Oral product with basic amine and ion pairing agent

Abstract

To provide a composition configured for oral use.SOLUTION: There is provided compositions including 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 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 the alkali metal salt thereof. The association is in the form of a basic amine-organic acid salt, an ion pair between the basic amine and a conjugate base of the organic acid, or a combination of both. There are further provided methods for stabilizing a composition configured for oral use and for enhancing a predicted buccal absorption of a composition configured for oral use.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present disclosure relates to compositions intended for human use. The compositions are adapted for oral use and deliver substances such as nicotine, flavorings, and / or active ingredients during use. Such compositions may include tobacco or tobacco-derived products or may be tobacco-free alternatives. [Background technology]

[0002] Tobacco can be enjoyed in so-called "smokeless" forms. Particularly common smokeless tobacco products are consumed by inserting some form of processed tobacco or tobacco-containing formulation into the user's mouth. Traditional forms of such smokeless tobacco products include moist snuff, snus, and chewing tobacco, which are typically formed from nearly entirely fine, granular, or shredded tobacco and are either divided by the user or presented to the user in discrete portions, such as single-serving pouches or sachets. Other traditional 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.See, for example, U.S. Pat. Nos. 1,376,586 to Schwartz, 4,513,756 to Pittman et al., 4,528,993 to Sensabaugh, Jr. et al., 4,624,269 to Story et al., 4,991,599 to Tibbetts, 4,987,907 to Townsend, and 5,092,352 to Sprinkle, III et al. Nos. 5,387,416 to White et al., 6,668,839 to Williams, 6,834,654 to Williams, 6,953,040 to Atchley et al., 7,032,601 to Atchley et al., 7,694,686 to Atchley et al., U.S. Patent Application Publication No. 2004 / 0020503 to Williams, Qui No. 2005 / 0115580 to nter 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 / 0029110 to Robinson et al. See, for example, the types of smokeless tobacco formulations, ingredients, and processing methods described in International Publication Nos. 2008 / 0029116 to Robinson et al., 2008 / 0173317 to Neilsen et al., 2008 / 0209586 to Neilsen et al., 2009 / 0065013 to Essen et al., and 2010 / 0282267 to Atchley, and WO 2004 / 095959 to Arnarp et al., each of which is incorporated herein by reference.

[0003] Smokeless tobacco product configurations that combine tobacco materials with various binders and fillers have been proposed more recently, with exemplary product forms including lozenges, troches, gels, extrudates, 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., and 2013 / 0139164 to Cantrell et al. See the types of products described in 2012 / 0138074 to Holton, Jr., 2013 / 0074855 to Holton, Jr., 2013 / 0074856 to Holton, Jr., 2013 / 0152953 to Mua et al., 2013 / 0274296 to Jackson et al., 2015 / 0068545 to Moldoveanu et al., 2015 / 0101627 to Marshall et al., and 2015 / 0230515 to Lampe et al., each of which is incorporated herein by reference. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] U.S. Patent No. 1,376,586 [Patent Document 2] U.S. Patent No. 4,513,756 [Patent Document 3] U.S. Patent No. 4,528,993 [Patent Document 4] U.S. Patent No. 4,624,269 [Patent Document 5] U.S. Patent No. 4,991,599 [Patent Document 6] U.S. Patent No. 4,987,907 [Patent Document 7] U.S. Patent No. 5,092,352 [Patent Document 8] U.S. Patent No. 5,387,416 [Patent Document 9] U.S. Patent No. 6,668,839 [Patent Document 10] U.S. Patent No. 6,834,654 [Patent Document 11] U.S. Patent No. 6,953,040 [Patent Document 12] U.S. Patent No. 7,032,601 [Patent Document 13] U.S. Patent No. 7,694,686 [Patent Document 14] US Patent Application Publication No. 2004 / 0020503 [Patent Document 15] US Patent Application Publication No. 2005 / 0115580 [Patent Document 16] US Patent Application Publication No. 2006 / 0191548 [Patent Document 17] US Patent Application Publication No. 2007 / 0062549 [Patent Document 18] US Patent Application Publication No. 2007 / 0186941 [Patent Document 19] US Patent Application Publication No. 2007 / 0186942 [Patent Document 20] US Patent Application Publication No. 2008 / 0029110 [Patent Document 21] US Patent Application Publication No. 2008 / 0029116 [Patent Document 22] US Patent Application Publication No. 2008 / 0173317 [Patent Document 23] US Patent Application Publication No. 2008 / 0209586 [Patent Document 24] US Patent Application Publication No. 2009 / 0065013 [Patent Document 25] US Patent Application Publication No. 2010 / 0282267 [Patent Document 26] International Publication No. 2004 / 095959 [Patent Document 27] US Patent Application Publication No. 2008 / 0196730 [Patent Document 28] US Patent Application Publication No. 2008 / 0305216 [Patent Document 29] US Patent Application Publication No. 2009 / 0293889 [Patent Document 30] US Patent Application Publication No. 2010 / 0291245 [Patent Document 31] US Patent Application Publication No. 2011 / 0139164 [Patent Document 32] US Patent Application Publication No. 2012 / 0037175 [Patent Document 33] US Patent Application Publication No. 2012 / 0055494 [Patent Document 34] US Patent Application Publication No. 2012 / 0138073 [Patent Document 35] US Patent Application Publication No. 2012 / 0138074 [Patent Document 36] US Patent Application Publication No. 2013 / 0074855 [Patent Document 37] US Patent Application Publication No. 2013 / 0074856 [Patent Document 38] US Patent Application Publication No. 2013 / 0152953 [Patent Document 39] US Patent Application Publication No. 2013 / 0274296 [Patent Document 40] US Patent Application Publication No. 2015 / 0068545 [Patent Document 41] US Patent Application Publication No. 2015 / 0101627 [Patent Document 42] US Patent Application Publication No. 2015 / 0230515 Summary of the Invention [Means for solving the problem]

[0005] The present disclosure generally provides compositions configured for oral use. The compositions include 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 are present in the form of a salt.

[0006] Oral nicotine products are used by placing a nicotine-containing matrix between the cheek and gum. Nicotine is then released from the product and absorbed through the oral mucosa, thereby entering the bloodstream, where it is distributed throughout the systemic circulation. Flavor stability and positive sensory attributes are important factors for consumer acceptance of oral nicotine products. The organoleptic impact of flavors has been shown to be particularly sensitive to product pH. If the product pH exceeds approximately 7.0, the visual, aroma, and taste impacts of some flavors deteriorate over time, and nicotine may evaporate from the product. This instability is particularly pronounced for certain flavors, such as ethyl vanillin, lime, and cinnamon, which also cause darkening of an otherwise white product over time. However, decreasing pH increases the degree to which nicotine is present in the protonated form. As a dibasic alkaloid, nicotine has two protons (on the pyridine ring nitrogen, logK a1 =3.41, pyrrolidine ring nitrogen, log K a2= 8.02), significantly changing polarity. The overall polarity of nicotine increases from log(P) = 1.09 (unprotonated nicotine) to -2.07 (nicotine protonated at the pyrrolidine ring nitrogen). Passive diffusion of substances such as nicotine across membranes (e.g., mucous 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] Without wishing to be bound by theory, it is believed that a downward shift in log(P) as a result of protonation state is the primary 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., for a nicotine solution at pH 6 (where nicotine is primarily monoprotonated), there was still some diffusion across human buccal tissue in a perfusion cell, but the rate was significantly reduced (approximately sevenfold) compared to a nicotine solution at pH 8.1.

[0008] Surprisingly, according to the present disclosure, it has been found that the presence of certain non-polar or lipophilic organic acids or salts thereof enhances the stability of the composition and enhances the availability of nicotine for oral absorption in compositions configured for oral use compared to compositions configured for oral use that contain polar organic acids. 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 about 1.4 to about 8.0, and at least a portion of the basic amine is associated 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.

[0009] In some embodiments, the organic acid has a logP value of about 1.4 to about 4.5. In some embodiments, the organic acid has a logP value of about 2.5 to about 3.5. In some embodiments, the organic acid has a logP value of 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 about 0.05, about 0.1, about 1, about 1.5, about 2, or about 5 to about 10, about 15, or about 20 molar equivalents of an organic acid, an alkali metal salt thereof, or a combination thereof, relative to the basic amine, calculated as the amine free base.

[0011] In some embodiments, the composition comprises about 0.05, about 0.1, about 1, about 1.5, about 2, or about 5 to about 10, about 15, or about 20 molar equivalents of an organic acid, an alkali metal salt thereof, or a combination thereof relative to the nicotine component, calculated as free base nicotine. In some embodiments, the composition comprises about 2 to about 10 molar equivalents of an organic acid, an alkali metal salt thereof, or a combination thereof relative to the 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, heptane sulfonic acid, or a 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, hi some embodiments, the ratio of organic acid to 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 a combination thereof.

[0016] In some embodiments, the pH of the composition is about 4.0 to about 9.0. In some embodiments, the pH of the composition is about 4.5 to about 7. In some embodiments, the pH of the composition is about 5.5 to about 7. In some embodiments, the pH of the composition is about 4.0 to about 5.5. In some embodiments, the pH of the composition is about 7.0 to about 9.0.

[0017] In some embodiments, the basic amine is nicotine, hi some embodiments, the nicotine is present in an amount of about 0.001 to about 10% by weight of the composition, calculated as the free base, 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, the 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 from about 10 to about 50% of at least one filler, and from about 5 to about 60% by weight of water, based on the total weight of the composition.

[0020] In some embodiments, the composition 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 about 10% or less by weight of tobacco material, excluding any nicotine component present, based on the total weight of the composition. In some embodiments, the composition is free of tobacco material.

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

[0024] In another aspect, there is provided a method of increasing the stability of a composition configured for oral use, the stabilized composition comprising at least one bulking agent, a basic amine, water, 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, the method comprising mixing the at least one bulking agent with the water, the basic amine, and the organic acid, the 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 in association 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 wherein the pH of the composition is less than about 8.

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

[0026] In some embodiments, the organic acid has a log P value of about 2.5 to about 3.5. In some embodiments, the organic acid has a log P value of 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 of less than about 7.0, wherein adjusting the pH further comprises adding an organic acid, a mineral acid, or both to the composition to result in a pH of less than about 7.0.

[0028] In some embodiments, increasing stability includes reducing evaporative loss of basic amine from the composition over storage periods compared to compositions configured for oral use having a pH greater than about 8.

[0029] In some embodiments, the shelf life 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 6 month storage period, hi some embodiments, the basic amine is nicotine.

[0031] In yet another embodiment, there is provided 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 bulking agent, a basic amine, water, 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 from about 1.4 to about 8.0, the method comprising mixing the at least one bulking agent with the water, the basic amine, and the organic acid, the 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 in association 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.

[0032] In some embodiments, the organic acid has a log P value of about 1.4 to about 4.5. In some embodiments, the organic acid has a log P value of about 2.5 to about 3.5. In some embodiments, the organic acid has a log P value of 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 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 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 organic acid has a log P value of less than about 1.4.

[0035] The present disclosure includes, but is not limited to, 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 an organic acid, or a combination thereof, wherein the organic acid has a logP value of from about 1.4 to about 4.5, or from about 4.5 to about 8.0, and at least a portion of the basic amine is in association 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 pair, an ion pair between the basic amine and the conjugate base of the organic acid, or both.

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

[0038] Embodiment 3. The composition of 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 of 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 of embodiment 4, wherein the solubility enhancer is glycerol or propylene glycol.

[0041] Embodiment 6. The composition of any one of embodiments 1-5, 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, an alkali metal salt thereof, or a combination thereof relative to the nicotine component, calculated as free base nicotine.

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

[0043] Embodiment 8 The composition of any one of embodiments 1-7, wherein the organic acid is an alkyl carboxylic acid, an aryl carboxylic acid, an alkyl sulfonic acid, an aryl sulfonic acid, or any combination thereof.

[0044] Embodiment 9. The composition of any one of embodiments 1-8, wherein the organic acid is octanoic acid, decanoic acid, benzoic acid, heptanesulfonic acid, or a combination thereof.

[0045] Embodiment 10. The composition of any one of embodiments 1-9, wherein the organic acid is octanoic acid.

[0046] Embodiment 11 The composition of any one of embodiments 1 to 10, wherein the alkali metal is sodium or potassium.

[0047] Embodiment 12. The composition of any one of embodiments 1-11, comprising an organic acid and a sodium salt of an organic acid.

[0048] Embodiment 13 The composition of any one of embodiments 1 to 12, wherein the ratio of organic acid to sodium salt of organic acid is from about 0.1 to about 10.

[0049] Embodiment 14. The composition of any one of embodiments 1-13, comprising benzoic acid and sodium benzoate, octanoic acid and sodium octanoate, decanoic acid and sodium decanoate, or a combination thereof.

[0050] Embodiment 15. The composition of any one of embodiments 1 to 14, wherein the pH of the composition is from about 4.0 to about 9.0.

[0051] Embodiment 16. The composition of any one of embodiments 1 to 15, wherein the pH of the composition is from about 4.5 to about 7.

[0052] Embodiment 17. The composition of any one of embodiments 1 to 16, wherein the pH of the composition is from about 5.5 to about 7.

[0053] Embodiment 18. The composition of any one of embodiments 1 to 17, wherein the pH of the composition is from about 4.0 to about 5.5.

[0054] Embodiment 19. The composition of any one of embodiments 1 to 18, wherein the pH of the composition is from about 7.0 to about 9.0.

[0055] Embodiment 20. The composition of any one of embodiments 1-19, wherein the basic amine is nicotine.

[0056] Embodiment 21. The composition of any one of embodiments 1 to 20, wherein the nicotine is present in an amount of about 0.001 to about 10% by weight of the composition, calculated as the free base, based on the total weight of the composition.

[0057] Embodiment 22. The composition of any one of embodiments 1-21, wherein at least one filler comprises a cellulosic material.

[0058] Embodiment 23. The composition of any one of embodiments 1 to 22, wherein the cellulosic material comprises microcrystalline cellulose.

[0059] Embodiment 24 The composition of any one of embodiments 1 to 23, wherein the 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] Embodiment 25. The composition of any one of embodiments 1 to 24, wherein the cellulose derivative is hydroxypropyl cellulose.

[0061] Embodiment 26. The composition of any one of embodiments 1 to 25, comprising from about 10 to about 50% of at least one filler, and from about 5 to about 60% by weight of water, based on the total weight of the composition.

[0062] Embodiment 27. The composition of any one of embodiments 1-26, 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 a combination thereof.

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

[0064] Embodiment 29. The composition of any one of embodiments 1-28, comprising about 10% or less by weight of tobacco material, excluding any nicotine component present, based on the total weight of the composition.

[0065] Embodiment 30. The composition of any one of embodiments 1 to 29, wherein the composition does not comprise tobacco material.

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

[0067] Embodiment 32 A method of enhancing the stability of a composition configured for oral use, wherein the stabilized composition comprises at least one bulking agent, a basic amine, water, 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 from about 1.4 to about 8.0, the method comprising mixing the at least one bulking agent with the water, the basic amine, and the organic acid, the 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 in association with at least a portion of the organic acid or its alkali metal salt, wherein 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, and wherein the pH of the composition is less than about 8.

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

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

[0070] Embodiment 35. The method of embodiment 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.

[0071] Embodiment 36. The method of any one of embodiments 32-35, 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 provide a pH of less than about 7.0.

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

[0073] Embodiment 38. The method of 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 of any one of embodiments 32-38, wherein the basic amine is nicotine.

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

[0076] Embodiment 42 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 bulking agent, a basic amine, water, 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 from about 1.4 to about 8.0, the method comprising mixing the at least one bulking agent with the water, the basic amine, and the organic acid, the 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 in association 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.

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

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

[0079] Embodiment 45. The method of 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 of any one of embodiments 42-45, further comprising adjusting the pH of the composition to a pH of about 4.0 to about 7.0.

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

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

[0083] Embodiment 49. The method of any one of embodiments 42-48, wherein enhancing predicted buccal absorption comprises increasing the percentage of total nicotine permeated for a composition comprising an organic acid, an alkali metal salt of an organic acid, or a combination thereof, wherein the organic acid has a logP value of less than about 1.4.

[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, as well as combinations of any two, three, four, or more features or elements described in this disclosure, whether or not such features or elements are explicitly combined in the description of a particular embodiment herein. The present disclosure, in any of its various aspects and embodiments, is intended to be read as a whole such that any separable features or elements of the disclosed invention(s) should be considered as intended to be combinable unless the context clearly dictates otherwise.

[0085] Having thus described aspects of the present disclosure in the preceding general terms, reference is now made to the accompanying drawings, which are not necessarily drawn to scale, and which are illustrative only and are not to be construed as limiting the disclosure. [Brief explanation of the drawings]

[0086] [Figure 1] 1 is a perspective view of an embodiment of a pouch product according to an exemplary embodiment of the present disclosure, comprising a pouch or fleece at least partially filled with a composition configured for oral use. FIG. [Figure 2] 1 is a bar graph showing the octanol / water partitioning of nicotine according to embodiments of the present disclosure. [Figure 3] 1 is a bar graph showing the octanol / water partitioning of nicotine according to embodiments of the present disclosure. [Figure 4] 1 is a bar graph showing the octanol / water partitioning of nicotine according to embodiments of the present disclosure. [Figure 5] 1 is a bar graph showing the octanol / water partitioning of nicotine for control and reference compositions. [Figure 6] 1 is a bar graph showing the octanol / water partitioning of nicotine of different organic acid salts and concentrations according to embodiments of the present disclosure. [Figure 7] 1 is a bar graph of total nicotine membrane permeability of an embodiment of the present disclosure. [Figure 8] 1 is a bar graph of nicotine membrane permeation of an embodiment of the present disclosure. [Figure 9] 1 is a bar graph showing nicotine recovery 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 exemplary embodiments thereof. These exemplary embodiments are described so that this disclosure will be thorough and complete, and will fully convey the scope of the disclosure to those skilled in the art. Indeed, the disclosure may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. As used in this specification and claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. References to "% by dry weight" or "dry weight basis" refer to weight based on dry ingredients (i.e., all ingredients excluding water). References to "wet weight" refer to the weight of the mixture, including water. Unless otherwise indicated, references to "% by 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 its initial basic amine content during storage and delivers substantially all of the amount of basic amine initially present in the composition. The present disclosure provides a composition that combines a basic amine and a non-polar or lipophilic organic acid salt in an acidic matrix that exhibits improved retention of the initial basic amine content during storage and is predicted to deliver more basic amine to the user upon use of the composition relative to compositions containing a polar organic acid salt in an acidic matrix (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, it has been found that the presence of a non-polar or lipophilic organic acid salt enhances the stability of compositions designed for oral use containing polar organic acid salts and enhances the membrane permeability of nicotine in a model system for oral absorption at acidic pH. The enhanced nicotine permeability is particularly surprising given the predicted decrease in permeability associated with nicotine protonation under acidic conditions.

[0090] composition The compositions disclosed herein comprise at least one filler, a basic amine, such as nicotine or a nicotine component, water, 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 a basic amine-organic acid salt, an ion pair between the basic amine and the conjugate base of the organic acid, or both. The relative amounts of the various components in the composition can vary and are typically selected to impart desired sensory and performance characteristics to the composition. Exemplary individual components of the composition are further described herein below.

[0091] Ion pairing As disclosed herein, at least a portion of the basic amine is associated with at least a portion of the organic acid or its alkali metal salt. Depending on several variables (concentration, pH, nature of the organic acid, etc.), the basic amine present in the composition may exist in several forms, including as an ion pair, 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 refers to the partial association of oppositely charged ions in a relatively concentrated solution to form distinct chemical species called ion pairs. The strength of the association (i.e., ion pairing) depends on the electrostatic attraction between the cation and anion (i.e., the protonated basic amine, such as nicotine, and the conjugate base of the organic acid). By "conjugate base" is meant the base resulting from the deprotonation of the corresponding acid (e.g., benzoate is the conjugate base of benzoic acid). On average, a certain population of these ion pairs exists at any given time, but the formation and dissociation of ion pairs is continuous. In the compositions disclosed herein and / or upon oral use of the compositions (e.g., upon contact with saliva), the basic amine, e.g., nicotine and the conjugate base of the organic acid, exist, at least partially, in the form of ion pairs. Without wishing to be bound by theory, it is believed that such ion pairing can minimize chemical degradation of the basic amine (e.g., nicotine) and / or increase the oral availability of the basic amine. At alkaline pH values (e.g., about 7.5 to about 9), certain basic amines, such as nicotine, exist predominantly in their free base form, which has relatively low water solubility and low stability with respect to evaporation and oxidative degradation, but high mucosal availability. Conversely, at acidic pH values (e.g., about 6.5 to about 4), certain basic amines, such as nicotine, exist predominantly in their protonated form, which has relatively high water solubility and higher stability with respect to evaporation and oxidative degradation, but low mucosal availability. Surprisingly, in accordance with the present disclosure, it has been discovered that the stability, solubility, and availability properties of nicotine in compositions configured 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, ion-pairing of moderately lipophilic nicotine with organic acids results in favorable stability and absorption properties. Lipophilicity is conveniently measured in terms of logP, which is the partition coefficient of a molecule between a lipophilic phase and an aqueous phase, typically octanol and water, respectively. Octanol / water partitioning, which promotes distribution of the basic amine and organic acid ion pair into the octanol, predicts good absorption of the basic amine present in the composition across the oral mucosa.

[0093] As noted above, at alkaline pH values (e.g., about 7.5 to about 9), nicotine exists primarily in the free base form (and thus, high partitioning into octanol), while at acidic pH values (e.g., about 6.5 to about 4), nicotine exists primarily in the protonated form (and thus, low partitioning into octanol). Surprisingly, in accordance with the present disclosure, it has been discovered that ion pairs between certain 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 into octanol consistent with that predicted for nicotine partitioning into octanol at pH 8.4.

[0094] Those skilled in the art will recognize that the degree of ion-pairing in the disclosed compositions, both before and during consumer use, 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 its conjugate base present in the composition, the water content of the composition, the ionic strength of the composition, etc. Those skilled in the art will also recognize that ion-pairing is an equilibrium process influenced by the aforementioned variables. Therefore, 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 partitioning of the basic amine between octanol and water, or membrane permeation of an aqueous solution of the basic amine and the organic acid and / or their conjugate base.

[0095] organic acid As used herein, the term "organic acid" refers to an organic (i.e., carbon-based) compound characterized by acidic properties. Typically, organic acids are relatively weak acids (i.e., they do not completely dissociate in the presence of water), such as carboxylic acids (-COH) or sulfonic acids (-SOOH). As used herein, reference to an organic acid refers to an organic acid that is intentionally added. In this regard, an organic acid may be intentionally added as a particular composition component, as opposed to being inherently present merely as a component of another composition component (e.g., a small amount of an organic acid that may be inherently 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 aqueous and organic solubility). Typically, the lipophilicity of suitable organic acids, as indicated by log P, varies between about 1.4 and about 4.5 (more soluble in octanol than in water). In some embodiments, the organic acid has a log P value of about 1.5 to about 4.0, e.g., 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 log P value of about 1.7 to about 4, e.g., 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 log P value of 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 may have a log P value greater than about 4.5, e.g., from about 4.5 to about 8.0. In particular, the presence of certain solvents or solubilizers (e.g., the inclusion of glycerin or propylene glycol in the composition) may extend the range of lipophilicity (i.e., log P values greater than 4.5, such as from about 4.5 to about 8.0).

[0097] Without wishing to be bound by theory, it is believed that moderately lipophilic organic acids (e.g., log P values of about 1.4 to about 4.5) form ion pairs with polar nicotine that result in favorable octanol / water partitioning of the ion pair and thus partitioning of nicotine into octanol versus water. As discussed above, such partitioning into octanol predicts favorable oral availability. In some embodiments, the organic acid has a log P value of about 1.4 to about 4.5, e.g., 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 log P 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 carboxylic acid or sulfonic acid functional group can have, for example, 1 to 20 carbon atoms (C1-C 20In some embodiments, the organic acid is an alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl carboxylic or sulfonic acid.

[0099] As used herein, "alkyl" refers to any straight or branched chain hydrocarbon. The alkyl group may be saturated (i.e., all sp 3 As used herein, the term "unsaturated" refers to a group having one or more positions in an alkyl group that is carbon-carbon, sp 2 It refers to the presence of a double bond. Unsaturated alkyl groups 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, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, and the like. Alkyl groups can be unsubstituted or substituted.

[0100] As used herein, "cycloalkyl" refers to a carbocyclic group that can be monocyclic or bicyclic. Cycloalkyl groups include rings having 3 to 7 carbon atoms as a monocycle or rings having 7 to 12 carbon atoms as a bicycle. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl groups can be unsubstituted or substituted and can contain one or more sites of unsaturation (e.g., cyclopentenyl or cyclohexenyl).

[0101] The term "aryl" as used herein refers to a carbocyclic aromatic group. Examples of aryl groups include, but are not limited to, phenyl and naphthyl. Aryl groups can be unsubstituted or substituted.

[0102] As used herein, "heteroaryl" and "heterocycloalkyl" refer to an aromatic or non-aromatic ring system in which one or more ring atoms are heteroatoms, such as nitrogen, oxygen, and sulfur, respectively. A heteroaryl or heterocycloalkyl group contains up to 20 carbon atoms and 1 to 3 heteroatoms selected from N, O, and S. A heteroaryl or heterocycloalkyl can be a monocyclic ring having 3 to 7 ring members (e.g., 2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, and S) or a bicyclic ring having 7 to 10 ring members (e.g., 4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, and S), such as a bicyclo[4,5], [5,5], [5,6], or [6,6] system. Examples of heteroaryl groups include 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, naphthalenyl, and the like. Examples include, but are not limited to, phthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, benzotriazolyl, benzisoxazolyl, and isothiinoyl. Examples of heterocycloalkyl include, by way of example and not limitation, dihydropyridyl, tetrahydropyridyl (piperidyl), tetrahydrothiophenyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, bis-tetrahydropyranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, piperazinyl, quinuclidinyl, and morpholinyl.The heteroaryl and heterocycloalkyl groups can be unsubstituted or substituted.

[0103] As used herein, "substituted" as applied to any of the above alkyl, aryl, cycloalkyl, heteroaryl, and heterocyclyl groups means that one or more hydrogen atoms are each independently replaced with a substituent. Typical substituents include, but are not limited to, -Cl, Br, F, alkyl, -OH, -OCH, NH, -NHCH, -N(CH), -CN, -NC(=O)CH, -C(=O)-, -C(=O)NH, and -C(=O)N(CH). Whenever a group is described as "optionally substituted," that group can be substituted with one or more of the above substituents, selected independently in each occurrence. In some embodiments, the substituents 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 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 succinic acid monoethyl ester, 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 aryl carboxylic acid or aryl sulfonic acid. Non-limiting examples of aryl carboxylic and sulfonic acids include benzoic acid, toluene acid, salicylic acid, benzene sulfonic acid, and p-toluene sulfonic 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 sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, furoic acid, ga Contains lactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, isovaleric acid, lactovalic acid, lauric acid, levulinic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, oleic acid, palmitic acid, pamoic acid, phenylacetic acid, pyroglutamic acid, pyruvic acid, sebacic acid, stearic acid, and undecylenic acid.

[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, monooctyl fumarate, and the like.

[0114] The selection of an organic acid may further depend on additional properties, in addition to or without considering the logP value. For example, the organic acid should be one that is recognized as safe for human consumption and has acceptable flavor, odor, volatility, stability, etc. Determining an appropriate organic acid is within the purview of one of ordinary skill in the art.

[0115] In some embodiments, the organic acid is benzoic acid, toluene 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, a composition may include two, three, four, or more organic acids. Thus, reference herein to an "organic acid" contemplates a mixture of two or more organic acids. The relative amounts of multiple organic acids may vary. For example, a composition may include equal amounts of two, three, or more organic acids, or different relative amounts. In this manner, it is possible to include a particular organic acid (e.g., citric acid or myristic acid) having a logP value outside the desired range if, in combination with other organic acids, it results in a desired average logP range for the combination. In some embodiments, it may be desirable to include an organic acid with a logP value outside the desired range in a composition for purposes such as, but not limited to, imparting desired organoleptic properties, stability, flavor components, etc. Furthermore, certain lipophilic organic acids have undesirable flavor and / or aroma properties that preclude their presence as the sole organic acid (e.g., in an amount equimolar to or greater than nicotine). Without wishing to be bound by theory, it is believed that combinations of different organic acids may provide the desired ion pairing, while the concentration of any single organic acid in the composition remains below the threshold that would be considered objectionable from a sensory standpoint.

[0117] For example, in some embodiments, the organic acid may include about 1 to about 5 or more molar equivalents of benzoic acid relative to nicotine, e.g., in combination with about 0.2 molar equivalents of octanoic acid or a salt thereof, and 0.2 molar equivalents of decanoic acid or a salt thereof.

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

[0119] In some embodiments, the composition comprises an alkali metal salt of an organic acid. For example, at least a portion of the organic acid may be present in the composition in the form of an alkali metal salt. Suitable alkali 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 comprises an organic acid and a sodium salt of the organic acid.

[0120] In some embodiments, the composition comprises 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 organic acid to its sodium salt is about 0.1 to about 10, e.g., 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 the other components of the composition, with the organic acid being added in excess of the sodium salt, in an equimolar amount with the sodium salt, or as part of the sodium salt. Those skilled in the art will recognize that the relative amounts will be determined by the desired pH and desired ionic strength of the composition. 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 those skilled in the art will understand, the amount of organic acid (i.e., protonated form) present in the composition relative to the alkali metal salt or conjugate base form present in the composition will vary depending on the pH of the composition and the pKa of the organic acid, as well as the actual relative amounts initially added to the composition.

[0122] The amount of 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 that is paired with the organic acid increases. This is typically expressed as logP (logarithm of the partition coefficient). 10 In some embodiments, the composition comprises about 0.05, about 0.1, about 1, about 1.5, about 2, or about 5 to about 10, about 15, or about 20 molar equivalents of an organic acid, an alkali metal salt thereof, or a combination thereof, relative to the nicotine component, calculated as free base nicotine.

[0123] In some embodiments, the composition comprises about 2 to about 10, or about 2 to about 5, molar equivalents of organic acid, alkali metal salt thereof, or combination thereof to nicotine, based on free base nicotine. In some embodiments, the organic acid, alkali metal salt thereof, or combination thereof is present in a molar ratio to nicotine of about 2, about 3, about 4, or about 5 to about 6, about 7, about 8, about 9, or about 10. In embodiments in which more than one organic acid, alkali metal salt thereof, or both are present, such molar ratio should be understood to reflect the total organic acids present.

[0124] In certain embodiments, the organic acid content is sufficient to provide a pH of the composition of about 4.0 to about 9.0, e.g., about 4.5 to about 7.0, or about 5.5 to about 7.0, about 4.0 to about 5.5, or about 7.0 to about 9.0. In some embodiments, the organic acid content is sufficient to provide a pH of the composition of about 4.5 to about 6.5, e.g., 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 pH of the composition of about 5.5 to about 6.5, e.g., 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, the pH of the composition is adjusted to the desired value by adding a mineral acid (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, etc.).

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

[0126] Basic amines The compositions disclosed herein include basic amines. "Basic amine" refers to 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" refers to a group containing a nitrogen atom with a lone electron pair. The basic amine functional group is attached to or incorporated into a molecule via one or more covalent bonds to the nitrogen atom. Basic amines may be primary, secondary, or tertiary amines, meaning that the nitrogen has one, two, or three covalent bonds to a carbon atom. Due to the lone electron pair of the nitrogen atom, such amines are called "basics," meaning that the lone electron pair is available for hydrogen bonding. The basicity of a basic amine (i.e., the electron density of the nitrogen atom, and therefore the availability and strength of hydrogen bonds to the nitrogen atom) can be affected by the nature of neighboring atoms, the steric bulk of the molecule, etc.

[0127] Generally, the basic amine is released from the composition and absorbed through the oral mucosa, thereby entering the bloodstream where it circulates systemically. Generally, the basic amine is present in a composition or as an active ingredient in a composition, as described herein below. In some embodiments, the basic amine is nicotine or a nicotine component. By "nicotine component" is meant any suitable form of nicotine (e.g., free base, salt, or ion pair) that provides oral absorption of at least a portion of the nicotine present. The nicotine is released from the composition and 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 salt. In some embodiments, at least a portion of the nicotine is in the form of a free base. In some embodiments, as previously disclosed herein, 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.

[0129] Typically, the nicotine component (calculated as the free base) is present at a concentration of at least about 0.001% by weight of the composition, e.g., 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, e.g., 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 is present at a concentration of from about 0.1% w / w to about 3% by weight, calculated as the free base, based on the total weight of the composition, e.g., from about 0.1% w / w to about 2.5%, from about 0.1% to about 2.0%, from about 0.1% to about 1.5%, or from about 0.1% to about 1% by weight.

[0130] Filler The compositions described herein include one or more fillers, which can serve multiple functions, such as improving certain organoleptic properties, 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 cellulosic. For example, a suitable filler is any non-tobacco plant material or derivative thereof, including cellulosic materials derived from such sources. Examples of cellulosic non-tobacco plant materials include grains (e.g., corn, oats, barley, rye, buckwheat, etc.), sugar beet (e.g., FIBREX® brand filler available from International Fiber Corporation), bran fiber, and mixtures thereof. Non-limiting examples of derivatives of non-tobacco plant materials include starch (e.g., from potato, 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 present in granular form in almost all green plants and in the tissues and organs of various types of plants (e.g., seeds, leaves, rhizomes, roots, tubers, shoots, fruits, grains, and stems). Starch can vary in composition and granular shape and size. Starches from different sources often have different chemical and physical properties. Specific starches can be selected for inclusion in a mixture based on the starch material's ability to impart specific organoleptic properties to the composition. Starches from various sources can be used. For example, major sources of starch include cereals (e.g., rice, wheat, and corn) and root vegetables (e.g., potato and cassava). Other examples of sources of starch include acorns, kudzu, peanuts, bananas, barley, beans (e.g., favas, lentils, mung beans, peas, chickpeas), breadfruit, buckwheat, canna, chestnut, caracas, katakuri, kudzu, malanga, millet, oats, oca, Polynesian arrowroot, sago, sorghum, sweet potato, quinoa, rye, tapioca, taro, tobacco, water chestnuts, and yams. Certain starches are modified starches. Modified starches frequently undergo one or more structural modifications designed to alter their high thermal properties. Some starches have been developed through genetic modification and are considered "modified" starches. Other starches are obtained and subsequently modified.For example, modified starches can be starches that have 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, enzyme treatment, acetylation, hydroxypropylation, and / or partial hydrolysis. Other starches are modified by heat treatments such as pregelatinization, dextrinization, and / or cold water swelling processes. Specific modified starches include monostarch phosphate, didarch glycerol, didarch phosphate esterified with sodium trimetaphosphate, didarch phosphate phosphate, acetylated didarch phosphate, starch acetate esterified with acetic anhydride, starch acetate esterified with vinyl acetate, acetylated didarch adipate, acetylated didarch glycerol, hydroxypropyl starch, hydroxypropyl didarch glycerol, and starch sodium octenylsuccinate.

[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 a glucose- and starch-derived polysaccharide or a mixture thereof. One such suitable mixture of glucose and starch-derived polysaccharides is EMDEX®, available from JRS PHARMA LP, USA, 2981 Route 22, Patterson, NY 12563-2359.

[0134] In some embodiments, the particulate filler is a cellulosic material or a cellulose derivative. One particularly suitable particulate filler for use in the compositions described herein is microcrystalline cellulose ("mcc"). mcc may be synthetic or semi-synthetic, or may be derived entirely from natural cellulose. mcc can be selected from the group consisting of AVICEL® grades PH-100, PH-102, PH-103, PH-105, PH-112, PH-113, PH-200, PH-300, PH-302, VIVACEL® grades 101, 102, 12, 20, and EMOCEL® grades 50M and 90M, and the like, and mixtures thereof. In one embodiment, the composition comprises mcc as a 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 for filler (e.g., MCC) in the composition can be about 10 to about 75% by weight of the total weight of the composition, e.g., 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, e.g., at least about 20%, or at least about 25%, or at least about 30%, or at least about 35%, 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 about 1 to about 10% by weight of the cellulose derivative, and certain embodiments comprise about 1 to about 5% by weight of the cellulose derivative, based on the total weight of the composition. In certain embodiments, the cellulose derivative is a cellulose ether (including a carboxyalkyl ether), which refers to a cellulose polymer in which the hydrogen of one or more hydroxyl groups in the cellulose structure has been replaced with an alkyl, hydroxyalkyl, or aryl group. Non-limiting examples of such cellulose derivatives include methylcellulose, hydroxypropylcellulose ("HPC"), hydroxypropylmethylcellulose ("HPMC"), hydroxyethylcellulose, and carboxymethylcellulose ("CMC"). In one embodiment, the cellulose derivative is one or more of methylcellulose, HPC, HPMC, hydroxyethylcellulose, and CMC. In one embodiment, the cellulose derivative is HPC. In some embodiments, the composition comprises 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, generally from about 1 to about 60% by weight of water, e.g., 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, with water contents of at least about 5%, at least about 10%, at least about 15%, and at least about 20% by weight.

[0138] Active ingredient In certain embodiments, the compositions disclosed herein comprise an active ingredient. As used herein, "active ingredient" refers to one or more substances belonging to any of the following categories: APIs (active pharmaceutical substances), food additives, natural medicines, and naturally occurring substances capable of exerting an effect on humans. Exemplary active ingredients include any ingredient known to affect one or more biological functions in the body, such as providing pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or affecting the structure or any function of the human body (e.g., providing a stimulating effect on the central nervous system, an energy-providing effect, a fever-reducing or analgesic effect, or other beneficial effect on the body). In some embodiments, the active ingredient may be of the type commonly referred to as a dietary supplement, nutraceutical, "phytochemical," or "functional food." These types of additives are sometimes defined in the art to encompass substances typically available from naturally occurring sources (e.g., botanical materials) that provide one or more beneficial biological effects (e.g., health promotion, disease prevention, or other medicinal properties) but that are not classified or regulated as drugs.

[0139] Non-limiting examples of active ingredients include those that fall into the categories of botanicals, 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 herein below. The specific choice of active ingredient will depend on the desired flavor, texture, and desired properties of the particular product.

[0140] The specific percentage of active ingredients present will vary depending on the desired characteristics of a particular product. Typically, the active ingredient or combination thereof is present in a total concentration of at least about 0.001% by weight of the composition, e.g., in the range of about 0.001% to about 20%. In some embodiments, the active ingredient or combination of active ingredients is present in a concentration of about 0.1% w / w to about 10% by weight, e.g., about 0.5% w / w to about 10%, about 1% to about 10%, or about 1% to about 5% by weight, based on the total weight of the composition. In some embodiments, the active ingredient or combination of active ingredients is present in an amount of about 0.001%, about 0.01%, about 0.1%, or about 1%, up to about 20% by weight, based on the total weight of the composition, such as 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%, The active ingredient is present in a concentration of about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, or about 0.9%, to about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20% by weight. Further suitable ranges for certain active ingredients are provided herein below.

[0141] vegetable In some embodiments, the active ingredient comprises a botanical ingredient. As used herein, the term "botanical ingredient" or "botanical" refers to any plant or fungal-derived material, including plant material in its natural form and plant material derived from natural plant material, such as an extract or isolate from plant material or processed plant material (e.g., plant material that has been subjected to heat treatment, fermentation, bleaching, or other treatment processes that can alter the physical and / or chemical properties of the material). For purposes of this disclosure, "plant-derived drugs" include, but are not limited to, "herbal materials," which refer to seed-producing plants that do not develop persistent woody tissue and are often valued for their medicinal or sensory properties (e.g., tea or tisane). Reference to botanical materials as "non-tobacco" is intended to exclude tobacco materials (i.e., not including any Nicotiana species).

[0142] When present, the botanical-derived agent is typically at a concentration of about 0.01% w / w to about 10% by weight, for example, 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 effervescent composition.

[0143] Botanical materials useful in the present disclosure may include, but are not limited to, any of the compounds and sources described herein, including mixtures thereof. Certain botanical materials of this type are sometimes referred to as dietary supplements, nutraceuticals, "phytochemicals," or "functional foods." Certain plant-derived drugs, as plant materials or extracts thereof, are used in traditional herbal medicines and are further described herein. Non-limiting examples of plant-derived drugs or materials include ashwagandha, Bacopa monniera, baobab, basil, Centella asiatica, Chai-hu, chamomile, cherry blossom, chlorophyll, cinnamon, citrus fruits, clove, cocoa, cordyceps, curcumin, damiana, Dorstenia arifolia, Dorstenia odorata, essential oils, eucalyptus, fennel, Galphimia glauca, ginger, Ginkgo biloba, ginseng (e.g., Panax ginseng), green tea, Griffonia simpifolia, and the like. simplicifolia, guarana, hemp, hops, jasmine, Kaempferia parviflora (Thai ginseng), kava, lavender, lemon balm, lemongrass, licorice, lutein, maca, matcha green tea, Nardostachys chinensis, Viola odorata oil extract, peppermint, quercetin, resveratrol, Rhizoma gastrodiae, Rhodiola, rooibos, rose essential oil, rosemary, Sceletium tortuosum, Schisandra chinensis, skullcap, spearmint extract, pepper, terpenes, tisane, turmeric, Turnera aphrodisiaca aphrodisiaca, valerian, white mulberry, and yerba mate.

[0144] stimulants In some embodiments, the active ingredient comprises one or more stimulants. As used herein, the term "stimulant" refers to a substance that increases central nervous system and / or physical activity, e.g., a substance that enhances focus, cognition, energy, mood, alertness, etc. Non-limiting examples of stimulants include caffeine, theacrine, theobromine, and theophylline. Theacrine (1,3,7,9-tetramethyluric acid) is a purine alkaloid structurally related to caffeine and has stimulating, analgesic, and anti-inflammatory properties. The stimulant may be natural, naturally derived, or completely synthetic. For example, certain plant materials (such as guarana, tea, coffee, and cocoa) can have a stimulating effect due to the presence of caffeine or related alkaloids, and are therefore "natural" stimulants. "Naturally derived" means that the stimulant (e.g., caffeine, theacrine) is in a purified form outside of its natural (e.g., plant) parent material. For example, caffeine can be obtained by extraction and purification from plant sources (e.g., tea). "Totally synthetic" means that the stimulant is obtained by chemical synthesis. In some embodiments, the active ingredient includes caffeine. In some embodiments, the active ingredient is caffeine. In some embodiments, the caffeine is present in encapsulated form. An example of encapsulated caffeine is Vitashure®, 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 present at a concentration of about 0.1% w / w to about 15% 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%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15% by weight, based on the total weight of the effervescent 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 (-NH2) and a carboxyl (-COOH) or sulfonic acid (SO3H) functional group, along 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 naturally occurring 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 produced directly by cellular machinery (e.g., is a product of post-translational modification). Non-limiting examples of non-proteinogenic amino acids include gamma-aminobutyric acid (GABA), taurine (2-aminoethanesulfonic acid), theanine (L-gamma-glutamylethylamide), hydroxyproline, and beta-alanine.

[0147] When present, the amino acid or combination of amino acids (e.g., taurine, theanine, and combinations thereof) is typically at a concentration of about 0.1% w / w to about 15% 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%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15% by weight, based on the total weight of the foamable 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 set of related molecules) that is an essential micronutrient required for the proper functioning of mammalian metabolism. There are 13 vitamins required for human metabolism: vitamin A (as all-trans retinol, all-trans retinyl esters, and all-trans beta-carotene and other provitamin A carotenoids), vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3 (niacin), vitamin B5 (pantothenic acid), vitamin B6 (pyridoxine), vitamin B7 (biotin), vitamin B9 (folic acid or folate), vitamin B12 (cobalamin), vitamin C (ascorbic acid), vitamin D (calciferol), vitamin E (tocopherols and tocotrienols), and vitamin K (quinones).

[0149] When present, the vitamin or combination of vitamins (e.g., vitamin B6, vitamin B12, vitamin E, vitamin C, or a combination thereof) is typically at a concentration of about 0.01% w / w to about 1% by weight, for example, 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 effervescent composition.

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

[0151] If present, the cannabinoid (e.g., CBD) is typically at a concentration of at least about 0.1% by weight of the composition, for example, about 0.1% to about 30%, for example, 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] antioxidants 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, slowing or preventing certain cellular damage. 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 phenol derivatives.

[0153] Examples of botanical materials associated with antioxidant properties include, but are not limited to, acai berry, alfalfa, allspice, anatomy, apricot oil, basil, bee balm, wild bergamot, black pepper, blueberry, borage seed oil, bugle weed, cacao, mustard root, canip, catuaba, cayenne pepper, chaga mushroom, chervil, cinnamon, dark chocolate, potato peel, grapeseed, ginseng, ginkgo biloba, St. John's wort, saw palmetto, green tea, black tea, black cocoa, cayenne, chamomile, cloves, cocoa powder, cranberry, dandelion, grapefruit, honeybush, echinacea, garlic, and pine bark. Saw, ginger, goldenseal, hawthorn, hibiscus flower, gynostemma, kava, lavender, licorice, marjoram, milk thistle, mint (menth), oolong tea, beetroot, orange, oregano, papaya, pennyroyal, peppermint, red clover, rooibos (red or green), rosehip, rosemary, sage, clary sage, savory, spearmint, spirulina, slippery elm bark, sorghum bran high tannin, sorghum grain high tannin, sumac bran, comfrey leaf and root, goji berry, gutkola, thyme, turmeric, uva ursi, valerian, yam root, wintergreen, yacon root, yellow dock, yobamate mate, Yerba Santa, Bacopa monniera, Ashwagandha (Withania somnifera), Lion's mane, and Milk thistle. Such botanical materials may be provided in fresh or dried form, in essential oil form, or in the form of an extract. Botanical materials (and their extracts) often contain various classes of compounds known to confer antioxidant benefits, such as minerals, vitamins, isoflavones, phytosterols, allyl sulfides, dithiolthiones, isothiocyanates, indoles, lignans, flavonoids, polyphenols, and carotenoids.Examples of compounds found in plant extracts or oils include ascorbic acid, peanut endocarp, resveratrol, sulforaphane, β-carotene, lycopene, lutein, coenzyme Q, carnitine, quercetin, kaempferol, etc. See, e.g., Santhosh et al., Phytomedicine, 12 (2005) 216-220, incorporated herein by reference.

[0154] Non-limiting examples of other suitable antioxidants include citric acid, vitamin E or a derivative thereof, tocopherol, epicatechol, epigallocatechol, epigallocatechol gallate, erythorbic acid, sodium erythorbate, 4-hexylresorcinol, theaflavin, theaflavin monogallate A or B, theaflavin digallate, phenolic acids, glycosides, quercitrin, isoquercitrin, hyposides, polyphenols, catechol, resveratrol, oleuropein, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tertiary butylhydroquinone (TBHQ), and combinations thereof.

[0155] When present, the antioxidant is typically at a concentration of about 0.001% w / w to about 10% by weight, e.g., 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%, based on the total weight of the composition.

[0156] Pharmaceutical ingredients In some embodiments, the active ingredient comprises an active pharmaceutical ingredient (API). The API can be any known agent adapted 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 with 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), citicoline (cytidine-5′-diphosphate-choline), and cotinine.

[0157] When present, the amount of API can vary. For example, when present, the API is typically present at a concentration of about 0.001% w / w to about 10% by weight, e.g., 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 hereinabove, the basic amine present in the composition may be nicotine or a nicotine component, or may be an active ingredient or a component of an active ingredient. Those skilled in the art will recognize that many active ingredients defined herein are composed of molecules that can be classified as basic amines. Accordingly, ion pairing of such basic amine-containing active ingredients with lipophilic organic acids described herein is contemplated. In such embodiments, ion pairing of the active ingredient with an organic acid, an alkali metal salt of an organic acid, or a combination thereof may improve the stability of a composition containing the ion pair, or the presence of an ion-paired form of the active ingredient may improve the expected oral mucosal absorption of the active ingredient.

[0159] Flavoring agents In some embodiments, the effervescent compositions described herein comprise a flavoring agent. As used herein, a "flavoring agent" or "flavoring agent" is any flavorful or aromatic substance that can alter the sensory properties associated with an oral product. Examples of sensory properties that can be modified by a flavoring agent can include taste, mouthfeel, moistness, coolness / heat, and / or aroma / fragrance. Flavoring agents may be natural or synthetic, and the flavor characteristics imparted thereby can be described as, but are not limited to, 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 of which is incorporated herein by reference in its entirety. Flavorings may also include ingredients considered humectants, coolants, or smoothing agents, such as eucalyptus. These flavors may be provided neat (i.e., alone) or in complexes, and may be used as concentrates or flavor packages (e.g., spearmint and menthol, orange and cinnamon, lime, pineapple, etc.). Representative types of ingredients are also described in U.S. Pat. No. 5,387,416 to White et al., U.S. Patent Application Publication No. 2005 / 0244521 to Strickland et al., and PCT Application WO 05 / 041699 to Quinter et al., each of which is incorporated herein by reference. In some cases, the flavoring agent may be provided in spray-dried or liquid form.

[0160] Flavoring agents generally include at least one volatile flavor component. As used herein, "volatile" refers to a chemical that readily forms vapor at ambient temperature (i.e., a chemical that has a higher vapor pressure at a given temperature compared to non-volatile substances). Typically, volatile flavor components have a molecular weight of less than about 400 Da and often contain at least one carbon-carbon double bond, a carbon-oxygen double bond, or both. In one embodiment, the at least one volatile flavor 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, cuminaldehyde, benzaldehyde, and citronellal. Non-limiting examples of ketones include 1-hydroxy-2-propanone and 2-hydroxy-3-methyl-2-cyclopentenon-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, gamma-terpinene, beta-farnesene, nerolidol, thujone, myrcene, geraniol, nerol, citronellol, linalool, and eucalyptol. In one embodiment, the at least one volatile flavor component comprises one or more of ethyl vanillin, cinnamaldehyde, sabinene, limonene, gamma-terpinene, beta-farnesene, or citral.

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

[0162] Flavor adjusters To improve the organoleptic properties of the compositions disclosed herein, the compositions may include one or more taste modifiers ("taste modifiers"), which may serve, for example, to mask, alter, block, or improve the flavor of the compositions described herein. Non-limiting examples of such taste modifiers include soothing or anesthetic herbs, spices, and flavors that produce a perceived cooling sensation (e.g., menthol, eucalyptus, mint), warming sensation (e.g., cinnamon), or painful sensation (e.g., capsaicin). Certain taste modifiers fall into two or more overlapping categories.

[0163] In some embodiments, the taste modifier modifies one or more of bitter, sweet, salty, or sour tastes. In some embodiments, the taste modifier targets pain receptors. In some embodiments, a composition includes an active ingredient having a bitter taste and a taste modifier that masks or blocks the perception of bitterness. In some embodiments, the taste modifier is a substance that targets pain receptors (e.g., vanilloid receptors) in the user's oral cavity, for example, to mask the bitter taste of another ingredient (e.g., an active ingredient). Suitable taste modifiers include, but are not limited to, capsaicin, gamma-aminobutyric acid (GABA), adenosine monophosphate (AMP), lactisole, or combinations thereof.

[0164] When present, a representative amount of taste modifier is about 0.01% by weight or more, about 0.1% by weight or more, or about 1.0% by weight or more, but typically comprises less than about 10% by weight 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% by weight of the total weight of the composition).

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

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

[0167] sweetener One or more sweeteners may be added to improve the sensory properties of the compositions of the present disclosure. The sweetener may be any sweetener or combination of sweeteners, whether natural or artificial, or a combination of natural and artificial sweeteners. Examples of natural sweeteners include fructose, sucrose, glucose, maltose, mannose, galactose, lactose, stevia, honey, etc. Examples of artificial sweeteners include sucralose, isomaltulose, maltodextrin, saccharin, aspartame, acesulfame K, neotame, etc. In some embodiments, the sweetener comprises one or more sugar alcohols. Sugar alcohols are polyols derived from mono- or disaccharides, which may be partially or fully hydrogenated. Sugar alcohols, for example, have from about 4 to about 20 carbon atoms and include erythritol, arabitol, ribitol, isomalt, maltitol, dulcitol, iditol, mannitol, xylitol, lactitol, sorbitol, and combinations thereof (e.g., hydrogenated starch hydrolysates). In some embodiments, the sweetener is sucralose, acesulfame K, or combinations thereof.

[0168] When present, the sweetener or combination of sweeteners may comprise from about 0.01 to about 20% or more by weight of the composition, e.g., 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, e.g., 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, e.g., 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 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 a combination 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 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, with certain embodiments characterized by a binder content of at least about 0.1% by weight, e.g., 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 gum refers to naturally occurring polysaccharide materials that have binding properties and are also useful as thickeners or gelling agents. Representative natural gums derived from plants, which are typically somewhat water-soluble, include xanthan gum, guar gum, gum arabic, gum ghatti, gum tragacanth, gum karaya, locust bean gum, gellan gum, and combinations thereof. When present, natural gum binders are typically present in an amount of up to about 5% by weight, for example, 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] moisturizer 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, etc.When included, humectant is typically provided in an amount sufficient to provide the composition with desired moisture properties.In addition, in some examples, humectant can provide the composition with desirable flow properties for depositing in mold.

[0172] If present, the humectant typically comprises about 5% or less by weight of the composition (e.g., about 0.5 to about 5% by weight). If present, a representative amount of humectant is about 0.1% to about 1% by weight, or 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 may contain a pH adjuster or buffer. Examples of pH adjusters and buffers that can be used include, but are not limited to, metal hydroxides (e.g., alkali metal hydroxides such as sodium hydroxide and potassium hydroxide), and other alkali metal buffers such as metal carbamates (e.g., potassium carbamate or sodium carbamate), or metal bicarbamates such as sodium bicarbamate. Non-limiting examples of suitable buffers include alkali metal acetates, glycine acetates, phosphates, glycerophosphates, citrates, carbamates, carbonate carbamates, borocarbamates, or mixtures thereof.

[0174] If present, the buffering agent is typically present in an amount less than about 5% by weight of the composition, e.g., from about 0.5% to about 5%, e.g., from about 0.75% to about 4%, from about 0.75% to about 3%, or from about 1% to about 2% by weight based on the total weight of the composition.

[0175] coloring agent The colorant may 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 colorant and titanium dioxide. Natural colorants, such as curcumin, beet juice extract, and spirulina, as well as various synthetic pigments, may also be used. The amount of colorant utilized in the composition may vary, but if present, is typically up to about 3% by weight, e.g., about 0.1%, about 0.5%, or about 1% to about 3% by weight, based on the total weight of the composition.

[0176] Tobacco Materials In some embodiments, the composition may include tobacco material. The tobacco material may vary in species, variety, and form. Generally, 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, and N. knigte. N. knightiana, N. langsdorffi, N. otophora, N. setchelli, N. sylvestris, N. tomentosa, N. tomentosiformis, N. undulata, N. × sanderae sanderae, N. africana, N. amplexicaulis, N. benavidesii, N. bonariensis, N. debneyi, N. longiflora, N. maritina, N. megalosiphon, N. occidentalis, N. paniculata, N. plumbaginifolia mbaginifolia, 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. hesperis subsp. Hersperis, N. pauciflora, N. petunioides, N. quadrivalvis, N. repanda, N. rotundifolia, N. solanifolia, and N. spegazzinii. Various representative other types of plants from the Nicotiana species are described in Goodspeed, The Genus Nicotiana, (Chonica Botanica) (1954), U.S. Patent Nos. 4,660,577 to Sensabaugh, Jr. et al., 5,387,416 to White et al., 7,025,066 to Lawson et al., 7,798,153 to Lawrence, Jr. et al., and 8,186,360 to Marshall et al., each of which is incorporated herein by reference. A description of various types of tobacco, growing practices, and harvesting practices is provided in Tobacco Production, Chemistry and Technology, Davis et al. (Eds.) (1999), which is incorporated herein by reference.

[0177] Nicotiana species from which suitable tobacco material 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 a component, characteristic, or trait). See, for example, the types of genetic modifications of plants described in U.S. Pat. No. 5,539,093 to Fitzmaurice et al., U.S. Pat. No. 5,668,295 to Wahab et al., U.S. Pat. No. 5,705,624 to Fitzmaurice et al., U.S. Pat. No. 5,844,119 to Weigl et al., U.S. Pat. No. 6,730,832 to Dominguez et al., U.S. Pat. No. 7,173,170 to Liu et al., U.S. Pat. No. 7,208,659 to Colliver et al., U.S. Pat. No. 7,230,160 to Benning et al., U.S. Pat. App. Pub. No. 2006 / 0236434 to Conkling et al., and U.S. Pat. App. Pub. No. WO 2008 / 103935 to Nielsen et al. See also the types of genetic modifications of plants described in U.S. Patent Nos. 4,660,577 to Sensabaugh, Jr. et al., 5,387,416 to White et al., and 6,730,832 to Dominguez et al., each of which is incorporated herein by reference.

[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 the plants' production of relatively large amounts of one or more of the compounds desired to be isolated therefrom. In certain embodiments, Nicotiana species (e.g., Galpao commun tobacco) plants are specifically cultivated for their abundance of leaf surface compounds. Tobacco plants can be grown in greenhouses, growth chambers, or outdoor fields, or grown hydroponically.

[0179] Various parts of Nicotiana species plants can be included in the compositions disclosed herein. For example, substantially the entire 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 for further use after harvesting. For example, flowers, leaves, stems, stalks, 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 combining extracted tobacco pulp with granulated aged natural tobacco lamina).

[0180] In certain embodiments, the tobacco material comprises a solid tobacco material selected from the group consisting of lamina and stem. The tobacco used in the mixture most preferably comprises tobacco lamina or a mixture of tobacco lamina and stem (at least a portion of which has been smoke-treated). The tobacco portion of the mixture may have a processed form, such as processed tobacco stem (e.g., cut wrapped stem, cut wrapped expanded stem, or cut puffed stem) or volume-expanded tobacco (e.g., expanded tobacco such as dry ice expanded tobacco (DIET)). See, for example, the tobacco growth processes described in U.S. Patent Nos. 4,340,073 to de la Burde et al., 5,259,403 to Guy et al., 5,908,032 to Poindexter et al., and 7,556,047 to Poindexter et al., all of which are incorporated by reference. Additionally, the mixture may optionally incorporate fermented tobacco. See also the types of tobacco processing techniques described in Atchley et al., WO 2005 / 063060, which is incorporated herein by reference.

[0181] Tobacco materials are typically used in what can be described as particulate (i.e., shredded, ground, granulated, or powdered). The method by which tobacco materials are provided in finely divided or powdered form can vary. Preferably, plant parts or fragments are comminuted, ground, or micronized using equipment and techniques for micronization, milling, and the like. Most preferably, the plant material is in a relatively dry form during grinding or milling, using equipment such as a hammer mill, cutter head, or air-controlled mill. For example, tobacco parts or fragments may be ground or milled when their moisture content is less than about 15% by weight or less than about 5% by weight. Most preferably, tobacco materials are used in the form of parts or fragments having an average particle size between 1.4 millimeters and 250 microns. In some instances, tobacco particles can be sized to pass through a screen mesh to obtain the desired particle size range. If desired, air classifiers can be used to ensure collection of small tobacco particles of a desired size or size range. Granular tobacco pieces of different sizes can be mixed together if desired.

[0182] The method by which tobacco is provided in finely divided or powdered form can vary. Preferably, tobacco parts or fragments are comminuted, ground, or micronized into a powder-type form using equipment and techniques for micronization, milling, and the like. Most preferably, the tobacco is in a relatively dry form during grinding or milling, using equipment such as a hammer mill, cutter head, or air-controlled mill. For example, tobacco parts or fragments may be ground or milled when their moisture content is less than about 15% to about 5% by weight. For example, tobacco plants or parts thereof can be separated into individual parts or fragments (e.g., leaves can be removed from the stems, and / or stems and leaves can be removed from the stems). Harvested plants or individual parts or fragments can be further subdivided into parts or fragments (e.g., leaves can be fragmented, cut, comminuted, micronized, milled, or ground into fragments or fragments that can be characterized as filler-type fragments, granules, particulates, or fines). The plant or part thereof can be subjected to external force or pressure (e.g., by being subjected to a pressing or rolling process). When such treatment conditions are implemented, the plant or part thereof can have a moisture content that is close to its natural moisture content (e.g., the moisture content immediately after harvest), a moisture content achieved by adding moisture to the plant or part thereof, or a moisture content resulting from drying the plant or part thereof. For example, powdered, micronized, crushed, or milled pieces of the plant or part thereof can have a moisture content of less than about 25% by weight, often less than about 20% by weight, and frequently less than about 15% by weight.

[0183] For the preparation of oral compositions, harvested plants of Nicotiana species are typically subjected to a curing process. The tobacco materials incorporated into the compositions disclosed herein are appropriately cured and / or aged. A description of various types of curing processes for various types of tobacco is provided in Tobacco Production, Chemistry and Technology, Davis et al. (Eds.) (1999). Examples of techniques and conditions for curing fully cured tobacco are provided in Nestor et al., Beitrage Tabakforsch. Int., 20, 467-475 (2003) and U.S. Patent No. 6,895,974 to Peele, which are incorporated herein by reference. Representative techniques and conditions for air-curing 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 flame-curing or sun-curing.

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

[0185] Tobacco materials may also be in the form of so-called "blends." For example, tobacco materials may include a mixture of parts or pieces of fully cured, burley (e.g., Malawian burley), and Oriental tobacco (e.g., tobacco composed of or derived from tobacco lamina, or as a mixture of tobacco lamina and tobacco stem). For example, a typical blend may incorporate, on a dry weight basis, about 30 to about 70 parts burley tobacco (e.g., lamina, or lamina and stem) and about 30 to about 70 parts fully cured tobacco (e.g., stem, lamina, or lamina and stem). Other example tobacco blends incorporate, on a dry weight basis, about 75 parts fully cured tobacco, about 15 parts burley tobacco, and about 10 parts Oriental tobacco, or about 65 parts fully cured tobacco, about 25 parts burley tobacco, and about 10 parts Oriental tobacco, or about 65 parts fully cured tobacco, about 10 parts burley tobacco, and about 25 parts Oriental tobacco. Another example tobacco blend incorporates, on a dry weight basis, about 20 to about 30 parts Oriental tobacco and about 70 to about 80 parts fully cured tobacco.

[0186] Tobacco materials used in the present disclosure can be subjected to, for example, fermentation, bleaching, etc. If desired, the tobacco material can be subjected to, for example, irradiation, pasteurization, or other controlled heat treatment. Such treatment processes are described in detail, for example, in U.S. Pat. No. 8,061,362 to Mua et al., which is incorporated herein by reference. In certain embodiments, the tobacco material can be treated with water and an additive capable of inhibiting the reaction of asparagine to form acrylamide upon heating of the tobacco material (e.g., an additive selected from the group consisting of lysine, glycine, histidine, alanine, methionine, cysteine, glutamic acid, aspartic acid, proline, phenylalanine, valine, arginine, compositions 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). 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 material is exposed to heat in the aforementioned processes.

[0187] In some embodiments, the type of tobacco material is selected to initially be visually lighter in color (e.g., whitened or bleached) than other tobacco materials. 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 include titanium dioxide, manganese dioxide, and combinations thereof.Methods of treating tobacco with bleaching agents are described, for example, in U.S. Pat. No. 787,611 to Daniels, Jr.; U.S. Pat. No. 1,086,306 to Oelenheinz; U.S. Pat. No. 1,437,095 to Delling; U.S. Pat. No. 1,757,477 to Rosenhoch; U.S. Pat. No. 2,122,421 to Hawkinson; U.S. Pat. No. 2,148,147 to Baier; U.S. Pat. No. 2,170,107 to Baier; U.S. Pat. No. 2,274,649 to Baier; U.S. Pat. No. 2,770,239 to Pratz et al.; U.S. Pat. No. 3,612 to Rosenhoch; ,065, 3,851,653 to Rosen, 3,889,689 to Rosen, 3,943,940 to Minami, 3,943,945 to Rosen, 4,143,666 to Rainer, 4,194,514 to Campbell, 4,366,823, 4,366,824, and 4,388,933 to Rainer et al., 4,641,667 to Schmekel et al., 5,713,376 to Berger, Byrd Nos. 9,339,058 to Jr. et al., 9,420,825 to Beeson et al., and 9,950,858 to Byrd Jr. et al., as well as U.S. Patent Application Publication Nos. 2012 / 0067361 to Bjorkholm et al., 2016 / 0073686 to Crooks, 2017 / 0020183 to Bjorkholm, and 2017 / 0112183 to Bjorkholm, and PCT Application Publication Nos. WO 1996 / 031255 to Giolvas and WO 2018 / 083114 to Bjorkholm, all of which are incorporated herein by reference.

[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 ranging from about 50% to about 90%, from about 55% to about 75%, or from about 60% to about 70%. ISO brightness can be measured according to ISO 3688:1999 or ISO 2470-1:2016.

[0189] In some embodiments, whitened tobacco materials can be characterized as being lighter in color (e.g., "whitened") compared to untreated tobacco materials. White is frequently defined with reference to the Commission Internationale de l'Eclairage (CIE) chromaticity diagram. Whitened tobacco materials, in certain embodiments, can be characterized as being closer to pure white on the chromaticity diagram than untreated tobacco materials.

[0190] In various embodiments, tobacco materials can be processed to extract soluble components of the tobacco material therefrom. As used herein, "tobacco extract" refers to isolated components of tobacco material extracted from solid tobacco pulp by a solvent that is contacted with the tobacco material in an extraction process. Various tobacco material extraction techniques 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., which is incorporated herein by reference. Other exemplary techniques for extracting tobacco components are disclosed in US Pat. Nos. 4,144,895 to Fiore, 4,150,677 to Osborne, Jr. et al., 4,267,847 to Reid, 4,289,147 to Wildman et al., 4,351,346 to Brummer et al., 4,359,059 to Brummer et al., 4,506,682 to Muller, 4,589,428 to Keritsis, 4,605,016 to Soga et al., 4,716,911 to Poulose et al., and Niven, Jr.Nos. 4,727,889 to Bernasek et al., 4,887,618 to Clapp et al., 4,941,484 to Clapp et al., 4,967,771 to Fagg et al., 4,986,286 to Roberts et al., 5,005,593 to Fagg et al., 5,018,540 to Grubbs et al., and 5,060,666 to White et al. No. 9, No. 5,065,775 to Fagg, No. 5,074,319 to White et al., No. 5,099,862 to White et al., No. 5,121,757 to White et al., No. 5,131,414 to Fagg, No. 5,131,415 to Munoz et al., No. 5,148,819 to Fagg, No. 5,197,4 No. 94, No. 5,230,354 to Smith et al., No. 5,234,008 to Fagg, No. 5,243,999 to Smith, No. 5,301,694 to Raymond et al., No. 5,318,050 to Gonzalez-Parra et al., No. 5,343,879 to Teague, No. 5,360,022 to Newton, No. 5,360,022 to Cla Nos. 5,435,325 to pp et al., 5,445,169 to Brinkley et al., 6,131,584 to Lauterbach, 6,298,859 to Kierulff et al., 6,772,767 to Mua et al., and 7,337,782 to Thompson, all of which are incorporated herein by reference.

[0191] Typical inclusion ranges of tobacco material can vary depending on the nature and type of tobacco material and its intended effect on the final blend, with exemplary ranges including up to about 30% by weight (or up to about 20% by weight, or up to about 10% by weight, or up to about 5% by weight), based on the total weight of the composition (e.g., about 0.1 to about 15% by weight). In some embodiments, compositions of the present disclosure can be characterized as being completely free or substantially free of tobacco material (other than purified nicotine as the active ingredient). For example, certain embodiments can be characterized as having less than 1% by weight, or less than 0.5% by weight, or less than 0.1% by weight, or 0% by weight of tobacco material.

[0192] Oral care additives In some embodiments, the composition comprises an oral care ingredient (or mixture of such ingredients) that provides the ability to inhibit dental caries or tooth loss, inhibit gum disease, relieve mouth pain, whiten or otherwise inhibit tooth staining, induce saliva stimulation, inhibit bad breath, freshen breath, etc. For example, effective amounts of ingredients such as thyme oil, eucalyptus oil, and zinc (such as ingredients in formulations commercially available as ZYTEX® from Discus Dental) can be incorporated into the composition. Other examples of ingredients that can be incorporated into the present compositions in desired effective amounts include those incorporated into oral care compositions of the type 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 U.S. Patent Application Publication No. 2006 / 02228308 to Cummins et al. Other exemplary ingredients of tobacco-containing compositions include those contained in the compositions sold by Rockette as MALTISORB® and by NatraRx as DENTIZYME®. When present, the typical amount of oral care additive is at least about 1%, often at least about 3%, and frequently at least about 5% of the total dry weight of the foamable composition. The amount of oral care additive in the foamable composition typically does not exceed about 30%, often does not exceed about 25%, and frequently does not exceed about 20% of the total dry weight of the foamable composition.

[0193] Processing aids Flow aids can also be added to the composition to improve the flowability of the composition when necessary for downstream processing, such as granulation, mixing, or molding. In some embodiments, the composition (e.g., melt and chew forms) may be surface-treated with an anti-adherent agent such as oil, silicone, etc. Exemplary flow aids include microcrystalline cellulose, silica, polyethylene glycol, stearic acid, calcium stearate, magnesium stearate, zinc stearate, sodium stearyl fumarate, canaba wax, and combinations thereof. In some embodiments, the flow aid is sodium stearyl fumarate.

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

[0195] Other additives Other additives can be included in the disclosed compositions. For example, the compositions can be processed, blended, compounded, combined, and / or mixed with other materials or ingredients. Additives can be artificial or can be obtained or derived from herbal 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.), disintegration aids, or combinations thereof. For example, for representative ingredients, combinations of ingredients, relative amounts of ingredients, and techniques and methods for using ingredients, see U.S. Pat. No. 9,237,769 to Mua et al., U.S. Pat. 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 content ranges of such additional additives can vary depending on the nature and function of the additive and its intended effect on the final composition, and are exemplified by ranges of up to about 10% by weight (e.g., about 0.1 to about 5% by weight) based on the total weight of the composition.

[0197] The aforementioned additives can be used together (e.g., as an additive blend) or separately (e.g., individual additive components can be added at different stages involved in preparing the final mixture). Additionally, additives of the aforementioned types can be encapsulated so as to be delivered to the final product or composition. Examples of encapsulated additives are described, for example, in WO 2010 / 132444 to Atchley, which has been previously incorporated by reference herein.

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

[0199] The particle size of particulate matter can be measured by sieve analysis. As those skilled in the art will readily understand, sieve analysis (otherwise known as gradient testing) is a method used to measure the particle size distribution of particulate materials. Typically, sieve analysis involves a nested column of sieves, each containing a screen, preferably in the form of a wire mesh fabric. A pre-weighed sample can be introduced into the top or uppermost sieve in the column, which has the largest sieve opening or mesh size (i.e., the largest pore size of the sieve). Each subsequent sieve in the column has progressively smaller screen openings or mesh sizes than the sieves above it. Typically, the base of the sieve column has a receiver section for collecting any particles having a particle size smaller than the sieve opening or mesh size of the bottom or lowest sieve in the column (which has the smallest screen opening or mesh size).

[0200] In some embodiments, the sieve column can be placed on or within a mechanical agitator. The agitator causes vibration of each sieve within the column. The mechanical agitator may be activated for a predetermined period of time to ensure that all particles are collected on the correct sieve. In some embodiments, the sieve column is agitated for a period of 0.5 to 10 minutes, e.g., 1 to 10 minutes, e.g., 1 to 5 minutes, e.g., about 3 minutes. Once agitation of the sieves within the column is complete, the material collected on each sieve is weighed. The weight of each sample on each sieve can then be divided by the total weight to obtain the percentage of mass retained on each sieve. As one skilled in the art would readily understand, the sieve opening size or mesh size of each sieve in a column used in 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 can contain 2 to 20 sieves, e.g., 5 to 15 sieves. In some embodiments, a column of sieves may be used in the sieve analysis, the column comprising 10 sieves. In some embodiments, the maximum sieve opening or mesh size of the sieve used in the sieve analysis may be 1000 μm, e.g., 500 μm, e.g., 400 μm, e.g., 300 μm.

[0201] In some embodiments, any particulate material referred to herein (e.g., filler, tobacco material, and overall composition) can be characterized as having at least 50% by weight of particles having a particle size, as measured by sieve analysis, of about 1000 μm or less, such as about 500 μm or less, for example about 400 μm or less, for example about 350 μm or less, such as about 300 μm or less. In some embodiments, at least 60% by weight of the particles of any particulate material referred to herein have a particle size, as measured by sieve analysis, of about 1000 μm or less, such as about 500 μm or less, for example about 400 μm or less, for example about 350 μm or less, for example about 300 μm or less. In some embodiments, at least 70% by weight of the particles of any particulate material referred to herein have a particle size, as measured by sieve analysis, of about 1000 μm or less, such as about 500 μm or less, for example about 400 μm or less, for example about 350 μm or less, for example about 300 μm or less. In some embodiments, at least 80% by weight 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, for example about 400 μm or less, such as about 350 μm or less, for example about 300 μm or less, as measured by sieve analysis. In some embodiments, at least 90% by weight 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, for example about 400 μm or less, such as about 350 μm or less, for example about 300 μm or less, as measured by sieve analysis. In some embodiments, at least 95% by weight 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, for example about 400 μm or less, such as about 350 μm or less, for example about 300 μm or less, as measured by sieve analysis. In some embodiments, at least 99% by weight 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, for example about 400 μm or less, such as about 350 μm or less, for example about 300 μm or less, as measured by sieve analysis.In some embodiments, about 100% by weight 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, for example about 400 μm or less, such as about 350 μm or less, for example about 300 μm or less, as measured by sieve analysis.

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

[0203] Preparation of the Composition The method for combining the various components of the mixture can vary. Thus, the overall mixture of the various components, for example, 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 pre-processing step before mixing with any remaining components of the mixture, or can simply be mixed with all other liquid or dry components. The various components of the mixture can be contacted, combined, or mixed together using any mixing technique or device known in the art. Any mixing method that brings the components of the mixture into intimate contact can be used, such as a mixing device featuring an impeller or other structure that allows agitation. Examples of mixing devices include casing drums, conditioning cylinders or drums, liquid spray 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, etc. See, 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 which is incorporated herein by reference. In some embodiments, the ingredients forming the mixture are prepared so that the mixture can be used in a starch molding process to form the mixture. Techniques and methods for blending the mixture will be apparent to those skilled in the art. See, 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, 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 which 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 the composition is provided in a form such that, during use, saliva in the user's mouth passes one or more of the composition's components (e.g., a basic amine, a flavoring agent, and / or an active ingredient) into the user's mouth. In certain embodiments, the composition is adapted to deliver an ingredient to the user through the user's oral mucosa, the user's digestive system, or both; in some examples, the ingredient is a nicotine ingredient or an active ingredient (including, but not limited to, for example, nicotine, a stimulant, a vitamin, an amino acid, a botanical, or a combination thereof) that can be absorbed through the oral mucosa or through the digestive tract when the product is used.

[0205] Compositions configured for oral use described herein can take various forms, including gels, troches, gums, chews, melts, tablets, lozenges, powders, and pouches. Gels can be soft or hard. Certain compositions configured for oral use are in the form of troches. As used herein, the term "lozenge" refers to a dissolvable oral composition made by solidifying a liquid or gel composition so that the final composition becomes a somewhat hardened, solid gel. The stiffness of gels is highly variable. Certain compositions of the present disclosure are in solid form. Certain compositions can exhibit one or more of the following characteristics: crispy, granular, chewy, syrupy, pasty, fluffy, smooth, and / or creamy. In certain embodiments, the desired texture characteristic can be selected from the group consisting of adhesiveness, cohesiveness, density, dryness, friability, granularity, rubberiness, hardness, weight, hygroscopicity, moisture release, mouthcoating, roughness, slipperiness, smoothness, viscosity, wettability, 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, ovals, oblong shapes, cylinders, beans, sticks, or rods. The cross-sectional shape of the composition can vary, with exemplary cross-sectional shapes including circles, squares, ovals, rectangles, etc. Such shapes can be formed in a variety of ways, using equipment such as moving belts, nips, extruders, granulators, compactors, etc.

[0207] The compositions of the present disclosure may be dissolvable. As used herein, the terms "dissolve," "dissolving," and "dissolvable" refer to compositions having water-soluble components that interact with the moisture in the oral cavity to go into solution, thereby causing gradual consumption of the composition. According to one aspect, a dissolvable composition can persist in the user's mouth for a given period of time until completely dissolved. The dissolution rate can vary over a wide range, from about 1 minute or less to about 60 minutes. For example, fast-release compositions typically dissolve and / or release the desired components (e.g., active ingredients, flavors, 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 degradation, or by disruption of interactions between the components of the composition. In other embodiments, the product does not dissolve while the product is in the user's mouth.

[0208] In some embodiments, the composition may be chewable, meaning that the composition has a gentle elasticity or "bounce" when chewed and a desirable degree of spreadability. Chewable compositions may be completely dissolved or may be in the form of a non-dissolving gum in which only certain ingredients (e.g., active ingredients, flavors, sweeteners) dissolve, leaving a non-dissolving matrix. Chewable embodiments generally include a binder, such as a natural gum or pectin. In some embodiments, chewable compositions include pectin and an organic acid, along 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 meltable, for example, as discussed in U.S. Patent Application Publication No. 2012 / 0037175 by Cantrell et al., which is incorporated herein by reference in its entirety. As used herein, "melt," "melting," and "meltable" refer to a composition's ability to change from a solid to a liquid state. That is, melting occurs when a substance (e.g., a composition disclosed herein) changes from a solid to a liquid, usually by the application of heat. The application of heat with respect to the compositions disclosed herein is achieved by the internal temperature of the user's mouth. Thus, the term "meltable" refers to a composition that can liquefy in the user's mouth when the composition changes phase from solid to liquid, and is intended to distinguish it from a composition that simply disintegrates in the oral cavity due to loss of cohesion within the composition, which simply dissolves in the oral cavity when the water-soluble components of the composition interact with moisture. Generally, meltable compositions include lipids, as described herein above. In some embodiments, the composition in meltable form comprises lipid in an amount of about 35 to about 50% by weight, based on the total weight of the composition, and sugar alcohol in an amount of about 35 to about 55% by weight, 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.

[0210] In certain embodiments, the composition is in the form of compressed or molded pellets. Exemplary pellet weights range from about 250 mg to about 1500 mg, e.g., 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 traditional pill or tablet shapes. Generally, compositions in tablet form comprise 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% by weight based on the total weight of the composition. The sugar alcohol is present in an amount of about 30 to about 45% by weight 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 compositions in the form of water-permeable pouches are typically used by placing one pouch containing the mixture in the mouth of a human subject / user. Generally, the pouch is placed somewhere in the user's oral cavity, for example, under the lips, similar to how 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., flavoring agent and / or nicotine) pass through, for example, the water-permeable pouch, providing flavor and a satisfying sensation to the user, without the user having to expel any portion of the mixture. After about 10 to about 60 minutes, typically about 15 to about 45 minutes, of use / enjoyment, 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 other ingredients described above are combined in a moisture-permeable packet or pouch that serves as a container for use of the composition to provide a pouch product configured for oral use. Certain embodiments of the present disclosure are described with reference to FIG. 1 of the accompanying drawings, and these described embodiments include snus-type products having an outer pouch and containing a mixture described herein. As described in more detail below, such embodiments are provided by way of example only, and pouch products of the present disclosure can include compositions in other forms. The mixture / structure of such packets or pouches, such as the reservoir 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 containing a material 104 that includes a 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 the pouch in the manner of, and using, the types of components used in the manufacture of traditional snus-type products. The pouch comprises a liquid-permeable container of a type that can be considered similar in characteristics to the mesh-type materials used in the construction of tea bags. The ingredients of the mixture readily diffuse 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 Nos. 5,167,244 to Kjerstad and 8,931,493 to Sebastian et al., U.S. Patent Application Publication Nos. 2016 / 0000140 to Sebastian et al., 2016 / 0073689 to Sebastian et al., 2016 / 0157515 to Chapman et al., and 2016 / 0192703 to Sebastian et al., each of which is incorporated herein by reference. The pouches can be provided as individual pouches, or multiple pouches (e.g., 2, 4, 5, 10, 12, 15, 20, 25, or 30 pouches) can be connected or linked together (e.g., in an end-to-end manner) so that single pouches or individual portions can be easily removed from a one-piece strand or matrix of pouches for use.

[0215] Exemplary pouches can be manufactured from materials in such a way that the pouch undergoes controlled dispensing or dissolution during use by the user. Such pouch materials can have the form of mesh, screen, perforated paper, permeable fabric, etc. For example, pouch materials manufactured from mesh-like or perforated rice paper can dissolve in the user's mouth. As a result, the pouch and the mixture can each completely disperse 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 materials combined with water-dispersible film-forming materials (e.g., binders such as alginate, carboxymethylcellulose, xanthan gum, pullulan, etc.) and materials such as comminuted cellulose (e.g., fine-particle-sized wood pulp). Preferred pouch materials are water-dispersible or soluble, but may be designed and manufactured so that a significant amount of the mixture contents will permeate the pouch material under normal use conditions before the pouch loses its physical integrity. If desired, flavoring ingredients, disintegration aids, and other desired ingredients may be incorporated into or applied to the pouch material.

[0216] The amount of material contained in each product unit, e.g., pouch, can vary. In some embodiments, the weight of the mixture in each pouch is at least about 50 mg, e.g., about 50 mg to about 1 g, about 100 to about 800 mg, or about 200 to about 700 mg. In some smaller embodiments, the weight of the mixture in each pouch can be about 100 to about 300 mg. In larger embodiments, the weight of the material in each pouch can be about 300 mg to about 700 mg. Other ingredients can be contained in each pouch as needed. For example, a strip, piece, or sheet of at least one flavored water-dispersible or water-soluble material (e.g., a fresh edible film-type material) can be placed in each pouch, with or without at least one capsule. Such strips or sheets can be folded or wrinkled to facilitate incorporation into 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, which are incorporated herein by reference.

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

[0218] Storage period Compositions of the present disclosure configured for oral use (e.g., pouch-shaped) can be packaged and stored in any suitable packaging in much the same way that conventional smokeless tobacco products are packaged and stored. For example, multiple packets or pouches may be contained in a cylindrical container. The shelf life of the prepared product 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., lack of color change, retention of volatile flavor components, retention of nicotine) are exhibited throughout some 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 storage period may be greater than 6 months, such as 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] How to improve stability In another aspect, a method for enhancing the stability of a composition 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 is associated 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, 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 comprises 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 result in a pH of less than about 7.0. In some embodiments, adjusting the pH comprises adding a mineral acid to the composition to result in 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 result in a pH of less than about 7.0.

[0222] In some embodiments, increasing stability includes reducing evaporative loss of a basic amine (e.g., nicotine) from the composition over storage periods compared to compositions configured for oral use having a pH greater than about 8.

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

[0224] Methods for enhancing predicted oral absorption In a further aspect, methods are provided for enhancing the predicted oral (e.g., buccal) absorption of a basic amine (e.g., nicotine) from a composition configured for oral use disclosed herein. While obtaining actual absorption data requires invasive experimentation, predictive data can be readily obtained using in vitro buccal membrane permeability. For example, the permeability of nicotine through such membranes, or the permeability versus time, can be assessed and compared for various embodiments of nicotine-containing oral compositions. For example, oral compositions according to the present disclosure can be compared to control compositions (e.g., nicotine in the absence of an organic acid, nicotine in the presence of an organic acid having a logP less than 1.4, etc.) to provide surrogate data predictive of actual buccal absorption.

[0225] In some embodiments, the predicted method of enhancing oral absorption 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 is associated 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.

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

[0227] In some embodiments, the method further comprises adjusting the pH of the composition to a pH of about 4.0 to about 7.0. In some embodiments, adjusting the pH comprises 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 comprises 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 comprises 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 comprises increasing the percentage of total basic amines permeated to a composition comprising an organic acid, an alkali metal salt of an organic acid, or a combination thereof, wherein the organic acid has a logP value of less than about 1.4.

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

[0230] Many modifications and other embodiments of the invention will come to mind to one skilled in the art to which this invention pertains having the benefit of the teachings presented in the foregoing description. It is to be understood, therefore, that the invention is not to be limited to the specific embodiments disclosed herein, and that modifications and other embodiments are intended to be included within the scope of the appended claims. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation. [Example]

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

[0232] [Example 1] Calculation of free nicotine as a function of pH Henderson-Hasselbalch equation (pH = pK a +log 10 (A- / HA)) was used to calculate the percentage of free nicotine present in solution at different pH values. The data shown in Table 2 demonstrate that the percentage of free nicotine is related to the pK of nicotine. a It has been demonstrated that this changes dramatically as the pH of the surrounding area changes.

[0233] [Table 2]

[0234] [Example 2] Calculated Nicotine Partitioning at pH 8.4 The theoretical octanol / water partition of nicotine solutions at pH 8.4 was calculated based on 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 % protonation was calculated using the Henderson-Hasselbalch equation (Table 3). Calculations indicate that at pH 8.4, approximately 65% of the total available nicotine is expected to reside in the octanol layer.

[0235] [Table 3]

[0236] [Example 3] Octanol / water partitioning of nicotine at 100 ppm and pH 5. A solution of nicotine (1000 ppm, 6.17 mM) was prepared by adding 0.2 grams of free base nicotine to a volumetric flask (200 mL) and filling to volume with reverse osmosis (RO) purified water. Individual 6.17 mM solutions of trisodium citrate, sodium benzoate, sodium heptanesulfonate, monosodium tartrate, and sodium levulinate were prepared. Aliquots of the nicotine solution (10 mL), RO water (60 mL), and each of the citrate, benzoate, heptanesulfonate, tartrate, and levulinate solutions (10 mL), along with a control without counterion, were added to a weighed 125 mL Erlenmeyer flask. A pH probe was immersed in the resulting liquid, and HCl (0.05 M) was added under stirring to bring the solution to pH 5. The flask was then brought up to 100 grams with RO water. The resulting solutions contained 1000 ppm nicotine at 1 molar equivalent of each sodium salt at pH 5. Partitioning was performed by removing 10 mL aliquots of each solution and 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 agitation, the vials were allowed to separate for 30 minutes, and an aliquot (100 μL) of each octanol layer was removed and diluted with 900 μL of octanol in a 2 mL GC / MS vial. The nicotine concentration of each sample was analyzed by GC / MS. Nicotine levels are shown in Figure 2, which shows increased octanol / water partitioning, moving from the control and polar citric acid (logP = -1.7), tartaric acid (and levulinic acid) to more lipophilic acids such as heptanesulfonic acid (log(P) = 0.88) and benzoic acid (log(P) = 1.9). Without wishing to be bound by theory, it is believed that this partitioning is the result of ion pair formation, which exhibits sufficient lipophilicity for the benzoic acid and heptanesulfonic acid samples to partition effectively into octanol. Notably, 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%).Again, without wishing to be bound by theory, it is believed that the degree of ion pairing at low pH values and nicotine / counterion concentrations reduced the potential degree of ion pairing by shifting the equilibrium towards the free ion.

[0237] [Example 4] Octanol / water partitioning of nicotine at 1000 ppm and pH 6.5. A solution of nicotine (10,000 ppm, 61.7 mM) was prepared by adding 2 grams of free base nicotine to a volumetric flask (200 mL) and filling to volume with reverse osmosis (RO) purified water. 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 weighed 125 mL Erlenmeyer flask. 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 flask was then brought up to 100 grams with RO water. The resulting solution contained 1,000 ppm nicotine at 2 molar equivalents of each sodium salt at pH 6.5. Partitioning was performed by removing 10 mL aliquots of each solution and 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 agitation, the vials were allowed to separate for 30 minutes, and an aliquot (100 μL) of each octanol layer was removed and diluted with 900 μL of octanol in a 2 mL GC / MS vial. The nicotine concentration of each sample was analyzed by GC / MS. Nicotine levels are shown in Figure 3, which shows an increase in octanol / water partitioning at pH 6.5, moving from polar citric acid (log(P) = -1.7) to more lipophilic acids such as benzoic acid (log(P) = 1.9) and octanoic acid (log(P) = 3.0). Notably, with two equivalents of octanoic acid, the majority of nicotine (approximately 67%) partitioned into octanol. Without wishing to be bound by theory, it is believed that this partitioning is the result of the formation of ion pairs, which exhibit sufficient lipophilicity to partition effectively into 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 of nicotine dissolved in 6 mL of saliva. Samples were subjected to octanol / water partitioning and analyzed for nicotine using the method described in Example 2. Samples were also analyzed for benzoic acid concentration in octanol (100 μl aliquots were diluted with 900 μl of octanol). Benzoic acid concentration was measured using an HPLC-UV procedure adapted from the literature (Phenomenex, Application, ID 14720). Separation was performed on a Luna 5 m C18 column (150 × 3 mm, Phenomenex, Torrance, CA, USA) using a mobile phase with the following composition: 75% H2O, 25% CH3CN, and 0.2 mM KH2PO4. The mobile phase was adjusted to pH 2.5 with H3PO4. The mobile phase flow rate was 1 mL / min, and the injection volume was 10 μL. The eluate was monitored at 254 nm. For sample quantification, a stock solution containing 260 ppm benzoic acid in H2O was first prepared. This solution was diluted to yield standard solutions of 260, 130, 65, 32.5, and 16.25 μg / mL, respectively. The peak area versus concentration obtained from these samples allowed the following calibration line to be fitted: 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. Therefore, 90% of the nicotine (25.5 / 28.3) partitioned into octanol due to benzoic acid, and 2.8% of the total nicotine (28.3-25.5) partitioned into octanol due to the tendency of free nicotine to partition into octanol (Figure 4). Theoretically, if nicotine and benzoic acid partitioned into octanol as an ion pair, there would be a 1:1 molar ratio of nicotine to benzoic acid in octanol, reflecting the proposed ion pair stoichiometry. However, in this experiment, the nicotine concentration in octanol relative to benzoic acid was found to be slightly higher than the theoretical value of 28.3 to 25.5 ppm. Without wishing to be bound by theory, it is believed that the higher concentration of nicotine in octanol is due to the spontaneous partitioning of nicotine into octanol at pH 6.5 (i.e., at pH 6.5, some of the nicotine is available as the free base and partitions without relying on ion pairing). This data further supports the theory that the change in octanol / water partitioning is due to the presence of ion pairs and not simply due to changes in the properties of the system (such as a change in solution polarity or the formation of micelles).

[0240] [Example 6] Reference (control) composition A reference sample of a composition comprising 6 mg of nicotine, microcrystalline cellulose (mcc), water, and the additional ingredients disclosed herein (salt, binder, sweetener, humectant, flavoring) was prepared without organic acids (pH about 9).

[0241] [Example 7] Reference composition (citric acid) A reference sample of a composition comprising 6 mg of nicotine, microcrystalline cellulose (mcc), water, and the additional ingredients disclosed herein (salt, binder, sweetener, humectant, flavoring) 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 in Example 6.

[0242] [Example 8] Octanol / Water Partitioning of Examples 6 and 7 Samples of each pouch fill material from Examples 6 and 7 (697.6 mg total, 10 mg nicotine) were accurately weighed into separate 20 mL scintillation vials. Partitioning was performed by adding water (10 mL, purified by reverse osmosis) to the sample, followed by 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 quinoline standard (1000 ppm in MeOH) was added. Samples were run in triplicate along with nicotine standards. Nicotine standards were prepared in octanol at 100, 50, 25, 12.5, 6.25, and 3.125 ppm. GC-MS analysis was performed according to standard methods. The results are shown in Figure 5 and demonstrate that approximately 80% of the nicotine partitioned into octanol in the citric acid-containing example, whereas only approximately 10% of the nicotine partitioned into octanol.

[0243] [Example 9] Comparison of nicotine partitioning with various ion-pairing agents and amounts - benzoate, octanoate, and decanoate A solution of nicotine (10,000 ppm, 61.7 mM) was prepared by adding 2 grams of free base nicotine to a volumetric flask (200 mL) and filling to volume with reverse osmosis (RO) purified water. 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 weighed 125 mL Erlenmeyer flask. 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 flask was then brought up to 100 grams with RO water. The resulting solutions contained 1,000 ppm nicotine (equivalent to a pouched composition containing 6 mg of nicotine dissolved in 6 mL of saliva) with 1, 2, 5, 10, or 20 molar equivalents of the respective sodium salt at pH 6.5. Partitioning was performed by removing 10 mL aliquots of each solution and 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 agitation, the vials were allowed to separate for 30 minutes, and an aliquot (100 μL) of each octanol layer was removed and diluted with 900 μL of octanol in a 2 mL GC / MS vial. The nicotine concentration of each sample was analyzed by GC / MS. The nicotine levels are shown in Figure 6, demonstrating 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 greater partitioning of nicotine into octanol compared with the more polar benzoic acid. Samples containing decanoic acid tended to become soapy during the vigorous mixing required to perform partitioning experiments. This may have been due to micelle formation, resulting in unreliable partitioning data. Furthermore, the soapy nature of the aqueous solutions made precise pH adjustment impossible. Therefore, the data points for 2, 10, and 20 equivalents were excluded from Figure 6.

[0244] The data in Figure 6 further demonstrated that the degree of ion-pairing, and therefore octanol / water partitioning, is concentration-dependent. For benzoic acid and octanoic acid, respectively, partitioning increased with acid concentration, reaching an apparent plateau at approximately 20 equivalents of benzoic acid, consistent with theory (suggesting that the maximum degree of ion-pairing was achieved). According to theory, as the number of acid equivalents increases, the equilibrium of ion-pairing versus non-ion-pairing of nicotine + organic acid shifts primarily to ion-pairing. 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 limited 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, the benzoic acid and octanoic acid compositions each exhibited different partitioning behavior. The percentage of nicotine partitioning into octanol was highest for the nonpolar acid (octanoic acid, log P ≈3, 10 equivalents of octanoic acid, approximately 75% nicotine in octanol). The benzoic acid example at the same concentration (benzoic acid log P ≈1.85) partitioned somewhat lower (approximately 52% nicotine in octanol). Each of the pH 6.5 examples partitioned nicotine into octanol less than Example 6 (79%, pH ≈9), but much higher than Example 7 (10%, polar citric acid, log(P) = -1.7, pH 6.5). However, nicotine partitioning for the octanoic acid example at 2 equivalents was nearly identical to that predicted for nicotine at pH 8.4 (65%, theoretical calculation using the Henderson-Haselbach equation and Log P). The results surprisingly demonstrate that compositions containing octanoic acid were able to achieve equivalent nicotine partitioning at pH 6.5 to that of nicotine alone at pH 8.4. Without wishing to be bound by theory, it is believed that ion pairing between nicotine and the relatively nonpolar octanoic acid facilitated the partitioning behavior. This therefore demonstrates that it is possible to obtain acidic compositions that are stabilized against nicotine evaporation and decomposition and have an octanol / water partitioning consistent with nicotine partitioning at higher pH. Such data predict favorable oral absorption of nicotine for embodiments containing relatively nonpolar organic acids.

[0246] [Example 10] Reference pouch product (control) A reference (control) composition containing 10 mg nicotine, microcrystalline cellulose (mcc), water, and the additional ingredients disclosed herein (salt, sodium bicarbonate, binder, sweetener, humectant, flavoring) was prepared without organic acids (pH ≈8.4) and packaged in a pouch. The pouch product was packaged in a standard flex-lid canister with a side seal and stored at room temperature (20-25°C).

[0247] [Example 11] Pouch products (reference) A reference composition containing 10 mg of nicotine, microcrystalline cellulose (mcc), water, and the additional ingredients disclosed herein (salt, binder, sweetener, humectant, flavoring) was prepared with citric acid (about 0.6% by weight, pH about 6.7) and placed into a pouch. The pouch product was packaged in a standard flex-lid canister with a side seal and stored at room temperature (20-25°C).

[0248] [Example 12] Pouch product (present invention) A composition of the present invention containing 10 mg of nicotine, microcrystalline cellulose (mcc), water, and the additional ingredients disclosed herein (salt, binder, sweetener, humectant, flavoring) was prepared using a combination of 2.4% by weight benzoic acid, 0.11% octanoic acid, and 0.13% decanoic acid to prepare approximately 2.4% sodium benzoate (pH approximately 6.4) and placed into a pouch. The pouch product was packaged in a standard flex-lid canister with a side seal and stored at room temperature (20-25°C). Except for the presence of the acid component, the ingredients and the relative amounts of each ingredient were essentially the same for Examples 10-12.

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

[0250] [Table 4]

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

[0252] A microcellulose (MCC)-based pouch fill composition was prepared containing 6 mg nicotine water and the additional ingredients disclosed herein (salt, binder, sweetener, humectant, flavor).

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

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

[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 a starting pH of about 6.5. The composition was filled into pouches and oversprayed to a standard 700 mg pouch weight.

[0256] Each pouch was individually extracted with whole artificial saliva (CAS) at a concentration of 300 mg / mL. The EpiOral™ (buccal) permeation assay was then used to assess absorption of the CAS extract. The assay consisted of a negative control (no EpiOral™ exposure), a vehicle control (CAS), and a positive control (caffeine, Triton X100). Tissues (0.6 cm ) were extracted with CAS. 2) were exposed apically to donor solution, and receiver solution, consisting of a PBS solution containing calcium, magnesium, and glucose, was collected at four time points (15, 30, 45, and 60 min) for each sample. All analyses were performed in sextuplicate (test article) or triplicate (control). Transepithelial electrical resistance was measured to verify tissue integrity at 0 min and the final time point. Receiver and donor solutions were analyzed for analytes (nicotine and control), and the resulting data were processed to calculate cumulative permeation, apparent permeation rate (P app ) and recovery rate were obtained. Cumulative % permeation was determined by quantifying the total permeated mass and dividing by the tissue area. Apparent permeation rate (P app ) was determined using Equation 2.

[0257] P app =(dQ / dt)*(1 / AC0)(Equation 2) where (dQ / dt) is the steady-state flux and A is the area of the cell (0.6 cm 2 ), where C0 is the initial concentration applied to the apical side of the tissue. Recovery was determined by dividing the final donor solution concentration, receiver solution concentration, and rinse solution concentration (tissue was rinsed with CAS after receiver solution removal) by the initial donor solution concentration.

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

Claims

1. 1. A composition adapted for oral use, comprising: at least one filler; basic amines, Water, and an organic acid, an alkali metal salt of an organic acid, or a combination thereof, wherein said organic acid has a log P value of from about 1.4 to about 8.0; Including, At least a portion of the basic amine is associated with at least a portion of the organic acid or alkali metal salt thereof, and the association is in the form of a basic amine-organic acid salt, an ion pair between the basic amine and a conjugate base of the organic acid, or both. , composition.

2. 10. The composition of claim 1, wherein the organic acid has a log P value of from about 1.4 to about 4.

5.

3. 10. The composition of claim 1, wherein the organic acid has a log P value of from about 2.5 to about 3.

5.

4. 10. The composition of claim 1, wherein the organic acid has a log P value of about 4.5 to about 8.0, and the composition further comprises a solubility enhancer.

5. The composition of claim 4 , wherein the solubility enhancer is glycerol or propylene glycol.

6. 10. The composition of claim 1, 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, an alkali metal salt thereof, or a combination thereof, relative to the basic amine, calculated as amine free base.

7. 10. The composition of claim 1, comprising about 2 to about 10 molar equivalents of an organic acid, an alkali metal salt thereof, or a combination thereof, relative to the basic amine, calculated as the amine free base.

8. The composition of claim 1 , wherein the organic acid is an alkyl carboxylic acid, an aryl carboxylic acid, an alkyl sulfonic acid, an aryl sulfonic acid, or any combination thereof.

9. 10. The composition of claim 1, wherein the organic acid is octanoic acid, decanoic acid, benzoic acid, heptane sulfonic acid, or a combination thereof.

10. The composition of claim 1 , wherein the organic acid is octanoic acid.

11. 2. The composition of claim 1, wherein the alkali metal is sodium or potassium.

12. The composition of claim 1 comprising an organic acid and a sodium salt of the organic acid.

13. 13. The composition of claim 12, wherein the ratio of organic acid to sodium salt of organic acid is from about 0.1 to about 10.

14. 10. The composition of claim 1 comprising benzoic acid and sodium benzoate, octanoic acid and sodium octanoate, decanoic acid and sodium decanoate, or a combination thereof.

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

0.

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

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

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

5.

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

0.

20. 2. The composition of claim 1, wherein the basic amine is nicotine.

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

22. The composition of claim 1 , wherein at least one filler comprises a cellulosic material.

23. 23. The composition of claim 22, wherein the cellulosic material comprises microcrystalline cellulose.

24. The composition of claim 1, wherein the 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. 25. The composition of claim 24, wherein the cellulose derivative is hydroxypropyl cellulose.

26. 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 The composition of claim 1 comprising:

27. 10. The composition of 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. 10. The composition of 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. 10. The composition of claim 1, comprising no more than about 10% by weight of tobacco material, excluding any nicotine component present, based on the total weight of the composition.

30. The composition of claim 1 , wherein the composition is free of tobacco materials.

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

32. 1. A method for enhancing the stability of a composition adapted for oral use, said stabilized composition comprising: at least one filler; basic amines, Water, and an organic acid, an alkali metal salt of an organic acid, or a combination thereof, wherein said organic acid has a log P value of from about 1.4 to about 8.0; wherein the method comprises:

10. A method of preparing a composition comprising: mixing the at least one filler with the water, the basic amine, and the organic acid, an 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 the alkali metal salt thereof, the association being in the form of a basic amine-organic acid salt, an ion pair between the basic amine and a conjugate base of the organic acid, or both, and wherein the pH of the composition is less than about 8.

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

5.

34. 33. The method of claim 32, wherein the organic acid has a log P value of about 2.5 to about 3.

5.

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

36. 33. The method of 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 result in the pH being less than about 7.

0.

37. 33. The method of claim 32, wherein the increased stability comprises reducing evaporative loss of basic amine from the composition over storage compared to compositions configured for oral use having a pH greater than about 8.

38. 38. The method of claim 37, wherein the shelf life 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. 38. The method of claim 37, wherein the loss of basic amine is less than about 5% after a storage period of 6 months.

40. 33. The method of claim 32, wherein the basic amine is nicotine.

41. 1. A method for enhancing the expected oral mucosal absorption of a basic amine from a composition configured for oral use, said composition comprising: at least one filler; basic amines, Water, and an organic acid, an alkali metal salt of an organic acid, or a combination thereof, wherein said organic acid has a log P value of from about 1.4 to about 8.0; wherein the method comprises: mixing the at least one filler with the water, the basic amine, and the organic acid, an 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 in association with at least a portion of the organic acid or the alkali metal salt thereof, the association being in the form of a basic amine-organic acid salt, an ion pair between the basic amine and a conjugate base of the organic acid, or both.

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

5.

43. 42. The method of claim 41, wherein the organic acid has a log P value of about 2.5 to about 3.

5.

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

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

0.

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

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

48. 48. The method of claim 47, wherein 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 organic acid has a log P value of less than about 1.4.

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