Vaporizable alkaloid compositions and methods of use thereof

Abstract

The present disclosure relates to gasified alkaloid compositions and methods of use thereof. In various embodiments of the present disclosure, vaporizing alkaloid compositions are described comprising: at least one substituted pyridine compound of formula (I), or a salt thereof, or a mixed salt thereof; and at least one solvent wherein the vaporizable alkaloid composition is completely free of (R) or (S) nicotine that is capable of forming an inhalable vapor when emanating from an electronic device, such as an electronic cigarette. A series of such gasified alkaloid compositions with decreasing amounts (w / v) of substituted pyridine compounds are provided as part of a smoking cessation plan. # imgabs0 #

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

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

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

[0004] It is well known that smokers can obtain health benefits from quitting smoking, and in general, most adult smokers in the United States have expressed a desire to quit smoking. Depending on the composition of the vaporized liquid, electronic nicotine delivery systems (ENDS) should, at least in principle, provide feasible cessation assistance for smoking. However, various studies have shown that users who use electronic devices to self-administer nicotine are not more likely to quit smoking. See, for example, 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] Electronically administered vapor that completely replaces actual tobacco smoking requires compliance, just like patient compliance with prescribed medications. In the case of smokers, compliance with electronic devices depends on the same or at least nearly the same sensory effects electronically delivered from the vaporizable composition as experienced by inhaling tobacco smoke from a lit cigarette. To date, and due to the lack of data showing cessation, this has not been achieved in the industry.

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

[0007] It has now been unexpectedly discovered 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 experiences 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 aid in compliance with smoking cessation programs by providing smokers with viable and complete smoking alternatives.

[0009] In various embodiments, the vaporizing alkaloid composition herein comprises: at least one substituted pyridine compound, or a salt thereof, or a mixed salt thereof, and at least one solvent; optionally, at least one chemosensory stimulant; 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 thereof, or a mixed salt thereof, wherein:

[0013] A is selected from:

[0014] as well as

[0015] 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

[0016] 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; R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 independently selected from the group consisting of: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl;

[0017] n is an integer from 1 to 10; and

[0018] 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,

[0019] 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;

[0020] at least one solvent;

[0021] Optionally, at least one chemosensory stimulant; and

[0022] Optionally, at least one flavoring agent,

[0023] The vaporizable alkaloid composition contains no (R) or (S) nicotine.

[0024] In various embodiments, the at least one substituted pyridine compound has a structure according to Formula (IA): or a salt thereof, or a mixed salt thereof.

[0025] In various embodiments, the at least one substituted pyridine compound has a structure according to Formula (IA-1):

[0026] or a salt thereof, or a mixed salt thereof.

[0027] In various embodiments, the at least one substituted pyridine compound has a structure according to Formula (IA-2):

[0028] or a salt thereof, or a mixed salt thereof.

[0029] In various embodiments, the at least one substituted pyridine compound has a structure according to Formula (IA-3):

[0030] or a salt thereof, or a mixed salt thereof.

[0031] In various embodiments, the at least one substituted pyridine compound has a structure according to Formula (IA-4):

[0032] or a salt thereof, or a mixed salt thereof.

[0033] In various embodiments, the at least one substituted pyridine compound has a structure according to Formula (IA-5):

[0034] or a salt thereof, or a mixed salt thereof.

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

[0036] or a salt thereof, or a mixed salt thereof.

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

[0038] or a salt thereof, or a mixed salt thereof.

[0039] In various embodiments, the at least one substituted pyridine compound has a structure according to Formula (ID):

[0040] or a salt thereof, or a mixed salt thereof.

[0041] In various embodiments, the at least one substituted pyridine compound has a structure according to Formula (IAA):

[0042] or its salt, or its mixed salt, provided that: if R 5 is CH3, then R 1 , R 2 , R 3 , and R 4 Cannot be all H.

[0043] 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,

[0044]

[0045] or a salt thereof, or a mixed salt thereof.

[0046] 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, tartronic acid, valeric acid, and mixtures thereof.

[0047] 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.

[0048] In various embodiments, the molar ratio of total substituted pyridine compounds to total organic acid is from about 25:1 to about 75:1.

[0049] In various embodiments, the solvent is selected from propylene glycol, water, ethanol, glycerol, and mixtures thereof.

[0050] In various embodiments, the vaporizing alkaloid composition further comprises at least one chemosensory stimulant.

[0051] 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-chlorobenzylidenemalononitrile, 1-chloroacetophenone, ethyl bromoacetate, 4-hydroxyhexenal, toluene diisocyanate, p-benzoquinone, methyl p-hydroxybenzoate, flufenamic acid, niflumic acid, acid, mefenamic acid, diclofenac, hydroxy-α-sanshool, paradol, linalool, carvacrol, eugenol, thymol, vanillin, methyl eugenol, 2,6-dimethylphenol, 2,5-dimethylphenol, 3,4-dimethylphenol, 2,6-diisopropylphenol 4-allylphenol, caffeine, farnesyl thiosalicylate, 4-allylanisole, curcumin, niacin, camphor, olvanil, arvanil, anandamide, baicalein, baicalin, wogonin, norwogonin, oroxylin A, β-sitosterol, and mixtures thereof.

[0052] 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).

[0053] 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, 1,2-piperine ... e), piperanine (4,5-dihydropiperine), piperamide, 4-pipericide, piperyline, piperlonguminine, piperettine, 6,7-dihydropiperetine, 5-sarmentodine, 6-sarmentine, 7-trichostachine, and mixtures thereof.

[0054] In various embodiments, the flavor additive is capsaicin, or a mixture of capsaicinoid compounds.

[0055] In various embodiments, the gasifying alkaloid composition comprises:

[0056] (a) from about 1% to about 80% by weight of a substituted pyridine compound of formula (I):

[0057] or a salt thereof, or a mixed salt thereof, wherein:

[0058] A is selected from:

[0059] as well as

[0060] 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

[0061] 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;

[0062] R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 independently selected from the group consisting of: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl;

[0063] n is an integer from 1 to 10; and

[0064] 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,

[0065] 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;

[0066] (b) from about 0.05% to about 1.5% by weight totaling at least one organic acid; and

[0067] (c) the remainder is solvent,

[0068] wherein the weight percentages are based on the total weight of the gasifiable alkaloid composition; and

[0069] 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.

[0070] 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)methanamine, and N-methyl-N-(pyridin-3-ylmethyl)ethanamine.

[0071] In various embodiments, the molar ratio of the substituted pyridine compound to the total moles of the organic acid is about 50:1.

[0072] In various embodiments, the at least one organic acid consists of a mixture of citric acid and acetic acid.

[0073] In various embodiments, the solvent is selected from the group consisting of propylene glycol, glycerol, ethanol, and mixtures thereof.

[0074] In various embodiments, a method of improving smoking cessation in an individual desiring to quit comprises administering to the individual, by vaporization, a series of vaporizable alkaloid compositions for inhalation by the individual during a period of time determined for quitting, each vaporizable alkaloid composition in the series comprising at least one substituted pyridine compound according to formula (I):

[0075] or a salt thereof, or a mixed salt thereof, wherein:

[0076] A is selected from:

[0077] as well as

[0078] 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

[0079] 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;

[0080] R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 independently selected from the group consisting of: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl;

[0081] n is an integer from 1 to 10;

[0082] R 15 and R 16are 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,

[0083] 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;

[0084] and at least one solvent;

[0085] wherein each of the series of gasifying alkaloid compositions comprises a decreasing (w / v) amount of the substituted pyridine compound of formula (I), or a salt thereof or a mixed salt thereof;

[0086] wherein the series of gasifying alkaloid compositions include: a gasifying alkaloid composition having the highest (w / v) level of the substituted pyridine compound of formula (I), or a salt thereof or a mixed salt thereof, and a gasifying alkaloid composition having the lowest (w / v) level of the substituted pyridine compound of formula (I), or a salt thereof or a mixed salt thereof; and

[0087] wherein by vaporization, the individual inhales each composition in the series, starting with the vaporizable alkaloid composition having the highest level (w / v) of the substituted pyridine compound of formula (I), or salt or mixed salt thereof at the beginning of the period of time determined for quitting, and ending with the composition having the lowest level (w / v) of the substituted pyridine compound of formula (I), or salt or mixed salt thereof at the end of the period of time determined for quitting, such that at the end of the period of time determined for quitting, the individual stops smoking.

[0088] In various embodiments, among the series of gasifiable alkaloid compositions, the gasifiable alkaloid composition having the highest level (w / v) of the substituted pyridine compound of formula (I), or a salt thereof, or a mixed salt thereof comprises about 100 mg / mL of the substituted pyridine compound of formula (I), or a salt thereof, or a mixed salt thereof.

[0089] In various embodiments, the vaporizing alkaloid composition having the lowest level (w / v) of the substituted pyridine compound of formula (I), or a salt thereof, or a mixed salt thereof in the series of vaporizing alkaloid compositions comprises no more than about 1 mg / mL of the substituted pyridine compound of formula (I), or a salt thereof, or a mixed salt thereof.

[0090] In various embodiments, the time period determined for quitting is part of a smoking cessation program, the smoking cessation program further comprising: dispensing the series of vaporized alkaloid compositions to the individual desiring to quit during the time period determined for quitting. DETAILED DESCRIPTION

[0091] Although the description of the exemplary embodiments is detailed enough to enable those skilled in the art to implement the invention, it should be understood that other embodiments may also be implemented, and logical, chemical and mechanical changes may be made without departing from the spirit and scope of the invention. Therefore, the specific embodiments are for illustrative purposes only, not for limiting purposes. 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 reference to the singular includes plural embodiments, and any reference to more than one component / component or step may include singular embodiments or steps. In addition, any reference to attached, fixed, connected, etc. may include permanent, movable, temporary, partial, complete and / or any other possible connection options. In addition, any reference to contactless (without contact) (or similar expressions) may also include reduced contact or minimal contact.

[0092] In various embodiments of the present disclosure, novel vaporizable alkaloid compositions are disclosed. The compositions herein are optimized to provide a balance between nose, throat, and head senses during vaporization and inhalation, thereby simulating as closely as possible the same sensory experience that an individual experiences when smoking traditional tobacco products. In general, the compositions herein are optimized to aid in following a smoking cessation plan. In various embodiments herein, a viable and complete smoking alternative is provided to smokers.

[0093] In various embodiments, the gasifying alkaloid composition herein comprises:

[0094] At least one substituted pyridine compound according to formula (I), or a salt thereof, or a mixed salt thereof; and

[0095] at least one solvent;

[0096] The vaporizable alkaloid composition is completely free of nicotine.

[0097] In various embodiments, the gasifying alkaloid composition can include an optional chemosensory stimulant.

[0098] In various embodiments, the vaporizing alkaloid composition may include an optional flavoring agent.

[0099] In various examples, the gasifying 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.

[0100] In certain examples, the compositions provided herein may be diluted with an appropriate solvent or solvent mixture (e.g., vegetable glycerin and / or propylene glycol) prior to vaporization and inhalation, for example by a third-party manufacturer or by an end user of a refillable electronic device, to provide a customized inhalable composition having a lesser amount of the substituted pyridine compound than the initial composition. In a preferred example, the third party will design and conduct a smoking cessation program for an individual, while providing an e-cigarette liquid with a gradually decreasing amount of the substituted pyridine compound during the program. In this way, a consumer can comply with the smoking cessation program by using an e-cigarette liquid with a decreasing amount of the substituted pyridine compound over time until the user essentially inhales a vaporized solvent with no other discernible material other than the flavoring.

[0101] Definitions and Explanations:

[0102] 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 those described herein may be used in the practice or testing of the subject matter of the present disclosure, preferred methods and materials are described. According to the usual practice of organic chemistry, chemical structures with chirality, either represented by substituents connected by wavy bonds, or not illustrated three-dimensionally with wedge-shaped bonds or dashed bonds, or not marked (R) or (S) adjacent to the chiral center or in the corresponding structure name, are considered to represent two enantiomers. Throughout the disclosure, attempts have been made to mark chiral centers with asterisks (*), at least to remind the reader that the carbon marked with (*) is a chiral center and that the (R) or (S) configuration may exist at the (*) center. Chemical structures with multiple chiral centers that are not presented or marked in three dimensions as having any particular chirality are considered to include all possible stereoisomers. Compounds of the present disclosure include any physicochemical or stereochemical forms they may take, for example, isomers, prodrugs, active metabolites, tautomers, stereoisomers, regioisomers, solvated forms, salts and polymorphic forms. Amorphous forms lack distinguishable lattices and therefore lack an ordered arrangement of structural units. Many alkaloids have amorphous forms, crystalline forms or their mixing. Beyond the crystallographic methods for determining the degree of crystallinity and type, methods for producing such chemical forms are known to those skilled in the art.

[0103] The compositions of the present disclosure include alkaloids that can be protonated by an acid that is also present in the composition, and therefore, in various compositions, the alkaloids can be at least partially, or even entirely, in the form of a salt. Alkaloid salts include any salt derived from an inorganic acid or an organic acid, preferably an organic acid or a mixture of organic acids. 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, alkaloid salts 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 (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, tartronic acid, valeric acid, and any combination thereof, or alkaloid salts of any other such acids currently known or not yet discovered or synthesized. Such alkaloid salts can be prepared by reacting a free base alkaloid compound with a suitable acid or mixture of acids 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 percentages of each individual alkaloid salt obtained, but rather the resulting alkaloid salt is referred to as a "mixed salt."

[0104] The term "alkyl" as used herein 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, and the like. The alkyl substituents herein may be substituted, i.e., one or more substituents are attached to the alkyl group or incorporated into the alkyl chain. Substitutions within the alkyl substituent chain may include, for example, ether, thioether, amino, or imine bonds, i.e., for example, -O-, -S-, -N(R')-, or -N=, or some other intervening 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 of the above 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), halo 1-6 Alkyl (e.g., -CF3, -CHF2, -CH2F) and halogenated C 1-6 Alkoxy (eg, -OCF3, -OC2F5). In various examples, in any of these functional groups, two R' substituents may form a ring structure.

[0105] 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, cyclooctyl, and the like. 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 of the above 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), halo 1-6 Alkyl (e.g., -CF3, -CHF2, -CH2F) and halogenated C 1-6 Alkoxy (e.g., -OCF3, -OC2F5).

[0106] 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 a molecule bearing an 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, an 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 / ethylene (-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., one or more substituents are attached to the alkenyl or incorporated into the alkenyl chain. Substitution within the alkenyl substituent may include, for example, ether, thioether, amino or imino linkages, 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'above 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), halo 1-6 Alkyl (e.g., -CF3, -CHF2, -CH2F) and halogenated C 1-6 Alkoxy (eg, -OCF3, -OC2F5). In various examples, in any of these functional groups, two R' substituents may form a ring structure.

[0107] As used herein, unless otherwise specified, the term "propylene glycol" or more simply "PG" refers to propane-1,2-diol (α-propylene glycol) rather than 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 the hydrolysis of propylene oxide. PG is generally considered to be responsible for the white vapor cloud seen in electronic cigarettes in gasifying compositions.

[0108] As used herein, the term "vegetable glycerin" or more simply "VG" has its usual 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 any source of glycerin, including animal or plant, or industrially synthesized or microbially produced glycerin.

[0109] As used herein, the term "inhalable" refers to a feature of the vaporizable alkaloid composition according to the present disclosure, namely that the composition is suitable for inhalation by a user. The inhalable alkaloid compositions disclosed herein are vaporizable and therefore suitable for use in electronic cigarette devices, which means that they can be vaporized by a heating element within such an electronic device, thereby allowing the user to inhale in a practice known as "vaping". In other words, the vaporizable alkaloid composition herein is an inhalable composition. Unless otherwise specified, the expression "inhalable composition" or "inhalable compositions" refers to the vaporizable alkaloid composition according to the present disclosure.

[0110] 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 used by an individual to inhale the vapor. Without limitation, "electronic cigarette" herein refers to any refillable or disposable design (e.g., a cigar, vape pen, or any other electronic device) that has a container for containing a vaporized liquid therein and is capable of vaporizing the vaporized liquid. For simplicity, the term "electronic device" may be used to refer to any and all refillable and disposable tools for electronic cigarettes.

[0111] As used herein, the term "throat hit" refers to a sensory effect experienced in the back of the throat that is perceived by an individual who inhales vapor, such as vapor obtained from a burning cigarette or vapor delivered by an electronic device that can vaporize a liquid composition (such as an e-cigarette). Throat hit is a type of irritating "bite" experienced in the back of the throat that, before the development of e-cigarettes, was not only experienced by smokers, but also expected and enjoyed by smokers. Although subjective rather than objective, throat hit can be quantified, for example, by using a sensory panel where participants rank the perceived throat hit on a scale of 1-10, or by comparing the perceived throat hit between e-cigarette products and / or between e-cigarette products relative to traditional cigarettes. In some instances, throat hit can be quantified as less than, equal to, or greater than the throat hit experienced by a particular cigarette being compared. A typical cigarette used to standardize throat hit (e.g., in a sensory panel where participants rank throat hit) is available from Phillips IGA Filter Cigarette, Gold Pack 100's. As explained herein, throat hit can often be perceived by an individual by including propylene glycol as a solvent and / or chemosensory stimulant in the vaporizable alkaloid composition of the present disclosure. In certain instances, flavor additives can be used as chemosensory stimulants to induce throat hit.

[0112] As used herein, the term "vaping" refers to the act of inhaling vapor electronically generated by vaporization of a liquid composition using an electronic cigarette or other ENDS device. Vaping is considered to be similar to the act of smoking tobacco products, and it is recognized that electronic cigarettes and vaping are not limited to nicotine. Vaping may include: personal inhalation of nicotine analogs, other physiologically active substances, flavorings, etc.

[0113] 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 liquid composition that can be inhaled by an individual who smokes an electronic cigarette. In various embodiments herein, an e-juice composition is described, and in some instances the e-juice composition includes a vaporized alkaloid composition and a dilution thereof.

[0114] As used herein, the term "cloud" refers to the white vapor that is visible when an e-cigarette juice is vaporized by an e-cigarette or other ENDS device, inhaled, and subsequently exhaled. As described herein, cloud is an important attribute of a successful e-cigarette juice because it is a feature that e-cigarette smokers seek. Although subjective rather than objective, the appearance of the cloud can be quantified, for example, by using a sensory panel in which participants rank the appearance of the cloud when smoking an e-cigarette on a scale of 1-10, or by comparing visible clouds between e-cigarette products and / or relative to the cloud seen in the air when smoking a traditional lit cigarette. In some examples, the cloud can be quantified as less than, equal to, or greater than the cloud seen when smoking a comparison cigarette. An example cigarette for standardizing the appearance of the cloud (e.g., in a sensory panel in which participants rank the appearance of the cloud) is available from Phillips IGA Filtered smoke, Gold Pack 100's.

[0115] 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, which triggers the release of adrenaline, which in turn causes the blood vessels of people who inhale active substances to tighten, and heart rate and blood pressure to temporarily increase. This sensory experience is personal, and due to differences in physiological tolerance, this sense varies between drug actives and between individuals. A head rush may occur within 10 seconds after inhaling nicotine, and the head rush can last up to 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. Although subjective rather than objective, a head-on feeling can be quantified, for example, by using a sensory panel in which participants rank the perceived head-on feeling on a scale of 1-10, or by comparing the perceived head-on feeling of e-cigarette products to each other and / or to traditional cigarettes. In some instances, a head-on feeling can be quantified as less than, equal to, or greater than the head-on feeling experienced by a particular cigarette being compared. An exemplary cigarette for standardizing throat hit (e.g., in a sensory panel in which participants rank throat hit) is available from Phillips IGA Filter cigarettes, Gold Pack 100's.

[0116] As used herein, the term "chemosensory irritant" is taken in its usual sense in physiology and neuroscience, i.e., a substance that can exhibit sensory irritation in individuals exposed to the substance. Depending on the individual and the irritant, the irritation caused by chemosensory irritants when inhaled can be felt in the nose, mouth, throat, esophagus, and / or lungs. In the definition herein, the sensory effect in the throat is referred to as "throat hit". Chemosensory irritation is most often studied in the context of environmental and occupational health and safety, involving air pollutants and indoor environmental irritants (such as formaldehyde). See, for example, "Inhalation Toxicology," 2nd edition, H. Salem et al., ed., Taylor & Francis Group (CRC), 2006. In addition to subjective measures of chemosensory irritation (e.g., panelists answering symptom questionnaires), chemically induced irritation can also be studied using a variety of experimental techniques, such as examining functional changes, such as respiratory rate and pattern in both humans and animals, changes in nasal, bronchial, and lung function parameters, nasal mucosal swelling, acoustic rhinometry, blink rate, tear film stability, and chemosensory evoked potentials (see SKKjaergaar et al., The Assessment of Irritation Using Clinical Methods and Questionnaires," American Industrial Hygiene Association, 62(6):711-6, November 2001).

[0117] Chemosensory irritants optionally used in the gaseous alkaloid compositions of the present disclosure include compounds that are capable of causing physiological irritation of any of the nose, mouth, throat, esophagus, and lungs of an individual, wherein the physiological irritation 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 dose-response relationships in controlled exposure studies.

[0118] In various embodiments, the chemosensory stimulants optionally used in the gasifying alkaloid compositions herein are substances capable of activating chemosensory ion channels, which are called transient receptor potential channels or TRP channels, as explained, for example, by 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 stimulants defined below as "fragrance additives," many seemingly unrelated compounds are receptor agonists. agonist) and is capable of activating one or more TRP channels (such as A1, V1, V2, V3, V4, V5 or V6, M1, M2, M3, M4, M5, M6, M7 or M8 ion channels, etc.), for example: olive aldehyde, 4-hydroxy-2-nonenal, 4-oxo-2-nonenal, allicin, allyl isothiocyanate, gingerol (included in the fragrance subset of irritants), eserin, polygonadial, cinnamaldehyde, trans-p-methoxycinnamaldehyde, methyl syringaldehyde, 2-chlorobenzylidenemalononitrile, 1-chloroacetophenone, ethyl bromoacetate, 4-hydroxyhexenal, toluene diisocyanate Esters, p-benzoquinone, methyl paraben, flufenamic acid, niflumic acid, mefenamic acid, diclofenac, hydroxy-α-sanshool, 6-shogaol (included in the flavor subset of irritants), 6-gingerol, 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, avanafil, and avanafil. Although nicotine is a known activator of TRPA1, nicotine is excluded from consideration as 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 disclosure is to provide vaporized alkaloid compositions that are explicitly free of nicotine, so that they can be used as viable alternatives to smoking.

[0119] In addition, chemosensory stimulants that activate TRP ion channels and can be included in the gasification alkaloid compositions herein include a variety of compounds naturally present in various plants, trees, shrubs, roots, flowers, fruits, seeds and kernels. Such compounds are disclosed, for example, by J. Vriens et al. in "Herbal Compounds and Toxins Modulating TRP Channels," Curr. Neuropharmacol., 2008 Mar; 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 shogaols obtained by heating or dehydrating gingerols or from seeds of Aframomum melgueta, Evodia compounds from Evodia rutaecarpa, and shogaols from Drymis winteri), such as polyglyodial, isovelleral, and drimanial, other 1,4-dialdehyde terpenes from Cinnamosma fragrans, such as cinnamodial, cinnamosmolide, and cinnamolide, or warbuganal from Warburgia plants. In vitro assays for measuring TRP ion channel activation can be found, for example, in R. Lehmann et al., "Alternative in vitro assays to assess the potency of sensory irritant–Is one TRP channel enough?", Neurotoxicology, May 2017; 60: 178-186, and JM Martinez et al., "Activation of TRPA1 by volatile organic chemicals leading to sensoryirritation," ALTEX 2019; 36(4): 572-582.Also useful herein are phytochemicals present in Scutellaria 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, Commiphora myrrha, Echinophora platyloba, Nypafruticans, Zingiber officiale (presented under the fragrance additive subset of irritants), Corydalis saxicola, Coptis chinensis, chinensis), Ononis spinosa, Parkia platycephala, Piper nigrum (presented under the flavor additive subset of irritants), and Cymbopogon citratus. The chemical sensory irritants used herein can be evaluated first by in vitro non-animal sensory irritation tests and then by consumer sensory panels to evaluate subtle physiological effects and determine dosage levels and user acceptance.

[0120] As used herein, the term "flavor additive" refers to an organic substance that is capable of producing a throat hit or other similar "hot," "pungent," or other "burning" sensation in at least the back of the throat, and optionally in the mouth and on the lips, when the flavor additive is in a vaporized alkaloid composition that is vaporized and inhaled by an individual, such as a person smoking an e-cigarette. Flavor additives herein form a subset of chemosensory stimulants and are known to activate one or more TRP ion channels. Since a group of these compounds may be structurally unrelated at first glance, a "flavor additive" herein may be specifically defined as an organic substance having a heat or "heat" ranging from about 1,000 to about 20,000,000 Scoville heat units (SHU). At the low end of the Scoville scale, 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 additive used in the gasifying alkaloid composition described herein has a Scoville score of about 100,000 to about 20,000,000 SHU, more preferably about 10,000,000 to about 20,000,000 SHU, and will include all known capsaicinoid compounds, such as capsaicin (16,000,000 SHU) and dihydrocapsaicin (15,000,000 SHU), 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. The capsaicinoid compound flavor additive used herein includes, but is not limited to, capsaicin, dihydrocapsaicin, norcapsaicin, nordihydrocapsaicin, homocapsaicin, homodihydrocapsaicin, and mixtures thereof. Chemically pure or otherwise isolated capsaicinoids are not necessary for the vaporizing alkaloid compositions herein, as it is convenient to prepare various compositions using extracts of flavor 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 capsaicinoid mixture (the red color is believed to come from beta-carotene).See, e.g., F. Martins et al., “Novel Approaches to Extraction Methods in Recovery of Capsaicin from Habanero Pepper (CNPH 15.192),” Pharmacogn. Mag. 2017 Jul; 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.

[0121] 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 Capsicum annuum (e.g., various peppers). Liquid capsaicin optionally used herein comprises an ethanol solution of about 0.9% by weight of capsaicinoid compounds and can be obtained from Olive Nation, LLC, Avon, MA under the name Capsicum Flavor Extract.

[0122] It should be noted that "flavoring agents," which are optional for the purposes of the bioalkaloid compositions herein, are defined separately and are completely distinct from "chemesthetic sensory stimulants" and the subset of stimulants referred to herein as "flavor additives."

[0123] As used herein, "flavoring agent" is taken in its usual meaning in food science, but it is noted that the flavoring agent herein specifically 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 distinguished from the flavor additives defined above. The flavoring agent used herein includes, but is not limited to, ethyl maltitol, ethyl butyrate, ethyl acetate, maltitol, 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.

[0124] 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.

[0125] As used herein, the term "smoking cessation program" refers to a program provided by a medical clinic, a pharmacy, or any other commercial enterprise to a current smoker in order to help the individual quit smoking. In various embodiments, the smoking cessation program herein includes providing electronic cigarette liquids (or providing disposable electronic devices pre-loaded with electronic cigarette liquids) to individuals who need smoking cessation programs, designed to help individuals 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 who are included in the quitting program on a regular basis, communicate with the individual about compliance with the plan, and provide the individual with a customized vaporizing composition designed to gradually transfer the smoker completely to electronic cigarettes. In a preferred embodiment, over the course of the smoking cessation program, an electronic cigarette composition containing an increasingly small amount of a substituted pyridine compound is provided to the individual.

[0126] General Implementation

[0127] The vaporizable alkaloid compositions according to the present disclosure are optimized to provide an improved user experience. The experience a person experiences from inhaling a vaporized liquid delivered from an electronic device can (and arguably should) be similar to, if not identical to, the user's experience of inhaling a burning cigarette, but only if certain interrelated sensory effects are balanced, including throat hit, head feel, nasal and oral sensations and taste, and cloud appearance. These factors make up the user experience.

[0128] It has now been unexpectedly discovered that the improved user experience relies on the substituted pyridine compound, or a salt or mixed salt thereof, and a specific solvent providing a throat hit similar to that experienced by inhaling cigarette smoke. In addition, having at least some of the corresponding organic acid salt of the substituted pyridine compound in the inhalable composition reduces the harshness and ensures 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 an organic acid.

[0129] In various embodiments, the gasifying alkaloid composition herein comprises:

[0130] At least one substituted pyridine compound of formula (I):

[0131] or its salt, or a mixed salt thereof;

[0132] at least one solvent;

[0133] Optionally, at least one chemosensory stimulant; and

[0134] Optionally, at least one flavoring agent,

[0135] The vaporizable alkaloid composition contains no (R) or (S) nicotine.

[0136] When present, the optional chemosensory stimulant may comprise phytochemicals, such as compounds present in Scutellaria baicalensis, such as baicalein, baicalin, wogonin, norwogonin, melaleucain A, β-sitosterol, and anandamide. In other embodiments, the chemosensory stimulant, if present, comprises a flavor additive having a heat intensity of about 1,000 to about 20,000,000 Scoville Heat Units (SHU), such as capsaicin, shogaol, and gingerol.

[0137] Alternatives for each of these components in the compositions are described below and in the definitions section above.

[0138] 1. Alkaloid compounds, their salts or mixed salts

[0139] In various embodiments, the gasifying alkaloid composition herein comprises at least one substituted pyridine compound, or a salt thereof or a mixed salt thereof according to formula (I):

[0140]

[0141] in:

[0142] A is selected from:

[0143]

[0144] 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

[0145] R 6 and R 7 are independently selected from: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl, or R6 and R 7 Together = O;

[0146] R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 independently selected from the group consisting of: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl;

[0147] n is an integer from 1 to 10; and

[0148] 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,

[0149] 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.

[0150] This proviso language expressly excludes the (R) and (S) enantiomers of nicotine from consideration in the compositions of the present disclosure.The vaporizable alkaloid compositions of the present disclosure are designed for use in smoking cessation programs and are expressly nicotine-free.

[0151] In various embodiments, and independent of all other variables, A is:

[0152] 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.

[0153] In various embodiments, and independent of all other variables, A is:

[0154] And R 5 Selected from:

[0155]

[0156] as well as

[0157] 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.

[0158] In various embodiments, and independent of all other variables, A is:

[0159] And R 5 for Where n is 1-10; and R 17 is H or CH3. In various embodiments, the substituted pyridine compound used herein has a structure according to formula (IA):

[0160] The variables mentioned are as defined above.

[0161] In various embodiments, the substituted pyridine compounds used herein have a structure according to Formula (IA-1):

[0162] The variables mentioned are as defined above.

[0163] In various embodiments, the substituted pyridine compounds used herein have a structure according to Formula (IA-2):

[0164] The variables mentioned are as defined above.

[0165] In various embodiments, the substituted pyridine compounds used herein have a structure according to Formula (IA-3):

[0166] The variables mentioned are as defined above.

[0167] In various embodiments, the substituted pyridine compounds used herein have a structure according to Formula (IA-4):

[0168] The variables mentioned are as defined above.

[0169] In various embodiments, the substituted pyridine compounds used herein have a structure according to Formula (IA-5):

[0170] The variables mentioned are as defined above.

[0171] In various embodiments, the substituted pyridine compounds used herein have a structure according to Formula (IB):

[0172] The variables mentioned are as defined above.

[0173] In various embodiments, the substituted pyridine compounds used herein have a structure according to Formula (IC):

[0174] The variables mentioned are as defined above.

[0175] In various embodiments, the substituted pyridine compounds used herein have a structure according to Formula (ID):

[0176] The variables mentioned are as defined above.

[0177] In various embodiments, the gasifying alkaloid composition herein comprises a substituted pyridine compound selected from the group consisting of:

[0178]

[0179]

[0180]

[0181] as well as or a salt thereof, or a mixed salt thereof.

[0182] In various embodiments, the gasifying alkaloid composition herein comprises at least one substituted pyridine compound, or a salt or a mixed salt thereof according to formula (IAA):

[0183] Where R 1 , R2 , R 3 , R 4 , and R 5 As defined above, provided that: if R 5 is CH3, then R 1 , R 2 , R 3 , and R 4 It cannot all be H. This proviso language explicitly excludes the (R) and (S) enantiomers of nicotine from consideration of compositions according to the present disclosure, as is the case with formula (I) and its subgenus structures.

[0184] As can be seen from the selection of substituted pyridine compounds depicted, the chiral center of many compounds can be (R) or (S). In most instances, the (S) enantiomer is preferred, while the (R) enantiomer may be intentionally excluded due to possible toxicity or undesirable physiological effects, or at least because it cannot provide any identifiable benefits to the gasifying alkaloid composition. In various instances, the substituted pyridine compound according to formula (I) with a chiral center is a racemic mixture of (R) and (S) at the chiral center (*), which is obtained, for example, by achiral synthesis. The (R) or (S) enantiomer can be obtained by chiral synthesis or by separation of enantiomers from a racemic mixture.

[0185] In various embodiments, the gasifying alkaloid composition according to the present disclosure comprises from about 1 wt % to about 80 wt % of a substituted pyridine compound of formula (I), which is added to the composition. In a more preferred embodiment, the gasifying alkaloid composition according to the present disclosure comprises from about 4 wt % to about 20 wt % of a substituted pyridine compound, which is added to the composition, for example, such that the w / v amount of the substituted pyridine compound reaches 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 wt % to about 12 wt % of a substituted pyridine compound, which is added to the composition, for example, such that the w / v amount of the substituted pyridine compound in the gasifying alkaloid composition reaches about 100 mg / mL.

[0186] "As added" refers to a substance that is added to the 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.

[0187] In various embodiments, the substituted pyridine compound has the structure of Formula (IAA),

[0188] and is independent of R 5 , R 1 , R 2 , R3 , and R 4 At least one of the R is a methyl group, and the remaining R is not a methyl group 1 , R 2 , R 3 , and R 4 The substituent is H.

[0189] In various embodiments of Formula (IAA), R 5 is CH3, and R 1 , R 2 , R 3 , and R 4 At least one of them is not H.

[0190] In various embodiments of Formula (IAA), R 1 , R 2 , R 3 , R 4 and R 5 Both are H.

[0191] In various embodiments of Formula (IAA), R 5 -(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, including, for example, aziridine, azetidine, pyrrolidine, piperidine, 1,4-piperazine, and morpholine. In various embodiments, and independently of R 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.

[0192] In various embodiments, R 5 is H, and R 1 , R 2 , R 3 , 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.

[0193] In various embodiments, the substituted pyridine compound has the structure (IAA),

[0194] Where R 5 is CH3, and 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.

[0195] In various embodiments of Formula (IAA), R 5 is CH3, and R 1 , R 2 , R 3 , and R 4 At least one of them is -(CH2) n-N(CH3)2, wherein n is an integer from 1 to 10.

[0196] In various embodiments, the substituted pyridine compounds of formula (IAA) used in the gasifying alkaloid composition herein 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) -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.

[0197] In each of the alkaloid examples herein having a chiral center, 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, no racemic mixture of these alkaloids is used in the gasifying alkaloid compositions herein.

[0198] In various embodiments of Formula (IAA), R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from: H, methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, provided that: if R 5 If R is methyl, 1 , R 2 , R 3 , and R 4 Cannot be all H.

[0199] In certain embodiments of Formula (IAA), R 1 and R 5 Both are methyl, R 2 , R 3 and R 4 Each is H, while the alkaloids are in (S)-configuration.

[0200] 1a. Salts and mixed salts of alkaloids of formula (I), and methods for preparing the salts

[0201] The salts or mixed salts of the alkaloids of formula (I) are used herein and can be obtained by reacting a substituted pyridine compound of formula (I) with an inorganic acid, or preferably an organic acid R in a suitable solvent under ambient reaction conditions or with heating. 18 -CO2H or organic acid mixture directly reacts.18 The desired organic acid is selected accordingly (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 heterocyclyl, any of which may be optionally substituted.

[0202] Although people can accurately know that in the gasification alkaloid composition, the free base alkaloid of formula (I) and the acid R 18 The molar ratio of -CO2H or acid mixtures is not attempted to quantify or characterize the resulting salt or salt mixtures, or to quantify the completeness of the reaction, given the recognition that some options of formula (I) have more than two nitrogen atoms, and that some organic acids present more than one -CO2H group and thus may act as chelating agents. Various molar ratios of acid to base may be formed (i.e., the ratio of acid to free base alkaloid salt may not be 1:1). For example, nicotine salts prepared from various organic acids are described by T.A. Perfetti, "Structural Study of Nicotine Salts," zur Tabakforschung International, 12(2), 43-54, 1983, where 1:1, 2:1, and 3:1 acid to base ratios are found for nicotine. In this reference, Perfetti discloses that nicotine forms a 3:1 acid to base salt with an aliphatic monocarboxylic acid (e.g., acetic acid) in which one acid molecule is bound as in a 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 to base salt. Perfetti discloses that the citrate salt of nicotine is a 2:1 acid to base salt. Thus, 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.

[0203] 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, tartronic acid, valeric acid, and mixtures thereof. Preferred for use herein are: citric acid, acetic acid, benzoic acid, tartaric acid, lactic acid, salicylic acid, malic acid, levulinic acid, and mixtures thereof.

[0204] The solvent for the reaction between the free base alkaloid and the organic acid can be selected according to whether it is appropriate, i.e., pharmaceutically acceptable or otherwise considered "safe" for the composition intended to be vaporized and inhaled. In other words, it is recognized that this acid / base reaction can be carried out in situ, the alkaloid salt will not be separated, and on the contrary, the resulting reaction mixture becomes a vaporizable alkaloid composition according to the present disclosure. In these cases, the solvent is selected from 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 and a small amount of water (e.g., due to the use of 190 proof ethanol and entrained in the reaction). If necessary, the final reaction mixture can be cooled and filtered before being used in electronic equipment.

[0205] In a preferred embodiment, a molar deficiency of an organic acid R is used. 18 -CO2H, so that a mixture of alkaloid salt and unreacted alkaloid is obtained, which are kept 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 to drive the salt formation to completion, making it possible for there to be no remaining free base alkaloid.

[0206] In various embodiments, it is preferred that the substituted pyridine free base compound of formula (I) is substituted with respect to the one or more organic acids R 18 The molar excess of -CO2H results in an incomplete reaction of the formation of the alkaloid salt and in the gasifiable alkaloid composition comprising both the alkaloid organic acid salt and the unreacted alkaloid free base.

[0207] In various embodiments, considering that the typical amount of substituted pyridine compounds is from about 1 wt % to about 80 wt %, the gasifying alkaloid composition herein comprises 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.

[0208] 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, and more preferably about 50:1. This ratio can be kept constant so that in the composition with increasing amounts 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.

[0209] It should be emphasized that it is not necessary to isolate the salt of any desired substituted pyridine compound used in the gasifying alkaloid composition. The gasifying alkaloid composition can be prepared by combining a substituted pyridine free base compound of formula (I) with a 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.

[0210] 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.

[0211] In a more preferred embodiment, the substituted pyridine compound according to formula (I) is reacted with a molar deficiency of a combination of citric acid and acetic acid.

[0212] For the gasifying alkaloid composition of the present disclosure, the 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, as well as mixed salts.

[0213] In various embodiments, the gasifying alkaloid composition herein comprises about 1 wt % to about 20 wt % of at least one substituted pyridine compound of formula (I), or a salt thereof, or a mixed salt thereof, and more preferably about 4 wt % to about 12 wt % of at least one substituted pyridine compound of formula (I), or a salt thereof, or a 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 can reach 100 mg / mL (w / v), recognizing that such a composition can always be diluted (even by the end user) with an acceptable solvent (e.g., PG and / or VG), so that the actual composition used by an individual in an electronic device may have an alkaloid amount (w / v) of less than 100 mg / mL.

[0214] 2. Solvent

[0215] In various embodiments, the vaporizing alkaloid compositions herein include at least one solvent. Solvents in vaporizing compositions 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 can be entrained in compositions comprising aqueous solutions of ethanol (e.g., 190 proof ethanol). Similarly, additional ethanol is entrained in compositions utilizing capsaicin liquids (e.g., capsaicinoids in ethanol).

[0216] In various embodiments, the gasifying alkaloid composition 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 mainly vegetable glycerin, and lesser amounts of propylene glycol and ethanol (and trace amounts of water).

[0217] In various embodiments, the vaporizing alkaloid composition herein comprises a solvent mixture including about 85.0 wt % to about 95.0 wt % vegetable glycerin, based on the total weight of the composition, 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 the component) may be expressed as a "sufficient amount" or "qs", i.e., the amount of solvent necessary for the composition to sum to 100 wt %.

[0218] 3. Optional chemical sensory stimulants

[0219] In the gaseous alkaloid compositions of the present disclosure, the inclusion of chemosensory stimulants is optional. In various embodiments, the gaseous alkaloid compositions herein are completely free of any chemosensory stimulants, particularly in those embodiments where an inhalation "throat hit" is delivered by another component of the composition (e.g., solvent).

[0220] When used in the compositions herein, chemosensory stimulants include any natural, endogenous, phytochemical or synthetic compounds, including those derived from naturally occurring compounds by organic chemistry, which are capable of activating TRP ion channels. Analysis 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.

[0221] The chemosensory irritants used herein include, but are not limited to, olive aldehyde, 4-hydroxy-2-nonenal, 4-oxo-2-nonenal, allicin, allyl isothiocyanate, eserin, polygonadial, cinnamaldehyde, trans-p-methoxycinnamaldehyde, methyl syringate, 2-chlorobenzylidenemalononitrile, 1-chloroacetophenone, ethyl bromoacetate, 4-hydroxyhexenal, toluene diisocyanate, p-benzoquinone, methyl p-hydroxybenzoate, flufenamic acid, niflumic acid, mefenamic acid, diclofenac, hydroxy-α-sanshool, 6-gingerol, linalool, carvacrol, eugenol, thymol, vanillin, methyl eugenol, 2,6-dimethylphenol, 2,5-di Methylphenol, 3,4-dimethylphenol, 2,6-diisopropylphenol, caffeine, farnesylthiosalicylic acid, 4-allylanisole, curcumin, niacin, camphor, avanafil, arachidonic acid ethanolamide (AEA), 2-AG, NADA, OLDA, PEA, NGABA, NGly, NAsp, NSer, WIN55, 212-2, AM630, (R)-AM1241, (S)-AM1241, SR141716A, Gp-1a, AM251, SR144528, JWH133, HU308, HU910, CP55,940. Nabilone, various phytochemicals from: Euphorbia reinifera, Euenia carophyllata, Ocimum gratissiumum, Panax, Aframomum melgueta, Evodiarutaecarpa, Drymis winteri, Cinnamosma fragrans, Warburgia, Scutellaria baicalensis, Vitex agnus, Pterodon pubescens, Croton macrostachyus, Angelica epubescentis, Ephedra sinica, Amphilophium crucigerum, Bosewellia carterii, Commiphora myrrha, Echinophora platyloba), Nypa fruticans, Corydalis Saxicola, Coptis chinensis, Ononis spinosa, Parkia platycephala, and Cymbopogon citratus, as well as the entire subset of chemosensory stimulants individually defined as flavor additives with a heat level of about 1,000 SHU to about 20,000,000 SHU. The various flavor additives used herein are phytochemicals found in various herbs and fruits, such as compounds from Capsicum annuum, Zingiber officiale, and Piper nigrum.

[0222] 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 heat or spiciness of about 1,000 to about 20,000,000 Scoville heat units (SHU), and more preferably about 100,000 to about 20,000,000 Scoville heat units (SHU). Therefore, the flavor additive for the purposes of this invention is a defined group of compounds. The calculation of Scoville heat units can be found in the American Spice Trade Association (ASTA) 1985 Official Analytical Methods of the American Spice Trade Association, Third Edition, Amer. Spice Trade Assn., Englewood Cliffs, NJ

[0223] In various embodiments, the flavor additive herein comprises a capsaicinoid compound or a mixture of capsaicinoid compounds. In certain instances, the liquid extract comprises a mixture of capsaicinoid compounds prepared by solvent extraction of a chili pepper known to contain a mixture of capsaicinoid compounds rather than just capsaicin. In other embodiments, capsaicin is sourced and used.

[0224] In other examples, flavor additives that are chemically unrelated to capsaicinoid compounds but have measurable levels of pungency reported in Scoville units are used. These compounds are typically extracted from peppers other than Capsicum annuum, such as black pepper (Piper nigrum L.), with the most useful flavor additive of non-capsaicinoid compounds being piperine (E, E or trans-trans isomers). Other non-capsaicinoid flavor additives used herein include, but are not limited to, shogaol, gingerol, isopiperine, melanin, isomelanin, 2-piperamine, piperine (4,5-dihydropiperine), piperamide, pipericide, piperinine, piperhalgine, piperidine, piperdardine (6,7-dihydropiperidine), 5-sarmentotine, 6-pseudopogonine, and 7-trichostachine.

[0225] 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 the compositions herein, other capsaicinoid compounds other than the explicitly mentioned capsaicinoid compounds may be used, noting that it has been described that there are at least seven different capsaicinoid compounds in the genus Capsicum, and perhaps two of them (possibly capsaicin and dihydrocapsaicin) are capsaicinoid compounds that together contribute to the spiciness 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 compounds belong to the general category of chemical sensory irritants, it is convenient to classify these compounds as a subset of the following chemical sensory irritants, which are defined as flavor additives having a spiciness of about 1,000 to about 20,000,000 Scoville heat units (SHU).

[0226] 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 exhibits a heat or hotness of about 1,000 to about 20,000,000 Scoville heat units (SHU). For flavor additives having a heat greater than about 10,000,000 SHU, the amount can be significantly reduced, for example, from about 0.0001 wt % of a flavor additive to about 0.01 wt % of a flavor additive, based on the total weight of the composition.

[0227] 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). In pure form (100% active), capsaicin is a white crystalline solid with an MP of 65° C. The purified material can be used directly in the composition herein and can be obtained, for example, from chemical suppliers such as Sigma-Aldrich Co., VWR Avantor, and Alfa Chemistry.

[0228] In various embodiments, the gasifying alkaloid composition herein comprises 0 wt % to about 0.01 wt % capsaicin ((E)-N-[(4-hydroxy-3-methoxyphenyl)methyl]-8-methylnon-6-enamide), based on the total weight of the gasifying alkaloid composition. In other embodiments, the amount of capsaicin is 0 wt % to about 0.0015 wt %, based on the total weight of the composition.

[0229] In various examples, "liquid capsaicin" is used in the gasifiable alkaloid compositions herein, for example, for reasons of cost and practicality. For example, a chili pepper flavor extract can be used, which is available from Olive Nation, LLC, Avon, MA in gallon to drum quantities. This product is an ethanol extract of chili peppers, has a clear reddish-brown appearance, and has a specific gravity of about 0.8 g / mL at 20° C. This commercial material is about 99.1% by weight ethanol and about 0.9% by weight capsaicinoid actives.

[0230] In various embodiments, the gasifiable alkaloid compositions herein comprise from 0 wt % to about 0.15 wt % capsicum liquid (e.g., a chili flavor extract from Olive Nation LLC having about 0.9 wt % active capsaicinoid compounds), based on the total weight of the gasifiable alkaloid composition.

[0231] 4. Optional flavoring

[0232] In various embodiments, the gasifying alkaloid composition herein may optionally contain up to about 1.0 wt% of at least one flavoring agent, based on the total weight of the composition. The wt% of the flavoring agent used in the composition herein will vary based on the flavor type and the desired sensory results, and in some cases, the amount will be much lower than 1.0 wt% (e.g., 0.1 wt% or less). The optional flavoring agents used herein include, but are not limited to, geraniol, geranyl, valeric acid, methyl salicylate, ethyl maltitol, ethyl butyrate, ethyl acetate, maltitol, ethyl vanillin, 3-methyl-3-phenyl epoxypropionic acid ethyl ester, furanone, methylcyclopentenolone, methylcyclopentenolone, ethylcyclopentenolone, δ-decalactone, γ-decalactone, α-nonanolactam, β-nonanolactam, cis-3-hexanol, isoamyl acetate, ethyl 2-methylbutyrate, butyric acid, ethyl butyrate, 2-methyl Butyric acid, benzyl alcohol, ethyl hexanoate, benzaldehyde, isopentyl isovalerate, hexanoic acid, ethyl propionate, γ-undecalactone, acetylpropionyl, raspberry ketone, furfural, 5-methylfurfural, maltitol, 2-acetylpyrazine, 2,3,5-trimethylpyrazine, 2-acetylpyrrole, 2-isopropyl-4-methylthiazole, 2-isobutylthiazole, furfurylthiol, thiomenthone, p-menthene-8-thiol, 2-methyl-4-propyl-1,3-oxathiol, hexyl acetate, and mixtures thereof.

[0233] Example composition

[0234] 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 examples, 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 resulting composition is a thin, transparent and uniform liquid.

[0235] Table 1 provides general embodiments of gasifying alkaloid compositions according to the present disclosure.

[0236] Table 1: General gasification alkaloid composition

[0237]

[0238]

[0239] Note 1The compositions according to Table 1 are designed to achieve a specific w / v level of substituted pyridine compound in the finished composition, for example, 1000 mg / mL, 750 mg / mL, 500 mg / mL, 250 mg / mL, or 100 mg / mL. As described herein, the compositions of Table 1 having relatively high levels of substituted pyridine compound (e.g., ≥ 100 mg / mL) can be considered as concentrates, and thus can be further diluted by a third party manufacturer, or compounder, or even by an end user who may be refilling a refillable electronic device.

[0240] Note 2 In the preferred composition from 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, and more preferably about 50: 1. Therefore, regardless of the molecular weight of the free base alkaloid and the organic acid, it is expected that in any composition provided in the above weight percentage range, the majority of the substituted pyridine compound of formula (I) will remain as the free base.

[0241] Note 3 In these compositions, the range of 0 wt % to about 0.01 wt % normalized to capsaicin active is a preferred range for the optional flavor additive in the composition, while the wider range provided in Table 1, i.e., 0 wt % to about 0.5 wt %, reflects a general range including any of the above-mentioned chemosensory stimulants, including substances within the subset of flavor additives, but not necessarily capsaicinoids. If desired, the TRP channel activator EC measured therefrom may be 50 or [A] 50 The amount of chemosensory stimulant used in the gasifying alkaloid composition is adjusted by the EC 50 or [A] 50 The value is the molar concentration of the activator that produces 50% of the maximal possible effect of that activator. Activators of human TRP receptors and their EC 50Lists of values ​​are available, for example, see "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 so that they are specifically used in the gasifying alkaloid compositions of the present disclosure.

[0242] When selected as an optional chemesthetic sensory stimulant, for flavor additives with a heat level lower or higher than capsaicin (< or > 16,000,000 SHU), the amount of flavor additive (expressed as weight %) can be adjusted accordingly. In other words, alternative flavor additives for capsaicin can be standardized to capsaicin. As a rough estimate, the ratio of the SHU of the alternative flavor additive to the SHU of capsaicin (16,000,000 SHU) can be used to calculate a reasonable amount of a different flavor additive to replace capsaicin. For example, shogaol (160,000 SHU) can be used 100 times the preferred range of 0.0001 weight % to about 0.01 weight % for active capsaicin (16,000,000 SHU) because the ratio of the Scoville number is 16,000,000 SHU / 160,000 SHU=100. Therefore, the appropriate range of gingerol actives in the composition can be: 0.01% by weight to about 1% by weight gingerol, based on the total weight of the composition. If a flavor additive with a spiciness greater than 16,000,000 SHU is used, less flavor additive can be added. Focus groups and sensory panels can certainly help refine these estimated ranges, but being able to calculate in this way is a starting point. If there are supply / cost issues with a particular flavor additive, or if some users expect 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 % of the flavor additive active in the composition of Table 1 is increased accordingly.

[0243] Note 4: In these compositions, flavoring agents are optional, as they can be added later if desired (e.g., 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 may initially be unflavored, and then a third party or end user may dilute the composition (e.g., using VG and / or PG) and add flavoring agents of their own choice.

[0244] Note 5 In these compositions, the solvent is selected based in part on being acceptable for inhalation, because the composition will ultimately be used in electronic devices for vaping, and for providing at least some perceived throat hit in the absence of chemosensory stimulants. Thus, the solvents in Table 1 are typically selected from: propylene glycol, glycerol, ethanol, water, and mixtures thereof. Each composition may include a majority of propylene glycol, a majority of vegetable glycerin, or a mixture of the two as a majority of the solvent component. When a chemosensory stimulant is included in the composition, the amount of propylene glycol may be adjusted accordingly to optimize the perceived throat hit.

[0245] As previously mentioned, 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 is further noted that at higher levels (e.g., greater than about 20 wt%) of the substituted pyridine compound of formula (I), the solubility of the alkaloid may be problematic, in which case the solvent ratio is adjusted to increase solubility, such as by increasing the ethanol wt% and reducing the glycerin and / or propylene glycol wt%. In general, the substituted pyridine compound of formula (I) is more likely to be soluble in ethanol (compared to VG or PG). Compositions having about 4 wt% to about 12 wt% of the substituted pyridine compound of formula (I) are generally homogeneous with a mixture of VG / PG and very little ethanol.

[0246] Table 2 sets forth embodiments of vaporizable alkaloid compositions according to the present disclosure. The compositions are derived from the broad embodiments set forth 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 merely illustrative and should not be construed as limiting the scope of the present disclosure in any way. For example, other substituted pyridine compounds of formula (I) may be used in place of the five exemplary substituted pyridine compounds, mixtures of substituted pyridine compounds may be used in any single composition, and other organic acids may be used in addition to citric acid and acetic acid. In addition, the relative amounts of solvents may be varied for each composition to at least improve the solubility of the particular substituted pyridine compound used.

[0247] Table 2: Exemplary gasifying alkaloid compositions

[0248]

[0249] Numerical entries in Table 2 are ingredients "as added" and are rounded.

[0250] In various embodiments, the 1.28 wt% propylene glycol described in Table 2 may be reduced if a chemosensory stimulant is included in the composition. The amount of propylene glycol may be increased for additional perceived throat hit, even with or without the use of a chemosensory stimulant in the composition.

[0251] As described herein, due to the presence of citric acid and acetic acid, it is expected that a small amount of the corresponding alkaloid salt will be formed in each composition, and given the large molar excess of the substituted pyridine compound, it is unlikely that any free citric acid or acetic acid will remain as the free acid. The molar ratio of free base to organic acid for compositions 1-5 in Table 2 is from about 25:1 to about 75:1.

[0252] For compositions that use 190 proof alcohol instead of absolute alcohol, a small amount of water that is not added separately will be present in the composition and is therefore not noted as it is not "added". Any composition showing 190 proof alcohol as an ingredient can be converted to a composition with absolute alcohol and water added if desired.

[0253] Each exemplary composition in Table 2 contains about 100 mg / mL of the substituted pyridine compound shown. It is important to note that these exemplary compositions can be adjusted so that the target w / v of the alkaloid is between about 1 mg / mL and about 1000 mg / mL. The 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. The advantage of producing concentrates, especially super concentrates with a total w / v of 1000 mg / mL of substituted pyridine compounds, is that it reduces transportation costs for manufacturers, compounders, and retailers. It is contemplated that a third party compound manufacturer or end user would take any of these "concentrates" (e.g., 1000 mg / mL, 750 mg / mL, 500 mg / mL, 250 mg / mL, or 100 mg / mL) and dilute it with PG, or VG, or a blend of PG and VG to a <100 mg / mL substituted pyridine compound w / v target, e.g., 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.

[0254] Method for preparing gasifying alkaloid composition

[0255] The gasifying alkaloid compositions in Tables 1 and 2 can be prepared by directly mixing the ingredients shown in the table in a laboratory container with magnetic or overhead stirring, or in a food industry mixer, and then heating if necessary to obtain complete solubility and clarity. In a preferred embodiment, a premix is ​​prepared first and then combined.

[0256] In various embodiments, a first premix, designated as premix A, comprises propylene glycol, an optional chemosensory stimulant, an organic acid, and 190 proof alcohol. In some examples, two or more organic acids are present in premix A, and / or VG may be substituted for PG or PG may be incorporated with VG.

[0257] In various embodiments, the second premix, designated as premix B, comprises the desired substituted pyridine compound of formula (I) dissolved in a compatible solvent, such as vegetable glycerin, propylene glycol, a 50 / 50 (v / v) blend of vegetable glycerin and propylene glycol, and / or ethanol. As previously described, in order to obtain highly concentrated compositions, such as those having >20 wt% substituted pyridine compound and >100 mg / mL of the finished substituted pyridine compound, the level of a solvent (e.g., ethanol) may be increased. In some cases, other solvents may be necessary in addition to the above solvents.

[0258] In certain examples, Premix A is then mixed with Premix B and the resulting mixture, if hazy, 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.

[0259] One way to obtain a final composition with >100 mg / mL alkaloid 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 be an issue. In those cases, the vegetable glycerin in premix B may be at least partially replaced by another solvent, such as ethanol. For compounds according to formula (I), solubility data for a particular alkaloid in various solvents may suggest which solvent to use in premix B.

[0260] How to use

[0261] 1. Quitting smoking by inhaling a vaporized alkaloid composition

[0262] The vaporizable alkaloid composition or dilution thereof according to the present disclosure is intended to be emitted from an electronic device (eg, an electronic cigarette) in the form of a vapor, which a user can inhale, just like smoking a traditional tobacco product (eg, a cigarette).

[0263] As mentioned above, one object of the present disclosure is to provide a vaporizable alkaloid composition and progressive dilutions thereof to smokers involved in a smoking cessation program.

[0264] In various embodiments, a method of quitting smoking comprises: administering a series of vaporizing alkaloid compositions to an individual who desires to quit smoking during a period of time determined for quitting, wherein the vaporizing alkaloid compositions in the series each comprise:

[0265] At least one substituted pyridine compound having formula (I), or a salt or mixed salt thereof:

[0266]

[0267] wherein each gasifying alkaloid composition in the series comprises a decreasing (w / v) amount of the substituted pyridine compound, or a salt or a mixed salt thereof;

[0268] and at least one solvent,

[0269] wherein the individual desiring to quit is subjected to each composition in the series in descending order of the amount (w / v) of the substituted pyridine compound, or salt or mixed salt thereof; and

[0270] Therein, an individual desiring to quit using each of the compositions by vaporizing and inhaling the respective compositions by an electronic device during a period of time determined for quitting.

[0271] In various embodiments, the series of vaporizing alkaloid compositions includes the composition having the highest w / v level of the substituted pyridine compound of formula (I) and includes the composition having the lowest w / v level of the substituted pyridine compound of formula (I).

[0272] In various embodiments, an individual who wishes to quit smoking begins a smoking cessation program by using a composition having the highest w / v level of a substituted pyridine compound of formula (I) and ends the smoking cessation program by using a composition having the lowest w / v level of a substituted pyridine compound of formula (I). A series of compositions are used throughout the entire length of the smoking cessation program.

[0273] In various embodiments, the individual desiring to quit is a tobacco smoker who wishes to stop smoking.

[0274] In various embodiments, the time period determined for abstinence may be in the range of days, weeks, months, or years, preferably in the range of several months to a year.

[0275] In various embodiments, the time period determined for withdrawal is part of a withdrawal program, the withdrawal program further comprising: emitting the series of vaporized alkaloid compositions during the time period determined for withdrawal.

[0276] In various embodiments, the time period determined for quitting is divided into successive time periods of shorter duration, wherein in each of the shorter time periods, the individual desiring quitting receives and uses a different vaporized alkaloid composition instead of smoking tobacco. In a preferred embodiment, in each of the successive time periods of shorter duration, the individual desiring quitting receives a vaporized alkaloid composition with a gradually decreasing amount of alkaloid (in units of (w / v)).

[0277] In various embodiments, the vaporized alkaloid composition series includes the compositions shown in Table 3. This exemplary e-cigarette liquid series can be administered during a 25-week detoxification program. The table shows that during each week of the detoxification program, the individual will receive a new e-cigarette composition with a lower content of substituted pyridine compounds. At the end of the program, the individual who wishes to detox will smoke a vaporized alkaloid composition that does not contain alkaloids.

[0278] Table 3: Series of gaseous alkaloid compositions for use in detoxification programs

[0279]

[0280]

[0281] Note 1 The alkaloids in compositions P1-P25 include any substituted pyridine compound according to formula (I), or a salt thereof, or a mixed salt thereof. In certain examples, compositions P1-P25 consist of the compositions in Tables 1 and 2 and dilutions thereof.

[0282] Note 2 For plans starting with a composition of 100 mg / mL alkaloid w / v, the composition from Table 2 can be used as P1. For compositions of P2 to P25, P1 is diluted accordingly with VG and / or PG as described, with flavoring added as needed and adjusted based on personal preference and history of compliance.

[0283] In various embodiments, individuals who join the smoking cessation program will check in with their program manager regularly (e.g., weekly) for personal consultation and to receive new and further diluted e-cigarette liquids. In these regular check-ins, individual compliance with the program can be assessed and adjusted accordingly. Some changes to the program may be to keep individuals at a specific w / v alkaloid level for a longer period of time than a week, or to replace or adjust flavorings. A series of other changes can be made to the e-cigarette composition, such as adding chemical sensory stimulants to the diluted composition, switching between chemical sensory stimulants, or adding more or less chemical sensory stimulants and / or propylene glycol to adjust the throat hit sensed by the individual who inhaled the provided composition. In some instances, a liquid composition is provided to an individual, and the individual places the composition into a reservoir of his / her own refillable electronic device (e.g., a refillable electronic cigarette). In other instances, a disposable (closed) device is provided to an individual, which is pre-filled with a specific composition.

[0284] In various embodiments, an individual who has reached the end of the program will smoke only flavored solvents that do not contain alkaloids. At this point, it is expected that the individual will not smoke traditional tobacco products at all and may choose to stop smoking completely.

[0285] In various embodiments, the method of inhalation comprises: vaporizing and inhaling a composition according to the present disclosure from a disposable (closed) or refillable (open) electronic device. In some embodiments, the electronic device comprises.

[0286] 2. Alkaloid dispensing bag for oral use

[0287] In various embodiments, forms of vaporizable alkaloid compositions according to the present disclosure may also be used by manufacturers of "dispensing pouches". The pouch for oral use comprises a relatively small (e.g., 0.5 inch x 0.75 inch) saliva-permeable fabric material enclosure containing a powder sealed therein, which is capable of releasing alkaloid actives into the oral cavity of an individual when the pouch is placed sublingually or in the buccal cavity of an individual. The alkaloid dispensing pouch according to the present disclosure is configured to release the alkaloid of formula (I) over time. In some embodiments, releasing the alkaloid from the alkaloid dispensing pouch into the oral cavity of an individual may be described as "time release".

[0288] In various embodiments, the alkaloid dispensing bag comprises a saliva permeable nonwoven fabric and a powdered alkaloid composition sealed therein. In certain instances, the powdered alkaloid composition sealed in the bag comprises a gasifiable 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 granulate. In other embodiments, the powdered alkaloid composition in the alkaloid dispensing bag comprises a substituted pyridine compound according to formula (I), a solvent, and a carrier, wherein a mixture of alkaloid and solvent is adsorbed on the carrier.

[0289] 2a. General Implementation Methods of Alkaloid Dispensing Bags

[0290] In general embodiments, an alkaloid-dispensing pouch adapted to release an alkaloid therefrom into the oral cavity of a subject comprises:

[0291] A saliva-permeable nonwoven fabric defining an enclosure containing an alkaloid composition therein, the alkaloid composition comprising:

[0292] At least one substituted pyridine compound according to formula (I), or a salt thereof:

[0293]

[0294] in:

[0295] A is selected from:

[0296] as well as

[0297] 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

[0298] 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;

[0299] R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 independently selected from the group consisting of: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl;

[0300] n is an integer from 1 to 10; and

[0301] 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,

[0302] 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

[0303] carrier,

[0304] The alkaloid dispensing bag contains no (R) or (S) nicotine at all.

[0305] In various embodiments, the alkaloid composition is a blend of a substituted pyridine compound of formula (I) (in a solid or oily physical form) and a carrier.

[0306] In various embodiments, the carrier comprises microcrystalline cellulose.

[0307] In various embodiments, the alkaloid composition optionally comprises a chemosensory stimulant and / or a flavoring agent.

[0308] In various embodiments, the alkaloid composition further comprises a solvent, so that the alkaloid composition can be adsorbed onto the carrier to form a powdered or granular composition that can be filled into the enclosed space. In some examples, the solvent is selected from: propylene glycol, glycerol, water, ethanol, and mixtures thereof.

[0309] 2b. Saliva-permeable fabric for the bag

[0310] The bag material used herein is selected because it is insoluble in water and permeable to water and saliva. The material size is varied so that the filled bag is suitable for long-term sublingual or buccal placement. Subjectively, the alkaloid-emitting bag is configured for a comfortable mouth feel, including the size of the filled and sealed bag and the texture of the bag fabric.

[0311] The bag material used herein can be made of any number of various water-insoluble nonwoven materials, referred to as "fabrics". Nonwoven fabrics are well known to those skilled in the art for their many uses. Nonwovens are very thoroughly described in "Nonwoven Fabrics: Raw Materials, Manufacture, Applications, Characteristics, Testing Processes," (ed. W. Albrecht, H. Fuchs and W. Kittelmann, Wiley-VCH Verlag GmbH & Co. Kga A Weinheim, 2003). Such materials can be prepared by forming a continuous web of filaments and / or staple fibers, and optionally combining these fibers at fiber-fiber contact points to provide a fabric with desired properties. The term "bonded nonwoven fabric" is used to include nonwoven fabrics in which the majority of the fiber-fiber bonding is achieved by heat melting of adjacent fibers, or adhesive bonding (achieved by incorporating a binder into the web to "bond" the fibers together), or by other bonding, such as by making the fibers cohesive using a liquid or gaseous binder (usually in conjunction with heating). Chemical bonding can be accomplished by using a binder or latex powder dispersed between the fibers of the web, which can then be activated by heat, ultraviolet or infrared radiation, or other suitable activation methods. Thermally bonded and chemically bonded carded webs are described in U.S. Pat. No. 6,689,242 to Bodaghi, the subject matter of which has been incorporated herein. Thermally bonded and / or chemically bonded nonwoven fabrics can be used as bag materials herein. Powder bonding is a dry process that begins with carding staple fibers to form a web that is then treated with a powdered thermoplastic binder or latex material and subjected to a series of ovens and calender rolls to produce the nonwoven.

[0312] Nonwovens may also include fibers known as "bi-component fibers," such as "sheath / core bi-component fibers," which are fibers having an outer sheath region or layer having a lower melting point than the inner core region, allowing efficient and controlled thermal bonding by melting only the outer layer of each fiber. That is, the outer surface of the bi-component fiber may be made to have a lower melting point than the core of the fiber. For example, binder bi-component fibers, in which one component has adhesive properties under bonding conditions, are widely used to provide integrity to fiber webs used as absorbents in personal care products or filtration products. In addition, similarly, multi-component fibers are also known and commercially incorporated into nonwovens. Examples of such multi-component fibers are described in U.S. Pat. No. 5,382,400 (Pike et al.) and U.S. Pat. No. 5,866,488 (Terada et al.), and the patents are incorporated herein in their entirety.

[0313] During fiber bonding, the web may be simultaneously subjected to mechanical compression in order to obtain the desired bonding, weight, and thickness in a process known as "thermal compression bonding." Thermal compression bonding can be achieved by using heat embossing rolls and heat flat calendar rolls, as well as by incorporating methods in which thermal compression bonding is performed using heat treatment machinery such as hot blast-circulating, hot through-air, infrared heaters, or vertical blast-blowing. 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, while increasing bonding and compression decreases loft.

[0314] Nonwoven webs can be formed by a variety of processes, such as melt-blown, spun-bonded or spun-laid, toe-opened, wet-laid, air-laid, carded, and water-entangled. The basis weight of nonwoven webs is usually expressed in ounces of material per square yard (osy) or grams per square meter (gsm), while the fiber diameter is usually expressed in microns, or in the case of staple fibers, in "denier". Denier is defined as 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 (in microns) multiplied by the density (in grams per cubic centimeter), multiplied by 0.00707. A lower denier indicates a finer fiber, and a higher denier indicates a thicker or heavier fiber. "Average fiber denier" is the sum of the lay-flat 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 particular value. As used herein, the term "bulk density" refers to the weight of a material per unit volume, and is usually expressed in units of mass per unit bulk volume (e.g., grams per cubic centimeter). Nonwovens can be produced from fibers having a single average diameter or denier value, or fibers of two or more average diameter values ​​can be used simultaneously. For example, two or more fiber denier distributions can be combined into a single web (e.g., combining two or more fiber denier distributions into a single web). 1 / 2 denier and 4 denier fibers combed together). Individual webs may be laminated together. For example, a single nonwoven may contain 2 1 / 2, 4, 6 and 15 denier fibers, meaning that the nonwoven is composed of four different denier fibers (four different average fiber diameters).

[0315] "Spunbond fibers" refer to fibers formed by extruding molten thermoplastic material into filaments, as 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 contents of each of which are incorporated herein by reference. Spunbond fibers are generally not tacky when deposited onto a collecting surface. Spunbond fibers are generally continuous and have an average diameter of about 7 microns to about 60 microns, most commonly between about 15 and 25 microns.

[0316] "Meltblown" refers to fibers formed by extruding molten thermoplastic material as molten filaments or filaments through a plurality of fine (usually circular) die capillaries into a converging high-speed (usually hot) gas / air stream that attenuates the filaments of molten thermoplastic material, thereby reducing their diameter, which may eventually reach a microfiber diameter. Thereafter, the meltblown fibers are carried by the tile high-speed gas stream and deposited on a collecting surface to form a web of randomly dispersed fibers. Such a process is disclosed, for example, in U.S. Pat. No. 3,849,241 (Butin et al.). Meltblown fibers are microfibers that may be continuous or discontinuous, typically have an average diameter of less than 10 microns, and are typically tacky when deposited on a collecting surface.

[0317] "Air laying" is a well-known process by which a fibrous nonwoven layer can be formed. In the air laying process, a bundle of small fibers of about 3 to about 52 millimeters in length is separated and entrained in an air supply, and (usually under vacuum assistance) is deposited on a forming screen. Subsequently, the randomly deposited fibers are combined with each other using a method such as hot air to activate an adhesive component or a latex adhesive. For example, U.S. Patent No. 4,640,810 (attributed to Laursen) and U.S. Patent No. 5,885,516 (attributed to Christensen) teach an air laying process.

[0318] The preferred fibers incorporated into the bag fabric used herein can be monocomponent, bicomponent (e.g., sheath / core), or multicomponent fibers made from: polyolefins, such as polypropylene, polyethylene; various polyesters, such as poly(ethylene terephthalate)-PET, poly(butylene terephthalate)-PBT, or poly(trimethylene terephthalate)-PTT, polycarbonate, or polybutyrate, or tile, etc.; viscose rayon; various polyamides, such as nylon; polyacrylates; and modified acrylics (modacrylic), as well as mixtures of these types of polymers. In various preferred examples, viscose is used as the saliva permeable nonwoven bag fabric of the alkaloid dispensing bag herein.

[0319] The filling and sealing method of the bag comprising nonwoven fabric is disclosed in U.S. Patent Application Publication US2023 / 0211907 (published on July 6, 2023, and attributed to Swedish Match North Europe AB), which is incorporated herein by reference. In various embodiments, the alkaloid dispensing bag herein comprises an alkaloid composition (dry powder or granules) of a filling weight of about 100 mg to about 500 mg, preferably about 200 mg to about 400 mg. When the bag is no longer comfortably adapted under the tongue or in the buccal cavity, the upper limit is reached. Due to the negligible weight of the small piece of nonwoven fabric compared to the weight of a single bag, the filling weight of the alkaloid dispensing bag herein is about 100 mg to about 500 mg dry powder or granular alkaloid composition / bag.

[0320] In various embodiments, the alkaloid-emitting bag measures about 0.12 inches to about 0.50 inches in width (or diameter) and about 0.25 to about 0.75 inches in height. In some instances, the bag may look like a small pillow (e.g., square), or more like a capsule.

[0321] 2c. Powder filling composition for alkaloid dispensing bag

[0322] In various embodiments, the alkaloid dispensing bag herein comprises a powdered or granular composition, which further comprises an alkaloid blended with a carrier, or a gasifiable alkaloid composition according to the present disclosure adsorbed onto a carrier. Both routes are intended to obtain a dry powdered or granular alkaloid filling material for sealing inside the enclosed space of a nonwoven fabric.

[0323] Gasifying alkaloid compositions for alkaloid dispensing bags are described above in full. Any composition of substituted pyridine compounds of formula (I) ranging from about 1 mg / mL to about 1000 mg / mL can be used. Finally, the selected liquid composition is adsorbed onto a suitable carrier and the resulting powder or granules are used as the filling material for each bag.

[0324] The carriers used in this article include, but are not limited to, agar, agarose, albumin, alginate, casein, chitin, chondroitin, dextrin, fibroin, fucoidan, galactan, gellan, guar gum, scleroglucan, pullulan, xyloglucan, pectin, xanthan gum, psyllium, silica gel, etc.

[0013] The invention also includes but is not limited to gel, fumed silica, magnesium aluminum silicate, clay, bentonite, hectorite, mesoporous silica, cellulose, cellulose acetate, hyaluronan, various elastin-like polypeptides, beta-cyclodextrin, collagen, gelatin, chitosan, carrageenan, polylactic acid, polyglycolic acid, poly(lactic-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, polyvinyl copolymers, 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).

[0325] The carrier may be selected based on absorption capacity (and to a lesser extent based on taste). In the case where the carrier is completely insoluble in the saliva present in the oral cavity, taste will not be a factor, and any insoluble carrier is unlikely to pass between the fibers of the nonwoven fabric. In other examples, the carrier may be soluble and will pass through the porous bag fabric along with the alkaloid composition. In a preferred embodiment, the carrier comprises microcrystalline cellulose.

[0326] Tables 4, 5 and 6 illustrate general embodiments of alkaloid compositions that may be used as filler materials for the alkaloid emitting bags of the present disclosure.

[0327] Table 4: Filling composition of alkaloid dispensing bag: dry blend

[0328] 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

[0329] Table 5: Filling composition of alkaloid emission bag: liquid absorption

[0330]

[0331] Table 6: Filling composition of alkaloid emission bag: liquid absorption

[0332]

[0333] Each of the resulting filling compositions in Tables 4, 5 or 6 is in the physical form of dry powder or granules. The resulting material is filled into non-woven bags at a filling level of about 100 mg to about 500 mg of the dry powder or granular alkaloid composition per bag, and then sealed to prepare individual alkaloid dispensing bags for oral administration.

[0334] In the detailed description, the expressions "various embodiments", "one embodiment", "embodiment", "exemplary embodiment", etc., indicate that the described embodiments may include specific features, structures, or characteristics, but each embodiment does not necessarily include the specific features, structures, or characteristics. In addition, such expressions 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 that it is within the knowledge of those skilled in the art that the specific feature, structure, or characteristic affects 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 disclosure in alternative embodiments.

[0335] 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 reference to the singular includes plural embodiments, and any reference to more than one component / assembly or step may include singular embodiments or steps. In addition, any reference to attached, fixed, connected, coupled, etc. may include permanent (e.g., integral), removable, temporary, partial, full, and / or any other attachment options. Any components may be coupled to each other by friction, snap, sleeve, bracket, clip, or other means now known in the art or developed thereafter. In addition, any reference to without contact (or similar phrases) may also include reduced contact or minimal contact.

[0336] Benefits, other advantages, and solutions to problems have been described herein with respect to 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 the key to the present disclosure, the requirements of the present disclosure, or the basic features or elements of the present disclosure. Therefore, the scope of the present disclosure is limited only by the appended claims, and unless otherwise specified, the reference to a single element therein is not intended to mean "one and only one", but "one or more". In addition, if a statement similar to "at least one / item / kind of A, B, and C" is used in the claims or specification, it is intended that the statement be interpreted as: A may exist alone in the embodiment, B may exist alone in the embodiment, C may exist alone in the embodiment, or any combination of elements A, B, and C (e.g., A and B, A and C, B and C, or A and B and C) may exist in the embodiment.

[0337] 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 present claims. In addition, the device or component of the device, or the method of using the device does not have to solve each of the problems sought to be solved by the present disclosure in order to be covered by the present claims. In addition, any element / element, component / assembly or method step in the present disclosure is not intended to be disclosed to the public specifically, regardless of whether the element / element, component / assembly or method step is explicitly stated in the claims. No claim element is intended to invoke 35 U.S.C.112 (f) unless the phrase "means for" is used to explicitly state the element. As used herein, the term "comprises, comprising" or any other variant thereof is intended to cover non-exclusive inclusion, so that the chemical, chemical composition, process / process, method, product or device containing the list of elements / elements not only includes these elements / elements, but also may include other elements / elements that are not explicitly listed or inherent to such chemicals, chemical compositions, processes / processes, methods, and products.

Claims

1. A gasifying alkaloid composition comprising: At least one substituted pyridine compound of formula (I): or a salt thereof, or a mixed salt thereof, wherein: A is selected from: as well as 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 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, 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, The vaporizable alkaloid composition contains no (R) or (S) nicotine.

2. The gasifying alkaloid composition of claim 1, wherein the at least one substituted pyridine compound has a structure according to formula (IA): or a salt thereof, or a mixed salt thereof, or having a structure according to formula (IA-1): or a salt thereof, or a mixed salt thereof; or a compound having a structure according to formula (IA-2): or a salt thereof, or a mixed salt thereof; or having a structure according to formula (IA-3): or a salt thereof, or a mixed salt thereof, or having a structure according to formula (IA-4): or a salt thereof, or a mixed salt thereof; or having a structure according to formula (IA-5): or a salt thereof, or a mixed salt thereof.

3. The gasifying alkaloid composition of claim 1, wherein the at least one substituted pyridine compound has a structure according to formula (IB): or a salt thereof, or a mixed salt thereof; or having a structure according to formula (IC): or a salt thereof, or a mixed salt thereof; or having a structure according to formula (ID): or a salt thereof, or a mixed salt thereof; or having a structure according to formula (IE): or a salt thereof, or a mixed salt thereof; or having a structure according to formula (IAA): or its salt, or its mixed salt, provided that: if R 5 is CH3, then R 1 , R 2 , R 3 , and R 4 Cannot be all H.

4. 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 thereof, or a mixed salt thereof.

5. The gasifying alkaloid composition according to 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, tartronic acid, valeric acid, and mixtures thereof.

6. The gasifiable alkaloid composition of claim 1, further comprising at least one chemesthetic sensory stimulant, wherein the chemesthetic sensory stimulant is a flavor additive having a heat level of about 1,000 to about 20,000,000 Scoville Heat Units (SHU).

7. 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 thereof, or a mixed salt 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 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, 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; (b) from about 0.05% to about 1.5% by weight totaling at least one organic acid; and (c) the remainder is solvent, wherein the weight percentages are based on the total weight of the gasifiable alkaloid composition; and The molar ratio of the substituted pyridine compound to the total molar number of the organic acid is about 25:1 to about 75:1, or the molar ratio of the substituted pyridine compound to the total molar number of the organic acid is about 50:

1.

8. The gasifying alkaloid composition of claim 7, wherein the substituted pyridine compound is selected from the group consisting of nicotinamide, (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.

9. A method of improving smoking cessation in an individual desiring to quit, the method comprising: During a period of time determined for withdrawal, a series of vaporized alkaloid compositions are administered to the individual by vaporization for inhalation by the individual, each vaporized alkaloid composition in the series comprising at least one substituted pyridine compound according to formula (I): or a salt thereof, or a mixed salt 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 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, 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 each of the series of gasifying alkaloid compositions comprises a decreasing (w / v) amount of the substituted pyridine compound of formula (I), or a salt thereof or a mixed salt thereof; wherein the series of gasifying alkaloid compositions include: a gasifying alkaloid composition having the highest (w / v) level of the substituted pyridine compound of formula (I), or a salt thereof or a mixed salt thereof, and a gasifying alkaloid composition having the lowest (w / v) level of the substituted pyridine compound of formula (I), or a salt thereof or a mixed salt thereof; as well as wherein by vaporization, the individual inhales each composition in the series, starting with the vaporizable alkaloid composition having the highest level (w / v) of the substituted pyridine compound of formula (I), or salt or mixed salt thereof at the beginning of the period of time determined for quitting, and ending with the composition having the lowest level (w / v) of the substituted pyridine compound of formula (I), or salt or mixed salt thereof at the end of the period of time determined for quitting, such that at the end of the period of time determined for quitting, the individual stops smoking.

10. The method of claim 9, wherein the vaporizing alkaloid composition having the highest level (w / v) of the substituted pyridine compound of formula (I), or a salt thereof, or a mixed salt thereof, among the series of vaporizing alkaloid compositions comprises about 100 mg / mL of the substituted pyridine compound of formula (I), or a salt thereof, or a mixed salt thereof, or comprises no more than about 1 mg / mL of the substituted pyridine compound of formula (I), or a salt thereof, or a mixed salt thereof.

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