Oral product

Abstract

The present disclosure provides compositions configured for oral use, pouch products comprising such compositions, and methods of making the compositions and products. Exemplary compositions configured for oral use comprise a bulking agent component, water, and 3-(1-methylpyrrolidin-2-yl)pyridine bearing one or more substituents on the pyridine ring.

Description

Technical Field

[0001] This disclosure relates to oral products. In particular, this disclosure relates to products intended for human ingestion. The products are configured for oral use and deliver substances such as flavoring agents and / or active ingredients during use. Background Technology

[0002] There are many product categories designed for oral use and enjoyment. For example, oral tobacco products containing nicotine, which is known to have both stimulant and anti-anxiety properties, have been available for many years. Common forms of so-called "smokeless" tobacco products include snuff, snus, and chewing tobacco, which are typically made almost entirely of particulate, granular, or fragmented tobacco and are dispensed by the user or provided to the user in individual portions (e.g., in pouches or sachets). See, for example, the types, ingredients, and processing methods of smokeless tobacco formulations described in the following patents: U.S. Patent No. 6,668,839 to Williams; U.S. Patent No. 6,834,654 to Williams; U.S. Patent No. 6,953,040 to Atchley et al.; U.S. Patent No. 7,032,601 to Atchley et al.; U.S. Patent No. 7,694,686 to Atchley et al.; U.S. Patent No. 7,810,507 to Dube et al.; U.S. Patent No. 7,819,124 to Strickland et al.; U.S. Patent No. 7,861,728 to Holton, Jr. et al.; U.S. Patent No. 7,901,512 to Quinter et al.; U.S. Patent No. 8,627,828 to Strickland et al.; and U.S. Patent No. 11,246,334 to Atchley, each of which is incorporated herein by reference. In addition, traditional tobacco and non-tobacco materials have been combined with other ingredients to form product forms that differ from traditional smokeless products, such as lozenges, tablets, and gels.See, for example, the product types described in the following patents: U.S. Patent Application Publication No. 2008 / 0196730, Engstrom et al.; U.S. Patent Application Publication No. 2008 / 0305216, Crawford et al.; U.S. Patent Application Publication No. 2009 / 0293889, Kumar et al.; U.S. Patent Application Publication No. 2010 / 0291245, Gao et al.; U.S. Patent Application Publication No. 2011 / 0139164, Mua et al.; U.S. Patent Application Publication No. 2012 / 0037175, Cantrell et al.; U.S. Patent Application Publication No. 2012 / 0055494, Hunt et al.; U.S. Patent Application Publication No. 2012 / 0138073, Cantrell et al.; U.S. Patent Application Publication No. 2012 / 0138074, Cantrell et al.; U.S. Patent Application Publication No. 2013 / 0074855, Holton, Jr.; Holton, The following U.S. Patent Application Publication No. 2013 / 0074856 by Jr.; U.S. Patent Application Publication No. 2013 / 0152953 by Mua et al.; U.S. Patent Application Publication No. 2013 / 0274296 by Jackson et al.; U.S. Patent Application Publication No. 2015 / 0068545 by Moldovanu et al.; U.S. Patent Application Publication No. 2015 / 0101627 by Marshall et al.; and U.S. Patent Application Publication No. 2015 / 0230515 by Lampe et al. are each incorporated herein by reference.

[0003] There is a growing interest in developing new types of oral products that deliver beneficial sensory or bioactive effects. These products typically contain flavoring agents and / or active ingredients such as nicotine, caffeine, or botanical materials. The forms of these products can vary and include pouches containing powdered or granular compositions, lozenges, tablets, liquids, gels, emulsions, meltable compositions, etc. See, for example, the product types described in the following patents: U.S. Patent Application Publication No. 2022 / 0160675, Gerardi et al.; U.S. Patent Application Publication No. 2022 / 0071984, Poole et al.; U.S. Patent Application Publication No. 2021 / 0378948, Gerardi et al.; U.S. Patent Application Publication No. 2021 / 0330590, Hutchens et al.; U.S. Patent Application Publication No. 2021 / 0186081, Gerardi et al.; U.S. Patent Application Publication No. 2021 / 0177754, Keller et al.; U.S. Patent Application Publication No. 2021 / 0177043, Gerardi et al.; U.S. Patent Application Publication No. 2021 / 0177038, Gerardi et al.; U.S. Patent Application Publication No. 2021 / 0169867, Holton, Jr. et al.; Holton, U.S. Patent Application Publication No. 2021 / 0169792, Jr. et al.; U.S. Patent Application Publication No. 2021 / 0169132, Holton, Jr. et al.; U.S. Patent Application Publication No. 2021 / 0169121, St. Charles; and U.S. Patent Application Publication No. 2021 / 0169122, St. Charles, are each incorporated herein by reference.

[0004] Brief Overview

[0005] This disclosure generally provides compositions configured for oral use, products comprising such compositions, and methods of manufacturing such compositions and products. The compositions comprise a filler component, water, and 3-(1-methylpyrrolidone-2-yl)pyridine having one or more substituents on a pyridine ring. This disclosure includes, but is not limited to, the following embodiments.

[0006] Embodiment 1: A composition formulated for oral use, the composition comprising: a composition formulated for oral use, the composition comprising: a filler component; water, in an amount of about 1 to about 60% by weight based on the total weight of the composition; and a substituted 3-(1-methylpyrrolidone-2-yl)pyridine having a structure according to Formula I: (I), Where R 1 R 2 R3 and R 4 Each is independently selected from the group consisting of: hydrogen, alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl, aryl, alkylaryl, amino, halogen, and cyano, wherein any one of the alkyl, alkoxy, cycloalkyl, alkenyl, alkenyl, alkynyl, aryl, alkylaryl, and amino groups may optionally be substituted; and R 1 R 2 R 3 and R 4 At least one of them is not hydrogen.

[0007] Embodiment 2: The composition as described in Embodiment 1, wherein R 1 R 2 and R 3 Each is represented by H.

[0008] Embodiment 3: The composition as described in Embodiment 1 or 2, wherein R 4 It can be an optional substituted C1-C6 alkyl, F, Cl, Br, OCH3, OCH2CH3 or CN.

[0009] Embodiment 4: The composition as described in any one of Embodiments 1-3, wherein R 1 R 2 and R 3 Each is H, and R 4 It is a C1-C3 alkyl group; preferably, R 4 It is CH3.

[0010] Embodiment 5: The composition of any one of Embodiments 1-4, wherein the substituted 3-(1-methylpyrrolidone-2-yl)pyridine is racemic.

[0011] Embodiment 6: The composition of any one of Embodiments 1-4, wherein the substituted 3-(1-methylpyrrolidone-2-yl)pyridine has an (R)-configuration or an (S)-configuration; preferably, wherein the substituted 3-(1-methylpyrrolidone-2-yl)pyridine has an (S)-configuration.

[0012] Embodiment 7: The composition of any one of Embodiments 1-6, wherein the calculated logP of the substituted 3-(1-methylpyrrolidone-2-yl)pyridine is about 1 or greater, for example about 1.2 to about 1.7.

[0013] Embodiment 8: A composition as described in any one of Embodiments 1-7, wherein the composition is substantially free of 3-(1-methylpyrrolidone-2-yl)pyridine; optionally, wherein the composition is completely free of 3-(1-methylpyrrolidone-2-yl)pyridine.

[0014] Embodiment 9: The composition as described in any one of Embodiments 1-8, wherein the composition is substantially free of acid components; optionally, the composition is completely free of acid components.

[0015] Embodiment 10: The composition of any one of Embodiments 1-8 further comprises an organic acid, an alkali metal salt of an organic acid, or a combination thereof, wherein the organic acid has a logP value in the range of about 1 to about 12; optionally, wherein the logP value of the organic acid is about 3 to about 12, about 3 to about 10, or about 3 to about 8, and wherein the substituted 3-(1-methylpyrrolidone-2-yl)pyridine is present at least in part in the form of an ion pair with the organic acid, the alkali metal salt of the organic acid, or a combination thereof.

[0016] Example 11: The composition of any one of Examples 1-8, wherein at least a portion of the substituted 3-(1-methylpyrrolidone-2-yl)pyridine is present in the form of a salt, a eutectic or a salt eutectic.

[0017] Example 12: The composition of any one of Examples 1-8, wherein at least a portion of the substituted 3-(1-methylpyrrolidone-2-yl)pyridine is incorporated into the polymer resin.

[0018] Example 13: A composition as described in any one of Examples 1-12, wherein the substituted 3-(1-methylpyrrolidone-2-yl)pyridine is present in an amount of about 0.01 to about 10% by weight based on the total weight of the composition, calculated as a free base.

[0019] Embodiment 14: The composition of any one of Embodiments 1-13, wherein the filler component is cellulose-based, and optionally, wherein the filler component comprises microcrystalline cellulose.

[0020] Embodiment 15: The composition of any one of Embodiments 1-14 further comprises one or more flavoring agents, one or more salts, one or more sweeteners, one or more binders, one or more humectants, one or more gums, or combinations thereof.

[0021] Embodiment 16: The composition as described in any one of Embodiments 1 to 15 is in the form of gel, lozenge, gum, chewable substance, melt, tablet, lozenge, film, granular material or powder.

[0022] Embodiment 17: The composition as described in any one of Embodiments 1-15, which is packaged in a bag to form a bagged product, wherein the composition is optionally in granular form.

[0023] Embodiment 18: The composition as described in Embodiment 17 has a moisture content of about 30 to about 60% by weight based on the weight of the bagged product.

[0024] Embodiment 19: A composition formulated for oral use, the composition comprising 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine in an amount of about 0.01 to about 10% by weight based on the total weight of the composition; a filler component; and water in an amount of about 1 to about 60% by weight or about 30 to about 60% by weight based on the total weight of the composition.

[0025] Embodiment 20: The composition as described in Embodiment 19, wherein the filler component is cellulose-based, and optionally, wherein the filler component comprises microcrystalline cellulose.

[0026] Embodiment 21: The composition as described in Embodiment 19 further comprises a buffer; optionally, the buffer is an alkali metal salt of citrate.

[0027] Example 22: The composition of any one of Examples 1-21, wherein when the composition is placed in 500 mL of pH 7.4 phosphate buffer and stirred at 50 RPM for 50 minutes in a USP basket dissolution apparatus at 37°C, at least about 60% by weight of the total weight of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine present in the composition is released.

[0028] Example 23: The composition as described in Example 22, wherein at least about 20% of the total weight of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine present in the composition is released after 10 minutes.

[0029] Embodiment 24: A method for preparing a composition comprising substituted 3-(1-methylpyrrolidone-2-yl)pyridine for oral use, the method comprising: One or more fillers are mixed with one or more additional powder components (e.g., one or more salts and / or one or more sweeteners) to form a dry blend; A dilute aqueous solution of substituted 3-(1-methylpyrrolidone-2-yl)pyridine is mixed with water and an optional humectant to form a solution; The solution is mixed with the dry blend to form a mixture; The resulting mixture is mixed to form a wet blend; and Optionally, flavoring agents and / or water may be added to the wet blend to form a composition.

[0030] Example 25: The method as described in Example 22, wherein the substituted 3-(1-methylpyrrolidone-2-yl)pyridine is 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine.

[0031] These and other features, aspects, and advantages of this disclosure will become apparent from the following detailed description of the embodiments, which are briefly described below. The scope of this disclosure includes any combination of two, three, four, or more of the above-described embodiments, as well as any combination of two, three, four, or more features or elements set forth in this disclosure, whether or not such features or elements are explicitly combined in the description of the specific embodiments herein. This disclosure is intended to be read holistically; therefore, any separable features or elements of the disclosed embodiments should be considered as intended to be composable or implementable individually / independently, unless the context clearly indicates otherwise. Attached Figure Description

[0032] Having given a general overview of various aspects of this disclosure above, the description will now take place with reference to the accompanying drawings, which are not necessarily drawn to scale. The drawings are merely illustrative and should not be construed as limiting the scope of this disclosure.

[0033] Figure 1 This is a cross-sectional view of a non-limiting embodiment of the bagged product, taken along the width of the product, showing the outer bag filled with the mixture of the present disclosure.

[0034] Figure 2 This is an illustration of a bagged product according to an embodiment of the present disclosure, formed from a permeable fabric bag, containing a composition and comprising encapsulated active contents (payload).

[0035] Figure 3 This is an illustration of a bagged product according to an embodiment of the present disclosure, formed from a water-permeable fabric bag, wherein the composition is contained and includes a plurality of capsules encapsulating active contents.

[0036] Figure 4 The steps of a method for preparing a composition configured for oral use according to a non-limiting embodiment of the present disclosure are shown.

[0037] Figure 5 This is a graph showing the change of active ingredient release % over time according to a non-limiting embodiment of the present disclosure.

[0038] Detailed Explanation

[0039] This disclosure will now be described more fully below with reference to exemplary embodiments thereof. These exemplary embodiments are described so that this disclosure will be thorough and complete, and will fully convey the scope of this disclosure to those skilled in the art. In fact, this disclosure may be implemented in many different forms and should not be construed as limited to the embodiments shown herein; rather, these embodiments are provided to enable this disclosure to meet applicable legal requirements.

[0040] As used in this specification and claims, the singular forms “a,” “an,” and “the” include plural references unless the context clearly indicates otherwise.

[0041] The term "about" as used in this specification describes and covers minor fluctuations. For example, the term "about" can mean less than or equal to ±10%, such as less than or equal to ±5%, less than or equal to ±2%, less than or equal to ±1%, less than or equal to ±0.5%, less than or equal to ±0.2%, less than or equal to ±0.1%, or less than or equal to ±0.05%. All numerical values ​​herein are modified by the term "about," whether explicitly stated or not. Values ​​modified by the term "about" naturally include specific values. For example, "about 5.0" must include 5.0.

[0042] References to "percentage by dry weight" or "based on dry weight" refer to the weight of the dry components (i.e., all components except water). References to "wet weight" refer to the weight of the composition, including water. Unless otherwise stated, references to "percentage by weight" of a composition reflect the total wet weight of the composition (i.e., including water).

[0043] Compositions formulated for oral use

[0044] This disclosure provides compositions configured for oral use, products comprising such compositions, and methods for preparing said compositions. The compositions typically comprise substituted 3-(1-methylpyrrolidone-2-yl)pyridine, a filler component, and water. The compositions, products comprising such compositions, and their respective components are further described below.

[0045] Substituted 3-(1-methylpyrrolidone-2-yl)pyridine

[0046] This document discloses compositions comprising substituted 3-(1-methylpyrrolidone-2-yl)pyridine formulated for oral use. As used herein, the term "substituted 3-(1-methylpyrrolidone-2-yl)pyridine" refers to a compound having a 3-(1-pyrrolidone-2-yl)pyridine skeleton and having one or more non-hydrogen substituents on the pyridine ring. The compositions disclosed herein are nicotine-free and do not contain any compounds obtained through chemical reactions using nicotine as a starting material. In a preferred embodiment, the substituted 3-(1-methylpyrrolidone-2-yl)pyridine present is not derived from nicotine synthesis.

[0047] In some embodiments, the compositions and products of this disclosure are characterized by being completely or substantially free of nicotine (3-(1-methylpyrrolidone-2-yl)pyridine). "Substantially free" means that no nicotine has been actively added, and it is only permitted as a trace impurity in the other components (including small amounts of impurities as substitutes for 3-(1-methylpyrrolidone-2-yl)pyridine). For example, some embodiments are characterized by having less than 0.01% by weight of nicotine, or less than 0.001% by weight of nicotine, or less than 0.0001% by weight of nicotine, or even 0% by weight of nicotine, calculated as free base and based on the total weight of the composition. In some embodiments, the composition is completely free of ( R )-、( S )-and( R / S 3-(1-methylpyrrolidone-2-yl)pyridine (e.g., nicotine having 0% by weight, including racemic nicotine and nicotine enantiomers, calculated as free base and based on the total weight of the composition).

[0048] In some embodiments, the substituted 3-(1-methylpyrrolidone-2-yl)pyridine has a structure according to Formula I: (I), in: R 1 R 2 R 3 and R 4 Each is independently selected from the group consisting of: hydrogen, alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl, aryl, alkylaryl, amino, halogen, and cyano, wherein any one of the alkyl, alkoxy, cycloalkyl, alkenyl, alkenyl, alkynyl, aryl, alkylaryl, and amino groups may optionally be substituted; and R 1 R 2 R 3 and R 4 At least one of them is not hydrogen.

[0049] With various R 1 R 2 R 3 and R 4Substituent 3-(1-methylpyrrolidone-2-yl)pyridines have been previously reported. See, for example, U.S. Patent Nos. 4,321,387, 4,155,909; 5,015,741, 5,138,062 and 5,703,100, each incorporated herein by reference and describing such substituted 3-(1-methylpyrrolidone-2-yl)pyridines, their synthesis and pharmacological properties. Substituent 3-(1-methylpyrrolidone-2-yl)pyridines and their pharmacological characteristics are also disclosed in Wang et al., Drug Development Research 1998, Vol. 45, No. 1, pp. 10-16; and Dukat et al., European Journal of Medicinal Chemistry 1999, 34(1): 31-40.

[0050] In some implementations, R 1 R 2 and R 4 Each is H, and R 3 It is a non-hydrogen substituent. In some embodiments, R 3 It is an optionally substituted C1-C6 alkyl group, F, Cl, Br, OMe, OEt, or CN. In some embodiments, R 3 It is Me or Et. In some implementations, R 3 It is F.

[0051] In some implementations, R 1 R 2 R3 and R4 are both H, and R4 is a non-hydrogen substituent.

[0052] In some implementations, R 4 It can be an optional substituted C1-C6 alkyl, F, Cl, Br, OMe, OEt or CN.

[0053] In some implementations, R 1 R 2 and R 3 Each is H, and R 4 It can be an optional substituted C1-C6 alkyl group, F, Cl, Br, OCH3, OEt, or CN.

[0054] In some implementations, R 1 R 2 and R 3 Each is H, and R 4 It is a C1-C3 alkyl group.

[0055] In some implementations, R 1 R 2 and R3 Each is H, and R 4 It is CH3. In such embodiments, the compound of formula I may be referred to as 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine.

[0056] For example, Dukat et al. reported the pharmacology of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine in the *European Journal of Medicinal Chemistry*, Vol. 31, No. 11, 1996, pp. 875-888 (incorporated hereby by reference), and Carmines et al. discussed the pharmacological characteristics of the (S)-enantiomer of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine in the form of its benzoate salt at the 76th TSRC meeting, Norfolk, VA, USA, on poster board #6 (CAS 2861225-70-7; referred to as Imotine). TM ).

[0057] Without being bound by any particular theory, it is believed that replacing hydrogen atom on the pyridine ring of substituted 3-(1-methylpyrrolidone-2-yl)pyridine compounds with certain substituents can preserve the general pharmacological characteristics and physiological effects of nicotine, while providing one or more of the following potentials: higher potency, lower product consumption, faster and / or more complete absorption, etc. In particular, it is believed that in some embodiments, the substituted 3-(1-methylpyrrolidone-2-yl)pyridine of this disclosure is readily absorbed through the oral mucosa due to its lipophilicity. Lipophilicity is conveniently measured as logP, which is the partition coefficient of the molecule between the lipophilic phase and the aqueous phase (typically octanol and water, respectively). Thus, in some embodiments, the substituted 3-(1-methylpyrrolidone-2-yl)pyridine of Formula I has a calculated or experimental logP of about 1 or greater, where logP is the log of the partition coefficient of the substituted 3-(1-methylpyrrolidone-2-yl)pyridine between octanol and water. 10The logP value can be measured experimentally using methods well known to those skilled in the art. Alternatively, the logP value can be calculated using commercially available software. In some embodiments, the calculated logP of the substituted 3-(1-methylpyrrolidone-2-yl)pyridine of Formula I is 1 to about 2, for example 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, or 1.9. In some embodiments, the calculated logP of the substituted 3-(1-methylpyrrolidone-2-yl)pyridine of Formula I is about 1.2 to about 1.7. In some embodiments, the substituted 3-(1-methylpyrrolidone-2-yl)pyridine with a calculated logP of about 1.2 to about 1.7 has 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 positions 2, 4, 5, or 6 of the pyridine ring. In some embodiments, the lipophilically substituted 3-(1-methylpyrrolidone-2-yl)pyridine is 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine.

[0058] Substituted 3-(1-methylpyrrolidone-2-yl)pyridine (e.g., 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine) can be present as a single enantiomer or as a mixture of enantiomers. In some embodiments, the substituted 3-(1-methylpyrrolidone-2-yl)pyridine is present in a racemic form other than substituted 3-(1-methylpyrrolidone-2-yl)pyridine, meaning that equal amounts of (R)- and (S)-enantiomers are present. In some embodiments, the composition comprises unequal amounts of (R)- and (S)-enantiomers (i.e., rich in (R)- or (S)-enantiomers). In some embodiments, the composition primarily comprises substituted 3-(1-methylpyrrolidone-2-yl)pyridine (e.g., 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine) in the (R)- configuration, for example, about 90% or more of the total amount of substituted 3-(1-methylpyrrolidone-2-yl)pyridine present is in the (R)- configuration. In some embodiments, the composition primarily comprises (S)-configured substituted 3-(1-methylpyrrolidone-2-yl)pyridine (e.g., 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine), for example, about 90% or more of the total amount of substituted 3-(1-methylpyrrolidone-2-yl)pyridine present being (S)-configured. In some embodiments, the composition comprises 95% or more of (S)-configured substituted 3-(1-methylpyrrolidone-2-yl)pyridine (e.g., 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine) based on the total amount of substituted 3-(1-methylpyrrolidone-2-yl)pyridine present.

[0059] The amount of substituted 3-(1-methylpyrrolidone-2-yl)pyridine (e.g., 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine) present in the composition can vary. Typically, the substituted 3-(1-methylpyrrolidone-2-yl)pyridine (e.g., 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine, calculated as a free base) is present at a concentration of at least about 0.001% by weight (based on the weight of the composition), for example, in the range of about 0.01% to about 10%. In some embodiments, the substituted 3-(1-methylpyrrolidone-2-yl)pyridine (e.g., 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine) is present at a concentration of about 0.1 wt% to about 10 wt%, for example about 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, or 0.9 wt% to about 1 wt%, 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, or 10 wt%, calculated as free base and based on the total weight of the composition. In some embodiments, the substituted 3-(1-methylpyrrolidone-2-yl)pyridine (e.g., 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine) is present at a concentration of about 0.1 wt% to about 3 wt%, for example, about 0.1 wt% to about 2.5 wt%, about 0.1 wt% to about 2.0 wt%, about 0.1 wt% to about 1.5 wt%, or about 0.1 wt% to about 1 wt%, calculated as free base and based on the total weight of the composition. In some embodiments, the composition comprises about 0.01 to about 10 wt% of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine based on the total weight of the composition.

[0060] The substituted 3-(1-methylpyrrolidone-2-yl)pyridine (e.g., 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine) may exist in the composition as a free base, a salt formed with a suitable acid, a co-crystal formed with a suitable coformer, or an ion pair formed with a suitable organic acid. Each of these forms is further described below.

[0061] Free base

[0062] In some embodiments, the substituted 3-(1-methylpyrrolidone-2-yl)pyridine exhibits sufficient stability, water solubility, and oral bioavailability to make the free base suitable for inclusion in the composition. Therefore, in some embodiments, the substituted 3-(1-methylpyrrolidone-2-yl)pyridine is present substantially or entirely as a free base. In such embodiments, those skilled in the art will recognize that the composition is substantially free of acidic components. “Substantially free” means that only trace amounts of acidic components are permitted as impurities of other components, and no acidic components (e.g., inorganic acids, organic acids, or acids capable of forming salts, ion pairs, or eutectics) are actively added. For example, some embodiments may be characterized by having less than 0.001% by weight of any acidic component, or less than 0.0001% by weight, or even 0% by weight of any acidic component, based on the total weight of the composition. In some embodiments, the composition is completely free of any acidic component (i.e., characterized as 0% or in amounts below the detection limit). In some embodiments, the substituted 3-(1-methylpyrrolidone-2-yl)pyridine exists as a free base and is adsorbed onto a support (such as a microcrystalline cellulose material) to form an adsorption complex.

[0063] Salt

[0064] In some embodiments, at least a portion of the substituted 3-(1-methylpyrrolidone-2-yl)pyridine may be used in the form of a salt. A “salt” of substituted 3-(1-methylpyrrolidone-2-yl)pyridine is a form characterized by an interaction between the ionic substituted 3-(1-methylpyrrolidone-2-yl)pyridine and an ionic co-formation (e.g., an acid) through the transfer of one or more protons from the co-formation donor to the nicotine acceptor. The structure of the substituted 3-(1-methylpyrrolidone-2-yl)pyridine disclosed herein comprises two nitrogen atoms capable of accepting protons from the co-formation, and thus it may exist in a deprotonated, monoprotonated, and / or diprotonated form in a given sample. Salts that replace 3-(1-methylpyrrolidone-2-yl)pyridine can be provided using the types of components and techniques described for nicotine in Cox et al., U.S. Patent No. 2,033,909, and in the International Proceedings of the Tobacco Research Conference (Beitrage Tabakforschung Int.), 12:43-54 (1983), which are incorporated herein by reference. Suitable salts are generally water-soluble. Suitable acids for forming salts (monosal and diosal) include, but are not limited to, acetic acid, adipic acid, ascorbic acid, decanoic acid, citric acid, D-glucuronic acid, D-gluconic acid, lactic acid, galactobionic acid, hippuric acid, hydrochloric acid, L-aspartic acid, L-glutamic acid, L-glutamate, glycerophosphate, glycolic acid, lauric acid, DL-malic acid, L-malic acid; tartaric acid, palmitic acid, phosphoric acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, thiocyanate, (+)-camphoric acid, 1,5-naphthalenedisulfonic acid, 1-hydroxy-2-naphthoic acid, 2,5-dihydroxybenzoic acid, benzenesulfonic acid, benzoic acid, caprylic acid, cyclohexylaminosulfonic acid, ethanesulfonic acid, fumaric acid, D-glucoheponic acid, 4-hydroxybenzoic acid, isocyanate, etc. Butyric acid, ketoglutarate, 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, tervaline, propionic acid, L-pyroglutamic acid, p-toluenesulfonic acid, (1S)-camphor-10-sulfonic acid, 4-acetaminobenzoic acid, 4-aminosalicylic acid, N-acetyl-4-aminosalicylic acid, hexanoic acid, dichloroacetic acid, hydrobromic acid, DL-mandelic acid, L-mandelic acid, nitric acid, formic acid, salicylic acid, cinnamic acid, undecenoic acid, hydroxyethylsulfonic acid, lauric acid, 2-hydroxybenzoic acid, trans-2-hexenoic acid, trimesic acid, 5-nitroisophthalic acid, and zinc chloride monohydrate (forming a zinc chloride complex salt).

[0065] In some embodiments, a hydrophilic acid is chosen to increase the water solubility of the salt and / or decrease its lipophilicity. The lipophilicity of substituted 3-(1-methylpyrrolidone-2-yl)pyridinium salts can also be expressed as logD, where logD is the logarithm of the partition coefficient, a measure of the pH-dependent difference in solubility of all substances (ionized and unionized) in the octanol / water system between the octanol and aqueous phases, and is expressed by the following formula: .

[0066] logD is a commonly used descriptor for the lipophilicity of ionic compounds. The logD value can be calculated using commercially available software, or it can be determined experimentally in a manner similar to logP, but instead of using water, a buffer solution is used to adjust the aqueous phase to a specific pH. Since logD is pH-dependent, the pH at which logD is measured must be specified.

[0067] When substituted 3-(1-methylpyrrolidone-2-yl)pyridine is present in salt form, it is generally preferred that the salt has a relatively low logD, indicating good water solubility. It is not desirable to be bound by theory, but it is believed that highly water-soluble salt forms can exhibit high dissolution rates, which can be advantageous in some embodiments. Therefore, in some embodiments, the logD of substituted 3-(1-methylpyrrolidone-2-yl)pyridine salts is about -1.0 to about 3 in a pH range of about 3 to about 11, for example, about -0.5 to about 2, about -0.3 to about 1, or about -0.1 to about 0.

[0068] In some embodiments, the substituted 3-(1-methylpyrrolidone-2-yl)pyridine exists in the form of a salt of tartaric acid, succinic acid, orotic acid, fumaric acid, pyroglutamic acid, or galactosic acid.

[0069] The stoichiometric ratio of the salts described herein can vary. For example, in some embodiments, the stoichiometric ratio of substituted 3-(1-methylpyrrolidone-2-yl)pyridine to acid can range from about 5:1 to about 1:5. In some embodiments, the ratio of substituted 3-(1-methylpyrrolidone-2-yl)pyridine to acid is 2:1, 1:1, or 1:2. Hydrates and other solvates of the salts are also considered herein.

[0070] The salts described herein can exist in various polymorphic and pseudopolymorphic forms in some embodiments. Polymorphism is the ability of a crystalline material to exist in more than one form or crystal structure. Polymorphism can arise, for example, from the presence of different crystal packing structures (packing polymorphism) or from the presence of different conformational isomers of the same molecule (conformational polymorphism). Pseudopolymorphism is the result of hydration or solvation of the material, also known as solvation polymorphism.

[0071] resin complex

[0072] In some embodiments, at least a portion of the substituted 3-(1-methylpyrrolidone-2-yl)pyridine may be present in the form of a polymeric complex, wherein the substituted 3-(1-methylpyrrolidone-2-yl)pyridine is incorporated into an acidic polymer. The polymer of the substituted 3-(1-methylpyrrolidone-2-yl)pyridine-polymeric complex may be any polymer having an acidic functional group (including homopolymers or all types of copolymers), such as a polymeric cation exchange resin. In some embodiments, the polymer contains acidic sites, which may be classified as strongly acidic, weakly acidic, or moderately acidic (depending on, for example, the strength of its derived acid). In some embodiments, the polymer contains weakly acidic sites and may be referred to as a weakly acidic cation exchange resin. Non-limiting examples of acidic sites include, for example, carboxylic acids, sulfonic acids, phosphonic acids, phosphonic acids, phosphoric acids, iminodiacetic acids, and phenolic groups (e.g., as described by Adams et al. in the Journal of Chemical Industry). J. Soc. Chem. Ind. The polymers disclosed in 54, IT (1935), which is incorporated herein by reference. Suitable polymers include, but are not limited to, addition polymers of styrene and divinylbenzene, addition polymers of divinylbenzene and methacrylic acid, addition polymers of divinylbenzene and acrylic acid, phenolic resins, or cellulose, dextran, or pectin crosslinked with epichlorohydrin, etc. In some embodiments, the polymers comprise a crosslinked portion. Various acidic ion exchange resins known in the art and suitable for forming substituted 3-(1-methylpyrrolidone-2-yl)pyridine complexes include, but are not limited to, polymethacrylic acid resins such as DuPont™ Amberlite™ IRP64, DuPont™ Amberlite™ IRP69, Purolite™ C115HMR, Doshion™ P551, and polyacrylic acid carbomers such as Carbopol 974P. See, for example, U.S. Patent No. 3,901,248 to Lichtneckert et al., which is incorporated herein by reference. In some embodiments, when the substituted 3-(1-methylpyrrolidone-2-yl)pyridine is present in the form of a polymeric complex, the composition further comprises a divalent metal buffer, such as a calcium or magnesium salt (e.g., carbonate, bicarbonate, oxide, acetate, etc.).

[0073] Eutectic

[0074] In some embodiments, at least a portion of the substituted 3-(1-methylpyrrolidone-2-yl)pyridine may be present in a cocrystal form. A “cocrystal” of substituted 3-(1-methylpyrrolidone-2-yl)pyridine is a form comprising the substituted 3-(1-methylpyrrolidone-2-yl)pyridine as described herein and at least one other component (“co-formation”), both in a neutral state. Specifically, as defined in the U.S. Food and Drug Administration (FDA) Industry Guidance document, a cocrystal is a solid crystalline material composed of two or more molecules in the same lattice, wherein the components are in a neutral state and interact through nonionic interactions. See the U.S. Department of Health and Human Services FDA Industry Guidance: Regulatory Classification of Pharmaceutical Cocrystals (April 2013), which is incorporated herein by reference. This form is distinct from and differentiated from both salts and ion pairs as described herein. Specifically, cocrystals are generally distinguished from salts (and ion pairs) by the absence of proton transfer between the components (i.e., between the substituted 3-(1-methylpyrrolidone-2-yl)pyridine and one or more co-formations). The crystal structure of a cocrystal is typically maintained by freely reversible non-covalent interactions. The cocrystal typically comprises stoichiometrically substituted 3-(1-methylpyrrolidone-2-yl)pyridines and co-formations. In some embodiments, the cocrystal may encompass hydrates, solvates, and inclusion compounds. The cocrystal may comprise a combination of substituted 3-(1-methylpyrrolidone-2-yl)pyridines with organic and / or inorganic co-formations.

[0075] Examples of suitable co-formulated compounds include, but are not limited to, acetaminophen, L-proline, tromethamine, urea, xylitol, caffeine, glycine / glycine anhydride, vanillin, methylparaben, succinimide, L-alanine, mannitol, L-phenylalanine, saccharin, propylparaben, N-methylglucosamine, L-tyrosine, gentian acid, sorbic acid, benzoic acid, L-methionine, maltol, and L-lysine. Tromethamine, nicotinamide, isonicotinamide, phenylalanine, benzoquinone, terephthalaldehyde, 4-hydroxybenzoic acid, pyruvic acid, 1-hydroxy-2-naphthylcarboxylic acid, 4-aminobenzoic acid, vanillic acid, ethyl vanillin, isonicotinic acid, gallic acid, menthol (e.g., racemic menthol or (-)-menthol), acetaminophen, aspirin, ibuprofen, naproxen, ketoprofen, flurbiprofen, glucose, serine, malic acid, acetamide, sulfaacetyl, benzoic acid Creatine, 2-hydroxyethanesulfonic acid, clofibrate, taurine, isoniazid, L-histidine, L-arginine, L-asparagine, glutamine, L-cysteine, alanine, valine, isoleucine, leucine, morpholine, threonine, N-methylglucosamine, 3-hydroxy-2-oxopropionic acid; 2-oxobutyric acid (2-ketobutyric acid), 3-methyl-2-oxobutyric acid; 3-methyl-2-oxovalerate; 4-methyl-2-oxovalerate ; as well as 2-oxoglutaric acid, 2-oxo-3-phenylpropionic acid; 5-oxooctanoic acid; and 5-oxodecanoic acid, aldonic acids (e.g., glyceric acid, xylic acid, gluconic acid and ascorbic acid), ketonic acids (e.g., neuraminic acid and ketodeoxyoctanoic acid), uronic acids (e.g., glucuronic acid, galacturonic acid and iduronic acid), glycolic acids (e.g., tartaric acid, mesogalactoic acid / mucoic acid and D-gluconic acid / glycolic acid), galactoic acid) and polyfunctional aromatic acids.

[0076] In some embodiments, the co-formed product is a polyfunctional aromatic acid. Polyfunctional aromatic acids typically contain a substituted or unsubstituted phenyl group as the aromatic component, but may alternatively contain another aromatic moiety, such as pyridine, pyrazine, imidazole, pyrazole, oxazole, thiophene, naphthalene, anthracene, and phenanthrene. The substituents on the optionally substituted aromatic acid can be of any type, including but not limited to halogens (e.g., Cl, F, Br, and I); alkyl, haloalkyl (e.g., CF3, 2-Br-ethyl, CH2F, CH2Cl, CH2CF3, or CF2CF3); alkenyl, hydroxyl; amino; carboxyl; carboxamidyl; alkylamino; arylamino; alkoxy; aryloxy; nitro; azide; cyano; thio; sulfonic acid; sulfate; phosphonic acid; phosphate ester and phosphonate group. Exemplary polyfunctional aromatic acids may be, for example: Substituted and unsubstituted aromatic dicarboxylic acids (e.g., 1,2-phthalic acid (orthophthalic acid), 1,3-phthalic acid (isophthalic acid), 1,4-phthalic acid (terephthalic acid), 2-iodo-1,3-phthalic acid, 2-hydroxy-1,4-phthalic acid, 2-nitro-1,4-phthalic acid, 3-fluoro-1,2-phthalic acid, 3-amino-1,2-phthalic acid, 3-nitro-1,2-phthalic acid, 4-bromo-1,3-phthalic acid, 4-hydroxy-1,3-phthalic acid, 4-amino-1,2- Phthalic acid, 4-nitro-1,2-phthalic acid, 4-sulfon-1,2-phthalic acid, 4-amino-1,3-phthalic acid, 5-bromo-1,3-phthalic acid, 5-hydroxy-1,3-phthalic acid, 5-amino-1,3-phthalic acid, 5-nitro-1,3-phthalic acid, 5-ethynyl-1,3-phthalic acid, 5-cyano-1,3-phthalic acid, 5-nitro-1,3-phthalic acid, 2,5-hydroxy-1,4-phthalic acid and 2,3,5,6-tetrafluoro-1,4-phthalic acid); 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) Formic 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-(acetamido)-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-Diiodo-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); Substituted and unsubstituted dihydroxybenzoic acids (e.g., 2,3-dihydroxybenzoic acid (pyrocatechin / hypogallic acid), 2,4-dihydroxybenzoic acid (β-resorcinolic acid), 2,5-dihydroxybenzoic acid (gentianic acid / hydroquinone carboxylic acid), 2,6-dihydroxybenzoic acid (γ-resorcinolic acid), 3,4-dihydroxybenzoic acid (protocatechinic acid), 3,5-dihydroxybenzoic acid (α-resorcinolic acid), 4-hydroxy-3-methoxy Benzoic acid (vanillic acid), 6-methyl-2,4-dihydroxybenzoic acid (tesuric 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); 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)); Substituted and unsubstituted aromatic tricarboxylic acids (e.g., 1,2,3-benzenetricarboxylic acid, 1,2,4-benzenetricarboxylic acid (tribenzoic acid)); and Substituted and unsubstituted aromatic tetracarboxylic acids (e.g., 1,2,3,4-benzenetetracarboxylic acid (metrexed) and 1,2,4,5-benzenetetracarboxylic acid (pyromellitic)). Various combinations of any of the aforementioned acids are also considered.

[0077] In some embodiments, the co-formed product is L-malic acid, succinic acid, or a combination thereof. In some embodiments, the co-formed product is 1,1,6,6-tetraphenyl-2,4-hexadiyne-1,6-diol. In some embodiments, the co-formed product is diiodotetrafluorobenzene, 4,4'-diiodooctafluorobiphenyl, or 1,4-bis(diphenylhydroxymethyl)benzene. In some embodiments, the co-formed product is orotic acid.

[0078] In some embodiments, the substituted 3-(1-methylpyrrolidone-2-yl)pyridine exists in the form of a salt cocrystal. A "salt cocrystal" is a hybrid structure exhibiting characteristics of both a salt and a cocrystal. Typically, the substituted 3-(1-methylpyrrolidone-2-yl)pyridine molecule in the salt cocrystal is associated with at least two co-formations (which may be the same or different), one of which is in ionic form (e.g., an acid) and transfers a proton to the substituted 3-(1-methylpyrrolidone-2-yl)pyridine molecule, while the second co-formation does not transfer a proton to the substituted 3-(1-methylpyrrolidone-2-yl)pyridine molecule. Suitable acids and co-formations are typically those described above regarding salts and cocrystals.

[0079] The stoichiometric ratios of the cocrystals and salt cocrystals described herein can vary. For example, in some embodiments, when both components are present, the stoichiometric ratio of substituted 3-(1-methylpyrrolidone-2-yl)pyridine to co-formed product can range from about 5:1 to about 1:5. When more than one co-formed product is used to form the cocrystal or salt cocrystal, the proportions of the co-formed product relative to substituted 3-(1-methylpyrrolidone-2-yl)pyridine and between them can also vary.

[0080] The eutectic and salt eutectic described herein can exist in various polymorphic and pseudopolymorphic forms, as well as as solvates and hydrates, in some embodiments.

[0081] In some embodiments, the substituted 3-(1-methylpyrrolidone-2-yl)pyridine exists in the form of a salt co-crystal. In some embodiments, the salt co-crystal is a di-lactate co-crystal. In some embodiments, the di-lactate co-crystal is a hemihydrate.

[0082] ion pairs

[0083] In some embodiments, at least a portion of the substituted 3-(1-methylpyrrolidin-2-yl)pyridine is present in ion-pair form. An ion-pair describes the partial association of oppositely charged ions in a relatively concentrated solution to form a unique chemical substance called an ion pair. The strength of the association (i.e., the ion pair) depends on the electrostatic attraction between the positive and negative ions (i.e., the conjugate base of the substituted 3-(1-methylpyrrolidin-2-yl)pyridine and a suitable acid). A “conjugate base” refers to a base produced by the deprotonation of the corresponding acid (e.g., benzoate is the conjugate base of benzoic acid). In embodiments containing ion pairs, on average, certain groups of these ion pairs are present at any given time, although the formation and dissociation of ion pairs are continuous. In some embodiments, in the compositions disclosed herein, and / or during oral use of the compositions (e.g., upon contact with saliva), at least a portion of the conjugate base of the substituted 3-(1-methylpyrrolidin-2-yl)pyridine and the acid is present in ion-pair form. Ion pairs are further described in, for example, International Patent Application Publication No. WO2021 / 050741 by Poole et al., U.S. Patent Application Publication No. 2021 / 0068447 by Keller et al., U.S. Patent Application Publication No. 2023 / 0138306A1 by Zawadzki et al., and U.S. Patent Application Publication No. 2022 / 0346434 by Von Cosmos et al., each of which is incorporated herein by reference.

[0084] Those skilled in the art will recognize that the degree of ion association in the disclosed compositions, whether before or during consumer use, can vary depending on factors such as pH, the nature of the acid, the concentration of substituted 3-(1-methylpyrrolidone-2-yl)pyridine, the concentration of the acid or its conjugate base present in the composition, the water content of the composition, and the ionic strength of the composition. Those skilled in the art will also recognize that ion pairing is an equilibrium process influenced by the aforementioned variables. Therefore, quantifying the degree of ion pairing is difficult or impossible by calculation or direct observation. However, the presence of ion pairs can be demonstrated by alternative measurements, such as the partitioning of substituted 3-(1-methylpyrrolidone-2-yl)pyridine between octanol and water, or by membrane permeation studies of aqueous solutions of substituted 3-(1-methylpyrrolidone-2-yl)pyridine with acid and / or its conjugate base. The favorable octanol-water partitioning to octanol suggests that substituted 3-(1-methylpyrrolidone-2-yl)pyridines (e.g., 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine) can be well absorbed through the oral mucosa. However, as mentioned above, in some embodiments, the nature of the substituted 3-(1-methylpyrrolidone-2-yl)pyridines (e.g., 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine) makes ion pairing unnecessary, and therefore the composition is substantially or completely free of any ion pairs. "Substantially free" means that there is no measurable degree of ion association.

[0085] In embodiments where ion pairing with substituted 3-(1-methylpyrrolidone-2-yl)pyridine is desired, the composition comprises an organic acid, an alkali metal salt of the organic acid, or both. In such embodiments, at least a portion of the substituted 3-(1-methylpyrrolidone-2-yl)pyridine is associated in ion-pair form with at least a portion of an organic acid, its alkali metal salt, or a combination thereof. As used herein, the term “organic acid” refers to an organic (i.e., carbon-based) compound characterized by acidity. Typically, organic acids are relatively weak acids (i.e., they do not completely dissociate in the presence of water), such as carboxylic acids (-CO2H) or sulfonic acids (-SO2OH). As used herein, reference to organic acid refers to an intentionally added organic acid. In this respect, an organic acid may be intentionally added as a component of a particular composition, rather than simply being inherent as a component of another composition (e.g., a small amount of organic acid that may be inherent in a composition component). For the avoidance of doubt, the reference herein to “organic acid” is intended to distinguish between acids present in ion-pair form and acids that may be present in salts, eutectic crystals, and salt eutectic crystals. While those skilled in the art will recognize that certain organic acids suitable for forming ion pairs overlap with acids identified as suitable for forming salts or cocrystals, it should be understood that the specific acid used for each of the salts, cocrystals, and ion pairs should be specifically selected for each of these embodiments, and the organic acids mentioned herein specifically refer to acids suitable for ion pairing. Therefore, even if such organic acids are also suitable for forming salts or cocrystals, the presence of an organic acid in the composition as defined below should be interpreted only with respect to ion association, and the presence of such organic acids does not imply the presence of a salt or cocrystal unless explicitly stated. Furthermore, in embodiments not intended for ion pairing, the composition may be characterized by being substantially or completely free of organic acids (i.e., having less than 0.001% by weight of organic acid, or less than 0.0001% by weight, or even 0% by weight of organic acid, based on the total weight of the composition, or having an amount of organic acid below the detection limit). This should not be construed as meaning that the composition is substantially or completely free of substituted 3-(1-methylpyrrolidone-2-yl)pyridine salts or substituted 3-(1-methylpyrrolidone-2-yl)pyridine cocrystals unless explicitly stated.

[0086] organic acids

[0087] In embodiments where ion pairing with substituted 3-(1-methylpyrrolidone-2-yl)pyridine is desired, the composition comprises an organic acid and / or its alkali metal salt as defined above. Suitable organic acids for ion pairing typically have a range of lipophilicity (i.e., polarity providing a suitable balance between water and organic solubility). Generally, the lipophilicity of a suitable organic acid, as indicated by logP, will vary from about 0 to about 12 (a value greater than 0 indicates higher solubility in octanol than in water). In some embodiments, the logP value of the organic acid is from about -0.05 to about 1, for example, from about -0.05, about 0.1, about 0.2, about 0.3, about 0.4, or about 0.5 to about 0.6, about 0.7, about 0.8, or about 0.9, or about 1.0. In some embodiments, the logP value of the organic acid is from about 1 to about 12, for example, from about 1.0, about 1.5, about 2.0, about 2.5, about 3.0, about 3.5, about 4.0, about 4.5, about 5.0, about 5.5, about 6.0, about 6.5, about 7.0, about 7.5 or about 8.0 to about 8.5, about 9.0, about 9.5, about 10.0, about 10.5, about 11.0, about 11.5 or about 12.0.

[0088] Without being bound by theory, it is believed that the ion pairs formed by moderately lipophilic organic acids (e.g., logP of about 1.4 to about 4.5) and substituted 3-(1-methylpyrrolidone-2-yl)pyridine are somewhat polar, which allows the ion pairs to partition well between octanol and water, thus causing the substituted 3-(1-methylpyrrolidone-2-yl)pyridine to partition into octanol rather than water. As discussed above, this partitioning into octanol suggests favorable oral bioavailability.

[0089] In specific embodiments, the logP value of the organic acid used for ion pairing is from about 3.0 to about 8.0, about 10.0, or even 12.0. In some embodiments, for highly lipophilic organic acids (e.g., above about 4.5), the presence of certain solvents or solubilizers (e.g., glycerol or propylene glycol in the composition) may be beneficial in solubilizing the organic acid and its corresponding salt or ion pair with substituted 3-(1-methylpyrrolidone-2-yl)pyridine.

[0090] In some embodiments, the organic acid is a carboxylic acid or a sulfonic acid. The functional group of the carboxylic acid or sulfonic acid may be linked to any alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, having, for example, one to twenty carbon atoms (C1-C2). 20 In some embodiments, the organic acid is an alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl carboxylic acid or a sulfonic acid.

[0091] As used herein, "alkyl" refers to any straight-chain or branched hydrocarbon. Alkyl groups can be saturated (i.e., entirely composed of...). sp 3The carbon atom in the alkyl group can be either unsaturated (i.e., having at least one unsaturated site) or it can be unsaturated. As used herein, the term "unsaturated" means that there is a carbon-carbon atom in one or more positions within the alkyl group. sp2 Double bonds. Unsaturated alkyl groups can be monounsaturated or polyunsaturated. Representative straight-chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl. Branched 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, vinyl (or alkenyl), allyl, 1-butenyl, 2-butenyl, isobutenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, etc. Alkyl groups can be unsubstituted or unsubstituted.

[0092] As used herein, "cycloalkyl" refers to a carbocyclic group, which can be monocyclic or bicyclic. Cycloalkyl groups include monocyclic rings having 3 to 7 carbon atoms, and bicyclic rings having 7 to 12 carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl groups can be substituted or unsubstituted and may contain one or more unsaturated sites (e.g., cyclopentenyl or cyclohexenyl).

[0093] As used herein, the term "aryl" refers to a carbocyclic aromatic group. Examples of aryl groups include, but are not limited to, phenyl and naphthyl groups. Aryl groups can be substituted or unsubstituted.

[0094] As used herein, “heteroaryl” and “heterocyclic alkyl” refer to aromatic or non-aromatic ring systems, respectively, in which one or more ring atoms are heteroatoms, such as nitrogen, oxygen, and sulfur. A heteroaryl or heterocyclic alkyl group comprises up to 20 carbon atoms and 1 to 3 heteroatoms selected from N, O, and S. A heteroaryl or heterocyclic alkyl group can be a monocyclic group having 3 to 7 ring members (e.g., 2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, and S), or a bicyclic group having 7 to 10 ring members (e.g., 4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, and S), such as bicyclic [4,5], [5,5], [5,6], or [6,6] systems. Examples of heteroaryl groups, as exemplary and not limiting, include: pyridyl, thiazolyl, tetrahydrothiophene, pyrimidinyl, furanyl, thiophene, pyrroleyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thionaphthyl, indoleyl, indoleenyl, quinolinyl, isoquinolinyl, benzimidazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indoleyl, isoindoleyl, 3H-indoleyl, 1H-indazolyl, purineyl, 4 H-quinazinyl, phthalazinyl, naphridinyl, quinoxalinyl, quinazolinyl, cinnaphthyl, pteridinyl, 4aH-carbazoyl, carbazoyl, phenanthridine, acridineyl, pyrimidinyl, phenanthrololinyl, phenazinyl, phenothiazinyl, furazinyl, phenotoxazinyl, isochromyl, chromanyl, imidazoalkyl, imidazolinyl, pyrazolyl, pyrazolyl, benzotriazolyl, benzisoxazolyl, and isatinoyl. Examples of heterocyclic alkyl groups, as exemplary and not limiting, include: dihydropyridinyl, tetrahydropyridinyl (piperidinyl), tetrahydrothiophenyl, piperidinyl, 4-piperidinoneyl, pyrrolylyl, 2-pyrrolylyl, tetrahydrofuranyl, tetrahydropyranyl, bis-tetrahydropyranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, piperazinyl, quininecycloyl, and morpholinyl. Heteroaryl and heterocyclic alkyl groups can be substituted or unsubstituted.

[0095] As used herein and applicable to any of the alkyl, aryl, cycloalkyl, heteroaryl, or heterocyclic groups described above, "substituted" means that one or more hydrogen atoms are independently substituted by a substituent. Typical substituents include, but are not limited to, -Cl, -Br, F, alkyl, -OH, -OCH3, NH2, -NHCH3, -N(CH3)2, -CN, -NC(=O)CH3, -C(=O)-, -C(=O)NH2, and -C(=O)N(CH3)2. Whenever a group is described as "optionally substituted," the group may be substituted by one or more of the above substituents, each chosen independently. In some embodiments, the substituent may be one or more methyl groups or one or more hydroxyl groups.

[0096] In some embodiments, the organic acid used for the ion pair is an alkyl carboxylic acid. Non-limiting examples of alkyl carboxylic acids include formic acid, acetic acid, propionic acid, butyric acid, valeric acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, undecanoic acid, dodecanoic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, etc.

[0097] In some embodiments, the organic acid used for ion pairing is an alkyl sulfonic acid. Non-limiting examples of alkyl sulfonic acids include propanesulfonic acid, heptanesulfonic acid, and octanesulfonic acid.

[0098] In some embodiments, the alkyl carboxylic acid or sulfonic acid is substituted with one or more hydroxyl groups. Non-limiting examples include glycolic acid, 4-hydroxybutyric acid, and lactic acid.

[0099] In some embodiments, the organic acid used for ion pairing may contain 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., two to four carboxylic acid groups), one or more of the carboxylic acid groups may be esterified. Non-limiting examples include monoethyl succinate, monomethyl fumarate, monomethyl citrate, or dimethyl succinate.

[0100] In some embodiments, the organic acid used for ion pairing may contain more than one carboxylic acid group and one or more hydroxyl groups. Non-limiting examples of such acids include tartaric acid, citric acid, etc.

[0101] In some embodiments, the organic acid used for ion pairing is an aryl carboxylic acid or an aryl sulfonic acid. Non-limiting examples of aryl carboxylic acids and sulfonic acids include benzoic acid, methylbenzoic acid, salicylic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

[0102] Other non-limiting examples of organic acids that can be used for ion pairing in some embodiments include: 2-(4-isobutylphenyl)propionic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetaminobenzoic acid, 4-aminosalicylic acid, adipic acid, ascorbic acid (L), aspartic acid (L), α-methylbutyric acid, camphoric acid (+), camphor-10-sulfonic acid (+), cinnamic acid, cyclohexylaminosulfonic acid, dodecyl sulfuric acid, Ethane-1,2-disulfonic acid, ethanesulfonic acid, furoic acid, galactobionic acid, gentian acid, glucoheponic acid, gluconic acid, glucuronic acid, glutamic acid, glycerophosphate, 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 undecenoic acid. Examples of suitable acids for ion pairing include, but are not limited to, the list of organic acids in Table 1.

[0103] Table 1. Non-limiting examples of suitable organic acids for ion pairing Values ​​obtained from PubChem or calculated.

[0104] The selection of organic acids for ion pairing can be based not only on logP values ​​but also on other properties. For example, the organic acid should be recognized as safe for human consumption and possess acceptable flavor, odor, volatility, stability, etc. Determining suitable organic acids is within the capabilities of those skilled in the art.

[0105] In some embodiments, the organic acid used for ion pairing is a monoester of a dicarboxylic acid or a polycarboxylic acid. In some embodiments, the dicarboxylic acid is malonic acid, succinic acid, glutaric acid, adipic acid, fumaric acid, maleic acid, or a combination thereof. In some embodiments, the dicarboxylic acid is succinic acid, glutaric acid, fumaric acid, maleic acid, or a combination thereof. In some embodiments, the dicarboxylic acid is succinic acid, glutaric acid, or a combination thereof.

[0106] In some embodiments, the alcohol forming the monoester of the dicarboxylic acid is a lipophilic alcohol. Examples of suitable lipophilic alcohols include, but are not limited to, octanol, menthol, and tocopherol. In some embodiments, the organic acid is an octyl monoester of the dicarboxylic acid, such as octyl succinate, octyl fumarate, etc. In some embodiments, the organic acid is a monomenthyl ester of the dicarboxylic acid. Certain menthyl esters are desirable in oral compositions as described herein because they can provide a cooling sensation when used in products containing the compositions. In some embodiments, the organic acid is monomenthyl succinate, monomenthyl fumarate, monomenthyl glutarate, or combinations thereof. In some embodiments, the organic acid is a monotocopherol ester of the dicarboxylic acid. Certain tocopherol esters are desirable in oral compositions as described herein because they can provide antioxidant effects. In some embodiments, the organic acid is tocopherol succinate, tocopherol fumarate, tocopherol glutarate, or combinations thereof.

[0107] In some embodiments, the organic acid used for ion pairing is a carotenoid derivative having one or more carboxylic acids. Carotenoids are tetraterpenes, meaning they are produced from eight isoprene molecules and contain 40 carbon atoms. Therefore, they are generally lipophilic due to the presence of long unsaturated aliphatic chains and are typically yellow, orange, or red. Certain carotenoid derivatives may be advantageous in oral compositions because they both provide ion pairs and act as colorants in the composition. In some embodiments, the organic acid is (2E,4E,6E,8E,10E,12E,14E,16Z,18E)-20-methoxy-4,8,13,17-tetramethyl-20-oxoeicosano-2,4,6,8,10,12,14,16,18-nonenoic acid (annatto) or its isomers. annatto is produced from the annatto tree (Annona squamosa). Bixa orellana A carotenoid, a naturally occurring pigment found in the seeds of the annatto tree, provides its red-orange color. Natarotin is soluble in fats and alcohols but insoluble in water. When isolated, it is chemically unstable and undergoes isomerization to become the double-bonded isomer trans-annatto (β-annatto), with the following structure: . In some embodiments, the organic acid used for ion pairing is (2E,4E,6E,8E,10E,12E,14E,16E,18E)-4,8,13,17-tetramethyleicosicocarbon-2,4,6,8,10,12,14,16,18-nonanediol (norannatin), the water-soluble hydrolysis product of annatin has the following structure: . In some embodiments, the organic acid used for ion pairing is selected from the group consisting of nicotinic acid, propionic acid, 3-hydroxybutyric acid, pimelic acid, and succinic acid. In some embodiments, the organic acid used for ion pairing is benzoic acid.

[0108] In some embodiments, more than one organic acid for ion pairing may be present. For example, the composition may contain two, three, four, or more organic acids for ion pairing. Therefore, when "one organic acid" is mentioned herein, it also includes a mixture of two or more organic acids. The relative amounts of the various organic acids can vary. For example, the composition may contain equal amounts of two, three, or more organic acids, or it may contain different relative amounts. In this way, when combined with other organic acids to provide the desired average logP range to the composition, some organic acids with logP values ​​outside the desired range (e.g., citric acid or myristic acid) may be included. In some embodiments, it is desirable to include organic acids with logP values ​​outside the desired range for ion pairing in the composition for purposes such as, but not limited to, providing desired sensory properties, stability, or as a flavor component. Furthermore, some lipophilic organic acids have undesirable flavor and / or aroma characteristics, which would preclude their presence as the sole organic acid (e.g., present in equimolar or greater amounts relative to nicotine). Without being bound by theory, it is believed that combinations of different organic acids can provide the desired ion pairings, while the concentration of any single organic acid in the composition remains below a threshold that is considered sensorily unacceptable.

[0109] In some embodiments, the composition comprises an organic acid for ion pairing, which is a monoester of a dicarboxylic acid or a carotenoid derivative having one or more carboxylic acids as described above, and further comprises an additional organic acid or a salt thereof. In some embodiments, the additional organic acid is benzoic acid, its alkali metal salt, or a combination thereof.

[0110] In some embodiments, the composition comprises an alkali metal salt of an organic acid. For example, at least a portion of the organic acid may be present in the composition in the form of an alkali metal salt. Suitable alkali metal salts include lithium, sodium, and potassium. In some embodiments, the alkali metal is sodium or potassium. In some embodiments, the alkali metal is sodium. In some embodiments, the composition comprises an organic acid and a sodium salt of the organic acid.

[0111] In some embodiments, the molar ratio of the organic acid to its sodium salt (or other alkali metal salt) is from about 0.1 to about 10, for example, about 0.1, about 0.25, about 0.3, about 0.5, about 0.75, or about 1 to about 2, about 5, or about 10. For example, in some embodiments, both the organic acid and its sodium salt are added to the other components of the composition, wherein the added organic acid is in greater quantity than the sodium salt, is equimolar with the sodium salt, or is part of the sodium salt. Those skilled in the art will recognize that the relative amounts will be determined by the desired pH and ionic strength of the composition. For example, a certain amount of organic acid may be added to provide the desired pH level of the composition, while a certain amount of alkali metal (e.g., sodium) salt is added to provide the desired degree of ion pairing. As those skilled in the art will understand, the amount of organic acid present in the composition (i.e., in its protonated form) relative to the alkali metal salt or conjugate base form present in the composition will vary depending on the pH of the composition and the pKa of the organic acid, as well as based on the actual relative amount initially added to the composition.

[0112] The amount of an organic acid or its alkali metal salt present in the composition relative to a substituted 3-(1-methylpyrrolidone-2-yl)pyridine (e.g., 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine) can vary. Generally, as the concentration of the organic acid (or its conjugate base) increases, the percentage of substituted 3-(1-methylpyrrolidone-2-yl)pyridine that ion-pairs with the organic acid increases. This typically increases the degree of partitioning of 3-(1-methylpyrrolidone-2-yl)pyridine (in ion-pair form) in octanol relative to water, as logP (log of partition coefficient). 10 The composition comprises, in some embodiments, about 0.05, about 0.1, about 1, about 1, about 1.5, about 2 or about 5 to about 10, about 15 or about 20 molar equivalents of an organic acid, its alkali metal salt or a combination thereof, relative to substituted 3-(1-methylpyrrolidone-2-yl)pyridine (calculated as a free base of substituted 3-(1-methylpyrrolidone-2-yl)pyridine).

[0113] In some embodiments, the composition comprises an organic acid, its alkali metal salt, or a combination thereof in a molar amount of about 2 to about 10, or about 2 to about 5, of substituted 3-(1-methylpyrrolidone-2-yl)pyridine (as a free base). In some embodiments, the molar ratio of the organic acid, its alkali metal salt, or a combination thereof to substituted 3-(1-methylpyrrolidone-2-yl)pyridine is about 2, about 3, about 4, or about 5 to about 6, about 7, about 8, about 9, or about 10. In embodiments where more than one organic acid, its alkali metal salt, or both are present, it should be understood that such molar ratios reflect the total amount of organic acids present. In some embodiments, the composition comprises benzoic acid and sodium benzoate, wherein the total amount of benzoate (i.e., benzoic acid and benzoate salt) in the molar ratio of substituted 3-(1-methylpyrrolidone-2-yl)pyridine ranges from about 3 to about 5. In some embodiments, the total amount of benzoate to the molar ratio of substituted 3-(1-methylpyrrolidone-2-yl)pyridine is about 3.2 or about 4.8.

[0114] In some embodiments, the amount of organic acid contained is sufficient to provide a composition pH of about 4.0 to about 9.0, for example, about 4.5 to about 7.0, or about 5.5 to about 7.0, about 4.0 to about 5.5, or about 7.0 to about 9.0. As used herein, “composition pH” refers to the pH of an aqueous solution of the composition prepared by dissolving or suspending 5 grams of the composition in 95 grams of water and measuring the pH of the resulting solution using a calibrated pH meter.

[0115] In some embodiments, the organic acid is contained in an amount sufficient to provide a composition pH of about 4.5 to about 6.5, for example, 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 about 4.5 to about 6.5, and the organic acid is provided in an amount sufficient to provide that pH. In some embodiments, the organic acid is provided in an amount sufficient to provide a composition pH of about 5.5 to about 6.5, for example, 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.

[0116] In some embodiments, an inorganic acid (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, etc.) is added alone or in combination with an organic acid to adjust the pH of the composition to a desired value. In some embodiments, a buffer (e.g., a buffer described below) is added to the composition to achieve a desired value and / or to maintain the pH of the composition at a desired value.

[0117] In some embodiments, the oral composition further comprises a solubilizer to increase the solubility of one or more organic acids or their salts. Suitable solubilizers include, but are not limited to, the humectants described herein, such as glycerin or propylene glycol.

[0118] Other surfactants

[0119] In some embodiments, the oral composition further comprises one or more other active agents, such as caffeine, theanine, herbal extracts, and agonists or allosteric modulators of the α7 nicotinic acetylcholine receptor (α7 nAChR).

[0120] In some embodiments, the oral composition further comprises caffeine, theanine, or a combination thereof.

[0121] In some embodiments, the oral composition also comprises herbal extracts.

[0122] In some embodiments, the oral composition further comprises an agonist of α7 nAChR.

[0123] In some embodiments, the agonist of α7 nAChR is pentylsedinine, an alkaloid found in species of the genus *Lobelia*. See, for example, *Nat Prod Co mmun.* 2015 Aug;10(8):1355-7. In some embodiments, the agonist of α7 nAChR is lobeline or a related natural product from species of the genus *Lobelia*. In some embodiments, the agonist of α7 nAChR is lobeline. In some embodiments, the agonist of α7 nAChR is lobelanidine. In some embodiments, the agonist of α7 nAChR is an extract from species of the genus *Lobelia*. See, for example, *Front. Pharmacol.* March 7, 2021, Ethnopharmacology, Volume 12 (2021), which describes lobeline and other natural products found in extracts from species of the genus *Lobelia*. In some embodiments, the agonist of α7 nAChR is 3-(2,4-dimethoxybenzyl)-pseudoestiline (GTS-21). See, for example, Briggs et al., Pharmacology, Biochemistry, and Behavior, 1997, 57 (1-2): 231-241.

[0124] In some embodiments, the agonist of α7 nAChR is cytidine-5-bisphosphate choline. In some embodiments, the agonist of α7 nAChR is α-GPC (L-α-glycerophosphate choline).

[0125] In some implementations, the agonist of α7 nAChR is 5-hydroxyindole.

[0126] In some embodiments, the oral composition further comprises an allosteric modulator of α7 nAChR. In some embodiments, the allosteric modulator is galantamine. In addition to its activity as an acetylcholinesterase inhibitor, galantamine has been reported to function as an allosteric modulator of α7 nAChR. See, for example, Drugs.com. August 8, 2023.

[0127] The amount of other active agents may vary depending on the product type and its desired characteristics. In some embodiments, the composition comprises about 0.01 to about 30% by weight of one or more other active agents based on the total weight of the composition.

[0128] filler

[0129] The compositions described herein comprise one or more fillers. Fillers can perform a variety of functions, such as enhancing certain sensory properties (e.g., texture and mouthfeel), enhancing the cohesiveness or compressibility of the product, etc. Typically, fillers are porous particulate materials and can be inorganic or organic (e.g., cellulose-based). Suitable organic fillers, for example, are any non-tobacco plant material or its derivatives, including cellulose materials derived from such sources. Other examples of organic fillers include maltodextrin, dextrose, lactose, and sugar alcohols. Examples of cellulose-based non-tobacco plant materials include cereals (e.g., corn, oats, barley, rye, buckwheat, etc.), sugar beets [e.g., FIBREX® brand fillers available from International Fiber Corporation], bran fibers, and mixtures thereof. Non-limiting examples of non-tobacco plant material derivatives include starches (e.g., from potatoes, wheat, rice, corn), natural cellulose, and modified cellulose materials. Combinations of fillers, such as multiple organic fillers, inorganic fillers, or a combination of organic and inorganic fillers, can also be used.

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

[0131] In some embodiments, the filler comprises starch or starch-derived starch. As used herein, the term "starch" can refer to pure starch, modified starch, or starch derivatives from any source. Starch is generally found in granular form in almost all green plants and in various types of plant tissues and organs, such as seeds, leaves, rhizomes, roots, tubers, buds, fruits, grains, and stems. The composition of starch, as well as the shape and size of its granules, can vary. Typically, starches from different sources have different chemical and physical properties. Specific starches can be selected for addition to mixtures based on their ability to impart sensory properties to the composition. Starches derived from a variety of sources can be used. For example, major sources of starch include cereals (e.g., rice, wheat, and corn) and root vegetables (e.g., potatoes and cassava). Other examples of starch sources include acorns, arrowroot, Peruvian carrots (arracacha), bananas, barley, legumes (such as broad beans, lentils, mung beans, peas, chickpeas), breadfruit, buckwheat, canna lilies, chestnuts, taro, kudzu root, malanga, millet, oats, oxalis, Polynesian arrowroot, sago, sorghum, sweet potatoes, quinoa, rye, cassava, taro, tobacco, water chestnuts, and yams. Some starches are modified starches. Modified starches undergo one or more structural modifications, often aimed at altering their high-heat properties. Some starches have been developed through genetic modification and are considered "modified" starches. Other starches are modified after acquisition. For example, modified starch can be starch that has undergone chemical reactions such as esterification, etherification, oxidation, depolymerization (thinning) by acid catalysis or oxidation in the presence of a base, bleaching, transglycosylation and depolymerization (e.g., dextrinization in the presence of a catalyst), crosslinking, enzymatic treatment, acetylation, hydroxypropylation, and / or partial hydrolysis. Other starches are modified by heat treatment, such as pregelatinization, dextrinization, and / or cold water swelling processes. Some modified starches include monostarch phosphate, distarch glycerides, distarch phosphate esterified with sodium trimetaphosphate, phosphorylated distarch phosphate, acetylated distarch phosphate, acetic anhydride esterified starch acetate, vinyl acetate esterified starch acetate, acetylated distarch adipate, acetylated distarch glycerides, hydroxypropyl starch, hydroxypropyl distarch glycerides, and sodium octenyl succinate starch. In some embodiments, the filler comprises or is a mixture of glucose and starch-derived polysaccharides. One such suitable mixture of glucose and starch-derived polysaccharides is EMDEX®, available from JRS PHARMA LP, 2981 22nd Route, Paterson, NY, 12563-2359.

[0132] In some implementations, the filler comprises or is an inorganic material. Examples of potential inorganic fillers include calcium carbonate, calcium phosphate, and bioceramic materials (e.g., porous hydroxyapatite).

[0133] In some embodiments of this disclosure, substantially spherical fillers in granular form are utilized, and such fillers can be defined by their sphericity, a measure of how close an object is to a perfect sphere. Sphericity (Ψ) can be measured using the following equation, where V p It is the volume of the object, A p It is the surface area of ​​an object.

[0134] Ψ = ( (6V p ) ) / A p

[0135] By definition, a sphere has a sphericity of 1, and any shape that is not a perfect sphere will have a sphericity of less than 1. In some embodiments, the sphericity of the substantially spherical filler of this disclosure will be about 0.7 or higher, for example about 0.8 or higher or about 0.9 or higher (e.g., about 0.7 to 1, or about 0.75 to 1, or about 0.8 to 1, or about 0.85 to 1, or about 0.9 to 1).

[0136] The average diameter (mean) or D50 (median) particle size of the substantially spherical particulate filler particles provided herein can vary and is not particularly limited. For example, in some embodiments, the average diameter and / or D50 value of the spherical filler particles is from about 100 μm to about 2000 μm, such as from about 250 μm to about 750 μm. For example, in some embodiments, the average diameter is from about 100 µm to about 500 µm, such as from about 100 µm to about 400 µm, from about 100 µm to about 300 µm, from about 100 µm to about 200 µm, from about 200 µm to about 500 µm, from about 200 µm to about 400 µm, from about 200 µm to about 300 µm, from about 300 µm to about 500 µm, from about 300 µm to about 400 µm, or from about 400 µm to about 500 µm. In some embodiments, the average diameter is about 500 µm to about 1000 µm, for example, about 500 µm to about 900 µm, about 500 µm to about 800 µm, about 500 µm to about 700 µm, about 500 µm to about 600 µm, about 600 µm to about 1000 µm, about 600 µm to about 900 µm, about 600 µm to about 800 µm, about 600 µm to about 700 µm, about 700 µm to about 1000 µm, about 700 µm to about 900 µm, about 700 µm to about 800 µm, about 800 µm to about 1000 µm, about 800 µm to about 900 µm, or about 900 µm to about 1000 µm. In some embodiments, the average diameter and / or D50 value of the substantially spherical filler component is about 300 to 650 micrometers, for example about 350 to about 500 micrometers.

[0137] The diameter distribution (i.e., particle size distribution) around the average diameter can also vary; in some embodiments, the diameter distribution approximates the listed values ​​(e.g., + / - about 25%, + / - about 20%, + / - about 15%, + / - about 10%, + / - about 5%, or + / - about 1%). However, this disclosure is not limited to materials with such a narrow distribution; in other embodiments, the diameter of the MCC spheres within a given material can vary over a wider range. The particle size distribution can be determined using sieve analysis.

[0138] In some embodiments, the substantially spherical filler comprises microcrystalline cellulose (“MCC”). The MCC may be synthetic or semi-synthetic, or may be entirely derived from natural cellulose. “Substantially spherical MCC” refers to a material comprising, consisting primarily of, or composed of MCC, wherein the material is a substantially spherical particulate filler component as described above.

[0139] The diameter of substantially spherical MCC particles can vary within the range of this disclosure, for example, according to the values ​​generally disclosed herein regarding substantially spherical particle filler components. Various commercial suppliers offer MCC spheres in specified diameter sizes, and such commercially available materials may be used in some embodiments of this disclosure. Examples of suitable MCC spheres include, but are not limited to, Vivapur® MCC spheres from JRS Pharma, with available particle sizes such as 100-200 μm (Vivapur® 100), 200-355 μm (Vivapur® 200), 355-500 μm (Vivapur® 350), 500-710 μm (Vivapur® 500), 710-1000 μm (Vivapur® 700), and 1000-1400 μm (Vivapur® 1000). Further examples of suitable MCC spheres include, but are not limited to, Celphere™ MCC spheres from Asahi Kasei Corporation, such as commercially available spheres with particle sizes of 75-212 μm (Celphere™ SCP-100), 106-212 μm (Celphere™ CP-102), 150-300 μm (Celphere™ CP-203), 300-500 μm (Celphere™ CP-305), and 500-710 μm (Celphere™ CP-507). It should be noted that this application focuses on the use of substantially spherical MCCs; however, this disclosure is not restrictive. Other types of materials capable of performing the functions of the fillers described herein and capable of being formed in a substantially spherical form may be used to replace (or supplement) the substantially spherical MCC fillers exemplified, without departing from the scope of this disclosure.

[0140] Advantageously, using fillers in the form of substantially spherical particles can impart unique physical properties to the composition and products containing the composition. For example, in some embodiments, replacing at least a portion of the conventional granular filler in a bagged composition with a substantially spherical particle filler can result in a different moisture content within the bagged composition compared to a composition containing all conventional granular fillers. For example, in some embodiments, using the disclosed substantially spherical filler can provide a drier bag than that achievable using conventional fillers (e.g., all other components and their amounts are substantially equivalent). For example, in some embodiments, the disclosed composition (comprising a substantially spherical particulate filler) can provide bagged products with a moisture content / oven volatile content of about 32% or less, about 30% or less, about 28% or less, about 27% or less, about 26% or less, about 25% or less, about 24% or less, about 23% or less, about 22% or less, about 21% or less, about 20% or less, about 19% or less, about 18% or less, about 17% or less, about 16% or less, or about 15% or less. In some embodiments, the moisture content of the disclosed composition can be from about 5% to about 32%, for example, from about 5% to about 25%, from about 5% to about 20%, from about 5% to about 15%, from about 10% to about 25%, from about 10% to about 20%, or from about 10% to about 15%. Moisture / oven volatile content can be measured by drying the sample in an oven and accurately measuring the weight of the sample before and after drying; the difference is the amount of evaporated water or other oven volatiles.

[0141] In some embodiments, providing a drier bag (e.g., about 32% or less moisture, as described in the previous paragraph) due to the inclusion of a granular filler in the form of substantially spherical granules allows for the appropriate inclusion of different components within the bag compared to the inclusion of a conventional form of granular filler. For example, certain components that might be desired to be included in the bagged composition can be more easily incorporated into a drier composition (e.g., when such components are water-soluble or react with water). For example, certain components encapsulated in a water-soluble shell can be more advantageously included in a drier composition / product (e.g., compositions / products having a moisture content within the range described herein).

[0142] In some embodiments, replacing at least a portion of the conventional particulate filler in the pouch composition with a substantially spherical particulate filler alters the release rate of the substituted 3-(1-methylpyrrolidone-2-yl)pyridine relative to a composition containing all conventional particulate fillers. At the same moisture content, substantially spherical MCCs typically release the disclosed substituted 3-(1-methylpyrrolidone-2-yl)pyridine faster than conventional particulate MCCs. Similarly, in some embodiments, at the same moisture content, substantially spherical particulate fillers will release the flavoring agent faster than conventional particulate fillers.

[0143] The amount of filler can vary, but is typically at most about 75% by weight based on the total weight of the composition. Typical ranges for fillers (e.g., MCCs, including spherical MCCs) in the composition can be from about 10 to about 75% by weight based on the total weight of the composition, for example, about 10, about 15, about 20, about 25, or about 30 to about 35, about 40, about 45, or about 50% by weight (e.g., about 20 to about 50% by weight or about 25 to about 45% by weight). In some embodiments, the amount of filler is at least about 10% by weight, for example, at least about 20% by weight, or at least about 25% by weight, or at least about 30% by weight, or at least about 35% by weight, or at least about 40% by weight, based on the total weight of the composition.

[0144] In some embodiments, the filler further comprises a cellulose derivative or a combination of such derivatives. In some embodiments, the composition comprises about 1 to 10% by weight of a cellulose derivative based on the total weight of the composition, wherein certain embodiments comprise about 1 to 5% by weight of a cellulose derivative. In some embodiments, the cellulose derivative is a cellulose ether (including carboxyl ethers), referring to a cellulose polymer in which one or more hydrogen atoms of the hydroxyl groups in the cellulose structure are substituted with alkyl, hydroxyalkyl, or aryl groups. Non-limiting examples of such cellulose derivatives include methylcellulose, hydroxypropylcellulose (“HPC”), hydroxypropyl methylcellulose (“HPMC”), hydroxyethylcellulose, and carboxymethylcellulose (“CMC”). In one embodiment, the cellulose derivative is one or more of methylcellulose, HPC, HPMC, hydroxyethylcellulose, and CMC. In some embodiments, the cellulose derivative is HPC. In some embodiments, the composition comprises about 1 to 3% by weight of HPC based on the total weight of the composition.

[0145] water

[0146] The water content of the composition (before consumer use) can vary depending on desired properties. Typically, the water content of the composition is less than about 60% by weight, and is generally from about 1% to about 60% by weight, for example, about 5% to about 55%, about 10% to about 50%, about 20% to about 45%, or about 25% to about 40% by weight, including water contents of at least about 5% by weight, at least about 10% by weight, at least about 15% by weight, and at least about 20% by weight. As described below, in some embodiments, the composition is packaged in a bag to form a bagged product. In some embodiments, the water content of the bagged product ranges from about 40% by weight to about 60% by weight based on the total weight of the bagged product (i.e., the total weight of the composition and the bag). In some embodiments, the water content of the bagged product ranges from about 15% by weight to about 60% by weight based on the total weight of the bagged product (i.e., the total weight of the composition and the bag). In some embodiments, the water content of the bagged product ranges from about 15% by weight to about 20% by weight based on the total weight of the bagged product (i.e., the total weight of the composition and the bag). In some embodiments, the water content of the bagged product ranges from about 30% to about 50% by weight, for example from about 32% to about 49% by weight, based on the total weight of the bagged product (i.e., the total weight of the composition and the bag). In some embodiments, the water content of the bagged product is about 32% by weight, about 35% by weight, or about 48% by weight, based on the total weight of the bagged product.

[0147] Flavorings

[0148] In some embodiments, the compositions described herein comprise flavoring agents. As used herein, a "flavoring agent" or "flavoring agent" is any substance having a flavor or aroma capable of altering sensory properties associated with an oral product. Examples of sensory properties that can be altered by flavoring agents include taste, mouthfeel, moisture, cool / warm sensation, and / or aroma / fragrance. Flavoring agents can be natural or synthetic, and the flavor characteristics imparted thereby can be described as, but are not limited to, fresh, sweet, herbal, candy, floral, fruity, or spicy.

[0149] Flavorings can be imitations, synthetic or natural ingredients or blends thereof. Flavorings may include naturally occurring flavoring materials, plant materials, plant extracts, synthetically obtained materials or combinations thereof (e.g., tobacco, licorice, hydrangea, eugenol, magnolia officinalis leaf, chamomile, fenugreek, clove, maple, matcha, menthol, Japanese mint, fennel seeds (anise), cinnamon, turmeric, Indian spices, Asian spices, herbs, wintergreen, cherry, berries, red berries, cranberries, peach, apple, orange, mango, tangerine, lemon, lime, tropical fruits, papaya, rhubarb). Grapes, durian, dragon fruit, cucumber, blueberries, mulberries, citrus fruits, Durum Brand, bourbon whiskey, Scotch whiskey, whiskey, gin, tequila, rum, spearmint, peppermint, lavender, aloe vera, cardamom, celery, tartare bark, nutmeg, sandalwood, bergamot, geranium, khat, naswah, areca nut, hookah, pine, honey extract, rose oil, vanilla, lemon oil, orange oil, orange blossom, cherry blossom, cinnamon, coriander, brandy, jasmine, ylang-ylang, mouse Peppermint, fennel, wasabi, bell pepper, ginger, coriander, coffee, peppermint oil from any species of the peppermint genus, eucalyptus, star anise, cocoa, lemongrass, rooibos, flax, ginkgo, hazelnut, hibiscus, bay leaf, yerba mate, orange peel, rose, tea such as green or black tea, thyme, juniper, elderflower, basil, bay leaf, cumin, oregano, paprika, rosemary, saffron, lemon peel, mint, perilla, turmeric, coriander, myrtle, blackcurrant, valerian, allspice, nutmeg, damiensis, ink Flavor enhancers, bitter taste receptor blockers, sensory receptor activators or stimulants, sugars and / or sugar substitutes (e.g., sucralose, acesulfame potassium, aspartame, saccharin, cyclohexylsulfamic acid, lactose, sucrose, glucose, fructose, sorbitol or mannitol) and other additives such as charcoal, chlorophyll, minerals, botanical materials or breath fresheners.

[0150] Flavoring agents may also include flavor enhancers, sensory receptor site activators or stimulants, and trigeminal nerve sensory agents. As used herein, "trigeminal nerve sensory agent" refers to a flavoring agent that affects the trigeminal nerve, producing sensations including heat, coolness, and tingling. Non-limiting examples of trigeminal nerve sensory flavoring agents include capsaicin, citric acid, menthol, Sichuan pepper, erythritol, and pichia pastoris.

[0151] In some embodiments, the composition includes a sensate that provides a cooling effect to the user of the composition. Suitable cooling agents include, but are not limited to, menthol, menthone, menthone ketal, menthone glycerol ketal, substituted p-menthol, acyclic carboxamides, glutaric acid monomenthol, substituted cyclohexylamide, substituted cyclohexaneformamide, substituted urea and sulfonamides, substituted menthol, hydroxymethyl and hydroxymethyl derivatives of p-menthol, 2-mercaptocyclodecone, hydroxycarboxylic acids having 2-6 carbon atoms, cyclohexylamide, menthyl acetate, menthyl salicylate, N-ethyl-p-menthol-3-carboxamide (WS-3), N-[[5-methyl-2-(1-methylethyl)cyclohexyl]carbonyl]glycine ethyl ester (WS-5), WS-14, N,2,3-trimethyl-2-isopropylbutyramide (WS-23), WS-27, WS-30, (-)-menthoxyethanol (Coolact® 5), WS-NA (FEMA4693), WS-116 (FEMA 4603), N-ethyl-2,2-diisopropylbutyramide, isopreneol, menthol, 3-(1-menthol)propane-1,2-diol, 3-(1-menthol)-2-methylpropane-1,2-diol, p-menthol-2,3-diol, p-menthol-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-methylcyclohexaneformamide, Japanese peppermint oil, peppermint essential oil, 3-(1-menthol)ethyl-1-ol, 3-(1-menthol)propane-1-ol, 3-(1-menthol)butane-1-ol, 1-menthylacetic acid N-acetamide, 1-menthyl-4-hydroxyvalerate, 1-menthyl-3-hydroxybutyrate, pentaethyl... Menthyl diacid ester, N,2,3-trimethyl-2-(1-methylethyl)-butyramide, N-ethyl-trans-2-cis-6-nonadienamide, N,N-dimethylmenthyl succinamide, N-(2-hydroxyethyl)-2,3-dimethyl-2-isopropylbutyramide, substituted p-menthane, substituted p-menthane formamide, 2-isopropyl-5-methylcyclohexanol, menthyl glycol carbonate, menthone glycerol ketal (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 glyceride, methyl-2-isopropylbicyclo[2.2].[1] Heptane-2-carboxamide, (1R,2S,5R)-N-(4-(carbamoylmethyl)phenyl)menthylcarboxamide, 2-[2-(p-menthyl-3-yloxy)ethoxy]ethanol, (1R,2R,4R)-1-(2-hydroxy-4-methylcyclohexyl)ethyl ketone, 2-(p-tolyloxy)-N-(1H-pyrazol-5-yl)-N-((thiophen-2-yl)methyl)acetamide, menthol methyl ether, menthylpyrrolidone carboxylate, 2,5-dimethyl-4-(1-pyrrolidinyl)-3(2H)-furanone, cyclic α-ketoenylamines and cyclopentenone 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 α-ketoenamines disclosed in U.S. Patent No. 6,592,884 to Hofmann et al., the entire contents of which are incorporated herein by reference. These and other suitable cooling agents are further described in the following U.S. Patents, all of which are incorporated herein by reference in their entirety: U.S. Patent 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; and 7,030,273. Other suitable cooling agents are also described in U.S. Patent Application Publications Nos. 2005 / 0222256 and 2005 / 0265930, each of which is incorporated herein by reference in its entirety. In some embodiments, the cooling agent comprises menthol, eucalyptus, peppermint, menthol, menthyl ester, eucalyptol, WS-3, WS-23, WS-5, (1R,2S,5R)-N-(4-(cyanomethyl)phenyl)menthylformamide (Evercool™ 180), (1R,2S,5R)-N-(2-(pyridin-2-yl)ethyl)menthylformamide (Evercool™ 190), or combinations thereof.

[0152] In some embodiments, the composition contains no flavoring agents and only a cooling agent to provide the desired user experience. In some embodiments, the cooling agent is WS-3.

[0153] In some embodiments, the composition comprises a sensory agent or modulator that provides a warming effect to the user of the composition. Suitable warming agents include, but are not limited to, ethers of vanillin (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, isopentyl, n-hexyl), gingerol, shogaol, gingerone, gingerol, 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 combinations thereof.

[0154] Flavoring agents can be in any suitable form, such as liquids (e.g., oils) or solids (e.g., powders or waxes). In some cases, flavoring agents may be provided in spray-dried or liquid form. In some embodiments, liquid flavoring agents are loaded (i.e., adsorbed or absorbed therein or on) onto a porous particulate carrier (e.g., microcrystalline cellulose), which is then combined with other compositional components.

[0155] The amount of flavoring agent used in the composition may vary, but is typically up to about 10% by weight, and some embodiments are characterized by a flavoring agent content of at least about 0.1% by weight, such as about 0.5% to about 10%, about 1% to about 5%, or about 2% to about 4% by weight, based on the total weight of the composition.

[0156] Flavor modifiers

[0157] To improve the sensory properties of the compositions disclosed herein, the compositions may include one or more flavor modifiers (“flavor modifiers”) that can mask, alter, block, or enhance the flavor of, for example, the compositions described herein. Non-limiting examples of such flavor modifiers include analgesic or narcotic herbs, spices, and flavorings that produce a cooling (e.g., menthol, eucalyptus, peppermint), warming (e.g., cinnamon), or aching (e.g., capsaicin) sensation. Some flavor modifiers fall into more than one overlapping category.

[0158] In some embodiments, the flavor modifier modulates one or more of bitterness, sweetness, saltiness, or sourness. In some embodiments, the flavor modifier targets pain receptors. In some embodiments, the composition includes a bitter component and a flavor modifier that masks or blocks the perception of bitterness. In some embodiments, the flavor modifier is a substance that targets pain receptors (e.g., vanilloid receptors) in the user's oral cavity to mask the bitterness of, for example, another component. Suitable flavor modifiers include, but are not limited to, capsaicin, gamma-aminobutyric acid (GABA), adenosine monophosphate (AMP), lactitol, or combinations thereof.

[0159] When present, the representative amount of the flavor modifier is about 0.01% by weight or more, about 0.1% by weight or more, or about 1.0% by weight or more, but typically less than about 10% by weight of the total weight of the composition (e.g., about 0.01%, about 0.05%, about 0.1% or about 0.5% to about 1%, about 5% or about 10% by weight of the total weight of the composition).

[0160] Salt

[0161] In some embodiments, the composition may further comprise a salt (e.g., an alkali metal salt), typically used in an amount sufficient to provide the desired sensory properties to the mixture. Non-limiting examples of suitable salts include sodium chloride, potassium chloride, ammonium chloride, flour salt, etc.

[0162] When present, the salt is typically present in amounts of about 0.5% by weight or more, about 1.0% by weight or more, or about 1.5% by weight or more, but generally constitutes about 10% or less, about 7.5% or less, or about 5% or less (e.g., about 0.5% to about 5% by weight) of the total weight of the composition.

[0163] sweeteners

[0164] To improve the sensory properties of the compositions according to this disclosure, one or more sweeteners may be added. The sweetener may 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, etc. Examples of artificial sweeteners include sucralose, isomaltulose, maltodextrin, saccharin, aspartame, acesulfame potassium, neotame, etc. In some embodiments, the sweetener comprises one or more sugar alcohols. Sugar alcohols are polyols derived from monosaccharides or disaccharides, having a partially or fully hydrogenated form. Sugar alcohols have, for example, from about 4 to about 20 carbon atoms, and include erythritol, arabinitol, ribitol, isomaltulitol, maltitol, eurythritol, idotitol, mannitol, xylitol, lactitol, sorbitol, and combinations thereof (e.g., hydrogenated starch hydrolysate). In some embodiments, the sweetener is sucralose, acesulfame potassium, or a combination thereof.

[0165] When present, the sweetener or sweetener combination may comprise from about 0.01 to about 20% by weight or more of the composition, 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 total weight of the composition. In some embodiments, the sweetener combination is present at a concentration of from about 0.01% to about 0.1% by weight of the composition, for example, 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% by weight of the composition. In some embodiments, the sweetener combination is present at a concentration of from about 0.1% to about 0.5% by weight of the composition, for example, from about 0.1%, about 0.2%, about 0.3%, about 0.4%, or about 0.5% by weight of the composition. In some embodiments, the sweetener combination is present at a concentration of about 1% to about 3% by weight of the composition.

[0166] Composition adhesive

[0167] In some embodiments, an adhesive (or combination of adhesives) may be used. Typical adhesives may be organic or inorganic, or combinations thereof. Representative adhesives include povidone, sodium alginate, starch-based adhesives, pectin, carrageenan, pullulan, zein, and combinations thereof. An amount of adhesive may be used sufficient to provide the desired physical properties and physical integrity to the composition. The amount of adhesive used in the composition may vary, but is typically up to about 30% by weight, and some embodiments are characterized by an adhesive content of at least about 0.1% by weight, for example about 1% to about 30% by weight or about 5% to about 10% by weight, based on the total weight of the composition.

[0168] Other suitable binders include gums, such as natural gums. As used herein, natural gums refer to polysaccharide materials of natural origin that have adhesive properties and can also be used as thickeners or gelling agents. Representative natural gums derived from plants (which are usually water-soluble to some extent) include xanthan gum, guar gum, gum arabic, solanum, astragalus gum, ebony gum, locust bean gum, gellan gum, and combinations thereof. When present, natural gum binder materials are typically present in amounts of up to about 5% by weight, for example about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, or about 1% to about 2, about 3, about 4, or about 5% by weight, based on the total weight of the composition.

[0169] Moisturizer

[0170] In some embodiments, one or more humectants may be used in the composition. Examples of humectants include, but are not limited to, polyols such as glycerin, propylene glycol, etc. When a humectant is included, it is typically provided in an amount sufficient to provide the desired moisture properties to the composition. Furthermore, in some cases, the humectant may impart the desired flow properties to the composition for deposition into a mold.

[0171] When present, the humectant typically constitutes about 5% or less of the composition by weight (e.g., about 0.5% to about 5% by weight). When present, a representative amount of the humectant is about 0.1% to about 1% by weight or about 1% to about 5% by weight, based on the total weight of the composition.

[0172] buffer

[0173] In some embodiments, the compositions of this disclosure may comprise a buffer. Examples of buffers that may be used include, but are not limited to, alkali metal buffers such as metal carbonates (e.g., potassium carbonate or sodium carbonate), metal bicarbonates (e.g., sodium bicarbonate), alkali metal citrate salts, etc. Non-limiting examples of suitable buffers include alkali metal or alkaline earth metal (e.g., sodium, potassium, calcium, magnesium) acetates, glycine salts, phosphates, glycerol phosphates, citrates, carbonates, bicarbonates, borates, and mixtures thereof. In some embodiments, the buffer comprises an acetate, phosphate, or carbonate, such as an alkali metal acetate, phosphate, or carbonate. In some embodiments, the buffer comprises a citrate. In some embodiments, the buffer comprises trisodium citrate or is trisodium citrate. In some embodiments, the buffer is a mixture of trisodium citrate and citric acid. In some embodiments, the buffer is a solution of trisodium citrate and citric acid with a pH of approximately 6.3, for example, a solution with a citrate concentration of 0.5 mol.

[0174] When present, the buffer is typically present in an amount less than about 5% by weight of the composition, for example, about 0.5% to about 5%, about 0.75% to about 4%, about 0.75% to about 3%, or about 1% to about 2% by weight, based on the total weight of the composition. As described above, such a buffer can be added in an amount sufficient to provide a specific pH value or range or to maintain the pH of the composition within a desired range or value.

[0175] Colorant

[0176] Colorants may be used in an amount sufficient to provide the desired physical properties to the composition. Natural or synthetic colorants may be used, such as natural or synthetic dyes, food-grade colorants, and pharmaceutical-grade colorants. Examples of colorants include a variety of dyes and pigments, such as caramel color and titanium dioxide. Natural colorants such as curcumin, beet juice extract, and spirulina, as well as a variety of synthetic pigments, may also be used. The amount of colorant used in the composition can vary, but when present, it is typically up to about 3% by weight, for example, about 0.1%, about 0.5%, or about 1% to about 3% by weight, based on the total weight of the composition.

[0177] Oral care additives

[0178] In some embodiments, the composition comprises an oral care ingredient (or a mixture of such ingredients). The oral care ingredient provides the ability to inhibit tooth decay or loss, inhibit gum disease, relieve oral pain, whiten teeth or otherwise inhibit tooth staining, induce salivary irritation, inhibit halitosis, freshen breath, etc. For example, effective amounts of ingredients such as thyme oil, eucalyptus oil, and zinc (e.g., ingredients available from Discus Dental's ZYTEX® formulation) may be incorporated into the composition. Other examples of ingredients that may be incorporated into the compositions of the present invention in desired effective amounts may include those ingredients included in the types of oral care compositions described in the following patents: Takahashi et al., Oral Microbiology and Immunology, 19(1), 61-64 (2004); Thistle's U.S. Patent No. 6,083,527; and Jakubowski's U.S. Patent Application Publication No. 2006 / 0210488 and Cummins et al.'s U.S. Patent Application Publication No. 2006 / 02228308. Other exemplary ingredients include those contained in formulations marketed by Roquette as MALTISORB® and NatraRx as DENTIZYME®. When present, the representative amount of the oral care additive is at least about 1%, typically at least about 3%, and often at least about 5% of the total dry weight of the composition. The amount of the oral care additive in the composition typically does not exceed about 30%, typically does not exceed about 25%, and often does not exceed about 20% of the total weight of the composition.

[0179] Processing aids

[0180] If downstream processing of the composition (such as granulation, mixing, or molding) requires it, flow aids may be added to the composition to enhance its flowability. In some embodiments, the composition (e.g., in melt and chewable forms) may be surface-treated with anti-sticking agents such as oils, silicones, etc. Exemplary flow aids include microcrystalline cellulose, silica, silanized microcrystalline cellulose, polyethylene glycol, stearic acid, calcium stearate, magnesium stearate, zinc stearate, sodium stearoyl fumarate, carnauba wax, and combinations thereof. In some embodiments, the flow aid is sodium stearoyl fumarate. In some embodiments, the composition contains silanized microcrystalline cellulose as a flow aid and / or to enhance tablet compressibility. Silanized microcrystalline cellulose is a combination of microcrystalline cellulose and colloidal silica and is available from JRS Pharma PROSOLV® SMCC.

[0181] When present, the representative amount of the flow aid may be at least about 0.5% by weight or at least about 1% by weight of the total dry weight of the composition. Typically, the amount of flow aid in the composition usually does not exceed about 5% by weight of the total weight of the composition, and often does not exceed about 3% by weight.

[0182] lipids

[0183] The composition may comprise a lipid component, such as a fat, oil, or wax (or a combination thereof). The lipid component used in the composition may be derived from animal or plant material and typically comprises primarily triglycerides and small amounts of free fatty acids and mono- or diglycerides. In some embodiments, the lipid is a plant-derived fatty material that is solid or semi-solid at room temperature (i.e., about 25°C) and at least partially liquefied when placed at the user's oral temperature. Such plant-derived fats consist primarily of saturated or unsaturated fatty acid chains having about 10 to about 26 carbon atoms, more typically about 14 to about 20 carbon atoms, and most commonly about 14 to about 18 carbon atoms (mostly bound in a triglyceride structure). Exemplary fats that may be used include palm oil, palm kernel oil, soybean oil, cottonseed oil, and mixtures thereof. According to some aspects, the lipid substance may be hydrogenated, partially hydrogenated, or non-hydrogenated. In some cases, the lipid substance may comprise a blend of lipid components. For example, the lipid substance may comprise a blend of palm oil and palm kernel oil.

[0184] There are several methods for determining the melting point of lipids. However, many naturally occurring lipids are not chemically homogeneous and therefore do not have a true single melting point, i.e., the transition temperature from solid to liquid. Therefore, lipids are sometimes characterized by their melting range. One test for determining the melting point of lipids is the Mettler dropping point method (ASTM Standard D3954, 2010, "Standard Test Method for Wax Dropping Point", ASTM International, West Conshohocken Pa., 2003, DOI 10.1520 / D3954-94R10, www.astm.org.). Unless otherwise stated, the melting temperature of lipids or products containing such lipids as described herein refers to a melting temperature point or range determined based on the Mettler dropping point method.

[0185] The melting point of the lipid component can be selected such that the resulting composition has a melting point within an appropriate range to provide the desired melting characteristics when the product is placed in the user's mouth. In some embodiments, it may be desirable to use lipids with higher melting points so that the final product remains substantially solid in the mouth during use, meaning the user must chew the product to break it into smaller pieces. In other embodiments, lower melting points can be selected so that the final product melts easily in the user's mouth during use. Typically, the melting point of the lipid component is from about 29°C to about 49°C, typically from about 36°C to about 45°C, and most typically from about 38°C to about 41°C. In some embodiments, the melting point of the product made using the lipid component will also be within the above-mentioned range.

[0186] The lipid substances that can be used according to this disclosure are available, for example, from Loders Croklaan and Aarhus Karlshamn USA. Exemplary lipid substances include 108-24-B (a non-hydrogenated laurate-coated fat containing a blend of palm kernel oil and palm oil) from Aarhus Karlshamn USA Inc.; PARAMOUNT™ X (a partially hydrogenated vegetable oil containing a blend of palm kernel oil, soybean oil, and cottonseed oil) from Loders Croklaan; CENTERNAL™ 625 (a vegetable fat) from Loders Croklaan; PARAMOUNT™ C (a laurate-coated fat containing partially hydrogenated palm kernel oil and lecithin) from Loders Croklaan; KAOKOTE™ 102 (a laurate-coated fat containing partially hydrogenated palm kernel oil) from Loders Croklaan; SILKO™ 35-08 (an exchange-hydrogenated laurate fat containing palm kernel oil) from Aarhus Karlshamn USA Inc.; and CEBES™ from Aarhus Karlshamn USA Inc. 27-70 (fractionated lauric cocoa butter substitute containing hydrogenated palm kernel oil); CISAO™ 82-53 (non-hydrogenated palm oil) from Aarhus Karlshamn USA Inc.; CEBES™ 29-21 (fractionated cocoa butter substitute containing palm kernel oil and palm oil) from Aarhus Karlshamn USA Inc.; CEBES™ 27-55 (lauric fat containing partially hydrogenated palm kernel oil and hydrogenated soybean oil) from Aarhus Karlshamn USA Inc.; 108-48-B (non-hydrogenated lauric fat of palm kernel oil and palm oil blend) from Aarhus Karlshamn USA Inc.; CEBES™ 29-07 (fractionated non-hydrogenated cocoa butter substitute) from Aarhus Karlshamn USA Inc.; CEBES™ 21-20 (fractionated lauric cocoa butter substitute); CEBES™ 29-07 (fractionated lauric cocoa butter substitute) from AarhusKarlshamn USA Inc.; and CISAO™ 78-33 (non-hydrogenated structured fat) from AarhusKarlshamn USA Inc.

[0187] The relative amount of lipids in the composition can vary. In some embodiments, the amount of lipids in the composition is at least about 10%, at least about 20%, or at least about 30%, based on the dry weight of the composition. In some embodiments, the amount of lipid material is less than about 60%, less than about 50%, or less than about 40%, based on dry weight. Exemplary lipid weight ranges include about 10% to about 60% dry weight, more typically about 20% to about 40% dry weight.

[0188] Other additives

[0189] Other additives may be included in the disclosed compositions. For example, the compositions may be processed, blended, formulated, combined, and / or mixed with other materials or ingredients. The additives may be artificial or may be obtained or derived from herbal or biological sources. Examples of other types of additives include thickeners or gelling agents (e.g., fish gelatin), emulsifiers, preservatives, antioxidants, disintegrants, or combinations thereof. See, for example, U.S. Patent No. 9,237,769 to Mua et al., U.S. Patent No. 7,861,728 to Holton Jr. et al., U.S. Patent Publication No. 2010 / 0291245 to Gao et al., and U.S. Patent Publication No. 2007 / 0062549 to Holton Jr. et al., each incorporated herein by reference.

[0190] In some embodiments, the composition comprises one or more antioxidants, one or more preservatives, one or more antimicrobial agents, or combinations thereof. Suitable antioxidants and preservatives include, but are not limited to, ascorbic acid (vitamin C), sodium ascorbate, ascorbyl palmitate, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), tert-butylhydroquinone (TBHQ), methylparaben, propylparaben, sodium propionate, potassium sorbate, sodium benzoate, propyl gallate, monostearate citrate, vitamin E, vitamin E derivatives, tocopherol, and combinations thereof.

[0191] Typical ranges of the amount of such additives may vary depending on the nature and function of the additive and the expected effect on the final composition. An exemplary range is up to about 10% by weight (e.g., about 0.1% to about 5% by weight) based on the total weight of the composition.

[0192] The aforementioned additives may be used together (e.g., as an additive formulation) or separately (e.g., individual additive components may be added at different stages of the preparation of the final mixture). Furthermore, additives of the aforementioned types may be encapsulated as provided in the final product or composition. Exemplary encapsulating additives are described, for example, in Atchley's WO2010 / 132444, which has previously been incorporated herein by reference.

[0193] Configured for oral use

[0194] This document provides compositions configured for oral use. As used herein, the term "configured for oral use" means that the composition or product comprising such a composition is provided in a manner such that, during use, saliva in the user's mouth allows one or more releasable components of the composition (e.g., flavoring agents and / or substituted 3-(1-methylpyrrolidone-2-yl)pyridine) to enter the user's mouth. In some embodiments, the composition or product is adapted to deliver the component to the user through the mucosa in the user's oral cavity, and in some cases, the component is a flavoring agent and / or substituted 3-(1-methylpyrrolidone-2-yl)pyridine as described herein, which can be absorbed through the oral mucosa during use of the composition or product.

[0195] In some embodiments, the composition or a product containing such a composition may have the potential to serve as a smoking cessation aid, nicotine replacement therapy, and / or treatment for nicotine addiction.

[0196] Products configured for oral use as described herein can take various forms, including gels, lozenges, gels, tablets, powders, and sachets. Some products disclosed herein are in solid form. Some products may exhibit one or more of the following characteristics: brittleness, granularity, chewiness, syrupiness, pasteiness, fluffiness, smoothness, and / or creaminess. In some embodiments, the desired texture properties may be selected from the group consisting of: adhesiveness, cohesiveness, density, dryness, brittleness, granularity, adhesiveness, hardness, heaviness, hygroscopicity, moisture release, oral coating properties, roughness, slipperiness, smoothness, viscosity, humidity, and combinations thereof.

[0197] Any product form disclosed herein can also be formulated as an effervescent product by incorporating an effervescent material capable of causing effervescence in the oral cavity into the composition. Suitable effervescent materials may comprise an acidic component and a basic component, wherein the basic component is a carbonate material, a bicarbonate material, or a mixture thereof, and the acidic component is a tricarboxylic acid, a dicarboxylic acid, a monocarboxylic acid, or a combination thereof. Alternatively, suitable effervescent materials may comprise a sugar material containing an embedded gaseous component such that the embedded gaseous component is released when the sugar material dissolves in the oral cavity.

[0198] The compositions disclosed herein can be formed into various shapes, including pills, tablets, spheres, strips, films, sheets, coin-shaped, cubic, bead-shaped, oval, flattened oval, cylindrical, bean-shaped, rod-shaped, or bar-shaped. The cross-sectional shape of the composition can vary, with examples including circular, square, elliptical, rectangular, etc.

[0199] The compositions disclosed herein may be at least partially soluble. As used herein, the terms “dissolved,” “soluble,” and “soluble (soluble)” refer to compositions having water-soluble components that interact with moisture in the oral cavity and enter into a solution, resulting in the gradual consumption of the composition. In some embodiments, the soluble composition is capable of remaining in the user's mouth for a given period of time until it is completely dissolved. The dissolution rate can vary over a wide range, from about 1 minute or less to about 60 minutes. For example, rapid-release compositions typically dissolve and / or release substituted 3-(1-methylpyrrolidone-2-yl)pyridine within about 2 minutes or less, typically 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 destruction (e.g., chewing), enzymatic or other chemical degradation, or by disrupting the interactions between the components of the composition.

[0200] In some embodiments, the composition may be fusible, as discussed, for example, in U.S. Patent Application Publication No. 2012 / 0037175 by Cantrell et al., the entire contents of which are incorporated herein by reference. As used herein, “melting,” “fusible,” and “fusible” refer to the ability of a composition to change from a solid to a liquid state. That is, melting occurs when a substance (e.g., the composition disclosed herein) changes from a solid to a liquid, typically by applying heat. For the compositions disclosed herein, the application of heat is provided by the internal temperature of the user’s oral cavity. Therefore, the term “fusible” refers to a composition capable of liquefying in the user’s oral cavity as the composition changes from a solid to a liquid state, intended to distinguish it from compositions that disintegrate merely due to loss of cohesion within the composition or dissolve in the oral cavity merely as the water-soluble components of the composition interact with water. Typically, fusible compositions comprise lipids as described above. In some embodiments, the fusible form of the composition comprises about 35% to about 50% by weight of lipids based on the total weight of the composition, and about 35% to about 55% by weight of sugar alcohols based on the total weight of the composition. In some embodiments, the sugar alcohol is isomaltitol, erythritol, sorbitol, arabinitol, ribitol, maltitol, euonymus alcohol, idutitol, mannitol, xylitol, lactitol, or a combination thereof. In some embodiments, the sugar alcohol is isomaltitol.

[0201] In some embodiments, the composition is in the form of compressed or molded pellets or tablets. Such pellets or tablets typically comprise at least one filler, at least one sugar alcohol, and may also include flavoring agents, binders, salt, sweeteners, buffers, colorants, humectants, oral care additives, preservatives, disintegration aids, flow aids, compressibility aids, or combinations thereof, each as described above. Typically, compositions in tablet form comprise a glucose-polysaccharide blend and a sugar alcohol. In some embodiments, the glucose-polysaccharide blend is present in an amount of about 35 to about 50% by weight based on the total weight of the composition; the sugar alcohol is present in an amount of about 30 to about 45% by weight based on the total weight of the composition. Exemplary pellet weight ranges from about 250 mg to about 1500 mg, for example, about 250 mg to about 700 mg, or about 700 mg to about 1500 mg. The pellets may have any of a variety of shapes, including conventional pill or tablet shapes.

[0202] In some embodiments, the composition may be chewable, meaning that the composition has a mild elasticity or "resilience" when chewed and possesses a desired degree of plasticity. The chewable form of the composition may be completely soluble or may be in an insoluble gum form, wherein only certain components (e.g., active ingredients, flavoring agents, sweeteners) dissolve, leaving an insoluble matrix. Chewable embodiments typically include binders such as natural gums or pectin. In some embodiments, the chewable form of the composition comprises pectin and organic acids, and one or more sugar alcohols at least 50% by weight of the total composition. Typically, pectin is present in an amount of about 1 to about 3% by weight of the total composition.

[0203] In some embodiments, the composition is in the form of a gum, such as chewing gum. Chewing gum compositions typically comprise a gum base and one or more fillers, and may also include emulsifiers, flavoring agents, salts, sweeteners, humectants, binders, buffers, colorants, oral care additives, preservatives, or combinations thereof, each as described above. The term "gum base" refers to a component that is generally insoluble in water and hydrophobic, providing the desired texture to the gum. Chewing gum may contain about 5 to about 95% by weight of a gum base. Typically, the gum base comprises an elastomer. The elastomer provides rubbery, cohesive properties to the gum base and the chewing gum as a whole. Elastomers suitable for the gum base of this disclosure may include natural, synthetic, or combinations thereof. Non-limiting examples of suitable natural elastomers include latex, gum arabic, crown gum, nispero, rosedinha, jelutong, perillo, niger gutta, tunu, balata, guttapercha, lechi caspi, sorva, guttakay, massaranduba balata, massaranduba chocolate, nispero, rosedinha, gutta hangkang, chiquibul, pendare, leche de vaca, tunu, chilte, and mixtures thereof. Non-limiting examples of suitable synthetic elastomers include styrene-butadiene copolymers (SBR), polyisobutylene, isobutylene-isoprene copolymers, polyethylene, polyvinyl acetate, biodegradable polymers, and mixtures thereof. Further examples of synthetic elastomers include, but are not limited to, those listed in Section 172,615 of Title 21 of the U.S. Food and Drug Administration's CFR, "Masticatory Substances, Synthetic".

[0204] Suitable bulking agents include sweeteners such as sugar, sugar alcohols, and combinations thereof.

[0205] The adhesive base, particularly those based on synthetic elastomers, may also contain one or more of the following: fillers, plasticizers, softeners, emulsifiers, waxes, anti-sticking agents, and further components such as antioxidants, colorants, flavorings, buffers, etc. Suitable fillers include, but are not limited to, magnesium carbonate, calcium carbonate, ground limestone, silicates such as magnesium silicate and aluminum silicate, clay, alumina, talc, titanium dioxide, monocalcium phosphate, dicalcium phosphate and tricalcium phosphate, cellulose polymers and combinations thereof. In some embodiments, the filler is calcium carbonate, talc, or a combination thereof. In some embodiments, the filler is talc. Suitable plasticizers include natural resins, synthetic resins, waxes, and combinations thereof. Suitable emulsifiers and / or softeners include, but are not limited to, tallow, hydrogenated tallow, hydrogenated and partially hydrogenated vegetable oils, cocoa butter, glyceryl monostearate, glyceryl acetate, glyceryl diacetate, glyceryl triacetate, lecithin, monoglycerides, diglycerides and triglycerides, acetylated monoglycerides, fatty acids (e.g., stearic acid, palmitic acid, oleic acid and linoleic acid), sorbitan fatty acid esters, lanolin and combinations thereof.

[0206] In some embodiments, the composition may be in the form of a soluble and mildly chewable lozenge. As used herein, the term "lozenge" refers to a soluble oral product made by solidifying a liquid or gel composition (e.g., a composition containing a gel or binder) such that the final product is a hardened solid gel. Lozenge products may also be referred to as soft lozenges. In some embodiments, the lozenge products of this disclosure are characterized by having sufficient cohesiveness to withstand mild chewing in the oral cavity without rapid disintegration. The lozenge products of this disclosure generally do not exhibit the highly deformable chewing quality found in conventional chewing gum. See, for example, U.S. Patent Nos. 9,204,667, Cantrell et al.; 9,775,376, Cantrell et al.; and 10,357,054, Marshall et al., for example, for the lozenge formulations, lozenge configurations, lozenge characteristics, and techniques for formulating or manufacturing lozenges, all of which are incorporated herein by reference.

[0207] In some embodiments, the products disclosed herein may be in the form of soluble lozenge products configured for oral use. Lozenge products are generally described as “hard” and are thus distinguished from soft lozenges (i.e., tablets). Exemplary lozenge products are in the form of lozenges, tablets, microtablets, or other tablet-type products. See, for example, U.S. Patent No. 4,967,773 to Shaw; U.S. Patent No. 5,110,605 to Acharya; U.S. Patent No. 5,733,574 to Dam; U.S. Patent No. 6,280,761 to Santus; U.S. Patent No. 6,676,959 to Andersson et al.; U.S. Patent Nos. 6,248,760 and 7,374,779 to Wilhelmsen; and U.S. Patent Publication No. 2001 / 0016593 to Wilhelmsen; Liu The types, formulations, forms and configurations, characteristics, and manufacturing techniques of nicotine lozenges described in U.S. Patent Publication No. 2004 / 0101543 of the United States Patent and Trademark Offices (USPTO) et al.; U.S. Patent Publication No. 2006 / 0120974 of Mcneight et al.; U.S. Patent Publication No. 2008 / 0020050 of Chau et al.; U.S. Patent Publication No. 2009 / 0081291 of Gin et al.; and U.S. Patent Publication No. 2010 / 0004294 of Axelsson et al. are each incorporated herein by reference.

[0208] In some embodiments, the products disclosed herein may be in the form of transparent or translucent lozenges. Transparency / translucency can be determined by any method commonly used in the art; however, it is typically measured by spectrophotometric transmittance over a wavelength range (e.g., about 400-700 nm). Transmittance measurements of such transparent or translucent lozenge products are generally higher than those of conventional (i.e., non-translucent) products. Translucency can also be visually confirmed by simply holding the product in front of a light source and determining whether light passes through the product in a diffuse manner. Translucent lozenge products typically contain at least about 80% by weight of a sugar substitute and a sugar alcohol syrup as the lozenge matrix. The amount and type of sugar substitute can vary. In some embodiments, the sugar substitute is a non-hygroscopic sugar alcohol capable of forming a glassy matrix. For example, in some embodiments, the sugar substitute is isomaltitol. In some embodiments, the sugar substitute is present in an amount of at least about 85% by weight or at least about 90% by weight. In some embodiments, the sugar alcohol syrup is maltitol syrup. While sugar alcohol syrups are preferred, in some embodiments, syrups may be used instead of or in combination with sugar alcohol syrups. For example, in some embodiments, corn syrup, gold syrup, and / or molasses may be used.

[0209] In some embodiments, the products disclosed herein may be in film form, such as edible films or dissolving films. Such films typically comprise a mixture of one or more fillers, emulsifiers, gelling agents, and binders to provide the desired film form, as well as additional components such as buffers, humectants, salts, sweeteners, etc. In some embodiments, the composition may be chewable, meaning that the composition exhibits mild elasticity or "resilience" when chewed and has a desired degree of plasticity. Chewable compositions may be completely soluble or may be in an insoluble gel form, wherein only certain components (e.g., substituted 3-(1-methylpyrrolidone-2-yl)pyridine, flavoring agents, sweeteners) dissolve, leaving an insoluble matrix.

[0210] In some embodiments, the composition may be fusible, as discussed, for example, in U.S. Patent Application Publication No. 2012 / 0037175 by Cantrell et al., the entire contents of which are incorporated herein by reference. As used herein, “melting,” “fusible,” and “fusible” refer to the ability of a composition to change from a solid to a liquid state. That is, melting occurs when a substance (e.g., the composition disclosed herein) changes from a solid to a liquid, typically by applying heat. For the compositions disclosed herein, the application of heat is provided by the internal temperature of the user’s oral cavity. Therefore, the term “fusible” refers to a composition capable of liquefying in the user’s oral cavity as the composition changes from a solid to a liquid state, intended to distinguish it from compositions that disintegrate merely due to loss of cohesion within the composition or dissolve in the oral cavity merely as the water-soluble components of the composition interact with water.

[0211] Certain types of products disclosed herein (e.g., lozenges, tablets, etc.) may also have an external coating composed of ingredients capable of providing an acceptable external coating (e.g., the external coating may consist of ingredients such as carnauba wax and pharmaceutically acceptable forms of shellac, glaze compositions, and surface polishing agents). The coating can be applied using techniques such as airless spraying, fluidized bed coating, or coating pans. Materials used as coatings can be polymeric, such as cellulose materials (e.g., cellulose butyrate, hydroxypropyl methylcellulose phthalate, and carboxymethyl ethyl cellulose), and polymers and copolymers of acrylic acid, methacrylic acid, and their esters.

[0212] The compositions can be co-extruded, laminated, or formed into products with a sandwich structure, thus allowing control over the placement of components (e.g., substituted 3-(1-methylpyrrolidone-2-yl)pyridine) to provide desired characteristics such as properties, behavior, interactions or non-interactions with other components, storage stability, etc. Furthermore, mixtures of component components can be formulated and manufactured as core / shell structures (e.g., products having an internal region and at least one additional covering layer), where different regions of such products have different overall composition or properties. Thus, for example, substituted 3-(1-methylpyrrolidone-2-yl)pyridine can have a relatively high concentration in the internal region of the product or a relatively high concentration in the external region of the product. Other configurations are also considered herein, such as multilayer compositions comprising two or more formulations with different sensory properties. Non-limiting embodiments of multilayer compositions include, but are not limited to, lozenges / meltablets, lozenges / chewables, lozenges / hard coatings, meltable / lozenges, meltable / hard coatings, molded / meltablets, molded / lozenges, lozenges / meltable / hard coatings, and molded / lozenges / meltablets. In some embodiments, the composition is a core formulation surrounded by one or more continuous layers, or a core formulation coated with one or more discontinuous (e.g., partial) layers, thereby forming a layered or side-by-side configuration of two or more formulations. The number of layers can vary; for example, a multilayer composition may contain two to ten layers in some embodiments, such as two to five layers. Such layered or core-shell embodiments can be formed into the desired form (e.g., tablets, lozenges, tablets, gels, films, etc.) by pouring or otherwise introducing the first mixture into a mold, injection molding the first mixture, or using other suitable means for providing the formulation. In some embodiments, the second mixture can be applied by spraying, dipping, or by forming the second mixture into a sheet and applying the sheet as a sandwich coating to the first mixture. Spraying or dipping can be carried out at a temperature that allows the first mixture to maintain substantially its intact form. In some embodiments, a third mixture is applied as a coating to the second mixture. Various mixtures used for layers or cores and shells can vary in the following aspects: physical properties (hardness, fusibility, chewability, solubility, etc.), flavor, presence or absence of substituted 3-(1-methylpyrrolidone-2-yl)pyridine, concentration of substituted 3-(1-methylpyrrolidone-2-yl)pyridine, or combinations thereof.

[0213] In some embodiments, the compositions of this disclosure are disposed within a moisture-permeable container (e.g., a water-permeable bag) to form a pouch-packaged oral product. Such pouch-packaged products are typically used by placing a pouch containing the composition into the mouth of a human subject / user. Typically, the pouch is placed somewhere in the user's mouth, such as between the lips and gums, similar to the usual use of wet snuff products. Exposure to saliva then causes certain components of the composition therein (e.g., flavoring agents and / or nicotine) to pass through, for example, the water-permeable bag and provide flavor and satisfaction to the user, and the user does not need to spit out any part of the composition. After approximately 10 to approximately 60 minutes, typically approximately 15 to approximately 45 minutes of use / enjoyment, a substantial portion of the composition has been absorbed by the human subject, and the pouch can be removed from the human subject's mouth for disposal. The pouch is generally not chewed, nor is it typically swallowed, nor is it intended for ingestion. In other words, certain components present in the composition (such as flavoring agents and / or substituted 3-(1-methylpyrrolidone-2-yl)pyridine) are consumed during the use of the bagged product, but the bag itself is not ingested (unless the bag is a soluble bag as further described below).

[0214] Therefore, in some embodiments, the compositions disclosed herein, along with any other components described above, are combined within a breathable pack or bag, which acts as a container for the composition to provide a pouch-packaged product configured for oral use. Some embodiments of this disclosure may be referenced. Figure 1 The description includes an illustration of an exemplary bagged product. (Reference) Figure 1 The illustration shows an embodiment of the pouch product 100. The pouch product 100 includes a moisture-permeable container in the form of a bag 102 containing material 104 of the oral composition described herein.

[0215] Exemplary bag 102 may be constructed from a fleece material, which is a fibrous material that can be formed from various types of fibers, such as conventional cellulose fibers (e.g., viscose, regenerated cellulose, cellulose fibers, and wood pulp), cotton fibers, wool fibers, other natural fibers, polymer / synthetic fibers, and combinations thereof, capable of forming a fabric. For example, the fleece material may be provided in the form of a woven or nonwoven fabric. Suitable types of fleece materials are described, for example, in U.S. Patent No. 8,931,493 to Sebastian et al., U.S. Patent Application Publication No. 2016 / 0000140 to Sebastian et al., and U.S. Patent Application Publication No. 2016 / 0073689 to Sebastian et al., all of which are incorporated herein by reference.

[0216] Exemplary bags can be made from materials in such a way that they undergo controlled dispersion or dissolution during user use. Such bag materials can be in the form of mesh, sieve, perforated paper, permeable fabric, etc. For example, bag materials made from rice paper in mesh or perforated rice paper can dissolve in the user's mouth. As a result, both the bag and the composition can be completely dispersed in the user's oral cavity under normal use conditions, and therefore both the bag and the composition can be consumed by the user. Other examples of bag materials can be made using water-dispersible film-forming materials (e.g., binders such as alginate, carboxymethyl cellulose, xanthan gum, pullulan, etc.), and combinations of these materials with materials such as milled cellulose (e.g., fine-particle wood pulp). If desired, flavoring ingredients, disintegrants, and other desired components can be incorporated into or applied to the bag material.

[0217] The amount of material contained in each product unit (e.g., a bag) can vary. In some embodiments, the dry weight of the composition in each bag is at least about 50 mg, for example, about 50 mg to about 1.3 g, about 100 to 800 mg, about 200 to about 750 mg, or about 700 to about 1330 mg. In some embodiments, the product is in small bags, and the dry weight of the composition in each bag may be about 100 to about 300 mg. In some embodiments, the product is in large bags, and the dry weight of the material in each bag may be about 700 mg to about 1.3 g. If desired, other components may be included in each bag. For example, at least one flavoring strip, sheet, or flake-shaped water-dispersible or water-soluble material (e.g., a breath-freshening edible film-type material) may be provided in each bag. Such strips or sheets may be folded or crumpled for easy inclusion in the bag. See, for example, U.S. Patent No. 6,887,307 to Scott et al., U.S. Patent No. 6,923,981 to Leung et al.; and the types of materials and techniques shown in The EFSA Journal (2004) 85, 1-32, all of which are incorporated herein by reference.

[0218] In some embodiments, the pouch may include one or more capsules, such as microcapsules. In some embodiments, the capsules contain at least a portion of substituted 3-(1-methylpyrrolidone-2-yl)pyridine. The capsules may contain a capsule wall formed of a material configured to allow dispersion of contents under desired conditions. For example, the capsule wall may contain a material configured to dissolve or degrade under oral conditions. As another non-limiting example, the capsule wall may contain a material configured to rupture or degrade by shear forces (e.g., chewing). While suitable encapsulation materials may be described herein as materials associated with microcapsules, it should be understood that this term is not intended to limit the size of the capsules.

[0219] The crush strength of suitable microcapsules is sufficient to allow them to be handled and stored normally without significant premature or undesirable rupture. Capsules that provide suitable integrity during storage and are capable of rupturing or otherwise disintegrating upon use can be determined experimentally, depending on factors such as capsule size and type, and are a matter of design choice. See, for example, U.S. Patent Publication No. 2007 / 0068540 to Thomas et al., which is incorporated herein by reference.

[0220] In some embodiments, the capsule may comprise an outer shell doped with a material (such as wax, gelatin, cyclodextrin, or alginate) and an internal active content (payload). In some embodiments, the internal active content (e.g., substituted 3-(1-methylpyrrolidone-2-yl)pyridine) is present in particulate form or as an aqueous or non-aqueous solution or dispersion in water or an organic liquid (such as alcohol, oil, glycerol, or combinations thereof). Thus, for example, multiple such capsules may be incorporated into a bag with the composition to be retained therein, and during product use, crushing or other forms of disruption of the capsules may release the active content contained therein.

[0221] The capsules can be uniform or varied in size, weight, and shape. A representative capsule may be generally spherical. However, suitable capsules may have other types of shapes, such as generally linear, rectangular, elliptical, or oval. In some embodiments, the diameter of the microcapsules may be less than about 100 micrometers, for example, microcapsules with diameters ranging from about 1 to about 40 micrometers or from about 1 micrometer to about 20 micrometers.

[0222] In some implementations, larger capsules may be used. For example, the capsule size (diameter) for pouch products may be from about 0.5 mm to about 5 mm or from about 0.6 mm to about 3 mm.

[0223] The number of capsules incorporated into a bagged product can vary depending on factors such as capsule size, the characteristics or properties of the active contents, and the desired properties of the composition within the bag. In some embodiments, only a single capsule is included. The size of the single capsule can be relatively large. For example, as... Figure 2 As shown in the bagged product 200, a capsule 220 having an active content (e.g., substituted 3-(1-methylpyrrolidone-2-yl)pyridine) disposed therein may be located together with the composition 230 within a water-permeable fabric 240. Thus, a single capsule 220 may be relatively large.

[0224] In some embodiments, multiple capsules may be included, and the capsules may be located within a fabric bag together with the composition. The size of the multiple capsules may be relatively small. In particular, microcapsules may be used. For example, such as Figure 3As shown in the pouch product 300, each of a plurality of capsules 320 has the same or different active contents (e.g., substituted 3-(1-methylpyrrolidone-2-yl)pyridine) disposed therein, and the capsules may be located together with the composition therein 330 within a water-permeable fabric 340. Therefore, the plurality of capsules 320 can be relatively small. The number of capsules incorporated into the pouch product can, for example, exceed about 5, about 10, about 20, about 40, or even about 100. In some embodiments, the number of capsules / microcapsules can be greater than about 500, or even greater than about 1,000.

[0225] The total weight of the capsules contained in the product may vary, but is generally greater than about 10 mg, generally greater than about 20 mg, and may be greater than about 30 mg. The total weight of the capsules is generally less than about 200 mg, generally less than about 100 mg, and may be less than about 50 mg.

[0226] Capsules can be formed using any encapsulation technique known in the art. For example, microcapsules can be formed using a variety of chemical encapsulation techniques, such as solvent evaporation, solvent extraction, organic phase separation, interfacial polymerization, simple and complex aggregation, in-situ polymerization, liposome encapsulation, and nanoencapsulation. Alternatively, physical encapsulation methods can be used, such as spraying, pan coating, fluidized bed coating, annular jet coating, rotary disc atomization, spray cooling, spray drying, spray chilling, fixed nozzle co-extrusion, centrifugal head co-extrusion, or submersible nozzle co-extrusion.

[0227] Regardless of the encapsulation method used, the materials and solvents used to form the outer wall or shell of the capsule can vary. Commonly used material categories for the wall or shell include proteins, polysaccharides, starches, waxes, fats, natural and synthetic polymers, and resins. Exemplary materials used in the microencapsulation process for forming microcapsules include gelatin, gum arabic, polyvinyl acetate, potassium alginate, carob gum, potassium citrate, carrageenan, potassium polymetaphosphate, citric acid, potassium tripolyphosphate, dextrin, polyvinyl alcohol, povidone, dimethyl polysiloxane, dimethyl silicone, refined paraffin wax, ethyl cellulose, bleached shellac, modified food starch, sodium alginate, guar gum, sodium carboxymethyl cellulose, hydroxypropyl cellulose, sodium citrate, hydroxypropyl methylcellulose, sodium ferrocyanide, sodium polyphosphate, locust bean gum, methyl cellulose, sodium trimetaphosphate, methyl ethyl cellulose, sodium tripolyphosphate, microcrystalline wax, tannic acid, petroleum wax, terpene resins, astragalus gum, polyethylene, xanthan gum, and polyethylene glycol.

[0228] Microcapsules are commercially available, and exemplary types of microcapsule technologies are those described in the following literature: 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, and US Patent No. 3,550,598 of McGlumphy, US Patent No. 4,889,144 of Tateno et al., US Patent No. 5,004,595 of Cherukuri et al., US Patent No. 5,690,990 of Bonner, US Patent No. 5,759,599 of Wampler et al., US Patent No. 6,039,901 of Soper et al., US Patent No. 6,045,835 of Soper et al., US Patent No. 6,056,992 of Lew, US Patent No. 6,106,875 of Soper et al., T U.S. Patent No. 6,117,455 to Akada et al., U.S. Patent No. 6,325,859 to DeRoos et al., U.S. Patent No. 6,482,433 to DeRoos et al., U.S. Patent No. 6,612,429 to Dennen, and U.S. Patent No. 6,929,814 to Bouwmeesters et al.; U.S. Patent Application Publication No. 2006 / 0174901 to Karles et al. and U.S. Patent Application Publication No. 2007 / 0095357 to Besso et al.; and PCT International Publication WO2007 / 037962 to Holton et al. are all incorporated herein by reference. Suitable types of microcapsules are available from companies such as Microtek Laboratories, Dayton, Ohio. Exemplary types of commercially available microencapsulation technologies include those marketed under the trade names ULTRASEAL™ and PERMASEAL™, available from Givaudan, Geneva, Switzerland.

[0229] Representative capsule types are those marketed by Yosha! as "Momints" and by The Hershey Company as "Ice Breakers Liquid Ice." Representative capsule types have also been incorporated into chewing gum, such as the type marketed by Cadbury Adams USA under the brand name "Cinnaburst." Representative capsule types and their components are also described in Waterbury's U.S. Patent No. 3,339,558 and Irby's... U.S. Patent No. 3,390,686 to Jr., U.S. Patent No. 3,685,521 to Dock, U.S. Patent No. 3,916,914 to Brooks et al., U.S. Patent No. 4,889,144 to Tateno et al., U.S. Patent No. 6,631,722 to MacAdam et al., and U.S. Patent No. 7,115,085 to Deal; U.S. Patent Publication No. 2004 / 0261807 to Dube et al., U.S. Patent Publication No. 2006 / 0272663 to Dube et al., U.S. Patent Publication No. 2006 / 0133096 to Luan et al., U.S. Patent Publication No. 2006 / 0144412 to Mishra et al., U.S. Patent Publication No. 2007 / 0012327 to Karles et al., and U.S. Patent Publication No. 2007 / 0068540 to Thomas et al.; and Kim's PCT International Publication WO The following documents are incorporated herein by reference: 03 / 009711, PCT International Publication WO 2006 / 136197 by Hartmann et al., PCT International Publication WO 2006 / 136199 by Mane et al., PCT International Publication WO 2007 / 010407 and PCT International Publication WO 2007 / 060543, and in filtered cigarettes sold by RJ Reynolds Tobacco Company under the trade name “CamelLights with Menthol Boost”.See also the capsule types and their components described in the following patents: U.S. Patent No. 5,223,185 to Takei et al., U.S. Patent No. 5,387,093 to Takei, U.S. Patent No. 5,882,680 to Suzuki et al., U.S. Patent No. 6,719,933 to Nakamura et al., and U.S. Patent No. 6,949,256 to Fonkwe et al.; and U.S. Patent Application Publication No. 2004 / 0224020 to Schoenhard, U.S. Patent Application Publication No. 2005 / 0123601 to Mane et al., U.S. Patent Application Publication No. 2005 / 0196437 to Bednarz et al., and U.S. Patent Application Publication No. 2005 / 0249676 to Scott et al., all of which are incorporated herein by reference. Capsules may be colored, have a smooth or rough surface, have a rigid or flexible shell, have a brittle or durable shell, or other desired features or properties.

[0230] In bagged embodiments comprising woolen fabric material as the bag, the amount of substituted 3-(1-methylpyrrolidone-2-yl)pyridine (e.g., 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine) present in the woolen fabric material can vary. For example, some substituted 3-(1-methylpyrrolidone-2-yl)pyridine (e.g., 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine) may migrate from the composition into the woolen fabric during storage. In some embodiments, a portion of the substituted 3-(1-methylpyrrolidone-2-yl)pyridine (e.g., 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine) is added to the woolen fabric material during manufacturing. Therefore, the amount (i.e., adsorption or absorption) of substituted 3-(1-methylpyrrolidine-2-yl)pyridine (e.g., 2-methyl-5-(1-methylpyrrolidine-2-yl)pyridine) present in the wool fabric can range from 0% by weight to up to 75% by weight or more, based on the total amount of substituted 3-(1-methylpyrrolidine-2-yl)pyridine (e.g., 2-methyl-5-(1-methylpyrrolidine-2-yl)pyridine present in the entire product. In some embodiments, the wool fabric contains less than 10% by weight, such as less than 5% by weight, less than 1% by weight, less than 0.1% by weight, or even 0% by weight of substituted 3-(1-methylpyrrolidine-2-yl)pyridine (e.g., 2-methyl-5-(1-methylpyrrolidine-2-yl)pyridine) present in the product, by weight. In some embodiments, at least a portion (by weight) of the total amount of substituted 3-(1-methylpyrrolidone-2-yl)pyridine (e.g., 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine) in the product is present in the wool fabric (i.e., adsorbed or absorbed), for example, from at least 1% by weight to up to 75% by weight or more. In some embodiments, the wool fabric contains about 1% by weight, about 5% by weight, about 10% by weight, about 20% by weight, about 30% by weight, about 40% by weight, about 50% by weight, about 60% by weight, about 70% by weight, about 80% by weight, or about 90% by weight of substituted 3-(1-methylpyrrolidone-2-yl)pyridine (e.g., 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine) present in the product.

[0231] In some embodiments, the composition is in snuff or "dip" form, which may be in bulk or packaged in a woven material to form a bagged product. The snuff-form composition, in addition to the substituted 3-(1-methylpyrrolidone-2-yl)pyridine described herein, also contains non-tobacco plant materials. The composition may also contain components such as water, salts, humectants, buffers, sweeteners, binders, lipids, and flavorings, each as described herein.

[0232] Suitable non-tobacco materials are typically fibrous plant-derived materials, such as corn silk, red clover, wheat fiber, oat fiber, sugarcane fiber, beet pulp, barley fiber, rye fiber, buckwheat fiber, beet fiber, bran fiber, bamboo fiber, wood pulp fiber, cotton fiber, citrus fiber, grass fiber, willow fiber, poplar fiber, cocoa fiber, and combinations thereof. In some embodiments, the non-tobacco plant fiber material is bamboo fiber or sugarcane fiber. For the avoidance of doubt, non-tobacco plant fiber materials do not include microcrystalline cellulose. Suitable non-tobacco plant fiber materials include, but are not limited to, commercially available products, such as those sold under the brand name ALBAFIBER (Azelis), products sold under the brand name JELUCEL (Jelu-Werk; J. Ehrler GmbH & Co. KG), products sold by Natural Fiber Solutions (NFS), products sold under the brand name UNICELL (InterFiber), and products sold by Domsjö Fiber AB, etc.

[0233] In some embodiments, the snuff composition further comprises sensory agents (such as N-ethyl-p-menthane-3-carboxamide [WS-3], capsaicin, α-sanshool, etc.), natural and / or artificial sweeteners (such as allulose, sucralose, saccharin, acesulfame potassium, glycyrrhizic acid (licorice extract), stevia, mogroside, xylitol and combinations thereof, etc.), binders (such as guar gum, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, etc.), colorants (dyes, caramel color, etc.), and glycerides (such as MCT oil).

[0234] In some embodiments, the product of this disclosure exhibits favorable pharmacokinetic properties (e.g., time to reach maximum concentration (T0)) when placed in the user's oral cavity. max ), maximum concentration (C) max Exposure (AUC) or half-life (T) 1 / 2 For example, in some embodiments, when a pouch containing 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine is placed in the user's mouth, it exhibits pharmacokinetic properties consistent with or better than those of a pouch containing nicotine.

[0235] In some embodiments, when the bagged product of this disclosure containing 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine is placed in the user's mouth, it exhibits the Ti of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine. 1 / 2 T-type pouch products containing nicotine 1 / 2 Similar or longer. Not wanting to be bound by theory, a longer T is believed. 1 / 2 This is because 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine is metabolized less than nicotine.

[0236] In some embodiments, when the bagged product of this disclosure containing 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine is placed in the user's mouth, it exhibits the Ti of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine. max T-type pouch products containing nicotine max Similar or shorter. Not wanting to be bound by theory, a longer T is believed. max This is because its LogP increases relative to nicotine.

[0237] In some embodiments, when a bagged product of this disclosure containing 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine is placed in a user's mouth, it exhibits the C60-C ... max The C value of nicotine is greater than that of equivalent bagged products containing an equal weight of nicotine. max In some embodiments, a smaller amount of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine can be used to achieve physiological effects comparable to nicotine (i.e., pouch products containing 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine exhibit greater potency relative to nicotine). Not wishing to be bound by theory, it is believed that higher C... max This is because, relative to nicotine, its LogP increases, its metabolism decreases, or both.

[0238] In some embodiments, when a pouch product of the present disclosure containing 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine is placed in a user's mouth, the AUC of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine exhibits a value similar to or greater than the AUC of nicotine in a comparable pouch product containing an equal weight of nicotine. In some embodiments, a smaller amount of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine may be used to achieve a physiological effect comparable to nicotine (i.e., the pouch product containing 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine exhibits greater potency relative to nicotine). Not wishing to be bound by theory, it is believed that the higher AUC is due to an increase in LogP, a decrease in metabolism, or both, relative to nicotine.

[0239] Preparation of the composition

[0240] The compositions disclosed herein, regardless of their form (e.g., granules, pouches, tablets, melts, chewables, gums, etc.), are typically prepared by mixing the substituted 3-(1-methylpyrrolidone-2-yl)pyridine described herein with additional compositional components (e.g., water, fillers, sweeteners, binders, flavorings, buffers, salts, etc.). The manner in which the various components of the composition are combined can vary. Therefore, the overall mixture of the various components can be relatively homogeneous in nature. The aforementioned components (which can be in liquid or dry solid form) can be mixed in a pretreatment step prior to mixing with any remaining components of the composition, or simply mixed together with all other liquid or dry components.

[0241] In some embodiments, the method for preparing the composition includes: Combining one or more fillers, one or more salts and one or more sweeteners to form a dry blend; A dilute aqueous solution of substituted 3-(1-methylpyrrolidone-2-yl)pyridine is combined with water and an optional humectant to form a solution; The solution is combined with the dry blend to form a mixture; The resulting mixture is mixed to form a wet blend; and Optionally, flavoring agents and water are added to the wet blend to form the composition.

[0242] Figure 4 A non-limiting flow chart of such a method for forming a composition is shown. This method 400 is generally suitable for forming compositions in granular form, for example, for encapsulation in bags to form bagged products. (See reference...) Figure 4 In some embodiments, 410 provides one or more fillers, one or more salts, one or more sweeteners, and optionally a buffer, and combines them 420 to form a dry blend. Continuing with reference to... Figure 4 In some embodiments, the substituted 3-(1-methylpyrrolidone-2-yl)pyridine is provided in the form of a dilute aqueous solution, for example, the substituted 3-(1-methylpyrrolidone-2-yl)pyridine in water is about 4 to about 20% by weight. In some embodiments, the substituted 3-(1-methylpyrrolidone-2-yl)pyridine in the solution is present as a free base. In some embodiments, the solution contains about 8 to about 14% by weight of free base substituted 3-(1-methylpyrrolidone-2-yl)pyridine based on the total weight of the solution, for example, about 8, about 9, about 10, or about 11 to about 12, about 13, or about 14% by weight. Continuing to refer to... Figure 4In some embodiments, 430 combines a dilute aqueous solution of substituted 3-(1-methylpyrrolidone-2-yl)pyridine with water and an optional humectant (e.g., glycerin) to form a solution. Then 440 combines the solution with a dry blend by adding the solution to the dry blend or adding the dry blend to the solution and mixing to form a wet blend. Then 450 adds water and an optional flavoring agent to the wet blend and mixes to form a composition.

[0243] In some embodiments, the substituted 3-(1-methylpyrrolidone-2-yl)pyridine is provided as a solid, such as a solid free base or a salt or eutectic as disclosed herein. Therefore, in some embodiments, the solid form of the substituted 3-(1-methylpyrrolidone-2-yl)pyridine is combined with a dry blend, or may be combined with water and optionally a humectant (e.g., glycerin) to form a solution. Then, at 440, the solution is combined with the dry blend by adding the solution to the dry blend or adding the dry blend to the solution and mixing to form a wet blend. Then, at 450, water and optionally a flavoring agent are added to the wet blend and mixed to form a composition.

[0244] In some embodiments, substituted 3-(1-methylpyrrolidone-2-yl)pyridine is adsorbed onto a porous particulate support material, such as microcrystalline cellulose (MCC), prior to incorporation into the compositions disclosed herein. In some embodiments, the MCC material has an average particle size ranging from about 15 to about 250 micrometers. The particulate support material with adsorbed substituted 3-(1-methylpyrrolidone-2-yl)pyridine can then be combined with other compositional components as described herein.

[0245] In some embodiments, the substituted 3-(1-methylpyrrolidone-2-yl)pyridine is complexed with a cyclodextrin (e.g., β-cyclodextrin or a derivative thereof) prior to incorporation into the compositions disclosed herein. For example, in some embodiments, a slurry of β-cyclodextrin, substituted 3-(1-methylpyrrolidone-2-yl)pyridine, and water is heated to form a solution. Upon cooling, the precipitate is collected and dried to form a free-flowing powder. The ratio of β-cyclodextrin to substituted 3-(1-methylpyrrolidone-2-yl)pyridine can vary, but is typically about a 1:1 molar ratio. Other cyclodextrins, such as hydroxylated and sulfonyl-β-ether cyclodextrins, are also considered herein.

[0246] In some embodiments, the substituted 3-(1-methylpyrrolidone-2-yl)pyridine is complexed with pectin prior to incorporation into the compositions disclosed herein. For example, in some embodiments, the substituted 3-(1-methylpyrrolidone-2-yl)pyridine in water is mixed with a sufficient amount of apple-derived pectin to form a thick paste.

[0247] The various components of the composition (e.g., fillers, substituted 3-(1-methylpyrrolidone-2-yl)pyridine (optionally in a dilute aqueous solution), flavoring agents, sweeteners, salts, etc.) can be contacted, combined, or mixed using any mixing technique or equipment known in the art. Any mixing method that allows for close contact between the composition components can be used, such as mixing devices with impellers or other agitating structures. Examples of mixing equipment include shell drums, conditioning cylinders or drums, liquid spray devices, cone mixers, belt mixers, mixers from Littleford Day (models FKM130, FKM600, FKM1200, FKM2000, and FKM3000), plowshare mixer cylinders, Hobart brand mixers, etc. See also the types of methods described in, for example, U.S. Patent No. 4,148,325 to Solomon et al., U.S. Patent No. 6,510,855 to Korte et al., and U.S. Patent No. 6,834,654 to Williams, each of which is incorporated herein by reference. The manner and methods of formulating the compositions will be apparent to those skilled in the art. See also the types of methods described in, for example, U.S. Patent No. 4,148,325 to Solomon et al., U.S. Patent No. 6,510,855 to Korte et al., U.S. Patent No. 6,834,654 to Williams, U.S. Patent No. 4,725,440 to Ridgway et al., and U.S. Patent No. 6,077,524 to Bolder et al., each of which is incorporated herein by reference.

[0248] In some embodiments, the composition is in the form of a gel, chewable substance, lozenge, tablet, film, or melt. Methods for preparing such forms are generally known in the art, and non-limiting methods are provided in the following examples. In each case, the method generally involves combining a dilute aqueous solution of substituted 3-(1-methylpyrrolidone-2-yl)pyridine with other suitable components appropriate for the particular composition.

[0249] In some embodiments, the composition is in the form of a translucent or transparent lozenge. The methods and approaches for formulating and manufacturing translucent lozenge products can vary. For example, the composition can be prepared by any method commonly used in the preparation of hard candy. Exemplary methods for preparing hard candy can be found, for example, in the LFRA Ingredients Manual, Sweeteners, ed. Janet M. Dalzell, Leatherhead Food RA (December 1996), pp. 21-44, which is incorporated herein by reference. Typically, translucent lozenges contain substituted 3-(1-methylpyrrolidone-2-yl)pyridine, sugar substitutes, and sugar alcohols, and may contain various additional substances as described herein (e.g., salts, preservatives, other sweeteners, water, organic acids, buffers, flavorings, etc.). Typically, a mixture of the composition components is formed and heated until it melts. Subsequently, the mixture is heated to or beyond the hard-crack stage. In confectionery manufacturing, the hard-crack stage is defined as the temperature at which the filaments of the heated mixture (obtained by stretching a cooled syrup sample with the thumb and forefinger) become brittle, or at which cracking occurs when attempting to mold the syrup. The temperature at which the hard-crack stage is reached can vary depending on the specific composition of the product mixture, but is typically between about 145°C and about 170°C. Generally, the mixture is not heated above about 171°C, which is the temperature at which caramelization begins. Typically, the mixture is heated to the hard-crack stage temperature or above and then cooled. Heating can be performed at atmospheric pressure or under vacuum. The mixture is then shaped into the desired shape. In some embodiments, the mixture is poured directly into a mold, shaped (e.g., rolled or pressed) into the desired shape, or extruded. If desired, the mixture can be extruded or injection molded. In some embodiments, the mixture is shaped or extruded into a mold of the desired shape in a closed system, which may require lower temperatures and may limit the evaporation of certain mixture components. For example, such systems may limit the evaporation of volatile components (including, but not limited to, flavorings). This document also aims to cover other methods of producing lozenges.

[0250] As disclosed above, in some embodiments, the composition is in the form of snuff or smear, optionally packaged in a woolen bag. To prepare the composition in this form, non-tobacco plant material (typically in shredded or granular form) is typically treated with a mixture containing other compositional components, such as activators (e.g., substituted 3-(1-methylpyrrolidone-2-yl)pyridine), water, salt, humectants, flavoring agents, sweeteners, pH adjusters, buffers, colorants, binders, etc. The non-tobacco plant material is shredded to an acceptable size for oral chewing, for example, a sieve size of about 4 to about 40 mesh. In some embodiments, the wet snuff may be pasteurized by heat, pressure, and / or radiation. Additionally, preservatives such as sodium benzoate, sorbic acid, and / or essential oils may be present. In some embodiments, the composition is packaged in a bag as described herein. In bagged embodiments, the non-tobacco plant material may be shredded to a suitable particle size for bagging (e.g., a US sieve size of about 16 to 64 mesh).

[0251] Many modifications and other embodiments of this disclosure will arise to those skilled in the art upon having benefited from the teachings presented in the foregoing description. Therefore, it should be understood that this disclosure is not limited to the specific embodiments disclosed, and that modifications and other embodiments are intended to be included within the scope of the appended claims. Although specific terminology is used herein, it is used only in a general and descriptive sense and not for limiting purposes.

[0252] Example

[0253] The following embodiments will provide a more complete illustration of various aspects of this disclosure. These embodiments are described to illustrate certain aspects of this disclosure and should not be construed as limiting the disclosure.

[0254] Example 1. Preparation of Bagged Oral Products

[0255] A pouch-packaged oral product comprising a composition according to the present disclosure, comprising about 0.25 mg to 2.5 mg of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine as an active ingredient. The filler composition comprises 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine, microcrystalline cellulose (MCC), a sweetener, water, and additional components as disclosed herein (salts, humectants, buffers, flavorings). The formulation of the filler composition is shown in Table 2.

[0256] To prepare the filler composition, a dry blend of MCC, salt, sodium bicarbonate, and sweetener was mixed in a mixer. A mixture of water, a solution of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine, and propylene glycol was added to the dry mixture and mixed simultaneously. A flavoring agent and additional water were added to the wet mixture to prepare the filler composition. A portion of the filler composition (approximately 440 mg) was placed into a woolen bag (approximately 38 mm × 12 mm). Additional water was added to the bag to achieve a bag weight of approximately 576 mg and a calculated oven volatile content of approximately 35% by weight.

[0257] Table 2. Filler Composition

[0258] Example 2. Preparation of flavored chewing gum

[0259] Gum tablets containing flavoring agents and approximately 0.25 mg to 2 mg of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine were prepared using the formulation components shown in Table 3.

[0260] Sorbitol, isomaltitol, and sodium benzoate were combined to obtain a dry mixture. Maltitol syrup (aqueous solution, 75 wt%), glycerol, and a solution of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridinebenzoate (aqueous solution, 11 wt%) were combined separately to form a liquid mixture. The gum base (Artica T, CAFOSA Gum S / A, Barcelona, ​​Spain) was heated in a microwave oven on low power for approximately five minutes to soften. The softened gum base was mixed by hand until homogeneous and transferred to the bowl of a commercially available mixer. Approximately 1 / 3 of the liquid mixture was added to the gum base, and then mixed for two minutes. Approximately 1 / 3 of the dry mixture and sucralose were added to the gum base-liquid mixture, and then mixed for two minutes. The addition of both the dry and liquid mixtures was repeated twice, followed by a further two-minute mixing to incorporate the remaining dry and liquid mixtures. The flavoring was added to the mixture, and then mixed for 45 seconds. The mixture is removed from the mixer bowl, sprinkled with mannitol powder, and then passed through a tablet press to provide a composition of uniform thickness. Square tablets weighing 1.7g are punched out from the composition sheet.

[0261] Table 3. Oral adhesive composition components and dosage

[0262] Example 3. Preparation of tablets

[0263] A tablet composition was prepared from the composition comprising a filler, about 0.25 mg to 2 mg of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine, and a mixture of additional components (salt, sweetener, processing aids) as disclosed herein. 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine benzoate (aqueous solution, 11 wt%) and microcrystalline cellulose were mixed. The filler, sweetener, salt, mixture of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine benzoate, microcrystalline cellulose, and processing aids were combined and thoroughly mixed. The mixture was compressed and tableted using a Fette 1200i tablet press. The tablets were optionally coated with wax and shellac. The components of the composition and their concentrations (wt%) in the composition are shown in Table 4. Each tablet weighs 800 mg.

[0264] Table 4. Tablet Ingredients

[0265] Example 4. Preparation of chewable food

[0266] A chewable composition was prepared from the composition, the composition comprising a filler, about 0.25 mg to 2 mg of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine, and a mixture of additional components (salt, sweetener, flavoring agent, water, binder, citric acid, gelling agent) as disclosed herein. The components of the composition and their concentrations (wt%) in the composition are shown in Table 5.

[0267] Premix the pectin binder with a portion of isomaltitol. Add water and heat the mixture to a boil with stirring. Add maltitol syrup (aqueous solution, 75% by weight) and any remaining isomaltitol to the boiling mixture, then add trisodium citrate. Cook the mixture to 78 Brix. Remove the heat source, add the sweetener (e.g., sucralose and acesulfame potassium), coloring and flavoring agents, as well as citric acid, dicalcium phosphate, and 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine, thoroughly mix the mixture, and deposit the composition into starch molds for storage at ambient temperature. Each chewable tablet weighs 2600 mg.

[0268] Table 5. Composition of chewable food

[0269] Example 5. Preparation of fusible materials

[0270] The meltable composition is prepared from a composition containing a filler, a lipid, about 0.25 mg to 2 mg of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine, and additional components (salt, sweetener, flavoring agent) as disclosed herein. The compositional composition and its concentration (wt%) in the composition are shown in Table 6.

[0271] A portion of the palm oil is melted and mixed with isomalt in a mixer. The mixture is transferred to a dry roller mill and ground until the particle size is less than 20 microns. In the mixer, the ground isomalt-palm oil is combined with the remaining palm oil portion. The matrix is ​​heated to a fluid consistency. Sunflower oil, dry ingredients, 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine, and flavoring are mixed in. The isomalt-palm oil-ingredient mixture is transferred to a heated deposition funnel. An appropriate weight of sample is deposited into a shaped mold. If necessary, the mold is placed on a vibrator to ensure uniform filling. The product is allowed to cool and solidify, then removed from the mold. Each melt weighs 1300 mg.

[0272] Table 6. Composition of fusible material

[0273] Example 6. Preparation of Tablets

[0274] An oral product in tablet form is prepared, containing approximately 0.25 mg to 2 mg of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine. An aqueous mixture is prepared by mixing water, salt, a sweetener (e.g., sucralose), a humectant (e.g., glycerin), sodium benzoate, and a flavoring agent. Next, an aqueous solution of gum arabic (50% by weight) is heated to approximately 71°C, and a solution of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine is stirred into the heated gum component. The heated gum is then added to the aqueous composition to form a mixture. A sugar alcohol (e.g., isomaltitol and maltitol) is then heated to approximately 175°C and cooled to approximately 150°C. The cooled sugar alcohol is then added to the mixture and stirred to form the tablet composition, which is then cooled.

[0275] The tablet composition is then heated to approximately 71°C and deposited into a starch mold. The tablet composition is held in the starch mold at approximately 60°C for approximately 24 hours. The tablet composition is then cooled and removed from the starch mold. The oral composition is then cured at ambient room temperature for approximately 24 hours to provide the tablet product, each weighing approximately 2000 mg. The tablets are optionally coated with an anti-sticking agent (such as MCT oil or Capol®). Table 7 below shows the relative percentage of each individual component in the tablets.

[0276] Table 7 – Tablet Ingredients

[0277] Example 7. Preparation of translucent lozenges

[0278] Prepare an oral product in the form of a translucent lozenge containing approximately 0.25 mg to 2 mg of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine. Without stirring, heat isomalt and maltitol syrup to a melt temperature, to the hard-crack temperature (e.g., 165°C). Cool the melt to approximately 143°C while stirring very gently and discontinuously. Add the other components (2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine benzoate (aqueous solution, 11%), sodium benzoate, salt, sweetener, and / or flavoring agent) to the mixture and carefully fold with a spatula, avoiding introducing excessive air into the melt. Further cool the melt to approximately 120°C. Pour the mixture into a glass beaker, then pour the contents from the beaker in a string onto a metal block, into a separable mold with appropriately sized grooves, or into a mold (for individual lozenges, each weighing approximately 2000 mg). Optionally, the mixture is reheated to obtain a suitable melt viscosity. The melt is cooled for a period of time until it is suitable for solidification (e.g., room temperature). The lozenges are optionally coated with an anti-sticking agent (e.g., MCT oil or Capol®). Table 8 below shows the relative percentage of each individual component in the lozenges.

[0279] Table 8 – Lozenge Ingredients

[0280] Example 8. Preparation of Bagged Oral Products

[0281] A pouch-packaged oral product comprising a filling composition according to the present disclosure has been prepared, comprising 5 mg of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine as the active ingredient. The filling composition comprises 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine, microcrystalline cellulose (MCC), a sweetener, water, and additional components as disclosed herein (salts, humectants, flavoring agents, ion-pairing agents). The formulation of the filling composition is shown in Table 9.

[0282] To prepare the filler composition, a dry blend of MCC, salt, approximately half the total amount of sodium benzoate, and sweetener is mixed in a mixer. A mixture of water, a solution of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine, the remaining sodium benzoate, the flavoring agent, and propylene glycol is added to the dry blend and mixed simultaneously.

[0283] A portion of the filler composition (approximately 440 mg) was placed into a woolen bag (approximately 38 mm × 12 mm). Additional water was added to the bag to achieve a bag weight of approximately 720 mg and a calculated oven volatile content of approximately 48% by weight.

[0284] A portion of the filler composition (approximately 440 mg) was placed into a woolen bag (approximately 38 mm × 12 mm). Additional water was added to the bag to achieve a bag weight of approximately 576 mg and a calculated oven volatile content of approximately 35% by weight.

[0285] Table 9. Filler Composition Components

[0286] Example 9. Preparation of Bagged Oral Products - Premixing Method

[0287] A pouch-packaged oral product comprising a composition according to the present disclosure has been prepared, comprising 1 mg to 3 mg of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine as an active ingredient. The composition comprises 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine, microcrystalline cellulose (MCC), a sweetener, water, and additional components as disclosed herein (salts, humectants, flavoring agents, ion-pairing agents). Formulations of the premixed filling compositions are shown in Table 10A.

[0288] To prepare the premixed filler composition, a dry blend of MCC, salt, sodium benzoate, and sweetener was mixed in a mixer. Water, a solution of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine, a mixture of sodium benzoate and propylene glycol were added to the dry mixture and mixed simultaneously. The flavoring agent, propylene glycol, additional water, and optionally a sodium bicarbonate solution were added to the wet mixture to prepare the final filler composition shown in Table 10B. A portion of the filler composition (approximately 440 mg) was placed into a woolen bag (approximately 38 mm × 12 mm). Additional water was added to the bag to achieve a bag weight of approximately 720 mg and a calculated oven volatile content of approximately 48% by weight.

[0289] A portion of the filler composition (approximately 440 mg) was placed into a woolen bag (approximately 38 mm × 12 mm). Additional water was added to the bag to achieve a bag weight of approximately 576 mg and a calculated oven volatile content of approximately 35% by weight.

[0290] Table 10A: Composition of Premixed Filler Compositions

[0291] Table 10B: Filler Composition Components

[0292] Example 10. Preparation of dry-packaged oral products

[0293] A pouch-packaged oral product with low moisture content and containing the composition according to this disclosure was prepared. The composition contains 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine as the active ingredient, with each pouch containing 1 mg of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine. The composition also contains microcrystalline cellulose (MCC), a sweetener, water, and additional components as disclosed herein (salt, humectant, buffer, flavoring agent). The formulation of the composition is shown in Table 11. To prepare the composition, a blend of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine (free base aqueous solution and benzoate aqueous solution, 12 wt% and 11 wt%, respectively), MCC, salt, maltitol, hydroxypropyl cellulose, sodium benzoate, sweetener, and flavoring agent was mixed in a mixer.

[0294] Place a portion of the filler composition (approximately 370 mg) into a woolen bag (approximately 30 mm × 12 mm). Add additional water to the bag to achieve approximately 400 mg of bag weight and approximately 4% by weight of calculated oven volatiles content.

[0295] Table 11. Filler Composition

[0296] Example 11. Preparation of Bagged Oral Products - Spherical MCC

[0297] A pouch-packaged oral product comprising a filling composition according to the present disclosure was prepared. The composition comprises 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine as the active ingredient, with each pouch containing approximately 0.25 mg of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine. The composition also comprises spherical microcrystalline cellulose (MCC), a sweetener, water, and additional components as disclosed herein (salt, humectant, buffer, flavoring agent). The formulation of the composition is shown in Table 12. To prepare the filling composition, a blend of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine (an aqueous solution of monomenthyl succinate, 5 wt%), water, spherical MCC (JRS 350), salt, sodium bicarbonate, propylene glycol, sweetener, and flavoring agent was mixed in a mixer. A portion of the filling composition (approximately 416 mg) was placed into a woolen pouch (approximately 30 mm × 12 mm). Add additional water to the bag to achieve a bag weight of approximately 509 mg and a calculated oven volatile content of approximately 23% by weight. The bag pH is approximately 7.5.

[0298] Table 12. Filler Composition

[0299] Example 12. Preparation of Bagged Oral Products - Spherical MCC

[0300] A pouch-packaged oral product comprising a filling composition according to the present disclosure was prepared. The composition comprises 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine as the active ingredient, with each pouch containing 0.25 mg of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine. The composition also comprises spherical microcrystalline cellulose (MCC), a sweetener, water, and additional components as disclosed herein (salt, propylene glycol, sodium benzoate, flavoring agent). The formulation of the composition is shown in Table 13. To prepare the filling composition, a blend of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine (free alkaline aqueous solution, 12 wt%), water, spherical MCC, salt, sodium benzoate, sodium bicarbonate, propylene glycol, sweetener, and flavoring agent was mixed in a mixer. A portion of the filling composition (approximately 416 mg) was placed into a woolen pouch (approximately 30 mm × 12 mm). Add additional water to the bag to achieve a bag weight of approximately 509 mg and a calculated oven volatile content of approximately 23% by weight.

[0301] Table 13. Filler Composition

[0302] Example 13. Preparation of Bagged Oral Products - Pectin Salt Complex

[0303] A pouch-packaged oral product comprising a filling composition according to the present disclosure was prepared. The composition comprises 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine as the active ingredient, with each pouch containing 1 mg of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine. The composition also comprises microcrystalline cellulose (MCC), a sweetener, water, and additional components as disclosed herein (salt, propylene glycol, sodium benzoate, flavoring agent). The formulation of the filling composition is shown in Table 14. The pectinate complex was first prepared by combining 309 g of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine with 60 g of low-methoxyamidized apple pectin to form a thick paste, and then combining it with MCC to form a dry powder containing 2 wt% 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine. To prepare this composition, a mixture of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine pectinate complex and MCC, water, MCC, salt, sodium benzoate, propylene glycol, sodium bicarbonate, sweetener, and flavoring agent were mixed in a mixer. A portion of the filling composition (approximately 440 mg) was placed into a woolen bag (approximately 38 mm × 12 mm). Additional water was added to the bag to achieve approximately 720 mg of bag weight and approximately 49% by weight of calculated oven volatiles content. The bag pH was approximately 7.2.

[0304] Table 14. Filler Composition

[0305] Example 14. Preparation of Bagged Oral Products - HCl Mixture

[0306] A pouch-packaged oral product comprising the filling composition according to the present disclosure was prepared. The composition comprises 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine as the active ingredient, with each pouch containing 1 mg of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine. The composition also comprises microcrystalline cellulose (MCC), a sweetener, water, and additional components as disclosed herein (salt, propylene glycol, sodium benzoate, flavoring agent). The formulation of the filling composition is shown in Table 15. A 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine hydrochloric acid solution was first prepared from 48 g of a 12% aqueous solution of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine, 0.32 g of concentrated hydrochloric acid (approximately 37 wt%), and 9 g of water. To prepare this composition, an aqueous solution (10 wt%) of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine and hydrochloric acid, water, MCC, salt, sodium benzoate, propylene glycol, sweetener, and flavoring agent were mixed in a mixer. Approximately 440 mg of the filling composition was placed in a woolen bag (approximately 38 mm × 12 mm). Additional water was added to the bag to achieve approximately 720 mg of bag weight and approximately 48 wt% of calculated oven volatiles content. The bag pH was approximately 6.3.

[0307] Table 15. Filler Composition

[0308] Example 15. Preparation of Bagged Oral Products

[0309] A pouch-packaged oral product comprising a filling composition according to the present disclosure was prepared. The composition comprises 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine as the active ingredient, with each pouch containing 0.5 mg of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine. The composition also comprises microcrystalline cellulose (MCC), a sweetener, water, and additional components as disclosed herein (salt, humectant, sodium benzoate, sodium bicarbonate solution, flavoring agent). The formulation of the filling composition is shown in Table 16. To prepare the composition, a blend of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine (free alkaline aqueous solution, 12 wt%), water, MCC, salt, sodium benzoate, sodium bicarbonate (4% aqueous solution), propylene glycol, sweetener, and flavoring agent was mixed in a mixer. A portion of the filling composition (approximately 440 mg) was placed in a woolen pouch (approximately 38 mm × 12 mm). Add additional water to the bag to achieve a bag weight of approximately 720 mg and a calculated oven volatile content of approximately 48% by weight.

[0310] Table 16. Filler Composition

[0311] Example 16. Preparation of Bagged Oral Products

[0312] A pouch-packaged oral product comprising the filling composition according to the present disclosure has been prepared. The composition comprises 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine as the active ingredient, with each pouch containing 1 mg of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine. The filling composition also comprises microcrystalline cellulose (MCC), a sweetener, water, and additional components as disclosed herein (salt, humectant, sodium benzoate, flavoring agent). The formulation of the composition is shown in Table 17.

[0313] To prepare this composition, a dry blend of MCC, sodium chloride, and sweetener was prepared by combining the components in a mixer. A wet blend was prepared by mixing water, 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine (aqueous solution of free base, 12 wt%), 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine (aqueous solution of benzoate, 11 wt%), propylene glycol, and sodium benzoate in a mixer. The wet blend, dry blend, and flavoring agent were combined and mixed in a mixer to obtain a filling composition. A portion of the filling composition (approximately 440 mg) was placed in a woolen bag (approximately 38 mm × 12 mm). Additional water was added to the bag to achieve a bag weight of approximately 720 mg and a calculated oven volatile content of approximately 48 wt%. The bag pH was approximately 6.

[0314] Table 17. Filler Composition Components

[0315] Example 17. Preparation of Bagged Oral Products

[0316] A pouch-packaged oral product comprising the filling composition according to the present disclosure was prepared. The composition comprises 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine as the active ingredient, with each pouch containing 1 mg of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine. The composition also comprises microcrystalline cellulose (MCC), a sweetener, water, and additional components (salt, humectant, flavoring agent) as disclosed herein. The formulation of the filling composition is shown in Table 18. To prepare the composition, a dry blend of MCC, sodium chloride, and the sweetener was prepared by combining the components in a mixer. Alternatively, a wet blend was prepared by mixing water, 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine (aqueous solution of free base, 12 wt%), 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine (aqueous solution of benzoate, 11 wt%), propylene glycol, and sodium benzoate in a mixer. The wet blend, dry blend, and flavoring agent were combined and mixed in a mixer to obtain a filling composition. A portion of the filling composition (approximately 323 mg) was placed into a woolen bag (approximately 30 mm × 12 mm). Additional water was added to the bag to achieve a bag weight of approximately 421 mg and a calculated oven volatile content of approximately 35% by weight. The bag pH was approximately 6.4.

[0317] Table 18. Filler Composition Components

[0318] Example 18. Preparation of Bagged Oral Products

[0319] A pouch-packaged oral product comprising a filling composition according to the present disclosure was prepared. The composition comprises 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine as the active ingredient, with each pouch containing 3 mg of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine. The composition also comprises microcrystalline cellulose (MCC), a sweetener, water, and additional components as disclosed herein (salt, humectant, sodium benzoate, flavoring agent). The formulation of the filling composition is shown in Table 19. To prepare this composition, a dry blend of MCC, sodium chloride, sweetener, and approximately half the total amount of sodium benzoate was prepared by combining the components in a mixer. Additionally, a wet blend was prepared by mixing water, 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine (free alkaline aqueous solution, 12 wt%), 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine (benzoate aqueous solution, 11 wt%), propylene glycol, and the remaining sodium benzoate in a mixer. The wet blend, dry blend, and flavoring agent were combined and mixed in a mixer to obtain a filling composition. A portion of the filling composition (approximately 323 mg) was placed in a woolen bag (approximately 30 mm × 12 mm). Additional water was added to the bag to achieve a bag weight of approximately 426 mg and a calculated oven volatile content of approximately 35 wt%.

[0320] Table 19. Filler Composition Components

[0321] Example 19. Preparation of Bagged Oral Products

[0322] A pouch-packaged oral product comprising a filling composition according to the present disclosure was prepared. The composition comprises 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine as the active ingredient, with each pouch containing 1 mg of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine. The composition also comprises microcrystalline cellulose (MCC), a sweetener, water, sodium benzoate, and additional components as disclosed herein (salt, sweetener, humectant, flavoring agent). The formulation of the filling composition is shown in Table 20. To prepare the composition, a dry blend of MCC, sodium chloride, and sweetener was prepared by combining the components in a mixer. Alternatively, a wet blend was prepared by mixing water, 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine (aqueous solution of free base, 12 wt%), 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine (aqueous solution of benzoate, 11 wt%), propylene glycol, and sodium benzoate in a mixer. The wet blend, dry blend, and flavoring agent are combined and mixed in a mixer to obtain a filling composition. A portion of the filling composition (approximately 440 mg) is placed into a woolen bag (approximately 38 mm × 12 mm). Additional water is added to the bag to achieve a bag weight of approximately 720 mg and a calculated oven volatile content of approximately 48% by weight.

[0323] Table 20. Filler Composition Components

[0324] Example 20. Preparation and dissolution study of bagged oral products

[0325] Bagged oral products comprising the filling composition according to the present disclosure were prepared. The filling composition comprises 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine as the active ingredient, with each bag containing 0.5 mg, 1 mg, or 2 mg of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine. The composition also comprises microcrystalline cellulose (MCC), a sweetener, water, and one or more additional components as disclosed herein (e.g., salt, sweetener, humectant, flavoring agent). A reference bag product comprising nicotine (5.5 mg) was also prepared (Example 20E). A citrate buffer composition was also prepared using a pH 6.3 buffer containing trisodium citrate and citric acid (0.5 M citrate) (Example 20G). Additional samples (Examples 20H and 20I) were also prepared in the same manner as in Example 20G, but with different citrate concentrations. Each bag product was prepared as in Example 19, using the filling formulation shown in Table 21.

[0326] Table 21. Composition of Bag Filling Composition Calculate the volatile content of the oven after adding excess water to the bag. #Does not reflect benzoic acid present as benzoate or generated in situ from benzoate. For the dissolution test, each bag of product was individually placed in 500 mL of 12 mm ammonium phosphate buffer (pH 7.4) using a basket apparatus at 37°C. The basket was stirred at 50 RPM for 60 min, followed by stirring at 250 RPM for 30 min. Samples were taken at 1.42, 3.5, 6, 8.5, 11, 15, 20, 30, 60, and 90 min to analyze the concentration of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine. Results are expressed as a percentage of the total 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine present in each bag, with the analysis repeated three times. Results are shown as the percentage of release at each time point. Figure 5 In this model, time points are represented on a logarithmic scale to enhance linearity.

[0327] Reference Figure 5 The sample released approximately 70% to approximately 100% of the total 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine after 90 minutes, and the release was roughly linear over time. (Continue to refer to...) Figure 5 Surprisingly, the addition of citrate buffer (Example 20G, containing 4.8 molar equivalents of benzoate and 4.5% of 0.5M citrate) increased the dissolution rate and yielded a dissolution profile similar to that of the reference ion-paired nicotine formulation sample (Example 20E; 4.8 molar equivalents of benzoate). Continue to refer to... Figure 5Data indicate that the dissolution rate increases with increasing benzoate concentration (4.8 molar equivalents of total benzoate versus 3.2 molar equivalents of total benzoate; Example 20F versus Examples 20A to 20D). This effect is believed to be more pronounced in formulations with lower concentrations of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine. Without being bound by theory, it is believed that acidic sites in the woolen bag material, and possibly in the MCC, can interact with and chelate a portion of the basic 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine, and that increased ionic strength in the presence of benzoate and / or citrate may facilitate the release of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine from the woolen fabric or reduce the migration of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine from the formulation to the woolen fabric. Therefore, the concentrations of ion-pairing agents (such as benzoates) and / or buffers such as citrates, acetates, carbonates, phosphates, etc., can be varied to modulate the release characteristics of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine in the pouch product. This modulation can provide a more gradual or faster release profile, thereby customizing the user experience.

[0328] LogP, composition pH, and bag pH were evaluated for samples from Examples 20F, 20G, 20H, and 20I. The data are presented in Table 22, which shows that adding 0.5 M citrate buffer to the 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine composition resulted in a closer pH between the bag filler and the finished bagged product. Surprisingly, the presence of citrate buffer had little effect on logP. This result is unexpected because the citrate anion was expected to compete with the benzoate anion for ion-pair complex formation; however, instead, benzoate ion-pair complexes were found to form even in the presence of citrate.

[0329] Table 22. LogP and pH values

[0330] Example 21. Preparation of oral strip products

[0331] Oral products in strip form were prepared using the formulations shown in Table 23. A solution of glyceryl monostearate and polyoxyethylene 40 stearate (emulsifier) ​​was prepared by dissolving the emulsifier in hot water with stirring. Hydroxypropyl methylcellulose and Agaroid® 300 (a mixture of agar and locust bean gum) were added to the resulting solution and then mixed. Glycerin was added to the thickening solution, followed by the remaining ingredients. Mixing was continued until homogeneous. The resulting slurry was cast onto a flat carrier, dried to approximately 3% moisture, and then cut into strips approximately 11 mm × 32 mm in size and approximately 140 mg in weight. Optionally, the cut strips could be perforated to divide each strip into several portions. Each strip contained 0.5 mg of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine.

[0332] Table 23. Composition of the Composition

[0333] Example 22. Preparation of oral products containing additional active ingredients

[0334] Oral products in the form of pouches, gels, tablets, chewables, melts, lozenges, or strips are prepared as described in any one of Examples 1-21, but in each case further comprising an α7 nicotinic receptor subtype (α7 nAChR) agonist. In each case, the product is prepared as described in any one of Examples 1-21, having a composition as described in any one of Tables 2-21 or 23, and comprising 0.2 mg to 5 mg of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine and about 0.1 to about 350 mg of the α7 nAChR agonist.

[0335] Example 23. Preparation of a pouch-type oral care product (slender, sweet flavor)

[0336] A pouch-packaged oral product comprising a filling composition according to the present disclosure has been prepared. The composition comprises 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine as the active ingredient, with each pouch containing 0.25 mg to 3 mg of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine. The composition also comprises microcrystalline cellulose (MCC), a sweetener, water, and additional components as disclosed herein (salts, buffers, humectants, flavorings). The formulation of the filling composition is shown in Table 24. To prepare the composition, a blend of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine (an aqueous solution of benzoate, 11 wt%), water, MCC, salt, sodium benzoate, sodium bicarbonate (4% aqueous solution), propylene glycol, sodium citrate solution (approximately pH 6.3), sweetener, and flavoring is mixed in a mixer. A portion of the filling composition (approximately 440 mg) is placed in a woolen pouch (approximately 38 mm × 12 mm). Add additional water to the bag to achieve a bag weight of approximately 720 mg and a calculated oven volatile content of approximately 48% by weight. The bag pH is approximately 6.

[0337] Table 24. Composition of Oral Product Compositions

[0338] Example 24. Preparation of a pouch-type oral care product (slender, low-sweetness)

[0339] A pouch-packaged oral product comprising a filling composition according to the present disclosure has been prepared. The composition comprises 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine as the active ingredient, with each pouch containing 0.25 mg to 3 mg of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine. The composition also comprises microcrystalline cellulose (MCC), a sweetener, water, and additional components as disclosed herein (salts, buffers, humectants, flavorings). The formulation of the filling composition is shown in Table 25. To prepare the composition, a blend of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine (an aqueous solution of benzoate, 11 wt%), water, MCC, salt, sodium benzoate, sodium bicarbonate solution, propylene glycol, sodium citrate solution (approximately pH 6.3), sweetener, and flavoring is mixed in a mixer. A portion of the filling composition (approximately 440 mg) is placed in a woolen pouch (37.5 mm × 12 mm). Add additional water to the bag to achieve a bag weight of approximately 720 mg and a calculated oven volatile content of approximately 48% by weight. The bag pH is approximately 6.

[0340] Table 25. Composition of Oral Product Filling Compositions

[0341] Example 25. Preparation of a pouch-packaged oral care product (mini, sweet flavor)

[0342] A pouch-packaged oral product comprising a filling composition according to the present disclosure has been prepared. The composition comprises 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine as the active ingredient, with each pouch containing 0.25 mg to 2 mg of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine. The composition also comprises microcrystalline cellulose (MCC), a sweetener, water, and additional components as disclosed herein (salts, buffers, humectants, flavorings). The formulation of the filling composition is shown in Table 26. To prepare the composition, a blend of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine (an aqueous solution of benzoate, 11 wt%), water, MCC, salt, sodium benzoate, sodium bicarbonate solution, propylene glycol, sodium citrate solution (approximately pH 6.3), sweetener, and flavoring is mixed in a mixer. A portion of the filling composition (approximately 323 mg) is placed in a woolen pouch (approximately 30 mm × 12 mm). Add additional water to the bag to achieve a bag weight of approximately 426 mg and a calculated oven volatile content of approximately 35% by weight. The bag pH is approximately 6.

[0343] Table 26. Composition of Oral Product Filling Compositions

[0344] Example 26. Preparation of a pouch-packaged oral care product (mini size, less sweet)

[0345] A pouch-packaged oral product comprising a filling composition according to the present disclosure has been prepared. The composition comprises 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine as the active ingredient, with each pouch containing 0.25 mg to 2 mg of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine. The composition also comprises microcrystalline cellulose (MCC), a sweetener, water, and additional components (salts, buffers, humectants, flavorings) as disclosed herein. The formulation of the filling composition is shown in Table 27. To prepare the composition, a blend of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine (an aqueous solution of benzoate, 11 wt%), water, MCC, salt, sodium benzoate, sodium bicarbonate solution, propylene glycol, sodium citrate solution (approximately pH 6.3), sweetener, and flavoring is mixed in a mixer. A portion of the composition (approximately 323 mg) is placed in a woolen pouch (approximately 30 mm × 12 mm). Add additional water to the bag to achieve a bag weight of approximately 426 mg and a calculated oven volatile content of approximately 35% by weight. The bag pH is approximately 6.

[0346] Table 27. Composition of Oral Product Filling Compositions

[0347] Example 27. Preparation of high pH dipping smoke

[0348] An oral product in the form of snuff (“nose”) has been prepared comprising the composition according to this disclosure. The composition comprises 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine as the active ingredient, wherein each 2g portion contains 0.1 mg to 1.5 mg of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine. The composition also comprises non-tobacco plant material, a sweetener, water, and additional components as disclosed herein (salt, buffer, humectant, flavoring agent, preservative, colorant). The formulation of the composition is shown in Table 28. To prepare the composition, an aqueous solution (12 wt%) of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine, water, plant material, salt, sodium benzoate, sodium bicarbonate, humectant, sweetener, flavoring agent, colorant, and preservative are mixed in a mixer. The mixture is divided into portions of about 2g. The final moisture content is about 50%. When the composition is placed in water, the pH is in the range of about 7 to about 9. In some embodiments, the composition (about 1.3g) is placed in a cellulose wool fabric to form a bagged product.

[0349] Table 28. Composition of High pH Oral Product Compositions

[0350] Example 28. Preparation of low-pH dipping smoke

[0351] An oral product in the form of snuff (“nose”) has been prepared comprising the composition according to this disclosure. The composition comprises 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine as the active ingredient, wherein each 2g portion contains 0.1 mg to 1.5 mg of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine. The composition also comprises non-tobacco plant material, a sweetener, water, and additional components as disclosed herein (salt, buffer, humectant, flavoring agent, preservative, colorant). The formulation of the composition is shown in Table 29. To prepare the composition, an aqueous solution (11 wt%) of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine benzoate, water, plant material, salt, sodium benzoate, sodium bicarbonate, humectant, sweetener, flavoring agent, colorant, and preservative are mixed in a mixer. The mixture is divided into portions of about 2g. The final moisture content is about 50%. When the composition is placed in water, the pH is in the range of about 5 to about 7. In some embodiments, the composition (about 1.3g) is placed in a cellulose wool fabric to form a bagged product.

[0352] Table 29. Composition of Low pH Oral Product Compositions

[0353] Example 29. Preparation of Effervescent Tablets

[0354] Effervescent tablets according to embodiments of the present disclosure were prepared. A composition in tablet form was prepared comprising a filler, about 0.25 mg to 2 mg of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine, and a mixture of additional components (salt, sweetener, sodium carbonate, sodium bicarbonate, citric acid, processing aids) as disclosed herein. 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine benzoate (aqueous solution, 11 wt%) and microcrystalline cellulose were mixed. The filler, sweetener, salt, the mixture of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine benzoate and microcrystalline cellulose, sodium carbonate, sodium bicarbonate, citric acid, and processing aids were combined and thoroughly mixed. The mixture was compressed and tableted using a Fette 1200i tablet press. The tablets were optionally coated with wax and shellac. The components of the composition and their concentrations (wt%) in the composition are shown in Table 30. Each tablet weighs 800 mg.

[0355] Table 30. Composition of Effervescent Tablets

[0356] Example 30. Study on long-term storage stability and accelerated storage stability

[0357] The pouch-packaged oral products according to embodiments of this disclosure (prepared according to Examples 8, 9, 16, 17, 18, and 19) were subjected to storage stability assessments under long-term and accelerated conditions in a stability testing chamber. The pouches were packaged into conventional oral product containers with side-sealed seals (20 pouches / container) for stability testing. Long-term storage conditions (environment) were a temperature of 25°C ± 2°C and a relative humidity of 60% ± 5%. Accelerated storage conditions were a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5%. The results are shown in Table 31 (long-term conditions) and Table 32 (accelerated conditions), respectively.

[0358] Referring to Table 31, a pH difference is observed between the filler material and the bagged product, which varies with, for example, bag size, concentration of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine, and / or moisture content. The difference between the filler pH and the bag pH shown in Table 31 indicates that the pH difference increases as the concentration of the compound in the filler composition decreases. Continuing to refer to Table 31, this data shows that the initial bag pH (approximately 6) of the various bagged products of this disclosure is maintained over a six-month storage period under ambient conditions. Notably, these compositions do not contain citrate buffer.

[0359] Similarly, continuing with reference to Table 31, the initial moisture content (i.e., about 35% or about 48% moisture content) of the various bagged products of this disclosure is maintained during a six-month storage period under ambient conditions. Finally, continuing with reference to Table 31, the initial concentration of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine (about 1, 3 or 5 mg per bag) is maintained during a six-month storage period under ambient conditions.

[0360] Referring to Table 32, the data shows that the initial pH value, moisture content, and 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine concentration of the various bagged products of this disclosure were maintained during a six-month storage period under accelerated aging conditions.

[0361] The results in Tables 31 and 32 collectively demonstrate that the products of this disclosure containing 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine are unexpectedly stable with respect to pH, moisture content, and 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine concentration during storage. Particularly surprising is the retention of the initial concentration of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine over time. This is unexpected given the very small amount present per bag and the tendency of a considerable number of nicotine bags to show a decrease in nicotine concentration over time.

[0362] Therefore, in some embodiments, the bagged product of this disclosure containing substituted 3-(1-methylpyrrolidone-2-yl)pyridine (e.g., 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine) can maintain one or more of the following when stored for up to 6 months at a temperature of 25°C ± 2°C and a relative humidity of 60% ± 5%: - The concentration of substituted 3-(1-methylpyrrolidone-2-yl)pyridine (e.g., 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine) is within ±10% of the initial concentration of substituted 3-(1-methylpyrrolidone-2-yl)pyridine (e.g., 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine), wherein the initial concentration is approximately 1 mg, 3 mg or 5 mg per sachet; - The moisture content is within ±5% of the initial moisture content, wherein the initial moisture content is approximately 35% or 48%; - The pH value is within ±10% of the initial pH value, wherein the initial pH value is approximately 6.

[0363] In some embodiments, the bagged product of this disclosure containing substituted 3-(1-methylpyrrolidone-2-yl)pyridine (e.g., 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine) can maintain one or more of the following when stored for up to 6 months at a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5%: - The concentration of substituted 3-(1-methylpyrrolidone-2-yl)pyridine (e.g., 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine) is within ±10% of the initial concentration of substituted 3-(1-methylpyrrolidone-2-yl)pyridine (e.g., 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine), wherein the initial concentration is approximately 1 mg, 3 mg or 5 mg per sachet; - The moisture content is within ±5% of the initial moisture content, wherein the initial moisture content is approximately 35% or 48%; - The pH value is within ±10% of the initial pH value, wherein the initial pH value is approximately 6.

[0364] Table 31. Long-term storage (environment) The active ingredient refers to 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine. = Moisture content (%) calculated based on dry weight loss No flavor = 0% flavoring Table 32. Long-term storage (accelerated) The active ingredient refers to 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine. = Moisture content (%) calculated based on dry weight loss No flavor = 0% flavoring No flavor = 0% flavoring

Claims

1. A composition configured for oral use, the composition comprising: Filler components; Water, in an amount of about 1 to about 60% by weight based on the total weight of the composition; and Substituted 3-(1-methylpyrrolidone-2-yl)pyridines having the structure according to Formula I: (I)， in: R 1 R 2 R 3 and R 4 Each is independently selected from the group consisting of: hydrogen, alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl, aryl, alkylaryl, amino, halogen, and cyano, wherein any one of the alkyl, alkoxy, cycloalkyl, alkenyl, alkenyl, alkynyl, aryl, alkylaryl, and amino groups may optionally be substituted; and R 1 R 2 R 3 and R 4 At least one of them is not hydrogen.

2. The composition of claim 1, wherein R 1 R 2 and R 3 Each is represented by H.

3. The composition according to claim 1 or 2, wherein R 4 It can be an optional substituted C1-C6 alkyl, F, Cl, Br, OCH3, OCH2CH3 or CN.

4. The composition according to any one of claims 1-3, wherein R 1 R 2 and R 3 Each is H, and R 4 It is a C1-C3 alkyl group; preferably, R 4 It is CH3.

5. The composition according to any one of claims 1-4, wherein the substituted 3-(1-methylpyrrolidone-2-yl)pyridine is racemic.

6. The composition according to any one of claims 1-4, wherein the substituted 3-(1-methylpyrrolidone-2-yl)pyridine has an (R)-configuration or an (S)-configuration; preferably, wherein the substituted 3-(1-methylpyrrolidone-2-yl)pyridine has an (S)-configuration.

7. The composition of any one of claims 1-6, wherein the calculated logP of the substituted 3-(1-methylpyrrolidone-2-yl)pyridine is about 1 or greater, for example about 1.2 to about 1.

7.

8. The composition of any one of claims 1-7, wherein the composition is substantially free of 3-(1-methylpyrrolidone-2-yl)pyridine; preferably, wherein the composition is completely free of 3-(1-methylpyrrolidone-2-yl)pyridine.

9. The composition of any one of claims 1-8, wherein the composition is substantially free of acid components; optionally, wherein the composition is completely free of acid components.

10. The composition of any one of claims 1-8, further comprising an organic acid, an alkali metal salt of an organic acid, or a combination thereof, wherein the organic acid has a logP value in the range of about 1 to about 12; optionally, wherein the organic acid has a logP value of about 3 to about 12, about 3 to about 10, or about 3 to about 8, and wherein at least a portion of the substituted 3-(1-methylpyrrolidone-2-yl)pyridine is present in the form of an ion pair with the organic acid, the alkali metal salt of the organic acid, or a combination thereof.

11. The composition of any one of claims 1-8, wherein at least a portion of the substituted 3-(1-methylpyrrolidone-2-yl)pyridine is present in the form of a salt, a eutectic, or a salt eutectic.

12. The composition of any one of claims 1-8, wherein at least a portion of the substituted 3-(1-methylpyrrolidone-2-yl)pyridine is incorporated into the polymer resin.

13. The composition of any one of claims 1-12, wherein the substituted 3-(1-methylpyrrolidone-2-yl)pyridine is present in an amount of about 0.01 to about 10% by weight based on the total weight of the composition, calculated as a free base.

14. The composition of any one of claims 1-13, wherein the filler component is cellulose-based; optionally, wherein the filler component comprises microcrystalline cellulose.

15. The composition of any one of claims 1-14, further comprising one or more flavoring agents, one or more salts, one or more sweeteners, one or more binders, one or more humectants, one or more gums, or combinations thereof.

16. The composition according to any one of claims 1 to 15, wherein it is in the form of a gel, lozenge, gel, chewable substance, melt, tablet, lozenge, film, granular material, snuff, or powder.

17. The composition of any one of claims 1-15, wherein it is packaged in a bag to form a bagged product.

18. The composition of claim 17, wherein the moisture content is about 30 to about 60% by weight based on the weight of the bagged product.

19. A composition configured for oral use, the composition comprising: Based on the total weight of the composition, approximately 0.01 to approximately 10% by weight of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine; Filler components; and Water, in an amount of about 1 to about 60% by weight, or about 30 to about 60% by weight, based on the total weight of the composition.

20. The composition of claim 19, wherein the filler component is cellulose-based, and optionally, wherein the filler component comprises microcrystalline cellulose.

21. The composition of any one of claims 1-20, further comprising a buffer; optionally, said buffer is an alkali metal citrate salt.

22. The composition of any one of claims 19-21, wherein when the composition is placed in 500 mL of pH 7.4 phosphate buffer and stirred at 50 RPM for 50 minutes at 37°C in a USP basket dissolution apparatus, at least about 60% by weight of the total weight of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine present in the composition is released.

23. The composition of claim 22, wherein at least about 20% of the total weight of 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine present in the composition is released at 10 minutes.

24. A method for preparing a composition comprising substituted 3-(1-methylpyrrolidone-2-yl)pyridine for oral use, the method comprising: One or more fillers are mixed with one or more additional powder components to form a dry blend, said additional powder components being, for example, one or more salts and / or one or more sweeteners; A dilute aqueous solution of substituted 3-(1-methylpyrrolidone-2-yl)pyridine is mixed with water and a humectant to form a solution; The solution is mixed with the dry blend to form a mixture; The resulting mixture is mixed to form a wet blend; as well as Optionally, flavoring agents and / or water may be added to the wet blend to form a composition.

25. The method of claim 24, wherein the substituted 3-(1-methylpyrrolidone-2-yl)pyridine is 2-methyl-5-(1-methylpyrrolidone-2-yl)pyridine.

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