Vaporizable alkaloid compositions and methods of use thereof

Abstract

In various embodiments of the present disclosure, vaporizable alkaloid compositions comprising a substituted pyridine compound of formula (I) and being completely nicotine-free are described that are capable of forming inhalable vapors when dispensed from an electronic device, such as an electronic cigarette. As part of the smoking cessation plan, there is provided a series of such gasified alkaloid compositions having a decreasing amount (w / v) of substituted pyridine compounds.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application is a continuation-in-part of U.S. Application Serial No. 18 / 227,815, entitled “Vaporizable Alkaloid Compositions and Methods of Use Thereof,” filed on July 28, 2023. The '815 Application claims priority to and the benefit of U.S. Provisional Patent Application Serial No. 63 / 439,650, entitled “Vaping Liquid With Analogs For Vaping Devices,” filed on January 18, 2023. These disclosures are incorporated herein in their entirety for all purposes. Technical Field

[0003] The present disclosure generally relates to vaporizable and inhalable compositions containing physiologically and sensory active substances, and in particular to vaporizable compositions containing one or more substituted pyridine compounds or salts or mixed salts thereof. Background Art

[0004] It is well known that smokers gain health benefits from quitting smoking, and generally, most adult smokers in the United States express a desire to quit. Electronic nicotine delivery systems (ENDS), based on the composition of vaporized liquids, should, at least in principle, provide a viable smoking cessation aid. However, multiple studies have shown that users who self-administer nicotine using electronic devices are unlikely to actually stop smoking tobacco products. For example, see B. Kaplan et al., “Effectiveness of ENDS, NRT and Medication for Smoking Cessation Among Cigarette-Only Users,” Tob Control 2023;32:302-307 and R. El Dib et al., “Electronic Nicotine Delivery Systems and / or Electronic Non-Nicotine Delivery Systems for Tobacco Smoking Cessation or Reduction: A Systematic Review and Meta-Analysis,” BMJ Open 2017;7:e012680.

[0005] Complete replacement of actual tobacco smoking with electronically delivered vapor requires compliance, much like patient compliance with a pharmaceutical prescription. In the case of smokers, compliance with electronic devices relies on obtaining the same, or at least nearly the same, sensory effects from the vaporized composition electronically as from inhaling tobacco smoke from a lit cigarette. To date, the industry has not been able to do this, as evidenced by data showing poor smoking cessation outcomes.

[0006] Therefore, there is a need for new vaporizable compositions that can provide an acceptable personal experience to former tobacco smokers when vaporized and inhaled via an electronic device. Summary of the invention

[0007] It has now surprisingly been found that vaporizable compositions can be optimized to provide a balance between sensory experiences upon vaporization and inhalation, thereby simulating as closely as possible the sensory experience that an individual has when smoking a traditional tobacco product.

[0008] According to the present disclosure, novel vaporizable alkaloid compositions and compounding methods are provided. Generally speaking, the compositions herein are optimized to facilitate compliance with smoking cessation programs by providing smokers with a viable and complete alternative to tobacco smoking.

[0009] In various embodiments, the vaporizing alkaloid composition herein comprises: at least one substituted pyridine compound or a salt or mixed salt thereof, and at least one solvent; optionally at least one chemosensory irritant; and optionally at least one flavoring agent, wherein the vaporizing alkaloid composition is completely free of nicotine.

[0010] In various embodiments, the gasifying alkaloid composition comprises:

[0011] at least one substituted pyridine compound of formula (I);

[0012] or a salt or a mixture of salts thereof, wherein:

[0013] A is selected from:

[0014] and

[0015] R 1 , R 2 , R 3 , R 4 and R 5are independently selected from the group consisting of: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, and

[0016] R 6 and R 7 are independently selected from: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl, or R 6 and R 7 Together = O;

[0017] R 8 , R 9 , R 10 , R 11 and R 12 independently selected from the group consisting of: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl;

[0018] R 13 and R 14 are independently selected from: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl, or R 13 and R 14 Together = O;

[0019] n is an integer from 1 to 10; and

[0020] R 15 and R 16 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 15 and R 16 Together with the N atom to which they are bound, they form a 3-8 membered optionally substituted heterocyclic ring,

[0021] The condition is: If A is And R 5 is methyl, then R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 It can’t all be H;

[0022] at least one solvent;

[0023] Optionally at least one chemosensory stimulant; and

[0024] Optionally at least one flavoring agent,

[0025] Wherein, the vaporizable alkaloid composition contains no (R) or (S) nicotine at all.

[0026] In various embodiments, the at least one substituted pyridine compound has the structure of Formula (IA):

[0027] or a salt or a mixture of salts thereof.

[0028] In various embodiments, the at least one substituted pyridine compound has a structure of Formula (IA-1): or a salt or a mixture of salts thereof.

[0029] In various embodiments, the at least one substituted pyridine compound has the structure of Formula (IA-2): or a salt or a mixture of salts thereof.

[0030] In various embodiments, the at least one substituted pyridine compound has a structure of Formula (IA-3): or a salt or a mixture of salts thereof.

[0031] In various embodiments, the at least one substituted pyridine compound has a structure of Formula (IA-4): or a salt or a mixture of salts thereof.

[0032] In various embodiments, the at least one substituted pyridine compound has a structure of Formula (IA-5): or a salt or a mixture of salts thereof.

[0033] In various embodiments, the at least one substituted pyridine compound has the structure of Formula (IB):

[0034] or a salt or a mixture of salts thereof.

[0035] In various embodiments, the at least one substituted pyridine compound has a structure of Formula (IC):

[0036] or a salt or a mixture of salts thereof.

[0037] In various embodiments, the at least one substituted pyridine compound has a structure of Formula (ID):

[0038] or a salt or a mixture of salts thereof.

[0039] In various embodiments, the substituted pyridine compounds used herein have the structure of Formula (ID):

[0040] Where R 1 , R 2, R 3 and R 4 Each is -H, n is an integer 1, R 13 and R 14 =O; and R 15 and R 16 Both are -H;

[0041] In various embodiments, the substituted pyridine compounds used herein have the structure of Formula (IE):

[0042] or a salt or a mixture of salts thereof.

[0043] In various embodiments, the substituted pyridine compounds used herein have the structure of Formula (IE):

[0044] Where R 15 and R 16 Both are -H.

[0045] In various embodiments, the at least one substituted pyridine compound has the structure of Formula (IAA):

[0046] or a salt or a mixture of salts thereof, provided that: if R 5 is CH3, then R 1 , R 2 , R 3 and R 4 It can’t be all H.

[0047] In various embodiments, the at least one substituted pyridine compound is selected from: (R) or (S)-3-(pyrrolidin-2-yl)pyridine, (R) or (S)-2-methyl-3-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-4-methyl-3-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-3-methyl-5-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-2,6-dimethyl- 3-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-2,4-dimethyl-5-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-2,3-dimethyl-5-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-2,4-dimethyl-3-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-2,5-dimethyl-3-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-3,4-dimethyl-5-(1-methylpyrrolidin-2-yl)pyridine,

[0048]

[0049]

[0050] or a salt or a mixture of salts thereof.

[0051] In various embodiments, the gasifying alkaloid composition further comprises an organic acid selected from the group consisting of formic acid, acetic acid, trifluoroacetic acid, aspartic acid, butyric acid, butyric acid, 2-methylbutyric acid, 3-methylbutyric acid, benzoic acid, caprylic acid, citric acid, crotonic acid, ethylenediaminetetraacetic acid, fumaric acid, gluconic acid, glutamic acid, glyceric acid, glycolic acid, lactic acid, lauric acid, levulinic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, oxalic acid, phenylacetic acid, phthalic acid, picric acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, hydroxymalonic acid, valeric acid, and mixtures thereof.

[0052] In various embodiments, the organic acid is selected from the group consisting of citric acid, acetic acid, benzoic acid, tartaric acid, lactic acid, salicylic acid, malic acid, levulinic acid, and mixtures thereof.

[0053] In various embodiments, the molar ratio of total substituted pyridine compounds to total organic acid is from about 25:1 to about 75:1.

[0054] In various embodiments, the solvent is selected from the group consisting of propylene glycol, water, ethanol, glycerol, and mixtures thereof.

[0055] In various embodiments, the vaporizing alkaloid composition further comprises at least one chemosensory stimulant.

[0056] In various embodiments, the chemosensory irritant is selected from the group consisting of oleocanthal, 4-hydroxy-2-nonenal, 4-oxo-2-nonenal, allicin, allyl isothiocyanate, icilin, Polygodial, cinnamaldehyde, trans-p-methoxycinnamaldehyde, methyl syringate, 2-chlorobenzylmalononitrile, 1-chloroacetophenone, ethyl bromoacetate, 4-hydroxyhexenal, toluene diisocyanate, p-benzoquinone, methyl p-hydroxybenzoate, flufenamic acid, acid, niflumic acid, mefenamic acid, diclofenac, hydroxy-α-sanshool, 6-paradol, linalool, carvacrol, eugenol, thymol, vanillin, methyl eugenol, 2,6-dimethylphenol, 2,5-dimethylphenol, 3,4-dimethylphenol, 2,6-diisopropylphenol, caffeine, farnesylthiosalicylic acid, 4-allylanisole, curcumin, niacin, camphor, olvanil, arvanil, anandamide, baicalein, baicalin, wogonin, norwogonin, melaleuca A, β-sitosterol, and mixtures thereof.

[0057] In various embodiments, the chemesthetic sensory stimulant is a flavor additive having a heat intensity of about 1,000 to about 20,000,000 Scoville Heat Units (SHU).

[0058] In various embodiments, the flavor additive is selected from the group consisting of capsaicin, dihydrocapsaicin, norcapsaicin, nordihydrocapsaicin, homocapsaicin, homodihydrocapsaicin, gingerol, piperine, shogaol, isopiperine, chavicine, isochavicine, 2-piperamine, 2-piperamine), piperonine (4,5-dihydropiperine), piperonamide, 4-pipericide, piperyline, piperlonguminine, piperettine, 6,7-dihydropiperettine, 5-sarmentodine, 6-sarmentine, 7-trichostachine, and mixtures thereof.

[0059] In various embodiments, the flavor additive is capsaicin or a mixture of capsaicinoids.

[0060] In various embodiments, the gasifying alkaloid composition comprises:

[0061] (a) from about 1% to about 80% by weight of a substituted pyridine compound of formula (I):

[0062] or a salt or a mixture of salts thereof, wherein:

[0063] A is selected from:

[0064] and

[0065] R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from the group consisting of: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, and

[0066] R 6 and R 7are independently selected from: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl, or R 6 and R 7 Together = O;

[0067] R 8 , R 9 , R 10 , R 11 and R 12 independently selected from the group consisting of: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl;

[0068] R 13 and R 14 are independently selected from: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl, or R 13 and R 14 Together = O;

[0069] n is an integer from 1 to 10; and

[0070] R 15 and R 16 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 15 and R 16 Together with the N atom to which they are bound, they form a 3-8 membered optionally substituted heterocyclic ring,

[0071] The condition is: If A is And R 5 is methyl, then R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 It can’t all be H;

[0072] (b) from about 0.05% to about 1.5% by weight totaling at least one organic acid; and

[0073] (c) the remaining solvent,

[0074] wherein the weight percentage is based on the total weight of the gasifiable alkaloid composition; and

[0075] The molar ratio of the substituted pyridine compound to the total molar ratio of the organic acid is about 25:1 to about 75:1.

[0076] In various embodiments, the substituted pyridine compound is selected from (S)-N,N-dimethyl-3-(5-(1-methylpyrrolidin-2-yl)pyridin-2-yl)propan-1-amine, (S)-N,N-dimethyl-2-(2-(pyridin-3-yl)pyrrolidin-1-yl)ethan-1-amine, (S)-N,N-dimethyl-3-(2-(pyridin-3-yl)pyrrolidin-1-yl)propan-1-amine, N,N-dimethyl-1-(pyridin-3-yl)methylamine and N-methyl-N-(pyridin-3-ylmethyl)ethylamine.

[0077] In various embodiments, the molar ratio of the substituted pyridine compound to the total moles of the organic acid is about 50:1.

[0078] In various embodiments, the at least one organic acid consists of a mixture of citric acid and acetic acid.

[0079] In various embodiments, the solvent is selected from the group consisting of propylene glycol, glycerol, ethanol, and mixtures thereof.

[0080] In various embodiments, the vaporizing alkaloid composition further comprises at least one chemosensory stimulant.

[0081] In various embodiments, the chemosensory irritant is selected from the group consisting of oleocanthal, 4-hydroxy-2-nonenal, 4-oxo-2-nonenal, allicin, allyl isothiocyanate, eserin, Polygodial, cinnamaldehyde, trans-p-methoxycinnamaldehyde, methyl syringate, 2-chlorobenzylmalononitrile, 1-chloroacetophenone, ethyl bromoacetate, 4-hydroxyhexenal, toluene diisocyanate, p-benzoquinone, methyl p-hydroxybenzoate, flufenamic acid, acid, niflumic acid, mefenamic acid, diclofenac, hydroxy-α-sanshool, 6-paradol, linalool, carvacrol, eugenol, thymol, vanillin, methyl eugenol, 2,6-dimethylphenol, 2,5-dimethylphenol, 3,4-dimethylphenol, 2,6-diisopropylphenol, caffeine, farnesylthiosalicylic acid, 4-allylanisole, curcumin, niacin, camphor, olvanil, arvanil, anandamide, baicalein, baicalin, wogonin, norwogonin, melaleuca A, β-sitosterol, and mixtures thereof.

[0082] In various embodiments, the chemesthetic sensory stimulant is a flavor additive having a heat intensity of about 1,000 to about 20,000,000 Scoville Heat Units (SHU).

[0083] In various embodiments, the flavor additive is selected from the group consisting of capsaicin, dihydrocapsaicin, norcapsaicin, nordihydrocapsaicin, homocapsaicin, homodihydrocapsaicin, gingerol, piperine, shogaol, isopiperine, chavicine, isochavicine, 2-piperamine, 4,5-dihydropiperine, piperamide, 4-pipericide, piperyline, piperlonguminine, piperettine, 6,7-dihydropiperettine, 5-sarmentodine, 6-sarmentine, 7-trichostachine, and mixtures thereof.

[0084] In various embodiments, the flavor additive is capsaicin or a mixture of capsaicinoid compounds.

[0085] In various embodiments, a method for promoting smoking cessation in an individual who wishes to quit smoking comprises: administering to the individual a series of vaporized alkaloid compositions for inhalation by the individual through an electronic cigarette within a period of time determined for quitting smoking, wherein each vaporized alkaloid composition in the series comprises at least one substituted pyridine compound of formula (I):

[0086] or a salt or a mixture of salts thereof, wherein:

[0087] A is selected from:

[0088] and

[0089] R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from the group consisting of: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, and

[0090] R 6 and R 7 are independently selected from: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl, or R 6 and R 7 Together = O;

[0091] R8 , R 9 , R 10 , R 11 and R 12 independently selected from the group consisting of: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl;

[0092] R 13 and R 14 are independently selected from: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl, or R 13 and R 14 Together = O;

[0093] n is an integer from 1 to 10; and

[0094] R 15 and R 16 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 15 and R 16 Together with the N atom to which they are bound, they form a 3-8 membered optionally substituted heterocyclic ring,

[0095] The condition is: If A is And R 5 is methyl, then R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 It can’t all be H;

[0096] and at least one solvent;

[0097] Wherein, each of the gasifying alkaloid compositions in the gasifying alkaloid composition series contains a decreasing (w / v) amount of the substituted pyridine compound of formula (I), or a salt or mixed salt thereof;

[0098] The series of gasifying alkaloid compositions include the gasifying alkaloid composition having the highest (w / v) level of the substituted pyridine compound of formula (I) or its salt or mixed salt, and also include the gasifying alkaloid composition having the lowest (w / v) level of the substituted pyridine compound of formula (I) or its salt or mixed salt; and

[0099] Wherein, the individual inhales each composition in the series through an electronic cigarette, starting with the vaporizable alkaloid composition having the highest level (w / v) of the substituted pyridine compound of formula (I) or its salt or mixed salt at the beginning of the time period determined for quitting smoking, and ending with the composition having the lowest level (w / v) of the substituted pyridine compound of formula (I) or its salt or mixed salt at the end of the time period determined for quitting smoking, so that the individual stops smoking at the end of the time period determined for quitting smoking.

[0100] In various embodiments, the gasifying alkaloid composition having the highest level (w / v) of the substituted pyridine compound of formula (I) or its salt or mixed salts in the series of gasifying alkaloid compositions comprises about 100 mg / mL of the substituted pyridine compound of formula (I) or its salt or mixed salts.

[0101] In various embodiments, the gasifying alkaloid composition having the lowest level (w / v) of the substituted pyridine compound of formula (I) or its salt or mixed salts in the series of gasifying alkaloid compositions comprises no more than about 1 mg / mL of the substituted pyridine compound of formula (I) or its salt or mixed salts.

[0102] In various embodiments, the time period determined for quitting smoking is part of a smoking cessation program, the program further comprising dispensing a series of vaporizable alkaloid compositions to an individual who wishes to quit smoking during the time period determined for quitting smoking. DETAILED DESCRIPTION

[0103] The detailed description of the exemplary embodiments refers to the accompanying drawings, which illustrate the exemplary embodiments and their best modes in a graphical manner. Although these exemplary embodiments are described in sufficient detail to enable those skilled in the art to implement the invention, it should be understood that other embodiments may also be implemented and that logical, chemical and mechanical changes may be made without departing from the spirit and scope of the invention. Therefore, the specific embodiments are only for illustration and not limitation. For example, unless otherwise specified, the steps described in any method or process description may be performed in any order and are not necessarily limited to the order presented. In addition, any singular reference includes plural embodiments, and any reference to more than one composition or step may include singular embodiments or steps. In addition, any reference to attachment, fixing, connection or the like may include permanent, removable, temporary, partial, complete and / or any other possible attachment options. In addition, reference to contactless (or similar phrases) may also include reduced contact or minimal contact.

[0104] In various embodiments of the present disclosure, novel vaporizable alkaloid compositions are disclosed. The compositions herein are optimized to provide a balance between nasal, throat, and head senses during vaporization and inhalation to simulate as closely as possible the sensory experience of an individual when smoking a traditional tobacco product. In general, the compositions herein are optimized to facilitate compliance with a smoking cessation program. In various embodiments herein, a viable and complete smoking alternative is provided for tobacco smokers.

[0105] In various embodiments, the gasifying alkaloid composition herein comprises:

[0106] At least one substituted pyridine compound of formula (I) or a salt or mixed salt thereof; and

[0107] at least one solvent,

[0108] Wherein, the vaporizable alkaloid composition contains no nicotine at all.

[0109] In various embodiments, the gasifying alkaloid composition may include an optional chemosensory stimulant.

[0110] In various embodiments, the vaporizing alkaloid composition may include an optional flavoring agent.

[0111] In various embodiments, the vaporizing alkaloid composition may include at least one organic acid, such that at least a portion of the substituted pyridine compound of formula (I) is present in the composition as a salt or a mixed salt.

[0112] In certain embodiments, the compositions provided herein can be diluted with an appropriate solvent or solvent mixture (such as vegetable glycerin and / or propylene glycol) prior to vaporization and inhalation, for example, by a third-party manufacturer or an end user of a refillable electronic device, to provide a customized inhalable composition having a lesser amount of substituted pyridine compound than the initial composition. In a preferred example, the third party will design and implement a smoking cessation program for the individual and provide an e-liquid with a gradually decreasing amount of substituted pyridine compound during the implementation of the program. In this way, the consumer can follow the smoking cessation program by using an e-liquid with less and less substituted pyridine compound content over time until the user essentially inhales the vaporized solvent with no other discernible substances except the flavoring agent.

[0113] Definitions and Interpretation

[0114] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art of chemical technology and medicinal chemistry to which the present disclosure relates. Although any methods and materials similar or equivalent to the methods and materials described herein may be used in the practice or testing of the subject matter of the present disclosure, preferred methods and materials are described herein. According to common practice in organic chemistry, chemical structures having chiral centers are assumed to represent two enantiomers if they are represented by substituents connected by wavy bonds, or are not represented three-dimensionally by wedge-shaped or dashed bonds, or are not marked (R) or (S) near the chiral center or in the corresponding structure name. Throughout the disclosure, chiral centers are marked with asterisks (*) as much as possible, at least to remind the reader that the carbon marked with (*) is a chiral center and that the (*) center may have an (R) or (S) configuration. Chemical structures having multiple chiral centers are assumed to include all possible stereoisomers if they are not presented in three dimensions or marked as having any specific chirality. Compounds of the present disclosure include any physicochemical or stereochemical forms they may have, such as isomers, prodrugs, active metabolites, tautomers, stereoisomers, regioisomers, solvated forms, salts and polymorphs. Amorphous forms lack distinguishable lattices and therefore lack an ordered arrangement of structural units. Many alkaloids have amorphous forms, crystalline forms or mixtures thereof. In addition to the crystallographic methods for determining the degree and type of crystallization, methods for producing these chemical forms are also known to those skilled in the art.

[0115] The compositions of the present disclosure include alkaloids that can be protonated by acids also present in the composition, so that in various compositions the alkaloids may be present at least partially or even completely in the form of salts. Alkaloid salts include any salt derived from an inorganic or organic acid, preferably an organic acid or an organic acid mixture. Examples of inorganic salts include, but are not limited to, alkaloid salts of hydrobromic acid, hydrochloric acid, nitric acid, phosphoric acid, and sulfuric acid. Examples of organic acid salts include, for example, formic acid, acetic acid, trifluoroacetic acid, aspartic acid, butyric acid, butyric acid, 2-methylbutyric acid, 3-methylbutyric acid, benzoic acid, caprylic acid, citric acid, crotonic acid, ethylenediaminetetraacetic acid (EDTA), fumaric acid, gluconic acid, glutamic acid, glyceric acid, glycolic acid, lactic acid, lauric acid, levulinic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, oxalic acid, phenylacetic acid, phthalic acid, picric acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, hydroxymalonic acid, valeric acid, and combinations thereof, or any other such acid alkaloid salts currently known or to be discovered or synthesized. Such alkaloid salts can be prepared by reacting the alkaloid free base compound with a suitable acid or acid mixture in a manner known to those skilled in the art. When a mixed acid is reacted with an alkaloid disclosed herein to prepare an alkaloid salt, no attempt is made to quantify the mole percentage of each alkaloid salt produced, but rather the resulting alkaloid salt is referred to as a "mixed salt."

[0116] As used herein, the term "alkyl" refers to a linear or branched monovalent saturated hydrocarbon substituent, which is optionally substituted with one or more functional groups at any position on or within the substituent. Unless otherwise specified, an alkyl group may contain any number of carbon atoms, e.g., C1-C 24 、C1-C 18 、C1-C 10 , C1-C8 or C1-C6. Examples of alkyl substituents include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, octadecyl, dodecyl, etc. The alkyl substituents herein may be substituted, i.e., have one or more substituents attached to the alkyl or incorporated into the alkyl chain. Substitution within the alkyl substituent chain may include, for example, ether, thioether, amino (amine) or imine bonds, i.e., -O-, -S-, -N(R')- or -N=, or some other inserted heteroatoms. Examples of substitutions on alkyl substituents include, but are not limited to, -CN, -N3, -NH2, -NHR', -N(R')2, -NO2, -NH-NH2, -NH-NHR', -NH-NR'2, -halogen, -SH, -SR', -S(=O)R', -SO2R', -OPO3 2- 、-PO3 2- , -OH, -OR', -C(=O)R', -OC(=O)R', -CO2R', -NHC(=O)R', -NR'C(=O)R', -C(=O)NHR', -C(=O)NR'2, alkyl, alkenyl, cycloalkyl, heterocyclyl and aryl, wherein each R' is independently selected from hydrogen-H and alkyl moieties, including, for example, C 1-6 Alkyl (e.g. -CH3, -C2H5, -isopropyl, -tert-butyl, etc.), C 1-6 Alkoxy (e.g. -OCH3, -OC2H5), halogenated C 1-6 Alkyl (such as -CF3, -CHF2, -CH2F) and halogenated C 1-6 Alkoxy (eg, -OCF3, -OC2F5). In various examples, two R' substituents in any of these functional groups may form a ring structure.

[0117] As used herein, the term "cycloalkyl" includes any 3-, 4-, 5-, 6-, 7- or 8-membered saturated or unsaturated non-aromatic carbocyclic ring, which is optionally substituted with one or more functional groups at any position of the cyclic substituent. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-, 2- or 5-cyclopentadienyl, cyclohexyl, 1-, 3- or 4-cyclohexenyl, 1-, -2- or 5-(1,3-cyclohexadienyl), 1- or 3-(1,4-cyclohexadienyl), cycloheptyl, 1-, 3-, 4- or 5-cycloheptenyl, cyclooctenyl, etc. Examples of substitutions on cycloalkyl substituents include, but are not limited to, -CN, -N3, -NH2, -NHR', -N(R')2, -NO2, -NH-NH2, -NH-NHR', -NH-NR'2, -halogen, -SH, -SR', -S(=O)R', -SO2R', -OPO3 2- 、-PO3 2- , -OH, -OR', -C(=O)R', -OC(=O)R', -CO2R', -NHC(=O)R', -NR'C(=O)R', -C(=O)NHR', -C(=O)NR'2, alkyl, alkenyl, cycloalkyl, heterocyclyl and aryl, wherein each R' is independently selected from -H and alkyl moieties, including, for example, C 1-6 Alkyl (e.g. -CH3, -C2H5, -isopropyl, -tert-butyl, etc.), C 1-6 Alkoxy (e.g. -OCH3, -OC2H5), halogenated C 1-6 Alkyl (such as -CF3, -CHF2, -CH2F) and halogenated C 1-6 Alkoxy (e.g., -OCF3, -OC2F5).

[0118] As used herein, the term "alkenyl" refers to a linear or branched monovalent or divalent unsaturated hydrocarbon substituent, which is optionally substituted with one or more functional groups at any position on or within the substituent. 2 If carbon is part of the molecule bearing the alkenyl substituent, the alkenyl substituent may be considered divalent. An illustrative example is methylenecyclohexane, which may be considered cyclohexane substituted with a methylene group (i.e., a divalent alkenyl substituent, =CH2). Unless otherwise specified, the alkenyl group may contain any number of carbon atoms, e.g., C1-C 24 、C1-C 18 、C1-C 10, C1-C8 or C1-C6, and any degree of unsaturation. Examples of alkenyl substituents include, but are not limited to, methylene / methylene (=CH2), ethylene / vinyl (-CH=CH2 or =CH-CH3), propylene / propylene (-CH2-CH=CH2, cis or trans-CH=CH-CH3, =C(CH3)2, or cis or trans=CH-CH2CH3), etc. The alkenyl substituents herein may be substituted, i.e., have one or more substituents attached to the alkenyl or incorporated into the alkenyl chain. Substitution within the alkenyl substituent may include, for example, ether bonds, thioether bonds, amino bonds, or imine bonds, i.e., -O-, -S-, -N(R')-, or -N=, or some other intervening heteroatoms. Examples of substitutions on alkenyl substituents include, but are not limited to, -CN, -N3, -NH2, -NHR', -N(R')2, -NO2, -NH-NH2, -NH-NHR', -NH-NR'2, -halogen, -SH, -SR', -S(=O)R', -SO2R', -OPO3 2- 、-PO3 2- , -OH, -OR', -C(=O)R', -OC(=O)R', -CO2R', -NHC(=O)R', -NR'C(=O)R', -C(=O)NHR', -C(=O)NR'2, alkyl, alkenyl, cycloalkyl, heterocyclyl and aryl, wherein each R' is independently selected from an alkyl moiety, including, for example, C 1-6 Alkyl (e.g. -CH3, -C2H5, -isopropyl, -tert-butyl, etc.), C 1-6 Alkoxy (e.g. -OCH3, -OC2H5), halogenated C 1-6 Alkyl (such as -CF3, -CHF2, -CH2F) and halogenated C 1-6 Alkoxy (eg, -OCF3, -OC2F5). In each example, two R' substituents in any of these functional groups may form a cyclic structure.

[0119] As used herein, unless otherwise specified, the term "propylene glycol" or more simply "PG" refers to propane-1,2-diol (α-propylene glycol), not the 1,3-diol isomer. In addition, unless otherwise specified, propylene glycol as used herein includes a racemic mixture of isomers and is typically produced on a global industrial scale by hydrolysis of propylene oxide. PG is generally considered to be the cause of the white vapor cloud in gasifying compositions when vaping electronic cigarettes.

[0120] As used herein, the term "vegetable glycerin" or more simply "VG" has its ordinary meaning in organic chemistry and food science, i.e., HOCH2-CH(OH)-CH2OH, a triglyceride derived from plant sources. The scope of the present disclosure includes glycerin from any source, including animal or plant, or industrially synthesized or microbially produced.

[0121] As used herein, the term "inhalable" refers to a characteristic of the vaporizable alkaloid compositions according to the present disclosure, i.e., the compositions are suitable for inhalation by a user. The inhalable alkaloid compositions disclosed herein are vaporizable and therefore suitable for use in electronic cigarette devices, meaning that they can be vaporized by a heating element within such electronic devices, thereby allowing a user to inhale in a practice known as "vaping". In other words, the vaporizable alkaloid compositions herein are inhalable compositions. Unless otherwise specified, the phrase "inhalable composition" or "inhalable compositions" refers to the vaporizable alkaloid compositions according to the present disclosure.

[0122] As used herein, the term "electronic cigarette" or "ENDS" (electronic nicotine delivery system) generally refers to any electronic device capable of vaporizing a liquid composition into a vapor that can be inhaled by an individual using the device. To avoid limitation, "electronic cigarette" herein refers to any design, such as a cigar, a vape pen, or any other refillable or disposable electronic device, which has a reservoir containing a vaporized liquid and has the ability to vaporize the vaporized liquid. For simplicity, the term "electronic device" can be used to refer to any and all refillable and disposable electronic smoking tools.

[0123] As used herein, the term "throat hit" refers to the sensory effect felt in the back of the throat when an individual inhales vapor, such as vapor obtained from a burning cigarette or vapor delivered from an electronic device such as an electronic cigarette that is capable of vaporizing a liquid composition. Throat hit is an irritating "bite" experienced in the back of the throat that, before the development of electronic cigarettes, was not only experienced by smokers, but also expected and enjoyed by smokers. Although subjective rather than objective, throat hit can be quantified through the use of a sensory panel, for example, where participants in the panel rate the perceived throat hit on a scale of 1-10, or compare the perceived throat hit of electronic cigarette products to each other and / or relative to traditional cigarettes. In some instances, throat hit can be quantified as less than, equal to, or greater than the throat hit felt by a particular cigarette. An exemplary cigarette for standardizing throat hit, such as an exemplary cigarette used in a sensory panel where participants rate throat hit, is available from Phillips IGA Filter cigarette Gold Pack 100's. As described herein, by adding propylene glycol as a solvent and / or a chemical sensory stimulant to the gasifiable alkaloid composition of the present disclosure, individuals can generally experience a throat hit. In certain examples, flavor additives can be used as chemical stimulants to induce a throat hit.

[0124] As used herein, the term "vaping" refers to the act of inhaling a vapor electronically generated by vaporization of a liquid composition using an electronic cigarette or other ENDS device. Vaping is considered to be an act similar to smoking tobacco products, given that electronic cigarettes and vaping are not limited to nicotine. Vaping may include an individual inhaling nicotine analogs, other physiologically active substances, flavorings, etc.

[0125] As used herein, the term "vape juice" or "e-juice" refers to a liquid composition that can be vaporized in an electronic cigarette or other ENDS device to produce a vapor that can be inhaled by an individual smoking an electronic cigarette. In various embodiments herein, an e-juice composition is described, which in some instances includes a vaporized alkaloid composition and dilutions thereof.

[0126] As used herein, the term "cloud" refers to the visible white vapor that is inhaled and then exhaled when an e-cigarette juice is vaporized by an e-cigarette or other ENDS device. As described herein, cloud is an important attribute of a successful e-cigarette juice because it is a characteristic that e-cigarette users seek. Although subjective rather than objective, the appearance of cloud can be quantified through the use of a sensory panel, for example, where participants in the panel rate the appearance of the cloud on a scale of 1-10 when smoking an e-cigarette, or comparing visible cloud between e-cigarette products and / or relative to the cloud seen in the air when smoking a traditional lit cigarette. In some instances, cloud can be quantified as less than, equal to, or greater than the cloud seen when smoking a particular cigarette. An exemplary cigarette for standardizing cloud appearance, such as an exemplary cigarette used in a sensory panel where participants rate the appearance of cloud, is available from Phillips IGA Filter cigarettes, Gold Pack 100's.

[0127] As used herein, the term "head rush" refers to the lightheadedness experienced by tobacco smokers and electronic cigarette users who inhale nicotine, nicotine analogs, and other products containing physiologically active substances. Smokers describe this sensory experience as a ringing sense in their minds, or a rush of adrenaline. It is believed that this sensory effect is caused by nicotine or other drugs in the blood and brain triggering the release of adrenaline, which in turn causes vasoconstriction of people who inhale active substances, and a temporary increase in heart rate and blood pressure. This sensory experience is individual, and due to differences in physiological tolerance, the sensory experience between active ingredients of the drug and between individuals is different. A head rush can occur within 10 seconds of inhaling nicotine, and the head rush can last for 10-30 minutes. However, as smokers or electronic cigarette users continue to smoke or smoke electronic cigarettes, they become more tolerant, and over time, the head rush often experienced becomes shorter and lasts longer. Although subjective rather than objective, headiness can be quantified through the use of a sensory panel, for example, where participants in the panel rate perceived headiness on a scale of 1-10, or compare perceived headiness between e-cigarette products and / or relative to traditional cigarettes. In some instances, headiness can be quantified as less than, equal to, or greater than the headiness experienced from a particular cigarette. An exemplary cigarette for standardizing headiness, such as an exemplary cigarette used in a sensory panel where participants rate headiness, is available from Phillips IGA Filter cigarettes, Gold Pack 100's.

[0128] As used herein, the term "chemical sensory irritant" has its common meaning in physiology and neuroscience, i.e., a substance that can produce sensory irritation to an individual exposed to the substance. Depending on the individual and the irritant, the irritation caused by inhaling chemical sensory irritants can be felt in the nose, mouth, throat, esophagus and / or lungs. In the definition herein, the sensory effect in the throat is called "throat hit". Chemical sensory irritation is most studied in environmental and occupational health and safety, involving air pollutants and indoor environmental irritants (such as formaldehyde). For example, see "Inhalation Toxicology", 2nd edition, H. Salem et al., edited by Taylor & Francis Group (CRC), 2006. In addition to subjective measures of chemosensory irritation, such as panelists answering symptom questionnaires, a variety of experimental techniques can be used to study chemically induced irritation, such as examining functional changes, such as respiratory rate and pattern, nasal, bronchial and lung function parameters, nasal mucosal swelling, rhinometry, blink rate, tear film stability and changes in chemosensory evoked potentials in humans and experimental animals (see SK Kjaergaar et al., "The Assessment of Irritation Using Clinical Methods and Questionnaires", American Industrial Hygiene Association, 62(6):711-6, November 2001).

[0129] The chemosensory irritants optionally used in the gasifying alkaloid compositions of the present disclosure include those compounds that can cause physiological stimulation to any one of the nose, mouth, throat, esophagus and lungs of an individual, wherein the physiological stimulation is quantifiable. Examples of quantitative methods include, but are not limited to, measuring swelling of the nasal mucosa, peak airflow through the nose, acoustic rhinometry, and rhino-stereometry for measuring the thickness of the anterior nasal turbinate. Questionnaires can also be used to define symptom groups in order to characterize the dose-response relationship in controlled exposure studies.

[0130] In various embodiments, the chemosensory stimulants optionally used in the gasifying alkaloid compositions herein are substances capable of activating chemosensory ion channels known as transient receptor potential channels or TRP channels, such as, for example, HJ Son et al., "Activation of the Chemosensory Ion Channels TRPA1 and TRPV1 by Hydroalcohol Extract of Kalopanax pictus Leaves," Biomol. Ther. (Seoul), November 2012; 20(6): 550-555. In addition to the subset of chemosensory irritants defined below as "flavor additives," many seemingly unrelated compounds are also receptor agonists that are capable of activating one or more TRP channels (e.g., A1, V1, V2, V3, V4, V5 or V6, M1, M2, M3, M4, M5, M6, M7 or M8 ion channels, etc.), for example, oleocanthal, 4-hydroxy-2-nonenal, 4-oxo-2-nonenal, allicin, allyl isothiocyanate, gingerols (included in the flavor subset of irritants), eserin, Polygodial, cinnamaldehyde, trans-p-methoxycinnamaldehyde, methyl syringate, 2-chlorobenzylmalononitrile, 1-chloroacetophenone, ethyl bromoacetate, 4-hydroxyhexenal, toluene diisocyanate, p-benzoquinone, methyl p-hydroxybenzoate, flufenamic acid, acid), niflumic acid, mefenamic acid, diclofenac, hydroxy-α-sanshool, 6-shogaol (included in the flavor subset of irritants), 6-paradol, linalool, carvacrol, eugenol, thymol, vanillin, methyl eugenol, 2,6-dimethylphenol, 2,5-dimethylphenol, 3,4-dimethylphenol, 2,6-diisopropylphenol, caffeine, farnesylthiosalicylic acid, 4-allylanisole, curcumin, capsicin (included in the flavor subset of irritants), nicotinic acid, camphor, olvanil, and arvanil. Although nicotine is a known TRPA1 activator, it is not considered a chemosensory irritant of the vaporizing alkaloid composition herein. See, for example, K. Talavera et al., "Nicotine activates the chemosensory cation channel TRPA1," Nature Neuroscience, 12, 1293-1299 (2009).One aspect of the present invention is to provide vaporizable alkaloid compositions that are specifically free of nicotine, making them useful as viable alternatives to smoking.

[0131] In addition, chemosensory stimulants that activate TRP ion channels and thus may be included in the gasifying alkaloid compositions herein include a variety of compounds naturally present in a variety of plants, trees, shrubs, roots, flowers, fruits, seeds and kernels. For example, such compounds are disclosed in, for example, J. Vriens et al., "Herbal Compounds and Toxins Modulating TRP Channels", Curr. Neuropharmacol., March 2008; 6(1): 79-96. In various embodiments, in addition to the "spice additives" defined and discussed herein (which include compounds such as capsaicinoids, gingerols and shogaols), other TRP channel activators are used herein, including but not limited to resiniferanoids from Euphorbia reinifera, eugenols from Euenia carophyllata and Ocimum gratissiumum, ginsenosides from Panax, zingerone and paradol from gingerols heated or dehydrated, or from seeds of Aframomum melgueta, Evodia compounds from Evodia rutaecarpa, isolated from Drymis winteri), such as hydrodialdehyde, isovelleral, and drimanial, other 1,4-diadehydic terpenes from Cinnamosma fragrans, such as cinnamodial, cinnamosmolide, and cinnamosmolide, or warbuganal from Warburgia.In vitro assays for measuring TRP ion channel activation are described, for example, in R. Lehmann et al., “Alternative in vitro assays to assess the potency of sensory irritant–Is one TRP channel enough?” Neurotoxicology 2017 May;60:178-186, and JM Martinez et al., “Activation of TRPA1 by volatile organic chemicals leading to sensoryirritation” ALTEX 2019;36(4):572-582. Phytochemicals found in Scutellaria baicalensis are also used herein. baicalensis (particularly the phytochemicals baicalein, baicalin, wogonin, norwogonin, , melaleuca A, and beta-sitosterol), Vitex agnus, Pterodon pubescens, Croton macrostachyus, Angelicae pubescentis, Ephedra sinica, Amphilophium crucigerum, Bosewellia carterii, Commiphoramyrrha, Echinophora platyloba, Nypa fruticans, Zingiber officinale (present in the irritant subset of fragrance additives), Corydalis saxicola, Coptis chinensis chinensis), Ononis spinosa, Parkia platycephala, Piper nigrum (present in the spice additive subset of stimulants), and Cymbopogon citrates. The chemical sensory irritants used herein can be first evaluated by in vitro non-animal sensory irritation tests, and then evaluated by consumer sensory panels for subtle physiological effects and determine dosage levels and user acceptance.

[0132] As used herein, the term "flavor additive" refers to an organic substance that is capable of producing a throat hit or other similar "hot," "irritating," or "burning" sensation at least in the back of the throat and optionally in the mouth and lips when the flavor additive is in a vaporizable alkaloid composition and the alkaloid composition is vaporized and inhaled by an individual (e.g., a person smoking an e-cigarette). The flavor additives herein form a subset of chemosensory stimulants and are known to activate one or more TRP ion channels. Since the groups of these compounds may be structurally unrelated at first glance, the "flavor additives" herein can be specifically defined as organic substances having a spicy or "burning" sensation in the range of about 1,000 to about 20,000,000 Scoville Heat Units (SHU). At the low end of the Scoville scale, the compounds used herein include, but are not limited to, gingerols (60,000 SHU), piperine (100,000 SHU), and shogaols (160,000 SHU). In a more preferred embodiment, the flavor additives used in the gasifying alkaloid composition herein will have a Scoville score of about 100,000 to about 20,000,000 SHU, more preferably about 10,000,000 to about 200,000,000 SHU, and will include all known capsaicinoid compounds, such as capsaicin (16,000,000 SHU) and dihydrocapsaicin (15,000,000 SHO), as well as uncharacterized capsaicinoid compounds that may be isomers of known capsaicinoid compounds. Although chemically unrelated to capsaicinoid compounds, compounds such as piperine (100,000 SHU) and shogaol (160,000 SHU) can be used in the present composition. Capsaicinoid flavor additives used herein include, but are not limited to, capsaicin, dihydrocapsaicin, norcapsaicin, nordihydrocapsaicin, homocapsaicin, homodihydrocapsaicin, and mixtures thereof. For the gasifiable alkaloid compositions herein, chemically pure or otherwise isolated capsaicinoids are not required, as it is convenient to prepare various compositions using extracts of spice additives. For example, capsaicinoids can be extracted from chili peppers or other peppers using room temperature or boiling ethanol (e.g., in a Soxhlet extractor). The resulting red ethanol solution can then be used as is (referred to as "liquid capsaicin" or "liquid capsaicin"), or evaporated to leave a thick, dark red, viscous mixture of capsaicinoids (the red color is believed to come from beta-carotene).For example, see F. Martins et al., "Novel Approaches to Extraction Methods in Recovery of Capsaicin from Habanero Pepper (CNPH 15.192)", Pharmacogn. Mag., Aug-Jul 2017; 13(Suppl 2): ​​S375-S379 and Y. Zhu, "Multi-Dimensional Pungency and Sensory Profiles of Powder and Oil of Seven Chili Peppers Based on Descriptive Analysis and Scoville Heat Units", Food Chemistry, 411, Jun 15, 2023, Article 135488.

[0133] As used herein, the term "liquid capsaicin" or "capsaicin liquid" refers to an ethanol or other solvent extract of the fruit obtained from a plant of the genus Capsicumannuum (e.g., various peppers). The liquid capsaicin optionally used herein comprises an ethanol solution of about 0.9% by weight of a capsaicinoid compound, which can be purchased from Olive Nation, LLC, Avon, Massachusetts, under the name Capsicum Flavor Extract.

[0134] It should be noted that "flavoring agents," which are optional for the purposes of the vaporizing alkaloid compositions herein, are defined separately and are completely distinct from "chemesthetic sensory stimulants" and the subset of stimulants referred to herein as "flavor additives."

[0135] As used herein, "flavoring agent" has its ordinary meaning in food science, but it should be noted that the flavoring agent herein intentionally excludes compounds containing capsaicinoid compounds, which means that the flavoring agent herein has no measurable or calculable Scoville heat score by definition, and is therefore different from the spice additives defined above. The flavoring agent used herein includes, but is not limited to, ethyl maltol, ethyl butyrate, ethyl acetate, maltol, ethyl vanillin, furanone, methyl cyclopenenolone, δ-decalactone, γ-decalactone, cis-3-hexanol, isoamyl acetate, ethyl 2-methylbutyrate, butyric acid, linalool, benzyl alcohol, ethyl caproate, benzaldehyde, isoamyl isovalerate, caproic acid, ethyl propionate, γ-undecalactone and hexyl acetate.

[0136] As used herein, the term "about" refers to an amount, level, value, number, frequency, percentage, dimension, size, amount, weight, or length that varies by up to 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1% from the nominal amount, level, value, number, frequency, percentage, dimension, size, amount, weight, or length. For example, an amount expressed as "about 5% by weight" includes variations of up to 4.5 to 5.5% by weight.

[0137] The term "smoking cessation program" as used herein refers to a program provided by a medical clinic, pharmacy, or any other commercial enterprise to a current smoker to help the individual quit smoking. In various embodiments, the smoking cessation program herein includes providing e-liquid (or providing a disposable electronic device pre-loaded with e-liquid) to individuals in need, with the aim of helping the individual follow the prescribed program and reduce and / or ultimately eliminate smoking. In some instances, the clinic, pharmacy, or other commercial enterprise will meet with individuals included in the smoking cessation program on a regular basis, ask the individual about compliance, and provide the individual with a customized vaporized composition, with the aim of gradually converting the smoker completely to electronic cigarettes. In a preferred embodiment, during the course of the smoking cessation program, an electronic cigarette composition containing increasingly smaller amounts of a substituted pyridine compound is provided to the individual.

[0138] General Implementation

[0139] The vaporizable alkaloid compositions according to the present disclosure are optimized to provide an improved user experience. The experience of an individual inhaling a vaporized liquid delivered by an electronic device can (and arguably should) be similar to the user's experience of smoking a burning cigarette (if different), but this can only be achieved if certain interrelated sensory effects are balanced, including throat hit, head feel, nasal and oral sensations and taste, and cloud appearance. These factors constitute the user experience.

[0140] Surprisingly, an improved user experience relies on having a substituted pyridine compound or a salt or mixed salt thereof, and a specific solvent to provide a throat hit similar to inhaling cigarette smoke. In addition, having at least some organic acid salt of the corresponding substituted pyridine compound in the inhalable composition can reduce the harshness and ensure that the user experiences the desired heady feeling, but with a perceptible smoothness. Therefore, in a preferred embodiment, the gasifiable alkaloid composition includes a small amount of organic acid.

[0141] In various embodiments, the gasifying alkaloid composition herein comprises:

[0142] At least one substituted pyridine compound of formula (I):

[0143] or a salt or mixture of salts thereof;

[0144] at least one solvent;

[0145] Optionally at least one chemosensory stimulant; and

[0146] Optionally at least one flavoring agent,

[0147] Wherein, the vaporizable alkaloid composition contains no (R) or (S) nicotine at all.

[0148] When present, the optional chemosensory stimulants may include phytochemicals, such as compounds found in Scutellaria baicalensis, such as baicalein, baicalin, wogonin, norwogonin, melaleucain A, β-sitosterol, and anandamide. In other embodiments, when present, the chemosensory stimulants include flavor additives having a heat level of about 1000 to about 20,000,000 Scoville Heat Units (SHU), such as capsaicin, shogaol, and gingerols.

[0149] Alternatives for each of these components in the compositions are described below and in the definitions section above.

[0150] 1. Alkaloid compounds and their salts or mixed salts

[0151] In various embodiments, the gasifying alkaloid composition herein comprises at least one substituted pyridine compound of formula (I) or a salt or mixed salt thereof:

[0152]

[0153] in:

[0154] A is selected from:

[0155] and

[0156] R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from the group consisting of: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, and

[0157] R 6 and R 7 are independently selected from: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl, or R 6 and R 7 Together = O;

[0158] R 8 , R 9 , R 10 , R 11 and R 12 independently selected from the group consisting of: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl;

[0159] R 13 and R 14 are independently selected from: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl, or R 13 and R 14 Together = O;

[0160] n is an integer from 1 to 10; and

[0161] R 15 and R 16 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 15 and R 16 Together with the N atom to which they are bound, they form a 3-8 membered optionally substituted heterocyclic ring,

[0162] The condition is: If A is And R 5 is methyl, then R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 It can’t be all H.

[0163] The proviso language specifically excludes the (R) and (S) enantiomers of nicotine from the compositions of the present disclosure.The vaporizable alkaloid compositions of the present disclosure are designed for use in smoking cessation programs and are explicitly nicotine-free.

[0164] In various embodiments, and independent of all other variables, A is

[0165] And R 5 Selected from: -(CH2)-NH2; -(CH2)2-NH2; -(CH2)3-NH2; -(CH2)4-NH2; -(CH2)5-NH2; -(CH2)6-NH2; -(CH2)7-NH2; -(CH2)8-NH2; -(CH2)9-NH2; -(CH2) 10 -NH2; -(CH2)-N(CH3)2; -(CH2)2-N(CH3)2; -(CH2)3-N(CH3)2; -(CH2)4-N(CH3)2; -(CH2)5-N (CH3)2; -(CH2)6-N(CH3)2; -(CH2)7-N(CH3)2; -(CH2)8-N(CH3)2; -(CH2)9-N(CH3)2; and -(CH2) 10 -N(CH3)2.

[0166] In various embodiments, and independent of all other variables, A is

[0167] And R 5 Selected from:

[0168]

[0169] Where n is 1-10; and R 17 is selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl.

[0170] In various embodiments, and independent of all other variables, A is

[0171] Where R 5 yes and n is 1-10; and R 17 It is H or CH3.

[0172] In various embodiments, the substituted pyridine compounds used herein have a structure that conforms to Formula (IA):

[0173] All variables are defined as above.

[0174] In various embodiments, the substituted pyridine compounds used herein have a structure conforming to Formula (IA-1):

[0175] All variables are defined as above.

[0176] In various embodiments, the substituted pyridine compounds used herein have a structure conforming to Formula (IA-2): All variables are defined as above.

[0177] In various embodiments, the substituted pyridine compounds used herein have a structure conforming to Formula (IA-3): All variables are defined as above.

[0178] In various embodiments, the substituted pyridine compounds used herein have a structure conforming to Formula (IA-4): All variables are defined as above.

[0179] In various embodiments, the substituted pyridine compounds used herein have a structure conforming to Formula (IA-5): All variables are defined as above.

[0180] In various embodiments, the substituted pyridine compounds used herein have a structure that conforms to Formula (IB): All variables are defined as above.

[0181] In various embodiments, the substituted pyridine compounds used herein have a structure that conforms to Formula (IC):

[0182] All variables are defined as above.

[0183] In various embodiments, the substituted pyridine compounds used herein have a structure that conforms to Formula (ID):

[0184] All variables are defined as above.

[0185] In various embodiments, the substituted pyridine compounds used herein have a structure that conforms to Formula (ID):

[0186] Where R 1 , R 2 , R 3 and R 4 Each is -H, n is an integer 1, R 13 and R 14 Together = O; and R 15 and R 16 All are -H;

[0187] In various embodiments, the substituted pyridine compounds used herein have a structure that conforms to Formula (IE):

[0188] All variables are defined as above.

[0189] In various embodiments, the substituted pyridine compounds used herein have a structure that conforms to Formula (IE):

[0190] Where R 15 and R 16 In various embodiments of Formula (IE), R 1 , R 2 , R 3 and R 4 Each is -H. In other examples of Formula (IE), R 1 is CH3, and R 2 , R 3 and R 4 Each is -H.

[0191] In various embodiments, the gasifying alkaloid composition herein comprises a substituted pyridine compound selected from the group consisting of:

[0192]

[0193]

[0194]

[0195]

[0196]

[0197] and

[0198] or a salt or a mixture of salts thereof.

[0199] In various embodiments, the gasifying alkaloid composition herein comprises at least one substituted pyridine compound of formula (IAA) or a salt or mixed salt thereof:

[0200] Where R 1 , R 2 , R 3 , R 4 and R 5 As defined above, the condition is: if R 5 is CH3, then R1 , R 2 , R 3 and R 4 It cannot be all H. This proviso language expressly excludes the (R) and (S) enantiomers of nicotine from compositions according to the present disclosure, as is the case with formula (I) and subgeneric structures thereof.

[0201] As can be seen from the selection of substituted pyridine compounds, many compounds have chiral centers, which can be (R) or (S). In most instances, the (S) enantiomer is preferred, while the (R) enantiomer may be deliberately excluded due to possible toxicity or undesirable physiological effects, or at least because it does not provide any identifiable benefit to the gasifying alkaloid composition. In various embodiments, the substituted pyridine compound conforming to formula (I) having a chiral center is a racemic mixture of (R) and (S) at the chiral center (*), for example obtained by achiral synthesis. The (R) or (S) enantiomer can be obtained by chiral synthesis or separation of the enantiomers from the racemic mixture.

[0202] In various embodiments, the gasifying alkaloid composition according to the present disclosure comprises from about 1% to about 80% by weight of a substituted pyridine compound of formula (I) added to the composition. In a more preferred embodiment, the gasifying alkaloid composition according to the present disclosure comprises from about 4% to about 20% by weight of a substituted pyridine compound of formula (I) added to the composition, such as to provide a w / v amount of the substituted pyridine compound of about 100 to about 250 mg / mL. In a more preferred embodiment, the gasifying alkaloid composition according to the present disclosure comprises from about 4% to about 12% by weight of a substituted pyridine compound of formula (I) added to the composition, such as to provide a w / v amount of the substituted pyridine compound in the gasifying alkaloid composition of about 100 mg / mL.

[0203] "As added" refers to a substance that is added to a batch, whether or not a reaction occurs between components of the composition, such as a free base alkaloid reacting with an organic acid to form at least some alkaloid salt.

[0204] In various embodiments, the substituted pyridine compound has the structure of Formula (IAA):

[0205] and is independent of R 5 , R 1 , R 2 , R 3 and R 4 At least one of them is a methyl group, R 1 , R 2 , R 3 and R 4The rest that are not methyl groups are H.

[0206] In various embodiments of Formula (IAA), R 5 For CH3, R 1 , R 2 , R 3 and R 4 At least one of them is not H.

[0207] In various embodiments of Formula (IAA), R 1 , R 2 , R 3 , R 4 and R 5 Each is H.

[0208] In various embodiments of Formula (IAA), R 5 Yes -(CH2)n-NR 15 R 16 , wherein n is an integer from 1 to 10, and wherein R 15 and R 16 are independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 15 and R 16 Together with the N atom to which they are bound, they form a 3-8 membered optionally substituted heterocyclic ring, including, for example, aziridine, azetidine, pyrrolidine, piperidine, 1,4-piperazine and morpholine. 1 , R 2 , R 3 and R 4 , R 5 Selected from -(CH2)-NH2; -(CH2)2-NH2; -(CH2)3-NH2; -(CH2)4-NH2; -(CH2)5-NH2; -(CH2)6-NH2; -(CH2)7-NH2; -(CH2)8-NH2; -(CH2)9-NH2; -(CH2) 10 -NH2; -(CH2)-N(CH3)2; -(CH2)2-N(CH3)2; -(CH2)3-N(CH3)2; -(CH2)4-N(CH3)2; -(CH2)5-N (CH3)2; -(CH2)6-N(CH3)2; -(CH2)7-N(CH3)2; -(CH2)8-N(CH3)2; -(CH2)9-N(CH3)2; and -(CH2) 10 -N(CH3)2.

[0209] In various embodiments, R 5 Yes H, R 1 , R 2 , R3 and R 4 At least one of them is –(CH2)n-NR 6 R 7 , wherein n is an integer from 1 to 10, and wherein R 6 and R 7 are independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 6 and R 7 Together with the nitrogen atom to which they are bound, they form a 3-8 membered optionally substituted heterocyclic ring.

[0210] In various embodiments, the substituted pyridine compound has the structure of Formula (IAA):

[0211] Where R 5 For CH3, R 1 , R 2 , R 3 and R 4 At least one of them is –(CH2)n-NR 15 R 16 , wherein n is an integer from 1 to 10, and wherein R 15 and R 16 are independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 15 and R 16 Together with the nitrogen atom to which they are bound, they form a 3-8 membered optionally substituted heterocyclic ring.

[0212] In various embodiments of Formula (IAA), R 5 For CH3, R 1 , R 2 , R 3 and R 4 At least one of them is –(CH2)nN(CH3)2, wherein n is an integer from 1 to 10.

[0213] In various embodiments, the substituted pyridine compounds of formula (IAA) used in the gasifying alkaloid composition of the present invention include, but are not limited to: (R) or (S)-3-(pyrrolidin-2-yl)pyridine, (R) or (S)-2-methyl-3-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-4-methyl-3-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-3-methyl-5-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S) -2,6-dimethyl-3-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-2,4-dimethyl-5-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-2,3-dimethyl-5-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-2,4-dimethyl-3-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-2,5-dimethyl-3-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-3,4-dimethyl-5-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)- ) or (S) -1-(2-aminoethyl)-2-(3-pyridyl)pyrrolidine, (R) or (S) -1-(3-aminopropyl)-2-(3-pyridyl)pyrrolidine, (R) or (S) -1-(4-aminobutyl)-2-(3-pyridyl)pyrrolidine, (R) or (S) -1-(5-aminopentyl)-2-(3-pyridyl)pyrrolidine, (R) or (S) -1-(2-dimethylaminoethyl)-2-(3-pyridyl)pyrrolidine, (R) or (S) -1-(3-dimethylaminopropyl)-2-(3-pyridyl)pyrrolidine, (R) or (S)-1-(4-dimethylaminobutyl)-2-(3-pyridyl)pyrrolidine, (R) or (S)-3-(2-(6-methylpyridin-3-yl)pyrrolidin-1-yl)propionitrile, (R) or (S)-4-(2-(6-methylpyridin-3-yl)pyrrolidin-1-yl)butyronitrile, (R) or (S)-1-(3-aminopropyl)-2-(6-methyl-3-pyridyl)pyrrolidine, (R) or (S)-1-[3-(N,N-dimethylamino)propyl]-2-(6-methyl-3-pyridyl)pyrrolidine, (R) or (S)-1-(N,N-diethyl-3-aminopropyl-2-(3-pyridyl)pyrrolidine, (R) or (S)-3-(1-(2-(pyrrolidin-1-yl)ethyl)pyrrolidin-2-yl)pyridine, (R) or (S)-3-(1-(2-(piperidin-1-yl)ethyl)pyrrolidin-2-yl)pyridine, (R) or (S)-4-(2-(2-(pyridin-3-yl)pyrrolidone) (R) or (S)-3-(1-(3-(pyrrolidin-1-yl)propyl)pyrrolidin-2-yl)pyridine, (R) or (S)-3-(1-(3-(piperidin-1-yl)propyl)pyrrolidin-2-yl)pyridine, and (R) or (S)-4-(3-(2-(pyridin-3-yl)pyrrolidin-1-yl)propyl)morpholine.

[0214] In each of the examples of alkaloids with chiral centers herein, the (S) enantiomer may be active as a nicotinic acetylcholine receptor ligand and is preferred, while the (R) enantiomer may be physiologically inert and may even be metabolically toxic. Therefore, in a preferred embodiment, the racemic mixture of any of these alkaloids is not used in the gasifying alkaloid compositions herein.

[0215] In various embodiments of Formula (IAA), R 1 , R 2 , R 3 , R 4 and R 5 independently selected from H, methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, provided that: if R 5 is methyl, then R 1 , R 2 , R 3 and R 4 It can’t be all H.

[0216] In certain embodiments of Formula (IAA), R 1 and R 5 Both are methyl, R 2 , R 3 and R 4 Each is H, and the alkaloids are in (S)-configuration.

[0217] 1a. Salts and mixed salts of alkaloids of formula (I) and salt preparation methods

[0218] The salts or mixed salts of the alkaloids of formula (I) can be used herein and can be prepared by reacting the substituted pyridine compound of formula (I) with an inorganic acid or preferably an organic acid R 18 -CO2H or an organic acid mixture in a suitable solvent, under ambient reaction conditions or under heating to obtain R 18Select the corresponding organic acid according to the desired one (for example, for formic acid, R 18 =H, for acetic acid, R 18 =CH3, for citric acid, R 18 =-CH(CO2H)-CH2-CO2H, etc.), so R 18 is selected from alkyl, cycloalkyl, aryl and heterocyclic groups, any of which may be optionally substituted.

[0219] Although it is known that the free base alkaloid of formula (I) and the acid R in the gasifiable alkaloid composition are 18 The molar ratio of -CO2H or acid mixtures is not attempted to quantify or characterize the salt or salt mixtures produced, or to quantify the completeness of the reaction, since it is recognized that certain choices of formula (I) have more than two nitrogen atoms and certain organic acids have more than one -CO2H group and thus can act as chelating agents. A variety of acid-base molar ratios (i.e., the ratio of acid to free base alkaloid salt is not 1:1) can be formed. For example, in TAPerfetti, "Structural Study of Nicotine Salts" zur Tabakforschung International, 12(2), 43-54, 1983, describes nicotine salts made from a variety of organic acids, wherein the acid-base ratio of nicotine is 1:1, 2:1, and 3:1. In this reference, Perfetti discloses that nicotine forms a 3:1 acid-base salt with an aliphatic monocarboxylic acid (such as acetic acid), wherein one acid molecule is bound in the 1:1 salt and the other two acid molecules are bound to the nitrogen of the pyridine ring, and that benzoate is a 1:1 acid-base salt. Perfetti discloses that nicotine citrate is a 2:1 acid-base salt. Therefore, if R 18 -CO2H represents a mixture of organic acids and the resulting alkaloid salt may not be characterised, particularly if the free base alkaloid of formula (I) contains more than two nitrogen atoms.

[0220] Organic acid R 18 -CO2H can be any acid disclosed herein, including formic acid, acetic acid, trifluoroacetic acid, aspartic acid, butyric acid, butyric acid, 2-methylbutyric acid, 3-methylbutyric acid, benzoic acid, caprylic acid, citric acid, crotonic acid, ethylenediaminetetraacetic acid, fumaric acid, gluconic acid, glutamic acid, glyceric acid, glycolic acid, lactic acid, lauric acid, levulinic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, oxalic acid, phenylacetic acid, phthalic acid, picric acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, hydroxymalonic acid, valeric acid, and mixtures thereof. Preferred acids herein are citric acid, acetic acid, benzoic acid, tartaric acid, lactic acid, salicylic acid, malic acid, levulinic acid, and mixtures thereof.

[0221] The choice of solvent for the reaction between the free base alkaloid and the organic acid can be based on its suitability for the composition for vaporization and inhalation, i.e., pharmaceutically acceptable or considered "safe". In other words, it is recognized that the acid / base reaction can be carried out in situ, the alkaloid salt is not separated, but the reaction mixture produced thereby becomes the vaporizable alkaloid composition according to the present disclosure. In these cases, the solvent is selected from the group consisting of propylene glycol, glycerol, ethanol, water and mixtures thereof. Typically, the acid / alkaloid reaction can be carried out in a solvent mixture of propylene glycol / ethanol with a small amount of water (e.g., water entrained in the reaction using 190 proof ethanol). If necessary, the final reaction mixture can be cooled and filtered before use in the electronic device.

[0222] In a preferred embodiment, an organic acid R is used. 18 -CO2H is insufficient in molar amount, thereby producing a mixture of alkaloid salt and unreacted alkaloid free base, which are therefore present together in the gasifiable alkaloid composition. In a less preferred embodiment, a sufficient molar amount or even an excess molar amount of organic acid R is used in the reaction. 18 -CO2H completes the salt formation so that there may be no free base alkaloid remaining at all.

[0223] In various embodiments, it is preferred that a molar excess of the substituted pyridine free base compound of formula (I) and one or more organic acids R 18 -CO2H, thereby the formation of the alkaloid salt is an incomplete reaction and the gasifiable alkaloid composition comprises the alkaloid organic acid salt and the unreacted alkaloid free base.

[0224] In various embodiments, the gasifying alkaloid compositions herein comprise from about 0.05 wt % to about 1.5 wt %, preferably from about 0.05 wt % to about 0.15 wt % of total organic acid, based on the total weight of the composition, given that typical amounts of substituted pyridine compounds are from about 1 wt % to about 80 wt %.

[0225] In various embodiments, the substituted pyridine free base compound and the total organic acid R 18 The molar ratio of -CO2H is about 25:1 to about 75:1, more preferably about 50:1. This ratio can be kept constant so that in the composition with increasing amount of substituted pyridine free base compound, the total organic acid R 18 The amount of -CO2H can also be increased proportionally to maintain this molar ratio.

[0226] It should be emphasized that it is not necessary to isolate any desired salt of the substituted pyridine compound for use in the gasifying alkaloid composition. The gasifying alkaloid composition can be prepared by combining the substituted pyridine free base compound of formula (I) with the desired organic acid in a selected solvent system, wherein the alkaloid salt is formed in situ, and the reaction mixture thus formed is the gasifying alkaloid composition.

[0227] In various preferred embodiments, the substituted pyridine compound according to formula (I) is reacted with an organic acid selected from the group consisting of acetic acid, benzoic acid, citric acid, lactic acid, levulinic acid, malic acid, salicylic acid, tartaric acid, and mixtures thereof.

[0228] In a more preferred embodiment, the substituted pyridine compound according to formula (I) is reacted with a submolar combination of citric acid and acetic acid.

[0229] For the gasifying alkaloid composition disclosed herein, salts and mixed salts of the substituted pyridine compound of formula (I) include, but are not limited to, acetate, citrate, citrate / acetate, benzoate, tartrate, bitartrate, lactate, levulinate, malate and salicylate and mixed salts.

[0230] In various embodiments, the gasifying alkaloid composition of the present invention comprises about 1 wt% to about 20 wt% of at least one substituted pyridine compound of formula (I) or a salt or mixed salt thereof, more preferably about 4 wt% to about 12 wt% of at least one substituted pyridine compound of formula (I) or a salt or mixed salt thereof, based on the total weight of the gasifying alkaloid composition. In a preferred embodiment, the amount of the substituted pyridine compound of formula (I) in the gasifying alkaloid composition is targeted at 100 mg / mL (w / v), recognizing that such a composition can always be diluted (even by the end user) with an acceptable solvent (such as PG and / or VG), so the amount of alkaloid (w / v) in the actual composition used by an individual in an electronic device can be lower than 100 mg / mL.

[0231] 2. Solvent

[0232] In various embodiments, the vaporizing alkaloid composition herein comprises at least one solvent. Solvents in the vaporizing composition intended to be vaporized and inhaled by humans include, but are not limited to, propylene glycol, water, ethanol, glycerol, and mixtures thereof. As can be seen from the exemplary compositions herein, water may be entrained in compositions comprising aqueous ethanol (e.g., 190-degree ethanol). Similarly, additional ethanol (e.g., capsaicinoids in ethanol) may be introduced into compositions utilizing capsaicin liquids.

[0233] In various embodiments, the gasifying alkaloid combination herein comprises about 85 wt % to about 99.9 wt % of total solvent, based on the total weight of the gasifying alkaloid composition. In certain examples, the solvent comprises mostly vegetable glycerin, and small amounts of propylene glycol and ethanol (and trace amounts of water).

[0234] In various embodiments, the gasifiable alkaloid composition herein comprises a mixture of solvents, the mixture of solvents comprising about 85.0 wt % to about 95.0 wt % vegetable glycerin and about 0.5 wt % to about 3 wt % propylene glycol, based on the total weight of the composition. In certain instances, the amount of total solvent (regardless of composition) may be expressed as a "sufficient amount" or "qs," which is the amount of solvent required to bring the total amount of the composition to 100 wt %.

[0235] 3. Optional chemical sensory stimulants

[0236] The addition of chemosensory stimulants to the gaseous alkaloid compositions of the present disclosure is optional. In various embodiments, the gaseous alkaloid compositions of the present disclosure are completely free of any chemosensory stimulants, especially in embodiments where the "throat hit" of inhalation is provided by other components of the composition (e.g., solvent).

[0237] When used in the compositions herein, chemosensory stimulants include any natural, endogenous, phytochemical or synthetic compound capable of activating TRP ion channels, including compounds derived from natural compounds by organic chemistry. Detection methods that can be used to determine whether a compound is indeed a TRP ion channel activator can be found in, for example, HP Fallah et al., "A Review on the Role of TRP Channels and Their Potential as Drug Targets: An Insight Into the TRP Channel Drug Discovery Methodologies", Front. Pharmacol., 2022 13: 914499.

[0238] Chemical irritants used herein include, but are not limited to, oleocanthal, 4-hydroxy-2-nonenal, 4-oxo-2-nonenal, allicin, allyl isothiocyanate, TRPM8 ion channel agonist (Eserin), Polygodial, cinnamaldehyde, trans-p-methoxycinnamaldehyde, methyl syringate, 2-chlorobenzylmalononitrile, 1-chloroacetophenone, ethyl bromoacetate, 4-hydroxyhexenal, toluene diisocyanate, p-benzoquinone, methyl p-hydroxybenzoate, flufenamic acid, acid), niflumic acid, mefenamic acid, diclofenac, hydroxy-α-sanshool, 6-paradol, linalool, carvacrol, eugenol, thymol, vanillin, methyl eugenol, 2,6-dimethylphenol, 2,5-dimethylphenol, 3,4-dimethylphenol, 2,6-diisopropylphenol, caffeine, farnesylthiosalicylic acid, 4-allylanisole, curcumin, niacin, camphor, olvanil, arvanil, anandamide (AEA), 2-AG, NADA, OLDA, PEA, NGABA, NGly, NAsp, NSer, various phytochemicals from Euphorbiareinifera, Euenia carophyllata, Ocimum gratissiumum, Panax ginseng, Aframomum melgueta), Evodia rutaecarpa, Drymis winteri, Cinnamosma fragrans, Cinnamomum camphora, Scutellaria baicalensis, Vitex agnus, Pterodon pubescens, Croton macrostachyus, Angelicae pubescentis, Ephedra sinica, Amphilophium crucigerum, Bosewellia carterii, Commiphoramyrrha, Echinophora platyloba, Nypa fruticans, Corydalissa xicola, Coptis chinensis, Ononis spinosa, Parkia platycephala, and Cymbopogon citrates) and the entire subset of chemical sensory stimulants defined individually as flavor additives having a heat level of about 1,000 SHU to about 20,000,000 SHU.Many of the flavor additives used herein are phytochemicals found in various herbs and fruits, such as compounds from chili pepper (Capsicum annuum), ginger (Zingiberofficiale), and pepper (Piper nigrum).

[0239] According to various embodiments, the flavor additive used as a chemosensory stimulant in the gasifying alkaloid composition of the present disclosure is an organic compound having a spiciness or heat of about 1000 to about 20,000,000 Scoville heat units (SHU), more preferably about 100,000 to about 200,000,000 Scoville heat units (SHU). Thus, flavor additives for the purposes of this document are a well-defined group of compounds. The calculation of Scoville heat units can be found in the American Spice Trade Association (ASTA) 1985, Official Methods of Analysis of the American Spice Trade Association, 3rd Edition, American Spice Trade Association, Englewood Cliffs, New Jersey.

[0240] In various embodiments, the flavor additives herein include capsaicinoid compounds or mixtures of capsaicinoid compounds. In certain instances, the liquid extract includes a mixture of capsaicinoid compounds prepared by solvent extraction of a pepper known to contain a mixture of capsaicinoid compounds rather than just capsaicin. In other embodiments, the source and use is capsaicin.

[0241] In other instances, flavor additives are used that are chemically unrelated to capsaicinoids but still have a measurable level of heat (expressed in Scoville units). These compounds are typically extracted from peppers other than chili peppers, such as black pepper (Piper nigrum L.), with the most useful non-capsaicinoid flavor additive being piperine (E, E, or trans-trans isomers). Other flavor additives that are not capsaicinoids include, but are not limited to: shogaol, gingerol, isopiperine, chavicine, isochavicine, 2-piperamine, piperanine (4,5-dihydropiperine), piperonamide, 4-pipericide4-pipericide, piperyline, piperlonguminine, piperettine, piperdardine 6,7-dihydropiperettine, 5-sarmentodine, 6-sarmentine, 7-trichostachine, and mixtures thereof.

[0242] In various embodiments, the flavor additive is selected from the group consisting of capsaicin, dihydrocapsaicin, norcapsaicin, nordihydrocapsaicin, homocapsaicin, homodihydrocapsaicin, gingerol, piperine, shogaol, and mixtures thereof. In addition to the above six, other capsaicinoid compounds can also be used in the composition herein, because it is described that there are at least seven different capsaicinoid compounds in the genus Capsicum, of which two capsaicinoid compounds (possibly capsaicin and dihydrocapsaicin) may be the capsaicinoid compounds that cause the spicy taste of peppers. See MD Collins et al., "Improved Method for Quantifying Capsaicinoids in Capsicum Using High-Performance Liquid Chromatography", Hort Science 30 (1): 137-139, 1995. Although the above mentioned compounds belong to the general class of chemosensory irritants, for convenience, these compounds are grouped into a subset of chemosensory irritants, namely, flavor additives having a heat intensity of about 1,000 to about 20,000,000 Scoville Heat Units (SHU).

[0243] In various embodiments, the gasifying alkaloid composition herein comprises 0 wt% to about 0.5 wt% of a flavor additive, based on the total weight of the gasifying alkaloid composition, wherein the flavor additive has a spiciness or heat of about 1,000 to about 20,000,000 Scoville heat units (SHU). For flavor additives with a spiciness greater than about 10,000,000 SHU, the amount used can be greatly reduced, for example, the amount of the flavor additive can be reduced to about 0.0001 wt% to about 0.01 wt% based on the total weight of the composition.

[0244] In certain embodiments, the gasifying alkaloid composition may optionally include capsaicin ((E)-N-[(4-hydroxy-3-methoxyphenyl)methyl]-8-methylnon-6-enamide, CAS No.: 404-86-4). Capsaicin in pure form (100% active) is a white crystalline solid with a melting point of 65° C. Purified capsaicin can be used directly in the compositions herein and can be purchased from chemical suppliers such as Sigma-Aldrich Co., VWR Avantor, and Alfa Chemistry.

[0245] In various embodiments, the gasifying alkaloid composition herein comprises 0 wt % to about 0.01 wt % of capsaicin ((E)-N-[(4-hydroxy-3-methoxyphenyl)methyl]-8-methylnon-6-enamide), based on the total weight of the gasifying alkaloid composition. In other examples, the amount of capsaicin is 0 wt % to about 0.0015 wt %, based on the total weight of the composition.

[0246] In various embodiments, for reasons of cost and practicality, "liquid capsaicin" is used in the gasifying alkaloid composition herein. For example, gallons to barrels of pepper flavor extracts produced by Olive Nation, LLC in Avon, Massachusetts can be used. The product is an ethanol extract of peppers with a clear reddish-brown appearance and a specific gravity of about 0.8 g / mL at 20°C. This commercial material contains about 99.1% by weight of ethanol and about 0.9% by weight of capsaicinoid active ingredients.

[0247] In various embodiments, the gasifying alkaloid combinations herein comprise 0 wt % to about 0.15 wt % chili liquid (e.g., chili flavor extract from Olive Nation, LLC, having about 0.9 wt % active capsaicinoids), based on the total weight of the gasifying alkaloid composition.

[0248] 4. Optional flavoring

[0249] In various embodiments, based on the total weight of the composition, the gasification alkaloid composition of the present invention may optionally contain at least one flavoring agent of up to about 1.0 weight %. Depending on the flavor type and the desired sensory effect, the weight percentage of the flavoring agent used in the composition of the present invention will vary greatly, and in some cases, the amount used will be much less than 1.0 weight percent (e.g., 0.1 weight % or less). The optional flavoring agents used herein include, but are not limited to, geraniol, geranyl aldehyde, valeric acid, methyl salicylate, ethyl maltol, ethyl butyrate, ethyl acetate, maltol, ethyl vanillin, 3-methyl-3-phenylglycine ethyl ester, furanone, methylcyclopentenolone, methylcyclopentenolone, ethylcyclopentenolone, δ-decalactone, γ-decalactone, α-nonalactone, β-nonalactone, cis-3-hexanol, isoamyl acetate, ethyl 2-methylbutyrate, butyric acid, ethyl butyrate, 2-methylbutyric acid, benzyl alcohol , ethyl hexanoate, benzaldehyde, isopentyl isovalerate, hexanoic acid, ethyl propionate, γ-undecalactone, levulinic acid, raspberry ketone, furfural, 5-methylfurfural, maltol, 2-acetylpyrazine, 2,3,5-trimethylpyrazine, 2-acetylpyrrole, 2-isopropyl-4-methylthiazole, 2-isobutylthiazole, furfurylthiol, thiomenthone, p-men-8-thiol, 2-methyl-4-propyl-13-oxathiol (tropathiane), hexyl acetate and mixtures thereof.

[0250] Exemplary compositions

[0251] In various embodiments, the gasifying alkaloid composition herein comprises at least one substituted pyridine compound of formula (I) or a salt or mixed salt thereof, and a suitable solvent, and optionally a chemical sensory stimulant and optionally a flavoring agent. In various embodiments, the composition further comprises at least one organic acid to convert at least some of the substituted pyridine compounds of formula (I) into their corresponding salts or mixed salts. The composition thus obtained is a thin, transparent and uniform liquid.

[0252] Table 1 provides general embodiments of gasifying alkaloid compositions according to the present disclosure.

[0253] Table 1: General gasification alkaloid composition

[0254]

[0255]

[0256] Note 1: The compositions according to Table 1 are intended to target a certain w / v level of substituted pyridine compound in the finished composition, such as 1000 mg / mL, 750 mg / mL, 500 mg / mL, 250 mg / mL, or 100 mg / mL of substituted pyridine compound. As described herein, the compositions in Table 1 having these relatively high levels of substituted pyridine compound (e.g., ≥ 100 mg / mL) can be considered as concentrates and, therefore, can be further diluted by a third party manufacturer or formulator, or even by an end user, who can refill a refillable electronic device.

[0257] Note 2 In the preferred composition of Table 1, the substituted pyridine free base and the total organic acid R 18 The molar ratio of -CO2H is from about 25: 1 to about 75: 1, more preferably about 50: 1. Therefore, regardless of the molecular weight of the free base alkaloid and the organic acid, in any composition within the above weight percentage range, it is expected that most of the substituted pyridine compound of formula (I) will remain as the free base.

[0258] Note 3 : In these compositions, standardized to capsaicin actives, the range of 0 wt % to about 0.01 wt % is a preferred range for optional flavor additives in the compositions, as shown in Table 1, while the broader range provided in Table 1, i.e., 0 wt % to about 0.5 wt %, reflects a general range that includes any of the above-mentioned chemosensory stimulants, including a subset of flavor additives that are not necessarily capsaicinoids. If desired, the amount of chemosensory stimulant used in the gastrointestinal alkaloid composition can be determined based on the TRP channel activator EC measured therein. 50 or [A] 50 The value is adjusted to the molar concentration of the activator that produces 50% of the maximum possible effect of the activator. Human TRP receptor activators and their EC 50For a chart of values, see, for example, L. Premkumar, "Transient Receptor Potential Channels as Targets for Phytochemicals", ACS Chem. Neurosci., 5 (11) 1117-1130, 2014, and R. Neubig et al., "International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. XXXVIII. Update on Terms and Symbols in Quantitative Pharmacology", Pharmacological Reviews, 55 (4), 597-606 (2003). The phytochemicals disclosed by Premkumar are incorporated herein by reference for explicit use in the gasifying alkaloid compositions disclosed herein.

[0259] When a flavoring additive is selected as an optional chemical irritant, for a flavoring additive with a spiciness lower or higher than capsaicin (< or > 16,000,000 SHU), the amount (weight percentage) of the flavoring additive can be adjusted accordingly. In other words, the alternative flavoring additive for capsaicin can be standardized to capsaicin. As a rough estimate, the ratio of the SHU of the alternative flavoring additive to the SHU of capsaicin (16,000,000 SHU) can be used to calculate the reasonable amount of different flavoring additives that replace capsaicin. For example, the amount of gingerol (160,000 SHU) can be 100 times that of 0.0001 wt % to about 0.01 wt % of active capsaicin (16,000,000 SHU), because the ratio of Scoville values ​​is 16,000,000 SHU / 160,000 SHU=100. Therefore, based on the total weight of the composition, the appropriate addition amount of the gingerol active ingredient in the composition ranges from 0.01 wt % to about 1 wt %. If a flavor additive with a spicy taste greater than 16,000,000 SHU is used, the amount of the flavor additive added should be reduced. Of course, focus groups and sensory panels can help refine these estimated ranges, but calculations need to be made in this way as a starting point. If there are supply / cost issues with a certain flavor additive, or if some users want a different sensory experience, being able to replace the flavor additive is particularly useful. In addition, if a liquid extract is used instead of an active flavor additive, such as liquid capsaicin, the weight percentage of the active flavor additive in the composition of Table 1 will also increase accordingly.

[0260] Note 4 : In these compositions, flavoring agents are optional, as they can be added later if desired, for example, if the composition of Table 1 is diluted by a third party supplier or an end user capable of filling a refillable device. Thus, for example, a composition according to Table 1 can be initially free of flavoring agents, and then a third party or end user can dilute the composition (e.g., with VG and / or PG) and add a flavoring agent of their own choice.

[0261] Note 5 : In these compositions, the choice of solvent is based in part on acceptability for inhalation, since the compositions will ultimately be used in electronic devices for vaping and provide at least some perceptible throat hit in the absence of chemosensory stimulants. Thus, the solvents in Table 1 are typically selected from the group consisting of propylene glycol, glycerin, ethanol, water, and mixtures thereof. The bulk solvent component of each composition may be propylene glycol, vegetable glycerin, or a mixture of the two. When chemosensory stimulants are present in the composition, the amount of propylene glycol may be adjusted accordingly to optimize the perceived throat hit.

[0262] As described above, a third party or end user may further dilute the composition of Table 1 and may choose to use propylene glycol, vegetable glycerin, or a mixture thereof (e.g., 50 / 50 VG / PG) for this purpose. It should also be noted that when the content of the substituted pyridine compound of formula (I) is relatively high, for example, exceeding about 20% by weight, the solubility of the alkaloid may be problematic, in which case the solvent ratio may be adjusted to improve solubility, such as increasing the weight percentage of ethanol and reducing the weight percentage of glycerin and / or propylene glycol. In general, the substituted pyridine compound of formula (I) is more soluble in ethanol than VG or PG. A mixture containing about 4% to about 12% by weight of the substituted pyridine compound of formula (I) can generally be mixed evenly with a VG / PG mixture and a very small amount of ethanol.

[0263] Table 2 lists embodiments of vaporizable alkaloid compositions according to the present disclosure. These compositions are derived from the general embodiments listed in Table 1 and have been shown to be vaporizable and acceptable to consumers as shown in the table or after dilution to a lower w / v alkaloid. The exemplary compositions in Table 2 are examples only and should not be considered to limit the scope of the present disclosure in any way. For example, other substituted pyridine compounds of formula (I) can be used to replace these five substituted pyridine compounds, and mixtures of substituted pyridine compounds can be used in any single composition. In addition, other organic acids can be used in addition to citric acid and acetic acid. In addition, the relative amount of solvent in each composition can also be changed to at least increase the solubility of the specific substituted pyridine compound used.

[0264] Table 2: Exemplary gasifying alkaloid compositions

[0265]

[0266]

[0267] The numerical entries in Table 2 are the "added" ingredients and are rounded.

[0268] In various embodiments, if a chemical irritant is added to the composition, the recommended 1.28 wt% propylene glycol in the composition of Table 2 may be reduced. To increase the perceived throat hit, the amount of propylene glycol may be increased even with or without the use of a chemical irritant in the composition.

[0269] As described herein, the presence of citric acid and acetic acid in each composition is expected to form a small amount of the corresponding alkaloid salt, and given the large molar excess of the substituted pyridine compound, any free citric acid or acetic acid is unlikely to remain in the free acid state. Compositions 1-5 in Table 2 have a molar ratio of free base to organic acid of about 25:1 to about 75:1.

[0270] For compositions that use 190 proof alcohol instead of absolute ethanol, there will be a small amount of water in the composition that is not added separately and is therefore not noted as it is not "added". Any composition that uses 190 proof alcohol as an ingredient can be converted to a composition containing absolute alcohol and water if desired.

[0271] Each exemplary composition in Table 2 contains about 100 mg / mL of the substituted pyridine compound shown. It is worth noting that these exemplary compositions can be adjusted so that the target w / v value of the alkaloid is about 1 mg / mL to about 1000 mg / mL. Target w / v includes but is not limited to 1000 mg / mL, 750 mg / mL, 500 mg / mL, 250 mg / mL and 100 mg / mL. One benefit of producing concentrates, especially super concentrates containing 1000 mg / mL of substituted pyridine compounds in total w / v, is reduced transportation costs to manufacturers, formulators and retailers. A third party formulator or end user desires to obtain any of these "concentrates" (e.g., 1000 mg / mL, 750 mg / mL, 500 mg / mL, 250 mg / mL, or 100 mg / mL) and then dilute with PG or VG or a mixture of PG and VG to a w / v target value of the substituted pyridine compound that is less than 100 mg / mL, such as 1 mg / mL, 3 mg / mL, 6 mg / mL, 9 mg / mL, 12 mg / mL, 15 mg / mL, 18 mg / mL, 21 mg / mL, 24 mg / mL, 27mg / mL, 30mg / mL, 33mg / mL, 36mg / mL, 39mg / mL, 42mg / mL, 45mg / mL, 48mg / mL, 51mg / mL, 54mg / mL, 57mg / mL, 60mg / mL, 63mg / mL, 66mg / mL, 69mg / mL, 72mg / mL, 75mg / mL, 78mg / mL, 81mg / mL, 84mg / mL, 87mg / mL, 90mg / mL, 93mg / mL, 96mg / mL or 99mg / mL.

[0272] Method for preparing gasifying alkaloid composition

[0273] The gasifying alkaloid compositions in Tables 1 and 2 can be prepared by directly mixing the compositions shown in the tables in a laboratory container by magnetic stirring or overhead stirring, or in a food industry blender, and then heating if necessary to obtain complete solubility and clarity. In a preferred embodiment, a premix is ​​first made and then combined.

[0274] In various embodiments, the first premix (denoted as premix A) comprises propylene glycol, an optional chemical irritant, an organic acid, and 190 proof alcohol. In some examples, premix A may contain two or more organic acids, and / or may replace PG with VG or include PG and VG.

[0275] In various embodiments, the second premix (denoted as premix B) comprises the desired substituted pyridine compound of formula (I) dissolved in a compatible solvent (e.g., vegetable glycerin, propylene glycol, a 50 / 50 (v / v) mixture of vegetable glycerin and propylene glycol, and / or ethanol). As previously mentioned, in order to obtain a high concentration composition, such as a composition having a substituted pyridine compound content of greater than 20% by weight and a substituted pyridine compound content of greater than 100 mg / mL, the content of a certain solvent, such as ethanol, may be increased. In some cases, other solvents may be required in addition to the above solvents.

[0276] In certain embodiments, Premix A is then combined with Premix B and the resulting mixture, if cloudy, is heated at about 190° F. for about 1 hour, or until the mixture is completely clear. Upon cooling, the mixture will remain clear as it appears that the composition is thermodynamically stable.

[0277] To obtain a final composition with an alkaloid content greater than 100 mg / mL, one approach is to prepare a more concentrated premix B. Depending on the nature and desired concentration of the substituted pyridine compound of formula (I) used in premix B, solubility may become an issue. In this case, the vegetable glycerin in premix B may be at least partially replaced with other solvents such as ethanol. For the compound of formula (I), the solubility data of a particular alkaloid in various solvents can provide a basis for which solvent to use in premix B.

[0278] How to use

[0279] 1. Quitting smoking by inhaling a bioactive alkaloid composition

[0280] The vaporizable alkaloid composition or its dilution according to the present disclosure is intended to be dispensed from an electronic device (such as an electronic cigarette) in the form of a vapor, which can be inhaled by the user like a traditional tobacco product (such as a cigarette).

[0281] As stated above, one object of the present disclosure is to provide a vaporizable alkaloid composition and a stepwise dilution thereof to smokers participating in a smoking cessation program.

[0282] In various embodiments, a method of quitting smoking comprises administering to an individual who wishes to quit smoking a series of vaporizing alkaloid compositions over a period of time determined for quitting smoking, wherein each vaporizing alkaloid composition in the series comprises:

[0283] At least one substituted pyridine compound having formula (I) or a salt or mixed salt thereof:

[0284]

[0285] wherein each gasifying alkaloid composition in the series comprises a decreasing (w / v) amount of the substituted pyridine compound or a salt or mixed salt thereof;

[0286] and at least one solvent,

[0287] wherein the smoking cessation process of an individual who wishes to quit smoking is carried out by using each composition in the series with a decreasing (w / v) amount of the substituted pyridine compound or a salt or mixed salt thereof; and

[0288] Therein, an individual who wishes to quit smoking uses each of the compositions by vaporizing and inhaling each composition from an electronic device for a period of time determined for quitting smoking.

[0289] In various embodiments, the series of gasifiable alkaloid compositions includes the composition with the highest w / v content of the substituted pyridine compound of formula (I), and also includes the composition with the lowest w / v content of the substituted pyridine compound of formula (I).

[0290] In various embodiments, an individual who wishes to quit smoking begins a smoking cessation program by using a composition having the highest w / v content of the substituted pyridine compound of formula (I), and ends the smoking cessation program by using a composition having the lowest w / v content of the substituted pyridine compound of formula (I). The use of this series of compositions is distributed over the entire time period of the smoking cessation program.

[0291] In various embodiments, the individual who wishes to quit smoking is a tobacco smoker who wants to stop smoking.

[0292] In various embodiments, the time period determined for quitting smoking can be a few days, weeks, months, or years, preferably a few months to a year.

[0293] In various embodiments, the time period determined for quitting smoking is part of a smoking cessation program, which further comprises dispensing a series of vaporizing alkaloid compositions during the time period determined for quitting smoking.

[0294] In various embodiments, the time period determined for quitting smoking is divided into successive time periods of shorter duration, wherein in each shorter time period, the individual who wishes to quit smoking receives and uses a different vaporized alkaloid composition to replace tobacco smoking. In a preferred embodiment, in each successive shorter duration, the individual who wishes to quit smoking receives a vaporized alkaloid composition with a gradually decreasing alkaloid content in (w / v) units.

[0295] In various embodiments, the series of vaporized alkaloid compositions includes the individual compositions listed in Table 3. This series of exemplary e-liquids can be used in a 25-week smoking cessation program. The table shows that during each week of the smoking cessation program, the individual will receive a new inhaler composition with a lower amount of a substituted pyridine compound. At the end of the smoking cessation program, the individual who wishes to quit smoking will smoke a vaporized alkaloid composition that does not contain alkaloids.

[0296] Table 3: A range of vaporized alkaloid compositions for use in smoking cessation programs

[0297]

[0298] Note 1 : The alkaloid in the composition P1-P25 includes any substituted pyridine compound of formula (I) or a salt or mixed salt thereof. In certain examples, the composition P1-P25 consists of the composition in Table 1 and Table 2 and dilutions thereof.

[0299] Note 2 : For plans using a composition starting with 100 mg / mL alkaloid w / v, the composition in Table 2 can be used as P1. For compositions P2 to P25, P1 is diluted accordingly with VG and / or PG as previously described, flavoring is added as needed, and adjustments are made based on individual preference and compliance history.

[0300] In various embodiments, individuals participating in a smoking cessation program will contact their program manager regularly (e.g., once a week) for individual counseling and to receive new, further diluted e-cigarette liquids. During these periodic checks, the individual's compliance with the program can be assessed and adjusted accordingly. Some modifications to the program may be to allow individuals to maintain a certain alkaloid w / v level for longer periods of time than a week, or to change or adjust flavorings. Other changes may also be made to a series of electronic cigarette compositions, such as adding chemical sensory stimulants to diluted compositions, changing between different chemical sensory stimulants, or adding more or less chemical sensory stimulants and / or propylene glycol to adjust the throat hit felt by individuals who inhale the provided composition. In some instances, a liquid composition is provided to an individual, who places the composition into a reservoir of his or her own refillable electronic device (e.g., a refillable electronic cigarette). In other instances, a disposable (enclosed) device is provided to an individual, which is pre-filled with a specific composition.

[0301] In various embodiments, the individual who reaches the end of the program will smoke only flavored solvents that do not contain alkaloids. At this point in time, it is expected that the individual will no longer smoke traditional tobacco products at all and may choose to stop smoking electronic cigarettes completely.

[0302] In various embodiments, a method of vaping comprises vaporizing and inhaling a composition according to the present disclosure from a disposable (closed) or refillable (open) electronic device. In certain embodiments, the electronic device comprises an electronic cigarette.

[0303] 2. Alkaloid dispensing pouches for oral use

[0304] In various embodiments, versions of the vaporizable alkaloid compositions according to the present disclosure may also be used by manufacturers of "alkaloid dispensing pouches". The pouches for oral use include a relatively small (e.g., 0.5 inch x 0.75 inch) saliva-permeable fabric material housing in which a powder is sealed, capable of releasing the alkaloid active ingredient into the individual's oral cavity when the pouch is placed in the individual's sublingual or buccal cavity. The alkaloid dispensing pouches according to the present disclosure are configured to release the alkaloid of formula (I) over time. In some embodiments, the release of the alkaloid from the alkaloid dispensing pouch into the individual's oral cavity may be characterized as "timed release".

[0305] In various embodiments, the alkaloid dispensing pouch comprises a saliva permeable nonwoven fabric and a powdered alkaloid composition sealed therein. In certain instances, the powdered alkaloid composition sealed in the pouch comprises a vaporizable alkaloid composition according to the present disclosure adsorbed on a carrier or a carrier mixture so that it presents a physical form of powder or granules. In other embodiments, the powdered alkaloid composition in the alkaloid dispensing pouch comprises a substituted pyridine compound of formula (I), a solvent, and a carrier, wherein the mixture of alkaloid and solvent is adsorbed on the carrier.

[0306] 2a. General Embodiments of Alkaloid Dispensing Pouches

[0307] In a general embodiment, an alkaloid dispensing pouch is used to release an alkaloid into the oral cavity of a subject, comprising:

[0308] A saliva-permeable nonwoven fabric defining a shell containing an alkaloid composition comprising

[0309] At least one substituted pyridine compound according to formula (I) or a salt or mixed salt thereof:

[0310]

[0311] in:

[0312] A is selected from:

[0313] and

[0314] R 1 , R2 , R 3 , R 4 and R 5 are independently selected from the group consisting of: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, and

[0315] R 6 and R 7 are independently selected from: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl, or R 6 and R 7 Together = O;

[0316] R 8 , R 9 , R 10 , R 11 and R 12 independently selected from the group consisting of: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl;

[0317] R 13 and R 14 are independently selected from: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl, or R 13 and R 14 Together = O;

[0318] n is an integer from 1 to 10; and

[0319] R 15 and R 16 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 15 and R 16 Together with the nitrogen atom to which they are bound, they form a 3-8 membered optionally substituted heterocyclic ring,

[0320] The condition is: If A is And R 5 is methyl, then R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 Cannot be all H; and

[0321] carrier,

[0322] Wherein, the alkaloid dispensing pouch is completely free of (R) or (S) nicotine.

[0323] In various embodiments, the alkaloid composition is a mixture of a substituted pyridine compound of formula (I) and a carrier in a solid or oily physical form.

[0324] In various embodiments, the carrier comprises microcrystalline cellulose.

[0325] In various embodiments, the alkaloid composition optionally comprises a chemical irritant and / or a flavoring agent.

[0326] In various embodiments, the alkaloid composition further comprises a solvent, so that the alkaloid composition can be adsorbed on the carrier to form a powdered or granular composition that can be filled into the shell. In some examples, the solvent is selected from the group consisting of propylene glycol, glycerol, water, ethanol, and mixtures thereof.

[0327] 2b. Saliva-permeable fabric for pouches

[0328] The pouch material used herein is selected based on its insolubility in water and its permeability to water and saliva. The size of the material should be such that the filled pouch is suitable for prolonged placement under the tongue or in the buccal cavity. Subjectively, the construction of the alkaloid dispensing pouch should be comfortable in the mouth, including the size of the filling and sealing pouch and the texture of the pouch fabric.

[0329] The sac material used herein can be composed of any number of a variety of water-insoluble nonwoven materials (referred to as "fabrics"). Nonwoven fabrics have a variety of uses and are well known to those skilled in the textile field. Nonwoven fabrics are described in detail in: "Nonwoven Fabrics: Raw Materials, Manufacture, Applications, Characteristics, Testing Processes", edited by W. Albrecht, H. Fuchs and W. Kittelmann, Wiley-VCH Verlag GmbH & Co. Kga A Weinheim, 2003. Such materials can be prepared by forming a web of continuous filament fibers and / or staple fibers and bonding these fibers at fiber-to-fiber contact points to provide a fabric with desired properties. The term "bonded nonwoven fabric" includes nonwoven fabrics in which the major portion of the inter-fiber bonding is achieved by thermal fusion of adjacent fibers, or by adding an adhesive to the web to "stick" the fibers together, or by other bonding achieved by using a liquid or gaseous adhesive (usually in combination with heat) to make the fibers adhesive. Chemical bonding can be achieved by using an adhesive or latex powder dispersed between the fibers of the web and then activated by heat, ultraviolet or infrared radiation or other suitable activation methods. Thermally bonded and chemically bonded carded fabrics are described in U.S. Patent No. 6,689,242 to Bodaghi, the contents of which are incorporated herein. Thermally bonded and / or chemically bonded nonwovens can be used as sack materials herein. Powder bonding is a dry process in which short fibers are first carded into a web, which is then treated with a powdered thermoplastic adhesive or latex material and then passed through a series of ovens and calendar rolls to produce a nonwoven.

[0330] Nonwovens can also include fibers called "bicomponent fibers", such as "sheath / core bicomponent fibers", where the sheath region or outer layer of such fibers has a lower melting point than the inner core region, thereby enabling efficient, controllable thermal bonding by only melting the outer layer of each fiber. In other words, the outer surface of the bicomponent fiber can be made to have a lower melting point than the fiber core. For example, adhesive bicomponent fibers (wherein one component has adhesive properties under bonding conditions) are widely used to provide integrity for fiber webs used as absorbents in individual care products or filtration products. In addition, multicomponent fibers are also well known and have been commercially applied in nonwovens. Examples of such multicomponent fibers are described in U.S. Patent No. 5,382,400 (Pike et al.) and U.S. Patent No. 5,866,488 (Terada et al.), all of which are incorporated herein.

[0331] During the fiber bonding process, the web can be mechanically compressed simultaneously to obtain the desired bonding, weight, and thickness in a process known as "thermocompression bonding." Thermocompression bonding can be accomplished by using heated press rolls and heated flat calender rolls in conjunction with a process in which heat treatment machines such as hot air circulation, hot ventilation, infrared heaters, or vertical hot air blasts are used for heat compression bonding. Mechanical compression can be used to set the loft or thickness of fabrics with similar basis weights. Generally, increasing basis weight or mass per square area increases thickness, and increasing bonding and compression decreases loft.

[0332] Nonwoven webs can be formed by a variety of processes, such as meltblown, spunbond or spun-laid, toe-opened, wet-laid, air-laid, carded and high pressure hydro-entangled. The basis weight of nonwoven webs is usually measured in ounces per square yard (osy) or grams per square meter (gsm), and the fiber diameter is usually measured in microns, or in the case of staple fibers, in "denier". Denier is defined as the number of grams per 9000 meters of fiber length. For fibers with a circular cross-section, denier can be calculated as the square of the fiber diameter (microns) multiplied by the density (grams per cubic centimeter) and then multiplied by 0.00707. A lower denier indicates that the fiber is finer, and a higher denier indicates that the fiber is thicker or heavier. "Average fiber denier" is the sum of the deniers of each fiber divided by the number of fibers. Denier distribution or "average fiber denier" refers to the distribution of fiber diameters around a specific value. As used herein, the term "bulk density" refers to the weight of a material per unit volume, usually expressed as mass units per unit bulk volume (e.g., grams per cubic centimeter). Nonwovens can be produced from fibers having a single average diameter or denier, or fibers of two or more average diameters can be used. For example, two or more fiber denier distributions can be combined into a single fiber web (e.g., 2 1 / 2 denier and 4 denier fibers are combed together). The individual webs can then be laminated together. For example, a nonwoven may contain 2 1 / 2, 4, 6 and 15 denier fibers, which means that it is composed of four individual denier fibers (fibers of four individual average diameters).

[0333] "Spunbond fibers" refer to fibers formed by extruding molten thermoplastic material into filaments. They are described, for example, in U.S. Pat. No. 4,340,563 to Appel; U.S. Pat. No. 3,692,618 to Dorschner; U.S. Pat. No. 3,802,817 to Matsuki; U.S. Pat. No. 3,338,992 and U.S. Pat. No. 3,341,394 to Kinney; U.S. Pat. No. 3,502,763 to Hartman; U.S. Pat. No. 3,542,615 to Dobo; and U.S. Pat. No. 5,382,400 to Pike, the entire contents of which are incorporated herein by reference. Spunbond fibers are generally not sticky when deposited onto a collecting surface. Spunbond fibers are typically continuous and have an average diameter of about 7 microns to about 60 microns, most commonly between about 15 and 25 microns.

[0334] "Meltblowing" refers to the process of reducing the diameter of filaments of molten thermoplastic material to a microfiber diameter by extruding the molten thermoplastic material as molten threads or filaments from a plurality of fine, usually circular die capillaries into a converging high-speed (usually hot) gas / air stream. Thereafter, the meltblown fibers are carried by the high-speed gas stream and deposited on a collecting surface to form a randomly dispersed fibrous web. Such processes are disclosed, for example, in U.S. Pat. No. 3,849,241 to Butin et al. Meltblown fibers are microfibers that may be continuous or discontinuous, have an average diameter generally less than 10 microns, and are generally tacky when deposited on a collecting surface.

[0335] "Air laying" is a well-known process by which a fibrous nonwoven layer can be formed. In the air laying process, small fiber bundles having a typical length of about 3 to about 52 millimeters are separated and entrained in an air source, usually with the aid of a vacuum, and deposited on a forming screen. The randomly deposited fibers are then bonded to one another using, for example, hot air to activate a binder component or a latex binder. The air laying process is taught in, for example, U.S. Patent No. 4,640,810 to Laursen and U.S. Patent No. 5,885,516 to Christensen.

[0336] The preferred fibers included in the pouch fabric used herein can be monocomponent fibers, bicomponent fibers (e.g., sheath / core) or multicomponent fibers made of the following materials: polyolefins, such as polypropylene, polyethylene; various polyesters, such as polyethylene terephthalate-PET, polybutylene terephthalate-PBT or polytrimethylene terephthalate-PTT, polycarbonate or polybutyrate, etc.; viscose rayon; various polyamides, such as nylon; polyacrylates; and modified acrylic resins and mixtures of these types of polymers. In various preferred embodiments, viscose fibers are used as the saliva-permeable nonwoven pouch fabric of the alkaloid dispensing pouch herein.

[0337] A filling and sealing method for a pouch including a nonwoven fabric is disclosed in U.S. Patent Application Publication No. US2023 / 0211907, which was published on July 6, 2023 and assigned to Swedish Match North Europe AB, which is incorporated herein by reference. In various embodiments, the filling weight of the alkaloid composition (dry powder or granules) of the alkaloid distribution pouch is about 100 mg to 500 mg, preferably 200 mg to 400 mg. When the pouch can no longer fit comfortably under the tongue or in the buccal cavity, the upper limit is reached. Since the weight of the small piece of nonwoven fabric is negligible compared to the weight of a single small pouch, the filling weight of the alkaloid distribution pouch is about 100 mg to about 500 mg of dry powder or granular alkaloid composition per pouch.

[0338] In various embodiments, the alkaloid dispensing pouch has a width (or diameter) of about 0.12 inches to about 0.50 inches and a height of about 0.25 inches to about 0.75 inches. In some instances, the pouch looks like a small pillow (eg, square), or more like a capsule.

[0339] 2c. Powder filling composition for alkaloid dispensing pouches

[0340] In various embodiments, the alkaloid dispensing pouch comprises a powdered or granular composition, and further comprises an alkaloid mixed with a carrier or a gasifiable alkaloid composition according to the present disclosure adsorbed on a carrier. In any case, the dry powdered or granular alkaloid filling material is sealed in a nonwoven fabric shell.

[0341] The vaporizable alkaloid compositions for use in the alkaloid dispensing pouches have been fully described above. Any composition of a substituted pyridine compound of formula (I) in the range of about 1 mg / mL to about 1000 mg / mL may be used. The selected liquid composition is then adsorbed onto a suitable carrier, and the resulting powder or granules may be used as the filling material for each pouch.

[0342] The carriers used herein include, but are not limited to, agar, agarose, albumin, alginate, casein, chitin, chondroitin, dextrin, silk protein, fucoidan, galactan, gellan gum, guar gum, scleroglucan, pullulan, xyloglucan, pectin, xanthan gum, psyllium, silica gel, fumed silica, magnesium aluminum silicate, clay, bentonite, hectorite, mesoporous silica, cellulose, cellulose acetate, hyaluronic acid, various elastin-like polypeptides, β-cyclodextrin, collagen, gelatin, chitosan, carrageenan, poly Lactic acid, polyglycolic acid, poly(lactic acid-glycolic acid) (PLGA), poly(2-hydroxyethyl methacrylate), poly(2-hydroxypropyl methacrylate), poly(acrylic acid), carboxymethyl cellulose, carboxyethyl cellulose, hydroxyethyl cellulose, hydrophobically modified hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, microcrystalline cellulose, nitrocellulose, polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl methacrylate, carboxyvinyl polymer, polyvinyl acetate, polyethylene copolymer, various starches, modified starches and combinations thereof. See SMFijul Kabir et al., "Cellulose-based hydrogel materials: chemistry, properties and their prospective applications", Prog. Biomater., 7, 153-174 (2018).

[0343] The carrier can be selected based on absorptive capacity and secondarily on taste. In the case where the carrier is completely insoluble in saliva in the oral cavity, taste will no longer be a factor of choice, and any insoluble carrier is unlikely to pass between the fibers of the nonwoven fabric. In other examples, the carrier can be soluble and will pass through the porous pouch fabric along with the alkaloid composition. In a preferred embodiment, the carrier comprises microcrystalline cellulose.

[0344] Table 4, Table 5 and Table 6 list general embodiments of alkaloid compositions that can be used as filling materials for the alkaloid dispensing pouches of the present disclosure.

[0345] Table 4: Fill composition of alkaloid dispensing pouch: dry mix

[0346] Ingredients (weight %) weight% Substituted pyridine compounds of formula (I) 0.1 wt% to 99.9 wt% Fillers (e.g. microcrystalline cellulose) 0.1 wt% to 99.9 wt% total 100.00% by weight

[0347] Table 5: Fill composition of alkaloid dispensing pouch: liquid absorption

[0348]

[0349] Table 6: Fill composition of alkaloid dispensing pouch: liquid absorption

[0350] Ingredients (weight %) weight% Gasifying alkaloid composition (1 mg / mL to 1000 mg / mL w / v alkaloid) 0.1 wt% to 15 wt% Fillers (e.g. microcrystalline cellulose) 85 wt% to 99.9 wt% total 100.00% by weight

[0351] The physical form of each filling composition shown in Table 4, Table 5 or Table 6 is dry powder or granules. The obtained material is filled into a non-woven fabric pouch at a filling amount of about 100 mg to about 500 mg of the dry powder or granule alkaloid composition per pouch, and then sealed to prepare a single alkaloid dispensing pouch for oral use.

[0352] The references to "multiple embodiments", "an embodiment", "an embodiment", etc. in the specification indicate that the described embodiments may include specific features, structures, or characteristics, but each embodiment may not necessarily include the specific features, structures, or characteristics. Moreover, such phrases do not necessarily refer to the same embodiment. In addition, when a specific feature, structure, or characteristic is described in conjunction with an embodiment, it is considered to be within the knowledge of those skilled in the art to affect such feature, structure, or characteristic in conjunction with other embodiments, whether or not explicitly described. After reading the specification, it will be clear to those skilled in the relevant art how to implement the present disclosure in alternative embodiments.

[0353] The steps recited in any method or process description may be performed in any order and are not necessarily limited to the order presented. In addition, any singular reference includes plural embodiments, and reference to any component or step more than one may include singular embodiments or steps. In addition, any reference to attachment, fixing, connection, coupling, or the like may include permanent (e.g., integral), removable, temporary, partial, complete, and / or any other possible attachment options. Any components may be connected to each other by friction, snaps, sleeves, brackets, clips, or other means known in the art or developed below. In addition, references to contactless (or similar phrases) may also include reduced contact or minimal contact.

[0354] Benefits, other advantages, and solutions to problems have been described herein for specific embodiments. However, benefits, advantages, solutions to problems, and any elements that may cause any benefit, advantage, or solution to occur or become more apparent should not be interpreted as key, essential, or basic features or elements of the present disclosure. Therefore, the scope of the present disclosure is limited only by the appended claims, in which references to singular elements do not mean "one and only one" but "one or more" unless explicitly stated. In addition, if a phrase similar to "at least one of A, B, and C" or "at least one of A, B, or C" is used in a claim or specification, the phrase should be interpreted as A can exist alone in one embodiment, B can exist alone in one embodiment, C can exist alone in one embodiment, or any combination of A, B, and C elements can exist in one embodiment; for example, A and B, A and C, B and C, or A and B and C.

[0355] All structural, chemical and functional equivalents of the elements of the various embodiments described above known to those of ordinary skill in the art are expressly incorporated herein by reference and are intended to be included in the claims. In addition, the devices or parts of the devices or methods of using the devices contained in the claims do not necessarily solve every problem to be solved by the present disclosure. In addition, any element, component or method step in the present disclosure is not intended to be dedicated to the public, regardless of whether the element, component or method step is explicitly cited in the claims. Unless the element is explicitly stated using the phrase "device for...", no claim element is intended to invoke 35 USC112 (f). As used herein, the terms "include", "comprise" or any other variant thereof are intended to cover non-exclusive inclusion, so that the chemistry, chemical composition, process, method, product or equipment containing the list of elements includes not only these elements, but may also include other elements that are not explicitly listed or other elements inherent to such chemistry, chemical composition, process, process, product or equipment.

[0356] Some aspects of this application include:

[0357] 1. A gasifying alkaloid composition comprising:

[0358] At least one substituted pyridine compound of formula (I):

[0359] or a salt or a mixture of salts thereof, wherein:

[0360] A is selected from:

[0361] and

[0362] R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from the group consisting of: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, and

[0363] R 6 and R 7 are independently selected from: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl, or R 6 and R 7 Together = O;

[0364] R 8 , R 9 , R 10 , R 11 and R 12independently selected from the group consisting of: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl;

[0365] R 13 and R 14 are independently selected from: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl, or R 13 and R 14 Together = O;

[0366] n is an integer from 1 to 10; and

[0367] R 15 and R 16 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 15 and R 16 Together with the N atom to which they are bound, they form a 3-8 membered optionally substituted heterocyclic ring,

[0368] The condition is: If A is And R 5 is methyl, then R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 Cannot be all H; and

[0369] at least one solvent,

[0370] Wherein, the vaporizable alkaloid composition contains no (R) or (S) nicotine at all.

[0371] 2. The gasifying alkaloid composition of aspect 1, wherein the at least one substituted pyridine compound has a structure conforming to formula (IA):

[0372] or a salt or a mixture of salts thereof.

[0373] 3. The gasifying alkaloid composition according to aspect 1, wherein the at least one substituted pyridine compound has a structure conforming to formula (IA-1):

[0374] or a salt or a mixture of salts thereof.

[0375] 4. The gasifying alkaloid composition according to aspect 1, wherein the at least one substituted pyridine compound has a structure conforming to formula (IA-2):

[0376] or a salt or a mixture of salts thereof.

[0377] 5. The gasifying alkaloid composition of aspect 1, wherein the at least one substituted pyridine compound has a structure conforming to formula (IA-3):

[0378] or a salt or a mixture of salts thereof.

[0379] 6. The gasifying alkaloid composition of aspect 1, wherein the at least one substituted pyridine compound has a structure conforming to formula (IA-4):

[0380] or a salt or a mixture of salts thereof.

[0381] 7. The gasifying alkaloid composition of aspect 1, wherein the at least one substituted pyridine compound has a structure conforming to formula (IA-5):

[0382] or a salt or a mixture of salts thereof.

[0383] 8. The gasifying alkaloid composition of aspect 1, wherein the at least one substituted pyridine compound has a structure conforming to formula (IB):

[0384] or a salt or a mixture of salts thereof.

[0385] 9. The gasifying alkaloid composition of aspect 1, wherein the at least one substituted pyridine compound has a structure conforming to formula (IC):

[0386] or a salt or a mixture of salts thereof.

[0387] 10. The gasifying alkaloid composition of aspect 1, wherein the at least one substituted pyridine compound has a structure conforming to formula (ID):

[0388] or a salt or a mixture of salts thereof.

[0389] 11. The gasifying alkaloid composition of aspect 1, wherein the at least one substituted pyridine compound has a structure conforming to formula (IE):

[0390] or a salt or a mixture of salts thereof.

[0391] 12. The gasifying alkaloid composition of aspect 1, wherein the at least one substituted pyridine compound has a structure conforming to formula (IAA):

[0392] or a salt or a mixture of salts thereof, provided that: if R 5 is CH3, then R 1 , R 2 , R 3 and R 4 It can’t be all H.

[0393] 13. The gasifying alkaloid composition of aspect 1, wherein the at least one substituted pyridine compound is selected from (R) or (S)-2-methyl-3-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-4-methyl-3-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-3-methyl-5-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-2,6-dimethyl-3-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S) -2,4-dimethyl-5-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S) -2,3-dimethyl-5-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S) -2,4-dimethyl-3-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S) -2,5-dimethyl-3-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S) -3,4-dimethyl-5-(1-methylpyrrolidin-2-yl)pyridine,

[0394]

[0395]

[0396]

[0397] or a salt or a mixture of salts thereof.

[0398] 14. The gasifying alkaloid composition as described in aspect 1 further comprises an organic acid selected from the group consisting of formic acid, acetic acid, trifluoroacetic acid, aspartic acid, butyric acid, butyric acid, 2-methylbutyric acid, 3-methylbutyric acid, benzoic acid, caprylic acid, citric acid, crotonic acid, ethylenediaminetetraacetic acid, fumaric acid, gluconic acid, glutamic acid, glyceric acid, glycolic acid, lactic acid, lauric acid, levulinic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, oxalic acid, phenylacetic acid, phthalic acid, picric acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, hydroxymalonic acid, valeric acid, and mixtures thereof.

[0399] 15. The gasifying alkaloid composition according to aspect 14, wherein the organic acid is selected from the group consisting of citric acid, acetic acid, benzoic acid, tartaric acid, lactic acid, salicylic acid, malic acid, levulinic acid, and mixtures thereof.

[0400] 16. The vaporizing alkaloid composition of aspect 14, wherein the molar ratio of total substituted pyridine compounds to total organic acid is from about 25:1 to about 75:1.

[0401] 17. The vaporizing alkaloid composition according to aspect 1, wherein the solvent is selected from the group consisting of propylene glycol, water, ethanol, glycerol, and mixtures thereof.

[0402] 18. The vaporizing alkaloid composition according to aspect 1, further comprising at least one chemosensory stimulant.

[0403] 19. The gasifying alkaloid composition according to aspect 18, wherein the chemosensory irritant is selected from the group consisting of oleocanthal, 4-hydroxy-2-nonenal, 4-oxo-2-nonenal, allicin, allyl isothiocyanate, TRPM8 ion channel agonist (Eserin), Polygodial, cinnamaldehyde, trans-p-methoxycinnamaldehyde, methyl syringate, 2-chlorobenzylmalononitrile, 1-chloroacetophenone, ethyl bromoacetate, 4-hydroxyhexenal, toluene diisocyanate, p-benzoquinone, methyl p-hydroxybenzoate, flufenamic acid, acid, niflumic acid, mefenamic acid, diclofenac, hydroxy-α-sanshool, 6-paradol, linalool, carvacrol, eugenol, thymol, vanillin, methyl eugenol, 2,6-dimethylphenol, 2,5-dimethylphenol, 3,4-dimethylphenol, 2,6-diisopropylphenol, caffeine, farnesylthiosalicylic acid, 4-allylanisole, curcumin, niacin, camphor, olvanil, arvanil, anandamide, baicalein, baicalin, wogonin, norwogonin, melaleuca A, β-sitosterol, and mixtures thereof.

[0404] 20. The vaporizing alkaloid composition of aspect 18, wherein the chemesthetic sensory stimulant is a flavor additive having a heat intensity of about 1,000 to about 20,000,000 Scoville Heat Units (SHU).

[0405] 21. The gasifying alkaloid composition of aspect 20, wherein the flavor additive is selected from the group consisting of capsaicin, dihydrocapsaicin, norcapsaicin, nordihydrocapsaicin, homocapsaicin, homodihydrocapsaicin, gingerol, piperine, shogaol, isopiperine, chavicine, isochavicine, 2-piperamine, 4,5-dihydropiperine, piperamide, 4-pipericide, piperyline, piperlonguminine, piperettine, 6,7-dihydropiperettine, 5-sarmentodine, 6-sarmentine, 7-trichostachine, and mixtures thereof.

[0406] 22. The gasifiable alkaloid composition according to aspect 20, wherein the flavor additive is capsaicin or a mixture of capsaicinoid compounds.

[0407] 23. A gasifying alkaloid composition comprising:

[0408] (a) from about 1% to about 80% by weight of a substituted pyridine compound of formula (I):

[0409] or a salt or a mixture of salts thereof, wherein:

[0410] A is selected from:

[0411] and

[0412] R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from the group consisting of: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, and

[0413] R 6 and R 7 are independently selected from: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl, or R 6 and R 7 Together = O;

[0414] R 8 , R9 , R 10 , R 11 and R 12 independently selected from the group consisting of: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl;

[0415] R 13 and R 14 are independently selected from: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl, or R 13 and R 14 Together = O;

[0416] n is an integer from 1 to 10; and

[0417] R 15 and R 16 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 15 and R 16 Together with the nitrogen atom to which they are bound, they form a 3-8 membered optionally substituted heterocyclic ring,

[0418] The condition is: If A is And R 5 is methyl, then R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 It can’t all be H;

[0419] (b) at least one organic acid in a total amount of about 0.05% to about 1.5% by weight; and

[0420] (c) the remaining solvent,

[0421] wherein the weight percentages are based on the total weight of the gasifiable alkaloid composition; and

[0422] The molar ratio of the substituted pyridine compound to the total molar ratio of the organic acid is about 25:1 to about 75:1.

[0423] 24. The vaporizing alkaloid composition of aspect 23, wherein the substituted pyridine compound is selected from (S)-N,N-dimethyl-3-(5-(1-methylpyrrolidin-2-yl)pyridin-2-yl)propan-1-amine, (S)-N,N-dimethyl-2-(2-(pyridin-3-yl)pyrrolidin-1-yl)ethan-1-amine, (S)-N,N-dimethyl-3-(2-(pyridin-3-yl)pyrrolidin-1-yl)propan-1-amine, N,N-dimethyl-1-(pyridin-3-yl)methylamine and N-methyl-N-(pyridin-3-ylmethyl)ethanamine.

[0424] 25. The vaporizing alkaloid composition according to aspect 23, wherein the molar ratio of the substituted pyridine compound to the total molar number of the organic acid is about 50:1.

[0425] 26. The vaporizing alkaloid composition of aspect 23, wherein the at least one organic acid consists of a mixture of citric acid and acetic acid.

[0426] 27. The vaporizing alkaloid composition according to aspect 23, wherein the solvent is selected from the group consisting of propylene glycol, glycerol, ethanol, and mixtures thereof.

[0427] 28. The vaporizing alkaloid composition of aspect 23, further comprising at least one chemosensory stimulant.

[0428] 29. The gasifying alkaloid composition according to aspect 28, wherein the chemosensory irritant is selected from the group consisting of oleocanthal, 4-hydroxy-2-nonenal, 4-oxo-2-nonenal, allicin, allyl isothiocyanate, TRPM8 ion channel agonist (Eserin), Polygodial, cinnamaldehyde, trans-p-methoxycinnamaldehyde, methyl syringate, 2-chlorobenzylmalononitrile, 1-chloroacetophenone, ethyl bromoacetate, 4-hydroxyhexenal, toluene diisocyanate, p-benzoquinone, methyl p-hydroxybenzoate, flufenamic acid, acid, niflumic acid, mefenamic acid, diclofenac, hydroxy-α-sanshool, 6-paradol, linalool, carvacrol, eugenol, thymol, vanillin, methyl eugenol, 2,6-dimethylphenol, 2,5-dimethylphenol, 3,4-dimethylphenol, 2,6-diisopropylphenol, caffeine, farnesylthiosalicylic acid, 4-allylanisole, curcumin, niacin, camphor, olvanil, arvanil, anandamide, baicalein, baicalin, wogonin, norwogonin, melaleuca A, β-sitosterol, and mixtures thereof.

[0429] 30. The vaporizing alkaloid composition of aspect 28, wherein the chemesthetic sensory stimulant is a flavor additive having a heat intensity of about 1,000 to about 20,000,000 Scoville Heat Units (SHU).

[0430] 31. The gasifiable alkaloid composition of aspect 30, wherein the flavor additive is selected from the group consisting of capsaicin, dihydrocapsaicin, norcapsaicin, nordihydrocapsaicin, homocapsaicin, homodihydrocapsaicin, gingerol, piperine, shogaol, isopiperine, chavicine, isochavicine, 2-piperamine, 4,5-dihydropiperine, piperamide, 4-pipericide, piperyline, piperlonguminine, piperettine, 6,7-dihydropiperettine, 5-sarmentodine, 6-sarmentine, 7-trichostachine, and mixtures thereof.

[0431] 32. The vaporizing alkaloid composition of aspect 30, wherein the flavor additive is capsaicin or a mixture of capsaicinoid compounds.

[0432] 33. A method of promoting smoking cessation in an individual who wishes to quit smoking, the method comprising:

[0433] During a time period determined for quitting smoking, a series of vaporized alkaloid compositions are administered to the individual for inhalation by the individual through an electronic cigarette, wherein each vaporized alkaloid composition in the series comprises at least one substituted pyridine compound conforming to formula (I):

[0434] or a salt or a mixture of salts thereof, wherein:

[0435] A is selected from:

[0436] and

[0437] R 1 , R 2 , R 3 , R 4 and R 5are independently selected from the group consisting of: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, and

[0438] R 6 and R 7 are independently selected from: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl, or R 6 and R 7 Together = O;

[0439] R 8 , R 9 , R 10 , R 11 and R 12 independently selected from the group consisting of: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl;

[0440] R 13 and R 14 are independently selected from: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl, or R 13 and R 14 Together = O;

[0441] n is an integer from 1 to 10; and

[0442] R 15 and R 16 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 15 and R 16 Together with the N atom to which they are bound, they form a 3-8 membered optionally substituted heterocyclic ring,

[0443] The condition is: If A is And R 5 is methyl, then R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 It can’t all be H;

[0444] and at least one solvent;

[0445] wherein each of the series of the gasifying alkaloid compositions comprises a decreasing (w / v) amount of the substituted pyridine compound of formula (I) or a salt or mixed salt thereof;

[0446] wherein the series of the gasifying alkaloid compositions includes the gasifying alkaloid composition having the highest (w / v) content of the substituted pyridine compound of formula (I) or its salt or mixed salt, and also includes the gasifying alkaloid composition having the lowest (w / v) content of the substituted pyridine compound of formula (I) or its salt or mixed salt; and

[0447] wherein the individual inhales each composition in the series through an electronic cigarette, starting with the vaporizable alkaloid composition having the highest level (w / v) of the substituted pyridine compound of formula (I) or its salt or mixed salts at the beginning of the time period determined for quitting smoking, and ending with the composition having the lowest level (w / v) of the substituted pyridine compound of formula (I) or its salt or mixed salts at the end of the time period determined for quitting smoking, so that the individual stops smoking at the end of the time period determined for quitting smoking.

[0448] 34. The method of aspect 33, wherein in the series of gasifiable alkaloid compositions, the gasifiable alkaloid composition having the highest content (w / v) of the substituted pyridine compound of formula (I) or its salt or mixed salts comprises about 100 mg / mL of the substituted pyridine compound of formula (I) or its salt or mixed salts.

[0449] 35. The method of aspect 33, wherein in the series of gasifying alkaloid compositions, the gasifying alkaloid composition having the lowest level (w / v) of the substituted pyridine compound of formula (I) or its salt or mixed salts comprises no more than about 1 mg / mL of the substituted pyridine compound of formula (I) or its salt or mixed salts.

[0450] 36. The method of aspect 33, wherein the time period determined for quitting smoking is part of a smoking cessation program, the smoking cessation program further comprising dispensing a series of vaporizable alkaloid compositions to an individual who wishes to quit smoking during the time period determined for quitting smoking.

Claims

1. A gasifying alkaloid composition comprising: At least one substituted pyridine compound of formula (I): or a salt or a mixture of salts thereof, wherein: A is selected from: R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from the group consisting of: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, and R 6 and R 7 are independently selected from: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl, or R 6 and R 7 Together = O; R 8 , R 9 , R 10 , R 11 and R 12 independently selected from the group consisting of: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl; R 13 and R 14 are independently selected from: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl, or R 13 and R 14 Together = O; n is an integer from 1 to 10; and R 15 and R 16 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 15 and R 16 Together with the N atom to which they are bound, they form a 3-8 membered optionally substituted heterocyclic ring, The condition is: If A is And R 5 If R is methyl, 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 Cannot be all H; and at least one solvent, Wherein, the vaporizable alkaloid composition contains no (R) or (S) nicotine at all.

2. The gasifying alkaloid composition of claim 1, wherein the structure of the at least one substituted pyridine compound conforms to formula (IA): or a salt or mixture of salts thereof; or Comply with formula (IA-1): or a salt or mixture of salts thereof; or Comply with formula (IA-2): or a salt or mixture of salts thereof; or Comply with formula (IA-3): or its salt or mixed salt; or conforming to formula (IA-4): or its salt or mixed salt; or conforming to formula (IA-5): or its salt or mixed salt; or conforming to formula (IB): or its salt or mixed salt; or conforming to formula (IC): or its salt or mixed salt; or conforming to formula (ID): or its salt or mixed salt; or conforming to formula (IE): or its salt or mixed salt; or conforming to formula (IAA): or a salt or a mixture of salts thereof, provided that: if R 5 is CH3, then R 1 , R 2 , R 3 and R 4 It can’t be all H.

3. The gasifying alkaloid composition of claim 1, wherein the at least one substituted pyridine compound is selected from the group consisting of: (R) or (S)-3-(pyrrolidin-2-yl)pyridine, (R) or (S)-2-methyl-3-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-4-methyl-3-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-3-methyl-5-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-2 ,6-dimethyl-3-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-2,4-dimethyl-5-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-2,3-dimethyl-5-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-2,4-dimethyl-3-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-2,5-dimethyl-3-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-3,4-dimethyl-5-(1-methylpyrrolidin-2-yl)pyridine, or a salt or a mixture of salts thereof.

4. The gasifying alkaloid composition of claim 1, further comprising an organic acid selected from the group consisting of formic acid, acetic acid, trifluoroacetic acid, aspartic acid, butyric acid, butyric acid, 2-methylbutyric acid, 3-methylbutyric acid, benzoic acid, caprylic acid, citric acid, crotonic acid, ethylenediaminetetraacetic acid, fumaric acid, gluconic acid, glutamic acid, glyceric acid, glycolic acid, lactic acid, lauric acid, levulinic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, oxalic acid, phenylacetic acid, phthalic acid, picric acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, hydroxymalonic acid, valeric acid, and mixtures thereof.

5. The vaporizing alkaloid composition of claim 14, wherein the molar ratio of total substituted pyridine compounds to total organic acid is from about 25:1 to about 75:

1.

6. The gasifiable alkaloid composition according to claim 1, wherein the solvent is selected from the group consisting of propylene glycol, water, ethanol, glycerol and mixtures thereof.

7. The gasifying alkaloid composition of claim 1, further comprising at least one chemosensory stimulant.

8. The vaporizing alkaloid composition of claim 7, wherein the chemesthetic sensory stimulant is a flavoring additive having a heat intensity of about 1,000 to about 20,000,000 Scoville Heat Units (SHU).

9. A gasifying alkaloid composition comprising: (a) from about 1% to about 80% by weight of a substituted pyridine compound of formula (I): or a salt or a mixture of salts thereof, wherein: A is selected from: R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from the group consisting of: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, and R 6 and R 7 are independently selected from: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl, or R 6 and R 7 Together = O; R 8 , R 9 , R 10 , R 11 and R 12 independently selected from the group consisting of: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl; R 13 and R 14 are independently selected from: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl, or R 13 and R 14 Together = O; n is an integer from 1 to 10; and R 15 and R 16 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 15 and R 16 Together with the N atom to which they are bound, they form a 3-8 membered optionally substituted heterocyclic ring, The condition is: If A is And R 5 If R is methyl, 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 It can’t all be H; (b) at least one organic acid in a total amount of about 0.05% to about 1.5% by weight; and (c) the remaining solvent, wherein the weight percentage is based on the total weight of the gasifiable alkaloid composition; and The molar ratio of the substituted pyridine compound to the total molar ratio of the organic acid is about 25:1 to about 75:

1.

10. A method for promoting smoking cessation in an individual who wishes to quit smoking, the method comprising: During a time period determined for quitting smoking, a series of vaporized alkaloid compositions are administered to the individual for inhalation by the individual through an electronic cigarette, wherein each vaporized alkaloid composition in the series comprises at least one substituted pyridine compound conforming to formula (I): or a salt or a mixture of salts thereof, wherein: A is selected from: R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from the group consisting of: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, and R 6 and R 7 are independently selected from: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl, or R 6 and R 7 Together = O; R 8 , R 9 , R 10 , R 11 and R 12 independently selected from the group consisting of: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl; R 13 and R 14 are independently selected from: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl, or R 13 and R 14 Together = O; n is an integer from 1 to 10; and R 15 and R 16 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 15 and R 16 Together with the N atom to which they are bound, they form a 3-8 membered optionally substituted heterocyclic ring, The condition is: If A is And R 5 If R is methyl, 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 It can’t all be H; and at least one solvent; wherein each of the series of the gasifying alkaloid compositions comprises a decreasing (w / v) amount of the substituted pyridine compound of formula (I) or a salt or mixed salt thereof; wherein the series of the gasifying alkaloid compositions includes the gasifying alkaloid composition having the highest (w / v) content of the substituted pyridine compound of formula (I) or its salt or mixed salt, and also includes the gasifying alkaloid composition having the lowest (w / v) content of the substituted pyridine compound of formula (I) or its salt or mixed salt; and wherein the individual inhales each composition in the series through an electronic cigarette, starting with the vaporizable alkaloid composition having the highest level (w / v) of the substituted pyridine compound of formula (I) or its salt or mixed salt at the beginning of the time period determined for quitting smoking, and ending with the composition having the lowest level (w / v) of the substituted pyridine compound of formula (I) or its salt or mixed salt at the end of the time period determined for quitting smoking, so that the individual stops smoking at the end of the time period determined for quitting smoking.

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