Treated sheet materials adapted for use as oral products

Abstract

Treated sheet articles for oral use including a treated sheet material are described herein. The sheet material includes a structural component and a treatment composition, which can include one or more substituted 3-(1-methylpyrrolidin-2-yl)pyridines. The material can be used independently as an article for oral use or can be combined with other components. Methods for preparing such materials and articles are also provided herein.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims the benefit of U.S. Provisional Patent Application No. 63 / 770,089, filed Mar. 11, 2025, which is incorporated herein by reference in its entirety.FIELD OF THE DISCLOSURE

[0002] The present disclosure relates to oral products and to methods for forming the oral products. In particular, the present disclosure relates to products intended for human consumption. The products are configured for oral use and deliver substances such as flavors and / or active ingredients during use.BACKGROUND

[0003] There are many categories of products intended for oral use and enjoyment. For example, oral tobacco products containing nicotine, which is known to have both stimulant and anxiolytic properties, have been available for many years. Conventional formats for so-called “smokeless” tobacco products include moist snuff, snus, and chewing tobacco, which are typically formed almost entirely of particulate, granular, or shredded tobacco, and which are either portioned by the user or presented to the user in individual portions, such as in single-use pouches or sachets. See for example, the types of smokeless tobacco formulations, ingredients, and processing methodologies set forth in U.S. Pat. No. 6,668,839 to Williams; U.S. Pat. No. 6,834,654 to Williams; U.S. Pat. No. 6,953,040 to Atchley et al.; U.S. Pat. No. 7,032,601 to Atchley et al.; and 7,694,686 to Atchley et al.; U.S. Pat. No. 7,810,507 to Dube et al.; U.S. Pat. No. 7,819,124 to Strickland et al.; U.S. Pat. No. 7,861,728 to Holton, Jr. et al.; 7,901,512 to Quinter et al.; U.S. Pat. No. 8,627,828 to Strickland et al.; U.S. Pat. No. 11,246,334 to Atchley, each of which is incorporated herein by reference. In addition, traditional tobacco materials and non-tobacco materials have been combined with other ingredients to form product formats distinct from traditional smokeless products, with example formats including lozenges, pastilles, gels, and the like. See, for example, the types of products described in US Patent App. Pub. Nos. 2008 / 0196730 to Engstrom et al.; 2008 / 0305216 to Crawford et al.; 2009 / 0293889 to Kumar et al.; 2010 / 0291245 to Gao et al; 2011 / 0139164 to Mua et al.; 2012 / 0037175 to Cantrell et al.; 2012 / 0055494 to Hunt et al.; 2012 / 0138073 to Cantrell et al.; 2012 / 0138074 to Cantrell et al.; 2013 / 0074855 to Holton, Jr.; 2013 / 0074856 to Holton, Jr.; 2013 / 0152953 to Mua et al.; 2013 / 0274296 to Jackson et al.; 2015 / 0068545 to Moldoveanu et al.; 2015 / 0101627 to Marshall et al.; and 2015 / 0230515 to Lampe et al., each of which is incorporated herein by reference.

[0004] There is continuing interest in the development of new types of oral products that deliver advantageous sensorial or biological activity. Such products typically contain flavorants and / or active agents such as nicotine, caffeine, botanicals, or cannabidiol. The format of such products can vary and include pouched products containing a powdered or granular composition, lozenges, pastilles, liquids, gels, emulsions, meltable compositions, and the like. See, for example, the types of products described in US Patent App. Pub. Nos. 2022 / 0160675 to Gerardi et al.; 2022 / 0071984 to Poole et al.; 2021 / 0378948 to Gerardi et al.; 2021 / 0330590 to Hutchens et al.; 2021 / 0186081 to Gerardi et al.; 2021 / 0177754 to Keller et al; 2021 / 0177043 to Gerardi et al.; 2021 / 0177038 to Gerardi et al.; 2021 / 0169867 to Holton, Jr. et al.; 2021 / 0169792 to Holton, Jr. et al.; 2021 / 0169132 to Holton, Jr. et al.; 2021 / 0169121 to St. Charles, and 2021 / 0169122 to St. Charles, each of which is incorporated herein by reference.BRIEF SUMMARY

[0005] The present disclosure is generally directed to treated sheet materials suitable for oral use, and to oral products in the form of treated sheet articles comprising such treated sheet materials. The treated sheet materials can comprise a structural component and an active agent associated with the structural component, wherein the active agent comprises at least a substituted 3-(1-methylpyrrolidin-2-yl)pyridine. The structural component is generally fibrous in nature, e.g., such that the treated sheet materials provided herein are in the form of materials comprising fibrous woven and / or non-woven sheet materials. The active agent (and other optional ingredients) can be, e.g., adsorbed on or absorbed in the fibers of the structural component.

[0006] Some aspects of the present disclosure provide treated sheet materials and oral products comprising such treated sheet materials, in the form of treated sheet articles. The treated sheet article provided herein is distinguished from a pouched product (which also contains a fleece material), as it does not contain a composition (e.g., a particulate composition) enclosed within the sheet material of the article. In some embodiments, the treated sheet articles provided herein consist essentially of the treated sheet material. In some embodiments, the treated sheet articles provided herein further comprise one or more further elements, e.g., a support element for the treated sheet material.

[0007] The present disclosure includes, without limitation, the following embodiments.

[0008] Embodiment 1: A treated sheet article for oral use comprising a treated sheet material, the treated sheet material comprising a structural component and a treatment composition associated therewith, wherein the treatment composition comprises one or more active agents selected from:

[0009] (i) a substituted 3-(1-methylpyrrolidin-2-yl)pyridine having a structure according to Formula I:wherein R1, R2, R3, and R4 are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl, aryl, alkylaryl, amino, halogen, and cyano, wherein any of said alkyl, alkoxy, cycloalkyl, alkenyl, alkenyl, alkynyl, aryl, alkylaryl, and amino may optionally be substituted; and at least one of R1, R2, R3, and R4 are not hydrogen;(ii) a substituted 3-(1-methylpyrrolidin-2-yl)pyridine having a structure according to Formula II:wherein R5 and R6 are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl, aryl, alkylaryl, amino, halogen, and cyano, wherein any of said alkyl, alkoxy, cycloalkyl, alkenyl, alkenyl, alkynyl, aryl, alkylaryl, and amino may optionally be substituted;R7 is selected from the group consisting of hydrogen and CH3;R8 is selected from the group consisting of hydrogen and C1-C3 alkyl; and

[0015] at least one of R7 and R8 is not hydrogen; and

[0016] (iii) a 3-(azetidin-2-yl)pyridine or 3-(azetidin-2-ylmethoxy)pyridine having a structure according to Formula III:wherein L is a bond or —OCH2—*, where the asterisk indicates an attachment point to the azetidine ring;R9, R10, R11, and R12 are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, and cyano;

[0019] R13 is H or CH3; and

[0020] R14 is H or CH3.

[0021] Embodiment 2: The treated sheet article of Embodiment 1, wherein the active ingredient has a structure according to Formula I, optionally wherein R1, R2, and R3 are each H, and R4 is optionally substituted C1-C6 alkyl, F, Cl, Br, OCH3, OEt, or CN, or optionally wherein R1, R2, and R3 are each H, and R4 is C1-C3 alkyl.

[0022] Embodiment 3: The treated sheet article of Embodiment 1, wherein the active ingredient has a structure according to Formula II, optionally wherein R5 is optionally substituted C1-C6 alkyl, F, Cl, Br, OCH3, OCH2CH3, or CN; and R6 is H, or optionally wherein R5 is H; and R6 is optionally substituted C1-C6 alkyl, F, Cl, Br, OCH3, OCH2CH3, or CN.

[0023] Embodiment 4: The treated sheet article of Embodiment 1, wherein the active ingredient has a structure according to Formula III, optionally wherein R9 is H or CH3; and R10, R11, and R12 are each H.

[0024] Embodiment 5: The treated sheet article of any of Embodiments 1-4, wherein the active ingredient is in the form of a free base, a salt with an acid, an ion pair with an organic acid, or a resin complex wherein the active ingredient is bound to a polymeric resin.

[0025] Embodiment 6: The treated sheet article of any one of Embodiments 1-5, wherein the treatment composition further comprises a flavorant (e.g., a sensate), a salt, a colorant, a sweetener, a pH-adjusting component, or any combination thereof.

[0026] Embodiment 7: The treated sheet article of any of Embodiments 1-6, wherein the treatment composition further comprises one or more additional active agents selected from the group consisting of a nicotine component, a cannabinoid, a terpene, caffeine, an amino acid, a vitamin, melatonin, a botanical extract, or any combination thereof.

[0027] Embodiment 8: The treated sheet article of any of Embodiments 1-7, wherein the treatment composition further comprises a nicotine component.

[0028] Embodiment 9: The treated sheet article of any of Embodiments 1-7, wherein the treated sheet article is substantially free of a nicotine component.

[0029] Embodiment 10: The treated sheet article of any of Embodiments 1-9, wherein the treated sheet material comprises a single layer.

[0030] Embodiment 11: The treated sheet article of any of Embodiments 1-9, wherein the treated sheet material comprises two or more layers.

[0031] Embodiment 12: The treated sheet article of any of Embodiments 1-9, comprising four or more layers.

[0032] Embodiment 13: The treated sheet article of any of Embodiments 1-9, comprising six or more layers.

[0033] Embodiment 14: The treated sheet article of any of Embodiments 1-9, comprising eight or more layers.

[0034] Embodiment 15: The treated sheet article of any of Embodiments 11-14, wherein the two or more layers comprise two or more layers with different compositions (e.g., different structural components).

[0035] Embodiment 16: The treated sheet article of any of Embodiments 11-15, wherein the two or more layers comprise two or more layers with identical structural components.

[0036] Embodiment 17: The treated sheet article of any of Embodiments 11-16, wherein the two or more layers are stacked on top of one another.

[0037] Embodiment 18: The treated sheet article of Embodiment 17, wherein adjacent layers are held together via lamination.

[0038] Embodiment 19: The treated sheet article of Embodiment 17, wherein adjacent layers are held together via stitching, hydroentangling of fibers in the adjacent layers, needle punching, embossing, ultrasonic bonding, thermal bonding, or any combination thereof.

[0039] Embodiment 20: The treated sheet article of any of Embodiments 1-19, consisting essentially of the treated sheet material.

[0040] Embodiment 21: The treated sheet article of any of Embodiments 1-19, comprising one or more additional components.

[0041] Embodiment 22: The treated sheet article of Embodiment 21, wherein the one or more additional components comprise a substrate (e.g., scrim sheet).

[0042] Embodiment 23: A method of preparing the treated sheet article of any of Embodiments 1-22, comprising: providing a sheet material; treating the sheet material, wherein the treating comprises providing one or more solutions, each of the one or more solutions comprising one or more dissolved ingredients of the treatment composition; applying the one or more solutions to a surface of the sheet material; and drying to give the treated sheet material; and optionally combining the treated sheet material with one or more additional components to give the treated sheet article.

[0043] These and other features, aspects, and advantages of the present disclosure will be apparent from a reading of the following detailed description together with the accompanying figures, which are briefly described below. The present disclosure includes any combination of two, three, four or more features or elements set forth in this disclosure, regardless of whether such features or elements are expressly combined or otherwise recited in a specific example implementation described herein. This disclosure is intended to be read holistically such that any separable features or elements of the disclosure, in any of its aspects and example implementations, should be viewed as combinable, unless the context of the disclosure clearly dictates otherwise.BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Having thus described aspects of the disclosure in the foregoing general terms, reference will now be made to the accompanying figures, which are not necessarily drawn to scale, and wherein:

[0045] FIG. 1 is a depiction of various non-limiting shapes relevant to certain treated sheet materials and articles according to some embodiments of the disclosure; and

[0046] FIGS. 2A and 2B are a top down view (FIG. 2A) and side-on cross-sectional view (FIG. 2B) of a non-limiting treated sheet material with multiple layers according to some embodiments of the disclosure.DETAILED DESCRIPTION

[0047] The present disclosure will now be described more fully hereinafter with reference to example embodiments thereof. These example 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.

[0048] As used in this specification and the claims, the singular forms “a,”“an,” and “the” include plural referents unless the context clearly dictates otherwise.

[0049] Reference to “dry weight percent” or “dry weight basis” refers to weight on the basis of dry ingredients (i.e., all ingredients except water). All weight percent values herein are dry weight percent unless otherwise indicated.

[0050] Unless otherwise defined herein, by “substantially free” it is meant that the noted component (e.g., nicotine, acid, or a botanical material) has not been intentionally added, beyond trace amounts that may be present e.g., as an impurity in another component, or small amounts which may be present in certain flavor packages. For example, some embodiments can have less than 0.01% by weight of the noted component, or less than 0.001%, or even 0% by weight of the noted component, based on the weight of the treatment composition associated with the treated sheet material on a dry weight basis and some embodiments can be described as having less than such amounts based on the weight of the entire treated sheet material and / or article. In some embodiments, the materials and articles provided herein are completely free of the noted component (i.e., having 0% or as having an amount below the limit of detection).

[0051] The present disclosure is generally directed to treated sheet materials that comprise a structural component (generally comprising a plurality of fibers) and a treatment composition associated therewith. The treatment composition comprises one or more active agents as defined herein. The treatment composition can optionally further comprise various other components including, but not limited to, flavorants, colorants, additional active agents, humectants, salts, sweeteners, pH adjusters, and the like. The disclosure is further directed to oral products in the form of treated sheet articles comprising treated sheet materials.

[0052] In some embodiments, the treated sheet articles provided herein resemble a pouched product in shape, size, and / or organoleptic properties, but are substantially uniform in composition throughout the thickness thereof, i.e., no separate oral composition is enclosed within the treated sheet articles as is found in pouched products. One or more of the components generally associated with a pouched product may, in some embodiments, be associated with the treated sheet materials. The relative amounts of the various components may vary, and typically are selected so as to provide the desired sensory and performance characteristics to the treated sheet material or article.

[0053] As noted above, a treated sheet material generally comprises a structural component and an active agent (along with a wide range of optional ingredients, as will be described herein below). The treated sheet material can comprise a single layer or multiple layers. As such, the treated sheet material can, in some embodiments, comprise multiple layers of the same composition (e.g., the same structural component and the same treatment composition) or can comprise multiple layers having different compositions (e.g., different structural components and / or different treatment compositions). Each of the treated sheet materials, treated sheet articles comprising such treated sheet materials, and optional ingredients / components thereof are further described herein below.Structural Component

[0054] The “structural component” of treated sheet materials and articles as provided herein can include a wide range of woven and non-woven fibrous materials. Such materials may have the form of a mesh, screen, perforated paper, permeable fabric, or the like. Structural components are generally employed in the form of a sheet or other relatively flat structure, and the structure components can be used in layered form containing a plurality of sheet materials bound together. In some embodiments, the sheet material is not in the form of a pouch, meaning the sheet material does not have an internal cavity adapted to contain a particulate composition.

[0055] The structural component can be fibrous in nature, i.e., comprising one or more types of fibers in a woven or non-woven structure. In some embodiments, the fibers comprising the structural component comprise synthetic fibers, natural fibers, or a combination of synthetic and natural fibers (e.g., wood and / or non-wood fibers). In some embodiments, the structural component comprises a composite of synthetic and natural fibers. Although not limited thereto, structural components include, but are not limited to, cellulose-based materials. In some embodiments, the structural component comprises a paper material. In some embodiments, the structural component comprises a cellulose sheet material, e.g., an air-laid or wet-laid cellulose sheet. For example, sheet materials may be provided in the form of a woven or nonwoven fabric, such as fleece materials used in pouched products. Suitable types of fleece materials, for example, are described in U.S. Pat. No. 8,931,493 to Sebastian et al.; US Patent App. Pub. Nos. 2014 / 0083438 to Sebastian et al.; 2016 / 0000140 to Sebastian et al.; and 2016 / 0073689 to Sebastian et al., which are all incorporated herein by reference.

[0056] In some embodiments, the fibers within the sheet material may be selected from wool, cotton, fibers made of cellulosic material (e.g. regenerated cellulose, cellulose acetate, cellulose triacetate, cellulose nitrate, ethyl cellulose, cellulose acetate propionate, cellulose acetate butyrate, hydroxypropyl cellulose, or methyl hydroxypropyl cellulose), wood pulp fibers, protein fibers, synthetic polymer fibers (e.g., polyester fibers) and combinations thereof. In some embodiments, the fibers within the sheet material can comprise natural fibers such as wood fibers, bamboo fibers, sugarcane fibers, wheat fiber, oat fibers, and similar types of natural fibers. In some embodiments, natural fibers can be initially in pulp form and “fiberized” or “individualized” by mechanical means such as hammermilling; these individual fibers can then be employed in the sheet material preparation methods described herein. In some embodiments, the fibers within the sheet material may include a polymer selected from the group consisting of polyglycolide or polyglycolic acid (PGA), polylactide or polylactic acid (PLA), polycaprolactone (PCL), polyethylene adipate (PEA), polybutylene succinate (PBS), polybutylene succinate adipate (PBSA) polyhydroxyalkonoate (PHA), polyhydroxybutyrate (PHB), poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), polylactide-co-glycolide, and copolymers or blends thereof.

[0057] Regenerated cellulose fibers (e.g., viscose or lyocell fibers) can be particularly advantageous, and are typically prepared by extracting non-cellulosic compounds from wood, contacting the extracted wood with caustic soda, followed by carbon disulfide and then by sodium hydroxide, giving a viscous solution. The solution is subsequently forced through spinneret heads to create viscous threads of regenerated fibers. Example methods for the preparation of regenerated cellulose are provided in U.S. Pat. No. 4,237,274 to Leoni et al; U.S. Pat. No. 4,268,666 to Baldini et al; U.S. Pat. No. 4,252,766 to Baldini et al.; U.S. Pat. No. 4,388,256 to Ishida et al.; U.S. Pat. No. 4,535,028 to Yokogi et al.; U.S. Pat. No. 5,441,689 to Laity; U.S. Pat. No. 5,997,790 to Vos et al.; and U.S. Pat. No. 8,177,938 to Sumnicht, which are incorporated herein by reference. The manner in which the regenerated cellulose is made is not limiting, and can include, for example, both the rayon and the TENCEL processes. Various suppliers of regenerated cellulose are known, including Lenzing (Austria), Cordenka (Germany), Aditya Birla (India), and Daicel (Japan).

[0058] The size, including the diameter of the fibers of the structural component is not particularly limited and the fibers can be continuous fibers and / or staple fibers. In some embodiments, the structural component comprises one or more layers of a fleece material such as those commonly used to form pouched products.

[0059] The term “nonwoven” is used herein in reference to fibrous materials, webs, mats, batts, or sheets in which fibers are aligned in an undefined or random orientation. The nonwoven fibers are initially presented as unbound fibers or filaments. An important step in the manufacturing of nonwovens involves binding the various fibers or filaments together. The manner in which the fibers or filaments are bound can vary, and include thermal, mechanical and chemical techniques that are selected in part based on the desired characteristics of the final product, as discussed in more detail below.

[0060] The fibers used in the nonwoven web according to the present disclosure can vary, and include fibers having any type of cross-section, including, but not limited to, circular, rectangular, square, oval, triangular, and multilobal. In certain embodiments, the fibers can have one or more void spaces, wherein the void spaces can have, for example, circular, rectangular, square, oval, triangular, or multilobal cross-sections. As noted previously, the fibers can be selected from single-component (i.e., uniform in composition throughout the fiber) or multicomponent fiber types including, but not limited to, fibers having a sheath / core structure and fibers having an islands-in-the-sea structure, as well as fibers having a side-by-side, segmented pie, segmented cross, segmented ribbon, or tipped multilobal cross-sections.

[0061] The physical parameters of the fibers present in the sheet material can vary. For example, the fibers used in the sheet material can have varying size (e.g., length, dpf) and crimp characteristics. In some embodiments, fibers used in the sheet material can be nano fibers, sub-micron fibers, and / or micron-sized fibers. In certain embodiments, fibers of the sheet materials useful herein can measure about 1.5 dpf to about 2.0 dpf, or about 1.6 dpf to about 1.90 dpf. In some staple fiber embodiments, each fiber length can measure about 35 mm to about 60 mm, or about 38 mm to about 55 mm, for example. In some embodiments, each fiber can measure about 4-10 crimps per cm, or about 5-8 crimps per cm.

[0062] The sheet materials can have varying thicknesses, porosities and other parameters. In some embodiments, the treated sheet material has a thickness of from about 0.015 mm to about 1.0 mm. Suitably, the thickness may be in the range of from about 0.05 mm, about 0.1 mm or about 0.15 mm to about 0.5 mm or about 0.3 mm. The treated sheet material may comprise more than one layer, and the thickness described herein refers to the aggregate thickness of those layers. The example thicknesses noted herein are mean thicknesses for the material. In some embodiments, the thickness may vary by no more than about 25%, about 20%, about 15%, about 10%, about 5% or about 1%.

[0063] The sheet material can have any suitable basis weight, such as from about 30 g / m2 to about 500 g / m2. In some embodiments, the sheet material may have a basis weight of from about 30 to about 400 g / m2, or from about 40 to about 300 g / m2. In some embodiments, the sheet material may have an area density of from about 80 to about 300 g / m2, or from about 100 to about 300 g / m2, or particularly from about 200 to about 300 g / m2. Basis weight of a fabric can be measured using ASTM D3776 / D3776M-09a (2013) (Standard Test Methods for Mass Per Unit Area (Weight) of Fabric), for example.

[0064] The sheet material can have an elongation of about 70% to about 80%, e.g., about 78%. In some embodiments, the sheet material can have a peak load of about 4 lbs. to about 8 lbs., e.g., about 5.5 lbs. Elongation and breaking strength of textile fabrics can be measured using ASTM D5034-09(2013) (Standard Test Method for Breaking Strength and Elongation of Textile Fabrics (Grab Test)), for example. In various embodiments, the sheet material can have a Tensile Energy Absorption (TEA) of about 35 to about 40, e.g., about 37. In some embodiments, the sheet material can have a porosity of greater than about 10,000 ml / min / cm2. TEA can be measured, for example, as the work done to break the specimen under tensile loading per lateral area of the specimen. Porosity, or air permeability of textile fabrics can be measured using ASTM D737-04(2012) (Standard Test method for Air Permeability of Textile Fabrics), for example.

[0065] The structural component of the sheet materials generally defines the two-dimensional shape of the treated sheet material. The two-dimensional shape of the structural component is not particularly limited. In some embodiments, the structural component can be described as having a quadrilateral shape (e.g., trapezoid, parallelogram, rectangle, rhombus, or square). In some embodiments, the structural component can be described as having a generally circular or oval structure. In some embodiments, the structural component can be described as having rounded edges. In some embodiments, the structural component can be described as having a shape as generally depicted in FIG. 1.

[0066] The thickness of the structural component can vary as noted above. Further, as noted, the sheet material can, in some embodiments, comprise multiple layers, each comprising a structural component (which can each be the same or different in each layer). A layered sheet material can be produced and treated to produce a treated sheet material as shown in FIG. 2, as will be described in further detail herein below.Treatment CompositionActive Agent

[0067] The active agent of the treatment composition associated with the treated sheet materials and articles of the disclosure includes, but is not limited to, a substituted 3-(1-methylpyrrolidin-2-yl)pyridine. Alternatively, the active agent may include components such as botanical materials, cannabinoids, terpenes, vitamins, melatonin, caffeine, nicotine compounds, tobacco extracts, or combinations thereof. The various components are described further herein below.

[0068] In some embodiments, the materials and articles of the disclosure can be characterized as completely free or substantially free of nicotine (3-(1-methylpyrrolidin-2-yl)pyridine). By “substantially free” it is meant that no nicotine has been intentionally added, beyond trace amounts that may be present e.g., as an impurity in another component, including as a minor impurity in the substituted 3-(1-methylpyrrolidin-2-yl)pyridine. For example, some embodiments can be characterized as having less than 0.01% by weight of nicotine, or less than 0.001% by weight of nicotine, or less than 0.0001%, or even 0% by weight of nicotine, calculated as the free base and based on the total weight of the treatment composition on a dry weight basis. In some embodiments the composition or article is completely free of (R)-, (S)-, and (R / S)-3-(1-methylpyrrolidin-2-yl)pyridine (e.g., having 0% by weight of nicotine, including racemic nicotine and nicotine enantiomers, calculated as the free base and based on the total weight of the composition). In some embodiments, compositions of the disclosure do not contain any compounds obtained by chemical reactions utilizing nicotine as a starting material. In preferred embodiments, the substituted 3-(1-methylpyrrolidin-2-yl)pyridine present is not synthetically derived from nicotine.Substituted 3-(1-methylpyrrolidin-2-yl)pyridine

[0069] As used herein, the term “substituted 3-(1-methylpyrrolidin-2-yl)pyridine” refers to a compound having a 3-(1-pyrrolidin-2-yl)pyridine) scaffold and bearing one or more non-hydrogen substituents on the pyridine ring.

[0070] In some embodiments, the substituted 3-(1-methylpyrrolidin-2-yl)pyridine has a structure according to Formula I:wherein R1, R2, R3, and R4 are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl, aryl, alkylaryl, amino, halogen, and cyano, wherein any of said alkyl, alkoxy, cycloalkyl, alkenyl, alkenyl, alkynyl, aryl, alkylaryl, and amino may optionally be substituted; and at least one of R1, R2, R3, and R4 are not hydrogen.Substituted 3-(1-methylpyrrolidin-2-yl)pyridines according to Formula I with various R1, R2, R3, and R4 substituents have been reported previously. See for example, U.S. Pat. Nos. 4,321,387, 4,155,909; 5,015,741, 5,138,062, and 5,703,100, each of which is incorporated by reference herein and describe such substituted 3-(1-methylpyrrolidin-2-yl)pyridines, their synthesis, and pharmacological properties. Substituted 3-(1-methylpyrrolidin-2-yl)pyridines and their pharmacological profiles have also been disclosed in Wang et al., Drug Development Research 1998, Volume 45, Issue 1, Pages 10-16; and Dukat et al. European Journal of Medicinal Chemistry 1999, 34(1): 31-40.

[0072] In some embodiments, R1, R2, and R3 are each H, and R4 is a non-hydrogen substituent.

[0073] In some embodiments, R4 is optionally substituted C1-C6 alkyl, F, Cl, Br, OMe, OEt, or CN.

[0074] In some embodiments, R1, R2, and R3 are each H, and R4 is optionally substituted C1-C6 alkyl, F, Cl, Br, OCH3, OEt, or CN.

[0075] In some embodiments, R1, R2, and R3 are each H, and R4 is C1-C3 alkyl.

[0076] In some embodiments, R1, R2, and R3 are each H, and R4 is CH3. In such embodiments, the compound of Formula I may be referred to as 2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine.

[0077] The pharmacology of 2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine has been reported in, for example, Dukat et al. European Journal of Medicinal Chemistry, Volume 31, Issue 11, 1996, Pages 875-888 (incorporated herein by reference), and the pharmacological profile of the (S)-enantiomer of 2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine in the form of the benzoate salt (CAS 2861225-70-7; referred to as Imotine™) is discussed in Carmines et al, Poster #6; 76th TSRC Conference 2023, Norfolk, VA, USA).

[0078] Without wishing to be bound by any particular theory, it is believed that certain substitutions for hydrogen on the pyridine ring of the substituted 3-(1-methylpyrrolidin-2-yl)pyridine compound of Formula I preserve the general pharmacological profile and physiological effects of nicotine while offering the potential for one or more of greater potency, reduced product consumption, more rapid and / or complete absorption, and the like. Particularly, it is believed that in some embodiments, substituted 3-(1-methylpyrrolidin-2-yl)pyridines of the disclosure according to Formula I are readily absorbed through oral mucosa by virtue of their lipophilicity. Lipophilicity is conveniently measured in terms of log P, the partition coefficient of a molecule between a lipophilic phase and an aqueous phase, usually octanol and water, respectively. Accordingly, in some embodiments, the substituted 3-(1-methylpyrrolidin-2-yl)pyridine of Formula I has a calculated or experimental log P of about 1 or greater, where log P is the log10 of the partitioning coefficient of the substituted 3-(1-methylpyrrolidin-2-yl)pyridine between octanol and water. Log P values may be measured experimentally according to protocols well known to one of skill in the art. Alternatively, log P values may be calculated using commercially available software. In some embodiments, the substituted 3-(1-methylpyrrolidin-2-yl)pyridine of Formula I has a calculated log P from 1 to about 2, such as 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, or 1.9. In some embodiments, the substituted 3-(1-methylpyrrolidin-2-yl)pyridine of Formula I has a calculated log P from about 1.2 to about 1.7. In some embodiments, the substituted 3-(1-methylpyrrolidin-2-yl)pyridine having a calculated log P from about 1.2 to about 1.7 bears one or more lipophilic substituents on the pyridine ring, such as C1-C6 alkyl, or C1-C3 alkyl. In some embodiments, the lipophilic substituent is methyl, and is present at the 2, 4, 5, or 6 position of the pyridine ring. In some embodiments, the lipophilic substituted 3-(1-methylpyrrolidin-2-yl)pyridine of Formula I is 2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine.

[0079] The substituted 3-(1-methylpyrrolidin-2-yl)pyridine (e.g., 2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine) of Formula I may be present as a single enantiomer or as a mixture of enantiomers. In some embodiments, the substituted 3-(1-methylpyrrolidin-2-yl)pyridine is present in racemic form, meaning there are equal amounts of (R)- and (S)-enantiomers present. In some embodiments, the treatment composition comprises unequal amounts of (R)- and (S)-enantiomer (i.e., is enriched in either the (R)- or (S)-enantiomer. In some embodiments, the treatment composition predominantly comprises the substituted 3-(1-methylpyrrolidin-2-yl)pyridine (e.g., 2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine) in the (R)-configuration, for example, about 90% or more of the total quantity of substituted 3-(1-methylpyrrolidin-2-yl)pyridine present is in the (R)-configuration. In some embodiments, the treatment composition predominantly comprises the substituted 3-(1-methylpyrrolidin-2-yl)pyridine (e.g., 2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine) in the (S)-configuration, for example, about 90% or more of the total quantity of substituted 3-(1-methylpyrrolidin-2-yl)pyridine present is in the (S)-configuration. In some embodiments, the treatment composition comprises 95% or more of the (S)-configuration of the substituted 3-(1-methylpyrrolidin-2-yl)pyridine (e.g., 2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine), based on the total amount of substituted 3-(1-methylpyrrolidin-2-yl)pyridine present.

[0080] The quantity of substituted 3-(1-methylpyrrolidin-2-yl)pyridine of Formula I (e.g., 2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine) present in the disclosed treated sheet materials and treated sheet articles may vary. Typically, the substituted 3-(1-methylpyrrolidin-2-yl)pyridine of Formula I (e.g., 2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine, calculated as the free base) is present in a concentration of at least about 0.001% by weight of the treatment composition associated with the treated sheet material on a dry weight basis, such as in a range from about 0.01% to about 10%. In some embodiments, the substituted 3-(1-methylpyrrolidin-2-yl)pyridine of Formula I (e.g., 2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine) is present in a concentration from about 0.1% w / w to about 10% by weight, such as, e.g., from about from 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, calculated as the free base and based on the total weight of the treatment composition on a dry weight basis. In some embodiments, the substituted 3-(1-methylpyrrolidin-2-yl)pyridine of Formula I (e.g., 2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine) is present in a concentration from about 0.1% w / w to about 3% by weight, such as, 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, calculated as the free base and based on the total weight of the treatment composition on a dry weight basis. In some embodiments, the treatment composition comprises 2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine in an amount from about 0.01 to about 10% by weight, based on the total weight of the treatment composition on a dry weight basis.

[0081] The substituted 3-(1-methylpyrrolidin-2-yl)pyridine of Formula I (e.g., 2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine) may be present in the treatment composition as the free base, as a salt with a suitable acid, or in the form of an ion pair with an organic acid. Each of these forms is described further herein below.

[0082] In some embodiments, the substituted 3-(1-methylpyrrolidin-2-yl)pyridine has a structure according to Formula II:wherein:

[0084] R5 and R6 are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl, aryl, alkylaryl, amino, halogen, and cyano, wherein any of said alkyl, alkoxy, cycloalkyl, alkenyl, alkenyl, alkynyl, aryl, alkylaryl, and amino may optionally be substituted;

[0085] R7 is selected from the group consisting of hydrogen and CH3;

[0086] R8 is selected from the group consisting of hydrogen and C1-C3 alkyl; and

[0087] at least one of R7 and R8 is not hydrogen.

[0088] In some embodiments, R5 is optionally substituted C1-C6 alkyl, F, Cl, Br, OCH3, OCH2CH3, or CN; and R6 is H.

[0089] In some embodiments, R5 is H; and R6 is optionally substituted C1-C6 alkyl, F, Cl, Br, OCH3, OCH2CH3, or CN.

[0090] Certain substituted 3-(1-methylpyrrolidin-2-yl)pyridines with various R5, R6, R7, and R8 substituents have been reported previously. See for example, U.S. Pat. Nos. 4,321,387, 4,155,909; 5,015,741, 5,138,062, and 5,703,100, each of which is incorporated by reference herein and describe example substituted 3-(1-methylpyrrolidin-2-yl)pyridines, their synthesis, and pharmacological properties. Certain substituted 3-(1-methylpyrrolidin-2-yl)pyridines and their pharmacological profiles have also been disclosed in Wang et al., Drug Development Research 1998, Volume 45, Issue 1, Pages 10-16; Dukat et al. European Journal of Medicinal Chemistry 1999, 34(1): 31-40; Lin et al., J. Med. Chem. (1994), 37, 3542-3553.

[0091] In some embodiments, R5 and R6 are H; R7 is CH3; and R8 is H. In such embodiments, the compound of Formula II may be referred to as 3-(1,2-dimethylpyrrolidin-2-yl)pyridine, or 2′-methyl-5-(1-methylpyrrolidin-2-yl)pyridine, and has a structure:The compound 3-(1,2-dimethylpyrrolidin-2-yl)pyridine is known in the literature, and has a Chemical Abstracts Registry Number of 220650-38-4. The synthesis of this compound has been reported in Rouchaud et al., J Het Chem 2012, 49(1), 161-166; Wang et al., Drug Dev Res 1998, 45(1), 10-16; Secor et al., Tetrahedron Lett. (1981), 22(33), 3151-3154; US Patent Application Publication No. 2013 / 0157995; PCT Application Publication No. WO2012 / 031220; and U.S. Pat. No. 9,440,948, each of which are incorporated by reference herein with respect to the synthesis of 3-(1,2-dimethylpyrrolidin-2-yl)pyridine.In some embodiments, R5 and R6 are H; R7 is H; and R8 is CH3. In such embodiments, the compound of Formula II may be referred to as 3-(1,4-dimethylpyrrolidin-2-yl)pyridine, or 4′-methyl-5-(1-methylpyrrolidin-2-yl)pyridine, and has a structure:The compound 3-(1,4-dimethylpyrrolidin-2-yl)pyridine is known in the literature, has a Chemical Abstracts Registry Number of 74805-00-8, and is commercially available from, for example, Enamine Stock Building Blocks and Aurora Building Blocks. The synthesis of this compound has been reported in U.S. Pat. No. 9,440,948; and EP Patent No. 559495, each of which are incorporated by reference herein with respect to the synthesis of 3-(1,4-dimethylpyrrolidin-2-yl)pyridine.In some embodiments, R5 is CH3; R6 is H; R7 is CH3; and R8 is H. In such embodiments, the compound of Formula II may be referred to as 5-(1,2-dimethylpyrrolidin-2-yl)-2-methylpyridine, and has a structure:The compound 5-(1,2-dimethylpyrrolidin-2-yl)-2-methylpyridine may be readily synthesized according to known reactions. For example, commercially available 2-methyl-5-(2-methylpyrrolidin-2-yl)pyridine (Chemical Abstracts Registry Number of 1528955-30-7; Aurora Building Blocks, Adlab Chemicals Building Blocks) can be N-methylated with formaldehyde and formic acid, or alternatively with formaldehyde and a reducing agent such as sodium cyanoborohydride to afford 5-(1,2-dimethylpyrrolidin-2-yl)-2-methylpyridine. Alternatively, 5-(1,2-dimethylpyrrolidin-2-yl)-2-methylpyridine may be synthesized by lithiation of 2-methyl-5-bromopyridine, reaction of the lithiated pyridine with N-methylpyrrolidone, and addition of methyl lithium to the perchlorate salt of the resulting imine. This reaction sequence is shown below in Scheme 1.In some embodiments, R5 is H or CH3, R6 is H, R7 is H or CH3, and R8 is H or CH3, provided that at least one of R7 and R8 is CH3. Accordingly, in some embodiments, the substituted 3-(1-methylpyrrolidin-2-yl)pyridine has a structure selected from the group consisting of:In some embodiments, R5 is H, R6 is F, CH3, or OCH3, R7 is H or CH3, and R8 is H or CH3, provided that at least one of R7 and R8 is CH3. Accordingly, in some embodiments, the substituted 3-(1-methylpyrrolidin-2-yl)pyridine has a structure selected from the group consisting of:A substituted 3-(1-methylpyrrolidin-2-yl)pyridine of Formula II as described herein may be present as a single enantiomer or as a mixture of enantiomers. In some embodiments, the substituted 3-(1-methylpyrrolidin-2-yl)pyridine of Formula II is present in racemic form, meaning there are equal amounts of (R)- and (S)-enantiomers present. In some embodiments, the treatment composition comprises unequal amounts of (R)- and (S)-enantiomer (i.e., is enriched in either the (R)- or (S)-enantiomer). In some embodiments, the treatment composition predominantly comprises the substituted 3-(1-methylpyrrolidin-2-yl)pyridine of Formula II in the (R)-configuration, for example, about 90% or more of the total quantity of substituted 3-(1-methylpyrrolidin-2-yl)pyridine present is in the (R)-configuration. In some embodiments, the treatment composition predominantly comprises the substituted 3-(1-methylpyrrolidin-2-yl)pyridine of Formula II in the (S)-configuration, for example, about 90% or more of the total quantity of substituted 3-(1-methylpyrrolidin-2-yl)pyridine present is in the (S)-configuration. In some embodiments, the treatment composition comprises 95% or more of the (S)-configuration of the substituted 3-(1-methylpyrrolidin-2-yl)pyridine of Formula II, based on the total amount of substituted 3-(1-methylpyrrolidin-2-yl)pyridine present.In some embodiments, the substituted 3-(1-methylpyrrolidin-2-yl)pyridine of Formula II is non-racemic, and has one of the following structures:In some embodiments, the substituted 3-(1-methylpyrrolidin-2-yl)pyridine of Formula II is non-racemic, and has a structure selected from the group consisting of:Such single enantiomer or enantiomerically enriched compounds may be obtained through classical resolution techniques using salt formation with chiral acids to form diastereomeric salts separable by crystallization. Suitable chiral acids include, but are not limited to, (R)- or (S)-dibenzoyl tartaric acid, di-p-toluoyl tartaric acid, or di-p-anisolyl tartaric acid; (R)- or (S)-mandelic acid, and (R)- or (S)-10-camphorsulfonic acid. Alternatively, one of skill in the art will recognize opportunities for chiral syntheses using either commercially available starting materials with established chiral centers or through the use of chiral auxiliary chemistries. For example, preparation of the 2S,4R enantiomer of 3-(1,4-dimethylpyrrolidin-2-yl)pyridine has been reported in, for example, U.S. Pat. No. 4,332,945, incorporated herein by reference with respect to syntheses of chiral nicotine analogs.

[0101] The pharmacology of various substituted 3-(1-methylpyrrolidin-2-yl)pyridines of Formula II such as those described herein has been reported in, for example, Lin et al., J. Med. Chem., 1994, 37, 3542-3553; Dukat et al. European Journal of Medicinal Chemistry, 31(11), 1996, 875-888; U.S. Pat. No. 9,440,948; Wang et al., Drug Dev Res 1998, 45(1), 10-16 (each of which is incorporated herein by reference), among many others. Generally, small substituents such as methyl groups are well tolerated at the 2′- or 4′-positions of the nicotine pyrrolidine ring, and small substituents such as alkyl, halogen, alkoxy, and the like are well tolerated at the 5- or 6-position of the nicotine pyridine ring. For example, 3-(1-methylpyrrolidin-2-yl)pyridines bearing a methyl substituent at the 2′ or 4′ position are equipotent or even more potent than nicotine with respect to binding affinity to the nicotinic acetylcholine receptor, and are expected to preserve the pharmacological effects of nicotine in vivo. See, for example U.S. Pat. No. 5,278,176, Lin et al., J. Med. Chem., 1994, 37, 3542-3553, and is believed that certain alkyl substitutions for hydrogen on the pyridine and / or pyrrolidine rings of the substituted 3-(1-methylpyrrolidin-2-yl)pyridine compound preserve the general pharmacological Wang et al., Drug Dev Res 1998, 45(1), 10-16. Without wishing to be bound by any particular theory, these compounds are believed to provide the general pharmacological profile and physiological effects of nicotine while offering the potential for one or more of greater potency, reduced product consumption, more rapid and / or complete absorption, and the like. Particularly, it is believed that in some embodiments, substituted 3-(1-methylpyrrolidin-2-yl)pyridines of the disclosure according to Formula II are readily absorbed through oral mucosa by virtue of their lipophilicity.

[0102] In some embodiments, the substituted 3-(1-methylpyrrolidin-2-yl)pyridine of Formula II has a calculated log P from 1 to about 2, such as 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, or 1.9. In some embodiments, the substituted 3-(1-methylpyrrolidin-2-yl)pyridine of Formula II has a calculated log P from about 1.2 to about 1.7.

[0103] The quantity of substituted 3-(1-methylpyrrolidin-2-yl)pyridine of Formula II present in the treatment composition may vary. Typically, the substituted 3-(1-methylpyrrolidin-2-yl)pyridine of Formula II, calculated as the free base) is present in a concentration of at least about 0.001% by weight of the treatment composition of the disclosed treated sheet material on a dry weight basis, such as in a range from about 0.01% to about 10%. In some embodiments, the substituted 3-(1-methylpyrrolidin-2-yl)pyridine of Formula II is present in a concentration from about 0.1% w / w to about 10% by weight, such as, e.g., from about from 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, calculated as the free base and based on the total weight of the treatment composition on a dry weight basis. In some embodiments, the substituted 3-(1-methylpyrrolidin-2-yl)pyridine of Formula II is present in a concentration from about 0.1% w / w to about 3% by weight, such as, 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, calculated as the free base and based on the total weight of the treatment composition on a dry weight basis. One of skill in the art will recognize that the amount of any particular substituted 3-(1-methylpyrrolidin-2-yl)pyridine present in the treatment composition may vary based on the potency of the compound, the other components of the treated sheet material and / or treated sheet article, and the desired physiological effect for the treatment composition and associated material and article.

[0104] In some embodiments, the amount of substituted 3-(1-methylpyrrolidin-2-yl)pyridine of Formula II in the treatment composition is determined by potency relative to nicotine. For example, in some embodiments, the amount of substituted 3-(1-methylpyrrolidin-2-yl)pyridine is determined based on the ratio of the α4β2 nicotinic receptor binding affinity (Ki) for nicotine to the α4β2 Ki for the specific substituted 3-(1-methylpyrrolidin-2-yl)pyridine. This ratio is referred to herein as the “potency factor.” Such potency factors indicate the amount of substituted 3-(1-methylpyrrolidin-2-yl)pyridine estimated to provide physiological activity in a user which is roughly equivalent to that of a given weight of nicotine.

[0105] In some embodiments, a substituted 3-(1-methylpyrrolidin-2-yl)pyridine of the disclosure has a potency factor from about 0.5 to about 2 (i.e., the Ki of the substituted 3-(1-methylpyrrolidin-2-yl)pyridine is from about twice to about half that of nicotine).

[0106] In some embodiments, the amount of substituted 3-(1-methylpyrrolidin-2-yl)pyridine in the treatment composition is 1 nicotine equivalent. Accordingly, in some embodiments, 1 nicotine equivalent of substituted 3-(1-methylpyrrolidin-2-yl)pyridine is an amount by weight from about 2 to about 0.5 times that of nicotine. For example, a product comprising 2 mg of nicotine, when the nicotine is replaced by a substituted 3-(1-methylpyrrolidin-2-yl)pyridine of the disclosure, may include from about 1 mg to about 4 mg of the substituted 3-(1-methylpyrrolidin-2-yl)pyridine. Similarly, a product comprising 20 mg of nicotine, when the nicotine is replaced by a substituted 3-(1-methylpyrrolidin-2-yl)pyridine, may contain from about 10 mg to about 40 mg of the substituted 3-(1-methylpyrrolidin-2-yl)pyridine.

[0107] In some embodiments, the substituted 3-(1-methylpyrrolidin-2-yl)pyridine of Formula II has the structure:having a potency factor of about 1.35, meaning that embodiments, the amount of substituted 3-(1-methylpyrrolidin-2-yl)pyridine present may be about 74% of the amount of nicotine required to achieve the same effect.In some embodiments, the substituted 3-(1-methylpyrrolidin-2-yl)pyridine of Formula II has the structure:having a potency factor of about 0.9, meaning that in some embodiments, the amount of substituted 3-(1-methylpyrrolidin-2-yl)pyridine present may be about 110% of the amount of nicotine required to achieve the same effect.The substituted 3-(1-methylpyrrolidin-2-yl)pyridine of Formula II may be present in the treatment composition (and in the corresponding treated sheet material and article) as the free base, as a salt with a suitable acid, or in the form of an ion pair with an organic acid. Each of these forms is described further herein below.3-(azetidin-2-yl)pyridines and 3-(azetidin-2-ylmethoxy)pyridinesIn some embodiments, disclosed herein are treated sheet materials comprising treatment compositions configured for oral use comprising an optionally substituted 3-(azetidin-2-yl)pyridine or an optionally substituted 3-(azetidin-2-ylmethoxy)pyridine. As used herein, the term “substituted 3-(azetidin-2-yl)pyridine” refers to a compound having a 3-(azetidin-2-yl)pyridine scaffold and bearing one or more non-hydrogen substituents on the azetidine ring, and optionally on the pyridine ring. As used herein, the term “substituted 3-(azetidin-2-ylmethoxy)pyridine” refers to a compound having a 3-(azetidin-2-ylmethoxy)pyridine scaffold and bearing one or more non-hydrogen substituents on the azetidine ring, and optionally on the pyridine ring.

[0111] As described above, some treatment compositions of the disclosure do not contain nicotine and do not contain any compounds obtained by chemical reactions utilizing nicotine as a starting material.

[0112] In some embodiments, the 3-(azetidin-2-yl)pyridine or 3-(azetidin-2-ylmethoxy)pyridine has a structure according to Formula III:wherein:

[0114] L is a bond or —OCH2—*, where the asterisk indicates an attachment point to the azetidine ring;

[0115] R9, R10, R11, and R12 are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, and cyano;

[0116] R13 is H or CH3; and

[0117] R14 is H or CH3.

[0118] In some embodiments, L is a bond.

[0119] In some embodiments, R9 is CH3, F, Cl, Br, OCH3, OEt, or CN.

[0120] In some embodiments, R9 is H or CH3; and R6, R7, and R8 are each H.

[0121] In some embodiments:

[0122] R13 and R14 are both H;

[0123] R13 and R14 are both CH3;

[0124] R13 is H and R14 is CH3; or

[0125] R13 is CH3 and R14 is H.

[0126] In some embodiments, the 3-(azetidin-2-yl) pyridine is 3-(azetidin-2-yl)pyridine, and has a structure:

[0127] The compound 3-(azetidin-2-yl)pyridine is known in the literature. The synthesis of this compound has been reported in JOC 1979, 44(18), 3136; Med Chem Res (1993) 2:552-5633; in International Patent Application Publication No. WO2012 / 031220, and in U.S. Pat. Nos. 4,163,855 and 4,163,856, all of which are incorporated herein in their entireties.

[0128] In some embodiments, the 3-(azetidin-2-yl) pyridine is 3-(1-methylazetidin-2-yl)pyridine, having the structure:The compound 3-(1-methylazetidin-2-yl)pyridine is known in the literature. The synthesis of this compound has been reported in International Patent Application Publication No. WO2012 / 031220, previously incorporated by reference herein.In some embodiments, the 3-(azetidin-2-yl) pyridine has a structure selected from the group consisting of:Such compounds are either known, or may be readily prepared according to adaptations of methods utilized for preparation of related 3-(azetidin-2-yl) pyridines and 3-(1-methylpyrrolidin-2-yl)pyridines described herein above. See, e.g., U.S. Pat. No. 4,163,855, previously incorporated by reference herein. The compound 5-(2-azetidinyl)-2-methylpyridine is known in the literature and has a Chemical Abstracts Registry (CAS) Number of 1270467-65-6, and the R- and S-enantiomers have CAS numbers 1213081-15-2 and 1212969-96-4, respectively.

[0131] In some embodiments, the treatment composition comprises a 3-(azetidin-2-ylmethoxy)pyridine (i.e., L is —OCH2—*).

[0132] In some embodiments, R9 is CH3, F, Cl, Br, OCH3, OEt, or CN.

[0133] In some embodiments, R9 is H or CH3; and R10, R11, and R12 are each H.

[0134] In some embodiments:

[0135] R13 and R14 are both H;

[0136] R13 and R14 are both CH3;

[0137] R13 is H and R14 is CH3; or

[0138] R13 is CH3 and R14 is H.

[0139] In some embodiments, the 3-(azetidin-2-ylmethoxy)pyridine has a structure selected from the group consisting of:These compounds are known in the literature. The synthesis of these compounds has been reported in International Patent Application Publication No. WO2012 / 031220, previously incorporated by reference herein.In some embodiments, the 3-(azetidin-2-ylmethoxy)pyridine has a structure selected from the group consisting of:Such compounds are either known, or may be readily prepared according to adaptations of methods utilized for preparation of related the 3-(azetidin-2-ylmethoxy)pyridine, and / or the 3-(azetidin-2-yl)pyridines and substituted 3-(1-methylpyrrolidin-2-yl)pyridines described herein above.

[0142] An optionally substituted 3-(azetidin-2-yl)pyridine or optionally substituted 3-(azetidin-2-ylmethoxy)pyridine as described herein may be present as a single enantiomer or as a mixture of enantiomers. In some embodiments, the optionally substituted 3-(azetidin-2-yl)pyridine or optionally substituted 3-(azetidin-2-ylmethoxy)pyridine is present in racemic form, meaning there are equal amounts of (R)- and (S)-enantiomers present. In some embodiments, the treatment composition comprises unequal amounts of (R)- and (S)-enantiomer (i.e., is enriched in either the (R)- or (S)-enantiomer). In some embodiments, the treatment composition predominantly comprises the optionally substituted 3-(azetidin-2-yl)pyridine or optionally substituted 3-(azetidin-2-ylmethoxy)pyridine in the (R)-configuration, for example, about 90% or more of the total quantity of optionally substituted 3-(azetidin-2-yl)pyridine or optionally substituted 3-(azetidin-2-ylmethoxy)pyridine present is in the (R)-configuration. In some embodiments, the treatment composition predominantly comprises the optionally substituted 3-(azetidin-2-yl)pyridine or optionally substituted 3-(azetidin-2-ylmethoxy)pyridine in the (S)-configuration, for example, about 90% or more of the total quantity of optionally substituted 3-(azetidin-2-yl)pyridine or optionally substituted 3-(azetidin-2-ylmethoxy)pyridine present is in the (S)-configuration. In some embodiments, the treatment composition comprises 95% or more of the (S)-configuration of the optionally substituted 3-(azetidin-2-yl)pyridine or optionally substituted 3-(azetidin-2-ylmethoxy)pyridine, based on the total amount of optionally substituted 3-(azetidin-2-yl)pyridine or optionally substituted 3-(azetidin-2-ylmethoxy)pyridine present.

[0143] In some embodiments, the optionally substituted 3-(azetidin-2-yl)pyridine is non-racemic, and has one of the following structures:

[0144] In some embodiments, the optionally substituted 3-(azetidin-2-ylmethoxy)pyridine is non-racemic, and has one of the following structures:

[0145] Such single enantiomer or enantiomerically enriched compounds may be obtained through classical resolution techniques using salt formation with chiral acids to form diastereomeric salts separable by crystallization. Suitable chiral acids include, but are not limited to, (R)- or (S)-dibenzoyl tartaric acid, di-p-toluoyl tartaric acid, or di-p-anisolyl tartaric acid; (R)- or (S)-mandelic acid, and (R)- or (S)-10-camphorsulfonic acid. Alternatively, one of skill in the art will recognize opportunities for chiral syntheses using either commercially available starting materials with established chiral centers or through the use of chiral auxiliary chemistries. For example, preparation of the 2S,4R enantiomer of 3-(1,4-dimethylpyrrolidin-2-yl)pyridine has been reported in, for example, U.S. Pat. No. 4,332,945, incorporated herein by reference with respect to syntheses of chiral nicotine analogs.

[0146] The pharmacology of certain 3-(azetidin-2-yl)pyridines and 3-(azetidin-2-ylmethoxy)pyridines has been previously disclosed, for example, in the references cited herein with respect to synthesis of such compounds. Generally, these compounds exhibit high affinity for one or more subtypes of nicotinic acetylcholine receptors, particularly the α4β2 subtype. The overall pharmacological profiles have been shown to be or are expected to be comparable to that of nicotine.

[0147] The quantity of optionally substituted 3-(azetidin-2-yl)pyridine or 3-(azetidin-2-ylmethoxy)pyridine present in the treatment composition may vary. Typically, the optionally substituted 3-(azetidin-2-yl)pyridine or 3-(azetidin-2-ylmethoxy)pyridine, calculated as the free base, is present in a concentration of at least about 0.001% by weight of the treatment composition on a dry weight basis, such as in a range from about 0.01% to about 10%. In some embodiments, the optionally substituted 3-(azetidin-2-yl)pyridine or 3-(azetidin-2-ylmethoxy)pyridine is present in a concentration from about 0.05% w / w to about 5% by weight, such as, e.g., from about from about 0.05% w / w. 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%, or about 5% by weight, calculated as the free base and based on the total weight of the treatment composition associated with a given sheet material on a dry weight basis. In some embodiments, the optionally substituted 3-(azetidin-2-yl)pyridine or 3-(azetidin-2-ylmethoxy)pyridine is present in a concentration from about 0.05% w / w to about 4% by weight, such as, e.g., from about 0.05% w / w to about 3.5%, from about 0.07% 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, calculated as the free base and based on the total weight of the composition. One of skill in the art will recognize that the amount of any particular optionally substituted 3-(azetidin-2-yl)pyridine or 3-(azetidin-2-ylmethoxy)pyridine present in the composition may vary based on the potency of the compound, the other components of the treated sheet material and / or treated sheet article, and the desired physiological effect for the treatment composition and associated material and article.

[0148] In some embodiments, the amount of optionally substituted 3-(azetidin-2-yl)pyridine or 3-(azetidin-2-ylmethoxy)pyridine in the treatment composition is determined by potency relative to nicotine. For example, in some embodiments, the amount of optionally substituted 3-(azetidin-2-yl)pyridine or 3-(azetidin-2-ylmethoxy)pyridine is based on the potency factor as described above for substituted 3-(1-methylpyrrolidin-2-yl)pyridines. In some embodiments, an optionally substituted 3-(azetidin-2-yl)pyridine or 3-(azetidin-2-ylmethoxy)pyridine of the disclosure has a potency factor from about 0.1 to about 30, such as from about 2 to about 30.

[0149] In some embodiments, the amount of optionally substituted 3-(azetidin-2-yl)pyridine or 3-(azetidin-2-ylmethoxy)pyridine in the treatment composition is 1 nicotine equivalent. Accordingly, in some embodiments, 1 nicotine equivalent of optionally substituted 3-(azetidin-2-yl)pyridine or 3-(azetidin-2-ylmethoxy)pyridine is an amount by weight from about 10 to about 0.03 times that of nicotine. In some embodiments, 1 nicotine equivalent of optionally substituted 3-(azetidin-2-yl)pyridine or 3-(azetidin-2-ylmethoxy)pyridine is an amount by weight from about 0.5 to about 0.03 times that of nicotine.

[0150] For example, a product comprising 2 mg of nicotine, when the nicotine is replaced by an optionally substituted 3-(azetidin-2-yl)pyridine or 3-(azetidin-2-ylmethoxy)pyridine of the disclosure, may include from about 0.06 mg to about 1 mg of the optionally substituted 3-(azetidin-2-yl)pyridine or 3-(azetidin-2-ylmethoxy)pyridine. Similarly, a product comprising 20 mg of nicotine, when the nicotine is replaced by an optionally substituted 3-(azetidin-2-yl)pyridine or 3-(azetidin-2-ylmethoxy)pyridine, may contain from about 0.6 mg to about 100 mg of the optionally substituted 3-(azetidin-2-yl)pyridine or 3-(azetidin-2-ylmethoxy)pyridine.

[0151] In some embodiments, the optionally substituted 3-(azetidin-2-yl)pyridine has the structure:having a potency factor of about 30, meaning that in some embodiments, the amount of optionally substituted 3-(azetidin-2-yl)pyridine present may be about 3% of the amount of nicotine required to achieve the same effect.In some embodiments, the optionally substituted 3-(azetidin-2-ylmethoxy)pyridine has the structure:having a potency factor of about 3, meaning that in some embodiments, the amount of 3-(azetidin-2-ylmethoxy)pyridine present may be about 33% of the amount of nicotine required to achieve the same effect.The optionally substituted 3-(azetidin-2-yl)pyridine or 3-(azetidin-2-ylmethoxy)pyridine may be present in the treatment composition as the free base, as a salt with a suitable acid, or in the form of an ion pair with an organic acid. Each of these forms is described further herein below.Other Active IngredientsIn some embodiments, the substituted 3-(1-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, or optionally 3-(azetidin-2-ylmethoxy)pyridine of the present disclosure is replaced with, or combined with, other active ingredients that provide the same general pharmacological profile and / or physiological effects of nicotine. Certain of these active ingredients may be equipotent or even more potent than nicotine with respect to binding affinity to the nicotinic acetylcholine receptor, and are expected to preserve the pharmacological effects of nicotine in vivo. Without wishing to be bound by any particular theory, in some embodiments, these compounds are believed to provide the general pharmacological profile and physiological effects of nicotine while offering the potential for one or more of greater potency, reduced product consumption, more rapid and / or complete absorption, and the like.

[0155] Example active ingredients of this type include, without limitation, cytisine, varenicline, acetylcholine, choline, epibatidine, lobeline, analogs thereof, or combinations thereof. Suitable analogs include any of the above-noted compounds having one or more substituents on any of the carbon atoms thereof, with example substituents including alkyl (e.g., C1-C3 alkyl), alkoxy, cycloalkyl, alkenyl, alkynyl, aryl, alkylaryl, amino, halogen, and cyano.

[0156] In some embodiments, the other active ingredient is cytisine or an analog thereof. Cytisine is a naturally occurring alkaloid present in certain plant genera, such as Laburnum and Cytisus of the family Fabaceae. Cytisine (CAS Registry No. 485-35-8) has the structure:Cytisine is commercially available and has been utilized in post-Soviet states for more than 40 years as an aid to smoking cessation under the brand name Tabex (Sopharma AD). Cytisine is a partial agonist of the α4β2 nicotinic acetylcholine receptor.In some embodiments, the optional other active ingredient is varenicline or an analog thereof. Varenicline is commercially available as Chantix® (Pfizer) and is a medication used as an aid for smoking cessation. Varenicline (CAS Registry No. 249296-44-4) has the structure:Like cytisine, varenicline is a partial agonist of the α4β2 nicotinic acetylcholine receptor.The quantity of the other active ingredient present in the treatment composition associated with the disclosed materials and articles may vary. Typically, the optional other active ingredient, calculated as the free base, is present in a concentration of at least about 0.001% by weight of the treatment composition, such as in a range from about 0.01% to about 10%. In some embodiments, the other active ingredient is present in a concentration from about 0.05% w / w to about 5% by weight, such as, e.g., from about from about 0.05% w / w. 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%, or about 5% by weight, calculated as the free base and based on the total weight of the composition. In some embodiments, the other active ingredient is present in a concentration from about 0.05% w / w to about 4% by weight, such as, e.g., from about 0.05% w / w to about 3.5%, from about 0.07% 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, calculated as the free base and based on the total weight of the treatment composition. One of skill in the art will recognize that the amount of any particular other active ingredient present in composition may vary based on the potency of the compound, the other components of the treated sheet material and / or treated sheet article, and the desired physiological effect for the treatment composition and associated material and article.The optional other active ingredient may be present in the composition as the free base, as a salt with a suitable acid, or in the form of an ion pair with an organic acid. Each of these forms is described further herein below.Free Base

[0160] In some embodiments, the substituted 3-(1-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient exhibits sufficient stability, aqueous solubility, and oral bioavailability such that the free base is suitable for inclusion in the composition. Accordingly, in some embodiments, the substituted 3-(1-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine or other active ingredient is present substantially or completely as the free base. In such embodiments, one of skill in the art will recognize that the composition is substantially free of acidic components. By “substantially free” it is meant that no acidic component (e.g., inorganic acid, organic acid, or acids capable of salt, ion pair, or co-crystal formation) has been intentionally added, beyond trace amounts that may be present e.g., as an impurity in another component. For example, some embodiments can be characterized as having less than 0.001% by weight of any acid component, or less than 0.0001%, or even 0% by weight of any acid component, based on the total weight of the composition. In some embodiments, the composition is completely free of any acid component (i.e., characterized as 0% or as having an amount below the limit of detection). In some embodiments, the substituted 3-(1-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient is present in the free base form and is adsorbed in a carrier such as a microcrystalline cellulose material to form an adsorption complex.Salt

[0161] In some embodiments, at least a portion of the substituted 3-(1-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient can be employed in the form of a salt. A “salt” of such compounds is a form characterized by interaction between the said compound in ionic form and a coformer in ionic form (e.g., an acid) via the transfer of one or more protons from the coformer donor to the compound acceptor. The structure of substituted 3-(1-methylpyrrolidin-2-yl)pyridines, optionally substituted 3-(azetidin-2-yl)pyridines, and optionally 3-(azetidin-2-ylmethoxy)pyridines as disclosed herein are such that they comprise two nitrogen atoms that are capable of accepting protons from a coformer and, accordingly, can be present in non-protonated, mono-protonated, and / or di-protonated form in a given sample. Salts of substituted 3-(1-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient can be provided using the types of ingredients and techniques set forth for nicotine in U.S. Pat. No. 2,033,909 to Cox et al. and Perfetti, Beitrage Tabakforschung Int., 12: 43-54 (1983), which are incorporated herein by reference. Suitable salts are generally water soluble. Suitable acids for formation of salts (mono- and di-) include, but are not limited to, acetic acid, adipic acid, ascorbic acid, capric acid, citric acid, D-glucuronic acid, D-gluconic acid, lactic acid, galactaric acid, hippuric acid, hydrochloric acid, L-aspartic acid, L-glutamic acid, L-glutaric acid, glycerophosphoric acid, glycolic acid, lauric acid, DL-malic acid, L-malic acid; tartaric acid, palmitic acid, phosphoric acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, thiocyanic acid, (+)-camphoric acid, 1,5-naphthalenedisulfonic acid, 1-hydroxy-2-naphthoic, 2,5-dihydroxybenzoic acid, benzenesulfonic acid, benzoic acid, caprylic acid, cyclamic acid, ethanesulfonic acid, fumaric acid, D-glucoheptonic acid, 4-hydroxybenzoic acid, isobutyric acid, ketoglutaric acid, 2-ketobutyric acid, lactobionic acid, maleic acid, malonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, pamoic acid, pivalic acid, propionic acid, L-pyroglutamic acid, p-toluenesulfonic acid, (1S)-camphor-10-sulfonic acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, N-acetyl-4-aminosalicylic acid, caproic acid, dichloroacetic acid, hydrobromic acid, DL-mandelic acid, L-mandelic acid, nitric acid, formic acid, salicylic acid, cinnamic acid, undecylenic acid, isothionic acid, lauric acid, 2-hydroxybenzoic acid, trans-2-hexenoic acid, trimesic acid, 5-nitroisophthalic acid, and zinc chloride monohydrate (forming a hydrated zinc chloride complex salt).

[0162] In some embodiments, a hydrophilic acid is chosen so as to increase water solubility and / or decrease lipophilicity of the salt. Lipophilicity of a salt of a compound as disclosed herein can also be expressed as log D, which is the logarithm of the distribution coefficient, a measure of the pH-dependent differential solubility between an octanol phase and an aqueous phase of all species (ionized and un-ionized) in an octanol / aqueous system, represented by the formula:log⁢Doct / wat=log⁡([solute]octanol[solute]waterionized+[solute]waterneutral).Log D is a commonly used descriptor for the lipophilicity of ionizable compounds. Log D values can be calculated using commercial software or may be determined experimentally in a similar manner to log P but instead of using water, the aqueous phase is adjusted to a specific pH using a buffer. Log D is pH dependent and therefore requires that the pH at which the log D was measured be specified.When the substituted 3-(1-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient is present in the form of a salt, it is generally preferred that the salt have a relatively low log D, indicative of good water solubility. Without wishing to be bound by theory, it is believed that highly water-soluble salt forms may exhibit a high rate of dissolution, which may be favorable in certain embodiments. Accordingly, in some embodiments, the substituted 3-(1-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient salt has a log D from about −1.0 to about 3 at a pH in a range from about 3 to about 11, such as from about −0.5 to about 2, about −0.3 to about 1, or about −0.1 to about 0.

[0164] In some embodiments, the selection of acid used to make a salt is performed on the basis of sensory effects of the salt, such as taste. Surprisingly, according to the present disclosure, it has been found that salts of certain organic acids, such as galactaric acid, offer a better taste sensation relative to salts of acids such as tartaric or phthalic acids.

[0165] In some embodiments, the substituted 3-(1-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient is present in the form of a salt with tartaric acid, succinic acid, orotic acid, fumaric acid, pyroglutamic acid, or galactaric acid. In some embodiments, the substituted 3-(1-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, or optionally 3-(azetidin-2-ylmethoxy)pyridine is present in the form of a salt with succinic acid or galactaric acid.

[0166] The stoichiometry of the salts as described herein can vary. For example, in some embodiments, the stoichiometry can range from about 5:1 to about 1:5 compound:acid. In some embodiments, the ratio of compound to acid is 2:1, 1:1, or 1:2. Hydrates and other solvates of salts are further contemplated herein.

[0167] The salts as described herein can, in some embodiments, exist in various polymorphic and pseudopolymorphic forms. Polymorphism is the ability of a crystalline material to exist in more than one form or crystal structure. Polymorphism can result, e.g., from the existence of different crystal packing structures (packing polymorphism) or from the existence of different conformers of the same molecule (conformational polymorphism). Pseudopolymorphism is the result of hydration or solvation of a material and is also referred to as solvomorphism.Resin Complex

[0168] In some embodiments, at least a portion of the substituted 3-(1-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient may be present in the form of a polymer complex, where the compound is bound to an acidic polymer. The polymer of such a complex can be any polymer (including homopolymers or all types of copolymers) with acidic functionalities, e.g., a polymeric cation exchange resin. In some embodiments, the polymer comprises acidic sites that can be classified as strongly acidic, weakly acidic, or of intermediate acidity (depending, e.g., on the strength of the acid from which they are derived). In some embodiments, the polymer comprises weakly acidic sites and can be referred to as a weakly acidic cation exchange resin. Non-limiting examples of acidic sites include, e.g., carboxylic acids, sulfonic acids, phosphonous acids, phosphonic acids, phosphoric acids, iminodiacetic acids, and phenolic groups (e.g., as disclosed in Adams et al., J. Soc. Chem. Ind. 54, IT (1935), which is incorporated herein by reference). Suitable polymers include, but are not limited to, addition polymers of styrene and divinylbenzene, divinylbenzene and methacrylic acid, divinylbenzene and acrylic acid, phenolic resins, or cellulose, dextran or pectin cross-linked with, e.g., epichlorohydrin. In some embodiments, the polymer comprises cross-linked moieties. Various acidic ion-exchange resins which are known in the art and are suitable for formation of complexes, include, but are not limited to, polymethacrylic acid resins such as DuPont™ Amberlite™ IRP64, DuPont™ Amberlite™ IRP69, Purolite™ C115HMR, Doshion™ P551, and polyacrylic carbomers, such as Carbopol 974P. See, for example, U.S. Pat. No. 3,901,248 to Lichtneckert et al., which is incorporated herein by reference. In some embodiments, when the substituted 3-(1-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, or optionally 3-(azetidin-2-ylmethoxy)pyridine is present in the form of a polymer complex, the treatment composition further comprises a divalent metal buffer, such as a calcium or magnesium salt (e.g., carbonate, bicarbonate, oxide, acetate, or the like).Cocrystal

[0169] In some embodiments, at least a portion of the substituted 3-(1-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient may be present in the form of a co-crystal with at least one other component (“coformer”), both in neutral form. Specifically, as defined in a US FDA industry guidance document, a co-crystal is a solid that is a crystalline material composed of two or more molecules in the same crystal lattice, where the components are in a neutral state and interact via nonionic interactions. See U.S. Department of Health and Human Services, Food and Drug Administration, Guidance for Industry: Regulatory Classification of Pharmaceutical Co-Crystals (April 2013), which is incorporated herein by reference. This form is different and distinct from both salts and ion pairs, each described herein. Specifically, co-crystals can generally be distinguished from salts (and ion pairs) by the absence of a proton transfer between the components (i.e., a substituted 3-(1-methylpyrrolidin-2-yl)pyridine and the one or more coformers) in a co-crystal. The crystalline structure of the co-crystal is generally held together by freely reversible, non-covalent interactions. Co-crystals typically comprise the substituted 3-(1-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, or optionally 3-(azetidin-2-ylmethoxy)pyridine and coformer in a defined stoichiometric ratio. In some embodiments, co-crystals can encompass hydrates, solvates, and clathrates. Co-crystals can comprise the substituted 3-(1-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient in combination with an organic and / or an inorganic coformer.

[0170] Examples of suitable coformers include, but are not limited to, acetamidobenzoic acid, L-proline, tromethamine, urea, xylitol, caffeine, glycine / glycine anhydride, vanillin, methyl 4-hydroxybenzoate(methylparaben), succinimide, L-alanine, mannitol, L-phenylalanine, saccharin, propylparaben, N-methylglucamine, L-tyrosine, gentisic acid, sorbic acid, benzoic acid, L-methionine, maltol, L-lysine, tromethamine, nicotinamide, isonicotinamide, phenylalanine, benzoquinone, terephthalaldehyde, 4-hydroxybenzoic acid, pyruvic acid, 1-hydroxy-2-naphthoic acid, 4-aminobenzoic acid, vanillic acid, ethyl vanillin, isonicotinic acid, gallic acid, menthol (e.g., racemic menthol or (−)-menthol), paracetamol, aspirin, ibuprofen, naproxen, ketoprofen, flurbiprofen, glucose, serine, malic acid, acetamide, sulfacetamide, benzoic acid, creatine, 2-hydroxyethanesulfonic acid, clofibric acid, taurine (tauric acid), iproniazid, L-histadine, L-arginine, L-asparagine, glutamine, L-cysteine, alanine, valine, isoleucine, leucine, morpholine, theronine, N-methylglucamine, 3-hydroxy-2-oxopropionic acid; 2-oxobutyric acid (2-ketobutyric acid), 3-methyl-2-oxobutanoic acid; 3-methyl-2-oxopentanoic acid; 4-methyl-2-oxopentanoic acid; and 2-oxopentanedioic acid, 2-oxo-3-phenylpropionic acid; 5-oxooctanoic acid; and 5-oxodecanoic acid, aldonic acids (e.g., glyceric acid, xylonic acid, gluconic acid, and ascorbic acid), ulosonic acids (e.g., neuraminic acid and ketodeoxyoctulosonic acid), uronic acids (e.g., glucuronic acid, galacturonic acid, and iduronic acid), aldaric acids (e.g., tartaric acid, meso-galactaric acid / mucic acid, and D-glucaric acid / saccharic acid), galactaric acid), and polyfunctional aromatic acids.

[0171] In some embodiments, the conformer is a polyfunctional aromatic acid. Polyfunctional aromatic acids often comprise a substituted or unsubstituted phenyl group as the aromatic component, but can alternatively comprise another aromatic moiety, e.g., pyridine, pyrazine, imidazole, pyrazole, oxazole, thiophene, naphthalene, anthracene, and phenanthrene. Substituents on the optionally substituted aromatic acids may be any type of substituent, including, but not limited to, halo (e.g., Cl, F, Br, and I); alkyl, halogenated alkyl (e.g., CF3, 2-Br-ethyl, CH2F, CH2Cl, CH2CF3, or CF2CF3); alkenyl, hydroxyl; amino; carboxylate; carboxamido; alkylamino; arylamino; alkoxy; aryloxy; nitro; azido; cyano; thio; sulfonic acid; sulfate; phosphonic acid; phosphate; and phosphonate groups. Example polyfunctional aromatic acids can be, for example:

[0172] substituted and unsubstituted aromatic dicarboxylic acids (e.g., 1,2-benzenedicarboxylic acid (phthalic acid), 1,3-benzenedicarboxylic acid (isophthalic acid), 1,4-benzenedicarboxylic acid (terephthalic acid), 2-iodo-1,3-benzenedicarboxylic acid, 2-hydroxy-1,4-benzenedicarboxylic acid, 2-nitro-1,4-benzenedicarboxylic acid, 3-fluoro-1,2-benzenedicarboxylic acid, 3-amino-1,2-benzenedicarboxylic acid, 3-nitro-1,2-benzenedicarboxylic acid, 4-bromo-1,3-benzenedicarboxylic acid, 4-hydroxy-1,3-benzenedicarboxylic acid, 4-amino-1,2-benzenedicarboxylic acid, 4-nitro-1,2-benzenedicarboxylic acid, 4-sulfo-1,2-benzenedicarboxylic acid, 4-amino-1,3-benzenedicarboxylic acid, 5-bromo-1,3-benzenedicarboxylic acid, 5-hydroxy-1,3-benzenedicarboxylic acid, 5-amino-1,3-benzenedicarboxylic acid, 5-nitro-1,3-benzenedicarboxylic acid, 5-ethynyl-1,3-benzenedicarboxylic acid, 5-cyano-1,3-benzenedicarboxylic acid, 5-nitro-1,3-benzenedicarboxylic acid, 2,5-hydroxy-1,4-benzenedicarboxylic acid, and 2,3,5,6-tetrafluoro-1,4-benzenedicarboxylic acid;

[0173] substituted and unsubstituted hydroxybenzoic acids (e.g., 2-hydroxybenzoic acid (salicylic acid), 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, 2-methyl-4-hydroxybenzoic acid, 3-tert-butyl-4-hydroxybenzoic acid, 4-ethoxy-2-hydroxybenzoic acid, 3-chloro-5-hydroxybenzoic acid, 5-chloro-2-hydroxybenzoic acid, 3-bromo-4-hydroxybenzoic acid, 3-bromo-5-hydroxybenzoic acid, 4-bromo-2-hydroxybenzoic acid, 5-bromo-2-hydroxybenzoic acid, 2-fluoro-5-hydroxybenzoic acid, 3-fluoro-4-hydroxybenzoic acid, 3-fluoro-2-hydroxybenzoic acid, 3-fluoro-5-hydroxybenzoic acid, 2-fluoro-6-hydroxybenzoic acid, 4-fluoro-3-hydroxybenzoic acid, 2-fluoro-4-hydroxybenzoic acid, 5-fluoro-2-hydroxybenzoic acid, 2-amino-3-hydroxybenzoic acid, 2-amino-5-hydroxybenzoic acid, 3-amino-2-hydroxybenzoic acid, 3-amino-4-hydroxybenzoic acid, 3-amino-5-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid, 4-amino-3-hydroxybenzoic acid, 5-amino-2-hydroxybenzoic acid (mesalamine), 5-aminomethyl-2-hydroxybenzoic acid, 4-formyl-3-hydroxybenzoic acid, 3-formyl-4-hydroxybenzoic acid, 5-(acetylamino)-2-hydroxybenzoic acid), 4-nitro-2-hydroxybenzoic acid, 3,5-diethyl-4-hydroxybenzoic acid, 3,5-di-tert-butyl-4-hydroxybenzoic acid, 3,5-diisopropyl-2-hydroxybenzoic acid, 3,4-dimethoxy-4-hydroxybenzoic acid (syringic acid), 3,5-dichloro-2-hydroxybenzoic acid, 3,5-dichloro-4-hydroxybenzoic acid, 3,6-dichloro-2-hydroxybenzoic acid, 2,3-difluoro-4-hydroxybenzoic acid, 3,4-difluoro-2-hydroxybenzoic acid, 3,5-dibromo-2-hydroxybenzoic acid, 3,5-diodo-2-hydroxybenzoic acid, 4-amino-5-chloro-2-hydroxybenzoic acid, 3,5-dinitro-2-hydroxybenzoic acid, 2,4,6-tribromo-2-hydroxybenzoic acid, 2,3,5,6-tetrafluoro-4-hydroxybenzoic acid, and 2,3,4,5-tetrafluoro-6-hydroxybenzoic acid);

[0174] substituted and unsubstituted dihydroxybenzoic acids (e.g., 2,3-dihydroxybenzoic acid (pyrocatechuic acid / hypogallic acid), 2,4-dihydroxybenzoic acid (β-resorcylic acid), 2,5-dihydroxybenzoic acid (gentisic acid / hydroquinonecarboxylic acid), 2,6-dihydroxybenzoic acid (γ-resorcylic acid), 3,4-dihydroxybenzoic acid (protocatechuic acid), 3,5-dihydroxybenzoic acid (α-resorcylic acid), 4-hydroxy-3-methoxybenzoic acid (vanillic acid), 6-methyl-2,4-dihydroxybenzoic acid (orsellenic acid), 4-bromo-3,5-dihydroxybenzoic acid, 5-bromo-2,4-dihydroxybenzoic acid, 5-bromo-3,4-dihydroxybenzoic acid, 6-carboxymethyl-2,3-dihydroxybenzoic acid, 3,5-dibromo-2,4-dihydroxybenzoic acid, 3,5-dichloro-2,6-dihydroxybenzoic acid, and 5-amino-3-chloro-2,4-dihydroxybenzoic acid);

[0175] substituted and unsubstituted trihydroxybenzoic acids (e.g., 2,3,4-trihydroxybenzoic acid, 2,4,5-trihydroxybenzoic acid, 2,4,6-trihydroxybenzoic acid (phloroglucinol carboxylic acid), and 3,4,5-trihydroxybenzoic acid (gallic acid));

[0176] substituted and unsubstituted aromatic tricarboxylic acids (e.g., 1,2,3-benzenetricarboxylic acid, 1,2,4-benzenetricarboxylic acid (trimellitic acid); and

[0177] substituted and unsubstituted aromatic tetracarboxylic acids (e.g., 1,2,3,4-benzenetetracarboxylic acid (mellophanic acid) and 1,2,4,5-benzenetetracarboxylic acid (pyromellitic acid). Further contemplated are various combinations of any of the foregoing acids.

[0178] In some embodiments, the coformer is L-malic acid, succinic acid, or a combination thereof. In some embodiments, the coformer is 1,1,6,6-tetraphenyl-2,4-hexidiyne-1,6-diol. In some embodiments, the coformer is di-iodotetrafluoro benzene, 4,4′-diiodooctafluorobiphenyl, or 1,4-bis(diphenylhydroxymethyl)benzene. In some embodiments, the coformer is orotic acid.

[0179] In some embodiments, the substituted 3-(1-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient is present in the form of a salt co-crystal. A “salt co-crystal” is a type of hybrid structure with both salt and co-crystal characteristics. Typically, a substituted 3-(1-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine molecule, or other active ingredient within a salt co-crystal is associated with at least two coformers (which may be the same or different), wherein one coformer is in ionic form (e.g., an acid) and transfers a proton to the substituted 3-(1-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine molecule, or other active ingredient, and wherein a second coformer does not transfer a proton to the substituted 3-(1-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine molecule, or other active ingredient. Suitable acids and coformers are generally those described herein above with respect to salts and co-crystals.

[0180] The stoichiometry of the co-crystals and salt co-crystals described herein can vary. For example, in certain embodiments, where two components are present, the stoichiometry can range in certain embodiments from about 5:1 to about 1:5 compound:coformer. Where more than one coformer is used to form a co-crystal or salt co-crystal, the ratios of the coformers with respect to both the substituted 3-(1-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient and to one another can also vary.

[0181] The co-crystals and salt co-crystals described herein can, in some embodiments, exist in various polymorphic and pseudopolymorphic forms, as well as solvates and hydrates.

[0182] In some embodiments, the substituted 3-(1-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient is present in the form of a salt-co-crystal. In some embodiments, the salt-co-crystal is a bis-orotic acid salt-co-crystal. In some embodiments, the bis-orotic acid salt-co-crystal is a hemi-hydrate.Ion Pairing

[0183] In some embodiments, at least a portion of the substituted 3-(1-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient is present in the form of an ion pair. Ion pairing describes the partial association of oppositely charged ions in relatively concentrated solutions to form distinct chemical species called ion pairs. The strength of the association (i.e., the ion pairing) depends on the electrostatic force of attraction between the positive and negative ions (e.g., a substituted 3-(1-methylpyrrolidin-2-yl)pyridine and the conjugate base of a suitable acid). By “conjugate base” is meant the base resulting from deprotonation of the corresponding acid (e.g., benzoate is the conjugate base of benzoic acid). In embodiments comprising ion pairing, on average, a certain population of these ion pairs exists at any given time, although the formation and dissociation of ion pairs is continuous. In some embodiments, in the composition as disclosed herein, and / or upon oral use of the disclosed sheet material / article, said treatment composition (e.g., upon contact with saliva), the substituted 3-(1-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient and the conjugate base of an acid exist at least partially in the form of an ion pair. Ion pairing is further described in, for example, International Patent Application Publication No. WO2021 / 050741 to Poole et al., and US Application Publication Nos. 2021 / 0068447 to Keller et al., 2023 / 0138306A1 to Zawadzki et al., and 2022 / 0346434 to Von Cosmos et al., each of which is incorporated herein by reference.

[0184] One of skill in the art will recognize that the extent of ion pairing in the disclosed treatment composition associated with the treated sheet material / article, both before and during use by the consumer, may vary based on, for example, pH, the nature of the acid, the concentration of substituted 3-(1-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient, the concentration of the acid or conjugate base of the acid present in the composition, the moisture content of the composition, the ionic strength of the composition, and the like. One of skill in the art will also recognize that ion pairing is an equilibrium process influenced by the foregoing variables. Accordingly, quantification of the extent of ion pairing is difficult or impossible by calculation or direct observation. However, the presence of ion pairing may be demonstrated through surrogate measures, such as partitioning of the substituted 3-(1-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient between octanol and water, or by performing membrane permeation studies of aqueous solutions of, for example, the substituted 3-(1-methylpyrrolidin-2-yl)pyridine plus acids and / or their conjugate bases. An octanol-water partitioning favoring distribution of an ion pair into octanol is predictive of good absorption of the substituted 3-(1-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine (e.g., 2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine), or other active ingredient through the oral mucosa. However, as described above, in some embodiments, the properties of the substituted 3-(1-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine (e.g., 2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine), or other active ingredient are such that no ion pairing is required, and accordingly, the composition is substantially or completely free of any ion pairing. By “substantially free” it is meant that no measurable degree of ion pairing is present.

[0185] In embodiments where ion pairing is desired, the treatment composition comprises an organic acid, an alkali metal salt of an organic acid, or both. In such embodiments, at least a portion of the substituted 3-(1-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient is associated with at least a portion of the organic acid, the alkali metal salt thereof, or a combination thereof in the form an ion pair. As used herein, the term “organic acid” refers to an organic (i.e., carbon-based) compound that is characterized by acidic properties. Typically, organic acids are relatively weak acids (i.e., they do not dissociate completely in the presence of water), such as carboxylic acids (—CO2H) or sulfonic acids (—SO2OH). As used herein, reference to organic acid means an organic acid that is intentionally added. In this regard, an organic acid may be intentionally added as a specific composition ingredient as opposed to merely being inherently present as a component of another composition ingredient (e.g., the small amount of organic acid which may inherently be present in a composition ingredient). For the avoidance of doubt, reference herein to an “organic acid” is intended to distinguish the acid present in ion paired forms over the acid which may be present in salts, co-crystal, and salt co-crystals. While one of skill in the art will recognize that certain organic acids suitable for formation of ion pairs overlap with those identified as suitable for salt or co-crystal formation, it is to be understood that the particular acid used for each of salts, co-crystals, and ion pairs are to be selected specifically for each such embodiment, and reference herein to an organic acid is specific to acids suitable for ion pairing. Accordingly, the presence in the treatment composition of an organic acid as defined below is to be interpreted solely with respect to ion pairing, even if such organic acid is also suitable for salt formation or co-crystal formation, and the presence of such an organic acid does not imply that a salt or co-crystal is present unless explicitly identified. Further, in embodiments where there is no ion pairing intended, the treatment composition may be characterized as substantially or completely free of organic acids (i.e., having less than 0.001% by weight of organic acid, or less than 0.0001%, or even 0% by weight of organic acid, based on the total weight of the composition, or as having an amount of organic acid below the limit of detection). This is not to be interpreted as meaning that the treatment composition is substantially or completely free of substituted 3-(1-methylpyrrolidin-2-yl)pyridine salts or substituted 3-(1-methylpyrrolidin-2-yl)pyridine co-crystals unless explicitly recited.Organic Acid

[0186] In embodiments where ion pairing is desired, the treatment composition comprises an organic acid as defined herein above, and / or an alkali metal salt thereof. Suitable organic acids for ion pairing will typically have a range of lipophilicities (i.e., a polarity giving an appropriate balance of water and organic solubility). Typically, lipophilicities of suitable organic acids, as indicated by log P, will vary between about 0 and about 12 (more soluble in octanol than in water). In some embodiments, the organic acid has a log P value from about 0 to about 12, e.g., from about 0.5, 1.0. about 1.5, about 2.0, about 2.5, about 3.0, about 3.5, about 4.0, about 4.5, about 5.0, about 5.5, about 6.0, about 6.5, about 7.0, about 7.5, or about 8.0, to about 8.5, about 9.0, about 9.5, about 10.0, about 10.5, about 11.0, about 11.5, or about 12.0.

[0187] Without wishing to be bound by theory, it is believed that moderately lipophilic organic acids (e.g., log P of from about 1.4 to about 4.5) produce ion pairs which are of a polarity providing good octanol-water partitioning of the ion pair, and hence partitioning of substituted 3-(1-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient, into octanol versus water. As discussed above, such partitioning into octanol is predictive of favorable oral availability.

[0188] In some embodiments, the organic acid for ion pairing has a log P value from about 3.0 to about 8.0, about 10.0, or even 12.0. In some embodiments, the presence of certain solvents or solubilizing agents (e.g., inclusion in the treatment composition of glycerin or propylene glycol) may be beneficial in solubilizing organic acids and the corresponding salts or ion pairs thereof for highly lipophilic organic acids (e.g., higher than about 4.5).

[0189] In some embodiments, the organic acid is a carboxylic acid or a sulfonic acid. The carboxylic acid or sulfonic acid functional group may be attached to any alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group having, for example, from one to twenty carbon atoms (C1-C20). In some embodiments, the organic acid is an alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl carboxylic or sulfonic acid.

[0190] As used herein, “alkyl” refers to any straight chain or branched chain hydrocarbon. The alkyl group may be saturated (i.e., having all sp3 carbon atoms), or may be unsaturated (i.e., having at least one site of unsaturation). As used herein, the term “unsaturated” refers to the presence of a carbon-carbon, sp2 double bond in one or more positions within the alkyl group. Unsaturated alkyl groups may be mono- 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. An alkyl group can be unsubstituted or substituted.

[0191] “Cycloalkyl” as used herein refers to a carbocyclic group, which may be mono- or bicyclic. Cycloalkyl groups include rings having 3 to 7 carbon atoms as a monocycle or 7 to 12 carbon atoms as a bicycle. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. A cycloalkyl group can be unsubstituted or substituted, and may include one or more sites of unsaturation (e.g., cyclopentenyl or cyclohexenyl).

[0192] 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. An aryl group can be unsubstituted or substituted.

[0193] “Heteroaryl” and “heterocycloalkyl” as used herein refer to an aromatic or non-aromatic ring system, respectively, in which one or more ring atoms is a heteroatom, e.g., nitrogen, oxygen, and sulfur. The heteroaryl or heterocycloalkyl group comprises up to 20 carbon atoms and from 1 to 3 heteroatoms selected from N, O, and S. A heteroaryl or heterocycloalkyl may be a monocycle having 3 to 7 ring members (for example, 2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, and S) or a bicycle having 7 to 10 ring members (for example, 4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, and S), for example: a bicyclo[4,5], [5,5], [5,6], or [6,6] system. Examples of heteroaryl groups include by way of example and not limitation, pyridyl, thiazolyl, tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, benzotriazolyl, benzisoxazolyl, and isatinoyl. Examples of heterocycloalkyls include by way of example and not limitation, dihydroypyridyl, tetrahydropyridyl (piperidyl), tetrahydrothiophenyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, tetrahydrofuranyl, tetrahydropyranyl, bis-tetrahydropyranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, piperazinyl, quinuclidinyl, and morpholinyl. Heteroaryl and heterocycloalkyl groups can be unsubstituted or substituted.

[0194] “Substituted” as used herein and as applied to any of the above alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, 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, —OCH3, —NH2, —NHCH3, —N(CH3)2, —CN, —NC(═O)CH3, —C(═O)—, —C(═O)NH2, and —C(═O)N(CH3)2. Wherever a group is described as “optionally substituted,” that group can be substituted with one or more of the above substituents, independently selected for each occasion. In some embodiments, the substituent may be one or more methyl groups or one or more hydroxyl groups.

[0195] In some embodiments, the organic acid for ion pairing 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.

[0196] In some embodiments, the organic acid for ion pairing is an alkyl sulfonic acid. Non-limiting examples of alkyl sulfonic acids include propanesulfonic acid, heptanesulfonic acid, and octanesulfonic acid.

[0197] 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.

[0198] In some embodiments, an organic acid for ion pairing may include more than one carboxylic acid group or more than one sulfonic acid group (e.g., two, three, or more carboxylic acid groups). Non-limiting examples include oxalic acid, fumaric acid, maleic acid, and glutaric acid. In organic acids containing multiple carboxylic acids (e.g., from 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 or dimethyl citrate, and the like.

[0199] In some embodiments, the organic acid for ion pairing may include 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.

[0200] In some embodiments, the organic acid for ion pairing is an aryl carboxylic acid or an aryl sulfonic acid. Non-limiting examples of aryl carboxylic and sulfonic acids include benzoic acid, toluic acids, salicylic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

[0201] Further non-limiting examples of organic acids which may be useful for ion pairing in certain embodiments include 2-(4-isobutylphenyl)propanoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, adipic acid, ascorbic acid (L), aspartic acid (L), alpha-methylbutyric acid, camphoric acid (+), camphor-10-sulfonic acid (+), cinnamic acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, furoic acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, isovaleric acid, lactobionic acid, lauric acid, levulinic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, oleic acid, palmitic acid, pamoic acid, phenylacetic acid, pyroglutamic acid, pyruvic acid, sebacic acid, stearic acid, and undecylenic acid. Examples of suitable acids for ion pairing include, but are not limited to, the list of organic acids in Table 1.TABLE 1Non-limiting examples of suitable organic acids for ion pairingAcid Namelog(P)*benzoic acid1.9phenylacetic1.4p-toluic acid2.3ethyl benzoic acid2.9isopropyl benzoic acid3.54-phenylbutyric2.42-(4-isobutylphenyl)propanoic acid3.52-napthoxyacetic acid2.5napthylacetic acid2.7heptanoic acid2.5octanoic acid3.05nonanoic acid3.5decanoic acid4.099-deceneoic acid3.32-deceneoic acid3.810-undecenoic acid3.9dodecandioic acid3.2dodecanoic acid4.6myristic acid5.3palmitic acid6.4stearic acid7.6cyclohexanebutanoic acid3.41-heptanesulfonic acid2.01-octanesulfonic acid2.51-nonanesulfonic acid3.1monooctyl succinate2.8tocopherol succinate10.2monomenthyl succinate3monomenthyl glutarate3.4norbixin ((2E,4E,6E,8E,10E,12E,14E,16E,18E)-4,8,13,17-7.2tetramethylicosa-2,4,6,8,10,12,14,16,18-nonaenedioicacid)bixin ((2E,4E,6E,8E,10E,12E,14E,16Z,18E)-20-methoxy-7.54,8,13,17-tetramethyl-20-oxoicosa-2,4,6,8,10,12,14,16,18-nonaenoic acid)*Values obtained from PubChem or calculated

[0202] The selection of organic acid for ion pairing may further depend on additional properties in addition to consideration of the log P value. For example, an organic acid should be one recognized as safe for human consumption, and which has acceptable flavor, odor, volatility, stability, and the like. Determination of appropriate organic acids is within the purview of one of skill in the art.

[0203] In some embodiments, the organic acid for ion pairing is a mono ester of a dicarboxylic acid or a poly-carboxylic acid. In some embodiments, the dicarboxylic acid is malonic acid, succinic acid, glutaric acid, adipic acid, fumaric acid, maleic acid, or a combination thereof. In some embodiments, the dicarboxylic acid is succinic acid, glutaric acid, fumaric acid, maleic acid, or a combination thereof. In some embodiments, the dicarboxylic acid is succinic acid, glutaric acid, or a combination thereof.

[0204] In some embodiments, the alcohol forming the mono ester of the dicarboxylic acid is a lipophilic alcohol. Examples of suitable lipophilic alcohols include, but are not limited to, octanol, menthol, and tocopherol. In some embodiments, the organic acid is an octyl mono ester of a dicarboxylic acid, such as monooctyl succinate, monooctyl fumarate, or the like. In some embodiments, the organic acid is a monomenthyl ester of a dicarboxylic acid. Certain menthyl esters may be desirable in treated sheet materials and articles as described herein by virtue of the cooling sensation they may provide upon use of the product comprising the composition. In some embodiments, the organic acid is monomenthyl succinate, monomenthyl fumarate, monomenthyl glutarate, or a combination thereof. In some embodiments, the organic acid is a monotocopheryl ester of a dicarboxylic acid. Certain tocopheryl esters may be desirable in treated sheet materials and articles as described herein by virtue of the antioxidant effects they may provide. In some embodiments, the organic acid is tocopheryl succinate, tocopheryl fumarate, tocopheryl glutarate, or a combination thereof.

[0205] In some embodiments, the organic acid for ion pairing is a carotenoid derivative having one or more carboxylic acids. Carotenoids are tetraterpenes, meaning that they are produced from 8 isoprene molecules and contain 40 carbon atoms. Accordingly, they are usually lipophilic due to the presence of long unsaturated aliphatic chains, and are generally yellow, orange, or red in color. Certain carotenoid derivatives can be advantageous in in the disclosed treated sheet materials and articles by virtue of providing both ion pairing and serving as a colorant in the materials and articles. In some embodiments, the organic acid is 2E,4E,6E,8E,10E,12E,14E,16Z,18E)-20-methoxy-4,8,13,17-tetramethyl-20-oxoicosa-2,4,6,8,10,12,14,16,18-nonaenoic acid (bixin) or an isomer thereof. Bixin is an apocarotenoid found in annatto seeds from the achiote tree (Bixa orellana) and is the naturally occurring pigment providing the reddish orange color to annatto. Bixin is soluble in fats and alcohols but insoluble in water, and is chemically unstable when isolated, converting via isomerization into the double bond isomer, trans-bixin (β-bixin), having the structure:

[0206] In some embodiments, the organic acid for ion pairing is (2E,4E,6E,8E,10E,12E,14E,16E,18E)-4,8,13,17-tetramethylicosa-2,4,6,8,10,12,14,16,18-nonaenedioic acid (norbixin), a water-soluble hydrolysis product of bixin having the structure:

[0207] In some embodiments, more than one organic acid for ion pairing may be present. For example, the treatment composition may comprise two, or three, or four, or more organic acids for ion pairing. Accordingly, reference herein to “an organic acid” contemplates mixtures of two or more organic acids. The relative amounts of the multiple organic acids may vary. For example, a treatment composition may comprise equal amounts of two, or three, or more organic acids, or may comprise different relative amounts. In this manner, it is possible to include certain organic acids (e.g., citric acid or myristic acid) which have a log P value outside the desired range, when combined with other organic acids to provide the desired average log P range for the combination. In some embodiments, it may be desirable to include organic acids in the treatment composition for ion pairing which have log P values outside the desired range for purposes such as, but not limited to, providing desirable organoleptic properties, stability, as flavor components, and the like. Further, certain lipophilic organic acids have undesirable flavor and or aroma characteristics which would preclude their presence as the sole organic acid (e.g., in equimolar or greater quantities relative to nicotine). Without wishing to be bound by theory, it is believed that a combination 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 which would be found objectionable from a sensory perspective.

[0208] In some embodiments, the treatment composition comprises an organic acid for ion pairing which is a monoester of a dicarboxylic acid or is a carotenoid derivative having one or more carboxylic acids as described herein above, and further comprises an additional organic acid or salt thereof. In some embodiments, the additional organic acid is benzoic acid, an alkali metal salt thereof, or a combination thereof.

[0209] In some embodiments, the treatment 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 treatment composition comprises an organic acid and a sodium salt of the organic acid.

[0210] In some embodiments, the molar ratio of the organic acid to the sodium salt (or other alkali metal) of the organic acid is from about 0.1 to about 10, such as from 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 an organic acid and the sodium salt thereof are added to the other components of the composition, wherein the organic acid is added in excess of the sodium salt, in equimolar quantities with the sodium salt, or as a fraction of the sodium salt. One of skill in the art will recognize that the relative amounts will be determined by the desired pH of the composition, as well as the desired ionic strength. For example, the organic acid may be added in a quantity to provide a desired pH level of the composition, while the alkali metal (e.g., sodium) salt is added in a quantity to provide the desired extent of ion pairing. As one of skill in the art will understand, the quantity of organic acid (i.e., the protonated form) present in the composition, relative to the alkali metal salt or conjugate base form present in the composition, will vary according to the pH of the composition and the pKa of the organic acid, as well as according to the actual relative quantities initially added to the treatment composition.

[0211] The amount of organic acid or alkali metal salt thereof present in the composition, relative to the substituted 3-(1-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine (e.g., 2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine), or other active ingredient, may vary. Generally, as the concentration of the organic acid (or the conjugate base thereof) increases, the percent of substituted 3-(1-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient that is ion paired with the organic acid increases. This typically increases the partitioning of the substituted 3-(1-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient in the form of an ion pair, into octanol versus water as measured by the log P (the log10 of the partitioning coefficient). In some embodiments, the treatment composition comprises from about 0.05, about 0.1, about 1, about 1.5, about 2, or about 5, to about 10, about 15, or about 20 molar equivalents of the organic acid, the alkali metal salt thereof, or the combination thereof, relative to the substituted 3-(1-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient, calculated as the free base of the substituted 3-(1-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient.

[0212] In some embodiments, the treatment composition comprises from about 2 to about 10, or from about 2 to about 5 molar equivalents of the organic acid, the alkali metal salt thereof, or the combination thereof, relative to the substituted 3-(1-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient on a free-base basis. In some embodiments, the organic acid, the alkali metal salt thereof, or the combination thereof, is present in a molar ratio with the substituted 3-(1-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient from about 2, about 3, about 4, or about 5, to about 6, about 7, about 8, about 9, or about 10. In embodiments wherein more than one organic acid, alkali metal salt thereof, or both, are present, it is to be understood that such molar ratios reflect the totality of the organic acids present. In some embodiments, the treatment composition comprises benzoic acid and sodium benzoate wherein a total amount of benzoate (i.e., benzoic acid and benzoate) is in a molar ratio in a range from about 3 to about 5 relative to the substituted 3-(1-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient. In some embodiments, the molar ratio of the total amount of benzoate to the substituted 3-(1-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient is about 3.2 or about 4.8.

[0213] In some embodiments, the organic acid inclusion is sufficient to provide a composition pH of from about 4.0 to about 9.0, such as from about 4.5 to about 7.0, or from about 5.5 to about 7.0, from about 4.0 to about 5.5, or from about 7.0 to about 9.0. Reference herein to “a composition pH” means the pH of an aqueous solution of the treatment composition prepared by dissolving or suspending 5 grams of treatment composition in 95 grams of water and measuring the pH of the resulting solution with a calibrated pH meter.

[0214] In some embodiments, the organic acid inclusion is sufficient to provide a composition pH of from about 4.5 to about 6.5, for example, from about 4.5, about 5.0, or about 5.5, to about 6.0, or about 6.5. In some embodiments, the desired composition pH is from about 4.5 to about 6.5, and the organic acid is provided in a quantity sufficient to provide such a pH. In some embodiments, the organic acid is provided in a quantity sufficient to provide a pH of the composition of from about 5.5 to about 6.5, for example, from about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, or about 6.0, to about 6.1, about 6.2, about 6.3, about 6.4, or about 6.5.

[0215] In some embodiments, a mineral acid (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, or the like), alone or in combination with an organic acid, is added to adjust the pH of the composition to the desired value. In some embodiments, a buffer (e.g., a buffer as described herein below) is added to the composition to the desired value, and / or to maintain the pH of the composition at the desired value.

[0216] In some embodiments, the oral composition further comprises a solubility enhancer to increase the solubility of one or more of the organic acid or salt thereof. Suitable solubility enhancers include, but are not limited to, humectants as described herein, such as glycerol or propylene glycol.Additional (Optional) Active Agents

[0217] In some embodiments, the treated sheet material, article, or both comprise one or more active agents in addition to (or in lieu of) the substituted 3-(1-methylpyrrolidin-2-yl)pyridine (and in place of, or in addition to the “other” optional active agents referenced above). The additional active agent may be a physiologically active material, which is a material intended to achieve or enhance a physiological response. The active agent may for example be selected from nutraceuticals, nootropics, psychoactives. The active agent may be naturally occurring or synthetically obtained. The active agent may comprise for example nicotine, caffeine, taurine, theanine, vitamins such as B6 or B12 or C, melatonin, cannabinoids, or constituents, derivatives, or combinations thereof. The active agent may comprise one or more constituents, derivatives or extracts of cannabis or another botanical (other than tobacco).Nicotine

[0218] In some embodiments, the treated sheet material and / or the article comprises nicotine as an active agent. In some embodiments, this nicotine may be derived from a botanical extract included in the sheet material and / or the sheet article. In other embodiments, the nicotine is an additional active substance. In some embodiments, the treated sheet material and / or article has a nicotine content of from about 1.5 wt % to about 7 wt % of the treatment composition of the treated sheet material and / or article.

[0219] In some embodiments, the treatment composition associated with the treated sheet material and / or article may comprise from at least about 1.5 wt %, about 2 wt %, about 2.5 wt %, about 3 wt %, about 3.5 wt %, about 4 wt %, about 4.5 wt % or about 5 wt % of nicotine on a dry weight basis. The treatment composition may comprise no more than about 7 wt %, about 6.5 wt %, about 6 wt %, about 5.5 wt %, about 5 wt %, about 4.5 wt %, about 4 wt %, about 3.5 wt % or about 3 wt % of nicotine on a dry weight basis. For example, the treatment composition associated with the treated sheet material and / or article may comprise from about 2 to about 6 wt %, or from about 4 to about 5 wt % nicotine by weight on a dry weight basis.

[0220] In some embodiments, the treatment composition associated with the treated sheet material and / or article comprises from about 1 wt %, about 1.5 wt % or about 2 wt % to about 6 wt %, about 5 wt %, about 4 wt % or about 3 wt % of nicotine on a dry weight basis.

[0221] In some embodiments, the treated sheet material and / or article of the disclosure as a whole can be completely free or substantially free of nicotine (3-(1-methylpyrrolidin-2-yl)pyridine). By “substantially free” it is meant that no nicotine has been intentionally added, beyond trace amounts that may be present e.g., as an impurity in another component, including as a minor impurity in the substituted 3-(1-methylpyrrolidin-2-yl)pyridine. Cannabinoid

[0222] In some embodiments, the optional additional active agent comprises one or more cannabinoids. As used herein, the term “cannabinoid” refers to a class of diverse natural or synthetic chemical compounds that acts on cannabinoid receptors (e.g., CB1 and CB2) in cells that alter neurotransmitter release in the brain. Cannabinoids are cyclic molecules exhibiting particular properties such as the ability to easily cross the blood-brain barrier. Cannabinoids may be naturally occurring (Phytocannabinoids) from plants such as cannabis, (endocannabinoids) from animals, or artificially manufactured (synthetic cannabinoids).

[0223] Cannabis species express at least 85 different phytocannabinoids, and these may be divided into subclasses, including cannabigerols, cannabichromenes, cannabidiols, tetrahydrocannabinols, cannabinols and cannabinodiols, and other cannabinoids, such as cannabigerol (CBG), cannabichromene (CBC), cannabidiol (CBD), tetrahydrocannabinol (THC), cannabinol (CBN) and cannabinodiol (CBDL), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), cannabinerolic acid, cannabidiolic acid (CBDA), Cannabinol propyl variant (CBNV), cannabitriol (CBO), tetrahydrocannabmolic acid (THCA), and tetrahydrocannabivarinic acid (THCV A).

[0224] In some embodiments, the cannabinoid is selected from the group consisting of cannabigerol (CBG), cannabichromene (CBC), cannabidiol (CBD), tetrahydrocannabinol (THC), cannabinol (CBN) and cannabinodiol (CBDL), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), cannabinerolic acid, cannabidiolic acid (CBDA), Cannabinol propyl variant (CBNV), cannabitriol (CBO), tetrahydrocannabmolic acid (THCA), tetrahydrocannabivarinic acid (THCV A), and mixtures thereof.

[0225] In certain embodiments, the cannabinoid is selected from tetrahydrocannabinol (THC), the primary psychoactive compound in cannabis, and cannabidiol (CBD), another major constituent of the plant, but which is devoid of psychoactivity. All of the above compounds can be used in the form of an isolate from plant material or synthetically derived. Certain cannabinoids, including but not limited to CBD and THC, may exist in more than one isomeric form, for example Δ8- and Δ9-THC. Such isomeric forms may be naturally occurring or may be synthetic. For avoidance of doubt, reference within the present disclosure to a “cannabinoid” is intended to be inclusive of any and all isomeric forms thereof.

[0226] In some embodiments, the cannabinoid comprises at least tetrahydrocannabinol (THC). In some embodiments, the cannabinoid is tetrahydrocannabinol (THC). In some embodiments, the THC is Δ8-THC. In some embodiments, the THC is Δ9-THC.

[0227] In some embodiments, the cannabinoid comprises at least cannabidiol (CBD). In some embodiments, the cannabinoid is cannabidiol (CBD). In some embodiments, the CBD is synthetic CBD. In some embodiments, the CBD is Δ8-CBD. In some embodiments, the CBD is Δ9-CBD.

[0228] In some embodiments, a cannabinoid (e.g., CBD) is incorporated within a treated sheet material in the form of an isolate. An isolate is an extract from a plant, such as cannabis, where the active material of interest (in this case the cannabinoid, such as CBD) is present in a high degree of purity, for example greater than 95%, greater than 96%, greater than 97%, greater than 98%, or around 99% purity.

[0229] In some embodiments, the cannabinoid is an isolate of CBD in a high degree of purity, and the amount of any other cannabinoid in the treatment composition associated with the disclosed treated sheet material and / or article is no greater than about 1% by weight on a dry weight basis, such as no greater than about 0.5% by weight, no greater than about 0.1% by weight, or no greater than about 0.01% by weight, based on the weight of the treatment composition associated with the treated sheet material and / or article on a dry weight basis.

[0230] The choice of cannabinoid and the particular percentages thereof which may be present within the treated sheet material and / or article will vary depending upon the desired characteristics of the material.

[0231] In some embodiments, the cannabinoid (such as CBD) is present in the sheet material and / or the sheet article in a concentration of at least about 0.001% by weight of the sheet material and / or the sheet article, such as in a range from about 0.001% to about 2% by weight of the treated sheet material and / or article. In some embodiments, the cannabinoid (such as CBD) is present in the treated sheet material and / or article in a concentration of from about 0.1% to about 1.5% by weight, based on the total weight of the treatment composition associated with the treated sheet material. In some embodiments, the cannabinoid (such as CBD) is present in a concentration from about 0.4% to about 1.5% by weight, based on the total weight of the treatment composition associated with the sheet material and / or article.

[0232] Alternatively, or in addition to a cannabinoid, the active agent may include a cannabimimetic, which is a class of compounds derived from plants other than cannabis that have biological effects on the endocannabinoid system similar to cannabinoids. Examples include yangonin, alpha-amyrin or beta-amyrin (also classified as terpenes), cyanidin, curcumin (tumeric), catechin, quercetin, salvinorin A, N-acylethanolamines, and N-alkylamide lipids. Such compounds can be used in the same amounts and ratios noted herein for cannabinoids.Terpenes

[0233] Active agents suitable for use in the treated sheet materials and articles can also be classified as terpenes, many of which are associated with biological effects, such as calming effects. Terpenes are understood to have the general formula of (C5H8)n and include monoterpenes, sesquiterpenes, and diterpenes. Terpenes can be acyclic, monocyclic or bicyclic in structure. Some terpenes provide an entourage effect when used in combination with cannabinoids or cannabimimetics. Examples include beta-caryophyllene, linalool, limonene, beta-citronellol, linalyl acetate, pinene (alpha or beta), geraniol, carvone, eucalyptol, menthone, iso-menthone, piperitone, myrcene, beta-bourbonene, and germacrene, which may be used singly or in combination.

[0234] In some embodiments, the terpene is a terpene derivable from a phytocannabinoid producing plant, such as a plant from the stain of the Cannabis sativa species, such as hemp. Suitable terpenes in this regard include so-called “C10” terpenes, which are those terpenes comprising 10 carbon atoms, and so-called “C15” terpenes, which are those terpenes comprising 15 carbon atoms. In some embodiments, the active agent comprises more than one terpene. For example, the active agent may comprise one, two, three, four, five, six, seven, eight, nine, ten or more terpenes as defined herein. In some embodiments, the terpene is selected from pinene (alpha and beta), geraniol, linalool, limonene, carvone, eucalyptol, menthone, iso-menthone, piperitone, myrcene, beta-bourbonene, germacrene and mixtures thereof.

[0235] Terpenes and / or cannabinoids may be present as an active agent and / or as a flavorant. The amount of terpene and / or cannabinoid present may vary accordingly based on their intended purpose.

[0236] In some embodiments, the active agent comprises caffeine, melatonin, an amino acid, a vitamin, or combinations thereof. In some embodiments, the active agent comprises taurine, theanine, vitamin B6, B12, or C, melatonin, cannabinoids, or constituents, derivatives, or combinations thereof.Botanical

[0237] In some embodiments, the active ingredient comprises a botanical ingredient. As used herein, the term “botanical ingredient” or “botanical” refers to any plant material or fungal-derived material, including plant material in its natural form and plant material derived from natural plant materials, such as extracts or isolates from plant materials or treated plant materials (e.g., plant materials subjected to heat treatment, fermentation, bleaching, or other treatment processes capable of altering the physical and / or chemical nature of the material). For the purposes of the present disclosure, a “botanical” includes, but is 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 characteristics (e.g., teas or tisanes). Reference to botanical material as “non-tobacco” is intended to exclude tobacco materials (i.e., does not include any Nicotiana species). In some embodiments, the materials and / or articles as disclosed herein can be characterized as free of any tobacco material (e.g., any embodiment as disclosed herein may be completely or substantially free of any tobacco material). By “substantially free” is meant that no tobacco material has been intentionally added. For example, some embodiments can be characterized as having less than 0.001% by weight of tobacco, or less than 0.0001%, or even 0% by weight of tobacco (exclusive of any nicotine content, if present).

[0238] In some embodiments, the treated sheet material and / or article comprises a botanical in an amount from about 0.01% w / w to about 10% by weight, such as, e.g., from 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 weight of the treatment composition associated with the treated sheet material on a dry weight basis.

[0239] In some embodiments, the treated sheet material and / or article comprises one or more botanical materials in the form of one or more botanical extracts. In some embodiments, the botanical extract is a liquid or solid that has been isolated from a botanical material. The botanical materials used in the present disclosure may comprise, without limitation, any of the compounds and sources set forth herein, including mixtures thereof. Certain botanical materials of this type are sometimes referred to as dietary supplements, nutraceuticals, “phytochemicals” or “functional foods.” Certain botanicals, as the plant material or an extract thereof, have found use in traditional herbal medicine, and are described further herein.

[0240] Non-limiting examples of botanicals or botanical-derived materials include acai berry (Euterpe oleracea martius), acerola (Malpighia glabra), alfalfa, allspice, Angelica root, anise (e.g., star anise), annatto seed, apple (Malus domestica), apricot oil, ashwagandha, Bacopa monniera, baobab, basil (Ocimum basilicum), bay, bee balm, beet root, bergamot, blackberry (Morus nigra), black cohosh, black pepper, black tea, blueberries, boldo (Peumus boldus), borage, bugleweed, cacao, calamus root, camu (Myrciaria dubia), cannabis / hemp, caraway seed, cardamom, cassis, catnip, catuaba, cayenne pepper, Centella asiatica, chaga mushroom, Chai-hu, chamomile, cherry, chervil, chive, chlorophyll, chocolate, cilantro, cinnamon (Cinnamomum cassia), citron grass (Cymbopogon citratus), citrus, clary sage, cloves, coconut (Cocos nucifera), coffee, comfrey leaf and root, cordyceps, coriander seed, cranberry, cumin, curcumin, damiana, dandelion, Dorstenia arifolia, Dorstenia odorata, Echinacea, elderberry, elderflower, endro (Anethum graveolens), evening primrose, eucalyptus, fennel, feverfew, flax, Galphimia glauca, garlic, ginger (Zingiber officinale), gingko biloba, ginseng, goji berries, goldenseal, grape seed, grapefruit, grapefruit rosé (Citrus paradisi), graviola (Annona muricata), green tea, guarana, gutu kola, hawthorn, hazel, hemp, hibiscus flower (Hibiscus sabdariffa), honeybush, hops, jiaogulan, jambu (Spilanthes oleraceae), jasmine (Jasminum officinale), juniper berry (Juniperus communis), Kaempferia parviflora (Thai ginseng), kava, laurel, lavender, lemon (Citrus limon), lemon balm, lemongrass, licorice, lilac, Lion's mane, lutein, maca (Lepidium meyenii), mace, marjoram, matcha, milk thistle, mints (menthe), mulberry, Nardostachys chinensis, nutmeg, olive, oolong tea, orange (Citrus sinensis), oregano, papaya, paprika, pennyroyal, peppermint (Mentha piperita), pimento, potato peel, primrose, quercetin, quince, red clover, resveratrol, Rhizoma gastrodiae, Rhodiola, rooibos (red or green), rosehip (Rosa canina), rosemary, saffron, sage, Saint John's Wort, sandalwood, salvia (Salvia officinalis), savory, saw palmetto, Sceletium tortuosum, Schisandra, Silybum marianum, Skullcap, spearmint, Spikenard, spirulina, slippery elm bark, sorghum bran hi-tannin, sorghum grain hi-tannin, spearmint (Mentha spicata), spirulina, star anise, sumac bran, tarragon, thyme, tisanes, turmeric, Turnera aphrodisiaca, uva ursi, valerian, vanilla, Viola odorata, white mulberry, wild yam root, wintergreen, withania somnifera, yacon root, yellow dock, yerba mate, and yerba santa.

[0241] In some embodiments, the additional active agent comprises lemon balm. Lemon balm (Melissa officinalis) is a mildly lemon-scented herb from the same family as mint (Lamiaceae). The herb is native to Europe, North Africa, and West Asia. The tea of lemon balm, as well as the essential oil and the extract, are used in traditional and alternative medicine. In some embodiments, the active ingredient comprises lemon balm extract. In some embodiments, the lemon balm extract is present in an amount of from about 1 to about 4% by weight, based on the weight of the treatment composition associated with the treated sheet material on a dry weight basis.

[0242] In some embodiments, the optional additional active agent comprises ginseng. Ginseng is the root of plants of the genus Panax, which are characterized by the presence of unique steroid saponin phytochemicals (ginsenosides) and gintonin. Ginseng finds use as a dietary supplement in energy drinks or herbal teas, and in traditional medicine. Cultivated species include Korean ginseng (P. ginseng), South China ginseng (P. notoginseng), and American ginseng (P. quinquefolius). American ginseng and Korean ginseng vary in the type and quantity of various ginsenosides present. In some embodiments, the ginseng is American ginseng or Korean ginseng. In some embodiments, the active ingredient comprises Korean ginseng. In some embodiments, ginseng is present in an amount of from about 0.4 to about 0.6% by weight, based on the weight of the treatment composition associated with the treated sheet material on a dry weight basis.

[0243] In some embodiments, the botanical extract is selected from eucalyptus, star anise, cocoa and hemp. In some embodiments, the botanical extract is selected from rooibos and fennel.

[0244] A botanical extract may be prepared by processing techniques such as expression (such as juicing or pressing) or solvent extraction. Optionally, the extract is concentrated and / or purified, for example by distillation. In some embodiments, the botanical material is macerated, frequently without heating, to soften and degrade the material prior to extraction. In some embodiments, the botanical extract is an aqueous extract, obtained by extraction with water. Additionally or alternatively, other solvents may be used, including supercritical fluids.

[0245] In some embodiments, the botanical extract is a tobacco extract. In some embodiments, the tobacco extract may be an aqueous extract, obtained by extraction with water. The tobacco extract may be an extract from any suitable tobacco, such as single grades or blends, cut rag or whole leaf, including Virginia and / or Burley and / or Oriental. It may also be an extract from tobacco particle ‘fines’ or dust, expanded tobacco, stems, expanded stems, and other processed stem materials, such as cut rolled stems. The extract may be obtained from a ground tobacco or a reconstituted tobacco material.Stimulant

[0246] In some embodiments, the optional additional active agent comprises one or more stimulants. As used herein, the term “stimulant” refers to a material that increases activity of the central nervous system and / or the body, for example, enhancing focus, cognition, vigor, mood, alertness, and the like. Non-limiting examples of stimulants include caffeine, theacrine, theobromine, and theophylline. Theacrine (1,3,7,9-tetramethyluric acid) is a purine alkaloid which is structurally related to caffeine, and possesses stimulant, analgesic, and anti-inflammatory effects. Present stimulants may be natural, naturally derived, or wholly synthetic. For example, certain botanical materials (guarana, tea, coffee, cocoa, and the like) may possess a stimulant effect by virtue of the presence of e.g., caffeine or related alkaloids, and accordingly are “natural” stimulants. By “naturally derived” is meant the stimulant (e.g., caffeine, theacrine) is in a purified form, outside its natural (e.g., botanical) matrix. For example, caffeine can be obtained by extraction and purification from botanical sources (e.g., tea). By “wholly synthetic”, it is meant that the stimulant has been obtained by chemical synthesis. In some embodiments, the active agent comprises caffeine. In some embodiments, the caffeine is present in an encapsulated form. On example of an encapsulated caffeine is Vitashure®, available from Balchem Corp., 52 Sunrise Park Road, New Hampton, NY, 10958.

[0247] When present, a stimulant or combination of stimulants (e.g., caffeine, theacrine, and combinations thereof) is typically at a concentration of from about 0.1% w / w to about 15% by weight, such as, e.g., from 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 weight of the treatment composition associated with the treated sheet material on a dry weight basis. In some embodiments, the sheet material and / or article comprises caffeine in an amount of from about 1.5 to about 6% by weight, based on the weight of the treatment composition associated with the treated sheet material on a dry weight basis.Amino Acids

[0248] In some embodiments, the optional additional active agent comprises an amino acid. As used herein, the term “amino acid” refers to an organic compound that contains amine (—NH2) and carboxyl (—COOH) or sulfonic acid (SO3H) functional groups, along with a side chain (R group), which is specific to each amino acid. Amino acids may be proteinogenic or non-proteinogenic. By “proteinogenic” is meant that the amino acid is one of the twenty naturally occurring amino acids found in proteins. The 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. By “non-proteinogenic” is meant that either the amino acid is not found naturally in protein or is not directly produced by cellular machinery (e.g., is the product of post-translational modification). Non-limiting examples of non-proteinogenic amino acids include gamma-aminobutyric acid (GABA), taurine (2-aminoethanesulfonic acid), theanine (L-y-glutamylethylamide), hydroxyproline, and beta-alanine. In some embodiments, the active ingredient comprises theanine. In some embodiments, the active ingredient comprises GABA. In some embodiments, the active ingredient comprises a combination of theanine and GABA. In some embodiments, the active ingredient is a combination of theanine, GABA, and lemon balm. In some embodiments, the active ingredient is a combination of caffeine, theanine, and ginseng. In some embodiments, the active ingredient comprises taurine. In some embodiments, the active ingredient is a combination of caffeine and taurine.

[0249] When present, an amino acid or combination of amino acids (e.g., theanine, GABA, and combinations thereof) is typically at a concentration of from about 0.1% w / w to about 15% by weight, such as, e.g., from 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 weight of the treatment composition associated with the treated sheet material on a dry weight basis.Vitamin and / or Mineral

[0250] In some embodiments, the additional active agent comprises a vitamin or combination of vitamins. As used herein, the term “vitamin” refers to an organic molecule (or related set of molecules) that is an essential micronutrient needed for the proper functioning of metabolism in a mammal. There are thirteen vitamins required by human metabolism, which are: vitamin A (as all-trans-retinol, all-trans-retinyl-esters, as well as 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 (cobalamins), vitamin C (ascorbic acid), vitamin D (calciferols), vitamin E (tocopherols and tocotrienols), and vitamin K (quinones). In some embodiments, the active ingredient comprises vitamin C. In some embodiments, the active ingredient is a combination of vitamin C, caffeine, and taurine. In some embodiments, the active ingredient comprises one or more of vitamin B6 and B12. In some embodiments, the active ingredient comprises theanine and one or more of vitamin B6 and B12.

[0251] In some embodiments, the optional additional active agent comprises vitamin A. In some embodiments, the vitamin A is encapsulated. In some embodiments, the active agent comprises vitamin B6, vitamin B12, vitamin E, vitamin C, or a combination thereof.

[0252] In some embodiments, the optional additional active agent comprises a mineral. As used herein, the term “mineral” refers to an inorganic molecule (or related set of molecules) that is an essential micronutrient needed for the proper functioning of various systems in a mammal. Non-limiting examples of minerals include iron, zinc, copper, selenium, chromium, cobalt, manganese, calcium, phosphorus, sulfur, magnesium, and the like. In some embodiments, the active ingredient comprises iron. Suitable sources of iron include, but are not limited to, ferrous salts such as ferrous sulfate and ferrous gluconate. In some embodiments, the iron is encapsulated.

[0253] When present, a vitamin or mineral (or combinations thereof such as vitamin B6, vitamin B12, vitamin E, vitamin C, or a combination thereof) is typically at a concentration of from about 0.01% w / w to about 6% by weight, such as, e.g., from 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%, about 1%, about 2%, about 3%, about 4%, about 5%, or about 6% by weight, based on the weight of the treatment composition associated with the treated sheet material on a dry weight basis.Antioxidant

[0254] In some embodiments, the optional additional active agent comprises one or more antioxidants. As used herein, the term “antioxidant” refers to a substance which prevents or suppresses oxidation by terminating free radical reactions and may delay or prevent some types of cellular damage. Antioxidants may be naturally occurring or synthetic. Naturally occurring antioxidants include those found in foods and botanical materials. Non-limiting examples of antioxidants include certain botanical materials, vitamins, polyphenols, and phenol derivatives.

[0255] Examples of botanical materials which are associated with antioxidant characteristics include without limitation acai berry, alfalfa, allspice, annatto seed, apricot oil, basil, bee balm, wild bergamot, black pepper, blueberries, borage seed oil, bugleweed, cacao, calamus root, catnip, catuaba, cayenne pepper, chaga mushroom, chervil, cinnamon, dark chocolate, potato peel, grape seed, ginseng, gingko biloba, Saint John's Wort, saw palmetto, green tea, black tea, black cohosh, cayenne, chamomile, cloves, cocoa powder, cranberry, dandelion, grapefruit, honeybush, echinacea, garlic, evening primrose, feverfew, ginger, goldenseal, hawthorn, hibiscus flower, jiaogulan, kava, lavender, licorice, marjoram, milk thistle, mints (menthe), oolong tea, beet root, orange, oregano, papaya, pennyroyal, peppermint, red clover, rooibos (red or green), rosehip, rosemary, sage, clary sage, savory, spearmint, spirulina, slippery elm bark, sorghum bran hi-tannin, sorghum grain hi-tannin, sumac bran, comfrey leaf and root, goji berries, gutu kola, thyme, turmeric, uva ursi, valerian, wild yam root, wintergreen, yacon root, yellow dock, yerba mate, yerba santa, bacopa monniera, withania somnifera, Lion's mane, and Silybum marianum. Such botanical materials may be provided in fresh or dry form, essential oils, or may be in the form of an extracts. The botanical materials (as well as their extracts) often include compounds from various classes known to provide antioxidant effects, such as minerals, vitamins, isoflavones, phytoesterols, allyl sulfides, dithiolthiones, isothiocyanates, indoles, lignans, flavonoids, polyphenols, and carotenoids. Examples of compounds found in botanical extracts or oils include ascorbic acid, peanut endocarb, resveratrol, sulforaphane, beta-carotene, lycopene, lutein, co-enzyme Q, carnitine, quercetin, kaempferol, and the like. See, e.g., Santhosh et al., Phytomedicine, 12(2005) 216-220, which is incorporated herein by reference.

[0256] Non-limiting examples of other suitable antioxidants include citric acid, Vitamin E or a derivative thereof, a tocopherol, epicatechol, epigallocatechol, epigallocatechol gallate, erythorbic acid, sodium erythorbate, 4-hexylresorcinol, theaflavin, theaflavin monogallate A or B, theaflavin digallate, phenolic acids, glycosides, quercitrin, isoquercitrin, hyperoside, polyphenols, catechols, resveratrols, oleuropein, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tertiary butylhydroquinone (TBHQ), and combinations thereof.

[0257] When present, an antioxidant is typically at a concentration of from about 0.001% w / w to about 10% by weight, such as, e.g., from 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 weight of the treatment composition associated with the treated sheet material on a dry weight basis.Pharmaceutical Ingredient

[0258] In some embodiments, the optional additional active agent 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, nitrate), neurotransmitters or precursors thereof (e.g., serotonin, 5-hydroxytryptophan, oxitriptan, acetylcholine, dopamine, melatonin), and nucleic acid sequences, having therapeutic, prophylactic, or diagnostic activity. Non-limiting examples of APIs include analgesics and antipyretics (e.g., acetylsalicylic acid, acetaminophen, 3-(4-isobutylphenyl)propanoic acid), phosphatidylserine, myoinositol, docosahexaenoic acid (DHA, Omega-3), arachidonic acid (AA, Omega-6), S-adenosylmethionine (SAM), beta-hydroxy-beta-methylbutyrate (HMB), citicoline (cytidine-5′-diphosphate-choline), and cotinine. In some embodiments, the active ingredient comprises citicoline. In some embodiments, the active ingredient is a combination of citicoline, caffeine, theanine, and ginseng. In some embodiments, the active ingredient comprises sunflower lecithin. In some embodiments, the active ingredient is a combination of sunflower lecithin, caffeine, theanine, and ginseng.

[0259] The amount of API may vary. For example, when present, an API is typically at a concentration of from about 0.001% w / w to about 10% by weight, such as, e.g., from 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 weight of the treatment composition associated with the treated sheet material on a dry weight basis.

[0260] In some embodiments, the material or article is substantially free of any API. By “substantially free of any API” means that the material or article does not contain, and specifically excludes, the presence of any API as defined herein, such as any Food and Drug Administration (FDA) approved therapeutic agent intended to treat any medical condition.Other Optional IngredientsFlavoring Agent

[0261] In some embodiments, the treated sheet material and / or article as described herein comprises a flavoring agent. As used herein, a “flavoring agent” or “flavorant” is any flavorful or aromatic substance capable of altering the sensory characteristics associated with the treated sheet material and / or article. Examples of sensory characteristics that can be modified by the flavoring agent include taste, mouthfeel, moistness, coolness / heat, and / or fragrance / aroma. Flavoring agents may be imitation, natural, or synthetic or blends thereof. The character of the flavors imparted thereby may be described, without limitation, as fresh, sweet, herbal, confectionary, floral, fruity, or spicy.

[0262] Flavoring agents may include naturally occurring flavor materials, botanicals, extracts of botanicals, synthetically obtained materials, or combinations thereof, e.g., tobacco, cannabis, licorice (liquorice), hydrangea, eugenol, Japanese white bark magnolia leaf, chamomile, fenugreek, clove, maple, matcha, menthol, Japanese mint, aniseed (anise), cinnamon, turmeric, Indian spices, Asian spices, herb, wintergreen, cherry, berry, red berry, cranberry, peach, apple, orange, mango, clementine, lemon, lime, tropical fruit, papaya, rhubarb, grape, durian, dragon fruit, cucumber, blueberry, mulberry, citrus fruits, Drambuie, bourbon, scotch, whiskey, gin, tequila, rum, spearmint, peppermint, lavender, aloe vera, cardamom, celery, cascarilla, nutmeg, sandalwood, bergamot, geranium, khat, naswar, betel, shisha, pine, honey essence, rose oil, vanilla, lemon oil, orange oil, orange blossom, cherry blossom, cassia, caraway, cognac, jasmine, ylang-ylang, sage, fennel, wasabi, piment, ginger, coriander, coffee, hemp, a mint oil from any species of the genus Mentha, eucalyptus, star anise, cocoa, lemongrass, rooibos, flax, Ginkgo biloba, hazel, hibiscus, laurel, mate, orange skin, rose, tea such as green tea or black tea, thyme, juniper, elderflower, basil, bay leaves, cumin, oregano, paprika, rosemary, saffron, lemon peel, mint, beefsteak plant, curcuma, cilantro, myrtle, cassis, valerian, pimento, mace, damien, marjoram, olive, lemon balm, lemon basil, chive, carvi, verbena, tarragon, limonene, thymol, camphene), flavor enhancers, bitterness receptor site blockers, sensorial receptor site activators or stimulators, sugars and / or sugar substitutes (e.g., sucralose, acesulfame potassium, aspartame, saccharine, cyclamates, lactose, sucrose, glucose, fructose, sorbitol, or mannitol), and other additives such as charcoal, chlorophyll, minerals, botanicals, or breath freshening agents.

[0263] 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 combinations thereof. See also, Leffingwell et al., Tobacco Flavoring for Smoking Products, R. J. Reynolds Tobacco Company (1972), which is incorporated herein by reference. Flavorings also may include components that are considered moistening, cooling or smoothening agents, such as eucalyptus. These flavors may be provided neat (i.e., alone) or in a composite and may be employed as concentrates or flavor packages (e.g., spearmint and menthol, orange and cinnamon, lime, pineapple, and the like). Representative types of components also are set forth in U.S. Pat. No. 5,387,416 to White et al.; US Pat. App. Pub. No. 2005 / 0244521 to Strickland et al.; and PCT Application Pub. No. WO 05 / 041699 to Quinter et al., each of which is incorporated herein by reference. In some instances, the flavoring agent may be provided in a spray-dried form or a liquid form.

[0264] The flavoring agent generally comprises at least one volatile flavor component. As used herein, “volatile” refers to a chemical substance that forms a vapor readily at ambient temperatures (i.e., a chemical substance that has a high vapor pressure at a given temperature relative to a nonvolatile substance). Typically, a volatile flavor component has a molecular weight below about 400 Da, and often include at least one carbon-carbon double bond, carbon-oxygen double bond, or both. In one embodiment, the at least one volatile flavor component comprises one or more alcohols, aldehydes, aromatic hydrocarbons, ketones, esters, terpenes, terpenoids, or a combination 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-cyclopentenone-1-one. Non-limiting examples of esters include allyl hexanoate, ethyl heptanoate, ethyl hexanoate, isoamyl acetate, and 3-methylbutyl acetate. Non-limiting examples of terpenes include sabinene, limonene, 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.

[0265] Flavorants may further include flavor enhancers, sensorial receptor site activators or stimulators, and trigeminal sensates, As used herein, “trigeminal sensate” refers to a flavoring agent which has an effect on the trigeminal nerve, producing sensations including heating, cooling, tingling, and the like. Non-limiting examples of trigeminal sensate flavoring agents include capsaicin, citric acid, menthol, Sichuan buttons, erythritol, and cubebol.

[0266] In some embodiments, the treated sheet material and / or article comprises a sensate which provides to the user of such article a cooling effect. Suitable cooling agents include, but are not limited to, menthane, menthone, menthone ketals, menthone glycerol ketals, substituted p-menthanes, acyclic carboxamides, monomenthyl glutarate, substituted cyclohexanamides, substituted cyclohexane carboxamides, substituted ureas and sulfonamides, substituted menthanols, hydroxymethyl and hydroxymethyl derivatives of p-menthane, 2-mercapto-cyclo-decanone, hydroxycarboxylic acids with 2-6 carbon atoms, cyclohexanamides, menthyl acetate, menthyl salicylate, N-ethyl-p-menthane-3-carboxamide (WS-3), ethyl ester of N-[[5-methyl-2-(1-methylethyl)cyclohexyl]carbonyl]glycine (WS-5), WS-14, N,2,3-trimethyl-2-isopropyl butanamide (WS-23), WS-27, WS-30, (−)-Menthyloxyethanol (Coolact® 5), WS-NA (FEMA 4693), WS-116 (FEMA 4603), N-ethyl-2,2-diisopropylbutanamide, isopulegol, menthyloxy propane diol, 3-(1-menthoxy)propane-1,2-diol, 3-(1-menthoxy)-2-methylpropane-1,2-diol, p-menthane-2,3-diol, p-menthane-3,8-diol, 6-isopropyl-9-methyl-1,4-dioxaspiro[4,5]decane-2-methanol, menthyl succinate and its alkaline earth metal salts, trimethylcyclohexanol, N-ethyl-2-isopropyl-5-methylcyclohexanecarboxamide, Japanese mint oil, peppermint oil, 3-(1-menthoxy)ethan-1-ol, 3-(1-menthoxy)propan-1-ol, 3-(1-menthoxy)butan-1-ol, 1-menthylacetic acid N-ethylamide, 1-menthyl-4-hydroxypentanoate, 1-menthyl-3-hydroxybutyrate, menthyl glutarate, N,2,3-trimethyl-2-(1-methylethyl)-butanamide, N-ethyl-trans-2-cis-6-nonadienamide, N,N-dimethyl menthyl succinamide, N-(2-hydroxyethyl)-2,3-dimethyl-2-isopropylbutanamide, substituted p-menthanes, substituted p-menthane-carboxamides, 2-isopropanyl-5-methylcyclohexanol, menthyl ethylene glycol carbonate, menthone glycerol ketals (e.g., menthone 1,2-glycerol ketal), menthone (S)-lactic acid ketal, menthyl acetoacetate, 3-1-menthoxypropane-1,2-diol, menthyl lactate, eucalyptus extract, menthol propylene glycol carbonate, menthol ethylene glycol carbonate, menthol glyceryl ether, N-tert-butyl-p-menthane-3-carboxamide, p-menthane-3-carboxylic acid glycerol ester, methyl-2-isopropyl-bicyclo[2.2.1]heptane-2-carboxamide, (1R,2S,5R)—N-(4-(carbamoylmethyl)phenyl)-menthylcarboxamide, 2-[2-(p-menthan-3-yloxy)ethoxy]ethanol, (1R,2R,4R)-1-(2-Hydroxy-4-methylcyclohexyl)ethenone, 2-(p-tolyloxy)-N-(1H-pyrazol-5-yl)-N-((thiophen-2-yl)methyl)acetamide, menthol methyl ether, menthyl pyrrolidone carboxylate, 2,5-dimethyl-4-(1-pyrrolidinyl)-3(2H)-furanone, cyclic a-keto enamines, and cyclotene derivatives (e.g., 3-methyl-2-(1-pyrrolidinyl)-2-cyclopenten-1-one and 5-methyl-2-(1-pyrrolidinyl)-2-cyclopenten-1-one). Other compounds include the alpha-keto enamines disclosed in U.S. Pat. No. 6,592,884 to Hofmann et al., which is incorporated in its entirety herein. These and other suitable cooling agents are further described in the following U.S. patents, all of which are incorporated in their entireties by reference hereto: U.S. Pat. Nos. 4,230,688; 4,032,661; 4,459,425; 4,178,459; 4,296,255; 4,136,163; 5,009,893; 5,266,592; 5,698,181; 6,277,385; 6,627,233; 7,030,273. Still other suitable cooling agents are further described in US Patent Application Publications Nos. 2005 / 0222256 and 2005 / 0265930, each of which is incorporated in its entirety by reference hereto. In some embodiments, the cooling agent comprises menthol, eucalyptus, mint, menthol, menthyl esters, eucolyptol, WS-3, WS-23, WS-5, (1R,2S,5R)—N-(4-(cyanomethyl)phenyl)menthylcarboxamide (Evercool™ 180), (1R,2S,5R)—N-(2-(pyridin-2-yl)ethyl)menthylcarboxamide (Evercool™ 190), or a combination thereof.

[0267] In some embodiments, the treated sheet material and / or article does not comprise a flavoring agent, and comprises only a cooling agent to provide the desired user experience. In some embodiments, the cooling agent is WS-3.

[0268] In some embodiments, the treated sheet material and / or article comprises a modulator or sensate which provides to the user of such composition a warming effect. Suitable warming agents include, but are not limited to, ethers of vanillyl alcohol (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, isoamyl, n-hexyl), gingerol, shogaol, paradol, zingerone, capsaicin, dihydrocapsaicin, nordihydrocapsaicin, homocapsaicin, homodihydrocapsaicin, benzyl alcohol, and combinations thereof. In some embodiments, the warming agent comprises vanillyl butyl ether, vanillyl ethyl ether, capsaicin, or a combination thereof.

[0269] Flavoring agents may be in any suitable form, for example, a liquid such as an oil, or a solid such as a powder or wax. In some instances, the flavoring agent may be provided in a spray-dried form or a liquid form.

[0270] The amount of flavoring agent utilized in the treated sheet materials can vary, but is typically up to about 60% by weight based on the weight of the treatment composition associated with the treated sheet material on a dry weight basis. For example, the material and / or article may comprise up to about 60 wt %, about 50 wt %, about 40 wt %, about 30 wt %, about 20 wt %, about 10 wt % or about 5 wt % of a flavoring agent based on the weight of the treatment composition associated with the treated sheet material on a dry weight basis. In some embodiments, the material and / or article may comprise at least about 0.5 wt %, about 1 wt %, about 2 wt %, about 5 wt %, about 10 wt %, about 20 wt % or about 30 wt % of flavoring agent (based on the weight of the treatment composition associated with the treated sheet material on a dry weight basis). For example, the material and / or article may comprise from about 10 to about 60 wt %, from about 20 to about 50 wt % or from about 30 to about 40 wt % of flavoring agent based on the weight of the treatment composition associated with the treated sheet material on a dry weight basis.

[0271] In some embodiments, the flavor comprises menthol, spearmint and / or peppermint.

[0272] In some embodiments, the flavor comprises flavor components of cucumber, blueberry, citrus fruits and / or redberry.

[0273] In some embodiments, the flavor comprises eugenol.

[0274] In some embodiments, the flavoring agent (if present) comprises, consists essentially of, or consists of, menthol. In some embodiments, the sheet material and / or article does not comprise an added flavor.Taste Modifier

[0275] In order to improve the organoleptic properties of a treated sheet material or article as disclosed herein, the treatment composition may include one or more taste modifying agents (“taste modifiers”) which may serve to mask, alter, block, or improve the flavor of a material as described herein. Non-limiting examples of such taste modifiers include analgesic or anesthetic herbs, spices, and flavors which produce a perceived cooling (e.g., menthol, eucalyptus, mint), warming (e.g., cinnamon), or painful (e.g., capsaicin) sensation. Certain taste modifiers fall into more than one overlapping category.

[0276] 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, the material and / or article comprises an active ingredient having a bitter taste, and a taste modifier which masks or blocks the perception of the bitter taste. In some embodiments, the taste modifier is a substance which targets pain receptors (e.g., vanilloid receptors) in the user's mouth to mask e.g., a bitter taste of another component (e.g., an active ingredient). In some embodiments, the taste modifier is capsaicin.

[0277] In some embodiments, the taste modifier is the amino acid gamma-amino butyric acid (GABA), referenced herein above with respect to amino acids. Studies in mice suggest that GABA may serve function(s) in taste buds in addition to synaptic inhibition. See, e.g., Dvoryanchikov et al., J Neurosci. 2011 Apr. 13; 31(15):5782-91. Without wishing to be bound by theory, GABA may suppress the perception of certain tastes, such as bitterness. In some embodiments, the composition comprises caffeine and GABA.

[0278] In some embodiments, the taste modifier is adenosine monophosphate (AMP). AMP is a naturally occurring nucleotide substance which can block bitter food flavors or enhance sweetness. It does not directly alter the bitter flavor but may alter human perception of “bitter” by blocking the associated receptor.

[0279] In some embodiments, the taste modifier is lactisole. Lactisole is an antagonist of sweet taste receptors. Temporarily blocking sweetness receptors may accentuate e.g., savory notes.

[0280] 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 will typically make up less than about 10% by weight of the total weight of the treatment composition associated with the treated sheet material on a dry weight basis (e.g., from 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 weight of the treatment composition associated with the treated sheet material on a dry weight basis).Salt

[0281] In some embodiments, the treated sheet material or article may further comprise a salt (e.g., alkali metal salts), typically employed in an amount sufficient to provide desired sensory attributes to the material or article. In some embodiments, a salt can be included, e.g., to modify the ionic strength of the product. Non-limiting examples of salts include sodium chloride, potassium chloride, ammonium chloride, flour salt, and the like.

[0282] When present, a representative amount of salt is about 0.5 percent by weight or more, about 1.0 percent by weight or more, or at about 1.5 percent by weight or more, but will typically make up about 20 percent or less of the total weight of the composition, or about 15 percent or less or about 10 percent or less (e.g., about 0.5 to about 10 percent by weight) based on the weight of the treatment composition associated with the treated sheet material on a dry weight basis.Sweetener

[0283] In order to improve the sensory properties of the treated sheet materials and articles according to the disclosure, one or more sweeteners may be added. The sweeteners can be any sweetener or combination of sweeteners, in natural or artificial form, or as a combination of natural and artificial sweeteners. Examples of natural sweeteners include fructose, sucrose, glucose, maltose, mannose, galactose, lactose, stevia, honey, and the like. Examples of artificial sweeteners include sucralose, isomaltulose, maltodextrin, saccharin, aspartame, acesulfame K, neotame, and the like. In some embodiments, the sweetener comprises one or more sugar alcohols. Sugar alcohols are polyols derived from monosaccharides or disaccharides that have a partially or fully hydrogenated form. Sugar alcohols have, for example, 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 a combination thereof.

[0284] When present, a sweetener or combination of sweeteners may make up from about 0.01 to about 20% or more of the weight of the treatment composition associated with the treated sheet material on a dry weight basis, for example, 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 weight of the treatment composition associated with the treated sheet material on a dry weight basis. In some embodiments, a combination of sweeteners is present at a concentration of from about 0.01% to about 0.1%, such as about 0.01, about 0.02, about 0.03, about 0.04, about 0.05, about 0.06, about 0.07, about 0.08, about 0.09, or about 0.1% based on the weight of the treatment composition associated with the treated sheet material on a dry weight basis. In some embodiments, a combination of sweeteners is present at a concentration of from about 0.1% to about 0.5% by weight of the composition, such as about 0.1, about 0.2, about 0.3, about 0.4, or about 0.5% based on the weight of the treatment composition associated with the treated sheet material on a dry weight basis. In some embodiments, a combination of sweeteners is present at a concentration of from about 1% to about 3% based on the weight of the treatment composition associated with the treated sheet material on a dry weight basis.Binding Agent

[0285] A binder (or combination of binders) can optionally be employed in the sheet material or article described herein in an amount sufficient to provide the desired physical attributes and physical integrity. The binder material can serve to add cohesiveness to a material and can also serve as gelling agents. Typically, the amount of binder present is up to about 50% by weight, and some embodiments are characterized by a binder content of at least about 5% by weight, based on the total weight of the treatment composition associated with the treated sheet material on a dry weight basis. In some embodiments, the binder is present in an amount by weight in a range from about 5 to about 50% based on the total weight of the composition, such as from about 5%, about 10%, about 15%, about 20%, about 25%, or about 30%, to about 35%, about 40%, or about 45% by weight, based on the weight of the treatment composition associated with the treated sheet material on a dry weight basis.

[0286] Typical binders can be organic or inorganic, or a combination thereof. Representative binders include povidone, sodium alginate, pectin, gums, carrageenan, pullulan, zein, cellulose derivatives, and the like, and combinations thereof. In some implementations, combinations or blends of two or more binder materials may be employed. Other examples of binder materials are described, for example, in U.S. Pat. No. 5,101,839 to Jakob et al.; and U.S. Pat. No. 4,924,887 to Raker et al., each of which is incorporated herein by reference in its entirety.

[0287] In some embodiments, the binder is selected from the group consisting of agar, alginates, carrageenan and other seaweed hydrocolloids, exudate gum hydrocolloids, cellulose ethers, starches, gums, dextrans, povidone, pullulan, zein, or combinations thereof.

[0288] In some embodiments, the binder is a cellulose ether (including carboxyalkyl ethers), meaning a cellulose polymer with the hydrogen of one or more hydroxyl groups in the cellulose structure replaced with an alkyl, hydroxyalkyl, or aryl group. Non-limiting examples of such cellulose derivatives include methylcellulose, hydroxypropylcellulose (“HPC”), hydroxypropylmethylcellulose (“HPMC”), hydroxyethyl cellulose, and carboxymethylcellulose (“CMC”). Suitable cellulose ethers include hydroxypropylcellulose, such as Klucel H from Aqualon Co.; hydroxypropylmethylcellulose, such as Methocel K4MS from DuPont; hydroxyethylcellulose, such as Natrosol 250 MRCS from Aqualon Co.; methylcellulose, such as Methocel A4M, K4M, and E15 from DuPont.; and sodium carboxymethylcellulose, such as CMC 7HF, CMC 7LF, and CMC 7H4F from Aqualon Co. In some embodiments, the binder is one or more cellulose ethers (e.g., a single cellulose ether or a combination of several cellulose ethers, such as two or three, for example). In some embodiments, the binder is a cellulose ether selected from the group consisting of methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethyl cellulose, carboxymethylcellulose, and combinations thereof.Humectant

[0289] In some embodiments, one or more humectants may be employed in the materials and articles described herein. Examples of humectants include, but are not limited to, polyols such as glycerin, propylene glycol, and the like. Where included, the humectant is typically provided in an amount sufficient to provide desired moisture attributes to the composition. When present, a humectant will typically make up about 20% or less of the weight of the treatment composition associated with the treated sheet material on a dry weight basis or 15% or less of the weight of the treatment composition associated with the treated sheet material on a dry weight basis (e.g., from about 1% to about 20% by weight or about 5% to about 15% by weight).Buffering Agent

[0290] In some embodiments, the material or article of the present disclosure can comprise one or more pH adjusters or buffering agents. Examples of pH adjusters and buffering agents 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 carbonates (e.g., potassium carbonate or sodium carbonate), or metal bicarbonates such as sodium bicarbonate, and the like. Non-limiting examples of suitable buffers include alkali metals acetates, glycinates, phosphates, glycerophosphates, citrates, carbonates, hydrogen carbonates, borates, or mixtures thereof.

[0291] Where present, the buffering agent is typically present in an amount less than about 5 percent based on the weight of the treatment composition associated with the treated sheet material on a dry weight basis, for example, from about 0.5% to about 20%, such as, e.g., from about 0.75% to about 15%, from about 1% to about 10%, or from about 1% to about 5% by weight, based on the weight of the treatment composition associated with the treated sheet material on a dry weight basis.Colorant

[0292] A colorant may optionally be employed in amounts sufficient to provide the desired physical attributes to the sheet material and / or article. Examples of colorants include various dyes and pigments, such as caramel coloring and titanium dioxide. Natural colorants such as curcumin, beet juice extract, spirulina may be used; also, a variety of synthetic pigments may be used. The amount of colorant utilized in the material can vary, but when present is typically up to about 3% by weight, such as from about 0.1%, about 0.5%, or about 1%, to about 3% by weight, based on the weight of the treatment composition associated with the treated sheet material on a dry weight basis.Oral Care Additive

[0293] In some embodiments, the material or article comprises an oral care ingredient (or mixture of such ingredients). Oral care ingredients provide the ability to inhibit tooth decay or loss, inhibit gum disease, relieve mouth pain, whiten teeth, or otherwise inhibit tooth staining, elicit salivary stimulation, inhibit breath malodor, freshen breath, or the like. For example, effective amounts of ingredients such as thyme oil, eucalyptus oil and zinc (e.g., such as the ingredients of formulations commercially available as ZYTEX® from Discus Dental) can be incorporated into the composition. Other examples of ingredients that can be incorporated in desired effective amounts within the present composition can include those that are incorporated within the types of oral care compositions set forth in Takahashi et al., Oral Microbiology and Immunology, 19(1), 61-64 (2004); U.S. Pat. No. 6,083,527 to Thistle; and US Pat. Appl. Pub. Nos. 2006 / 0210488 to Jakubowski and 2006 / 02228308 to Cummins et al. Other exemplary ingredients include those contained in formulations marketed as MALTISORB® by Roquette and DENTIZYME® by NatraRx. When present, a representative 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 treatment composition associated with the treated sheet material on a dry weight basis. The amount of oral care additive within the material or article will not typically exceed about 30%, often will not exceed about 25%, and frequently will not exceed about 20% of the weight of the treatment composition associated with the treated sheet material on a dry weight basis.Thickening Agent

[0294] In some embodiments, the oral compositions will include one or more thickening agents to adjust the viscosity of the oral composition. Example thickening agents povidone, alginates, starches, pectin, carrageenan, pullulan, zein, natural gums, cellulose derivatives and the like, and combinations thereof. In some embodiments, the thickening agent is a gum, for example, a natural gum. As used herein, a natural gum refers to polysaccharide materials of natural origin that have binding properties, and which are also useful as a thickening or gelling agents. Representative natural gums derived from plants, which are typically water soluble to some degree, include xanthan gum, guar gum, gum arabic, ghatti gum, gum tragacanth, karaya gum, locust bean gum, gellan gum, and combinations thereof. In some embodiments, the thickening agent comprises a cellulose derivative or a combination of such derivatives. Example cellulose derivatives include cellulose ethers (including carboxyalkyl ethers), meaning a cellulose polymer with the hydrogen of one or more hydroxyl groups in the cellulose structure replaced with an alkyl, hydroxyalkyl, or aryl group. Non-limiting examples of such cellulose derivatives include methylcellulose, hydroxypropylcellulose (“HPC”), hydroxypropylmethylcellulose (“HPMC”), hydroxyethyl cellulose, and carboxymethylcellulose (“CMC”).

[0295] A thickening agent may be employed in amounts sufficient to provide the desired physical attributes, such as viscosity, to the composition. The amount of thickening agent utilized in the composition can vary, but is typically up to about 10 weight percent, and certain embodiments are characterized by a thickening agent content of at least about 0.1% by weight, such as about 1 to about 10% by weight, or about 2 to about 5% by weight, based on the total weight of the composition.Other Additives

[0296] Other additives can optionally be included in the disclosed materials and articles. The additives can be artificial or can be obtained or derived from herbal or biological sources. Examples of further types of additives include gelling agents (e.g., fish gelatin), emulsifiers, preservatives (e.g., potassium sorbate and the like), disintegration aids, or combinations thereof. See, for example, those representative components, combination of components, relative amounts of those components, and manners and methods for employing those components, set forth in U.S. Pat. No. 9,237,769 to Mua et al., U.S. Pat. No. 7,861,728 to Holton, Jr. et al., US Pat. App. Pub. No. 2010 / 0291245 to Gao et al., and US Pat. App. Pub. No. 2007 / 0062549 to Holton, Jr. et al., each of which is incorporated herein by reference.

[0297] In addition, in some embodiments, inorganic granular materials can be incorporated, including, but not limited to, insoluble phosphates, clays, and the likes. In some embodiments, these types of components can serve as fillers, modifying the stiffness of the disclosed sheet material. In some embodiments, these types of components can provide further effects, i.e., they may be functional in one or more additional ways. For example, certain such inorganic granular materials can modify product pH, can have a surface functionality to interact with one or more other components of the disclosed products (e.g., the active agent(s)), such as surface acidic properties including granular cationic resins or various calcium phosphate, hydroxyapatite, apatite, or calcium phosphate bioceramics (which all may, in some embodiments, serve to moderate or control release of one or more components from the disclosed product).

[0298] Typical inclusion ranges for such additional additives can vary depending on the nature and function of the additive and the intended effect on the final material or article, with an example range of up to about 10% by weight, based on the weight of the treatment composition associated with the treated sheet material on a dry weight basis (e.g., about 0.1 to about 5% by weight).

[0299] The aforementioned additives can be employed together (e.g., as additive formulations) or separately (e.g., individual additive components can be added at different stages involved in the preparation of the treated material). Furthermore, the aforementioned types of additives may be encapsulated as provided in the final product or composition. Example encapsulated additives are described, for example, in WO2010 / 132444 to Atchley, which has been previously incorporated by reference herein.Treated Sheet Material

[0300] To prepare a treated sheet material according to the disclosure, a sheet material is generally first prepared. As noted above, various types of fibers (e.g., cellulosic fibers) may be used in forming the sheet materials according to the present disclosure. As various types and combinations of fibers and ingredients may be incorporated into treated fleece materials prepared according to the methods described herein, such methods as described herein below with respect to one embodiment should not be construed as limiting in any way.

[0301] A sheet material may be formed, for example, using any method of forming a woven or nonwoven fabric as detailed herein above. For example, certain non-limiting fleece materials of the present disclosure can be formed, e.g., using a spunlaid or spunmelt process, for example, which includes both spunbond and meltblown processes, wherein such processes are understood to typically entail melting, extruding, collecting and bonding fibrous materials to form a fibrous nonwoven web. The extruding parameters may vary and may be altered based on the types of materials or components used within the fleece materials. In some embodiments, the sheet material can be formed via wetlaying and / or air laying.

[0302] In some embodiments, the fleece material may optionally be extruded prior to treating the fleece material to associate the active agent and optionally, other components therewith. Fleece materials may be extruded by any means commonly known in the art. In some embodiments, the fleece materials may be extruded prior to, during, or after treatment with the active agent and optionally, other components.

[0303] As referenced above, in some embodiments, the sheet materials can comprise a single layer or multiple layers. As such, some embodiments require a step of combining two or more sheet materials in a layered fashion to give the desired multi-layered sheet material comprising two or more sheet materials, which can be the same or different. The layers of a multilayered sheet material can be combined by any means known in the art. In some embodiments, layers are held together via one or more of stitching, hydroentangling of fibers in the adjacent layers, needle punching, embossing, ultrasonic bonding, thermal bonding, or any combination thereof. Correspondingly, the method of preparing a sheet material provided herein can, in some embodiments, comprise subjecting layered sheet materials to one or more of a stitching operation, a hydroentangling operation, a needle-punching operation, an embossing process, ultrasonic bonding, thermal bonding, or any combination thereof.

[0304] The sheet material can be produced so as to have a desired size and shape or can be produced and then subsequently processed to have a desired size and shape. For example, a sheet material or sheet fleece material can be produced and subdivided into discrete portions. The “discrete portions” as described herein are basically cut segments of a continuous sheet material as described herein that have been cut to the desired dimensions; e.g., the length and width of the desired oral article. In some embodiments, a sheet material or treated fleece material can be cut into a desired size and / or shape, e.g., by mechanical or laser cutting of the material. Such processes can be conducted on a single layer or, where the sheet material comprises two or more layers, can be conducted on a composite material of two or more layers, before or after they are joined together. In some embodiments, the sheet material is prepared and subjected to such processes before or after being treated with the active agent and / or other optional additional ingredients.

[0305] Suitable shapes and sizes are not particularly limited. Suitable shapes are as referenced herein above with respect to the structural component, with non-limiting examples of shapes shown in FIG. 1. Sizes can be any size sufficient to fit within a user's oral cavity, including in flat / planar form, as well as in rolled-up, crumpled, or folded form. In some embodiments, the size and shape can be designed to conform to a user's jaw size and / or shape or gumline size and / or shape.

[0306] Once the sheet material is prepared, the active agent and any additional optional ingredients are combined therewith to give the treated sheet material. The sheet material can be combined with the active agent and any additional optional ingredients in various ways and at different times in the method of preparing the treated sheet material. An example treated sheet material or article may be manufactured from materials, and in such a manner, such that during use by the user, the material undergoes a controlled dispersion or dissolution of the active agent and / or any additional optional ingredients.

[0307] In some embodiments, the sheet material may be treated with active agent and any additional optional ingredients prior to, during, or after forming the sheet material and / or or the sheet article as a whole. For example, in some embodiments, the sheet material may be treated with the active agent and any additional optional ingredients by treating individual layers; in other embodiments, two or more layers are first associated with one another and then the layered structure is treated (which can include treating the final sheet material or combinations of layers thereof) with the solution. In some embodiments, a single liquid solution is employed, comprising the active agent and any additional optional ingredients; however, the disclosure is not limited thereto. In some embodiments, the active agent and any additional optional ingredients can be contained in separate solutions and applied separately.

[0308] Generally, in some embodiments, the active agent and any additional optional ingredients can be adapted to or configured to absorb, adsorb, or otherwise become directly entrained / embedded within the porous structure of the sheet material (e.g., associated with the fibers and / or within the voids between fibers). In this manner, the active agent and any additional optional ingredients may be retained with a desired level of stability and / or may be configured for controlled release from the naturally porous structure of the sheet material. In some embodiments, the active agent and any additional optional ingredients may simply be applied as a coating on the surface of the sheet material. Thus, the active agent and any additional optional ingredients may be considered to be contained in and / or on the treated sheet materials described herein.

[0309] In some embodiments, treating comprises contacting one or more layers, the sheet material, or an assembled sheet article with a solution, e.g., an aqueous solution, comprising the active agent and any additional optional ingredients. In some embodiments, the active agent and any additional optional ingredients are applied to the sheet via printing, coating, dipping, dip coating, spraying, and other similar methods as would be understood by a person of ordinary skill in the art.

[0310] In some embodiments, one or more of the active agent and the optional additional ingredients can be used in encapsulated form (e.g., in the form of microcapsules). In some embodiments, encapsulated components (e.g., microcapsules) could be added to the sheet material (e.g., via surface application on a substrate sheet) or otherwise incorporated, e.g., during the fiber laying process. Microcapsules comprise the active agent and / or one or more additional optional ingredients in an encapsulated form, typically in the form of a core / shell structure, wherein the encapsulated form comprises a wall or barrier structure defining an inner region and isolating the inner region permanently or temporarily from the surrounding material(s). The inner region includes a payload of the ion-pairing agent. See, for example, the subject matter of US Pat. Appl. Pub. No. 2009 / 0025738 to Mua et al., which is incorporated herein by reference.

[0311] A representative microcapsule embodiment has an outer cover, shell, or coating that envelopes a liquid, gel, or solid core region, and in some embodiments, the microcapsule can have a generally spherical shape. By encapsulating an active agent and / or any additional optional ingredients within the core region of a microcapsule, the ability of such ingredients to interact with other components of the treated sheet article prior to use of the product can be reduced or eliminated, which can enhance the storage stability of the product. The core region, which typically releases the active agent and / or any additional optional ingredients when the outer shell undergoes some type of physical destruction, breakage, or other loss of physical integrity (e.g., through dispersion, softening, crushing, application of pressure, or the like), thereby provides for altering the sensory properties of the pouched product. Thus, in some embodiments, the outer shell of the microcapsules is designed to rupture during use or is water soluble under conditions of normal use, such as under conditions of at least about 45 weight percent moisture based on the total weight of the article.

[0312] Microcapsules optionally used in the disclosed products may be uniform or varied in size, weight, and shape. A representative encapsulated unit comprising an active agent and / or additional optional ingredient(s) is generally spherical in shape. However, suitable encapsulated units may have other types of shapes, such as generally rectilinear, oblong, elliptical, or oval shapes. Example encapsulated units may have diameters of less than about 1,000 microns, such as diameters in the range of about 1 to about 750 microns, or about 10 micron to about 500 microns. In some embodiments, larger encapsulated units may be utilized. For example, encapsulated units utilized in the product may have a size of about 0.5 mm to about 5 mm or about 0.6 mm to about 3 mm in diameter. In certain embodiments, capsules having sizes of diameter up to about the thickness of the sheet material are employed, e.g., to avoid a “bumpy” feel / texture associated with the resulting capsule-containing product.

[0313] Microcapsules can be formed using, for example, any encapsulating technology known in the art. For example, the capsules can be formed using any of various chemical encapsulation techniques such as solvent evaporation, solvent extraction, organic phase separation, interfacial polymerization, simple and complex coacervation, in-situ polymerization, liposome encapsulation, and nanoencapsulation. Alternatively, physical methods of encapsulation could be used, such as injection molding, spheronization, granulation, extrusion, microfluidics, spray coating, pan coating, fluid bed coating, annular jet coating, spinning disk atomization, spray cooling, spray drying, spray chilling, stationary nozzle coextrusion, centrifugal head coextrusion, or submerged nozzle coextrusion.

[0314] Coacervation is a colloid phenomenon that begins with a solution of a colloid in an appropriate solvent. Depending on the nature of the colloid, various changes can bring about a reduction of the solubility of the colloid. As a result of this reduction, a significant portion of the colloid can be separated out into a new phase, thus forming a two-phase system, with one being rich and the other being poor in colloid concentration. The colloid-rich phase in a dispersed state appears as amorphous liquid droplets called coacervate droplets. Upon standing, these coalesce into one clear homogenous colloid-rich liquid layer, known as the coacervate layer, which can be deposited so as to produce the wall material of the resultant encapsulated ion-pairing agent.

[0315] Simple coacervation can be effected either by mixing two colloidal dispersions, one having a high affinity for water, or it can be induced by adding a strongly hydrophilic substance such as alcohol or sodium sulfate. A water-soluble polymer is concentrated in water by the action of a water miscible, non-solvent for the emerging polymer (e.g., gelatin) phase. Ethanol, acetone, dioxane, isopropanol and propanol are exemplary solvents that can cause separation of a coacervate such as gelatin, polyvinyl alcohol, or methyl cellulose. Phase separation can be effected by the addition of an electrolyte such as an inorganic salt to an aqueous solution of a polymer such as gelatin, polyvinyl alcohol, or carboxymethylcellulose. Complex coacervation can be induced in systems having two dispersed hydrophilic colloids of opposite electric charges. Neutralization of the overall positive charges on one of the colloids by the negative charge on the other is used to bring about separation of the polymer-rich complex coacervate phase. The gelatin-gum arabic (gum acacia) system is one known complex coacervation system.

[0316] Organic phase separation is sometimes more simply referred to as “water-in-oil” encapsulation. In this case, the polar core is dispersed into an oily or non-polar continuous medium. The wall material is then dissolved in this continuous medium.

[0317] Regardless of the encapsulation methodology employed, the outer wall or matrix material and / or coating material and solvents used to form the microcapsules associated with some embodiments of the disclosure can vary. Classes of materials that are typically used as wall / shell or coating materials include proteins, polysaccharides, starches, waxes, fats, natural and synthetic polymers, and resins. Suitable materials for use in the encapsulation process used to form the encapsulated oral composition units include gelatin, acacia (gum arabic), polyvinyl acetate, potassium alginate, carob bean gum, potassium citrate, carrageenan, potassium polymetaphosphate, citric acid, potassium tripolyphosphate, dextrin, polyvinyl alcohol, povidone, dimethylpolysiloxane, mannitol, dimethyl silicone, refined paraffin wax, ethylcellulose, bleached shellac, maltodextrin, modified food starch, sodium alginate, guar gum, sodium carboxymethylcellulose, hydroxypropyl cellulose, sodium citrate, hydroxypropylmethylcellulose, sodium ferrocyanide, sodium polyphosphates, locust bean gum, methylcellulose, sodium trimetaphosphate, methyl ethyl cellulose, sodium tripolyphosphate, wax, microcrystalline wax, tannic acid, petroleum wax, terpene resin, tragacanth, polyethylene, xanthan gum, gelatin, alginate, gelatin, and polyethylene glycol.

[0318] Microcapsules are commercially available and can, in some embodiments, be used or modified for use according to the present disclosure. Certain examples of microcapsule technologies are of the type set forth in Gutcho, Microcapsules and Microencapsulation Techniques (1976); Gutcho, Microcapsules and Other Capsules Advances Since 1975 (1979); Kondo, Microcapsule Processing and Technology (1979); Iwamoto et al., AAPS Pharm. Sci. Tech. 2002 3(3): article 25; U.S. Pat. No. 3,550,598 to McGlumphy; U.S. Pat. No. 4,889,144 to Tateno et al.; U.S. Pat. No. 5,004,595 to Cherukuri et al.; U.S. Pat. No. 5,690,990 to Bonner; U.S. Pat. No. 5,759,599 to Wampler et al.; U.S. Pat. No. 6,039,901 to Soper et al.; U.S. Pat. No. 6,045,835 to Soper et al.; U.S. Pat. No. 6,056,992 to Lew; U.S. Pat. No. 6,106,875 to Soper et al.; U.S. Pat. No. 6,117,455 to Takada et al.; U.S. Pat. No. 6,325,859 to DeRoos et al.; U.S. Pat. No. 6,482,433 to DeRoos et al.; U.S. Pat. No. 6,612,429 to Dennen; and U.S. Pat. No. 6,929,814 to Bouwmeesters et al.; U.S. Pat. Appl. Pub. Nos. 2006 / 0174901 to Karles et al. and 2007 / 0095357 to Besso et al.; and PCT WO2007 / 037962 to Holton et al.; each of which is incorporated herein by reference. Suitable types of microcapsules are available from sources such as Microtek Laboratories of Dayton, Ohio. Exemplary types of commercially available microencapsulating techniques include those marketed under the trade names ULTRASEAL™ and PERMASEAL™ available from Givaudan headquartered in Vernier, Switzerland.

[0319] The payload of the microcapsules can consist or consist essentially of one ingredient (e.g., the active agent) or may incorporate one or more alternative or additional components. For example, the payload may comprise water and / or can comprise any of the oral composition components noted herein including, but not limited to, humectants.

[0320] Various methods can be used to form a sheet material comprising microcapsules. For example, in some embodiments, microcapsules can be associated with a fiber by adding microcapsules to a polymer melt, solution, or dispersion from which the fibers are produced (e.g., spun or extruded). In some embodiments, microcapsules can be associated with a sheet material by adhering microparticles to a surface of the sheet material, which can in some embodiments, be facilitated by an adhesive material. The association of the microparticles with the sheet material can be before nonwoven web formation, during nonwoven web formation, or after nonwoven web formation. The resulting microcapsules can be, e.g., embedded in the fibers of the nonwoven web / sheet material or otherwise adhered to or associated with the fibers of the nonwoven web / sheet material.

[0321] In some embodiments, the treated sheet material comprises, in addition to a structural component and an active agent, one or more of the optional ingredients provided above. In certain non-limiting embodiments, the treated sheet material comprises a structural component, an active agent, and one or more of a salt, a sweetener, a flavorant, a humectant, and an ion pairing agent.

[0322] In some embodiments, the treated sheet material may be dissolvable or disintegrable, such that the treated sheet material may be ingested by the user. As used herein, the terms “dissolve,”“dissolving,” and “dissolvable” refer to materials having aqueous-soluble components that interact with moisture in the oral cavity and enter into solution, thereby causing gradual consumption of the material. According to one aspect, a dissolvable material is capable of lasting in the user's mouth for a given period of time until it completely dissolves. Dissolution rates 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 component(s) (e.g., active ingredient, flavor, and the like) 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 the interaction between the components of the composition. In some embodiments, the treated sheet materials provided herein do not dissolve during the product's residence in the user's mouth.Treated Sheet Article

[0323] The disclosed treated sheet materials can be used as or incorporated in various ways within oral products.

[0324] In some embodiments, the sheet material can be directly used as an oral product, i.e., the oral product is a treated sheet article that consists or consists essentially of a treated sheet material.

[0325] In some embodiments, one or more additional components are included within the oral product. For example, in some embodiments, an oral product is provided that comprises a treated sheet material and one or more substrates. For example, the substrate in some embodiments can be a material on which the treated sheet material is provided. This substrate may ease manufacture and / or handling through, for example, (a) providing a surface onto which the structural component can be produced (and which the treated sheet material does not need to be separated from later) or (b) providing some rigidity to the treated sheet article, to facilitate handling, packaging, storage, and / or use.

[0326] In some embodiments, the substrate may be formed from any of the materials described herein above with respect to structural components. For example, the substrate can be an untreated fibrous material comprising any of the materials referenced above. In some embodiments, the substrate is paper, cardboard, or wood or combinations thereof. In some embodiments, the substrate may be polymeric. The substrate can be dissolvable or can be designed to be removed from the user's mouth after use. In some embodiments, the substrate itself can be a layered structure comprising layers of materials selected from the preceding disclosure. In some embodiments, the substrate may also function as a flavor carrier. For example, the substrate may be impregnated with a flavorant and / or with botanical extract.

[0327] Where the treated sheet article comprises one or more other components, the treated sheet material can be incorporated in various manners. In some embodiments, the treated sheet material may be incorporated into an article as a planar sheet, a bunched or gathered sheet, as a crimped sheet, or a rolled sheet.

[0328] The articles provided herein are described as being “configured for oral use.” The term “configured for oral use” as used herein means that the composition is provided in a form such that during use, saliva in the mouth of the user causes one or more of the components of the treated sheet material (e.g., the active agent and, optionally, flavorants and / or other optional ingredients) to pass into the mouth of the user. In some embodiments, the article is adapted to deliver such components to a user through mucous membranes in the user's mouth, the user's digestive system, or both, and, in some instances, the components can be released and absorbed through the mucous membranes in the mouth or absorbed through the digestive tract when the product is used.

[0329] The disclosed treated sheet articles are typically used by placing one treated sheet article in the mouth of a human subject / user. Generally, the article is placed somewhere in the oral cavity of the user, for example under the lips, in the same way as moist snuff products or pouched products are generally used. The treated sheet article preferably is not chewed or swallowed, but in some embodiments, the article can reasonably be chewed. Exposure to saliva then causes at least the active agent and, in some embodiments, any one or more of the additional optional components of the treated sheet material (e.g., flavorants) to pass out of the sheet and provide the user with flavor and satisfaction, and the user is not required to spit out any component. After about 10 minutes to about 60 minutes, typically about 15 minutes to about 45 minutes of use / enjoyment, substantial amounts of the active agent and, in some embodiments, any one or more of the additional optional components, have been ingested by the human subject, and the sheet article may be removed from the mouth of the human subject for disposal.

[0330] Many modifications and other implementations of the disclosure will come to mind to one skilled in the art to which this disclosure pertains having the benefit of the teachings presented in the foregoing descriptions and the associated figures. Therefore, it is to be understood that the disclosure is not to be limited to the specific implementations disclosed herein and that modifications and other implementations 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.EXAMPLESCellulose Fleece Sheet Material

[0331] Eight layers of a cellulosic fleece were layered upon each other to give a material with a basis weight of about 250 g / m2. This material was cut into the desired size and shape (a rectangle with length and width of about 32 mm×15 mm).Active Agent-Containing Solutions

[0332] A first solution (“Solution A”) was prepared using the composition provided in Table 2 below. The solution was made by combining the ingredients and mixing with stirring for about 30 min. The pH of Solution A was found to be 7.25.TABLE 2Solution composition (“Solution A”)Componentwt %Methyl Cellulose Solution59.5%Sodium Chloride2.0%Propylene Glycol31.2%Sucralose0.9%Aqueous 2-methyl-5-(1-4.5%methylpyrrolidin-2-yl)pyridine tocopherolsuccinate solution (5.06%active agent solution)Sodium benzoate0.4%Polyoxyl (40) stearate0.5%Flavor (mint)1.0%

[0333] The aqueous 2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine tocopherol succinate solution in Table 2 was made as follows. About 28.7 g of tocopherol succinate were mixed with about 79.9 g of 12% aqueous 2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine solution and about 81.1 g water. The mixture was heated on a water bath to a temperature of about 40° C. Then the mixture was mixed using a homogenizer for about 2 min at 12,000 rpm to yield a thick paste. A portion of aqueous 2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine tocopherol succinate was diluted about 10,000:1 with water and analyzed by a Malvern Zetasizer Nano-ZS. The 2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine tocopherol succinate was found to have a particle size of about 173 nm.

[0334] The methyl cellulose solution in Table 2 was made as follows. About 2.0 g of 4000 Cps methyl cellulose (Fisher, M352) was dispersed in about 485.5 g water heated to 75° C. About 12.5 g sodium citrate was added to the methyl cellulose-water dispersion. The solution was cooled on an ice bath, yielding a translucent solution.

[0335] A second solution (“Solution B”) was prepared using the composition provided in Table 3 below. The solution was made by combining the ingredients and mixing with stirring for about 30 min. The pH of Solution B was found to be 6.99.TABLE 3Solution composition (“Solution B”)Componentwt %Methyl Cellulose Solution60.5%Sodium Chloride3.5%Propylene Glycol31.2%Sucralose0.9%Aqueous 2-methyl-5-(1-2.0%methylpyrrolidin-2-yl)pyridine benzoate (11.08%active agent solution)Sodium benzoate0.4%Polyoxyl (40) stearate0.5%Flavor (mint)1.0%Oral Sheet MaterialsExample 1

[0336] A roughly 32 mm×15 mm rectangular sample of the Cellulose Sheet Material, having a weight of about 135 mg, was treated with about 233 mg of solution A. The resulting oral sheet material contained about 0.5 mg of 2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine. The pH of this material was measured as 6.88.Example 2

[0337] A roughly 32 mm×15 mm rectangular sample of the Cellulose Sheet Material, having a weight of about 148 mg, was treated with about 202 mg of solution B. The resulting oral sheet material contained about 0.5 mg of 2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine. The pH of this material was measured as 6.45.

Claims

1. A treated sheet article for oral use comprising a treated sheet material, the treated sheet material comprising a structural component and a treatment composition associated therewith,wherein the treatment composition comprises one or more active agents selected from:(i) a substituted 3-(1-methylpyrrolidin-2-yl)pyridine having a structure according to Formula I:wherein R1, R2, R3, and R4 are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl, aryl, alkylaryl, amino, halogen, and cyano, wherein any of said alkyl, alkoxy, cycloalkyl, alkenyl, alkenyl, alkynyl, aryl, alkylaryl, and amino may optionally be substituted; and at least one of R1, R2, R3, and R4 are not hydrogen;(ii) a substituted 3-(1-methylpyrrolidin-2-yl)pyridine having a structure according to Formula II:wherein R5 and R6 are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl, aryl, alkylaryl, amino, halogen, and cyano, wherein any of said alkyl, alkoxy, cycloalkyl, alkenyl, alkenyl, alkynyl, aryl, alkylaryl, and amino may optionally be substituted;R7 is selected from the group consisting of hydrogen and CH3;R8 is selected from the group consisting of hydrogen and C1-C3 alkyl; andat least one of R7 and R8 is not hydrogen; and(iii) a 3-(azetidin-2-yl)pyridine or 3-(azetidin-2-ylmethoxy)pyridine having a structure according to Formula III:wherein L is a bond or —OCH2—*, where the asterisk indicates an attachment point to the azetidine ring;R9, R10, R11, and R12 are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, and cyano;R13 is H or CH3; andR14 is H or CH3.

2. The treated sheet article of claim 1, wherein the active ingredient has a structure according to Formula I, optionally wherein R1, R2, and R3 are each H, and R4 is optionally substituted C1-C6 alkyl, F, Cl, Br, OCH3, OEt, or CN, or optionally wherein R1, R2, and R3 are each H, and R4 is C1-C3 alkyl.

3. The treated sheet article of claim 1, wherein the active ingredient has a structure according to Formula II, optionally wherein R5 is optionally substituted C1-C6 alkyl, F, Cl, Br, OCH3, OCH2CH3, or CN; and R6 is H, or optionally wherein R5 is H; and R6 is optionally substituted C1-C6 alkyl, F, Cl, Br, OCH3, OCH2CH3, or CN.

4. The treated sheet article of claim 1, wherein the active ingredient has a structure according to Formula III, optionally wherein R9 is H or CH3; and R10, R11, and R12 are each H.

5. The treated sheet article of claim 1, wherein the active ingredient is in the form of a free base, a salt with an acid, an ion pair with an organic acid, or a resin complex wherein the active ingredient is bound to a polymeric resin.

6. The treated sheet article of claim 1, wherein the treatment composition further comprises a flavorant (e.g., a sensate), a salt, a colorant, a sweetener, a pH-adjusting component, or any combination thereof.

7. The treated sheet article of claim 1, wherein the treatment composition further comprises one or more additional active agents selected from the group consisting of a nicotine component, a cannabinoid, a terpene, caffeine, an amino acid, a vitamin, melatonin, a botanical extract, or any combination thereof.

8. The treated sheet article of claim 1, wherein the treatment composition further comprises a nicotine component.

9. The treated sheet article of claim 1, wherein the treated sheet article is substantially free of a nicotine component.

10. The treated sheet article of claim 1, wherein the treated sheet material comprises a single layer.

11. The treated sheet article of claim 1, wherein the treated sheet material comprises two or more layers, optionally comprising four or more layers, optionally comprising six or more layers, and optionally comprising eight or more layers.

12. The treated sheet article of claim 11, wherein the two or more layers comprise two or more layers with different compositions.

13. The treated sheet article of claim 11, wherein the two or more layers comprise two or more layers with identical structural components.

14. The treated sheet article of claim 11, wherein the two or more layers are stacked on top of one another.

15. The treated sheet article of claim 14, wherein adjacent layers are held together via lamination.

16. The treated sheet article of claim 14, wherein adjacent layers are held together via stitching, hydroentangling of fibers in the adjacent layers, needle punching, embossing, ultrasonic bonding, thermal bonding, or any combination thereof.

17. The treated sheet article of claim 1, consisting essentially of the treated sheet material.

18. The treated sheet article of claim 1, comprising one or more additional components.

19. The treated sheet article of claim 18, wherein the one or more additional components comprise a substrate.

20. A method of preparing the treated sheet article of claim 1, comprising:providing a sheet material;treating the sheet material, wherein the treating comprises providing one or more solutions, each of the one or more solutions comprising one or more dissolved ingredients of the treatment composition; applying the one or more solutions to a surface of the sheet material; and drying to give the treated sheet material; andoptionally combining the treated sheet material with one or more additional components to give the treated sheet article.

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