Vaporizable alkaloid compositions and methods of use thereof

Abstract

Various embodiments of the present disclosure describe vaporizable alkaloid compositions that can form an inhalable vapor when dispensed from an electronic device, such as an electronic cigarette. The compositions herein include a substituted pyridine compound in combination with a chemosensory stimulant, which in certain instances includes a spice additive having a heat intensity of about 1,000 to about 20,000,000 Scoville Pungency Units (SHU). A suite of vaporizable alkaloid compositions with decreasing amounts (w / v) of the substituted pyridine compound are provided as part of a smoking cessation program.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 439,650, filed January 18, 2023, entitled "Vaping Liquid With Analogs For Vaping Devices," the disclosure of which is incorporated herein by reference in its entirety and for all purposes.

[0002] The present disclosure relates generally to vaporizable, inhalable compositions containing both physiologically and sensory active substances, and more particularly to vaporizable compositions containing one or more substituted pyridine compounds or salts thereof or mixed salts thereof. [Background technology]

[0003] It is well known that smokers can achieve health benefits from tobacco cessation, and in general, most adult smokers in the United States wish to quit smoking. Electronic nicotine delivery systems (ENDS) should, at least in principle, provide a viable cessation aid, depending on the composition of the vaporizable liquid. However, various studies suggest that users of electronic devices that self-administer nicotine are not actually more likely to quit smoking tobacco products. 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.

[0004] Complete replacement of actual tobacco smoking with electronically administered vapor will require compliance similar to patient compliance with a pharmaceutical subscription. For smokers, compliance with electronic devices depends on the electronic delivery of sensory effects from vaporizable compositions that are the same as, or at least approximate, those experienced by inhaling tobacco smoke from a combusted cigarette. To date, this has not been achieved in the industry, as evidenced by data showing an inability to quit. Summary of the Invention [Problem to be solved by the invention]

[0005] Therefore, there is a need for new vaporizable compositions that, when vaporized and inhaled via an electronic device, can provide an acceptable experience to former cigarette smokers. [Means for solving the problem]

[0006] Surprisingly, it has now been discovered that vaporizable compositions can be optimized to balance the vapor and inhalation sensations so as to simulate as closely as possible the sensory experience an individual has when smoking a traditional tobacco product.

[0007] In accordance with the present disclosure, novel vaporizable alkaloid compositions and formulation methods are provided. Generally, the compositions herein are optimized to aid in compliance with smoking cessation programs by providing smokers with a viable and complete alternative to tobacco smoking.

[0008] In various embodiments, the vaporizable alkaloid composition herein comprises at least one substituted pyridine compound or a salt thereof or a mixed salt thereof, at least one chemosensory stimulant, at least one solvent, and optionally at least one flavoring agent, and the vaporizable alkaloid composition is completely devoid of nicotine.

[0009] In various embodiments, the vaporizable alkaloid composition comprises: At least one substituted pyridine compound of formula (I) or a salt or mixed salt thereof,

[0010] [ka]

[0011] In the formula, R 1 , R 2 , R 3 , R 4 , and R 5 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl, with R 5 If is CH3, then R 1 , R 2 , R 3 , and R 4 at least one substituted pyridine compound of formula (I) or a salt or mixed salt thereof, with the proviso that all of at least one chemosensory stimulant; at least one solvent; optionally at least one flavoring agent; The vaporizable alkaloid composition is completely devoid of (R) or (S) nicotine.

[0012] In various embodiments, R 5 is CH3 and R 1 , R 2 , R 3 , and R 4 At least one of them is not H.

[0013] In various embodiments, R 5 is -(CH2)n-NR 6 R 7 where n is an integer from 1 to 10, and 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 with the N atom to which they are attached form a 3- to 8-membered optionally substituted heterocyclic ring.

[0014] In various embodiments, R 5 is H and R 1 , R 2 , R 3 , and R 4 At least one of the groups is -(CH2)n-NR 6 R 7 where n is an integer from 1 to 10, 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 with the N atom to which they are attached form a 3- to 8-membered optionally substituted heterocyclic ring.

[0015] In various embodiments, the substituted pyridine compound or salt thereof or mixed salt thereof is (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)propanenitrile, (R) or (S)-4-(2-(6-methylpyridin-3-yl)pyrrolidin-1-yl)butanenitrile, (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)pyrrolidin-1-yl)pyrrolidin-1-yl)pyridine )ethyl)morpholine, (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.

[0016] In various embodiments, the substituted pyridine compound or a salt thereof or a mixed salt thereof is (S)-2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine.

[0017] In various embodiments, the substituted pyridine compound or salt or mixed salt thereof is selected from (2S)-1-methyl-2-(6-methylpyridin-3-yl)pyrrolidin-1-ium acetate, (2S)-1-methyl-2-(6-methylpyridin-3-yl)pyrrolidin-1-ium citrate, or a mixture thereof.

[0018] In various embodiments, the chemosensory stimulant is 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, fluoxetane, methyl benzoate ... Fenamic acid, niflumic acid, mefenamic acid, diclofenac, hydroxy-α-sanshool, 6-paradol, linalool, carvacrol, eugenol, thymol, vanillin, methyleugenol, 2,6-dimethylphenol, 2,5-dimethylphenol, 3,4-dimethylphenol, 2,6-diisopropylphenol, caffeine, farnesylthiosalicylic acid, 4-allylanisole, curcumin, niacin, camphor, olvanil, arvanil, anandamide, cannabidiol, Δ 9 - selected from the group consisting of tetrahydrocannabinol, baicalein, baicalin, wogonin, norwogonin, oroxylin A, β-sitosterol, and mixtures thereof.

[0019] In various embodiments, the at least one substituted pyridine compound of formula (I) or a salt or mixed salts thereof comprises a mixture of (S)-2-methyl-3-(1-methylpyrrolidin-2-yl)pyridine free base and (2S)-1-methyl-2-(6-methylpyridin-3-yl)pyrrolidin-1-ium citrate / acetate mixed salt.

[0020] In various embodiments, the chemosensory stimulant is a spice additive that provides a heat intensity of about 1,000 to about 20,000,000 Scoville Pungency Units (SHU).

[0021] In various embodiments, the spice additive is selected from the group consisting of capsaicin, dihydrocapsaicin, norcapsaicin, nordihydrocapsaicin, homocapsaicin, homodihydrocapsaicin, gingerol, piperine, shogaol, isopiperine, chavicine, isochavicin, 2-piperamine, piperanine (4,5-dihydropiperine), piperamide, 4-piperiside, piperiline, piperlonguminine, piperettine, piperduldine (6,7-dihydropiperetine), 5-sarmentodine, 6-sarmentine, 7-trichostatin, and mixtures thereof.

[0022] In various embodiments, the spice additive is capsaicin or a mixture of capsaicinoids.

[0023] In various embodiments, the solvent is selected from the group consisting of propylene glycol, water, ethanol, glycerin, and mixtures thereof.

[0024] In various embodiments, the vaporizable alkaloid composition further comprises an organic acid selected from the group consisting of formic acid, acetic acid, trifluoroacetic acid, aspartic acid, butanoic 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.

[0025] 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.

[0026] In various embodiments, the molar ratio of total substituted pyridine compounds to total organic acids is from about 25:1 to about 75:1.

[0027] In various embodiments, the vaporizable alkaloid composition comprises: about 1% by weight to about 80% by weight of a substituted pyridine compound according to formula (I) or a salt or mixed salt thereof,

[0028] [ka]

[0029] In the formula, R 1 , R 2 , R 3 , R 4 , and R 5 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl, with R 5 If is CH3, then R 1 , R 2 , R 3 , and R 4 a substituted pyridine compound according to formula (I) or a salt or mixed salt thereof, with the proviso that a total of about 0.05% to about 1.5% by weight of at least one organic acid; About 0.0001% to about 0.50% by weight of a spice additive having a spiciness of about 1,000 to about 20,000,000 Scoville Pungency Units (SHU); and a balance of solvent, Weight percentages are based on the total weight of the vaporizable alkaloid composition, and the molar ratio of moles of substituted pyridine compound to total moles of organic acid is from about 25:1 to about 75:1.

[0030] In various embodiments, the substituted pyridine compound is (S)-2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine.

[0031] In various embodiments, the molar ratio of moles of (S)-2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine to total moles of organic acid is about 50:1.

[0032] In various embodiments, the concentration (w / v) of (S)-2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine in the vaporizable alkaloid composition is from about 1 mg / mL to about 1,000 mg / mL.

[0033] In various embodiments, the concentration (w / v) of (S)-2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine in the vaporizable alkaloid composition is about 100 mg / mL.

[0034] In various embodiments, the at least one organic acid comprises a mixture of citric acid and acetic acid.

[0035] In various embodiments, the spice additive comprises capsaicin.

[0036] In various embodiments, the solvent is selected from the group consisting of propylene glycol, glycerin, ethanol, and mixtures thereof.

[0037] In various embodiments, the method of producing a vaporizable alkaloid composition comprises: preparing a first premix comprising a chemosensory stimulant and at least one organic acid dissolved in a suitable solvent or solvent mixture; Preparing a second premix comprising at least one substituted pyridine compound dissolved in a suitable solvent or mixture of solvents, wherein the substituted pyridine compound has the structure of formula (I):

[0038] [ka]

[0039] or a salt thereof or a mixed salt thereof, wherein R 1 , R 2 , R 3 , R 4 , and R 5 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl, with R 5If is CH3, then R 1 , R 2 , R 3 , and R 4 provided that the compound cannot be all H; combining the first premix with the second premix; Optionally, heating the resulting mixture until the resulting mixture is optically clear, thereby producing a vaporizable alkaloid composition.

[0040] In various embodiments, the first premix comprises capsaicin or a mixture of capsaicinoids, acetic acid, and citric acid dissolved in a mixture of propylene glycol and ethanol, and the second premix comprises (S)-2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine dissolved in glycerin.

[0041] In various embodiments, a method for promoting smoking cessation in an individual desiring to quit comprises: administering to an individual, for a period of time determined for cessation, a battery of vaporizable alkaloid compositions for the individual to inhale by vaping, wherein each vaporizable alkaloid composition in the battery comprises at least one substituted pyridine compound having formula (I), or a salt or mixed salt thereof:

[0042] [ka]

[0043] In the formula, R 1 , R 2 , R 3 , R 4 , and R 5 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl, with R 5 If is CH3, then R 1 , R 2 , R 3 , and R 4may not all be H, or a salt or mixed salt thereof; each of the vaporizable alkaloid compositions in the set contains decreasing amounts (w / v) of the substituted pyridine compound or a salt or mixed salt thereof; An individual inhales by vaping each composition in the series, starting with the compound having the highest level (w / v) of the substituted pyridine compound, or its salt or mixed salt, and completing the period determined for cessation with the composition having the lowest level (w / v) of the substituted pyridine compound, or its salt or mixed salt, so that at the end of the period determined for cessation, the individual ceases smoking.

[0044] In various embodiments, each vaporizable alkaloid composition in the battery of vaporizable alkaloid compositions comprises (S)-2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine or a salt or mixed salt thereof.

[0045] In various embodiments, the vaporizable alkaloid composition in the suite of vaporizable alkaloid compositions having the highest level (w / v) of the substituted pyridine compound or salt or mixed salt thereof comprises about 100 mg / mL of (S)-2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine.

[0046] In various embodiments, the vaporizable alkaloid composition in the set of vaporizable alkaloid compositions having a minimum level (w / v) of the substituted pyridine compound or salt or mixed salt thereof comprises about 1 mg / mL or less of (S)-2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine.

[0047] In various embodiments, the determined period for cessation is part of a smoking cessation program that further includes dispensing a battery of vaporizable alkaloid compositions to individuals desiring to quit for the determined period for cessation.

[0048] In various embodiments, the alkaloid dispensing pouch adapted for release of an alkaloid into the oral cavity of an individual comprises: a saliva-permeable nonwoven fabric defining an enclosure containing an alkaloid composition loaded therein, the alkaloid composition comprising: At least one substituted pyridine compound according to formula (I) or a salt or mixed salt thereof,

[0049] [ka]

[0050] In the formula, R 1 , R 2 , R 3 , R 4 , and R 5 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl, with R 5 If is CH3, then R 1 , R 2 , R 3 , and R 4 at least one substituted pyridine compound according to formula (I) or a salt or mixed salt thereof, with the proviso that a carrier; The alkaloid dispensing pouches are completely devoid of (R) or (S) nicotine.

[0051] In various embodiments, the alkaloid composition comprises a mixture of the substituted pyridine compound of formula (I) and a carrier.

[0052] In various embodiments, the carrier comprises microcrystalline cellulose.

[0053] In various embodiments, the alkaloid composition further comprises a solvent, and the alkaloid composition consists of a liquid composition adsorbed on a carrier.

[0054] In various embodiments, the alkaloid composition further comprises a chemosensory stimulant, hi various embodiments, the chemosensory stimulant comprises a spice having a heat intensity of from about 1,000 SHU to about 20,000,000 SHU.

[0055] In various embodiments, an alkaloid dispensing pouch adapted for the release of an alkaloid into the oral cavity of an individual comprises a saliva-permeable nonwoven fabric defining an enclosure containing an alkaloid composition loaded therein, the alkaloid composition being at least one substituted pyridine compound of formula (I) or a salt thereof or a mixed salt thereof,

[0056] [ka]

[0057] In the formula, R 1 , R 2 , R 3 , R 4 , and R 5 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl, with R 5 If is CH3, then R 1 , R 2 , R 3 , and R 4 a vaporizable alkaloid composition further comprising at least one substituted pyridine compound of formula (I) or a salt thereof or a mixed salt thereof, with the proviso that * cannot all be H, at least one chemosensory stimulant, at least one solvent, and optionally at least one flavoring agent, wherein the vaporizable alkaloid composition is completely devoid of (R) or (S) nicotine, and the vaporizable alkaloid composition is adsorbed onto a carrier.

[0058] In various embodiments, the vaporizable alkaloid composition comprises (S)-2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine, citric acid, and acetic acid.

[0059] In various embodiments, the carrier comprises microcrystalline cellulose.

[0060] In various embodiments, the chemosensory stimulant comprises capsaicin or a mixture of capsaicinoids.

[0061] In various embodiments, the solvent is selected from the group consisting of propylene glycol, water, ethanol, glycerin, and mixtures thereof. DETAILED DESCRIPTION OF THE INVENTION

[0062] The detailed description of exemplary embodiments refers to the accompanying drawings, which illustrate exemplary embodiments and the best mode thereof. These exemplary embodiments are described in sufficient detail to enable those skilled in the art to practice the invention, but it should be understood that other embodiments may be realized and that logical, chemical, and mechanical changes may be made without departing from the spirit and scope of the present invention. Accordingly, the detailed description is presented for purposes of illustration only and not limitation. For example, unless otherwise specified, the steps recited in any method or process description may be performed in any order and are not necessarily limited to the order presented. Furthermore, any reference to the singular encompasses multiple embodiments, and any reference to more than one component or step may include a singular embodiment or step. Also, any reference to attached, fixed, connected, etc. may include permanent, detachable, temporary, partial, complete, and / or any other possible attachment options. Additionally, non-contact (or similar phrases) may also include reduced or minimal contact.

[0063] In various embodiments of the present disclosure, novel vaporizable alkaloid compositions are disclosed. The compositions herein are optimized to balance the sensations in the nose, throat, and head when vaporized and inhaled, so as to simulate as closely as possible the same sensory experience an individual gets when smoking a traditional tobacco product. Generally, the compositions herein are optimized to aid in compliance with smoking cessation programs. In various embodiments of the present disclosure, tobacco smokers are provided with a viable and complete alternative to smoking.

[0064] In various embodiments, the vaporizable alkaloid compositions herein comprise: at least one substituted pyridine compound or a salt or mixed salt thereof; at least one chemosensory stimulant; at least one solvent; Optionally, at least one flavoring agent, and the vaporizable alkaloid composition is completely devoid of nicotine.

[0065] In certain examples, the compositions provided herein may be diluted with a suitable solvent or mixture of solvents, such as vegetable glycerin and / or propylene glycol, prior to vaporization and inhalation, such as by a third-party manufacturer or end user of a refillable electronic device, to provide a custom inhalable composition having a lower amount of substituted pyridine compound and spice additive than the starting composition. In a preferred example, a third party will design and implement a smoking cessation program for an individual in combination with providing a vaping liquid having gradually decreasing amounts of substituted pyridine compound and spice additive over the course of the program. In this way, a consumer can comply with the smoking cessation program and use a vaping liquid having decreasing amounts of substituted pyridine compound and spice additive over time until the user is essentially inhaling the vaporized solvent without any other discernible substance, other than perhaps flavoring.

[0066] (Definitions and Interpretation) Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art of chemistry and medicinal chemistry to which this disclosure pertains. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the presently disclosed subject matter, preferred methods and materials are described. In accordance with common practice in organic chemistry, chemical structures in which chiral centers are either depicted above with wavy bonds, or are not illustrated three-dimensionally with wedge or dashed bonds, or are not labeled with (R) or (S) adjacent to the chiral center or with the corresponding structure name, are assumed to represent both enantiomers. Similarly, chemical structures in which multiple chiral centers are not depicted three-dimensionally or labeled as having a specific chirality are assumed to include all possible stereoisomers. The compounds of the present disclosure include any physicochemical or stereochemical forms they may assume, such as, for example, isomers, prodrugs, active metabolites, tautomers, stereoisomers, positional isomers, solvated forms, salts, and polymorphic forms. Amorphous forms lack a distinguishable crystal lattice and therefore lack an ordered arrangement of structural units. Many alkaloids have amorphous forms, crystalline forms, or mixtures thereof. Methods for producing such chemical forms, in addition to crystallographic methods for determining the degree and type of crystallinity, are known to those skilled in the art.

[0067] The compositions of the present disclosure contain alkaloids that may be protonated by the acid present in the compositions, and therefore may be at least partially or even entirely in the form of salts in various compositions.Salts of alkaloids include any salts derived from inorganic or organic acids, preferably organic acids or mixtures thereof.Examples of inorganic salts include, but are not limited to, salts of hydrobromic acid, hydrochloric acid, nitric acid, phosphoric acid, and sulfuric acid. Examples of organic acid salts include, for example, formic acid, acetic acid, trifluoroacetic acid, aspartic acid, butanoic 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 any other such acid salt now known or hereafter discovered or synthesized. Such alkaloid salts can be prepared by reacting an alkaloid free base compound with a suitable acid or mixture of acids in a manner known to those skilled in the art. When mixed acids are reacted with alkaloids disclosed herein to make alkaloid salts, no attempt is made to quantify the resulting mole percentage of each individual alkaloid salt, and the resulting alkaloid salts are referred to as "mixed salts."

[0068] As used herein, the term "alkyl" refers to a straight- or branched-chain monovalent saturated hydrocarbon substituent that is optionally substituted on or anywhere within the substituent with one or more functional groups. Unless otherwise specified, alkyl groups include, for example, 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, iso-pentyl neo-pentyl, n-hexyl, iso-hexyl, octadecyl, dodecyl, and the like. The alkyl substituents herein may be substituted, i.e., one or more substituents may be attached to the alkyl group or incorporated within the alkyl chain. Substitution within the alkyl substituent chain may include ether, sulfide, amino, or imine linkages, i.e., for example, -O-, -S-, -N(R')-, or -N=, or some other intervening heteroatom(s). Examples of substitutions on alkyl substituents include, but are not limited to, -CN, -N, -NH, -NHR, -N(R), -NO, -NH-NH, -NH-NHR, -NH-NR, -halo, -SH, -SR, -S(=O)R, -SO,R, -OPO 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, where each R' is independently selected from hydrogen, -H, and alkyl moieties, including, for example, C 1-6 Alkyl (e.g., -CH3, -C2H5, -isopropyl, -tert-butyl, etc.), C 1-6 Alkoxy (e.g., -OCH3, -OC2H5), halogenated C 1-6 Alkyl (e.g., -CF3, -CHF2, -CH2F), and halogenated C 1-6 Alkoxy (eg, -OCF3, -OC2F5) is included. In various examples, two R' substituents of any of these functional groups may form a ring structure.

[0069] As used herein, the term "cycloalkyl" includes any 3-, 4-, 5-, 6-, 7-, or 8-membered saturated or unsaturated non-aromatic carbocyclic ring optionally substituted at any position on the ring substituent with one or more functional groups. Examples of cycloalkyl groups 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, cyclooctanyl, and the like. Examples of substitutions on a cycloalkyl substituent include, but are not limited to, -CN, -N, -NH, -NHR, -N(R), -NO, -NH-NH, -NH-NHR, -NH-NR, -halo, -SH, -SR, -S(=O)R, -SO,R, -OPO 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, where each R' is independently selected from -H and alkyl moieties, including, for example, C 1-6 Alkyl (e.g., -CH3, -C2H5, -isopropyl, -tert-butyl, etc.), C 1-6 Alkoxy (e.g., -OCH3, -OC2H5), halogenated C 1-6 Alkyl (e.g., -CF3, -CHF2, -CH2F), and halogenated C 1-6 Alkoxy (e.g., -OCF3, -OC2F5) is included.

[0070] As used herein, the term "alkenyl" refers to a straight- or branched-chain monovalent or divalent unsaturated hydrocarbon substituent, optionally substituted with one or more functional groups anywhere on or within the substituent. An alkenyl substituent is a group selected from the group consisting of sp 2If a carbon is part of a molecule bearing an alkenyl substituent, it can be considered divalent. An illustrative example is methylenecyclohexane, which can be considered a cyclohexane substituted with a methylene group (i.e., a divalent alkenyl substituent, =CH). Unless otherwise specified, an alkenyl group can be, for example, C1-C 24 , C1~C 18 , C1~C 10 , C1-C8, or C1-C6, and any number of carbon atoms, and any degree of unsaturation. Examples of alkenyl substituents include, but are not limited to, methylene / methylidyne (=CH2), ethylene / ethenyl (-CH=CH2 or =CH-CH3), propylene / propenyl (-CH2-CH=CH2, cis or trans-CH=CH-CH3, =C(CH3)2, or cis or trans =CH-CH2CH3), and the like. Alkenyl substituents herein may be substituted, i.e., one or more substituents may be attached to the alkenyl group or incorporated within the alkenyl chain. Substitution within an alkenyl substituent may include ether, sulfide, amino, or imine linkages, i.e., for example, -O-, -S-, -N(R')-, or -N=, or some other intervening heteroatom(s). Examples of substitutions on an alkenyl substituent include, but are not limited to, -CN, -N, -NH, -NHR, -N(R), -NO, -NH-NH, -NH-NHR, -NH-NR, -halo, -SH, -SR, -S(=O)R, -SO,R, -OPO 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 alkyl moieties, including, for example, C 1-6 Alkyl (e.g., -CH3, -C2H5, -isopropyl, -tert-butyl, etc.), C 1-6 Alkoxy (e.g., -OCH3, -OC2H5), halogenated C 1-6Alkyl (e.g., -CF3, -CHF2, -CH2F), and halogenated C 1-6 Alkoxy (eg, -OCF3, -OC2F5) is included. In various examples, two R' substituents of any of these functional groups may form a ring structure.

[0071] As used herein, the term "propylene glycol" or more simply "PG" refers to propane-1,2-diol (α-propylene glycol), as opposed to the 1,3-diol isomer, unless otherwise indicated. Furthermore, propylene glycol, as used herein, includes a racemic mixture of isomers unless otherwise indicated, and is typically produced on a global industrial scale by hydrolysis of propylene oxide. PG is generally the component in vaporizable compositions recognized as responsible for the white cloud of vapor seen during vaping.

[0072] As used herein, the term "vegetable glycerin" or more simply "VG" takes its ordinary meaning in organic chemistry and food science, which is HOCH-CH(OH)-CHOH derived triglycerides of vegetable origin.

[0073] As used herein, the term "inhalable" refers to a characteristic of vaporizable alkaloid compositions according to the present disclosure, namely, that the compositions are suitable for inhalation by a user. The inhalable alkaloid compositions disclosed herein are suitable for use in electronic cigarette devices because they are vaporizable, meaning that they can be vaporized by a heating element within such electronic devices, thereby enabling them to be inhaled by a user in an act known as "vaping." In other words, the vaporizable alkaloid compositions herein are inhalable compositions. Unless otherwise specified, the phrase "inhalable composition" or "inhalable compositions" refers to vaporizable alkaloid compositions according to the present disclosure.

[0074] As used herein, the terms "electronic cigarette" or "ENDS" (electronic nicotine delivery systems) generally refer to any electronic device capable of vaporizing a liquid composition into a vapor that can be inhaled by an individual using the device. Without being limiting, "electronic cigarette" herein refers to any design having a reservoir containing a vaporizable liquid therein and capable of vaporizing the vaporizable liquid, such as a cigar, vape pen, or any other electronic device, refillable or disposable. For simplicity, the term "electronic device" may be used to refer to any and all refillable and disposable appliances for vaping.

[0075] As used herein, the term "throat hit" refers to a sensory effect experienced in the back of the throat perceived by an individual inhaling vapor, such as vapor derived from burning tobacco or vapor delivered from an electronic device, such as an e-cigarette, capable of vaporizing a liquid composition. Throat hit is a type of pungent "bite" experienced in the back of the throat that smokers not only experienced but also anticipated and enjoyed before the development of e-cigarettes. While subjective rather than objective, throat hit can be quantified, for example, through the use of a sensory panel in which panel participants rank their perceived throat hit on a scale of 1 to 10, or by comparing throat hits between e-cigarette products and / or for e-cigarette products relative to conventional cigarettes. In some instances, throat hit may be quantified as being less than, equal to, or greater than the throat hit experienced from a particular cigarette. An exemplary cigarette used to standardize throat hit, such as a sensory panel in which participants rank the throat hit, is Marlboro® Filter Cigarettes, Gold Pack 100's, available from Phillips IGA. As described herein, throat hit can be achieved in an individual generally by including a chemosensory stimulant in the vaporizable alkaloid compositions of the present disclosure, and particularly by using a spice additive as the chemosensory stimulant.

[0076] As used herein, the term "vaping" refers to the act of using an electronic cigarette or other ENDS device to inhale electronically generated vapor from the vaporization of a liquid composition. Vaping is considered an endeavor similar to smoking tobacco products, recognizing that electronic cigarettes and vaping are not limited to nicotine. Vaping may also include personal inhalation of cannabinoids, nicotine analogs, other physiologically active substances, flavorings, etc.

[0077] As used herein, the terms "vape juice" or "e-juice" refer to a liquid composition that can be vaporized in an e-cigarette or other ENDS device to produce a vapor that can be inhaled by a vaping individual. Various embodiments herein describe vape juice compositions, which, in certain instances, include vaporizable alkaloid compositions and dilutions therefrom.

[0078] As used herein, the term "smoke cloud" refers to the white vapor visible when vape juice is vaporized, inhaled, and then exhaled by an e-cigarette or other ENDS device. As discussed herein, the smoke cloud is a characteristic sought by vapers and is therefore an important attribute for the success of a vape juice. While subjective rather than objective, the appearance of the smoke cloud can be quantified, for example, through the use of a sensory panel in which panel participants rank the appearance of the smoke cloud during vaping on a scale of 1 to 10, or by comparing the visible smoke cloud between e-cigarette products and / or to that seen in the air when smoking a conventional combustible cigarette. In some instances, the smoke cloud may be quantified as being less than, equal to, or greater than the smoke cloud seen when smoking a particular cigarette. An exemplary cigarette used to standardize the appearance of the smoke cloud, such as in a sensory panel in which participants rank the appearance of the smoke cloud, is Marlboro® Filter Cigarettes, Gold Pack 100's, available from Phillips IGA.

[0079] As used herein, the term "headache" refers to the lightheadedness experienced by cigarette smokers and vapers who inhale nicotine, nicotine analogs, THC, and other products containing physiologically active substances. Smokers describe this sensory experience as a ringing sensation in the head or a surge of adrenaline. This sensory effect is thought to be caused by nicotine or other drugs in the bloodstream, triggering the brain to release adrenaline, which causes blood vessels to constrict and temporarily increases the heart rate and blood pressure of those who inhale the active substance. This sensory experience is individual and varies between drug active substances and between individuals due to variations in physiological tolerance. Headaches can occur within 10 seconds of inhaling nicotine, or can take as long as 10 to 30 minutes. However, as smokers and vapers continue smoking or vaping, they become more tolerant, and the headache they typically experience shortens over time. Although subjective rather than objective, headiness can be quantified, for example, through the use of a sensory panel in which panel participants rank perceived headiness on a scale of 1 to 10 or compare perceived headiness between e-cigarette products and / or for e-cigarette products to conventional cigarettes. In some instances, headiness may be quantified as being less than, equal to, or greater than the headiness experienced from a particular cigarette, in comparison. An exemplary cigarette used to standardize throat hit, such as a sensory panel in which participants rank throat hit, is Marlboro® Filter Cigarettes, Gold Pack 100's, available from Phillips IGA.

[0080] As used herein, the term "chemosensory stimulant" has its ordinary meaning in physiology and neuroscience, i.e., a substance capable of producing a sensory irritation in an individual exposed to the substance. The irritation caused by a chemosensory stimulant upon inhalation may be sensed in the nose, mouth, throat, esophagus, and / or lungs, depending on the individual and the irritant. The sensory effect in the throat is referred to as a "throat hit" in the definition herein. Chemosensory irritants are most studied in the context of environmental and occupational health and safety, involving air pollutants and indoor environmental irritants such as formaldehyde. See, e.g., "Inhalation Toxicology,"2 nd Edition, H. Salem et al., editors, Taylor & Francis Group (CRC), 2006. In addition to subjective measurements of chemosensory irritation, such as panelists completing symptom questionnaires, various experimental techniques can be used to study chemical-induced irritation, such as examining functional changes in both humans and experimental animals, e.g., respiratory frequency and pattern, changes in nasal, bronchial, and pulmonary function parameters, nasal mucosal swelling, acoustic rhinometry, blink frequency, tear film stability, and chemosensory evoked potentials (see S.K.K. Jaergaar, et al., "The Assessment of Irritation Using Clinical Methods and Questionnaires," American Industrial Hygiene Association, 62(6):711-6, November 2001).

[0081] Chemosensory stimulants for use in the vaporizable alkaloid compositions of the present disclosure include compounds capable of causing physiological irritation in any one of an individual's nose, mouth, throat, esophagus, and lungs, where the physiological irritation is quantifiable. Examples of quantification methods include, but are not limited to, measuring nasal mucosal swelling, peak nasal airflow, acoustic rhinometry, and rhinostereometry to measure anterior turbinate thickness. Questionnaires are also useful for defining a set of symptoms to characterize dose-response relationships from controlled exposure studies.

[0082] In various embodiments, chemosensory stimulants for use in the vaporizable alkaloid compositions herein are substances capable of activating chemosensory ion channels known as transient receptor potential channels, or TRP channels, as described, 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), 2012 November;20(6):550-555. In addition to the subset of chemosensory stimulants defined hereinafter as "spice additives," many seemingly unrelated compounds are receptor agonists and can activate one or more TRP channels (e.g., A1, V1, V2, V3, V4, V5, or V6, M1, M2, M3, M4, M5, M6, M7, or M8 ion channels, etc.). These compounds include, for example, oleocanthal, 4-hydroxy-2-nonenal, 4-oxo-2-nonenal, allicin, allyl isothiocyanate, gingerol (found in the spice subset of stimulants), icilin, polygodial, cinnamaldehyde, trans-p-methoxycinnamaldehyde, various cannabinoids, methyl syringate, 2-chlorobenzylidenemalononitrile, 1-chloroacetophenone, ethyl bromoacetate, 4-hydroxyhexenal, toluene diisocyanate, p-benzoquinone, methyl p-hydroxybenzoate, flufenamic acid, and nif These include lumic acid, mefenamic acid, diclofenac, hydroxy-α-sanshool, 6-shogaol (in the spice subset of stimulants), 6-paradol, linalool, carvacrol, eugenol, thymol, vanillin, methyleugenol, 2,6-dimethylphenol, 2,5-dimethylphenol, 3,4-dimethylphenol, 2,6-diisopropylphenol, caffeine, farnesylthiosalicylic acid, 4-allylanisole, curcumin, capsaicin (in the spice subset of stimulants), niacin, camphor, olvanil, and arvanil.Nicotine is a known activator of TRPA1, but is excluded herein as a chemosensory stimulant for vaporizable alkaloid compositions. See, e.g., 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 vaporizable alkaloid compositions that specifically lack nicotine so that they can be used as an alternative to smoking. An inventive aspect of this composition is that it includes a chemosensory stimulant instead of nicotine so as to mimic the stimulating effects of tobacco smoke.

[0083] Chemosensory stimulants that are particularly useful in the vaporizable alkaloid compositions of the present invention include cannabinoids. Indeed, certain TRP receptors are referred to as cannabinoid receptors, such as CB1 and CB2. Six ion channels, TRPV1, TRPV2, TRPV3, TRPV4, TRPA1, and TRPM8, are known as ionotropic cannabinoid receptors. Therefore, cannabinoids that can bind to these receptors and activate the ion channels are considered chemosensory stimulants for use in the vaporizable alkaloid compositions described herein. For a review of cannabinoids and TRP ion channel activation, see C. Muller, et al., "Cannabinoid Ligands Targeting TRP Channels," Front. Mol. Neurosci., 11, 487 (2019).

[0084] Cannabinoids (endo, phyto, and synthetic) that can activate TRP ion channels and therefore can be used as chemosensory stimulants in the vaporizable alkaloid compositions of the present disclosure include, but are not limited to, anandamide (AEA), 2-AG, NADA, OLDA, PEA, NGABA, NGly, NAsp, NSer, Δ 9 -Tetrahydrocannabinol (Δ 9 -THC), Δ 9 -THCA, Δ9 -THCV, Δ 9 These include THCVA, CBD, CBDA, CBDV, CBG, CBGA, CBGV, CBN, and CBC, as well as the synthetic cannabinoids WIN55,212-2, AM630, (R)-AM1241, (S)-AM1241, SR141716A, Gp-1a, AM251, SR144528, JWH133, HU308, HU910, CP55,940, and nabilone. Of particular importance here is CBD (cannabidiol), which has been shown to be the most potent and effective phytocannabinoid agonist for TRPV1. Also, ΔCBD is considered to be the most potent phytocannabinoid for activating TRPV2. 9 -THC is identified, but Δ 9 -THC is not selective, as it also activates TRPA1.

[0085] Additionally, chemosensory stimulants that activate TRP ion channels and thus find use in the vaporizable alkaloid compositions herein include numerous compounds naturally occurring in various plants, trees, shrubs, roots, flowers, fruits, seeds, and nuts. Such compounds are disclosed, for example, by J. Vriens, et al., "Herbal Compounds and Toxins Modulating TRP Channels," Curr. Neuropharmacol., 2008 Mar;6(1):79-96. In various embodiments, in addition to the "spice additives" as defined and discussed herein, including compounds such as capsaicinoids, gingerols, and shogaols, other TRP channel activators are useful herein, including those used herein and including resiniferoids from Euphorbia reinifera, eugenols from Euenia carophyllata and Ocimum gratissiumum, ginsenosides from Panax, zingerone and paradol obtained from heating or drying gingerols or from Aframomum melgueta seeds, goshuyu compounds from Evodia rutaecarpa, 1,4-dialdehyde sesquiterpenes isolated from Drymis winteri, such as polygodial, isovelleral, and drimanial, Cinnamosma, such as cinnamodial, cinnamosmolide, and cinnamolides. Other 1,4-dialdehyde terpenes include those derived from Saccharomyces fragrans, or warbuganal, derived from the Warburgia plant.In vitro assays used to measure activation of TRP ion channels 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, 2017 May;60:178-186, and J.M. Martinez, et al., "Activation of TRPA1 by volatile organic chemicals leading to sensory irritation," ALTEX 2019;36(4):572-582. As used herein, other in vitro assays include those derived from Scutellaria baicalensis (most specifically the phytochemicals baicalein, baicalin, wogonin, norwogonin, oroxylin A, and β-sitosterol), Vitex agnus, Pterodon pubescens, Croton macrostachyus, Angelicae pubescentis, Ephedra sinica, Amphilophium crucigerum, Bosewellia Further important are phytochemicals present in Scutellaria barbata, Scutellaria barbata, Scutellaria barbata (listed in the spice additive subset of irritants), Scutellaria barbata, ...

[0086] As used herein, the term "spice additive" refers to an organic substance that can produce a throat hit or other similar "hot," "stinging," or otherwise "burning" sensation at least in the back of the throat, and optionally in the mouth and on the lips, when the spice additive is vaporized and inhaled by an individual, such as a vaper. The spice additives herein form a subset of chemosensory stimulants, known to activate one or more TRP ion channels. Because these groups of compounds may initially appear structurally unrelated, "spice additives" herein can be clearly defined as organic substances having a heat or "hotness" ranging from about 1,000 to about 20,000,000 Scoville Pungency Units (SHU). At the lower end of the Scoville scale, compounds for use herein include, but are not limited to, gingerol (60,000 SHU), piperine (100,000 SHU), and shogaol (160,000 SHU). In a more preferred embodiment, the spice additives for use in the vaporizable alkaloid compositions herein have a Scoville rating of about 100,000 to about 20,000,000 SHU, more preferably about 10,000,000 to about 20,000,000 SHU, and include all of the known capsaicinoids, such as capsaicin (16,000,000 SHU) and dihydrocapsaicin (15,000,000 SHU), as well as uncharacterized capsaicinoids that are likely isomers of known capsaicinoids. Although chemically unrelated to capsaicinoids, compounds such as piperine (100,000 SHU) and shogaol (160,000 SHU) find use in the compositions of the present invention. Capsaicinoid spice additives for use herein include, but are not limited to, capsaicin, dihydrocapsaicin, norcapsaicin, nordihydrocapsaicin, homocapsaicin, homodihydrocapsaicin, and mixtures thereof. Chemically pure or otherwise isolated capsaicinoids are not required for the vaporizable alkaloid compositions of the present invention, as it is also convenient to prepare various compositions using extracts of spice additives.For example, capsaicinoids can be extracted from chili peppers or other peppers using room temperature or boiling ethanol (such as 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 yield a dark red, viscous mixture of capsaicinoids (the red color is believed to come from β-carotene). See, for example, 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, 15 June 2023, Article 135488.

[0087] As used herein, the terms "liquid capsaicin" or "capsaicin liquid" refer to an ethanol or other solvent extract of fruit obtained from plants of the genus Capsicum annuum, such as various chili peppers. A preferred liquid capsaicin for use herein contains about 0.9% capsaicinoids by weight in ethanol and is available from Olive Nation, LLC, Avon, MA, under the name Capsicum Flavor Extract.

[0088] It should be noted that the "flavoring agents" that are optional in the vaporizable alkaloid compositions herein are defined separately and entirely distinct from "chemosensory stimulants and the subset of stimulants referred to herein as 'spice additives'."

[0089] As used herein, "flavoring agent" has its conventional meaning in food science, with the caveat that flavoring agents herein intentionally exclude compounds containing capsaicinoids. This means that flavoring agents herein are distinct from spice additives, as defined herein, because, by definition, they do not have a measurable or calculable Scoville pungency rating. Flavoring agents for use herein include, but are not limited to, ethyl maltol, ethyl butyrate, ethyl acetate, maltol, ethyl vanillin, furaneol, methylcyclopenenolone, δ-decalactone, γ-decalactone, cis-3-hexanol, isoamyl acetate, ethyl 2-methylbutyrate, butyric acid, linalool, benzyl alcohol, ethyl hexanoate, benzaldehyde, isoamyl isovalerate, hexanoic acid, ethyl propionate, γ-undecalactone, and hexyl acetate.

[0090] As used herein, the term "about" refers to an amount, level, value, number, frequency, percentage, dimension, size, amount, weight, or length that varies by as much as 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1% relative to a reference amount, level, value, number, frequency, percentage, dimension, amount, weight, or length. For example, an amount expressed as "about 5% by weight" includes a variation of up to 4.5-5.5% by weight.

[0091] As used herein, the term "smoking cessation program" refers to a plan provided to current smokers by a medical clinic, pharmacy, or any other entity to help the individual quit smoking. In various embodiments, the smoking cessation program herein involves providing an individual in need thereof with a vaping liquid (or providing a disposable electronic device pre-filled with the vaping liquid) designed to help the individual follow a predetermined program and reduce and / or ultimately eliminate smoking. In certain instances, the clinic, pharmacy, or other entity meets periodically with individuals in the cessation program, interviews the individual regarding compliance, and supplies the individual with a customized vaporizable composition designed to gradually transition the smoker completely to e-vaping.

[0092] (General embodiment) The vaporizable alkaloid compositions of the present disclosure are optimized to provide an improved user experience. An individual's experience from inhaling vaporized liquid delivered from an electronic device can, and arguably should, be similar, if not the same, as the experience a user would get from smoking a combusted tobacco, but this can only be achieved if certain interrelated sensory effects, including throat hit, lightheadedness, nose and mouth sensation and taste, and the appearance of the smoke cloud, are balanced. These factors constitute the user experience.

[0093] Surprisingly, it has now been discovered that an improved user experience depends on having a unique combination, precise amounts, and ratio of a substituted pyridine compound or its salt or mixed salt, and a spice additive that can provide a stronger throat-burning sensation than that obtained by inhaling propylene glycol vapor alone. The vaporizable inhalable compositions of the present disclosure depend on the precise amounts and ratios of the substituted pyridine compound or its salt or mixed salt and the spice additive. Furthermore, having some of the corresponding organic acid salt of the substituted pyridine compound in the inhalable composition reduces the harshness, ensuring that the user experiences the desired headiness while still perceiving a smoothness.

[0094] In various embodiments, the vaporizable alkaloid compositions herein comprise: At least one substituted pyridine compound of formula (I) or a salt or mixed salt thereof,

[0095] [ka]

[0096] In the formula, R 1 , R 2 , R 3 , R 4 , and R 5 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl, with R 5 If is CH3, then R 1 , R 2 , R 3 , and R 4 at least one substituted pyridine compound of formula (I) or a salt or mixed salt thereof, with the proviso that all of at least one chemosensory stimulant; at least one solvent; optionally at least one flavoring agent; The vaporizable alkaloid composition is completely devoid of nicotine.

[0097] In various embodiments, the at least one chemosensory stimulant is a phytochemical, such as baicalein, baicalin, wogonin, norwogonin, oroxylin A, β-sitosterol, cannabidiol, anandamide, and Δ 9 -Tetrahydrocannabinol, or compounds found in Scutellaria baicalensis, Cannabis sativa, or Cannabis indica, or extracts thereof.

[0098] In various embodiments, the at least one chemosensory stimulant is a spice additive that provides a heat intensity of about 1,000 to about 20,000,000 Scoville Pungency Units (SHU), such as capsaicin, shogaol, and gingerol.

[0099] Alternatives for each of these components in the present compositions are described below and above in the definitions section.

[0100] (1. Alkaloid compounds and their salts or mixed salts) In various embodiments, the vaporizable alkaloid composition comprises at least one substituted pyridine compound according to formula (I) or a salt or mixed salt thereof,

[0101] [ka]

[0102] In the formula, R 1 , R 2 , R 3 , R 4 , and R 5 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl, with R 5 If is CH3, then R 1 , R 2 , R 3 , and R 4The vaporizable alkaloid compositions of the present disclosure include at least one substituted pyridine compound according to formula (I), or a salt or mixed salt thereof, with the proviso that (R) and (S) enantiomers of nicotine cannot all be H. This conditional language explicitly excludes both the (R) and (S) enantiomers of nicotine from consideration in compositions according to the present disclosure. The vaporizable alkaloid compositions of the present disclosure are designed for use in smoking cessation programs and preferably do not contain nicotine. Thus, the chemosensory stimulant for use in the vaporizable alkaloid compositions herein explicitly excludes both the (R) and (S) enantiomers of nicotine from consideration, even though nicotine is a known chemosensory stimulant.

[0103] In various embodiments, vaporizable alkaloid compositions according to the present disclosure contain from about 1% to about 80% by weight of a substituted pyridine compound of Formula (I) when added to the composition. In more preferred embodiments, vaporizable alkaloid compositions according to the present disclosure contain from about 4% to about 20% by weight of a substituted pyridine compound when added to the composition, e.g., to target a w / v amount of from about 100 to about 250 mg / mL of the substituted pyridine compound. In even more preferred embodiments, vaporizable alkaloid compositions according to the present disclosure contain from about 4% to about 12% by weight of a substituted pyridine compound when added to the composition, e.g., to target a w / v amount of from about 100 mg / mL of the substituted pyridine compound.

[0104] "Upon addition" refers to what is added to the batch regardless of whether any reaction occurs between components in the composition, such as reaction of the free base alkaloid with an organic acid to form at least some alkaloid salt.

[0105] In formula (I), the carbon centre of the pyrrolidine ring marked with (*) is R 1 , R 2 , R 3 , R 4 , and R 5 Note that regardless of the choice of , it is always a chiral center.

[0106] In various examples, the substituted pyridine compounds according to formula (I) are racemic mixtures of (R) and (S) at the indicated chiral center (*), as obtained by non-chiral synthesis.

[0107] In various examples, the substituted pyridine compounds according to formula (I) are only the (S) enantiomer of the indicated chiral center (*), as obtained by chiral synthesis or by separation of enantiomers from a racemic mixture. In certain examples, the (S)-substituted pyridine compounds of formula (I) are preferred alkaloids for the vaporizable alkaloid compositions herein.

[0108] In various instances, the substituted pyridine compounds according to formula (I) are only the (R) enantiomer of the indicated chiral center (*), as obtained by chiral synthesis or separation of enantiomers. In certain instances, the (R)-substituted pyridine compounds of formula (I) are not preferred alkaloids for the vaporizable alkaloid compositions herein due to the potential for adverse physiological effects upon inhalation.

[0109] In various embodiments, R 5 Independently of R 1 , R 2 , R 3 , and R 4 At least one of the R is methyl, and the remaining R is not methyl. 1 , R 2 , R 3 , and R 4 The substituent is H.

[0110] In various embodiments, R 5 is CH3 and R 1 , R 2 , R 3 , and R 4 At least one of them is not H.

[0111] In various embodiments, R 1 , R 2 , R 3 , R 4 , and R 5 are H, respectively.

[0112] In various embodiments, R 5 is -(CH2)n-NR 6 R 7 where n is an integer from 1 to 10, 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 taken together with the N atom to which they are attached form a 3-8 membered optionally substituted heterocyclic ring, including, for example, aziridine, azetidine, pyrrolidine, piperidine, 1,4-piperazine, and morpholine. In various embodiments, R 1 , R 2 , R 3 , and R 4 Independently of R 5 are -(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.

[0113] In various embodiments, R 1 , R 2 , R 3 , and R 4 Independently of R 5 teeth,

[0114] [ka]

[0115] (wherein n is 1 to 10),

[0116] [ka]

[0117] (wherein n is 1 to 10),

[0118] [ka]

[0119] (wherein n is 1 to 10),

[0120] [ka]

[0121] (wherein n is 1 to 10), and

[0122] [ka]

[0123] wherein n is 1 to 10; and R 8 is selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl.

[0124] In various embodiments, R 1 , R 2 , R 3 , and R 4 Independently of R 5 teeth,

[0125] [ka]

[0126] (wherein n is 1 to 10), and R 8is H or CH3.

[0127] In various embodiments, R 5 is H and R 1 , R 2 , R 3 , and R 4 At least one of the groups is -(CH2)n-NR 6 R 7 where n is an integer from 1 to 10, 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 with the N atom to which they are attached form a 3- to 8-membered optionally substituted heterocyclic ring.

[0128] In various embodiments, R 5 is CH3 and R 1 , R 2 , R 3 , and R 4 At least one of the groups is -(CH2)n-NR 6 R 7 where n is an integer from 1 to 10, 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 with the N atom to which they are attached form a 3- to 8-membered optionally substituted heterocyclic ring.

[0129] In various embodiments, R 5 is CH3 and R 1 , R 2 , R 3 , and R 4 At least one of the groups is -(CH2)nN(CH3)2, where n is an integer of 1 to 10.

[0130] In various embodiments, substituted pyridine compounds of formula (I) for use in the vaporizable alkaloid compositions herein include, but are not limited to, (R) or (S)-3-(pyrrolidin-2-yl)pyridine, (R) or (S)-2-methyl-3-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-4-methyl-3-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-3-methyl-5-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-2,6-dimethyl-3-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-2,4-dimethyl-5-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-2,3-dimethyl-5-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-2,4-dimethyl-3-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-2,5-dimethyl-3-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-3,4-dimethyl-5-(1-methylpyrrolidin-2-yl)pyridine , (R) or (S)-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)propanenitrile, (R) or (S)-4-(2-(6-methylpyridin-3-yl)pyrrolidin-1-yl)butanenitrile, (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)pyrrolidin-1-yl)ethyl)pyrrolidin-1-yl)pyridine (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.

[0131] In various embodiments, substituted pyridine compounds of formula (I) for use in the vaporizable alkaloid compositions herein include, but are not limited to:

[0132] [ka]

[0133] [ka]

[0134] [ka]

[0135] [ka]

[0136] [ka]

[0137] [ka]

[0138]

change

[0139]

change

[0140]

change

[0141]

change

[0142]

change

[0143]

change

[0144]

change

[0145]

change

[0146]

change

[0147]

change

[0148]

change

[0149] [ka]

[0150] Also included.

[0151] In each of the above examples, the (S) enantiomer is likely to be active as a nicotinic acetylcholine receptor ligand and is preferred, while the (R) enantiomer is likely to be physiologically inactive or even metabolically toxic in some cases. For this reason, in preferred embodiments, racemic mixtures are not used for any of these alkaloids.

[0152] In various embodiments, R 1 , R 2 , R 3 , R 4 , and R 5 is independently selected from H, methyl, ethyl, n-propyl, iso-propyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, while R 5 If is methyl, then R 1 , R 2 , R 3 , and R 4 However, the condition is that they cannot all be H.

[0153] In a preferred example, R 1 and R 5 are both methyl, and R 2 , R 3 , and R 4 are each H, and the chiral center (*) has the (S) configuration.

[0154] Of particular interest for the present compositions is (S)-2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine, which has the chemical structure (1):

[0155] [ka]

[0156] or a salt thereof or a mixed salt thereof.

[0157] A chiral synthesis of alkaloid (1) was disclosed by C.G. Chavdarian, et al. in U.S. Pat. No. 4,321,387, issued to Philip Morris, Inc. in 1982. This compound can be made by the Philip Morris synthetic route or by another suitable chiral synthetic route known or devised by one of ordinary skill in the art, or can be obtained from a commercial supplier such as, for example, Toronto Research Chemicals, Toronto, Ontario, Canada, catalog number M323270.

[0158] Salts or mixed salts of the alkaloids of formula (I) are useful herein and are prepared by reacting the substituted pyridine compound (I) with an inorganic or preferably organic acid R 9 R can be obtained by simple reaction with —COH or a mixture of organic acids in a suitable solvent under ambient reaction conditions or with heating. 9 is selected according to the desired corresponding organic acid (e.g., R for formic acid). 9 =H, R for acetic acid 9 =CH3, R for citric acid 9 =-CH(CO2H)-CH2-CO2H, etc.), so R 9 is selected from alkyl, cycloalkyl, aryl, and heterocyclyl, any of which may be optionally substituted.

[0159] Reaction Scheme A shows the basic synthesis of alkaloid salts for use in the vaporizable alkaloid compositions of the present disclosure when an organic acid rather than an inorganic acid is used.

[0160] (Reaction Scheme A - Basic Synthesis of Alkaloid Salts)

[0161] [ka]

[0162] In the above Reaction Scheme A, the free base alkaloid (I) and the acid R 9 While the molar ratio of -COH or a mixture of acids may be precisely known, recognizing that some organic acids are more than monovalent and may also act as chelating agents, no attempt is made to quantify or characterize the resulting salt or mixed salt (Ia) or to quantify the reaction completeness. Various acid-to-base ratios may be formed (i.e., salts other than 1:1 acid-to-base ratios). For example, nicotine salts made from various organic acids are described by TA Perfetti, "Structural Study of Nicotine Salts," Beitrage zur Tabakforschung International, 12(2), 43-54, 1983, in which acid-to-base ratios of 1:1, 2:1, and 3:1 were found with nicotine. In this reference, Perfetti discloses that nicotine forms 3:1 acid to base salts with aliphatic monocarboxylic acids such as acetic acid, where one acid molecule is attached as in a 1:1 salt and two other acid molecules are attached to the nitrogens of the pyridine ring; 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. Therefore, R 9 If -CO2H represents a mixture of organic acids, the resulting alkaloid salt (Ia) may not be able to be characterized.

[0163] In the above reaction scheme A, the organic acid R 9-COH can be any of the acids disclosed herein, including formic acid, acetic acid, trifluoroacetic acid, aspartic acid, butanoic 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. Citric acid, acetic acid, benzoic acid, tartaric acid, lactic acid, salicylic acid, malic acid, levulinic acid, and mixtures thereof are preferred for use herein.

[0164] In Reaction Scheme A above, the solvent may be selected based on its suitability, i.e., its pharmaceutically acceptable or otherwise deemed "safe," for a composition intended to be vaporized and inhaled. In other words, recognizing that this acid / base reaction may occur in situ, the alkaloid salt (Ia) is not isolated; rather, the resulting reaction mixture becomes a vaporizable alkaloid composition according to the present disclosure. In these cases, the solvent is selected from the group consisting of propylene glycol, glycerin, ethanol, water, and mixtures thereof. Typically, Reaction Scheme A can be carried out in a solvent mixture of propylene glycol / ethanol with a small amount of water (such as that incorporated in the reaction from the use of 190-proof ethanol). If necessary, the final reaction mixture can be cooled and filtered before use in an electronic device.

[0165] In a preferred embodiment, a deficient amount of organic acid R is added to produce a mixture of alkaloid salt and unreacted alkaloid free base, which then remain together in the vaporizable alkaloid composition. 9-COH is used in Reaction Scheme A (or in the composition if performed in situ). In a less preferred embodiment, a sufficient amount or excess of organic acid R is used so that it is likely that no free base alkaloid remains. 9 -CO2H is used in the reaction to drive the salt formation to completion.

[0166] In various embodiments, it is preferred to have a molar excess of the substituted pyridine free base compound relative to the one or more organic acids such that the formation of the alkaloid salt is an incomplete reaction and the vaporizable alkaloid composition contains both the alkaloid organic acid salt and unreacted alkaloid free base.

[0167] In various embodiments, the vaporizable alkaloid compositions herein comprise from about 0.05% to about 1.5%, preferably from about 0.05% to about 0.15%, by weight of total organic acid(s), based on the total weight of the composition, with typical amounts of substituted pyridine compounds being from about 1% to about 80% by weight.

[0168] In various embodiments, the substituted pyridine free base compound and the total organic acid(s) R 9 The molar ratio of —COH to —COH is from about 25:1 to about 75:1, more preferably about 50:1. This ratio can be kept constant, so that in compositions with increasing amounts of substituted pyridine free base compound, the total organic acid(s) R is increased to maintain this molar ratio. 9 The amount of -CO2H may also increase.

[0169] It should be emphasized that it is not necessary to isolate any of the desired salts of the substituted pyridine compounds for use in the present vaporizable alkaloid compositions. The vaporizable alkaloid compositions can be prepared by combining the substituted pyridine free base compounds with the desired organic acid(s) in a solvent system, with the alkaloid salts formed in situ, and the reaction mixture thus formed being the vaporizable alkaloid composition.

[0170] In various preferred embodiments, (S)-2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine 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. In more preferred embodiments, (S)-2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine is reacted with a molar deficiency combination of citric acid and acetic acid.

[0171] For the vaporizable alkaloid compositions of the present disclosure, preferred salts and mixed salts of the substituted pyridine compounds of formula (I) include, but are not limited to: (2S)-1-methyl-2-(6-methylpyridin-3-yl)pyrrolidin-1-ium acetate, (2S)-1-methyl-2-(5-methylpyridin-3-yl)pyrrolidin-1-ium acetate, (2S)-1-methyl-2-(4-methylpyridin-3-yl)pyrrolidin-1-ium acetate, (2S)-1-methyl-2-(2-methylpyridin-3-yl)pyrrolidin-1-ium acetate, (2S)-2-(2,4-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium acetate, (2S)-2-(2,5-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium acetate, (2S)-2-(2,6-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium acetate, (2S)-2-(4,5-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium acetate, (2S)-2-(4,6-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium acetate, (2S)-2-(5,6-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium acetate, (2S)-1-methyl-2-(6-methylpyridin-3-yl)pyrrolidin-1-ium citrate, (2S)-1-methyl-2-(5-methylpyridin-3-yl)pyrrolidin-1-ium citrate, (2S)-1-methyl-2-(4-methylpyridin-3-yl)pyrrolidin-1-ium citrate, (2S)-1-methyl-2-(2-methylpyridin-3-yl)pyrrolidin-1-ium citrate, (2S)-2-(2,4-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium citrate, (2S)-2-(2,5-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium citrate, (2S)-2-(2,6-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium citrate, (2S)-2-(4,5-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium citrate, (2S)-2-(4,6-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium citrate, (2S)-2-(5,6-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium citrate, (2S)-1-methyl-2-(6-methylpyridin-3-yl)pyrrolidin-1-ium citrate / acetate, (2S)-1-methyl-2-(5-methylpyridin-3-yl)pyrrolidin-1-ium citrate / acetate, (2S)-1-methyl-2-(4-methylpyridin-3-yl)pyrrolidin-1-ium citrate / acetate, (2S)-1-methyl-2-(2-methylpyridin-3-yl)pyrrolidin-1-ium citrate / acetate, (2S)-2-(2,4-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium citrate / acetate, (2S)-2-(2,5-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium citrate / acetate, (2S)-2-(2,6-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium citrate / acetate, (2S)-2-(4,5-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium citrate / acetate, (2S)-2-(4,6-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium citrate / acetate, (2S)-2-(5,6-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium citrate / acetate, (2S)-1-methyl-2-(6-methylpyridin-3-yl)pyrrolidin-1-ium benzoate, (2S)-1-methyl-2-(5-methylpyridin-3-yl)pyrrolidin-1-ium benzoate, (2S)-1-methyl-2-(4-methylpyridin-3-yl)pyrrolidin-1-ium benzoate, (2S)-1-methyl-2-(2-methylpyridin-3-yl)pyrrolidin-1-ium benzoate, (2S)-2-(2,4-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium benzoate, (2S)-2-(2,5-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium benzoate, (2S)-2-(2,6-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium benzoate, (2S)-2-(4,5-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium benzoate, (2S)-2-(4,6-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium benzoate, (2S)-2-(5,6-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium benzoate, (2S)-1-methyl-2-(5-methylpyridin-3-yl)pyrrolidin-1-ium bitartrate, (2S)-1-methyl-2-(4-methylpyridin-3-yl)pyrrolidin-1-ium bitartrate, (2S)-1-methyl-2-(2-methylpyridin-3-yl)pyrrolidin-1-ium ditartrate, (2S)-2-(2,4-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium bitartrate, (2S)-2-(2,5-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium bitartrate, (2S)-2-(2,6-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium bitartrate, (2S)-2-(4,5-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium bitartrate, (2S)-2-(4,6-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium bitartrate, (2S)-2-(5,6-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium ditartrate, (2S)-1-methyl-2-(5-methylpyridin-3-yl)pyrrolidin-1-ium lactate, (2S)-1-methyl-2-(4-methylpyridin-3-yl)pyrrolidin-1-ium lactate, (2S)-1-methyl-2-(2-methylpyridin-3-yl)pyrrolidin-1-ium lactate, (2S)-2-(2,4-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium lactate, (2S)-2-(2,5-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium lactate, (2S)-2-(2,6-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium lactate, (2S)-2-(4,5-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium lactate, (2S)-2-(4,6-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium lactate, (2S)-2-(5,6-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium lactate, (2S)-1-methyl-2-(5-methylpyridin-3-yl)pyrrolidin-1-ium levulinate, (2S)-1-methyl-2-(4-methylpyridin-3-yl)pyrrolidin-1-ium levulinate, (2S)-1-methyl-2-(2-methylpyridin-3-yl)pyrrolidin-1-ium levulinate, (2S)-2-(2,4-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium levulinate, (2S)-2-(2,5-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium levulinate, (2S)-2-(2,6-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium levulinate, (2S)-2-(4,5-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium levulinate, (2S)-2-(4,6-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium levulinate, (2S)-2-(5,6-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium levulinate, (2S)-1-methyl-2-(4-methylpyridin-3-yl)pyrrolidin-1-ium malate, (2S)-1-methyl-2-(2-methylpyridin-3-yl)pyrrolidin-1-ium malate, (2S)-2-(2,4-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium malate, (2S)-2-(2,5-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium malate, (2S)-2-(2,6-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium malate, (2S)-2-(4,5-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium malate, (2S)-2-(4,6-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium malate, (2S)-2-(5,6-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium malate, (2S)-1-methyl-2-(4-methylpyridin-3-yl)pyrrolidin-1-ium salicylate, (2S)-1-methyl-2-(2-methylpyridin-3-yl)pyrrolidin-1-ium salicylate, (2S)-2-(2,4-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium salicylate, (2S)-2-(2,5-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium salicylate, (2S)-2-(2,6-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium salicylate, (2S)-2-(4,5-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium salicylate, (2S)-2-(4,6-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium salicylate, and (2S)-2-(5,6-dimethylpyridin-3-yl)-1-methylpyrrolidin-1-ium salicylate is included.

[0172] In various embodiments, the vaporizable alkaloid compositions herein comprise about 1% to about 20% by weight of at least one substituted pyridine compound of Formula (I) or a salt thereof or a mixed salt thereof, more preferably about 4% to about 12% by weight 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 vaporizable alkaloid composition. In preferred embodiments, the amount of substituted pyridine compound of Formula (I) in the vaporizable alkaloid composition can be targeted for 100 mg / mL (w / v), recognizing that the vaporizable alkaloid 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 amount or alkaloid (w / v) less than 100 mg / mL.

[0173] In a more preferred embodiment, the vaporizable alkaloid composition herein comprises from about 4% to about 12% by weight of (S)-2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine, when added to the composition, based on the total weight of the vaporizable alkaloid composition.

[0174] (1a. Alternative alkaloids) In another embodiment of the present disclosure, the vaporizable alkaloid composition herein comprises at least one substituted pyridine compound according to formula (II) or a salt or mixed salt thereof,

[0175] [ka]

[0176] In the formula, R 1 , R 2 , R 3 , R 4 , R 10 , R 11 , and R 12 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl, and n is an integer from 1 to 10, or a salt or mixed salt thereof.

[0177] In various embodiments, R 11 and R 12 are both H.

[0178] In various embodiments, R 11 is CH3 and R 12 is H.

[0179] In various embodiments, R 11 and R 12 are both CH3.

[0180] In various embodiments, n is an integer from 1 to 4.

[0181] Preferred R1 , R 2 , R 3 , and R 4 The substituents follow the options set out above for compounds of formula (I).

[0182] In various examples, substituted pyridine compounds of formula (II) for use in the vaporizable alkaloid compositions of the present disclosure include, but are not limited to:

[0183] [ka]

[0184] [ka]

[0185] [ka]

[0186] [ka]

[0187] [ka]

[0188] [ka]

[0189] Includes:

[0190] (2. Chemosensory Stimulants) Chemosensory stimulants for use in the vaporizable alkaloid compositions of the present disclosure include any natural, endogenous, phytochemical, or synthetic compound, including those derived from naturally occurring compounds by organic chemistry, that can activate TRP ion channels. Assays that can be used to determine whether a compound is in fact a TRP ion channel activator can be found, for example, in H.P. 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.

[0191] Chemosensory stimulants for use herein include, but are not limited to, 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, Mefenamic acid, diclofenac, hydroxy-α-sanshool, 6-paradol, linalool, carvacrol, eugenol, thymol, vanillin, methyl eugenol, 2,6-dimethylphenol, 2,5-dimethylphenol, 3,4-dimethylphenol, 2,6-diisopropylphenol, caffeine, farnesylthiosalicylic acid, 4-allylanisole, curcumin, niacin, camphor, olvanil, arvanil, anandamide (AEA), 2-AG, NADA, OLDA, PEA, NGABA, NGly, NAsp, NSer, Δ 9 -Tetrahydrocannabinol (Δ 9 -THC), Δ 9 -THCA, Δ 9 -THCV, Δ9 -THCVA, CBD, CBDA, CBDV, CBG, CBGA, CBGV, CBN, CBC, WIN55,212-2, AM630, (R)-AM1241, (S)-AM 1241, SR141716A, Gp-1a, AM251, SR144528, JWH133, HU308, HU910, CP55,940, Nabilone, Euphorbia reinifera, Euenia carophyllata, Ocimum gratissiumum, Panax, Aframomum melgueta, Evodia rutaecarpa, Drymis winteri, Cinnamosma fragrans, Warburgia, Scutellaria baicalensis, Vitex agnus, Pterodon pubescens, Croton macrostachyus, Angelicae pubescentis, Ephedra The term "spice additives" includes various phytochemicals derived from plants such as Capsicum annuum, Zingiber officinale, and Piper nigrum, as well as various phytochemicals derived from plants such as Capsicum annuum, Zingiber officinale, and Piper nigrum. The term "spice additives" includes various phytochemicals derived from plants such as Capsicum annuum, Zingiber officinale, and Piper nigrum, as well as various phytochemicals derived from plants such as Capsicum annuum, Zingiber officinale, and Piper nigrum. The term "spice additives" includes various phytochemicals derived from Capsicum annuum, Zingiber officinale, and Piper nigrum, as well as various phytochemicals derived from Capsicum annuum, Zingiber officinale, and Piper nigrum. The term "spice additives" includes ...

[0192] According to various embodiments, spice additives for use as chemosensory stimulants in the vaporizable alkaloid compositions of the present disclosure are organic compounds having a spiciness or heat of about 1,000 to about 20,000,000 Scoville Pungency Units (SHU), more preferably about 100,000 to about 20,000,000 Scoville Pungency Units (SHU). Thus, for purposes of this specification, spice additives are a defined group of chemical compounds. The calculation of Scoville Pungency Units is based on the American Spice Trade Associate (ASTA) 1985 Official Analytical Methods of the American Spice Trade Association, 3 rd ed., American Spice Trade Assn., Englewood Cliffs, NJ.

[0193] In various embodiments, the spice additives herein comprise a capsaicinoid or a mixture of capsaicinoids. In one particular example, the liquid extract comprises a mixture of capsaicinoids prepared by solvent extraction of chili peppers, which are known to contain a mixture of capsaicinoids rather than just capsaicin. In other embodiments, the capsaicin is sourced and used.

[0194] In other examples, spice additives that are not chemically related to capsaicinoids but nevertheless have measurable pungency levels reported in Scoville units are used. These compounds are typically extracted from peppers other than chili peppers (Capsicum annuum), such as black pepper (Piper nigrum L.), and the most useful spice additive that is not a capsaicinoid is piperine (E,E or trans-trans isomer). Other spice additives for use herein that are not capsaicinoids include, but are not limited to, shogaol, gingerol, isopiperine, chavicin, isochavicin, 2-piperamine, piperanine (4,5-dihydropiperine), piperamide, 4-piperiside, piperiline, piperlonguminine, piperettine, piperdaldine (6,7-dihydropiperettine), 5-sarmentodine, 6-sarmentine, and 7-trichostatin.

[0195] In various embodiments, the spice additive is selected from the group consisting of capsaicin, dihydrocapsaicin, norcapsaicin, nordihydrocapsaicin, homocapsaicin, homodihydrocapsaicin, gingerol, piperine, shogaol, and mixtures thereof. While capsaicinoids other than the six specifically identified may be used in the compositions herein, it should be noted that at least seven different capsaicinoids exist in the genus Capsicum annuum, and two of these, possibly capsaicin and dihydrocapsaicin, together, are described as being responsible for the heat of chili peppers. See MD Collins, et al., "Improved Method for Quantifying Capsaicinoids in Capsicum Using High-Performance Liquid Chromatography," HortScience 30(1):137-139, 1995. Although the compounds referred to above fall within the general class of chemosensory stimulants, it is convenient to categorize these compounds into a subset of chemosensory stimulants, defined as spice additives having a heat intensity of about 1,000 to about 20,000,000 Scoville Pungency Units (SHU).

[0196] In various embodiments, the vaporizable alkaloid compositions herein comprise from about 0.0001% to about 0.5% by weight of a spice additive, based on the total weight of the vaporizable alkaloid composition, and the spice additive exhibits a heat or pungency of from about 1,000 to about 20,000,000 Scoville Pungency Units (SHU). For spice additives having a heat intensity of more than about 10,000,000 SHU, this amount can be significantly reduced, such as from 0.0001% to about 0.01% by weight of the spice additive, based on the total weight of the composition.

[0197] In a preferred embodiment, the vaporizable alkaloid compositions herein comprise capsaicin ((E)-N-[(4-hydroxy-3-methoxyphenyl)methyl]-8-methylnon-6-enamide, CAS number 404-86-4). In its pure form (100% active), capsaicin is a white crystalline solid with an MP of 65° C. Purified material may be used directly in the compositions herein and is available, for example, from Sigma-Aldrich Co., VWR Avantor, and Alfa Chemistry, among other chemical suppliers.

[0198] In a preferred embodiment, the vaporizable alkaloid composition herein contains about 0.0001% to about 0.01% by weight of capsaicin ((E)-N-[(4-hydroxy-3-methoxyphenyl)methyl]-8-methylnon-6-enamide), based on the total weight of the vaporizable alkaloid composition. In a more preferred example, the amount of capsaicin is about 0.0005% to about 0.0015% by weight, based on the total weight of the composition.

[0199] In various instances, "liquid capsaicin" is used in the vaporizable alkaloid compositions herein for reasons of cost and practicality, among others. For example, Capsicum Flavor Extract, available in drum-to-gallon quantities from OliveNation, LLC, Avon, MA, can be used. 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 commercially available material is about 99.1% ethanol by weight and about 0.9% capsaicinoid active substance by weight.

[0200] In various embodiments, the vaporizable alkaloid compositions herein comprise about 0.05% to about 0.15% by weight of capsicum juice (e.g., Capsicum Flavor Extract from Olive Nation LLC, having about 0.9% by weight of active capsaicinoids), based on the total weight of the vaporizable alkaloid composition.

[0201] (3. Solvent) In various embodiments, the vaporizable alkaloid compositions herein comprise at least one solvent. Solvents in vaporizable compositions intended to be vaporized and inhaled by humans include, but are not limited to, propylene glycol, water, ethanol, glycerin, and mixtures thereof. As can be seen from the exemplary compositions herein, water can be incorporated into compositions containing aqueous ethanol (e.g., 190-proof ethanol). Similarly, additional ethanol can be added to compositions utilizing capsaicin solution (e.g., capsaicinoid in ethanol).

[0202] In various embodiments, the vaporizable alkaloid compositions herein comprise from about 85% to about 99.9% by weight of total solvent, based on the total weight of the vaporizable alkaloid composition. In one particular example, the solvent comprises a majority of vegetable glycerin, with lesser amounts of propylene glycol and ethanol (and trace amounts of water).

[0203] In various embodiments, the vaporizable alkaloid compositions herein comprise a mixture of solvents comprising about 85.0% to about 95.0% by weight of vegetable glycerin, based on the total weight of the composition, and about 0.5% to about 3% by weight of propylene glycol, based on the total weight of the composition. In certain instances, the amount of total solvent (regardless of composition) may be indicated as "qs," or "qs," which is the amount of solvent needed to bring the composition up to 100% by weight.

[0204] 4. Optional Flavoring Agents In various embodiments, the vaporizable alkaloid compositions herein may optionally include up to about 1.0% by weight of at least one flavoring agent, based on the total weight of the composition. The weight percent of the flavoring agent(s) used in the compositions herein will vary widely based on the type of flavoring agent and the desired sensory outcome, and in some cases the amount used will be much less than 1.0% by weight (e.g., 0.1% by weight or less). Optional flavoring agents for use herein include, but are not limited to, geraniol, geranial, valeric acid, methyl salicylate, ethyl maltol, ethyl butyrate, ethyl acetate, maltol, ethyl vanillin, ethyl 3-methyl-3-phenylglycidate, furaneol, methyl cyclopentenolone, methyl cyclopentenolone, ethyl cyclopentenolone, δ-decalactone, γ-decalactone, α-nonalactone, β-nonalactone, cis-3-hexanol, isoamyl acetate, ethyl 2-methylbutyrate, butyric acid, ethyl butyrate, 2-methylbutyric acid , benzyl alcohol, ethyl hexanoate, benzaldehyde, isoamyl isovalerate, hexanoic acid, ethyl propionate, gamma-undecalactone, acetylpropionyl, raspberry ketone, furfural, 5-methylfurfural, maltol, 2-acetylpyrazine, 2,3,5-trimethylpyrazine, 2-acetylpyrrole, 2-isopropyl-4-methylthiazole, 2-isobutylthiazole, furfuryl mercaptan, thiomenthone, p-menthene-8-thiol, tropathione, hexyl acetate, and mixtures thereof.

[0205] Exemplary Compositions In various embodiments, the NO vaporizable alkaloid composition herein comprises at least one substituted pyridine compound of Formula (I) or a salt or mixed salt thereof and a chemosensory stimulant in a suitable solvent. In various examples, the chemosensory stimulant comprises a spice additive having a heat intensity of about 1,000 to about 20,000,000 SHU. In various examples, the composition further comprises at least one organic acid for converting at least a portion of the substituted pyridine compound of Formula (I) to its corresponding salt or mixed salt. The resulting composition is a thin, clear, homogeneous liquid.

[0206] Table 1 provides a basic embodiment of a vaporizable alkaloid composition according to the present disclosure.

[0207] [Table 1]

[0208] Note 1: The compositions according to Table 1 are designed to target a certain w / v level of substituted pyridine compound in the final composition, such as 1000 mg / mL, 750 mg / mL, 500 mg / mL, 250 mg / mL, or 100 mg / mL. As discussed herein, the compositions of Table 1 having these relatively high levels of substituted pyridine compound (e.g., 100 mg / mL or greater) may be considered concentrates and therefore may be further diluted by third party manufacturers or formulators, or even by end users who may fill refillable electronic devices.

[0209] NOTE 2: In the preferred compositions from Table 1, the substituted pyridine free base and total organic acid(s) R 9 The molar ratio of -COH is from about 25:1 to about 75:1, more preferably about 50:1. Thus, it is expected that the majority of the substituted pyridine compound of formula (I) in any composition subject to the weight percent ranges recited above will remain as the free base, regardless of the molecular weight of the free base alkaloid(s) and organic acid(s).

[0210] NOTE 3: In these compositions, the range of about 0.0001% to about 0.01% by weight is the preferred range of spice additive in the composition standardized to capsaicin active agent, however, the broader range provided in Table 1, i.e., about 0.0001% to about 0.5% by weight, reflects a general range that includes any of the chemosensory stimulants listed above, including those within the subset of spice additives that are not necessarily capsaicinoids. The amount of chemosensory stimulant used in the vaporizable alkaloid composition is determined by its measured TRP channel activator EC. 50 or [A] 50These values ​​are the molar concentrations of the activators that produce 50% of the maximum possible effect of that activator. 50 Charts of values ​​are available, see, e.g., L. Premkumar, "Transient Receptor Potential Channels as Targets for Phytochemicals," ACS Chem. Neurosci., 5(11) 1117-1130, 2014, and also R. Neubig, et al., "International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. XXXVIII. Update on Terms and Symbols in Quantitative Pharmacology," Pharmacological Reviews, 55(4), 597-606 (2003). The phytochemicals disclosed by Premkumar are incorporated herein by reference for their express use in the vaporizable alkaloid compositions of the present disclosure.

[0211] The amount (wt%) of the spice additive, when selected as a chemosensory stimulant, can be adjusted accordingly for spice additives with lower or higher heat intensity (less than or greater than 16,000,000 SHU) than capsaicin. In other words, spice additives that substitute for capsaicin can be standardized to capsaicin. As a rough estimate, the ratio of the SHU of the substitute spice additive to that of capsaicin (16,000,000 SHU) can be used to calculate a reasonable amount of a different spice additive to use in place of capsaicin. For example, since the ratio of Scoville numbers is 16,000,000 SHU / 160,000 SHU = 100, shogaol (160,000 SHU) may be used at 100 times the preferred range of 0.0001 wt% to about 0.01 wt% of active capsaicin (16,000,000 SHU). Therefore, a suitable range of gingerol active in the composition may be 0.01% by weight to about 1% by weight, based on the total weight of the composition. When a spice additive with a heat intensity above 16,000,000 SHU is used, less spice additive is added. Focus groups and sensory panels will, of course, help refine these estimated ranges, but these calculations provide a starting point. The ability to substitute spice additives is particularly useful when there are supply / cost issues with a particular spice additive or when a particular user desires a different sensory experience. Additionally, when using a liquid extract rather than an active spice additive, such as liquid capsaicin, the weight percent of the spice additive active in the compositions of Table 1 is increased accordingly.

[0212] Note 4: In these compositions, flavoring is optional as it can be added later if desired, such as when the composition of Table 1 is diluted by a third party provider or end user who can fill a refillable device. Thus, for example, a composition according to Table 1 can start without flavoring, and then a third party or end user can dilute the composition (e.g., with VG and / or PG) and add a flavoring of their choice.

[0213] Note 5: In these compositions, the solvent is selected in part based on its acceptability for inhalation, since the composition will ultimately be used in an electronic device for vaping. Thus, the solvents in Table 1 will typically be selected from the group consisting of propylene glycol, glycerin, ethanol, water, and mixtures thereof. Each composition may contain a majority of propylene glycol, a majority of vegetable glycerin, or a mixture of the two as the majority of the solvent component. As noted, a third party or end user may further dilute the compositions in Table 1 and, for this purpose, may choose to use propylene glycol, vegetable glycerin, or a mixture thereof (e.g., 50 / 50 VG / PG). It is also worth noting that high levels of the substituted pyridine compound(s) of Formula (I), such as greater than about 20% by weight, may pose problems with alkaloid solubility, in which case the solvent ratio is adjusted to improve solubility, such as by increasing the weight percent of ethanol and decreasing the weight percent of glycerin and / or propylene glycol. In general, the substituted pyridine compounds of formula (I) are more likely to be soluble in ethanol compared to VG or PG. Compositions having about 4% to about 12% by weight of the substituted pyridine compounds of formula (I) are generally homogeneous mixtures of VG / PG with very little ethanol.

[0214] Table 2 illustrates embodiments of vaporizable alkaloid compositions according to the present disclosure. The compositions are derived from the generalized embodiments presented in Table 1 and the notes above referencing Table 1, in which the chemosensory stimulant is selected from a subset designated as a spice additive, and have been shown to be vaporizable and consumer-acceptable, as presented in Table 1 or after dilution to a lower alkaloid w / v. The exemplary compositions in Table 2 are merely examples 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 (S)-2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine, other organic acids other than citric acid and acetic acid may be used, and other chemosensory stimulants other than spice additives may be used to provide a perceptible throat hit. Furthermore, the relative amount of solvent may be varied for each composition to improve solubility.

[0215] [Table 2]

[0216] The numerical items in Table 2 are "as added" components and are rounded off.

[0217] As discussed herein, a small amount of alkaloid salt (in this case, (2S)-1-methyl-2-(6-methylpyridin-3-yl)pyrrolidin-1-ium salt) is expected to form from the presence of citric acid and acetic acid in the compositions, and given the large molar excess of (S)-2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine, it is unlikely that any free citric acid or acetic acid will remain as the free acid. Compositions 1-5 in Table 2 each contain about 0.04 moles of total organic acid and about 2.15 moles of (S)-2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine, resulting in a molar ratio of free base to organic acid of about 54:1.

[0218] Compositions that use 190-proof alcohol rather than pure alcohol are not listed because there is a small amount of water in the composition that is not added separately, making it not "as added." Any composition that lists 190-proof alcohol as an ingredient can be converted to a composition incorporating absolute alcohol and water, if desired.

[0219] Compositions 1 and 2 simply represent two recipes for achieving the same end result, with Composition 1 using 95% or greater crystalline solid capsaicin and Composition 2 using an ethanol extract of capsaicinoids (i.e., Capsicum Liquid Extract obtained from OliveNation, LLC). As noted, using liquid capsaicin is more convenient and cost-effective.

[0220] The entries in Table 2 demonstrate the use of other spice additives (shogaol, piperine, and gingerol in these examples) in place of capsaicin or capsaicinoids by adjusting the amount of the alternative spice additive based on its relative heat (SHU units) to capsaicin. As noted, the solvent can be slightly varied to accommodate differences in the solubility of various spice additives. Compositions 1-5 are expected to have a similar throat hit for users based on the equated heat (SHU units) between the compositions, although personal experience may still vary based on one's physiology and perception.

[0221] Each of the exemplary compositions in Table 2 contains about 100 mg / mL of (S)-2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine. It is important to note that these exemplary compositions can be adjusted so that the target w / v of (S)-2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine in the composition is anywhere from about 1 mg / mL to about 1000 mg / mL. Target w / vs include, but are not limited to, 1000 mg / mL, 750 mg / mL, 500 mg / mL, 250 mg / mL, and 100 mg / mL (disclosed in Table 2). An advantage of producing concentrates, especially ultra concentrates having even 1000 mg / mL of substituted pyridine compounds, is reduced shipping costs to manufacturers, formulators, and retailers. A third party formulator or end user can take any of these "concentrates" (e.g., 1000mg / mL, 750mg / mL, 500mg / mL, 250mg / mL, or 100mg / mL) and dilute them with PG or VG or blends of PG and VG to concentrations less than 100mg / mL, e.g., 1mg / mL, 3mg / mL, 6mg / mL, 9mg / mL, 12mg / mL, 15mg / mL, 18mg / mL, 21mg / mL, 24mg / mL, 27mg / mL, 30mg / mL, It is expected that the substituted pyridine compound will be diluted to a w / v target of 33 mg / mL, 36 mg / mL, 39 mg / mL, 42 mg / mL, 45 mg / mL, 48 mg / mL, 51 mg / mL, 54 mg / mL, 57 mg / mL, 60 mg / mL, 63 mg / mL, 66 mg / mL, 69 mg / mL, 72 mg / mL, 75 mg / mL, 78 mg / mL, 81 mg / mL, 84 mg / mL, 87 mg / mL, 90 mg / mL, 93 mg / mL, 96 mg / mL, or 99 mg / mL, etc.

[0222] (Method of Preparing a Vaporizable Alkaloid Composition) The vaporizable alkaloid compositions of Tables 1 and 2 can be prepared by simply mixing the ingredients shown in the tables in a laboratory vessel using magnetic or overhead stirring, or in a food industry mixer, followed by heating, if necessary, to achieve complete solubility and clarity. In a preferred embodiment, a premix is ​​made first and then combined.

[0223] In various embodiments, a first premix, designated Premix A, includes propylene glycol, a chemical sensory stimulant such as a spice additive, an organic acid, and 190 proof alcohol. In some examples, Premix A may have more than one organic acid and / or PG may be substituted for or included in VG.

[0224] In various embodiments, a second premix, designated Premix B, comprises the desired substituted pyridine compound(s) 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 noted, other solvents, such as ethanol, may be required to reach highly concentrated compositions, such as those having greater than 20% by weight of substituted pyridine compound(s) and ending with greater than 100 mg / mL of substituted pyridine compound(s).

[0225] In one particular example, Premix A is then combined with Premix B and the resulting mixture, if hazy, is heated to about 190° F. for about 1 hour or until the mixture becomes completely clear. Upon cooling, the mixture remains clear because the composition appears to be thermodynamically stable.

[0226] Table 3 shows a non-limiting example of Premix A.

[0227] [Table 3]

[0228] Table 4 shows a non-limiting example of Premix B.

[0229] [Table 4]

[0230] In a non-limiting example of combining premixes to produce a final vaporizable alkaloid composition with a target of 100 mg / mL (S)-2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine, Premix A1 and Premix B1 are combined in the weight percentages shown in Table 5, and the resulting mixture is heated to 190°F for approximately 1 hour.

[0231] [Table 5]

[0232] One way to obtain a final composition with greater than 100 mg / mL of alkaloid is to prepare more concentrated versions of Premix B, as shown in Table 4, where the alkaloid increases from Premix B1 to B4. 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 these cases, the vegetable glycerin in Premix B is at least partially replaced by another solvent, such as ethanol, as exemplified by the example in Table 4, when the substituted pyridine compound of Formula (I) is (S)-2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine.

[0233] The above strategy, using Premix A and Premix B, in which the substituted pyridine compound of Formula (I) is (S)-2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine, can be reliably used to reach up to about 225 mg / mL to about 250 mg / mL w / v of (S)-2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine in the final concentrated vaporizable alkaloid composition. To exceed about 250 mg / mL w / v of (S)-2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine in the final composition requires changing the solvent in Premix B from entirely vegetable glycerin to a mixture of solvents containing at least some ethanol.

[0234] (How to use) 1. Smoking Cessation via Vaping of a Vaporizable Alkaloid Composition The vaporizable alkaloid compositions according to the present disclosure, or dilutions thereof, are intended to be dispensed from electronic devices, such as electronic cigarettes, in the form of a vapor that can be inhaled by a user in the same manner as smoking a traditional tobacco product, such as a cigarette.

[0235] As noted hereinabove, one object of the present disclosure is to provide vaporizable alkaloid compositions and progressive dilutions thereof to smokers engaged in smoking cessation programs.

[0236] In various embodiments, a method for smoking cessation comprises administering to an individual desiring to quit a battery of vaporizable alkaloid compositions for a period determined for cessation, wherein each vaporizable alkaloid composition in the battery comprises at least one substituted pyridine compound having formula (I) or a salt or mixed salt thereof:

[0237] [ka]

[0238] In the formula, R 1 , R 2 , R 3 , and R 4 are independently selected from H, alkyl, cycloalkyl, and alkenyl, with R 1 , R 2 , R 3 , and R 4 However, it is not possible for all of them to be H. each of the vaporizable alkaloid compositions in the set contains decreasing amounts (w / v) of the substituted pyridine compound or a salt or mixed salt thereof; Individuals desiring to discontinue may proceed with each of the compositions in a series in decreasing order of amount (w / v) of the substituted pyridine compound or salt or mixed salt thereof; An individual wishing to quit would use each of the compositions by vaporizing and inhaling each composition from the electronic device for the period determined for quitting.

[0239] In various embodiments, the individual wishing to quit is a tobacco smoker who wishes to quit smoking.

[0240] In various embodiments, the time period determined for discontinuation may be days, weeks, months, or years in length, preferably several months to a year in length.

[0241] In various embodiments, the period determined for discontinuation is part of a discontinuation program that further includes dispensing a battery of vaporizable alkaloid compositions over the period determined for discontinuation.

[0242] In various embodiments, the determined time period for cessation is divided into successive shorter time periods, and during each of the shorter time periods, the individual desiring to quit receives and uses a different vaporizable alkaloid composition in place of tobacco smoking. In a preferred embodiment, during each of the successive shorter time periods, the individual desiring to quit receives a vaporizable alkaloid composition having a decreasing amount (w / v) of alkaloid.

[0243] In various embodiments, the panel of vaporizable alkaloid compositions includes the individual compositions shown in Table 6. This exemplary panel of vaping liquids can be administered over the course of a 25-week cessation program. The table shows that individuals receive a new vaping composition with a lower amount of the substituted pyridine compound each week of the cessation program. At the end of the program, individuals wishing to quit will vape a vaporizable alkaloid composition lacking the alkaloid.

[0244] [Table 6]

[0245] Note 1: The alkaloid in compositions P1 to P25 includes any substituted pyridine compound of formula (I) or a salt thereof or a mixed salt thereof. In a preferred example, the alkaloid in compositions P1 to P25 includes (S)-2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine or a salt thereof or a mixed salt thereof. In a more preferred example, compositions P1 to P25 consist of composition 1 (or 2) from Table 2 and dilutions therefrom.

[0246] Note 2: In programs utilizing compositions containing (S)-2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine, P1 can be any of the compositions illustrated in Table 2 (each targeting 100 mg / mL of (S)-2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine), preferably composition 1 (or 2). For compositions P2 through P25, P1 is diluted appropriately with VG and / or PG as noted, and flavoring is added as needed and adjusted based on personal preference.

[0247] In various embodiments, individuals enrolled in a smoking cessation program will report to a program administrator periodically, such as weekly, for a personalized consultation and to receive new, further diluted vaping liquid. These periodic visits can assess the individual's compliance with the program and make adjustments accordingly. Some modifications to the program may involve placing the individual on a particular w / v level of alkaloids for a period longer than one week, or changing or adjusting the flavoring agent. Other modifications can be made to a set of vaping compositions, such as switching spice additives or adding more or less spice additives to adjust the throat hit perceived by the individual vaping the provided composition. In one particular example, a liquid composition is provided to the individual, who places the composition into the reservoir of their refillable electronic device, such as a refillable electronic cigarette. In another example, a disposable (closed) device is provided to the individual, pre-filled with a particular composition.

[0248] In various embodiments, an individual who reaches the end of the program will be vaping only an alkaloid-free flavored solvent, at which point it is expected that the individual will no longer smoke traditional tobacco products and may choose to quit vaping entirely.

[0249] In various embodiments, the method of vaping comprises vaporizing and inhaling a composition according to the present disclosure from a disposable (closed) or refillable (open) electronic device. In certain embodiments, the electronic device comprises an electronic cigarette.

[0250] (2. Alkaloid dispensing pouch for oral use) In various embodiments, versions of vaporizable alkaloid compositions according to the present disclosure also find use in manufacturers of "alkaloid dispensing pouches." Pouches for oral use include a relatively small (e.g., 0.5 inch x 0.75 inch) saliva-permeable textile enclosure with a powder sealed therein that can release the alkaloid active agent into an individual's oral cavity when the pouch is placed under the tongue or in an individual's oral cavity. Alkaloid dispensing pouches according to the present disclosure are configured to release an alkaloid of formula (I), or in alternative embodiments, an alkaloid of formula (II) over time. In some embodiments, the release of the alkaloid from the alkaloid dispensing pouch into an individual's oral cavity may be characterized as a "sustained release."

[0251] In various embodiments, the alkaloid dispensing pouch comprises a saliva-permeable nonwoven fabric and a powdered alkaloid composition sealed therein. In one particular example, the powdered alkaloid composition sealed within the pouch comprises a vaporizable alkaloid composition according to the present disclosure adsorbed onto a carrier or mixture of carriers such that the composition is in the physical form of a powder or granules. In other embodiments, the powdered alkaloid composition within the alkaloid dispensing pouch comprises a substituted pyridine compound according to either Formula (I) or (II), a solvent, and a carrier, wherein the mixture of alkaloid and solvent is adsorbed onto the carrier.

[0252] 2a. General Embodiments of Alkaloid Dispensing Pouches In a general embodiment, an alkaloid dispensing pouch adapted for release of an alkaloid into the oral cavity of an individual comprises: a saliva-permeable nonwoven fabric defining an enclosure containing an alkaloid composition therein, the alkaloid composition comprising: At least one substituted pyridine compound according to formula (I) or a salt or mixed salt thereof,

[0253] [ka]

[0254] In the formula, R 1 , R 2 , R 3 , R 4 , and R 5 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl, with R 5 If is CH3, then R 1 , R 2 , R 3 , and R 4 at least one substituted pyridine compound according to formula (I) or a salt or mixed salt thereof, with the proviso that and a carrier, and the alkaloid dispensing pouch is completely devoid of (R) or (S) nicotine.

[0255] In various embodiments, the alkaloid composition is a mixture of a substituted pyridine compound of formula (I) and a carrier in either a solid or oil physical form.

[0256] In various embodiments, the alkaloid composition further comprises a solvent so that the alkaloid composition can be adsorbed onto a carrier to form a powder or granular composition that can be filled into the encapsulation. In certain examples, the solvent is selected from the group consisting of propylene glycol, vegetable glycerin, water, ethanol, and mixtures thereof.

[0257] In various embodiments, the carrier comprises microcrystalline cellulose.

[0258] In various embodiments, the substituted pyridine compound according to formula (I) includes (S)-2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine.

[0259] In an alternative general embodiment, an alkaloid dispensing pouch adapted for release of an alkaloid into the oral cavity of an individual comprises: a saliva-permeable nonwoven fabric defining an enclosure containing an alkaloid composition therein, the alkaloid composition comprising: At least one substituted pyridine compound according to formula (II) or a salt or mixed salt thereof,

[0260] [ka]

[0261] In the formula, R 1 , R 2 , R 3 , R 4 , R 10 , R 11 , and R 12 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl, and n is an integer from 1 to 10, or a salt or mixed salt thereof; and a carrier, and the alkaloid dispensing pouch is completely devoid of (R) or (S) nicotine.

[0262] In various embodiments, the alkaloid composition is a mixture of a substituted pyridine compound of formula (II) and a carrier in either a solid or oil physical form.

[0263] In various embodiments, the alkaloid composition further comprises a solvent so that the alkaloid composition can be adsorbed onto a carrier to form a powder or granular composition that can be filled into the encapsulation. In certain examples, the solvent is selected from the group consisting of propylene glycol, vegetable glycerin, water, ethanol, and mixtures thereof.

[0264] In various embodiments, the carrier comprises microcrystalline cellulose.

[0265] In various embodiments, the substituted pyridine compound according to formula (II) includes 3-[N-methyl-N-(3-aminopropyl)]aminomethylpyridine.

[0266] In various embodiments, the alkaloid dispensing pouch adapted for release of an alkaloid into the oral cavity of an individual comprises: a saliva-permeable nonwoven fabric defining an enclosure containing an alkaloid composition therein, the alkaloid composition comprising a vaporizable alkaloid composition adsorbed on a carrier, the vaporizable alkaloid composition comprising: At least one substituted pyridine compound of formula (I) or a salt or mixed salt thereof,

[0267] [ka]

[0268] In the formula, R 1 , R 2 , R 3 , R 4 , and R 5 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl, with R 5 If is CH3, then R 1 , R 2 , R 3 , and R 4 at least one substituted pyridine compound of formula (I) or a salt or mixed salt thereof, with the proviso that all of at least one chemosensory stimulant; at least one solvent; Optionally, at least one flavoring agent, and the alkaloid dispensing pouch is completely devoid of (R) or (S) nicotine.

[0269] In certain instances, a selected vaporizable alkaloid composition according to the present disclosure is adsorbed onto a carrier, such as microcrystalline cellulose, such that the resulting material for the pouch is in the physical form of a powder or granules.

[0270] Details of chemical sensory stimulants such as spice additives, solvents, and optional flavoring agents are found herein above under the general description of "Vaporizable Alkaloid Compositions."

[0271] (2b. Saliva-permeable fabric for pouches) The pouch material for use herein is selected for its water insolubility and permeability to water and saliva. The material is sized so that the filled pouch is suitable for extended sublingual or buccal placement. Subjectively, the alkaloid dispensing pouch is configured for a comfortable mouthfeel, including the size of the filled and sealed pouch and the feel of the pouch fabric.

[0272] Pouch materials for use herein may be constructed from any number of different water-insoluble nonwoven materials, referred to as "fabrics." Nonwoven fabrics, with their diverse uses, are well known to those skilled in the art of textiles. Nonwoven fabrics are thoroughly described in "Nonwoven Fabrics: Raw Materials, Manufacture, Applications, Characteristics, Testing Processes," editors W. Albrecht, H. Fuchs and W. Kittelmann, Wiley-VCH Verlag GmbH & Co. KgaA Weinheim, 2003. Such materials can be prepared by forming a web of continuous filaments and / or staple fibers and optionally bonding these fibers at inter-fiber contact points to provide fibers with desired properties. The term "bonded nonwoven" is used to include nonwoven fabrics in which the majority of interfiber bonding is achieved by thermal fusion of adjacent fibers, or by adhesive bonding achieved by incorporating an adhesive into the web to "glue" the fibers together, or by other bonding (usually in conjunction with heat), such as that obtained by the use of a liquid or gas binder to cohere the fibers. Chemical bonding may be achieved through the use of adhesive or latex powder dispersed between the fibers in the web, which is then activated by heat, ultraviolet or infrared radiation, or other suitable activation methods. Thermally and chemically bonded carded webs are described in U.S. Pat. No. 6,689,242 to Bodaghi, the subject matter of which is incorporated herein by reference. Thermally and / or chemically bonded nonwoven fabrics may also be used as pouch materials herein. Powder bonding is a dry process that begins with carding staple fibers to form a fibrous web, which is then treated with a powdered thermoplastic adhesive or latex material and subjected to a series of ovens and calender rolls to produce the nonwoven fabric.

[0273] Nonwoven fabrics may also include fibers known as "bicomponent fibers," such as "sheath / core bicomponent fibers," which have a layer with a lower melting point than the outer sheath region or inner core region, thereby enabling efficient and controlled thermal bonding through melting of only the outer layer of each fiber. In other words, the outer surface of a bicomponent fiber can have a lower melting point than the core of the fiber. For example, binder bicomponent fibers, in which one component has adhesive properties under bonding conditions, are widely used to provide integrity to fibrous webs used as absorbents in personal care or filtration products. Additionally, multicomponent fibers are also known and commercially incorporated into nonwoven fabrics. Examples of such multicomponent 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.), which are incorporated herein by reference in their entireties.

[0274] During fiber bonding, the web may simultaneously undergo mechanical compression to achieve the desired bond, weight, and thickness in a process known as "thermocompression bonding." Thermocompression bonding may be achieved by incorporating methods using hot embossing rolls and heated flat calendar rolls, and by using heat treatment machines such as hot blast-circulating, hot through-air, infrared heater, or vertical hot blast-blowing types to achieve thermocompression bonding. Mechanical compression may also be used to set the loft or thickness of fabrics with similar basis weights. Generally, increasing the basis weight, or mass per square area, increases thickness, while increasing bonding and compression decreases loft.

[0275] Nonwoven webs may be formed from a number of processes, such as meltblowing, spunbond or spunlaid, toe-opened, wetlaid, airlaid, carded, and high-pressure hydroentangled. The basis weight of a nonwoven web is typically expressed in ounces of material per square yard (osy) or grams per square meter (gsm), and fiber diameter is typically expressed in microns or, for staple fibers, "denier." Denier is defined as grams per 9000 meters of fiber length. For fibers with a circular cross-section, denier may be calculated by multiplying the fiber diameter (microns squared) by the density (grams / cc) and multiplying 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 tile denier of each fiber divided by the number of fibers. The distribution of denier 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 of volume, usually expressed in units of mass per unit of bulk density (e.g., grams per cubic centimeter). A nonwoven fabric may be made with fibers having a single average diameter or denier, or fibers of two or more average diameters may be used together. For example, two or more distributions of fiber denier may be combined into separate fiber webs (e.g., 2 1 / 2 denier fibers and 4 denier fibers carded together). The separate fiber webs may then be laminated together. For example, a single nonwoven fabric may contain fibers of 2 1 / 2, 4, 6, and 15 denier, meaning that the nonwoven fabric is constructed with fibers of four separate deniers (fibers of four separate average diameters).

[0276] "Spunbond fibers" refer to fibers formed by extrusion of molten thermoplastic material as filaments, as described, for example, in U.S. Patent No. 4,340,563 to Appel, U.S. Patent No. 3,692,618 to Dorschner, U.S. Patent No. 3,802,817 to Matsuki, U.S. Patent Nos. 3,338,992 and 3,341,394 to Kinney, U.S. Patent No. 3,502,763 to Hartman, U.S. Patent No. 3,542,615 to Dobo, and U.S. Patent No. 5,382,400 to Pike, each of which is incorporated herein by reference in its entirety. Spunbond fibers are generally not tacky when they are deposited onto a collecting surface. Spunbond fibers are generally continuous and have an average diameter of about 7 microns to about 60 microns, most often between about 15 and 25 microns.

[0277] "Meltblown" refers to fibers formed by extruding molten thermoplastic material through multiple fine, usually circular die capillaries into a converging, high-velocity, usually hot gas / air stream, which attenuates the filaments of the molten thermoplastic material and reduces their diameter (which may ultimately result in a microfiber diameter). The meltblown fibers are then carried by the tangled high-velocity 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, generally have an average diameter less than 10 microns, and are generally tacky when deposited on a collecting surface.

[0278] "Airlaid" is a well-known process by which fibrous nonwoven layers can be formed. In the airlaid process, small fiber bundles, typically having lengths of about 3 to about 52 millimeters, are separated, entrained in an air supply, and deposited onto a forming screen, usually with the aid of a vacuum. The randomly deposited fibers are then bonded together, for example, using hot air to activate a binder component or latex adhesive. The airlaid process is taught, for example, in U.S. Patent No. 4,640,810 to Laursen and U.S. Patent No. 5,885,516 to Christensen.

[0279] Preferred fibers incorporated into pouch fabrics for use herein may 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 and tile-like materials, viscose rayon, various polyamides such as nylon, polyacrylates, and modacrylics, as well as mixtures of these types of polymers. In various preferred examples, viscose is used as the saliva-permeable nonwoven pouch fabric for the alkaloid dispensing pouches herein.

[0280] A filling and sealing method for pouches containing nonwoven fabric is disclosed in U.S. Patent Application Publication No. US2023 / 0211907, published July 6, 2023, and assigned to Swedish Match North Europe AB, which is incorporated herein by reference. In various embodiments, the alkaloid dispensing pouches herein contain a fill weight of about 100 mg to about 500 mg, preferably about 200 mg to about 400 mg, of alkaloid composition (dry powder or granules). The upper limit is reached when the pouch no longer fits comfortably under the tongue or in the oral cavity. Because the weight of the nonwoven fabric pieces is negligible compared to the weight of an individual pouch, the fill weight of the alkaloid dispensing pouches herein is about 100 mg to about 500 mg of dry powder or granular alkaloid composition per pouch.

[0281] In various embodiments, the alkaloid dispensing pouch has a width (or diameter) of about 0.12 inches to about 0.50 inches and a height of about 0.25 inches to about 0.75 inches. In some instances, the pouch may resemble a small pillow (e.g., square) or may appear more like a capsule.

[0282] 2c. Powder Fill Composition for Alkaloid Dispensing Pouches In various embodiments, the alkaloid dispensing pouches herein comprise a powder or granular composition further comprising an alkaloid mixed with a carrier or a liquid alkaloid composition adsorbed onto a carrier, both routes contemplate sealing the dry powder or granular alkaloid fill material within a nonwoven fabric enclosure.

[0283] Vaporizable alkaloid compositions for use in the alkaloid dispensing pouches are fully described herein. Any composition having a substituted pyridine compound of Formula (I) or Formula (II) in the range of about 1 mg / mL to about 1000 mg / mL may be used. The selected liquid composition is then adsorbed onto a suitable carrier, and the resulting powder or granules are used as the fill material for each pouch.

[0284] Carriers for use herein include, but are not limited to, agar, agarose, albumin, alginate, casein, chitin, chondroitin, dextrin, fibroin, fucoidan, galactan, gellan, guar, scleroglucan, pullulan, xyloglucan, pectin, xanthan, psyllium, silica gel, fumed silica, magnesium aluminum silicate, clay, bentonite, hectorite, mesoporous silica, cellulose, cellulose acetate, hyaluronan, various elastin-like polypeptides, β-cyclodextrin, collagen, gelatin, chitosan, carrageenan, polylactic acid, polyglycolic acid, poly(lactic-co-glycolic acid), Examples of suitable hydrogel materials include poly(2-hydroxyethyl methacrylate), poly(2-hydroxypropyl methacrylate), poly(acrylic acid), carboxymethyl cellulose, carboxyethyl cellulose, hydroxyethyl cellulose, hydrophobically modified hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, ethyl cellulose, microcrystalline cellulose, nitrocellulose, polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl methacrylate, carboxyvinyl polymers, 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).

[0285] The carrier may be selected based on its adsorption capacity and, to a lesser extent, its taste. If the carrier does not dissolve at all in the saliva present in the oral cavity, taste is not 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 pouch fabric along with the alkaloid composition. In a preferred embodiment, the carrier comprises microcrystalline cellulose.

[0286] Tables 7, 8, and 9 show general embodiments of alkaloid compositions that can be used as fill materials for the alkaloid dispensing pouches of the present disclosure.

[0287] [Table 7]

[0288] [Table 8]

[0289] [Table 9]

[0290] Each of the resulting fill compositions from Tables 7, 8, or 9 is in the physical form of a dry powder or granules. The resulting material is filled into nonwoven pouches at a fill level of about 100 mg to about 500 mg of dry powder or granular alkaloid composition per pouch, which are subsequently sealed to produce individual alkaloid dispensing pouches for oral use.

[0291] In the detailed description, references to "various embodiments," "one embodiment," "an embodiment," "exemplary embodiment," etc. indicate that the described embodiment may include a particular feature, structure, or characteristic, but not all embodiments necessarily include that particular feature, structure, or characteristic. Moreover, such phrases do not necessarily refer to the same embodiment. Furthermore, when a particular feature, structure, or characteristic is described in connection with an embodiment, it is submitted that causing such feature, structure, or characteristic to occur in connection with other embodiments, whether or not explicitly stated. After reading the description, it will be apparent to one skilled in the relevant art(s) how to implement the present disclosure in alternative embodiments.

[0292] The steps listed in any of the method or process descriptions may be performed in any order and are not necessarily limited to the order presented. Furthermore, any reference to the singular encompasses multiple embodiments, and any reference to more than one component or step may include a singular embodiment or step. Also, any reference to attached, fixed, connected, coupled, etc. may include permanent (e.g., integral), detachable, temporary, partial, complete, and / or any other possible attachment options. Any of the components may be coupled to one another via friction, snaps, sleeves, brackets, clips, or other means now known or hereafter developed in the art. Additionally, non-contact (or similar phrases) may also include reduced or minimal contact.

[0293] Benefits, other advantages, and solutions have been described herein with respect to specific embodiments. However, benefits, advantages, solutions, and any elements that may cause or enhance any benefit, advantage, or solution should not be construed as key, essential, or essential features or elements of the present disclosure. Accordingly, the scope of the present disclosure is not limited except by the appended claims, and references to elements in the singular are not intended to mean "only one," but rather "one or more," unless expressly stated otherwise. Moreover, when phrases similar to "at least one of A, B, and C" or "at least one of A, B, or C" are used in the claims or specification, these phrases are intended to be interpreted to mean that only A may be present in an embodiment, that only B may be present in an embodiment, that only C may be present in an embodiment, or that any combination of elements A, B, and C, e.g., A and B, A and C, B and C, or A, B, and C, may be present in a single embodiment.

[0294] All structural, chemical, and functional equivalents to the elements of the various embodiments described above that are known to those skilled in the art are expressly incorporated herein by reference and are intended to be encompassed by the claims of the present invention. Moreover, devices or device components, or methods of using devices to address every single problem sought to be solved by the present disclosure, are not necessarily encompassed by the claims. Furthermore, no element, component, or method step of the present disclosure is intended to be open to the public, regardless of whether it is explicitly recited in the claims. No claim element is intended to invoke 35 U.S.C. 112(f) unless that element is expressly recited using the phrase "means for." As used herein, "comprise," "comprising," or any other variation thereof, is intended to cover a non-exclusive inclusion, such that a chemical, chemical composition, process, method, article, or device that includes a list of elements does not include only those elements, but may include other elements not expressly recited or not inherent in such chemical, chemical composition, process, method, article, or device.

Claims

1. 1. A vaporizable alkaloid composition comprising: At least one substituted pyridine compound of formula (I) or a salt or mixed salt thereof, 【Chemistry 1】 In the formula, R １ , R ２ , R ３ , R ４ , and R ５ is independently selected from alkyl, H, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl, with R ５ is CH ３ If １ , R ２ , R ３ , and R ４ at least one substituted pyridine compound of formula (I) or a salt or mixed salt thereof, with the proviso that all of at least one chemosensory stimulant; at least one solvent; optionally at least one flavoring agent; The vaporizable alkaloid composition, wherein the vaporizable alkaloid composition is completely devoid of (R) or (S) nicotine.

2. R ５ But CH ３ and R １ , R ２ , R ３ , and R ４ 2. The vaporizable alkaloid composition of claim 1, wherein at least one of is not H.

3. R ５ But -(CH ２ ) n-NR ６ R ７ where n is an integer from 1 to 10, 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 The vaporizable alkaloid composition of claim 1, wherein: together with the N atom to which they are attached, form a 3-8 membered optionally substituted heterocyclic ring.

4. R ５ is H and R １ , R ２ , R ３ , and R ４ At least one of the groups is -(CH ２ ) n-NR ６ R ７ where n is an integer from 1 to 10, 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 The vaporizable alkaloid composition of claim 1, wherein: together with the N atom to which they are attached, form a 3-8 membered optionally substituted heterocyclic ring.

5. The substituted pyridine compound, a salt thereof, or a mixed salt thereof is preferably (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-dimethyl-5-(1-methylpyrrolidin-2-yl)pyridine (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-dimethylaminoethyl)-2-(3-pyridyl)pyrrolidine (R) or (S)-3-(2-(6-methylpyridin-3-yl)pyrrolidin-1-yl)propanenitrile, (R) or (S)-4-(2-(6-methylpyridin-3-yl)pyrrolidin-1-yl)butanenitrile, (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)pyrrolidin-1-yl)ethyl)morpholine, The vaporizable alkaloid composition according to claim 1, which is selected from (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.

6. The vaporizable alkaloid composition according to claim 1, wherein the substituted pyridine compound or a salt thereof or a mixed salt thereof is (S)-2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine.

7. The chemosensory stimulant is 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, flufenam Acid, niflumic acid, mefenamic acid, diclofenac, hydroxy-α-sanshool, 6-paradol, linalool, carvacrol, eugenol, thymol, vanillin, methyl eugenol, 2,6-dimethylphenol, 2,5-dimethylphenol, 3,4-dimethylphenol, 2,6-diisopropylphenol, caffeine, farnesylthiosalicylic acid, 4-allylanisole, curcumin, niacin, camphor, olvanil, arvanil, anandamide, cannabidiol, Δ ９ 2. The vaporizable alkaloid composition of claim 1, wherein the alkaloid is selected from the group consisting of tetrahydrocannabinol, baicalein, baicalin, wogonin, norwogonin, oroxylin A, β-sitosterol, and mixtures thereof.

8. 2. The vaporizable alkaloid composition according to claim 1, wherein the at least one substituted pyridine compound of formula (I) or a salt thereof or a mixed salt thereof comprises a mixture of (S)-2-methyl-3-(1-methylpyrrolidin-2-yl)pyridine free base and (2S)-1-methyl-2-(6-methylpyridin-3-yl)pyrrolidin-1-ium citrate / acetate mixed salt.

9. 2. The vaporizable alkaloid composition of claim 1, wherein the chemosensory stimulant is a spice additive that exhibits a heat intensity of about 1,000 to about 20,000,000 Scoville Pungency Units (SHU).

10. 10. The vaporizable alkaloid composition of claim 9, wherein the spice additive is selected from the group consisting of capsaicin, dihydrocapsaicin, norcapsaicin, nordihydrocapsaicin, homocapsaicin, homodihydrocapsaicin, gingerol, piperine, shogaol, isopiperine, chavicine, isochavicin, 2-piperamine, piperanine (4,5-dihydropiperine), piperamide, 4-piperiside, piperiline, piperlonguminine, piperettine, piperduldine (6,7-dihydropiperetine), 5-sarmentdine, 6-sarmentine, 7-trichostatine, and mixtures thereof.

11. 10. The vaporizable alkaloid composition of claim 9, wherein the spice additive is capsaicin or a mixture of capsaicinoids.

12. 2. The vaporizable alkaloid composition of claim 1, wherein the solvent is selected from the group consisting of propylene glycol, water, ethanol, glycerin, and mixtures thereof.

13. 10. The vaporizable alkaloid composition of claim 1, further comprising an organic acid selected from the group consisting of formic acid, acetic acid, trifluoroacetic acid, aspartic acid, butanoic 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.

14. 14. The vaporizable alkaloid composition of claim 13, wherein the organic acid is selected from the group consisting of citric acid, acetic acid, benzoic acid, tartaric acid, lactic acid, salicylic acid, malic acid, levulinic acid, and mixtures thereof.

15. 14. The vaporizable alkaloid composition of claim 13, wherein the molar ratio of total substituted pyridine compounds to total organic acids is from about 25:1 to about 75:

1.

16. 1. A vaporizable alkaloid composition comprising: about 1% to about 80% by weight of a substituted pyridine compound according to formula (I) or a salt or mixed salt thereof, 【Chemistry 1】 In the formula, R １ , R ２ , R ３ , R ４ , and R ５ is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl, with R ５ is CH ３ If １ , R ２ , R ３ , and R ４ a substituted pyridine compound according to formula (I) or a salt or mixed salt thereof, with the proviso that all of a total of about 0.05% to about 1.5% by weight of at least one organic acid; about 0.0001% to about 0.50% by weight of a spice additive having a heat intensity of about 1,000 to about 20,000,000 Scoville Pungency Units (SHU); and a balance of solvent, the weight percentages are based on the total weight of the vaporizable alkaloid composition; The vaporizable alkaloid composition, wherein the molar ratio of moles of substituted pyridine compound to total moles of organic acid is from about 25:1 to about 75:

1.

17. 17. The vaporizable alkaloid composition of claim 16, wherein the substituted pyridine compound is (S)-2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine.

18. 18. The vaporizable alkaloid composition of claim 17, wherein the molar ratio of moles of (S)-2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine to total moles of organic acids is about 50:

1.

19. 18. The vaporizable alkaloid composition of claim 17, wherein the concentration (w / v) of (S)-2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine in the vaporizable alkaloid composition is from about 1 mg / mL to about 1,000 mg / mL.

20. 18. The vaporizable alkaloid composition of claim 17, wherein the concentration (w / v) of (S)-2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine in the vaporizable alkaloid composition is about 100 mg / mL.

21. 17. The vaporizable alkaloid composition of claim 16, wherein the at least one organic acid comprises a mixture of citric acid and acetic acid.

22. 17. The vaporizable alkaloid composition of claim 16, wherein the spice additive comprises capsaicin.

23. 17. The vaporizable alkaloid composition of claim 16, wherein the solvent is selected from the group consisting of propylene glycol, glycerin, ethanol, and mixtures thereof.

24. 1. A method for producing a vaporizable alkaloid composition, comprising: preparing a first premix comprising a chemosensory stimulant and at least one organic acid dissolved in a suitable solvent or solvent mixture; Preparing a second premix comprising at least one substituted pyridine compound dissolved in a suitable solvent or mixture of solvents, wherein the substituted pyridine compound has the structure of formula (I): 【Chemistry 1】 or a salt thereof or a mixed salt thereof, wherein R １ , R ２ , R ３ , R ４ , and R ５ is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl, with R ５ is CH ３ If １ , R ２ , R ３ , and R ４ can not all be H; combining the first premix and the second premix; and optionally heating the resulting mixture until the resulting mixture is optically clear, thereby producing the vaporizable alkaloid composition.

25. 25. The vaporizable alkaloid composition of claim 24, wherein the first premix comprises capsaicin or a mixture of capsaicinoids, acetic acid, and citric acid dissolved in a mixture of propylene glycol and ethanol, and the second premix comprises (S)-2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine dissolved in glycerin.

26. 1. A method for promoting smoking cessation in an individual desiring to quit, comprising: administering to the individual, for a period of time determined for cessation, a battery of vaporizable alkaloid compositions for the individual to inhale by vaping, wherein each vaporizable alkaloid composition in the battery is at least one substituted pyridine compound having formula (I), or a salt or mixed salt thereof: 【Chemistry 1】 In the formula, R １ , R ２ , R ３ , R ４ , and R ５ is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl, with R ５ is CH ３ If １ , R ２ , R ３ , and R ４ may not all be H, or a salt or mixed salt thereof; each of the vaporizable alkaloid compositions in the set comprises decreasing amounts (w / v) of the substituted pyridine compound or a salt or mixed salt thereof; The method comprises the individual inhaling by vaping each composition in the set, starting with the compound having the highest level (w / v) of the substituted pyridine compound or its salt or mixed salt and completing the period determined for cessation with the composition having the lowest level (w / v) of the substituted pyridine compound or its salt or mixed salt, so that at the end of the period determined for cessation, the individual has ceased smoking.

27. 27. The method of claim 26, wherein each vaporizable alkaloid composition in the battery of vaporizable alkaloid compositions comprises (S)-2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine or a salt or mixed salt thereof.

28. 28. The method of claim 27, wherein the vaporizable alkaloid composition in the battery of vaporizable alkaloid compositions having the highest level (w / v) of the substituted pyridine compound or salt or mixed salt thereof comprises about 100 mg / mL of (S)-2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine.

29. 28. The method of claim 27, wherein the vaporizable alkaloid composition in the battery of vaporizable alkaloid compositions having the minimum level (w / v) of the substituted pyridine compound, or a salt or mixed salt thereof, comprises about 1 mg / mL or less of (S)-2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine.

30. 27. The method of claim 26, wherein the determined time period for cessation is part of a smoking cessation program further comprising dispensing the suite of vaporizable alkaloid compositions to an individual desiring to quit for the determined time period for cessation.

31. 1. An alkaloid-dispensing pouch adapted for the release of an alkaloid into the oral cavity of an individual, said alkaloid-dispensing pouch comprising: a saliva-permeable nonwoven fabric defining an enclosure containing an alkaloid composition loaded therein, said alkaloid composition comprising: At least one substituted pyridine compound according to formula (I) or a salt or mixed salt thereof, 【Chemistry 1】 In the formula, R １ , R ２ , R ３ , R ４ , and R ５ is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl, with R ５ is CH ３ If １ , R ２ , R ３ , and R ４ at least one substituted pyridine compound according to formula (I) or a salt or mixed salt thereof, with the proviso that all of a carrier; The alkaloid dispensing pouch, wherein the alkaloid dispensing pouch is completely devoid of (R) or (S) nicotine.

32. 32. The alkaloid-dispensing pouch of claim 31 , wherein the alkaloid composition comprises a mixture of the substituted pyridine compound of formula (I) and the carrier.

33. 32. The alkaloid dispensing pouch of claim 31 , wherein the carrier comprises microcrystalline cellulose.

34. 32. The alkaloid-dispensing pouch of claim 31 , wherein said alkaloid composition further comprises a solvent, said alkaloid composition consisting of a liquid composition adsorbed onto said carrier.

35. 35. The alkaloid-dispensing pouch of claim 34, wherein the alkaloid composition further comprises a chemosensory stimulant.

36. 10. An alkaloid-dispensing pouch adapted for the release of an alkaloid into the oral cavity of an individual, said alkaloid-dispensing pouch comprising a saliva-permeable nonwoven fabric defining an enclosure containing an alkaloid composition loaded therein, said alkaloid composition comprising the vaporizable alkaloid composition of claim 1 adsorbed onto a carrier.

37. 37. The alkaloid-dispensing pouch of claim 36, wherein the vaporizable alkaloid composition comprises (S)-2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine, citric acid, and acetic acid.

38. 37. The alkaloid dispensing pouch of claim 36, wherein the carrier comprises microcrystalline cellulose.

39. 37. The alkaloid-dispensing pouch of claim 36, wherein the chemosensory stimulant comprises capsaicin or a mixture of capsaicinoids.

40. 37. The alkaloid-dispensing pouch of claim 36, wherein the solvent is selected from the group consisting of propylene glycol, water, ethanol, glycerin, and mixtures thereof.

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