Nicotine complexes and methods of use in the adjustment of nicotine harshness and release kinetics

Abstract

The present disclosure describes innovative complexes of (S)-nicotine, and formulations, characterizations, and applications thereof, useful in modulating mouth and throat sensations such as harshness and "throat-hit." In various embodiments, novel nicotine complexes are designed to adjust the perceptual experience of nicotine in both smoking and smokeless products. Several embodiments of these complexes provided for herein exhibit the ability to make absorption kinetics adjustable, allowing for a tailored nicotine delivery experience. Additionally, the disclosure introduces not only methods for predicting nicotine harshness through dialysis experiments capable of measuring lipophilic permeation, but also novel techniques for actively modulating both harshness and absorption kinetics.

Description

NICOTINE COMPLEXES AND METHODS OF USE IN THE ADJUSTMENT OF NICOTINE HARSHNESS AND RELEASE KINETICSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to United States Provisional Patent Application No. 63 / 541,709, filed September 29, 2023, the entire contents of which is incorporated by reference herein.FIELD

[0002] The present disclosure primarily pertains to innovative complexes of nicotine formulations, characterizations, and their applications, particularly in modulating mouth and throat sensations such as harshness and “throat-hit” through use of novel nicotine complexes designed to adjust the perceptual experience of nicotine in both smoking and smokeless products. A key feature of these complexes is their ability to make absorption kinetics adjustable, allowing for a tailored nicotine delivery experience. Additionally, the disclosure introduces not only methods for predicting nicotine harshness but also novel techniques for actively modulating both harshness and absorption kinetics.BACKGROUND

[0003] The harshness an individual feels in their throat upon inhaling nicotine remains a poorly understood phenomenon. Throat harshness, a type of sensory irritation from the chemosensory irritant nicotine, could be a response of human nicotinic acetylcholine receptors (nAChRs), such as mediated by a neuronal nAchR. In addition to this mechanism, or as an alternative, tracheal brush cells (BCs) in the trachea may be involved. Tracheal brush cells are specialized epithelial chemosensors that use the canonical taste transduction cascade to detect irritants. See, for example, C.J. Saunders, et al., “Chemosensory Brush Cells of the Trachea,” Am. J. Respir. Cell Mol. Biol., 49(2), 190-196 (2013). Or, given that (S)-nicotine is a chemosensory irritant, perhaps the harshness is the result of activation of chemosensory ion channels known as Transient Receptor Potential Channels, or TRP channels. See, for example, K. Talavera, et al., “Nicotine activates the chemosensory cation channel TRPA1,” Nature Neuroscience, 12, 1293-1299 (2009).

[0004] With only a limited understanding of the possible biochemical pathways leading to a perceived nicotine harshness, it is not surprising that both the tobacco industry and the vapingindustry empirically find ways to mitigate nicotine harshness. For example, it has been known for years that certain nicotine salts are less irritating in the throat than free-base nicotine, but there is little reasoning as to why some nicotine salts mitigate harshness to a greater extent than other nicotine salts. See, for example, U.S. Patent Application Publication No. US 2020 / 0315241 filed by Nude Nicotine, Inc., and PCT International Application Publication No. WO 2014 / 182736 filed by Ploom, Inc. See also, V. Gholap, et al., “Nicotine Forms: Why and how do they matter in nicotine delivery from electronic cigarettes,” Expert Opin. Drug Deliv., 17(12), 1727-1736, (2020).

[0005] Given this lack of understanding in the tobacco and vaping industries, there remains a need to apply scientific and analytical methods to predict and fine-tune nicotine harshness. What remains in serious need are new laboratory methods capable of scientifically correlating nicotine harshness with an easily measured variable, such that harshness can be reasonably predicted and fine-tuned.SUMMARY

[0006] In several embodiments, there is provided a nicotine complex or product comprising (S)-nicotine primarily (greater than 50%) in the form of a free base alkaloid (e.g., non-salt) with less than 50% monoprotonated nicotine (e.g., salt) and one or more ingredients suitable for forming a complex with the (S)-nicotine.

[0007] In several embodiments, there is provided a nicotine complex or product comprising (S)-nicotine in the form of a free base alkaloid or without a positive formal charge one or more ingredients suitable for forming a complex with the (S)-nicotine. In several embodiments, the (S)- nicotine in the nicotine complexes or products provided for herein comprises, consists of, or consists essentially of (S)-nicotine in the form of a free base alkaloid or (S)-nicotine without a positive formal charge. In several embodiments, the nicotine complexes or products provided herein are substantially free or free of monoprotonated or diprotonated nicotine.

[0008] In several embodiments, the complex is in a form selected from: a charge transfer complex, a hydrogen bonded complex, a Van der Waals complex, a complex stabilized by nonionic interactions, a solubilized complex, a micellular complex, and an inclusion complex.

[0009] In several embodiments, the one or more ingredients for forming a complex with the (S)-ni cotine is selected from the group consisting of: a fatty acid having a polar and / or hydrophilicfunctional group, a surfactant, a solubilizer (such as an oil), and / or a polysaccharide. In several embodiments, the one or more ingredients for forming a complex with the (S)-nicotine is selected from the group consisting of: a fatty acid having a polar and / or hydrophilic functional group, a surfactant, a solubilizer (such as an oil), and a polysaccharide.

[0010] In several embodiments, the acid having a polar and / or hydrophilic functional group comprises at least one carboxyl group. In several embodiments, the acid having a polar and / or hydrophilic functional group comprises a C8-C24 saturated fatty acid. In several embodiments, the acid having a polar and / or hydrophilic functional group comprises a C8-C24 monounsaturated fatty acid. In several embodiments, the acid having a polar and / or hydrophilic functional group comprises a C8-C24 polyunsaturated fatty acid.

[0011] In several embodiments, the acid having a polar and / or hydrophilic functional group comprises at least one hydroxyl group, at least one double bond, at least one conjugated double bond, at least one carboxyl group, or combinations thereof. In several embodiments, the acid having a polar and / or hydrophilic functional group comprises at least one hydroxyl group. In several embodiments, the acid having a polar and / or hydrophilic functional group comprises at least one double bond. In several embodiments, the acid having a polar and / or hydrophilic functional group comprises at least one conjugated double bond. In several embodiments, the acid having a polar and / or hydrophilic functional group comprises at least one carboxyl group.

[0012] In several embodiments, the C8-C24 fatty acid is saturated and is selected from the group consisting of caprylic acid, decanoic acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid, octadecanoic acid, icosanoic acid, docosanoic acid, and tetracosanoic acid. In several embodiments, the C8-C24 fatty acid is monounsaturated and is selected from the group consisting of myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, gadoleic acid, eicosenoic acid, erucic acid, and nervonic acid. In several embodiments, the C8-C24 fatty acid is polyunsaturated and is selected from the group consisting of linoleic acid, a-linolenic acid, y-linolenic acid, mead acid, stearidonic acid, arachidonic acid, eicosapentaenoic acid, and cervonic acid (docosahexaenoic acid). In several embodiments, the C -C24 fatty acid is polyunsaturated and is selected from the group consisting of conjugated linoleic acid, eicosadienoic acid, docosadienoic acid, pinolenic acid, a-eleostearic acid, P-eleostearic acid, catalpic acid, dihomo-y-linolenic acid, eicosatri enoic acid, eicosatetraenoic acid, adrenic acid, bosseopentaenoic acid, ozubondo acid, sardine acid, tetracosapentaenoic acid, and herring acid. In several embodiments, the acid havinga polar and / or hydrophilic functional group comprises a conjugated fatty acid and is selected from the group consisting of conjugated linoleic acid, punicic acid, jacaric acid, calendid acid, catapic acid, alpha-eleostearic acid, beta-eleostearic acid, parinaric acid, anadiplosis acid, and tung acid. In several embodiments, the acid having a polar and / or hydrophilic functional group comprises conjugated linoleic acid.

[0013] In several embodiments, the surfactant is selected from the group consisting of an anionic surfactant, a nonionic surfactant, a cationic surfactant, a zwitterionic surfactant, and mixtures thereof. In several embodiments, the surfactant is selected from the group consisting of lecithin, phosphatidylcholine, EO / PO block copolymers, EO / PO / EO triblock copolymers, polyethylene glycol, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, span 20, span 40, span 60, span 80, and mixtures thereof.

[0014] In several embodiments, the solubilizer comprises a mono-, di-, or tri-fatty acid glyceride. In several embodiments, the solubilizer comprises a mono-fatty acid glyceride. In several embodiments, the solubilizer comprises a di-fatty acid glyceride. In several embodiments, the solubilizer comprises a tri-fatty acid glyceride. In several embodiments, the solubilizer comprises a mono-, di-, or tri-fatty acid glyceride. In several embodiments, the fatty acid glyceride comprises medium-chain length triglyceride (MCT) oil. In several embodiments, the fatty acid glyceride comprises one or more of sunflower oil, canola oil, palm oil, coconut oil, safflower oil, olive oil, sesame oil, peanut oil, avocado oil, or soybean oil. In several embodiments, the fatty acid glyceride comprises sunflower oil. In several embodiments, the fatty acid glyceride comprises canola oil. In several embodiments, the fatty acid glyceride comprises palm oil. In several embodiments, the fatty acid glyceride comprises coconut oil. In several embodiments, the fatty acid glyceride comprises safflower oil. In several embodiments, the fatty acid glyceride comprises olive oil. In several embodiments, the fatty acid glyceride comprises sesame oil. In several embodiments, the fatty acid glyceride comprises peanut oil. In several embodiments, the fatty acid glyceride comprises avocado oil. In several embodiments, the fatty acid glyceride comprises soybean oil.

[0015] In several embodiments, the polysaccharide comprises a cyclodextrin. In several embodiments, the cyclodextrin is selected from the group consisting of P-cyclodextrin, hydroxypropyl-P-cyclodextrin, methyl-P-cyclodextrin, dimethyl-P-cyclodextrin, heptakis(2,6-di- O-)ethyl-P-cyclodextrin, 6-O-a-maltosyl-P-cyclodextrin, randomly methylated P-cyclodextrin(RAMEB), sulfobutylether-P-cyclodextrin, sulfolipo-P-cyclodextrin, y-cyclodextrin, hydroxypropyl-y-cyclodextrin, octakis-(6-bromo-6- deoxy)-y-cyclodextrin, octakis-(6-amino-6- deoxy)-y-cyclodextrin, octakis-(6-chloro-6-deoxy)-y- cyclodextrin, octakis-(6-deoxy-6-iodo)-y- cyclodextrin, octakis-(6-deoxy-6-mercapto)-y-cyclodextrin, octakis-(2,3,6-tri-O-methyl)-y- cyclodextrin, octakis-(2,3-diacetyl-6-sulfato)-y-cyclodextrin, octakis-(3-O-butyryl-2,6-di-O- pentyl)-y-cyclodextrin, octakis-6-sulfato-y-cyclodextrin, and mixtures thereof. In several embodiments, the polysaccharide comprises an unsubstituted P-cyclodextrin. In several embodiments, the polysaccharide comprises hydroxypropyl-P-cyclodextrin.

[0092]

[0016] In several embodiments, the nicotine complexes and products provided for herein further comprise a sugar alcohol from the group consisting of sorbitol, xylitol, erythritol, lactitol, maltitol, mannitol, isomalt, hydrogenated starch hydrolyzates, and combinations thereof.

[0017] In several embodiments, the nicotine complexes and products provided for herein further comprise a flavoring agent or a plurality of flavoring agents.

[0018] In several embodiments, the nicotine complexes and products provided for herein further comprise an antioxidant selected from the group consisting of tocopherols (vitamin E), butylated hydroxy anisole (BHA), butylated hydroxy toluene (BHT), propyl gallate, tertiary butylhydroquinone (TBHQ), rosemary extracts, green tea extract, and combinations thereof. In several embodiments, the nicotine complexes and products provided for herein further comprise tocopherols (vitamin E). In several embodiments, the nicotine complexes provided for herein further comprise butylated hydroxy anisole (BHA). In several embodiments, the nicotine complexes and products provided for herein further comprise butylated hydroxytoluene (BHT). In several embodiments, the nicotine complexes and products provided for herein further comprise propyl gallate. In several embodiments, the nicotine complexes provided for herein further comprise tertiary butylhydroquinone (TBHQ). In several embodiments, the nicotine complexes and products provided for herein further comprise rosemary (or other herbal) extracts. In several embodiments, the nicotine complexes provided for herein further comprise green tea extract.

[0019] In several embodiments, the nicotine complexes and products provided for herein comprise a pH adjuster selected from sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, magnesium carbonate, and any combination thereof. In several embodiments, the nicotine complexes and products provided for herein comprise sodium bicarbonate. In several embodiments, the nicotine complexes and products provided for hereincomprise sodium carbonate. In several embodiments, the nicotine complexes and products provided for herein comprise potassium bicarbonate. In several embodiments, the nicotine complexes and products provided for herein comprise potassium carbonate. In several embodiments, the nicotine complexes and products provided for herein comprise magnesium carbonate.

[0020] In several embodiments, the nicotine complexes and products provided for herein further comprise a substrate. In several embodiments, the substrate contributes to a physical form or a function of the nicotine product. In several embodiments, the substrate comprises a nonwoven fabric, a latex or rubber swatch, a fabric swatch, a wood splint, polymer fibers, cellulose viscose, paper, cotton, or a combination thereof. In several embodiments, substrate comprises spunbonded cotton, melt blown cotton, needle punched cotton, thermally bonded cotton, chemically bonded cotton, hydroentangled cotton, spun-laced cotton, or air-laid cotton. In several embodiments, the substrate comprises a nonwoven fabric, wherein the nonwoven fabric is saliva-permeable.

[0021] In several embodiments, the nicotine complexes and products provided for herein further comprise a carrier. In several embodiments, the carrier is selected from the group consisting of water insoluble fibers, microcrystalline cellulose, bamboo fibers, lignin, wheat fibers, pea fibers, maize fibers, rice fiber, oat fibers, barley fibers, buckwheat fibers, cellulose fibers, bran fibers, powdered cellulose, and combinations thereof. In several embodiments, the carrier comprises water insoluble fibers. In several embodiments, the carrier comprises microcrystalline cellulose. In several embodiments, the carrier comprises bamboo fibers. In several embodiments, the carrier comprises lignin. In several embodiments, the carrier wheat fibers. In several embodiments, the carrier comprises pea fibers. In several embodiments, the carrier comprises maize fibers. In several embodiments, the carrier comprises rice fibers. In several embodiments, the carrier comprises oat fibers. In several embodiments, the carrier comprises barley fibers. In several embodiments, the carrier comprises buckwheat fibers. In several embodiments, the carrier comprises cellulose fibers. In several embodiments, the carrier bran fibers. In several embodiments, the carrier comprises powdered cellulose.

[0022] In several embodiments, the nicotine complexes and products provided for herein are devoid of a crystal lattice structure. In several embodiments, the nicotine complexes and products provided for herein are substantially free of nicotine salt formed by an ionic bond. In several embodiments, the nicotine complexes and products provided for herein comprise (S)-nicotinehaving an alkaline pH. Tn several embodiments, the (S)-nicotine has pH greater than pH 7. In several embodiments, the pH value of (S)-nicotine complex is between 7 and 10.

[0023] In several embodiments, there is also provided an oral nicotine pouch, comprising a saliva-permeable nonwoven fabric, wherein the saliva-permeable nonwoven fabric defines an enclosure and a fill material within the enclosure and comprising an (S)-nicotine complex to the present disclosure and a carrier. In several embodiments, the fill material is sealed within the enclosure. In several embodiments, the carrier comprises microcrystalline cellulose. In several embodiments, the (S)-nicotine complex comprises a non-salt nicotine complex emulsion. In several embodiments, the non-salt nicotine complex emulsion comprises micelles, colloidal particles, or self-assembled structures. In several embodiments, the non-salt nicotine complex emulsion comprises micelles. In several embodiments, the non-salt nicotine complex emulsion comprises colloidal particles. In several embodiments, the non-salt nicotine complex emulsion comprises self-assembled structures. In several embodiments, the non-salt nicotine complex emulsion comprises micelles, colloidal particles, or self-assembled structures have a particle size between 10 nm to 10 pm. In several embodiments the non-salt nicotine complex emulsion comprises an unsaturated fatty acid complexed with the (S)-nicotine. In several embodiments, the unsaturated fatty acid comprises a C8-C24 fatty acid. In several embodiments, the C8-C24 fatty acid comprises conjugated linoleic acid. In several embodiments, the amount of nicotine is from about 0.1 to about 4% by weight of the pouch, including about 0.1% to about 0.5%, about 0.5% to about 1.0%, about 1.0% to about 1.5%, about 1.5% to about 2.0%, about 2.0% to about 2.5%, about 2.5% to about 3.0%, about 3.0% to about 3.5%, about 3.5% to about 4.0%, and any percentage in between those listed, including endpoints. In several embodiments, the amount of C8-C24 fatty acid is from about 0.1 to about 10% by weight of the pouch, including about 0.1% to about 0.5%, about 0.%% to about 1.0%, about 1.0% to about 2.0%, about 2.0% to about 3.0%, about 3.0% to about 4.0%, about 4.0% to about 5.0%, about 5.0% to about 6.0%, about 6.0% to about 7.0%, about 7.0% to about 8.0%, about 8.0% to about 9.0%, about 9.0% to about 10.0%, and and any percentage in between those listed, including endpoints. In several embodiments, the amount of moisture is at least about 15% by weight of the pouch, including about 20%, about 25% about 30%, about 40%, about 50%, about 60%, about 70% and greater. In several embodiments, the amount of pH adjuster is from about 0.01% to about 10% by weight of the pouch, including about 0.01% to about 0.05%, about 0.05% to about 0.1%, about 0.1% ot about 0.5%, about 0.5% to about1 .0%, about 1 .0% to about 2.0%, about 2.0% to about 3.0%, about 3.0% to about 4.0%, about 4.0% to about 5.0%, about 5.0% to about 6.0%, about 6.0% to about 7.0%, about 7.0% to about 8.0%, about 8.0% to about 9.0%, about 9.0% to about 10.0%, and and any percentage in between those listed, including endpoints.. In several embodiments, the amount of surfactant is from about 0.1 to about 10% by weight of the pouch, , including about 0.1% to about 0.5%, about 0.%% to about 1.0%, about 1.0% to about 2.0%, about 2.0% to about 3.0%, about 3.0% to about 4.0%, about 4.0% to about 5.0%, about 5.0% to about 6.0%, about 6.0% to about 7.0%, about 7.0% to about 8.0%, about 8.0% to about 9.0%, about 9.0% to about 10.0%, and any percentage in between those listed, including endpoints. In several embodiments, the amount of solubilizer is from about 0.1 to about 40% by weight of the pouch, including about 0.1% to about 0.5%, about 0.%% to about 1.0%, about 1.0% to about 2.0%, about 2.0% to about 3.0%, about 3.0% to about 4.0%, about 4.0% to about 5.0%, about 5.0% to about 6.0%, about 6.0% to about 7.0%, about 7.0% to about 8.0%, about 8.0% to about 9.0%, about 9.0% to about 10.0%, about 10.0% to about 15.0%, about 15.0% to about 20.0%, about 20.0% to about 25.0%, about 25.0% to about 30.0%, about 30.0% to about 35.0%, about 35.0% to about 40.0% and any percentage in between those listed, including endpoints.. In several embodiments, the amount of polysaccharide is from 0.1 to 5% by weight of the pouch, , including about 0.1% to about 0.5%, about 0.5% to about 1.0%, about 1.0% to about 2.0%, about 2.0% to about 3.0%, about 3.0% to about 4.0%, about 4.0% to about 5.0%, and any percentage in between those listed, including endpoints..

[0024] In several embodiments, there is provided a nicotine product comprising (i) a nicotine complex, (ii) at least one unsaturated fatty acid, (iii) at least one oil, (iv) at least one surfactant, and (v) at least one of a pouch, a carrier, an antioxidant, a flavorant, or a sugar alcohol. In several embodiments, there is a provided a nicotine product comprising (i) a nicotine complex, (ii) at least one unsaturated fatty acid, (iii) at least one surfactant, and (iv) at least one of a pouch, a carrier, an antioxidant, a flavorant, or a sugar alcohol. In several embodiments, there is provided a nicotine product comprising (i) a nicotine complex, (ii) at least one polysaccharide, (iii) at least one oil, (iv) at least one surfactant, and (v) at least one of a pouch, a carrier, an antioxidant, a flavorant, or a sugar alcohol.

[0025] In several embodiments of the nicotine products provided for herein, the nicotine within the nicotine complex comprises at least 40% nicotine in the form of a free base alkaloid and having less than 40% in a monoprotonated form.

[0026] In several embodiments of the nicotine products provided for herein, the at least one unsaturated fatty acid comprises conjugated linoleic acid. In several embodiments of the nicotine products provided for herein, the at least one oil comprises on or both of MCT oil and sunflower oil. In several embodiments of the nicotine products provided for herein, the at least one polysaccharide comprises a cyclodextrin. In several embodiments, the cyclodextrin comprises hydroxypropyl-|3-cyclodextrin. In several embodiments of the nicotine products provided for herein, the product comprises at least two of a pouch, a carrier, an antioxidant, a flavorant, or a sugar alcohol. In several embodiments of the nicotine products provided for herein, the product comprises at least three of a pouch, a carrier, an antioxidant, a flavorant, or a sugar alcohol. In several embodiments, the at least one surfactant comprises polysorbate 80.

[0027] In several embodiments, there is provided a method of tailoring a subject’s nicotine experience comprising administering to the subject a nicotine complex, an oral nicotine pouch, or a nicotine product according to the present disclosure.

[0028] In several embodiments there is provided the use of a nicotine complex, an oral nicotine pouch, or a nicotine product according to the present disclosure for modulation of nicotine release rate and / or quantity to a subject. In several embodiments, the nicotine release rate and / or quantity is increased as compared to free base nicotine, or an oral nicotine pouch or nicotine product not comprising a nicotine complex. In several embodiments the nicotine release rate and / or quantity is reduced as compared to free base nicotine, or an oral nicotine pouch or nicotine product not comprising a nicotine complex.

[0029] Additionally provided for herein is a method of modulating mouth and throat sensations including harshness and throat hit from inhalation of vapors from a smoking or smokeless product comprising (S)-nicotine, the method comprising, providing an (S)-nicotine complex comprising (S)-nicotine in association with at least one other molecule, wherein the (S)-nicotine complex is devoid of a crystal lattice structure, characterizing an (S)-nicotine absorption rate and predicting relative harshness and throat hit expected from the smoking or smokeless product when the (S)- nicotine is replaced by the (S)-nicotine complex by measuring lipophilic permeation of the (S)- nicotine complex through a dialysis membrane, repeating the aforementioned steps using at least one additional (S)-nicotine complex, and modulating mouth and throat sensations including harshness and throat hit from inhalation of vapors from the smoking or smokeless product by substituting the (S)-nicotine for one of the (S)-nicotine complexes having a higher or a lowerlipophilic permeation measured through the dialysis membrane compared to lipophilic permeation of (S)-nicotine measured through the dialysis membrane.

[0030] In several embodiments, the at least one other molecule is selected from a surfactant, a polymer, a polysaccharide, a metal, or an inorganic compound.

[0031] In several embodiments, the at least one other molecule comprises a cyclodextrin selected from the group consisting of P-cyclodextrin, hydroxypropyl-P-cyclodextrin, methyl-P- cyclodextrin, dimethyl-P-cyclodextrin, heptakis(2,6-di-O-)ethyl-P-cyclodextrin, 6-O-a-maltosyl- P-cyclodextrin, randomly methylated P-cyclodextrin (RAMEB), sulfobutylether-P-cyclodextrin, sulfolipo-p-cyclodextrin, y-cyclodextrin, hydroxypropyl-y-cyclodextrin, octakis-(6-bromo-6- deoxy)-y-cyclodextrin, octakis-(6-amino-6-deoxy)-y-cyclodextrin, octakis-(6-chloro-6-deoxy)-y- cyclodextrin, octakis-(6-deoxy-6-iodo)-y-cyclodextrin, octakis-(6-deoxy-6-mercapto)-y- cyclodextrin, octakis-(2,3,6-tri-O-methyl)-y-cyclodextrin, octakis-(2,3-diacetyl-6-sulfato)-y- cyclodextrin, octakis-(3-O-butyryl-2,6-di-O-pentyl)-y-cyclodextrin, octakis-6-sulfato-y- cyclodextrin, and mixtures thereof.

[0032] In several embodiments, the at least one other molecule comprises a surfactant selected from the group consisting of anionic surfactants, nonionic surfactants, cationic surfactants, zwitterionic surfactants, and mixtures thereof.

[0033] In several embodiments, the surfactant is selected from the group consisting of lecithin, phosphatidylcholine, EO / PO block copolymers, EO / PO / EO triblock copolymers, polyethylene glycol, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, and mixtures thereof.

[0034] In several embodiments, the smokeless product comprises a vaping liquid.

[0035] In several embodiments, there is provided a method for characterizing nicotine absorption rate and predicting its relative throat harshness expected from a smoking or smokeless product by simulating lipophilic permeation of an (S)-nicotine complex during use of said product by an individual relative to the smoking or smokeless product formulated only with (S)-nicotine free base by measuring lipophilic permeation through dialysis membranes, the method comprising providing the (S)-nicotine complex in an aqueous solution inside a dialysis bag, submerging the dialysis bag inside a lipophilic-like medium, measuring (S)-nicotine concentration in the hydrophobic medium over time, preparing a mathematical plot of (S)-nicotine concentration in the hydrophobic medium versus time to show a rate of lipophilic permeation of the (S)-nicotine complex, comparing the rate of lipophilic permeation of the (S)-nicotine complex to a rate oflipophilic permeation of (S)-ni cotine from a dialysis bag containing a solution of (S)-ni cotine free base, and predicting relative harshness expected from the smoking or smokeless product formulated with an (S)-ni cotine complex during use of said product by an individual.

[0036] In several embodiments, the (S)-nicotine complex comprises (S)-nicotine in association with at least one other molecule, the at least one other molecule selected from a surfactant, a polymer, a polysaccharide, a metal, and an inorganic compound, wherein the (S)-ni cotine complex is devoid of a crystal lattice structure.

[0037] In several embodiments, the polysaccharide comprises a cyclodextrin selected from the group consisting of P-cyclodextrin, hydroxypropyl-P-cyclodextrin, methyl-P-cyclodextrin, dimethyl-P-cyclodextrin, heptakis(2,6-di-O-)ethyl -P-cyclodextrin, 6-O-a-maltosyl-P- cyclodextrin, randomly methylated P-cyclodextrin (RAMEB), sulfobutylether-P-cyclodextrin, sulfolipo-P-cyclodextrin, y-cyclodextrin, hydroxypropyl-y-cyclodextrin, octakis-(6-bromo-6- deoxy)-y-cyclodextrin, octakis-(6-amino-6-deoxy)-y-cyclodextrin, octakis-(6-chloro-6-deoxy)-y- cyclodextrin, octakis-(6-deoxy-6-iodo)-y-cyclodextrin, octakis-(6-deoxy-6-mercapto)-y- cyclodextrin, octakis-(2,3,6-tri-O-methyl)-y-cyclodextrin, octakis-(2,3-diacetyl-6-sulfato)-y- cyclodextrin, octakis-(3-O-butyryl-2,6-di-O-pentyl)-y-cyclodextrin, octakis-6-sulfato-y- cyclodextrin, and mixtures thereof.

[0038] In several embodiments, the surfactant is selected from the group consisting of anionic surfactants, nonionic surfactants, cationic surfactants, zwitterionic surfactants, and mixtures thereof.

[0039] In several embodiments, the surfactant is selected from the group consisting of lecithin, phosphatidylcholine, EO / PO block copolymers, EO / PO / EO triblock copolymers, polyethylene glycol, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, and mixtures thereof.

[0040] In several embodiments, the smokeless product comprises a vaping liquid.

[0041] In several embodiments, there is provided a vaporizable composition comprising an (S)-nicotine complex, at least one solvent, and optionally, at least one flavoring agent. In several embodiments, the solvent is selected from the group consisting of propylene glycol, water, ethanol, glycerin, and mixtures thereof. In several embodiments, the (S)-nicotine complex comprises (S)- nicotine in association with at least one other molecule, the at least one other molecule selected from a surfactant, a polymer, a polysaccharide, a metal, and an inorganic compound, and wherein the (S)-nicotine complex is devoid of a crystal lattice structure.

[0042] In several embodiments, the polysaccharide comprises a cyclodextrin selected from the group consisting of P-cyclodextrin, hydroxypropyl-P-cyclodextrin, methyl-P-cyclodextrin, dimethyl-P-cyclodextrin, heptakis(2,6-di-O-)ethyl -P-cyclodextrin, 6-O-a-maltosyl-P- cyclodextrin, randomly methylated P-cyclodextrin (RAMEB), sulfobutylether-P-cyclodextrin, sulfolipo-P-cyclodextrin, y-cyclodextrin, hydroxypropyl-y-cyclodextrin, octakis-(6-bromo-6- deoxy)-y-cyclodextrin, octakis-(6-amino-6-deoxy)-y-cyclodextrin, octakis-(6-chloro-6-deoxy)-y- cyclodextrin, octakis-(6-deoxy-6-iodo)-y-cyclodextrin, octakis-(6-deoxy-6-mercapto)-y- cyclodextrin, octakis-(2,3,6-tri-O-methyl)-'y-cyclodextrin, octakis-(2,3-diacetyl-6-sulfato)-y- cyclodextrin, octakis-(3-O-butyryl-2,6-di-O-pentyl)-y-cyclodextrin, octakis-6-sulfato-y- cyclodextrin, and mixtures thereof.

[0043] In several embodiments, the surfactant is selected from the group consisting of anionic surfactants, nonionic surfactants, cationic surfactants, zwitterionic surfactants, and mixtures thereof.

[0044] In several embodiments, the surfactant is selected from the group consisting of lecithin, phosphatidylcholine, EO / PO block copolymers, EO / PO / EO triblock copolymers, polyethylene glycol, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, and mixtures thereof.

[0045] In several embodiments, there is provided a nicotine product comprising, an (S)- nicotine complex, at least one excipient, and optionally, at least one substrate. In several embodiments, the at least one substrate, when present, contributes to a physical form or a function of the nicotine product. In several embodiments, the excipient is selected from a binder, a diluent, a syrup, a sugar, a sweetener, a solubilizer, a solvent, a polyol, an emollient, a humectant, an oil, a polymer, a surfactant, a carrier, a stabilizer, a preservative, and mixtures thereof. In several embodiments, the substrate contributes to a physical form or a function of the nicotine product. In several embodiments, the substrate comprises a nonwoven fabric, a latex or rubber swatch, a fabric swatch, a wood splint, polymer fibers, cellulose viscose, paper, cotton, or a combination thereof. In several embodiments, substrate comprises spunbonded cotton, melt blown cotton, needle punched cotton, thermally bonded cotton, chemically bonded cotton, hydroentangled cotton, spun- laced cotton, or air-laid cotton. In several embodiments, the substrate comprises a nonwoven fabric, wherein the nonwoven fabric is saliva-permeable.

[0046] In several embodiments, the (S)-nicotine complex comprises (S)-nicotine in association with at least one other molecule, the at least one other molecule selected from a surfactant, apolymer, a polysaccharide, a metal, and an inorganic compound, and wherein the (S)-nicotine complex is devoid of a crystal lattice structure.

[0047] In several embodiments, the polysaccharide comprises a cyclodextrin selected from the group consisting of P-cyclodextrin, hydroxypropyl-P-cyclodextrin, methyl-P-cyclodextrin, dimethyl-P-cyclodextrin, heptakis(2,6-di-O-)ethyl -P-cyclodextrin, 6-O-a-maltosyl-P- cyclodextrin, randomly methylated P-cyclodextrin (RAMEB), sulfobutylether-P-cyclodextrin, sulfolipo-P-cyclodextrin, y-cyclodextrin, hydroxypropyl-y-cyclodextrin, octakis-(6-bromo-6- deoxy)-y-cyclodextrin, octakis-(6-amino-6-deoxy)-y-cyclodextrin, octakis-(6-chloro-6-deoxy)-y- cyclodextrin, octakis-(6-deoxy-6-iodo)-y-cyclodextrin, octakis-(6-deoxy-6-mercapto)-y- cyclodextrin, octakis-(2,3,6-tri-O-methyl)-y-cyclodextrin, octakis-(2,3-diacetyl-6-sulfato)-y- cyclodextrin, octakis-(3-O-butyryl-2,6-di-O-pentyl)-y-cyclodextrin, octakis-6-sulfato-y- cyclodextrin, and mixtures thereof.

[0048] In several embodiments, the surfactant is selected from the group consisting of anionic surfactants, nonionic surfactants, cationic surfactants, zwitterionic surfactants, and mixtures thereof. In several embodiments, the surfactant is selected from the group consisting of lecithin, phosphatidylcholine, EO / PO block copolymers, EO / PO / EO triblock copolymers, polyethylene glycol, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, span 20, span 40, span 60, span 80, and mixtures thereof.

[0049] In several embodiments, the nicotine product is configured in the form of a transdermal patch, a dissolving oral film, a lozenge, a chewing gum, an oral nicotine pouch (ONP), impregnated toothpicks, a mouth spray, a gummy candy, a sublingual disintegrating tablet, or a topical cream. In several embodiments, the nicotine product further comprises an (S)-nicotine salt further comprising protonated (S)-nicotine cation and a negatively charged counterion comprising a conjugate base of an organic acid. In several embodiments, the organic acid is selected from adipic acid, citric acid, L-(+)-tartaric acid, succinic acid, and vanillic acid.

[0050] In several embodiments, there is provided a method of modulating mouth and throat sensations including harshness and throat hit from inhalation of vapors from a smoking or smokeless product comprising (S)-nicotine, the method comprising providing an (S)-nicotine salt comprising protonated (S)-nicotine cation and a negatively charged counterion comprising a conjugate base of an organic acid, characterizing an (S)-nicotine absorption rate and predicting relative harshness and throat hit expected from the smoking or smokeless product when the (S)-nicotine is replaced by the (S)-nicotine salt by measuring lipophilic permeation of the (S)-ni cotine salt through a dialysis membrane, repeating the aforementioned steps using at least one additional (S)-nicotine salt, and modulating mouth and throat sensations including harshness and throat hit from inhalation of vapors from the smoking or smokeless product by substituting the (S)-ni cotine for one of the (S)-nicotine salts having a higher or a lower lipophilic permeation measured through the dialysis membrane compared to lipophilic permeation of (S)-nicotine measured through the dialysis membrane.

[0051] In several embodiments, there is provided a method for characterizing nicotine absorption rate and predicting its relative throat harshness expected from a smoking or smokeless product by simulating lipophilic permeation of an (S)-nicotine salt during use of said product by an individual relative to the smoking or smokeless product formulated only with (S)-nicotine free base by measuring lipophilic permeation through dialysis membranes, the method comprising providing the (S)-nicotine salt in an aqueous solution inside a dialysis bag, the (S)-nicotine salt comprising protonated (S)-nicotine cation and a negatively charged counterion comprising a conjugate base of an organic acid, submerging the dialysis bag inside a lipophilic-like medium; and measuring (S)-nicotine concentration in the hydrophobic medium over time; preparing a mathematical plot of (S)-nicotine concentration in the hydrophobic medium versus time to show a rate of lipophilic permeation of the (S)-nicotine salt; comparing the rate of lipophilic permeation of the (S)-nicotine salt to a rate of lipophilic permeation of (S)-nicotine from a dialysis bag containing a solution of (S)-nicotine free base; and predicting relative harshness expected from the smoking or smokeless product formulated with an (S)-nicotine salt during use of said product by an individual.

[0052] It has now been surprisingly discovered that oral and / or throat harshness of (S)- nicotine, and salts and complexes thereof, can be correlated to rate and / or extent of membrane permeability towards a lipophilic-like medium. As such, it has now been discovered that a laboratory dialysis measurement in vitro can be used to predict nicotine harshness in both smoking and smokeless products. Having discovered and optimized a quantifiable method for predicting harshness, it is now possible to fine-tune, i.e., optimize, the harshness of nicotine containing products.

[0053] In various aspects of the present disclosure, it appears the greater and / or faster the membrane permeability, the harsher the nicotine tastes and feels in the back of the throat. Therationale is that (S)-nicotine free base has higher permeability across human buccal cell membranes than various salts and complexes of (S)-nicotine, and therefore such salts and complexes of (S)-nicotine can exhibit a lighter perceived harshness or throat irritancy. See, for example, C. Adrian, et al., “In vivo human buccal permeability of nicotine,” Int. J. Pharm., 311(1- 2), 196-202 (2006).

[0054] In various aspects of the present disclosure, harshness of nicotine containing smoking and smokeless products is modulated by complexing nicotine and / or forming salts of nicotine to slow membrane permeability.

[0055] In accordance with various embodiments of the present disclosure, novel (S)-nicotine salts and (S)-nicotine complexes are described, wherein the (S)-nicotine salts and (S)-nicotine complexes slow rate of membrane permeability of (S)-nicotine as demonstrated in dialysis experiments. Comparative studies show the ability of salts and complexes to retard the membrane permeability of (S)-nicotine and thus lower perceived oral and throat harshness of (S)-nicotine compared to free base alkaloid.

[0056] In accordance with various embodiments of the present disclosure, novel (S)-nicotine complexes comprise both inclusion complexes, such as formed between (S)-nicotine and a cyclodextrin, and micellular complexes, such as formed between (S)-nicotine and a surfactant.

[0057] In accordance with various embodiments of the present disclosure, vaporizable compositions comprising novel (S)-nicotine salts and / or (S)-nicotine complexes are described, wherein the compositions exhibit lower oral cavity and throat harshness compared to vaporizable compositions comprising only (S)-ni cotine free base alkaloid.

[0058] In accordance with various embodiments of the present disclosure, various nicotine containing products comprising novel (S)-nicotine salts and / or (S)-nicotine complexes are described that are not smoking or vaping products, wherein the compositions exhibit lower oral cavity harshness compared to products comprising only (S)-ni cotine free base alkaloid.BRIEF DESCRIPTION OF THE DRAWING FIGURES

[0059] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0060] The subject matter is pointed out with particularity and claimed distinctly in the concluding portion of the specification. A more complete understanding, however, may best be obtained by referring to the detailed description and claims when considered in connection with the following drawing figures:

[0061] FIG. 1 schematically illustrates a non-limiting example of an in vitro dialysis method for measuring membrane permeability of (S)-nicotine from various nicotine complexes in either hydrophilic (e.g., PBS buffer) or lipophilic-like media (e.g., propylene glycol), with the method comprising dialysis tubing as a membrane for measuring membrane permeability;

[0062] FIGS. 2A-2B illustrate two plots of membrane permeability measured for (S)-nicotine and (S)-nicotine from various nicotine salts and nicotine complexes, plotted in concentration (mg / mL) of NCT versus time, in hydrophilic media (phosphate buffered saline (PBS), presented in FIG. 2A) and in lipophilic-like media (propylene glycol (PG), presented in FIG. 2B);

[0063] FIG. 3 illustrates membrane permeability measured for (S)-nicotine and (S)-nicotine from various nicotine salts and nicotine complexes, conducted in lipophilic-like media (propylene glycol (PG)) and plotted in concentration (mg / mL) of NCT versus time;

[0064] FIG. 4 illustrates membrane permeability measured for (S)-nicotine in comparison to (S)-nicotine from nicotine adipate, citrate, decanoate, L-(+) tartrate, succinate and vanillate salts, conducted in lipophilic-like media (propylene glycol (PG)) and plotted in concentration (mg / mL) of NCT versus time;

[0065] FIG. 5 illustrates membrane permeability measured for (S)-nicotine in comparison to (S)-nicotine from (S)-nicotine-L-(+)-tartrate and two non-limiting embodiments of complexes of (S)-nicotine, namely an inclusion complex with hydroxypropyl-P-cyclodextrin and a micellular complex with polysorbate-80, conducted in lipophilic-like media (propylene glycol (PG)) and plotted in concentration (mg / mL) of NCT versus time. The block arrows in FIG. 5 emphasize the lowering of the membrane permeability of (S)-nicotine free base made possible by salt formation and complexation;

[0066] FIG. 6 illustrates membrane permeability measured for (S)-nicotine and (S)-nicotine from various non-limiting examples of nicotine salts, conducted in lipophilic-like media (propylene glycol (PG)) and plotted in concentration (mg / mL) of NCT versus time;

[0067] FIG 7 illustrates membrane permeability measured for (S)-nicotine and (S)-nicotine from various non-limiting examples of nicotine salts, conducted in lipophilic-like media (propylene glycol (PG)) and plotted in concentration (mg / mL) of NCT versus time;

[0068] FIG. 8 illustrates the chemical structures of various non-limiting examples of organic acids that were used to prepare the (S)-nicotine salts that generated the membrane permeability data in FIG. 7. The dashed-line box on each structure points out the additional polar hydrophilic functionality responsible for significantly reducing nicotine membrane permeability in lipophilic- like medium (PG);

[0069] FIG. 9 illustrates membrane permeability measured for (S)-nicotine and (S)-nicotine from various non-limiting examples of nicotine salts from monocarboxylic acids, conducted in lipophilic-like media (propylene glycol (PG)) and plotted in concentration (mg / mL) of NCT versus time;

[0070] FIG. 10 illustrates the chemical structures of various non-limiting examples of monocarboxylic acids that were used to prepare the (S)-nicotine salts that generated the membrane permeability data in FIG. 9. These acids, lacking additional hydrophilic functionality, only mildly reduce lipophilic permeability in lipophilic-like medium (PG);

[0071] FIG. 11 illustrates membrane permeability measured for (S)-nicotine and (S)-nicotine from various nicotine complexes with non-limiting examples of surfactants, conducted in lipophilic-like media (propylene glycol (PG)) and plotted in concentration (mg / mL) of NCT versus time;

[0072] FIG. 12 illustrates membrane permeability measured for (S)-nicotine and (S)-nicotine from various nicotine inclusion complexes with different non-limiting examples of cyclodextrins, conducted in lipophilic-like media (propylene glycol (PG)) and plotted in concentration (mg / mL) of NCT versus time in the upper graph and as percentage (%) if 6-hour release over time; and

[0073] FIG. 13 schematically summarizes the relative abilities for salts and complexes to mitigate lipophilic permeability of (S)-nicotine from low lipophilic permeability to high lipophilic permeability depending on whether the (S)-nicotine is: (1) in the form of a salt with an organic acid having additional polar hydrophilic functionality; (2) in the form of a salt with an monocarboxylic acid having no additional polar hydrophilic functionality; (3) in the form of a micellular complex with zwitterionic, amphoteric or nonionic surfactants; and (4) in the form of cyclodextrin inclusion complex.

[0074] FIGS. 14A-14F depict schematic drawings that illustrate certain differences between nicotine salts and nicotine complexes, the latter as described herein. FIG. 14A shows a schematic depiction of a nicotine salt formed from nicotine and an acid. FIG. 14B shows a schematic of a non-limiting example of a nicotine charge transfer complex. FIG. 14C shows a schematic of a non-limiting example of a nicotine Van der Waals complex. FIG. 14D shows a schematic of a non-limiting example of a nicotine hydrogen bonded complex. FIG. 14E shows a schematic of a non-limiting example of a nicotine micellular complex. FIG. 14F shows a schematic of a nonlimiting example of a nicotine inclusion complex.

[0075] FIG. 15 schematically summarizes a Non-salt-Nicotine-Complex-Emulsion (NNCE). In particular, FIG. 15 shows a NNCE-based Oral Nicotine Pouch (ONP). According to several embodiments a combination of cellulose, such as microcrystalline cellulose, with nicotine (e.g., (S)-nicotine and a fatty acid (e.g., an unsaturated fatty acid) form a complex (in the form of an emulsion) in which the nicotine is not in the form of a salt. As schematically illustrated, the nonsalt emulsion can be an oil-water emulsion, a water-oil emulsion, a water-oil -water emulsion, or an oil-water-oil emulsion, depending on the embodiment.

[0076] FIGS 16A-16B show non-limiting examples of fatty acids that can be used in the generation of an emulsion according to embodiments disclosed herein. FIG. 16A shows the resulting physical characteristics of mixtures when the indicated fatty acids are used. FIG. 16B shows the chemical structure of examples of fatty acids which can be used in combination with a nicotine complex to result in a NNCE.

[0077] FIGS. 17A-17D show information relating to the non-salt nature of nicotine complexes produced according to embodiments provided for herein. FIG. 17A shows three forms of nicotine, namely, diprotonated nicotine, monoprotonated nicotine, and free base nicotine. FIG. 17B shows a graph depicting the relative abundance of each of the forms of nicotine at various pH values. FIG. 17C shows a histogram depicting the form of nicotine present in an emulsion when various fatty acids are used. A pH value of about 8 or less represents nicotine present in the salt form, while a pH value of about 8 or greater represents nicotine present in the free base form. FIG. 17D shows the related physical characteristics of the resulting mixture when the indicated fatty acids are used.

[0078] FIGS. 18A-18B show a non-limiting example of an apparatus to test dissolution of nicotine complexes provided for herein and measure the rate of nicotine release. FIG. 18A showsan image of an experimental setup for dissolution analysis. FIG. 18B shows a schematic of the components of the experimental setup and their respective functions.

[0079] FIGS. 19A-19B show data related to nicotine release rate for emulsions made using the indicated fatty acids. FIG. 19A shows data related to nicotine release rate over time from emulsions made using a conjugated fatty acid, medium chain triglyceride oil or nicotine alone as a control. The inset photos depict the physical appearance of each mixture tested. FIG. 18B shows additional data for nicotine release rate when nicotine complexes are combined with additional fatty acids. The inset photos depict the physical appearance of the indicated mixture tested.

[0080] FIGS. 20A-20B show data related to nicotine sensation experienced by users of oral nicotine pouches carrying the indicated nicotine complex mixture. FIG. 20A shows data related to nicotine headrush perceived by users of the indicated oral nicotine pouches. FIG. 20B shows additional data related to nicotine headrush perceived by users of the indicated oral nicotine pouches.

[0081] FIGS. 21A-21C show data related to nicotine stability when the indicated mixtures are used to fill oral nicotine pouches. FIG. 21A shows data related to mass of the pouch over time. FIG. 2 IB shows data related to the pH of the pouches over time. FIG. 21C shows data related to nicotine mass of the pouches over time.DETAILED DESCRIPTION

[0082] The detailed description of exemplary embodiments makes reference to the accompanying drawings, which show exemplary embodiments by way of illustration and their best mode. While these exemplary embodiments are described in sufficient detail to enable those skilled in the art to practice the invention, 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 inventions. Thus, the detailed description is presented for purposes of illustration only and not of limitation. For example, unless otherwise noted, the steps recited in any of the method or process descriptions may be executed in any order and are not necessarily limited to the order presented. Furthermore, any reference to singular includes plural 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 or the like may include permanent, removable, temporary, partial, full and / or any other possible attachment option.Additionally, any reference to without contact (or similar phrases) may also include reduced contact or minimal contact.

[0083] In various embodiments of the present disclosure, a method of predicting nicotine harshness is disclosed. The method is based on measurement of (S)-nicotine membrane permeability such as measured in a laboratory dialysis experiment.

[0084] In various embodiments, harshness of smoking and smokeless products is modulated by complexing nicotine and / or forming salts of nicotine to slow membrane permeability of nicotine.

[0085] In various embodiments, novel (S)-nicotine salts are described that provide for mitigated membrane permeability of (S)-nicotine in dialysis experiments and thus a predictably lower harshness of (S)-nicotine compared to (S)-nicotine free base alkaloid.

[0086] In various embodiments, novel (S)-nicotine complexes are described that provide for mitigated membrane permeability in dialysis experiments and thus a predictably lower harshness compared to (S)-ni cotine free base alkaloid. Novel (S)-nicotine complexes comprise both inclusion complexes, such as formed between (S)-nicotine and a cyclodextrin, and micellular complexes, such as formed between (S)-nicotine and a surfactant.

[0087] In various embodiments, vaporizable compositions comprising novel (S)-nicotine salts and / or novel (S)-ni cotine complexes are described, wherein said compositions exhibit lower oral cavity and throat harshness compared to vaporizable compositions comprising only (S)-nicotine free base alkaloid.

[0088] In various embodiments, end use products comprising novel (S)-nicotine salts and / or novel (S)-nicotine complexes are described, wherein said compositions exhibit lower oral cavity and throat harshness compared to vaporizable compositions comprising only (S)-ni cotine free base alkaloid. These products include, but are not limited to, a transdermal patch, a dissolving film, a lozenge, a chewing gum, an oral pouch, impregnated toothpicks, a gummy candy, sublingual disintegrating tablets, and a topical cream.

[0089] In various embodiments, a reduction in oral and / or laryngeal irritancy correlates to a reduction in skin irritancy for dermal delivery product forms such as a transdermal patch or a tropical cream, with these products benefiting from fine-tuning of harshness of nicotine through use of salts and / or complexes, even though these end use products are not for oral use.Definitions and Interpretations:

[0090] As used herein, the acronym “NCT” refers to (S)-nicotine, such as the free base alkaloid and the (S)-ni cotine that might have dissociated from a salt or a complex of (S)-nicotine. In some examples, the term “NCT” is used to simplify having to write out the full name (S)-nicotine on an axis of a graph.

[0091] As used herein, the term “nicotine salt” refers to a compound comprising protonated (S)-nicotine in association with a negatively charged counterion (an anion), where the counterion is usually the conjugate base of the acid used to protonate (S)-nicotine free base alkaloid. Typically, a nicotine salt is formed by proton transfer between (S)-nicotine and an inorganic or organic acid, or a mixture of acids, in any combination, to protonate (S)-nicotine free base and form the corresponding salt. (S)-Nicotine salts are known and depending on the acid used to form the salt or mixed salt, stoichiometries besides a 1 : 1 acid to alkaloid ratio is formed. For example, (S)-nicotine salts made from a variety of organic acids have been described by T. A. Perfetti, “Structural Study of Nicotine Salts,” Beitrage zur Tabakforschung International, 12(2), 43-54, 1983, where 1 : 1, 2: 1 and 3 : 1 acid to free base nicotine ratios were observed. Perfetti discloses that nicotine forms 3: 1 acid to base salts with aliphatic monocarboxylic acids, such as acetic acid, wherein one acid molecule is bound as in 1 : 1 salts and the other two acid molecules are bound to the nitrogen of the pyridine ring. Perfetti also observed that nicotine benzoate salts are 1 : 1 acid to base salts and that the citrate salt of nicotine is a 2: 1 acid to base salt. (S)-nicotine lactate and (S)- nicotine benzoate, for example, find use in vaping. Examples of organic acids that may be used to form salts of (S)-nicotine include, but are not limited to, formic acid, acetic acid, adipic 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, L-(-)-malic acid, malonic acid, mandelic acid, methane sulfonic acid, oxalic acid, phenylacetic acid, phthalic acid, picric acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tannic acid, L-(+)-tartaric acid, tartronic acid, valeric acid, vanillic acid, and combinations thereof. Such (S)-nicotine salts can be prepared by reaction of the alkaloid free base with a suitable acid or mixture of acids in a manner known by those skilled in the art.

[0092] As used herein, the term “nicotine complex” refers to a compound comprising an unprotonated (S)-nicotine molecule in association with at least one other compound, wherein the complex is not crystalline, z.c., does not comprise a crystal lattice. The one other compound in association with (S)-nicotine may be, for example, a surfactant, a polymer, a polysaccharide such as a cyclodextrin, a metal, or an inorganic compound. Complexes may be characterized as a hydrogen bonded complex, a complex stabilized by nonionic interactions, a solubilized or micellular complex, or an inclusion complex. In some embodiments, complexes may be ionic, with charge transfer between (S)-nicotine and the at least one other compound, but not protonation. In some instances, the nature of a particular (S)-nicotine complex may be intractable, overly complicated, and not characterizable structurally. In various embodiments, (S)-nicotine-surfactant complexes are of interest, such as complexes formed from (S)-nicotine and preferably a nonionic or anionic surfactants. These types of complexes may comprise micellular structures. Also, of interest herein are (S)-nicotine / cyclodextrin complexes. These types of complexes are known to be inclusion complexes wherein at least one (S)-nicotine molecule is enclosed within the cavity of the cyclodextrin molecule.

[0093] As used herein, the term “cyclodextrin” refers to the entire class of cyclic polysaccharides obtained from starch. The bare term cyclodextrin used without further designation refers to any and all a-, P-, and y- forms of cyclodextrin, characterized as having six glucose subunits, seven glucose subunits, and eight glucose subunits, respectively, wherein the subunits are linked by 1,4-glycosidic bonds. At least 150 cyclodextrin compounds are known. Cyclodextrins are known to have a toroidal shape, with an exterior sufficiently hydrophilic to impart water solubility and an interior cavity being less hydrophilic than the exterior but not entirely hydrophobic. Of particular interest herein is P-cyclodextrin, hydroxypropyl-P- cyclodextrin and methyl-P-cyclodextrin and the nicotine inclusion complexes formed by exposing (S)-nicotine to any of these or other cyclodextrin. The inner cavity of a cyclodextrin into which small molecules may be enclosed has been well studied. See, for example, A.A. Sandilya, et al., “Molecular View into the Cyclodextrin Cavity: Structure and Hydration,” ACS Omega, 5, 25655- 25667, (2020). This study finds the inner cavity of a cyclodextrin molecule to have a conical hourglass shape, measuring about 4-8 angstroms (A).

[0094] As used herein, the term “lipophilic-like” refers to solvents that are less hydrophilic (and hence more hydrophobic) than water. For example, solvents such as alcohols and diols areconsidered “lipophilic-like” since they are at least somewhat more hydrophobic than water. For purposes herein, buffered water such as PBS is considered hydrophilic whereas propylene glycol (PG) is considered lipophilic-like.

[0095] As used herein, the term “propylene glycol” or more simply “PG” refers to propane- 1 ,2-diol (a-propylene glycol) and not the 1 ,3 -diol isomer, unless indicated otherwise. Further, the propylene glycol used herein comprises a racemic mixture of isomers, unless indicated otherwise, and is typically produced on a global industrial scale by hydrolysis of propylene oxide. PG is generally the ingredient recognized in vaporizable compositions as being responsible for the white cloud of vapor seen in vaping. PG is often used to enhance lipophilicity of a vaping liquid, where it assists in dissolving lipophilic substances such as menthol and other water-insoluble and glycerin-insoluble flavoring agents. As such, PG is a preferred solvent in which to conduct membrane permeability experiments in accordance with the present disclosure. For dialysis experiments herein, PG is referred to as being “lipophilic-like,” meaning it is relatively less hydrophilic than an aqueous buffer such as phosphate buffered saline (PBS).

[0096] As used herein, the term “vegetable glycerin” or more simply “VG” takes on its ordinary meaning in organic chemistry and food science, which is HOCH2-CH(OH)-CH2OH, having been derived from a triglyceride of vegetable origin. The scope of the present disclosure includes any source of glycerin, including animal or vegetable, or industrially synthesized or microbially produced. VG is recognized as a solvent in vaporizable compositions used in vaping.

[0097] As used herein, the term “surfactant” takes on its ordinary meaning in physical chemistry and surface science. Of interest herein are any and all zwitterionic / amphoteric, nonionic, and cationic polymers to form micellular complexes with (S)-nicotine. Included in the present definition of surfactant for the sake of convenience are nonionic polymers that may or may not be capable of acting as surface active agents but nonetheless are capable of at least emulsifying (S)- nicotine or micellizing (S)-nicotine. Of particular interest are lecithin, phosphatidylcholine, EO / PO block copolymers e.g., under the brand name Synperonic® from Croda), EO / PO / EO triblock copolymers (e.g., the poloxamers, available under the trade name Pluronic®, particularly poloxamer 188), and any polyethylene glycol (PEG, of any molecular weight, including for example, PEG-400, PEG-2000, etc.). Exemplary anionic substances include, but are not limited to, fatty acids, alkyl sulfates, alkyl ether sulfates, alkyl aryl sulfonates, alkyl succinates, alkyl sulfosuccinates, N-alkoyl sarcosinates, alkyl phosphates, alkyl ether phosphates, alkyl ethercarboxylates, alkylamino acids, alkyl peptides, alkoyl taurates, acyl and alkyl glutamates, alkyl isethionates, a-olefin sulfonates, and combinations thereof. Exemplary amphoteric substances include, but are not limited to, alkyl betaines, alkyl amidopropyl betaines, alkyl sulphobetaines, alkyl glycinates, alkyl carboxyglycinates, alkyl amphopropionates, alkyl amidopropyl hydroxysultaines, acyl taurates, acyl glutamates, and mixtures thereof. Exemplary nonionic surfactants include, but are not limited to, aliphatic primary or secondary linear or branched chain fatty alcohols or phenols, fatty acid esters, mono-, di-, and tri-fatty acid glycerides, alkyl alkoxylates, alkyl phenol alkoxylates, block alkylene oxide condensates of alkyl phenols, alkylene oxide condensates of alkanols, ethylene oxide / propylene oxide (EO / PO) block copolymers, EO / PO / EO triblock copolymers, amine oxides, phosphine oxides, mono- or di- alkyl alkanolamides, alkyl polysaccharides, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene sorbitol esters, polyoxyethylene esters, polyoxyethylene alcohols, mono- and diethanolamides, polyglycosides, polyglucosides, diglucoside, alkyl polyglucoside, polysorbates, alkoxylated fatty alcohols, alkoxylated fatty acid glycerides, and mixtures thereof. Of particular interest herein are the polysorbates, the group of nonionic emulsifiers characterized chemically as polyoxyethylene sorbitan fatty acid esters. Of use herein are polysorbate-20 (polyoxyethylene-20-sorbitan monolaurate), polysorbate-40 (polyoxyethylene-20-sorbitan monopalmitate), polysorbate-60 (polyoxyethylene-20-sorbitan monostearate) and polysorbate-80 (polyoxyethylene-20-sorbitan monooleate), amongst others. Polysorbate-80 may be obtained under the brand name Tween® 80 from several suppliers including WEGO Chemical Group, Great Neck, NY and Croda International, Snaith, England. Surfactants and polymeric substances under this broad definition are capable of forming complexes with (S)-nicotine. These complexes may be micellular in form, although no theories are proffered as to the structure of (S)-nicotine- surfactant complexes.

[0098] As used herein, the terms “vaporizable composition” or “aerosolizable composition” refer to a liquid mixture capable of vaporization into an inhalable vapor, such as by heating to convert the liquid to the vapor state, or by nebulizing, atomizing or spraying the liquid into fine droplets resembling a vapor. An electronic device such as an e-cigarette may be used to vaporize a vaporizable composition into its corresponding vapor. In other examples, ultrasonics, such as in a nebulizer or atomizer, may convert a liquid into an inhalable vapor. In other examples, an aerosolizable liquid may be combined with a propellant capable of accelerating the liquid througha nozzle into an aerosol made up of fine droplets resembling a vapor. In various embodiments, a vaporizable composition herein may be homogeneous or inhomogeneous, turbid or optically transparent, solutions or microemulsions, and may have any viscosity. Vaporizable compositions according to the present disclosure are typically thin or slightly viscous, clear liquids ranging from colorless to yellow, orange or red.

[0099] As used herein, the term “inhalable” refers to a characteristic of vaporizable compositions in accordance with the present disclosure, namely that the compositions are suitable for inhalation by a user. A composition comprising (S)-nicotine or a salt or complex thereof are vaporizable and thus suitable for use in an electronic cigarette device, meaning that they can be vaporized by the heating element or atomizer within such electronic devices, thereby allowing inhalation by a user in a practice called “vaping.” Stated another way, vaporizable compositions herein are inhalable compositions, and inhalation of said vapor results in at least some exposure of the oral cavity and / or throat of the individual inhaling to the (S)-nicotine, nicotine salt, and / or nicotine complex present in the vaporized composition, possibly resulting in a harshness perceived as a taste and / or a harshness perceived as an oral irritation or a throat irritation regarded as a “throat hit.” Unless otherwise specified, the phrase “the inhalable composition” refers to vaporizable compositions in accordance with the present disclosure comprising (S)-nicotine or a salt or complex thereof.

[0100] As used herein, the terms “e-cigarette” or “ENDS” (electronic nicotine delivery system) refer generally to any electronic device capable of vaporizing a liquid composition into a vapor that can be inhaled by an individual using the device. So as not to be limiting, an “e- cigarette” herein means any design, such as a cigar, a vape pen, or any other electronic device, refillable or disposable, having a reservoir containing a vaporizable liquid therein and having the capability of vaporizing the vaporizable liquid. For simplicity, the term “electronic device” may be used to refer to any and all refillable and disposable instruments for vaping.

[0101] As used herein, the term “throat hit” refers to a sensory effect experienced at the back of the throat, perceived by an individual inhaling a vapor, such as vapor obtained from a burning cigarette, or a vapor delivered from an electronic device like an e-cigarette capable of vaporizing a liquid composition. Throat hit is a type of irritating “bite” experienced at the back of the throat, which prior to the development of e-cigarettes was something not only experienced by smokers but also anticipated and enjoyed by smokers. Although subjective rather than objective, throat hitcan be quantified through the use of sensory panels where participants in the panel rank the perceived throat hit on a scale of 1-10, for example, or compare perceived throat hit between e- cigarette products and / or for an e-cigarette product relative to traditional cigarettes. In some examples, throat hit may be quantified as being less than, equal to, or more than the throat hit experienced from a particular cigarette in comparison. An exemplary cigarette used to standardize throat hit, such as in a sensory panel where participants rank throat hit, is Marlboro® Filter Cigarettes, Gold Pack 100’s, available from Phillips IGA. As explained herein, throat hit is a harshness in the throat upon inhalation of (s)-nicotine, and in accordance with various embodiments herein, throat hit is modulated by the conversion of (S)-nicotine into a salt or a complex.

[0102] As used herein, the term “vaping” refers to the act of using an e-cigarette or other ENDS device to inhale a vapor generated electronically from the vaporization of a liquid composition. Vaping is seen as a similar endeavor to smoking tobacco products, recognizing that an e-cigarette and vaping is not limited to (S)-nicotine free base, but may include at least some, or entirely, a salt or a complex of (S)-nicotine. Vaping necessarily includes personal inhalation of solvents that carry the (S)-nicotine or salt or complex thereof, such as for example, any one of PG, VG and alcohol. Vaping may also involve personal inhalation of flavorings incorporated in the vaporizable composition.

[0103] As used herein, the term “vape juice” or “e-juice” refers to a liquid composition capable of vaporization in an e-cigarette or other ENDS device to produce a vapor that can be inhaled by an individual who is vaping. In various embodiments herein, vape juice compositions are described, and which in certain examples comprise vaporizable (S)-nicotine compositions and dilutions therefrom, wherein the (S)-nicotine is at least partly present in the form of a salt or a complex.

[0104] As used herein, the term “head rush” refers to the lightheadedness experienced by tobacco smokers and vapers that inhale (S)-nicotine or a nicotine salt or nicotine complex. Smokers have described this sensory experience as a ringing sensation in their heads, or a rush of adrenaline. The sensory effect is believed to be caused by nicotine or other drug in the blood and brain triggering release of adrenaline that in turn causes a tightening of the blood vessels and a temporary rise in heart rate and blood pressure of the person inhaling the active substance. This sensory experience is personal, and it varies between drug actives and between individuals becauseof variances in physiological tolerance. A head rush might appear within 10 seconds of inhaling nicotine, and it might last as long as 10-30 minutes. However, as a smoker or vaper continues smoking or vaping, they become more tolerant, and the head rush regularly experienced becomes shorter-lasting over time. Although subjective rather than objective, head rush can be quantified through the use of sensory panels where participants in the panel rank the perceived head rush on a scale of 1-10, for example, or compare the perceived head rush between e-cigarette products and / or for an e-cigarette product relative to traditional cigarettes. In some examples, head rush may be quantified as being less than, equal to, or more than the head rush experienced from a particular cigarette in comparison. An exemplary cigarette used to standardize head rush, such as in a sensory panel where participants rank head rush, is Marlboro® Filter Cigarettes, Gold Pack 100’s, available from Phillips IGA.

[0105] As used herein, the term “flavoring agent” takes on its ordinary meaning in food science. Flavoring agents for use herein include, but are not limited to, cinnamaldehyde, ethyl maltol, ethyl butyrate, ethyl acetate, maltol, ethyl vanillin, menthol, furaneol, methyl cyclopenenolone, 5-decalactone, y-decalactone, / .v-3-hexanol, / .w-amyl acetate, ethyl -2-methyl butyrate, butyric acid, linalool, benzyl alcohol, ethyl hexanoate, benzaldehyde, Ao-amyl isovalerate, hexanoic acid, ethyl propionate, y-undecalactone, linalool, carvacrol, eugenol, thymol, vanillin, methyl eugenol, 2,6-dimethylphenol, 2,5-dimethylphenol, 3,4-dimethylphenol, 2,6- diisopropylphenol and hexyl acetate.

[0106] As used herein, the term “about” refers to a quantity, 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% to a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length. For example, a quantity expressed as being “about 5 wt.%” includes implied range of 4.5 to 5.5 wt.%.General and Specific EmbodimentsMethods of Measuring Membrane Permeability

[0107] In various embodiments, membrane permeability of (S)-nicotine relates to perceived oral and / or throat harshness or irritancy, and in various aspects of the present disclosure, a nicotine salt or complex is capable of retarding membrane permeability of (S)-nicotine. Therefore, the present disclosure provides for a relatively simple and reliable test method for measuringmembrane permeability based on dialysis experiments. Results can then be used to rate expected levels of oral and / or throat harshness or irritancy of (S)-nicotine when the (S)-ni cotine is provided in the form of a nicotine salt or a nicotine complex. Results can be shown relative to one another for various nicotine species and / or relative to (S)-nicotine free base.

[0108] Methods herein can be based on literature teachings, such as described by C.K. Colton, et al., “Permeability Studies With Cellulose Membranes,” J, Biomed. Mat. Res., 5(5), 459-488, (1971). For newer methods using phospholipid membranes, see for example, U.S. Patent No. 7,022,528 assigned to Pion, Inc. The simplest method is to use cellulosic dialysis tubing tied at both ends to form a dialysis bag and then placing the filled bag into a vessel containing the chosen dialysis medium (e.g., hydrophilic PBS or lipophilic-like PG).

[0109] FIG. 1 schematically illustrates the general concept of a method of measuring membrane permeability as it pertains to nicotine complexes, dissociation of nicotine from a complex, and diffusion of nicotine through the membrane selected.

[0110] (S)-Nicotine, being a relatively small molecule, diffuses freely from the inside of a cellulosic dialysis bag to the outside medium surrounding the bag. In certain examples, the initial solution beginning inside the bag comprises (S)-nicotine free base or (S)-ni cotine formulated with at least one other compound such that the (S)-nicotine beginning inside the dialysis bag is in the form of a salt or a complex. Propylene glycol is the preferred dialysis medium because it is both a water and lipid miscible solvent. It is ideal for testing lipophilic permeability of various molecules wherein molecules diffuse from hydrophilic environment to lipophilic-like environment when diffusing out of the dialysis bag. By measuring and plotting the concentration of nicotine permeating into the surrounding PG environment over time, lipophilic permeability as well as the modulating effects of providing (S)-nicotine in the form of a salt or a complex can be determined.

[0111] With reference now to FIG. 1, about 5 to 20 mb of a test solution is placed into a 2 to 6-inch length of dialysis tubing previously tied or clamped with a dialysis tubing clamp at one end. The solution may be standardized to 1.0 wt.% of the nicotine salt or nicotine complex to be tested. Salts and complexes are formed by mixing the (S)-nicotine and the one other compound (acid, surfactant, cyclodextrin, polymer, etc.) in a 1 : 1 molar ratio. As a control, 1.0 wt.% solution of (S)- nicotine is used in the dialysis bag in a permeability measurement. The open end of the tubing is then clamped or tied and the filled bag is placed into a vessel containing about 50 to 200 mb PBS buffer or PG. Over the course of about 6 hr., the solution outside the dialysis bag can beperiodically assessed for (S)-nicotine concentration (mg / mL). Tn this way, a plot of NCT concentration (mg / mL) over time can be made. The measurement of (S)-ni cotine over time can be measured, for example, by taking absorbance reading (in conjunction with a colorimetric dye such as alizarin red), potentiometrically, or spectrophotometrically, such as by oxidation of nicotine by N-bromo succinimide (NBS) and determination of the unreacted NBS by measurement of the decrease in absorbance of methyl orange dye at a suitable max = 507 nm.

[0112] With reference now to FIG. 2, plots of (S)-nicotine (NCT) concentration (mg / mL) versus time show how certain nicotine salts and complexes cause faster or slower membrane permeability of (S)-nicotine relative to (S)-nicotine presented as only the free base. The results obtain vary depending on the medium and the nature of the NCT species. For example, in PBS, the fastest migrating species observed was nicotine lactate, whereas the slowest migrating NCT species was nicotine-hydroxypropyl-P-cyclodextrin inclusion complex. In propylene glycol (PG), although the results were mostly the same, the fastest migrating species was (S)-ni cotine free base, whereas the slowest migrating NCT species was again nicotine-hydroxypropyl-P-cyclodextrin inclusion complex. These results clearly show the ability for hydroxypropyl-P-cyclodextrin to retard membrane permeability of (S)-nicotine. The assumption is that out of the NCT species in the plots of FIG. 2, nicotine-hydroxypropyl-P-cyclodextrin inclusion complex when used in a smoking or smokeless product will exhibit the lightest throat irritation given it exhibits the slowest membrane permeability of (S)-nicotine.

[0113] FIG. 2 also shows differences in the membrane permeability between different nicotine salts. For example, in both PBS and PG media, nicotine decanoate exhibited slower membrane permeability than nicotine lactate. This could be explained as a size exclusion phenomena, the decanoate salt being much larger sterically than the lactate salt. Or perhaps explainable by theorizing the nicotine decanoate forms stable micelles, like a biosurfactant, that then has retarded membrane migration. Regardless, given the assumed correlation to throat irritation, it is predicted that nicotine decanoate will exhibit a lighter throat irritation than nicotine lactate given that nicotine decanoate exhibits a slower membrane permeability.

[0114] As also evidenced in the results presented in FIG. 2, polysorbate-80 reduces the membrane permeability of nicotine, but only in the lipophilic-like PG medium. Thus, a nicotine / polysorbate-80 complex could exhibit a lighter throat irritation than (S)-nicotine free base.

[0115] FIGS. 3-6 set forth more detailed results from more extensive membrane permeability experiments where (S)-nicotine membrane permeability released in PG media from 16 NCT species are compared to (S)-nicotine migration as the free base. Two of the NCT species included the complexes nicotine-hydroxypropyl-P-cyclodextrin inclusion complex and nicotinepoly sorbate-80 complex, while the remaining 14 NCT species were true (S)-nicotine salts. With the assumption that the larger and faster membrane permeability correlates to harsher nicotine tastes and throat irritancy, it was evident that some acids and or complexing agents reduce nicotine permeability and therefore attenuate nicotine harshness. The results set forth in FIGS. 3-6 also show that adipic acid, citric acid, decanoic acid, L-(+)-tartaric acid, succinic acid and vanillic acid provide more reduction in nicotine membrane permeability. In contrast, acetic acid, benzoic acid, butyric acid, glycolic acid, L-(-)-maleic acid, and valeric acid provide less reduction in nicotine membrane permeability.

[0116] FIG. 5 sets forth membrane permeability results in lipophilic-like medium (PG) for (S)- nicotine-L-(+)-tartrate, nicotine-hydroxypropyl-P-cyclodextrin inclusion complex, and nicotine- polysorbate-80 complex, in comparison to (S)-nicotine free base. As emphasized by the vertically oriented block arrows in FIG. 5, it was evident from the experiments that (S)-nicotine-L-(+) tartrate exhibited the most reduction in membrane permeability compared to (S)-nicotine free base. Further, the results show that hydroxypropyl-P-cyclodextrin has comparable or an even greater capability of reducing the membrane permeability of (S)-nicotine without addition of acid, and that polysorbate-80 is also capable of reducing membrane permeability without addition of acids.

[0117] As demonstrated, a carboxylic acid such as tartaric acid forms a nicotine salt that reduces nicotine membrane permeability in PG. But surprisingly, hydroxypropyl-P-cyclodextrin, not being an acid, is also capable of reducing nicotine membrane permeability in lipophilic-like medium by forming a nicotine-hydroxypropyl-P-cyclodextrin inclusion complex. Further, polysorbate-80 can also reduce nicotine membrane permeability in lipophilic-like medium without addition of acids to form salts.

[0118] The membrane permeability results for cyclodextrin complexes are entirely contrary to reports that nicotine inclusion complexes with P-cyclodextrin enhance skin permeation. See, S. Chulurks, et al., “Stability Enhancement and Skin Permeation Application of Nicotine by Forming Inclusion Complex with P-Cyclodextrin and Methyl-P-Cyclodextrin,” Sci. Pharm., 89(4), 43, (2021). Given the expectation that P-cyclodextrin can facilitate permeation of nicotine throughskin, the results found here are entirely unexpected. In the present work, it is clear that P- cyclodextrins retard nicotine permeation through a membrane rather than enhance it.

[0119] FIG. 7 sets forth membrane permeability results released in PG media for several nicotine salts and (S)-nicotine free base for comparison. The plot sets forth NCT concentration (mg / mL) in solution over a 6 hr time period. The (S)-nicotine salts were salts from carboxylic acids having additional polar and hydrophilic functionality. The observed significant reduction in the membrane permeability of (S)-nicotine when the (S)-nicotine is present as a salt where the counterion has additional polar hydrophilic functionality is astounding.

[0120] FIG. 8 shows the chemical structures of the various acids used in the salts exhibiting the membrane permeability data presented in FIG. 7, with dashed-line boxes on each molecule pointing out the additional polar functionality. The conclusion is that organic acids having a polar and / or hydrophilic functional groups are capable of significantly reducing membrane permeability of (S)-nicotine. For example, L- (+)-tartaric acid is capable of significantly reducing the membrane permeability of (S)-nicotine, presumably due to the presence of the additional polar hydroxy and carboxylic acid groups. Other acids having at least an additional hydroxyl group or additional carboxylic acid group show promise at reducing the membrane permeability of (S)- ni cotine.

[0121] FIG. 9 illustrates membrane permeability released in PG media measured for (S)- nicotine and (S)-nicotine from various nicotine salts made from monocarboxylic acids, conducted in lipophilic-like media (propylene glycol (PG)) and plotted in concentration (mg / mL) of NCT in solution over a 6 hr time period. Evident from these results is that although salts from monocarboxylic acids do show reduced membrane permeability of (S)-nicotine compared to (S)- nicotine as the free base, the reduction is not as large as the reduction seen for salts made from organic acids having the additional polar hydrophilic functionality (see FIGS. 7 and 8).

[0122] FIG. 10 illustrates the chemical structures of various monocarboxylic acids that were used to prepare the (S)-nicotine salts that generated the membrane permeability data in FIG. 9. These acids, lacking additional hydrophilic functionality, only mildly reduce lipophilic permeability in lipophilic-like medium (PG).

[0123] FIG. 11 illustrates membrane permeability released in PG media measured for (S)- nicotine and (S)-nicotine from various nicotine complexes obtained with surfactants, conducted in lipophilic-like media (propylene glycol (PG)) and plotted in concentration (mg / mL) of NCT insolution over a 6 hr time period. The results here show mildly reduced permeability when (S)- nicotine is complexed with various zwitterionic / amphoteric or nonionic surfactants.

[0124] FIG. 12 illustrates membrane permeability measured for (S)-nicotine and (S)-nicotine from various nicotine inclusion complexes with different cyclodextrins, conducted in lipophilic- like media (propylene glycol (PG)) and plotted in concentration (mg / mL) of NCT in solution over a 6 hr time period. The inclusion complexes included |3-cyclodextrin, hydroxypropyl-P- cyclodextrin and methyl-P-cyclodextrin (S)-nicotine complexes. The block arrow emphasizes the significant reduction in (S)-nicotine membrane permeability observed when (S)-nicotine is in the form of a nicotine-cyclodextrin supram olecul ar complex. It appears the presence of polar -OH groups on the polysaccharide chains provide for higher polarity and thus a consequently lower lipophilic permeability. This theory fits with the observation that (S)-nicotine permeability when present as the methyl-P-cyclodextrin complex is greater than the (S)-nicotine permeability when present as either the P-cyclodextrin or hydroxypropyl-P-cyclodextrin complex.

[0125] FIG. 13 schematically summarizes the relative abilities of salts and complexes to mitigate lipophilic permeability of (S)-nicotine, with the range from low lipophilic permeability to high lipophilic permeability depending on whether the (S)-nicotine is: (1) in the form of a salt with an organic acid having additional polar hydrophilic functionality; (2) in the form of a salt with an monocarboxylic acid having no additional polar hydrophilic functionality; (3) in the form of a micellular complex with zwitterionic, amphoteric or nonionic surfactants; and (4) in the form of cyclodextrin inclusion complex. The salts of nicotine where the counterion had additional polar hydrophilic functionality and the cyclodextrin inclusion complexes exhibited the most significant reduction in (S)-nicotine membrane permeation, z.e., these species had the lowest lipophilic permeability. The salts of nicotine where the counterion did not have additional polar hydrophilic functionality showed low but not the lowest lipophilic permeability. Lastly, the surfactant complexes of nicotine showed the least dramatic reduction in membrane permeability. Thus, in order of increasing lipophilic permeability, the results show salts with polar functionalized counterions ~ cyclodextrin inclusion complexes < salts without polar functionalized counterions < nicotine-surfactant micellular complexes « (S)-nicotine free base alkaloid in the absence of acids or complexing agents.

[0126] Given these observations summarized in FIG. 13, it is evident that the harshness of (S)- ni cotine in smoking and smokeless products can be attenuated by using salts or complexes of (S)-nicotine, either as a total replacement for (S)-nicotine free base or a partial replacement in a nicotine product. Of the salts and complexes studied, it is evident that the cyclodextrin inclusion complexes will provide the greatest attenuation of (S)-nicotine harshness in smoking and smokeless products containing (S)-nicotine.Nicotine Salts

[0127] In various embodiments, an (S)-nicotine salt herein comprises protonated (S)-nicotine cation and a counterion comprising a conjugate base of an organic acid.

[0128] In various embodiments, the conjugate base of an organic acid may comprise at least one additional functional group besides the primary -CCh substituent, such as hydroxyl, oxo, carboxylate, thiol, heterocyclyl, aryl, heteroaryl, and so forth. In some examples, the organic may comprise an amino acid.

[0129] In various embodiments, (S)-nicotine salts herein have anionic counterions corresponding to the conjugate base of an organic acid selected from, for example, formic acid, acetic acid, adipic acid, trifluoroacetic acid, aspartic acid, butanoic acid, butyric acid, 2- methylbutyric acid, 3 -methylbutyric acid, benzoic acid, caprylic acid, citric acid, crotonic acid, butanoic acid, ethylenedi aminetetraacetic acid (EDTA), fumaric acid, gluconic acid, glutamic acid, glyceric acid, glycidic acid, glycolic acid, glyoxylic acid, hexanoic acid, heptanoic acid, lactic acid, lauric acid, levulinic acid, maleic acid, L-(-)-malic acid, malonic acid, mandelic acid, mesooxalic acid, methane sulfonic acid, oxalic acid, pentanoic acid, phenylacetic acid, phthalic acid, picric acid, propionic acid, 3-oxopropanoic acid, 2,3-dioxopropanoic acid, 2,3,-dihyroxypropanedioic acid, propiolic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tannic acid, L-(+)- tartaric acid, tartronic acid, valeric acid, vanillic acid, and mixtures thereof. This listing is not meant to be limiting, as any C1-C26 organic acid could be used to form a salt with (S)-ni cotine free base.

[0130] Depending on the nature of the counterion to the protonated (S)-nicotine cation in a (S)-nicotine salt, certain salts will attenuate lipophilic migration of (S)-nicotine, and therefore act to reduce nicotine harshness from various smoking and smokeless compositions and products, including acting to reduce nicotine irritancy, such as skin irritancy, from nicotine containing products not intended for oral use.Nicotine Complexes

[0131] In various embodiments, a nicotine complex herein comprises (S)-nicotine in association with at least one other molecule, wherein the complex is devoid of a crystal lattice structure.

[0132] For each nicotine complex herein, the (S)-nicotine is not predominantly or primarily (e.g., >50% unprotonated) protonated and does not carry a formal positive charge. Depending on the embodiment, the degree of (S)-nicotine in an unprotonated form can vary (with protonated (either monoprotonated or diprotonated) (S)-nicotine being present in reciprocally varied amounts). In several embodiments, unprotonated (S)-nicotine makes up about 15% to about 100% of the nicotine in a given complex, including about 15% to about 20%, about 20% to about 30%, about 30% to about 40%, about 40% to about 50%, about 50% to about 60%, about 60% to about 70%, about 70% to about 75%, about 75% to about 80%, about 80% to about 90%, about 90% to about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%, including any values in between those ranges (including endpoints). In several embodiments, unprotonated (S)-ni cotine makes up about 70% to about 99% of the nicotine in a given complex, including about 70% to about 75%, about 75% to about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%, including any values in between those ranges (including endpoints). In several embodiments, unprotonated (S)-nicotine makes up about 70% to about 98%, about 72 to about 98%, about 74% to about 98%, about 76% to about 98%, about 78% to about 98%, about 80% to about 98%, about 88% to about 95%, about 84 to about 98%, about 86 to about 98%, about 88 to about 98%, about 90 to about 98%, about 92% to about 98%, about 94% to about 98%, about 96% to about 98% of the nicotine in a given complex, including any values in between those ranges (including endpoints). However, certain complexes may involve charge transfer such that a “6+” charge may be present on one of the nitrogen atoms of the (S)-nicotine molecule and a corresponding “5-” charge may be present on the one other compound associated with the (S)-nicotine molecule. Such charge transfer may be important for (S)-nicotine transition metal complexes.

[0133] In various embodiments, the at least one other compound in association with the (S)- nicotine molecule in the complex comprises at least one of a surfactant, a polymer, apolysaccharide such as a cyclodextrin, a metal, or an inorganic compound. Depending on the nature of this compound, the complex may be characterizable as a charge transfer complex, a Van der Waals complex, a hydrogen bonded complex, a micellular complex, or an inclusion complex, or some other complex that might not be readily characterizable, such as a microemulsion.

[0134] In certain embodiments, an (S)-ni cotine salt may be complexed with a surfactant, and the resulting complex may be characterized as reverse micelles wherein the nicotine salt and perhaps associated water molecules may be surrounded by the polar ends of surfactant molecules. (a) Micellular Complexes with Surfactants and Non-salt-Nicotine Complex Emulsions

[0135] In various embodiments, a nicotine complex herein comprises (S)-nicotine in association with a surfactant, wherein the complex is devoid of a crystal lattice structure, and wherein at least a portion of the (S)-nicotine resides within micelles of the surfactant.

[0136] In various embodiments, the surfactant may be anionic, nonionic, cationic or zwitterionic. In some instances, a surfactant is chosen for its ability to form stable micelles in water, PG or VG, or mixtures therefore, and / or for its ability to micellize (S)-ni cotine.

[0137] In various embodiments, micelles may be orientated either way, such as with polar heads forming a spherical structure with the micellized compound inside or organized with hydrophobic tails organizing around the micellized compound and the polar heads projecting out into a polar solution.

[0138] Additional experimental investigations were performed to assess the ability of various ingredients provided for herein to generate emulsions comprising a Non-Salt-Nicotine Complex Emulsion (NNCE). Complexes as provided for elsewhere with the present application (e.g., described in other sections of the specification) can also be used in generation of a NNCE.

[0139] In several embodiments, there is provided for herein a nicotine complex comprising nicotine (e.g., (S)-nicotine) and one or more ingredients suitable for forming a complex with the (S)-nicotine, wherein the complex is in a form selected from: a charge transfer complex, a hydrogen bonded complex, a Van der Waals complex, a complex stabilized by nonionic interactions, a solubilized complex, a micellular complex, and an inclusion complex, wherein the one or more ingredients for forming a complex with the (S)-nicotine is selected from the group consisting of: a fatty acid having a polar and / or hydrophilic functional group, a surfactant, a solubilizer [oil], and / or a polysaccharide.

[0140] FIG. 15 schematically summarizes a non-limiting embodiment of a NNCE. In particular, FIG. 15 shows a NNCE-based Oral Nicotine Pouch (ONP). ONPs are described in greater detail below. According to several embodiments a combination of cellulose, such as microcrystalline cellulose, with nicotine (e.g., (S)-nicotine and a fatty acid (e.g., an unsaturated fatty acid) form a complex (in the form of a of an emulsion). In several such embodiments, the nicotine is not in the form of a salt. As schematically illustrated, the non-salt emulsion can be an oil in water (“O / W”) emulsion, a water in oil (“W / O”) emulsion, a water in oil in water (“W / O / W / ”) emulsion, or an oil in water in oil (“O / W / O”) emulsion, depending on the embodiment. Each of these emulsion types are depicted in the central portion of FIG. 15. Shown in expanded format in the lower right portion of FIG. 15 are selected components of a NNCE. As shown, nicotine is complexed with a fatty acid, such as an unsaturated fatty acid (e.g., a fatty acid having at least one polar group or other hydrophilic functional group). In several embodiments, the nicotine complexed with the fatty acid is in the form of a free base alkaloid (e.g., a non-salt form). In several embodiments, the nicotine comprises less than about 60%, less than about 50%, less than about 40%, less than about 30%, less than about 20%, or less than about 10% monoprotonated (e.g., salt) nicotine. In other words, according to several embodiments, the nicotine is substantially in a form without a positive formal charge.

[0141] A variety of fatty acids are suitable for formulation of a NNCE. As shown in FIGS. 16A-16B, various fatty acids or oils can be used in combination with nicotine. FIG. 16A shows the resulting physical characteristics (stability) of mixtures (stoichiometric ratio of 1 : 1 of the fatty acid and nicotine) when the indicated fatty acids or oils are used. As shown, steric acid (Cis) and myristic acid (Cu) resulted in heterogenous mixtures with nicotine. In contrast, lauric acid (C12) and decanoic acid (Cio) each resulted in clear mixtures. The lower portion of FIG. 16A shows that other fatty acids comprising unsaturated carbon backbones result in unclear but homogenous mixtures with nicotine (e.g., emulsions). As shown, each of linoleic acid (e.g., conjugated linoleic acid), medium chain triglycerides and sunflower oil resulted in unclear but homogenous emulsions with nicotine.

[0142] In several embodiments, oils can serve as a solubilizer and a source of the fatty acid. In several embodiments, the solubilizer comprises a mono-, di-, or tri-fatty acid glyceride. For example, in several embodiments, the fatty acid glyceride comprises medium-chain length triglyceride (MCT) oil. In several embodiments, the fatty acid comprises sunflower oil, canola oil,palm oil, coconut oil, safflower oil, olive oil, sesame oil, peanut oil, avocado oil, and soybean oil. FIG. 16B shows the chemical structure of each of the non-limiting examples of fatty acids tested for use in combination with a nicotine complex to result in a NNCE. While stearic acid, myristic acid, lauric acid, and decanoic acid did not readily form unclear but homogeneous emulsions with nicotine under the experimental conditions used (i.e., 1 : 1 stoichiometric ratio of fatty acid to nicotine), according to some embodiments, other stoichiometric ratios utilizing those acids do form such emulsions. For example, in some embodiments, the ratio stoichiometric ratio of fatty acid to nicotine can range from about 100:1, about 75: 1, about 50: 1, about 40: 1, about 30: 1, about 20: 1, about 15: 1, about 10: 1, about 5:1, about 1:5, about 1 : 10, about 1 : 15, about 1:20, about 1 :30, about 1 :40, about 1:50, about 1 :75, about 1: 100, or ratios between those listed.

[0143] In several embodiments, the fatty acids have at least one carboxyl group. In several embodiments, the fatty acids are unsaturated. In several embodiments, the unsaturated fatty acids comprise monounsaturated fatty acids. In several embodiments, the unsaturated fatty acids comprise polyunsaturated fatty acids. In several embodiments, however, the fatty acids are saturated. In several embodiments, the fatty acids include between 6 and 30 carbons in the backbone. In several embodiments, the fatty acid is a Ce fatty acid. In several embodiments, the fatty acid is a Cx fatty acid. In several embodiments, the fatty acid is a Cio fatty acid. In several embodiments, the fatty acid is a C12 fatty acid. In several embodiments, the fatty acid is a C14 fatty acid. In several embodiments, the fatty acid is a Ci6 fatty acid. In several embodiments, the fatty acid is a Ci8 fatty acid. In several embodiments, the fatty acid is a C20 fatty acid. In several embodiments, the fatty acid is a C22 fatty acid. In several embodiments, the fatty acid is a C24 fatty acid. In several embodiments, the fatty acid is a C26 fatty acid. In several embodiments, the fatty acid is a C28 fatty acid. In several embodiments, the fatty acid is a C30 fatty acid. In several embodiments, the fatty acid comprises a C8-C24 fatty acid. In several embodiments, the fatty acid comprises a C -C24 unsaturated fatty acid.

[0144] In several embodiments, the fatty acids comprises caprylic acid, decanoic acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid, octadecanoic acid, icosanoic acid, docosanoic acid, tetracosanoic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, gadoleic acid, eicosenoic acid, erucic acid, nervonic acid, linoleic acid, a-linolenic acid, y-linolenic acid, mead acid, stearidonic acid, arachidonic acid, eicosapentaenoic acid, cervonic acid (docosahexaenoic acid), conjugated linoleic acid, eicosadienoic acid,docosadienoic acid, pinolenic acid, a-eleostearic acid, P-eleostearic acid, catalpic acid, dihomo-y- linolenic acid, eicosatrienoic acid, eicosatetraenoic acid, adrenic acid, bosseopentaenoic acid, ozubondo acid, sardine acid, tetracosapentaenoic acid, herring acid, conjugated linoleic acid, punicic acid, jacaric acid, calendid acid, catapic acid, alpha-eleostearic acid, beta-eleostearic acid, parinaric acid, anadiplosis acid, tung acid, or combinations of any of the foregoing. In various embodiments, a saturated, monounsaturated, or polyunsaturated fatty acid usable in the formation of (S)-nicotine complex include, but are not limited to, decanoic acid, dodecanoic acid, tetradecanoic acid, hexadecenoic acid, octadecanoic acid, icosanoic acid, docosanoic acid, tetracosanoic acid, a-linolenic acid, stearidonic acid, eicosapentaenoic acid, cervonic acid, linoleic acid, linolelaidic acid, y-linolenic acid, arachidonic acid, docosatetraenoic acid, palmitoleic acid, vaccenic acid, paullinic acid, oleic acid, elaidic acid, gondoic acid, erucic acid, nervonic acid, mead acid, and the like.

[0145] In several embodiments, the fatty acid comprises conjugated linoleic acid.

[0146] In several embodiments, medium chain triglycerides are used. In several embodiments, sunflower oil is used.

[0147] To further investigate the nature of the emulsions formed, experiments were performed to elucidate more information about the nicotine complexes within the emulsions. FIGS. 17A- 17D show information relating to the non-salt nature of nicotine complexes produced. FIG. 17A shows three forms of nicotine, namely, diprotonated nicotine, monoprotonated nicotine, and free base nicotine. FIG. 17B shows a graph depicting the relative abundance of each of the forms of nicotine at various pH values (open circles = nonprotonated free base, filled squares = monoprotonated, filled triangles = diprotonated). At low pH (high concentration of hydrogen ions) the majority of nicotine exists as the diprotonated form, with monoprototnated representing a much lower percentage of the nicotine (nonprotonated, e.g., free base, is not present). As pH increases (reduced concentration of hydrogen ions), the concentrations of monoprotonated nicotine increases, while diprotonated nicotine decreases. At approximately pH 5, diprotonated nicotine has essentially be removed from the population of nicotine atoms. In contrast monoprotonated nicotine represents nearly 100% of the nicotine. As pH continues to increase, monoprotonated nicotine decreases while nonprotonated nicotine increases to an “inflection point” at pH 8. Above pH 8, nonprotonated nicotine represents the most prevalent form of nicotine, with monoprotonated nicotine continuing to decrease. As such, a pH of 8 is viewed as a cutoff of sorts to divide theform of nicotine predominantly or primarily (e.g., greater than about 50%) into salt form (when pH is below 8) and predominantly or primarily (e.g., greater than about 50%) into free base form (when pH is above 8).

[0148] FIG. 17C shows a histogram depicting the form of nicotine present in an emulsion when various fatty acids are used, based on the pH of the emulsion. As discussed above, a pH value of about 8 or less suggests majority of nicotine (e.g., greater than about 50%) is present in the salt form, while a pH value of about 8 or greater suggests majority of nicotine (e.g., greater than about 50%) is present in the free base form. A decanoic acid-nicotine complex, which resulted in a clear mixture (FIG. 17D) has a pH of less than 8 (salt form of nicotine). A lauric acid-nicotine complex, which also results in a clear mixture (FIG. 17D), has a pH of 8, meaning approximately equivalent amounts of the salt form and free base form of nicotine. In contrast, the resultant complexes of nicotine with myristic acid, stearic acid, or conjugated linoleic acid (each of which result in unclear mixtures (either heterogeneous or homogeneous)) each have pH values of over 8 indicating that the nicotine present in the emulsion is primarily, if not completely, present in the free base form. Thus, such complexes have been identified herein as NNCE’s.

[0149] FIGS. 18A-18B show a non-limiting example of an apparatus to test dissolution of nicotine complexes provided for herein and measure the rate of nicotine release. FIG. 18A shows an image of an experimental setup for dissolution analysis intended to function similarly to a commercially available apparatus. FIG. 18B shows a schematic of the conceptual components of the experimental setup and their respective functions. As shown in FIG. 18B, the system 1800 comprises a piston pump 1830 that draws media from a media reservoir 1810 and pumps media along a closed-loop fluid flow pathway 1820 through a heat exchanger 1840 and a flow through cell 1850, with the heat exchanger 1840 functioning to maintain the temperature of the media passing through the cell 1850. The dosage form 1860 being tested is positioned within the flow cell 1850 and the media is passed through the flow cell 1850 and returns to the media reservoir 1810 in a closed-loop fashion. Samples can be withdrawn from the media reservoir at predetermined time intervals either manually 1870 or by an automated syringe system 1880. The samples can be analyzed for concentration of API release from the dosage form (here, nicotine release from a non-limiting example of a dosage form, an oral nicotine pouch).

[0150] FIGS. 19A-19B show data resulting from the experimental setup described above. FIG. 19A shows mean nicotine mass measured over time to determine the release rate of nicotine fromthe indicated complexes housed within an oral pouch. In this experiment, two NNCE ((i) nicotine + conjugated linoleic acid and (ii) nicotine + medium chain triglycerides (MCT) oil) were compared to control (nicotine alone). These data show that the NNCE’ s provided for herein allow for modulation of nicotine release rate. As shown, the nicotine-conjugated linoleic acid emulsion yields an increase in nicotine release rate, as compared to control. Notably, the rate is also higher than that of the nicotine-MCT emulsion. Additionally, the nicotine-MCT emulsion exhibits a reduced release rate as compared to the nicotine only control. Thus, depending on the desired release rate profile, NNCE’s provided for herein can modulate (e.g., increase or decrease) nicotine release rate.

[0151] FIG. 19B shows additional data for release rate of nicotine for other embodiments of nicotine complexes provided for herein. As shown, of the complexes tested, nicotine-conjugated linoleic acid (thick plot trace) provided the most rapid release rate. Other complexes were similar at early time points but show the ability to modulate nicotine release over time to a desired degree. For example, the nicotine-decanoic acid and nicotine-lauric acid complexes showed lower release rates. Other complexes showed intermediate release rates. These data thus demonstrate the ability to use certain components of a nicotine complex to modulate or tune nicotine release rate to achieve a desired profile, whether that be rapid release or extended release, or a rate of release between those two. In several embodiments, the release rate is correlated with the length of the number of carbons in the fatty acid, as MCT oil comprises a mixture of Cs, Cio, and C12 triglycerides while conjugated linoleic acid comprises a Ci8 backbone. In some embodiments, the degree of unsaturated carbons in the backbone are involved in modulation of release rate. In several embodiments, the length of the backbone and the degree of unsaturated carbons in the backbone work in tandem to allow for a desired modulation of nicotine release rate from a carrier (here an oral nicotine pouch as a non-limiting example).

[0152] The experimental data described above and shown in FIGS 19A-19B was an in vitro setup. To determine the effect in an in vivo setting, subjects (3 subjects in each group) were given an oral nicotine pouch loaded with the indicated nicotine complexes (or free base as a control) and asked to rate the nicotine headrush sensation on a scale of 0 to 3 (0 = no sensation, 1 = weak sensation, 2 = medium sensation, and 3 = strong sensation). The subjects were asked to provide the rating at various time points throughout the duration of the experiment. The resultant data are shown in FIGS. 20A-20B. FIG. 20A shows data related to nicotine headrush perceived by usersof the oral nicotine pouches loaded with a nicotine-decanoic acid complex (closed diamonds), a nicotine-myristic acid complex (closed squares), or a nicotine-conjugated linoleic acid complex (closed circles). These data show that neither of the nicotine-decanoic acid complex nor the nicotine-myristic acid complex resulted in notable nicotine headrush sensation until nearly 8 minutes of exposure had elapsed, and then only the nicotine-myristic acid complex yielded any sensation. In contrast, as early at 4.5 minutes, subjects reported a medium nicotine headrush sensation. This perception was maintained for another ~1 minute at which point the reported sensation was increased to a strong headrush sensation, lasting for another ~1 minute. At ~7.5 minutes, the reported nicotine headrush sensation dropped to medium, where it remained for the duration of the experiment.

[0153] FIG. 20B shows additional data related to nicotine headrush perceived by users of the indicated oral nicotine pouches (data for the nicotine-conjugated linoleic acid complex (closed circles) is the same as from FIG. 20A. Additional test articles include nicotine free base (dashed line of circles), a nicotine-MCT oil complex (closed squares), and a nicotine-conjugated linoleic + MCT complex (dashed line). The nicotine-MCT oil complex exhibited a similar profde as the nicotine-conjugated linoleic acid complex. However, two notable distinctions are evident. The first is that the nicotine headrush sensation was perceived about 15 seconds earlier with the nicotine-MCT oil complex. Second, the nicotine headrush sensation was consistently reported as medium by the subjects. Taken together these data suggest that, as compared to a more powerful sensation with the nicotine-conjugated linoleic acid complex, a nicotine-MCT oil complex can provide users with an earlier onset, but less intense, nicotine headrush sensation. Likewise, the reported nicotine headrush sensation from the nicotine-conjugated linoleic + MCT complex was slower onset than any other complex tested and provided a medium sensation for almost 2 minutes before decreasing to weak at the termination of the experiment. Thus, the presence of the MCT oil slowed the release of the nicotine and also tempered the headrush perception as compared to the nicotine-conjugated linoleic acid complex. Thus, as discussed above, combinations of ingredients, such as fatty acids, can be used to modulate the nicotine release profde in terms of both timing and perceived intensity. This allows the generation of nicotine complexes as provided for herein to yield a user-specific release profile, be that rapid and intense, slow and mild, or any combination of such experiences.

[0154] Recognizing that the nicotine complexes provided for herein can modulate nicotine release rate and duration, stability of the complexes was evaluated. Four different complexes were tested as compared to nicotine in the free base format. Oral pouches were filled with 5.0 ± 0.1 mg of nicotine in the free base format (solid line in FIGS. 21A-21C), a nicotine-MCT oil complex (dashed line in FIGS. 21A-21C), a nicotine-conjugated linoleic acid complex (long dashed line in FIGS. 21A-21C), a nicotine-stearic acid complex (long- short-long dashed line in FIGS. 21A-21C) or a nicotine-decanoic acid complex (long-short-short dashed line in FIGS. 21A-21C). Total pouch weight for each test group was measured after filling. Pouches were placed into closed container (glass vial) and held at 40 °C for the duration of the experiment. These experimental conditions are designed to simulate a harsh environment and represent what would be considered suitable to induce accelerated loss of stability. At the middle and end of the experiment (7 and 14 days, respectively), total pouch weight was measured again. The results are shown in FIG. 21 A. Despite having different and tunable nicotine release profiles, the test nicotine complexes show comparable stability as comparted to non-complexed nicotine free base. Each of the tested pouches exhibited a decline in total mass throughout the experiment, but none of the test groups showed significant variability from the steady decline exhibited by the control group. Similar results are shown for pH. Each pouch was placed in 10 mL of deionized water and stirred for 10 minutes, followed by obtaining the pH of the deionized water. Other than the nicotine-decanoic acid test group, which started with a lower pH (see also FIG. 17C), and seemed to hold steady or slightly decline, the other test groups exhibited relatively similar profiles. The other groups each started with a pH of 9 or higher, which increased to about pH 10 midway through the experiment and remained approximately at that value for the duration of the experiment. See FIG. 2 IB. After pH measurements, the deionized water in which the pouches resided was stirred for an additional 60 minutes to allow complete nicotine extraction. Finally, HPLC was used to determine the mass of extracted nicotine. The data are shown in FIG. 21C. As seen in this figure, the eluted nicotine mass was substantially similar for each of the test groups over time. Thus, taken together, these data demonstrate that nicotine complexes as provided for herein exhibit similar stability and degrees of degradation over time as compared to non-complexed nicotine.( ) Cyclodextrin Inclusion Complexes

[0155] In various embodiments, a nicotine complex comprises (S)-nicotine in association with cyclodextrin, wherein the complex is devoid of a crystal lattice structure. In various examples, the (S)-nicotine molecule is occluded within the inner cavity of the cyclodextrin molecule, and thus the complex may be characterized as an inclusion complex.

[0156] In various examples, the cyclodextrin may comprise any known or yet to be discovered a-, P-, or y-cyclodextrin. In preferred examples, the cyclodextrin comprises P-cyclodextrin (unsubstituted) or a P-cyclodextrin such as hydroxypropyl-P-cyclodextrin. In various embodiments, cyclodextrins for use in an (S)-ni cotine complex include, but are not limited to, the group consisting of P-cyclodextrin, hydroxypropyl-P-cyclodextrin, methyl-P-cyclodextrin, dimethyl-P-cyclodextrin, heptakis(2,6-di-O-)ethyl -P-cyclodextrin, 6-O-a-maltosyl-P- cyclodextrin, randomly methylated P-cyclodextrin (RAMEB), sulfobutylether-P-cyclodextrin, sulfolipo-P-cyclodextrin, y-cyclodextrin, hydroxypropyl-y-cyclodextrin, octakis-(6-bromo-6- deoxy)-y-cyclodextrin, octakis-(6-amino-6-deoxy)-y-cyclodextrin, octakis-(6-chloro-6-deoxy)-y- cyclodextrin, octakis-(6-deoxy-6-iodo)-y-cyclodextrin, octakis-(6-deoxy-6-mercapto)-y- cyclodextrin, octakis-(2,3,6-tri-O-methyl)-y-cyclodextrin, octakis-(2,3-diacetyl-6-sulfato)-y- cyclodextrin, octakis-(3-O-butyryl-2,6-di-O-pentyl)-y-cyclodextrin, octakis-6-sulfato-y- cyclodextrin, and mixtures thereof. The present disclosure is not bound by any theories as to how may (S)-nicotine molecules may be occluded inside the same inner cavity of a cyclodextrin molecule.Vaporizable Compositions Comprising Nicotine Salts and / or Nicotine Complexes

[0157] Vaporizable alkaloid compositions in accordance with the present disclosure are optimized to provide an improved user experience. The sensory effects an individual experiences from inhaling a vaporized liquid delivered from an electronic device can be, and arguably should be, similar if not identical to the experience a user would have from smoking a burning cigarette, but this can only be achieved if certain interrelated sensory effects are balanced, including throat hit, head rush, nasal and oral sensations and taste, and cloud appearance. These factors make up the user experience.

[0158] In various embodiments, throat hit is optimized by incorporating certain (S)-nicotine salts and / or certain (S)-nicotine complexes in the vaporizable composition, as either a partial or acomplete replacement of (S)-nicotine free base. The choice of which salt(s) and / or complex(es) to use can be made based on membrane permeability, per above, and to what degree a particular salt or a particular complex can reduce the lipophilic migration of (S)-nicotine through a membrane.

[0159] In various embodiments, a vaporizable composition comprises:

[0160] at least one of an (S)-nicotine salt and (S)-nicotine complex;

[0161] at least one solvent; and

[0162] optionally, at least one flavoring agent.

[0163] In various embodiments, the at least one (S)-nicotine salt comprises protonated (S)- nicotine cation and a counterion comprising a conjugate base of an organic acid, wherein the conjugate base of the organic acid comprises at least one additional polar hydrophilic group. In certain examples, the one additional polar hydrophilic group is selected from hydroxyl, oxo, carboxylate, thiol, heterocyclyl, substituted heterocyclyl, aryl, heteroaryl and substituted heterocyclyl. In various embodiments, the organic acid is selected from adipic acid, citric acid, L- (+) tartaric acid, succinic acid, and vanillic acid.

[0164] In various embodiments, the (S)-nicotine complex comprises (S)-nicotine in association with at least one other molecule, wherein the complex is devoid of a crystal lattice structure.

[0165] In various embodiments, the at least one other molecule in the (S)-nicotine complex is selected from a surfactant, a polymer, a polysaccharide, a metal, or an inorganic compound.

[0166] In various embodiments, the (S)-nicotine complex in the vaporizable composition comprises a micellular complex with at least one surfactant, or an inclusion complex with at least one cyclodextrin.

[0167] In various embodiments, a vaporizable alkaloid composition herein comprises at least one solvent. Solvents in vaporizable compositions intended to be vaporized and inhaled by an individual include, but are not limited to, propylene glycol, water, ethanol, glycerin, and mixtures thereof. In certain examples, glycerin is vegetable glycerin (VG).

[0168] In various embodiments, a vaporizable alkaloid composition herein comprises from about 85 wt.% to about 99.9 wt.% total solvent, based on the total weight of the vaporizable alkaloid composition. In certain examples, the solvent comprises a majority of vegetable glycerin and / or propylene glycol, with much lesser amounts of water and / or ethanol. In certain examples,the amount of total solvent (regardless of composition) may be indicated as “quantity sufficient” or “q.s.” which is that amount of solvent necessary to total a composition up to 100 wt.%.

[0169] Flavoring agents for use herein include, but are not limited to, oleocanthal, 4-hydroxy- 2-nonenal, 4-oxo-2-nonenal, allicin, allyl isothiocyanate, icilin, polygodial, cinnamaldehyde, / / ZM / .s-p-methoxycinnamaldehyde, methyl syringate, 2-chlorobenzylidene malononitrile, 1- chloroacetophenone, ethyl bromoacetate, 4-hydroxyhexenal, toluene diisocyanate, p- benzoquinone, methyl p-hydroxybenzoate, flufenamic acid, niflumic acid, mefenamic acid, diclofenac, hydroxy-a-sanshool, 6-paradol, linalool, carvacrol, eugenol, thymol, vanillin, methyl eugenol, 2,6-dimethylphenol, 2,5-dimethylphenol, 3,4-dimethylphenol, 2,6-diisopropylphenol, caffeine, farnesyl thiosalicylic acid, 4-allylanisole, curcumin, niacin, camphor, olvanil, arvanil, nabilone, various phytochemicals from Euphorbia rsinifera, Euenia carophyllata, Ocimum gratissiumum, Panax, Aframomum melgueta, Evodia rutaecarpa, Drymis wintsri, Cinnamosma fragrans, Warburgia, Scutellaria baicalensis, Vitex agnus, Pterodon pubsscens, Croton macrostachyus. Angelicas pubescentis. Ephedra sinica, Amphilophium crucigerum, Bosewellia carterii, Commiphora myrrha, Echinophora platyloba, Nypa fruticans, Corydalis saxicola, Coptis chinensis, Ononis spinosa, Parkia platycsphala, Cymbopogon citratus, Capsicum annuum, Zingiber officials, and Pipsr nigrum, geraniol, geranial, valeric acid, methyl salicylate, ethyl maltol, ethyl butyrate, ethyl acetate, maltol, menthol, ethyl vanillin, ethyl 3-methyl-3- phenylglycidate, furaneol, methyl cyclopentenolone, methyl cyclopentenolone, ethyl cyclopentenolone, 8-decalactone, y-decalactone, a-nonalactone, P-nonalactone, cis-3 -hexanol, iso- amyl acetate, ethyl-2-methyl butyrate, butyric acid, ethyl butyrate, 2-methylbutyric acid, benzyl alcohol, ethyl hexanoate, benzaldehyde, z o-amyl isovalerate, hexanoic acid, ethyl propionate, y- undecalactone, acetyl propionyl, raspberry ketone, furfural, 5-methylfurfural, maltol, 2- acetylpyrazine, 2, 3, 5 -trimethylpyrazine, 2-acetylpyrrole, 2-isopropyl-4-methylthiazole, 2- isobutylthi azole, furfuryl mercaptan, thiomenthone, p-menthene-8-thiol, tropathiane, hexyl acetate and mixtures thereof. This listing is by no means meant to be limiting, as many other flavoring agents exist in the food, beverage, and tobacco industries, and many more are yet to be discovered.

[0170] In various embodiments, a vaporizable composition herein is packaged into disposable vaping cartridges for use in a vaping device or is provided to an individual desirous of fdling refillable vaping cartridges for use in a vaping device.Correlating Harshness of Nicotine Salts and Complexes to Membrane Permeability Data

[0171] Membrane permeability rates can be correlated to perceived nicotine harshness (oral, throat), and skin irritancy for non-oral products, by comparing laboratory data for lipophilic permeability to sensory data obtained from sensory panels using participants. a) Sensory panel data

[0172] In various embodiments, sensory panels are used to subjectively rate irritancy of various nicotine products. A group of participants use their senses to judge harshness, such as on a scale of 1 - 10 so that what is ordinarily subj ective becomes numerically obj ective. Sensory panels generally use a sufficient number of panelists and multiple locations to acquire large amounts of data that can be statistically analyzed. Panelists would rate harshness of nicotine products having different (S)-nicotine salts or different (S)-nicotine complexes, such as in comparison to the same type of product having only (S)-ni cotine free base compound.(b) Scatter Plots

[0173] Scatter plots can be used to indicate the relationship between changes observed in two different sets of variables, in this case, between rate of membrane permeability for a particular (S)- nicotine salt or complex and the perceived harshness for a smoking or smokeless product comprising the same (S)-nicotine salt or complex.

[0174] In various embodiments, a scatter plot between membrane permeability rates and sensory harshness data will establish the type of correlation between variables.Transdermal Patch

[0175] In various embodiments, a nicotine delivery product in the form of a transdermal patch comprises:

[0176] at least one of an (S)-nicotine salt and (S)-ni cotine complex;

[0177] at least one solubilizer or polymer matrix; and

[0178] a substrate,

[0179] wherein the (S)-nicotine salt or (S)-nicotine complex and the solubilizer comprise a solubilized mixture disposed on a surface of the substrate.Dissolving oral films

[0180] In various embodiments, a nicotine delivery product in the form of a mucoadhesive film configured for oral use comprises:

[0181] at least one of an (S)-nicotine salt and (S)-ni cotine complex;

[0182] at least one polymer;

[0183] at least one polyol; and

[0184] optionally, at least one surfactant.Lozenges

[0185] In various embodiments, a nicotine delivery product comprises a dissolvable lozenge. In certain examples, a lozenge resembles a typical cough lozenge, intended to dissolve slowly in the mouth of an individual, such as over the course of several minutes.

[0186] In various examples, a nicotine delivery lozenge comprises:

[0187] at least one of an (S)-nicotine salt and (S)-nicotine complex;

[0188] a binder;

[0189] a sweetener; and

[0190] water.Chewing gum

[0191] In various embodiments, a nicotine delivery product is provided in the form of a chewing gum. For purposes herein, a chewing gum can be any type of product, such as a candy- coated gum, small beads, flat sticks of gum, bubble gum, shredded bubble gum that resembles chewing tobacco, paper wrapped short sticks of gum resembling cigarettes, and so forth.

[0192] In various embodiments, a nicotine chewing gum comprises:

[0193] at least one of an (S)-nicotine salt and (S)-nicotine complex; and

[0194] a water-insoluble chewing gum base.Oral Nicotine Pouches (ONPs)

[0195] In various embodiments, a nicotine delivery product is provided in the form of an oral pouch. A pouch for oral use comprises a relatively small (e.g., 0.5in x 0.75in) saliva-permeable fabric material enclosure containing a powder sealed therein, capable of releasing (S)-nicotine into the oral cavity of an individual when the pouch is placed sublingually or in the buccal cavity of the individual. A nicotine delivery pouch according to the present disclosure is configured torelease a (S)-nicotine over time. In some embodiments, release of a (S)-nicotine into the oral cavity of an individual from an alkaloid dispensing pouch may be characterized as “time release.”

[0196] In various embodiments, an alkaloid dispensing pouch comprises a saliva-permeable nonwoven fabric and a powdered composition sealed therein comprising at least one of an (S)- nicotine salt and (S)-nicotine complex. In certain examples, the powdered composition sealed within the pouch comprises an admixture of crystalline or other solid form of an (S)-nicotine salt and / or (S)-nicotine complex and a solid carrier, or a solution of (S)-nicotine salt or (S)-nicotine complex, adsorbed onto a solid carrier. In either scenario, the mixture is preferably a powder or granulate.

[0197] In various embodiments, carriers for use in an oral nicotine pouch include, but are not limited to, agar, agarose, albumin, alginate, casein, chitin, chondroitin, dextrin, fibroin, fucoidans, galactans, gellan, guar, scleroglucan, pullulan, xyloglucan, pectin, xanthan, psyllium, silica gel, fumed silica, magnesium aluminum silicates, clay, bentonite, hectorite, mesoporous silica, cellulose, cellulose acetate, hyaluronan, various elastin-like polypeptides, [3-cyclodextrin, collagen, gelatin, chitosan, carrageenan, polylactic acid, polyglycolic acid, poly actic-glycolic acid) (PLGA), poly(2 -hydroxyethyl methacrylate), poly(2-hydroxypropyl methacrylate), poly(acrylic acid), carboxymethyl cellulose, carboxyethyl cellulose, hydroxyethyl cellulose, hydrophobically-modified hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, microcrystalline cellulose, nitrocellulose, polyvinyl alcohol, polyvinylpyrrolidone, poly(vinyl methacrylate), carboxy vinyl polymers, poly(vinyl acetate), polyvinyl co-polymers, various starches, modified starches, and combinations thereof.

[0198] In preferred embodiments, an oral nicotine pouch according to the present disclosure comprises a saliva-permeable nonwoven fabric defining an enclosure and a fill material sealed within the enclosure, the fill material comprising an (S)-nicotine complex and a carrier. In certain examples, the carrier is preferably powdered microcrystalline cellulose.Impregnated toothpicks

[0199] In various embodiments, a nicotine product for oral use comprises impregnated toothpicks. In many regards, nicotine impregnated toothpicks resemble familiar cinnamontoothpicks, but are not necessarily cinnamon flavored as countless other flavoring agents can be used. Cinnamon toothpicks generally comprise a sliver of wood impregnated with cinnamon oil.

[0200] In various examples herein, a nicotine toothpick comprises a sliver of wood impregnated with at least one of an (S)-nicotine salt and (S)-nicotine complex.Mouth Spray

[0201] In various embodiments, a nicotine mouth spray comprises:

[0202] at least one of an (S)-nicotine salt and (S)-nicotine complex; and

[0203] a diluent.

[0204] In certain examples, the diluent is selected from water, alcohol, and mixtures thereof. In some examples, a nicotine mouth spray comprises from about 10 wt.% to about 30 wt.%, and preferably from about 15 wt.% to about 25 wt.% alcohol, based on the total weight of the mouth spray composition.Gummy candies

[0205] In various embodiments, a nicotine gummy comprises:

[0206] at least one of an (S)-nicotine salt and (S)-nicotine complex;

[0207] a sugar and / or sugar syrup;

[0208] a binder;

[0209] a starch; and

[0210] a wax.

[0211] In various embodiments, the binder is selected from natural gums such as gum Arabic or gum tragacanth, gelatin, pectin, starch, and mixtures thereof, with the preference being gelatin.

[0212] Wax is optionally used as a coating or polish on each of the candies and preferably comprises carnauba wax.Sublingual disintegrating tablets

[0213] In various embodiments, a nicotine sublingual tablet comprises:

[0214] at least one of an (S)-nicotine salt and (S)-ni cotine complex; and

[0215] a carrier.

[0216] In various embodiments, the carrier comprises any combination of filler, binder, disintegrant, lubricant, glidant, surfactant, acidic agent, alkaline agent, pH buffering agent, preservative, drug release modifier, coating material, coloring, flavoring, and sweetener, totaling at least 90 wt.%, at least 95 wt.%, or preferably, at least 99 wt.% of the total weight of the nicotine sublingual tablet composition.Topical cream

[0217] In various embodiments, a nicotine topical cream comprises:

[0218] at least one of an (S)-nicotine salt and (S)-nicotine complex;

[0219] a solubilizer; and

[0220] a humectant.

[0221] In various embodiments, a (S)-nicotine salt and (S)-nicotine complex is chosen for its lower lipophilic membrane permeability, which is correlated to reduced skin irritancy in comparison to topical creams with identical base composition but formulated with only (S)- nicotine free base.

[0222] The solubilizer is selected from partially hydrogenated, or fully hydrogenated vegetable oils such as soybean oil, olive oil, sesame oil, palm oil, coconut oil, and the like. Solubilizers may also be fractionated cuts of fatty acids, fatty acid mixtures, mono-, di-, or triglycerides of fatty acids, wherein the fatty acids and / or glycerides may have a particular chain length distribution (e.g., short-, medium-, or long-chain fatty acids). Of particular use herein are “medium-chain triglycerides” (or “MCT’s”), which refers to the glycerin triesters of fatty acids having from about 6 to about 12 carbon atoms, such as caprylic acid, caproic acid, lauric acid, and / or capric acid in any combination, (z.e., C6-C12 fatty acid triglycerides). In various examples, medium-chain triglycerides can be obtained by fractionating palm kernel oil and coconut oil. Medium-chain triglycerides, USP / NF, CAS No. 73398-61-5, for use in transdermal nicotine compositions herein is available, for example, from Specialized Rx Products, LLC, Circle Pines, MN. Also of use herein is Organic MCT Oil-Fractionated Coconut Oil (caprylic / capric triglyceride), CAS Nos. 73398-61-5 and 65381-09-1, having a specific gravity of about 0.930- 0.960 g / mL (typically on average, 0.951 g / mL)

[0223] A solubilizer for use in various nicotine topical creams may comprise a terpene, such as geraniol, citronellol, geranial, citronellal, linalool, menthone, rose oxide, ct-terpineol and limonene.

[0224] Humectants for use in various nicotine topical creams include glycerin, honey, 1,2- propylene glycol, 1,3-propylene glycol, various carboxylic acid esters of terpene alcohols, lecithin, lanolin, triethylene glycol, xylitol, sorbitol, hexylene glycol, and urea.

[0225] In the detailed description, references to “various embodiments”, "one embodiment", "an embodiment", "an example embodiment", etc., indicate that the embodiment described may include a particular feature, structure, or characteristic, but every embodiment may not necessarily include the particular feature, structure, or characteristic. Moreover, such phrases are not necessarily referring to the same embodiment. Further, when a particular feature, structure, or characteristic is described in connection with an embodiment, it is submitted that it is within the knowledge of one skilled in the art to affect such feature, structure, or characteristic in connection with other embodiments whether or not explicitly described. After reading the description, it will be apparent to one skilled in the relevant art(s) how to implement the disclosure in alternative embodiments.

[0226] Steps recited in any of the method or process descriptions may be executed in any order and are not necessarily limited to the order presented. Furthermore, any reference to singular includes plural 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 or the like may include permanent (e.g., integral), removable, temporary, partial, full, and / or any other possible attachment option. Any of the components may be coupled to each other via friction, snap, sleeves, brackets, clips or other means now known in the art or hereinafter developed. Additionally, any reference to without contact (or similar phrases) may also include reduced contact or minimal contact.

[0227] With respect to ingredients that are grouped by function or characterized herein, unless otherwise expressly stated herein, it is not precluded that such an ingredient could be grouped with or characterized by another function. For example, an ingredient discussed herein as a solubilizer could also function as a surfactant and vice versa. The ranges disclosed herein also encompass any and all overlap, sub-ranges, and combinations thereof. Language such as “up to,” “at least,” “greater than,” “less than,” “between,” and the like includes the number recited. Numbers preceded by a term such as “about” or “approximately” include the recited numbers. For example, “about 90%” includes “90%. ” Language such as “at least 95% (S)-nicotine in the form of a free base alkaloid includes 96%, 97%, 98%, 99%, and 100% (S)-nicotine in the form of a free base alkaloid.Any titles or subheadings used herein are for organization purposes and should not be used to limit the scope of embodiments disclosed herein.

[0228] Benefits, other advantages, and solutions to problems have been described herein with regard to specific embodiments. However, the benefits, advantages, solutions to problems, and any elements that may cause any benefit, advantage, or solution to occur or become more pronounced are not to be construed as critical, required, or essential features or elements of the disclosure. The scope of the disclosure is accordingly to be limited by nothing other than the appended claims, in which reference to an element in the singular is not intended to mean "one and only one" unless explicitly so stated, but rather "one or more." Moreover, where a phrase similar to 'at least one of A, B, and C or 'at least one of A, B, or C is used in the claims or specification, it is intended that the phrase be interpreted to mean that A alone may be present in an embodiment, B alone may be present in an embodiment, C alone may be present in an embodiment, or that any combination of the elements A, B and C may be present in a single embodiment; for example, A and B, A and C, B and C, or A and B and C.

[0229] All structural, chemical, and functional equivalents to the elements of the abovedescribed various embodiments that are known to those of ordinary skill in the art are expressly incorporated herein by reference and are intended to be encompassed by the present claims. Moreover, it is not necessary for an apparatus or component of an apparatus, or method in using an apparatus to address each and every problem sought to be solved by the present disclosure, for it to be encompassed by the present claims. Furthermore, no element, component, or method step in the present disclosure is intended to be dedicated to the public regardless of whether the element, component, or method step is explicitly recited in the claims. No claim element is intended to invoke 35 U.S.C. 112(f) unless the element is expressly recited using the phrase “means for.” As used herein, the terms “comprises”, “comprising”, or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a chemical, chemical composition, process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such chemical, chemical composition, process, method, article, or apparatus.

Claims

CLAIMS1) A nicotine complex comprising:(S)-ni cotine in the form of a free base alkaloid or without a positive formal charge; and one or more ingredients suitable for forming a complex with the (S)-nicotine, wherein the complex is in a form selected from: a charge transfer complex, a hydrogen bonded complex, a Van der Waals complex, a complex stabilized by nonionic interactions, a solubilized complex, a micellular complex, and an inclusion complex; wherein the one or more ingredients for forming a complex with the (S)- nicotine is selected from the group consisting of: a fatty acid having a polar and / or hydrophilic functional group, a surfactant, a solubilizer, and a polysaccharide.2) The nicotine complex of Claim 1, wherein the acid having a polar and / or hydrophilic functional group comprises at least one carboxyl group and comprises a C8-C24 saturated, monounsaturated, or polyunsaturated fatty acid.3) The nicotine complex of Claim 1, wherein the acid having a polar and / or hydrophilic functional group comprises one or more of: at least one hydroxyl group, at least one double bond, at least one conjugated double bond, at least one carboxyl group, and combinations thereof.4) The nicotine complex of Claim 2, wherein the C8-C24 fatty acid is saturated and is selected from the group consisting of caprylic acid, decanoic acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid, octadecanoic acid, icosanoic acid, docosanoic acid, and tetracosanoic acid.5) The nicotine complex of Claim 2, wherein the C8-C24 fatty acid is monounsaturated and is selected from the group consisting of myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, gadoleic acid, eicosenoic acid, erucic acid, and nervonic acid.6) The nicotine complex of Claim 2, wherein the C8-C24 fatty acid is polyunsaturated and is selected from the group consisting of linoleic acid, a-linolenic acid, y -linolenic acid, mead acid, stearidonic acid, arachidonic acid, eicosapentaenoic acid, and cervonic acid (docosahexaenoic acid).7) The nicotine complex of Claim 2, wherein the C8-C24 fatty acid is polyunsaturated and is selected from the group consisting of conjugated linoleic acid, eicosadienoic acid, docosadienoic acid, pinolenic acid, a-eleostearic acid, 0-eleostearic acid, catalpic acid, dihomo-y- linolenic acid, eicosatrienoic acid, eicosatetraenoic acid, adrenic acid, bosseopentaenoic acid, ozubondo acid, sardine acid, tetracosapentaenoic acid, and herring acid.8) The nicotine complex of Claim 2, wherein the acid having a polar and / or hydrophilic functional group comprises a conjugated fatty acid and is selected from the group consisting of conjugated linoleic acid, punicic acid, jacaric acid, calendid acid, catapic acid, alphaeleostearic acid, beta-eleostearic acid, parinaric acid, anadiplosis acid, and tung acid.9) The nicotine complex of Claim 2, wherein the acid having a polar and / or hydrophilic functional group comprises conjugated linoleic acid.10) The nicotine complex of Claim 1, wherein the surfactant is selected from the group consisting of an anionic surfactant, a nonionic surfactant, a cationic surfactant, a zwitterionic surfactant, and mixtures thereof.11) The nicotine complex of Claim 1, wherein the surfactant is selected from the group consisting of lecithin, phosphatidylcholine, EO / PO block copolymers, EO / PO / EO triblock copolymers, polyethylene glycol, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, span 20, span 40, span 60, span 80, and mixtures thereof.12) The nicotine complex of Claim 1, wherein the solubilizer comprises a mono-, di-, or tri-fatty acid glyceride.13) The nicotine complex of Claim 12, wherein the fatty acid glyceride comprises medium-chain length triglyceride (MCT) oil.14) The nicotine complex of Claim 12, wherein the fatty acid glyceride comprises one or more of sunflower oil, canola oil, palm oil, coconut oil, safflower oil, olive oil, sesame oil, peanut oil, avocado oil, or soybean oil.15) The nicotine complex of Claim 1, wherein the polysaccharide comprises a cyclodextrin.16) The nicotine complex of Claim 15, wherein the cyclodextrin is selected from the group consisting of P-cyclodextrin, hydroxypropyl-P-cyclodextrin, methyl-P-cyclodextrin, dimethyl-P-cyclodextrin, heptakis(2,6-di-O-)ethyl -P-cyclodextrin, 6-O-a-maltosyl-P- cyclodextrin, randomly methylated P-cyclodextrin (RAMEB), sulfobutylether-P-cyclodextrin, sulfolipo-P-cyclodextrin, y-cyclodextrin, hydroxypropyl-y-cyclodextrin, octakis-(6-bromo-6- deoxy)-y-cyclodextrin, octakis-(6-amino-6-deoxy)-y-cyclodextrin, octakis-(6-chloro-6-deoxy)-y- cyclodextrin, octakis-(6-deoxy-6-iodo)-y-cyclodextrin, octakis-(6-deoxy-6-mercapto)-y- cyclodextrin, octakis-(2,3,6-tri-O-methyl)-y-cyclodextrin, octakis-(2,3-diacetyl-6-sulfato)-y- cyclodextrin, octakis-(3-O-butyryl-2,6-di-O-pentyl)-y-cyclodextrin, octakis-6-sulfato-y- cyclodextrin, and mixtures thereof.17) The nicotine complex of 15, wherein the polysaccharide comprises an unsubstituted P-cyclodextrin.18) The nicotine complex of Claim 15, wherein the polysaccharide comprises hydroxypropyl-P-cyclodextrin.19) The nicotine complex of Claim 1 , further comprising a sugar alcohol from the group consisting of sorbitol, xylitol, erythritol, lactitol, maltitol, mannitol, isomalt, hydrogenated starchhydrolyzates, and combinations thereof, and wherein the nicotine complex further comprises (S)- nicotine in a protonated form.20) The nicotine complex of Claim 1, further comprising a flavoring agent.21) The nicotine complex of Claim 1, further comprising an antioxidant selected from the group consisting of tocopherols (vitamin E), butylated hydroxy anisole (BHA), butylated hydroxytoluene (BHT), propyl gallate, tertiary butylhydroquinone (TBHQ), rosemary extracts, green tea extract, and combinations thereof.22) The nicotine complex of Claim 1, further comprising a pH adjuster selected from sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, magnesium carbonate, and any combination thereof.23) The nicotine complex of Claim 1, further comprising a substrate.24) The nicotine complex of Claim 23, wherein the substrate contributes to a physical form or a function of the nicotine product.25) The nicotine complex of Claim 23, wherein the substrate comprises a nonwoven fabric.26) The nicotine complex of Claim 23, wherein the substrate is selected the group consisting of polymer fibers, cellulose viscose, paper, and cotton.27) The nicotine complex of Claim 26, wherein the cotton comprises spunbonded cotton, melt blown cotton, needle punched cotton, thermally bonded cotton, chemically bonded cotton, hydroentangled cotton, spun-laced cotton, or air-laid cotton.28) The nicotine complex of Claim 23, wherein the substrate comprises a nonwoven fabric, wherein the nonwoven fabric is saliva-permeable.29) The nicotine complex of Claim 28, further comprising a carrier.30) The nicotine complex of Claim 29, wherein the carrier comprises water insoluble fibers.31) The nicotine complex of Claim 30, wherein the carrier comprises microcrystalline cellulose.32) The nicotine complex of Claim 30, wherein the carrier is selected from the group consisting of microcrystalline cellulose, bamboo fibers, lignin, wheat fibers, pea fibers, maize fibers, rice fiber, oat fibers, barley fibers, buckwheat fibers, cellulose fibers, bran fibers, powdered cellulose, and combinations thereof.33) The nicotine complex of any one of Claims 1 to 32, wherein the nicotine complex is devoid of a crystal lattice structure.34) The nicotine complex of any one of Claims 1 to 32, wherein the complex is substantially free of nicotine salt formed by an ionic bond.35) The nicotine complex of any one of Claims 1 to 32, wherein the (S)-nicotine has an alkaline pH.36) The nicotine complex of any one of Claims 1 to 20, wherein the (S)-nicotine has pH greater than pH 7.37) The nicotine complex of any one of Claims 1 to 26, wherein the pH value of (S)- nicotine complex is between 7 and 10.38) An oral nicotine pouch, comprising: a saliva-permeable nonwoven fabric, wherein the saliva-permeable nonwoven fabric defines an enclosure; a fill material comprising an (S)-nicotine complex according to any one of Claims 1 to 32 and a carrier, wherein the fill material is sealed within the enclosure.39) The oral nicotine pouch of Claim 38, wherein the carrier comprises microcrystalline cellulose.40) The oral nicotine pouch of Claim 38 or 39, wherein the (S)-ni cotine complex comprises a non-salt nicotine complex emulsion.41) The oral nicotine pouch of Claim 40, wherein the non-salt nicotine complex emulsion comprises micelles, colloidal particles, or self-assembled structures having a particle size between 10 nm to 10 pm.42) The oral nicotine pouch of Claim 40 or 41, wherein the non-salt nicotine complex emulsion comprises an unsaturated fatty acid complexed with the (S)-nicotine.43) The oral nicotine pouch of Claim 42, wherein the unsaturated fatty acid comprises a C8-C24 fatty acid.44) The oral nicotine pouch of Claim 43, wherein the C8-C24 fatty acid comprises conjugated linoleic acids.45) The oral nicotine pouch of any one of Claims 38-44, wherein the amount of nicotine is from 0.1 to 4% by weight of the pouch composition.46) The oral nicotine pouch of Claim 43 or 44, wherein the amount of C8-C24 fatty acid is from 0.1 to 10% by weight of the pouch composition.47) The oral nicotine pouch of any one of Claims 38 to 46, wherein the amount of moisture is at least 15% by weight of the pouch composition.48) The oral nicotine pouch of any one of Claims 38 to 47, wherein the amount of pH adjuster is from 0.01% to 10% by weight of the pouch composition.49) The oral nicotine pouch of any one of Claims 38 to 48, wherein the amount of surfactant is from 0.1 to 10% by weight of the pouch composition.50) The oral nicotine pouch of any one of Claims 38 to 49, wherein the amount of solubilizer is from 0.1 to 40% by weight of the pouch composition.51) The oral nicotine pouch of any one of Claims 38 to 50, wherein the amount of polysaccharide is from 0.1 to 5% by weight of the pouch composition.52) A nicotine product comprising:(i) a nicotine complex;(ii) at least one unsaturated fatty acid;(iii) at least one oil;(iv) at least one surfactant; and(v) at least one of a pouch, a carrier, an antioxidant, a flavorant, or a sugar alcohol.53) A nicotine product comprising:(i) a nicotine complex;(ii) at least one unsaturated fatty acid;(iii) at least one surfactant; and(iv) at least one of a pouch, a carrier, an antioxidant, a flavorant, or a sugar alcohol.54) A nicotine product comprising:(i) a nicotine complex;(ii) at least one polysaccharide;(iii) at least one oil;(iv) at least one surfactant; and(v) at least one of a pouch, a carrier, an antioxidant, a flavorant, or a sugar alcohol.55) A nicotine product according to any one of Claims 52 to 54, wherein the nicotine within the nicotine complex comprises at least 30% nicotine in the form of a free base alkaloid and having less than 30% in a monoprotonated form.56) A nicotine product according to any one of Claims 52 to 53 and 55, wherein at least one unsaturated fatty acid comprises conjugated linoleic acid.57) A nicotine product according to any one of Claims 52 or 54 to 55, wherein at least one oil comprises on or both of MCT oil and sunflower oil.58) A nicotine product according to any one of Claims 54 to 55, wherein the at least one polysaccharide comprises a cyclodextrin.59) The nicotine product of Claim 58, wherein the cyclodextrin comprises hydroxypropyl-P-cyclodextrin.60) A nicotine product according to any one of Claims 52 to 59, at least two of a pouch, a carrier, an antioxidant, a flavorant, or a sugar alcohol.61) Anicotine product according to any one of Claims 52 to 59, at least three of a pouch, a carrier, an antioxidant, a flavorant, or a sugar alcohol.62) A nicotine product according to any one of Claims 52 to 61, wherein the at least one surfactant comprises polysorbate 80.63) A method of tailoring a subject’s nicotine experience comprising administering to the subject a nicotine complex, an oral nicotine pouch, or a nicotine product according to any one of the preceding Claims.64) Use of a nicotine complex, an oral nicotine pouch, or a nicotine product according to any one of Claims 1 to 62 for modulation of nicotine release rate and / or quantity to a subject.65) The use of Claim 64, wherein the nicotine release rate and / or quantity is increased as compared to free base nicotine, or an oral nicotine pouch or nicotine product not comprising a nicotine complex.66) The use of Claim 64, wherein the nicotine release rate and / or quantity is reduced as compared to free base nicotine, or an oral nicotine pouch or nicotine product not comprising a nicotine complex.

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