Methods for stabilizing compositions adapted for oral use and for enhancing the expected buccal absorption of compositions adapted for oral use are further provided.

Description

Technical Field

[0001] The present disclosure relates to compositions intended for use in humans. The compositions are suitable for oral use and deliver substances such as nicotine, flavorants, and / or active ingredients during use. Such compositions may include tobacco or tobacco-derived products, or may be alternatives that do not include tobacco.

Background Art

[0002] Tobacco can be enjoyed in so-called "smokeless" forms. In particular, common smokeless tobacco products are used by inserting some form of processed tobacco or tobacco-containing formulation into the user's mouth. Conventional forms of such smokeless tobacco products include moist snuff, snus, and chewing tobacco, which are typically formed from substantially complete particulate, granular, or shredded tobacco and are either divided by the user or presented to the user in individual divided amounts such as single pouches or sachets. Other conventional forms of smokeless products include compressed or agglomerated forms such as plugs, tablets, or pellets. Alternative product forms such as tobacco-containing gums and mixtures of tobacco with other plant materials are also known.For example, see the types of smokeless tobacco blends, ingredients, and processing methods described in U.S. Patent No. 1,376,586 to Schwartz, No. 4,513,756 to Pittman et al., No. 4,528,993 to Sensabaugh, Jr. et al., No. 4,624,269 to Story et al., No. 4,991,599 to Tibbetts, No. 4,987,907 to Townsend, No. 5,092,352 to Sprinkle, III et al., No. 5,387,416 to White et al., No. 6,668,839 to Williams, No. 6,834,654 to Williams, No. 6,953,040 to Atchley et al., No. 7,032,601 to Atchley et al., No. 7,694,686 to Atchley et al., U.S. Patent Application Publication No. 2004 / 0020503 to Williams, No. 2005 / 0115580 to Quinter et al., No. 2006 / 0191548 to Strickland et al., No. 2007 / 0062549 to Holton, Jr. et al., No. 2007 / 0186941 to Holton, Jr. et al., No. 2007 / 0186942 to Strickland et al., No. 2008 / 0029110 to Dube et al., No. 2008 / 0029116 to Robinson et al., No. 2008 / 0173317 to Robinson et al., No. 2008 / 0209586 to Neilsen et al., No. 2009 / 0065013 to Essen et al., No. 2010 / 0282267 to Atchley, and International Publication No. 2004 / 095959 pamphlet to Arnarp et al. These are each incorporated herein by reference.

[0003] The configuration of smokeless tobacco products that combine tobacco materials with various binders and fillers has been proposed more recently and has exemplary product forms including lozenges, troches, gels, extruded forms, etc. See, for example, 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 these is incorporated herein by reference.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

Patent Document 6

Patent Document 7

Patent Document 8

Patent Document 9

Patent Document 10

Patent Document 11

Patent Document 12

Patent Document 13

Patent Document 14

Patent Document 15

Patent Document 16

Patent Document 17

Patent Document 18

Patent Document 19

Patent Document 20

Patent Document 21

Patent Document 22

Patent Document 23

Patent Document 24

Patent Document 25

Patent Document 26

Patent Document 27

Patent Document 28

Patent Document 29

Patent Document 30

Patent Document 31

Patent Document 32

Patent Document 33

Patent Document 34

Patent Document 35

Patent Document 36

Patent Document 37

Patent Document 38

Patent Document 39

Patent Document 40

Patent Document 41

Patent Document 42

Summary of the Invention

Means for Solving the Problems

[0005] The present disclosure generally provides a composition configured for oral use. The composition includes one or more fillers, water, an organic acid or a salt thereof, and a basic amine. The organic acid has a logP value of about 0 to about 8, and at least a portion of the basic amine and the organic acid or a salt thereof is present in the form of a salt.

[0006] Oral nicotine products are used by placing a nicotine-containing matrix between the cheek and the gum. The nicotine is then released from the product and absorbed through the oral mucosa, thereby entering the bloodstream where it is circulated throughout the body. Flavor stability and positive sensory attributes are important factors for an oral nicotine product that can be accepted by consumers. The sensory stimulating effect of the flavor has been shown to be particularly sensitive to the pH of the product. When the pH of the product exceeds about 7.0, the visual, olfactory, and gustatory effects of some flavoring agents deteriorate over time, and nicotine may evaporate from the product. This instability is particularly pronounced for certain flavoring agents such as ethyl vanillin, lime, and cinnamon, which also cause darkening of otherwise white products over time. However, a decrease in pH increases the extent of nicotine present in the protonated form. As a dibasic alkaloid, nicotine has two protons (pyridine ring nitrogen, logK a1 = 3.41, pyrrolidine ring nitrogen, logK a2can accept (log(P)=8.02), and significantly changes the polarity. The overall polarity of nicotine increases from log(P)=1.09 (non-protonated nicotine) to -2.07 (in the case of nicotine protonated at the pyrrolidine ring nitrogen). Passive diffusion of substances such as nicotine across membranes (e.g., mucosal membranes) is a function of molecular polarity and membrane properties, as well as molecular size and ionization (Kokate et al., PharmSciTech 2008, 9, 501 - 504).

[0007] While not wishing to be bound by theory, a downward shift in log(P) as a result of the protonation state is thought to be the main driving force behind the decrease in nicotine absorption with decreasing pH. (Nair et al., Journal of Pharmaceutical Sciences 1997, 86, 257 - 262; Chen et al., International Journal of Pharmaceutics 1999, 184, 63 - 72; Adrian et al., International Journal of Pharmaceutics 2006, 311, 196 - 202). Specifically, as reported by Adrian et al., in a nicotine solution at pH = 6 (when nicotine is mainly monoprotonated), some diffusion across human buccal tissue in a perfusion cell still occurred, but the ratio was significantly reduced (by about 7-fold) compared to a nicotine solution at pH 8.1.

[0008] Surprisingly, according to the present disclosure, the presence of certain non-polar or lipophilic organic acids or salts thereof enhances the stability of the composition and increases the availability of nicotine for oral absorption in a composition configured for oral use, compared to a composition configured for oral use containing a polar organic acid. Thus, in one aspect, the present disclosure provides a composition configured for oral use, comprising at least one filler, a basic amine, water, and an organic acid, an alkali metal salt of the organic acid, or a combination thereof, wherein the organic acid has a logP value of from about 1.4 to about 8.0, and at least a portion of the basic amine 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 thereof.

[0009] In some embodiments, the organic acid has a logP value of from about 1.4 to about 4.5. In some embodiments, the organic acid has a logP value of from about 2.5 to about 3.5. In some embodiments, the organic acid has a logP value of from about 4.5 to about 8.0 and the composition further comprises a solubility enhancer. In some embodiments, the solubility enhancer is glycerol or propylene glycol.

[0010] In some embodiments, the composition comprises 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 the organic acid, its alkali metal salt, or a combination thereof, relative to the basic amine, calculated as the amine free base.

[0011] In some embodiments, the composition comprises 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 the organic acid, its alkali metal salt, or a combination thereof, relative to the nicotine component, calculated as free base nicotine. In some embodiments, the composition comprises from about 2 to about 10 molar equivalents of the organic acid, its alkali metal salt, or a combination thereof, relative to the nicotine component, calculated as free base nicotine.

[0012] 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.

[0013] In some embodiments, the organic acid is octanoic acid, decanoic acid, benzoic acid, heptanesulfonic acid, or any combination thereof. In some embodiments, the organic acid is octanoic acid. In some embodiments, the alkali metal is sodium or potassium.

[0014] 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 from about 0.1 to about 10.

[0015] In some embodiments, the composition comprises benzoic acid and sodium benzoate, octanoic acid and sodium octanoate, decanoic acid and sodium decanoate, or any combination thereof.

[0016] 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, 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.

[0017] In some embodiments, the basic amine is nicotine. In some embodiments, the nicotine is calculated as the free base and is present in an amount of from about 0.001 to about 10% by weight of the composition, based on the total weight of the composition.

[0018] 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.

[0019] In some embodiments, the composition comprises about 10 to about 50% of at least one filler and about 5 to about 60% by weight of water, based on the total weight of the composition.

[0020] In some embodiments, it further comprises one or more active ingredients, one or more flavoring agents, one or more salts, one or more sweeteners, one or more binders, one or more humectants, one or more gums, tobacco materials, or combinations thereof.

[0021] In some embodiments, the composition further comprises one or more active ingredients selected from the group consisting of dietary supplements, botanicals, stimulants, amino acids, vitamins, and cannabinoids.

[0022] In some embodiments, the composition comprises tobacco material in an amount of about 10% by weight or less, excluding any nicotine components present, based on the total weight of the composition. In some embodiments, the composition does not comprise tobacco material.

[0023] In some embodiments, the composition is enclosed in a pouch to form a pouch product, and the composition is optionally in a granular form.

[0024] In another aspect, a method of enhancing the stability of a composition configured for oral use, the stabilized composition comprising at least one filler, a basic amine, water, and an organic acid, an alkali metal salt of the organic acid, or a combination thereof (wherein the organic acid has a logP value of from about 1.4 to about 8.0), the method comprising mixing at least one filler with water, a basic amine, and an organic acid, an alkali metal salt of the organic acid, or a combination thereof to form a composition, wherein at least a portion of the basic amine is associated with at least a portion of the organic acid or its alkali metal salt, the association being 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, and the pH of the composition being less than about 8, is provided.

[0025] In some embodiments, the organic acid has a logP value of from about 1.4 to about 4.5.

[0026] In some embodiments, the organic acid has a logP value of from about 2.5 to about 3.5. In some embodiments, the organic acid has a logP value of from about 4.5 to about 8.0 and the method further comprises adding a solubility enhancer to the composition.

[0027] In some embodiments, the method further comprises adjusting the pH of the composition to a pH less than about 7.0, adjusting the pH comprising adding an organic acid, a mineral acid, or both to the composition to effect a pH less than about 7.0.

[0028] In some embodiments, enhancing the stability comprises reducing loss of the basic amine by evaporation from the composition over a storage period as compared to a composition configured for oral use having a pH greater than about 8.

[0029] In some embodiments, the storage period is one or more of 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 9 months, or 1 year after preparation.

[0030] In some embodiments, the loss of the basic amine is less than about 5% after a six-month storage period. In some embodiments, the basic amine is nicotine.

[0031] In yet another embodiment, a method of enhancing the predicted oral mucosal absorption of a basic amine from a composition configured for oral use, the composition comprising at least one filler, a basic amine, water, and an organic acid, an alkali metal salt of the organic acid, or a combination thereof (the organic acid having a logP value of from about 1.4 to about 8.0), the method comprising mixing at least one filler with water, a basic amine, and an organic acid, an alkali metal salt of the organic acid, or a combination thereof to form a composition, wherein at least a portion of the basic amine is associated with at least a portion of the organic acid or its alkali metal salt, the association being 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, is provided.

[0032] In some embodiments, the organic acid has a logP value of from about 1.4 to about 4.5. In some embodiments, the organic acid has a logP value of from about 2.5 to about 3.5. In some embodiments, the organic acid has a logP value of from about 4.5 to about 8.0 and the method further comprises adding a solubility enhancer to the composition.

[0033] In some embodiments, the method further comprises adjusting the pH of the composition to a pH of from about 4.0 to about 7.0. In some embodiments, adjusting the pH comprises adding a mineral acid to the composition.

[0034] In some embodiments, the basic amine is nicotine. In some embodiments, enhancing the predicted oral mucosal absorption comprises increasing the percentage of total nicotine permeated through a composition comprising an organic acid, an alkali metal salt of the organic acid, or a combination thereof, wherein the logP value of the organic acid is less than about 1.4.

[0035] The present disclosure includes, without limitation, the following embodiments.

[0036] Embodiment 1 A composition configured for oral use, comprising at least one filler, a basic amine, water, and an organic acid, an alkali metal salt of the organic acid, or a combination thereof, wherein the organic acid has a logP value of about 1.4 to about 4.5, or about 4.5 to about 8.0, and at least a portion of the basic amine 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 thereof.

[0037] Embodiment 2 The composition according to Embodiment 1, wherein the organic acid has a logP value of about 1.4 to about 4.5.

[0038] Embodiment 3 The composition according to Embodiment 1 or 2, wherein the organic acid has a logP value of about 2.5 to about 3.5.

[0039] Embodiment 4 The composition according to Embodiment 1, wherein the organic acid has a logP value of about 4.5 to about 8.0, and the composition further comprises a solubility enhancer.

[0040] Embodiment 5 The composition according to Embodiment 4, wherein the solubility enhancer is glycerol or propylene glycol.

[0041] Embodiment 6 The composition according to any one of Embodiments 1 to 5, comprising 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, its alkali metal salt, or a combination thereof, based on the nicotine component calculated as free base nicotine.

[0042] Embodiment 7 The composition according to any one of Embodiments 1 to 6, comprising about 2 to about 10 molar equivalents of an organic acid, its alkali metal salt, or a combination thereof, based on the nicotine component calculated as free base nicotine.

[0043] Composition according to any one of Embodiments 1 to 7, wherein the organic acid is an alkylcarboxylic acid, an arylcarboxylic acid, an alkylsulfonic acid, an arylsulfonic acid, or a combination thereof.

[0044] Composition according to any one of Embodiments 1 to 8, wherein the organic acid is octanoic acid, decanoic acid, benzoic acid, heptanesulfonic acid, or a combination thereof.

[0045] Composition according to any one of Embodiments 1 to 9, wherein the organic acid is octanoic acid.

[0046] Composition according to any one of Embodiments 1 to 10, wherein the alkali metal is sodium or potassium.

[0047] Composition according to any one of Embodiments 1 to 11, comprising an organic acid and a sodium salt of the organic acid.

[0048] Composition according to any one of Embodiments 1 to 12, wherein the ratio of the organic acid to the sodium salt of the organic acid is from about 0.1 to about 10.

[0049] Composition according to any one of Embodiments 1 to 13, comprising benzoic acid and sodium benzoate, octanoic acid and sodium octanoate, decanoic acid and sodium decanoate, or a combination thereof.

[0050] Composition according to any one of Embodiments 1 to 14, wherein the pH of the composition is from about 4.0 to about 9.0.

[0051] Composition according to any one of Embodiments 1 to 15, wherein the pH of the composition is from about 4.5 to about 7.

[0052] Composition according to any one of Embodiments 1 to 16, wherein the pH of the composition is from about 5.5 to about 7.

[0053] The composition according to any one of Embodiments 1 to 17, wherein the pH of the composition is from about 4.0 to about 5.5.

[0054] The composition according to any one of Embodiments 1 to 18, wherein the pH of the composition is from about 7.0 to about 9.0.

[0055] The composition according to any one of Embodiments 1 to 19, wherein the basic amine is nicotine.

[0056] The composition according to any one of Embodiments 1 to 20, wherein the nicotine is calculated as the free base and is present in an amount of about 0.001 to about 10% by weight of the composition based on the total weight of the composition.

[0057] The composition according to any one of Embodiments 1 to 21, wherein at least one filler comprises a cellulose material.

[0058] The composition according to any one of Embodiments 1 to 22, wherein the cellulose material comprises microcrystalline cellulose.

[0059] The composition according to any one of Embodiments 1 to 23, 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.

[0060] The composition according to any one of Embodiments 1 to 24, wherein the cellulose derivative is hydroxypropyl cellulose.

[0061] The composition according to any one of Embodiments 1 to 25, comprising about 10 to about 50% of at least one filler and about 5 to about 60% by weight of water based on the total weight of the composition.

[0062] Embodiment 27 The composition according to any one of Embodiments 1 to 26, further comprising one or more active ingredients, one or more flavoring agents, one or more salts, one or more sweeteners, one or more binders, one or more humectants, one or more gums, tobacco materials, or combinations thereof.

[0063] Embodiment 28 The composition according to any one of Embodiments 1 to 27, further comprising one or more active ingredients selected from the group consisting of dietary supplements, plant-derived drugs, stimulants, amino acids, vitamins, and cannabinoids.

[0064] Embodiment 29 The composition according to any one of Embodiments 1 to 28, comprising tobacco materials of about 10% by weight or less, excluding any nicotine components present, based on the total weight of the composition.

[0065] Embodiment 30 The composition according to any one of Embodiments 1 to 29, wherein the composition does not contain tobacco materials.

[0066] Embodiment 31 The composition according to any one of Embodiments 1 to 30, which is enclosed in a pouch to form a pouch product, and the composition is optionally in a granular form.

[0067] Embodiment 32 A method for enhancing the stability of a composition configured for oral use, wherein the stabilized composition comprises at least one filler, a basic amine, water, and an organic acid, an alkali metal salt of an organic acid, or a combination thereof (the organic acid having a logP value of about 1.4 to about 8.0), and the method comprises mixing at least one filler with water, a basic amine, and an organic acid, an alkali metal salt of an organic acid, or a combination thereof to form a composition, wherein at least a portion of the basic amine is associated with at least a portion of the organic acid or its alkali metal salt, the association being 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, and the pH of the composition being less than about 8, the method comprising forming the composition.

[0068] Embodiment 33: The method according to embodiment 32, wherein the organic acid has a logP value of about 1.4 to about 4.5.

[0069] Embodiment 34: The method according to embodiment 32, wherein the organic acid has a logP value of about 2.5 to about 3.5.

[0070] Embodiment 35: The method according to embodiment 32, wherein the organic acid has a logP value of about 4.5 to about 8.0, and the method further comprises adding a solubility enhancer to the composition.

[0071] Embodiment 36: The method according to any one of embodiments 32 to 35, further comprising adjusting the pH of the composition to a pH of less than about 7.0, wherein adjusting the pH comprises adding an organic acid, a mineral acid, or both to the composition to result in a pH of less than about 7.0.

[0072] Embodiment 37: The method according to any one of embodiments 32 to 36, wherein enhancing stability comprises reducing loss of the basic amine from the composition by evaporation over a storage period as compared to a composition configured for oral use having a pH greater than about 8.

[0073] Embodiment 38: The method according to any one of embodiments 32 to 37, wherein the storage period is one or more of 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 9 months, or 1 year after preparation.

[0074] Embodiment 39: The method according to any one of embodiments 32 to 38, wherein the basic amine is nicotine.

[0075] Embodiment 40: The method according to embodiment 39, wherein the loss of nicotine is less than about 5% after a 6-month storage period.

[0076] Embodiment 42 A method for enhancing the predicted oral mucosal absorption of a basic amine from a composition configured for oral use, the composition comprising at least one filler, a basic amine, water, and an organic acid, an alkali metal salt of the organic acid, or a combination thereof (the organic acid having a logP value of from about 1.4 to about 8.0), the method comprising mixing at least one filler with water, a basic amine, and an organic acid, an alkali metal salt of the organic acid, or a combination thereof to form a composition, wherein at least a portion of the basic amine is associated with at least a portion of the organic acid or its alkali metal salt, the association being 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, forming a composition.

[0077] Embodiment 43 The method according to Embodiment 42, wherein the organic acid has a logP value of from about 1.4 to about 4.5.

[0078] Embodiment 44 The method according to Embodiment 43, wherein the organic acid has a logP value of from about 2.5 to about 3.5.

[0079] Embodiment 45 The method according to Embodiment 44, wherein the organic acid has a logP value of from about 4.5 to about 8.0 and the method further comprises adding a solubility enhancer to the composition.

[0080] Embodiment 46 The method according to any one of Embodiments 42 - 45, further comprising adjusting the pH of the composition to a pH of from about 4.0 to about 7.0.

[0081] Embodiment 47 The method according to Embodiment 46, wherein adjusting the pH comprises adding a mineral acid to the composition.

[0082] Embodiment 48 The method according to any one of Embodiments 42 - 47, wherein the basic amine is nicotine.

[0083] Embodiment 49 Enhancing the predicted buccal absorption includes increasing the proportion of total nicotine permeated through a composition containing an organic acid, an alkali metal salt of an organic acid, or a combination thereof, and the logP value of the organic acid is less than about 1.4, the method according to any one of Embodiments 42 to 48.

[0084] These and other features, aspects and advantages of the present disclosure will become apparent from the following detailed description read in conjunction with the accompanying drawings, which are briefly described below. The present invention includes any combination of two, three, four, or more of the above-described embodiments, and further any combination of 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. The present disclosure is intended to be read as a whole such that, in any of its various aspects and embodiments, any separable feature or element of the disclosed invention is considered combinable unless the context clearly indicates otherwise.

[0085] Having described aspects of the present disclosure in this way under prior general conditions, reference is now made to the accompanying drawings, which are not necessarily drawn to scale. The drawings are illustrative only and should not be construed as limiting the present disclosure.

Brief Description of the Drawings

[0086] [Figure 1] A perspective view of an embodiment of a pouch product according to an exemplary embodiment of the present disclosure, including a pouch or fleece at least partially filled with a composition configured for oral use. [Figure 2] A bar graph showing the octanol / water partition of nicotine in an embodiment of the present disclosure. [Figure 3] A bar graph showing the octanol / water partition of nicotine in an embodiment of the present disclosure. [Figure 4] A bar graph showing the octanol / water partition of nicotine in an embodiment of the present disclosure. [Figure 5] A bar graph showing the octanol / water partition of nicotine in the control and reference compositions. [Figure 6] A bar graph showing the octanol / water partition of nicotine in embodiments of the present disclosure with different organic acid salts and concentrations. [Figure 7] A bar graph of the total nicotine membrane permeability in embodiments of the present disclosure. [Figure 8] A bar graph of nicotine membrane permeation in embodiments of the present disclosure. [Figure 9] A bar graph showing the recovery rate of nicotine for embodiments of the present disclosure.

DETAILED DESCRIPTION OF THE INVENTION

[0087] The present disclosure will now be described more fully hereinafter with reference to its exemplary embodiments. These exemplary embodiments are described so that the present disclosure will be thorough and complete, and will fully convey the scope of the present disclosure to those skilled in the art. In fact, the present 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 meet the applicable legal requirements. As used herein and in the claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. References to "dry weight %" or "dry weight basis" refer to the weight based on the dry components (i.e., all components excluding water). References to "wet weight" refer to the weight of a mixture containing water. Unless otherwise indicated, references to "weight %" of a mixture reflect the total wet weight of the mixture (i.e., including water).

[0088] For customer satisfaction, it is desirable to produce a basic amine-containing composition configured for oral use that retains the initial basic amine content during storage and delivers substantially all of the amount of basic amine initially present in the composition. The present disclosure combines a basic amine and a nonpolar or lipophilic organic acid salt in an acidic matrix material that exhibits improved retention of the initial basic amine content during storage, and provides a composition that is predicted to deliver more basic amine to a user upon use of the composition, relative to a composition containing a polar organic acid salt in an acidic matrix material (e.g., citric acid or sodium citrate).

[0089] In some embodiments, the basic amine is nicotine. Surprisingly, according to the present disclosure, in certain embodiments, the presence of the nonpolar or lipophilic organic acid salt has been found to enhance the stability of the composition and enhance the membrane permeability of nicotine in a model system of oral absorption at acidic pH, relative to a composition configured for oral use that contains a polar organic acid salt. The enhancement of nicotine permeation is particularly surprising considering the predicted decrease in permeability associated with nicotine protonation under acidic conditions.

[0090] Composition The compositions disclosed herein include at least one filler, a basic amine such as nicotine or a nicotine component, water, and an organic acid, an alkali metal salt of the organic acid, or a combination thereof, provided that the organic acid has a logP value of from about 1.4 to about 8.0. At least a portion of the basic amine is associated with at least a portion of the organic acid or its alkali metal salt. 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. The relative amounts of the various components in the composition can 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.

[0091] Ion pair formation As disclosed herein, at least a portion of the basic amine is associated with at least a portion of an organic acid or its alkali metal salt. Depending on a plurality of variables (concentration, pH, nature of the organic acid, etc.), the basic amine present in the composition can exist in multiple forms, including ion pairs, in solution (i.e., fully solvated), as a free base, as a cation, as a salt, or any combination thereof. In some embodiments, the association between the basic amine and at least a portion of the organic acid or its alkali metal salt is in the form of an ion pair between the basic amine and the conjugate base of the organic acid.

[0092] Ion pairing represents 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 attraction between the cation and the anion (i.e., protonated basic amines such as nicotine, and the conjugate bases of organic acids). "Conjugate base" means a base resulting from the deprotonation of the corresponding acid (e.g., benzoate is the conjugate base of benzoic acid). On average, a particular population of these ion pairs exists at any given time, but the formation and dissociation of ion pairs are continuous. In the compositions disclosed herein and / or upon oral use of said compositions (e.g., upon contact with saliva), basic amines such as nicotine and the conjugate bases of organic acids are present, at least in part, in the form of ion pairs. Without wishing to be bound by theory, it is believed that such ion pairing can minimize the chemical decomposition of basic amines (e.g., nicotine) and / or enhance the oral bioavailability of basic amines. At alkaline pH values (e.g., about 7.5 to about 9, etc.), certain basic amines such as nicotine are mostly present in the free base form, having relatively low water solubility and low stability with respect to evaporation and oxidative decomposition, but high mucosal availability. Conversely, at acidic pH values (e.g., about 6.5 to about 4, etc.), certain basic amines such as nicotine are mainly present in the protonated form, having relatively high water solubility and higher stability with respect to evaporation and oxidative decomposition, but low mucosal availability. Surprisingly, according to the present disclosure, it has been found that the stability, solubility, and bioavailability characteristics of nicotine in compositions formulated for oral use can be mutually enhanced by ion pairing or salt formation of nicotine with suitable organic acids and / or their conjugate bases. Specifically, an ion pair of moderately lipophilic nicotine and an organic acid results in good stability and absorption characteristics. Lipophilicity is conveniently measured in terms of logP. This is the partition coefficient of molecules between a lipophilic phase and an aqueous phase, which are usually octanol and water, respectively. Octanol / water partitioning that promotes the distribution of the ion pair of basic amine and organic acid into octanol predicts good absorption of the basic amine present in the composition through the oral mucosa.

[0093] As described above, at alkaline pH values (e.g., about 7.5 to about 9, etc.), nicotine mainly exists in the form of a free base (and thus has a high partition to octanol), while at acidic pH values (about 6.5 to about 4, etc.), nicotine mainly exists in the protonated form (and thus has a low partition to octanol). Surprisingly, according to the present disclosure, it has been found that ion pairs between specific organic acids (e.g., having logP values of about 1.4 to about 8.0, e.g., about 1.4 to about 4.5) enable nicotine partitioning to octanol that is consistent with what was predicted for nicotine partitioning to octanol at pH 8.4.

[0094] One of ordinary skill in the art will recognize that the degree of ion pairing in the disclosed compositions can vary based on, for example, pH, the nature of the organic acid, the concentration of the basic amine, the concentration of the organic acid or conjugate base of the organic acid present in the composition, the water content of the composition, the ionic strength of the composition, etc., both before and during consumer use. One of ordinary skill in the art will also recognize that ion pairing is an equilibrium process that is affected by the aforementioned variables. Thus, it is difficult or impossible to quantify the degree of ion pairing by calculation or direct observation. However, as disclosed herein, the presence of ion pairing can be demonstrated by surrogate means such as the partitioning of a basic amine between octanol and water, or the membrane permeation of an aqueous solution of a basic amine and an organic acid and / or their conjugate bases.

[0095] Organic acid As used herein, the term "organic acid" refers to an organic (i.e., carbon-based) compound characterized by acidic properties. Typically, an organic acid is a carboxylic acid (-CO 2 H) or a sulfonic acid (-SO 2They are relatively weak acids such as (OH) (i.e., they do not completely dissociate in the presence of water). As used herein, reference to an organic acid means an intentionally added organic acid. In this regard, an organic acid may be intentionally added as a specific composition component, as opposed to being essentially present as a component of another composition component (e.g., a small amount of an organic acid that may be essentially present in a composition component such as a tobacco material).

[0096] Suitable organic acids typically have a range of lipophilicity (i.e., polarity that provides an appropriate balance of water and organic solubility). Typically, as indicated by logP, the lipophilicity of suitable organic acids varies between about 1.4 and about 4.5 (soluble in octanol rather than in water). In some embodiments, the organic acid has a logP value from about 1.5 to about 4.0, such as from about 1.5, about 2.0, about 2.5, or about 3.0 to about 3.5, about 4.0, about 4.5, or about 5.0. Particularly suitable organic acids have a logP value from about 1.7 to about 4, such as from about 2.0, about 2.5, or about 3.0 to about 3.5, or about 4.0. In certain embodiments, the organic acid has a logP value from about 2.5 to about 3.5. In some embodiments, organic acids outside this range can also be utilized for various purposes and in various amounts, as further described herein below. For example, in some embodiments, the organic acid can have a logP value greater than about 4.5, such as from about 4.5 to about 8.0. In particular, the presence of a specific solvent or solubilizer (e.g., inclusion of glycerin or propylene glycol in the composition) can expand the range of lipophilicity (i.e., values of logP greater than 4.5, such as from about 4.5 to about 8.0).

[0097] While not wishing to be bound by theory, moderately lipophilic organic acids (e.g., having a logP of about 1.4 to about 4.5) are thought to form ion pairs with polar nicotine, resulting in good octanol / water partitioning of the ion pair and thus partitioning of nicotine from octanol into water. As described above, such partitioning into octanol predicts favorable oral bioavailability. In some embodiments, the organic acid has a logP value of about 1.4 to about 4.5, such as about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, or about 4.5. In some embodiments, the organic acid has a logP value of about 2.5 to about 3.5.

[0098] In some embodiments, the organic acid is a carboxylic acid or a sulfonic acid. The functional group of the carboxylic acid or sulfonic acid may be attached to any alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group having, for example, from 1 to 20 carbon atoms (C 1 ~C 20 ). In some embodiments, the organic acid is an alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl carboxylic acid or sulfonic acid.

[0099] As used herein, "alkyl" refers to any straight-chain or branched-chain hydrocarbon. The 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 a carbon-carbon, sp 2Refers to the presence of a double bond. The unsaturated alkyl group can 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. The alkyl group may be unsubstituted or substituted.

[0100] As used herein, "cycloalkyl" refers to a carbocyclic group that can be monocyclic or bicyclic. The 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. The cycloalkyl group may be unsubstituted or substituted and may contain one or more unsaturated sites (e.g., cyclopentenyl or cyclohexenyl).

[0101] 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. The aryl group may be unsubstituted or substituted.

[0102] As used herein, "heteroaryl" and "heterocycloalkyl" each refer to an aromatic or non-aromatic ring system in which one or more ring atoms are heteroatoms such as nitrogen, oxygen, and sulfur. A heteroaryl or heterocycloalkyl group contains up to 20 carbon atoms and 1 to 3 heteroatoms selected from N, O, and S. Heteroaryl or heterocycloalkyl has 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, but are not limited to, 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 isothionoyl. Examples of heterocycloalkyl include, but are not limited to, dihydropyridyl, tetrahydropyridyl (piperidyl), tetrahydrothiophenyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, bis-tetrahydropyranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, piperazinyl, quinuclidinyl, and morpholinyl.Heteroaryl and heterocycloalkyl groups may or may not be substituted.

[0103] As used herein, "substituted" as applied to any of the above alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl means that one or more hydrogen atoms are each independently replaced by a substituent. Typical substituents include -Cl, Br, F, alkyl, -OH, -OCH 3 , NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -CN, -NC(=O)CH 3 , -C(=O)-, -C(=O)NH 2 and -C(=O)N(CH 3 ) 2 , but are not limited thereto. Whenever a group is described as "optionally substituted", the group can be substituted with one or more of the above substituents, each independently selected in each case. In some embodiments, the substituent can be one or more methyl groups or one or more hydroxyl groups.

[0104] In some embodiments, the organic acid is an alkyl carboxylic acid. Non-limiting examples of alkyl carboxylic 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.

[0105] In some embodiments, the organic acid is an alkyl sulfonic acid. Non-limiting examples of alkyl sulfonic acids include propane sulfonic acid, heptane sulfonic acid, and octane sulfonic acid.

[0106] In some embodiments, the alkyl carboxylic acid or sulfonic acid is substituted with one or more hydroxyl groups. Non-limiting examples include glycolic acid, 4-hydroxybutyric acid, and lactic acid.

[0107] In some embodiments, the organic acid may contain more than one carboxylic acid group or more than one sulfonic acid group (e.g., two, three, or four or more carboxylic acid groups). Non-limiting examples include oxalic acid, fumaric acid, maleic acid, and glutaric acid. In organic acids containing multiple carboxylic acids (e.g., two to four carboxylic acid groups), one or more of the carboxylic acid groups may be esterified. Non-limiting examples include monoethyl succinate, monomethyl fumarate, monomethyl citrate, or dimethyl citrate.

[0108] In some embodiments, the organic acid may contain more than one carboxylic acid group and one or more hydroxyl groups. Non-limiting examples of such acids include tartaric acid, citric acid, and the like.

[0109] 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.

[0110] Further non-limiting examples of organic acids that may be useful in certain embodiments include 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, fluoric 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, undecylenic acid.

[0111] Examples of suitable acids include, but are not limited to, the list of organic acids in Table 1.

[0112]

Table 1

[0113] In some embodiments, the organic acid is a monoester of a diacid or polyacid such as monooctyl succinate or monooctyl fumarate.

[0114] The selection of the organic acid may further depend on additional properties, in addition to or without considering the logP value. For example, the organic acid should be recognized as safe for human consumption and have acceptable flavor, odor, volatility, stability, etc. The determination of suitable organic acids is within the understanding of those skilled in the art.

[0115] In some embodiments, the organic acid is benzoic acid, toluic acid, benzenesulfonic acid, toluenesulfonic acid, hexanoic acid, heptanoic acid, decanoic acid, or octanoic acid. In some embodiments, the organic acid is benzoic acid, octanoic acid, or decanoic acid. In some embodiments, the organic acid is octanoic acid.

[0116] In some embodiments, more than one organic acid may be present. For example, the composition may contain two, or three, or four, or more organic acids. Thus, references herein to "organic acid" are intended to encompass mixtures of two or more organic acids. The relative amounts of the plurality of organic acids can vary. For example, the composition may contain equal amounts of two, or three, or more organic acids, or may contain different relative amounts. In this way, in combination with other organic acids, a particular organic acid having a logP value outside the desired range (e.g., citric acid or myristic acid) can be included if it results in the desired average logP range for the combination. In some embodiments, for purposes including, but not limited to, imparting desired sensory stimulation characteristics, stability, flavor components, etc., it may be desirable to include in the composition an organic acid having a logP value outside the desired range. Further, certain lipophilic organic acids have undesirable flavor and / or aroma characteristics that 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, while combinations of different organic acids can result in the desired ion pairing, the concentration of any single organic acid in the composition is thought to remain below a threshold that would be considered undesirable from a sensory perspective.

[0117] For example, in some embodiments, the organic acid may include benzoic acid in an amount of about 1 to about 5 molar equivalents or more relative to nicotine, in combination with, for example, about 0.2 molar equivalent of octanoic acid or its salt, and 0.2 molar equivalent of decanoic acid or its salt.

[0118] In some embodiments, the organic acid is a combination of any two organic acids selected from the group consisting of benzoic acid, toluic acid, benzenesulfonic acid, toluenesulfonic acid, hexanoic acid, heptanoic acid, decanoic acid, and octanoic acid. In some embodiments, the organic acid is a combination of benzoic acid, octanoic acid, and decanoic acid, or benzoic acid and octanoic acid. In some embodiments, the composition includes citric acid in addition to one or more of benzoic acid, toluic acid, benzenesulfonic acid, toluenesulfonic acid, hexanoic acid, heptanoic acid, decanoic acid, and octanoic acid.

[0119] In some embodiments, the composition includes an alkali metal salt of the 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 metal salts 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 includes the organic acid and the sodium salt of the organic acid.

[0120] In some embodiments, the composition includes benzoic acid and sodium benzoate, octanoic acid and sodium octanoate, decanoic acid and sodium decanoate, or a combination thereof.

[0121] In some embodiments, the ratio of the organic acid to the sodium salt 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, and the organic acid is added in excess of the sodium salt, in equimolar amounts with the sodium salt, or as part of the sodium salt. One of ordinary skill in the art will recognize that the relative amounts are determined by the desired pH of the composition as well as the desired ionic strength. For example, the organic acid may be added in an amount that results in the desired pH level of the composition, while the alkali metal (e.g., sodium) salt is added in an amount that results in 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 form of the alkali metal salt or conjugate base present in the composition is variable depending on the pH of the composition and the pKa of the organic acid, as well as the actual relative amounts initially added to the composition.

[0122] The amount of the organic acid or its alkali metal salt present in the composition relative to nicotine can vary. Generally, as the concentration of the organic acid (or its conjugate base) increases, the proportion of nicotine, which is the ion paired with the organic acid, increases. This typically increases the partitioning of nicotine in the form of the ion pair into octanol relative to water, as measured by logP (the logarithm of the partition coefficient). In some embodiments, the composition comprises 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 the organic acid, its alkali metal salt, or a combination thereof, relative to the nicotine component, calculated as free base nicotine. 10 ). In some embodiments, the composition comprises 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 the organic acid, its alkali metal salt, or a combination thereof, relative to the nicotine component, calculated as free base nicotine.

[0123] 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, its alkali metal salt, or a combination thereof, based on free base nicotine. In some embodiments, the organic acid, its alkali metal salt, or a combination thereof is present in a molar ratio to nicotine of from about 2, about 3, about 4, or about 5 to about 6, about 7, about 8, about 9, or about 10. In embodiments where two or more organic acids, their alkali metal salts, or both are present, such molar ratios should be understood to reflect the total of the organic acids present.

[0124] In certain embodiments, the organic acid content is sufficient to provide a composition 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 organic acid content is sufficient to provide a composition pH of from about 4.5 to about 6.5, such as from about 4.5, about 5.0, or about 5.5 to about 6.0, or about 6.5. In some embodiments, the organic acid is provided in an amount sufficient to provide a composition pH of from about 5.5 to about 6.5, such as from about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, or 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.

[0125] In some embodiments, the organic acid is added to other composition components as the free acid, neat (i.e., in its natural solid or liquid form) or in solution, such as an aqueous solution. In some embodiments, the alkali metal salt of the organic acid is added to other composition components neat or in solution, such as an aqueous solution. In some embodiments, the organic acid and a basic amine (e.g., nicotine) are combined prior to addition to the composition to form a salt, or the salt is formed in the composition and remains present therein. In other embodiments, the organic acid and a basic amine (e.g., nicotine) are present as individual components in the composition and form ion pairs upon contact with moisture (e.g., saliva in the consumer's mouth).

[0126] Basic amine The compositions disclosed herein contain a basic amine. "Basic amine" means a molecule containing at least one basic amine functional group. Examples of basic amines include, but are not limited to, alkaloids. "Basic amine functional group" means a group containing a nitrogen atom with a lone pair of electrons. The basic amine functional group is bonded or incorporated into the molecule via one or more covalent bonds to the nitrogen atom. The basic amine may be a primary, secondary or tertiary amine, meaning that the nitrogen has 1, 2 or 3 covalent bonds to carbon atoms. Due to the lone pair of electrons on the nitrogen atom, such amines are called "bases", meaning that the lone pair of electrons is available for hydrogen bonding. The basicity of a basic amine (i.e., the electron density of the nitrogen atom and thus the availability and strength of the hydrogen bonded to the nitrogen atom) can be affected by the nature of the adjacent atoms, the steric bulk of the molecule, etc.

[0127] Generally, the basic amine is released from the composition, absorbed through the oral mucosa, thereby entering the bloodstream where it circulates systemically. Generally, the basic amine is present in the composition or as an active ingredient in the composition as described hereinafter. In some embodiments, the basic amine is nicotine or a nicotine component. "Nicotine component" means any suitable form of nicotine (e.g., free base, salt or ion pair) to effect oral absorption of at least a portion of the nicotine present. Nicotine is released from the composition, absorbed through the oral mucosa, thereby entering the bloodstream where it circulates systemically.

[0128] 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 the form of the free base. In some embodiments, at least a portion of the nicotine is present as a nicotine salt 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, as already disclosed herein.

[0129] Typically, the nicotine component (calculated as the free base) is present in the composition at a concentration of at least about 0.001% by weight, 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, for example, about 0.1% w / w, 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% or about 10% by weight, based on the total weight of the composition. 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, for example, about 0.1% w / w to about 2.5%, about 0.1% to about 2.0%, about 0.1% to about 1.5%, or about 0.1% to about 1% by weight, based on the total weight of the composition.

[0130] Filler The compositions described herein include one or more fillers. The fillers can serve multiple functions such as improving specific sensory stimulation characteristics such as texture and mouthfeel, and improving the cohesiveness or compressibility of the product.

[0131] Generally, the filler is a porous particulate material and is cellulose-based. For example, suitable fillers are any non-tobacco plant material or derivatives thereof that contain cellulose materials derived from such sources. Examples of cellulose-based non-tobacco plant materials include grains (e.g., corn, oats, barley, rye, buckwheat, etc.), sugar beets (e.g., the FIBREX(R) brand filler available from International Fiber Corporation), bran fibers, and mixtures thereof. Non-limiting examples of derivatives of non-tobacco plant materials include starches (e.g., derived from potatoes, wheat, rice, corn), natural cellulose, and modified cellulose materials.

[0132] As used herein, "starch" can refer to pure starch, modified starch, or starch derivatives from any source. Starch is typically in granular form and is present in almost all green plants and various types of plant tissues and organs (e.g., seeds, leaves, rhizomes, roots, tubers, shoots, fruits, grains, and stems). Starch can vary in composition, as well as in granular shape and size. Often, starches from different sources have different chemical and physical properties. Certain starches can be selected for inclusion in a mixture based on the ability of the starch material to impart specific sensory stimulus properties to the composition. Starches from various sources can be used. For example, the major sources of starch include cereals (e.g., rice, wheat, and corn) and root vegetables (e.g., potatoes and cassava). Other examples of starch sources include acorns, kudzu, peanuts, bananas, barley, beans (e.g., favas, lentils, mung beans, peas, chickpeas), breadfruit, buckwheat, canna, chestnuts, castor beans, katakuri, kudzu, malanga, millet, oats, oca, Polynesian arrowroot, sago, sorghum, sweet potatoes, quinoa, rye, tapioca, taro, tobacco, water chestnuts, and yams. Certain starches are modified starches. Modified starches have undergone one or more structural modifications that are frequently designed to alter their high-temperature properties. Some starches have been developed by genetic modification and are considered "modified" starches. Other starches are obtained and subsequently modified.For example, the modified starch can be starch that has been subjected to chemical reactions such as esterification, etherification, oxidation, depolymerization (thinning) by acid catalysis or oxidation in the presence of a base, bleaching, transglycosylation, and depolymerization (e.g., dextrinization in the presence of a catalyst), crosslinking, enzymatic treatment, acetylation, hydroxypropylation, and / or partial hydrolysis. Other starches are modified by heat treatment, e.g., gelatinization, dextrinization, and / or cold water swelling processes. Specific modified starches include monophosphated starch, didextrin glycerol, diphosphated starch esterified with sodium trimetaphosphate, diphosphated starch phosphate, acetylated diphosphated starch, starch acetate esterified with acetic anhydride, starch acetate esterified with vinyl acetate, acetylated adipic acid didextrin, acetylated didextrin glycerol, hydroxypropyl starch, hydroxypropyl didextrin glycerol, starch sodium octenyl succinate.

[0133] Further examples of possible fillers include maltodextrin, dextrose, calcium carbonate, calcium phosphate, lactose, and sugar alcohols. Fillers can also be used in combination. In some embodiments, the filler comprises glucose and starch-derived polysaccharides or a mixture thereof. One such suitable mixture of glucose and starch-derived polysaccharides is EMDEX(R) available from JRS PHARMA LP, USA, 2981 Route 22, Patterson, NY 12563-2359.

[0134] In some embodiments, the particulate filler is a cellulose material or a cellulose derivative. One particulate filler particularly suitable for use in the compositions described herein is microcrystalline cellulose (“mcc”). The mcc may be synthetic or semi-synthetic, or may be obtained entirely from natural cellulose. The mcc can be selected from the group consisting of AVICEL(R) grades PH-100, PH-102, PH-103, PH-105, PH-112, PH-113, PH-200, PH-300, PH-302, VIVACEL(R) grades 101, 102, 12, 20 and EMOCEL(R) grades 50M and 90M, and mixtures thereof. In one embodiment, the composition comprises mcc as the particulate filler. The amount of mcc present can vary depending on the desired properties.

[0135] The amount of filler can vary, but typically is up to about 75% by weight of the composition, based on the total weight of the composition. Typical ranges of filler (e.g., mcc) in the composition are from about 10 to about 75% by weight of the total weight of the composition, such as about 10, about 15, about 20, about 25, or about 30 to about 35, about 40, about 45, or about 50% by weight (e.g., about 20 to about 50% by weight or about 25 to about 45% by weight). In certain embodiments, the amount of filler is at least about 10% by weight, such as at least about 20% by weight, or at least about 25% by weight, or at least about 30% by weight, or at least about 35% by weight, or at least about 40% by weight, based on the total weight of the composition.

[0136] 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% by weight of a cellulose derivative, based on the total weight of the composition, and certain embodiments comprise from about 1% to about 5% by weight of a cellulose derivative. In certain embodiments, the cellulose derivative is a cellulose ether (including carboxyalkyl ethers), meaning a cellulose polymer in which the hydrogen of one or more hydroxyl groups in the cellulose structure is replaced by an alkyl, hydroxyalkyl, or aryl group. 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% by weight of HPC, based on the total weight of the composition.

[0137] Water The water content of the composition can vary according to the desired properties prior to consumer use of the composition. Typically, the composition is less than about 60% by weight of water and generally from about 1% to about 60% by weight of water, such as 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% by weight of water, and contains a water content of at least about 5% by weight, at least about 10% by weight, at least about 15% by weight, and at least about 20% by weight.

[0138] Active ingredient In certain embodiments, the compositions disclosed herein contain 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 medicines, and substances that occur naturally and can act on humans. Exemplary active ingredients include components that produce a pharmacological activity or other direct effect in the diagnosis, cure, alleviation, treatment, or prevention of disease, or that affect the structure or any function of the human body (e.g., those that exert a stimulating effect on the central nervous system, provide an energy supply effect, antipyretic or analgesic effect, or other useful effects to the body), etc., any component known to affect one or more biological functions in the body. In some embodiments, the active ingredient can generally be of the type commonly referred to as dietary supplements, nutraceuticals, "phytochemicals" or "functional foods". These types of additives include substances typically obtainable from natural sources (e.g., plant materials) that produce one or more beneficial biological effects (e.g., health promotion, disease prevention, or other pharmaceutical properties), but are not classified or regulated as drugs, as sometimes defined in the art.

[0139] Non-limiting examples of active ingredients include those falling into the categories of plant-based ingredients, stimulants, amino acids and / or pharmaceuticals, nutraceuticals and medicinal 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 below in this specification. The specific selection of the active ingredient will vary depending on the desired flavor, texture and desired properties of the particular product.

[0140] The specific proportion of the active ingredients present varies according to the desired properties of the particular product. Typically, the active ingredient or combination thereof is present at least about 0.001% by weight of the total concentration of the composition, for example in the range of about 0.001% to about 20%. 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% by weight, for example about 0.5% w / w to about 10%, about 1% to about 10%, 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 about 0.001%, about 0.01%, about 0.1%, or about 1%, up to about 20% by weight, 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%, up 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 presented below in this specification.

[0141] Plant-based In some embodiments, the active ingredient comprises a botanical ingredient. As used herein, the term "botanical ingredient" or "botanical" refers to any plant material or material derived from fungi, such as plant material in its natural form and plant material derived from natural plant material, such as extracts or isolates from plant material or processed plant material (e.g., plant material subjected to heat treatment, fermentation, bleaching, or other processing processes that can alter the physical and / or chemical properties of the material). For the purposes of the present disclosure, "herbal medicine" includes, but is not limited to, "herbal material", which refers to seed-producing plants that do not develop persistent woody tissue and whose medical or sensory properties (e.g., tea or tisane) are typically evaluated. Referring to a botanical material as "non-tobacco" is intended to exclude materials for tobacco (i.e., not including any Nicotiana species).

[0142] When present, the herbal medicine is 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%, about 0.1% or about 0.5% to about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9% or about 10%, about 11%, about 12%, about 13%, about 14% or about 15% by weight, based on the total weight of the foaming composition.

[0143] Plant materials useful in the present disclosure can include, without limitation, any of the compounds and sources described herein, including mixtures thereof. This type of specific plant material may sometimes be referred to as a dietary supplement, a nutritional supplement, a "phytochemical" or a "functional food". Specific plant-derived medicines as plant materials or extracts thereof have been used in traditional herbal medicines and are further described herein. Non-limiting examples of plant-derived medicines or plant-derived materials include ashwagandha, Bacopa monniera, baobab, basil, Centella asiatica, Chai-hu, chamomile, cherry, chlorophyll, cinnamon, citrus fruits, clove, cocoa, Cordyceps, curcumin, damiana, Dorstenia arifolia, Dorstenia odorata, essential oil, eucalyptus, fennel, Galphimia glauca, ginger, Ginkgo biloba, ginseng (e.g., Panax ginseng), green tea, Griffonia simplicifolia, guarana, hemp, hops, jasmine, Kaempferia parviflora (Thai ginseng), kava, lavender, lemon balm, lemongrass, licorice, lutein, maca, matcha, Nardostachys chinensis, the oily extract of Viola odorata, peppermint, quercetin, resveratrol, Rhizoma gastrodiae, Rhodiola, rooibos, rose essential oil, rosemary, Sceletium tortuosum, Schisandra chinensis, Stellaria media, spearmint extract, Glycyrrhiza glabra, terpene, chrysanthemum, turmeric, Turnera aphrodisiaca, valerian, white mulberry, and Yerba mate.

[0144] Stimulant In some embodiments, the active ingredient comprises one or more stimulants. As used herein, the term "stimulant" refers to a substance that increases the activity of the central nervous system and / or the body, such as a substance that enhances 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 that is structurally related to caffeine and has stimulant, analgesic, and anti-inflammatory effects. The stimulant can be natural, natural-derived, or fully synthetic. For example, certain plant materials (guarana, tea, coffee, cocoa, etc.) can have a stimulating effect due to the presence of, for example, caffeine or related alkaloids, and are thus "natural" stimulants. "Natural-derived" means that the stimulant (e.g., caffeine, theacrine) is in a purified form outside its natural (e.g., plant) parent matrix. For example, caffeine can be obtained by extraction and purification from a plant source (e.g., tea). "Fully synthetic" means that the stimulant is obtained by 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 encapsulated form. An example of encapsulated caffeine is Vitashure(R) available from Balchem Corp., 52 Sunrise Park Road, New Hampton, NY, 10958.

[0145] When present, the stimulant or combination of stimulants (e.g., caffeine, theacrine, and combinations thereof) is typically from about 0.1% w / w to about 15% by weight, such as about 0.1% w / w, 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%, or about 15% by weight, based on the total weight of the foaming composition.

[0146] Amino acid In some embodiments, the active ingredient comprises an amino acid. As used herein, the term "amino acid" refers to an organic compound containing an amine (-NH 2 ) and a carboxyl (-COOH) or sulfonic acid (SO 3 H) functional group, together with a side chain (R group) specific to each amino acid. Amino acids can be proteinogenic or non-proteinogenic. "Proteinogenic" means that the amino acid is one of the 20 natural amino acids found in proteins. 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 that the amino acid is not naturally found in proteins or is not directly produced by cellular machinery (e.g., is a product of post-translational modification). Non-limiting examples of non-proteinogenic amino acids include γ-aminobutyric acid (GABA), taurine (2-aminoethanesulfonic acid), theanine (L-γ-glutamylethylamide), hydroxyproline, and β-alanine.

[0147] 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%, 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%, or about 15% by weight, based on the total weight of the foaming composition.

[0148] Vitamin In some embodiments, the active ingredient comprises a vitamin or a combination of vitamins. As used herein, the term "vitamin" refers to an organic molecule (or a 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, namely vitamin A (all-trans retinol, all-trans retinyl-esters, and as all-trans β-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).

[0149] When present, the vitamin or combination of vitamins (e.g., vitamin B6, vitamin B12, vitamin E, vitamin C, or combinations thereof) is typically at a concentration of about 0.01% w / w to about 1% by weight, such as 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% w / w to 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% by weight, based on the total weight of the foaming composition.

[0150] Cannabinoid In some embodiments, the active ingredient comprises one or more cannabinoids. As used herein, the term "cannabinoid" refers to a class of diverse compounds that act on cannabinoid receptors, also known as the endocannabinoid system, in cells that alter neurotransmitter release in the brain. Ligands for these receptor proteins include endocannabinoids that are naturally produced in the body by animals, phytocannabinoids found in cannabis, and synthetic cannabinoids that are artificially manufactured. Non-limiting examples of cannabinoids include tetrahydrocannabinol (THC), the main psychoactive compound of cannabis, and cannabidiol (CBD), another major component of the plant that lacks psychoactivity. In some embodiments, the active ingredient comprises CBD.

[0151] When present, the cannabinoid (e.g., CBD) is typically present in the composition at a concentration in the range of at least about 0.1% by weight, such as about 0.1% to about 30% 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%, 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 15%, about 20%, or about 30% by weight, based on the total weight of the composition.

[0152] Antioxidant In some embodiments, the active ingredient comprises one or more antioxidants. As used herein, the term "antioxidant" refers to a substance that can prevent or inhibit oxidation by terminating free radical reactions and can delay or prevent damage to certain cells. Antioxidants can be naturally occurring or synthetic. Naturally occurring antioxidants include those found in foods and plant materials. Non-limiting examples of antioxidants include certain plant materials, vitamins, polyphenols, and phenolic derivatives.

[0153] Examples of plant materials related to antioxidant properties include, but are not limited to, acai berry, alfalfa, allspice, anise seed, anise oil, basil, bee balm, wild bergamot, black pepper, blueberry, borage seed oil, bugleweed, cocoa, horseradish root, cannip, cat's claw, cayenne pepper, chaga mushroom, chervil, cinnamon, dark chocolate, potato peel, grape seed, ginseng, Ginkgo biloba, St. John's wort, saw palmetto, green tea, black tea, black cohosh, cayenne, chamomile, clove, cocoa powder, cranberry, dandelion, grapefruit, honeybush, echinacea, garlic, Japanese butterbur, ginger, hydrastis, hawthorn, hibiscus flower, amacha tsuru, kava, lavender, licorice, marjoram, milk thistle, mint (menthe), oolong tea, beetroot, orange, oregano, papaya, pennyroyal, peppermint, red clover, rooibos (red or green), rose hip, rosemary, sage, clary sage, savory, spearmint, spirulina, acerola bark, sorghum bran high tannin, sorghum grain high tannin, urushi bran, comfrey leaves and roots, goji berry, gotu kola, thyme, turmeric, euonymus, valerian, sweet potato root, wintergreen, yacon root, yellow dock, yerba mate, yerba santa, bacopa monnieri, ashwagandha (Withania somnifera), lion's mane, and maria thistle. Such plant materials may be provided in fresh or dried form, as essential oils, or in the form of extracts. Plant materials (and their extracts) often contain various classes of compounds known to confer antioxidant effects, such as minerals, vitamins, isoflavones, phytosterols, allyl sulfides, dithiothiones, isothiocyanates, indoles, lignans, flavonoids, polyphenols, and carotenoids.Examples of compounds found in botanical extracts or oils include ascorbic acid, peanut endocarp, resveratrol, sulforaphane, β-carotene, lycopene, lutein, coenzyme Q, carnitine, quercetin, kaempferol, and the like. See, for example, Santhosh et al., Phytomedicine, 12(2005)216-220, which is incorporated herein by reference.

[0154] 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 monogallate A or B, theaflavin digallate, phenolic acids, glycosides, quercitrin, isoquercitrin, hyperoside, polyphenols, catechol, resveratrol, oleuropein, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tertiary butylhydroquinone (TBHQ), and combinations thereof.

[0155] When present, the antioxidant is typically present at a concentration of about 0.001% w / w to about 10% by weight, based on the total weight of the composition, for example, about 0.001%, about 0.005%, about 0.01% w / w, about 0.05%, about 0.1%, or about 0.5% to about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9% or about 10%.

[0156] Pharmaceutical ingredient In some embodiments, the active ingredient comprises an active pharmaceutical ingredient (API). The API can be any known drug suitable for therapeutic, prophylactic, or diagnostic use. These can 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, melatonin), 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), β-hydroxy-β-methylbutyrate (HMB), cytidine (cytidine-5'-diphosphate-choline), and cotinine.

[0157] 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%, 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% w / w, 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%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% by weight, based on the total weight of the composition.

[0158] As described above in this specification, the basic amine present in the composition may be nicotine or a nicotine component, or may be an active ingredient or a constituent of an active ingredient. One of ordinary skill in the art will recognize that many of the active ingredients defined in this specification are composed of molecules that can be classified as basic amines. Accordingly, ion pairing of such basic amine-containing active ingredients with the lipophilic organic acids described herein is contemplated. In such embodiments, the ion pair of the active ingredient with the organic acid, the alkali metal salt of the organic acid, or a combination thereof can improve the stability of the composition containing the ion pair or improve the predicted oral mucosal absorption of the active ingredient due to the presence of the ion-paired form of the active ingredient.

[0159] Flavoring agent In some embodiments, the foaming composition described herein includes a flavorant. As used herein, "flavorant" or "flavor" is any flavored or aromatic substance that can alter the sensory characteristics associated with an oral product. Examples of sensory characteristics that can be altered by a flavorant include taste, mouthfeel, moistness, coolness / warmth, and / or smell / aroma. The flavorant may be natural or synthetic, and the flavor characteristics imparted thereby may be described, but are not limited to, as fresh, sweet, herbal, confectionery, floral, fruity, or spicy. Specific types of flavors include, but are not limited to, vanilla, coffee, chocolate / cocoa, cream, mint, spearmint, menthol, peppermint, wintergreen, eucalyptus, lavender, cardamom, nutmeg, cinnamon, clove, cascarilla, sandalwood, honey, jasmine, ginger, anise, sage, licorice, lemon, orange, apple, peach, lime, cherry, strawberry, pineapple, and any combination thereof. See also Leffingwell et al., Tobacco Flavoring for Smoking Products, R.J. Reynolds Tobacco Company (1972). The disclosure thereof is incorporated herein by reference in its entirety. The flavor may also include components that may be considered humectants, coolants or emollients such as eucalyptus. These flavorants may be provided neat (i.e., alone) or in complexes and may be used as concentrates or flavorant packages (e.g., spearmint and menthol, orange and cinnamon, lime, pineapple, etc.). Representative types of components are also described in U.S. Patent No. 5,387,416 to White et al., U.S. Patent Application Publication No. 2005 / 0244521 to Strickland et al. and International Publication No. 05 / 041699 pamphlet of the PCT application to Quinter et al. Each is incorporated herein by reference. In some cases, the flavorant may be provided in spray-dried form or in liquid form.

[0160] A fragrance typically contains at least one volatile fragrance component. As used herein, "volatile" refers to a chemical substance that readily forms vapor at ambient temperature (i.e., a chemical substance with a higher vapor pressure at a given temperature compared to non-volatile substances). Typically, volatile fragrance components have a molecular weight of less than about 400 Da and often contain at least one carbon-carbon double bond, carbon-oxygen double bond, or both. In one embodiment, at least one volatile fragrance component includes one or more alcohols, aldehydes, aromatic hydrocarbons, ketones, esters, terpenes, terpenoids, or combinations thereof. Non-limiting examples of aldehydes include vanillin, ethyl vanillin, p-anisaldehyde, hexanal, furfural, isovaleraldehyde, cumin aldehyde, benzaldehyde, and citronellal. Non-limiting examples of ketones include 1-hydroxy-2-propanone and 2-hydroxy-3-methyl-2-cyclopentenone-1-one. Non-limiting examples of esters include allyl hexanoate, ethyl heptanoate, ethyl hexanoate, isoamyl acetate, and 3-methylbutyl acetate. Non-limiting examples of terpenes include sabinene, limonene, γ-terpinene, β-farnesene, nerolidol, cedrol, myrcene, geraniol, nerol, citronellol, linalool, and eucalyptol. In one embodiment, at least one volatile fragrance component includes one or more of ethyl vanillin, cinnamaldehyde, sabinene, limonene, γ-terpinene, β-farnesene, or citral.

[0161] The amount of fragrance used in the composition can vary, but is typically up to about 10 wt%, and certain embodiments feature a fragrance content of at least about 0.1 wt%, e.g., about 0.5 to about 10 wt%, about 1 to about 6 wt%, or about 2 to about 5 wt%, based on the total weight of the composition. The amount of fragrance present in the composition can change over a period of time (e.g., the storage period after preparation of the composition). For example, certain volatile components present in the composition can evaporate or undergo chemical transformation, resulting in a decrease in the concentration of one or more volatile fragrance components.

[0162] Taste regulator To improve the sensory stimulation properties of the compositions disclosed herein, the compositions can, for example, be useful in masking, altering, blocking, or improving the fragrance of the compositions described herein, and can include one or more flavor modifiers (which may include "flavor regulators"). Non-limiting examples of such flavor regulators include analgesic or anesthetic herbs, spices, and flavors that produce a perceived cooling sensation (e.g., menthol, eucalyptus, mint), a warming sensation (e.g., cinnamon), or a painful sensation (e.g., capsaicin). Certain flavor modifiers are classified into two or more overlapping categories.

[0163] In some embodiments, the flavor modifier modifies one or more of bitterness, sweetness, saltiness, or sourness. In some embodiments, the flavor modifier targets pain receptors. In some embodiments, the composition includes an active ingredient having bitterness and a flavor modifier that hides or blocks the perception of bitterness. In some embodiments, the flavor modifier is a substance that targets pain receptors (e.g., vanilloid receptors) in the user's oral cavity to, for example, hide the bitterness of another component (e.g., the active ingredient). Suitable flavor modifiers include, but are not limited to, capsaicin, gamma-aminobutyric acid (GABA), adenosine monophosphate (AMP), lactisol, or combinations thereof.

[0164] When present, a representative amount of the flavor modifier is about 0.01 wt% or more, about 0.1 wt% or more, or about 1.0 wt% or more, but typically less than about 10 wt% of the total weight of the composition (e.g., about 0.01%, about 0.05%, about 0.1% or about 0.5% to about 1%, about 5%, or about 10 wt% of the total weight of the composition).

[0165] Salt In some embodiments, the composition may further include a salt (e.g., an alkali metal salt) that is typically used in an amount sufficient to impart the desired sensory properties to the composition. Non-limiting examples of suitable salts include sodium chloride, potassium chloride, ammonium chloride, salt of wheat flour, and the like.

[0166] When present, representative amounts of the salt are about 0.5 wt% or more, about 1.0 wt% or more, or about 1.5 wt% or more, but typically constitute about 10% or less, or about 7.5% or less, or about 5% or less (e.g., about 0.5 to about 5 wt%) of the total weight of the composition.

[0167] Sweetener To improve the sensory properties of the compositions 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 includes one or more sugar alcohols. A sugar alcohol is a polyol derived from a monosaccharide or disaccharide having a partially or fully hydrogenated form. Sugar alcohols have, for example, from about 4 to about 20 carbon atoms and include erythritol, arabinitol, ribitol, isomalt, maltitol, xylitol, 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.

[0168] When present, the sweetener or combination of sweeteners can constitute, by weight, from about 0.01% to about 20% or more of the composition, such as from about 0.01% to about 0.1%, from about 0.1% to about 1%, from about 1% to about 5%, from about 5% to about 10%, or from about 10% to about 20% by weight, based on the total weight of the composition. In some embodiments, the combination of sweeteners is present at a concentration of from about 0.01% to about 0.1% by weight of the composition, such as 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% by weight of the composition. In some embodiments, the combination of sweeteners is present at a concentration of from about 0.1% to about 0.5% by weight of the composition, such as about 0.1, about 0.2, about 0.3, about 0.4 or about 0.5% by weight of the composition. In some embodiments, the combination of sweeteners is present at a concentration of from about 1% to about 3% by weight of the composition.

[0169] Binder In certain embodiments, a binder (or combination of binders) can be used. Typical binders can be organic or inorganic, or combinations thereof. Representative binders include povidone, sodium alginate, starch-based binders, pectin, carrageenan, pullulan, zein, and the like, and combinations thereof. The binder can be used in an amount sufficient to impart the desired physical attributes and physical integrity to the composition. The amount of binder utilized in the composition can vary, but is typically up to about 30% by weight, and certain embodiments are characterized by a binder content of at least about 0.1% by weight, such as from about 1% to about 30% by weight, or from about 5% to about 10% by weight, based on the total weight of the composition.

[0170] Other suitable binders include gums, such as natural gums. As used herein, natural gums refer to polysaccharide materials of natural origin that have binding properties and are also useful as thickeners or gelling agents. Representative natural gums derived from plants that are typically somewhat water-soluble 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.

[0171] Humectant In certain embodiments, one or more humectants can be used in the composition. Examples of humectants include, but are not limited to, glycerin, propylene glycol, and the like. When included, the humectant is typically provided in an amount sufficient to impart the desired moisture attributes to the composition. Further, in some examples, the humectant can impart desirable flow characteristics to the composition for deposition on the mold.

[0172] When present, the humectant typically constitutes about 5% or less of the weight of the composition (e.g., about 0.5 to about 5% by weight). When present, representative amounts of the humectant are from about 0.1% to about 1% by weight, or from about 1% to about 5% by weight, based on the total weight of the composition.

[0173] Buffer In certain embodiments, the compositions of the present disclosure can include a pH adjuster or a buffer. Examples of pH adjusters and buffers that can be used include metal hydroxides (such as alkali metal hydroxides like sodium hydroxide and potassium hydroxide), and other alkali metal buffers such as metal carbamates (such as potassium carbamate or sodium carbamate), or metal bicarbonamates such as sodium bicarbonamate, but are not limited thereto. Non-limiting examples of suitable buffers include alkali metal acetates, glycine acetates, phosphates, glycerophosphates, citrates, carbamates, carbonate carbamates, borate carbamates, or mixtures thereof.

[0174] When present, the buffer is typically present in an amount of less than about 5%, for example, about 0.5% to about 5%, for example, about 0.75% to about 4%, about 0.75% to about 3%, or about 1% to about 2% by weight based on the weight of the composition.

[0175] Colorant Colorants can be used in an amount sufficient to impart the desired physical attributes to the composition. Examples of colorants include various dyes and pigments such as caramel colorants and titanium dioxide. Natural colorants such as curcumin, beet juice extract, spirulina, etc., or various synthetic pigments may also be used. The amount of colorant utilized in the composition can vary, but when present, it is typically up to about 3% by weight, for example, about 0.1%, about 0.5%, or about 1% to about 3% by weight based on the total weight of the composition.

[0176] Tobacco material In some embodiments, the composition may include a tobacco material. The tobacco material can vary in species, type, and form. Generally, the tobacco material is obtained from harvested plants of the Nicotiana species. Examples of Nicotiana species include N. tabacum, N. rustica, N. alata, N. arentsii, N. excelsior, N. forgetiana, N. glauca, N. glutinosa, N. gossei, N. knightiana, N. langsdorffi, N. otophora, N. setchelli, N. sylvestris, N. tomentosa, N. tomentosiformis, N. undulata, N. x sanderae, N. africana, N. amplexicaulis, N. benavidesii, N. bonariensis, N. debneyi, N. longiflora, N. maritina, N. megalosiphon, N. occidentalis, N. paniculata, N. plumbaginifolia, N. raimondii, N. rosulata, N. simulans, N. stocktonii, N. suaveolens, N. umbratica, N. velutina, N. wigandioides, N. acaulis, N. acuminata, N. attenuata, N. benthamiana, N.benthamiana), N. cavicola, N. clevelandii, N. cordifolia, N. corymbosa, N. fragrans, N. goodspeedii, N. linearis, N. miersii, N. nudicaulis, N. obtusifolia, N. occidentalis subsp. Hersperis, N. pauciflora, N. petunioides, N. quadrivalvis, N. repanda, N. rotundifolia, N. solanifolia, and N. spegazzinii. Various other representative types of plants from Nicotiana species are described in Goodspeed, The Genus Nicotiana, (Chonica Botanica) (1954), U.S. Patent No. 4,660,577 to Sensabaugh, Jr. et al., U.S. Patent No. 5,387,416 to White et al., U.S. Patent No. 7,025,066 to Lawson et al., U.S. Patent No. 7,798,153 to Lawrence, Jr. et al., and U.S. Patent No. 8,186,360 to Marshall et al. Each of these is incorporated herein by reference. Descriptions of various types of tobacco, cultivation practices, and harvesting practices are described in Tobacco Production, Chemistry and Technology, Davis et al. (Eds.) (1999), which is incorporated herein by reference.

[0177] Nicotiana species from which suitable tobacco materials can be obtained can be derived using genetic modification or breeding techniques (e.g., tobacco plants can be genetically engineered or bred to increase or decrease the production of components, characteristics, or traits). See, for example, U.S. Patent No. 5,539,093 to Fitzmaurice et al., No. 5,668,295 to Wahab et al., No. 5,705,624 to Fitzmaurice et al., No. 5,844,119 to Weigl et al., No. 6,730,832 to Dominguez et al., No. 7,173,170 to Liu et al., No. 7,208,659 to Colliver et al., No. 7,230,160 to Benning et al., U.S. Patent Application Publication No. 2006 / 0236434 to Conkling et al., and International Publication No. 2008 / 103935 pamphlet to Nielsen et al. See also U.S. Patent No. 4,660,577 to Sensabaugh, Jr. et al., No. 5,387,416 to White et al., and No. 6,730,832 to Dominguez et al. Each is hereby incorporated by reference herein.

[0178] In some embodiments, Nicotiana species can be selected for the content of various compounds present therein. For example, plants can be selected based on their relatively high production of one or more of the compounds from which it is desired to isolate them. In certain embodiments, plants of Nicotiana species (e.g., Galpao commun tobacco) are cultivated specifically for the compounds on the surface of their abundant leaves. Tobacco plants can be cultivated in a greenhouse, growth chamber, or outdoor field, or hydroponically.

[0179] Various parts of Nicotiana species plants can be included within the compositions disclosed herein. For example, substantially all of the plant (e.g., the whole plant) can be harvested and used as is. Alternatively, various parts or fragments of the plant can be harvested or separated after harvest for further use. For example, flowers, leaves, stems, petioles, roots, seeds, and various combinations thereof can be isolated for further use or processing. In some embodiments, the tobacco material includes tobacco leaves (lamina). The compositions disclosed herein can include processed tobacco parts or fragments, cured and aged tobacco in essentially natural lamina and / or stem form, tobacco extracts, extracted tobacco pulp (e.g., using water as a solvent), or mixtures of the foregoing (e.g., a mixture of extracted tobacco pulp combined with granulated aged natural tobacco lamina).

[0180] In certain embodiments, the tobacco material includes a solid tobacco material selected from the group consisting of lamina and stem. The tobacco used in the mixture most preferably includes tobacco lamina, or a mixture of tobacco lamina and stem (at least a portion of which has been smoke treated). The tobacco portion within the mixture may have a processed form such as a processed tobacco stem (e.g., a cut and rolled stem, a cut and rolled and expanded stem, or a cut and puffed stem) or a volume-expanded tobacco (e.g., a puffed tobacco such as dry ice expanded tobacco (DIET)). See, for example, U.S. Patent No. 4,340,073 to de la Burde, U.S. Patent No. 5,259,403 to Guy, U.S. Patent No. 5,908,032 to Poindexter, and U.S. Patent No. 7,556,047 to Poindexter. These are all incorporated by reference. Further, the mixture may optionally incorporate fermented tobacco. See also the types of tobacco processing techniques described in International Publication No. 2005 / 063060 pamphlet by Atchley et al., which is incorporated herein by reference.

[0181] Tobacco materials are typically used in a form that can be described as particulate (i.e., fragmented, pulverized, granulated, or powdered). The ways in which tobacco materials are provided in a finely divided or powdered form can vary. Preferably, plant parts or fragments are subdivided, pulverized, or micronized using devices and techniques for micronization, milling, etc. Most preferably, the plant material is in a relatively dry form during pulverization or milling using devices such as hammer mills, cutter heads, air control mills, etc. For example, tobacco parts or fragments may be pulverized or milled when their moisture content is less than about 15% by weight or less than about 5% by weight. Most preferably, the tobacco material is used in the form of parts or fragments having an average particle size of 1.4 millimeters to 250 microns. In some examples, the tobacco particles can be sized to pass through a screen mesh to obtain the required particle size range. If desired, an air classification device can be used to reliably collect small tobacco particles of the desired size or size range. If desired, granular tobacco pieces of different sizes may be mixed together.

[0182] There can be various ways in which tobacco is provided in a finely divided form or in powder form. Preferably, the tobacco parts or fragments are subdivided, pulverized or atomized into a powder-type form using devices and techniques for atomization, milling, etc. Most preferably, the tobacco is in a relatively dry form during pulverization or milling using devices such as a hammer mill, cutter head, air control mill, etc. For example, the tobacco parts or fragments may be pulverized or milled when their moisture content is less than about 15% by weight to less than about 5% by weight. For example, a tobacco plant or a part thereof can be separated into individual parts or fragments (e.g., the leaves can be removed from the stem, and / or the stem and leaves can be removed from the stem). The harvested plant or individual parts or fragments can be further subdivided into parts or fragments (e.g., the leaves can be fragmented, cut, subdivided, atomized, milled or pulverized into fragments or parts that can be characterized as filler-type fragments, granules, microparticles or fine powder). The plant or a part thereof can be subjected to an external force or pressure (e.g., by being subjected to a press or roll treatment). When carrying out such treatment conditions, the plant or a part thereof can have a moisture content close to its natural moisture content (e.g., the moisture content immediately after harvesting), a moisture content achieved by adding moisture to the plant or a part thereof, or a moisture content resulting from the drying of the plant or a part thereof. For example, the powdered, atomized, pulverized or milled fragments of the plant or a part thereof can have a moisture content of less than about 25% by weight, often less than about 20% by weight, frequently less than about 15% by weight.

[0183] For the preparation of oral compositions, it is typical for harvested plants of Nicotiana species to be subjected to a curing process. The tobacco materials incorporated within the compositions disclosed herein are appropriately cured and / or aged. Descriptions of various types of curing processes for various types of tobacco are set forth in Tobacco Production, Chemistry and Technology, Davis et al. (Eds.) (1999). Examples of techniques and conditions for curing flue-cured tobacco are described in Nestor et al., Beitrage Tabakforsch.Int., 20, 467-475 (2003) and U.S. Patent No. 6,895,974 to Peele. These are incorporated herein by reference. Representative techniques and conditions for air-cured tobacco are described in U.S. Patent No. 7,650,892 to Groves et al., Roton et al., Beitrage Tabakforsch.Int., 21, 305-320 (2005) and Staaf et al., Beitrage Tabakforsch.Int., 21, 321-330 (2005), which are incorporated herein by reference. Certain types of tobacco can be subjected to alternative types of curing processes such as fire curing or sun drying curing.

[0184] In certain embodiments, tobacco materials that can be used include flue-cured or Virginia (e.g., K326), burley, sun-dried cured (e.g., Indian Kurnool and Oriental tobacco including Katerini, Prelip, Komotini, Xanthi and Yambol tobacco), Maryland, dark, dark fire, dark air-cured (e.g., Madole, Passanda, Cubano, Jatin and Bezuki tobacco), light air-cured (e.g., North Wisconsin and Galpao tobacco), Indian air-cured, Red Russian and Rustica tobacco, as well as various other rare or special tobaccos and various blends of any of the foregoing tobaccos.

[0185] The tobacco material may also have a so-called "blend" form. For example, the tobacco material can include a mixture of parts or fragments of flue-cured, burley (e.g., burley tobacco from Malawi), and Oriental tobacco (e.g., tobacco composed of or derived from tobacco lamina, or a mixture of tobacco lamina and tobacco stems). For example, a typical blend can incorporate from about 30 to about 70 parts of burley tobacco (e.g., lamina, or lamina and stems) and from about 30 to about 70 parts of flue-cured tobacco (e.g., stems, lamina, or lamina and stems) on a dry weight basis. Other examples of tobacco blends incorporate, on a dry weight basis, about 75 parts of flue-cured tobacco, about 15 parts of burley tobacco, and about 10 parts of Oriental tobacco, or about 65 parts of flue-cured tobacco, about 25 parts of burley tobacco, and about 10 parts of Oriental tobacco, or about 65 parts of flue-cured tobacco, about 10 parts of burley tobacco, and about 25 parts of Oriental tobacco. Other examples of tobacco blends incorporate from about 20 to about 30 parts of Oriental tobacco and from about 70 to about 80 parts of flue-cured tobacco on a dry weight basis.

[0186] The tobacco materials used in the present disclosure can be subjected to, for example, fermentation, bleaching, etc. If desired, the tobacco materials can be subjected to, for example, irradiation, pasteurization, or otherwise controlled heat treatment. Such treatment processes are detailed, for example, in U.S. Patent No. 8,061,362 to Mua et al., which is incorporated herein by reference. In certain embodiments, the tobacco materials are treated with water and an additive (e.g., lysine, glycine, histidine, alanine, methionine, cysteine, glutamic acid, aspartic acid, proline, phenylalanine, valine, arginine, a composition incorporating divalent and trivalent cations, asparaginase, certain non-reducing sugars, certain reducing agents, phenolic compounds, certain compounds having at least one free thiol group or functional group, oxidizing agents, oxidation catalysts, natural plant extracts (e.g., rosemary extract), and combinations thereof) that can inhibit the reaction of asparagine upon heating of the tobacco materials to form acrylamide. See, for example, the types of treatment processes described in U.S. Patent Nos. 8,434,496, 8,944,072, and 8,991,403 to Chen et al., all of which are incorporated herein by reference. In certain embodiments, this type of treatment is useful when the original tobacco materials are subjected to heat in the aforementioned processes.

[0187] In some embodiments, the type of tobacco material is initially selected to be somewhat visually brighter in color than other tobacco materials (e.g., whitened or bleached). In certain embodiments, the tobacco pulp can be whitened according to any means known in the art. For example, whitened tobacco materials produced by various bleaching methods using various bleaching agents, oxidizing agents, and oxidation catalysts can be used. Examples of oxidizing agents include peroxides (e.g., hydrogen peroxide), chlorites, chlorates, perchlorates, hypochlorites, ozone, ammonia, potassium permanganate, and combinations thereof. Examples of oxidation catalysts are titanium dioxide, manganese dioxide, and combinations thereof.Methods of treating tobacco with bleaching agents are described, for example, in U.S. Patent No. 787,611 to Daniels, Jr.; Patent No. 1,086,306 to Oelenheinz; Patent No. 1,437,095 to Delling; Patent No. 1,757,477 to Rosenhoch; Patent No. 2,122,421 to Hawkinson; Patent No. 2,148,147 to Baier; Patent No. 2,170,107 to Baier; Patent No. 2,274,649 to Baier; Patent No. 2,770,239 to Prats et al.; Patent No. 3,612,065 to Rosen; Patent No. 3,851,653 to Rosen; Patent No. 3,889,689 to Rosen; Patent No. 3,943,940 to Minami; Patent No. 3,943,945 to Rosen; Patent No. 4,143,666 to Rainer; Patent No. 4,194,514 to Campbell; Patent Nos. 4,366,823, 4,366,824 and 4,388,933 to Rainer et al.; Patent No. 4,641,667 to Schmekel et al.; Patent No. 5,713,376 to Berger; Patent No. 9,339,058 to Byrd, Jr. et al.; Patent No. 9,420,825 to Beeson et al. and Patent No. 9,950,858 to Byrd, Jr. et al., and in U.S. Patent Application Publication No. 2012 / 0067361 to Bjorkholm et al.; Patent No. 2016 / 0073686 to Crooks; Patent No. 2017 / 0020183 to Bjorkholm and Patent No. 2017 / 0112183 to Bjorkholm, and in PCT Application International Publication No. 1996 / 031255 to Giolvas and International Publication No. 2018 / 083114 to Bjorkholm. All of these are hereby incorporated by reference into this specification.

[0188] In some embodiments, the whitened tobacco material can have an ISO brightness of at least about 50%, at least about 60%, at least about 65%, at least about 70%, at least about 75% or at least about 80%. In some embodiments, the whitened tobacco material can have an ISO brightness in the range of about 50% to about 90%, about 55% to about 75%, or about 60% to about 70%. The ISO brightness can be measured in accordance with ISO 3688:1999 or ISO 2470-1:2016.

[0189] In some embodiments, the whitened tobacco material can be characterized as having a lighter color (e.g., "whitened") compared to the non-treated tobacco material. White is frequently defined with reference to the chromaticity diagram of the International Commission on Illumination (CIE). The whitened tobacco material can be characterized as being closer to pure white in the chromaticity diagram than the non-treated tobacco material in certain embodiments.

[0190] In various embodiments, the tobacco material can be processed to extract soluble components of the tobacco material therefrom. As used herein, "tobacco extract" refers to isolated components of the tobacco material that are extracted from solid tobacco pulp by a solvent that contacts the tobacco material in an extraction process. Various extraction techniques for the tobacco material can be used to provide tobacco extracts and tobacco solid materials. See, for example, the extraction process described in U.S. Patent Application Publication No. 2011 / 0247640 to Beeson et al. This is incorporated herein by reference. Other exemplary techniques for extracting components of tobacco are U.S. Patent No. 4,144,895 to Fiore, U.S. Patent No. 4,150,677 to Osborne, Jr. et al., U.S. Patent No. 4,267,847 to Reid, U.S. Patent No. 4,289,147 to Wildman et al., U.S. Patent No. 4,351,346 to Brummer et al., U.S. Patent No. 4,359,059 to Brummer et al., U.S. Patent No. 4,506,682 to Muller, U.S. Patent No. 4,589,428 to Keritsis, U.S. Patent No. 4,605,016 to Soga et al., U.S. Patent No. 4,716,911 to Poulose et al., Niven, Jr.U.S. Patent No. 4,727,889 to [name]; U.S. Patent No. 4,887,618 to Bernasek; U.S. Patent No. 4,941,484 to Clapp; U.S. Patent No. 4,967,771 to Fagg; U.S. Patent No. 4,986,286 to Roberts; U.S. Patent No. 5,005,593 to Fagg; U.S. Patent No. 5,018,540 to Grubbs; U.S. Patent No. 5,060,669 to White; U.S. Patent No. 5,065,775 to Fagg; U.S. Patent No. 5,074,319 to White; U.S. Patent No. 5,099,862 to White; U.S. Patent No. 5,121,757 to White; U.S. Patent No. 5,131,414 to Fagg; U.S. Patent No. 5,131,415 to Munoz; U.S. Patent No. 5,148,819 to Fagg; U.S. Patent No. 5,197,494 to Kramer; U.S. Patent No. 5,230,354 to Smith; U.S. Patent No. 5,234,008 to Fagg; U.S. Patent No. 5,243,999 to Smith; U.S. Patent No. 5,301,694 to Raymond; U.S. Patent No. 5,318,050 to Gonzalez-Parra; U.S. Patent No. 5,343,879 to Teague; U.S. Patent No. 5,360,022 to Newton; U.S. Patent No. 5,435,325 to Clapp; U.S. Patent No. 5,445,169 to Brinkley; U.S. Patent No. 6,131,584 to Lauterbach; U.S. Patent No. 6,298,859 to Kierulff; U.S. Patent No. 6,772,767 to Mua; and U.S. Patent No. 7,337,782 to Thompson, all of which are hereby incorporated by reference.

[0191] The typical inclusion range of tobacco materials can vary depending on the nature and type of the tobacco materials, as well as the intended effect on the final mixture, and ranges up to about 30 wt% (or up to about 20 wt% or up to about 10 wt%, or up to about 5 wt%) are exemplified based on the total weight of the composition (e.g., from about 0.1 to about 15 wt%). In some embodiments, the compositions of the present disclosure can be characterized as containing no or substantially no tobacco materials (other than purified nicotine as the active ingredient). For example, certain embodiments can be characterized as having less than 1 wt%, or less than 0.5 wt% or less than 0.1 wt% of tobacco materials, or 0 wt% of tobacco materials.

[0192] 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 dental caries or tooth loss, the ability to inhibit gum disease, the ability to reduce mouth pain, the ability to whiten teeth, or otherwise inhibit tooth discoloration, the ability to induce saliva stimulation, the ability to inhibit bad breath, the ability to freshen bad breath, etc. For example, an effective amount of components such as thyme oil, eucalyptus oil, and zinc (such as components of formulations commercially available as ZYTEX(R) 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 include those described in Takahashi et al., Oral Microbiology and Immunology, 19(1), 61-64 (2004), U.S. Patent No. 6,083,527 to Thistle, U.S. Patent Application Publication No. 2006 / 0210488 to Jakubowski, and Publication No. 2006 / 02228308 to Cummins et al., which are incorporated into oral care compositions of the types described therein. Other exemplary components of tobacco-containing formulations include those included in formulations sold as MALTISORB(R) by Roquette and formulations sold as DENTIZYME(R) by NatraRx. When present, representative amounts of the oral care additive 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 the oral care additive in the foaming composition typically does not exceed about 30% of the total dry weight of the foaming composition, often does not exceed about 25%, and frequently does not exceed about 20%.

[0193] Processing aid If downstream processing of the composition, such as granulation, mixing, or molding, is required, a flow aid can also be added to the composition to enhance its fluidity. In some embodiments, the composition (e.g., in melt and chew form) may be surface-treated with an anti-sticking agent such as oil, silicone. Exemplary flow aids include microcrystalline cellulose, silica, polyethylene glycol, stearic acid, calcium stearate, magnesium stearate, zinc stearate, sodium stearyl fumarate, candelilla wax, and combinations thereof. In some embodiments, the flow aid is sodium stearyl fumarate.

[0194] When present, a representative amount of the flow aid can constitute at least about 0.5% or at least about 1% of the total dry weight of the composition. Preferably, the amount of the flow aid in the composition does not exceed about 5% of the total dry weight of the composition and frequently does not exceed about 3%.

[0195] Other additives Other additives can be included in the disclosed composition. For example, the composition can be processed, blended, compounded, combined, and / or mixed with other materials or components. The additives can be artificial or can be obtained from or derived from herbs or biological sources. Examples of additional types of additives include thickeners or gelling agents (e.g., fish gelatin), emulsifiers, preservatives (e.g., potassium sorbate, etc.), disintegrants, or combinations thereof. For example, representative components thereof, combinations of components, relative amounts of those components, as well as techniques and methods for using those components, can be found in 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. Each of which is incorporated herein by reference.

[0196] Typical ranges of such additional additives can vary depending on the nature and function of the additive and the intended effect on the final composition, and ranges up to about 10 wt% are exemplified, based on the total weight of the composition (e.g., from about 0.1 to about 5 wt%).

[0197] The foregoing additives can be used together (e.g., as an additive formulation) or separately (e.g., the individual additive components can be added at different stages involved in the preparation of the final mixture). Further, additives of the foregoing types may be encapsulated so as to be supplied to the final product or composition. Examples of encapsulated additives are described, for example, in International Publication No. WO 2010 / 132444 to Atchley, which is hereby incorporated by reference herein in its entirety.

[0198] Fine particles In some embodiments, any one or more of the fillers, tobacco materials, other composition components, and overall compositions described herein can be described as particulate materials. As used herein, the term "particulate" refers to a material in the form of a plurality of individual particles, some of which may be in the form of aggregates of a plurality of particles, and the particles have an average length-to-width ratio of less than 2:1, such as less than 1.5:1, such as about 1:1. In various embodiments, the particles of the particulate material can be described as being substantially spherical or granular.

[0199] The particle size of the particulate matter can be measured by sieve analysis. As will be readily understood 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 particulate materials. Typically, sieve analysis involves a nested column of sieves, preferably including a screen in the form of a wire mesh cloth. A pre-weighed sample can be introduced onto the top or uppermost sieve within the column, which has the largest sieve opening or mesh size (i.e., the largest pore diameter of the sieve). Each successive sieve within the column has a screen opening or mesh size that is progressively smaller than the sieve above it. Typically, at the base of the column of sieves there is a receiver portion for collecting any particles having a particle size smaller than the sieve opening size or mesh size of the bottom or lowermost sieve of the column (which has the smallest screen opening or mesh size).

[0200] In some embodiments, the sieve column can be placed on or in a mechanical stirrer. The stirrer causes vibration of each sieve within the column. The mechanical stirrer may be activated for a predetermined period to ensure that all particles are collected in the correct sieve. In some embodiments, the sieve column is stirred for a period of 0.5 minutes to 10 minutes, such as 1 minute to 10 minutes, such as 1 minute to 5 minutes, such as about 3 minutes. Once the stirring of the sieves within the column is complete, the substances collected on each sieve are weighed. Then, the weight of each sample on each sieve can be divided by the total weight to obtain the percentage of the mass retained on each sieve. As will be readily understood by those skilled in the art, the sieve opening size or mesh size of each sieve of the column used for sieve analysis can be selected based on the particle size of the sample being analyzed or the known maximum / minimum particle size. In some embodiments, a sieve column can be used for sieve analysis, and the column includes 2 to 20 sieves, such as 5 to 15 sieves. In some embodiments, a sieve column can be used for sieve analysis, and the column includes 10 sieves. In some embodiments, the maximum sieve opening or mesh size of the sieves used for sieve analysis can be 1000 μm, such as 500 μm, such as 400 μm, such as 300 μm.

[0201] In some embodiments, any particulate material referred to herein (e.g., fillers, tobacco materials, and the overall composition) can be characterized as having at least 50 wt% of 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 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 when measured by sieve analysis. In some embodiments, at least 70 wt% of the particles of any particulate material referred to herein 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 when measured by sieve analysis. In some embodiments, at least 80 wt% of the particles of any particulate material referred to herein 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 when measured by sieve analysis. In some embodiments, at least 90 wt% of the particles of any particulate material referred to herein 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 when measured by sieve analysis. In some embodiments, at least 95 wt% of the particles of any particulate material referred to herein 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 when measured by sieve analysis. In some embodiments, at least 99 wt% of the particles of any particulate material referred to herein 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 when measured by sieve analysis.In some embodiments, for about 100% by weight of the particles of any particulate material referred to herein, when measured by sieve analysis, they 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.

[0202] In some embodiments, at least 50% by weight, such as at least 60% by weight, such as at least 70% by weight, such as at least 80% by weight, such as at least 90% by weight, such as at least 95% by weight, such as at least 99% by weight of the particles of any particulate material referred to herein, when measured by sieve analysis, have a particle size of about 0.01 μm to about 1000 μm, such as about 0.05 μm to about 750 μm, such as about 0.1 μm to about 500 μm, such as about 0.25 μm to about 500 μm. In some embodiments, at least 50% by weight, such as at least 60% by weight, such as at least 70% by weight, such as at least 80% by weight, such as at least 90% by weight, such as at least 95% by weight, such as at least 99% by weight of the particles of any particulate material referred to herein, when measured by sieve analysis, have a particle size of about 10 μm to about 400 μm, such as about 50 μm to about 350 μm, such as about 100 μm to about 350 μm, such as about 200 μm to about 300 μm.

[0203] Preparation of composition The ways of combining the various components of a mixture can be diverse. Thus, the overall mixture of the various components and, for example, the powdered mixture components can be relatively homogeneous in nature. The above components, which may be in liquid or dry solid form, can be mixed in a pretreatment step before mixing with any remaining components of the mixture or simply mixed with all other liquid or dry components. The various components of the mixture can be brought into contact, combined, or mixed together using any mixing technique or apparatus known in the art. Any mixing method that closely contacts the components of the mixture can be used, such as a mixing apparatus characterized by an impeller or other stirrable structure. Examples of mixing devices include casing drums, conditioning cylinders or drums, liquid spraying devices, conical blenders, ribbon blenders, mixers available from Littleford Day, Inc. as FKM130, FKM600, FKM1200, FKM2000, and FKM3000, Plough Share type mixer cylinders, Hobart mixers, and the like. See also, for example, the types of methods described in U.S. Patent No. 4,148,325 to Solomon et al., U.S. Patent No. 6,510,855 to Korte et al., and U.S. Patent No. 6,834,654 to Williams et al. Each of these is incorporated herein by reference. In some embodiments, the components forming the mixture are prepared such that the mixture can be used in a starch forming process for forming the mixture. The techniques and methods for formulating the mixture will be apparent to those skilled in the art. See also, for example, the types of methods described in U.S. Patent No. 4,148,325 to Solomon et al., U.S. Patent No. 6,510,855 to Korte et al., U.S. Patent No. 6,834,654 to Williams, U.S. Patent No. 4,725,440 to Ridgway et al., and U.S. Patent No. 6,077,524 to Bolder et al. Each of these is incorporated herein by reference.

[0204] Oral composition Compositions configured for oral use are provided herein. As used herein, the term "configured for oral use" means that, during use, the composition is provided in a form such that saliva in the user's mouth passes one or more of the components of the composition (e.g., a basic amine, a flavorant, and / or an active ingredient) into the user's mouth. In certain embodiments, the composition is adapted to deliver the components to the user through the mucous membranes of the user's mouth, the user's digestive system, or both, and in some examples, the components are nicotine components or active ingredients (including, but not limited to, for example, nicotine, stimulants, vitamins, amino acids, plants, or combinations thereof) that can be absorbed through the mucous membranes of the mouth or through the digestive tract when the product is used.

[0205] The compositions configured for oral use described herein can take various forms including gels, lozenges, gums, chewables, melts, tablets, troches, powders, and pouches. The gels can be soft or hard. A particular composition configured for oral use is in the form of a lozenge. As used herein, the term "lozenge" refers to a soluble oral composition made by solidifying a liquid or gel composition such that the final composition is a somewhat hardened solid gel. The rigidity of the gel is highly variable. Particular compositions of the present disclosure are in solid form. Particular compositions can exhibit one or more of, for example, crispy, granular, chewy, syrupy, pasty, fluffy, smooth, and / or creamy characteristics. In certain embodiments, the desired texture characteristics can be selected from the group consisting of adhesiveness, cohesiveness, density, dryness, friability, granulosity, rubberiness, hardness, weight, hygroscopicity, moisture release, mouth coating, coarseness, slipperiness, smoothness, viscosity, wetness, and combinations thereof.

[0206] The compositions disclosed herein can be formed into a variety of shapes including pills, tablets, spheres, strips, films, sheets, coins, cubes, beads, ovoids, oblongs, cylinders, lentils, sticks, or rods. The cross-sectional shape of the composition can be varied and exemplary cross-sectional shapes include circular, square, oval, rectangular, and the like. Such shapes can be formed in a variety of ways using equipment such as moving belts, nips, extruders, granulators, compression devices, and the like.

[0207] The compositions of the present disclosure can be soluble. As used herein, the terms “dissolve,” “dissolving,” and “soluble” refer to compositions having water-soluble components that interact with the moisture in the oral cavity to enter into solution, thereby causing the composition to be consumed slowly. According to one aspect, the soluble composition can persist in the user's mouth for a given period of time until it is completely dissolved. The dissolution rate can vary over a wide range from about 1 minute or less to about 60 minutes. For example, an immediate-release composition typically dissolves and / or releases the desired component (e.g., active ingredient, flavor, etc.) in about 2 minutes or less, often 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, mechanical disruption (e.g., chewing), enzymatic or other chemical decomposition, 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.

[0208] In some embodiments, the composition may be chewable, which means that the composition has a gentle elasticity or "rebound" during chewing and has a desirable degree of extensibility. The chewable form of the composition may be completely dissolved or may be in the form of a non-dissolving gum in which only certain components (e.g., active ingredients, flavors, sweeteners) are dissolved leaving a non-dissolving matrix. Chewable embodiments generally include a binder, such as natural rubber or pectin. In some embodiments, the chewable form of the composition includes pectin and an organic acid together with one or more sugar alcohols in an amount of at least 50% by weight based on the total weight of the composition. Generally, pectin is present in an amount of about 1 to about 3% by weight based on the total weight of the composition.

[0209] In some embodiments, the composition can be made meltable, as discussed, for example, in U.S. Patent Application Publication No. 2012 / 0037175 to Cantrell et al., which is hereby incorporated by reference in its entirety. As used herein, "melt," "melting," and "meltable" refer to the ability of the composition to change from a solid state to a liquid state. That is, melting occurs when a substance (e.g., the compositions disclosed herein) changes from a solid to a liquid, typically by the application of heat. The application of heat to the compositions disclosed herein is effected by the internal temperature of the user's mouth. Accordingly, the term "meltable" refers to a composition that can liquefy in the user's mouth when the composition undergoes a phase change from a solid to a liquid, distinguishing it from a composition that simply disintegrates in the mouth due to loss of cohesion within the composition that simply dissolves in the mouth when the water-soluble components of the composition interact with moisture. Generally, meltable compositions contain lipids as described above herein. In some embodiments, the meltable form of the composition contains 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, zylitol, iditol, mannitol, xylitol, lactitol, or a combination thereof. In some embodiments, the sugar alcohol is isomalt.

[0210] In certain embodiments, the composition is in the form of compressed or molded pellets. Examples of pellet weights range from about 250 mg to about 1500 mg, such as from about 250 mg to about 700 mg, or from about 700 mg to about 1500 mg. The pellets can have any of a variety of shapes including the shape of a conventional pill or tablet. Generally, the composition in tablet form comprises a glucose-polysaccharide blend and a sugar alcohol. In some embodiments, the glucose-polysaccharide blend 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, arabitol, ribitol, maltitol, dulcitol, iditol, mannitol, xylitol, lactitol, or a combination thereof. In some embodiments, the sugar alcohol is isomalt.

[0211] In one embodiment, the composition of the present disclosure is disposed within a moisture-permeable container (e.g., a water-permeable pouch). Such a composition in the form of a water-permeable pouch is typically used by placing one pouch containing the mixture into the mouth of a human subject / user. Generally, the pouch is placed somewhere in the user's oral cavity, such as under the lip, in the same manner as a moist snuff is commonly used. The pouch is preferably not chewed or swallowed. Then, upon exposure to saliva, some of the components of the composition therein (e.g., flavorants and / or nicotine) pass through, for example, the water-permeable pouch, providing flavor and satisfaction to the user, and the user does not have to spit out any portion of the mixture. After about 10 to about 60 minutes of use / enjoyment, typically about 15 to about 45 minutes, a substantial amount of the mixture is ingested by the human subject, and the pouch can be removed from the human subject's mouth for disposal.

[0212] Thus, in certain embodiments, the compositions disclosed herein and any of the other ingredients described above are combined within a moisture-permeable packet or pouch that functions 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 FIG. 1 of the accompanying drawings, and these described embodiments include snus-type products having an outer pouch and containing the mixtures described herein. As will be described in more detail below, such embodiments are provided by way of example only, and the pouch products of the present disclosure can include other forms of compositions. The mixture / structure of such a packet or pouch, such as container pouch 102 in the embodiment shown in FIG. 1, can vary. Referring to FIG. 1, 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 includes a material 104 containing the composition described herein.

[0213] Suitable packets, pouches or containers of the type used in 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 and packaged in a pouch in the manner and using the types of components used in the manufacture of conventional snus-type products. The pouch comprises a liquid-permeable container of a type that may be considered to be similar in characteristics to the mesh-type materials used in the construction of tea bags. The components of the mixture diffuse easily through the pouch into the user's mouth.

[0214] Non-limiting examples of suitable types of pouches are described, for example, in U.S. Patent No. 5,167,244 to Kjerstad and U.S. Patent No. 8,931,493 to Sebastian et al., U.S. Patent Application Publication No. 2016 / 0000140 to Sebastian et al., U.S. Patent Application Publication No. 2016 / 0073689 to Sebastian et al., U.S. Patent Application Publication No. 2016 / 0157515 to Chapman et al., and U.S. Patent Application Publication No. 2016 / 0192703 to Sebastian et al. These are hereby incorporated by reference into this specification. The pouches can be provided as individual pouches or a plurality of pouches (e.g., 2, 4, 5, 10, 12, 15, 20, 25, or 30 pouches) can be connected or linked to each other (e.g., in an end-to-end manner) such that a single pouch or individual portions can be easily removed from the one-piece strand or parent material of the pouch for use.

[0215] Exemplary pouches can be manufactured from materials in such a way that the pouches undergo controlled dispensing or dissolution during use by the user. Such pouch materials can have forms such as mesh, screen, perforated paper, permeable cloth, etc. For example, a pouch material made from rice paper in a mesh form or perforated rice paper can dissolve in the user's mouth. As a result, the pouch and the mixture can each be completely dispersed in the user's mouth during normal use conditions, and thus both the pouch and the mixture can be ingested by the user. Other examples of pouch materials can be manufactured using a water-dispersible film-forming material (e.g., binders such as alginate, carboxymethyl cellulose, xanthan gum, pullulan, etc.) in combination with materials such as ground cellulose (e.g., particulate-sized wood pulp). Preferred pouch materials are water-dispersible or soluble but can be designed and manufactured such that a significant amount of the mixture contents can permeate through the pouch material before the pouch loses its physical integrity under normal use conditions. If desired, flavor components, disintegrants, and other desired components can be incorporated into or applied to the pouch material.

[0216] The amount of material contained within each product unit, such as within a pouch, can vary. In some embodiments, the weight of the mixture within each pouch is at least about 50 mg, such as from about 50 mg to about 1 g, from about 100 to about 800 mg, or from about 200 to about 700 mg. In some smaller scale embodiments, the weight of the mixture within each pouch can be from about 100 to about 300 mg. In larger scale embodiments, the weight of the material within each pouch may be from about 300 mg to about 700 mg. Optionally, other components can be included within each pouch. For example, a strip, piece or sheet of at least one flavored water dispersible or water soluble material (such as a fresh 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 crinkled to be easily incorporated within the pouch. See, for example, the types of materials and techniques described in U.S. Patent No. 6,887,307 to Scott et al., and U.S. Patent No. 6,923,981 to Leung et al. and The EFSA Journal (2004) 85, 1-32. These are hereby incorporated by reference into this specification.

[0217] The pouch products described herein can be packaged inside any suitable inner packaging material and / or outer container. For example, see various types of containers for smokeless type products described in U.S. Patent No. 7,014,039 to Henson et al., No. 7,537,110 to Kutsch et al., No. 7,584,843 to Kutsch et al., No. 8,397,945 to Gelardi et al., D592,956 to Thiellier, D594,154 to Patel et al., and D625,178 to Bailey et al., U.S. Patent Application Publication No. 2008 / 0173317 to Robinson et al., No. 2009 / 0014343 to Clark et al., No. 2009 / 0014450 to Bjorkholm, No. 2009 / 0250360 to Bellamah et al., No. 2009 / 0266837 to Gelardi et al., No. 2009 / 0223989 to Gelardi, No. 2009 / 0230003 to Thiellier, No. 2010 / 0084424 to Gelardi, and No. 2010 / 0133140 to Bailey et al., No. 2010 / 0264157 to Bailey et al., and No. 2011 / 0168712 to Bailey et al. These are hereby incorporated by reference into this specification.

[0218] Shelf life The compositions of the present disclosure configured for oral use (e.g., in the form of a pouch) can be packaged and stored in any suitable packaging in substantially the same manner as conventional types of smokeless tobacco products are packaged and stored. For example, a plurality of packets or pouches may be housed in a cylindrical container. The shelf life of the product after preparation can vary. As used herein, "shelf life" refers to the period after preparation of the disclosed product. In some embodiments, one or more of the characteristics of the products disclosed herein (e.g., absence of color change, retention of volatile flavor components, retention of nicotine) are exhibited over part or all of the shelf life. In some embodiments, the shelf life (i.e., the period after preparation) is at least 1 day. In some embodiments, the shelf life is about 1 day, about 2 days, or about 3 days, about 1 week, or about 1 week to about 2 weeks, about 2 weeks to about 1 month, or about 1 month to about 2 months, about 3 months, about 4 months, about 5 months, or about 6 months. In some embodiments, the shelf life is any number of days from about 1 to about 180 days. In certain embodiments, the shelf life may be longer than 6 months, for example, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 18 months, or about 24 months.

[0219] Method for improving stability In another aspect, a method for enhancing the stability of the compositions configured for oral use disclosed herein is provided. In some embodiments, the method includes mixing at least one filler with water, a basic amine, and an organic acid, an alkali metal salt of an organic acid, or a combination thereof to form a composition, wherein at least a portion of the basic amine 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, and the composition has a pH of less than about 8. In some embodiments, the basic amine is nicotine.

[0220] In some embodiments, the method further includes adding a solubility enhancer to the composition.

[0221] In some embodiments, the method further comprises adjusting the pH of the composition to a pH of less than about 7.0. In some embodiments, adjusting the pH comprises adding an organic acid to the composition to provide a pH of less than about 7.0. In some embodiments, adjusting the pH comprises adding a mineral acid to the composition to provide a pH of less than about 7.0. In some embodiments, adjusting the pH comprises adding both an organic acid and a mineral acid to the composition to provide a pH of less than about 7.0.

[0222] In some embodiments, enhancing stability comprises reducing loss of a basic amine (e.g., nicotine) from the composition by evaporation over a storage period as compared to a composition configured for oral use having a pH greater than about 8.

[0223] In some embodiments, the storage period is one or more of 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months after preparation. In some embodiments, loss of the basic amine (e.g., nicotine) is less than about 5% after a 6-month storage period. In some embodiments, the storage period is greater than 6 months, greater than 12 months, greater than 18 months, or even greater than 24 months.

[0224] Method for enhancing predicted oral absorption In a further aspect, a method is provided for enhancing predicted oral (e.g., buccal) absorption of a basic amine (e.g., nicotine) from a composition configured for oral use disclosed herein. Although invasive experiments are required to obtain actual absorption data, predictive data can be readily obtained by using buccal membrane permeability in vitro. For example, the permeability rate of nicotine through such a membrane, or the permeability rate versus time, can be evaluated and compared for various embodiments of the nicotine-containing oral composition. For example, an oral composition according to the present disclosure can be compared to a control composition (e.g., nicotine in the absence of an organic acid, nicotine in the presence of an organic acid having a logP of less than 1.4, etc.) to provide surrogate data for predicting actual buccal absorption.

[0225] In some embodiments, a method of enhancing predicted oral absorption includes mixing at least one filler with water, a basic amine, and an organic acid, an alkali metal salt of the organic acid, or a combination thereof to form a composition, wherein at least a portion of the basic amine 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 thereof.

[0226] In some embodiments, the method further includes adding a solubility enhancer to the composition.

[0227] In some embodiments, the method further includes adjusting the pH of the composition to a pH of about 4.0 to about 7.0. In some embodiments, adjusting the pH includes adding an organic acid to the composition to provide a pH of about 4.0 to about 7.0. In some embodiments, adjusting the pH includes adding a mineral acid to the composition to provide a pH of about 4.0 to about 7.0. In some embodiments, adjusting the pH includes adding both an organic acid and a mineral acid to the composition to provide a pH of about 4.0 to about 7.0.

[0228] In some embodiments, enhancing predicted oral absorption includes increasing the percentage of total basic amine that permeates through a composition comprising an organic acid, an alkali metal salt of the organic acid, or a combination thereof, wherein the logP value of the organic acid is less than about 1.4.

[0229] In some embodiments, the basic amine is nicotine, and in some embodiments, enhancing predicted oral absorption includes increasing the percentage of total nicotine that permeates through a composition comprising an organic acid, an alkali metal salt of the organic acid, or a combination thereof, wherein the logP value of the organic acid is less than about 1.4.

[0230] Many modifications and other embodiments of the present invention will come to mind to those skilled in the art to which the present invention pertains, having the benefit of the teachings presented in the foregoing description. Accordingly, it is to be understood that the present invention is not to be limited to the specific embodiments disclosed herein, and that modified forms and other embodiments are intended to be included within the scope of the appended claims. Specific terms are used herein, but they are used in a general and descriptive sense only and not for purposes of limitation.

Example

[0231] Aspects of the present invention are more fully described by the following examples, which are set forth to illustrate specific aspects of the invention and should not be construed as limiting thereof.

[0232] [Example 1] Calculation of free nicotine as a function of pH Using the Henderson-Hasselbalch equation (pH = pK a + log 10 (A− / HA)), the proportion of free nicotine present in the solution at different pH values was calculated. The data shown in Table 2 demonstrate that the proportion of free nicotine changes dramatically as the pH near the pK of nicotine changes. a

[0233]

Table 2

[0234] [Example 2] Calculated nicotine partitioning at pH 8.4 The theoretical octanol / water partition of the nicotine solution at pH 8.4 was calculated based on the partition coefficients obtained from Molinspiration software (https: / / www.molinspiration.com / services / logp.html). The values used were log(P) = 1.09 for free nicotine and log(P) = -2.07 for protonated nicotine. The percentage of protonation was calculated using the Henderson-Hasselbalch equation (Table 3). The calculation indicates that at pH 8.4, approximately 65% of the total available nicotine is expected to be present in the octanol layer.

[0235]

Table 3

[0236] [Example 3] Octanol / water partitioning of nicotine at 100 ppm and pH 5 Free base nicotine (0.2 grams) was added to a volumetric flask (200 mL) and filled to volume with reverse osmosis (RO) purified water to prepare a nicotine solution (1000 ppm, 6.17 mM). Individual 6.17 mM solutions of trisodium citrate, sodium benzoate, sodium heptanesulfonate, sodium tartrate, and sodium levulinate were prepared. Aliquots of the nicotine solution (10 mL), RO water (60 mL), and each citrate, benzoate, heptanesulfonate, tartrate, and levulinate solution (10 mL) were added to a weighted Erlenmeyer flask (125 mL) along with a counterion-free control. A pH probe was immersed in the resulting liquid and HCl (0.05 M) was added with stirring to bring the solution to pH 5. The weight of the flask was then brought up to 100 grams with RO water. The resulting solution contained 1000 ppm nicotine at pH 5 with 1 molar equivalent of each sodium salt. Aliquots (10 mL) of each solution were removed and partitioned by placing them in separate 20 ml scintillation vials. Octanol (10 ml) was added to each vial. The vials were then placed on a wrist action shaker for 20 minutes. After stirring, the vials were separated for 30 minutes and aliquots (100 μl) of each octanol layer were removed and diluted with 900 μl of octanol in 2 mL GC / MS vials. The nicotine concentration of each sample was analyzed by GC / MS. The levels of nicotine are shown in Figure 2, which shows an increase in octanol / water partitioning moving from the control and polar citrate (logP = -1.7), tartrate (and levulinate) to more lipophilic acids such as heptanesulfonate (log(P) = 0.88) and benzoate (log(P) = 1.9). Without wishing to be bound by theory, this partitioning is the result of ion pair formation, and the ion pairs are thought to exhibit sufficient lipophilicity to effectively partition into octanol for the samples of benzoic acid and heptanesulfonic acid. In particular, at this acidic pH and low concentrations of nicotine and counterions, the overall partitioning for all samples was very low (i.e., 1.2 - 8.5%).Although we do not wish to be bound by theory, it is believed that the pH value and the degree of ion pairing at low nicotine / counterion concentrations decrease the degree of potential ion pairing by shifting the equilibrium towards free ions.

[0237] [Example 4] Octanol / water partitioning of nicotine at 1000 ppm and pH 6.5 Free base nicotine (2 grams) was added to a volumetric flask (200 mL) and filled to volume with reverse osmosis (RO) purified water to prepare a nicotine solution (10,000 ppm, 61.7 mM). Individual 123.2 mM solutions of trisodium citrate, sodium benzoate, and sodium octanoate were prepared. Aliquots of the nicotine solution (10 mL), RO water (60 mL), and each sodium citrate, benzoate, or octanoate solution (10 mL) were added to a weighted Erlenmeyer flask (125 mL). A pH probe was immersed in the resulting liquid and HCl (0.05 M) was added with stirring to bring the solution to pH 6.5. The weight of the flask was then brought up to 100 grams with RO water. The resulting solution contained 1,000 ppm of nicotine at pH 6.5 with 2 molar equivalents of each sodium salt. Aliquots (10 mL) of each solution were removed and dispensed by placing them into separate 20 ml scintillation vials. Octanol (10 ml) was added to each vial. The vials were then placed on a wrist action shaker for 20 minutes. After stirring, the vials were separated for 30 minutes and aliquots (100 μl) of each octanol layer were removed and diluted with 900 μl of octanol in 2 mL GC / MS vials. The nicotine concentration of each sample was analyzed by GC / MS. The nicotine levels are shown in Figure 3, which shows an increase in octanol / water partitioning at pH 6.5 moving from the polar citrate (log(P)= -1.7) to more lipophilic acids such as benzoate (log(P)= 1.9) and octanoate (log(P)= 3.0). In particular, in the presence of 2 equivalents of octanoic acid, the majority (about 67%) of the nicotine is partitioned into the octanol. Without wishing to be bound by theory, this partitioning is thought to be the result of ion pair formation, where the ion pair exhibits sufficient lipophilicity to be effectively partitioned into the octanol.

[0238] [Example 5] Octanol / water partitioning of nicotine and benzoic acid in unbuffered water A solution of 1000 ppm nicotine in unbuffered water containing 1 molar equivalent of sodium benzoate was prepared. This nicotine concentration was chosen as equivalent to a pouched composition containing 6 mg nicotine that would dissolve in 6 mL of saliva. Samples were subjected to octanol / water partitioning and analyzed for nicotine using the method of Example 2. Samples were also analyzed for the concentration of benzoic acid in octanol (100 μl aliquot diluted with 900 μl octanol). Benzoic acid concentration was measured using an HPLC-UV procedure adapted from the literature (Phenomenex, Application, ID14720). Separation yielded the following composition: H 2 O75%, CH 3 KH containing CN25% 2 PO 4 The analysis was carried out on a Luna 5m C18 column (150×3 mm, Phenomenex, Torrance, CA, USA) using a mobile phase of 0.2 mM H 3 PO 4 The pH was adjusted to 2.5 with 100 mL / min. The flow rate of the mobile phase was 1 mL / min, and the injection volume was 10 μL. The eluate was monitored at 254 nm. For sample quantification, H 2 A stock solution containing 260 ppm benzoic acid in 200 was first made. This solution was diluted to give standard solutions of 260, 130, 65, 32.5, and 16.25 μg / mL, respectively. The peak areas vs. concentration obtained from these samples gave the following calibration line: y=0.2573x+0.0372, R 2 =0.9999.

[0239] The concentrations in octanol were found to be 28.3 ppm for nicotine and 19.2 ppm for benzoic acid. The molar concentration of benzoic acid in terms of nicotine mass was calculated to be 25.5 ppm nicotine. Thus, 90% of the nicotine (25.5 / 28.3) was partitioned into octanol due to benzoic acid, and 2.8% of the total nicotine (28.3 - 25.5) was partitioned into octanol because free nicotine tends to be partitioned into octanol (Figure 4). Theoretically, when nicotine and benzoic acid are partitioned into octanol as an ion pair, nicotine and benzoic acid should be present in a 1:1 molar ratio in octanol, reflecting the stoichiometry of the proposed ion pair. However, in this experiment, it was found that the nicotine concentration in octanol relative to benzoic acid was slightly higher than the theoretical value of 28.3 to 25.5 ppm. While not wishing to be bound by theory, the higher concentration of nicotine in octanol is thought to be due to the natural partitioning of nicotine into octanol at pH 6.5 (i.e., at pH 6.5, a portion of the nicotine is available as the free base and is partitioned without relying on ion pairing). This data further supports the theory that the change in octanol / water partitioning is due to the presence of the ion pair and not simply due to a change in the properties of the system (such as a change in the polarity of the solution or micelle formation).

[0240] [Example 6] Reference (control) composition A reference sample of a composition containing 6 mg of nicotine, microcrystalline cellulose (mcc), water, and additional ingredients disclosed herein (salts, binders, sweeteners, wetting agents, flavorings) was prepared without an organic acid (pH approximately 9).

[0241] [Example 7] Reference composition (citric acid) A reference sample of a composition containing 6 mg of nicotine, microcrystalline cellulose (mcc), water, and the additional ingredients (salts, binders, sweeteners, wetting agents, flavorings) disclosed herein was prepared containing 0.34% citric acid (pH about 6.5). Except for the presence of citric acid, the ingredients and the relative amounts of each ingredient were essentially the same as for Example 6.

[0242] [Example 8] Octanol / water partitioning of Examples 6 and 7 Samples of each of the pouch fillers of Examples 6 and 7 (total 697.6 mg, 10 mg of nicotine) were accurately weighed into separate 20 mL scintillation vials. Partitioning was carried out by adding water (10 mL, purified by reverse osmosis) to the sample, followed by addition of octanol (10 mL). The vials were then placed on a wrist action shaker for 2 hours. After agitation, the vials were allowed to separate for 30 minutes and an aliquot (100 μl) of each octanol layer was removed and diluted with octanol (900 μl) in a 2 mL GC / MS vial. To each GC / MS vial, 50 μL of a quinoline standard (1000 ppm in MeOH) was added. The samples were run in triplicate along with nicotine standards. The nicotine standards were prepared at 100, 50, 25, 12.5, 6.25, and 3.125 ppm in octanol. GC-MS analysis was carried out according to standard methods. The results are shown in Figure 5, which demonstrated that about 80% of the nicotine was partitioned into octanol in the citric acid-containing example, while only about 10% of the nicotine was partitioned into octanol.

[0243] [Example 9] Comparison of nicotine partitioning with various ion pair formers and amounts - benzoate, octanoate and decanoate Free base nicotine (2 grams) was added to a volumetric flask (200 mL) and filled to volume with reverse osmosis (RO) purified water to prepare a nicotine solution (10,000 ppm, 61.7 mM). Individual solutions of sodium benzoate, sodium octanoate, and sodium decanoate were prepared (0.62, 1.23, 3.08, 6.16, 12.33 mmol). Aliquots of the nicotine solution (10 mL), RO water (60 mL), and each benzoate, octanoate, or decanoate solution (10 mL) were added to a weighted Erlenmeyer flask (125 mL). A pH probe was immersed in the resulting liquid and HCl (0.05 M) was added with stirring to bring the solution to pH 6.5. The weight of the flask was then brought up to 100 grams with RO water. The resulting solution contained 1,000 ppm nicotine (equivalent to a pourable composition containing 6 mg nicotine dissolved in 6 mL of saliva) with 1, 2, 5, 10, or 20 molar equivalents of each sodium salt at pH 6.5. Aliquots (10 mL) of each solution were removed and partitioned by placing them in separate 20 ml scintillation vials. Octanol (10 ml) was added to each vial. The vials were then placed on a wrist action shaker for 20 minutes. After stirring, the vials were allowed to separate for 30 minutes and aliquots (100 μl) of each octanol layer were removed and diluted with 900 μl of octanol in 2 mL GC / MS vials. The nicotine concentration of each sample was analyzed by GC / MS. The nicotine levels are shown in Figure 6, which demonstrated that the type of acid used significantly affected the octanol / water partitioning of each ion pair. Specifically, for each concentration, the more lipophilic octanoic acid resulted in a greater partitioning of nicotine into octanol compared to the more polar benzoic acid. Samples containing decanoic acid tended to become soapy during the vigorous mixing required to perform the partitioning experiment. This may be due to micelle formation and resulted in unreliable partitioning data. Furthermore, the soapiness of the aqueous solution made accurate pH adjustment impossible. Therefore, the 2, 10, and 20 equivalent data points were excluded from Figure 6.

[0244] The data in Figure 6 further demonstrated that ion pairing, and thus the extent of octanol / water partitioning, is concentration-dependent. For each of benzoic acid and octanoic acid, the partitioning increased with acid concentration and reached an apparent plateau of approximately 20 equivalents of benzoic acid, consistent with theory, suggesting that maximum ion pairing had been achieved. According to theory, as the acid equivalent number increases, the equilibrium of the ion pair nicotine + organic acid with respect to the non-ion pair shifts mainly to the ion pair. The data further demonstrated that there may be an upper limit to the lipophilicity of useful acids in aqueous systems. For example, decanoic acid (log(P) = 4.09) was shown to partition into octanol to a lesser extent than predicted by theory. This may be due to the limit of solubility of decanoic acid in water, or the formation of micelles, consistent with the "soapy" nature of decanoic acid-containing solutions.

[0245] Surprisingly, at the same pH, each of the benzoic acid composition and the octanoic acid composition showed different partitioning behaviors. The proportion of nicotine in the octanol partition was highest with the non-polar acid (octanoic acid, logP of about 3, 10 equivalents, with octanoic acid, about 75% nicotine in octanol). The partitioning of the benzoic acid example at the same concentration (benzoic acid logP of about 1.85) was somewhat lower (about 52% nicotine in octanol). Each of the examples at pH 6.5 had a lower partitioning of nicotine into octanol than Example 6 (79%, pH of about 9), but was much higher than Example 7 (10%, polar citric acid, log(P)= -1.7, pH 6.5). However, the nicotine partitioning in the octanoic acid example at 2 equivalents was almost the same as that predicted for nicotine at pH 8.4 (65%, theoretical calculation by the Henderson-Haselbach equation and LogP). This result surprisingly shows that the composition containing octanoic acid was able to achieve a partitioning of nicotine equivalent to that of nicotine alone at pH 8.4 and at pH 6.5. Without wishing to be bound by theory, it is thought that ion pairing between nicotine and the relatively non-polar octanoic acid promoted the partitioning behavior. Thus, it demonstrates that it is possible to obtain an acidic composition that is stabilized with respect to the evaporation and decomposition of nicotine and has an octanol / water partition that is consistent with the partitioning of nicotine at a higher pH. Such data predict the preferred oral absorption of nicotine in embodiments containing relatively non-polar organic acids.

[0246] [Example 10] Reference pouch product (control) A reference (control) composition containing 10 mg of nicotine, microcrystalline cellulose (mcc), water, and additional ingredients disclosed herein (salts, sodium bicarbonate, binders, sweeteners, humectants, flavorings) was prepared without an organic acid (pH of about 8.4) and placed in a pouch. The pouch product was packaged in a standard flex lid canister with side seals and stored at room temperature (20 - 25 °C).

[0247] [Example 11] Pouch product (reference) A reference composition containing 10 mg of nicotine, microcrystalline cellulose (mcc), water, and additional ingredients (salts, binders, sweeteners, wetting agents, flavorings) disclosed herein was prepared using citric acid (about 0.6 wt%, pH about 6.7) and placed in a pouch. The pouch product was packaged in a standard flex lid canister with side seals and stored at room temperature (20 - 25 °C).

[0248] [Example 12] Pouch product (present invention) The composition of the present invention containing 10 mg of nicotine, microcrystalline cellulose (mcc), water, and additional ingredients (salts, binders, sweeteners, wetting agents, flavorings) disclosed herein was prepared using a combination of 2.4% by weight benzoic acid, 0.11% octanoic acid, and 0.13% decanoic acid, and about 2.4% sodium benzoate (pH about 6.4) was prepared and placed in a pouch. The pouch product was packaged in a standard flex lid canister with side seals and stored at room temperature (20 - 25 °C). Except for the presence of the acid components, the ingredients and the relative amounts of each ingredient were essentially the same for Examples 10 - 12.

[0249] [Example 13] Stability and volatility test of nicotine The products of Examples 10, 11, and 12 were analyzed for nicotine, moisture content, and pH immediately after preparation, and at 3 months and 6 months from preparation (T0, T3 months, and T6, respectively). To evaluate volatility as a function of the pH of these samples, nicotine data was calculated on a dry weight basis to account for the loss of moisture and compared to the original nicotine concentration. The results shown in Table 4 demonstrated that up to 13% of the nicotine was lost during storage of the control (Example 10), while the original level of nicotine was substantially retained in both acidic compositions (Example 12 and Reference Example 11).

[0250]

Table 4

[0251] [Example 14] Buccal permeation To evaluate the true impact of ion pairing on buccal absorption in a human subject, several pouched embodiments were prepared and evaluated in a buccal absorption model using a tissue-based permeation assay (EpiOral™, MatTek Labs).

[0252] A filler composition for a microcrystalline cellulose (MCC) - based pouch containing 6 mg of nicotine solution and additional ingredients (salts, binders, sweeteners, wetting agents, flavorants) disclosed herein was prepared.

[0253] A control composition (Example 14A) was prepared by adding sodium bicarbonate to the composition to provide an initial pH of about 9.25. The composition was filled into the pouches and oversprayed to a standard pouch weight of 700 mg.

[0254] A reference composition (Example 14B) was prepared by adding 0.34% citric acid to the composition to provide an initial pH of about 6.5. The composition was filled into the pouches and oversprayed to a standard pouch weight of 700 mg.

[0255] A composition of the present invention (Example 14C) was prepared by adding 0.63% benzoic acid and 1.08% sodium benzoate (2.26 equivalents total benzoic acid, 0.925 equivalents benzoic acid) to the composition to provide an initial pH of about 6.5. The composition was filled into the pouches and oversprayed to a standard pouch weight of 700 mg.

[0256] Each pouch was individually extracted with complete artificial saliva (CAS) at a concentration of 300 mg / mL. Then, the absorption of the CAS extract was evaluated using the EpiOral™ (buccal) permeation assay. The analysis consisted of a negative control (EpiOral™ non - exposed), a vehicle control (CAS), and a positive control (caffeine, Triton X100). Tissue (0.6 cm 2) was exposed to the donor solution at the root tip, and the receiver solution consisting of PBS solution containing calcium, magnesium, and glucose was collected for each sample at four time points (15, 30, 45, 60 minutes). All analyses were performed in sextuplicate (test articles) or triplicate (controls). Trans-epithelial electrical resistance was measured to verify tissue integrity at 0 minutes and the final time point. The receiver solution and donor solution were analyzed for the analyte (nicotine and control), and the obtained data were processed to obtain cumulative permeation, apparent permeation rate (P app ) and recovery rate. The cumulative permeation % was determined by quantifying the total mass permeated and dividing by the tissue area. The apparent permeation rate (P app ) was determined using Equation 2.

[0257] P app = (dQ / dt)*(1 / AC 0 ) (Equation 2) where (dQ / dt) is the steady-state flux, A is the area of the cell (0.6 cm 2 ), and C 0 is the initial concentration applied to the apical side of the tissue. The recovery rate was determined by dividing the final donor solution concentration, receiver solution concentration, and rinse solution concentration (the tissue was rinsed with CAS after removal of the receiver solution) by the concentration of the initial donor solution.

[0258] The results of the assay are shown in Figures 7-9. Figure 7 shows the total nicotine permeation rates of Examples 14A, 14B, and 14C. Example 14A (control) showed the highest nicotine permeation at 25%, while Reference Example 14B showed only about 5% permeation. Example 14C of the present invention showed permeation between the reference example and the control example and correlated with the octanol / water partition experiment. Consistent with the permeation rate, the Papp data also followed the same trend (Figure 8). Together, these data demonstrated that the polarity of the acid used to adjust the pH of the nicotine-containing composition significantly affected the rate and total movement through oral tissue. The data in Figure 9 confirmed that all of the nicotine present was recovered in the experiment.

Claims

**Claim 1** A composition configured for oral use, comprising: at least one filler; a basic amine; water; and an organic acid, an alkali metal salt of the organic acid, or a combination thereof, provided that the organic acid has a logP value of from about 1.4 to about 8.0; wherein at least a portion of the basic amine 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; a composition. **Claim 2** The composition according to claim 1, wherein the organic acid has a logP value of from about 1.4 to about 4.

5. **Claim 3** The composition according to claim 1, wherein the organic acid has a logP value of from about 2.5 to about 3.

5. **Claim 4** The composition according to claim 1, wherein the organic acid has a logP value of from about 4.5 to about 8.0 and the composition further comprises a solubility enhancer. **Claim 5** The composition according to claim 4, wherein the solubility enhancer is glycerol or propylene glycol. **Claim 6** The composition according to claim 1, comprising 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 the organic acid, its alkali metal salt, or a combination thereof, based on the basic amine calculated as the amine free base. **Claim 7** The composition according to claim 1, comprising from about 2 to about 10 molar equivalents of the organic acid, its alkali metal salt, or a combination thereof, based on the basic amine calculated as the amine free base. **Claim 8** The composition according to claim 1, wherein the organic acid is an alkyl carboxylic acid, an aryl carboxylic acid, an alkyl sulfonic acid, an aryl sulfonic acid, or a combination of any of these. **Claim 9** The composition according to claim 1, wherein the organic acid is octanoic acid, decanoic acid, benzoic acid, heptanesulfonic acid, or a combination thereof. **Claim 10** The composition according to claim 1, wherein the organic acid is octanoic acid. **Claim 11** The composition according to claim 1, wherein the alkali metal is sodium or potassium. **Claim 12** The composition according to claim 1, comprising the organic acid and the sodium salt of the organic acid. **Claim 13** The composition according to claim 12, wherein the ratio of the organic acid to the sodium salt of the organic acid is from about 0.1 to about 10. **Claim 14** ​ The composition according to claim 1, comprising benzoic acid and sodium benzoate, octanoic acid and sodium octanoate, decanoic acid and sodium decanoate, or a combination thereof.

15. The composition according to claim 1, wherein the pH of the composition is from about 4.0 to about 9.

0.

16. The composition according to claim 1, wherein the pH of the composition is from about 4.5 to about 7.

17. The composition according to claim 1, wherein the pH of the composition is from about 5.5 to about 7.

18. The composition according to claim 1, wherein the pH of the composition is from about 4.0 to about 5.

5.

19. The composition according to claim 1, wherein the pH of the composition is from about 7.0 to about 9.

0.

20. The composition according to claim 1, wherein the basic amine is nicotine.

21. The composition according to claim 20, wherein the nicotine is calculated as the free base and is present in an amount of about 0.001 to about 10% by weight of the composition, based on the total weight of the composition.

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

23. The composition according to claim 22, wherein the cellulose material comprises microcrystalline cellulose.

24. The composition according to claim 1, 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.

25. The composition according to claim 24, wherein the cellulose derivative is hydroxypropyl cellulose.

26. About 10 to about 50% of at least one filler, and Based on the total weight of the composition, about 5 to about 60% by weight of water The composition according to claim 1, comprising.

27. The composition according to claim 1, further comprising one or more active ingredients, one or more flavoring agents, one or more salts, one or more sweeteners, one or more binders, one or more humectants, one or more gums, tobacco materials, or combinations thereof.

28. The composition according to claim 1, further comprising one or more active ingredients selected from the group consisting of dietary supplements, botanicals, stimulants, amino acids, vitamins, and cannabinoids.

29. The composition according to claim 1, comprising no more than about 10% by weight of tobacco materials, excluding any nicotine components present, based on the total weight of the composition.

30. The composition according to claim 1, wherein the composition does not contain tobacco materials.

31. The composition according to claim 1, enclosed in a pouch to form a pouch product, and the composition is optionally in granular form.

32. A method for enhancing the stability of a composition configured for oral use, the composition comprising at least one filler, a basic amine, water, and an organic acid, an alkali metal salt of an organic acid, or a combination thereof, provided that the organic acid has a logP value of from about 1.4 to about 8.0, comprising forming the composition by mixing the at least one filler with the water, the basic amine, and the organic acid, the alkali metal salt of the organic acid, or a combination thereof, wherein at least a portion of the basic amine is associated with at least a portion of the organic acid or its alkali metal salt, the association being 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, and the pH of the composition being less than about 8.

33. The method according to claim 32, wherein the organic acid has a logP value of from about 1.4 to about 4.

5.

34. The method according to claim 32, wherein the organic acid has a logP value of from about 2.5 to about 3.

5.

35. The method according to claim 32, wherein the organic acid has a logP value of from about 4.5 to about 8.0 and the method further comprises adding a solubility enhancer to the composition.

36. The method according to claim 32, further comprising adjusting the pH of the composition to a pH of less than about 7.0, wherein adjusting the pH comprises adding an organic acid, a mineral acid, or both to the composition to effect a pH of less than about 7.

0.

37. Enhancing stability includes reducing loss of basic amine by evaporation from the composition over a storage period as compared to a composition configured for oral use having a pH greater than about 8, according to the method of claim 32.

38. The method according to claim 37, wherein the storage period is one or more of 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 9 months or 1 year after preparation.

39. The method according to claim 37, wherein the loss of basic amine is less than about 5% after a 6-month storage period.

40. The method according to claim 32, wherein the basic amine is nicotine.

41. A method for enhancing the predicted oral mucosal absorption of a basic amine from a composition configured for oral use, the composition comprising at least one filler, a basic amine, water, and ​ An organic acid, an alkali metal salt of an organic acid, or a combination thereof, provided that the organic acid has a logP value of from about 1.4 to about 8.0, comprising, the method comprising: mixing the at least one filler with the water, the basic amine, and the organic acid, the alkali metal salt of the organic acid, or a combination thereof to form the composition, wherein at least a portion of the basic amine is associated with at least a portion of the organic acid or its alkali metal salt, the association being 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, forming the composition.

42. The method of claim 41, wherein the organic acid has a logP value of from about 1.4 to about 4.

5.

43. The method of claim 41, wherein the organic acid has a logP value of from about 2.5 to about 3.

5.

44. The method of claim 41, wherein the organic acid has a logP value of from about 4.5 to about 8.0 and the method further comprises adding a solubility enhancer to the composition.

45. The method of claim 41, further comprising adjusting the pH of the composition to a pH of from about 4.0 to about 7.

0.

46. The method of claim 45, wherein adjusting the pH comprises adding a mineral acid to the composition.

47. The method of claim 41, wherein the basic amine is nicotine.

48. Enhancing predicted oral mucosal absorption comprises increasing the percentage of total nicotine permeated through a composition comprising an organic acid, an alkali metal salt of an organic acid, or a combination thereof, wherein the logP value of the organic acid is less than about 1.4, the method of claim 47.

Images