Liquid oral products

Abstract

The disclosure provides liquid or gel compositions configured for oral use and products including such compositions, the liquid or gel compositions including an active ingredient according to Formula I, II, or III.

Description

AttyDktNo. R60999 17380WO 07022LIQUID ORAL PRODUCTSTECHNICAL FIELD

[0001] The present disclosure relates to an oral product. In particular, the present disclosure relates to products intended for human consumption. The products are configured for oral use and deliver substances such as flavors and / or active ingredients during use.BACKGROUND

[0002] There are many categories of products intended for oral use and enjoyment. For example, oral tobacco products containing nicotine, which is known to have both stimulant and anxiolytic properties, have been available for many years. Conventional formats for so-called "smokeless" tobacco products include moist snuff, snus, and chewing tobacco, which are typically formed almost entirely of particulate, granular, or shredded tobacco, and which are either portioned by the user or presented to the user in individual portions, such as in single-use pouches or sachets. See for example, the types of smokeless tobacco formulations, ingredients, and processing methodologies set forth in US Pat. Nos. 6,668,839 to Williams; 6,834,654 to Williams; 6,953,040 to Atchley et al.; 7,032,601 to Atchley et al.; and 7,694,686 to Atchley et al.; 7,810,507 to Dube et al.; 7,819,124 to Strickland et al.; 7,861,728 to Holton, Jr. et al.; 7,901,512 to Quinter et al.; 8,627,828 to Strickland et al.; 11,246,334 to Atchley, each of which is incorporated herein by reference. In addition, traditional tobacco materials and non-tobacco materials have been combined with other ingredients to form product formats distinct from traditional smokeless products, with example formats including lozenges, pastilles, gels, and the like. See, for example, the types of products described in US Patent App. Pub. Nos. 2008 / 0196730 to Engstrom et al.; 2008 / 0305216 to Crawford et al.; 2009 / 0293889 to Kumar et al.; 2010 / 0291245 to Gao et al; 2011 / 0139164 to Mua et al.; 2012 / 0037175 to Cantrell et al.; 2012 / 0055494 to Hunt et al.; 2012 / 0138073 to Cantrell et al.; 2012 / 0138074 to Cantrell et al.; 2013 / 0074855 to Holton, Jr.; 2013 / 0074856 to Holton, Jr.; 2013 / 0152953 to Mua et al.; 2013 / 0274296 to Jackson et al.; 2015 / 0068545 to Moldoveanu et al.; 2015 / 0101627 to Marshall et al.; and 2015 / 0230515 to Lampe et al., each of which is incorporated herein by reference.

[0003] There is continuing interest in the development of new types of oral products that deliver advantageous sensorial or biological activity. Such products typically contain flavorants and / or active ingredients such as nicotine, caffeine, botanicals, or cannabidiol. The format of such products can vary and include pouched products containing a powdered or granular composition, lozenges, pastilles, liquids, gels, emulsions, meltable compositions, and the like. See, for example, the types of products described in US Patent App. Pub. Nos.2022 / 0160675 to Gerardi et al.; 2022 / 0071984 to Poole et al.; 2021 / 0378948 to Gerardi et al.; 2021 / 0330590 to Hutchens et al.; 2021 / 0186081 to Gerardi et al.; 2021 / 0177754 to Keller et al; 2021 / 0177043 to Gerardi et al.; 2021 / 0177038 to Gerardi et al.; 2021 / 0169867 to Holton, Jr. et al.; 2021 / 0169792 to Holton, Jr. et al.; 2021 / 0169132 to Holton, Jr. et al.; 2021 / 0169121 to St. Charles, and 2021 / 0169122 to St. Charles, each of which is incorporated herein by reference.-1- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022BRIEF SUMMARY

[0004] The present disclosure generally provides liquid or gel compositions configured for oral use and products comprising such compositions. The disclosure includes, without limitations, the following embodiments.

[0005] Embodiment 1 : A liquid or gel composition adapted for oral use, comprising:water and / or a water-miscible solvent; andan active ingredient selected from (i) a substituted 3-(l-methylpyrrolidin-2-yl)pyridine having a structure according to Formula I:wherein R1, R2, R3, and R4are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl, aryl, alkylaryl, amino, halogen, and cyano, wherein any of said alkyl, alkoxy, cycloalkyl, alkenyl, alkenyl, alkynyl, aryl, alkylaryl, and amino may optionally be substituted; and at least one of R1, R2, R3, and R4are not hydrogen; (ii) a substituted 3-(l- methylpyrrolidin-2-yl)pyridine having a structure according to Formula II:"wherein R5and R6are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl, aryl, alkylaryl, amino, halogen, and cyano, wherein any of said alkyl, alkoxy, cycloalkyl, alkenyl, alkenyl, alkynyl, aryl, alkylaryl, and amino may optionally be substituted;R7is selected from the group consisting of hydrogen and CH ,:R8is selected from the group consisting of hydrogen and C1-C3 alkyl; andat least one of R7and R8is not hydrogen; and (iii) a 3-(azetidin-2-yl)pyridine or 3-(azetidin-2- ylmethoxy)pyridine having a structure according to Formula III:wherein L is a bond or -OCH2-*, where the asterisk indicates an attachment point to the azetidine ring; R9, R10, R11, and R12are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, and cyano;R13is H or CH3; andR14isH orCH3.-2- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022

[0006] Embodiment 2: The liquid or gel composition of Embodiment 1, wherein the active ingredient has a structure according to Formula I, optionally wherein R1, R2, and R3are each H, and R4is optionally substituted Ci-Ce alkyl, F, Cl, Br, OCH3, OEt, or CN, or optionally wherein R1, R2, and R3are each H, and R4is C1-C3 alkyl.

[0007] Embodiment 3: The liquid or gel composition of Embodiment 1, wherein the active ingredient has a structure according to Formula II, optionally wherein R5is optionally substituted Ci-Cs alkyl, F, Cl, Br, OCH3, OCH2CH3, or CN; and R6is H, or optionally wherein R5is H; and R6is optionally substituted Ci-Ce alkyl, F, Cl, Br, OCH3, OCH2CH3, or CN.

[0008] Embodiment 4: The liquid or gel composition of Embodiment 1, wherein the active ingredient has a structure according to Formula III, optionally wherein R9is H or CH3; and R10, R11,and R12are each H.

[0009] Embodiment 5: The liquid or gel composition of any one of Embodiments 1-4, wherein the active ingredient is in the form of a free base, a salt with an acid, an ion pair with an organic acid, or a resin complex wherein the active ingredient is bound to a polymeric resin.

[0010] Embodiment 6: The liquid or gel composition of any one of Embodiments 1-5, wherein the active ingredient is in the form of a salt or ion pair with benzoic acid or tocopherol succinate, optionally further comprising sodium benzoate.

[0011] Embodiment 7: The liquid or gel composition of any one of Embodiments 1-6, further comprising at least one thickening agent, such as a natural gum or cellulose derivative.

[0012] Embodiment 8: The liquid or gel composition of Embodiment 7, wherein the thickening agent is present in an amount of about 0.1 to about 10% by weight, based on the total weight of the composition.

[0013] Embodiment 9: The liquid or gel composition of any one of Embodiments 1-8, wherein the composition comprises water and at least one polyol, optionally wherein the weight ratio of water to the polyol is about 3:1 to about 1:3.

[0014] Embodiment 10: The liquid or gel composition of any one of Embodiments 1-9, wherein the water and / or water-miscible solvent is present in an amount of about 50% or higher, such as about 70 to about 99% by weight, based on the total weight of the composition.

[0015] Embodiment 11 : The liquid or gel composition of any one of Embodiments 1-10, wherein the composition is in the form of an emulsion and comprises at least one oil and at least one emulsifying agent, optionally wherein the emulsifying agent is selected from the group consisting of surfactants, phospholipids, amphiphilic polysaccharides, amphiphilic proteins, and combinations thereof.

[0016] Embodiment 12: The liquid or gel composition of Embodiment 11, wherein the at least one emulsifying agent is present in an amount of about 0.0 f to about f5% by weight, based on the total weight of the composition.

[0017] Embodiment 13: The liquid or gel composition of any one of Embodiments 1-12, wherein the active ingredient is present in an amount of about 0.05 to about 5% by weight of the composition, calculated as the free base and based on the total weight of the composition.-3- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022

[0018] Embodiment 14: The liquid or gel composition of any one of Embodiments 1-13, further comprising one or more components selected from the list consisting of salts, such as sodium chloride, sweeteners, flavorants, buffering agents, oral care additives, and combinations thereof.

[0019] Embodiment 15: The liquid or gel composition of any one of Embodiments 1-14, wherein the composition has a viscosity of about 1 to about 100,000 cP, such as about 60 to about 10,000 cP or about 10,000 to about 30,000 cP or about 30,000 to about 100,000 cP.

[0020] Embodiment 16: A spray container comprising a spray nozzle and an internal compartment housing the liquid or gel composition of any one of Embodiments 1-15.

[0021] Embodiment 17: The spray container of Embodiment 16, wherein the spray container is configured to expel about 25 mg to about 300 mg of the liquid or gel composition per spraying action.

[0022] These and other features, aspects, and advantages of the disclosure will be apparent from a reading of the following detailed description together with the accompanying drawing, which are briefly described below. The scope of the disclosure includes any combination of two, three, four, or more of the above-noted embodiments as well as combinations of any two, three, four, or more features or elements set forth in this disclosure, regardless of whether such features or elements are expressly combined in a specific embodiment description herein. This disclosure is intended to be read holistically such that any separable features or elements of the disclosed embodiments should be viewed as intended to be combinable or separately / in isolation unless the context clearly dictates otherwise.BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Having thus described aspects of the disclosure in the foregoing general terms, reference will now be made to the accompanying drawing, which is not necessarily drawn to scale. The drawing is an example only and should not be construed as limiting the disclosure.

[0024] FIG. 1 is a perspective view of a non-limiting example of a spray bottle for dispensing the liquid composition of the disclosure.DETAILED DESCRIPTION

[0025] The present disclosure will now be described more fully hereinafter with reference to example embodiments thereof. These example embodiments are described so that this disclosure will be thorough and complete, and will fully convey the scope of the disclosure to those skilled in the art. Indeed, the disclosure may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements.

[0026] As used in this specification and the claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0027] The term "about" used throughout this specification is used to describe and account for small fluctuations. For example, the term "about" can refer to less than or equal to ±10%, such as less than or equal -4- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022to ±5%, less than or equal to ±2%, less than or equal to ±1%, less than or equal to ±0.5%, less than or equal to ±0.2%, less than or equal to ±0.1% or less than or equal to ±0.05%. All numeric values herein are modified by the term "about," whether or not explicitly indicated. A value modified by the term "about" of course includes the specific value. For instance, "about 5.0" must include 5.0.

[0028] The present disclosure relates to liquid or gel oral compositions that include an active ingredient such as those disclosed herein. As used herein, reference to a “gel” refers to a semi-solid colloid comprising fine particles dispersed in a liquid medium and having a relatively high viscosity such that the gel behaves like a solid at steady state. The liquid or gel compositions are adapted for oral use and intended for application to the oral cavity. The liquid or gel compositions can be in the form of a solution or an emulsion, as discussed in greater detail below.

[0029] A solution is understood to refer to a solute (e.g., an active ingredient as disclosed herein) dissolved in a solvent such as water and / or a water-miscible solvent. An emulsion is a colloidal particulate system. The particulates (referred to herein also as droplets or particles) are generally solid spheres, and the surfaces of such particulates are amorphous and lipophilic with a negative charge. The emulsion can be, for example, an oil-in-water (O / W) emulsion or a water-in-oil (W / O) emulsion.

[0030] The emulsion can be a nanoemulsion, which comprises nano-scale particles having an average size of less than about 1,000 nm, for example, from about 10 to about 1,000 nm. Nanoemulsions as described herein comprise nanoparticles of oil emulsified in water and typically further comprise an emulsifying agent, an active ingredient, and a flavorant. The size of the nanoparticles may be determined by quasi-electric light scattering (QELS) as described in Bloomfield, Ann. Rev. Biophys. Bioeng., 10:421-450 (1981), incorporated herein by reference. It may also be measured by correlation spectroscopy that analyzes the fluctuation in scattering of light due to Brownian motion, or by transmission electron microscopy (TEM).

[0031] The emulsion as disclosed herein may be characterized by reference to a polydispersity index. Polydispersity indicates the uniformity of droplet size in a nanoemulsion. The higher the value of polydispersity, the lower will be the uniformity of droplet size. It may be defined as the ratio of standard deviation to mean droplet size. It may be measured by spectrophotometric methods. In some embodiments, it may be advantageous to provide nanoemulsions with a low polydispersity index, e.g., less than about 0.5. In some embodiments, the nanoemulsion has a polydispersity index of less than about 0.3.

[0032] The emulsion as disclosed herein may be characterized by reference to zeta potential. Zeta potential is a measure of the charge on the surface of droplet in emulsion. In some embodiments, the zeta potential of the particles is from about -40 mV to about 40 mV.

[0033] The liquid or gel compositions typically include one or more liquid carrier components, such as water and / or water-miscible solvents, such as polyols. Example water-miscible solvents include short chain mono-, di-, and polyhydric alcohols (polyols), such as ethanol, benzyl alcohol, glycerol, propylene glycol, 1,2-propanediol, propylene carbonate, polyethylene glycol with an average molecular weight of about 200 to about 10,000, diethylene glycol monoethyl ether, and combinations thereof. Use of polyols in addition to (or in lieu of) water can impact mouthfeel and other organoleptic properties of the composition, and will also impact -5- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022water activity of the composition. The total amount of water and / or water-miscible solvents can vary, but will typically make up about 50% by weight or more of the total weight of the composition, such as about 50% to about 99% by weight or about 60% to about 97.5% by weight or about 70% to about 95% by weight.

[0034] In some embodiments, the liquid or gel compositions will include both water and at least one water-miscible solvent, such as a polyol. Example weight ratios of water to water-miscible solvent include 3 : 1 to 1 :3 or 2.5 : 1 to 1 :2.5 or 2: 1 to 1 :2. In some embodiments, the weight ratio of water to water-miscible solvent is about 3:1 to about 1:1 or about 2.5:1 to about 1:1.

[0035] In some embodiments, the oral compositions will include one or more thickening agents to adjust the viscosity of the oral composition. Example thickening agents povidone, alginates, starches, pectin, carrageenan, pullulan, zein, natural gums, cellulose derivatives and the like, and combinations thereof. In some embodiments, the thickening agent is a gum, for example, a natural gum. As used herein, a natural gum refers to polysaccharide materials of natural origin that have binding properties, and which are also useful as a thickening or gelling agents. Representative natural gums derived from plants, which are typically water soluble to some degree, include xanthan gum, guar gum, gum arabic, ghatti gum, gum tragacanth, karaya gum, locust bean gum, gellan gum, and combinations thereof. In some embodiments, the thickening agent comprises a cellulose derivative or a combination of such derivatives. Example cellulose derivatives include cellulose ethers (including carboxyalkyl ethers), meaning a cellulose polymer with the hydrogen of one or more hydroxyl groups in the cellulose structure replaced with an alkyl, hydroxyalkyl, or aryl group. Non-limiting examples of such cellulose derivatives include methylcellulose, hydroxypropylcellulose ("HPC"), hydroxypropylmethylcellulose ("HPMC"), hydroxyethyl cellulose, and carboxymethylcellulose ("CMC").

[0036] In one embodiment, the thickening agent can also impart thixotropic properties to the liquid or gel composition, which may be advantageous for maintaining the active ingredient in a dispersed form. An example thickening agent of this type is VIVAPUR® MCG available from JRS Pharma GmbH & Co. KG, which is a mixture of microcrystalline cellulose and sodium carboxymethylcellulose.

[0037] A thickening agent may be employed in amounts sufficient to provide the desired physical attributes, such as viscosity, to the composition. The amount of thickening agent utilized in the composition can vary, but is typically up to about 10 weight percent, and certain embodiments are characterized by a thickening agent content of at least about 0.1% by weight, such as about 1 to about 10% by weight, or about 2 to about 5% by weight, based on the total weight of the composition.

[0038] The viscosity of the compositions of the disclosure can vary. Typical ranges of viscosity include about 1 to about 100,000 centipoise (cP), including lower viscosity embodiments within a range of about 60 to about 10,000 cP and higher viscosity embodiments within a range of about 10,000 to about 30,000 cP or 30,000 to about 100,000 cP. The viscosity of the composition may be measured using, for example, a Brookfield viscometer HA Series, SC4 water jacket, 27 / 13R sample chamber and a No. 27 spindle.

[0039] In some embodiments, the oral compositions can further include at least one emulsifying agent to stabilize the composition in an emulsion form. By "emulsifying agent" is meant a substance which aids in the formation and stabilization of emulsions by promoting dispersion of hydrophobic and hydrophilic (e.g., oil -6- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022and water) components. In general, emulsifiers are amphiphilic molecules chosen from, for example, nonionic and ionic amphiphilic molecules. The expression “amphiphilic molecule” means any molecule of bipolar structure comprising at least one hydrophobic portion and at least one hydrophilic portion and having the properly of reducing the surface tension of water and of reducing the interface tension between water and an oily phase. Emulsifying agents / amphiphilic molecules as provided herein are also referred to as, for example, surfactants and emulsifiers.

[0040] In some embodiments, the emulsifying agent comprises neutral, positively charged, or negatively charged natural or synthetic phospholipids molecules. Phospholipids are made up of two fatty acid tails and a phosphate group head, connected via a third molecule, glycerol. Non-limiting examples of natural phospholipids including soybean lecithin, egg lecithin, phosphatidylglycerol, phosphatidylinositol, phosphatidylethanolamine, phosphatidic acid, sphingomyelin, diphosphatidylglycerol, phosphatidylserine, phosphatidylcholine and cardiolipin; synthetic phospholipids including dimyristoylphosphatidylcholine, dimyristoylphosphatidylglycerol, distearoylphosphatidylglycerol and dipalmitoylphosphatidylcholine; and hydrogenated or partially hydrogenated lecithins and phospholipids. Non-limiting examples of synthetic phospholipid derivatives include phosphatidic acid (DMPA, DPP A, DSP A), phosphatidylcholine (DDPC, DLPC, DMPC, DPPC, DSPC, DOPC, POPC, DEPC), phosphatidylglycerol (DMPG, DPPG, DSPG, POPG), phosphatidylethanolamine (DMPE, DPPE, DSPE DOPE), phosphatidylserine (DOPS), PEG phospholipid (mPEG-phospholipid, polyglycerin-phospholipid, functionalized-phospholipid, and terminal activated-phospholipid).

[0041] In some embodiments, the emulsifying agent comprises a surfactant, which may be ionic or nonionic, and which may be hydrophobic or hydrophilic. Examples of hydrophobic surfactants include, but are not limited to, Maisine 35-1, Imwitor 742, Capmul MCM, Capmul PG 12, Lauroglycol 90, Lauroglycol FCC, Caproyl 90, Captex 250, a fatty acid selected from the group consisting of octanoic acid, decanoic acid, undecanoic acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, and linolenic acid. As used herein, a hydrophobic surfactant may also be referred to as a poorly water soluble surfactant or a lipophilic surfactant.

[0042] Examples of hydrophilic surfactants may include, but are not limited to polyoxyethylene sorbitan fatty acid esters, hydrogenated castor oil ethoxy lates, PEG mono- and di-esters of palmitic and stearic acids, fatty acid ethoxy lates, and combinations thereof.

[0043] Examples of suitable surfactants generally include, but are not limited to: polyoxyethylene- sorbitan-fatty acid esters; e.g., mono- and tri-lauryl, palmityl, stearyl and oleyl esters; e.g., products of the type known as polysorbates and commercially available under the trade name Tween®; polyoxyethylene fatty acid esters, e.g., polyoxyethylene stearic acid esters of the type known and commercially available under the trade name Myij®; polyoxyethylene castor oil derivatives, e.g., products of the type known and commercially available as Cremophors®. Particularly suitable are polyoxyl 35 castor oil (Cremophor®EL) and polyoxyl 40 hydrogenated castor oil (Cremophor®RH40); a- tocopherol, a-tocopheryl polyethylene glycol succinate (vitamin E TPGS), a- tocopherol palmitate and a-tocopherol acetate; PEG glyceryl fatty acid esters such as -7- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022PEG-8 glyceryl caprylate / caprate (commercially known as Labrasol®), PEG-4 glyceryl caprylate / caprate (Labrafac Hydro WL 1219), PEG-32 glyceryl laurate (Gelucire 44 / 14), PEG-6 glyceryl mono oleate (Labrafil® M 1944 CS), PEG-6 glyceryl linoleate (Labrafil® M 2125 CS); propylene glycol mono- and difatty acid esters, such as propylene glycol laurate, propylene glycol caprylate / caprate; also diethyleneglycolmonoethylether (DGME), commercially known as Transcutol® (Gattefosse, Westwood, N.J.); sorbitan fatty acid esters, such as the type known and commercially available under the name Span® (e.g., Span 85); polyoxy ethylene-polyoxypropylene co-polymers, e.g., products of the type known and commercially available as Pluronic® or Poloxamer®; glycerol triacetate; and monoglycerides and acetylated monoglycerides, e.g., glycerol monodicocoate (Imwitor® 928), glycerol monocaprylate (Imwitor® 308), and mono-and diacetylated monoglycerides.

[0044] In some embodiments, the emulsifying agent is a surfactant, a phospholipid, an amphiphilic polysaccharide, an amphiphilic protein, or a combination thereof. In some embodiments, the emulsifying agent is an ionic or non-ionic surfactant. In some embodiments, the emulsifying agent comprises Tween 20, Tween 80, Span 20, Span 40, Span 60, Span 80, lecithin, a hydrocolloid gum, a modified starch, or a combination thereof. The concentration of the emulsifying agent present in the disclosed nanoemulsion may vary. The concentration of the emulsifying agent may be in a range of up to about 15% by weight, for example from about 0.01% to about 15%, from about 0.1% to about 10%, or from about 1% to about 5% by weight based on the entirety of the composition.

[0045] In some embodiments, such as compositions in the form of an emulsion, the composition will further include at least one oil. Any suitable oil may be used to form the emulsion as disclosed herein, including petroleum- based (e.g., mineral oil) and natural or naturally derived oils (e.g., from plant materials or animal sources). In some embodiments, the oil is a food grade oil, including fractionated oils. Such oils include, but are not limited to, vegetable oils (e.g., acai oil, almond oil, amaranth oil, apricot oil, apple seed oil, argan oil, avocado oil, babassu oil, beech nut oil, ben oil, bitter gourd oil, black seed oil, blackcurrant seed oil, borage seed oil, bomeo tallow nut oil, bottle gourd oil, brazil nut oil, buffalo gourd oil, butternut squash seed oil, cape chestnut oil, canola oil, carob cashew oil, cocoa butter, cocklebur oil, coconut oil, com oil, cothune oil, coriander seed oil, cottonseed oil, date seed oil, dika oil, egus seed oil, evening primrose oil, false flax oil, flaxseed oil, grape seed oil, grapefruit seed oil, hazelnut oil, hemp oil, kapok seed oil, kenaf seed oil, lallemantia oil, lemon oil, linseed oil, macadamia oil, mafura oil, manila oil, meadowfoam seed oil, mongongo nut oil, mustard oil, niger seed oil, nutmeg butter, okra seed oil, olive oil, orange oil, palm oil, papaya seed oil, peanut oil, pecan oil, perilla seed oil, persimmon seed oil, pequi oil, pili nut oil, pine nut oil, pistachio oil, pomegranate seed oil, poppyseed oil, pracaxi oil, prune kernel oil, pumpkin seed oil, quinoa oil, ramtil oil, rapeseed oil, rice bran oil, royle oil, sacha inchi oil, safflower oil, sapote oil, seje oil, sesame oil, shea butter, soybean oil, sunflower oil, taramira oil, tea seed oil, thistle oil, tigemut oil, tobacco seed oil, tomato seed oil, walnut oil, watermelon seed oil, wheat germ oil, and combinations thereof), animal oils (e.g., cattle fat, buffalo fat, sheep fat, goat fat, pig fat, lard, camel fat, tallow, liquid margarine, fish oil, fish liver oil, whale oil, seal oil, and combinations thereof), and mineral oils.-8- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022

[0046] In some embodiments, the oil comprises mineral oil. In some embodiments, the oil comprises a long chain fatty acid, a monoacylglycerol, a diacylglycerol, a triacylglycerol, or a combination thereof, wherein the acyl group is a long chain fatty acid. As used herein, "long chain fatty acid" refers to a carboxylic (CO2H) acid having an aliphatic carbon chain of from about 11 to about 21 carbon atoms. The aliphatic carbon chain may be straight or branched. The aliphatic carbon chain may be saturated (i.e., having all sp3carbon atoms), or may be unsaturated (i.e., having at least one site of unsaturation). As used herein, the term "unsaturated" refers to the presence of a carbon-carbon, sp2double bond in one or more positions within the aliphatic carbon chain. Unsaturated alkyl groups may be mono- or polyunsaturated. Representative long chain fatty acids include, but are not limited to, undecylic acid, undecanoic acid, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, margaric acid, stearic acid, nonadecanoic acid, arachidic acid, heneicosanoic acid, a-linolenic acid, stearidonic acid, eicosapentaenoic acid, cervonic acid, linoleic acid, linolelaidic acid, g-linolenic acid, dihomo-y -linolenic acid, and arachidonic acid.

[0047] In some embodiments, the oil comprises an acyl glycerol, such as a monoacylglycerol, a diacylglycerol, or a triacylglycerol, wherein the acyl group is a long chain fatty acid as described herein. In some embodiments, the oil comprises polyunsaturated long chain fatty acids, or mono-di- or triacylglycerol containing polyunsaturated long chain fatty acids as the acyl component. The chain lengths of the fatty acids in naturally occurring triglycerides may vary, but is typically 16, 18, or 20 carbon atoms. In some embodiments, the concentration of polyunsaturated fatty acid (as free fatty acid or as e.g., triglycerides) in the oil can range from about 2% to 100% (w / w), such as from about 5% to 100% (w / w) or greater than 10%, e.g., 20%-80% (w / w).

[0048] In some embodiments, the oil comprises castor oil, com oil, coconut oil, cod liver oil, evening primrose oil, cottonseed oil, palm oil, rice bran oil, sesame oil, rapeseed oil, canola oil, cocoa butter, linseed oil, olive oil, peanut oil, soybean oil, safflower oil, flaxseed oil, sunflower oil, olive oil, or a combination thereof.

[0049] The amount of oil present within the disclosed emulsion can vary, but is typically from about 0.5% to about 80% by weight, or from about 1% to about 60% by weight, or from about 20% to about 50% by weight, based on the total weight of the composition.

[0050] In some embodiments, the composition may further comprise a stabilizer to assist in maintaining the emulsion. Representative examples of suitable types of stabilizers include polysaccharides, polyols, sorbitan esters, glycerol esters, polyethylene glycol esters, block polymers, acrylic polymers (such as Pemulen™ polymers), silicon based surfactants, and polysorbates. In some embodiments, the stabilizer is sodium oleate, glycerine, xylitol, sorbitol, ascorbic acid, sodium edetate, a sorbitan ester, a glycerol monoester, or a combination thereof.

[0051] The concentration of the stabilizer present in the composition may vary. When present, the concentration of the emulsifying agent may be in a range of up to about 10% by weight, for example from about 0.01% to about 10%, from about 0.1% to about 5%, or from about 0.5% to about 1% by weight based on the weight of the composition.-9- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022

[0052] The water content of the liquid composition may be described in terms of water activity. As used herein, the term "water activity" or "Aw" refers to the partial vapor pressure of water in a composition divided by the partial vapor pressure of pure water at the same temperature. According to this definition, pure distilled water has an Aw of exactly one. The water activity of the oral composition may vary according to the form and desired properties, but will typically be less than about 0.85, for example, from about 0.25 to about 0.85 or about 0.70 to about 0.85. Reducing the water activity of the composition is also believed to reduce the rate of microbial growth of the composition, which in turn, enhances the storage stability of the composition.

[0053] In some embodiments, the compositions and products of the disclosure can be characterized as completely free or substantially free of nicotine (3-(l-methylpyrrolidin-2-yl)pyridine). By "substantially free" it is meant that no nicotine has been intentionally added, beyond trace amounts that may be present e.g., as an impurity in another component, including as a minor impurity in the substituted 3-(l-methylpyrrolidin-2-yl)pyridine. For example, some embodiments can be characterized as having less than 0.001% by weight of nicotine, or less than 0.0001%, or even 0% by weight of nicotine, calculated as the free base and based on the total weight of the composition. In some embodiments the composition is completely free of (R)-, ( )-, and (R / S)-3-(l-methylpyrrolidin-2-yl)pyridine (e.g., having 0%by weight of nicotine, including racemic nicotine and nicotine enantiomers, calculated as the free base and based on the total weight of the composition). Active IngredientsSubstituted 3-(l-methylpyrrolidin-2-yl)pyridine

[0054] In some embodiments, the compositions of the disclosure comprise a substituted 3-(l-methylpyrrolidin-2-yl)pyridine. As used herein, the term "substituted 3-(l-methylpyrrolidin-2-yl)pyridine" refers to a compound having a 3-(l-pyrrolidin-2-yl)pyridine) scaffold and bearing one or more non-hydrogen substituents on the pyrrolidine ring, and optionally on the pyridine ring. In some embodiments, the compositions and products of the disclosure can be characterized as completely free or substantially free of nicotine (3-(l-methylpyrrolidin-2-yl)pyridine). By "substantially free" it is meant that no nicotine has been intentionally added, beyond trace amounts that may be present e.g., as an impurity in another component, including as a minor impurity in the substituted 3-(l-methylpyrrolidin-2-yl)pyridine. For example, some embodiments can be characterized as having less than 0.01% by weight of nicotine, or less than 0.001% by weight of nicotine, or less than 0.0001%, or even 0% by weight of nicotine, calculated as the free base and based on the total weight of the composition. In some embodiments the composition is completely free of (R)-, (S)-, and (RZS)-3-(l-methylpyrrolidin-2-yl)pyridine (e.g., having 0%by weight of nicotine, including racemic nicotine and nicotine enantiomers, calculated as the free base and based on the total weight of the composition). In some embodiments, compositions of the disclosure do not contain any compounds obtained by chemical reactions utilizing nicotine as a starting material. In preferred embodiments, the substituted 3-(l-methylpyrrolidin-2-yl)pyridine present is not synthetically derived from nicotine.

[0055] In some embodiments, the substituted 3-(l-methylpyrrolidin-2-yl)pyridine has a structure according to Formula I:-10- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022wherein R1, R2, R3, and R4are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl, aryl, alkylaryl, amino, halogen, and cyano, wherein any of said alkyl, alkoxy, cycloalkyl, alkenyl, alkenyl, alkynyl, aryl, alkylaryl, and amino may optionally be substituted; and at least one of R1, R2, R3, and R4are not hydrogen.

[0056] Substituted 3-(l-methylpyrrolidin-2-yl)pyridines according to Formula I with various R1, R2, R3, and R4substituents have been reported previously. See for example, U.S. Patent Nos. 4,321,387, 4,155,909; 5,015,741, 5,138,062, and 5,703,100, each of which is incorporated by reference herein and describe such substituted 3-(l-methylpyrrolidin-2-yl)pyridines, their synthesis, and pharmacological properties. Substituted 3-(l-methylpyrrolidin-2-yl)pyridines and their pharmacological profiles have also been disclosed in Wang et al., Drug Development Research 1998, Volume 45, Issue 1, Pages 10-16; and Dukat et al. European Journal of Medicinal Chemistry 1999, 34(1): 31-40.

[0057] In some embodiments, R1, R2, and R3are each H, and R4is a non-hydrogen substituent.

[0058] In some embodiments, R4is optionally substituted Ci-Ce alkyl, F, Cl, Br, OMe, OEt, or CN.

[0059] In some embodiments, R1, R2, and R3are each H, and R4is optionally substituted Ci-Ce alkyl, F, Cl, Br, OCH3, OEt, or CN.

[0060] In some embodiments, R1, R2, and R3are each H, and R4is C1-C3 alkyl.

[0061] In some embodiments, R1, R2, and R3are each H, and R4is CH3. In such embodiments, the compound of Formula I may be referred to as 2-methyl-5-(l-methylpyrrolidin-2-yl)pyridine.

[0062] The pharmacology of 2-methyl-5-(l-methylpyrrolidin-2-yl)pyridine has been reported in, for example, Dukat et al. European Journal of Medicinal Chemistry, Volume 31, Issue 11, 1996, Pages 875-888 (incorporated herein by reference), and the pharmacological profile of the (S)-enantiomer of 2-methyl-5-(l-methylpyrro lidin-2 -yl)pyridine in the form of the benzoate salt (CAS 2861225-70-7 ; referred to as Iniotinc™) is discussed in Carmines et al, Poster #6; 76thTSRC Conference 2023, Norfolk, VA, USA).

[0063] Without wishing to be bound by any particular theory, it is believed that certain substitutions for hydrogen on the pyridine ring of the substituted 3-(l-methylpyrrolidin-2-yl)pyridine compound of Formula I preserve the general pharmacological profile and physiological effects of nicotine while offering the potential for one or more of greater potency, reduced product consumption, more rapid and / or complete absorption, and the like. Particularly, it is believed that in some embodiments, substituted 3-(l-methylpyrrolidin-2-yl)pyridines of the disclosure according to Formula I are readily absorbed through oral mucosa by virtue of their lipophilicity. Lipophilicity is conveniently measured in terms of logP, the partition coefficient of a molecule between a lipophilic phase and an aqueous phase, usually octanol and water, respectively. Accordingly, in some embodiments, the substituted 3-(l-methylpyrrolidin-2-yl)pyridine of Formula I has a calculated or experimental logP of about 1 or greater, where logP is the logw of the partitioning coefficient of -11- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022the substituted 3-(l-methylpyrrolidin-2-yl)pyridine between octanol and water. LogP values may be measured experimentally according to protocols well known to one of skill in the art. Alternatively, logP values may be calculated using commercially available software. In some embodiments, the substituted 3-(l-methylpyrrolidin-2-yl)pyridine of Formula I has a calculated logP from 1 to about 2, such as 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, or 1.9. In some embodiments, the substituted 3-(l-methylpyrrolidin-2-yl)pyridine of Formula I has a calculated logP from about 1.2 to about 1.7. In some embodiments, the substituted 3-(l-methylpyrrolidin-2-yl)pyridine having a calculated logP from about 1.2 to about 1.7 bears one or more lipophilic substituents on the pyridine ring, such as Ci-Ce alkyl, or C1-C3 alkyl. In some embodiments, the lipophilic substituent is methyl, and is present at the 2, 4, 5, or 6 position of the pyridine ring. In some embodiments, the lipophilic substituted 3-(l-methylpyrrolidin-2-yl)pyridine of Formula I is 2-methyl-5-(l-methylpyrrolidin-2-yl)pyridine.

[0064] The substituted 3-(l-methylpyrrolidin-2-yl)pyridine (e.g., 2-methyl-5-(l-methylpyrrolidin-2-yl)pyridine) of Formula I may be present as a single enantiomer or as a mixture of enantiomers. In some embodiments, the substituted 3-(l-methylpyrrolidin-2-yl)pyridine is present in racemic form, meaning there are equal amounts of (R)- and (S)-enantiomers present. In some embodiments, the composition comprises unequal amounts of (R)- and (S)-enantiomer (i.e., is enriched in either the (R)- or (S)-enantiomer. In some embodiments, the composition predominantly comprises the substituted 3-(l-methylpyrrolidin-2-yl)pyridine (e.g., 2-methyl-5-(l-methylpyrrolidin-2-yl)pyridine) in the (R)-configuration, for example, about 90% or more of the total quantity of substituted 3-(l-methylpyrrolidin-2-yl)pyridine present is in the (R)-configuration. In some embodiments, the composition predominantly comprises the substituted 3-(l-methylpyrrolidin-2-yl)pyridine (e.g., 2-methyl-5-(l-methylpyrrolidin-2-yl)pyridine) in the (S)-configuration, for example, about 90% or more of the total quantity of substituted 3-(l-methylpyrrolidin-2-yl)pyridine present is in the (S)-configuration. In some embodiments, the composition comprises 95% or more of the (S)-configuration of the substituted 3-(l-methylpyrrolidin-2-yl)pyridine (e.g., 2-methyl-5-(l-methylpyrrolidin-2-yl)pyridine), based on the total amount of substituted 3-(l-methylpyrrolidin-2-yl)pyridine present.

[0065] The quantity of substituted 3-(l-methylpyrrolidin-2-yl)pyridine of Formula I (e.g., 2-methyl-5-(l-methylpyrrolidin-2-yl)pyridine) present in the composition may vary. Typically, the substituted 3-(l-methylpyrrolidin-2-yl)pyridine of Formula I (e.g., 2-methyl-5-(l-methylpyrrolidin-2-yl)pyridine, calculated as the free base) is present in a concentration of at least about 0.001% by weight of the composition, such as in a range from about 0.01% to about 10%. In some embodiments, the substituted 3-(l-methylpyrrolidin-2-yl)pyridine of Formula I (e.g., 2-methyl-5-(l-methylpyrrolidin-2-yl)pyridine) is present in a concentration from about 0.1% w / w to about 10% by weight, such as, e.g., from about from about 0.1% w / w, about 0.2%, about 0.3%, about 0.4%, about 0.5% about 0.6%, about 0.7%, about 0.8%, or about 0.9%, to about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% by weight, calculated as the free base and based on the total weight of the composition. In some embodiments, the substituted 3-(l-methylpyrrolidin-2-yl)pyridine of Formula I (e.g., 2-methyl-5-(l-methylpyrrolidin-2-yl)pyridine) is present in a concentration from about 0.1% w / w to about 3% by weight, such as, e.g., from -12- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022about 0.1% w / w to about 2.5%, from about 0.1% to about 2.0%, from about 0.1% to about 1.5%, or from about 0.1% to about 1% by weight, calculated as the free base and based on the total weight of the composition. In some embodiments, the composition comprises 2-methyl-5-(l-methylpyrrolidin-2-yl)pyridine in an amount from about 0.01 to about 10% by weight, based on the total weight of the composition.

[0066] The substituted 3-(l-methylpyrrolidin-2-yl)pyridine of Formula I (e.g., 2-methyl-5-(l-methylpyrrolidin-2-yl)pyridine) may be present in the composition as the free base, as a salt with a suitable acid, or in the form of an ion pair with an organic acid. Each of these forms is described further herein below.

[0067] In some embodiments, the substituted 3-(l-methylpyrrolidin-2-yl)pyridine has a structure according to Formula II:>wherein:R5and R6are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl, aryl, alkylaryl, amino, halogen, and cyano, wherein any of said alkyl, alkoxy, cycloalkyl, alkenyl, alkenyl, alkynyl, aryl, alkylaryl, and amino may optionally be substituted;R7is selected from the group consisting of hydrogen and CH,:R8is selected from the group consisting of hydrogen and C1-C3 alkyl; andat least one of R7and R8is not hydrogen.

[0068] In some embodiments, R5is optionally substituted Ci-Ce alkyl, F, Cl, Br, OCH3, OCH2CH3, or CN; and R6is H.

[0069] In some embodiments, R5is H; and R6is optionally substituted Ci-Cs alkyl, F, Cl, Br, OCH3, OCH2CH3, or CN.

[0070] Certain substituted 3-(l-methylpyrrolidin-2-yl)pyridines with various R5, R6, R7, and R8substituents have been reported previously. See for example, U.S. Patent Nos. 4,321,387, 4,155,909; 5,015,741, 5,138,062, and 5,703,100, each of which is incorporated by reference herein and describe example substituted 3-(l-methylpyrrolidin-2-yl)pyridines, their synthesis, and pharmacological properties. Certain substituted 3-(l-methylpyrrolidin-2-yl)pyridines and their pharmacological profdes have also been disclosed in Wang et al., Drug Development Research 1998, Volume 45, Issue 1, Pages 10-16; Dukat et al. European Journal of Medicinal Chemistiy 1999, 34(1): 31-40; Linet ai., J. Med. Chem. (1994), 37, 3542-3553.

[0071] In some embodiments, R5and R6areH; R7is CH3; and R8is H. In such embodiments, the compound of Formula II may be referred to as 3-(l,2-dimethylpyrrolidin-2-yl)pyridine, or 2'-methyl-5-(l-methylpyrrolidin-2-yl)pyridine, and has a structure:-13- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022

[0072] The compound 3-(l,2-dimethylpyrrolidin-2-yl)pyridine is known in the literature, and has a Chemical Abstracts Registry Number of 220650-38-4. The synthesis of this compound has been reported in Rouchaud et al., J Het Chem 2012, 49(1), 161-166; Wang et al., Drug Dev Res 1998, 45(1), 10-16; Secor et al., Tetrahedron Lett. (1981), 22(33), 3151-3154; US Patent Application Publication No. 2013 / 0157995; PCT Application Publication No. WO2012 / 031220; and US Patent Publication No. 9,440,948, each of which are incorporated by reference herein with respect to the synthesis of 3-(l,2-dimethylpyrrolidin-2-yl)pyridine.

[0073] In some embodiments, R5and R6areH; R7is H; and R8is CH3. In such embodiments, the compound of Formula II may be referred to as 3-(l,4-dimethylpyrrolidin-2-yl)pyridine, or 4'-methyl-5-(l-methylpyrrolidin-2-yl)pyridine, and has a structure:

[0074] The compound 3-(l,4-dimethylpyrrolidin-2-yl)pyridine is known in the literature, has a Chemical Abstracts Registry Number of 74805-00-8, and is commercially available from, for example, Enamine Stock Building Blocks and Aurora Building Blocks. The synthesis of this compound has been reported in US Patent Publication No. 9,440,948; and EP Patent No. 559495, each of which are incorporated by reference herein with respect to the synthesis of 3-(l,4-dimethylpyrrolidin-2-yl)pyridine.

[0075] In some embodiments, R5is CH3; R6is H; R7is CH3; and R8is H. In such embodiments, the compound of Formula II may be referred to as 5-(l,2-dimethylpyrrolidin-2-yl)-2 -methylpyridine, and has a stmcture:

[0076] The compound 5-(l,2-dimethylpyrrolidin-2-yl)-2-methylpyridine may be readily synthesized according to known reactions. For example, commercially available 2-methyl-5-(2-methylpyrrolidin-2-yl)pyridine (Chemical Abstracts Registry Number of 1528955-30-7; Aurora Building Blocks, Adlab Chemicals Building Blocks) can be N-methylated with formaldehyde and formic acid, or alternatively with formaldehyde and a reducing agent such as sodium cyanoborohydride to afford 5-(l,2-dimethylpyrrolidin-2-yl)-2 -methylpyridine. Alternatively, 5-(l,2-dimethylpyrrolidin-2-yl)-2 -methylpyridine maybe synthesized by lithiation of 2-methyl-5-bromopyridine, reaction of the lithiated pyridine with N-methylpyrrolidone, and addition of methyl lithium to the perchlorate salt of the resulting imine. This reaction sequence is shown below in Scheme 1.Scheme 1-14- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022

[0077] In some embodiments, R5is H or CH3, R6is H, R7is H or CH3, and R8is H or CH3, provided that at least one of R7and R8is CH3. Accordingly, in some embodiments, the substituted 3-(l-methylpyrrolidin-2-yl)pyridine has a structure selected from the group consisting of:

[0078] In some embodiments, R5is H, R6is F, CH3, or OCH3, R7is H or CH3, and R8is H or CH3, provided that at least one of R7and R8is CH3. Accordingly, in some embodiments, the substituted 3-(l-methylpyrrolidin-2-yl)pyridine has a structure selected from the group consisting of:

[0079] A substituted 3-(l-methylpyrrolidin-2-yl)pyridine of Formula II as described herein may be present as a single enantiomer or as a mixture of enantiomers. In some embodiments, the substituted 3-(l-methylpyrrolidin-2-yl)pyridine of Formula II is present in racemic form, meaning there are equal amounts of (R)- and (S)-enantiomers present. In some embodiments, the composition comprises unequal amounts of (R)-and (S)-enantiomer (i.e., is enriched in either the (R)- or (S)-enantiomer). In some embodiments, the composition predominantly comprises the substituted 3-(l-methylpyrrolidin-2-yl)pyridine of Formula II in the (R)-configuration, for example, about 90% or more of the total quantity of substituted 3-(l-methylpyrrolidin-2-yl)pyridine present is in the (R)-configuration. In some embodiments, the composition predominantly comprises the substituted 3-(l-methylpyrrolidin-2-yl)pyridine of Formula II in the (S)-configuration, for example, about 90% or more of the total quantity of substituted 3-(l-methylpyrrolidin-2-yl)pyridine present is in the (S)-configuration. In some embodiments, the composition comprises 95% or more of the (S)- -15- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022configuration of the substituted 3-(l-methylpyrrolidin-2-yl)pyridine of Formula II, based on the total amount of substituted 3-(l-methylpyrrolidin-2-yl)pyridine present.

[0080] In some embodiments, the substituted 3-(l-methylpyrrolidin-2-yl)pyridine of Formula II is non-racemic, and has one of the following structures:

[0081] In some embodiments, the substituted 3-(l-methylpyrrolidin-2-yl)pyridine of Formula II is non-racemic, and has a structure selected from the group consisting of:

[0082] Such single enantiomer or enantiomerically enriched compounds may be obtained through classical resolution techniques using salt formation with chiral acids to form diastereomeric salts separable by crystallization. Suitable chiral acids include, but are not limited to, (R)- or (S)-dibenzoyl tartaric acid, di-p-toluoyl tartaric acid, or di-p-anisolyl tartaric acid; (R)- or (S)-mandelic acid, and (R)- or (S)-10-camphorsulfonic acid. Alternatively, one of skill in the art will recognize opportunities for chiral syntheses using either commercially available starting materials with established chiral centers or through the use of chiral auxiliary chemistries. For example, preparation of the 2S,4R enantiomer of 3-(l,4-dimethylpyrrolidin- -16- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 070222-yl)pyridine has been reported in, for example, US Patent Publication No. 4,332,945, incorporated herein by reference with respect to syntheses of chiral nicotine analogs.

[0083] The pharmacology of various substituted 3-(l-methylpyrrolidin-2-yl)pyridines of Formula II such as those described herein has been reported in, for example, Lin et al., J. Med. Chem., 1994, 37, 3542-3553; Dukat et al. European Journal of Medicinal Chemistry, 31(11), 1996, 875-888; US9440948; Wang et al., Drug Dev Res 1998, 45(1), 10-16 (each of which is incorporated herein by reference), among many others. Generally, small substituents such as methyl groups are well tolerated at the 2'- or 4'-positions of the nicotine pyrrolidine ring, and small substituents such as alkyl, halogen, alkoxy, and the like are well tolerated at the 5-or 6-position of the nicotine pyridine ring. For example, 3-(l-methylpyrrolidin-2-yl)pyridines bearing a methyl substituent at the 2' or 4' position are equipotent or even more potent than nicotine with respect to binding affinity to the nicotinic acetylcholine receptor, and are expected to preserve the pharmacological effects of nicotine in vivo. See, for example US Patent Publication No. 5,278,176, Lin et al., J. Med. Chem., 1994, 37, 3542-3553, and is believed that certain alkyl substitutions for hydrogen on the pyridine and / or pyrrolidine rings of the substituted 3-(l-methylpyrrolidin-2-yl)pyridine compound preserve the general pharmacological Wang et al., Drug Dev Res 1998, 45(1), 10-16. Without wishing to be bound by any particular theory, these compounds are believed to provide the general pharmacological profile and physiological effects of nicotine while offering the potential for one or more of greater potency, reduced product consumption, more rapid and / or complete absorption, and the like. Particularly, it is believed that in some embodiments, substituted 3-(l-methylpyrrolidin-2-yl)pyridines of the disclosure according to Formula II are readily absorbed through oral mucosa by virtue of their lipophilicity.

[0084] In some embodiments, the substituted 3-(l-methylpyrrolidin-2-yl)pyridine of Formula II has a calculated logP from 1 to about 2, such as 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, or 1.9. In some embodiments, the substituted 3-(l-methylpyrrolidin-2-yl)pyridine of Formula II has a calculated logP from about 1.2 to about 1.7.

[0085] The quantity of substituted 3-(l-methylpyrrolidin-2-yl)pyridine of Formula II present in the composition may vary. Typically, the substituted 3-(l-methylpyrrolidin-2-yl)pyridine of Formula II, calculated as the free base) is present in a concentration of at least about 0.001% by weight of the composition, such as in a range from about 0.01% to about 10%. In some embodiments, the substituted 3-(l-methylpyrrolidin-2-yl)pyridine of Formula II is present in a concentration from about 0.1% w / w to about 10% by weight, such as, e.g., from about from about 0.1% w / w, about 0.2%, about 0.3%, about 0.4%, about 0.5% about 0.6%, about 0.7%, about 0.8%, or about 0.9%, to about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% by weight, calculated as the free base and based on the total weight of the composition. In some embodiments, the substituted 3-(l-methylpyrrolidin-2-yl)pyridine of Formula II is present in a concentration from about 0.1% w / w to about 3% by weight, such as, e.g., from about 0.1% w / w to about 2.5%, from about 0.1% to about 2.0%, from about 0.1% to about 1.5%, or from about 0.1% to about 1% by weight, calculated as the free base and based on the total weight of the composition. One of skill in the art will recognize that the amount of any particular substituted 3-(l-methylpyrrolidin-2- -17- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022yl)pyridine present in the composition may vary based on the potency of the compound, the composition matrix, and the desired physiological effect for the composition.

[0086] In some embodiments, the amount of substituted 3-(l-methylpyrrolidin-2-yl)pyridine of Formula II in the composition is determined by potency relative to nicotine. For example, in some embodiments, the amount of substituted 3-(l-methylpyrrolidin-2-yl)pyridine is determined based on the ratio of the a^2 nicotinic receptor binding affinity (Ki) for nicotine to the a-ibi I<> for the specific substituted 3-(l-methylpyrrolidin-2-yl)pyridine. This ratio is referred to herein as the "potency factor." Such potency factors indicate the amount of substituted 3-(l-methylpyrrolidin-2-yl)pyridine estimated to provide physiological activity in a user which is roughly equivalent to that of a given weight of nicotine.

[0087] In some embodiments, a substituted 3-(l-methylpyrrolidin-2-yl)pyridine of the disclosure has a potency factor from about 0.5 to about 2 (i.e., the K;of the substituted 3-(l-methylpyrrolidin-2-yl)pyridine is from about twice to about half that of nicotine).

[0088] In some embodiments, the amount of substituted 3-(l-methylpyrrolidin-2-yl)pyridine in the composition is 1 nicotine equivalent. Accordingly, in some embodiments, 1 nicotine equivalent of substituted 3-(l-methylpyrrolidin-2-yl)pyridine is an amount by weight from about 2 to about 0.5 times that of nicotine. For example, a product comprising 2 mg of nicotine, when the nicotine is replaced by a substituted 3-(l-methylpyrrolidin-2-yl)pyridine of the disclosure, may include from about 1 mg to about 4 mg of the substituted 3-(l-methylpyrrolidin-2-yl)pyridine. Similarly, a product comprising 20 mg of nicotine, when the nicotine is replaced by a substituted 3-(l-methylpyrrolidin-2-yl)pyridine, may contain from about 10 mg to about 40 mg of the substituted 3-(l-methylpyrrolidin-2-yl)pyridine.

[0089] In some embodiments, the substituted 3-(l-methylpyrrolidin-2-yl)pyridine of Formula II has the structure:having a potency factor of about 1.35, meaning that embodiments, the amount of substituted 3-(l-methylpyrrolidin-2-yl)pyridine present may be about 74% of the amount of nicotine required to achieve the same effect.

[0090] In some embodiments, the substituted 3-(l-methylpyrrolidin-2-yl)pyridine of Formula II has the structure:having a potency factor of about 0.9, meaning that in some embodiments, the amount of substituted 3-(l-methylpyrrolidin-2-yl)pyridine present may be about 110% of the amount of nicotine required to achieve the same effect.-18- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022

[0091] The substituted 3-(l-methylpyrrolidin-2-yl)pyridine of Formula II may be present in the composition as the free base, as a salt with a suitable acid, or in the form of an ion pair with an organic acid. Each of these forms is described further herein below.3-(azetidin-2-yl)pyridines and 3-(azetidin-2-ylmethoxy)pyridines

[0092] Disclosed herein are compositions configured for oral use comprising an optionally substituted 3-(azetidin-2-yl)pyridine or an optionally substituted 3-(azetidin-2-ylmethoxy)pyridine. As used herein, the term "substituted 3-(azetidin-2-yl)pyridine" refers to a compound having a 3-(azetidin-2-yl)pyridine scaffold and bearing one or more non-hydrogen substituents on the azetidine ring, and optionally on the pyridine ring. As used herein, the term "substituted 3-(azetidin-2-ylmethoxy)pyridine" refers to a compound having a 3-(azetidin-2-ylmethoxy)pyridine scaffold and bearing one or more non-hydrogen substituents on the azetidine ring, and optionally on the pyridine ring.

[0093] As described above, compositions of the disclosure do not contain nicotine and do not contain any compounds obtained by chemical reactions utilizing nicotine as a starting material.

[0094] In some embodiments, the 3-(azetidin-2-yl)pyridine or 3-(azetidin-2-ylmethoxy)pyridine has a structure according to Formula III:wherein:L is a bond or -OCH2-*, where the asterisk indicates an attachment point to the azetidine ring;R9, R10, R11, and R12are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, and cyano;R13is H or CH3; andR14is H orCH3.

[0095] In some embodiments, L is a bond.

[0096] In some embodiments, R9is CH3, F, Cl, Br, OCH3, OEt, or CN.

[0097] In some embodiments, R9is H or CH3; and R10, R11,and R12are each H.

[0098] In some embodiments:R13and R14are both H;R13and R14are both CH3;R13is H andR14is CH3; orR13is CH3andR14is H.

[0099] In some embodiments, the 3-(azetidin-2-yl) pyridine is 3-(azetidin-2-yl)pyridine, and has a structure:-19- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022

[0100] The compound 3-(azetidin-2-yl)pyridine is known in the literature. The synthesis of this compound has been reported in JOC 1979, 44(18), 3136; Med Chem Res (1993) 2:552-5633; in International Patent Application Publication No. W02012 / 031220, and in US Patent Nos. 4,163,855 and 4,163,856, all of which are incorporated herein in their entireties.

[0101] In some embodiments, the 3-(azetidin-2-yl) pyridine is 3-(l-methylazetidin-2-yl)pyridine, having the structure:

[0102] The compound 3-(l-methylazetidin-2-yl)pyridine is known in the literature. The synthesis of this compound has been reported in International Patent Application Publication No. WO2012 / 031220, previously incorporated by reference herein.

[0103] In some embodiments, the 3-(azetidin-2-yl) pyridine has a structure selected from the group consisting of:

[0104] Such compounds are either known, or may be readily prepared according to adaptations of methods utilized for preparation of related 3-(azetidin-2-yl) pyridines and 3 -(1-methylpyrro lidin-2 -yl)pyridines described herein above. See, e.g., U.S. Patent No 4,163,855, previously incorporated by reference herein. The compound 5-(2-azetidinyl)-2 -methylpyridine is known in the literature and has a Chemical Abstracts Registry (CAS) Number of 1270467-65-6, and the R- and S-enantiomers have CAS numbers 1213081-15-2 and 1212969-96-4, respectively.

[0105] In some embodiments, the composition comprises a 3-(azetidin-2-ylmethoxy)pyridine (i.e., L is -OCH2-*).

[0106] In some embodiments, R9is CH3, F, Cl, Br, OCH3, OEt, or CN.

[0107] In some embodiments, R9is H or CH3; and R10, R11,and R12are each H.

[0108] In some embodiments:R13and R14are both H;-20- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022R13and R14are both CH3;R13is H andR14is CH3; orR13is CH3andR14is H.

[0109] In some embodiments, the 3-(azetidin-2-ylmethoxy)pyridine has a structure selected from the group consisting of:

[0110] These compounds are known in the literature. The synthesis of these compounds has been reported in International Patent Application Publication No. WO2012 / 031220, previously incorporated by reference herein.

[0111] In some embodiments, the 3-(azetidin-2-ylmethoxy)pyridine has a structure selected from the group consisting of:

[0112] Such compounds are either known, or may be readily prepared according to adaptations of methods utilized for preparation of related the 3-(azetidin-2-ylmethoxy)pyridine, and / or the 3-(azetidin-2-yl)pyridines and substituted 3-(l-methylpyrrolidin-2-yl)pyridines described herein above.

[0113] An optionally substituted 3-(azetidin-2-yl)pyridine or optionally substituted 3-(azetidin-2-ylmethoxy)pyridine as described herein may be present as a single enantiomer or as a mixture of enantiomers. In some embodiments, the optionally substituted 3-(azetidin-2-yl)pyridine or optionally substituted 3-(azetidin-2-ylmethoxy)pyridine is present in racemic form, meaning there are equal amounts of (R)- and (S)-enantiomers present. In some embodiments, the composition comprises unequal amounts of (R)- and (S)-enantiomer (i.e., is enriched in either the (R)- or (S)-enantiomer). In some embodiments, the composition predominantly comprises the optionally substituted 3-(azetidin-2-yl)pyridine or optionally substituted 3-(azetidin-2-ylmethoxy)pyridine in the (Reconfiguration, for example, about 90% or more of the total quantity of optionally substituted 3-(azetidin-2-yl)pyridine or optionally substituted 3-(azetidin-2-ylmethoxy)pyridine -21- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022present is in the (R)-configuration. In some embodiments, the composition predominantly comprises the optionally substituted 3-(azetidin-2-yl)pyridine or optionally substituted 3-(azetidin-2-ylmethoxy)pyridine in the (S)-configuration, for example, about 90% or more of the total quantity of optionally substituted 3- (azetidin-2-yl)pyridine or optionally substituted 3-(azetidin-2-ylmethoxy)pyridine present is in the (S)- configuration. In some embodiments, the composition comprises 95% or more of the (S)-configuration of the optionally substituted 3-(azetidin-2-yl)pyridine or optionally substituted 3-(azetidin-2-ylmethoxy)pyridine, based on the total amount of optionally substituted 3-(azetidin-2-yl)pyridine or optionally substituted 3- (azetidin-2-ylmethoxy)pyridine present.

[0114] In some embodiments, the optionally substituted 3-(azetidin-2-yl)pyridine is non-racemic, and has one of the following structures:

[0115] In some embodiments, the optionally substituted 3-(azetidin-2-ylmethoxy)pyridine is non-racemic, and has one of the following structures:-22- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022

[0116] Such single enantiomer or enantiomerically enriched compounds may be obtained through classical resolution techniques using salt formation with chiral acids to form diastereomeric salts separable by crystallization. Suitable chiral acids include, but are not limited to, (R)- or (S)-dibenzoyl tartaric acid, di-p-toluoyl tartaric acid, or di-p-anisolyl tartaric acid; (R)- or (S)-mandelic acid, and (R)- or (S)-10-camphorsulfonic acid. Alternatively, one of skill in the art will recognize opportunities for chiral syntheses using either commercially available starting materials with established chiral centers or through the use of chiral auxiliary chemistries. For example, preparation of the 2S,4R enantiomer of 3-(l,4-dimethylpyrrolidin-2-yl)pyridine has been reported in, for example, US Patent Publication No. 4,332,945, incorporated herein by reference with respect to syntheses of chiral nicotine analogs.

[0117] The pharmacology of certain 3-(azetidin-2-yl)pyridines and 3-(azetidin-2-ylmethoxy)pyridines has been previously disclosed, for example, in the references cited herein with respect to synthesis of such compounds. Generally, these compounds exhibit high affinity for one or more subtypes of nicotinic acetylcholine receptors, particularly the a4b2 subtype. The overall pharmacological profiles have been shown to be or are expected to be comparable to that of nicotine.

[0118] The quantity of optionally substituted 3-(azetidin-2-yl)pyridine or 3-(azetidin-2-ylmethoxy)pyridine present in the composition may vary. Typically, the optionally substituted 3-(azetidin-2-yl)pyridine or 3-(azetidin-2-ylmethoxy)pyridine, calculated as the free base, is present in a concentration of at least about 0.001% by weight of the composition, such as in a range from about 0.01% to about 10%. In some embodiments, the optionally substituted 3-(azetidin-2-yl)pyridine or 3-(azetidin-2-ylmethoxy)pyridine is present in a concentration from about 0.05% w / w to about 5% by weight, such as, e.g., from about from about -23- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 070220.05% w / w. about 0.1% w / w, about 0.2%, about 0.3%, about 0.4%, about 0.5% about 0.6%, about 0.7%, about 0.8%, or about 0.9%, to about 1%, about 2%, about 3%, about 4%, or about 5% by weight, calculated as the free base and based on the total weight of the composition. In some embodiments, the optionally substituted 3-(azetidin-2-yl)pyridine or 3-(azetidin-2-ylmethoxy)pyridine is present in a concentration from about 0.05% w / w to about 4% by weight, such as, e.g., from about 0.05% w / w to about 3.5%, from about 0.07% to about 2.5%, from about 0.1% to about 2.0%, from about 0.1% to about 1.5%, or from about 0.1% to about 1% by weight, calculated as the free base and based on the total weight of the composition. One of skill in the art will recognize that the amount of any particular optionally substituted 3-(azetidin-2-yl)pyridine or 3-(azetidin-2-ylmethoxy)pyridine present in the composition may vary based on the potency of the compound, the composition matrix, and the desired physiological effect for the composition.

[0119] In some embodiments, the amount of optionally substituted 3-(azetidin-2-yl)pyridine or 3-(azetidin-2-ylmethoxy)pyridine in the composition is determined by potency relative to nicotine. For example, in some embodiments, the amount of optionally substituted 3-(azetidin-2-yl)pyridine or 3-(azetidin-2-ylmethoxy)pyridine is based on the potency factor as described above for substituted 3-(l-methylpyrrolidin-2-yl)pyridines. In some embodiments, an optionally substituted 3-(azetidin-2-yl)pyridine or 3-(azetidin-2-ylmethoxy)pyridine of the disclosure has a potency factor from about 0.1 to about 30, such as from about 2 to about 30.

[0120] In some embodiments, the amount of optionally substituted 3-(azetidin-2-yl)pyridine or 3-(azetidin-2-ylmethoxy)pyridine in the composition is 1 nicotine equivalent. Accordingly, in some embodiments, 1 nicotine equivalent of optionally substituted 3-(azetidin-2-yl)pyridine or 3-(azetidin-2-ylmethoxy)pyridine is an amount by weight from about 10 to about 0.03 times that of nicotine. In some embodiments, 1 nicotine equivalent of optionally substituted 3-(azetidin-2-yl)pyridine or 3-(azetidin-2-ylmethoxy)pyridine is an amount by weight from about 0.5 to about 0.03 times that of nicotine.

[0121] For example, a product comprising 2 mg of nicotine, when the nicotine is replaced by an optionally substituted 3-(azetidin-2-yl)pyridine or 3-(azetidin-2-ylmethoxy)pyridine of the disclosure, may include from about 0.06 mg to about 1 mg of the optionally substituted 3-(azetidin-2-yl)pyridine or 3-(azetidin-2-ylmethoxy)pyridine. Similarly, a product comprising 20 mg of nicotine, when the nicotine is replaced by an optionally substituted 3-(azetidin-2-yl)pyridine or 3-(azetidin-2-ylmethoxy)pyridine, may contain from about 0.6 mg to about 100 mg of the optionally substituted 3-(azetidin-2-yl)pyridine or 3-(azetidin-2-ylmethoxy)pyridine.

[0122] In some embodiments, the optionally substituted 3-(azetidin-2-yl)pyridine has the structure:"""-24- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022having a potency factor of about 30, meaning that in some embodiments, the amount of optionally substituted 3-(azetidin-2-yl)pyridine present may be about 3% of the amount of nicotine required to achieve the same effect.

[0123] In some embodiments, the optionally substituted 3-(azetidin-2-ylmethoxy)pyridine has the structure:having a potency factor of about 3, meaning that in some embodiments, the amount of 3-(azetidin-2-ylmethoxy)pyridine present may be about 33% of the amount of nicotine required to achieve the same effect.

[0124] The optionally substituted 3-(azetidin-2-yl)pyridine or 3-(azetidin-2-ylmethoxy)pyridine may be present in the composition as the free base, as a salt with a suitable acid, or in the form of an ion pair with an organic acid. Each of these forms is described further herein below.Other Active Ingredients

[0125] In some embodiments, the substituted 3-(l-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, or optionally 3-(azetidin-2-ylmethoxy)pyridine of the present disclosure is replaced with, or combined with, other active ingredients that provide the same general pharmacological profile and / or physiological effects of nicotine. Certain of these active ingredients may be equipotent or even more potent than nicotine with respect to binding affinity to the nicotinic acetylcholine receptor, and are expected to preserve the pharmacological effects of nicotine in vivo. Without wishing to be bound by any particular theory, in some embodiments, these compounds are believed to provide the general pharmacological profile and physiological effects of nicotine while offering the potential for one or more of greater potency, reduced product consumption, more rapid and / or complete absorption, and the like.

[0126] Example active ingredients of this type include, without limitation, cytisine, varenicline, acetylcholine, choline, epibatidine, lobeline, analogs thereof, or combinations thereof. Suitable analogs include any of the above-noted compounds having one or more substituents on any of the carbon atoms thereof, with example substituents including alkyl (e.g., C1-C3 alkyl), alkoxy, cycloalkyl, alkenyl, alkynyl, aryl, alkylaryl, amino, halogen, and cyano.

[0127] In some embodiments, the other active ingredient is cytisine or an analog thereof. Cytisine is a naturally occurring alkaloid present in certain plant genera, such as Laburnum and Cytisus of the family Fabaceae. Cytisine (CAS Registry No. 485-35-8) has the structure:-25- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022Cytisine is commercially available and has been utilized in post-Soviet states for more than 40 years as an aid to smoking cessation under the brand name Tabex (Sopharma AD). Cytisine is a partial agonist of the a4b2 nicotinic acetylcholine receptor.

[0128] In some embodiments, the other active ingredient is varenicline or an analog thereof. Varenicline is commercially available as Chantix® (Pfizer) and is a medication used as an aid for smoking cessation. Varenicline (CAS Registry No. 249296-44-4) has the structure:Like cytisine, varenicline is a partial agonist of the a4b2 nicotinic acetylcholine receptor.

[0129] The quantity of the other active ingredient present in the composition may vary. Typically, the other active ingredient, calculated as the free base, is present in a concentration of at least about 0.001% by weight of the composition, such as in a range from about 0.01% to about 10%. In some embodiments, the other active ingredient is present in a concentration from about 0.05% w / w to about 5% by weight, such as, e.g., from about from about 0.05% w / w. about 0.1% w / w, about 0.2%, about 0.3%, about 0.4%, about 0.5% about 0.6%, about 0.7%, about 0.8%, or about 0.9%, to about 1%, about 2%, about 3%, about 4%, or about 5% by weight, calculated as the free base and based on the total weight of the composition. In some embodiments, the other active ingredient is present in a concentration from about 0.05% w / w to about 4% by weight, such as, e.g., fromabout 0.05% w / w to about 3.5%, from about 0.07% to about 2.5%, from about 0.1% to about 2.0%, from about 0.1% to about 1.5%, or from about 0.1% to about 1% by weight, calculated as the free base and based on the total weight of the composition. One of skill in the art will recognize that the amount of any particular other active ingredient present in the composition may vary based on the potency of the compound, the composition matrix, and the desired physiological effect for the composition.

[0130] The other active ingredient may be present in the composition as the free base, as a salt with a suitable acid, or in the form of an ion pair with an organic acid. Each of these forms is described further herein below.Free base

[0131] In some embodiments, the substituted 3-(l-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient exhibits sufficient stability, aqueous solubility, and oral bioavailability such that the free base is suitable for inclusion in the composition. Accordingly, in some embodiments, the substituted 3-(l-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine or other active ingredient is present substantially or completely as the free base. In such embodiments, one of skill in the art will recognize that the composition is substantially free of acidic components. By "substantially free" it is meant that no acidic component (e.g., inorganic acid, organic acid, or acids capable of salt, ion pair, or cocrystal formation) has been intentionally added, beyond trace amounts that may be present e.g., as an impurity in another component. For example, some embodiments can be characterized as having less than 0.001% by -26- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022weight of any acid component, or less than 0.0001%, or even 0% by weight of any acid component, based on the total weight of the composition. In some embodiments, the composition is completely free of any acid component (i.e., characterized as 0% or as having an amount below the limit of detection). In some embodiments, the substituted 3 -(1-methylpyrro lidin-2 -yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient is present in the free base form and is adsorbed in a carrier such as a microcrystalline cellulose material to form an adsorption complex.Salt

[0132] In some embodiments, at least a portion of the substituted 3-(l-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient can be employed in the form of a salt. A "salt" of such compounds is a form characterized by interaction between the said compound in ionic form and a coformer in ionic form (e.g., an acid) via the transfer of one or more protons from the coformer donor to the compound acceptor. The structure of substituted 3-(l-methylpyrrolidin-2-yl)pyridines, optionally substituted 3-(azetidin-2-yl)pyridines, and optionally 3-(azetidin-2-ylmethoxy)pyridines as disclosed herein are such that they comprise two nitrogen atoms that are capable of accepting protons from a coformer and, accordingly, can be present in nonprotonated, mono-protonated, and / or di-protonated form in a given sample. Salts of substituted 3-(l-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient can be provided using the types of ingredients and techniques set forth for nicotine in US Pat. No. 2,033,909 to Coxet al. andPerfetti, Beitrage Tabakforschunglnt., 12: 43-54 (1983), which are incorporated herein by reference. Suitable salts are generally water soluble. Suitable acids for formation of salts (mono- and di-) include, but are not limited to, acetic acid, adipic acid, ascorbic acid, capric acid, citric acid, D-glucuronic acid, D-gluconic acid, lactic acid, galactaric acid, hippuric acid, hydrochloric acid, L-aspartic acid, L-glutamic acid, L-glutaric acid, glycerophosphoric acid, glycolic acid, lauric acid, DL-malic acid, L-malic acid; tartaric acid, palmitic acid, phosphoric acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, thiocyanic acid, (+)-camphoric acid, 1,5-naphthalenedisulfonic acid, 1-hydroxy-2 -naphthoic, 2,5-dihydroxybenzoic acid, benzene sulfonic acid, benzoic acid, caprylic acid, cyclamic acid, ethanesulfonic acid, fumaric acid, D-glucoheptonic acid, 4 -hydroxybenzoic acid, isobutyric acid, ketoglutaric acid, 2-ketobutyric acid, lactobionic acid, maleic acid, malonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, pamoic acid, pivalic acid, propionic acid, L-pyroglutamic acid, p-toluenesulfonic acid, (IS)-camphor-lO-sulfonic acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, N-acetyl-4-aminosalicylic acid, caproic acid, dichloroacetic acid, hydrobromic acid, DL-mandelic acid, L-mandelic acid, nitric acid, formic acid, salicylic acid, cinnamic acid, undecylenic acid, isothionic acid, lauric acid, 2-hydroxybenzoic acid, trans-2-hexenoic acid, trimesic acid, 5 -nitroisophthalic acid, and zinc chloride monohydrate (forming a hydrated zinc chloride complex salt).

[0133] In some embodiments, a hydrophilic acid is chosen so as to increase water solubility and / or decrease lipophilicity of the salt. Lipophilicity of a salt of a compound as disclosed herein can also be expressed as logD, which is the logarithm of the distribution coefficient, a measure of the pH-dependent differential -27- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022solubility between an octanol phase and an aqueous phase of all species (ionized and un-ionized) in an octanol / aqueous system, represented by the formula:toptopLogD is a commonly used descriptor for the lipophilicity of ionizable compounds. LogD values can be calculated using commercial software or may be determined experimentally in a similar manner to logP but instead of using water, the aqueous phase is adjusted to a specific pH using a buffer. LogD is pH dependent and therefore requires that the pH at which the logD was measured be specified.

[0134] When the substituted 3-(l-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yljpyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient is present in the form of a salt, it is generally preferred that the salt have a relatively low logD, indicative of good water solubility. Without wishing to be bound by theory, it is believed that highly water-soluble salt forms may exhibit a high rate of dissolution, which may be favorable in certain embodiments. Accordingly, in some embodiments, the substituted 3-(l-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient salt has a logD from about -1.0 to about 3 at a pH in a range from about 3 to about 11, such as from about -0.5 to about 2, about -0.3 to about 1, or about -0.1 to about 0.

[0135] In some embodiments, the selection of acid used to make a salt is performed on the basis of sensory effects of the salt, such as taste. Surprisingly, according to the present disclosure, it has been found that salts of certain organic acids, such as galactaric acid, offer a better taste sensation relative to salts of acids such as tartaric or phthalic acids.

[0136] In some embodiments, the substituted 3-(l-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient is present in the form of a salt with tartaric acid, succinic acid, orotic acid, fumaric acid, pyroglutamic acid, or galactaric acid. In some embodiments, the substituted 3-(l-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, or optionally 3-(azetidin-2-ylmethoxy)pyridine is present in the form of a salt with succinic acid or galactaric acid.

[0137] The stoichiometry of the salts as described herein can vary. For example, in some embodiments, the stoichiometry can range from about 5:1 to about 1:5 compound:acid. In some embodiments, the ratio of compound to acid is 2: 1, 1 : 1, or 1 :2. Hydrates and other solvates of salts are further contemplated herein.

[0138] The salts as described herein can, in some embodiments, exist in various polymorphic and pseudopolymorphic forms. Polymorphism is the ability of a crystalline material to exist in more than one form or crystal structure. Polymorphism can result, e.g., from the existence of different crystal packing structures (packing polymorphism) or from the existence of different conformers of the same molecule (conformational polymorphism). Pseudopolymorphism is the result of hydration or solvation of a material and is also referred to as solvomorphism.-28- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022Resin Complex

[0139] In some embodiments, at least a portion of the substituted 3-(l-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient may be present in the form of a polymer complex, where the compound is bound to an acidic polymer. The polymer of such a complex can be any polymer (including homopolymers or all types of copolymers) with acidic functionalities, e.g., a polymeric cation exchange resin. In some embodiments, the polymer comprises acidic sites that can be classified as strongly acidic, weakly acidic, or of intermediate acidity (depending, e.g, on the strength of the acid from which they are derived). In some embodiments, the polymer comprises weakly acidic sites and can be referred to as a weakly acidic cation exchange resin. Nonlimiting examples of acidic sites include, e.g. , carboxylic acids, sulfonic acids, phosphonous acids, phosphonic acids, phosphoric acids, iminodiacetic acids, and phenolic groups (e.g., as disclosed in Adams et al., J. Soc. Chem. Ind. 54, IT (1935), which is incorporated herein by reference). Suitable polymers include, but are not limited to, addition polymers of styrene and divinylbenzene, divinylbenzene and methacrylic acid, divinylbenzene and acrylic acid, phenolic resins, or cellulose, dextran or pectin cross-linked with, e.g., epichlorohydrin. In some embodiments, the polymer comprises cross-linked moieties. Various acidic ionexchange resins which are known in the art and are suitable for formation of complexes, include, but are not limited to, polymethacrylic acid resins such as DuPont™ Amberlite™ IRP64, DuPont™ Amberlite™ IRP69, Purolite™ C115HMR, Doshion™P551, and polyacrylic carbomers, such as Carbopol 974P. See, for example, US Pat. No. 3,901,248 to Lichtneckert et al., which is incorporated herein by reference. In some embodiments, when the substituted 3-(l-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, or optionally 3-(azetidin-2-ylmethoxy)pyridine is present in the form of a polymer complex, the composition further comprises a divalent metal buffer, such as a calcium or magnesium salt (e.g., carbonate, bicarbonate, oxide, acetate, or the like).Cocrystal

[0140] In some embodiments, at least a portion of the substituted 3-(l-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient may be present in the form of a co-crystal with at least one other component ("coformer"), both in neutral form. Specifically, as defined in a US FDA industry guidance document, a co-crystal is a solid that is a crystalline material composed of two or more molecules in the same crystal lattice, where the components are in a neutral state and interact via nonionic interactions. See U.S. Department of Health and Human Services, Food and Drug Administration, Guidance for Industry: Regulatory Classification of Pharmaceutical Co-Crystals (April 2013), which is incorporated herein by reference. This form is different and distinct from both salts and ion pairs, each described herein. Specifically, co-crystals can generally be distinguished from salts (and ion pairs) by the absence of a proton transfer between the components (i.e., a substituted 3-(l-methylpyrrolidin-2-yl)pyridine and the one or more coformers) in a co-crystal. The crystalline structure of the co-crystal is generally held together by freely reversible, non-covalent interactions. Co-crystals typically comprise the substituted 3-(l-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine,-29- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022or optionally 3-(azetidin-2-ylmethoxy)pyridine and coformer in a defined stoichiometric ratio. In some embodiments, co-crystals can encompass hydrates, solvates, and clathrates. Co-crystals can comprise the substituted 3-(l-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient in combination with an organic and / or an inorganic coformer.

[0141] Examples of suitable coformers include, but are not limited to, acetamidobenzoic acid, L-proline, tromethamine, urea, xylitol, caffeine, glycine / glycine anhydride, vanillin, methyl 4-hydroxybenzoate(methylparaben), succinimide, L-alanine, mannitol, L-phenylalanine, saccharin, propylparaben, N-methylglucamine, L-tyrosine, gentisic acid, sorbic acid, benzoic acid, L-methionine, maltol, L-lysine, tromethamine, nicotinamide, isonicotinamide, phenylalanine, benzoquinone, terephthalaldehyde, 4-hydroxybenzoic acid, pyruvic acid, 1 -hydroxy -2 -naphthoic acid, 4-aminobenzoic acid, vanillic acid, ethyl vanillin, isonicotinic acid, gallic acid, menthol (e.g., racemic menthol or (-)-menthol), paracetamol, aspirin, ibuprofen, naproxen, ketoprofen, flurbiprofen, glucose, serine, malic acid, acetamide, sulfacetamide, benzoic acid, creatine, 2-hydroxyethanesulfonic acid, clofibric acid, taurine (tauric acid), iproniazid, L-histadine, L-arginine, L-asparagine, glutamine, L-cysteine, alanine, valine, isoleucine, leucine, morpholine, theronine, N-methylglucamine, 3 -hydroxy -2 -oxopropionic acid; 2-oxobutyric acid (2-ketobutyric acid), 3-methyl-2-oxobutanoic acid; 3 -methy 1-2 -oxopentanoic acid; 4-methyl-2 -oxopentanoic acid; and 2-oxopentanedioic acid, 2-oxo-3 -phenylpropionic acid; 5-oxooctanoic acid; and 5-oxodecanoic acid, aldonic acids (e.g., glyceric acid, xylonic acid, gluconic acid, and ascorbic acid), ulosonic acids (e.g., neuraminic acid and ketodeoxyoctulosonic acid), uronic acids (e.g., glucuronic acid, galacturonic acid, and iduronic acid), aldaric acids (e.g., tartaric acid, meso-galactaric acid / mucic acid, and D-glucaric acid / saccharic acid), galactaric acid), and polyfunctional aromatic acids.

[0142] In some embodiments, the conformer is a polyfunctional aromatic acid. Polyfunctional aromatic acids often comprise a substituted or unsubstituted phenyl group as the aromatic component, but can alternatively comprise another aromatic moiety, e.g., pyridine, pyrazine, imidazole, pyrazole, oxazole, thiophene, naphthalene, anthracene, and phenanthrene. Substituents on the optionally substituted aromatic acids may be any type of substituent, including, but not limited to, halo (e.g., Cl, F, Br, and I); alkyl, halogenated alkyl (e.g., CF3, 2-Br-ethyl, CH2F, CH2C1, CH2CF3, or CF2CF3); alkenyl, hydroxyl; amino; carboxylate; carboxamido; alkylamino; arylamino; alkoxy; aryloxy; nitro; azido; cyano; thio; sulfonic acid; sulfate; phosphonic acid; phosphate; and phosphonate groups. Example polyfunctional aromatic acids can be, for example:

[0143] substituted and unsubstituted aromatic dicarboxylic acids (e.g., 1,2-benzenedicarboxylic acid (phthalic acid), 1,3 -benzenedicarboxy lie acid (isophthalic acid), 1,4-benzenedicarboxylic acid (terephthalic acid), 2-iodo- 1,3 -benzenedicarboxy lie acid, 2-hydroxy- 1,4-benzenedicarboxylic acid, 2-nitro-l,4-benzenedicarboxylic acid, 3 -fluoro- 1,2-benzenedicarboxylic acid, 3 -amino- 1,2-benzenedicarboxylic acid, 3-nitro- 1,2-benzenedicarboxylic acid, 4-bromo-l,3-benzenedicarboxylic acid, 4-hydroxy-l,3-benzenedicarboxylic acid, 4-amino- 1,2-benzenedicarboxylic acid, 4-nitro- 1,2-benzenedicarboxylic acid, 4-sulfo- 1,2-benzenedicarboxylic acid, 4-amino- 1,3 -benzenedicarboxy lie acid, 5-bromo-l,3- -30- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022benzenedicarboxylic acid, 5-hydroxy-l,3-benzenedicarboxylic acid, 5-amino-l,3-benzenedicarboxylic acid, 5-nitro-l,3-benzenedicarboxylic acid, 5-ethynyl-l,3-benzenedicarboxylic acid, 5-cyano-l,3-benzenedicarboxylic acid, 5-nitro- 1,3 -benzenedicarboxy lie acid, 2,5-hydroxy-l,4-benzenedicarboxylic acid, and 2,3,5,6-tetrafluoro-l,4-benzenedicarboxylic acid;

[0144] substituted and unsubstituted hydroxybenzoic acids (e.g., 2-hydroxybenzoic acid (salicylic acid), 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, 2-methyl-4-hydroxybenzoic acid, 3-tert-butyl-4-hydroxybenzoic acid, 4-ethoxy-2-hydroxybenzoic acid, 3-chloro-5-hydroxybenzoic acid, 5-chloro-2-hydroxybenzoic acid, 3-bromo-4-hydroxybenzoic acid, 3-bromo-5-hydroxybenzoic acid, 4-bromo-2-hydroxybenzoic acid, 5-bromo-2-hydroxybenzoic acid, 2-fluoro-5-hydroxybenzoic acid, 3-fluoro-4-hydroxybenzoic acid, 3 -fluoro-2 -hydroxybenzoic acid, 3-fluoro-5-hydroxybenzoic acid, 2-fluoro-6-hydroxybenzoic acid, 4-fluoro-3 -hydroxybenzoic acid, 2-fluoro-4-hydroxybenzoic acid, 5-fluoro-2-hydroxybenzoic acid, 2-amino-3-hydroxybenzoic acid, 2-amino-5-hydroxybenzoic acid, 3-amino-2-hydroxybenzoic acid, 3-amino-4-hydroxybenzoic acid, 3-amino-5-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid, 4-amino-3 -hydroxybenzoic acid, 5-amino-2-hydroxybenzoic acid (mesalamine), 5-aminomethy 1-2 -hydroxybenzoic acid, 4-formy 1-3 -hydroxybenzoic acid, 3-formyl-4-hydroxybenzoic acid, 5-(acetylamino)-2-hydroxybenzoic acid), 4-nitro-2-hydroxybenzoic acid, 3,5-diethyl-4-hydroxybenzoic acid, 3,5-di-tert-butyl-4-hydroxybenzoic acid, 3,5-diisopropyl-2-hydroxybenzoic acid, 3,4-dimethoxy-4-hydroxybenzoic acid (syringic acid), 3,5-dichloro-2-hydroxybenzoic acid, 3,5-dichloro-4-hydroxybenzoic acid, 3,6-dichloro-2-hydroxybenzoic acid, 2,3-difluoro-4-hydroxybenzoic acid, 3,4-difluoro-2-hydroxybenzoic acid, 3,5-dibromo-2-hydroxybenzoic acid, 3,5-diodo-2-hydroxybenzoic acid, 4-amino-5-chloro-2-hydroxybenzoic acid, 3,5-dinitro-2-hydroxybenzoic acid, 2, 4, 6-tribromo-2 -hydroxybenzoic acid, 2,3,5,6-tetrafluoro-4-hydroxybenzoic acid, and 2,3,4,5-tetrafluoro-6-hydroxybenzoic acid);

[0145] substituted and unsubstituted dihydroxybenzoic acids (e.g., 2,3-dihydroxybenzoic acid (pyrocatechuic acid / hypogallic acid), 2,4-dihydroxybenzoic acid ([3-resorcylic acid), 2,5-dihydroxybenzoic acid (gentisic acid / hydroquinonecarboxylic acid), 2,6-dihydroxybenzoic acid (y-resorcylic acid), 3,4-dihydroxybenzoic acid (protocatechuic acid), 3,5-dihydroxybenzoic acid (a-resorcylic acid), 4-hydroxy-3 -methoxybenzoic acid (vanillic acid), 6-methyl-2,4-dihydroxybenzoic acid (orsellenic acid), 4-bromo-3,5-dihydroxybenzoic acid, 5-bromo-2,4-dihydroxybenzoic acid, 5-bromo-3,4-dihydroxybenzoic acid, 6-carboxymethyl-2,3-dihydroxybenzoic acid, 3,5-dibromo-2,4-dihydroxybenzoic acid, 3,5-dichloro-2,6-dihydroxybenzoic acid, and 5-amino-3-chloro-2,4-dihydroxybenzoic acid);

[0146] substituted and unsubstituted trihydroxybenzoic acids (e.g., 2,3,4-trihydroxybenzoic acid, 2,4,5-trihydroxybenzoic acid, 2,4,6-trihydroxybenzoic acid (phloroglucinol carboxylic acid), and 3,4,5-trihydroxybenzoic acid (gallic acid));

[0147] substituted and unsubstituted aromatic tricarboxylic acids (e.g., 1,2, 3 -benzenetricarboxy lie acid, 1,2,4-benzenetricarboxylic acid (trimellitic acid); and-31- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022

[0148] substituted and unsubstituted aromatic tetracarboxylic acids (e.g., 1,2,3,4-benzenetetracarboxylic acid (mellophanic acid) and 1,2,4,5-benzenetetracarboxylic acid (pyromellitic acid). Further contemplated are various combinations of any of the foregoing acids.

[0149] In some embodiments, the coformer is L-malic acid, succinic acid, or a combination thereof. In some embodiments, the coformer is l,l,6,6-tetraphenyl-2,4-hexidiyne-l,6-diol. In some embodiments, the coformer is di-iodotetrafluoro benzene, 4,4'-diiodooctafluorobiphenyl, or l,4-bis(diphenylhydroxymethyl)benzene. In some embodiments, the coformer is orotic acid.

[0150] In some embodiments, the substituted 3-(l-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient is present in the form of a salt co-crystal. A "salt co-crystal" is a type of hybrid structure with both salt and co-crystal characteristics. Typically, a substituted 3-(l-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine molecule, or other active ingredient within a salt co-crystal is associated with at least two coformers (which may be the same or different), wherein one coformer is in ionic form (e.g., an acid) and transfers a proton to the substituted 3-(l-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine molecule, or other active ingredient, and wherein a second coformer does not transfer a proton to the substituted 3-(l-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine molecule, or other active ingredient. Suitable acids and coformers are generally those described herein above with respect to salts and co-crystals.

[0151] The stoichiometry of the co-crystals and salt co-crystals described herein can vary. For example, in certain embodiments, where two components are present, the stoichiometry can range in certain embodiments from about 5:1 to about 1:5 compound:coformer. Where more than one coformer is used to form a co-crystal or salt co-crystal, the ratios of the coformers with respect to both the substituted 3-(l-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient and to one another can also vary.

[0152] The co-crystals and salt co-crystals described herein can, in some embodiments, exist in various polymorphic and pseudopolymorphic forms, as well as solvates and hydrates.

[0153] In some embodiments, the substituted 3-(l-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient is present in the form of a salt-co-crystal. In some embodiments, the salt-co-crystal is a bis-orotic acid salt-co-crystal. In some embodiments, the bis-orotic acid salt-co-crystal is a hemi-hydrate.Ion pairing

[0154] In some embodiments, at least a portion of the substituted 3-(l-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient is present in the form of an ion pair. Ion pairing describes the partial association of oppositely charged ions in relatively concentrated solutions to form distinct chemical species called ion pairs. The strength of the association (i.e., the ion pairing) depends on the electrostatic force of attraction between the -32- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022positive and negative ions (e.g., a substituted 3 -(1-methylpyrro lidin-2 -yl)pyridine and the conjugate base of a suitable acid). By "conjugate base" is meant the base resulting from deprotonation of the corresponding acid (e.g., benzoate is the conjugate base of benzoic acid). In embodiments comprising ion pairing, on average, a certain population of these ion pairs exists at any given time, although the formation and dissociation of ion pairs is continuous. In some embodiments, in the composition as disclosed herein, and / or upon oral use of said composition (e.g., upon contact with saliva), the substituted 3-(l-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient and the conjugate base of an acid exist at least partially in the form of an ion pair. Ion pairing is further described in, for example, International Patent Application Publication No. WO2021 / 050741 to Poole et al., and US Application Publication Nos. 2021 / 0068447 to Keller et al., 2023 / 0138306A1 to Zawadzki et al., and 2022 / 0346434 to Von Cosmos et al., each of which is incorporated herein by reference.

[0155] One of skill in the art will recognize that the extent of ion pairing in the disclosed composition, both before and during use by the consumer, may vary based on, for example, pH, the nature of the acid, the concentration of substituted 3-(l-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yljpyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient, the concentration of the acid or conjugate base of the acid present in the composition, the moisture content of the composition, the ionic strength of the composition, and the like. One of skill in the art will also recognize that ion pairing is an equilibrium process influenced by the foregoing variables. Accordingly, quantification of the extent of ion pairing is difficult or impossible by calculation or direct observation. However, the presence of ion pairing may be demonstrated through surrogate measures, such as partitioning of the substituted 3-(l-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxyjpyridine, or other active ingredient between octanol and water, or by performing membrane permeation studies of aqueous solutions of, for example, the substituted 3-(l-methylpyrrolidin-2-yl)pyridine plus acids and / or their conjugate bases. An octanol-water partitioning favoring distribution of an ion pair into octanol is predictive of good absorption of the substituted 3-(l-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine (e.g., 2-methyl-5-(l-methylpyrrolidin-2-yl)pyridine), or other active ingredient through the oral mucosa. However, as described above, in some embodiments, the properties of the substituted 3-(l-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine (e.g., 2-methyl-5-(l-methylpyrrolidin-2-yl)pyridine), or other active ingredient are such that no ion pairing is required, and accordingly, the composition is substantially or completely free of any ion pairing. By "substantially free" it is meant that no measurable degree of ion pairing is present.

[0156] In embodiments where ion pairing is desired, the composition comprises an organic acid, an alkali metal salt of an organic acid, or both. In such embodiments, at least a portion of the substituted 3-(l-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxyjpyridine, or other active ingredient is associated with at least a portion of the organic acid, the alkali metal salt thereof, or a combination thereof in the form an ion pair. As used herein, the term "organic -33- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022acid" refers to an organic (i.e., carbon-based) compound that is characterized by acidic properties. Typically, organic acids are relatively weak acids (i.e., they do not dissociate completely in the presence of water), such as carboxylic acids (-CO2H) or sulfonic acids (-SO2OH). As used herein, reference to organic acid means an organic acid that is intentionally added. In this regard, an organic acid may be intentionally added as a specific composition ingredient as opposed to merely being inherently present as a component of another composition ingredient (e.g., the small amount of organic acid which may inherently be present in a composition ingredient). For the avoidance of doubt, reference herein to an "organic acid" is intended to distinguish the acid present in ion paired forms over the acid which may be present in salts, co-crystal, and salt co-crystals. While one of skill in the art will recognize that certain organic acids suitable for formation of ion pairs overlap with those identified as suitable for salt or co-crystal formation, it is to be understood that the particular acid used for each of salts, co-crystals, and ion pairs are to be selected specifically for each such embodiment, and reference herein to an organic acid is specific to acids suitable for ion pairing. Accordingly, the presence in the composition of an organic acid as defined below is to be interpreted solely with respect to ion pairing, even if such organic acid is also suitable for salt formation or co-crystal formation, and the presence of such an organic acid does not imply that a salt or co-crystal is present unless explicitly identified. Further, in embodiments where there is no ion pairing intended, the composition may be characterized as substantially or completely free of organic acids (i.e., having less than 0.001% by weight of organic acid, or less than 0.0001%, or even 0% by weight of organic acid, based on the total weight of the composition, or as having an amount of organic acid below the limit of detection). This is not to be interpreted as meaning that the composition is substantially or completely free of substituted 3-(l-methylpyrrolidin-2-yl)pyridine salts or substituted 3-(l-methylpyrrolidin-2-yl)pyridine co-crystals unless explicitly recited.Organic acid

[0157] In embodiments where ion pairing is desired, the composition comprises an organic acid as defined herein above, and / or an alkali metal salt thereof. Suitable organic acids for ion pairing will typically have a range of lipophilicities (i.e., a polarity giving an appropriate balance of water and organic solubility). Typically, lipophilicities of suitable organic acids, as indicated by logP, will vary between about 0 and about 12 (more soluble in octanol than in water). In some embodiments, the organic acid has a logP value from about 0 to about 12, e.g., from about 0.5, 1.0. about 1.5, about 2.0, about 2.5, about 3.0, about 3.5, about 4.0, about 4.5, about 5.0, about 5.5, about 6.0, about 6.5, about 7.0, about 7.5, or about 8.0, to about 8.5, about 9.0, about 9.5, about 10.0, about 10.5, about 11.0, about 11.5, or about 12.0.

[0158] Without wishing to be bound by theory, it is believed that moderately lipophilic organic acids (e.g., logP of from about 1.4 to about 4.5) produce ion pairs which are of a polarity providing good octanol-water partitioning of the ion pair, and hence partitioning of substituted 3-(l-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient, into octanol versus water. As discussed above, such partitioning into octanol is predictive of favorable oral availability.-34- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022

[0159] In some embodiments, the organic acid for ion pairing has a logP value from about 3.0 to about 8.0, about 10.0, or even 12.0. In some embodiments, the presence of certain solvents or solubilizing agents (e.g., inclusion in the composition of glycerin or propylene glycol) may be beneficial in solubilizing organic acids and the corresponding salts or ion pairs thereof for highly lipophilic organic acids (e.g., higher than about 4.5).

[0160] In some embodiments, the organic acid is a carboxylic acid or a sulfonic acid. The carboxylic acid or sulfonic acid functional group may be attached to any alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group having, for example, from one to twenty carbon atoms (C1-C20). In some embodiments, the organic acid is an alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl carboxylic or sulfonic acid.

[0161] As used herein, "alkyl" refers to any straight chain or branched chain hydrocarbon. The alkyl group may be saturated (i.e., having all sp3carbon atoms), or may be unsaturated (i.e., having at least one site of unsaturation). As used herein, the term "unsaturated" refers to the presence of a carbon-carbon, sp2double bond in one or more positions within the alkyl group. Unsaturated alkyl groups may be mono- or polyunsaturated. Representative straight chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl. Branched chain alkyl groups include, but are not limited to, isopropyl, sec -butyl, isobutyl, tert-butyl, isopentyl, and 2-methylbutyl. Representative unsaturated alkyl groups include, but are not limited to, ethylene or vinyl, allyl, 1-butenyl, 2-butenyl, isobutylenyl, 1 -pentenyl, 2-pentenyl, 3-methyl-l-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, and the like. An alkyl group can be unsubstituted or substituted.

[0162] "Cycloalkyl" as used herein refers to a carbocyclic group, which may be mono- or bicyclic. Cycloalkyl groups include rings having 3 to 7 carbon atoms as a monocycle or 7 to 12 carbon atoms as a bicycle. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. A cycloalkyl group can be unsubstituted or substituted, and may include one or more sites of unsaturation (e.g., cyclopentenyl or cyclohexenyl).

[0163] The term "aryl" as used herein refers to a carbocyclic aromatic group. Examples of aryl groups include, but are not limited to, phenyl and naphthyl. An aryl group can be unsubstituted or substituted.

[0164] "Heteroaryl" and "heterocycloalkyl" as used herein refer to an aromatic or non-aromatic ring system, respectively, in which one or more ring atoms is a heteroatom, e.g., nitrogen, oxygen, and sulfur. The heteroaryl or heterocycloalkyl group comprises up to 20 carbon atoms and from 1 to 3 heteroatoms selected from N, O, and S. A heteroaryl or heterocycloalkyl may be a monocycle having 3 to 7 ring members (for example, 2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, and S) or a bicycle having 7 to 10 ring members (for example, 4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, and S), for example: a bicyclo[4,5], [5,5], [5,6], or [6,6] system. Examples of heteroaryl groups include by way of example and not limitation, pyridyl, thiazolyl, tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, IH-indazolyl, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl,-35- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, benzotriazolyl, benzisoxazolyl, and isatinoyl. Examples of heterocycloalkyls include by way of example and not limitation, dihydroypyridyl, tetrahydropyridyl (piperidyl), tetrahydrothiophenyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, tetrahydrofuranyl, tetrahydropyranyl, bis-tetrahydropyranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, piperazinyl, quinuclidinyl, and morpholinyl. Heteroaryl and heterocycloalkyl groups can be unsubstituted or substituted.

[0165] "Substituted" as used herein and as applied to any of the above alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, means that one or more hydrogen atoms are each independently replaced with a substituent. Typical substituents include, but are not limited to, -Cl, Br, F, alkyl, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, -CN, -NC(=O)CH3, -C(=O)-, -C(=O)NH2, and -C(=O)N(CH3)2. Wherever a group is described as "optionally substituted," that group can be substituted with one or more of the above substituents, independently selected for each occasion. In some embodiments, the substituent may be one or more methyl groups or one or more hydroxyl groups.

[0166] In some embodiments, the organic acid for ion pairing is an alkyl carboxylic acid. Non-limiting examples of alkyl carboxylic acids include formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, undecanoic acid, dodecanoic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, and the like.

[0167] In some embodiments, the organic acid for ion pairing is an alkyl sulfonic acid. Non-limiting examples of alkyl sulfonic acids include propanesulfonic acid, heptanesulfonic acid, and octanesulfonic acid.

[0168] In some embodiments, the alkyl carboxylic or sulfonic acid is substituted with one or more hydroxyl groups. Non-limiting examples include glycolic acid, 4-hydroxybutyric acid, and lactic acid.

[0169] In some embodiments, an organic acid for ion pairing may include more than one carboxylic acid group or more than one sulfonic acid group (e.g. , two, three, or more carboxylic acid groups). Non-limiting examples include oxalic acid, fumaric acid, maleic acid, and glutaric acid. In organic acids containing multiple carboxylic acids (e.g., from two to four carboxylic acid groups), one or more of the carboxylic acid groups may be esterified. Non-limiting examples include succinic acid monoethyl ester, monomethyl fumarate, mo no methyl or dimethyl citrate, and the like.

[0170] In some embodiments, the organic acid for ion pairing may include more than one carboxylic acid group and one or more hydroxyl groups. Non-limiting examples of such acids include tartaric acid, citric acid, and the like.

[0171] In some embodiments, the organic acid for ion pairing is an aryl carboxylic acid or an aryl sulfonic acid. Non-limiting examples of aryl carboxylic and sulfonic acids include benzoic acid, toluic acids, salicylic acid, benzenesulfonic acid, and -tohicncsulfonic acid.

[0172] Further non-limiting examples of organic acids which may be useful for ion pairing in certain embodiments include 2-(4-isobutylphenyl)propanoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, adipic acid, ascorbic acid (L), aspartic acid (L), alpha-methylbutyric acid, camphoric acid (+), camphor-10-sulfonic acid (+), cinnamic acid,-36- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022cyclamic acid, dodecylsulfuric acid, ethane-l,2-disulfonic acid, ethanesulfonic acid, furoic acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, isovaleric acid, lactobionic acid, lauric acid, levulinic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene- 1,5 -disulfonic acid, naphthalene-2-sulfonic acid, oleic acid, palmitic acid, pamoic acid, phenylacetic acid, pyroglutamic acid, pyruvic acid, sebacic acid, stearic acid, and undecylenic acid. Examples of suitable acids for ion pairing include, but are not limited to, the list of organic acids in Table 1.Table 1. Non-limiting examples of suitable organic acids for ion pairing-37- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022*Values obtained from PubChem or calculated

[0173] The selection of organic acid for ion pairing may further depend on additional properties in addition to consideration of the logP value. For example, an organic acid should be one recognized as safe for human consumption, and which has acceptable flavor, odor, volatility, stability, and the like. Determination of appropriate organic acids is within the purview of one of skill in the art.

[0174] In some embodiments, the organic acid for ion pairing is a mono ester of a dicarboxylic acid or a polycarboxylic acid. In some embodiments, the dicarboxylic acid is malonic acid, succinic acid, glutaric acid, adipic acid, fumaric acid, maleic acid, or a combination thereof. In some embodiments, the dicarboxylic acid is succinic acid, glutaric acid, fumaric acid, maleic acid, or a combination thereof. In some embodiments, the dicarboxylic acid is succinic acid, glutaric acid, or a combination thereof.

[0175] In some embodiments, the alcohol forming the mono ester of the dicarboxylic acid is a lipophilic alcohol. Examples of suitable lipophilic alcohols include, but are not limited to, octanol, menthol, and tocopherol. In some embodiments, the organic acid is an octyl mono ester of a dicarboxylic acid, such as monooctyl succinate, monooctyl fumarate, or the like. In some embodiments, the organic acid is a monomenthyl ester of a dicarboxylic acid. Certain menthyl esters may be desirable in oral compositions as described herein by virtue of the cooling sensation they may provide upon use of the product comprising the composition. In some embodiments, the organic acid is monomenthyl succinate, monomenthyl fumarate, monomenthyl glutarate, or a combination thereof. In some embodiments, the organic acid is a monotocopheryl ester of a dicarboxylic acid. Certain tocopheryl esters may be desirable in oral compositions as described herein by virtue of the antioxidant effects they may provide. In some embodiments, the organic acid is tocopheryl succinate, tocopheryl fumarate, tocopheryl glutarate, or a combination thereof.

[0176] In some embodiments, the organic acid for ion pairing is a carotenoid derivative having one or more carboxylic acids. Carotenoids are tetraterpenes, meaning that they are produced from 8 isoprene molecules and contain 40 carbon atoms. Accordingly, they are usually lipophilic due to the presence of long unsaturated aliphatic chains, and are generally yellow, orange, or red in color. Certain carotenoid derivatives can be advantageous in oral compositions by virtue of providing both ion pairing and serving as a colorant in the composition. In some embodiments, the organic acid is 2E,4E,6E,8E,10E,12E,14E,16Z,18E)-20-methoxy-4,8,13,17-tetramethyl-20-oxoicosa-2,4,6,8,10,12,14,16,18-nonaenoic acid (bixin) or an isomer thereof. Bixin is an apocarotenoid found in annatto seeds from the achiote tree (Bixa orellana) and is the naturally occurring pigment providing the reddish orange color to annatto. Bixin is soluble in fats and alcohols but insoluble in-38- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022water, and is chemically unstable when isolated, converting via isomerization into the double bond isomer, / raw.s-bixin ((3-bixin), having the structure:

[0177] In some embodiments, the organic acid for ion pairing is (2 / i'.4 / i'.6 / :'.8 / i'. I() / :'.12 / :'.14 / :'.16 / :'.18 / :)-4,8,13,17-tetramethylicosa-2,4,6,8,10,12,14,16,18-nonaenedioic acid (norbixin), a water-soluble hydrolysis product of bixin having the structure:

[0178] In some embodiments, more than one organic acid for ion pairing may be present. For example, the composition may comprise two, or three, or four, or more organic acids for ion pairing. Accordingly, reference herein to "an organic acid" contemplates mixtures of two or more organic acids. The relative amounts of the multiple organic acids may vary. For example, a composition may comprise equal amounts of two, or three, or more organic acids, or may comprise different relative amounts. In this manner, it is possible to include certain organic acids (e.g., citric acid or myristic acid) which have a logP value outside the desired range, when combined with other organic acids to provide the desired average logP range for the combination. In some embodiments, it may be desirable to include organic acids in the composition for ion pairing which have logP values outside the desired range for purposes such as, but not limited to, providing desirable organoleptic properties, stability, as flavor components, and the like. Further, certain lipophilic organic acids have undesirable flavor and or aroma characteristics which would preclude their presence as the sole organic acid (e.g., in equimolar or greater quantities relative to nicotine). Without wishing to be bound by theory, it is believed that a combination of different organic acids may provide the desired ion pairing while the concentration of any single organic acid in the composition remains below the threshold which would be found objectionable from a sensory perspective.

[0179] In some embodiments, the composition comprises an organic acid for ion pairing which is a monoester of a dicarboxylic acid or is a carotenoid derivative having one or more carboxylic acids as described herein above, and further comprises an additional organic acid or salt thereof. In some embodiments, the additional organic acid is benzoic acid, an alkali metal salt thereof, or a combination thereof.

[0180] In some embodiments, the composition comprises an alkali metal salt of an organic acid. For example, at least a portion of the organic acid may be present in the composition in the form of an alkali metal salt. Suitable alkali metal salts include lithium, sodium, and potassium. In some embodiments, the alkali metal is sodium or potassium. In some embodiments, the alkali metal is sodium. In some embodiments, the composition comprises an organic acid and a sodium salt of the organic acid.-39- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022

[0181] In some embodiments, the molar ratio of the organic acid to the sodium salt (or other alkali metal) of the organic acid is from about 0.1 to about 10, such as from about 0.1, about 0.25, about 0.3, about 0.5, about 0.75, or about 1, to about 2, about 5, or about 10. For example, in some embodiments, both an organic acid and the sodium salt thereof are added to the other components of the composition, wherein the organic acid is added in excess of the sodium salt, in equimolar quantities with the sodium salt, or as a fraction of the sodium salt. One of skill in the art will recognize that the relative amounts will be determined by the desired pH of the composition, as well as the desired ionic strength. For example, the organic acid may be added in a quantity to provide a desired pH level of the composition, while the alkali metal (e.g., sodium) salt is added in a quantity to provide the desired extent of ion pairing. As one of skill in the art will understand, the quantity of organic acid (i.e., the protonated form) present in the composition, relative to the alkali metal salt or conjugate base form present in the composition, will vary according to the pH of the composition and the pKa of the organic acid, as well as according to the actual relative quantities initially added to the composition.

[0182] The amount of organic acid or alkali metal salt thereof present in the composition, relative to the substituted 3-(l-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine (e.g., 2-methyl-5-(l-methylpyrrolidin-2-yl)pyridine), or other active ingredient, may vary. Generally, as the concentration of the organic acid (or the conjugate base thereof) increases, the percent of substituted 3-(l-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yljpyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient that is ion paired with the organic acid increases. This typically increases the partitioning of the substituted 3-(l-methylpyrrolidin-2-yljpyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient in the form of an ion pair, into octanol versus water as measured by the logP (the logio of the partitioning coefficient). In some embodiments, the composition comprises from about 0.05, about 0.1, about 1, about 1.5, about 2, or about 5, to about 10, about 15, or about 20 molar equivalents of the organic acid, the alkali metal salt thereof, or the combination thereof, relative to the substituted 3-(l-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient, calculated as the free base of the substituted 3-(l-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient.

[0183] In some embodiments, the composition comprises from about 2 to about 10, or from about 2 to about 5 molar equivalents of the organic acid, the alkali metal salt thereof, or the combination thereof, relative to the substituted 3-(l-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient on a free-base basis. In some embodiments, the organic acid, the alkali metal salt thereof, or the combination thereof, is present in a molar ratio with the substituted 3-(l-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient from about 2, about 3, about 4, or about 5, to about 6, about 7, about 8, about 9, or about 10. In embodiments wherein more than one organic acid, alkali metal salt thereof, or both, are present, it is to be understood that such molar ratios reflect the totality of the organic -40- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022acids present. In some embodiments, the composition comprises benzoic acid and sodium benzoate wherein a total amount of benzoate (i.e., benzoic acid and benzoate) is in a molar ratio in a range from about 3 to about 5 relative to the substituted 3-(l-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient. In some embodiments, the molar ratio of the total amount of benzoate to the substituted 3-(l-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient is about 3.2 or about 4.8.

[0184] In some embodiments, the organic acid inclusion is sufficient to provide a composition pH of from about 4.0 to about 9.0, such as from about 4.5 to about 7.0, or from about 5.5 to about 7.0, from about 4.0 to about 5.5, or from about 7.0 to about 9.0. Reference herein to "a composition pH" means the pH of an aqueous solution of the composition prepared by dissolving or suspending 5 grams of composition in 95 grams of water and measuring the pH of the resulting solution with a calibrated pH meter.

[0185] In some embodiments, the organic acid inclusion is sufficient to provide a composition pH of from about 4.5 to about 6.5, for example, from about 4.5, about 5.0, or about 5.5, to about 6.0, or about 6.5. In some embodiments, the desired composition pH is from about 4.5 to about 6.5, and the organic acid is provided in a quantity sufficient to provide such a pH. In some embodiments, the organic acid is provided in a quantity sufficient to provide a pH of the composition of from about 5.5 to about 6.5, for example, from about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, or about 6.0, to about 6.1, about 6.2, about 6.3, about 6.4, or about 6.5.

[0186] In some embodiments, a mineral acid (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, or the like), alone or in combination with an organic acid, is added to adjust the pH of the composition to the desired value. In some embodiments, a buffer (e.g., a buffer as described herein below) is added to the composition to the desired value, and / or to maintain the pH of the composition at the desired value.

[0187] In some embodiments, the oral composition further comprises a solubility enhancer to increase the solubility of one or more of the organic acid or salt thereof. Suitable solubility enhancers include, but are not limited to, humectants as described herein, such as glycerol or propylene glycol.Flavoring agent

[0188] In some embodiments, the composition as described herein comprises a flavoring agent. As used herein, a "flavoring agent" or "flavorant" is any flavorful or aromatic substance capable of altering the sensory characteristics associated with the oral product. Examples of sensory characteristics that can be modified by the flavoring agent include taste, mouthfeel, moistness, coolness / heat, and / or fragrance / aroma. Flavoring agents may be natural or synthetic, and the character of the flavors imparted thereby may be described, without limitation, as fresh, sweet, herbal, confectionary, floral, fruity, or spicy.

[0189] Flavoring agents may be imitation, synthetic or natural ingredients or blends thereof. Flavoring agents may include naturally occurring flavor materials, botanicals, extracts of botanicals, synthetically obtained materials, or combinations thereof (e.g., tobacco, cannabis, licorice (liquorice), hydrangea, eugenol, Japanese white bark magnolia leaf, chamomile, fenugreek, clove, maple, matcha, menthol, Japanese mint, aniseed -41- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022(anise), cinnamon, turmeric, Indian spices, Asian spices, herb, Wintergreen, cherry, berry, red berry, cranberry, peach, apple, orange, mango, clementine, lemon, lime, tropical fruit, papaya, rhubarb, grape, durian, dragon fruit, cucumber, blueberry, mulberry, citrus fruits, Drambuie, bourbon, scotch, whiskey, gin, tequila, rum, spearmint, peppermint, lavender, aloe vera, cardamom, celery, cascarilla, nutmeg, sandalwood, bergamot, geranium, khat, naswar, betel, shisha, pine, honey essence, rose oil, vanilla, lemon oil, orange oil, orange blossom, cherry blossom, cassia, caraway, cognac, jasmine, ylang-ylang, sage, fennel, wasabi, piment, ginger, coriander, coffee, hemp, a mint oil from any species of the genus Mentha, eucalyptus, star anise, cocoa, lemongrass, rooibos, flax, ginkgo biloba, hazel, hibiscus, laurel, mate, orange skin, rose, tea such as green tea or black tea, thyme, juniper, elderflower, basil, bay leaves, cumin, oregano, paprika, rosemary, saffron, lemon peel, mint, beefsteak plant, curcuma, cilantro, myrtle, cassis, valerian, pimento, mace, damien, maijoram, olive, lemon balm, lemon basil, chive, carvi, verbena, tarragon, limonene, thymol, camphene), flavor enhancers, bitterness receptor site blockers, sensorial receptor site activators or stimulators, sugars and / or sugar substitutes (e.g., sucralose, acesulfame potassium, aspartame, saccharine, cyclamates, lactose, sucrose, glucose, fructose, sorbitol, or mannitol), and other additives such as charcoal, chlorophyll, minerals, botanicals, or breath freshening agents.

[0190] Flavorants may further include flavor enhancers, sensorial receptor site activators or stimulators, and trigeminal sensates, As used herein, "trigeminal sensate" refers to a flavoring agent which has an effect on the trigeminal nerve, producing sensations including heating, cooling, tingling, and the like. Non-limiting examples of trigeminal sensate flavoring agents include capsaicin, citric acid, menthol, Sichuan buttons, erythritol, and cubebol.

[0191] In some embodiments, the composition comprises a sensate which provides to the user of such composition a cooling effect. Suitable cooling agents include, but are not limited to, menthane, menthone, menthone ketals, menthone glycerol ketals, substituted p-menthanes, acyclic carboxamides, monomenthyl glutarate, substituted cyclohexanamides, substituted cyclohexane carboxamides, substituted ureas and sulfonamides, substituted menthanols, hydroxymethyl and hydroxymethyl derivatives of p-menthane, 2-mercapto-cyclo-decanone, hydroxycarboxylic acids with 2-6 carbon atoms, cyclohexanamides, menthyl acetate, menthyl salicylate, N-ethyl-p-menthane-3-carboxamide (WS-3), ethyl ester of N-[[5-methyl-2-(l-methylethyljcyclohexyl] carbonyl] glycine (WS-5), WS-14, N, 2, 3 -trimethyl-2 -isopropyl butanamide (WS-23), WS-27, WS-30, (-)-Menthyloxyethanol (Coolact® 5), WS-NA (FEMA 4693), WS-116 (FEMA 4603), N-ethyl-2,2-diisopropylbutanamide, isopulegol, menthyloxy propane diol, 3-(l-menthoxy)propane-l,2-diol, 3-( 1 -menthoxy)-2-methylpropane- 1 ,2-diol, p-menthane-2,3 -diol, p-menthane-3 ,8-diol, 6-isopropyl-9-methyl-l,4-dioxaspiro[4,5]decane-2-methanol, menthyl succinate and its alkaline earth metal salts, trimethylcyclohexanol, N-ethyl-2-isopropyl-5-methylcyclohexanecarboxamide, Japanese mint oil, peppermint oil, 3-(l-menthoxy)ethan-l-ol, 3-(l-menthoxy)propan-l-ol, 3-(l-menthoxy)butan-l-ol, 1-menthylacetic acid N-ethylamide, l-menthyl-4-hydroxypentanoate, 1-menthy 1-3 -hydroxybutyrate, menthyl glutarate, N,2,3-trimethyl-2-(l-methylethyl)-butanamide, N-ethyl-trans-2-cis-6-nonadienamide, N,N-dimethyl menthyl succinamide, N-(2-hydroxyethyl)-2,3-dimethyl-2-isopropylbutanamide, substituted p- -42- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022menthanes, substituted p-menthane-carboxamides, 2-isopropanyl-5-methylcyclohexanol, menthyl ethylene glycol carbonate, menthone glycerol ketals (e.g., menthone 1,2-glycerol ketal), menthone (S)-lactic acid ketal, menthyl acetoacetate, 3-l-menthoxypropane-l,2-diol, menthyl lactate, eucalyptus extract, menthol propylene glycol carbonate, menthol ethylene glycol carbonate, menthol glyceryl ether, N-tert-butyl-p-menthane-3-carboxamide, p-menthane-3 -carboxylic acid glycerol ester, methyl-2-isopropyl-bicyclo[2.2.1]heptane-2-carboxamide, (lR,2S,5R)-N-(4-(carbamoylmethyl)phenyl)-menthylcarboxamide, 2-[2-(p-menthan-3-yloxy)ethoxy]ethanol, (lR,2R,4R)-l-(2-Hydroxy-4-methylcyclohexyl)ethenone, 2-(p-tolyloxy)-N-(lH-pyrazol-5-yl)-N-((thiophen-2-yl)methyl)acetamide, menthol methyl ether, menthyl pyrrolidone carboxylate, 2,5-dimethyl-4-(l-pyrrolidinyl)-3(2H)-furanone, cyclic a-keto enamines, and cyclotene derivatives (e.g., 3-methyl-2-( 1 -py rrolidinyl)-2-cyclopenten- 1 -one and 5-methy l-2-( 1 -pyrrolidinyl)-2-cyclopenten- 1 -one). Other compounds include the alpha-keto enamines disclosed in U.S. Pat. No. 6,592,884 to Hofmann et al., which is incorporated in its entirety herein. These and other suitable cooling agents are further described in the following U.S. patents, all of which are incorporated in their entirety by reference hereto: U.S. Pat. No.4,230,688; 4,032,661; 4,459,425; 4,178,459; 4,296,255; 4,136,163; 5,009,893; 5,266,592; 5,698,181; 6,277,385; 6,627,233; 7,030,273. Still other suitable cooling agents are further described in US Patent Application Publications Nos. 2005 / 0222256 and 2005 / 0265930, each of which are incorporated in their entirety by reference hereto. In some embodiments, the cooling agent comprises menthol, eucalyptus, mint, menthol, menthyl esters, eucolyptol, WS-3, WS-23, WS-5, (lR,2S,5R)-N-(4- (cyanomethyl)phenyl)menthylcarboxamide (Evercool™ 180), (lR,2S,5R)-N-(2-(pyridin-2-yl)ethyl)menthylcarboxamide (Evercool™ 190), or a combination thereof.

[0192] In some embodiments, the composition does not comprise a flavoring agent, and comprises only a cooling agent(s) to provide the desired user experience. In some embodiments, the cooling agent is WS-3, but it will be appreciated that other suitable cooling agents, including other cooling agents disclosed herein, can be used in addition to or in lieu of WS-3 in such embodiments.

[0193] In some embodiments, the composition comprises a modulator or sensate which provides to the user of such composition a warming effect. Suitable warming agents include, but are not limited to, ethers of vanillyl alcohol (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, isoamyl, n-hexyl), gingerol, shogaol, paradol, zingerone, capsaicin, dihydrocapsaicin, nordihydrocapsaicin, homocapsaicin, homodihydrocapsaicin, benzyl alcohol, and combinations thereof. In some embodiments, the warming agent comprises vanillyl butyl ether, vanillyl ethyl ether, capsaicin, or a combination thereof.

[0194] Flavoring agents may be in any suitable form, for example, a liquid such as an oil, or a solid such as a powder or wax. In some instances, the flavoring agent may be provided in a spray -dried form or a liquid form. In some embodiments, a liquid flavorant is disposed (i.e., adsorbed or absorbed in or on) a porous particulate carrier, for example microcrystalline cellulose, which is then combined with the other composition ingredients.

[0195] In some embodiments, the flavorant is lipophilic. Without wishing to be bound by theory, formulation of a lipophilic flavorant in a liquid emulsion composition may enhance the stability of the flavorant (e.g.,-43- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022toward oxidation or evaporation). In some embodiments, the flavorant is susceptible to oxidation, meaning exposure to air results in the degradation of components in the flavorant due to chemical changes. Examples of functional groups which may be present in flavorant components exhibiting susceptibility to oxidation include, but are not limited to, alkenes, aldehydes, and / or ketones. In some embodiments, the flavorant comprises a citrus oil. Citrus oils contain, for example, terpene components which may be susceptible to oxidation, evaporation, or both and, thus, may particularly benefit from inclusion within a product in the form of an emulsion as provided herein.

[0196] The amount of flavoring agent utilized in the composition can vary, but is typically up to about 10% by weight, and certain embodiments are characterized by a flavoring agent content of at least about 0.1% by weight, such as about 0.5 to about 10%, about 1 to about 5%, or about 2 to about 4% weight, based on the total weight of the composition.Taste modifiers

[0197] In order to improve the organoleptic properties of a composition as disclosed herein, the composition may include one or more taste modifying agents ("taste modifiers") which may serve to mask, alter, block, or improve e.g., the flavor of a composition as described herein. Non-limiting examples of such taste modifiers include analgesic or anesthetic herbs, spices, and flavors which produce a perceived cooling (e.g., menthol, eucalyptus, mint), warming (e.g., cinnamon), or painful (e.g., capsaicin) sensation. Certain taste modifiers fall into more than one overlapping category.

[0198] In some embodiments, the taste modifier modifies one or more of bitter, sweet, salty, or sour tastes. In some embodiments, the taste modifier targets pain receptors. In some embodiments, the composition comprises an ingredient having a bitter taste, and a taste modifier which masks orblocks the perception of the bitter taste. In some embodiments, the taste modifier is a substance which targets pain receptors (e.g., vanilloid receptors) in the user's mouth to mask e.g., a bitter taste of another component. Suitable taste modifiers include, but are not limited to, capsaicin, gamma-amino butyric acid (GABA), adenosine monophosphate (AMP), lactisole, or a combination thereof.

[0199] When present, a representative amount of taste modifier is about 0.01% by weight or more, about 0.1% by weight or more, or about 1.0% by weight or more, but will typically make up less than about 10% by weight of the total weight of the composition, (e.g., from about 0.01%, about 0.05%, about 0.1%, or about 0.5%, to about 1%, about 5%, or about 10% by weight of the total weight of the composition).Salts

[0200] In some embodiments, the composition may further comprise a salt (e.g., alkali metal salts), typically employed in an amount sufficient to provide desired sensory attributes to the composition reduce water activity, and to impede microbial growth.. Non-limiting examples of suitable salts include sodium chloride, potassium chloride, ammonium chloride, flour salt, and the like.

[0201] When present, a representative amount of salt is about 0.5 percent by weight or more, about 1.0 percent by weight or more, or at about 1.5 percent by weight or more, but will typically make up about 10 percent or-44- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022less of the total weight of the composition, or about 7.5 percent or less or about 5 percent or less (e.g., about 0.5 to about 5 percent by weight).Sweeteners

[0202] In order to improve the sensory properties of the composition according to the disclosure, one or more sweeteners may be added. The sweeteners can be any sweetener or combination of sweeteners, in natural or artificial form, or as a combination of natural and artificial sweeteners. Examples of natural sweeteners include fructose, sucrose, glucose, maltose, mannose, galactose, lactose, stevia, honey, and the like. Examples of artificial sweeteners include sucralose, isomaltulose, maltodextrin, saccharin, aspartame, acesulfame K, neotame, and the like. In some embodiments, the sweetener comprises one or more sugar alcohols. Sugar alcohols are polyols derived from monosaccharides or disaccharides that have a partially or fully hydrogenated form. Sugar alcohols have, for example, about 4 to about 20 carbon atoms and include erythritol, arabitol, ribitol, isomalt, maltitol, dulcitol, iditol, mannitol, xylitol, lactitol, sorbitol, and combinations thereof (e.g., hydrogenated starch hydrolysates). In some embodiments, the sweetener is sucralose, acesulfame K, or a combination thereof. In addition to provide sweetness, sweeteners can also contribute to reduction in water activity of the liquid composition.

[0203] When present, a sweetener or combination of sweeteners may make up from about 0.01 to about 20% or more of the of the composition by weight, for example, from about 0.01 to about 0.1, from about 0.1 to about 1%, from about 1 to about 5%, from about 5 to about 10%, or from about 10 to about 20% by weight, based on the total weight of the composition. In some embodiments, a combination of sweeteners is present at a concentration offrom about 0.01% to about0.1%by weight of the composition, suchas aboutO.Ol, about 0.02, about 0.03, about 0.04, about 0.05, about 0.06, about 0.07, about 0.08, about 0.09, or about 0.1% by weight of the composition. In some embodiments, a combination of sweeteners is present at a concentration of fromabout 0.1% to about 1.5% by weight of the composition, such as about 0.1, about 0.3, about 0.5, about 0.7, or about 0.9% by weight of the composition. In some embodiments, a combination of sweeteners is present at a concentration of from about 0.1% to about 3% by weight of the composition.Buffering agents

[0204] In some embodiments, the composition of the present disclosure can comprise buffering agents. Examples of buffering agents that can be used include, but are not limited to, alkali metal buffers such as metal carbonates (e.g., potassium carbonate or sodium carbonate), metal bicarbonates such as sodium bicarbonate, alkali metal citrates, and the like. Non-limiting examples of suitable buffers include alkali or alkaline earth metal (e.g., sodium, potassium, calcium, magnesium) acetates, glycinates, phosphates, glycerophosphates, citrates, carbonates, hydrogen carbonates, borates, and mixtures thereof. In some embodiments, the buffer comprises acetate, phosphate or carbonate, such as an alkali metal acetate, phosphate, or carbonate. In some embodiments, the buffer comprises citrate. In some embodiments, the buffer comprises or is trisodium citrate. In some embodiments, the buffer is a mixture of trisodium citrate and citric acid. In some embodiments, the buffer is a solution of trisodium citrate and citric acid having a pH of about 6.3, such as a solution 0.5 molar in citrate.-45- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022

[0205] When present, the buffering agent is typically present in an amount less than about 5 percent based on the weight of the composition, for example, from about 0.5% to about 5%, such as, e.g., from about 0.75% to about 4%, from about 0.75% to about 3%, or from about 1% to about 2% by weight, based on the total weight of the composition. As described herein above, such buffering agents may be added in a quantity sufficient to provide a specific pH value or range, or to maintain the pH of the composition within a desired range or at a desired value.Colorants

[0206] A colorant may be employed in amounts sufficient to provide the desired physical attributes to the composition. Natural or synthetic colorants, such as natural or synthetic dyes, food-grade colorants and pharmaceutical-grade colorants may be used. Examples of colorants include various dyes and pigments, such as caramel coloring and titanium dioxide. Natural colorants such as curcumin, beet juice extract, and spirulina, as well as a variety of synthetic pigments may also be used. The amount of colorant utilized in the composition can vary, but when present is typically up to about 3% by weight, such as from about 0.1%, about 0.5%, or about 1%, to about 3% by weight, based on the total weight of the composition.Oral care additives

[0207] In some embodiments, the composition comprises an oral care ingredient (or mixture of such ingredients). Oral care ingredients provide the ability to inhibit tooth decay or loss, inhibit gum disease, relieve mouth pain, whiten teeth, or otherwise inhibit tooth staining, elicit salivary stimulation, inhibit breath malodor, freshen breath, or the like. For example, effective amounts of ingredients such as thyme oil, eucalyptus oil and zinc (e.g., such as the ingredients of formulations commercially available as ZYTEX® from Discus Dental) can be incorporated into the composition. Other examples of ingredients that can be incorporated in desired effective amounts within the present composition can include those that are incorporated within the types of oral care compositions set forth in Takahashi et al., Oral Microbiology and Immunology, 19(1), 61-64 (2004); U.S. Pat. No. 6,083,527 to Thistle; and US Pat. Appl. Pub. Nos. 2006 / 0210488 to Jakubowski and 2006 / 02228308 to Cummins et al. Other example ingredients include those contained in formulations marketed as MALTISORB® by Roquette and DENTIZYME® by NatraRx. When present, a representative amount of oral care additive is at least about 1%, often at least about 3%, and frequently at least about 5% of the total dry weight of the composition. The amount of oral care additive within the composition will not typically exceed about 30%, often will not exceed about 25%, and frequently will not exceed about 20%, of the total dry weight of the composition.Other additives

[0208] Other additives can be included in the disclosed composition. For example, the composition can be processed, blended, formulated, combined and / or mixed with other materials or ingredients. The additives can be artificial or can be obtained or derived from herbal or biological sources. Examples of further types of additives include preservatives, antioxidants, or combinations thereof. See, for example, those representative components, combination of components, relative amounts of those components, and manners and methods for employing those components, set forth in US Pat. No. 9,237,769 to Mua et al., US Pat. No. 7,861,728 to -46- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022Holton, Jr. et al., US Pat. App. Pub. No. 2010 / 0291245 to Gao et al., and US Pat. App. Pub. No. 2007 / 0062549 to Holton, Jr. et al., each of which is incorporated herein by reference.

[0209] In some embodiments, the composition comprises one or more antioxidants, one or more preservatives, one or more antimicrobial agents, or combinations thereof. Suitable antioxidants and preservatives include, but are not limited to, ascorbic acid (Vitamin C), sodium ascorbate, ascorbyl palmitate, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), tertiary butylhydroquinone (TBHQ), methyl paraben, propyl paraben, sodium propionate, potassium sorbate, sodium benzoate, propyl gallate, monosterol citrate, Vitamin E, derivatives of vitamin E, tocopherols, and combinations thereof.

[0210] Typical inclusion ranges for such additional additives can vary depending on the nature and function of the additive and the intended effect on the final composition, with an example range of up to about 10% by weight, based on total weight of the composition (e.g., about 0.1 to about 5% by weight).

[0211] The aforementioned additives can be employed together (e.g., as additive formulations) or separately (e.g., individual additive components can be added at different stages involved in the preparation of the final mixture). Furthermore, the aforementioned types of additives may be encapsulated as provided in the final product or composition. Example encapsulated additives are described, for example, in WO2010 / 132444 to Atchley, which has been previously incorporated by reference herein.Preparation of Liquid Composition

[0212] The liquid compositions of the disclosure can be prepared by mixing the various component together using any suitable mixing device. In some embodiments, it may be advantageous to form solutions of certain components, such as a solution of an active ingredient and an organic acid, prior to mixing the solution with the remaining components. Emulsions as disclosed herein can be prepared by mechanical processes which employ shear force to break large emulsion droplets into smaller ones, such as high-pressure homogenization (HPH, including microfluidization), high-amplitude ultrasonic processing, and ultrasound-assisted emulsification. In general, the emulsions of the present disclosure can be prepared by preparing an aqueous phase containing an emulsifying agent as disclosed herein (e.g., an amphiphilic molecule or surfactant) and homogenizing this solution with a homogenizer or mixer for a period of time; and preparing an oil phase containing an oil, as described herein above. One or more hydrophobic active ingredients, flavors, or combinations thereof, as desired, may be added to the aqueous and / or oil phase, followed by mixing the same with a suitable mixing device. The aqueous and oil phases are combined and homogenized with, for example, a probe sonicator (Sonics and Materials, USA), a high pressure homogenizer (such as one made by Gauline or Avestine, or the like), or a microfluidizer, to obtain the desired emulsion. The number of passes through a high pressure homogenizer / microfluidizer may vary, depending on the desired particle size for the emulsion. A variety of methods are known in the art for producing emulsions comprising nano-sized particles of particular size ranges, using for example, sonication or homogenization. One such method is described in U.S. Pat. No. 4,737,323, incorporated herein by reference.-47- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022Configured for Oral Use

[0213] Provided herein are compositions configured for oral use. The term "configured for oral use" as used herein means that the composition or product including such composition is provided in a form such that during use, saliva in the mouth of the user causes one or more of the releasable components of the composition (e.g., flavoring agents and / or substituted 3-(l-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient) to pass into the mouth of the user. In some embodiments, the composition or product is adapted to deliver components to a user through mucous membranes in the user's mouth and, in some instances, said component is a flavoring agent and / or a substituted 3-(l-methylpyrrolidin-2-yl)pyridine, optionally substituted 3-(azetidin-2-yl)pyridine, optionally 3-(azetidin-2-ylmethoxy)pyridine, or other active ingredient as described herein that can be absorbed through the mucous membranes in the mouth when the composition or product is used.

[0214] In some embodiments, the composition or product including such composition could have the potential to be used as an aid in smoking cessation, as a nicotine replacement therapy, and / or the treatment of nicotine addiction.

[0215] In some embodiments, the composition of the present disclosure is in a flowable liquid form capable of being delivered by, for example, spraying of the composition into the oral cavity. Upon spraying into the oral cavity, components of the composition therein (e.g., flavoring agents and / or active ingredients) provide the user with flavor and satisfaction. In some embodiments, the composition of the present disclosure is in the form of a gel that can be administered to the oral cavity, such as by administering discrete gel portions (e.g., gel “dots”) or by squeezing the gel from a container, such as a tube. An example dispenser is the Twist’n’brush™ single-dose application system available from Hoffmann Neopac AG.

[0216] Sprayable liquid compositions of the disclosure can be delivered to the oral cavity using bottles equipped with atomizer / sprayer structures. Typically, such bottles can be operated to produce different spray patterns ranging from a fine mist to a concentrated stream. Many such spray bottles comprise a container for holding the liquid composition and a spray head or hand-operated pump connected to the container for dispensing the liquid. See, for example, the spray bottles and spray heads set forth in U.S. Pat. Nos. 2,642,313 to Montenier; 3,004,708 to Gorman; 4,489,890 to Martin; 7,900,637 to Fagerstrom et al.; and 8,215,571 to Yu, which are hereby incorporated by reference. One example of a spray bottle for dispensing the liquid composition of the disclosure is shown in Fig. 1. As noted therein, such a spray bottle 10 can include a container portion 12 with a spray head 14 that typically includes a nozzle and enables the user to dispense liquid through a mechanical pumping action. Alternatively, such a container can house the liquid composition under pressure such that dispensing of the liquid is driven by a pressure difference between the exterior and interior of the spray bottle.

[0217] Spray containers typically provide a relatively uniform dose of the composition upon each manipulation of the sprayer or atomizer. For example, in certain embodiments, the amount of the composition of the disclosure administered per spraying action is between about 25 mg to about 300 mg, such as about 50-48- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022mg to about 250 mg. In some embodiments, the amount of active ingredient administered per spraying action is between about 0.1 mg to about 1.0 mg, such as about 0.2 to about 0.8 mg, or about 0.3 to about 0.6 mg.

[0218] Many modifications and other embodiments of the disclosure will come to mind to one skilled in the art to which this disclosure pertains having the benefit of the teachings presented in the foregoing description. Therefore, it is to be understood that the disclosure is not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.EXAMPLES

[0219] Aspects of the present disclosure are more fully illustrated by the following examples, which are set forth to illustrate certain aspects of the present disclosure and are not to be construed as limiting thereof. Any of the active ingredients noted in the examples below could be replaced with another active ingredient compound (or combination of compounds) disclosed herein. For example, the active ingredient in any of these examples could be replaced with cytisine, varenicline, acetylcholine, choline, epibatidine, iobeline, analogs thereof, or combinations thereof.Example 1 - Liquid Oral Product with Benzoic Acid and 2-methyl-5-(l-methylpyrrolidin-2-yl)pyridine

[0220] A methyl cellulose solution was prepared by heating about 485 g of deionized water to 75 °C and dispersing about 2 g methyl cellulose in the heated water. About 13 g of trisodium citrate was added thereafter to the solution. The solution was stirred and allowed to cool in an ice bath.

[0221] A 2-methyl-5-(l-methylpyrrolidin-2-yl)pyridine benzoate solution was prepared by mixing about 500 g of 2-methyl-5-(l-methylpyrrolidin-2-yl)pyridine (12% solution in glycerol) with about 42 g of benzoic acid to form a solution comprising about 11% by weight 2-methyl-5-(l-methylpyrrolidin-2-yl)pyridine.

[0222] A liquid oral product was formed by mixing the above-noted methyl cellulose solution and 2-methyl-5-(l-methylpyrrolidin-2-yl)pyridine benzoate solution with additional ingredients to form the composition set forth in Table 2 below.Table 2-49- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022

[0223] The pH of the above liquid oral product is about 7.0. This liquid can be adapted for use in a spray bottle to deliver, for example, about 200 mg of spray per use, which will contain about 0.45 mg of 2-methyl-5-( 1 -methylpyrrolidin-2-yl)pyridine.Example 2 - Liquid Oral Product with Tocopherol succinate and 2-methyl-5-(l-methylpyrrolidin-2-yl)pyridine

[0224] A methyl cellulose solution was prepared as described in Example 1.

[0225] A 2-methyl-5-(l-methylpyrrolidin-2-yl)pyridine tocopherol succinate solution was prepared by mixing about 80 g of 2-methyl-5-(l-methylpyrrolidin-2-yl)pyridine (12% solution in glycerol) with about 80 g of deionized water and about 29 g of tocopherol succinate to form a solution comprising about 5% by weight 2-methyl-5-(l-methylpyrrolidin-2-yl)pyridine. The solution was heated to 40 °C and homogenized in a mixer at 12,000 rpm for about 2 min to yield a thick paste. The resulting solution was diluted about 10,000: 1 with water and analyzed for particle size distribution with a Malvern Zetasizer (Nano-ZS). The 2-methyl-5-(l-methylpyrrolidin-2-yl)pyridine tocopherol succinate complex was found to have an average particle size of about 173 nm.

[0226] A liquid oral product was formed by mixing the above-noted methyl cellulose solution and 2-methyl-5-(l-methylpyrrolidin-2-yl)pyridine benzoate solution with additional ingredients to form the composition set forth in Table 3 below.Table 3

[0227] The pH of the above liquid oral product is about 7.3. This liquid can be adapted for use in a spray bottle to deliver, for example, about 205 mg of spray per use, which will contain about 0.47 mg of 2-methyl-5-( 1 -methylpyrrolidin-2-yl)pyridine.-50- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 07022Example 3 - Liquid Oral Product with 2-methyl-5-(l-methylpyrrolidin-2-yl)pyridine Benzoate

[0228] A 2-methyl-5-(l-methylpyrrolidin-2-yl)pyridine benzoate solution was prepared by mixing about 500 g of 2-methyl-5-(l-methylpyrrolidin-2-yl)pyridine (12% solution in glycerol) with about 42 g of benzoic acid to form a solution comprising about 11% by weight 2-methyl-5-(l-methylpyrrolidin-2-yl)pyridine.

[0229] A liquid oral product was formed by mixing the above-noted 2-methyl-5-(l-methylpyrrolidin-2-yl)pyridine benzoate solution with additional ingredients to form the composition set forth in Table 4 below, including a thickening agent having thixotropic properties.Table 4

[0230] The pH of the above liquid oral product is about 6-6.3. This liquid can be adapted for use in a spray bottle to deliver, for example, about 200 mg of spray per use, which will contain about 0.50 mg of 2-methyl-5-( 1 -methylpyrrolidin-2-yl)pyridine.-51- WBD (US) 4897-1338-9430vl

Claims

AttyDktNo. R60999 17380WO 07022CLAIMS1. A liquid or gel composition adapted for oral use, comprising:water and / or a water-miscible solvent; andan active ingredient selected from (i) a substituted 3-(l-methylpyrrolidin-2-yl)pyridine having a structure according to Formula I:wherein R1, R2, R3, and R4are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl, aryl, alkylaryl, amino, halogen, and cyano, wherein any of said alkyl, alkoxy, cycloalkyl, alkenyl, alkenyl, alkynyl, aryl, alkylaryl, and amino may optionally be substituted; and at least one of R1, R2, R3, and R4are not hydrogen; (ii) a substituted 3-(l- methylpyrrolidin-2-yl)pyridine having a structure according to Formula II:wherein R5and R6are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl, aryl, alkylaryl, amino, halogen, and cyano, wherein any of said alkyl, alkoxy, cycloalkyl, alkenyl, alkenyl, alkynyl, aryl, alkylaryl, and amino may optionally be substituted;R7is selected from the group consisting of hydrogen and CH3;R8is selected from the group consisting of hydrogen and C1-C3 alkyl; andat least one of R7and R8is not hydrogen; and (iii) a 3-(azetidin-2-yl)pyridine or 3-(azetidin-2- ylmethoxy)pyridine having a structure according to Formula III:wherein L is a bond or -OCH2-*, where the asterisk indicates an attachment point to the azetidine ring; R9, R10, R11, and R12are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, and cyano;R13is H or CH3; andR14isH orCH3.

2. The liquid or gel composition of claim 1, wherein the active ingredient has a structure according to Formula I, optionally wherein R1, R2, and R3are each H, and R4is optionally substituted Ci-Ce alkyl, F, Cl, Br, OCH3, OEt, or CN, or optionally wherein R1, R2, and R3are each H, and R4is C1-C3 alkyl.-52- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 070223. The liquid or gel composition of claim 1, wherein the active ingredient has a structure according to Formula II, optionally wherein R5is optionally substituted Ci-Ce alkyl, F, Cl, Br, OCH3, OCH2CH3, or CN; and R6is H, or optionally wherein R5is H; and R6is optionally substituted Ci-Ce alkyl, F, Cl, Br, OCH3, OCH2CH3, or CN.

4. The liquid or gel composition of claim 1, wherein the active ingredient has a structure according to Formula III, optionally wherein R9is H or CH3; and R10, R11,and R12are each H.

5. The liquid or gel composition of claim 1, wherein the active ingredient is in the form of a free base, a salt with an acid, an ion pair with an organic acid, or a resin complex wherein the active ingredient is bound to a polymeric resin.

6. The liquid or gel composition of claim 5, wherein the active ingredient is in the form of a salt or ion pair with benzoic acid or tocopherol succinate, optionally further comprising sodium benzoate.

7. The liquid or gel composition of claim 1, further comprising at least one thickening agent, such as a natural gum or cellulose derivative.

8. The liquid or gel composition of claim 7, wherein the thickening agent is present in an amount of about 0.1 to about 10% by weight, based on the total weight of the composition.

9. The liquid or gel composition of claim 1, wherein the composition comprises water and at least one polyol, optionally wherein the weight ratio of water to the polyol is about 3 : 1 to about 1:3.

10. The liquid or gel composition of claim 1, wherein the water and / or water-miscible solvent is present in an amount of about 50% or higher, such as about 70 to about 99% by weight, based on the total weight of the composition.

11. The liquid or gel composition of claim 1, wherein the composition is in the form of an emulsion and comprises at least one oil and at least one emulsifying agent, optionally wherein the emulsifying agent is selected from the group consisting of surfactants, phospholipids, amphiphilic polysaccharides, amphiphilic proteins, and combinations thereof.

12. The liquid or gel composition of claim 11, wherein the at least one emulsifying agent is present in an amount of about O.Of to about f5% by weight, based on the total weight of the composition.

13. The liquid or gel composition of claim 1, wherein the active ingredient is present in an amount of about 0.05 to about 5% by weight of the composition, calculated as the free base and based on the total weight of the composition.-53- WBD (US) 4897-1338-9430vlAttyDktNo. R60999 17380WO 0702214. The liquid or gel composition of claim 1, further comprising one or more components selected from the list consisting of salts, such as sodium chloride, sweeteners, flavorants, buffering agents, oral care additives, and combinations thereof.

15. The liquid or gel composition of claim 1, wherein the composition has a viscosity of about 1 to about 100,000 cP, such as about 60 to about 10,000 cP or about 10,000 to about 30,000 cP or about 30,000 to about 100,000 cP.

16. A spray container comprising a spray nozzle and an internal compartment housing the liquid or gel composition of claim 1.

17. The spray container of claim 16, wherein the spray container is configured to expel about 25 mg to about 300 mg of the liquid or gel composition per spraying action.-54- WBD (US) 4897-1338-9430vl

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