Tobacco harm reduction and pain relief products and methods thereof

Abstract

Tobacco harm reduction and pain relief products and methods thereof are disclosed. Tobacco harm reduction (THR) products according to the present disclosure include transdermally and orally administered products, each comprising at least one substituted pyridine compound of formula (I) and excipients tailored to the physical form or function of the product and optionally a substrate. In various examples, the THR product includes (a) a transdermal patch, (b) a dissolution film, (c) a lozenge, (d) chewing gum, (e) an oral pouch, (f) impregnated toothpicks, (g) impregnated or coated floss, (h) mouthwash, (i) soft sweets, (j) sublingual disintegrating tablets, or (k) a topical / transdermal cream.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application Serial No. 63 / 581,784, filed on September 11, 2023, entitled “Tobacco Harm Reduction And Pain Relief Products And Methods Thereof” and U.S. Provisional Patent Application Serial No. 63 / 642,241, filed on May 3, 2024, entitled “Tobacco Harm Reduction And Pain Relief Products And Methods Thereof”. These disclosures are incorporated herein by reference in their entirety for all purposes. Technical Field

[0002] The present disclosure relates generally to products and methods for smoking cessation and eliminating smoking-related harms, and more particularly to nicotine-free oral and dermal tobacco harm reduction products that promote smoking cessation when used alone or in combination with pain relief products. Background Art

[0003] It is well known that smokers can gain health benefits from quitting smoking, and in general, the majority of adult smokers in the United States express a desire to quit. Depending on the composition of the vaporizable liquid, electronic nicotine delivery systems (ENDS) should, at least in principle, provide a viable smoking cessation aid. However, various studies have shown that users who self-administer nicotine using electronic devices are not actually more likely to quit tobacco products. For example, see B. Kaplan et al., “Effectiveness of ENDS, NRT and Medication for Smoking Cessation Among Cigarette-Only Users,” Tob Control 2023;32:302-307 and R. El Dib et al., “Electronic Nicotine Delivery Systems and / or Electronic Non-Nicotine Delivery Systems for Tobacco Smoking Cessation or Reduction: A Systematic Review and Meta-Analysis,” BMJ Open 2017;7:e012680.

[0004] Quitting smoking requires commitment and compliance with alternative products. For smokers, compliance with alternative products relies on having the same, or at least nearly the same, sensory effects as experienced by inhaling tobacco smoke from a burning cigarette. To date, and as evidenced by the lack of data demonstrating smoking cessation, this has not been achieved in the industry.

[0005] Therefore, there is a need for new smoking alternatives that can provide an acceptable personal experience for former smokers. In particular, there is a need for non-nicotine products that can be used alone or in combination to reduce the harm of tobacco to individuals. Summary of the invention

[0006] Surprisingly, non-nicotine tobacco harm reduction products have now been found to be optimized to provide a balance of sensory benefits when used orally and / or transdermally to promote smoking cessation. In some cases, the combination of topical non-nicotine pain relief and oral or transdermal administration of non-nicotine alkaloids that stimulate nicotinic acetylcholine receptors (nAChRs) synergistically promote nicotine cessation.

[0007] In various embodiments of the present disclosure, tobacco harm reduction (THR) products include transdermal and orally administered products, each product comprising at least one substituted pyridine compound and excipients tailored to the physical form of the product.

[0008] In various examples, THR products include, but are not limited to, dissolving film strips, lozenges, chewing gum, transdermal patches, oral pouches, impregnated toothpicks, impregnated dental floss, mouthwashes, gummies, sublingual disintegrating tablets, topical creams, pain relief patches, oral sprays, inhalers, nasal sprays, alkaloid dispensing bags, electronic cigarettes, electronic nicotine delivery systems, or similar nicotine replacement products.

[0009] In some instances, the smoking cessation program includes the use of a THR product or a combination of two or more THR products. A smokeless THR product is disclosed. In some embodiments, the smokeless THR product is suitable for chewing, sucking, applying or oral manipulation in the mouth of a consumer. In some embodiments, the active ingredient of the smokeless THR product is about 0.1 wt % to about 10 wt %, based on the weight of the smokeless THR product.

[0010] In certain embodiments, a smoking cessation program includes the use of an oral or transdermal THR product in combination with a topical or transdermal pain relief product. These methods ensure that individuals who wish to quit smoking have a product that stimulates nicotinic acetylcholine receptors (nAChRs) and a product that relieves the pain of not smoking.

[0011] In various embodiments, a tobacco harm reduction (THR) product comprises:

[0012] at least one substituted pyridine compound of formula (I);

[0013] or a salt thereof, or a mixed salt thereof, wherein:

[0014] A is selected from:

[0015]

[0016] R 1 , R 2 , R 3 , R 4 and R 5 independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, and

[0017] R 6 and R 7 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 6 and R 7 Together = O;

[0018] R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl;

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

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

[0021] The condition is that if A is And R 5 is methyl, then R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 cannot all be H; and

[0022] Optional substrate,

[0023] Among them, THR products contain absolutely no (R) or (S) nicotine.

[0024] In various embodiments, the THR product further comprises at least one excipient, optionally at least one organic acid, optionally at least one chemosensory stimulant, and combinations thereof.

[0025] In various 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, and a preservative. The excipient and optional substrate contribute to the physical form or function of the THR product.

[0026] In various embodiments, the substrate is selected from nonwoven fabrics, latex, rubber or fabric swatches, wood chip strips, and ropes or tapes, such that the THR product is in the form of an oral alkaloid dispensing pouch, a transdermal or topical THR or pain relief patch, an impregnated toothpick, or an impregnated dental floss or tape, a coated dental floss or tape. DETAILED DESCRIPTION

[0027] Although the embodiments are described in sufficient detail to enable those skilled in the art to implement the invention, it should be understood that other embodiments may also be implemented and logical, chemical and mechanical changes may be made without departing from the spirit and scope of the invention. Therefore, the specific embodiments proposed are for illustrative purposes only and are not intended to be limiting. For example, unless otherwise specified, the steps described in any method or process description may be performed in any order and are not necessarily limited to the proposed order. In addition, the singular mentioned includes plural embodiments, and the more than one component or step mentioned may include a singular embodiment or step. Moreover, any attachment, fixing, connection, etc. mentioned may include permanent, removable, temporary, partial, complete and / or any other possible attachment options. In addition, any contactless (or similar terms) mentioned may also include reduced or minimized contact.

[0028] In various embodiments of the present disclosure, products and methods for tobacco harm reduction (THR) and related pain relief as part of THR are disclosed, wherein each product form includes at least one substituted pyridine compound, and wherein each product is completely free of (R) or (S) nicotine. In various examples, product forms include, but are not limited to, dissolving films, lozenges, chewing gums, transdermal patches, oral pouches, impregnated toothpicks, impregnated dental floss, mouthwashes, soft candies and other candies, sublingual disintegrating tablets, topical creams, and pain relief patches. In various examples, the THR method includes the use of a combination of THR products simultaneously or sequentially.

[0029] Definitions and Explanations:

[0030] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those of ordinary skill in the chemical field and medicinal chemistry field to which the present disclosure relates. Although any method and material similar or equivalent to the method and material described herein can be used to implement or test the subject matter of the present disclosure, preferred methods and materials are described. According to the convention in organic chemistry, chemical structures with chiral centers are either illustrated with substituents connected by wavy bonds, or are not illustrated three-dimensionally with wedges or dotted bonds, or are not marked (R) or (S) near the chiral center or in the corresponding structure name, which is considered to represent two enantiomers. Throughout the disclosure, attempts are made to mark chiral centers with asterisks (*), at least to remind readers that the carbon marked with (*) is a chiral center and can have (R) or (S) configuration on the (*) center. Chemical structures with multiple chiral centers are not presented or marked as having any specific chirality in a three-dimensional manner, and such chemical structures are considered to include all possible stereoisomers. The compounds of the present disclosure include any physicochemical or stereochemical forms they may assume, such as isomers, prodrugs, active metabolites, tautomers, stereoisomers, regioisomers, solvated forms, salts and polymorphic forms. Amorphous forms lack a distinguishable crystalline lattice and therefore lack an ordered arrangement of structural units.

[0031] As used herein, the term "tobacco harm reduction" or "THR" refers to any product ("THR product") or any method ("THR method") designed to help individuals quit smoking and thereby reduce harm to their own bodies. THR products according to the present disclosure include, but are not limited to, dissolving films, lozenges, chewing gum, transdermal patches, oral bags, impregnated toothpicks, impregnated dental floss, mouthwashes, soft candies and other candy forms, sublingual disintegrating tablets, topical pain relief creams, sprays and patches. The THR method includes the use of one or more of these product forms by individuals who wish to quit smoking. For the purposes of this article, pain relief is defined as a subcategory of THR, and therefore includes THR products and methods based on pain relief. THR products specifically used for pain relief include, but are not limited to, topical creams, topical sprays and pain relief patches. In various embodiments, these topical products and other topical products can provide pain relief by transdermal delivery of pain relief alkaloids, even if the product can be applied topically. In various methods of THR, individuals can use oral THR products and topical creams at the same time. Each THR product in this article contains alkaloids, and nicotine is explicitly absent from each product.

[0032] As used herein, the term "alkaloid" adopts its ordinary meaning in organic, pharmaceutical and natural product chemistry, meaning an organic compound containing a nitrogen atom, without further distinguishing whether the compound is naturally occurring or synthetically prepared. The tobacco harm reduction (THR) product of the present disclosure comprises a substituted pyridine alkaloid, which can be in the form of a free base compound (unprotonated), or partially or completely protonated by an acid also included in the composition, depending on the molar equivalent of the acid provided, and is therefore present in various THR products at least partially or even completely in the form of a salt. The salt of the alkaloid includes any salt derived from an inorganic acid or an organic acid, or a combination thereof, preferably a salt derived from an organic acid. Examples of inorganic salts include, but are not limited to, salts of hydrobromide, hydrochloric acid, nitric acid, phosphoric acid and sulfuric acid. Examples of organic acid salts include, for example, salts of formic acid, acetic acid, trifluoroacetic acid, aspartic acid, butanoic acid, butyric acid, 2-methylbutyric acid, 3-methylbutyric acid, benzoic acid, caprylic acid, citric acid, crotonic acid, ethylenediaminetetraacetic acid (EDTA), fumaric acid, gluconic acid, glutamic acid, glyceric acid, glycolic acid, lactic acid, lauric acid, levulinic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, oxalic acid, phenylacetic acid, phthalic acid, picric acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, tartronic acid, valeric acid, and any combination thereof, or any other such acid currently known or yet to be discovered or synthesized. Such alkaloid salts can be prepared by reacting the free base compound of the alkaloid with a suitable acid or mixture of acids in a manner known to those skilled in the art. When a mixed acid is reacted with an alkaloid disclosed herein to prepare an alkaloid salt, no attempt is made to quantify the resulting mole percentage of each individual alkaloid salt, but the resulting alkaloid salt is referred to as a "mixed salt." Therefore, the THR products herein are disclosed as comprising a substituted pyridine compound, or a salt thereof, or a mixed salt.

[0033] As used herein, the term "alkyl" refers to a linear or branched monovalent saturated hydrocarbon substituent, which is optionally substituted with one or more functional groups at any position on or in the substituent. Unless otherwise specified, an alkyl group may contain any number of carbon atoms, for example, C 1 -C 24 , C 1 -C 18 , C 1 -C 10 , C 1 -C 8 or C 1 -C 6. Examples of alkyl substituents include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, octadecyl, dodecyl, and the like. The alkyl substituents herein may be substituted, i.e., have one or more substituents appended to the alkyl group or incorporated into the alkyl chain. Substitutions within the alkyl substituent chain may include ether, thioether, amino, or imine linkages, i.e., for example, -O-, -S-, -N(R')-, or -N=, or some other intervening heteroatom. Examples of substitutions on alkyl substituents include, but are not limited to, -CN, -N 3 、-NH 2 、-NHR'、-N(R') 2 、-NO 2 、-NH-NH 2 、-NH-NHR'、-NH-NR' 2 , -halogen, -SH, -SR', -S(=O)R', -SO 2 R', -OPO 3 2- ,-PO 3 2- , -OH, -OR', -C(=O)R', -OC(=O)R', -CO 2 R', -NHC(=O)R', -NR'C(=O)R', -C(=O)NHR', -C(=O)NR' 2 , alkyl, alkenyl, cycloalkyl, heterocyclyl and aryl, wherein each R' above is independently selected from hydrogen-H and alkyl moieties, including, for example, C 1-6 Alkyl (e.g. -CH 3 , -C 2 H 5 , -isopropyl, -tert-butyl, etc.), C 1-6 Alkoxy (e.g. -OCH 3 、-OC 2 H 5 ), halogenated C 1-6 Alkyl (e.g. -CF 3 , -CHF 2 、-CH 2 F) and halogenated C 1-6 Alkoxy (e.g., -OCF 3 、-OC 2 F 5 ). In various examples, two R's of any of these functional groups may form a ring structure.

[0034] As used herein, the term "cycloalkyl" includes any 3, 4, 5, 6, 7 or 8-membered saturated or unsaturated non-aromatic carbocyclic ring, optionally substituted with one or more functional groups at any position on the ring substituent. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-, 2- or 5-cyclopentadienyl, cyclohexyl, 1-, 3- or 4-cyclohexenyl, 1-, 2- or 5-(1,3-cyclohexadienyl), 1- or 3-(1,4-cyclohexadienyl), cycloheptyl, 1-, 3-, 4- or 5-cycloheptenyl, cyclooctyl, etc. Examples of substitutions on cycloalkyl substituents include, but are not limited to, -CN, -N 3 、-NH 2 、-NHR'、-N(R') 2 、-NO 2 、-NH-NH 2 、-NH-NHR'、-NH-NR' 2 , -halogen, -SH, -SR', -S(=O)R', -SO 2 R', -OPO 3 2- ,-PO 3 2- , -OH, -OR', -C(=O)R', -OC(=O)R', -CO 2 R', -NHC(=O)R', -NR'C(=O)R', -C(=O)NHR', -C(=O)NR' 2 , alkyl, alkenyl, cycloalkyl, heterocyclyl and aryl, wherein each R' above is independently selected from -H and alkyl moieties, including, for example, C 1-6 Alkyl (e.g. -CH 3 , -C 2 H 5 , -isopropyl, -tert-butyl, etc.), C 1-6 Alkoxy (e.g. -OCH 3 、-OC 2 H 5 ), halogenated C 1-6 Alkyl (e.g. -CF 3 , -CHF 2 、-CH 2 F) and halogenated C 1-6 Alkoxy (e.g., -OCF 3 、-OC 2 F 5 ).

[0035] As used herein, the term "alkenyl" refers to a straight or branched monovalent or divalent unsaturated hydrocarbon substituent, which is optionally substituted with one or more functional groups at any position on or in the substituent. 2If a carbon is part of a molecule bearing an alkenyl substituent, the alkenyl substituent may be considered divalent. An illustrative example is methylenecyclohexane, which may be considered to be replaced by methylene (i.e., a divalent alkenyl substituent =CH 2 Unless otherwise specified, an alkenyl group may contain any number of carbon atoms, for example, C 1 -C 24 , C 1 -C 18 , C 1 -C 10 , C 1 -C 8 or C 1 -C 6 , and includes any degree of unsaturation. Examples of alkenyl substituents include, but are not limited to, methylene / methylidine (=CH 2 ), vinyl / ethylidene (-CH=CH 2 or =CH-CH 3 )), propenyl / propylidene (-CH 2 -CH=CH 2 , cis or trans -CH=CH-CH 3 =C(CH 3 ) 2 , either cis or trans = CH-CH 2 CH 3 ) and the like. The alkenyl substituents herein may be substituted, i.e., have one or more substituents attached to the alkenyl or incorporated into the alkenyl chain. Substitutions within the alkenyl substituent may include ether, thioether, amino or imine linkages, i.e., for example, -O-, -S-, -N(R')- or -N=, or some other intervening heteroatom. Examples of substitutions on the alkenyl substituent include, but are not limited to, -CN, -N 3 、-NH 2 、-NHR'、-N(R') 2 、-NO 2 、-NH-NH 2 、-NH-NHR'、-NH-NR' 2 , -halogen, -SH, -SR', -S(=O)R', -SO 2 R', -OPO 3 2- ,-PO 3 2- , -OH, -OR', -C(=O)R', -OC(=O)R', -CO 2 R', -NHC(=O)R', -NR'C(=O)R', -C(=O)NHR', -C(=O)NR' 2, alkyl, alkenyl, cycloalkyl, heterocyclyl and aryl, wherein each R' above is independently selected from an alkyl moiety, including, for example, C 1-6 Alkyl (e.g. -CH 3 , -C 2 H 5 , -isopropyl, -tert-butyl, etc.), C 1-6 Alkoxy (e.g. -OCH 3 、-OC 2 H 5 ), halogenated C 1-6 Alkyl (e.g. -CF 3 , -CHF 2 、-CH 2 F) and halogenated C 1-6 Alkoxy (e.g., -OCF 3 、-OC 2 F 5 ). In various examples, two R's of any of these functional groups may form a ring structure.

[0036] As used herein, the term "electronic cigarette" or "ENDS" (electronic nicotine delivery system) generally refers to any such electronic device that is capable of vaporizing a liquid composition into a vapor that can be inhaled by an individual using the device. Without limiting, "electronic cigarette" herein refers to any design, such as a cigar, an vape pen, or any other electronic device, which is refillable or disposable, having a reservoir to hold a vaporizable liquid therein and having the ability to vaporize the vaporizable liquid. For simplicity, the term "electronic device" may be used to refer to any and all refillable and disposable devices used for smoking electronic cigarettes.

[0037] As used herein, the term "throat hit" refers to the sensory effect experienced in the back of the throat as a dissolved irritant enters the throat, as perceived by an individual inhaling vapor, such as vapor obtained from a burning cigarette or vapor delivered from an electronic device such as an e-cigarette, or resulting from the dissolution of a stimulant-containing product in the mouth, such as a dissolving strip or lozenge. Throat hit is an irritating "tingling" experienced in the back of the throat that, prior to the development of e-cigarettes, was not only experienced by smokers, but also expected and enjoyed by smokers. Although subjective rather than objective, throat hit can be quantified through the use of a sensory panel, for example, where participants in the panel rank the perceived throat hit on a scale of 1-10, or compare throat hits between products and / or between THR products relative to traditional cigarettes. In some instances, throat hit can be quantified as being less than, equal to, or greater than the throat hit experienced from a particular cigarette in comparison. An exemplary cigarette for use in standardizing throat hit, such as for use in a sensory panel where participants rank throat hit, is the PHILIPS® available from Phillips IGA. Filter cigarette, Gold Pack 100. As explained herein, a throat hit sensation in an individual can generally be achieved by including a chemosensory stimulant in various THR products of the present disclosure, particularly by using a flavor additive as a chemosensory stimulant. In some examples of THR products, including all pain relief THR products, chemosensory stimulants may not be included in the product.

[0038] As used herein, the term "vaping" refers to the act of using an electronic cigarette or other ENDS device to inhale vapor electronically generated by evaporation of a liquid composition. Vaping is considered to be an act similar to smoking tobacco products, and it is understood that electronic cigarettes and vaping are not limited to nicotine. Vaping can include an individual inhaling nicotine analogs, other physiologically active substances, flavorings, etc.

[0039] As used herein, the term "dizziness" refers to the dizziness experienced by smokers and e-cigarette users who inhale nicotine, nicotine analogs, and other products containing physiologically active substances. Smokers describe this sensory experience as a buzz in the head or a surge of adrenaline. This sensory effect is believed to be caused by nicotine or other drugs in the blood and brain triggering the release of adrenaline, which in turn causes the blood vessels of the person who inhaled the active substance to tighten, and the heart rate and blood pressure to temporarily increase. This sensory experience is personal, and due to differences in physiological tolerance, it varies between drug active substances and between individuals. Dizziness may occur within 10 seconds after inhaling nicotine and may last up to 10-30 minutes. However, as smokers or e-cigarette users continue to smoke or smoke e-cigarettes, they become more tolerant, and the dizziness they often experience becomes shorter over time. Although subjective rather than objective, the dizziness can be quantified by using a sensory panel, for example, participants in the panel rank the perceived dizziness on a scale of 1-10, or compare the perceived dizziness between alternative products relative to traditional cigarettes. In some instances, the dizziness can be quantified as less than, equal to, or greater than the dizziness experienced from a particular cigarette. An exemplary cigarette for standardizing throat hit, such as for use in a sensory panel where participants rank throat hit, is available from Phillips IGA Filter cigarette, Gold Pack 100. In various examples herein, the THR product includes a non-nicotine alkaloid capable of stimulating nicotinic acetylcholine receptors (nAChRs) and thereby providing a dizzy sensation similar to that of inhaling nicotine.

[0040] As used herein, the term "chemical sensory irritant" has the common meaning in physiology and neuroscience, i.e., a substance that can show sensory stimulation in an individual exposed to the substance. Depending on the individual and the irritant, the stimulation caused by the chemical sensory irritant during inhalation can be perceived in the nose, mouth, throat, esophagus and / or lungs. The sensory effect in the throat is referred to as "throat hit" in the definition of this article. Chemical sensory stimulation is studied the most in the context of environmental and occupational health and safety, involving such as air pollutants and indoor environmental irritants (e.g., formaldehyde), etc. See, for example, "Inhalation Toxicology", 2nd edition, edited by H. Salem et al., Taylor & Francis Group (Taylor & Francis Group) (CRC), 2006. In addition to subjective measures of chemosensory irritation (e.g., panelists answering symptom questionnaires), various experimental techniques can be used to study chemically induced irritation, such as examination of functional changes, such as changes in respiratory rate and pattern, nasal, bronchial and lung function parameters, nasal mucosal swelling, acoustic rhinography, blink rate, tear film stability, and chemosensory evoked potentials in humans and experimental animals (see SKKjaergaar et al., "The Assessment of Irritation Using Clinical Methods and Questionnaires," American Industrial Hygiene Association, 62(6):711-6, November 2001).

[0041] Optionally, the chemosensory stimulants included in some THR products of the present disclosure include those compounds that can cause physiological stimulation to any one of the nose, oral cavity, throat, esophagus and lungs of an individual, wherein the physiological stimulation is quantifiable. Examples of quantitative methods include, but are not limited to, measuring nasal mucosal swelling, peak airflow through the nose, acoustic rhinography, and nasal stereometry for measuring the thickness of the anterior turbinate. Questionnaires can also be used to define a set of symptoms to characterize the dose-response relationship in controlled exposure studies.

[0042] In various embodiments, the chemosensory stimulants optionally used in the various THR products herein are substances capable of activating chemosensory ion channels known as transient receptor potential channels or TRP channels, for example, as explained by HJ Son et al., "Activation of the Chemosensory Ion Channels TRPA1 and TRPV1 by Hydroalcohol Extract of Kalopanax pictus Leaves (Hydroalcoholic Extract of Aralia striata Leaves Activates Chemosensory Ion Channels TRPA1 and TRPV1", Biomol. Ther (Seoul), 2012 Nov; 20(6): 550-555. In addition to the subset of chemosensory stimulants defined below as "flavor additives", many seemingly unrelated compounds are receptor agonists and are able to activate one or more TRP channels (e.g., A1, V1, V2, V3, V4, V5 or V6, M1, M2, M3, M4, M5, M6, M7 or M8 ion channels, etc.), for example, oleocanthal, 4-hydroxy-2-nonenal, 4-oxo-2-nonenal, allicin, allyl isothiocyanate, gingerol (included in the subset of stimulant flavors), eserin, polygonaldialdehyde, cinnamaldehyde, trans-p-methoxycinnamaldehyde, various hemp compounds, methyl syringate, 2-chlorobenzylidene propyl dinitrile, 1-chloroacetophenone, ethyl bromoacetate, 4-hydroxyhexenal, toluene diisocyanate, p-benzoquinone, methyl p-hydroxybenzoate, flufenamic acid, niflumic acid, mefenamic acid, diclofenac, hydroxy-α-sanshool, 6-shogaol (included in the irritant fragrance subset), 6-gingerol, linalool, carvacrol, eugenol, thymol, vanillin, methyl eugenol, 2,6-dimethylphenol, 2,5-dimethylphenol, 3,4-dimethylphenol, 2,6-diisopropylphenol, caffeine, farnesylthiosalicylic acid, 4-allylanisole, curcumin, capsaicin (included in the irritant fragrance subset), nicotinic acid, nicotinamide, camphor, avanafil and avanafil. Although nicotine is a known TRPA1 activator, it is excluded from the chemosensory stimulant of any THR product within the scope of the present disclosure herein. See, for example, K. Talavera et al., "Nicotine Nicotine activates the chemosensory cation channel TRPA1", Nature Neuroscience, 12, 1293-1299 (2009). One aspect of the present disclosure is to provide a THR product, which includes a pain relief THR product that is clearly free of nicotine and can therefore be used as a substitute for smoking.

[0043] Optional chemosensory stimulants for the THR products of the present invention also include cannabinoids. In fact, some TRP receptors are called cannabinoid receptors, such as CB1 and CB2. The six ion channels TRPV1, TRPV2, TRPV3, TRPV4, TRPA1 and TRPM8 are called ionotropic cannabinoid receptors, so those cannabinoids that can bind to these receptors and activate ion channels are considered to be chemosensory stimulants for various THR products described herein. For a review of cannabinoids and TRP ion channel activation, see C. Muller et al. "Cannabinoid Ligands Targeting TRP Channels", Front. Mol. Neurosci., 11, 487 (2019).

[0044] Cannabinoids (endogenous, plant and synthetic) that are capable of activating TRP ion channels and therefore can be used as chemosensory stimulants in certain THR products of the present disclosure include, but are not limited to, anandamide (AEA), 2-AG, NADA, OLDA, PEA, NGABA, NGly, NAsp, NSer, Δ 9 -Tetrahydrocannabinol (Δ 9 -THC), Δ 9 -THCA, Δ 9 -THCV, Δ 9 -THCVA, CBD, CBDA, CBDV, CBG, CBGA, CBGV, CBN, CBC and synthetic cannabinoids WIN55,212-2, AM630, (R)-AM1241, (S)-AM1241, SR141716A, Gp-1a, AM251, SR144528, JWH133, HU308, HU910, CP55,940 and Nabilone. Of particular importance here is CBD (cannabidiol), which has been found to be the most potent and effective plant cannabinoid agonist of TRPV1. Moreover, Δ 9 -THC has been identified as the most potent phytocannabinoid for activating TRPV2, although 9 -THC is not selective because it also activates TRPA1. Cannabinoids may also be included in the THR pain relief products herein because they have both local and systemic effects in relieving body pain.

[0045] In addition, chemosensory stimulants that activate TRP ion channels and are therefore optionally used in certain THR products herein include a variety of compounds naturally present in various plants, trees, shrubs, roots, flowers, fruits, seeds and nuts. Such compounds are described, for example, in "Herbal Compounds and Toxins Modulating TRP Channels" by J. Vriens et al., Curr. Neuropharmacol., March 2008; 6(1): 79-96. In various embodiments, in addition to the "spice additives" defined and discussed herein, including compounds such as capsaicinoids, gingerols, and shogaols, other TRP channel activators may also be used herein and include, but are not limited to, resinoids from Euphorbia reinifera, eugenols from Euenia carophyllata and Ocimum gratissiumum, ginsenosides from Panax, zingerone and shogaols derived from heated or dehydrated gingerols or from seeds of Aframomum melgueta, evodia compounds from Evodia rutaecarp, various unsaturated 1,4-dialdehyde sesquiterpenes isolated from Drymis winteri, such as polygonal aldehyde, isocyanuric acid aldehyde, and drimanial aldehyde, from Cinnamomum serrata. Other 1,4-dialdehydic terpenes from the family of fragrans, such as cinnamodial, cinnamosmolide and cinnamolide, or warbuganal from the Warburgia plant.In vitro assays for measuring TRP ion channel activation can be found, for example, in R. Lehmann et al., “Alternative in vitro assays to assess the potency of sensory irritant–Is one TRP channel enough?” Neurotoxicolog, May 2017;60:178-186; JM Martinez et al., “Activation of TRPA1 by volatile organic chemicals leading to sensory irritation,” ALTEX 2019;36(4):572-582. Of more importance for use herein are the phytochemicals present in Scutellaria baicalensis (most particularly the phytochemicals baicalein, baicalin, wogonin, norwogonin, melaleucain A and beta-sitosterol), in Vitex agnus, Pterodon pubescens, Croton macrostachyus, Angelica epubescentis, Ephedra sinica, Amphilophium crucigerum, Bosewellia carterii, Commiphora myrrha, Echinophora platyloba, Nypa fruticans, Zingiber officiale (under the subset of irritant flavor additives), Corydalis saxicola, Coptis chinensis, Phytochemicals in Psoralea chinensis, Ononis spinosa, Parkia platycephala, Piper nigrum (under the irritant flavor additive subset), and Cymbopogon citratus. Chemoreceptor stimulants for use herein can be evaluated first by in vitro non-animal sensory irritation assays, followed by consumer sensory panels to evaluate subtle physiological effects and determine dosage levels and user acceptance.

[0046] The term "flavor additive" as used herein refers to an organic substance that is capable of producing a throat hit or other similar "hot," "irritating," or other "burning" sensation at least in the back of the throat and optionally in the oral cavity and on the lips, which occurs when flavor additives are present in certain THR products used by individuals (e.g., people who experience dissolving strips or sucking on lozenges or flavored toothpicks). The flavor additives herein form a subset of chemosensory stimulants and are known to activate one or more TRP ion channels. Since these groups of compounds may appear structurally unrelated at first glance, the "flavor additives" herein can be specifically defined as organic substances having a spiciness or "heat" ranging from about 1,000 to about 20,000,000 Scoville heat units (SHU). At the lower end of the Scoville scale, the compounds used herein include, but are not limited to, gingerol (60,000 SHU), piperine (100,000 SHU), and shogaol (160,000 SHU). In a more preferred embodiment, the flavor additives optionally used in certain THR products herein will have a Scoville rating of about 100,000 to about 20,000,000 SHU, more preferably about 10,000,000 to about 20,000,000 SHU, and will include all known capsaicinoids, such as capsaicin (16,000,000 SHU) and dihydrocapsaicin (15,000,000 SHU), as well as uncharacterized capsaicinoids that may be isomers of known capsaicinoids. Although chemically unrelated to capsaicinoids, compounds such as piperine (100,000 SHU) and shogaol (160,000 SHU) can be used in the compositions of the present invention. Capsaicinoid flavor additives used herein include, but are not limited to, capsaicin, dihydrocapsaicin, norcapsaicin, nordihydrocapsaicin, homocapsaicin, homodihydrocapsaicin, and mixtures thereof. Chemically pure or otherwise isolated capsaicin is not necessary for the THR products herein, as it is also convenient to prepare THR products with extracts of spice additives. For example, capsaicinoids can be extracted from chili peppers or other peppers using room temperature or boiling ethanol (e.g., in a Soxhlet extractor). The resulting red ethanol solution can then be used directly (referred to as "capsaicinoid liquid" or "liquid capsaicin") or evaporated to leave a thick, deep red mixture of capsaicinoids (the red color is believed to come from beta-carotene).See, e.g., F. Martins et al., "Novel Approaches to Extraction Methods in Recovery of Capsaicin from Habanero Pepper (CNPH 15.192)", Pharmacogn. Mag. 2017 Jul; 13(Suppl 2): ​​S375-S379 and Y. Zhu, "Multi-Dimensional Pungency and Sensory Profiles of Powder and Oil of Seven Chili Peppers Based on Descriptive Analysis and Scoville Heat Units", Food Chemistry, 411, June 15, 2023, Article 135488.

[0047] As used herein, the term "liquid capsaicin" or "capsaicin liquid" refers to an ethanol extract or other solvent extract of the fruit obtained from a plant of the genus Capsicum annuum (e.g., various peppers). Liquid capsaicin optionally used herein contains about 0.9% by weight of capsaicinoids in ethanol and can be purchased from Olive Nation, LLC (Avon, Massachusetts) under the name Capsicum Flavor Extract. Such liquid extracts are easily added to the alkaloid compositions used in various THR products herein.

[0048] It should be noted that "flavoring agents" are defined separately and distinctly from "chemical sensory stimulants" and the subset of stimulants referred to herein as "flavor additives." In various instances of THR products, the inclusion of flavoring agents into the THR product may also be more important than chemical sensory stimulants.

[0049] As used herein, "flavoring agent" adopts its common meaning in food science, but it should be noted that the flavoring agent herein intentionally excludes compounds containing capsaicinoids, which means that the flavoring agent herein does not have a measurable or calculable Scoville heat rating according to definition, and is therefore different from the spice additive defined above. The flavoring agent used for this article includes but is not limited to ethyl maltol, ethyl butyrate, ethyl acetate, maltol, ethyl vanillin, furanol, methylcyclopentenol ketone, δ-decanoic acid, γ-decanoic acid, cis-3-hexanol, isoamyl acetate, ethyl 2-methylbutyrate, butyric acid, linalool, benzyl alcohol, ethyl caproate, benzaldehyde, isoamyl isovalerate, caproic acid, ethyl propionate, γ-undecanoic acid and hexyl acetate. Flavoring agents are more important for some THR products than other substances. For example, THR toothpicks may rely heavily on flavoring agents, while transdermal THR patches do not need flavoring agents at all.

[0050] As used herein, the term "about" refers to a quantity, level, value, amount, frequency, percentage, size, size, content, weight, or length that varies by up to 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1% relative to a reference quantity, level, value, amount, frequency, percentage, size, size, content, weight, or length. For example, a content expressed as "about 5% by weight" includes variations of up to 4.5% to 5.5%.

[0051] As used herein, the term "smoking cessation program" refers to a program provided by a medical clinic, pharmacy, or any other commercial enterprise to a current smoker to help the individual stop smoking. In various embodiments, the smoking cessation program herein includes providing a THR product or a combination of THR products to an individual in need, which is designed to help the individual comply with the prescribed program and reduce and / or ultimately eradicate smoking and its associated tobacco hazards. In some instances, the clinic, pharmacy, or other enterprise will meet with the individual undergoing the smoking cessation program on a regular basis, interview them about their compliance, and provide the individual with customized THR products and combinations thereof that gradually push the smoker to completely switch to non-nicotine products. In various instances, the clinic, pharmacy, or other enterprise will meet with the individual to manage perceived physical pain by prescribing a combination of THR products.

[0052] As used herein, the term "transdermal patch" refers to any viscous combination configured to adhere to the skin of an individual and deliver a physiologically effective amount of solubilized (solubilized) alkaloids through the skin of the individual. The combination can be a physical form of a flexible strip, comprising a desired amount of solubilized alkaloids and one or more optional active substances or excipients. For purposes herein, a transdermal patch can be a THR product or a pain relief THR patch.

[0053] General Implementation

[0054] In various embodiments of the present disclosure, THR products and THR pain relief products are described. Each category of products can be used alone at different times, or can be used in combination at the same time. For example, in a combination method of THR, an individual can use an oral smoking cessation THR product while the individual also uses a THR product disclosed herein to relieve pain.

[0055] The THR products and THR pain relief products according to the present disclosure have a common core technology, that is, each product comprises a substituted pyridine compound.Depending on the physical form of the THR product, the THR product may optionally comprise a chemical sensory stimulant.

[0056] Tobacco harm reduction products and methods

[0057] 1a. Transdermal patches

[0058] In various embodiments, a tobacco harm reduction (THR) product in the form of a transdermal patch comprises:

[0059] at least one substituted pyridine compound of formula (I);

[0060] or a salt thereof, or a mixed salt thereof, wherein:

[0061] A is selected from:

[0062]

[0063] R 1 , R 2 , R 3 , R 4 and R 5 independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, and

[0064] R 6 and R 7 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 6 and R 7 Together = O;

[0065] R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl;

[0066] n is an integer from 1 to 10; and

[0067] R 15 and R 16 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 15 and R 16 Together with the N atom to which they are bound, they form a 3-8 membered optionally substituted heterocyclic ring,

[0068] The condition is that if A is And R 5 is methyl, then R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 cannot all be H; and

[0070] wherein the substituted pyridine compound and the solubilizing agent comprise a solubilizing alkaloid mixture disposed on the surface of the substrate, and

[0071] The solubilized mixture contains no (R) or (S) nicotine.

[0072] In various embodiments, the tobacco harm reduction (THR) product further comprises at least one solubilizing agent; and a substrate.

[0073] In various embodiments, the solubilized substituted pyridine compound further comprises at least one organic acid such that the molar ratio of moles of substituted pyridine compound to moles of total organic acid is from about 25: 1 to about 75: 1. Organic acids as used herein are described below and in the definitions.

[0074] In various embodiments, the weight content of the substituted pyridine compound per patch is from about 1 mg to about 50 mg. A sufficient amount of solubilizer is used to dissolve the desired amount of alkaloid into an oily mixture or paste that is easily layered onto the surface of the substrate.

[0075] In various embodiments, the substrate has dimensions ranging from about 1 inch by 1 inch square up to about 2 inches by 2 inches square and is less than about 1 / 8 inch thick. Other shapes are envisioned, such as circular or rectangular, and other practical sizes for use on the skin.

[0076] In various embodiments, the substrate comprises a sample of a fabric, nonwoven material, or a plastic, rubber, or latex sheet. In some examples, an adhesive is provided around an outer portion of the sample, and a solubilizing mixture is provided near the center of the sample, on the same side, and spaced apart from the edge of the adhesive.

[0077] In various embodiments, the solubilizing agent is selected from partially hydrogenated or fully hydrogenated vegetable oils, such as soybean oil, olive oil, sesame oil, palm oil, coconut oil, etc. The solubilizing agent can also be a fraction of the following: fatty acids, fatty acid mixtures, monoglycerides, diglycerides or triglycerides of fatty acids, wherein the fatty acids and / or glycerides can have a specific chain length distribution (e.g., short chain, medium chain, or long chain fatty acids). Particularly used herein is "medium chain triglycerides" (or "MCT"), which refers to triglycerides of fatty acids having about 6 to about 12 carbon atoms, such as any combination of triglycerides of caprylic acid, caproic acid, lauric acid and / or capric acid (i.e., C 6 -C 12 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 transdermal THR compositions herein can be obtained from, for example, Specialized Rx Products, LLC (Circle Pines, Minnesota). Organic MCT oil fractionated coconut oil (caprylic / capric triglycerides), CAS Nos. 73398-61-5 and 65381-09-1, are also used herein, with a specific gravity of about 0.930-0.960 g / mL (typically 0.951 g / mL on average).

[0078] In various embodiments, the transdermal patch further comprises a permeation enhancer to solubilize the alkaloid mixture.

[0079] In various embodiments, the transdermal patches herein are prepared by methods well known in the art and are limited only by the alkaloid loading capacity of the respective transdermal technology employed.

[0080] For example, one common transdermal technology includes polymer matrix design, wherein the polymer matrix can be prepared using natural polymers, including, for example, but not limited to, cellulose derivatives, zein, gelatin, shellac, waxes, proteins, gums and their derivatives, natural rubber, starch, etc.; synthetic elastomers including, for example, but not limited to, polybutadiene, polyisobutylene, hydrogenated rubber, polysiloxanes and other silicone pressure-sensitive adhesives available from Dow Corning (Elizabethtown, Kentucky), silicone rubber, nitrile-containing compounds, acrylonitrile, butyl rubber, styrene-butadiene rubber, chloroprene rubber, etc.; synthetic homopolymers or copolymers including, for example, but not limited to, polyvinyl alcohol, polyvinyl chloride, polyethylene, polypropylene, polyacrylates, polystyrene, polyamides, polyureas, polyvinyl pyrrolidone, polymethyl methacrylate, epoxy resins, polyethylene / vinyl acetate, etc.

[0081] The substituted pyridine compound of at least one formula (I) is applied to the substrate and / or added, and in some instances, a penetration enhancer, at least one solvent and / or at least one surfactant are applied and / or added. Adhesive is used to fix the substrate portion of the transdermal patch to the skin of an individual. Such adhesive can be fixed to the substrate as a layer, or as one of the components for preparing the substrate, and the substrate is applied to the patch substrate as a layer. Other substrate technologies may include crystallization inhibitors and other acceptable excipients. Matrix technology can also be developed into a monolayer or multilayer patch. For example, referring to U.S. Patent No. 5,474,783; 5,958,446 and 6,440,454 and PCT Application Publication No. WO 97 / 43989, which are each incorporated herein by reference.

[0082] Also known in the field of transdermal patches are reservoir systems, which are characterized by typically comprising a reservoir, which is defined as a compartment containing a solubilized or suspended substituted pyridine compound, which is separate and distinct from the release liner. Various adhesive systems can also be used for reservoir-type systems. When a large amount of alkaloid loading is required, a reservoir system is typically the preferred system. For example, see U.S. Patent Nos. 7,387,789; 5,656,286; 8,114,434; 6,024,976 and PCT Patent Publication Nos. 2012 / 0269878 and 2012 / 0283671, each of which is incorporated herein by reference.

[0083] Other transdermal patch technologies include, but are not limited to, iontophoresis, electroporation, ultrasound / sound wave penetration, and microprotrusions (e.g., microneedles) (see Patel, D. et al., The Pharma Innovation, Transdermal Drug Delivery System: A Review, Vol. 1, No. 4, pp. 66-75 (2012)). Any of these and other transdermal systems can be used to prepare solubilized alkaloid transdermal patches.

[0084] 1b. Dissolving film

[0085] In various embodiments, the THR dissolving film is a mucoadhesive film that further comprises a substituted pyridine compound in combination with a water-soluble and / or water-dispersible polymer, a polyol, a surfactant, and other ingredients. Optionally, the THR dissolving film includes a chemical sensory stimulant, such as a flavoring additive, to provide a throat hit or other oral experience. Optionally, the THR dissolving film includes a flavoring agent.

[0086] In various embodiments, a mucoadhesive film configured for oral use comprises:

[0087] at least one substituted pyridine compound of formula (I);

[0088] or a salt thereof, or a mixed salt thereof, wherein:

[0089] A is selected from:

[0090]

[0091] R 1 , R 2 , R 3 , R 4 and R 5 independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, and

[0092] R 6 and R 7 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 6 and R 7 Together = O;

[0093] R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl;

[0094] n is an integer from 1 to 10; and

[0095] R 15 and R 16 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 15 and R 16 Together with the N atom to which they are bonded, they form a 3-8 membered optionally substituted heterocyclic ring,

[0096] The condition is that if A is And R 5 is methyl, then R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 cannot all be H; and

[0098] The mucoadhesive film contains absolutely no (R) or (S) nicotine.

[0099] In various embodiments, the mucoadhesive film further comprises at least one polymer, at least one polyol, optionally at least one surfactant, optionally at least one chemosensory stimulant, and combinations thereof.

[0100] In various embodiments, the dissolving film further comprises at least one organic acid such that the molar ratio of the moles of the substituted pyridine compound of formula (I) to the moles of the total organic acid is from about 25: 1 to about 75: 1. The organic acids used herein are described below and in the definitions.

[0101] In preferred examples, the mucoadhesive film in the form of a mini-strip is configured to completely dissolve in the oral cavity of a subject immediately or in no more than about 15-30 seconds.Each mini-strip may contain about 1 mg to about 10 mg of a substituted pyridine compound of formula (I).

[0102] In various embodiments, the polyols used herein include, but are not limited to, glycerol, 1,2-propylene glycol, 1,3-propylene glycol, polysaccharides, and sugar alcohols. Exemplary polysaccharides include pullulan and carrageenan.

[0103] In various embodiments, polymers useful in the mucoadhesive films herein include various hydrophilic and water dispersible gums, cellulosic materials, starches, and synthetic polymers.

[0104] In various embodiments, the polymers used herein include, but are not limited to, agar, gum arabic, agarose, albumin, alginate, gum arabic, casein, chitin, chondroitin, dextrin, fibroin, fucoidan, galactan, gellan gum, guar gum, scleroglucan, pullulan, xyloglucan, pectin, xanthan gum, tragacanth gum, psyllium, cellulose, cellulose acetate, hyaluronic acid, elastin-like polypeptide, β-cyclodextrin, collagen, gelatin, chitosan, carrageenan, polylactic acid, polyglycolic acid, poly(lactic-glycolic acid) (PLGA), poly(2-hydroxyethyl methacrylate), poly(2-hydroxypropyl methacrylate), polyacrylic acid, carboxymethyl cellulose, carboxyethyl cellulose, hydroxyethyl cellulose, hydrophobically modified hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, microcrystalline cellulose, nitrocellulose, polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl methacrylate, carboxyvinyl polymer, polyvinyl acetate, polyvinyl copolymer, starch, modified starch, polyethylene glycol (PEG) and mixtures thereof.

[0105] The mucoadhesive film according to the present disclosure comprises from about 20 wt % to about 75 wt % of the polymer, more preferably from 50 wt % to about 75 wt % of the polymer, based on the total weight of the film.

[0106] In various embodiments, the mucoadhesive film herein may optionally include at least one surfactant, such as one or more nonionic surfactants. Surfactants include, but are not limited to, sugar esters, such as those sold under the trade name Sorbitan fatty acid esters sold under the trade name Polyethoxylated (POE) sorbitan fatty acid esters are commercially available. Of particular interest herein is polysorbate 80, C 64 H 124 O 26 (Can be used as 80), which is an ethoxylated sorbitan monooleate having a total of about 20 (POE) units. Other polysorbates, such as lauryl esters instead of oleate, and other (POE) levels, may also be used herein. Polysorbates and sorbitan esters suitable for use as surfactants in the mucoadhesive films herein may be obtained, for example, from BASF Pharma, Florham Park, New Jersey.

[0107] In various embodiments, a THR mucoadhesive film may further comprise a plasticizer.

[0108] The THR mucoadhesive film according to the present disclosure can be prepared as follows. Polyols, optional surfactants and plasticizers and other ingredients except polymers are dissolved in a sufficient amount of compatible solvents such as water, alcohol or its mixture. After forming a clear solution, slowly add polymer or polymer mixture under stirring, heat if necessary, until a clear and uniform solution is formed, and then add the substituted pyridine compound and flavoring agent, preservative, etc. of the selected formula (I). The resulting solution is evenly coated on a suitable carrier material, such as with a scraper, and dried to form a film. The carrier material preferably has a surface tension that allows the polymer solution to spread and dry and can eventually be removed from the carrier material. Examples of suitable substrate materials include non-siliconized polyethylene terephthalate film, non-siliconized kraft paper, polyethylene impregnated kraft paper and non-siliconized polyethylene film. Applying the polymer solution to the carrier material can be carried out using any conventional coating equipment, such as a scraper coating method on a roller.

[0109] The thickness of the resulting THR mucoadhesive film depends on the concentration of alkaloids in the coating solution and is preferably about 5 to about 200 μm thick. The film is dried at ambient temperature or under heating. For a suitable mouthfeel, the THR mucoadhesive film herein is preferably <70 μm thick. In order to obtain the final THR dissolved film, the dry film is cut into sheets of suitable size and shape (e.g., 0.5 inch × 0.75 inch per sheet) and packaged in a suitable container, such as a small plastic box with a snap lid.

[0110] In various embodiments, the THR dissolving film strip also includes any combination of chemical sensory stimulants, flavoring agents, sweeteners, stabilizers, or preservatives (including antioxidants). These additional ingredients are further described below, and for many THR product forms, they are optional.

[0111] 1 c. 锭剂

[0112] In various embodiments, a THR product for oral administration includes a soluble lozenge. In certain instances, the THR lozenge is similar to a typical cough lozenge and is intended to dissolve slowly in the individual's mouth, such as over the course of several minutes.

[0113] In various embodiments, the THR lozenge comprises:

[0114] at least one substituted pyridine compound of formula (I);

[0115] or a salt thereof, or a mixed salt thereof, wherein:

[0116] A is selected from:

[0117]

[0118] R1 , R 2 , R 3 , R 4 and R 5 independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, and

[0119] R 6 and R 7 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 6 and R 7 Together = O;

[0120] R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl;

[0121] n is an integer from 1 to 10;

[0122] R 15 and R 16 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 15 and R 16 Together with the N atom to which they are bonded, they form a 3-8 membered optionally substituted heterocyclic ring,

[0123] The condition is that if A is And R 5 is methyl, then R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 cannot all be H; and

[0125] The lozenges contain absolutely no (R) or (S) nicotine.

[0126] In various embodiments, the THR lozenge further comprises a binder, a sweetener, water, and combinations thereof.

[0127] In various examples, the THR lozenge comprises from about 0.5 wt % to about 20 wt % of a binder; from about 75 wt % to about 90 wt % of a sweetener; and from about 10 wt % to about 20 wt % of water, based on the total weight of the lozenge.

[0128] In various embodiments, the binder is selected from natural gums, such as gum arabic or tragacanth, gelatin, pectin, starch, and mixtures thereof. The amount of the binder is about 0.5 wt % to about 20 wt %, preferably about 0.5 wt % to about 8 wt %, based on the total weight of the tablet.

[0129] In various embodiments, the sweetener is selected from dextrose, glucose, sucrose and mixtures thereof. Dextrose can replace the traditionally used sucrose.

[0130] In various embodiments, the lozenge further comprises at least one organic acid such that the molar ratio of moles of substituted pyridine compound of formula (I) to moles of total organic acid is from about 25: 1 to about 75: 1. Organic acids used herein are described below and in the definitions.

[0131] The THR lozenges according to the present disclosure are prepared by the following method, which includes (1) mixing a substituted pyridine compound of formula (I) and a sweetener with at least one binder in a solution, (2) kneading, rolling, and punching the resulting paste to produce lozenges, and (3) drying the obtained lozenges. In some instances, the binder is introduced into the sweetener and alkaloid mixture in several portions.

[0132] In some instances, the sweetener / alkaloid mixture is introduced into an optionally heated kneading machine with a zigzag paddle. The binder in the solution is then added to the sweetener component. Adding the binder in several portions provides a more acceptable surface condition. The binder can be added as two parts. The paste may also include flavorings, additional substituted pyridine compounds, coloring agents, and optional organic acids as described above to partially form alkaloid salts. The composition is thoroughly mixed, and the paste is then rolled, stamped, and dried in an oven at 30-50° C. for 8 to 24 hours to produce alkaloid lozenges.

[0133] In various examples, the THR lozenges may also include any combination of chemosensory stimulants, stabilizers, or preservatives (including antioxidants). These additional ingredients are further described below and are optional for many other THR product forms.

[0134] 1d. Chewing gum

[0135] In various embodiments, a THR product in the form of chewing gum is provided. For purposes herein, chewing gum can be any type of product, such as candy coated gum, beads, flat sticks of chewing gum, bubble gum, crushed bubble gum similar to chewing tobacco, short sticks of chewing gum in paper packaging similar to cigarettes, etc.

[0136] In various embodiments, the THR chewing gum comprises:

[0137] at least one substituted pyridine compound of formula (I);

[0138] or a salt thereof, or a mixed salt thereof, wherein:

[0139] A is selected from:

[0140]

[0141] R 1 , R 2 , R 3 , R 4 and R 5 independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, and

[0142] R 6 and R 7 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 6 and R 7 Together = O;

[0143] R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl;

[0144] n is an integer from 1 to 10; and

[0145] R 15 and R 16 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 15 and R 16 Together with the N atom to which they are bonded, they form a 3-8 membered optionally substituted heterocyclic ring,

[0146] The condition is that if A is And R 5 is methyl, then R 1, R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 cannot all be H; and

[0147] Water-insoluble chewing gum base,

[0148] The chewing gum contains absolutely no (R) or (S) nicotine.

[0149] In various embodiments, the THR chewing gum according to the present disclosure further comprises at least one organic acid such that the molar ratio of the moles of the substituted pyridine compound of formula (I) to the moles of the total organic acid is from about 25: 1 to about 75: 1. The organic acids used herein are described below and in the definitions.

[0150] In certain instances, the water-insoluble gum base may include elastomers, plasticizers, fillers, texturizers such as softeners, oils, thickeners, surfactants, stabilizers, coloring agents and flavoring agents. The water-insoluble gum base used herein is for example disclosed in U.S. Pat. Nos. 3,052,552 and 2,197,719.

[0151] Elastomers include, for example, polyisobutylene, isobutylene isoprene copolymers, styrene butadiene copolymers, polyvinyl acetate, polyisoprene, polyethylene, vinyl acetate vinyl laurate copolymers, natural rubber, and combinations thereof.

[0152] The water-insoluble gum base may contain elastomer plasticizers. These include, for example, natural rosin esters.

[0153] In addition, the water-insoluble gum base may include fillers, texturizing agents, softeners and emulsifiers. Softeners optimize the chewiness of the gum and optimize the mouthfeel of the gum. Commonly used softeners / emulsifiers for example include tallow, hydrogenated tallow, hydrogenated and partially hydrogenated vegetable oils, cocoa butter, glyceryl monostearate, glyceryl triacetate, lecithin and combinations thereof.

[0154] In addition to the water-insoluble gum base portion, the THR chewing gum composition herein includes a water-soluble portion. The water-soluble portion may include a substituted pyridine compound of formula (I) (e.g., emulsified in oil), a sweetener, a flavoring agent, a stabilizer, a softener, a surfactant, an emulsifier, a colorant, an acidulant, a filler, an antioxidant, and other components that optimize the user experience.

[0155] In various embodiments, water-insoluble gum bases are commercially available, for example, under the trade name Obtained from Dreyfus Company, South Plainfield, New Jersey.

[0156] In a non-limiting example, the THR chewing gum comprises about 0.05 wt % to about 1 wt % of a substituted pyridine compound of formula (I); 15 wt % to 70 wt % of Gum base; 27 wt % to 82 wt % of sorbitol and / or mannitol; 0.5 wt % to 1 wt % of flavoring; and 0.2 wt % to 1 wt % of oil.

[0157] 1e. Oral pockets

[0158] In various embodiments, the substituted pyridine compounds according to the present disclosure can also be used in oral alkaloid dispensing bags. The bag for oral use includes a relatively small (e.g., 0.5 inch × 0.75 inch) saliva-permeable fabric material shell containing a powder sealed therein, which can release alkaloids into the individual's oral cavity when the bag is placed in the individual's sublingual or buccal cavity. The alkaloid dispensing bag according to the present disclosure is configured to release the substituted pyridine compound of formula (I) over time. In some embodiments, the release of alkaloids from the alkaloid dispensing bag into the individual's oral cavity can be characterized as "release over time".

[0159] In various embodiments, the alkaloid distribution bag comprises a nonwoven fabric permeable to saliva and a powdered alkaloid composition sealed therein. In some instances, the powdered alkaloid composition sealed in the bag comprises a mixture of a substituted pyridine compound of formula (I) in a crystalline form or other solid forms and a solid carrier, or an oily substituted pyridine compound of formula (I), which is pure or in other forms, adsorbed on a solid carrier. In any case, the mixture is preferably a powder or granule. In other embodiments, the powdered alkaloid composition in the alkaloid distribution bag comprises a substituted pyridine compound, a solvent and a carrier according to formula (I), wherein the alkaloid dissolved in the solvent is adsorbed on the carrier.

[0160] 1e. (1) General implementation of the alkaloid dispensing bag:

[0161] In a general embodiment, an alkaloid dispensing bag suitable for releasing an alkaloid from the alkaloid dispensing bag into the oral cavity of a subject comprises:

[0162] A saliva-permeable nonwoven fabric defining an outer shell containing an alkaloid composition therein, the alkaloid composition comprising:

[0163] At least one substituted pyridine compound of formula (I), or a salt or mixed salt thereof:

[0164]

[0165] in:

[0166] A is selected from:

[0167]

[0168] R 1 , R 2 , R 3 , R 4 and R 5 independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, and

[0169] R 6 and R 7 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 6 and R 7 Together = O;

[0170] R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl;

[0171] n is an integer from 1 to 10; and

[0172] R 15 and R 16 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 15 and R 16 Together with the N atom to which they are bonded, they form a 3-8 membered optionally substituted heterocyclic ring,

[0173] The condition is that if A is And R 5 is methyl, then R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 cannot all be H; and

[0175] The alkaloid dispensing pouch contains absolutely no (R) or (S) nicotine.

[0176] In various embodiments, the alkaloid dispensing bag further comprises a carrier.

[0177] In various embodiments, the alkaloid composition is a mixture of a substituted pyridine compound of formula (I) and a carrier in solid or oily form.

[0178] In various embodiments, the carrier comprises microcrystalline cellulose.

[0179] In various embodiments, the alkaloid composition optionally comprises a chemosensory stimulant and / or a flavoring agent.

[0180] In various embodiments, the alkaloid composition disposed in the fabric bag further comprises at least one organic acid such that the molar ratio of the moles of the substituted pyridine compound of formula (I) to the moles of the total organic acid is from about 25: 1 to about 75: 1. The organic acids used herein are described below and in the definitions.

[0181] In various embodiments, the alkaloid composition further comprises a solvent, so that the alkaloid composition can be adsorbed onto the carrier as a solution to form a powdered or granular composition that can be filled into the shell. In certain examples, the solvent is selected from propylene glycol, glycerol, water, ethanol and mixtures thereof.

[0182] 1e.(2) Saliva-permeable fabric for bags:

[0183] The bag material used herein is selected based on its insolubility in water and its permeability to water and saliva. The size of the material is such that the filled bag is suitable for prolonged sublingual or buccal placement. Subjectively, the alkaloid dispensing bag is configured for a pleasant mouth feel, including the size of the filled and sealed bag and the texture of the bag fabric.

[0184] The bag material used herein can be constructed from any number of various water-insoluble nonwoven materials (referred to as "fabrics"). Nonwoven fabrics have a variety of uses and are well known to those skilled in the textile field. "Nonwoven Fabrics: Raw Materials, Manufacture, Applications, Characteristics, Testing Processes", edited by W. Albrecht, H. Fuchs and W. Kittelmann, Willy-VCH Linge Associates, Weinheim, 2003, describes nonwoven fabrics in great detail. Such materials can be prepared by forming a web of continuous filaments and / or staple fibers and optionally combining these fibers at fiber-to-fiber contact points to provide a fabric with desired properties. The term "bonded nonwoven fabric" is used to include nonwoven fabrics in which the major portion of the fiber-to-fiber bonding is achieved by thermal fusion of adjacent fibers; or by adhesive bonding, which is achieved by incorporating an adhesive into the fiber web to "glue" the fibers together; or by other connections, such as by using a liquid or gas adhesive (usually combined with heat) to make the fibers cohesive. Chemical bonding can be achieved by using an adhesive or latex powder dispersed between the fibers in the web and then activated by heat, ultraviolet or infrared radiation or other suitable activation methods. Thermally and chemically bonded carded webs are described in U.S. Pat. No. 6,689,242 to Bodaghi, the subject matter of which is incorporated herein. Thermally and / or chemically bonded nonwoven materials can be used as bag materials herein. Powder bonding is a dry process in which short fibers are first carded to form a fiber web, which is then treated with a powdered thermoplastic adhesive or latex material and passed through a series of ovens and calendar rolls to produce a nonwoven fabric.

[0185] Nonwoven materials also include fibers called "bicomponent fibers", such as "skin / core bicomponent fibers", which are fibers having a sheath region or layer with a melting point lower than that of an inner core region, thereby allowing effective and controlled thermal bonding by melting only the outer layer of each fiber. That is, the outer surface of the bicomponent fiber can be made to have a lower melting point than the fiber core. For example, a bonded bicomponent fiber in which one component has bonding properties under bonding conditions is widely used to provide integrity to a fiber web used as an absorbent in a personal care product or a filtration product. In addition, multicomponent fibers are also known and commercially incorporated into nonwoven materials. Examples of such multicomponent fibers are described in U.S. Pat. Nos. 5,382,400 (Pike et al.) and 5,866,488 (Terada et al.), which are incorporated herein in their entirety.

[0186] During the fiber bonding process, the web may be simultaneously subjected to mechanical compression to obtain the desired bond, weight, and thickness in a process known as "thermal compression bonding." Thermal compression bonding can be achieved by using a hot embossing roll and a hot flat calender roll in combination with a thermal compression bonding process using a heat treating machine such as a hot air circulation type, a hot ventilation type, an infrared heater type, or a vertical hot air blow type. Mechanical compression can be used to set the loft or thickness of fabrics with similar basis weights. Generally, increasing basis weight or mass per square area increases thickness, and increasing bonding and compression decreases loft.

[0187] Nonwoven webs can be formed by a variety of processes, such as meltblowing, spunbond or spunlaid, toe-opened, wet-laid, airlaid, combed and high-pressure hydraulic entanglement. The basis weight of nonwoven webs is usually expressed in ounces (osy) or grams per square meter (gsm) of material per square yard, and the fiber diameter is usually expressed in microns, or in the case of staple fibers, in "denier". Denier is defined as the number of grams per 9000 meters of fiber length. For fibers with a circular cross-section, denier can be calculated as the square of the fiber diameter in microns multiplied by the density in grams / cc, multiplied by 0.00707. Lower deniers represent finer fibers, and higher deniers represent thicker or heavier fibers. "Average fiber denier" is the sum of the tile deniers of each fiber divided by the number of fibers. The distribution of denier numbers or "average fiber denier" refers to the distribution of fiber diameters around a specific value. As used herein, the term "bulk density" refers to the weight of a material per unit volume and is usually expressed in units of mass per unit bulk volume (e.g., grams per cubic centimeter). Nonwovens can be produced from fibers having a single average diameter or denier value, or fibers of two or more average diameter values ​​can be used together. For example, two or more fiber denier distributions can be combined into a single web (e.g., 2 1 / 2 denier and 4 denier fibers are combed together). The individual webs can then be laminated together. For example, a single nonwoven may contain 2 1 / 2 , 4, 6 and 15 denier fibers, which means that it is constructed from four individual denier fibers (four individual average fiber diameters).

[0188] "Spunbond fibers" refer to fibers formed by extruding molten thermoplastic material as filaments, as described, for example, in U.S. Pat. No. 4,340,563 to Appel, U.S. Pat. No. 3,692,618 to Dorschner, U.S. Pat. No. 3,802,817 to Matsuki, U.S. Pat. No. 3,338,992 and U.S. Pat. No. 3,341,394 to Kinney; U.S. Pat. No. 3,502,763 to Hartman; U.S. Pat. No. 3,542,615 to Dobo and U.S. Pat. No. 5,382,400 to Pike, the entire contents of each of which are incorporated herein by reference. When spunbond fibers are deposited onto a collecting surface, they are generally not tacky. Spunbond fibers are typically continuous and have an average diameter of about 7 microns to about 60 microns, most typically about 15 microns to 25 microns.

[0189] "Meltblowing" refers to fibers formed by extruding molten thermoplastic material through a plurality of fine, usually circular die capillaries into molten strands or filaments and into converging high-speed, usually hot gas / air streams, which attenuate the filaments of molten thermoplastic material to reduce their diameter, which may ultimately reach microfiber diameter. Thereafter, the meltblown fibers are carried by the high-speed gas stream and deposited on a collecting surface to form a randomly dispersed fibrous web. This process is disclosed, for example, in U.S. Pat. No. 3,849,241 (Butin et al.). Meltblown fibers are microfibers that may be continuous or discontinuous, generally have an average diameter of less than 10 microns, and are generally tacky when deposited on a collecting surface.

[0190] "Air-laying" is a well-known method by which a nonwoven layer of fibers can be formed. In the air-laying process, small fiber bundles having a typical length of about 3 mm to about 52 mm are separated and entrained in an air supply and deposited onto a forming net, which is usually performed with the aid of a vacuum. Then, a binder component or a latex adhesive is activated using, for example, hot air to bind the randomly deposited fibers to each other. The air-laying process is taught, for example, in U.S. Pat. No. 4,640,810 to Laursen and U.S. Pat. No. 5,885,516 to Christensen.

[0191] Preferred fibers included in the bag fabric used herein can be monocomponent fibers, bicomponent fibers (e.g., sheath / core) or multicomponent fibers made of the following materials: polyolefins, such as polypropylene, polyethylene; various polyesters, such as poly(ethylene terephthalate)-PET, poly(butylene terephthalate)-PBT or poly(propylene terephthalate)-PTT, polycarbonate or polybutyrate, etc.; viscose rayon; various polyamides; such as nylon; polyacrylates; modified acrylic resins and mixtures of these types of polymers. In various preferred embodiments, viscose is used as the saliva permeable nonwoven bag fabric of the alkaloid dispensing bag herein.

[0192] The filling and sealing method for bags containing nonwoven fabrics is disclosed in U.S. Patent Application Publication US2023 / 0211907, published and transferred to Swedish Match North Europe AB on July 6, 2023, which is incorporated herein by reference. In various embodiments, the alkaloid distribution bag herein comprises a filling weight of about 100 mg to about 500 mg, preferably about 200 mg to about 400 mg of an alkaloid composition (dry powder or granules). When the bag is no longer comfortably fitted under the tongue or in the buccal cavity, the upper limit is reached. Since the weight of a small piece of nonwoven fabric is negligible compared to the weight of a single bag, the filling weight of the alkaloid distribution bag herein is about 100 mg to about 500 mg of dry powder or granular alkaloid composition per bag.

[0193] In various embodiments, the alkaloid dispensing bag has a width (or diameter) of about 0.12 inches to about 0.50 inches and a height of about 0.25 to about 0.75 inches. In some examples, the bag may look like a small pillow (e.g., square), or more like a capsule.

[0194] 1e. (3) Powdered filling composition for alkaloid dispensing bag:

[0195] In various embodiments, the alkaloid dispensing bag herein comprises a powdered or granular composition further comprising a substituted pyridine compound of formula (I) mixed with a carrier, or as a liquid composition comprising a substituted pyridine compound of formula (I) dissolved in a solvent and adsorbed onto a carrier. Either approach is intended to obtain a dry powdered or granular alkaloid filling material to be sealed in a nonwoven shell.

[0196] The carriers used herein include, but are not limited to, agar, agarose, albumin, alginate, casein, chitin, chondroitin, dextrin, silk protein, fucoidan, galactan, gellan gum, guar gum, scleroglucan, pullulan, xyloglucan, pectin, xanthan gum, psyllium, silica gel, fumed silica, magnesium aluminum silicate, clay, bentonite, hectorite, mesoporous silica, cellulose, cellulose acetate, hyaluronic acid, various elastin-like polypeptides, β-cyclodextrin, collagen, gelatin, chitosan, carrageenan, polylactic acid, polyethanol. Acid, polylactic glycolic acid (PLGA), poly(2-hydroxyethyl methacrylate), poly(2-hydroxypropyl methacrylate), polyacrylic acid, carboxymethyl cellulose, carboxyethyl cellulose, hydroxyethyl cellulose, hydrophobically modified hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, microcrystalline cellulose, nitrocellulose, polyvinyl alcohol, polyvinyl pyrrolidone, vinyl methacrylate, carboxyvinyl polymer, polyvinyl acetate, polyethylene copolymers, various starches, modified starches and combinations thereof. See SMFijul-Kabir et al., "Cellulose-based hydrogel materials: chemistry, properties and their prospective applications", Prog. Biomater., 7, 153-174 (2018).

[0197] The carrier may be selected based on absorptive capacity and, to a lesser extent, taste. In the case where the carrier is not soluble at all in the saliva present in the mouth, taste will not be a factor and any insoluble carrier is unlikely to pass between the fibers of the nonwoven material. In other examples, the carrier may be soluble and will pass through the porous bag fabric along with the alkaloid composition. In a preferred embodiment, the carrier comprises microcrystalline cellulose.

[0198] The resulting powdered or granular alkaloid filling material is filled into nonwoven bags at a filling level of about 100 mg to about 500 mg of the dry powdered or granular alkaloid composition per bag, and then sealed to make individual alkaloid dispensing bags for oral use.

[0199] 1f. Dipping toothpicks

[0200] In various embodiments, a THR product for oral use includes a dipped toothpick. In many respects, the THR dipped toothpick is similar to the familiar cinnamon toothpick, but is not necessarily cinnamon-flavored, as countless flavorings can be used. Cinnamon toothpicks typically include a wooden stick dipped in cinnamon oil.

[0201] In various examples herein, the THR toothpick comprises a wood strip impregnated with an alkaloid composition comprising at least one substituted pyridine compound of formula (I), or a salt or mixed salt thereof:

[00202]

[0203] in:

[0204] A is selected from:

[0205]

[0206] R 1 , R 2 , R 3 , R 4 and R 5 independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, and

[0207] R 6 and R 7 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 6 and R 7 Together = O;

[0208] R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl;

[0209] n is an integer from 1 to 10; and

[0210] R 15 and R 16 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 15 and R 16 Together with the N atom to which they are bonded, they form a 3-8 membered optionally substituted heterocyclic ring,

[0211] The condition is that if A is And R 5 is methyl, then R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10and R 11 cannot all be H; and

[0212] Among them, the dipped toothpicks contain absolutely no (R) or (S) nicotine.

[0213] In various embodiments, the alkaloid dispensing pouch (dipped toothpick) further comprises oil.

[0214] In various embodiments, the alkaloid composition comprises a substituted pyridine compound of formula (I) dissolved, dispersed or solubilized in oil.

[0215] In various embodiments, the alkaloid composition for forming a dipped toothpick according to the present disclosure further comprises at least one organic acid such that the molar ratio of the moles of the substituted pyridine compound of formula (I) to the moles of the total organic acid is from about 25: 1 to about 75: 1. The organic acids used herein are described below and in the definitions.

[0216] In various embodiments, the oil is selected from any partially hydrogenated or fully hydrogenated vegetable oil, such as soybean oil, olive oil, sesame oil, palm oil, coconut oil, etc. The oil can also be a fraction of the following: fatty acids, fatty acid mixtures, monoglycerides, diglycerides, or triglycerides of fatty acids, wherein the fatty acids and / or glycerides can have a specific chain length distribution (e.g., short chain, medium chain, or long chain fatty acids). Particularly used herein is "medium chain triglycerides" (or "MCT"), which refers to triglycerides of fatty acids having from about 6 to about 12 carbon atoms, such as any combination of triglycerides of caprylic acid, caproic acid, lauric acid, and / or capric acid (i.e., C 6 -C 12 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 transdermal THR compositions herein can be obtained from, for example, Specialized Rx Products, LLC (Circle Pines, Minnesota). Organic MCT oil fractionated coconut oil (caprylic / capric triglycerides), CAS Nos. 73398-61-5 and 65381-09-1, are also used herein, with a specific gravity of about 0.930-0.960 g / mL (typically 0.951 g / mL on average).

[0217] In other examples, the oil may include plant extracts such as cinnamaldehyde, anise oil, peppermint oil, tea tree oil, menthol, benzaldehyde, etc. These oils are selected because they impart flavor to the toothpick, and their ability to dissolve, solubilize or disperse the desired substituted pyridine compound. In various embodiments, the substituted pyridine compound of formula (I) is dissolved in cinnamaldehyde, anise oil, tea tree oil, peppermint oil or benzaldehyde, etc., and the resulting oily mixture is absorbed into the wood chip strips.

[0218] The wood chips used for the alkaloid-impregnated toothpicks herein may include birch or other wood suitable for absorbing the oily mixture.

[0219] 1g. Impregnated or coated dental floss

[0220] In various examples herein, the THR dental floss comprises a rope or tape impregnated or coated with an alkaloid composition comprising at least one substituted pyridine compound of formula (I), or a salt or mixed salt thereof:

[0221]

[0222] in:

[0223] A is selected from:

[0224]

[0225] R 1 , R 2 , R 3 , R 4 and R 5 independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, and

[0226] R 6 and R 7 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 6 and R 7 Together = O;

[0227] R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl;

[0228] n is an integer from 1 to 10; and

[0229] R 15and R 16 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 15 and R 16 Together with the N atom to which they are bonded, they form a 3-8 membered optionally substituted heterocyclic ring,

[0230] The condition is that if A is And R 5 is methyl, then R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 cannot all be H; and

[0231] Among them, the impregnated or coated dental floss is completely free of (R) or (S) nicotine.

[0232] In various embodiments, the impregnated or coated dental floss further comprises oil.

[0233] In various examples, the alkaloid composition comprises a substituted pyridine compound of formula (I) dissolved, dispersed or solubilized in oil. Depending on the nature of the rope or tape, the oily alkaloid composition may be coated and / or absorbed into the rope or tape.

[0234] In various embodiments, the alkaloid composition for forming an impregnated dental floss according to the present disclosure further comprises at least one organic acid such that the molar ratio of the moles of the substituted pyridine compound of formula (I) to the moles of the total organic acid is from about 25: 1 to about 75: 1. The organic acids used herein are described below and in the definitions.

[0235] In various embodiments, the oil is selected from any partially hydrogenated or fully hydrogenated vegetable oil, such as soybean oil, olive oil, sesame oil, palm oil, coconut oil, etc. The oil can also be a fraction of the following: fatty acids, fatty acid mixtures, monoglycerides, diglycerides, or triglycerides of fatty acids, wherein the fatty acids and / or glycerides can have a specific chain length distribution (e.g., short chain, medium chain, or long chain fatty acids). Particularly used herein is "medium chain triglycerides" (or "MCT"), which refers to triglycerides of fatty acids having from about 6 to about 12 carbon atoms, such as any combination of triglycerides of caprylic acid, caproic acid, lauric acid, and / or capric acid (i.e., C 6 -C 12Fatty 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 transdermal THR compositions herein can be obtained from, for example, Specialized Rx Products, LLC (Circle Pines, Minnesota). Organic MCT oil fractionated coconut oil (caprylic / capric triglycerides), CAS Nos. 73398-61-5 and 65381-09-1, are also used herein, with a specific gravity of about 0.930-0.960 g / mL (typically 0.951 g / mL on average).

[0236] In other examples, the oil may include plant extracts such as cinnamaldehyde, anise oil, peppermint oil, tea tree oil, menthol, benzaldehyde, etc. These oils are selected because they impart flavor to the dental floss and because of their ability to dissolve, solubilize or disperse the desired substituted pyridine compound. Similar or identical oily alkaloid compositions can be used for flavored THR toothpicks and flavored THR dental floss.

[0237] The dental rope or tape used for the dental floss impregnated or coated with alkaloid herein may include nylon or Teflon rope or tape. The substrate herein may include single or multiple filaments, which may be waxed or unwaxed. 1h. Mouthwash

[0239] In various embodiments, a THR mouthwash comprises:

[0240] At least one substituted pyridine compound of formula (I), or a salt or mixed salt thereof:

[0241]

[0242] in:

[0243] A is selected from:

[0244]

[0245] R 1 , R 2 , R 3 , R 4 and R 5 independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, and

[0246] R 6 and R 7 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 6 and R 7 Together = O;

[0247] R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl;

[0248] n is an integer from 1 to 10; and

[0249] R 15 and R 16 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 15 and R 16 Together with the N atom to which they are bonded, they form a 3-8 membered optionally substituted heterocyclic ring,

[0250] The condition is that if A is And R 5 is methyl, then R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 cannot all be H; and

[0252] The mouthwash contains absolutely no (R) or (S) nicotine.

[0253] In some instances, the mouthwash also includes a diluent.

[0254] In certain examples, the diluent is selected from water, alcohol and mixtures thereof. In some examples, the THR mouthwash comprises about 10 wt % to about 30 wt %, preferably about 15 wt % to about 25 wt % alcohol based on the total weight of the mouthwash composition.

[0255] In various embodiments, the THR mouthwash may further include a foaming surfactant, such as sodium lauryl sulfate.

[0256] In various embodiments, the THR mouthwash according to the present disclosure further comprises at least one organic acid such that the molar ratio of the moles of the substituted pyridine compound of formula (I) to the moles of the total organic acid is from about 25: 1 to about 75: 1. The organic acids used herein are described below and in the definitions.

[0257] 1i. Soft candy

[0258] In various embodiments, the THR gummies include:

[0259] At least one substituted pyridine compound of formula (I), or a salt or mixed salt thereof:

[0260]

[0261] in:

[0262] A is selected from:

[0263]

[0264] R 1 , R 2 , R 3 , R 4 and R 5 independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, and

[0265] R 6 and R 7 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 6 and R 7 Together = O;

[0266] R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl;

[0267] n is an integer from 1 to 10; and

[0268] R 15 and R 16 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 15 and R 16 Together with the N atom to which they are bonded, they form a 3-8 membered optionally substituted heterocyclic ring,

[0269] The condition is that if A is And R 5 is methyl, then R 1 , R 2 , R 3 , R 4 , R 6 , R 7, R 8 , R 9 , R 10 and R 11 cannot all be H; and

[0271] Wherein, the soft candy contains absolutely no (R) or (S) nicotine.

[0272] In certain examples, the fondant further comprises sugar and / or syrup, binders, starch, wax, and combinations thereof.

[0273] In certain examples, the sugar and / or syrup comprises a mixture of high fructose syrup (eg, corn syrup) and sucrose. The starch is preferably corn starch.

[0274] In various embodiments, the binder is selected from natural gums, such as gum arabic or gum tragacanth, gelatin, pectin, starch and mixtures thereof, preferably gelatin.

[0275] A wax is optionally used as a coating or glazing agent on each confection and preferably comprises carnauba wax.

[0276] In various embodiments, the THR gummies according to the present disclosure further include at least one organic acid such that the molar ratio of the moles of the substituted pyridine compound of formula (I) to the moles of the total organic acid is from about 25: 1 to about 75: 1. The organic acids used herein are described below and in the definitions.

[0277] 1j. Sublingual disintegrating tablets

[0278] In various embodiments, the THR sublingual disintegrating tablet comprises:

[0279] At least one substituted pyridine compound of formula (I), or a salt or mixed salt thereof:

[0280]

[0281] in:

[0282] A is selected from:

[0283]

[0284] R 1 , R 2 , R 3 , R 4 and R 5 independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, and

[0285] R 6 and R 7is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 6 and R 7 Together = O;

[0286] R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl;

[0287] n is an integer from 1 to 10; and

[0288] R 15 and R 16 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 15 and R 16 Together with the N atom to which they are bonded, they form a 3-8 membered optionally substituted heterocyclic ring,

[0289] The condition is that if A is And R 5 is methyl, then R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 cannot all be H; and

[0290] Among them, the sublingual disintegrating tablet contains no (R) or (S) nicotine.

[0291] In various embodiments, the sublingual disintegrating tablet further comprises a carrier.

[0292] In some instances, based on the total weight of the THR sublingual tablet composition, the THR sublingual tablet composition comprises at least 90 wt%, at least 95 wt% or at least 99 wt% of the carrier. In some instances, based on the total weight of the THR sublingual disintegrating tablet, the THR sublingual tablet composition comprises> 99.0 wt%,> 99.1 wt%,> 99.2 wt%,> 99.3 wt%,> 99.4 wt%,> 99.5 wt%,> 99.6 wt% or> 99.7 wt% of the carrier. The carrier of the THR sublingual tablet composition is a solid substance, or more preferably, a mixture of solid substances in the form of loose powder.

[0293] In certain examples, the carrier of the THR sublingual tablet composition comprises any combination of fillers, binders, disintegrants, lubricants, glidants, surfactants, acidic agents, alkaline agents, pH buffers, preservatives, drug release regulators, coating materials, colorants, flavoring agents and sweeteners, which together account for at least 90 weight %, at least 95 weight %, or preferably at least 99 weight % of the total weight of the THR sublingual tablet composition.

[0294] In certain embodiments, the carrier of THR sublingual tablet composition comprises filler and disintegrant.In most cases, filler accounts for the majority of carrier weight.

[0295] In certain examples, the carrier of the THR sublingual tablet composition comprises a filler, a lubricant, a glidant, and a disintegrant, wherein the filler accounts for the majority of the carrier weight.

[0296] In various examples, the carrier of the THR sublingual tablet composition comprises a filler. In certain examples, the filler will account for the majority of the carrier by weight percentage. Fillers include, for example, colloidal anhydrous silica (e.g. 200 or 300Pharma, or 300 Pharma), magnesium aluminum metasilicate ( US2), calcium silicate Microcrystalline cellulose powder (e.g. PH101 or PH102), silicified microcrystalline cellulose ( SMCC), various starches and various sugars. Common fillers used in pharmaceutical powders and tablets include microcrystalline cellulose (MCC) and / or silicified microcrystalline cellulose (SMCC), and / or simple sugars such as mannitol, fructose or lactose, or a combination of cellulose and a simple sugar, such as a combination of microcrystalline cellulose and fructose (where either one accounts for the majority weight %). In various embodiments, a combination of MCC and colloidal silicon dioxide (e.g., 98:2) can replace SMCC, although there is some evidence that physical mixtures result in some sticking of the die punch (see A. Aljaberi et al., "Functional performance of silicified microcrystalline cellulose versus microcrystalline cellulose: a case study", Drug Dev. Ind. Pharma., 35 (9) _, 1066-1071, (2009)).

[0297] Other fillers that can be used in the THR sublingual tablet composition of the present disclosure include, for example, cellulose acetate, sorbitol, sucrose, dextrin, dextrose, calcium hydrogen phosphate, calcium carbonate, maltose, maltodextrin, kaolin, tricalcium phosphate, calcium sulfate, cellulose acetate butyrate (cellulose acetate butyl), calcium lactate, cellulose acetate, erythritol, ethyl cellulose, ethyl acrylate / methyl methacrylate copolymer, isomalt, α-lactalbumin, lactitol, magnesium carbonate, magnesium oxide, methacrylic acid / ethyl acrylate copolymer, methacrylic acid / methyl methacrylate copolymer, polydextrose, sodium chloride, simethicone, hydrogenated pullulan, talc, amino methacrylate copolymer, trehalose and xylitol.

[0298] In various embodiments, the carrier of the THR sublingual tablet composition comprises a combination of microcrystalline cellulose, colloidal silicon dioxide, mannitol, and fructose as fillers at a level of about 70 wt % to about 99 wt % based on the total weight of the THR sublingual tablet composition.

[0299] In various embodiments, the carrier of the THR sublingual tablet composition comprises a lubricant. Examples of lubricants include, for example, magnesium stearate, calcium stearate, zinc stearate, sodium lauryl sulfate, sodium stearyl fumarate (SSF), magnesium lauryl sulfate, stearic acid, glyceryl behenate, behenyloxy polyoxyglyceryl esters (e.g. HD5), glyceryl dibehenate, lauric acid, glyceryl monostearate, glyceryl tristearate, myristic acid, palmitic acid, poloxamer, polyethylene glycol, polysorbate 20, polyoxyethylene-10-oleyl ether, polyoxyethylene-15-hydroxystearate, polysorbate 40, polyoxyethylene-20-cetostearyl ether, polyoxyethylene-40-stearate, polysorbate 60, polysorbate 80, potassium benzoate, sodium benzoate, sorbitan monolaurate, sorbitan monooleate, sodium stearate, sorbitan monopalmitate, sorbitan monostearate, zinc stearate, sorbitan sesquioleate, sorbitan trioleate, and talc.

[0300] In various embodiments, the carrier of the THR sublingual tablet composition comprises sodium stearyl fumarate (SSF) as a tablet lubricant at a level of about 0.1 wt % to about 5 wt % based on the total weight of the THR sublingual tablet composition. SSF is available, for example, under the trade name Available from JRS Pharma or under the brand name SSF was obtained from SPIPharma.

[0301] In various embodiments, the carrier of THR sublingual tablet compositions includes a binder. The example of a binder includes, for example, polyvinyl pyrrolidone (PVP or polyvidone), cross-linked polyvinyl pyrrolidone (crosspovidone) vinyl pyrrolidone-vinyl acetate copolymer (copolyvidone), carbomer, polyethylene glycol (PEG), starch and starch derivatives such as corn starch, pregelatinized starch, carboxymethyl cellulose (carboxymethyl cellulose), hydroxypropyl methyl cellulose (hydroxypropyl methyl cellulose), cellulose ethers (such as Methocel TM ), hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, calcium carboxymethyl cellulose, calcium cellulose glycolate, ethyl cellulose, chitosan, dextrin, inulin, magnesium aluminum silicate, maltodextrin, methyl cellulose, dextran, sodium alginate, zein, gelatin, polymethacrylate, sorbitol and gum arabic.

[0302] In various embodiments, the carrier of the THR sublingual tablet composition comprises from 0 up to about 20% by weight of a binder.

[0303] In various embodiments, the carrier of the THR sublingual tablet composition comprises a disintegrant. Examples of disintegrants include, for example, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose, sodium starch glycolate, cross-linked sodium carboxymethylcellulose, low-substituted hydroxypropyl cellulose, guar gum, chitosan hydrochloride, calcium alginate, sodium alginate, sodium docusate, magnesium aluminum silicate, methylcellulose, calcium carboxymethylcellulose and calcium cellulose glycolate.

[0304] In various embodiments, the carrier of the THR sublingual tablet composition comprises crospovidone as a disintegrant, based on the total weight of the THR sublingual tablet composition, at a level of about 0.1 wt % to about 30 wt %. In certain instances, the THR sublingual tablet composition for tableting comprises about 2 wt % to about 5 wt % of crospovidone as a disintegrant, based on the total weight of the THR sublingual tablet composition.

[0305] In various embodiments, the carrier of the THR sublingual tablet composition comprises a glidant. Examples of glidants include, for example, untreated fumed silica (e.g., M-5P or M-5DP), colloidal silicon dioxide, talc, tricalcium phosphate, calcium silicate, magnesium oxide, sodium stearate, magnesium silicate, magnesium trisilicate and hydrophobic colloidal silicon dioxide. In a preferred embodiment, untreated fumed silica is included in the carrier of the THR sublingual tablet composition, which is used as a glidant to improve tablet production.

[0306] In various embodiments, the carrier of the THR sublingual tablet composition comprises untreated fumed silica as a glidant at a level of about 0.5 wt % to about 1 wt % based on the total weight of the THR sublingual tablet composition. Untreated fumed silica acts as a free-flowing agent to improve tablet production efficiency, tablet uniformity, and tablet hardness.

[0307] In various embodiments, the carrier of the THR sublingual tablet composition consists essentially of a mixture of untreated fumed silica, sodium stearyl fumarate, microcrystalline cellulose, colloidal silicon dioxide, mannitol, fructose and crospovidone, with the total level being at least 99 weight percent based on the total weight of the THR sublingual tablet composition.

[0308] In various embodiments, commercially available carriers for pharmaceutical tablets can be used as all or part of the carrier in the THR sublingual tablet composition of the present disclosure. For example, ODT G2 can be used as a carrier or a majority of the carrier by weight of the THR sublingual tablet compositions for tableting of the present disclosure. The commercial product has a bulk density of about 0.45-0.65 g / mL, comprises a mixture of microcrystalline cellulose, colloidal silicon dioxide, mannitol, fructose and crospovidone, and is available from JRS Pharma, Cedar Rapids, Iowa.

[0309] In various embodiments, the carrier of the THR sublingual tablet composition comprises at least 85% by weight or at least 90% by weight of G2. In certain embodiments, the carrier for the THR sublingual tablet composition comprises at least 85 wt%, at least 86 wt%, at least 87 wt%, at least 88 wt%, at least 89 wt%, or at least 90 wt% of G2. In various embodiments, the carrier of the THR sublingual tablet composition comprises at least 90% by weight of G2 and about 0.5 wt % to 1 wt % of untreated fumed silica and about 0.1 wt % to about 5 wt % of sodium stearyl fumarate. In various formulations, The weight percentage of G2 may be expressed simply as "quantity sufficient" or "qs." In some instances, the amount of the carrier may be adjusted accordingly to accommodate changes in the formulation, such as the presence or absence of flavoring or higher or lower alkaloid levels.

[0310] Mainly contains by weight The carrier of G2 may also contain other separately added fillers, binders, lubricants, disintegrants and / or glidants as necessary to optimize tablet processing and tablet properties.

[0311] In various embodiments, the THR sublingual tablet according to the present disclosure further comprises at least one organic acid such that the molar ratio of the moles of the substituted pyridine compound of formula (I) to the moles of the total organic acid is from about 25: 1 to about 75: 1. The organic acids used herein are described below and in the definitions.

[0312] 1k.Topical / transdermal creams

[0313] In various embodiments, the THR topical / transdermal cream comprises:

[0314] At least one substituted pyridine compound of formula (I), or a salt or mixed salt thereof:

[0315]

[0316] in:

[0317] A is selected from:

[0318]

[0319] R 1 , R 2 , R 3 , R 4 and R 5 independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, and

[0320] R 6 and R 7 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 6 and R 7 Together = O;

[0321] R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl;

[0322] n is an integer from 1 to 10; and

[0323] R 15 and R 16 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 15 and R 16 Together with the N atom to which they are bonded, they form a 3-8 membered optionally substituted heterocyclic ring,

[0324] The condition is that if A is And R 5 is methyl, then R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 cannot all be H; and

[0325] Among them, the topical / transdermal cream contains absolutely no (R) or (S) nicotine.

[0326] In various embodiments, the THR topical cream further comprises a binder, a wetting agent, and combinations thereof.

[0327] In various embodiments, the THR topical cream according to the present disclosure further comprises at least one organic acid such that the molar ratio of the moles of the substituted pyridine compound of formula (I) to the moles of the total organic acid is from about 25: 1 to about 75: 1. The organic acids used herein are described below and in the definitions.

[0328] The solubilizing agent is selected from partially hydrogenated or fully hydrogenated vegetable oils, such as soybean oil, olive oil, sesame oil, palm oil, coconut oil, etc. The solubilizing agent can also be a fraction of the following: fatty acids, fatty acid mixtures, monoglycerides, diglycerides or triglycerides of fatty acids, wherein the fatty acids and / or glycerides can have a specific chain length distribution (e.g., short chain, medium chain, or long chain fatty acids). Particularly used herein is "medium chain triglycerides" (or "MCT"), which refers to triglycerides of fatty acids having about 6 to about 12 carbon atoms, such as any combination of triglycerides of caprylic acid, caproic acid, lauric acid and / or capric acid (i.e., C 6 -C 12 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 transdermal THR compositions herein can be obtained from, for example, Specialized Rx Products, LLC (Circle Pines, Minnesota). Organic MCT oil fractionated coconut oil (caprylic / capric triglycerides), CAS Nos. 73398-61-5 and 65381-09-1, are also used herein, with a specific gravity of about 0.930-0.960 g / mL (typically 0.951 g / mL on average).

[0329] The solubilizers used in the various THR topical creams may also include terpenes such as geraniol, citronellol, geranyl aldehyde, citronellal, linalool, menthone, rose oxide, alpha-terpineol, and limonene.

[0330] Wetting agents useful herein 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.

[0331] In various embodiments, the THR topical cream also contains a chemical sensory stimulant, for example, for imparting a cooling sensation or for relieving pain. In particular, hemp, and / or menthol and / or capsaicin may be included in the THR product.

[0332] 1l ion exchange resin

[0333] In various embodiments, any substituted pyridine compound or a salt or mixed salt thereof is combined with an ion exchange resin.

[0334] In various embodiments, the pyridine compound, its salt or mixed salt combined with the ion exchange resin includes a pyridine compound, its salt or mixed salt according to formula (I):

[0335]

[0336] A is selected from:

[0337]

[0338] R 1 , R 2 , R 3 , R 4 and R 5 independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, and

[0339] R 6 and R 7 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 6 and R 7 Together = O;

[0340] R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl;

[0341] n is an integer from 1 to 10; and

[0342] R 15 and R 16 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 15 and R 16 Together with the N atom to which they are bonded, they form a 3-8 membered optionally substituted heterocyclic ring,

[0343] The condition is that if A is And R 5 is methyl, then R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 cannot all be H; and

[0344] Wherein, the compound contains no (R) or (S) nicotine at all.

[0345] In some embodiments, the substituted pyridine compound or its salt or mixed salt further comprises a carrier.

[0346] In some embodiments, the pyridine compound is a derivative of a (S)-6-methylnicotine compound. In some embodiments, the derivative of a (S)-6-methylnicotine compound comprises formula (I):

[0347]

[0348] Among them, A includes:

[0349]

[0350] In some embodiments, any pyridine compound, its salt or mixed salt or (S)-6 methyl nicotine derivative is combined with a carrier. In some embodiments, the carrier comprises an ion exchange resin. In some embodiments, the ion exchange resin is configured to deliver and release any pyridine or (S)-6 methyl nicotine product described herein to the oral mucosa. In some embodiments, the ion exchange resin promotes any pyridine or (S)-6 methyl nicotine product described herein to be absorbed by the oral mucosa. In some embodiments, the ion exchange resin allows the pyridine compound or (S)-6-methyl nicotine derivative to be uniformly released.

[0351] In some embodiments, the ion exchange resin comprises an acid. In some embodiments, the ion exchange resin comprises a strong acid. In some embodiments, the ion exchange resin comprises a weak acid. In some embodiments, the ion exchange resin comprises a base. In some embodiments, the ion exchange resin comprises a strong base. In some embodiments, the ion exchange resin comprises a weak base.

[0352] In some embodiments, the ion exchange resin comprises an anion exchange resin. In some embodiments, the anion ion exchange resin comprises a functional group. In some embodiments, the functional group comprises an amine group. In some embodiments, the functional group comprises a quaternary ammonium. In some embodiments, the functional group comprises ammonium chloride. In some embodiments, the functional group comprises hydroxide.

[0353] In some embodiments, the anionic ion exchange resin comprises a copolymer. In some embodiments, the copolymer comprises styrene. In some embodiments, the copolymer comprises divinylbenzene.

[0354] In some embodiments, the ion exchange resin comprises a cation exchange resin. In some embodiments, the cation exchange resin comprises a functional group. In some embodiments, the functional group comprises a sulfonic acid. In some embodiments, the functional group comprises a carboxylic acid.

[0355] In some embodiments, the ion exchange resin comprises a cation exchange resin. In some embodiments, the cationic ion exchange resin comprises a polystyrene polymer. In some embodiments, the cation exchange resin comprises sodium polystyrene sulfonate. In some embodiments, the cation exchange resin comprises sodium zirconium cyclosilicate. In some embodiments, the cation exchange resin comprises sodium polystyrene sulfonate.

[0356] In some embodiments, the ion exchange resin comprises an acrylic polymer. In some embodiments, the acrylic polymer comprises a derivative of acrylic acid. In some embodiments, the acrylic polymer comprises a derivative of methacrylic acid. In some embodiments, the acrylic polymer comprises a derivative of acrylic acid and methacrylic acid.

[0357] In some embodiments, the ion exchange resin comprises a copolymer. In some embodiments, the copolymer comprises an acrylic polymer. In some embodiments, the acrylic polymer comprises a derivative of acrylic acid. In some embodiments, the acrylic polymer comprises a derivative of methacrylic acid. In some embodiments, the acrylic polymer comprises a derivative of acrylic acid and methacrylic acid. In some embodiments, the copolymer comprises a vinyl monomer. In some embodiments, the copolymer comprises an allyl monomer.

[0358] In some embodiments, the resin comprises polymethacrylic acid (PMAA) (poly (1-methylprop-1-enoic acid)). In some embodiments, PMAA comprises the formula (C 4 H 6 O 2 ) n .

[0359] In some embodiments, the ion exchange resin comprises a copolymer comprising polymethacrylic acid cross-linked with another compound.

[0360] In some embodiments, the ion exchange resin comprises a copolymer comprising polymethacrylic acid and divinylbenzene. In some embodiments, any pyridine compound or (S)-6-methylnicotine derivative is combined with an ion exchange resin comprising polymethacrylic acid.

[0361] In various embodiments, the copolymer comprising polymethacrylic acid and divinylbenzene comprises Amberlite IRP64 or a derivative thereof. In some embodiments, any pyridine compound or (S)-6-methylnicotine derivative is combined with an ion exchange resin comprising Amberlite IPR64 or a derivative thereof.

[0362] In some embodiments, the copolymer comprising polymethacrylic acid and divinylbenzene comprises Purolite C115HMR or a derivative thereof. In some embodiments, any pyridine compound or (S)-6-methylnicotine derivative is combined with an ion exchange resin comprising Purolite C115HMR or a derivative thereof.

[0363] In some embodiments, the copolymer comprising polymethacrylic acid and divinylbenzene comprises Doshion P551. In some embodiments, any pyridine compound or (S)-6-methylnicotine derivative is combined with an ion exchange resin comprising Doshion P551 or a derivative thereof.

[0364] In various embodiments, any pyridine compound, salt or mixed salt thereof bound to an ion exchange resin is added to a gum to be used as part of a smoking cessation treatment. In some embodiments, the gum comprises a gum coated with candy. In some embodiments, the gum comprises beads. In some embodiments, the gum comprises flat strips of gum. In some embodiments, the gum comprises bubble gum. In some embodiments, the gum comprises crushed bubble gum. In some embodiments, any pyridine compound, salt or mixed salt thereof, or (S)-6 methyl nicotine derivative bound to an ion exchange resin is added to any gum described herein.

[0365] In various embodiments, any pyridine compound, salt thereof or mixed salt thereof bound to an ion exchange resin is added to a hard lozenge to be used as part of a smoking cessation treatment. In some embodiments, the lozenge comprises a soluble lozenge. In some embodiments, the lozenge comprises a lozenge that dissolves slowly in the mouth of an individual, e.g., dissolves over the course of several minutes. In some embodiments, any pyridine compound, salt thereof or mixed salt thereof or (S)-6 methyl nicotine derivative bound to an ion exchange resin is added to any hard lozenge described herein.

[0366] 1m(S)-6-methylnicotine derivatives in salt form

[0367] In various embodiments, disclosed herein is (S)-6-methylnicotine or a derivative thereof. In some embodiments, the (S)-6-methylnicotine or a derivative thereof comprises a pyridine compound.

[0368] In various embodiments, the (S)-6-methylnicotine or a derivative thereof comprises a compound of formula (I).

[0369]

[0370] In an embodiment, A comprises the structure:

[0371]

[0372] R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from H, alkyl, substituted alkyl,

[0373] Cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl and

[0374] R 6 and R 7 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 6 and R 7 Together = O;

[0375] R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl;

[0376] n is an integer from 1 to 10; and

[0377] R 15 and R 16 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 15 and R 16 Together with the N atom to which they are bonded, they form a 3-8 membered optionally substituted heterocyclic ring,

[0378] The condition is that if R 5 is methyl, then R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 cannot all be H; and

[0379] Wherein, the compound contains no (R) or (S) nicotine at all.

[0380] In various embodiments, any of the (S)-6-methylnicotine or derivatives thereof comprises a carrier.

[0381] In various embodiments, any of the (S)-6-methylnicotine or derivatives thereof comprises a pharmaceutically acceptable salt. In some embodiments, the pharmaceutically acceptable salt comprises a bitartrate salt.

[0382] In some embodiments, the bitartrate comprises potassium bitartrate. In some embodiments, potassium bitartrate comprises formula KC 4 H 5 O 6 .

[0383] In some embodiments, the pharmaceutically acceptable salt comprises a dihydrate bitartrate salt or a derivative thereof. In some embodiments, the dihydrate bitartrate salt comprises a compound of formula 2C 4 H 6 O 6 ,2H 2 In some embodiments, the bitartrate dihydrate comprises formula 2C 4 H 6 O 6 ,2H 2 Derivatives of O.

[0384] In some embodiments, the pharmaceutically acceptable salts include any of the (S)-6-methylnicotine or derivatives thereof described herein, and Formula 2C 4 H 6 O 6,2H 2 O compound or its derivative.

[0385] In some embodiments, the pharmaceutically acceptable salt comprises at least one water molecule. In some embodiments, the pharmaceutically acceptable salt comprises at least two water molecules, such as a dihydrate. In some embodiments, the pharmaceutically acceptable salt comprises more than two water molecules, such as at least three water molecules, at least four water molecules, at least five water molecules, at least six water molecules, at least seven water molecules, at least eight water molecules, at least nine water molecules, or at least ten water molecules.

[0386] In various embodiments, the pharmaceutically acceptable salt comprises any (S)-6-methylnicotine structure or derivative thereof and a tartrate. In some embodiments, the tartrate comprises formula C 4 H 4 O 6 2- In some embodiments, the tartrate comprises C 4 H 4 O 6 2- Derivatives of. In some embodiments, the tartrate comprises sodium tartrate. In some embodiments, the sodium tartrate comprises any one or more of monosodium tartrate, sodium tartrate, and sodium ammonium tartrate. In some embodiments, the tartrate comprises potassium tartrate. In some embodiments, the potassium tartrate comprises any one or more of potassium bitartrate, potassium tartrate, potassium sodium tartrate, calcium tartrate, and stearyl tartrate.

[0387] In some embodiments, the pharmaceutically acceptable salt comprises bitartrate or bitartrate anion (3-carboxy-2,3-dihydroxypropionate). In some embodiments, bitartrate comprises choline bitartrate. In some embodiments, bitartrate comprises potassium bitartrate. In some embodiments, bitartrate comprises sodium bitartrate.

[0388] In some embodiments, a pharmaceutically acceptable salt of any (S)-6 methyl nicotine derivative described herein is added to a gum to be used as part of a smoking cessation treatment. In some embodiments, the gum comprises a gum coated with candy. In some embodiments, the gum comprises beads. In some embodiments, the gum comprises a flat strip of gum. In some embodiments, the gum comprises bubble gum. In some embodiments, the gum comprises crushed bubble gum. In some embodiments, a pharmaceutically acceptable salt of any (S)-6 methyl nicotine derivative described herein is added to any gum described herein.

[0389] In various embodiments, any pharmaceutically acceptable salt of the (S)-6-methyl nicotine derivative described herein is added to a hard lozenge to be used as part of a smoking cessation treatment. In some embodiments, the lozenge comprises a soluble lozenge. In some embodiments, the lozenge comprises a lozenge that dissolves slowly in the mouth of an individual, for example, dissolving over the course of several minutes. In some embodiments, any pharmaceutically acceptable salt of the (S)-6-methyl nicotine derivative described herein is added to any hard lozenge described herein.

[0390] Other ingredients

[0391] In various embodiments, the THR products including the THR pain relief product subset may also include any combination of flavorings, sweeteners, coloring agents, disintegrants, penetration enhancers, stabilizers, preservatives or chemical sensory stimulants. Any of these materials not specifically mentioned herein may be found in "Handbook of Pharmaceutical Excipients", 6th edition, edited by RC Rowe et al., Pharmaceutical Press, London, 2009.

[0392] Suitable flavorings can include, for example, natural flavors, artificial flavors and combinations thereof. The limiting examples of flavoring oils include spearmint oil, cinnamon oil (cinnamon oil), wintergreen oil (methyl salicylate), peppermint oil, clove oil, bay oil, anise oil, eucalyptus oil, thyme oil, cedar leaf oil, nutmeg oil, allspice, sage oil, nutmeg, bitter almond oil and cassia oil (cassia oil). Suitable flavorings also include, for example, artificial, natural and synthetic fruit flavors, such as vanilla, citrus oil (such as lemon, orange, lime and grapefruit) and fruit essence (such as apple, pear, peach, grape, strawberry, raspberry, cherry, plum, pineapple and apricot) etc., and combinations thereof.

[0393] Other flavoring and fragrance agents that may be included, alone or in combination, include, but are not limited to, anethole, menthol, menthone, menthyl acetate, eucalyptol, borneol, borneol acetate, camphor, 1,8-cineole, cinnamaldehyde, benzaldehyde, citral, thujone, eugenol, limonene, geraniol, citronellol, citronellal, pinene, linalool, thymol, carvone, caryophyllene, linalyl acetate, methyl salicylate, and mixtures thereof. In addition, substances that provide fragrance and flavor include, but are not limited to, 3,3,5-trimethylcyclohexanol, methoxycyclohexanol, benzyl alcohol, anise alcohol, cinnamyl alcohol, β-phenylethanol (2-phenylethanol), cis-3-hexenol, musk xylene, isoeugenol, methyl eugenol, α-amyl cinnamaldehyde, anisealdehyde, n-butyraldehyde, cuminaldehyde, cyclamen aldehyde, decanal, isobutyraldehyde, hexanal, heptaldehyde, n-nonanal, nonadienol, hydroxycitronellal, benzaldehyde, methylnonyl acetaldehyde, dodecanol, α-hexyl Cinnamaldehyde, undecenal, piperonal, vanillin, ethyl vanillin, methyl amyl ketone, methyl β-naphthyl ketone, methyl nonyl ketone, musk ketone, diacetyl, acetyl propionyl, acetobutyryl, acetophenone, p-methylacetophenone, ionone, methyl ionone, amyl butyrolactone, diphenyl ether, methyl phenyl glycidyl ester, γ-nonyl lactone, coumarin, eucalyptol, ethyl methyl phenyl glycidyl ester, methyl formate, isopropyl formate, linalyl formate, ethyl acetate, octyl acetate, methyl acetate, ethyl Benzyl acetate, butyl propionate, isoamyl acetate, isopropyl isobutyrate, geranyl isovalerate, allyl hexanoate, butyl heptanoate, octyl octyl ester, methyl heptanoate, methyl octylide, isoacyl octanoate, methyl laurate, ethyl myristate, methyl myristate, ethyl benzoate, benzyl benzoate, ethyl 1-phenylacetate, isobutyl phenylacetate, methyl cinnamate, cinnamyl cinnamate, ethyl anisate, methyl anthranilate, ethyl pyruvate, ethyl α-butylbutyrate, benzyl propionate, acetic acid Butyl ester, butyl butyrate, p-tert-butyl cyclohexyl acetate, cedryl acetate, citronellyl acetate, citronellyl formate, p-cresol acetate, ethyl butyrate, ethyl caproate, ethyl cinnamate, ethyl phenylacetate, vinyl tridecanoate, geranyl acetate, geranyl formate, isoamyl salicylate, isoamyl isovalerate, isobornyl acetate, linalyl acetate, methyl anthranilate, methyl dihydrojasmonate, β-phenylethyl acetate, trichloromethylphenyl acetate, terpineol acetate, vetiver acetate and mixtures thereof.

[0394] Suitable sweeteners include nutritive carbohydrates such as sucrose, glucose, fructose, dextrose, trehalose, galactose, mannitol, sorbitol and xylitol, as well as artificial sweeteners such as saccharin, aspartame, acesulfame K, cyclamate, neotame, sucralose and neohesperidin dihydrochalcone (NHDC) and the naturally derived non-sugar sweetener, steviol glycosides (i.e., steviol glycosides obtained from the plant species Stevia rebaudiana).

[0395] Exemplary colorants for THR products include pharmaceutically acceptable colorants, such as the FDA-approved pigments, dyes, and lakes found in pharmaceutical capsules, tablets, and syrups. These acceptable colorants include inorganic pigments such as titanium dioxide, yellow iron oxide, red iron oxide, and black iron oxide; organic pigments such as D&C Red 36, Red 30, and Red 34; solvent-soluble pigments D&C Yellow 11, Yellow 7, Red 27, Red 21, Red 17, Green 6, and Violet 2, and water-soluble pigments D&C Green 8, Yellow 10, Yellow 8, Orange 4, Red 22, Red 28, Red 33, Green 5, Quinoline Yellow, FD&C Yellow 5, Yellow 6, Red 4, Red 40, Red 3, Green 3, Blue 1, Blue 2, and Ponceau 4R, Carmine, Amaranth, Patent Blue V, and Black PN, as well as many "organic lakes".

[0396] THR oral R products designed to dissolve quickly, such as sublingual THR tablets and THR dissolving oral strips, may contain disintegrants. Suitable disintegrants include, but are not limited to, sodium starch glycolate, cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose, and crospovidone. For a review of disintegrants used in various THR products herein, see PM Desai, "Review of Disintegrants and the Disintegration Phenomena", J. Pharm. Sci., 105, 2545-2555 (2016).

[0397] The THR products (e.g., THR lozenges) herein may further include an intestinal permeation enhancer, which is different from the transdermal permeation enhancer of the pain relief THR products that can be used herein. Suitable intestinal permeation enhancers include, but are not limited to, surfactants that contribute to bioabsorption, including, for example, fatty acids and / or their esters or salts, bile acids and / or their salts. Bile acids / salts and fatty acids and their uses are further described in U.S. Patent No. 6,287,860, the full text of which is incorporated herein. In some embodiments of THR oral products, the disclosure provides a combination of absorption enhancers, such as a combination of fatty acids / salts and bile acids / salts. An exemplary combination is a sodium salt of lauric acid, capric acid, and ursodeoxycholic acid (UDCA), which is used to promote improvement in intestinal absorption of peptides and other substances. These excipients can be used in the THR compositions of the present invention to help the absorption of substituted pyridine compounds, their salts, or mixed salts. Other penetration enhancers include, but are not limited to, polyoxyethylene-9-lauryl ether, polyoxyethylene-20-hexadecyl ether. For a review of absorption enhancers useful herein, see BJ Aungst, "Intestinal Permeation Enhancers," J. Pharm. Sci., 89(4), 429 (2000).

[0398] In various embodiments, the THR products herein may also include stabilizers or preservatives. Such substances used in oral products include parabens, sorbitol, sodium benzoate, benzoic acid, sorbic acid, potassium sorbate, propionic acid and combinations thereof. Antioxidants include, but are not limited to, vitamin C, vitamin E, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) and propyl gallate. For review, see I.Himoudy, "Preservatives and their role in pharma and clinical research (preservatives and their role in pharmaceutical and clinical research)" International Journal of Pharma Sciences and Scientific Research ("International Journal of Pharmaceutical Sciences and Scientific Research"), 2: 4, 134-151 (2016).

[0399] Including chemosensory stimulants in various THR products disclosed herein is optional. When used in the compositions herein, chemosensory stimulants include any natural, endogenous, phytochemical or synthetic compounds capable of activating TRP ion channels, including those derived from naturally occurring compounds by organic chemistry. For example, in HP Fallah et al., "A Review on the Role of TRP Channels and Their Potential as Drug Targets: An Insight Into the TRP Channel Drug Discovery Methodologies (TRP channel effects and their potential as drug targets: A review of TRP channel drug discovery methods), "Front.Pharmacol., 2022 13: 914499, it was found that an assay method that can be used to determine whether a compound is indeed a TRP ion channel activator is found.

[0400] The chemical sensory stimulants used herein include, but are not limited to, oleic acid octanal, 4-hydroxy-2-nonenal, 4-oxo-2-nonenal, allicin, allyl isothiocyanate, eserin, polygonal aldehyde, cinnamaldehyde, trans-p-methoxycinnamaldehyde, methyl syringate, 2-chlorobenzylidenemalononitrile, 1-chloroacetophenone, ethyl bromoacetate, 4-hydroxyhexenal, toluene diisocyanate, p-benzoquinone, methyl p-hydroxybenzoate, flufenamic acid, niflumic acid, mefenamic acid, diclofenac, hydroxy-α-sanshool, 6-gingerol, linalool, carvacrol, eugenol, thymol, vanillin, methyl eugenol, 2,6-dimethylphenol, 2,5-dimethylphenol, 3,4-dimethylphenol, 2,6-diisopropylphenol, caffeine, farnesylthiosalicylic acid, 4-ene Propylbenzyl alcohol, curcumin, niacin, niacinamide, camphor, avanafil, avanil, anandamide (AEA), 2-AG, NADA, OLDA, PEA, NGABA, NGly, NAsp, NSer, Δ9-tetrahydrocannabinol (Δ9-THC), Δ9-THCA, Δ9-THCV, Δ9-THCVA, CBD, CBDA, CBDV, CBG, CBGA, CBGV, CBN, CBC, WIN55,212-2, AM630, (R)-AM1241, (S)-AM1241, SR141716A, Gp-1a, AM251, SR144528, JWH133, HU308, HU910, CP55,940, nabilone, from Euphorbia reinifera, Euenia carophyllata, Ocimum gratissiumum, Panax ginseng, Aframomum melgueta, Evodiarutaecarpa, Drymis winteri, Cinnamosma fragrans, Warburgia, Scutellaria baicalensis, Vitex agnus, Pterodon pubescens, Croton macrostachyus, Angelica epubescentis, Ephedra sinica, Amphilophium crucigerum, Bosewellia carterii, Commiphora myrrha), basil (Echinophoraplatyloba), water coconut (Nypa fruticans), stone pansy (Corydalis saxicola), Coptischinensis (Coptischinensis), Formononete (Ononis spinosa), pea wood (Parkia platycephala), and lemongrass (Cymbopogon citratus), as well as all of the subset of flavor additives individually defined as having a heat level of about 1,000 SHU to about 20,000,000 SHU among the chemosensory stimulants. Many of the flavor additives used herein are phytochemicals found in various herbs and fruits, such as compounds from capsicum (Capsicum annuum), ginger (Zingiber officiale), and pepper (Piper nigrum). ,

[0401] According to various embodiments, the flavor additive used as a chemical sensory stimulant in various THR products of the present disclosure is an organic compound having a spiciness or heat of about 1,000 to about 20,000,000 Scoville heat units (SHU), more preferably about 100,000 to about 20,000,000 Scoville heat units (SHU). Therefore, the flavor additive for the purposes of this article is a determined group of compounds. The calculation of Scoville heat units can be found in the following documents: American Spice Trade Association (ASTA) 1985 American Spice Trade Association Official Methods of Analysis, 3rd Edition, Amer.Spice Trade Assn., Englewood Cliffs, New Jersey.

[0402] In various embodiments, the flavor additive herein comprises capsaicin or a mixture of capsaicinoids. In certain instances, the liquid extract comprises a mixture of capsaicinoids, which is prepared by solvent extraction of a pepper known to contain a mixture of capsaicinoids rather than just capsaicinoids. In other embodiments, capsaicinoids are the source and used.

[0403] In other examples, the spice additives used are chemically unrelated to capsaicinoids, but still have a measurable heat level reported in Scoville units. These compounds are usually extracted from peppers other than Capsicum annuum, such as black pepper (Piper nigrum L.), and the most useful spice additive is not capsaicin but piperine (E, E or trans-trans isomers). Other spice additives for non-capsaicinoids used herein include but are not limited to shogaol, gingerol, isopiperine, piperine, isopiperine, 2-piperamide, piperine (4,5-dihydropiperine), piperamide (piperamide), pipericide (4-pipericide), piperine, pipergum, piperine, piperdardine (piperdardine) (6,7-dihydropipergum), 5-sarmentine (5-sarmentine), 6-sarmentine (6-sarmentine) and 7-trichostachine.

[0404] In various embodiments, the flavor additive is selected from capsaicin, dihydrocapsaicin, norcapsaicin, nordihydrocapsaicin, homocapsaicin, homodihydrocapsaicin, gingerol, piperine, shogaol, and mixtures thereof. Other capsaicinoids other than these six well-defined capsaicinoids may also be used in the compositions herein, noting that at least seven different capsaicinoids have been described in the genus Capsicumannuum, and perhaps two of them, possibly capsaicin and dihydrocapsaicin, together are responsible for the spicy taste of peppers. See MD Collins et al., "Improved Method for Quantifying Capsaicinoids in Capsicum Using High-Performance Liquid Chromatography", Hort Science 30 (1): 137-139, 1995. While the above compounds belong to the general class of chemessay stimulants, it is convenient to classify these compounds in the chemessay stimulant subset defined as flavor additives having a heat intensity of about 1,000 to about 20,000,000 Scoville Heat Units (SHU).

[0405] In certain embodiments, the THR product may comprise capsaicin ((E)-N-[(4-hydroxy-3-methoxyphenyl)methyl]-8-methylnon-6-enamide, CAS No. 404-86-4). In pure form (100% active), capsaicin is a white crystalline solid with an MP of 65° C. The purified material can be used directly in the products herein and can be obtained from chemical suppliers such as Sigma-Aldrich, VWR Avantor, and Alfa Chemistry.

[0406] In various embodiments, the THR product comprises 0 wt % to about 0.01 wt % of capsaicin ((E)-N-[(4-hydroxy-3-methoxyphenyl)methyl]-8-methylnon-6-enamide), based on the total weight of the alkaloid composition. In other examples, the amount of capsaicin is 0 wt % to about 0.0015 wt %, based on the total weight of the alkaloid composition used in the THR product.

[0407] In various examples, "liquid capsaicin" is used, for example, for reasons of cost and practicality. For example, a chili pepper flavor extract can be used, which is available from Olive Nation, LLC (Avon, Massachusetts) in quantities ranging from gallons to drums. This product is an ethanol extract of chili peppers, has a clear reddish-brown appearance, and has a specific gravity of about 0.8 g / mL at 20° C. This commercial material has about 99.1% by weight ethanol and about 0.9% by weight capsaicin active substance.

[0408] Other aspects of the substituted pyridine compounds of formula (I)

[0409] With reference to formula (I), independent of all other variables, A is:

[0410] And R 5 Selected from -(CH 2 )-NH 2 ;-(CH 2 ) 2 -NNH 2 ;-(CH 2 ) 3 -NH 2 ;-(CH 2 ) 4 -NH 2 ;-(CH 2 ) 5 -NH 2 ;-(CH 2 ) 6 -NH 2 ;-(CH 2 ) 7 -NH 2 ;-(CH 2 ) 8 -NH 2 ;-(CH 2 ) 9 -NH 2 ;-(CH 2 ) 10 -NH 2 ;-(CH 2 )-N(CH 3 ) 2 ;-(CH 2 ) 2 -N(CH 3 ) 2 ;-(CH 2 ) 3 -N(CH 3 ) 2 ;-(CH 2 ) 4 -N(CH3 ) 2 ;-(CH 2 ) 5 -N(CH 3 ) 2 ;-(CH 2 ) 6 -N(CH 3 ) 2 ;-(CH 2 ) 7 -N(CH 3 ) 2 ;-(CH 2 ) 8 -N(CH 3 ) 2 ;-(CH 2 ) 9 -N(CH 3 ) 2 and -(CH 2 ) 10 -N(CH 3 ) 2 .

[0411] In various embodiments, and independent of all other variables, A is:

[0412] And R 5 Selected from:

[0413]

[0414] wherein n is 1-10; and R 17 is selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl.

[0415] In various embodiments, and independent of all other variables, A is:

[0416] And R 5 yes wherein n is 1-10; and R 17 is H or CH 3 .

[0417] In various embodiments, the substituted pyridine compounds used herein have the structure of Formula (IA):

[0418] All variables are defined as above.

[0419] In various embodiments, the substituted pyridine compounds used herein have the structure of Formula (IA-1):

[0420] All variables are defined as above.

[0421] In various embodiments, the substituted pyridine compounds used herein have the structure of Formula (IA-2):

[0422] All variables are defined as above.

[0423] In various embodiments, the substituted pyridine compounds used herein have the structure of Formula (IA-3):

[0424] All variables are defined as above.

[0425] In various embodiments, the substituted pyridine compounds used herein have the structure of Formula (IA-4):

[0426] All variables are defined as above.

[0427] In various embodiments, the substituted pyridine compounds used herein have the structure of Formula (IA-5):

[0428] All variables are defined as above.

[0429] In various embodiments, the substituted pyridine compounds used herein have the structure of Formula (IB):

[0430] All variables are defined as above.

[0431] In various embodiments, the substituted pyridine compounds used herein have the structure of Formula (IC):

[0432] All variables are defined as above.

[0433] In various embodiments, the substituted pyridine compounds used herein have the structure of Formula (ID):

[0434] All variables are defined as above.

[0435] In various embodiments, the THR product herein comprises a substituted pyridine compound selected from the following, or a salt or mixed salt thereof:

[0436]

[0437]

[0438]

[0439]

[0440]

[0441]

[0442]

[0443]

[0444]

[0445]

[0446]

[0447]

[0448]

[0449]

[0450]

[0451]

[0452]

[0453]

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464]

[0465]

[0466]

[0467]

[0468]

[0469]

[0470]

[0471]

[0472]

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489] and

[0490]

[0491] In various embodiments, the THR products herein include at least one substituted pyridine compound of formula (IAA), or a salt or mixed salt thereof:

[0492] Among them, R 1 , R 2 , R 3 , R 4 and R 5 As defined above, the condition is that if R 5 In formula (IAA), CH 3 , then R 1 , R 2 , R 3 and R 4 They cannot all be H. For structure (I) and its subgeneric structures, this condition explicitly excludes the (R) and (S) enantiomers of nicotine from consideration in the compositions of the present disclosure.

[0493] As noted from the delineated selection of substituted pyridine compounds, many substituted pyridine compounds have a chiral center, which can be either (R) or (S). In most instances, the (S) enantiomer is preferred, and the (R) enantiomer may be intentionally excluded due to possible toxicity or undesirable physiological effects, or at least because it cannot provide any recognizable benefits. In various instances, the substituted pyridine compound of formula (I) with a chiral center is a racemic mixture with the chiral center (*) being (R) and (S), for example obtained by achiral synthesis. The (R) or (S) enantiomer can be obtained by chiral synthesis or by separation of enantiomers from a racemic mixture.

[0494] In various embodiments, the substituted pyridine compounds used herein have the structure of Formula (IAA):

[0495] and is independent of R 5 , R 1 , R 2 , R 3 and R 4 At least one of the R 1 , R 2 , R 3 and R 4 The remainder of the substituent is H.

[0496] In various embodiments of Formula (IAA), R 5 Yes CH 3 And R 1 , R2 , R 3 and R 4 At least one of them is not H.

[0497] In various embodiments of Formula (IAA), R 1 , R 2 , R 3 , R 4 and R 5 Each is H.

[0498] In various embodiments of Formula (IAA), R 5 Yes – (CH 2 )n-NR 15 R 16 , wherein n is an integer from 1 to 10, and wherein R 15 and R 16 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 15 and R 16 Together with the N atom to which they are bound, they form a 3-8 membered optionally substituted heterocyclic ring, including, for example, aziridine, azetidine, pyrrolidine, piperidine, 1,4-piperazine and morpholine. 1 , R 2 , R 3 and R 4 , R 5 Selected from -(CH 2 )-NH 2 ;-(CH 2 ) 2 -NH 2 ;-(CH 2 ) 3 -NH 2 ;-(CH 2 ) 4 -NH 2 ;-(CH 2 ) 5 -NH 2 ;-(CH 2 ) 6 -NH 2 ;-(CH 2 ) 7 -NH 2 ;-(CH 2 ) 8 -NH 2 ;-(CH 2 ) 9 -NH 2 ;-(CH 2 ) 10 -NH 2;-(CH 2 )-N(CH 3 ) 2 ;-(CH 2 ) 2 -N(CH 3 ) 2 ;-(CH 2 ) 3 -N(CH 3 ) 2 ;-(CH 2 ) 4 -N(CH 3 ) 2 ;-(CH 2 ) 5 -N(CH 3 ) 2 ;-(CH 2 ) 6 -N(CH 3 ) 2 ;-(CH 2 ) 7 -N(CH 3 ) 2 ;-(CH 2 ) 8 -N(CH 3 ) 2 ;-(CH 2 ) 9 -N(CH 3 ) 2 and -(CH 2 ) 10 -N(CH 3 ) 2 .

[0499] In various embodiments, R 5 is H, and R 1 , R 2 , R 3 and R 4 At least one of them is –(CH 2 )n-NR 6 R 7 , wherein n is an integer from 1 to 10, and wherein R 6 and R 7 R is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, 6 and R 7 Together with the nitrogen atom to which they are bonded, they form a 3-8 membered optionally substituted heterocyclic ring.

[0500] In various embodiments, the substituted pyridine compounds used herein have the structure of Formula (IAA):

[0501] Where R 5 Yes CH 3 , and R 1 , R 2 , R 3 and R 4 At least one of them is –(CH 2 )n-NR 15 R 16 , wherein n is an integer from 1 to 10, and wherein R 15 and R 16 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 15 and R 16 Together with the nitrogen atom to which they are bound, they form a 3-8 membered optionally substituted heterocyclic ring.

[0502] In various embodiments of Formula (IAA), R 5 Yes CH 3 , R 1 , R 2 , R 3 and R 4 At least one of them is –(CH 2 )nN(CH 3 ) 2 , wherein n is an integer from 1 to 10.

[0503] In various embodiments, substituted pyridine compounds of formula (IAA) for use in the THR products herein include, but are not limited to, (R) or (S)-3-(pyrrolidin-2-yl)pyridine, (R) or (S)-2-methyl-3-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-4-methyl-3-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-3-methyl-5-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-2,6-dimethyl-3-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-2,4-dimethyl-5-(1 -methylpyrrolidin-2-yl)pyridine, (R) or (S) -2,3-dimethyl-5-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S) -2,4-dimethyl-3-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S) -2,5-dimethyl-3-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S) -3,4-dimethyl-5-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S) -1-(2-aminoethyl)-2-(3-pyridyl)pyrrolidine, (R) or (S) -1-(3-aminopropyl)-2-(3-pyridyl)pyrrolidine, (R) or (S) -1-(4-aminobutyl)-2-(3-pyridyl)pyrrolidine Pyrrolidine, (R) or (S) -1-(5-aminopentyl)-2-(3-pyridyl)pyrrolidine, (R) or (S) -1-(2-dimethylaminoethyl)-2-(3-pyridyl)pyrrolidine, (R) or (S) -1-(3-dimethylaminopropyl)-2-(3-pyridyl)pyrrolidine, (R) or (S) -1-(4-dimethylaminobutyl)-2-(3-pyridyl)pyrrolidine, (R) or (S) -3-(2-(6-methylpyridin-3-yl)pyrrolidin-1-yl)propionitrile, (R) or (S) -4-(2-(6-methylpyridin-3-yl)pyrrolidin-1-yl)butyronitrile, (R) or (S) -1-(3-aminopropyl)-2-(6-methyl-3-pyridyl) Pyrrolidine, (R) or (S) -1-[3-(N,N-dimethylamino)propyl]-2-(6-methyl-3-pyridyl)pyrrolidine, (R) or (S) -1-(N,N-diethyl-3-aminopropyl-2-(3-pyridyl)pyrrolidine, (R) or (S) -3-(1-(2-(pyrrolidin-1-yl)ethyl)pyrrolidin-2-yl)pyrrolidine, (R) or (S) -3-(1-(2-(piperidin-1-yl)ethyl)pyrrolidin-2-yl)pyrrolidine, (R) or (S) -4-(2-(2-(pyridin-3-yl)pyrrolidin-1-yl)ethyl)morpholine, (R) or (S) -3-(1-(3-(pyrrolidin-1-yl)propyl)pyrrolidin-2-yl)pyrrolidine,(R) or (S)-3-(1-(3-(piperidin-1-yl)propyl)pyrrolidin-2-yl)pyridine and (R) or (S)-4-(3-(2-(pyridin-3-yl)pyrrolidin-1-yl)propyl)morpholine.

[0504] In each alkaloid example with a chiral center herein, the (S) enantiomer may be active as a nicotinic acetylcholine receptor ligand and is preferred, while the (R) enantiomer may be physiologically inert and may even have metabolic toxicity. Therefore, in a preferred embodiment, the racemic mixture of any of these alkaloids is not used in any THR product herein.

[0505] In various embodiments of Formula (IAA), R 1 , R 2 , R 3 , R 4 and R 5 independently selected from H, methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, provided that if R 5 is methyl, then R 1 , R 2 , R 3 and R 4 Cannot be all H.

[0506] In a preferred embodiment of formula (IAA), R 1 and R 5 All are methyl, R 2 , R 3 and R 4 Each is H, and the alkaloid is in the (S) configuration.

[0507] How to use

[0508] 1. Quit smoking by using THR products alone or in combination

[0509] As mentioned above, one purpose of the present disclosure is to provide THR products to current tobacco smokers who wish to and participate in a smoking cessation program. In some instances, THR products are used in combination to provide individuals with the sensation of smoking and to relieve the physical pain that comes with not smoking. In some instances, individuals in a smoking cessation program will be prescribed THR oral products and THR topical cream products for joints and muscles that may be considered "painful."

[0510] In various embodiments, the smoking cessation method comprises administering one or more THR products to an individual who wishes to quit smoking within a determined smoking cessation time, each THR product comprising at least one substituted pyridine compound having formula (I), or a salt or mixed salt thereof:

[0511]

[0512] In various embodiments, the time period for determining the stop may be a few days, weeks, months or years, preferably a few months to a year.

[0513] In various embodiments, the determined time period for discontinuation is part of a discontinuation plan that also includes dispensing a series of THR products during the determined time period for discontinuation.

[0514] In various embodiments, the time period determined for cessation is divided into consecutive time periods of shorter duration, wherein during each shorter time period, the individual who wishes to quit smoking receives and uses a different THR product in place of smoking cigarettes. Optionally, a combination of THR products are received and used. At the end of the program, individuals who wish to quit smoking will use only the THR products described herein, which, by definition, have no ((R) or (S) nicotine).

[0515] In various embodiments, individuals recruited into the smoking cessation program will be contacted with their program manager regularly (e.g., weekly) for personal counseling and receive different, adjusted, or other THR products, such as different combinations of THR products. During these periodic checks, the individual's compliance with the program can be assessed and adjusted accordingly. Some changes to the program can be to keep the individual at a certain weight / volume (w / v) level of the substituted pyridine compound for a longer period of more than one week, or to change or adjust the flavoring.

[0516] An important aspect of the present disclosure is to use a combination of THR products to quit smoking. As previously mentioned, not smoking tobacco may cause physical or psychological pain. Regardless of whether this pain is real, some THR products herein are intended to treat pain, particularly topical creams and pain relief patches. These types of THR products can be used in combination with one or more products (e.g., chewing gum or sublingual tablets) designed for oral delivery of substituted pyridine compounds for smoking cessation.

[0517] In the detailed description, references to "various embodiments", "one embodiment", "embodiment", "exemplary embodiment" indicate that the described embodiments may include specific features, structures, or characteristics, but each embodiment may not necessarily include the specific features, structures, or characteristics. Moreover, such phrases do not necessarily refer to the same embodiment. In addition, when a specific feature, structure, or characteristic is described in conjunction with an embodiment, it is considered to be within the knowledge of those skilled in the art to affect such feature, structure, or characteristic in conjunction with other embodiments, whether or not explicitly described. After reading the description, it will be clear to those skilled in the relevant art how to implement the present disclosure in alternative embodiments.

[0518] The steps described in any method or process description may be performed in any order and are not necessarily limited to the order presented. In addition, any reference to the singular includes plural embodiments, and reference to more than one component or step may include a singular embodiment or step. Moreover, any reference to attachment, fixing, connection, coupling, etc. may include permanent (e.g., integrated), removable, temporary, partial, complete and / or any other possible attachment options. Any components may be connected to each other by friction, snaps, sleeves, brackets, clips, or other devices now known in the art or developed thereafter. In addition, any reference to contactless (or similar terms) may also include reduced contact or contact minimization.

[0519] Benefits, other advantages, and solutions to problems have been described herein with respect to specific embodiments. However, these benefits, advantages, solutions to problems, and any elements that may produce any benefit, advantage, or solution or make it more significant should not be considered to be key, required, or essential features or elements of the present disclosure. The scope of the present disclosure is therefore limited only by the appended claims, in which, unless expressly stated, references to singular elements are not intended to mean "one and only one", but rather "one or more". In addition, when a phrase similar to "at least one of A, B, and C" or "at least one of A, B, or C" is used in a claim or specification, it is intended that the phrase be interpreted as indicating that A may exist alone in an embodiment, B may exist alone in an embodiment, C may exist alone in an embodiment, or any combination of elements A, B, and C may exist in a single embodiment; for example, A and B, A and C, B and C, or A and B and C. All structural, chemical and functional equivalents of the elements of the above-mentioned various embodiments known to those of ordinary skill in the art are expressly incorporated herein by reference, and are intended to be covered by the present claims. In addition, the device, or the parts of the device, or the method of using the device does not have to solve the problems that the present disclosure attempts to solve one by one, because it is included in the claims of the present application. In addition, the elements, parts or method steps in the present disclosure are not intended to be dedicated to the public, regardless of whether these elements, parts or method steps are clearly listed in the claims. Any claim element is not intended to cite 35 U.S.C.112 (f), unless the phrase "means of..." is used to clearly describe the element. As used herein, the term "includes", "comprising" or any other variation thereof is intended to cover non-exclusive inclusion, so that the chemistry, chemical composition, process, method, article or device including a list of elements not only includes these elements but also may include other elements that are not specifically listed or inherent to these chemistry, chemical composition, process, method, article or device.

Claims

1. A tobacco harm reduction (THR) product comprising: at least one substituted pyridine compound of formula (I); or a salt thereof, or a mixed salt thereof, wherein: A is selected from: R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, and R 6 and R 7 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 6 and R 7 Together = O; R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl; n is an integer from 1 to 10; and R 15 and R 16 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 15 and R 16 Together with the N atom to which they are bonded, they form a 3-8 membered optionally substituted heterocyclic ring, The condition is that if A is And R 5 is methyl, then R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 cannot all be H; and Among them, THR products contain absolutely no (R) or (S) nicotine.

2. The THR product of claim 1, further comprising at least one excipient, optionally at least one organic acid, optionally at least one chemical sensory stimulant, at least one flavoring agent, optionally a substrate, and combinations thereof.

3. The THR product according to claim 2, wherein: The excipient is selected from the group consisting of binders, diluents, syrups, sugars, sweeteners, solubilizers, solvents, polyols, emollients, humectants, oils, polymers, surfactants, carriers, stabilizers, preservatives and mixtures thereof.

4. A THR product as claimed in any of the preceding claims, comprising (a) a transdermal patch, (b) a dissolving film, (c) a lozenge, (d) a chewing gum, (e) an oral bag, (f) an impregnated toothpick, (g) an impregnated or coated dental floss, (h) a mouthwash, (i) a gummies, (j) a sublingual disintegrating tablet, (k) a topical / transdermal cream, (l) an oral spray, (m) an inhaler, (n) a nasal spray, (o) an alkaloid dispensing pouch, (p) an electronic cigarette, (q) an electronic nicotine delivery system or a similar nicotine replacement product.

5. A THR product as claimed in any preceding claim, wherein: The molar ratio of the moles of the substituted pyridine compound of formula (I) to the moles of the total organic acid is from about 25:1 to about 75:

1.

6. A THR product as claimed in any preceding claim, wherein: The at least one substituted pyridine compound is selected from (R) or (S)-3-(pyrrolidin-2-yl)pyridine, (R) or (S)-2-methyl-3-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-4-methyl-3-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-3-methyl-5-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-2-methyl-5-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S)-2,6-dimethyl-3-(1- (R) or (S) -2,4-dimethyl-5-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S) -2,3-dimethyl-5-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S) -2,4-dimethyl-3-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S) -2,5-dimethyl-3-(1-methylpyrrolidin-2-yl)pyridine, (R) or (S) -3,4-dimethyl-5-(1-methylpyrrolidin-2-yl)pyridine, or a salt or a mixture of salts thereof.

7. A method for promoting cessation of smoking in an individual who wishes to quit smoking, the method comprising: A series of alkaloid compositions is administered to the individual for use by the individual over the determined stopping period, each alkaloid composition in the series comprising at least one substituted pyridine compound of formula (I): or a salt thereof, or a mixed salt thereof, wherein: A is selected from: R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, and R 6 and R 7 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 6 and R 7 Together = O; R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl; n is an integer from 1 to 10; and R 15 and R 16 is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl, or R 15 and R 16 Together with the N atom to which they are bonded, they form a 3-8 membered optionally substituted heterocyclic ring, The condition is that if A is And R 5 is methyl, then R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 cannot all be H; and Among them, THR products contain absolutely no (R) or (S) nicotine.

8. The method of claim 7, wherein the individual inhales each composition in the series by smoking an electronic cigarette, starting from the beginning of the determined cessation period when the alkaloid composition has the highest level (w / v) of the substituted pyridine compound of formula (I) or its salt or mixed salt thereof, and ending at the end of the determined cessation period when the composition has the lowest level (w / v) of the substituted pyridine compound of formula (I) or its salt or mixed salt thereof, whereby the individual stops smoking at the beginning of the determined cessation period.

9. The method of claim 7, wherein: The individual (a) applies a transdermal patch, (b) applies a dissolving film, (c) consumes a lozenge, (d) consumes a chewing gum, (e) consumes a buccal pouch, (f) licks a dipped toothpick, (g) uses dipped or coated dental floss, (h) consumes a mouthwash, (i) consumes a gummies, (j) consumes a sublingual disintegrating tablet, or (k) applies a topical / transdermal cream.

10. The method according to any one of claims 7 to 9, wherein: The determined cessation period is part of a smoking cessation program that also includes dispensing a series of vaporizable alkaloid compositions to an individual who wishes to quit smoking during the determined cessation period.

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